PROCESS FOR PREPARING POLYCYCLIC CARBAMOYL PYRIDONE

DERIVATIVES AND INTERMEDIATES THEREOF

Field of the invention

The present invention relates to a novel process for the synthesis of polycyclic carbamoyl pyridone derivatives, and to novel intermediates which are produced during the course of carrying out the novel process. Background of the invention

Polycyclic carbamoyl pyridone derivatives are known to act as human immunodeficiency virus type- 1 (HIV- 1) integrase strand transfer inhibitors (INSTI) in combination with other antiretroviral medicinal products for the treatment of HIV- 1 infection in adults and children aged 12 years and older and weighing at least 40 kg.

US8129385 B2 and WO2014100323, incorporated herein in their entirety by reference, describe various polycyclic carbamoyl pyridone derivatives and processes for their preparation. Among these polycyclic compounds, are disclosed the following tricyclic carbamoyl pyridone derivatives, of formula (A) :

Formula A

or a stereoisomer or pharmaceutically acceptable salt thereof; wherein,

Ar is aryl substituted with one to three halogens;

W l and W2 are each independently, hydrogen, Ci-6 alkyl, or Ci-6 haloalkyl; or W l and W2, together with the carbon atom to which they are attached, form a carbocyclic ring having from 3 to 6 ring atoms or a heterocyclic ring having from 3 to 6 ring atoms, wherein the carbocyclic or heterocyclic ring is optionally substituted with one or more R ^x , wherein each R ^x is, independently, hydrogen, halo, hydroxyl or C i-6 alkyl, or wherein two R ^x groups together with the carbon atom to which they are attached, form =0;

Yi and Y ₂ are independently hydrogen, hydroxy, optionally substituted Ci-8 alkyl, Ci-8 haloalkyl, Ci-8 alkenyl or Ci-8 alkoxy, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted aryloxy or optionally substituted heterocyclic group; and

D ring is optionally substituted and optionally condensed 5 to 7 membered heterocycle containing 1 to 2 hetero atom(s) ; wherein heteroatom is selected from N, O or S.

Preferred tricyclic carbamoyl pyridone derivatives of formula (A) include those compounds of formula (B) :

Formula B

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;

Ar is aryl substituted with one to three halogens;

Wi and W2 are each independently, hydrogen, Ci-8 alkyl, or Ci-8 haloalkyl; or Wi and W ₂ , together with the carbon atom to which they are attached, form a carbocyclic ring having from 3 to 6 ring atoms or a heterocyclic ring having from 3 to 6 ring atoms, wherein the carbocyclic or heterocyclic ring is optionally substituted with one or more R ^x group;

X is -0- or -NW4 -or -CHW _4;

Y is -CHWs;

W3, W ₄ and W5 are each independently, hydrogen or Ci-8 alkyl, C6-14 aryl, Ci-8 alkyl, C6-14 aryl or alkoxy; or wherein W3 and W ₄ or W3 and W5 taken together form a carbocyclic ring containing having from 3 to 6 ring atoms or a heterocyclic ring having from 3 to 6 ring atoms wherein the carbocyclic or heterocyclic ring is optionally substituted with one or more R ^x group, wherein each R ^x is, independently, hydrogen, halo, hydroxyl or Ci-e alkyl, or wherein two R ^x groups together with the carbon atom to which they are attached, form =0;

Z is a bond, [-0¾-]η or Y and Z taken together form [-CH2-] _n ; wherein n is an integer of 0 to 3.

Preferred tricyclic carbamoyl pyridone derivatives of formula (B) include those compounds of formula (I) :

Formula I

wherein, n is an integer of 0 to 3. Structure-activity studies have demonstrated that these tricyclic series of carbamoyl pyridines have superior potency against resistant viral strains.

The fact that tricyclic series of carbamoyl pyridines are effective against viral strains is of utmost importance. At the same time it is necessary that these effective compounds are available at an economic rate and are easily manufactured. It is also necessary that these compounds are easily manufactured with no or minimal production hazards and that there exist simple and efficient methods to manufacture the same on the production floor. H. Wang et al., Organic Letters, 2015, 17(3), 564-567 discloses the synthesis of GSK1265744, a tricyclic carbamoyl pyridone derivative having antiretroviral activity. EP2527007A discloses certain polycyclic carbamoyl pyridine derivatives and a process for preparing such compounds.

Although a number of processes for preparing tricyclic carbamoyl pyridone derivatives have been previously disclosed and claimed, the processes disclosed in the prior art are multistep and hence cumbersome. Therefore, there exists a need to develop a simple, more economical, cost effective and efficient method of manufacturing the tricyclic carbamoyl pyridone derivatives that is suitable for industrial scale-up.

The process of the present invention provides a large scale synthesis of tricyclic carbamoyl pyridone derivatives having a high degree of chromatographic and optical purity and low residual solvent content.

Objects of the invention The object of the present invention is to provide a novel process for preparing tricyclic carbamoyl pyridone derivatives of formula (B) and of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a novel process which proceeds via novel chemical intermediates for the synthesis of tricyclic carbamoyl pyridone derivatives of formula (B) and of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof.

Yet another object of the present invention is to provide process for the preparation of the novel intermediates useful in the synthesis of the tricyclic carbamoyl pyridone derivatives of formula (B) and of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof. Yet another object of the present invention is to provide, large scale synthesis of tricyclic carbamoyl pyridone derivatives of formula (B) and of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof having high degree of chromatographic and optical purity and low residual solvent content.

Yet another object of the present invention is to provide a process for the synthesis of tricyclic carbamoyl pyridone derivatives of formula (B) and (I), or a stereoisomer or pharmaceutically acceptable salt thereof which is simple, economical and suitable for industrial scale-up.

Summary of the Invention

In a first aspect, the present invention provides a process for preparing tricyclic carbamoyl pyridone derivatives of formula (B) :

Formula B

or a stereoisomer or pharmaceutically acceptable salt thereof,

which process comprises converting a compound of formula (B-VIII) :

Formula B-VIII

into compound of formula (B) ; wherein Ar, Wi, W2, W3, X, Y and Z are as defined above; and wherein R is hydrogen, a protecting group selected from lower alkyl, preferably a straight or branched Ci-e alkyl group such as methyl, ethyl, propyl, butyl, pentyl or hexyl; Ci-8 haloalkyl, substituted or unsubstituted silyl, or Ce-14 aryl; and each R2 in formula (B-VIII) is either the same or different, and is selected from a lower alkyl group, preferably a straight or branched Ci-6 alkyl group, such as methyl, ethyl, propyl, butyl, pentyl or hexyl.

The tricyclic carbamoyl pyridone derivatives of formula (B) may be in the form of the R or S isomer or a mixture thereof.

In an embodiment, the conversion of a compound of formula (B-VIII) to a compound of formula (B) comprises cyclization of compound of formula (B-VIII) with an oxalic acid diester of formula (B-XV):

Formula B-XV in the presence of a compound of formula M ⁺ ORi , wherein, Ri is alkyl (such as Ci-6 alkyl), aryl (such as C6-12 aryl), or benzyl; and M+ is an alkali metal cation (such as Li+, Na+, K+, Rb+ or Cs+); to form a pyridinone compound of formula

(B-V) :

Formula B-V

wherein Ar, Wi, W2, R, Ri and R2 are as defined above.

Compounds of formula (B-V) may be converted to a compound of formula (B) by the methods disclosed in Indian Patent Application No. 1686 /MUM/ 2014, the content of which is incorporated herein by reference, or by methods known in the art.

In another aspect, the present invention provides a compound of formula (B-

VIII):

Formula B-VIII

wherein, Ar, Wi, W ₂ , R and f¾ are as defined above.

According to yet another aspect of the present invention, there is provided a process for preparing compound of formula (B-VIII), comprising the steps of: coupling a compound of formula (B-XII):

Formula B- XII wherein, m is an integer of 0 to 3;

with an amine of formula (B- VI) :

Formula B-VI wherein, Ar, Wi and W2 are as defined above;

in the presence of a coupling reagent to obtain an amide compound of formula (B-XI):

Formula B-XI deprotecting the amide compound of formula (B-XI) in the presence of an acid to obtain a 1 ,3-dicarbonyl com ound of formula (B-X) :

Formula B-X

reacting a 1 ,3-dicarbonyl compound of formula (B-X) with dimethylformamide dimethyl acetal (DMFDMA) to obtain compound of formula (B-IX) :

Formula B-IX

and,

reacting a compound of formula (B-IX) with either an aminoacetaldehyde dialkyl acetal of formula (B-XVIa) :

Formula B-XVIa or bromoacetaldehyde dialkyl acetal of formula (B-XVIb) :

Formula B-XVIb wherein, R3 and R ₄ are each hydrogen or lower alkyl, such as Ci-e alkyl, preferably a straight or branched Ci-6 alkyl group, such as methyl, ethyl, propyl, butyl, pentyl or hexyl, and f¾ is as defined above; to obtain a compound of formula (B-VIII).

In yet another aspect, the present invention provides a compound of

(B-XII) :

Formula B-XII

wherein, R and m are as defined above.

According to yet another aspect of the present invention, there is provided a process for preparing compound of formula (B-XII), comprising protecting compound of formula (B-XIV) :

,0

o o

Formula B-XIV

to obtain mixture of compounds of formula (B- Xllla) and (Xlllb):

Formula B-XII la Formula B-XII lb followed by hydrolysis to obtain a compound of formula (B-XII), wherein R and m are as defined above.

In another aspect, the present invention provides tricyclic carbamoyl pyridone derivatives of formula (B) obtainable by the processes substantially as herein described with reference to the examples. In another aspect, the present invention provides a use of tricyclic carbamoyl pyridone derivatives of formula (B) or a stereoisomer or pharmaceutically acceptable salt thereof, obtainable by the process of the present invention for the manufacture of therapeutic agent, preferably an antiretroviral for the treatment of HIV- AIDS.

In another aspect, the present invention provides a use of tricyclic carbamoyl pyridone derivatives of formula (B) or a stereoisomer or pharmaceutically acceptable salt thereof, obtainable by the process of the present invention, for treating HIV- AIDS.

In another aspect, the present invention provides a method of treating HIV- AIDS, comprising administering the tricyclic carbamoyl pyridone derivatives of formula (B) or a stereoisomer or pharmaceutically acceptable salt thereof, obtainable by a process of the present invention.

In another aspect, the present invention provides a process for preparing tricyclic carbamoyl pyridone derivatives of formula (I), or a pharmaceutically acceptable salt thereof:

Formula I which comprises converting a compound of formula (V):

Formula V into compound of formula (I), wherein n is an integer of 0 to 3, preferably 1 to 3 and R in formula (V) is a protecting group selected from lower alkyl, preferably a straight or branched Ci-6 alkyl group such as methyl, ethyl, propyl, butyl, pentyl or hexyl or substituted or unsubstituted silyl or C6-n aryl, and Ri and R ₂ in formula (V) are either the same or different, and are selected from a lower alkyl group, preferably a straight or branched Ci-6 alkyl group such as methyl, ethyl, propyl, butyl, pentyl or hexyl. The tricyclic carbamoyl pyridone derivatives of formula (I) may be in the form of the R or S isomer.

In an embodiment, the conversion comprises, contacting the compound of formula (V) with an acid to provide compound of formula (IV) :

Formula IV wherein R and Ri are as defined above in relation to Formula (V).

The process of the present invention may further comprise the step of contacting a compound of formula (IV) with an amine compound of formula (III):

Formula I II

optionally in the presence of an acid, to provide a compound of formula (II):

Formula I I

wherein, n and R are as defined above in relation to Formula (I) .

The amine compound of formula (III) and compound of formula (II) may be in the form of the R or S isomer.

The process of the present invention may further comprise the step of deprotecting a compound of formula (II) with a deprotecting agent to from a compound of formula (I).

The compound of formula (I) obtained by the process of the present invention may be optionally converted to a pharmaceutically acceptable salt thereof by reaction with a suitable base.

In another aspect, the present invention provides a compound of formula (V):

Formula V

wherein R, Ri and R ₂ are as defined above.

According to yet another aspect of the present invention, there is provided a process for preparing compound of formula (V), comprising converting a compound of formula (VII):

Formula VII

to compound of formula (V), wherein R, Ri and R ₂ are as defined above in relation to formula (V) .

In an embodiment, the conversion comprises coupling compound of formula (VII) with

2,4-diflurobenzyl amine of formula (VI) :

2,4-difluorobenzylamine

Formula VI in the presence of a coupling reagent to provide compound of formula (V) . In another aspect, the present invention provides tricyclic carbamoyl pyridone derivatives of formula (I) obtainable by the processes substantially as herein described with reference to the examples. In another aspect, the present invention provides a use of tricyclic carbamoyl pyridone derivatives of formula (I) obtainable by the process of the present invention for the manufacture of therapeutic agent, preferably an antiretroviral for the treatment of HIV-AIDS. In another aspect the present invention provides a use of tricyclic carbamoyl pyridone derivatives of formula (I) obtainable by the process of the present invention, for treating HIV-AIDS.

In another aspect the present invention provides a method of treating HIV- AIDS, comprising administering the tricyclic carbamoyl pyridone derivatives of formula (I) obtainable by a process of the present invention.

In another aspect, the present invention provides a process substantially as herein described with reference to the examples.

Further features of the present invention are defined in the dependent claims.

Detailed Description of the Invention In an embodiment of the present invention, there is provided a process for preparing tricyclic carbamoyl pyridone derivatives of formula (B) or a stereoisomer or pharmaceutically acceptable salt thereof, as depicted below in the general reaction Scheme 1. Scheme 1

Formula B-IX Formula B-X Formula B-XI

Formula B- VIII Formula B-V Formula B- IV

Formula B-ll

Formula B

(Bracket indicates that the intermediate could be isolated, but is not isolated in the preferred embodiment of the present invention.) wherein, Ar is aryl substituted with one to three halogens;

Wi and W2 are each independently, hydrogen, Ci-e alkyl, or Ci-8 haloalkyl; or Wi and W ₂ , together with the carbon atom to which they are attached, form a carbocyclic ring having from 3 to 6 ring atoms or a heterocyclic ring having from 3 to 6 ring atoms, wherein the carbocyclic or heterocyclic ring is optionally substituted with one or more R ^x ;

R is hydrogen, a protecting group selected from lower alkyl, preferably a straight or branched Ci-e alkyl group such as methyl, ethyl, propyl, butyl, pentyl or hexyl; Ci-8 haloalkyl, substituted or unsubstituted silyl or C6-14 aryl; Rl and R2 are same or different, and are selected from a lower alkyl group, preferably a straight or branched Ci-6 alkyl group such as methyl, ethyl, propyl, butyl, pentyl or hexyl;

X is -0- or -NW4 -or -CHW _4;

Y is -CHWs;

W3 is hydrogen or Ci-8 alkyl, C6-14 aryl Ci-8 alkyl, C6-14 aryl or alkoxy; W3, W ₄ and W5 are each independently, hydrogen or Ci-8 alkyl; or wherein

W3 and W ₄ or W3 and W5 taken together form carbocyclic ring containing having from 3 to 6 ring atoms or a heterocyclic ring having from 3 to 6 ring atoms wherein the carbocyclic or heterocyclic ring is optionally substituted with one or more R ^x , wherein each R ^x is, independently, hydrogen, halo, hydroxyl or Ci-8 alkyl, or wherein two R ^x groups together with the carbon atom to which they are attached, form =0;

Z is a bond, [-CH2-] _n or Y and Z taken together to form [-CH2-] _n ; wherein n is an integer of 0 to 3; m is an integer of 0 to 3 and

hal is "halo" or "halogen" and refers to bromo, chloro, fluoro or iodo.

Unless otherwise stated, the term "lower alkyl" means a Ci-8 alkyl group, preferably a straight or branched Ci-6 alkyl group, such as methyl, ethyl, propyl, butyl, pentyl or hexyl. Compounds of formula (B) and (B-II) may be in the form of the R or S isomer or a mixture thereof. The compounds of formula (B-XIIIa), (B-XIIIb), (B-XII), (B-XI), (B-X), (B-IX), and (B-VIII) are hitherto unreported intermediates useful in the process for the preparation of polycyclic carbamoyl pyridone derivatives of formula (B) as described herein.

In a preferred embodiment, Ar is 2,4-difluorophenyl; Wi and W ₂ are each independently, hydrogen; W3 is methyl; X is -0-;Y and Z taken together to form, [-CH ₂ -]n ; wherein n is an integer of 0 to 3; and R is hydrogen and the

compounds covered by the process of the present invention are of formula (I):

Formula I or pharmaceutically acceptable salts thereof. Accordingly, there is provided a process for preparing tricyclic carbamoyl pyridone derivatives of formula (I), as depicted below in the general reaction Scheme 2.

Scheme 2

Formula II

Formula I

(Bracket indicates that the intermediate could be isolated, but is not isolated in the preferred embodiment of the present invention) ;

Wherein, Ar, W _1; W ₂₎ W3, X, Y, Z and n are as defined above; and m is an integer of 0 to 3; R is a protecting group selected from lower alkyl, preferably a straight or branched Ci-6 alkyl group such as methyl, ethyl, propyl, butyl, pentyl or hexyl or C6- 1 1 aryl; and Ri and R2 are same or different, selected from a lower alkyl group, preferably a straight or branched Ci-6 alkyl group such as methyl, ethyl, propyl, butyl, pentyl or hexyl.

Compounds of formula (I), (II) and (III) may be in the form of the R or S isomer or a mixture thereof.

The compound of formula (VIII) is one of the hitherto unreported intermediates useful in the process for the preparation of polycyclic carbamoyl pyridone derivatives of formula (I) as described herein. In one embodiment of the invention, a compound of formula (VIII) is cyclised with an oxalic acid diester of formula (B-XV):

Formula B-XV in the presence of a compound of formula M ⁺ ORi, to form a pyridinone compound of formula (V), wherein each Ri is H, Ci-6 alkyl, cycloalkyl, aryl, toluyl or benzyl; and M+ is an alkali metal cation such as lithium, sodium, potassium, rubidium or cesium. Preferably, the alkali metal cation is sodium and the Ri group of the oxalate ester may be the same or different as the Ri group from M+-ORi . Preferably, Ri is a C1-5 alkyl, especially a C1-2 alkyl or aryl. Particularly preferred oxalate esters are dimethyl oxalate, diethyl oxalate and diphenyl oxalate. Particularly preferred alkali metal alkoxides are sodium methoxide, sodium tert-butoxide, sodium tert-pentoxide, potassium tert- butoxide, lithium methoxide, lithium ethoxide and titanium isopropoxide. The molar ratio of strong base (M ⁺ ORi) to the oxalic acid diester can vary from about 1 : 1 to about 2: 1 , preferably 1 : 1 to about 1.2: 1.

Generally, the reaction solvent must be inert. Examples of suitable solvents include, but are not limited to, alkanols, such as methanol, ethanol, propanol, and isopropanol; aromatic hydrocarbons, such as benzene, toluene, the xylenes, and the like; aliphatic hydrocarbons, such as pentane, hexane, octane, and the like; ethers, such as diether ether, diisopropyl ether, methyl butyl ether, tetrahydrofuran, 1 ,4-dioxane, and the like; and such miscellaneous solvents as Ν,Ν-dimethylformamide, N,Ndimethylacetamide, and dimethyl sulfoxide. The preferred solvents are alkanols. The reaction temperature, which can vary from about -40°C to about 100°C, is to some extent dependent upon the base-solvent combination employed. The reaction temperature is preferably in the range from about -20°C to about 20°C. The reaction time is not critical and can typically vary from about 15 minutes to about 24 hours.

In another embodiment of the invention, the compound of formula (V) is preferably converted to an aldehyde compound of formula (IV) by reacting with an acid. Preferably, the reaction is carried out in the presence of a catalytic amount of a strong protic acid. Examples of suitable acids include, but are not limited to, hydrobromic acid, phosphoric acid, formic acid, trifluoro acetic acid, maleic acid, benzoic acid, carbonic acid and oxalic acid. Examples of suitable strong protic acids include, but are not limited to, hydrochloric acid, nitric acid, methane sulfonic acid, sulfuric acid, p-toluene sulfonic acid. Preferably, acetic acid or formic acid are used as a solvent in combination with one or more of the strong protic acids described above.

The reaction is preferably carried out in a co-solvent. The co-solvent assists in enhancing solubility of compounds having poor water solubility, thereby increasing the overall rate of the reaction. Examples of co-solvent include, but are not limited to, polar solvents, non-polar solvents and mixtures thereof. Preferred solvents include acetonitrile, dioxane and THF.

The reaction is typically carried out at a temperature in the range of from about -70°C to about boiling point of the solvent used. Preferably, the reduction step is carried out at a temperature in the range of from about - 10°C to about 80°C. In still other embodiments, it is carried out at a temperature in the range of from about 20°C to about 75°C. In a particularly preferred embodiment the reaction is carried out at a temperature in the range from about 65 to about 70°C. The aldehyde compound of formula (IV) may be isolated by general purification methods known in the art or may be used in the next step without isolation. Preferably, the aldehyde compound of formula (IV) is used without isolation.

In another embodiment of the invention, the aldehyde compound of formula (IV) is reacted with an amine compound of formula (III), optionally in the presence of an acid, to provide a compound of formula (II) .

Examples of suitable acids include, but are not limited to, hydrobromic acid, phosphoric acid, formic acid, trifluoro acetic acid, maleic acid, benzoic acid, carbonic acid, oxalic acid hydrochloric acid, nitric acid, methane sulfonic acid, sulfuric acid and p-toluene sulfonic acid.

The reaction is preferably carried out in the presence of a solvent. The reaction solvents include but are not limited to polar solvents, non-polar solvents and mixture thereof. Preferred solvents include methylene chloride, toluene and acetonitrile.

The reaction is carried out at temperature ranging from 20°C to the reflux temperature of the solvent used, preferably 60°C to 80°C.

In another embodiment of the invention, the compound of formula (II) is deprotected to obtain a tricyclic carbamoyl pyridone derivative of formula (I).

When R is alkyl, the deprotection step is suitably carried out in the presence of a Lewis acid. Examples of suitable Lewis acids include, but are not limited to, boron trihalides such as BBr3 or BF3.Et ₂ 0, trialkyl silyl halides such as (CH3)3.Si-I or magnesium, calcium or lithium cation and a nucleophilic anion. The deprotection step is preferably carried out using magnesium or lithium cation and a nucleophilic anion. Examples of suitable magnesium cation and a nucleophilic anion include, but are not limited to, magnesium bromide, magnesium chloride, magnesium iodide and magnesium sulphide. Examples of suitable lithium cation and a nucleophilic anion include, but are not limited to, lithium bromide, lithium chloride, lithium iodide and lithium sulphide. Most preferably, the Lewis acid used is lithium bromide.

When R is silyl, the deprotection step is suitably carried out in in the presence of tetramethyl ammonium fluoride, tert- butyldimethylsilyl (TBDMS) ether or feri-butyldiphenylsilyl (TBDPS) ether.

When R is aryl, the deprotection step is suitably carried out in the presence of a hydrogenation catalyst such as Pd-C, Pt-C and Raney-Ni.

The reaction is carried out at a temperature in the range from about 20° C to the reflux temperature of the solvent used, and is preferably in the range from about 60°C to about 80°C.

The tricyclic carbamoyl pyridone derivatives of formula (I) may be optionally purified in a suitable solvent or mixture of solvents.

The tricyclic carbamoyl pyridone derivatives of formula (I) may be converted to the pharmaceutically acceptable salts thereof. Suitable pharmaceutically acceptable salts are base addition salts. The pharmaceutically acceptable salts include but are not limited to alkali metal salts such as sodium, potassium, calcium, lithium, magnesium; olamine and the like.

According to another aspect of the present invention, there is provided a process for preparing a compound of formula (VIII) as exemplified in Scheme 3. Scheme 3

la B-XII

Formula B-XVI Formula B-XIV

Formula VI

Formula XI

Formula IX Formula X

Formula VIII wherein hal, R and R2 are as defined above and m is an integer of 0 to 3.

In an embodiment, the keto group of the 1 ,3-dicarbonyl compound of formula (B-XIV) is selectively protected using a suitable protecting group, for example an enol ether or cyclic ketal group, according to methods known in the art. Preferably the keto group is protected using ethylene glycol, propylene glycol, trimethylene glycol, methyl alcohol, ethyl alcohol, or benzyl alcohol. In a preferred embodiment, the protecting agent used is ethylene glycol in the presence of an acidic catalyst in an inert solvent, to obtain a mixture of compounds of formula (B-XIIIa) and (B-XIIIb) . The preferred acidic catalysts are zirconium tetrachloride (ZrC14), a Bronsted or a Lewis acid catalyst. Alternatively, the protection may be carried out in the presence of trialkyl orthoformate or a catalytic amount of tetrabutyl ammonium tribromide in absolute alcohol.

A standard procedure for protection employs toluene sulfonic acid as a catalyst in refluxing toluene, which allows the continuous removal of water from the reaction mixture using a Dean-Stark apparatus. Alternatively, a mixture of orthoesters or molecular sieves can also provide effective water removal through chemical reaction or physical sequestration.

The protected compounds are hydrolyzed in an acid or a base in a suitable solvent or solvent mixture to provide a compound of formula (B-XII) . Optionally, the reaction may be performed in the presence of a phase-transfer catalyst Q ⁺ X ^~ wherein Q ⁺ is a quaternary ammonium or phosphonium cation and X ^" is any suitable anion, preferably halogenide. Examples of suitable Q ⁺ X ^" catalysts include, but are not limited to: tetrabutylammonium bromide, tetrabutylammonium bisulphate, benzyltriethylammonium chloride, tetrabutyl ammonium iodide benzyltributylammonium bromide, tetrabutylphosphonium bromide and benzyltriphenylphosphonium chloride. A particularly preferred Q ⁺ X ^" catalyst is tetrabutylammonium iodide (TBAI).

In an embodiment, the compound of formula (B-XII) is coupled with 2,4- difluorobenzyl amine of formula (VI) using a coupling reagent in the presence of an inert organic solvent or mixture of solvents thereof to provide compound of formula (XI) .

A suitable coupling reagent for use in a process according to the present invention can be selected from the group comprising of phenylsilane, 1 , 1 - carbonyldiimidazole (CDI), benzotriazol- 1-yloxytris (dimethylamino) phophonium hexafluorophosphate (BOP), 1 -hydroxy benzotriazole hydrate (HOBt), PyBOP (Analog of the BOP), 1 ,3-dicyclohexylcarbodiimide (DCC), N- Ethyl-N'-(3-dimethylaminopropyl)carbodidimide hydrochloride (EDC HC1), HATU, chloroformates such as Ethyl chloroformate or isobutyl chloro formate. These agents act in situ as activating reagents and convert the carboxylic acids to more reactive intermediates. Phenylsilane, can act as an in situ carboxylic acid activating agent, and can be effectively used as a coupling reagent to prepare carboxamides. A particularly suitable coupling reagent for use in the above process according to the present invention is ethyl chloroformate or isobutyl chloroformate.

By "inert organic solvent" is meant an organic solvent, which under the reaction conditions of a process according to the present invention, does not react with either the reactants or the products. A suitable inert organic solvent for use in a process according to the present invention can be selected from the group consisting of dimethylformamide (DMF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methyl pyrrolidone (NMP), sulfolane, diglyme, 1 ,4-dioxane, tetrahydrofuran(THF), acetonitrile, acetone, dichlromethane (MDC), toluene, xylene and other inert organic solvents known in the art. A particularly suitable inert organic solvent for use in the above process according to the present invention is NMP.

The coupling reaction is carried out at a temperature ranging from about 5°C to the boiling point of the reaction mass until no starting material is detectable. The compound of formula (XI) is deprotected by acid catalyzed transacetalization in acetone or hydrolysis in wet solvents or in aqueous acid to obtain a 1 ,3-dicarbonyl compound of formula (X) . Alternatively, some strong oxidation agents such as HC10 ₄ in MDC may cleave ketals. The reaction may be accelerated upon the addition of the phase-transfer catalyst such as tetra-n- butylammonium bromide (TBAB), tetra-n-butylammonium iodide (TBAI), methyltrioctylammonium chloride and the like. The 1 ,3-dicarbonyl compound of formula (X) is then reacted with dimethylformamide dimethyl acetal (DMFDMA) to obtain a N,N-dimethyl- enamine of formula (IX) . The reaction is preferably performed in a polar solvent such as dioxane, DMF and the like, at a temperature in the range of from about 20 °C to the reflux temperature of the solvent used.

N-alkylation of the intermediate Ν,Ν-dimethylenamine of formula (IX) comprises treatment with aminoacetaldehyde dialkylacetal of formula (B-XVIa) :

Formula B-XVIa wherein, i¾ is lower alkyl, and R3 and R ₄ are each hydrogen or lower alkyl, such as methyl, ethyl, propyl, butyl, pentyl or hexyl;

or bromoacetaldehyde diakyl acetal of formula (B-XVIb):

Formula B-XVIb wherein, R ₂ is lower alkyl, such as methyl, ethyl, propyl, butyl, pentyl or hexyl; preferably, in an inert solvent at a temperature ranging from about - 10°C to the reflux temperature of the solvent is used to obtain an intermediate enamine compound of formula (VIII), wherein R ₂ is selected from a lower alkyl group, preferably a straight or branched Ci-6 alkyl group such as methyl, ethyl, propyl, butyl, pentyl or hexyl. Preferably R ₂ is methyl and the reaction is performed using aminoacetaldehyde dimethylacetal.

In one preferred embodiment, when hal is chloro, R and Ri are ethyl, R ₂ is methyl, m is an integer of 1, n is an integer of 2 and wherein compound of formula (III) is in the form of R isomer, the compound obtained by the process of the invention includes compound of formula (la):

Accordingly, a process for preparing a compound of formula (la) according to the present invention is exemplified in Scheme 4.

Scheme 4

Formula Xlla

Formula XVIa Formula XlVa

Formula VI

Formula IXa Formula Xa Formula Xla

Formula Va

Formula Villa

Formula la

Formula Ma

An alternative process for preparing a compound of formula (la) according to the present invention is exemplified in Scheme 5. Scheme 5

Formula VII 2,4-difluorobenzyl Formula V

Formula VI

Formula la

In another preferred embodiment, when hal is chloro, R and Ri are ethyl and R ₂ is methyl, m is an integer of 1, n is an integer of 1 and wherein compound of formula (III) is in the form of S isomer, the compound obtained by the process of the invention includes compound of formula (lb):

Formula lb

Accordingly, a process for preparing a compound of formula (lb) according to the present invention is exemplified in Scheme 6.

An alternative process for preparing a compound of formula (lb) according to the present invention is exemplified in Scheme 7. Scheme 7

Formula VII 2,4-difluorobenzyl Formula V

Formula VI

Formula IV Formula lib

According to yet another aspect of the present invention, there is provided an alternate process for preparing tricyclic carbamoyl derivatives of formula (I) as exemplified in Scheme 8 below.

whererin, R, Ri, R ₂ and n are as defined above Compounds of formula (I) and (III) may be in the form of the R or S isomer or a mixture thereof.

The processes of the present invention allow the synthesis of tricyclic carbamoyl pyridone derivatives of formula (B) and of formula (I) with a high degree of chromatographic and optical purity.

According to a further aspect of the present invention, there is provided tricyclic carbamoyl pyridone derivatives of formula (B) and of formula (I) obtainable by (or obtained by) a process according to any process of the present invention as described in the present disclosure. According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a tricyclic carbamoyl pyridone derivative of formula (B) or of formula (I), obtainable by (or obtained by) any process of the present invention as described in the present disclosure, optionally together with one or more pharmaceutically acceptable excipients. Suitable pharmaceutically acceptable excipients are well known to those skilled in the art.

According to another aspect of the present invention, there is provided the use of a tricyclic carbamoyl pyridone derivative of formula (B) or of formula (I), obtainable by (or obtained by) any process of the present invention as described in the present disclosure, in the treatment of HIV-AIDS.

According to another aspect of the present invention, there is provided a method of treating HIV-AIDS in a patient in need of such treatment, which method comprises administering to the patient a therapeutically effective amount of a tricyclic carbamoyl pyridone derivative of formula (B) or of formula (I), obtainable by (or obtained by) any process of the present invention as described in the present disclosure.

In accordance with the invention as herein described, there is provided a process for preparation of a tricyclic carbamoyl pyridone derivative of formula (B) or of formula (I) which is simple, economical and suitable for industrial scale-up.

While considerable emphasis has been placed herein on the specific steps of the preferred process, it will be appreciated that many steps can be made and that many changes can be made in the preferred steps without departing from the principles of the invention. These and other changes in the preferred steps of the invention will be apparent to those skilled in the art from the disclosure herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the invention and not as a limitation.

The following non-limiting Examples illustrate the processes of the present invention.

Examples: -

Example 1: Preparation of compound of Formula Xlla (hal-chloro, R- ethyl, m-1)

Step 1: Preparation of compound of Formula XlVa

Sodium ethoxide (50.0 g, 0.76 moles), was stirred in a mixture of toluene (200 ml) and ethanol (21.0 g, 0.45 moles) at 25-30°C. The reaction mass was cooled to 10- 15°C and treated with ethyl-4-chloro acetoacetate (50 g, 0.30 moles). The reaction mass was further stirred for 4-5 hours at 25-30°C. The reaction mass was acidified to the pH 2-2.5 using 2N HC1, and extracted with toluene. The organic layer was washed with 10 % sodium bicarbonate solution, followed by water and used without purification in the next step.

Step 2: Preparation of mixture of compounds of Formula Xlllaa and Xlllba

The solution of compound XlVa from step 1 was treated with p-Toluenesulfonic acid (5.8 g, 0.03 moles) and ethylene glycol (24.6 g, 0.39 moles) and heated to 1 10°C for 4-5 hours. The reaction mass was cooled to 10- 15 °C and used without purification in the next step.

Step 3: Preparation of compound of Formula Xlla

The solution of compounds Xlllaa and Xlllba from step 2 was treated with 12 % solution of NaOH (330 ml) and TBAI (0.9 g, 0.002 moles). The reaction mass was further stirred at 25-30°C for 3-4 hrs. The layers were separated and the aqueous layer was washed with dichloromethane (2 X 134 ml). Aqueous layer was cooled to 5- 10°C. The pH of reaction mass was adjusted to 1-2 by using 6N HCl and extracted with dichloromethane. The organic layer was concentrated under vacuum to afford 41g of titled compound.

Efficiency: 70 % Example 2: Preparation of compound of Formula XIa

The compound Xlla (40 g, 0.21 moles) was stirred in a solution of THF (200 ml) and N-methyl morpholine (28.0 ml, 0.255 moles) at 25-30 °C. The reaction mass was cooled to 0-5 °C, ethyl chloro formate (24.0 ml, 0.25 moles) was added and stirred further for 30 min at 0-5 °C. The solution of 2, 4 difluoro benzyl amine (36.2 g, 0.25 moles) in THF was added. Reaction mass was stirred for 1 hour at 10- 15°C, quenched into ice water (200 ml) and extracted with ethyl acetate. The organic layer was washed with IN HCl solution, followed by saturated bicarbonate solution. The organic layer was concentrated under vacuum to afford 62.0 g of titled compound.

Efficiency: 94 %

Example 3: Preparation of compound of Formula Xa

Tetra-n- butyl ammonium iodide (0.1 g, 0.01 moles) was stirred in toluene (20 mL) at 25-30°C. A solution of compound of Formula XIa (10 g, 0.031 moles) in toluene containing 2N HCl was added at 25-30°C. The reaction mass was heated to 95- 100°C for 6-8 hours and then cooled to 25-30 °C. The layers were separated and the aqueous layer was extracted in toluene (50 mL). The organic layer was washed with saturated sodium bicarbonate solution, followed by water. The solvent was distilled off under reduced pressure. The reaction mass was stirred in diisopropyl ether (30 mL), heated to 50-55°C for 10- 15 min and cooled to 15-30°C.The solid was isolated by filtration, washed with a mixture of diisopropyl ether : n-heptane and dried to afford 6.2 g of titled compound.

Efficiency: 72% Example 4: Preparation of compound of Formula Villa Step 1: Preparation of compound of Formula IXa The compound Xa (6 g, 0.022 moles) was stirred in toluene (60 mL) at 25-30°C. The reaction mass was cooled to 0-5°C and added slowly DMF-DMA (7.9 g, 0.066moles). The temperature of the reaction mass was raised to 25-30°C and stirred further for 3-4 hours. The reaction mass was cooled to 0-5°C and used without purification in the next step.

Step 2: Preparation of compound of Formula Villa

The solution of compound IXa from step 1 was treated with amino acetaldehyde dimethyl acetate (3.0 g, 0.0286moles) at 0-5 °C. The reaction mass was stirred further for 24 hours, quenched into water and extracted with toluene (4 vol). The organic layer was washed with IN HCl solution and concentrated under vacuum to afford 5.1g of titled compound.

Efficiency: 85%

Example 5: Preparation of compound of Formula Va

To a solution of compound Villa (5 g, 0.013 moles) in toluene (5 volumes) were added diethyl oxalate (3 volumes) and sodium ethoxide (2.2 g, 0.032 eq.) at 25 - 30°C. The reaction mass was stirred at 80-85°C for 2-3 hours, cooled to 25- 30°C and water was added and the reaction mass was extracted with toluene. The organic layer was washed with sodium bicarbonate solution. The solvent was distilled off under reduced pressure to afford 5.8 g of titled compound. Example 6: Preparation of compound of Formula Ila (n =2)

Step 1: Preparation of compound of Formula IVa

The compound Va (5.8 g, 0.012 moles) was treated with formic acid at 25- 30°C.Reaction mass was heated to 80-85°C and then cooled to 25-30°C. The solid was isolated by filtration, washed with diisopropyl ether and used without purification in the next step. Step 2: Preparation of compound of Formula Ila

The solid obtained in step 1 was dissolved in toluene (10 vol) and treated with 3R- amino- 1-butanol (0.9 g, 1.2 eq.), acetic acid (1.3 g, 2.5 eq.) and methanol (0.83 g, 3 eq.) at 25 -30°C. Reaction mass was heated to 85-90°C and stirred further for 24 hours. The reaction mass was cooled to 25-30°C. The reaction mass quenched into water and extracted with toluene. The organic layer was washed with sodium bicarbonate solution and water. The solvent was distilled off under reduced pressure and recrystallized with ethyl acetate at 85-90° C to afford 2.8 g of titled compound.

Efficiency: 48.2%

Example 7: Preparation of compound of Formula la (n =2)

The compound Ila (1.8g, 0.004 moles) was dissolved in a mixture of ethanol (5 vol) and THF (5 vol) at 25-30°C. To this NaOH (1.6 g, 10 eq.) was added and stirred further for 12-24 hours. The solid was isolated by filtration, washed with ethanol and suck dried. The solid was suspended in water, acidified with diluted HC1 at 0-5° C, filtered and washed with water.

Example 8: Preparation of sodium salt of compound la (n =2)

The resulting solid (wet) was stirred in ethanol (5 vol). The reaction mass was heated to 80-85°C and treated with 2N aqueous NaOH solution (0.16 g, 1.0 eq.). The reaction mass was stirred further for 15 min and cooled to room temperature. The solid was isolated by filtration, washed with ethanol and dried to afford 1.1 g of titled compound.

Efficiency: 61 %

Example 9: Preparation of compound of Formula lib (n =1)

The solid obtained in Example 6, step 1 was dissolved in toluene (10 vol) and treated with (S)-2-amino-propan- l-ol (1.08 g, 0.0144 moles ), acetic acid (1.8 g, 0.03 moles) and methanol (1.15g, 0.036 moles ) at 25 -30°C. Reaction mass was heated to 85-90° C and stirred further for 24 hours. The reaction mass was cooled to 25-30°C. The reaction mass quenched into water and extracted with toluene. The organic layer was washed with sodium bicarbonate solution and water. The solvent was distilled off under reduced pressure and recrystallized with ethyl acetate at 85-90°C to afford 3.83 g of titled compound.

Efficiency: 73%

Example 10: Preparation of compound of Formula lb (n =1)

The compound lib (3.83g, 0.0088 moles) was dissolved in a mixture of ethanol (5 vol) and THF (5 vol) at 25-30° C. To this NaOH (3.5 g, 10 eq.) was added and stirred further for 12-24 hours. The solid was isolated by filtration, washed with ethanol and suck dried. The solid was suspended in water, acidified with diluted HC1 at 0-5° C, filtered and washed with water.

Preparation of sodium salt of compound lb (n =1)

The resulting solid (wet) was stirred in ethanol (5 vol). The reaction mass was heated to 80-85°C and treated with 2N aqueous NaOH solution (0. 25 g, 1.0 eq.). The reaction mass was stirred further for 15 min and cooled to room temperature. The solid was isolated by filtration, washed with ethanol and dried to afford 2.26 g of titled compound.

Efficiency: 60 %

Example 11: Preparation of compound (Ila) (n =2)

The compound (Va) (4 g, 0.0083 moles) was dissolved in acetonitrile (40 ml) and acetic acid (8ml) and methane sulfonic acid (2.4 ml) were added at 25 -28°C. After the reaction mass was stirred at 65-70°C for 9 hours, solution of compound (Ilia) (R)-3 -amino-butan- l-ol (1.63 g, 0.18 moles) in acetonitrile (4 ml) was added and the reaction mixture was further stirred for 5 hours. After the reaction mixture was cooled to 25-30°C, the solvent was distilled off under reduced pressure at 40-45°C.To the reaction mass was added MDC (40 ml) and quenched in dilute HC1 solution (40 ml). The organic layer was washed with water. The solvent was distilled off under reduced pressure to afford 3 g of titled compound.

Efficiency: 81% Example 12: Preparation of compound (la) (n =2)

To a solution of compound (Ila) (3 g, 0.0067 moles) in THF (30 ml) was added anhydrous LiBr ( 1. 15 g, 0.0134 moles). The reaction mixture was heated to 65- 70 °C for 4 hours. After the reaction mixture was cooled to room temperature, quenched in dilute HC1 solution (30 ml), extracted in MDC (30 ml) . The organic layer was washed with water and the solvent was distilled off under reduced pressure. The reaction mixture was stirred in methanol ( 15 ml) for 1 hour at room temperature. The solid was isolated by filtration, washed with methanol and dried to afford 1.94g of titled compound

Efficiency: 69 %

Example 13: Preparation of sodium salt of compound (la) (n =2)

The compound (la) (2 g, 0.047moles) was dissolved in methanol (20 ml) at 58- 60°C. To the reaction mixture was added 2N aqueous NaOH solution (2.2 ml) and stirred further for 1 hour. The reaction mixture was cooled to room temperature and stirred for 1 hour. The solid was isolated by filtration, washed with methanol and dried to offered 1.8 g of titled compound

Efficiency: 85 %

Example 14: Preparation of olamine salt of compound (la) (n =2)

The compound (la) ( 10 g, 0.0238 moles) was dissolved in methanol (50 ml) at 25-28°C. The reaction mass was heated to 58-60°C. The solution of ethanolamine ( 1.45g, 0.0238 moles) in methanol (50 ml) was added. The reaction mass was further stirred at for 58-60°C for 1 hour. The reaction mixture was cooled to room temperature and stirred further for 1 hour. The solid was isolated by filtration, washed with methanol and dried to afford 9 g of titled compound.

Efficiency: 78 % Example 15: Preparation of compound (lib) (n =1)

The compound (Va) (5 g, 0.0083 moles) was dissolved in acetonitrile (50 ml) and acetic acid (10 ml) and methane sulfonic acid (3 ml) were added at 25 -28°C. After the reaction mass was stirred at 65-70°C for 9 hours, solution of compound (Illb) (S)-2-amino-propan- l-ol ( 1.35 g, 0.018 moles) in acetonitrile (5 ml) was added and the reaction mixture was further stirred for 5 hours. After the reaction mixture was cooled to 25-30°C, the solvent was distilled off under reduced pressure at 40-45°C.To the reaction mass was added MDC (50 ml) and quenched in dilute HC1 solution (50 ml) . The organic layer was washed with water. The solvent was distilled off under reduced pressure to afford 3. 13 g of titled compound.

Efficiency: 70%

Example 16: Preparation of compound (lb) (n =1)

To a solution of compound (lib) (2 g, 0.00467 moles) in acetonitrile (80 ml) was added anhydrous MgBr ₂ (2.02 g, 0.01 1 moles) . The reaction mixture was heated to 50-55°C for 2 hours. After the reaction mixture was cooled to room temperature, quenched in dilute HC1 solution ( 100 ml), extracted in MDC (40 ml). The organic layer was washed with water and the solvent was distilled off under reduced pressure to afford 1.3 g of titled compound.

Efficiency: 70 %

Example 17: Preparation of sodium salt of compound (lb) (n =1)

The compound (lb) (2 g, 0.049moles) was dissolved in methanol (20 ml) at 58- 60°C. To the reaction mixture was added 2N aqueous NaOH solution (2.5 ml) and stirred further for 1 hour. The reaction mixture was cooled to room temperature and stirred for 1 hour. The solid was isolated by filtration, washed with methanol and dried to afford 1.68 g of titled compound.

Efficiency: 79 %

Example 18: Preparation of compound of Formula Xlla (hal-chloro, R- ethyl, m- 1) Step 1: Preparation of compound of Formula XlVa

Sodium ethoxide (104.0 g, 1.53 moles), was stirred in a mixture of toluene (400 ml) and ethanol (33.1 g, 0.72 moles) at 25-30°C. The reaction mass was cooled to 10- 15°C and treated with ethyl-4-chloro acetoacetate (100 g, 0.60 moles). The reaction mass was further stirred for 4-5 hours at 25-30°C and cooled toO-5°C. The reaction mass was acidified to the pH 2-2.5 using 2N HC1, extracted with toluene. The organic layer was washed with 10 % sodium bicarbonate solution, followed by water and used without purification in the next step.

Step 2: Preparation of mixture of compounds of Formula Xlllaa and Xlllba

The solution of compound XlVa from step 1 was treated with p-Toluenesulfonic acid (5.23 g, 0.03 moles) and ethylene glycol (48.0 g, 0.77 moles) and heated to 1 10°C for 4-5 hours. The reaction mass was cooled to 40°C, concentrated to 5 volumes and used without purification in the next step.

Step 3: Preparation of compound of Formula Xlla

The solution of compounds Xlllaa and Xlllba from step 2 was treated with 12 % solution of NaOH (600 ml) and TBAB (0.9 g, 0.0055 moles). The reaction mass was further stirred at 25-30°C for 3-4 hrs. The layers were separated and the aqueous layer was washed with toluene (2 X 60 ml) followed by solution of dichloromethane containing 10% methanol (2 X 240 ml). Aqueous layer was cooled to 5- 10 °C. The pH of reaction mass was adjusted to 1-2 by using 6N HC1 and extracted with solution of dichloromethane containing 10% methanol. The organic layer was concentrated under vacuum to afford 71g of titled compound.

Efficiency: 67 %

Example 19: Preparation of compound of Formula XIa

The compound Xlla (70.0 g, 0.368 moles) was stirred in a solution of THF (490 ml) and N-methyl morpholine (48.4 g, 0.48 moles) at 25-30 °C. The reaction mass was cooled to 0-5 °C, ethyl chloro formate (47.9 lg, 0.44 moles) was added and stirred further for 30 min at 0-5 °C. The solution of 2, 4-difluoro benzyl amine (73.74 g, 0.51 moles) in THF (350 ml) was added. Reaction mass was stirred for 1 hour at 10- 15°C, quenched into ice water (350 ml) and extracted with ethyl acetate. The organic layer was washed with IN HCl solution, followed by saturated bicarbonate solution. The organic layer was concentrated under vacuum to afford 105.0 g of titled compound.

Efficiency: 90 %

Example 20: Preparation of compound of Formula Xa

Tetra-n- butyl ammonium bromide (0.55 g, 0.001 moles) was stirred in toluene (1 10 mL) at 25-30°C. A solution of compound of Formula XIa (55 g, 0.175 moles) in toluene (165 ml) containing 2N HCl was added at 25-30°C. The reaction mass was heated to 95- 100°C for 6-8 hours and then cooled to 25-30 °C. The layers were separated and the aqueous layer was extracted in toluene (1 100 mL). The organic layer was washed with saturated sodium bicarbonate solution, followed by water. The solvent was distilled off under reduced pressure. The reaction mass was stirred in diisopropyl ether (165 mL), heated to 50-55°C for 10- 15 min, cooled to 15-30°C and n-heptane (275 ml) was added. The solid was isolated by filtration, washed with a mixture of diisopropyl ether : n-heptane and dried to afford 29.0 g of titled compound.

Efficiency: 87 %

Example 21: Preparation of compound of Formula Xa

Compound XIa (77 g, 0.24 moles) was stirred in methanol (770 ml) and cone. HCl (385 ml). The reaction mass was heated to 45-50°C for 3-5 hours and then cooled to 40°C. The solvent was distilled off under reduced pressure and toluene was added (77 ml). The layers were separated and the aqueous layer was extracted in toluene (50 mL). The organic layer was washed with saturated sodium bicarbonate solution, followed by water. The solvent was distilled off under reduced pressure. The reaction mass was stirred in diisopropyl ether (230 mL), heated to 50-55°C for 10- 15 min and cooled to 15-30°C. n-heptane was added ( 385 ml) and stirred. The solid was isolated by filtration, washed with a mixture of diisopropyl ether: n-heptane and dried to afford 47.0 g of titled compound.

Efficiency: 71% Example 22: Preparation of compound of Formula Villa

The compound Xa (45 g, 0.166 moles) was stirred in toluene (450 mL) at 25- 30°C. The reaction mass was cooled to 0-5°C and added slowly DMF-DMA (59.2 g 0.506moles). The temperature of the reaction mass was raised to 25-30°C and stirred further for 3-4 hours. The reaction mass was cooled to 0-5°C and treated with amino acetaldehyde dimethyl acetate (22.68 g, 0.216 moles) at 0-5 °C. The reaction mass was stirred further for 24 hours, quenched into water and extracted with toluene (4 volumes). The organic layer was washed with IN HC1 solution and concentrated under vacuum to afford 53.76 g of titled compound.

Efficiency: 84%

Example 23: Preparation of compound of Formula Va

To a solution of compound Villa (48 g, 0.124 moles) in toluene (5 volumes) were added diethyl oxalate (3 volumes) and sodium ethoxide (21.0 g, 0.31 moles) at 25 -30°C. The reaction mass was stirred at 80-85°C for 2-3 hours, cooled to 25- 30°C and water was added and the reaction mass was extracted with toluene. The organic layer was washed with sodium bicarbonate solution. The solvent was distilled off under reduced pressure to afford 57.0 g of titled compound. Efficiency: 99%

Example 24: Preparation of compound of Formula IVa

The compound Va (40.0 g, 0.0854 moles) was treated with formic acid (10 vol) at 25-30°C. The reaction mass was heated to 80-85°C and then cooled to 25- 30°C. Water (20 vol) was added and stirred. The solid was isolated by filtration, washed with diisopropyl ether (5 vol) to afford 19.0 g of titled compound. Efficiency = 53.88 %

Example 25: Preparation of compound of Formula IVa

The compound Va (35.0 g, 0.0747 moles) was treated with methane sulfonic acid (0.3 vol) and acetic acid (70 ml) in acetonitrile (350 ml) at 25-30°C. The reaction mass was heated to 70-75°C and then cooled to 25-30°C. Water (20 vol) was added and stirred. The solid was isolated by filtration, washed with diisopropyl ether (5 vol) to afford 19.0 g of titled compound.

Efficiency = 62 %

Example 26: Preparation of compound of Formula Ila

The compound IVa ( 20.0 g, 0,049 moles) was dissolved in toluene (10 vol) and treated with 3R-amino- 1-butanol (5.2 g, 0.059 moles, 1.2 eq.), acetic acid (7.3 g, 0.122 moles, 2.5 eq.) and methanol (4.7 g, 0.147 moles, 3 eq.) at 25 -30°C. Reaction mass was heated to 85-90°C and stirred further for 24 hours. The reaction mass was cooled to 25-30°C. The reaction mass quenched into water and extracted with toluene. The organic layer was washed with sodium bicarbonate solution and water. The solvent was distilled off under reduced pressure and re crystallized with ethyl acetate to afford 13.5 g of titled compound.

Efficiency: 61%

Example 27: Preparation of compound (la) (n =2)

To a solution of compound (Ila) (l lg, 0.025 moles) in THF (1 10 ml) was added anhydrous LiBr (32.0 g, 0.37 moles). The reaction mixture was heated to 60- 65°C for 24 hours. A solution of acetic acid (40 ml) in water (1 10 ml) was added and the reaction mixture was extracted in MDC (50 ml). The organic layer was washed with water and the solvent was distilled off under reduced pressure. The reaction mixture was stirred in methanol (75 ml) for 1 hour at room temperature. The solid was isolated by filtration, washed with methanol and dried to afford 8.8 g of titled compound

Efficiency: 85.44 % Example 28: Preparation of sodium salt of compound (la) (n =2)

The compound (la) (8.8 g, 0.021 moles) was dissolved in methanol (10 vol) at 60- 65°C. To the reaction mixture was added 2N aqueous NaOH solution (8.68 ml) and stirred further for 1 hour. The reaction mixture was cooled to room temperature and stirred for 1 hour. The solid was isolated by filtration, washed with methanol and dried to offered 8.4 g of titled compound

Efficiency: 90.27 % Example 29: Preparation of sodium salt of compound (la) (n =2)

To a solution of compound (Ila) (lOg, 0.022 moles) in ethanol (50 ml) and THF ( 50 ml) was added sodium hydroxide ( 8.8 g, 0.22 moles). The reaction mixture was stirred at 25-30°C for 24 hours. The solid was isolated by filtration, washed with ethanol and suck dried. The solid was acidified in dilute HC1.

The solid was stirred in ethanol (5 vol) at 80-85°C. To the reaction mixture was added 2N aqueous NaOH solution (1.0 eq.) and stirred further for 15 min. The reaction mass was cooled to room temperature. The solid was isolated by filtration and dried to give 4.0 g of titled compound.

Efficiency = 40.52 %

Example 30

Preparation of compound (V) (R, Rl and R2= methyl) The compound (VII) (5 g, 0.015 mol), was stirred in MDC (50 ml) at 25-30°C and CDI (4.37 g, 0.027 mol) was added. After the solution was stirred at 35- 40°C for 1 hour, cooled to 25-30°C. To this compound (VI) 2,4- difluorobenzylamine (2.72 g, 0.019 mol) was added and the reaction mixture was further stirred for 1 hour at 25-30°C. The reaction mixture was added to water (50 ml). To the reaction solution MDC was added, exacted and the organic layer was washed with dilute HC1 solution, brine solution, an aqueous saturated sodium bicarbonate solution and finally with brine solution. The solvent was distilled off under reduced pressure to obtain titled compound (4 g, 57 %).

Example 31

Preparation of compound (Ila) (R, Rl and R2= methyl; n =2)

The compound (V) (4 g, 0.009 mol) was dissolved in acetonitrile (40 ml) and acetic acid (8ml) and methane sulfonic acid (2.4 ml) were added at 25 -28°C. After the reaction mass was stirred at 65-70°C for 9 hours, solution of compound (Ilia) (R)-3 -amino-butan- l-ol (1.72 ml, 0.02 mol) in acetonitrile (4 ml) was added and the reaction mixture was further stirred for 5 hours. After the reaction mixture was cooled to 25-30°C, the solvent was distilled off under reduced pressure at 40-45°C.To the reaction mass was added MDC (40 ml) and quenched in dilute HC1 solution (40 ml) . The organic layer was washed with water. The solvent was distilled off under reduced pressure to obtain titled compound (3 g, 75 %) .