FIELD OF THE INVENTION

The present invention relates to a novel process for preparing a compound of Formula I, which is 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® in its hemifumarate salt, as an oral tablet with different dosage forms.

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, WO 2006/095020, WO 2007/054254, WO 2007/048620, WO 2007/118681, WO 2010/010165, WO 2007/006532, WO 2007/045420, WO 2008/155338, WO 2008/119804, WO 2009/049837; 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 1 958 666, 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 I, 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 I,
which comprises,
a) reacting a compound of Formula III, with a compound of Formula IV, HC(OR)3
wherein R is alkyl, aryl preparing Grignard reagent in polar aprotic solvents with stoichiometric quantity of magnesium metal to give a compound of Formula V;
b) reacting compound of Formula V with a compound of Formula VI,
to give a compound of Formula VII;
c) hydrolyzing the compound of Formula VII in the presence of base to give a compound of Formula VIII;
d) Sharpless asymmetric dihydroxylation of compound of Formula VIII to give a compound of Formula I; and
e) isolating the compound of Formula I.
In another embodiment of the present invention, also relates to a process for preparing Aliskiren of Formula II,
or its pharmaceutically acceptable salts thereof, using the compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a novel process for preparing a compound of Formula I,
which comprises, reacting a compound of Formula III with a compound of Formula IV by preparing Grignard reagent using magnesium in polar aprotic solvents to give a compound of Formula V, which is reacted with compound of Formula VI using NaH, LiH (or) NaOH, KOH to give compound of Formula VII.

Hydrolysis of compound of Formula VII in the presence of a base selected from NaOH, LiOH, H202 to give a compound of Formula VIII, which is subjected to asymmetric dihydroxylation using Sharpless asymmetric dihydroxylation or provost dihydroxylation to give a compound of Formula I.

In another embodiment the present invention also relates to a process for preparing compound of Formula VI,

which comprises:

a) reacting a compound of Formula IX, with 1,2-dibromoethane in the presence of organolithium bases in polar aprotic solvents, to give a compound of Formula X;
b) treating the compound of Formula X with triphenyl phosphene to give the compound of Formula VI; and
c) isolating the compound of Formula VI.
The present invention also relates to a process for preparing Aliskiren or its pharmaceutically acceptable salts thereof, which comprises: a) activating the hydroxyl group of compound of Formula I, to give compound of Formula XI; wherein X represents mesyl, tosyl.
b) azidation and hydrogenation of compound of Formula XI to give a compound of Formula XII;
c) optionally protecting the amino group of compound of Formula XII to give a compound of formula XIII wherein P represents BOC, Cbz, Bn
d) reacting the compound of Formula XIII with aminoamide of Formula XIV, to give a compound of Formula XV;
wherein P represents BOC, Cbz, Bn
e) deprotection of compound of Formula XV to give Aliskiren of Formula II; and
f) optionally converting Aliskiren of Formula II 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 activating the hydroxyl group of compound of Formula X to give a compound of Formula XI using MsCl, triethylamine (or) TsCl, triethylamine (or) pyridine which is azidated using NaN3 and thereafter hydrogenated using H2, Pd-C to give a compound of Formula XII.

Protection of the compound of Formula XII using using BOC20, BnBr, BnCl, CbzCl to give a compound of Formula XIII, which is reacted with amino amide of Formula XIV to give a compound of Formula XV.

Deprotection of compound of Formula XV using acids such as HC1, TFA, HCOOH and HCOONH4, H2, Pd-C furnishes Aliskiren of Formula II.

WE CLAIM

1. A novel process for preparing a compound of Formula I, which comprises,
a) reacting a compound of Formula III, wherein R is alkyl, aryl preparing Grignard reagent in polar aprotic solvents with stoichiometric quantity of magnesium metal to give a compound of Formula V;
b) reacting compound of Formula V with a compound of Formula VI, to give a compound of Formula VII;
c) hydrolyzing the compound of Formula VII in the presence of base to give a compound of Formula VIII;
d) Sharpless asymmetric dihydroxylation of compound of Formula VIII to give a compound of Formula I; and
e) isolating the compound of Formula I.

2. The process according to claim 1, compound of Formula V is reacted with compound of Formula VI using NaH, LiH (or) NaOH, KOH to give compound of Formula VII.

3. The process according to claim 1, wherein Hydrolysis of compound of Formula VII in the presence of a base selected from NaOH, LiOH, H2O2 to give a compound of Formula VIII

4. The process according to claim 1, wherein asymmetric dihydroxylation using Sharpless asymmetric dihydroxylation or provost dihydroxylation to give a compound of Formula I.

5. A process for preparing Aliskiren or its pharmaceutically acceptable salts from compound of formula I, prepared according to claim 1.