FIELD OF THE INVENTION

The present invention relates to a novel process for preparing Aliskiren and its pharmaceutically acceptable salts.

BACKGROUND OF THE INVENTION

Aliskiren is the first orally active non-peptidic rennin inhibitor, which is chemically known as (2S,4S,5S,7S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl]-octanamide, represented as Formula I.

Aliskiren is a direct renin inhibitor, decreasing plasma renin activity (PRA) and inhibiting the conversion of angiotensinogen to Ang I. Aliskiren is being marketed under the brand name Tekturna®, as an oral tablet with different dosage forms in the form of hemifumarate.

Aliskiren Hemifumarate is also marketed with Amlodipine Besylate and Hydrochlorothiazide as combination products under the brand names Tekamlo®, Amturnide®, as an oral tablet with different dosage forms.

US Patent US 5,559,111 and European patent EP 0 678 503 for the first time discloses Aliskiren. Since Aliskiren contains 4 chiral centers, synthesis of enantiomerically pure compound is very complex. The process disclosed in this patent is as shown below:


Alternative routes for preparing Aliskiren have been disclosed in PCT patent applications WO 01/09079, WO 02/02508, WO 02/02500, WO 02/02487, WO 02/092828, WO 02/02500, WO 03/103653, WO 2005/054177, WO 2005/090305, WO 2005/051895, WO2006/095020, WO2007/054254, WO2007/048620, WO2007/118681, WO2010/010165, WO 2007/006532, WO2007/045420, WO2008/155338, WO2008/119804, WO2009/049837; US 6,800,769, US 7,009,078, US 7,767,831, US 7,772,405, US 7,910,774, US 7,973,175, US 8,203,005, US2009/0076062, US 2011/0092706, US 2011/008852, US 2010/0130749, European patent EP 1 215 201, EP 2 062 874, EP 1958 666, EP 2 189 442; UK patents GB 2 431 640, GB 2 431 641, GB 2 431 642, GB 2 431 643, GB 2 431 644, GB 2 431 645, GB 2 431 646, GB 2 431 647, GB 2 431 48, GB 2 431 649, GB 2 431 650, GB 2 431 651, GB 2 431 652, GB 2 431 653, GB 2 431 654, Tetrahedron Letters 2000, 41, 10085, ibid. 2000, 41, 10091, ibid. 2001, 42, 4819, Drugs Fut. 2001, 1139, J. Org. Chem. 2002, 67, 4261, Helv. Chim Acta 2003, 86, 2848, Tetrahedron Letters 2005, 46, 6337, J. Org. Chem. 2006, 71, 4766, Organic Process & Develop 2007, 11, 584, Tetrahedron Letters 2008, 49, 5980 and Org. Lett. 2010, 12, 1816. Nevertheless, none of them fulfill requirements for a cost effective manufacturing process.

Although the existing processes may lead to the desired renin inhibitors, in particular the (2S,4S,5S,7S)-2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoyl amide derivatives, there is a need to provide an alternative synthetic route to ensure its manufacture in a simple and efficient manner.

OBJECTIVE OF THE INVENTION
The objective of the present invention is to provide a novel process for preparing Aliskiren and its pharmaceutically acceptable salts.

In yet another objective of the present invention is to provide a novel process for preparing Aliskiren and its pharmaceutically acceptable salts, which is simple, industrially applicable and economically viable.

SUMMARY OF THE INVENTION
The present invention relates to a novel process for preparing Aliskiren or its pharmaceutically acceptable salts of Formula I,
which comprises:

a) by protecting compound of Formula II
wherein R represents alkyl and atyl.
to yield a compound of Formula III;

wherein R represents alkyl and aryl; Pt & P2 represents same or different selected from H, alkyl and aryl.
b) reduction and bromination of compound of Formula III to yield the compound of Formula IV;

c) condensation of compound of Formula IV with a compound of Formula V,
in the presence of Organo lithium bases LiHMDS to yield a compound of Formula VI;

d) hydrolysing compound of Formula VI is to give acid of Formula XIV,
using LiOH/H202, which is thereafter condensed with aminoamide of compound of Formula XV,
to give protected Aliskiren of Formula XVI; and

e) deprotection of protected Aliskiren of Formula XVI to give Aliskiren of Formula I and optionally converting in to its pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a novel process for preparing Aliskiren and its pharmaceutically acceptable salts thereof, which comprises protecting a compound of Formula II to yield a compound of Formula III.

wherein R represents alkyl and aryl; P, & P2 represents same or different selected from H, alkyl and aryl.
Reduction and bromination of compound of Formula III to yield the compound of Formula IV,
Reduction is carried out using a hydride reducing agent selected from NaBJtyh, Zn(BH4)2/l2„ A1(BH4)3, LiAlFL, and NaCNBH3/H+ and Vitride® in aprotic organic solvent and bromination is carried out using a brominating agent selected from NBS, PPh3; CBr4, PPh3 in chlorinated solvents.

Condensation of compound of Formula IV with a compound of Formula V,
in the presence of Organo lithium bases LiHMDS, BuLi, LDA, 'BuLi and sec-BuLi in polar aprotic solvents to yield a compound of Formula VI.

Compound of Formula VI is hydrolysed to give acid of Formula XIV,
using LiOH/H2O2, which is thereafter condensed with aminoamide of compound of Formula XV,
to give protected Aliskiren of Formula XVI.

Deprotection of protected Aliskiren of Formula XVI to give Aliskiren of Formula I and optionally converted in to its pharmaceutically acceptable salts thereof.

In another embodiment the present invention relates to a process for preparing Aliskiren and its pharmaceutically acceptable salts thereof, which comprises protecting the compound of formula II with a protecting agent selected from dimethoxy propane, acetone, benzaldehyde using acid catalyst and BOC2O with inorganic or organic bases to give a compound of Formula HI, which is reduced using a reducing agent selected from NaBIVk, ZnCBFLtVb,, A1(BH4)3, LiAlFL* and NaCNBH3/H+ and Vitride® in aprotic organic solvent and thereafter brominated the obtained compound with a brominating agent selected from NBS/PPI13, PPh3/CBr4 in chlorinated solvent to give a compound of Formula IV. The compound of Formula IV is condensed with compound of Formula V in the presence of organo lithium bases selected from LiHMDS, BuLi, LDA, 'BuLi and sec-BuLi in polar aprotic solvents to give a compound of Formula VI. Compound of Formula VI is hydrolysed to give acid of Formula XIV using LiOH/ H2O2, which is thereafter condensed with aminoamide of compound of Formula XV to give protected Aliskiren of Formula XVI. Deprotection of compound of Formula XVI to give Aliskiren of Formula I and optionally converting in to its pharmaceutically acceptable salts thereof.

This present invention also relates to a process for preparing compound of Formula II,
wherein R represents alkyl and aryl. which comprises,

a) condensing aldehyde of Formula VII,
with alkyl-3-methylbutanoate of compound of Formula VIII,

in the presence of base, selected from LiHMDS, LDA, BuLi and amines such as piperidine, triethylamine, metal alkoxides such as NaOMe, NaOEt in polar organic solvents such as methanol, ethanol to give a compound of Formula IX,

b) asymmetric hydrogenation of the compound of Formula IX in the presence of chiral Ruthenium, Rhodium hydrogenation catalyst in the presence of H2 to yield a compound of Formula X,

c) reduction and bromination of compound of Formula X to yield the compound of Formula XI,

d) reacting the compound of Formula XI with a compound of Formula XII,
wherein R is alkyl, aryl

using organolithium bases such as BuLi, LDA, 'BuLi and sec-BuLi, in presence of HMPA in polar aprotic solvents to yield a compound of Formula XIII,

e) asymmetric aminohydroxylation of compound of Formula XIII to give a compound of Formula II.

In another embodiment the present invention relates to a process for preparing compound of Formula II, by condensing aldehyde of Formula VII with alkyl-3-methylbutanoate of compound of Formula VIII in the presence of base, selected from amines, metal alkoxides in polar organic solvents to give a compound of Formula IX and thereafter asymmetric hydrogenation of the compound of Formula IX in the presence of chiral hydrogenation catalyst to yield a compound of Formula X. Reduction of compound of Formula X using reducing agents selected from metal hydride such as NaBH4/I2, Zn(BH4)2/I2„ A1(BH4)3, LiAlFL, and NaCNBH3/H+ and Vitride®in polar aprotic organic solvent and thereafter brominated the obtained compound with a brominating agent selected from NBS, PPh3 (or) PPh3, CBr4 in chlorinated solvents to give a compound of Formula XI. The compound of Formula XI with a compound of Formula XII using organolithium bases BuLi, LDA, 'BuLi and sec-BuLi, HMPA in polar aprotic solvents to yield a compound of Formula XIII and then Sharpless asymmetric aminohydroxylation using cinchona alkaloids to give a compound of Formula II.

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLE 1
Preparation of (E)-methyl 2-(3-(3-methoxypropoxy)-4-methoxybenzylidene)- 3-methylbutanoate

To a solution of methyl 3-methylbutanoate (23.4 g, 0.2 mol) in THF (250ml) was added n-BuLi (0.21 mol) at -70°C followed by 3-(3-methoxypropoxy)-4-methoxy benzaldehyde (22.5 g, 0.1 mol) in THF (250ml) and stirred for 4h. Quenched the reaction mass with saturated ammonium chloride and distilled out THF and water was added and extracted with ethylacetate. This solution was purified by column chromatography using 15% EtOAc in hexanes as eluent. Evaporated the solvents to obtain (E)-methyl 2-(3-(3-methoxypropoxy)-4-methoxybenzylidene)-3- methylbutanoate.
Yield: 32g

EXAMPLE 2
Preparation of (R)-methyl-2-(3-(3-methoxypropoxy)-4-methoxybenzyl)-3-methyl butanoate
To a solution of (E)-methyl 2-(3-(3-methoxypropoxy)-4-methoxybenzylidene)-3-methylbutanoate (30g, 0.09 mol) in methanol (300ml) was added [(S,S)-Et Duphos-Rh] catalyst (842 mg, 0.0025 m.eq.), triethylamine (0.5 ml) and applied hydrogen pressure of 6 bar and slowly heated to 40 °C and stirring continued further. After the completion of reaction, reaction mass was filtered over celite
and evaporated methanol and crude compound was purified by column chromatography using 15% EtOAc in hexanes as eluent. Evaporated the solvent to obtain (R)-methyl-2-(3-(3-methoxypropoxy)-4-methoxybenzyl)-3-methyl butanoate. Yield: 27g

EXAMPLE 3
Preparation of (R)-2-(3-(3-methoxypropoxy)-4<-methoxybenzyl)-3- methylbutan-1-ol

To a solution of (R)-methyl-2-(3-(3-methoxypropoxy)-4-methoxybenzyl)-3-methylbutanoate (25g, 0.077mol) in THF (400ml) was cooled to 0 °C and added slowly portion wise L1AIH4 (4.4 g, 0.11 mol).
Stirred the reaction mass for 3h and quenched the reaction mass with saturated sodium sulfate solution.

Decanted the THF solution and evaporated the solvent. To the residue was added ethylacetate and washed with water. Ethylacetate layer was evaporated and crude compound was purified by column chromatography using 30% ethyl acetate in hexanes to obtain title compound Yield: 16g

EXAMPLE 4
Preparation of 2-(3-methoxypropoxy)-4-((R)-2-(bromomethyl)-3- methylbutyl)-l-methoxy benzene
To a solution of (R)-2-(3-(3-methoxypropoxy)-4-methoxybenzyl)-3-methylbutan-l-ol (30g, 0.1 mol) in dichloromethane (600ml) was added PPh3 (31.85g, 0.12mol) followed by CBr4 (40g, 0.12mol) and stirred for 6h. Filtered the reaction mass and water was added, stirred for lh and separated the organic layer and washed with brine and evaporated the solvent. Crude compound was purified by column chromatography by using 10% EtOAc in hexanes to obtain title compound. Yield: 32g

EXAMPLE 5
Preparation of (R)-methyl 5-(3-(3-methoxypropoxy)-4-methoxybenzyl)-6- methylhept-2-enoate
To a solution of 2-(3-methoxypropoxy)-4-((R)-2-(bromomethyl)-3-methylbutyl)-1-methoxybenzene (30g, 0.86mol) in THF (600 ml) was added n-butyllithium (39g, 15% solution, 0.95mol) at -78 °C and stirred for 2h. Raised the temperature of the reaction mass to -20 °C and stirred for 1 h. Cooled the reaction mixture to -78 °C and slowly added methyl propiolate (8.29g, 1.03mol). Stirring continued for further lh at -78 °C and 5h at 0 °C. Reaction was quenched with 5% aqueous acetic acid, distilled out THF and extracted with ethylacetate and evaporated. Residue was passed through column chromatography using 30% EtOAc in hexanes as eluent to obtain title compound. Yield: 17.6g

EXAMPLE 6
Preparation of (2R,3S,5S)-methyl 5-(3-(3-methoxypropoxy)-4-methoxybenzyl)-3-amino-2-hydroxy-6-methylheptanoate To a solution of tert-butyl carbamate (25.8g, 3.2 m.eq), NaOH (7.9g, 2.9 m.eq) l,3-dichloro-5,5-dimethylhydantoin (27g, 2.0 m.eq) in 0.2% - 1% aqueous THF (500 ml) was added a solution of (R)-methyl 5-(3-(3-methoxypropoxy)-4- methoxybenzyl)-6-methylhept-2-enoate (25g, 0.068mol) and (DHQD)2PHAL (2.67g, 0.05 m.eq) in THF and followed by the addition of potassium osmate dihydrate (1.26g, 0.05 m.eq). The resulting mixture was stirred at room temperature for 12h before the reaction was quenched with sodium sulfite (68g, 8.0 eq), diluted with water (500ml) and extracted into ethylacetate (2X500ml). The combined organic layers were dried, filtered and concentrated. Crude product was purified by column chromatography using 0.5% -10% MeOH in dichloromethane to obtain title compound. Yield: 20.4g

EXAMPLE 7
Preparation of tert-butyl (lR,2S,4S)-l-(methoxycarbonyl)-4-(3-(3-methoxy propoxy) -4-methoxybenzyl)-1 -hydroxy-5-methy lhexan-2-yIcarbamate To a solution of 20g, (2R,3S,5S)-methyl 5-(3-(3-methoxypropoxy)-4-methoxybenzyl)-3-amino-2-hydroxy-6-methylheptanoate in 1000 ml of ichloromethane there are added dropwise at 0° C 11.7 ml (1.3 eq) of ethyldiisopropylamine and then a solution of 14.3 g (1.3 eq) of di-tert-butyl dicarbonate in 150 ml of dichloromethane. The reaction mixture is stirred for 20 hours at room temperature and then concentrated by evaporation. The title compound is obtained after column chromatography using 30% EtOAc in hexanes as eluent. Yield: 17g

EXAMPLE 8
Preparation of (4S,5R)-3-tert-butyl 5-methyl 4-((S)-2-(3-(3-methoxypropoxy)-
4-methoxybenzyl)-3-methylbutyl)-2,2-dimethyloxazoIidine-3,5-dicarboxylate
2,2-Dimethoxypropane (30.2 ml (8.2 eq)) and p-toluenesulfonic acid (monohydrate) (14.3g (2.5 eq)) are added to 15g of tert-butyl (1R,2S,4S)-1-(methoxycarbonyl)-4-(3 -(3 -methoxypropoxy)-4-methoxybenzyl)-1 -hydroxy-5 -methylhexan-2-ylcarbamate in 4 liters of dichloromethane at room temperature. The reaction mixture was stirred at room temperature for 24 hours and concentrated. The residue obtained was purified by column chromatography using 20% EtOAc in hexanes as eluent to obtain title compound. Yield: 13g

EXAMPLE 9
Preparation of (4S,5R)-tert-butyl 4-((S)-2-(3-(3-methoxypropoxy)-4- methoxybenzyl) -3-methylbutyl)-5-(hydroxymethyI)-2,2-dimethyIoxazolidine- 3-carboxylate
To a solution of (4S,5R)-3-tert-butyl 5-methyl 4-((S)-2-(3-(3-methoxypropoxy)-4-methoxybenzyl)-3-methylbutyl)-2,2-dimethyloxazolidine-3,5-dicarboxylate (20g, 0.037mol) in THF was cooled to 0 °C and added slowly portion wise LiAlFLj (2.1 g, 1.5eq). Stirred the reaction mass for 3h and quenched the reaction mass with saturated sodium sulfate solution. Decanted the THF solution and evaporated the solvent. To the residue was added ethylacetate and washed with water. Ethylacetate layer was evaporated and crude compound was purified by column chromatography using 40% ethyl acetate in hexanes to obtain title compound. Yield: 13.6g

EXAMPLE 10
Preparation of (4S,5R)-tert-butyl 4-((S)-2-(3-(3-methoxypropoxy)-4-
methoxyben zyl)-3-methylbutyl)-5-(bromomethyl)-2,2-dimethyloxazolidine-3-carboxylate

To a solution of (4S,5R)-tert-butyl 4-((S)-2-(3-(3-methoxypropoxy)-4-methoxybenzyl) -3-methylbutyl)-5-(hydroxymethyl)-2,2-dimethyloxazolidine-3-carboxylate (15g, 0.23mol) in dichloromethane (300ml) was added PPI13 (9.25g, 1.2eq) followed by CBr4 (11.7g, 1.2eq) and stirred for 6h. Filtered the reaction mass and water was added, stirred for lh and separated the organic layer and washed with brine and evaporated the solvent. Crude compound was purified by column chromatography by using 10% EtOAc in hexanes to obtain title compound Yield: 13.5g

EXAMPLE 11
Preparation of [(4S,5S)-5-[(2S)-2-[(4R)-4-benzyl-2-oxo-oxazolidine-3-
carbonyl]-3-methyl-butyI]-4-[(2S)-2-[[4-methoxy-3-(3-methoxypropoxy)-
phenyI]methyl]-3-methylbutyl]-2,2-dimethyl-oxazolidin-3-yl]2,2-
dimethylpropanoate

A solution of 21 ml (1.2 eq) of 1M lithium hexamethyl-disilazide was diluted with 100 ml of tetrahydrofuran and cooled to -70° C. Then a solution of 5.47 g (1.2 eq) of 4(R)-benzyl-3-isovaleroyl-oxazolidin-2-one in 50 ml of tetrahydrofuran is added dropwise and the reaction mixture was stirred for a further 75 minutes at -70° C. Then a solution of 10 g of (4S,5R)-tert-butyl 4-((S)-2-(3-(3- methoxypropoxy)-4-methoxybenzyl)-3-methylbutyl)-5-(bromomethyl)-2,2- dimethyloxa zolidine-3-carboxylate in 100 ml of tetrahydrofuran was added drop wise and the temperature of the reaction mixture was allowed to rise from -70° to 0°C over a period of 2 hours. The reaction mixture was stirred for further 18 hours
at 4° C and then while stirring, 25 ml of saturated ammonium chloride solution was added.

Tetrahydrofuran was evaporated off and the residue extracted with ethyl acetate and purified by column chromatography using 50% EtOAc in hexanes as eluent.
Yield: 10.2 g

EXAMPLE 12
Preparation of (S)-2-(((4S,5S)-4-((S)-2-(3-(3-methoxypropoxy)-4-
methoxybenzyl)-3-methylbutyl)-2,2-dimethyl-3-(pivaloyloxy)oxazolidin-5-yl)methyl)-3-methylbutanoic acid
To [(4S,5S)-5-[(2S)-2-[(4R)-4-benzyl-2-oxo-oxazolidine-3-carbonyl]-3-methyl-butyl] -4- [(2 S)-2- [ [4-methoxy-3 -(3 -methoxypropoxy)phenyl]methy 1] -3 -methyl-butyl]-2,2-dimethyl-oxazolidin-3-yl]2,2-dimethylpropanoate (30 g) was added 27 ml of 30% hydrogen peroxide slowly, in 600ml of tetrahydrofuran/water (3:1) at 0° C. After the addition of 1.91 g of lithium hydroxide, the mixture is stirred for 6 hours at 0°-20° C. 300 ml of 1.5M sodium sulfite solution are then added to the reaction mixture at 0°-15° C. and stirring is continued for a further 1 h. 1 liter of saturated sodium hydrogen carbonate solution is added and the tetrahydrofuran is evaporated off. The aqueous solution is washed twice with dichloromethane and then acidified with 2N hydrochloric acid (pH 3.0). Extraction with dichloromethane and subsequent evaporation of the solvent yield the title compound. Yield: 16.8g

EXAMPLE 13
Preparation of Tert-butoxycarbonyl-5(S)-{2-[N-(l-carbamoyl-l-methyl-
ethyl)-carbamoyI]-2(S)-isopropyl-ethyl}-4(S)-{2(S)-isopropyI-3-[4-methoxy-3-
(3-methoxypropyl oxy)-phenyl]-propyl}-2,2-dimethyl-l,3-oxazolidine
10.6 ml of 4-methyl-morpholine, 6.6 g of 2-aminoisobutyric acid amide hydrochloride and 9.1 g of O-benzotriazol-l-yl-N.NjN'^'-tetramethyluronium hexafluorophosphate (HBTU) were added in succession to 11.9 g of 3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-l,3-oxazolidine in 800 ml of dimethylformamide. The reaction mixture was stirred for 8 days at 40° C and therafter concentrated by evaporation and the residue is partitioned between ethyl acetate and saturated sodium chloride solution. The organic phases are concentrated by evaporation and the residue is purified by using dichloromethane/methanol=95:5 as eluent. Yield: 6.8g

EXAMPLE 14
Preparation of 5(S)-Tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-
diisopropyl-8-4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoic acid [N-
(l-carbamoyl-l-methyl-ethyl)]-amide 3-tert-butoxycarbonyl-5(S)-{2-[N-(l-carbamoyl-l-methyl-ethyl)-carbamoyl]-2(S)-isopropyl-ethyl}-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-l ,3-oxazolidine (6g) was added p-toluenesulfonic acid (monohydrate) (365 mg) in 300 ml of methanol at 0°C. The reaction solution was stirred for further 24 hours at room temperature. After evaporation of the solvent, 1.5 lit of saturated sodium hydrogen carbonate solution was added to the residue and extraction is carried out twice with ethyl acetate. The organic extracts are concentrated by evaporation and purified by column chromatography using dichloromethane/methanol=9:l as eluent. Yield: 3.58g

EXAMPLE 15
Preparation of (2S,4S,5S,7S)-7-(3-(3-methoxypropoxy)-4-methoxybenzyl)-5-amino-N-(2-carbamoylpropan-2-yl)-4-hydroxy-2-isopropyI-8-methyI nonanamide hydrochloride
5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S)-7(S)-diisopropyl-8-[4-methoxy-3 -(3 -methoxypropyloxy)-phenyl] -octanoic acid [N-( 1 -carbamoyl-1 -methyl-ethyl)]-amide (3g) was added trifluoroacetic acid (80 ml) in 80 ml of dichloromethane at 0°C. The mixture is stirred for a further lh at 0°C. The reaction mixture was poured onto cooled IN sodium hydroxide and the product is extracted twice with dichloromethane. The organic phases are dried, and ethereal hydrochloric acid was added.

Concentration by evaporation given the title compound. Yield: 1.91g

WE CLAIM
1. A novel process for preparing Aliskiren or its pharmaceutically acceptable salts of Formula I,
which comprises:

a) by protecting compound of Formula II
wherein R represents alkyl and aryl; Pt & P2 represents same or different selected from H, alkyl and aryl.

b) reduction and bromination of compound of Formula III to yield the compound of Formula IV;

c) condensation of compound of Formula IV with a compound of Formula V, in the presence of Organo lithium bases LiHMDS to yield a compound of Formula VI;

d) hydrolysing compound of Formula VI is to give acid of Formula XIV,

using LiOH/H202, which is thereafter condensed with aminoamide of compound of Formula XV,
to give protected Aliskiren of Formula XVI; and

e) deprotection of protected Aliskiren of Formula XVI to give Aliskiren of Formula I and optionally converting in to its pharmaceutically acceptable salts thereof.

2. The process according to claim 2, wherein reduction is carried out using a hydride reducing agent selected from NaBFU/k, Zn(BH4)2/l2, Al(BFLt)3, LiAlFLj, NaCNBH3/H+, Vitride® and bromination is carried out using a brominating agent selected from NBS, PPh3; CBr4, PPI13.

3. The process for preparing compound of Formula II,
with alkyl-3-methylbutanoate of compound of Formula VIII,
wherein R is alkyl, aryl to give a compound of Formula IX,

b) asymmetric hydrogenation of the compound of Formula IX to yield a compound of Formula X,

c) reduction and bromination of compound of Formula X to yield the compound of Formula XI,

d) reacting the compound of Formula XI with a compound of Formula XII,
wherein R is alkyl, aryl using organolithium bases to yield a compound of Formula XIII, and

e) asymmetric aminohydroxylation of compound of Formula XIII to give compound of Formula II.

4. The process according to claim 4, wherein base is selected from amine, metal alkoxide in polar organic solvents.

5. The process according to claim 4, wherein asymmetric hydrogenation is carried out using chiral Ruthenium, Rhodium BINAP hydrogenation catalyst in the presence of H2.

6. The process according to claim 4, wherein reduction is carried out using a hydride reducing agent selected from NaBJVk, Zn(BH4)2/l2, A1(BH4)3, UAIH4, NaCNBH3/H+, Vitride® and bromination is carried out using a brominating agent selected from NBS, PPh3; CBr4, PPI13.

7. The process according to claim 4, wherein organolithium bases is selected from BuLi, LDA, 'BuLi and sec-BuLi.

8. The process according to claim 4, wherein asymmetric aminohydroxylation is carried out using cinchona alkaloids

9. Use of compounds of formula II and IV in the preparation of Aliskiren mi
wherein R represents alkyl and aryl.

wherein Pt & P2 represents same or different selected from H, alkyl and aryl.