FIELD OF THE INVENTION

The present invention relates to a novel process for preparing a compound of Formula II,
which is a useful intermediate in the preparation of Aliskiren.

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, as hemifumarate salt.

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 a compound of Formula II, which is an useful intermediate in the preparation of Aliskiren and its pharmaceutically acceptable salts.

In yet another objective of the present invention is to provide novel intermediates, which are useful in the preparation of Aliskiren and its pharmaceutically acceptable salts.

SUMMARY OF THE INVENTION

The present invention relates to a novel process for preparing a compound of Formula II,
which comprises,
a) reacting a compound of Formula III,
with alkyl-acrylate of compound of Formula IV,
wherein R is alky I, aryl using organolithium bases LiHMDS, BuLi, LDA, 'BuLi and sec-BuLi in polar aprotic solvents to give a compound of Formula V;
b) asymmetric epoxidation of the compound of Formula V using Sharpless or Shi asymmetric epoxidation to give a compound of Formula II; and
c) isolating the compound of Formula II.
In another embodiment of the present invention, also relates to a process for preparing Aliskiren of Formula I,
or its pharmaceutically acceptable salts thereof, using the compound of Formula II.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a novel process for preparing a compound of Formula II,
which comprises, reacting a compound of Formula HI with alkyl-acrylate of compound of Formula IV using organolithium bases selected from BuLi, LDA, lBuLi and sec-BuLi in polar aprotic solvents to give a compound of Formula V, which is epoxidised using Sharpless or Shi asymmetric epoxidation to give a compound of Formula II.

The present invention also relates to a process for preparing Aliskiren or its pharmaceutically acceptable salts thereof, which comprises: a) condensation of Formula II,
with a compound of Formula VI,
in the presence of organo Lithium base to give a compound of Formula VII,
b) reductive animation of compound of Formula VII using NH4OAc, NaCNBH4, NaBH(OAc)3, in alcoholic solvents (or) organic acid solvents (or) Benzylamine, CbzNH2, BOCNH2, Ti(OPr)4, PMHS to give a compound of Formula VIII;
c) protecting the amino and amino hydroxyl group to give compound of Formula VIII, to give compound of Formula IX;
wherein Pi & P2 represents same or different selected from H, alkyl & aryl
d) hydrolysis of compound of Formula IX using LiOH and H2O2 to give a compound of Formula X;
e) optionally converting the compound of Formula X in to Aliskiren of Formula I or 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 condensation of compound of Formula II with a compound of Formula VI in the presence of organo Lithium base selected from LiHMDS, BuLi, LDA, 'BuLi and sec-BuLi (or) T1CI3, T1CI4, ZnCb to give compound of Formula VII, which is reductive aminated using NH4OAc, NaCNBH4, NaBH(OAc)3, NaBItyfc, Zn(BH4)2/l2„ A1(BH4)3, LiAlH4 and NaCNBH3/H+ and Vitride® in alcoholic solvents (or) organic acid solvents (or) Benzylamine, CbzNFL:, BOCNH2, Ti(OPr)4, PMHS to give compound of Formula VIII optionally protecting the amino group using BOC2O, BnBr, BnCl, CbzCl and finally protecting the amino hydroxyl groups in compound of Formula VIII using a protecting agent selected from dimethoxy propane (or) acetone, benzaldehyde with a acid catalyst to give a compound of Formula IX, which is hydrolysed using LiOH, H2O2 to give a compound of Formula X.

The compound of Formula X is condensed with aminoamide of compound of Formula XI,
to give protected Aliskiren of Formula XVI.

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

WE CLAIM

1. A novel process for preparing a compound of Formula II, which comprises,
a) reacting a compound of Formula III,
with alkyl-acrylate of compound of Formula IV,
wherein R is alkyl, aryl
using organolithium bases LiHMDS, BuLi, LDA, lBuLi and sec-BuLi in polar aprotic solvents to give a compound of Formula V;
b) asymmetric epoxidation of the compound of Formula V using Sharpless or Shi asymmetric epoxidation to give a compound of Formula II; and
c) isolating the compound of Formula II.

2. The process according to claim 1, wherein asymmetric epoxidation is carried out using Sharpless or Shi asymmetric epoxidation.

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

a) preparing compound of formula II using the process as claimed in claim 1

b) condensation of Formula II, with a compound of Formula VI, in the presence of organo Lithium base to give a compound of Formula VII,

c) reductive amination of compound of Formula VII using NFLjOAc, NaCNBH4, NaBH(OAc)3) in alcoholic solvents (or) organic acid solvents (or) Benzylamine, CbzNH2, BOCNH2) Ti(OPr)4, PMHS to give a compound of Formula VIII;

d) protecting the amino and amino hydroxyl group to give compound of Formula VIII, to give compound of Formula IX; wherein Pi & P2 represents same or different selected from H, alkyl & aryl

f) hydrolysis of compound of Formula IX using LiOH and H2O2 to give a compound of Formula X;

g) optionally converting the compound of Formula X is converted to Aliskiren of Formula I or its pharmaceutically acceptable salts thereof comprises, condensing compound of formula X with aminoamide of compound of Formula XI to give protected Aliskiren of Formula XVI. deprotection of protected Aliskiren of Formula XII to give Aliskiren of Formula I and optionally converted in to its pharmaceutically acceptable salts thereof.

4. The process according to claim 3, wherein organo Lithium base selected from
LiHMDS, BuLi, LDA, 'BuLi and sec-BuLi (or) TiCl3, TiCl4, ZnCl2.

5. Use of compound of formula II in the preparation of Aliskiren