FIELD OF THE INVENTION:

The present invention relates to an improved process for the preparation of renin inhibitor Aliskiren intermediates and further conversion into Aliskiren and its pharmaceutically acceptable salts. BACKGROUND OF THE INVENTION:

Aliskiren, (2S, 4S, 5S, 7S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7- diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl] octanamide having the Formula-I, a new antihypertensive has been developed which interferes with the renin- angiotensin system at the beginning of angiotensin II biosynthesis.

Aliskiren is marketed by Novartis as TEKTURNA® in the form of its hemifumarate salt in a once-daily formulation.

U.S. pat. No. 5,559,1 1 1 discloses Aliskiren and related compounds along with the synthesis of Aliskiren. Further US 7132569, US 7009078, US 6730798 and US 6800769 claims novel intermediates used in the preparation of Aliskiren and process for the preparation of Aliskiren, which are incorporated here for reference. US 5,559,1 1 1 discloses compound of Formula-II, which is used as an intermediate in the preparation of Aliskiren.

l o A

Formula-II

As the Aliskiren comprises, 4 chiral carbon atoms, the synthesis of the enantiomerically pure compound is quite demanding. Therefore, novel routes of synthesis needed for the preparation of Aliskiren. The intermediates are commercially important in the synthesis of Aliskiren. Therefore an improved process for the preparation of Aliskiren intermediates is needed. The present invention provides an improved process for the preparation of Aliskiren intermediates and further process for the preparation of Aliskiren.

OBJECT AND SUMMARY OF THE INVENTION: Principle object of the present invention is to provide an improved process for the preparation of intermediate compounds of Formula-II and Formula-XIII of Aliskiren.

One more object of the present invention is to provide further conversion of intermediate compounds of Formula-II and Formula-XIII into Aliskiren or its pharmaceutically acceptable salts.

One aspect of the present invention provides, an improved process for the preparation of compound of Formula-XIII comprising the steps of

a) reacting the compound of Formula-II with magnesium in presence of Grignard reagents, and

b) condensing the obtained compound with compound of Formula-XII to get compound of Formula-XIII. Preparation of compound of Formula-XIII is depicted in Scheme-II.

Formula-XIII

SCHEME-II

Another aspect the present invention provides, an improved process for the preparation of compound of Formula-II comprising the steps of: ^N

a) condensing the compound of Formula-Ill with l-Bromo-3-methoxy-propane in presence of a base to give compound of Formula-IV followed by In-situ reduction to give compound of Formula- V,

b) chlorinating the compound of Formula-V to give compound of Formula-VI optionally converting chloro compound of formula VI to corresponding Iodo compound of formula VII, _^

c) reacting the compound of formula VI / formula VII with a compound of Formula- VIII to give . compound of formula IX,

d) hydrolyzing compound of formula IX to give compound of Formula-X, e) reducing compound of Formula-X with suitable reducing agent to give compound of Formula-XI, and

f) converting compound of formula XI to compound of formula II. Preparation of compound of Formula-II is depicted in scheme-I.

Formula-Ill

Formula-IV Formula-V

Formula-II

SCHEME-I DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to an improved process for the preparation of intermediate compounds of Formula-II and Formula-XIII of Aliskiren. The present invention also relates to further conversion of intermediate compounds of Formula-II and Formula-XIII into Aliskiren or its pharmaceutically acceptable salts.

The main aspect of the present invention provides an improved process for the preparation of compound of Formula-XIII comprising the steps of a) reacting the compound of Formula-II with magnesium in presence of Grignard reagents, and

b) condensing the obtained compound with compound of Formula-XII to get compound of Formula-XIII.

In one embodiment, the Grignard reagent used in this reaction is alkyl magnesium halide preferably Ci _-4 alkyl magnesium halide like methyl magnesium chloride or methyl magnesium bromide. The usage of the Grignard reagent as a primer initiates the reaction at lower temperature and kills the moisture present in the system and also minimizes the formation of methyl, hydroxyl, desmethoxy and phenoxy impurities.

Methyl Impurity Hydroxy Impurity

Phenoxy Impurity

Desmethoxy Impurity Prior art US 7132569, discloses that the compound of Formula-XIII is purified by using flash chromatography, which is not suitable on commercial scale. Present invention provides purification of compound of formula XIII by distillation.

Another aspect of the present invention provides an improved process for the preparation of compound of Formula-II comprising the steps of:

a) condensing the compound of Formula-Ill with l-Bromo-3-methoxy-propane in presence of a base to give compound of Formula-IV followed by In-situ reduction to give compound of Formula-V, b) chlorinating the compound of Formula-V to give compound of Formula-VI optionally converting chloro compound of formula VI to corresponding Iodo compound of formula VII,

c) reacting the compound of formula VI / formula VII with a compound of Formula- VIII to give compound of formula IX,

d) hydrolyzing compound of formula IX to give compound of Formula- X, e) reducing compound of Formula-X with suitable reducing agent to give compound of Formula-XI, and

f) converting compound of formula XI to compound of formula II.

In one embodiment, the compound of Formula-IV is prepared by condensing compound of Formula-Ill with l-Bromo-3-methoxy-propane in presence of a base. The base is selected from alkaline metal hydroxides or alkaline metal carbonates such as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate, preferably potassium carbonate. The reaction is carried out in solvents such as hydrocarbon like toluene. The compound of Formula-IV in toluene layer is reduced by using reducing agent to give compound of Formula-V. The suitable reducing agent is selected from sodium borohydride, Lithium borohydride, Lithium aluminum hydride, Tetrabutyl ammonium borohydride, potassium borohydride, preferably sodium borohydride.

In one more embodiment, the obtained compound of Formula-V is chlorinated in the presence of suitable chlorinating agent selected from . thionyl chloride, phosphoursoxychloride, oxalylch!oride, preferably thionyl chloride. Prior art process provides bromination of compound of formula V in which for isolation of bromo compound, aqueous work up is required. As bromo compound is unstable due to aqueous work up, yield of the bromo compound is very less. Present invention provides nonaqueous work up condition for isolation of chloro compound due to this yield of chloro compound (compound of formula VI) is higher when compared to its corresponding bromo compound. In another embodiment, the compound of Formula- VI is optionally reacted with sodium iodide to get the corresponding iodo compound of formula VII.

In one more embodiment, compound of formula VI or compound of formula VII is condensed with the Evans amide compound of Formula- VIII in presence of Lithium -diisopropylamide (LDA) to give compound of Formula-IX in an organic solvent. The preferable organic solvent is tetrahydrofuran.

In one more embodiment, the compound of Formula-IX hydrolyzed to give compound of Formula-X by using procedures known in the prior art for example as disclosed in US 5659065 in presence of Lithium hydroxide and hydrogen peroxide.

In one more embodiment, the compound of Formula-X is reduced by using reducing agent such as sodium borohydride in the presence of an acid such as sulfuric acid, hydrochloric acid, methane sulfonic acid, trifluoro acetic acid, preferably sulfuric acid to give compound of Formula-XL

In one another embodiment, the alcohol compound of Formula-XI is chlorinated in the presence of chlorinating agent such as thionyl chloride in presence of N,N-dimethyl acetamide to give compound of Formula-II.

One more aspect of the present invention provides an improved process for the preparation of compound of Evans amide compound of Formula-VIII comprising, reacting 4-Benzyl-oxazolidin-2-one with Isovalerylchloride in presence of sodium hydride and toluene.

In another embodiment of the present invention, the compound of Formula-XIII is further converted into Aliskiren or its pharmaceutically acceptable salts as disclosed in prior art US 7009078 or our co-pending application WO 2012052829 for example as shown in the following scheme-Ill.

Aliskiren

Scheme-Ill

The following examples are provided to illustrate the process of the present invention. They, are however, not intended to limiting the scope of the present invention in any way and several variants of these examples would be evident to person ordinarily skilled in the art. Experimental procedure:

Example-1: Preparation of compound of Formula- VI

A solution of compound of Formula-Ill (lOOg) in toluene (600 ml) and Dimethylsulfoxide (60 ml) was added to potassium carbonate (185g) and l-Bromo-3- methoxy propane (130g) at 25-30°C. The resulting reaction mixture was stirred at 85- 90°C for 16h. After cooling, the solid was filtered and washed with water. The toluene layer of compound of Formula-IV was cooled to 0-5°C and sodium borohydride (9gm) was added. To this reaction mixture methanol (50 ml) was added drop wise at 0-5°C over a period of lh and stirred the reaction mixture at the same temperature for 2h. The reaction was quenched with dilute hydrochloric acid and stirred for 30 minutes. pH of the reaction mixture was adjusted to 7.0-7.5 with aq. Sodium hydroxide solution. Organic layer was separated and aqueous layer was extracted with toluene. Combined organic layers were dried and evaporated under reduced pressure to give compound of Formula- IV as residue. The residue was dissolved in dichloromethane and added to a solution of thionyl chloride in dichloromethane at 0-5°C over a period of lh and stirred the reaction mixture at the same temperature for 2h. Dichloromethane was distilled under reduced pressure at 30-35°C till no more distillate was collect. The compound was re-crystallized in hexanes to give tile compound as white solid.

Yield: 125g; GC purity: 99%.

Example-2: Preparation of compound of Formula-VH

Sodium iodide (73g) was added to a solution of Compound of Formula- VI (100 g) in tetrahydrofuran (200 ml) and reaction mixture was stirred at 25-30°C for 16h and reaction mass was filtered. The filtrate was used in the next step with out any purification.

Example-3: Preparation of compound of Formula-X

A solution of Diisopropyl amine (45gm) in anhydrous tetrahydrofuran (200ml) was cooled in an ice-water bath. To this 1.6M butyl lithium in hexanes (275ml) was added drop wise over 30-45 minutes under nitrogen atmosphere. The reaction mixture was stirred at the same temperature for one hour, cooled to -78°C to -70°C and 100 g of compound of Formula-VIII in anhydrous tetrahydrofuran (200ml) was added drop wise over 45-60 minutes. After stirring for lh, temperature was slowly raised to -50°C to - 45°C. A solution of compound of Formula- VII obtained from above example-2 in tetrahydrofuran was added and the temperature was raised slowly to -25 to-20°C and stirred for lh at the same temperature. The reaction mixture was quenched with 10% ammonium chloride solution. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were concentrated under vacuum to give compound of Formula-IX as yellow color residue. The residue was dissolved in Tetrahydrofuran and water mixture and cooled to 0-5°C. To this 30% hydrogen peroxide solution (250 ml) was added at the same temperature. To this aqueous lithium hydroxide monohydrate solution (23g in 180 ml DM water) was added slowly and reaction mixture was stirred at 20-25°C for 6-8h. Then, aq. Na ₂ S0 ₃ (290g in 1.5 liter water) was added drop wise within lh and organic layer was separated and aqueous layer was extracted with ethyl acetate. Combined organic layers were dried and evaporated under reduced pressure to give a residue. This residue was dissolved in dichloromethane and extracted the required product in aqueous lithium hydroxide monohydrate solution. Aqueous lithium hydroxide solution pH was adjusted to 2-5-3.0 dilute hydrochloric acid and extracted the aqueous layer with dichloromethane. Combined organic layers were dried and evaporated under reduced pressure to give compound Formula-X as residue.

Yield: 95g; HPLC purity: 97%.

Example-4: Preparation of compound of Formula-XI

A solution of compound of Formula-X (lOOg) in THF (200ml) was added to a suspension of sodium borohydride in THF at 0-5°C over 60-90 minutes. A solution of sulfuric acid (32g) in THF was added slowly over a period of 90-120 minutes at 0-5°C and stirred the reaction mixture at the same temperature for another lh and at room temperature for 6h. 200ml of methanol was added slowly, followed by stirring for lh and evaporated the volatiles to give a residue. This residue was dissolved in ethyl acetate and wash with water, dried and evaporated under reduced pressure to give compound of Formula-XI as a residue.

Yield: 93g; HPLC purity: 97%.

Example-5: Preparation of compound of Formula-II

To a solution of compound of Formula-XI (lOOg) in toluene (750 ml) was added to N,N- dimethyl acetamide and reaction mixture was heated to 89-95°C. Thionyl chloride (61g) was added slowly drop wise over period of lh at 89-95°C and stirred the reaction mixture at the same temperature for 90 minutes. ~200ml of toluene was distilled at 40-50°C under reduced pressure to remove excess thionyl chloride. The reaction mass was cooled to 5-10°C and quenched in to pre cooled aq. Sodium hydroxide solution. Toluene layer was separated and washed with aq. Sodium hydroxide solution followed by DM water. Carbon was added to the toluene layer and stirred for 30 minutes at 40-45°C, filtered through hyflo and concentrated under reduced pressure to give a residue. The compound was re-crystallized in hexanes at -20°C to give of Formula-ll as off white solid.

Yield: 80g; HPLC purity: 98.0%.

Example-6: Alternative preparation of compound of Formula-II

To a solution of compound of Formula-XI (lOOg) in toluene (750 ml) was added to N,N- dimethyl formamide and reaction mixture was heated to 89-95°C. Thionyl chloride (61g) was added slowly drop wise over period of lh at 89-95°C and stirred the reaction mixture at the same temperature for 90 minutes. ~200ml of toluene was distilled at 40-50°C under reduced pressure to remove excess thionyl chloride. The reaction mass was cooled to 5-10°C and quenched in to pre cooled aq. Sodium hydroxide solution. Toluene layer was separated and washed with aq. Sodium hydroxide solution followed by DM water. Carbon was added to the toluene layer and stirred for 30 minutes at 40-45°C, filtered through hyflo and concentrated under reduced pressure to give a residue. The compound was re-crystallized in hexanes at -20°C to give of Formula-II as off white solid.

Yield: 85g; HPLC purity: 98.0%.

Example-7: Preparation of compound of Formula-XIII

A mixture of Magnesium powder (14 g) and tetrahydrofuran (75 ml) was heated to reflux and Iodine (1 g) was added. A solution of 2-{4-methoxy-3-(3-methoxypropoxyl)]- phenylmethyl-3-methyl-l-chlorobutane (100 g), Methyl magnesium chloride (3.0M solution in THF, 16g) l-Bromo-2-chloroethane (3g) and Tetrahydrofuran (350 ml) was added dropwise over a period of 90 minutes at 60-65 °C. The reaction mixture was stirred under reflux and cooled to ambient temperature. There after was added a solution of 5- chloro-2-isopropyl-n,n-dimethylpent-4-enamide-(2S,4E) (65 g), N-methylpyrrolidone (0.90 g) and iron (III) acetyl acetonate (1.4 g) in tetrahydrofuran (300 ml) at 0°C. The reaction mixture was stirred at 20-30°C for 2h and quenched with dilute hydrochloric acid. The reaction mixture was extracted with Toluene and the organic phases washed consecutively with water and saturated aqueous sodium chloride and concentrated under reduced pressure to obtain compound as a residue. The residue is subjected to high vacuum distillation to remove the volatile impurities (at -225-235° C temperature and at 0.1-1.0 mbar pressure). The remaining residue after distillation is the pure compound of Formula-XIII having the purity by HPLC 85-95%. Yield: 120g.

Example-8: Preparation of compound of Formula-VIII

A suspension of sodium hydride (26g of 65% assay) in Toluene (1 lit) was added to (R)- 4-Benzyl-2-oxazolidinone (lOOg) portion wise over 2h at 20-25°C and stirred the reaction mass for another 2h at the same temperature. The reaction mixture was cooled to 15- 30°C and isovaleryl chloride (78g) in toluene (200ml) was added drop wise over period of 30 minutes and stirred the reaction mass for lh at 25-30°C. The excess sodium hydride was destroyed by the addition of acetic acid and DM water. Organic layer was separated, dried and evaporated under reduced pressure. The compound was re- crystallized in heptanes to give of Formula-VIII as white solid.

Yield: 135g; HPLC purity: 99.0%