Process for the Preparation of (IS^S.SSJS N- l-Carbamoyl-l- methylpropyl)-5-amino-4-hvdroxy-2,7-diisopropyl-8-f4-methoxy -3-(3- methoxypropoxy)phenyll-octanamide hemifumarate and its

intermediates thereof

Related Application:

This application claims the benefit of priority of our Indian patent application numbers 1467/CHE/2010 filed on 28 ^th May 2010, 1468/CHE/2010 filed on 28 ^th May 2010 and 1735/CHE/2011 filed on 23 ^rd May 2011 which is incorporated herein by reference.

Field of the Invention:

The present invention relates to a process for the preparation of an orally active renin inhibitor such as (2S,4S,5S,7S)-N-(2-Carbamoyl-2-methylpropyl)-5-amino-4- hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phe nyl]-octanamide compound of formula- 1 and its intermediates and/or its salt thereof.

Formula- 1

Renin is the first enzyme in the renin-angiotensin-aldosterone system which plays a role in blood pressure control. Renin cleaves angiotensinogen to angiotensin I, which is in turn converted by (ACE) to angiotensin II. Angiotensin II has both direct and indirect effects on blood pressure. It directly causes arterial smooth muscle to contract, leading to vasoconstriction and increased blood pressure. Angiotensin II also stimulates the production of aldosterone from the adrenal cortex, which causes the tubles of the kidneys to increase reabsorption of sodium, with water following thereby increasing plasma volume and blood pressure.

Background of the Invention:

The process for the preparation of renin inhibitors have been reported in US

5559111. (2S,4S,5S,7S)-N-(2-Carbamoyl-2-methylpropyl)-5-amino-4-hydro xy-2,7- diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl]-octanam ide and its pharmaceutically acceptable salts are potent in these class of drugs. It is a very complex molecule having a number of chiral centers. Hence it involves the synthesis and the condensation of complex, stereo specific intermediates for effective synthesis of the final drug substance of the required structure. (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutan-l-ol is one of the most important intermediate used in the preparation of (2S,4S,5S,7S)-N-(2-Carbamoyl-2-methylpropyl)-5-amino-4-hydro xy-2,7- diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl]-octanam ide and its pharmaceutically acceptable salts. The reported process comprises of reacting the 3- hydroxy-4-methoxy-benzyl alcohol with l-bromo-3-methoxy-propane in presence of potassium carbonate in acetone to provide 4-methoxy-3-(3-methoxypropyloxy)-benzyl alcohol. It was further reacted with trimethyl bromosilane to provide 4-methoxy-3-(3- methoxypropyloxy)-benzyl bromide. In the subsequent step 4(R)-benzyl-3-isovaleroyl- oxazolidin-2-one was taken and reacted with lithium hexamethyl-disilazide to provide a lithiated compound which was in-situ reacted with 4-methoxy-3-(3-methoxypropyloxy)- benzyl bromide to provide 4(R)-benzyl-3-{2(R)-isopropyl-3-[4-methoxy-3-(3- methoxypropyloxy)-phenyl]-propionyl}-oxazolidine-2-one which was further treated with lithium hydroxide in presence of hydrogen peroxide to provide 2(R)-isopropyl-3[4- methoxy-3 -(3 -methoxypropyloxy)-phenyl] -propionic acid. The propionic acid derivative was treated with sodium borohydride and iodine to provide (R)-2-(4-methoxy-3-(3- methoxypropoxy) benzyl)-3-methylbutan-l-ol. The process involves numerous steps which are time consuming, providing low yield and inflating the cost of production.

Helvetica chimica acta- Vol. 86(2003) provides a process for the preparation of (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutan-l-ol which comprises of reacting 3-hydroxy-4-methoxybenzaldehyde with 1,3-dibromopropane to provide 3-(3- bromopropoxy)-4-methoxybenzaldehyde. Which on further reaction with sodium methoxide provided 4-methoxy-3-(3-methoxypropoxy)benzaldehyde. The obtained compound was reduced with sodium borohydride to provide 4-methoxy-3-(3- methoxypropoxy)benzene methanol. It was reacted with trimethyl bromosilane to provide 4-methoxy-3-(3-methoxypropoxy)benzyl bromide. This was further reacted with lithiated (R)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one, which was prepared by reacting lithium hexamethyl-disilazide with (R)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one to provide 4(R)-benzyl-3-{2(R)-isopropyl-3-[4-methoxy-3-(3-methoxypropy loxy)- phenyl]-propionyl}-oxazolidine-2-one. It was treated with lithium hydroxide in presence of hydrogen peroxide to provide 2(R)-isopropyl-3[4-methoxy-3-(3-methoxypropyloxy)- phenyl] -propionic acid. The obtained compound was treated with sodium borohydride in presence of iodine to provide (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3- methylbutan-l-ol.

Tetrahedron letters, volume 46(2005), Pages: 6337-6340, reported the process for the preparation of (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutan-l-ol. The said article reports the usage of lithium aluminium hydride instead of sodium borohydride in the conversion of 2(R)-isopropyl-3[4-methoxy-3-(3-methoxypropyloxy)- phenyl] -propionic acid to (R)-2-(4-methoxy-3 -(3 -methoxypropoxy)benzyl)-3 -methyl butan-l-ol.

The main disadvantage of the above processes is that the formation of 4-methoxy- 3-(3-methoxypropoxy) benzyl bromide an intermediate compound which is highly unstable and was found to be decompose during short contact with the surface metallic materials such as a spatula or metal stirrer, hence decreasing the yield.

US 6730798 disclosed a process for the preparation of (2S,7R,E)-2-isopropyl-7- (4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methylnon-4-enoic acid ester. The disclosed process involves condensation of (R)-4-(2-(chloromethyl)-3-methylbutyl)-l-methoxy-2- (3-methoxypropoxy)benzene with (S,E)-5-chloro-2-isopropylpent-4-enoic acid ester compound to provide (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy) benzyl)-8-methylnon-4-enoic acid ester, which is isolated using diethyl ether and purified by flash chromatography. US 7132569 disclosed a process for the preparation of aliskiren hemifumarate.

The disclosed process involves condensation of (R)-4-(2-(chloromethyl)-3-methylbutyl)- l-methoxy-2-(3-methoxy propoxy) benzene with (S,E)-5-chloro-2-isopropyl-N,N- dimethylpent-4-enamide to provide (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3- methoxypropoxy)benzyl)-N,N,8-trimethyl non-4-enamide, which is isolated using diisopropyl ether and purified by flash chromatography using ethylacetate-hexane (2:1). It was converted into its corresponding bromo lactone, which is isolated using diisopropyl ether and further purified by thin layer chromatography to provide pure bromo lactone compound. The bromo lactone on azidation provided azido lactone derivative, which is isolated using diisopropyl ether and further purified by flash chromatography to provide the azido lactone as an oil. Further, condensation of the azido lactone with 3-amino-2,2-dimethyl propanamide provides (2S,4S,5S,7S)-N-(3-amino-2,2- dimethyl-3-oxopropyl)-5-azido-4-hydroxy-2-isopropyl-7-(4-met hoxy-3-(3-methoxy propoxy) benzyl)-8-methyl nonanamide, which is isolated using ethylacetate and further purified by thin layer chromatography. The said compound was reduced to provide aliskiren and then converted into its hemifumarate salt.

The above processes involve chromatographic purification in each step. The use of chromatographic purification makes the process cumbersome, time consuming, uneconomical and difficult to handle on large scale. It also leads to the generation of lot of spent solvents and solid waste which are difficult to dispose which may lead to the pollution of the environment. Hence it becomes imperative to avoid chromatographic purification for the process to be more effective.

Henceforth, there is a need to develop an improved process which can reliably be carried out in an industrial scale, in a cost efficient manner and to provide highly pure intermediates, which in turn results in a highly pure aliskiren hemifumarate. Advantages of the present Invention:

• Provides the highly pure (R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3- methylbutan-l-ol with high yield.

• Provides the highly stable (R)-4-(2-(halomethyl)-3-methylbutyl)-l-methoxy-2-(3- methoxypropoxy)benzene with high yield.

· Provides the crystalline form of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3- methoxy propoxy) benzyl)-8-methylnon-4-enoic acid tertiary butyl amine salt.

• Provides the solid crystalline form of (3S,5S)-5-((lS,3S)-l-azido-3-(4-methoxy-3- (3-methoxypropoxy)benzyl)-4-methylpentyl)-3-isopropyldihydro furan-2(3H)- one.

• Avoids chromatographic purification, which is costly and difficult to handle on large scale.

· Uses simple, milder and non-toxic reagents making it eco-friendly process.

Brief description of the invention:

The present invention relates to a process for the preparation of an orally active renin inhibitor such as (2S,4S,5S,7S)-N-(2-Carbamoyl-2-methylpropyl)-5-amino-4- hydroxy-2,7-diisopropyl- 8- [4-methoxy-3 -(3 -methoxypropoxy)phenyl] -octanamide compound of formula- 1 and its intermediates and/or its salt thereof.

Further, the present invention also disclosed the improved processes for the preparation of (R)-4-(2-(halomethyl)-3-methylbutyl)- 1 -methoxy-2-(3-methoxypropoxy) benzene compound of general formula-2 and (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutan-l-ol compound of formula-23, useful intermediates in the synthesis of (2S,4S,5S,7S)-N-(2-Carbamoyl-2-methylpropyl)-5-amino-4-hydro xy-2,7- diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl]-octanam ide and its pharmaceutically acceptable salts.

The first aspect of the present invention is to provide an improved process for the preparation of aliskiren hemifumarate compound of formula- la, which comprising of the following steps:

a) Condensing the (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzy l)- 8-methyl non-4-enoic acid compound of formula-4 and/or its amine salt with a suitable amine hydrochloride salt compound of general formula-7 in the presence of a suitable condensing agent in a suitable solvent to provide (2S,7R,E)-2-isopropyl-7-(4- methoxy-3-(3-methoxypropoxy)benzyl)-8-methyl-4-nonene amide derivative compound of general formula-8,

b) treating the compound of general formula-8 with a suitable halogenating agent in the presence of aqueous acid in a suitable solvent to provide (3S,5S)-5-((lR,3S)-l-halo- 3 -(4-methoxy-3 -(3 -methoxypropoxy)benzyl)-4-methylpentyl)-3 -isopropyldihydro furan-2(3H)-one compound of general formula- 10, which is isolated using an ether solvent to provide pure compound of general formula- 10,

c) treating the compound of general formula- 10 with a suitable alkali metal azide in a suitable solvent to provide (3S,5S)-5-((lS,3S)-l-azido-3-(4-methoxy-3-(3-methoxy propoxy) benzyl)-4-methylpentyl)-3-isopropyldihydrofuran-2(3H)-one compound of formula-11, which is isolated using an ether solvent to provide pure compound of formula-11,

d) condensing the compound of formula-11 with 3-amino-2,2-dimethyl propanamide compound of formula- 12 in the presence of a proton donor in a suitable solvent to provide (2S,4S,5S,7S)-N-(3-amino-2,2-dimethyl-3-oxopropyl)-5-azido-4 -hydroxy-2- isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methyln onanamide compound of formula- 13, which is further purified from hydrocarbon solvent to provide pure compound of formula- 13,

e) reducing the compound of formula- 13 with a suitable reducing agent in a suitable solvent to provide aliskiren compound of formula- 1 ,

f) treating the compound of formula- 1 with fumaric acid in a suitable solvent to provide aliskiren hemifumarate compound of formula- la.

The second aspect of the present invention is to provide an improved process for the preparation of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzy l)-8- methyl non-4-enoic acid compound of formula-4 and its amine salt, which comprising of treating (R)-4-(2-(chloromethyl)-3-methylbutyl)-l-methoxy-2-(3-methox ypropoxy) benzene compound of formula-2a with magnesium turnings in the presence of alkenyl halides in a suitable solvent, followed by condensation with (S,E)-5-chloro-2- isopropylpent-4-enoic acid compound of formula-3 and/or its amine salt, in the presence of N-methyl pyrrolidone and a suitable metal complex, in a suitable solvent to provide (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy) benzyl)-8-methylnon-4- enoic acid compound of formula-4, which is isolated using an ester solvent to provide pure compound of formula-4, which is further converted into its amine salt.

The third aspect of the present invention is to provide a process for the preparation of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzy l)-8-methylnon-4- enoic acid compound of formula-4 and its amine salt, comprising of the following steps: a) Treating the (R)-4-(2-(chloromethyl)-3-methylbutyl)-l-methoxy-2-(3-methox y propoxy) benzene compound of formula-2a with magnesium turnings in the presence of alkenyl halides in a suitable solvent, followed by condensation with (S,E)-5- chloro-2-isopropylpent-4-enoic acid ester compound of general formula-5, in the presence of N-methyl pyrrolidone and a suitable metal complex, in a suitable solvent to provide (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy) benzyl)-8- methylnon-4-enoic acid ester compound of general formula-6, which is isolated using an ester solvent to provide pure compound of general formula-6,

b) hydrolyzing the compound of general formula-6 in the presence of an acid or a base in a suitable solvent to provide compound of formula-4,

c) further, the compound of formula-4 is converted into its amine salt.

The fourth aspect of the present invention is to provide an improved process for the preparation of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzy l)- 8-methyl-4-nonene amide derivative compound of general formula-8, which comprising of treating the (R)-4-(2-(chloromethyl)-3-methylbutyl)-l-methoxy-2-(3-methox y propoxy) benzene compound of formula-2a with magnesium turnings in the presence of alkenyl halides in a suitable solvent, followed by condensation with (S,E)-5-chloro-2- isopropyl-pent-4-ene amide derivative compound of general formula-9 in the presence of N-methyl pyrrolidone and a suitable metal complex, in a suitable solvent to provide compound of general formula-8, which is isolated using an ester solvent to provide pure compound of general formula-8.

The fifth aspect of the present invention is to provide one pot process for the preparation of aliskiren compound of formula- 1.

The sixth aspect of the present invention is to provide one pot process for the preparation(3S,5S)-5-((lR,3S)-l-halo-3-(4-methoxy-3-(3-metho xypropoxy)benzyl)-4- methyl pentyl)-3-isopropyl dihydrofuran-2(3H)-one compound of general formula-10.

The seventh aspect of the present invention is to provide a process for the preparation of (R)-4-(2-(chloromethyl)-3-methylbutyl)-l -methoxy-2-(3-methoxy propoxy)benzene compound of formula-2a.

The eighth aspect of the present invention is to provide an improved process for the preparation of (R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutan-l -ol compound of formula-23, which comprising of reducing the (R)-2-(4-methoxy-3-(3- methoxypropoxy)benzyl)-3 -methyl butanoic acid compound of formula-22, with sodium borohydride in the presence of boron trifluoro etherate under nitrogen atmosphere in the presence of ether solvent preferably tetrahydrofuran to provide (R)-2-(4-methoxy-3-(3- methoxypropoxy)benzyl)-3 -methylbutan- 1 -ol compound of formula-23.

The ninth aspect of present invention is to provide an improved process for the preparation of (R)-4-(2-(halomethyl)-3-methylbutyl)-l-methoxy-2-(3-methoxyp ropoxy) benzene, compound of formula-2, which comprising of,

a) Reacting 3-methoxypropan-l-ol compound of formula- 14 with methanesulfonyl chloride in the presence of base, to provide 3-methoxypropyl methane sulfonate compound of formula-15,

b) condensation of compound of formula-15 with 3-hydroxy-4-methoxy benzaldehyde compound of formula- 16, in the presence of base in a suitable solvent to provide 4- methoxy-3-(3-methoxypropoxy) benzaldehyde compound of formula-17,

c) reducing the 4-methoxy-3-(3-methoxypropoxy) benzaldehyde compound of formula- 17 in the presence of suitable reducing agent, in a suitable solvent to provide (4- methoxy)-3-(3-methoxypropoxy)benzyl alcohol compound of formula- 18,

d) brominating the compound of formula- 18 with a suitable brominating agent in presence of a suitable solvent to provide 4-(bromomethyl)-l-methoxy-2-(3-methoxy propoxy)benzene compound of formula- 19,

e) condensing the compound of formula- 19 with (R)-3-(3-methylbutanoyl)-4- phenyloxazolidin-2-one compound of formula-20 in the presence of suitable base in a suitable solvent to provide (R)-3-((R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)- 3-methylbutanoyl)-4-phenyloxazolidin-2-one compound of formula-21 , f) hydrolyzing the compound of formula-21 in the presence of a suitable base in a suitable solvent to provide (R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methyl butanoic acid compound of formula-22,

g) reducing the compound of formula-22 in the presence of suitable reducing agent, in a suitable solvent to provide (R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methyl butan-l-ol compound of formula-23,

h) treating the compound of formula-23 with a suitable halogenating agent in a suitable solvent to provide (R)-4-(2-(halomethyl)-3-methylbutyl)-l-methoxy-2-(3-methoxy propoxy) benzene, compound of formula-2.

The tenth aspect of the present invention is to provide a one pot process for the preparation of (4-methoxy)-3-(3-methoxypropoxy)benzyl alcohol compound of formula- 18 from 3-methoxypropyl methane sulfonate compound of formula- 15. The eleventh aspect of the present invention is to provide a process for the preparation of (R)-2-(4-methoxy-3 -(3 -methoxypropoxy)benzyl)-3 -methylbutan- 1 -ol compound of formula-23, which comprising of reducing the (R)-3-((R)-2-(4-methoxy-3- (3-methoxypropoxy) benzyl)-3-methylbutanoyl)-4-phenyloxazolidin-2-one compound of formula-21 with a suitable reducing agent in a suitable solvent to provide (R)-2-(4- methoxy-3 -(3 -methoxypropoxy)benzyl)-3 -methylbutan- l-ol compound of formula-23.

The twelfth aspect of the present invention is to provide an improved process for the preparation of 3-amino-2,2-dimethylpropanamide compound of formula-26, which comprising of,

a) Reacting ethyl 2-cyanoacetate compound of formula-24 with methyl iodide in the presence of a suitable base in a suitable solvent to provide ethyl 2-cyano-2- methylpropanoate compound of formula-25,

b) treating the compound of formula-25 with methanolic ammonia to provide 2-cyano-2- methylpropanamide compound of formula-26,

c) reducing the compound of formula-26 with a suitable reducing agent to provide 3- amino-2,2-dimethylpropanamide compound of formula-27. The thirteenth aspect of the present invention is to provide a novel process for the preparation of (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutan-l-ol compound of formula-23, which comprising of,

a) Reacting 3-methoxypropylmethanesulfonate compound of formula- 15 with 3- hydroxy-4-methoxybenzaldehyde compound of formula- 16 in the presence of suitable base in a suitable solvent to provide 4-methoxy-3-(3-methoxypropoxy)benzaldehyde compound of formula- 17,

b) reacting the 4-methoxy-3-(3-methoxypropoxy)benzaldehyde compound of formula- 17 with (R)-3-(3-methylbutanoyl)-4-phenyloxazolidin-2-one compound of formula- 20 in the presence of titanium tetrachloride or titanium(IV) isopropoxide or mixtures thereof and a base in a suitable solvent to provide (4R)-3-((2S)-2-(hydroxy(4- methoxy-3-(3-methoxypropoxy) phenyl) methyl)-3-methylbutanoyl)-4- phenyloxazolidin-2-one compound of formula-28,

c) hydrogenolysis of compound of formula-28 with a suitable hydrogen source in the presence of a suitable acid, in a suitable solvent to provide (R)-3-((R)-2-(4-methoxy- 3 -(3 -methoxypropoxy)benzyl)-3 -methylbutanoyl)-4-phenyloxazolidin-2-one compound of formula-21,

d) alkaline peroxide mediated hydrolysis of compound of formula-21 in a suitable solvent to provide (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3 -methyl butanoic acid compound of formula-22,

e) reducing the compound of formula-22 with a suitable reducing agent, in a suitable solvent to provide (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutan- l-ol compound of formula-23.

The fourteenth aspect of the present invention is to provide a process for the preparation of (4R)-3-((2S)-2-(hydroxy(4-methoxy-3-(3-methoxypropoxy) phenyl) methyl)-3 -methyl butanoyl)-4-phenyloxazolidin-2-one compound of formula-28, which comprising of reacting the 4-methoxy-3-(3-methoxypropoxy)benzaldehyde compound of formula-17 with (R)-3-(3-methylbutanoyl)-4-phenyloxazolidin-2-one compound of formula-20 in presence of titanium tetrachloride or titanium(IV) isopropoxide or mixtures thereof and a base in a suitable solvent to provide (4R)-3-((2S)-2-(hydroxy(4-methoxy-3- (3-methoxypropoxy)phenyl)methyl)-3-methylbutanoyl)-4-phenylo xazolidin-2-one compound of formula-28.

The fifteenth aspect of the present invention is to provide a process for the preparation of (R)-3-((R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methyl butanoyl)-4-phenyl oxazolidin-2-one compound of formula-21, which comprising of hydrogenolysis of (4R)-3-((2S)-2-(hydroxy(4-methoxy-3-(3-methoxypropoxy) phenyl) methyl)-3-methylbutanoyl)-4-phenyl oxazolidin-2-one compound of formula-28 with a suitable reducing agent in the presence of a suitable acid, in a suitable solvent to provide (R)-3-((R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methyl butanoyl)-4-phenyl oxazolidin-2-one compound of formula-21.

The sixteenth aspect of the present invention is to provide a novel process for the preparation of (R)-3 -((R)-2-(4-methoxy-3 -(3 -methoxypropoxy)benzyl)-3 -methyl butanoyl)-4-phenyloxazolidin-2-one compound of formula-21, which comprising of: a) Reacting the 4-methoxy-3-(3-methoxypropoxy)benzaldehyde compound of formula- 17 with (R)-3-(3-methylbutanoyl)-4-phenyloxazolidin-2-one compound of formula-

20 in presence of titanium tetrachloride or titanium(IV) isopropoxide or mixtures thereof and a base in a suitable solvent to provide (4R)-3-((2S)-2-(hydroxy(4- methoxy-3 -(3 -methoxypropoxy)phenyl)methyl)-3 -methylbutanoyl)-4- phenyloxazolidin-2-one compound of formula-28,

b) hydrogenolysis of the compound of formula-28 with a suitable hydrogen source in the presence of suitable acid, in a suitable solvent to provide (R)-3-((R)-2-(4-methoxy-3- (3 -methoxypropoxy)benzyl)-3 -methylbutanoyl)-4-phenyloxazolidin-2-one compound of formula-21. The seventeenth aspect of the present invention is to provide the novel (4R)-3-

((2S)-2-(hydroxy(4-methoxy-3-(3-methoxypropoxy)phenyl)met hyl)-3-methylbutanoyl)- 4-phenyloxazolidin-2-one compound of formula-28. The novel compound of formula-28 is useful as an intermediate in the preparation of (R)-2-(4-methoxy-3-(3- methoxypropoxy) benzyl)-3-methylbutan-l-ol compound of formula-23. The eighteenth aspect of the present invention is to provide a novel amine salts of (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutanoic acid compound of general foimula-29. These novel amine salts are useful in the preparation of highly pure (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutanoic acid compound of formula-22.

The nineteenth aspect of the present invention is to provide a process for the preparation of novel amine salts of (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3- methylbutanoic acid compound of general formula-29, which comprise of treating the (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutanoic acid compound of formula-22 with suitable amines in a suitable solvent to provide the corresponding amine salts compound of general formula-29.

The twentieth aspect of the present invention is to provide a novel crystalline form of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzy l)-8-methylnon-4- enoic acid tertiary butyl amine salt compound of formula-4a (herein designated as crystalline form-M) as well as process for its preparation.

The twenty-first aspect of the present invention is to provide a novel crystalline form of (3S,5S)-5-((l S,3S)-l-azido-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4- methyl pentyl)-3-isopropyldihydro furan-2(3H)-one compound of formula- 11 (herein designated as crystalline form-S) as well as process for its preparation. Brief Description of the drawings:

Figure 1 : Illustrates the PXRD pattern of crystalline form-M of (2S,7R,E)-2-isopropyl-7- (4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methylnon-4-enoic acid tertiary butyl amine salt compound of formula-4a.

Figure 2: Illustrates the DSC thermogram of crystalline form-M of compound of formula- 4a.

Figure 3: Illustrates the PXRD pattern of crystalline form-S of (3S,5S)-5-((lS,3S)-l- azido-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpenty l)-3-isopropyldihydro furan-2(3H)-one compound of formula-11.

Figure 4: Illustrates the DSC thermogram of crystalline form-S of compound of formula- 11. Detailed Description of Invention:

The suitable solvents, wherever necessary, used in the present invention are selected from "ester solvents" like ethyl acetate, methyl acetate, isopropyl acetate; "ether solvents" like tetrahydrofuran, diethyl ether, methyl tert-butyl ether; "hydrocarbon solvents" like toluene, hexane, heptane and cyclohexane; "polar aprotic solvents" like dimethyl acetamide, dimethyl sulfoxide, acetonitrile; "ketone solvents" like acetone, methyl ethyl ketone, methyl isobutyl ketone; and "alcoholic solvents" like methanol, ethanol, n-propanol, isopropanol, n-butanol and isobutanol; "chloro solvents" like dichloromethane, chloroform and dichloroethane, carbon tetrachloride and chloroform; polar solvents like water; and also mixtures thereof.

As used herein the present invention the term "suitable acids" refers to the acids selected from hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, trifluoroacetic acid, benzenesulfonic acid, methane sulfonic acid, camphorsulfonic acid, ethanesulfonic acid, para toluene sulfonic acid, fumaric acid, maleic acid, ortho phosphoric acid, oxalic acid, phosphoric acid and tartaric acid.

The term "base" herein the present invention is selected from inorganic bases like alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkali metal alkoxides such as sodium tert-butoxide, potassium tert-butoxide; alkali metal carbonates like sodium carbonate, potassium carbonate; alkali metal bicarbonates like sodium bicarbonate and potassium bicarbonate; and organic bases like triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, N- methyl morpholine, piperidine, dimethyl amino pyridine and pyridine.

The reaction is carried out in the presence/or absence of a phase transfer catalyst which is selected from the group consisting of but not limited to tetra butyl ammonium bromide, tetra propyl ammonium bromide, tributyl benzyl ammonium bromide, tetra octyl ammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium hydrogen sulfate, benzyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, tetra butyl ammonium acetate, tetra butyl ammonium iodide, ethyl triphenyl phosphonium bromide, more preferably tetra butyl ammonium bromide or alkali iodides like sodium iodide, potassium iodide and lithium iodide.

As used herein, the term "alkyl" refers to straight chain or branched hydrocarbon groups, generally having specified number of carbon atoms, preferably alkyl group having 1 to 12 carbon atoms. Examples of alkyl groups include, without limitation, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, t-butyl and the like.

As used herein, the term "cycloalkyl" refers to saturated monocyclic and bicyclic hydrocarbon rings, generally having a specified number of carbon atoms that comprise the ring i.e C _3-7 cycloalkyl refers to a cycloalkyl group having 3,4,5,6 and 7 carbon atoms as ring members.

As used herein, the term "aryl-Ci-6 alkyl" refers to an aryl group attached to the substrate through an alkyl group containing one to six carbon atoms. The term "aryl" refers to monovalent or divalent aromatic groups respectively including 5 and 6 membered monocyclic aromatic groups that contain zero to four heteroatom independently selected from nitrogen, oxygen and sulfur. The aryl groups may be attached to the substrate at any ring atom, unless such attachment would violate valence requirements. Aryl groups may include one or more non hydrogen substituents unless such substitution would violate valence requirements.

The suitable condensing agent is selected from carbodiimides such as Ν,Ν ¹ - diisopropylcarbodiimide (DIC), l-ethyl-3-(3-dimethyl aminopropyl)carbodiimide (EDC), Ν,Ν'-dicyclohexyl carbodiimide (DCC); alkyl or aryl chloroformates such as ethyl chloroformates, benzyl chloroformates, para-nitrophenyl chloroformates; 3-hydroxy-3,4- dihydro-l,2,3-benzotriazin-4-one, diethyl phosphoraro cyanidate (DEPC), di phenylphosphoroazidate (DPPA), Ρ ₂ 0 ₅ , 3-(diethoxyphosphoryloxy)-l,2,3-benzotriazine- 4(3H)-one (DEPBT), Ν,Ν'-carbonyl diimidazole. The carbodiimides can be used optionally in combination with 1 -hydroxybenzotriazole (HOBt), l-hydroxy-7-azatriazole (HO At), 1 -hydroxy- lH-l,2,3-triazole-4-carboxylate (HOCt), N-hydroxy succinimide (HOSu), (2-(lH-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium tetrafluoro borate (TBTU), dimethylamino pyridine (DMAP). The alkyl or aryl chloroformates can be used optionally in combination with a base. The suitable reducing agent is selected from heterogeneous catalysts containing from about 0.1% to about 20% by weight of transition metals such as Ni, Pd, Pt, Rh, Re, Ru and Ir, including oxides and combination thereof, raney nickel, palladium catalyst such as Pd/C, Pd/SrC0 ₃ , Pd/ A1 ₂ 0 ₃ , Pd/MgO, Pd/CaC0 ₃ , Pd/ BaS0 _4; PdO, Pd Black, PdCl _2, Rh/C, Ru/C, Re/C, Pt0 ₂ , Rh/C, Ru0 ₂ ; or hydride reagents like sodium borohydride, sodium cyanoborohydnde, lithium aluminium hydride and vitride etc in the presence or absence of hydrogen.

The first aspect of the present invention is to provide an improved process for the preparation of aliskiren hemifumarate compound of formula- la, which comprising of the following steps:

a) Condensing the (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzy l)- 8-methyl non-4-enoic acid compound of formula-4 and/or its amine salt with a suitable amine hydrochloride salt compound of general formula-7 in the presence of a suitable condensing agent in a suitable solvent to provide (2S,7R,E)-2-isopropyl-7- (4-methoxy-3 -(3 -methoxypropoxy)benzyl)-8-methyl-4-nonene amide derivative compound of general formula-8,

b) treating the compound of general formula-8 with a suitable halogenating agent in the presence of aqueous acid in a suitable solvent to provide (3S,5S)-5-((lR,3S)-l-halo- 3 -(4-methoxy-3 -(3 -methoxypropoxy)benzy l)-4-methylpentyl)-3 -isopropyl dihydro furan-2(3H)-one compound of general formula- 10, which is isolated using an ether solvent to provide pure compound of general formula- 10,

c) treating the compound of general formula- 10 with a suitable alkali metal azide in a suitable solvent to provide (3S,5S)-5-((lS,3S)-l-azido-3-(4-methoxy-3-(3-methoxy propoxy)benzyl)-4-methylpentyl)-3-isopropyldihydrofuran-2(3H )-one compound of formula-11, which is isolated using an ether solvent to provide pure compound of formula-11,

d) condensing the compound of formula-11 with 3-amino-2,2-dimethyl propanamide compound of formula- 12 in the presence of a proton donor in a suitable solvent to provide (2S,4S,5S,7S)-N-(3-amino-2,2-dimethyl-3-oxopropyl)-5-azido-4 -hydroxy-2- isopropyl-7-(4-methoxy-3-(3-methoxypropoxy) benzyl)-8-methylnonanamide compound of formula- 13, which is purified from hydrocarbon solvent to provide pure compound of formula- 13,

e) reducing the compound of formula- 13 with a suitable reducing agent in a suitable solvent to provide aliskiren compound of formula- 1,

f) treating the compound of formula- 1 with fumaric acid in a suitable solvent to provide aliskiren hemifumarate compound of formula- la.

wherein, in step a) the condensation may be alternatively carried out by converting the compound of formula-4 into its acid chloride using a suitable chlorinating agent selected from oxalyl chloride, phosphoryl chloride, thionyl chloride, phosphorous trichloride, phosphorous penta chloride and pivolyl chloride; and followed by reaction with the suitable amine hydrochloride salt compound of general formula-7 to provide compound of general formula-8,

In the step b) the suitable halogenating agent is selected from elemental bromine, iodine, N-bromo, N-chloro, N-iodo carboxamide, dicarboxamides, N-bromo, N-chloro, N-iodo phthalimide, N-chloro, N-bromo, N-iodo succinimide, tertiary butyl hypochlorite,

N-halogenated sulfonamides and imide.

In US 7132569, it is illustrated that bromo derivative of compound of formula- 10 is isolated using diisopropylether-hexane and further purified by thin layer chromatography using diethylether-hexane (2:1), which is a tedious process.

In the present invention the compound of formula- 10 is isolated using diisopropyl ether which provided the pure compound of formula- 10 without using chromatographic purification. Further it provided the compound with a purity of 95.85%.

In step c) the suitable alkali metal azide is lithium azide or sodium azide to provide compound of formula-11. In US 7132569, the compound of formula- 11 was obtained as an oil and further purified by flash chromatography using ethylacetate-hexane

(1 :3) to provide compound of formula-11 with a purity of 93.8% by HPLC.

Whereas, in the present invention the compound of formula-11 is directly isolated using diisopropyl ether as a solid, without the need for purification by flash chromatography and also obtained the compound with a purity of 96.6% by HPLC.

In step d) a proton donor used is 2-hydroxy pyridine. In US 7132569, the compound obtained in this step was purified by chromatographic purification using ethylacetate-hexane (4:1) to provide compound of formula-13 with a purity of 88.5% by HPLC. Whereas, in the present invention, the said compound is purified by recrystallization using cyclohexane solvent to provide highly pure compound of formula- 13 with a purity of 91.44% by HPLC.

Henceforth, the process of the present invention is more advantageous over the prior art processes, which avoids the frequent use of chromatography techniques. And also provides highly pure compounds by using simple isolation process.

Further a preferred embodiment of the present aspect provides an improved process for the preparation of aliskiren hemifumarate compound of formula- la, which comprising of the following steps:

a) Treating the (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzy l)-8- methyl non-4-enoic acid tertiary butyl amine salt compound of formula-4a with hydrochloric acid to provide (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxy propoxy) benzyl)-8-methyl non-4-enoic acid compound of formula-4, which on condensation with dimethyl amine hydrochloride compound of formula-7a in the presence of dicyclohexyl carbodiimide in combination with HOBT, in the presence triethylamine in dichloroethane to provide (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3- methoxy propoxy)benzyl)-N,N,8-trimethylnon-4-enamide compound of formula-8a, b) treating the compound of formula-8a with N-bromo succinimide, in the presence of aqueous ortho phosphoric acid in tetrahydrofuran to provide (3S,5S)-5-((lR,3S)-l- bromo-3 -(4-methoxy-3 -(3 -methoxypropoxy)benzy l)-4-methylpentyl)-3 - isopropyldihydrofuran-2(3H)-one compound of formula- 10a, which is isolated using diisopropyl ether to provide pure compound of formula- 10a,

c) treating the compound of formula- 10a with sodium azide in tripropylene glycol or diethylene glycol to provide (3S,5S)-5-((lS,3S)-l-azido-3-(4-methoxy-3-(3-methoxy propoxy)benzyl)-4-methylpentyl)-3 -isopropyldihydrofuran-2(3H)-one compound of formula-11, which is isolated using diisopropyl ether to provide pure compound of formula-11,

d) condensing the compound of formula-11 with 3-amino-2,2-dimethyl propanamide compound of formula- 12 in the presence of 2-hydroxy pyridine in triethylamine to provide (2S,4S,5S,7S)-N-(3-amino-2,2-dimethyl-3-oxopropyl)-5-azido-4 -hydroxy-2- isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methyln onanamide compound of formula- 13, which is further purified from cyclohexane to provide pure compound of formula- 13,

e) reducing the compound of formula- 13 with Pd/C in the presence or absence of ethanolamine under hydrogen pressure in isopropyl alcohol to provide aliskiren compound of formula- 1,

f) treating the compound of formula- 1 with fumaric acid in ethanol to provide aliskiren hemifumarate compound of formula- la.

The second aspect of the present invention is to provide an improved process for the preparation of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzy l)-8- methyl non-4-enoic acid compound of formula-4 and its amine salt, which comprising of treating (R)-4-(2-(chloromethyl)-3 -methylbutyl)- 1 -methoxy-2-(3 -methoxypropoxy) benzene compound of formula-

Formula-2a

with magnesium turnings in the presence of alkenyl halides in a suitable solvent, followed by condensation with (S,E)-5-chloro-2-isopropylpent-4-enoic acid compound of formula-3 and/or its amine salt, in the presence of N-methyl pyrrolidone and a suitable metal complex, in a suitable solvent to provide (2S,7R,E)-2-isopropyl-7-(4-methoxy-3- (3-methoxypropoxy)benzyl)-8-methylnon-4-enoic acid compound of formula-4, which is further isolating using ester solvent to provide pure compound of formula-4. Further it is converted into its amine salt.

Further in a preferred embodiment of the present aspect provides an improved process for the preparation of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3- methoxypropoxy) benzyl)-8-methylnon-4-enoic acid compound of formula-4 and its tertiary butyl amine salt compound of formula-4a, which comprising of treating the (R)- 4-(2-(chloromethyl)-3 -methylbutyl)- 1 -methoxy-2-(3 -methoxy propoxy) benzene compound of formula-2a with magnesium turnings in the presence of 1 ,2-dibromo ethane in tetrahydrofuran followed by condensation with (S,E)-5-chloro-2-isopropylpent-4-enoic acid compound of formula-3 in the presence of ferric acetyl acetonate and N-methyl pyrrolidone in tetrahydrofuran to provide (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3- methoxypropoxy)benzyl)-8-methylnon-4-enoicacid compound of formula-4, which is further treated with tertiary butylamine in a mixture of methyl tertiary butyl ether and acetonitrile to provide (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxy propoxy) benzyl) -8-methylnon-4-enoic acid tertiary butyl amine salt compound of formula-4a.

Further in a preferred embodiment of the present aspect provides an improved process for the preparation of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxy propoxy)benzyl)-8-methylnon-4-enoic acid compound of formula-4 and its tertiary butyl amine salt compound of formula-4a, which comprising of, treating the (R)-4-(2- (chloromethyl)-3-methylbutyl)-l-methoxy-2-(3-methoxypropoxy) benzene compound of formula-2a with magnesium turnings in the presence of 1,2-dibromo ethane in tetrahydrofuran followed by condensation with the (S,E)-5-chloro-2-isopropylpent-4- enoic acid tertiary butyl amine salt

Formula-3 a

in the presence of ferric acetyl acetonate and N-methyl pyrrolidone in tetrahydrofuran to provide (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzy l)-8-methyl non-4-enoic acid compound of formula-4, which is further treated with tertiary butylamine in a mixture of methyl tertiary butyl ether and acetonitrile to provide (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzy l)-8-methylnon-4- enoic acid tertiary butyl amine salt compound of formula-4a. The third aspect of the present invention is to provide a process for the preparation of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzy l)-8-methylnon-4- enoic acid compound of formula-4 and its amine salt, which comprising of the following steps:

a) Treating the (R)-4-(2-(chloromethyl)-3-methylbutyl)-l-methoxy-2-(3-methox y propoxy) benzene compound of formula-2a with magnesium turnings in the presence of alkenyl halides in a suitable solvent, followed by condensation with (S,E)-5- chloro-2-isopropylpent-4-enoic acid ester compound of general formula-5 in the presence of N-methyl pyrrolidone and a suitable metal complex, in a suitable solvent to provide (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy) benzyl)-8- methylnon-4-enoic acid ester compound of general formula-6, which is isolated using an ester solvent to provide pure compound of general formula-6.

b) hydrolyzing the compound of general formula-6 in the presence of an acid or a base in a suitable solvent to provide compound of formula-4,

c) further, the compound of formula-4 is converted into its amine salt.

Wherein, the alkenyl halides used is 1,2-dibromo ethane; and the suitable metal complex is iron complex such as Iron(III) acetyl acetonate (ferric acetyl acetonate).

In US 6730798, the compound of formula-6 was isolated using diethyl ether, which was further purified by flash chromatography using diethylether- hexane (1:4). Whereas, in the present invention the compound of formula-6 is directly isolated using ethyl acetate and thus avoiding chromatographic purification. Hence the present invention is more advantageous.

Further in the above aspect, the compound of general formula-5 is prepared directly from (S,E)-5-chloro-2-isopropylpent-4-enoic acid (S)-phenyl ethanamine salt compound of formula-3b,

Formula-3b

by treating with a suitable alcohol in the presence of acid to provide compound of general formula-5 (or) by converting it into its corresponding free acid and then treating it with an alcohol in the presence of an acid to provide compound of general formula-5.

A preferred embodiment of the present aspect, provides a process for the preparation of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzy l)-8- methylnon-4-enoic acid compound of formula-4 and its tertiary butyl amine salt compound of formula-4a, which comprising of the following steps:

a) Treating the (R)-4-(2-(chloromethyl)-3-methylbutyl)-l-methoxy-2-(3-methox y propoxy) benzene compound of formula-2a with magnesium turnings in the presence of 1,2-dibromo ethane in tetrahydrofuran, followed by condensation with (S,E)- methyl 5-chloro-2-isopropylpent-4-enoic acid methyl ester compound of formula-5a in the presence of ferric acetyl acetonate and N-methyl pyrrolidone in tetrahydrofuran to provide (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzy l)-8- methylnon-4-enoic acid methyl ester compound of formula-6a, which is isolated using an ethyl acetate to provide pure compound of formula-6a,

b) hydrolyzing the compound of formula-6a with aqueous lithium hydroxide in a mixture of tetrahydrofuran and methanol to provide compound of formula-4.

c) further, the compound of formula-4 reacts with tertiary butyl amine in a mixture of methyl tertiary butyl ether and acetonitrile to provide (2S,7R,E)-2-isopropyl-7-(4- methoxy-3-(3-methoxy propoxy )benzyl)-8-methylnon-4-enoic acid tertiary butyl amine salt compound of formula-4a.

In a preferred embodiment of the present aspect is to provide a process for the preparation of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzy l)-8- methylnon-4-enoic acid compound of formula-4 and its tertiary butyl amine salt compound of formula-4a, which comprising of the following steps:

a) Treating the (R)-4-(2-(chloromethyl)-3-methylbutyl)-l-methoxy-2-(3-methox y propoxy) benzene compound of formula-2a with magnesium turnings in the presence of 1,2-dibromo ethane in tetrahydrofuran, followed by condensation with (S,E)-ethyl 5-chloro-2-isopropylpent-4-enoic acid ethyl ester compound of formula-5b in the presence of ferric acetyl acetonate and N-methyl pyrrolidone in tetrahydrofuran to provide (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzy l)-8- methylnon-4-enoic acid ethyl ester compound of formula-6b,

b) hydrolyzing the compound of formula-6b in the presence of aqueous lithium hydroxide in a mixture of tetrahydrofuran and methanol to provide compound of formula-4,

c) further, the compound of formula-4 reacts with tertiary butylamine in a mixture of methyl tertiary butyl ether and acetonitrile to provide (2S,7R,E)-2-isopropyl-7-(4- methoxy-3-(3-methoxy propoxy)benzyl)-8-methylnon-4-enoic acid tertiary butyl amine salt compound of formula-4a. The fourth aspect of the present invention is to provide an improved process for the preparation of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzy l)-8- methyl-4-nonene amide derivative compound of general formula-8, which comprising of treating the (R)-4-(2-(chloromethyl)-3-methylbutyl)-l-methoxy-2-(3-methox y propoxy) benzene compound of formula-2a with magnesium turnings in the presence of alkenyl halides in a suitable solvent, followed by condensation with (S,E)-5-chloro-2-isopropyl- pent-4-enamide derivative compound of general formula-9 in the presence of N-methyl pyrrolidone and a suitable metal complex, in a suitable solvent to provide compound of general formula-8, which is isolated using an ester solvent to provide pure compound of formula-8.

In the above aspect the alkenyl halides used is 1,2-dibromo ethane and the suitable metal complex is iron complex such as Iron(III) acetyl acetonate. In US 7132569, the compound of formula-8 was isolated using diethyl ether, which is further purified by flash chromatography using diethylether- hexane (1 :4).

Whereas, in the present invention the said compound is isolated using ethyl acetate and thus avoiding chromatographic purification. Hence the present invention is more advantageous.

In a preferred embodiment of the present aspect is to provide an improved process for the preparation of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy) benzyl)-N,N,8-trimethyl non-4-enamide compound of formula-8a, which comprising of treating the (R)-4-(2-(chloromethyl)-3-methylbutyl)-l -methoxy-2-(3-methoxypropoxy) benzene compound of formula-2a with magnesium turnings in the presence of 1,2- dibromo ethane, followed by its condensation with (S,E)-5-chloro-2-isopropyl-N,N- dimethylpent-4-enamide compound of formula-9a in the presence of ferric acetyl acetonate and N-methyl pyrrolidone to provide compound of formula-8a, which is isolated using ethyl acetate to provide pure compound of formula-8a.

The fifth aspect of the present invention is to provide one pot process for the preparation of aliskiren compound of formula- 1, which comprising of the following steps:

a) Treating the (3S,5S)-5-((lR,3S)-l-halo-3-(4-methoxy-3-(3-methoxypropoxy) benzyl)-4-methyl pentyl)-3-isopropyldihydrofuran-2(3H)-one compound of general formula- 10 with a suitable alkali metal azide in a suitable solvent to provide (3S,5S)- 5-(( 1 S,3 S)- 1 -azido-3-(4-methoxy-3 -(3 -methoxypropoxy)benzyl)-4-methyl pentyl)-3- isopropyldihydro furan-2(3H)-one compound of formula-11,

b) condensing the compound of formula-11, in-situ with 3-amino-2,2-dimethyl propanamide compound of formula- 12 in the presence of a proton donor in a suitable solvent to provide (2S,4S,5S,7S)-N-(3-amino-2,2-dimethyl-3-oxopropyl)-5-azido-4 - hydroxy-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl) -8-methyl nonanamide compound of formula- 13,

c) reducing the compound of formula- 13 in-situ with a suitable reducing agent, optionally in the presence of ethanolamine in a suitable solvent to provide aliskiren compound of formula- 1.

Wherein, in step a) the suitable solvent used is l,3-Dimethyl-3,4,5,6-tetrahydro- 2(lH)-pyrimidinone (herein after referred as DMPU); the suitable alkali metal azide used is sodium azide,

in step b) proton donor used is 2-hydroxy pyridine.

In a preferred embodiment of the present aspect provides one pot process for the preparation of aliskiren compound of formula- 1, which comprising of the following steps of:

a) Treating the (3S,5S)-5-((lR,3S)-l-bromo-3-(4-methoxy-3-(3-methoxypropoxy) benzyl)-4-methyl pentyl)-3-isopropyldihydrofuran-2(3H)-one compound of formula- 10a with sodium azide in DMPU to provide (3S,5S)-5-((lS,3S)-l-azido-3-(4- methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentyl)-3-isopro pyl dihydrofuran- 2(3H)-one compound of formula-11,

b) condensing the compound of formula-11 in-situ with 3-amino-2,2-dimethyl propanamide compound of formula- 12 in the presence of 2-hydroxy pyridine in triethylamine to provide (2S,4S,5S,7S)-N-(3-amino-2,2-dimethyl-3-oxopropyl)-5- azido-4-hydroxy-2-isopropyl-7-(4-methoxy-3-(3-methoxy propoxy)benzyl)-8-methyl nonanamide compound of formula- 13,

c) reducing the compound of formula- 13 in-situ with Pd/C in the presence of hydrogen pressure and in the presence of ethanolamine in isopropyl alcohol to provide aliskiren compound of formula- 1.

The sixth aspect of the present invention is to provide one pot process for the preparation of compound of general formula- 10, which comprising of the following steps:

a) Treating the (R)-4-(2-(chloromethyl)-3-methylbutyl)-l-methoxy-2-(3-methox y propoxy) benzene compound of formula-2a with magnesium turnings in the presence of alkenyl halides in a suitable solvent, followed by condensing it with (S,E)-5- chloro-2-isopropyl-pent-4-enamide derivative compound of general formula-9 in the presence of N-methyl pyrrolidone and a suitable metal complex in a suitable solvent to provide (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxy propoxy)benzyl)-8- methyl-4-nonene amide derivative compound of general formula-8,

b) treating the compound of general formula-8 with a suitable halogenating agent in the presence of aqueous acid in a suitable solvent to provide (3S,5S)-5-((lR,3S)-l-halo- 3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentyl)-3-i sopropyldihydro furan-2(3H)-one compound of general formula- 10, which is isolated using an ether solvent to provide pure compound of general formula- 10.

Wherein, in step a) alkenyl halides used is 1 ,2-dibromo ethane; the suitable metal complex used is ferric acetyl acetonate,

In step b) the suitable halogenating agent is selected from elemental bromine, iodine, N-bromo, N-chloro, N-iodo carboxamide, dicarboxamides, N-bromo, N-chloro, N-iodo phthalimide, N-chloro, N-bromo, N-iodo succinimide, tertiary butyl hypochlorite, N-halogenated sulfonamides and imide; preferably N-bromo succinimide.

In a preferred embodiment of the present aspect provides one pot process for the preparation of (3 S,5 S)-5-((l R,3S)- 1 -bromo-3-(4-methoxy-3-(3-methoxypropoxy) benzyl)-4-methylpentyl)-3-isopropyldihydrofuran-2(3H)-one compound of formula- 10a, which comprising of the following steps:

a) Treating the (R)-4-(2-(chloromethyl)-3-methylbutyl)-l-methoxy-2-(3-methox y propoxy) benzene compound of formula-2a with magnesium turnings in the presence of 1 ,2-dibromo ethane in isopropyl alcohol, followed by condensing it with (S,E)-5- chloro-2-isopropyl-N,N-dimethylpent-4-enamide compound of formula-9a in the presence of ferric acetyl acetonate and N-methyl pyrrolidone to provide (2S,7R,E)-2- isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-N,N,8-tri methylnon-4- enamide compound of formula-8a,

b) treating the compound of formula-8a with N-bromo succinimide in the presence of aqueous ortho phosphoric acid in tetrahydrofuran to provide compound of formula- 10a, which is isolated using diisopropyl ether to provide pure compound of formula- 10a.

In the above fourth and sixth aspects, the (S,E)-5-chloro-2-isopropyl-pent-4-ene amide derivative compound of general formula-9 was prepared by reacting the (S,E)-5- chloro-2-isopropylpent-4-enoic acid compound of formula-3 with a suitable amine hydrochloride compound of general formula-7 in the presence of suitable condensing agent in a suitable solvent (or) by converting the compound of formula-3 into its acid chloride and followed by condensing it with compound of general formula-7 to provide compound of general formula-9.

The seventh aspect of the present invention is to provide a process for the preparation of (R)-4-(2-(chloromethyl)-3-methylbutyl)-l -methoxy-2-(3-methoxy propoxy)benzene compound of formula-2a, which comprising of the following steps: a) Condensing the 4-methoxy-3-(3-methoxypropoxy)benzaldehyde compound of formula- 17,

Formula- 17

with isovelarate under suitable conditions to provide compound of formula-30,

Formula-30

wherein, R is same as defined above,

b) hydrolyzing the compound of formula-30 in the presence of an acid or a base to provide (E)-2-(4-methoxy-3-(3-methoxypropoxy)benzylidene)-3-methylbu tanoic acid compound of formula-31 ,

Formula-31

treating the compound of formula-31 with a chiral auxiliary in a suitable solvent to provide compound of formula-32,

Formula-32

wherein, Aux* is a chiral auxiliary selected from 4-phenyloxazolidin-2-one or phenyl ethylamine,

reducing the compound of formula-32 with a suitable reducing agent in a suitable solvent to provide compound of formula-33 Formula-33

hydrolyzing the compound of formula-33 with an acid or base in a suitable solvent to provide (R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutanoi c acid compound of formula-22,

Formula-22

reducing the compound of formula-22 with a suitable reducing agent in a suitable solvent to provide (R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutan- l-ol compound of formula-23,

Formula-23

reacting the compound of formula-23 with a suitable chlorinating agent in a suitable solvent to provide compound of formula-2a.

Wherein, in step g) the suitable chlorinating agent is selected from phosphoryl chloride, phosphorous trichloride, phosphorous pentachloride, thionyl chloride and oxalyl chloride.

The eighth aspect of the present invention is to provide an improved process for the preparation of (R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutan-l -ol compound of formula-23, which comprising of, reducing the (R)-2-(4-methoxy-3-(3- methoxypropoxy)benzyl)-3 -methyl butanoic acid compound of formula-22 with sodium borohydride in the presence of boron trifluoro etherate in nitrogen atmosphere in ether solvent preferably tetrahydrofuran to provide (R)-2-(4-methoxy-3-(3-methoxy propoxy)benzyl)-3 -methy lbutan- 1 -ol compound of formula-23.

In the prior art the above reaction was carried out using sodium borohydride and iodine to provide (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutan-l-ol. The main disadvantage of prior art is that it takes a very long time i.e. around four days for completion of the reaction. Also lithium aluminium hydride was utilized in the place of sodium borohydride, which is difficult to handle on a large scale industrial process and also prove impurities. In our invention the reaction was completed within four to five hours and also the impurities were controlled by the specific reagent used. The ninth aspect of the present invention is to provide an improved process for the preparation of (R)-4-(2-(halomethyl)-3-methylbutyl)-l-methoxy-2-(3-methoxyp ropoxy) benzene, compound of formula-2 which comprising of;

a) Reacting 3 -methoxypropan- 1 -ol formula- 14,

Formula- 14

with methanesulfonyl chloride in the presence of a base in a suitable solvent gives 3- methoxypropyl methanesulfo la- 15,

Formula- 15

condensing the 3-methoxypropyl methanesulfonate compound of formula- 15 with 3- hydroxy-4-methoxybenzaldehyde compound of formula- 16,

Formula- 16

in the presence of a suitable base in a suitable solvent gives 4-methoxy-3-(3- methoxypropoxy)benzaldehyde compound of formula- 17,

Formula- 17

reducing the 4-methoxy-3-(3-methoxypropoxy)benzaldehyde compound of formula- 17 in the presence of suitable reducing agent in a suitable solvent gives (4-methoxy)- 3-(3-methoxypropoxy)benzyl alcohol compound of formula- 18,

Formula- 18

brominating the compound of formula- 18 with a suitable brominating agent in a suitable solvent to provide 4-(bromomethyl)-l-methoxy-2-(3-methoxypropoxy) benzene compound of formula- 19,

Formula- 19

condensing the 4-(bromomethyl)-l-methoxy-2-(3-methoxypropoxy) benzene compound of formula- 19 with (R)-3-(3-methylbutanoyl)-4-phenyloxazolidin-2-one compound of formula-20,

Formula-20

in the presence of suitable base in a suitable solvent gives (R)-3-((R)-2-(4-methoxy-3- (3 -methoxypropoxy)benzyl)-3 -methylbutanoyl)-4-phenyloxazolidin-2-one compound of formula-21,

Formula-21

hydrolyzing the compound of formula-21 with a suitable base in presence of peroxide in a suitable solvent to give (R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3- methyl butanoic acid compound of formula-22,

Formula-22

reducing the compound of formula-22 with a suitable reducing agent, in a suitable solvent to give (R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutan-l -ol compound of formula-23,

Formula-23

treating the compound of formula-23 with a suitable halogenating agent in a suitable solvent to provide (R)-4-(2-(halomethyl)-3-methylbutyl)-l-methoxy-2-(3-methoxy propoxy) benzene, compound of formula-2.

Formula-2

Wherein, X = CI (formula-2a) and X = Br (formula-2b) The reactions in the above process may where ever required, be carried out in the presence of a 'phase transfer catalyst' which are defined above. 3-methoxypropane-l-ol compound of formula- 14 is prepared by treating it with a potassium hydroxide to generate the anion. The anion reacts with methyl iodide to provide compound of formula- 14.

In the step a) invention provides, reacting 3-methoxypropane-l-ol compound of formula- 14 with methanesulfonyl chloride in the presence of suitable bases like inorganic bases such as alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates or organic bases like triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, N-methyl morpholine, piperidine and pyridine preferably triethyl amine and the suitable solvent is selected from chloro solvents; preferably methylene chloride to provide 3-methoxypropylmethanesulfonate compound of formula-15.

In the step b) involves reacting 3-methoxypropylmethanesulfonate compound of formula-15 with 3-hydroxy-4-methoxybenzaldehyde compound of formula- 16 in the presence of suitable base. The suitable base is selected from the group consisting of but is not limited to inorganic bases selected from alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates preferably potassium carbonate. When sodium carbonate was used in place of potassium carbonate then the impurity level slightly increases. Hence potassium carbonate was preferred. The solvents were selected from the group consisting of but is not limited to ester solvents, ether solvents, hydrocarbon solvents like toluene, xylene, cyclohexane, hexane, heptane; and suitable non polar aprotic solvent includes but is not limited to benzene, toluene, xylene, tetrahydofuran, 2-methyltetrahydrofuran, preferably toluene; and reflux about 6-10 hrs, 8- 10 hrs and 9-10 hrs; preferably 8-10 hrs to provide 4-methoxy-3-(3- methoxypropoxy)benzaldehyde compound of formula- 17. When the reaction was carried out using potassium carbonate using toluene as a solvent then the yield and purity of the product increased substantially.

Jn the step c) 4-methoxy-3-(3-methoxypropoxy)benzaldehyde compound of formula- 17 is reduced in the presence of suitable reducing agents like DIBAL, sodium borohydride, lithium tri-sec-butylborohydride ("L-selectride"), sodium dihydro-bis-(2- methoxyethoxy)aluminate (Vitride), bis diisobutyl aluminium hydride, lithium aluminium hydride, and the like, preferably sodium borohydride; and the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, polar solvents or mixtures thereof; preferably tetrahydrofuran to provide (4-methoxy-3-(3-methoxypropoxy) phenyl) methanol, compound of formula-18. In the step d) (4-methoxy-3-(3-methoxypropoxy) phenyl) methanol compound of formula- 18 is treated with suitable brominating agent selected form N-bromo succinimide, phosphorus tribromide, carbon tetrabromide preferably phosphorus tribromide in a suitable chloro solvents selected from methylene chloride, ethylene dichloride, carbon tetra chloride, chloroform preferably methylene chloride to provide 4- (bromo methyl)- l-methoxy-2-(3-methoxypropoxy) benzene compound of formula-19.

In the step e) invention provides, reacting 4-(bromomethyl)-l-methoxy-2-(3- methoxypropoxy) benzene compound of formula-19 with (R)-3-(3-methylbutanoyl)-4- phenyloxazolidin-2-one compound of formula-20 in the presence of strong bases selected from n-butyl lithium, LiHMDS (lithium hexamethyldisilazane), lithium diisoproypyl amide, sodium tertiary butoxide and potassium tertiary butoxide preferably LiHMDS and solvent includes but is not limited to ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, polar solvents or mixtures thereof; preferably tetrahydrofuran to provide (R)-3-((R)-2-(4-methoxy-3-(3- methoxypropoxy)benzyl)-3-methylbutanoyl)-4-phenyloxazolidin- 2-one compound of formula-21. When (R)-3-(3-methylbutanoyl)-4-phenyloxazolidin-2-one compound of formula-20 was used in the place of (R)-3-(3-methylbutanoyl)-4-benzyloxazolidin-2-one which is known in the art it was observed that there was substantial increase in the enantiomeric excess of required isomer.

In the step f) hydrolysis of (R)-3-((R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutanoyl)-4-phenyloxazolidin-2-one compound of formula-21 is carried out with a suitable alkaline base selected from inorganic bases like alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates or organic bases like triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, N-methyl morpholine, piperidine and pyridine; in the presence of suitable peroxide selected from hydrogen peroxide, per acids such as peracetic acid, trifluoro peracetic acid, perbenzoic acid, m-chloro perbenzoic acid and the like preferably lithium hydroxide in presence of hydrogen peroxide in a suitable polar aprotic solvents like tetrahydrofuran and hydrated lithium hydroxide to provide (R)-2-(4-methoxy-3-(3- methoxypropoxy)benzyl)-3-methylbutanoic acid compound of formula-22. In the step g) involves reduction of (R)-2-(4-methoxy-3-(3-methoxy propoxy) benzyl)-3-methylbutanoic acid compound of formula-22. The use of lithium aluminum hydride was reported in the prior art for this reaction, which is difficult to handle. In the present invention the reaction is performed in the combination of boron trifluoride etherate or BF3-THF and sodium borohydride complex preferably sodium borohydride in presence of suitable catalyst like BF ₃ .Et ₂ 0 in tetrahydrofuran to provide (R)-2-(4- methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutan-l-ol compound of formula-23. This reagent is easy to handle and hence useful for scaling up. The reaction can be carried out using DIBAL-H, vitride, etc in the presence of the suitable solvent selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, polar solvents or mixtures thereof preferably tetrahydrofuran.

In the step h) involves reacting (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)- 3-methylbutan-l-ol compound of formula-23 with a suitable halogenating agent selected from carbon tetra chloride, oxalyl chloride, thionyl chloride, phosphorous pentachloride, N-chloro succinimide, Phosphorus tribromide, carbon tetrabromide, N-bromo succinimide in presence or absence of triphenyl phosphene in a suitable solvent selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, polar solvents or mixtures thereof; preferably methylene chloride to provide (R)-4-(2-(halomethyl)-3-methylbutyl)-l- methoxy-2-(3-methoxypropoxy) benzene compound of formula-2.

The tenth aspect of the present invention is to provide one pot process for the preparation of (4-methoxy)-3-(3-methoxypropoxy) benzyl alcohol compound of formula- 18 which comprising of treating the 3-methoxypropyl methane sulfonate compound of formula- 15 with 3-hydroxy-4-methoxybenzaldehyde compound of formula- 16 in the presence of suitable base in a suitable solvent and subsequently treating the product formed without isolating it, with a suitable reducing agent like sodium borohydride to provide (4-methoxy)-3-(3-methoxypropoxy)benzyl alcohol compound of formula-18.

The suitable base is selected from inorganic bases like alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates or organic bases like triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, N- methyl morpholine, piperidine and pyridine preferably potassium carbonate and the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, polar solvents or mixtures thereof; preferably toluene.

The eleventh aspect of the present invention is to provide a process for the preparation of (R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutan-l -ol compound of formula-23, which comprising of, reducing the (R)-3-((R)-2-(4-methoxy-3- (3-methoxypropoxy) benzyl)-3-methylbutanoyl)-4-phenyloxazolidin-2-one compound of formula-21, with a suitable reducing agent in a suitable solvent at a suitable temperature to provide (R)-2-(4-methoxy-3 -(3 -methoxypropoxy)benzyl)-3 -methylbutan- 1 -ol compound of formula-23.

The suitable reducing agent is selected from the combination of boron trifluoride etherate or BF3-THF and sodium borohydride complex preferably sodium borohydride in presence of suitable catalyst like BF3.Et ₂ 0 in a suitable solvent selected from ether solvents, ester solvents, ketone solvents, polar aprotic solvents, hydrocarbon solvents or mixtures thereof; preferably tetrahydrofuran and the reaction is carried out at reflux temperature of the solvent used in the reaction.

The twelfth aspect of the present invention is to provide an improved process for the preparation of 3-amino-2,2-dimethylpropanamide compound of formula-27, which comprising of;

a) Reacting ethyl 2-cyanoacetate compound of formula-24

Formula-24

with methyl iodide in the presence of base in a suitable solvent to provide ethyl 2- cyano-2-methylpropanoate compound of formula-25,

Formula-25 b) treating the compound of formula-25 with methanolic ammonia to provide 2-cyano- 2-methylpropanamide compound of formula-26,

Formula-26

reducing the compound of formula-26 with raney nickel in the presence of ammonia in a suitable solvent to provide 3-amino-2,2-dimethylpropanamide compound of formula-27.

Formula-27

Wherein in the step a) the suitable base is selected from inorganic bases like alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates or organic bases preferably potassium carbonate solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, polar solvents or DMPU or mixtures thereof preferably dimethyl formamide. In the above reaction the methylation can be done by using dimethyl sulfate.

Wherein in step c) the reduction can be carried out by using vitride, DIBAL, Pd/C, vitride etc; and the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, polar solvents; preferably methanol.

The thirteenth aspect of present invention to provide a novel process for the preparation of (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutan-l-ol compound of formula-23, which comprising of;

a) Reacting the 3-methoxypropylmethanesulfonate compound of formula-15 with 3- hydroxy-4-methoxybenzaldehyde compound of formula- 16 in the presence of suitable base and in a suitable solvent to provide 4-methoxy-3-(3-methoxy propoxy) benzaldehyde compound of formula- 17, b) reacting the compound of formula- 17 with (R)-3-(3-methylbutanoyl)-4-phenyl oxazolidin-2-one compound of formula-20, in presence of titanium tetrachloride or titanium(IV) isopropoxide or mixtures thereof and a base in a suitable solvent to provide (4R)-3-((2S)-2-(hydroxy(4-methoxy-3-(3-methoxypropoxy)phenyl )methyl)- 3-methylbutanoyl)-4-phenyloxazolidin-2-one compound of formula-28,

Formula-28

c) hydrogenolysis of the compound of formula-28 with a suitable hydrogen source in the presence of acid in a suitable solvent to provide (R)-3-((R)-2-(4-methoxy-3-(3- methoxypropoxy)benzyl)-3-methylbutanoyl)-4-phenyloxazolidin- 2-one compound of formula-21, d) hydrolysis of compound of formula-21 with a suitable base in the presence of peroxide in a suitable solvent to provide (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutanoic acid compound of formula-22,

e) reducing the compound of formula-22 with a suitable reducing agent in a suitable solvent to provide (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutan- l-ol compound of formula-23.

wherein, in step a) the reaction between 3-methoxypropyl methanesulfonate, compound of formula- 15 and 3-hydroxy-4-methoxybenzaldehyde compound of formula- 16 is carried out in presence of a suitable bases, preferably inorganic base such as alkali metal carbonates like sodium carbonate, potassium carbonate; in a suitable solvents, preferably hydrocarbon solvents selected from toluene, xylene, cyclohexane, hexane, heptane; and at a suitable temperature;

wherein, in step b) the reaction of 4-methoxy-3-(3-methoxypropoxy) benzaldehyde compound of formula- 17 with (R)-3-(3-methylbutanoyl)-4-phenyl oxazolidin-2-one compound of formula-20 take place in presence of titanium tetrachloride or titanium(IV) isopropoxide or mixtures thereof and a suitable base is preferably organic base such as diisopropyl ethyl amine in a suitable solvent selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, polar solvents or mixtures thereof; preferably chloro solvents.

The reaction of 4-methoxy-3-(3-methoxypropoxy) benzaldehyde compound of formula- 17 with (R)-3-(3-methylbutanoyl)-4-phenyloxazolidin-2-one compound of formula-20 also takes place when the reagents like lithium diisopropyl amine(LDA), Lithium hexamethyldisilazide(LiHMDS), n-butyl lithium are utilized in the place of titanium tetrachloride or titanium(IV) isopropoxide or mixtures thereof.

Wherein in the step c), hydrogenolysis of (4R)-3-((2S)-2-(hydroxy (4-methoxy-3- (3 -methoxypropoxy)phenyl)methyl)-3 -methylbutanoyl)-4-phenyloxazolidin-2-one compound of formula-28 is carried out by reacting it with palladium on carbon in presence of suitable acid selected from hydrochloric acid, hydrobromic acid, acetic acid, benzenesulfonic acid, camphorsulfonic acid, ethanesulfonic acid, fumaric acid, maleic acid, methane sulfonic acid, oxalicacid, phosphoric acid and sulfuric acid in presence of hydrogen.

The hydrogenolysis can also be carried out by using the suitable reducing agents. The suitable reducing agent is selected from heterogeneous catalysts containing from about 0.1% to about 20% by weight of transition metals such as Ni, Pd, Pt, Rh, Re, Ru and Ir, including oxides and combination thereof, raney nickel, palladium catalyst such as Pd/C, Pd/SrC0 ₃ , Pd/ A1 ₂ 0 _3> Pd/MgO, Pd/CaC0 ₃ , Pd/ BaS0 ₄ , PdO, Pd Black, PdCl ₂ , Rh/C, Ru/C, Re/C, Pt0 ₂ , Rh/C, Ru0 ₂ ; or hydride reagents like sodium borohydride, sodium cyanoborohydride, lithium aluminium hydride and vitride etc in the presence or absence of hydrogen.

Wherein in the step d) alkaline peroxide mediated hydrolysis of (R)-3-((R)-2-(4- methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutanoyl)-4-phen yloxazolidin-2-one compound of formula-21 is carried out in the presence of suitable base such as inorganic bases like alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates or organic bases like triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, N-methyl morpholine, piperidine and pyridine in the presence of peroxides like hydrogen peroxide, per acids such as peracetic acid, trifluoro peracetic acid, perbenzoic acid, m-chloro perbenzoic acid and the like; the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, polar solvents or mixtures thereof; preferably lithium hydroxide in presence of hydrogen peroxide in tetrahydrofuran.

Wherein in step e) the conversion of (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3 -methyl butanoic acid compound of formula-22 into (R)-2-(4-methoxy-3-(3- methoxypropoxy) benzyl)-3-methylbutan-l-ol compound of formula-23 is carried out by the conventional methods.

The fourteenth aspect of the present invention to provide a process for the preparation of (4R)-3-((2S)-2-(hydroxy(4-methoxy-3-(3-methoxypropoxy)phenyl ) methyl)-3 -methyl butanoyl)-4-phenyloxazolidin-2-one compound of formula-28, which comprising of reacting the 4-methoxy-3-(3-methoxypropoxy)benzaldehyde compound of formula- 17, with (R)-3-(3-methylbutanoyl)-4-phenyloxazolidin-2-one compound of formula-20 in presence of titanium tetrachloride or titanium(IV) isopropoxide or mixtures thereof and a base in a suitable solvent to provide (4R)-3-((2S)-2-(hydroxy(4-methoxy- 3-(3-methoxypropoxy)phenyl)methyl)-3-methylbutanoyl)-4-pheny loxazolidin-2-one compound of formula-28.

The reaction of 4-methoxy-3-(3-methoxypropoxy) benzaldehyde compound of formula- 17 with (R)-3-(3-methylbutanoyl)-4-phenyloxazolidin-2-one compound of formula-20 takes place in presence of titanium tetrachloride or titanium(IV) isopropoxide or mixtures thereof and a suitable base is selected from organic bases preferably diisopropyl ethyl amine in a suitable solvent selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, polar solvents or mixtures thereof; preferably chloro solvents.

The reaction also takes place when the reagents like lithium diisopropyl amine (LDA), Lithium hexamethyldisilazide (LiHMDS), n-butyl lithium are utilized in the place of titanium tetrachloride or titanium (IV) isopropoxide or mixtures thereof.

The fifteenth aspect of the present invention is to provide a process for the preparation of (R)-3-((R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methyl butanoyl)-4-phenyl oxazolidin-2-one compound of formula-21, which comprising of hydrogenolysis of (4R)-3-((2S)-2-(hydroxy(4-methoxy-3-(3-methoxypropoxy)phenyl ) methyl)-3-methylbutanoyl) -4-phenyloxazolidin-2-one compound of formula-28, with a suitable hydrogen source in the presence of suitable acid in a suitable solvent to provide (R)-3-((R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methyl butanoyl)-4-phenyl oxazolidin -2 -one compound of formula-21.

The hydrogenolysis of (4R)-3-((2S)-2-(hydroxy(4-methoxy-3-(3-methoxy propoxy)phenyl)methyl)-3-methylbutanoyl)-4-phenyloxazolidin- 2-one compound of formula-28 is carried out by reacting it with palladium on carbon in presence of suitable acid selected from hydrochloric acid, hydrobromic acid, acetic acid, benzenesulfonic acid, camphorsulfonic acid, ethanesulfonic acid, fumaric acid, maleic acid, methane sulfonic acid, oxalic acid, phosphoric acid and sulfuric acid in the presence of hydrogen;

The hydrogenolysis can also be carried out by using the suitable reducing agents as defined above.

The sixteenth aspect of the present invention is to provide a novel process for the preparation of (R)-3 -((R)-2-(4-methoxy-3 -(3 -methoxypropoxy)benzyl)-3 -methyl butanoyl)-4-phenyloxazolidin-2-one compound of formula-21 , which comprising of: a) Reacting the 4-methoxy-3-(3-methoxypropoxy)benzaldehyde compound of formula- 17, with (R)-3-(3-methylbutanoyl)-4-phenyloxazolidin-2-one compound of formula- 20, in presence of a titanium tetrachloride or titanium(IV) isopropoxide or mixtures thereof, and a suitable base in a suitable solvent to provide (4R)-3-((2S)-2- (hydroxy(4-methoxy-3-(3-methoxypropoxy)phenyl)methyl)-3-meth ylbutanoyl)-4- phenyl oxazolidin-2-one compound of formula-28,

b) hydrogenolysis of compound of formula-28 with a suitable hydrogen source in the presence of suitable acid in a suitable solvent to provide (R)-3-((R)-2-(4-methoxy-3- (3-methoxypropoxy)benzyl)-3-methylbutanoyl)-4-phenyloxazolid in-2-one compound of formula-21.

Wherein in the step a) the reaction of 4-methoxy-3-(3-methoxypropoxy) benzaldehyde compound of formula- 17 with (R)-3-(3-methylbutanoyl)-4-phenyl oxazolidin-2-one compound of formula-20 take place in presence of titanium tetrachloride or titanium(IV) isopropoxide or mixtures thereof and a suitable base is selected from organic bases preferably diisopropyl ethyl amine in a suitable solvent selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, polar solvents or mixtures thereof; preferably chloro solvents.

The reaction also takes place when the reagents like lithium diisopropyl amine (LDA), Lithium hexamethyldisilazide (LiHMDS), n-butyl lithium are utilized in the place of titanium tetrachloride or titanium (IV) isopropoxide or mixtures thereof.

Wherein in the step b) hydrogenolysis of (4R)-3-((2S)-2-(hydroxy(4-methoxy-3- (3-methoxypropoxy)phenyl)methyl)-3-methylbutanoyl)-4-phenylo xazolidin-2-one compound of formula-28 is carried out by reacting it with palladium on carbon in presence of suitable acid selected from hydrochloric acid, hydrobromic acid, acetic acid, benzenesulfonic acid, camphorsulfonic acid, ethanesulfonic acid, fumaric acid, maleic acid, methane sulfonic acid, oxalic acid, phosphoric acid and sulfuric acid in presence of hydrogen.

The hydrogenolysis can also be carried out by using the suitable reducing agents as defined above.

The seventeenth aspect of the present invention to provide (4R)-3-((2S)-2- (hydroxy (4-methoxy-3 -(3 -methoxypropoxy)phenyl)methyl)-3 -methylbutanoyl)-4- phenyloxazolidin-2-one compound represented by the following structural formula-28,

Formula-28

The novel compound of formula-28 of the present invention is useful as an intermediate in the preparation of (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3- methylbutan-l-ol compound of formula-23. The eighteenth aspect of the present invention is to provide a novel amine salts of (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutanoic acid compound of general formula-29,

Formula-29

The novel amine salts compound of general formula-29 are useful in the preparation of highly pure (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3 -methyl butanoic acid compound of formula-22.

The term "Organic amine" refers to the amine selected from methyl amine, ethyl amine, di methyl amine, tri methyl amine, diethyl amine, tri ethyl amine n-propyl amine, isopropyl amine, n-butyl amine, tertiary butyl amine, (+/-)-sec-butyl amine, octyl amine, 2-ethyl hexylamine, benzyl amine, a-methyl-benzylamine, phenyl ethylamine, dibenzylamine, N-methylbenzylamine, N,N-dimethylbenzylamine, Ν,Ν-diethyl benzyl amine, N-ethyl-N-methylbenzylamine, tribenzyl amine, cyclopentylamine, cyclohexyl amine, cycloheptylamine, N-methylcyclopentylamine, N-ethylcyclohexyl amine, N-ethyl cycloheptylamine, dicyclohexylamine, Ν,Ν-dimethylcyclo pentylamine, N,N-dimethyl cyclohexylamine, Ν,Ν-diethylcycloheptylamine and the like.

The nineteenth aspect of the present invention is to provide a process for the preparation of novel amine salts of (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3- methylbutanoic acid compound of general formula-29 which comprising of reacting the (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutanoic acid compound of formula-22 with a suitable amine as discussed above, in a suitable solvent selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, polar solvents or mixtures thereof, at a suitable temperature to provide the corresponding amine salt of compound of general formula-29.

The obtained amine salts, compound of general formula-29 are useful in the preparation of highly pure (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methyl butanoic acid compound of formula-22 as well as compound of formula-23.

The intermediate compounds and salts prepared in the above aspect of the present invention are used in the preparation of highly pure (2S,4S,5S,7S)-N-(2-Carbamoyl-2- methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy -3-(3-methoxypropoxy) phenyl] -octanamide and its pharmaceutically acceptable salts.

The twentieth aspect of the present invention is to provide a novel crystalline form of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzy l)-8-methylnon-4- enoic acid tertiary butyl amine salt compound of formula-4a (herein designated as crystalline form-M). The crystalline form-M of compound of formula-4a, which is characterized by its powder XRD having peaks at about 8.4, 11.8, 19.8 and 20.1 ± 0.2 degrees two-theta and substantially as shown in figure- 1; or by its DSC thermogram showing endotherm at about 143.17°C as shown in figure-2.

The twenty-first aspect of the present invention is to provide a novel crystalline form of (3S,5S)-5-((l S,3S)-l-azido-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4- methyl pentyl)-3-isopropyl dihydro furan-2(3H)-one compound of formula-11 (herein designated as crystalline form-S). The crystalline form-S of compound of formula-11, which is characterized by its powder XRD having peaks at about 6.1, 9.3, 10.1, 15.4, 18.5 and 20.8 ± 0.2 degrees two-theta and substantially as shown in figure-3; or by its DSC thermogram showing endotherm at about 62.8°C as shown in figure-4.

The compounds of formula-4, 4a, 6 and 8 of the present invention were analyzed by HPLC using the following conditions:

Apparatus: A liquid chromatographic system is to be equipped with variable wavelength UV-detector; Column : Chiral pak-IC, 250 x 4.6 mm, 5 μπι or equivalent; Flow rate : 1.0 mL/minute; Wavelength : 230 nm; Column temperature : 15°C; Injection volume: 20 μί,; Run time : 50 minutes; Diluent: mobile phase n-hexane: IPA: Ethanol: TFA: DEA (90:05:05:0.1:0.1 v/v); Elution : Isocratic; Sample cone: 1.0 mg/ml Aliskiren hemifumarate was analyzed by HPLC using the following conditions:

Apparatus: A liquid chromatographic system is to be equipped with variable wavelength UV-detector; Column : Symmetry CI 8, 250 x 4.6 mm, 5 μπι or equivalent; Flow rate : 1.0 ml/minute; Wavelength : 230 nm; Column temperature : 45°C; Injection volume: 10 uL; Run time : 53 minutes; Diluent: water:acetonitrile (50:50 v/v); Elution : Gradient; Sample cone: 2.0 mg/ml; mobile phase-A: Buffenacetonitrile (70:30 v/v); mobile phase-B: acetonitrile: water (90:10 v/v); Buffer: 0.02M potassium dihydrogen phosphate and 0.03M 1 -octane sulphonic acid mono hydrate in 1000 ml of water, adjust pH to 2.0 with diluted orthophosphonc acid. Filtered this solution through 0.45μηι Nylon membrane filter paper and sonicate to degas it.

The compounds of formula-10, 11 and 13 of the present invention were analyzed by HPLC using the following conditions:

Apparatus: A liquid chromatographic system is to be equipped with variable wavelength UV-detector; Column : Kromasil 100 CI 8, 150 x 4.6 mm, 5 μπι or equivalent; Flow rate : 1.0 mL/minute; Wavelength : 230 nm; Column temperature : 20°C; Injection volume: 20 μί,; Run time : 50 minutes; Diluent: watenacetonitrile (50:50 v/v); Elution : Gradient; Sample cone: 1.0 mg/ml; mobile phase-A: 0.1% orthophosphonc acid: acetonitrile (50:50 v/v); mobile phase-B: acetonitrile: water (9:1 v/v);

The present invention is represented schematically as follows:

Formula-la Scheme-1:

I halogenating agent

Formula-2

Scheme-2:

Formula-21 Formula-23

Scheme-3:

Fromula-27 Fromula-26 Scheme-4:

Formula-22 Formula-23

Scheme-5:

Formula-17 Formula-20 Formula-28

Scheme-6:

Formula-22 Formula-29

The process described in the present invention is demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention: Examples:

Example- 1: Preparation of (S,E)-ethyl 5-chloro-2-isopropyIpent-4-enoate (Formula- 5b)

Purified water (1250 ml) and dichloromethane (1000 ml) were added to (S,E)-5- chloro-2-isopropyl pent-4-enoic acid phenyl ethanamine salt (250 gm) and cooled to 10- 15°C. The p ^H of the reaction mixture was adjusted to 1.8 with 50% aqueous hydrochloric acid. The reaction mixture temperature was raised to 25-30°C and both the organic and aqueous layers were separated. Extracted the aqueous layer with dichloromethane. Both the dichloro methane layers were combined and distilled off the solvent completely to get residue. Ethanol (1000 ml) was added to the obtained residue and cooled to 0-5°C. Sulfuric acid (832 gm) was added to the reaction mixture at 0-5°C and then heated to 70- 80°C. Stirred the reaction mixture for 16 hours at 70-80°C. After completion of the reaction, poured the reaction mixture into chilled water and extracted the product with dichloromethane. Both the dichloromethane and aqueous layers were separated. The dichloromethane layer was washed with 5% sodium bicarbonate solution and then distilled off the solvent completely under reduced pressure to get the title compound. Yield: 147.0 grams

Example-2: Preparation of (S,E)-ethyl 5-chloro-2-isopropyipent-4-enoate (Formula- 5b)

Sulfuric acid (16.5 gm) was added to a solution of (S,E)-5-chloro-2- isopropylpent-4-enoic acid phenyl ethanamine salt (10.0 gm) in ethanol (50 ml) at 0-5°C over a period of 2 hours. The reaction mixture was heated to 75-80°C and stirred for 10 hours at 75-80°C. After completion of the reaction, the reaction mixture was poured into chilled water and extracted the product with dichloromethane. Both the dichloromethane and aqueous layers were separated. The dichloro methane layer was washed with 5% sodium bicarbonate solution and then distilled off the solvent under reduced pressure to get the title compound. Yield: 7.0 grams

Example-3: Preparation of (S,E)-methyl 5-chloro-2-isopropylpent-4-enoate (Formula-5a)

Sulfuric acid (3.3 gm) was added to a solution of (S,E)-5-chloro-2-isopropylpent-

4-enoic acid phenyl ethanamine salt (10.0 gm) in methanol (50 ml) at 0-5°C over a period of 15 minutes. The reaction mixture was heated to 65-70°C and stirred for 10 hours at 75- 80°C. After completion of the reaction, the reaction mixture was poured into chilled water and extracted the product with dichloromethane. Both the dichloromethane and aqueous layers were separated. The dichloro methane layer was washed with 5% sodium bicarbonate solution and then distilled off the solvent under reduced pressure to get the title compound. Yield: 5.5 grams.

Example-4: Preparation of (2S,7R,E)-ethyl 2-isopropyl-7-(4-methoxy-3-(3-methoxy propoxy) benzyl)-8-methylnon-4-enoate (Formula-6b)

A mixture of magnesium turnings (27.4 gm) and tetrahydrofuran (480 ml) was heated to 63-68°C under nitrogen atmosphere. 1,2-dibromoethane (17.9 gm) was added to the reaction mixture and stirred for 10 minutes. (R)-4-(2-(chloromethyl)-3- methylbutyl)-l-methoxy-2-(3-methoxypropoxy)benzene compound of formula-2a (120 gm) and 1,2-dibromoethane (35.8 gm) were dissolved in tetrahydrofuran (480 ml) and added slowly to the above reaction mixture at 63-68°C over a period of 1 hour. The reaction mixture was stirred for 3 hours at 63-68°C. After completion of the reaction, the reaction mixture was cooled to 0-5°C and the mixture of (S,E)-ethyl 5-chloro-2- isopropylpent-4-enoate compound of formula-5b (70 gm), N-methyl pyrrolidone (18.8 gm) and Fe(AcAc) ₃ (6.7 gm) in tetrahydrofuran (480 ml) was slowly added to the reaction mixture at 0-5°C over a period of 1 hour and stirred for 11/2 hour at 0-5°C. After completion of the reaction, the reaction mixture was quenched with aqueous HC1 and extracted the product into ethyl acetate. Both the ethyl acetate and aqueous layers were separated. The ethyl acetate layer was washed with saturated sodium chloride solution and then distilled off the solvent completely under reduced pressure to get the title compound. Yield: 166.0 grams.

Example-5: Preparation of (2S,7R,E)-methyl 2-isopropyl-7-(4-methoxy-3-(3- methoxy propoxy) benzyI)-8-methyInon-4-enoate (Formula-6a)

A mixture of magnesium turnings (1.8 gm) and tetrahydrofuran (32 ml) was heated to 63-68°C under nitrogen atmosphere. 1,2-dibromoethane (1.2 gm) was added to the reaction mixture and stirred for 10 minutes. (R)-4-(2-(chloromethyl)-3-methylbutyl)- l-methoxy-2-(3-methoxypropoxy) benzene compound of formula-2a (8.0 gm) and 1,2- dibromoethane (2.4 gm) were dissolved in tetrahydrofuran (32 ml) and added slowly to the above reaction mixture at 63-68°C. Stirred the reaction mixture for 4 hours at the same temperature. After completion of the reaction, the reaction mixture was cooled to 0- 5°C and the mixture of (S,E)-methyl 5-chloro-2-isopropylpent-4-enoate compound of formula-5a (4.3 gm), N-methyl pyrrolidone (1.2 gm) and Fe(AcAc) ₃ (0.4 gm) dissolved in tetrahydrofuran (32 ml) was slowly added to the reaction mixture at 0-5 °C and stirred for 1 hour at the same temperature. After completion of the reaction, quenched the reaction mixture with aqueous HC1 and extracted the product in ethyl acetate. The ethyl acetate layer was washed with saturated sodium chloride solution and then distilled off the solvent completely under reduced pressure to get title compound. Yield: 9.2 grams. Example-6: Preparation of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxy propoxy)benzyl)-8-methyl non-4-enoic acid (Formula-4)

A mixture of magnesium turnings (4.9 gm) and tetrahydrofuran (80 ml) was heated to 63-68°C under nitrogen atmosphere. 1 ,2-dibromoethane (3.2 gm) was added to the reaction mixture and stirred for 10 minutes. (R)-4-(2-(chloromethyl)-3-methylbutyl)- l-methoxy-2-(3-methoxy propoxy) benzene compound of formula-2a (21.4 gm) and 1,2- dibromoethane (6.4 gm) were dissolved in tetrahydrofuran (80 ml) and added slowly to the above reaction mixture at 63-68°C. Stirred the reaction mixture for 4 hours at the same temperature. After completion of the reaction, the reaction mixture was cooled to 0- 5°C and the mixture of (S,E)-5-chloro-2-isopropylpent-4-enoic acid compound of formula-3 (6.0 gm), N-methyl pyrrolidone (1.57 gm) and Fe(AcAc) ₃ (0.56 gm) taken in tetrahydrofuran (80 ml) was slowly added to the reaction mixture at 0-5°C and stirred for 1 hour at the same temperature. After completion of the reaction, quenched the reaction mixture with aqueous HC1 and extracted the product in ethyl acetate. The ethyl acetate layer was washed with saturated sodium chloride solution and then distilled off the solvent completely under reduced pressure to get the title compound. Yield: 23.04 grams. Example-7: Preparation of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxy propoxy) benzyl) -8-methyl non-4-enoic acid tertbutyl amine salt (Formula-4a)

A mixture of magnesium turnings (2.28 gm) and tetrahydrofuran (40 ml) was heated to 63-68°C under nitrogen atmosphere. 1,2-dibromoethane (1.5 gm) was added to the reaction mixture and stirred for 10 minutes. (R)-4-(2-(chloromethyl)-3-methylbutyl)- l-methoxy-2-(3-methoxypropoxy) benzene compound of formula-2a (10 gm) and 1,2- dibromoethane (3.0 gm) were dissolved in tetrahydrofuran (40 ml) and added slowly to the above reaction mixture at 63-68°C. Stirred the reaction mixture for 4 hrs at the same temperature. After completion of the reaction, the reaction mixture was cooled to 0-5°C and the mixture of (S,E)-5-chloro-2-isopropylpent-4-enoic acid tertiary butyl amine salt compound of formula-3a (8.73 gm), N-methyl pyrrolidone (1.57 gm) and Fe(AcAc) ₃ (0.56 gm) taken in tetrahydrofuran (40 ml) was added slowly to the reaction mixture at 0- 5°C and stirred for 1 hour at the same temperature. After completion of the reaction, quenched the reaction mass with aqueous HCl and extracted the product in ethyl acetate. The ethyl acetate layer was washed with saturated sodium chloride solution and then distilled off the solvent completely to get the residue. Water was added to the obtained residue and washed repeatedly with methyl tertiarty butyl ether. Acetonitrile was added to the aqueous layer and adjusted the pH to 3.4 by using aqueous HCl at 0-5°C. Saturated the reaction mixture with sodium chloride and separated both the organic and aqueous layers. Tertiary butylamine was added to the organic layer at 0-5°C and stirred for 10-15 minutes. Distilled off the solvent completely under reduced pressure and isolated the title compound in acetonitrile. Yield: 2.0 grams.

The PXRD of the obtained compound is similar to the crystalline form-M as shown in figure- 1.

Example-8: Preparation of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxy propoxy) benzyl) -8-methyl non-4-enoic acid tert.butyl amine salt (Formula-4a)

Lithium hydroxide (78 gm), followed by water (400 ml) were added to a mixture of (2S,7R,E)-ethyl 2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8- methylnon-4-enoate compound of formula-6b (160 gm), tetrahydrofuran (600 ml) and methanol (400 ml). The reaction mixture was heated to 65-70°C and then stirred for 26 hours at 65-70°C. After completion of the reaction, distilled off the solvent completely under reduced pressure to obtained residue. Water was added to the reaction mixture. Extracted the product with pet.ether and both the pet.ether and aquoeus layers were separated. Extracted the aqueous layer with acetonitrile and both the acetonitrile layer and aqueous layers were separated. Both the pet.ether and acetonitrile layers were combined and cooled to 0-5°C. Tertiary butyl amine (27 ml) was added to the reaction mixture at 0-5°C and stirred for ½ hour at 0-5°C. Distilled off the solvent completely under reduced pressure and isolated the product in acetonitrile. Filtered the solid, washed with acetonitrile and then dried to get the title compound.

Yield: 87.0 grams; Purity by HPLC: 95.90%

Example-9: Preparation of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxy propoxy) benzyl) -8-methyI non-4-enoic acid tert.butyl amine salt (compound of formula-4a)

2N potassium hydroxide (150 ml) and water (260 ml) were added to a solution of (2S,7R,E)-methyl 2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methy l- non-4-enoate compound of formula-6a (65 gm) in dioxane (780 ml) and heated to reflux and then stirred for 24 hours at the same temperature. After completion of the reaction, distilled off the solvent completely under reduced pressure. Water was added to the reaction mixture and then repeatedly washed the reaction mixture with methyl tertiary butyl ether. Acetonitrile was added to the reaction mixture. Adjusted the pH to 3.0-4.0 by using aqueous hydrochloric acid at 0-5 °C and then saturated with sodium chloride and separated the organic layer from aqueous layer. Tertiary butyl amine was added to the organic layer at 0-5 °C and then distilled off the solvent completely. Isolated the compound in acetonitrile and dried to get the title compound.

Yield: 37.2 grams; purity by HPLC: 98.57 %.

Example-10: Preparation of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxy propoxy) benzyl) -N,N,8-trimethylnon-4-enamide (formula-8a)

A mixture of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzy l)- 8-methylnon-4-enoic acid tertiary butyl amine salt compound of formula-4a (75 gm), dichloroethane (300 ml) and water (300 ml) was cooled to 0-5°C. Adjusted the pH to 2.5 with 10% hydrochloric acid and separated the organic layer and kept a side. Dimethyl amine hydrochloride salt compound of formula-7a (22 gm) was added to dichloro ethane (150 ml) and cooled to 0-5°C. To this mixture HOBT (1.6 gm) and triethyl amine (22.8 gm) were added followed by the above organic layer at 0-5 °C and stirred the reaction mixture for 45 minutes at 0-5. A solution of DCC (32 gm) in dichloro ethane (150 ml) was added to the reaction mixture at 0-5°C over a period of 1 hour, then the temperature of the reaction mixture was raised to 25-30°C and stirred the reaction mixture for 12 hrs at 25-30°C. Cooled the reaction mixture to 0-5°C and stirred the reaction mixture for ½ hour. Filtered the reaction mixture, washed the filtrate with 5% HCl and 5% sodium bicarbonate followed by saturated sodium chloride, solution and distilled off the solvent completely from the organic layer to get the title compound as a residue.

Yield: 67.0 grams; Purity by HPLC: 90%.

Exaniple-ll: Preparation of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxy propoxy) benzyl) -N,N,8-trimethylnon-4-enamide (formula-8a)

A mixture of magnesium turnings (11.5 gm) and tetrahydrofuran (200 ml) was heated to 63-68°C under nitrogen atmosphere. 1,2-dibromoethane (7.5 gm) was added to the reaction mixture and stirred for 10 minutes. (R)-4-(2-(chloromethyl)-3-methylbutyl)- l-methoxy-2-(3-methoxypropoxy)benzene compound of formula-2a (50 gm) and 1,2- dibromoethane (7.5 gm) were dissolved in tetrahydrofuran (200 ml) and added slowly to the above reaction mixture at 63-68°C. Stirred the reaction mixture for 4 hours at the same temperature. After completion of the reaction, the reaction mixture was cooled to 0- 5°C and the mixture of (S,E)-5-chloro-2-isopropyl-N,N-dimethylpent-4-enamide compound of formula-9a (26.1 gm), N-methyl pyrrolidone (7.9 gm) and Fe(AcAc) ₃ (2.8 gm) in tetrahydrofuran (200 ml) was slowly added to the reaction mixture at 0-5 °C and stirred for 1 hour at the same temperature. After completion of the reaction, quenched the reaction mass with aqueous HCl and extracted the product in ethyl acetate. The ethyl acetate layer was washed with saturated sodium chloride solution and then distilled off the solvent completely under reduced pressure to get the title compound.

Yield: 66.0 grams.

Example-12: One pot process for the preparation of (3S,5S)-5-((lR,3S)-l-bromo-3- (4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentyl)-3-iso propyI dihydro furan-2(3H)-one (Formula-lOa)

A mixture of magnesium turnings (11.5 gm) and tetrahydrofuran (200 ml) was heated to 63-68°C under nitrogen atmosphere. 1,2-dibromoethane (7.5 gm) was added to the reaction mixture and stirred for 10 minutes. (R)-4-(2-(chloromethyl)-3-methylbutyl)- l-methoxy-2-(3-methoxypropoxy)benzene compound of formula-2a (50 gm) and 1,2- dibromoethane (7.5 gm) were dissolved in tetrahydrofuran (200 ml) and added slowly to the above reaction mixture at 63-68°C. Stirred the reaction mixture for 4 hours at the same temperature. After completion of the reaction, the reaction mixture was cooled to 0- 5°C and the mixture of (S,E)-5-chloro-2-isopropyl-N,N-dimethylpent-4-enamide compound of formula-9a (26.1 gm), N-methyl pyrrolidone (7.9 gm) and Fe(AcAc) ₃ (2.8 gm) in tetrahydrofuran (200 ml) was slowly added to the reaction mixture at 0-5 °C and stirred for 1 hour at the same temperature. After completion of the reaction, quenched the reaction mass with aqueous HC1 and extracted the product in ethyl acetate. The ethyl acetate layer was washed with saturated sodium chloride solution and then distilled off the solvent completely under reduced pressure to obtained a residue. Tetrahydrofuran (330 ml) and water (5.28 ml) were added to the above obtained residue and cooled to 0- 5°C. 88% orthophosphoric acid (7.92 ml) was slowly added to the reaction mixture at 0- 5°C and then added N-bromo succinimide (NBS) (21.67 gm) in 3 equal lots at 0-5°C. Stirred the reaction mixture for 45 minutes at 0-5 °C. After completion of the reaction, the reaction mixture was quenched with aqueous sodium metabisulfite and n-heptane was added to it. Both the organic layer and aqueous layers were separated and the aqeous layer was extracted with methyl tertiary butyl ether. Both the organic layers were combined and washed with 10% HC1, 5% sodium bicarbonate followed by sodiumchloride solution. Distilled off the solvent from the organic layer and co-distilled with pet.ether. Product was further purified from diisopropyl ether. Filtered the solid, washed with diisopropyl ether and then dried to get the title compound.

Yield: 25.08 grams; Purity by HPLC: 92.75%

Example- 13: Preparation of (3S,5S)-5-((lR,3S)-l-bromo-3-(4-methoxy-3-(3-methoxy propoxy) benzyl)-4-methylpentyl)-3-isopropyldihydrofuran-2(3H)-one (Formula- 10a)

A mixture of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzy l)- N,N,8-trimethyl non-4-enamide compound of formula-8a (150 gm), tetrahydrofuran (750 ml) and water (15 ml) was cooled to 0-5°C. 44% orthophosphoric acid (48 ml) was added slowly to the reaction mixture at 0-5 °C over a period 15 minutes. N-Bromo succinimide (60 gm) was added to the reaction mixture at 0-5°C and stirred for 1 hour at 0-5°C. After completion of the reaction, the reaction mixture was quenched with aqueous sodium metabisulfite and n-heptane was added to it. Both the organic layer and aqueous layers were separated and the aqeous layer was extracted with methyl tertiary butyl ether. Both the organic layers were combined and washed with 10% HC1, 5% sodium bicarbonate followed by sodiumchloride solution. Distilled off the solvent from the organic layer and co-distilled with pet.ether. Product was further purified from diisopropyl ether. Filtered the solid, washed with diisopropyl ether and then dried to get the title compound. Yield: 111.0 grams; M.R: 48-51°C; Purity by HPLC: 97.61%

Example-14: Preparation of (3S,5S)-5-((lS,3S)-l-azido-3-(4-methoxy-3-(3-methoxy propoxy) benzyl)-4-methylpentyl)-3-isopropyldihydrofuran-2(3H)-one (Formula-11) A mixture of (3S,5S)-5-((lR,3S)-l-bromo-3-(4-methoxy-3-(3-methoxy propoxy)benzyl)-4-methyl pentyl)-3-isopropyldi-hydrofuran-2(3H)-one compound of formula- 10a (100 gm), sodium azide (62 gm) and polyethylene glycol (700 ml) was heated to 80-85°C and stirred for 20 hours at 80-85°C. After completion of the reaction, the reaction mixture was quenched with water and the product was extracted with methyl tert.butyl ether. The methyl tert.butyl ether layer was washed with 5% sodium bicarbonate followed by 10% sodium chloride solution and dried with sodium sulfate. Distilled off the solvent and isolated the title compound in diisopropyl ether to get pure title compound as a solid.

Yield: 46.0 grams; M.R: 59.5-61.5°C; Purity by HPLC: 96.64%

The PXRD of the obtained compound is similar to the crystalline form-S as shown in figure-3.

Example-15: Preparation of (3S,5S)-5-((lS,3S)-l-azido-3-(4-methoxy-3-(3-methoxy propoxy) benzyl)-4-methylpentyl)-3-isopropyldihydrofuran-2(3H)-one (Formula-11)

A mixture of (3S,5S)-5-((lR,3S)-l-bromo-3-(4-methoxy-3-(3-methoxy propoxy) benzyl)-4-methyl pentyl)-3-isopropyldi-hydrofuran-2(3H)-one compound of formula-lOa (10 gm), sodium azide (6.2 gm) and tripropylene glycol (70 ml) was heated to 80-85°C and stirred the reaction mixture for 20 hours at 80-85°C. After completion of the reaction, the reaction mixture was quenched with water and the product was extracted with methyl tertbutyl ether. The methyl tert.butyl ether layer was washed with 5% sodium bicarbonate followed by 10% sodium chloride solution and dried with sodium sulfate. Distilled off the solvent and isolated the title compound in diisopropyl ether to get pure title compound as a solid.

Yield: 8.8 grams; M.R: 59-60.8°C; Purity by HPLC: 93%

Example-16: Preparation of (2S,4S,5S,7S)-N-(3-amino-2,2-dimethyl-3-oxopropyl)-5- azido-4-hydroxy-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy )ben.-yl)-8-methyl nonanamide (Formula-13)

A mixture of (3S,5S)-5-((lS,3S)-l-azido-3-(4-methoxy-3-(3-methoxypropoxy) benzyl)-4-methyl pentyl)-3-isopropyldihydrofuran-2(3H)-one compound of formula- 11 (45 gm), 3-Amino-2,2-dimethylpropanamide compound of formula- 12 (34 gm), 2- hydroxy pyridine (10.2 gm) and triethylamine (51 ml) was heated to 85-90°C and stirred for 16 hours at 85-90°C. After completion of the reaction, the reaction mixture was cooled to 25-30°C and the reaction mixture was quenched with 5% aqueous sodium bicarbonate solution. Extracted the product with ethyl acetate. Ethyl acetate layer was washed with 10% hydrochloric acid, 5% aqueous sodium bicarbonate followed by sodium chloride solution and dried with sodium sulfate. Distilled off the solvent completely to get the title compound as a residue and purified by repeated with cyclohexane. Yield: 56.0 grams; HPLC purity: 91.4%

Example-17: Preparation of (2S,4S,5S,7S)-5-amino-N-(3-amino-2,2-dimethyI-3- oxopropyl)-4-hydroxy-2-isopropyl-7-(4-methoxy-3-(3-methoxypr opoxy)benzyI)-8- methyl nonanamide (Formula-1)

Ethanol amine (37.3 ml) was added to a solution of (2S,4S,5S,7S)-N-(3-amino- 2,2-dimethyl-3-oxopropyl)-5-azido-4-hydroxy-2-isopropyl-7-(4 -methoxy-3-(3-methoxy propoxy)benzyl)-8-methyl nonanamide compound of formula-13 (55 gm) in isopropyl alcohol (550 ml). To the above reaction mixture 10% Pd/C (37.3 gm) was added and applied hydrogen pressure for 3 hours. After completion of the reaction, the reaction mixture was filtered through hyflow bed and washed the bed with isopropyl alcohol and distilled off the solvent from the filtrate under reduced pressure. Methyl tertiary butyl ether was added to the obtained residue and stirred for 10 minutes. Separated the ethanol amine layer and organic layer from the reaction mixture, washed the organic layer with saturated sodium chloride and then distilled off the solvent to get the title compound. Yield: 60.0 grams; purity by HPLC: 93.93%.

Example-18: Preparation of (2S,4S,5S,7S)-5-amino-N-(3-amino-2,2-dimethyI-3- oxopropyl)-4-hydroxy-2-isopropyl-7-(4-methoxy-3-(3-methoxypr opoxy)benzyl)-8- methylnonanamide (Formula-1)

Ethanol amine (1.23 ml) was added to a solution (2S,4S,5S,7S)-N-(3-amino-2,2- dimethyl-3-oxopropyl)-5-azido-4-hydroxy-2-isopropyl-7-(4-met hoxy-3-(3- methoxypropoxy)benzyl)-8-methyl nonanamide compound of formula- 13 (8.0 gm) in isopropyl alcohol (40 ml). To the above reaction mixture 10% Pd/C (1.23 gm) was added and applied hydrogen pressure for 3 hours. After completion of the reaction, the reaction mixture was filtered through hyflow bed and washed the bed with isopropyl alcohol and then distilled off isopropyl alcohol from the filtrate. Water and followed by methyl tert.butyl ether were added to the obtained residue and stirred for 10 minutes. Adjusted the pH to 3.0 with aqueous hydrochloric acid and separated the methyl tert.butyl ether layer. The aqueous layer was washed repeatedly with methyl tert.butyl ether and added dichloromethane into the aqueous layer. Adjusted the pH to 9.5 with aqueous sodium carbonate solution, then separated both the organic layer and aqueous layers. The organic layer was washed with water and then distilled off the solvent completely to get the title compound. Yield: 7.0 grams; purity by HPLC: 95.0%.

Example-19: One pot process for the preparation of (2S,4S,5S,7S)-5-amino-N-(3- amino-2,2-dimethyl-3-oxopropyl)-4-hydroxy-2-isopropyl-7-(4-m ethoxy-3-(3- methoxypropoxy) benzyl)-8-methylnonanamide (Formula-1)

A mixture of (3S,5S)-5-((lR,3S)-l-bromo-3-(4-methoxy-3-(3-methoxy propoxy)benzyl)-4-methyl pentyl)-3 -isopropyl dihydrofuran-2(3H)-one compound of formula- 10a (10 gm), sodium azide (3.9 gm) and DMPU (80 ml) was heated to 75-80°C and then stirred for 4 hours at 75-80°C. After completion of the reaction, the reaction mixture was quenched with water and the product was extracted with methyl tert.butyl ether. The methyl tert.butyl ether layer was washed with sodium bicarbonate solution followed by brine solution. Distilled off the solvent completely to get (3S,5S)-5-((lS,3S)- l-azido-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpen tyl)-3-iso- propyldihydrofuran-2(3H)-one compound of formula- 11 as a residue. 3-amino-2,2- dimethyl propanamide compound fo formula- 12 (8.8 gm), 2-hydroxy pyridine (2gm) and triethyl amine (10 ml) were added to the above residue and heated to 85-90°C and then stirred for 15 hours at 85-90°C. After completion of the reaction, the reaction mixture was cooled to 25-30°C and quenched with 5% aqueous sodium bicarbonate solution. Extracted the product with ethyl acetate and the ethyl acetate layer was washed with 5% aqueous sodium bicarbonate followed by brine solution. Distilled off the solvent completely under reduced pressure to get the (2S,4S,5S,7S)-N-(3-amino-2,2-dimethyl-3- oxopropyl)-5 -azido-4-hydroxy-2-isopropyl-7-(4-methoxy-3 -(3 -methoxypropoxy)benzy 1)- 8-methyl nonanamide compound of formula- 13 as a residue. The above residue was dissolved in isopropyl alcohol (100 ml), added Pd/C (5 gm) and applied hydrogen pressure for 3 hours. After completion of the reaction, the reaction mixture was filtered through hyflow bed and washed the bed with isopropyl alcohol. Distilled off isopropyl alcohol from the filtrate, water and methyl tert.butyl ether were added to the reaction mixture and stirred for 10 minutes. Adjusted the pH of the reaction mixture to 3.0 with aqueous HC1 and separated the methyl tert.butyl ether layer. The aqueous layer was washed repeatedly with methyl tert.butyl ether and added dichloromethane into the aqueous layer. Adjusted the pH to 9.5 with aqueous sodium carbonate solution, then separated both the organic layer and aqueous layers. The organic layer was washed with water. Distilled off the solvent completely to get the title compound. Yield: 4.0 grams; Purity by HPLC: 90%.

Example-20: Process for the preparation of Aliskiren hemifumarte amorphous form

Aliskiren free base (50 gm) was dissolved in ethanol (150 ml) and stirred for 10 minutes. To this solution fumaric acid (5.2 gm) was added and stirred for 10 minutes at 25-30°C. Filtered the reaction mixture and distilled off the solvent from the filtrate under reduced pressure and then co-distilled with dichloromethane to obtain the residue, n- pentane was added to the obtained residue, isolated the product in n-pentane and then dried to get aliskiren hemifumarate.

Yield: 51.0 grams; purity by HPLC: 99%.

Example-21: Process for the preparation of Aliskiren hemifumarte crystalline form- A

Aliskiren free base (50.0 gm) was dissolved in ethanol (150 ml) and stirred for 10 minutes. To this solution fumaric acid (5.2 gm) was added and stirred for 10 minutes at 25-30°C. Filtered the reaction mixture, distilled off the solvent from the filtrate under reduced pressure and then co-distilled with dichloromethane and n-pentane. Acetonitrile was added to the obtained residue and stirred for lhour at 25-30°C. Filtered the obtained solid, washed with acetonitrile and then dried to get the title compound.

Yield: 45.0 grams; purity by HPLC: 99.5%. The PXRD of the obtained compound matches with the PXRD of aliskiren hemifumerate crystalline form-A.

Example-22: Process for the preparation of Aliskiren hemifumarte amorphous form

Aliskiren hemifumarate (40.0 gm) was dissolved in dichloromethane (160 ml) and stirred for 10 minutes. Distilled off the solvent completely under reduced pressure and co-distilled with n-pentane. The product was isolated in n-pentane (40 ml) at 15°C and then dried to get the title compound. Yield: 33.0 gm; purity by HPLC: 99.35%.

The PXRD of the obtained compound matches with the PXRD of aliskiren hemifumerate amorphous form.

Example-23 : Preparation of (2S,4S,5S,7S)-5-amino-N-(3-amino-2,2-dimethyl-3- oxopropyl)-4-hydroxy-2-isopropyl-7-(4-methoxy-3-(3-methoxypr opoxy)benzyl)-8- methyl nonanamide (formula- 1)

(2S,4S,5S,7S)-N-(3-amino-2,2-dimethyl-3-oxopropyl)-5-azido-4 -hydroxy-2- isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methyln onanamide (35 gm) was dissolved in a mixture of methyl tert.butyl ether (175 ml) and methanol (3.5 ml). 5% Pd/C (2.0 gm) and ethanol amine (3.2 ml) were added to the reaction mixture and hydrogen gas bubbling was applied for 2-3 hours for completion of the reaction. Filtered the reaction mixture through hyflow bed and washed the bed with methyl tert.butyl ether (100 ml). Cooled the filtrate to 0-10°C, added dichloro methane (35 ml) and water (35 ml) to it at the same temperature. Separated both the organic and the aqueous layers and the aqueous layer was extracted with dichloro methane (35 ml) at 0-10°C. Both the organic layers were combined and washed with saturated sodium chloride solution and distilled off the solvent at below 40°C. Isopropyl alcohol was added to the residue and distilled off the solvent completely under reduced pressure at below 45°C. The obtained residue was washed with cyclohexane to get the pure title compound. Yield: 33.4 grams; Purity by HPLC: 96 %

Example-24: Preparation of 3-methoxypropan-l-ol (formula-14)

735 grams of KOH was added to 1500 grams of 1,3-Propanediol at 80°C in portion wise for 1 hour and stirred for 1 hour. Then added 815 grams of methyl iodide drop wise for 12 hours and the mixture is stirred for 6 hours at 80°C. Cooled the reaction mixture to room temperature and extracted with chloroform. Separated the organic and aqueous layers; organic layer was dried with sodium sulphate and distilled off the solvent to get the title compound. Yield: 466 grams. Boiling point: 149°C.

ExampIe-25: Preparation of 3-methoxypropyl methane sulfonate (formuIa-15)

To the solution of 3-methoxypropan-l-ol (100 gms) compound of formula-14 in dichloro methane (700 ml) added triethyl amine(168 gms) and cooled the reaction mixture to 0-5°C. Added methane sulfonyl chloride (153 gms) to the reaction mixture at 0-5°C. Stirred the reaction mixture for 6 hours at same temperature. Water (500 ml) was added to the reaction mixture and stirred for 30 minutes at 25-30°C. Separated the both aqueous and organic layers. The organic layer was washed with 5% sodium bicarbonate solution and water. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 165 grams.

Example-26: Preparation of 4-methoxy-3-(3-methoxypropoxy) benzaldehyde (formula-17)

A mixture of 2000 ml toluene, 100 grams 3-hydroxy-4-methoxybenzaldehyde compound of formula- 16, 136 grams of potassium carbonate and 150 grams of 3- methoxypropyl methanesulfonate (formula- 15) was heated to reflux temperature. Stirred the reaction mixture for 10 hours at the same temperature. After completion of the reaction, the reaction mixture was cooled to room temperature. The reaction was quenched with water. Separated the both aqueous and organic layers. The organic layer was washed with water and dried with sodium sulphate. Distilled off the solvent completely under reduced pressure to get the title compound. Yield: 127 grams.

Example-27: Preparation of 4-Methoxy-3-(3-methoxy propoxy) benzyl alcohol (formula- 18)

Added 11.87 grams of sodiumborohydride to 100 grams of 4-methoxy-3-(3- mehoxypropoxy)benzaldehyde (formula-17) in THF (1000 ml) at 0-5°C. The reaction mixture was allowed to cool to the 25-30°C and stirred for 7 hours at the same temperature. After completion of the reaction, the reaction was quenched with chilled water and the p ^H was adjusted to 2 with 2N HC1. The reaction mixture was extracted with dichloromethane and both the organic and aqueous layers were separated. The organic layer was dried with sodium sulphate and distilled under reduced pressure to get the title compound. Yield: 89 grams (88%).

Example-28: One pot process for the preparation of 4-Methoxy-3-(3-methoxy propoxy) benzyl alcohol (formula-18)

A mixture of 2000 ml of toluene, 100 grams of 3-hydroxy-4-methoxybenzaldehyde (formula-16), 136 grams of potassium carbonate and 143.6 grams of 3-methoxypropyl methanesulfonate (formula- 15) was heated to reflux temperature and stirred for 10 hours at the same temperature. After completion of the reaction, the reaction mixture was cooled to 25-30°C. Water was added to the reaction mixture and stirred for 30 minutes. Both the organic and aqueous layers were separated; The organic layer was washed with saturated sodium bicarbonate and dried with sodium sulphate. 24.9 grams of sodium borohydride was added to the reaction mixture and followed by 50 ml of methanol for about 60 minutes at 0-5°C. The reaction mixture was stirred for 7 hours at 25-30°C. After completion of the reaction, the reaction was quenched with ice cooled water with vigorous stirring and the p ^H of the reaction mixture was adjusted to 2 with 2N HC1. Both the organic and aqueous layers were separated and extracted the aqueous layer with dichloro methane. Both the dichloro methane layers were combined and washed with water. The dichloro methane layer was dried with sodium sulphate and distilled under reduced pressure to get the title compound. Yield: 114 grams.

Example-29: Preparation of 4-Methoxy-3-(3-methoxypropoxy) benzyl bromide (formula-19)

A solution of 145 ml of phosphorous tribromide in dichloromethane (350 ml) was added slowly to a mixture of (4-methoxy-3-(3-methoxypropoxy)benzyl alcohol (70 gm) (formula-18) and dichloromethane (1050 ml) at 0-5°C for about 2 hours. Stirred the reaction mixture for 10 minutes. After completion of the reaction, the reaction was quenched by pouring the reaction mixture slowly into ice cold water with constant stirring. Seperated the both organic and aqueous layers. Washed the organic layer with water. The organic layer was dried with sodium sulphate and distilled off the solvent completely under reduced pressure to get the title compound. Yield: 71 grams.

Example-30: Preparation of (R)-3-(3-methylbutanoyl)-4-phenyloxazolidin-2-one (formula-20)

Added a mixture of 250 ml of ethylene dichloride, 50 grams of 3-methylbutanoic acid, 8.0 grams of 4-dimethylamino pyridine and 80.17 grams of (R)-4-phenyloxazolidin-

2- one into a RB flask at ambient temperature and stirred for 30 minutes. Cooled the reaction mixture to 10-15°C and slowly added 107.4 grams of DCC for about 30 minutes and stirred for 2 hours at the same temperature. Raised the temperature to 25-30°C and stirred for 12 hours. After completion of the reaction, filtered the byproduct and washed with dichloro ethane. Then washed the filtrate with 2% hydrochloric acid and distilled off the solvent completely under reduced pressure to get semi-solid. Added cyclohexane to the semisolid and distilled off completely under reduced pressure to get crystalline solid, which is further treated with cyclohexane and stirred for 1.5 hour at RT. Filtered the solid and washed the cake with cyclohexane and dried to get the title compound.

Yield: 115 grams; Melting Point: 65-70°C.

Example-31: Preparation of (R)-3-((R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-

3- methylbutanoyl)-4-phenyloxazolidin-2-one (formula-21)

A solution of (R)-3-(3-methylbutanoyl)-4-phenyloxazolidin-2-one compound of formula-20 (51.9 grams) in tetrahydrofuran (150 ml) was added slowly to a mixture of tetrahydrofuran(150 ml) and lithium hexamethyl disilazide (LiHMDS) (350 ml) at -70°C under nitrogen atmosphere. Stirred the reaction mixture for 2 hours at the same temperature. Added a solution of 4-Methoxy-3-(3-methoxypropoxy) benzyl bromide compound of formula- 19 (50 grams) in tetrahydrofuran (150 ml) to the above reaction mixture at -70°C. Raised the temperature of reaction mixture to 0-5°C slowly. The reaction mixture was stirred for 7 hours at the same temperature. After completion of the reaction, the reaction was quenched with 10% ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution. Distilled off the solvent completely from organic layer under reduced pressure to get the title compound. Yield: 80 grams; ee: 98.8%.

ExampIe-32: Preparation of (R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3- methylbutanoic acid (formuIa-22)

To 80 grams of (R)-3-((R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methyl butanoyl)-4-phenyloxazolidin-2-one compound of formula-21 added 560 ml of tetrahydrofuran and 240 ml of water. Cooled the reaction mixture to 0-5°C and added

14.32 grams of lithium hydroxide mono hydrate to it. 30% hydrogen peroxide(69 ml) was added to the reaction mixture slowly at 0-5 °C Raised the temperature of reaction mixture to 25-30°C and stirred for 7 hours at same temperature. After completion of the reaction, the reaction mixture was cooled to 0-5°C. 10% sodium sulphite solution (500 ml) was added to the reaction mixture and followed by 10% sodium bicarbonate solution (500 ml) and stirred the reaction mixture for 1 hour. The reaction mixture was extracted with ethyl acetate. Acidify the reaction mixture using 2N hydrochloric acid. Added dichloro methane to the reaction mixture and stirred for 20 minutes. Separated the both aqueous and organic layers and dried the organic layer with sodium sulphate. Distilled off the solvent completely under reduce pressure to get the title compound. Yield: 25 grams. Example-33: Preparation of (R)-2-[4-methoxy-3-(3-methoxypropoxy) benzyl]-3- methyl-butan-l-ol (formuIa-23)

7.16 grams of sodium borohydride was added to the 0-5 °C pre cooled tetrahydrofuran (300 ml) under nitrogen atmosphere. A solution of (R)-2-(4-methoxy-3- (3-methoxypropoxy) benzyl)-3-methylbutanoic acid (50 grams) compound of formula-22 dissolved in tetrahydrofuran (200 ml) was added to the reaction mixture slowly. Stirred the reaction mixture for 1 hour at 0-5°C. Boron trifluoride etherate (BF ₃ .Et ₂ 0) (45.48 grams) was added slowly to the reaction mixture for about 45 minutes. Raised the temperature of reaction mixture to 25-30°C. The reaction mixture was stirred for 5 hours at same temperature. After completion of the reaction, cooled the reaction mixture to 0- 5°C and added 50% hydrochloric acid solution to it. Added water and followed by dichloro methane to the reaction mixture. Separated the both aqueous and organic layers and the organic layer was washed with 10% sodium bicarbonate solution, followed by 10% sodium chloride solution. The organic layer was dried with sodium sulphate and distilled off the solvent completely under reduced pressure to get the title compound. Yield: 36 grams.

Exaniple-34: Preparation of 2(R)-[4-Methoxy-3-(3-methoxy propoxy)-benzyl]-3- methyl-butan-l-ol (formula-23)

A solution of (R)-3-((R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3- methyl butanoyl)-4-phenyloxazolidin-2-one compound of formula-21 (2 gm) dissolved in tetrahydrofuran (10 ml) was added to the mixture of sodium borohydride (1.5 gm) and tetrahydrofuran (20 ml) at 0-5°C. Stirred the reaction mixure for 30 minutes at 10-15°C. Boron trifluoride etherate(BF ₃ .Et20)(4.3 grams) was added to reaction mixture and heated to 60-65°C. The reaction mixture was stirred for 11 hours at same temperature. After completion of the reaction, cooled the reaction mixture to 0-5 °C and quenched with 2N hydrochloric acid. The reaction mixture was extracted with ethyl acetate and washed with water. The organic layer was dried with sodium sulphate and distilled off the solvent completely under reduced pressure to get the title compound. Yield: 1.3 grams

Example-35: Preparation of (R)-4-(2-(bromomethyI)-3-methylbutyl)-l-methoxy-2- (3-methoxypropoxy) benzene (Formula-2b)

49 grams of triphenyl phosphine was added to the mixture of (R)-2-(4-methoxy- 3-(3-methoxypropoxy)benzyl)-3-methylbutan-l-ol compound of formula-23 (30 gm) and dichloro methane (450 ml) at -30 to -40°C. 35 grams of N-bromo succinimide was added to the reaction mixture at -30 to -40°C and stirred for 30 minutes at same temperature. The temperature of the reaction mixture was raised to 25-30°C and stirred for 5 hours at the same temperature. After completion of the reaction, the reaction mixture was quenched with sodium bicarbonate solution. Separated the both the organic and aqueous layers and the aqueous layer was extracted with dichloro methane. The organic layer was distilled off completely and the obtained residue was co-distilled with ethyl acetate. Cyclohexane was added to the obtained residue and stirred for 1 hour. The reaction mixture was filtered. Distilled off the solvent completely from filtrate under reduced pressure. N-hexane was added to the obtained residue and stirred for 1 hour at 0-5°C. The reaction mixture was filtered, and the solvent from the filtrate was distilled off completely. N-hexane and diethyl ether were added to the obtained residue and cooled to -20°C. The reaction mixture was stirred for 1 hour, filtered, washed with chilled N- hexane and dried to get the title compound as a solid. Yield: 20 grams.

Example-36: Preparation of (R)-4-(2-(bromomethyI)-3-methylbutyl)-l-methoxy-2- (3-methoxypropoxy) benzene (Formula-2b)

49 grams of triphenyl phosphine was added to the mixture of (R)-2-(4-methoxy- 3-(3-methoxypropoxy)benzyl)-3-methylbutan-l-ol compound of formula-23 (30 gm) and dichloro methane (450 ml) at -30 to -40°C. 35 grams of N-bromo succinimide was added to the reaction mixture at -30 to -40°C and stirred for 30 minutes at same temperature.

The temperature of the reaction mixture was raised to 25-30°C and stirred for 5 hours at the same temperature. The reaction mixture was distilled off completely and the obtained residue was co-distilled with ethyl acetate. Cyclohexane was added to the obtained residue and stirred for 1 hour. The reaction mixture was filtered. Distilled off the solvent completely from filtrate under reduced pressure. N-hexane was added to the obtained residue and stirred for 1 hour at 0-5°C. The reaction mixture was filtered, and the solvent from the filtrate was distilled off completely. N-hexane and diethyl ether were added to the obtained residue and cooled to -20°C. The reaction mixture was stirred for 1 hour, filtered, washed with chilled N-hexane and dried to get the title compound as a solid. Yield: 22 grams.

Example-37: Preparation of (R)-4-(2-(chloromethyl)-3-methylbutyl)-l-methoxy-2- (3-methoxypropoxy) benzene (Formula-2a)

49 grams of triphenyl phosphine was added to the mixture of (R)-2-(4-methoxy- 3-(3-methoxypropoxy)benzyl)-3-methylbutan-l-ol compound of formula-23 (30 gm) and dichloro methane (450 ml) at -30 to -40°C. 26.5 grams of N-chloro succinimide was added to the reaction mixture at -30 to -40°C and stirred for 30 minutes at same temperature. The temperature of the reaction mixture was raised to 25-30°C and stirred for 5 hours at the same temperature. After completion of the reaction, the reaction mixture was quenched with sodium bicarbonate solution. Separated the both the organic and aqueous layers and the aqueous layer was extracted with dichloro methane. The organic layer was distilled off completely and the obtained residue was co-distilled with ethyl acetate. Cyclohexane was added to the obtained residue and stirred for 1 hour. The reaction mixture was filtered. Distilled off the solvent completely from filtrate under reduced pressure. N-hexane was added to the obtained residue and stirred for 1 hour at 0- 5°C. The reaction mixture was filtered, and the solvent from the filtrate was distilled off completely. N-hexane and diethyl ether were added to the obtained residue and cooled to -20°C. The reaction mixture was stirred for 1 hour, filtered, washed with chilled N- hexane and dried to get the title compound as a solid. Yield: 25 grams.

Example-38: Preparation of ethyl-2-cyano-2-methylpropanoate (formula-25)

376 grams of methyl iodide was added to a mixture of 244 grams of potassium carbonate, 300 ml of Ν,Ν-dimethylformamide and cooled the reaction mixture to 0-5°C.

100 grams of ethyl 2-cyano acetate compound of formula-24 was added to the reaction mixture at 0-5°C and stirred for 9 hours at the same temperature. After completion of the reaction, the reaction mixture was filtered and washed with methyl tert-butyl ether. Aqueous hydrochloric acid was added to the obtained filtrate. Separated the both organic and aqueous layers. Extracted the aqueous layer with methyl tert-butyl ether. Both the organic layers were combined, washed with brine solution and followed by sodium thio sulphate solution. Distilled off the solvent completely from organic layer under reduced pressure to get the title compound. Yield: 106 grams.

ExampIe-39: Preparation of 2-cyano-2-methylpropanamide (formula-26)

1000 ml of methanolic ammonia was added to 100 grams of ethyl 2-cyano-2- methylpropanoate compound of formula-25 and stirred the reaction mixture for 12 hours at 25-30°C. After the reaction was completed, the reaction mixture was distilled off completely under reduced pressure. Cyclohexane was added to the reaction mixture and stirred for 1 hour at 25-30°C. The reaction mixture was filtered, washed with cyclohexane and then dried to get the title compound. Yield: 67.5 grams.

Example-40: Preparation of 3-amino-2, 2-dimethylpropanamide (formula-27)

33 grams of raney nickel was added to a mixture of 50 grams of 2-cyano-2- methylpropanamide compound of formula-26 and 750 ml of methanolic ammonia and followed by 50 ml of methanol. 4 kg of hydrogen pressure was applied to the reaction mixture. The reaction mixture was stirred for 14 hours at 40-45°C. After completion of the reaction, the reaction mixture was filtered on hyflow bed and washed with methanol. Distilled off the solvent completely to get the title compound as semi solid.

Yield: 41.5 grams.

Example-41: Preparation of 4-methoxy-3-(3-methoxypropoxy) benzaldehyde

(formuIa-17)

To a solution of 3-hydroxy-4-methoxybenzaldehyde (100 gm) compound of formula-16, toluene (2000 ml) and potassium carbonate (136 gm), added 3-methoxy propylmethane sulfonate compound of formula- 15 (143.6 grams) and then heated the reaction mixture to reflux temperature. After completion of the reaction, cooled the reaction mixture to 25-30°C, added water and stirred for 30 minutes. Both organic and aqueous layers were separated. Washed the organic layer with 5% sodium bicarbonate solution. Distilled off the solvent completely from organic layer under reduced pressure to get the title compound. Yield: 130 grams.

Example-42: Preparation of (4R)-3-(2S)-2-(hydroxy(4-methoxy-3-(3-methoxy propoxy) phenyl)methyl)-3-methylbutanoyI)-4-phenyloxazolidin-2-one (formula-28)

To 77 grams of titanium tetrachloride added 1200 ml of dichloro methane under nitrogen atmosphere. Cooled the reaction mixture to 0-5°C, and added 40.5 grams of titanium IV isopropoxide at the same temperature. To the above reaction mixture added a solution of (R)-3-(3-methylbutanoyl)-4-phenyloxazolidin-2-one compound of formula-20 (100 grams) dissolved in dichloro methane (200 ml) at 0-5°C and stirred for 30 minutes at same temperature. Then added a solution of N-ethyl diisopropylamine (DIPEA)(115 grams) at 0-5 °C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to -25 to -30°C and then added a mixture of 4-methoxy-3-(3-methoxypropoxy) benzaldehyde compound of formula- 17 (91 grams) dissolved in methylene chloride(100 ml) and stirred at the same temperature. After completion of the reaction, added a mixture of acetic acid in dichloro methane at -25 to-30°C. Then raised the temperature to 0-5 °C and added 2N solution of sulfuric acid to the reaction mixture. Stirred the reaction mixture for 1 hour. Separated the both organic and aqueous layers. The organic layer was washed twice water and distilled off the solvent completely under reduced pressure to get the title compound. Yield: 175 grams.

Example-43: Preparation of (R)-3-((R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyI)-3-methylbutanoyl)-4-phenyloxazolidin-2-one (formula-21)

To a mixture of 60 grams of wet Pd/C and 300 ml of acetic acid added a solution of (4R)-3-(2S)-2-(hydroxy(4-methoxy-3-(3-methoxypropoxy)phenyl) methyl)-3-methyl butanoyl)-4-phenyloxazolidin-2-one compound of formula-28 (100 gm) in acetic acid (300 ml) at 25-30°C. Applying 4.0 Kgs/cm ² hydrogen pressure to the reaction mixture. Heated the reaction mixture to 60-70°C and stirred. After completion of the reaction, the reaction mixture was cooled to 25-30°C. Filtered the reaction mixture and washed with acetic acid. Added water to the filtrate and extracted with dichloro methane. Washed the organic layer with water and 5% sodium bicarbonate solution. The solvent from the organic layer was completely distilled off under reduced pressure to get the title compound. Yield: 90 grams.

Example-44: Preparation of (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3- methylbutanoic acid (formuIa-22)

90 ml of 30% hydrogen peroxide was added to 0-5 °C pre cooled tetrahydrofuran (500 ml). 200 ml of water was added to the reaction mixture. Aqueous lithium hydroxide solution (18.5 grams in 100 ml of water) was added to the reaction mixture at 0-5 °C and stirred for 15 minutes. A solution of (R)-3-((R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3 -methyl butanoyl)-4-phenyloxazolidin-2-one compound of formula-21 (100 gm) in tetrahydrofuran (200 ml) was added to the above reaction mixture at 0-5°C. Raised the temperature to 25-30°C and stirred the reaction mixture. After completion of the reaction, cooled the reaction mixture to 0-5°C. Added 15% sodium bicarbonate solution followed by 15% sodium sulphite solution to the reaction mixture at same temperature. Added ethyl acetate (650 ml) to the reaction mixture and stirred for 10 minutes. Separated the organic and aqueous layers. The aqueous layer was cooled to 0-10°C and acidified with 2N hydrochloric acid and extracted with dichloro methane. Separated the both aqueous and organic layers. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 52 grams.

Example-45: Preparation of S-phenylethanamine salt of (R)-2-(4-methoxy-3-(3- methoxypropoxy) benzyI)-3-methylbutanoic acid.

To a solution of (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutanoicacid compound of formula-22 (100 gm) in a mixture of acetonitrile (200 ml) and cyclohexane (400 ml) was added S-phenylethylamine (39 grams) at 25-30°C. The reaction mixture was stirred for 30 minutes and cooled to 0-10°C. Stirred the reaction mixture for 60 minutes at 0-10°C, filtered the obtained solid and washed with mixture of acetonitrile and cyclohexane. The material was dried for 3hrs at 40-4 °C. The dried material was dissolved in dichloromethane (200 ml) and then water (200 ml) was added. Reaction mixture was stirred for 10 min at 30°C, and then cooled to 0-10°C. The pH of the reaction mixture was adjusted to 1.5 by adding 50% HC1 solution at 0-10°C. Temperature of the reaction mixture was raised to 15-25°C. Both the organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined and washed with 10% NaCl solution, distilled of the solvent completely under reduced pressure to get the title compound. Yield : 102 grams. ExampIe-46: Preparation of tert.Butyl amine salt of (R)-2-(4-methoxy-3-(3- methoxypropoxy) benzyl)-3-methylbutanoic acid.

To a solution of (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutanoicacid (100 gm) compound of formula-22 in mixture of acetonitrile (200 ml) and cyclohexane (400 ml), added tert.Butyl amine (39 gm) at 25-30°C. The reaction mixture was stirred for 30 minutes and cooled to 0-10°C. Stirred the reaction mixture for 60 minutes at 0- 10°C, filtered the obtained solid and washed with mixture of acetonitrile and cyclohexane. The material was dried for 3 hours at 40-45°C. The dried material was dissolved in dichloromethane (200 ml) and then water (200 ml) was added. Reaction mixture was stirred for 10 min at 30°C, and cooled to 0-10°C. The pH of the reaction mixture was adjusted to 1.5 by adding 50% HC1 (70 ml) solution at 0-10°C. Temperature of the reaction mixture was raised to 15-25°C. Both the organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined and washed with 10% NaCl solution, distilled of the solvent completely under reduced pressure to get the title compound.

Yield : 90 grams.