Field of the Invention:

The present invention relates to an improved process for the preparation of an orally active renin inhibitor such as (2S,4S,5S,7S)-N-(2-Carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl]-octanamide hemifumarate represented by the following structural formula-la.

Renin is the first enzyme in the renin-angiotensin-aldosterone system which plays a role in blood pressure control. Renin cleaves angiotensinogen to angiotensin I, which is in turn converted by (ACE) to angiotensin II. Angiotensin II has both direct and indirect effects on blood pressure. It directly causes arterial smooth muscle to contract, leading to vasoconstriction and increased blood pressure. Angiotensin II also stimulates the production of aldosterone from the adrenal cortex, which causes the tubles of the kidneys to increase reabsorption of sodium, with water following thereby increasing plasma volume and blood pressure.

Background of the Invention:

(2S,4S,5S,7S)-N-(2-Carbamoyl-2-methylpropyl)-5amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl]-octanamide hemifumarate and its process was first disclosed in US 5559111. The disclosed process involves the deprotection of tert-butyl (3S,5S,6S,8S)-8-(3-amino-2,2-dimethyl-3-oxopropylcarbamoyl)-6-hydroxy-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-2,9-dimethyldecan-5-ylcarbamate with 4N hydrochloric acid in dioxane to provide (2S,4S,5S,7S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl]-octanamide hydrochloride. Further the obtained compound was converted into its fiimarate salt by treating it with fumaric acid.

As the dioxane is toxic and the usage of aqueous hydrochloric acid leading to the formation of amino lactone and aliskiren acid impurities. Hence usages of dioxane as solvent and aqueous hydrochloric acid for deprotection are not suitable on commercial scale up. Therefore there is a need to provide an improved process for the preparation of (2S,4S,5S,7S)-N-(2- carbamoyl-2-methylpropyl)-5amino-4-hydroxy-2,7-diisopropyl-8-[4-inethoxy-3-(3-methoxy propoxy)phenyl]-octanamide hemifumarate which avoids the said difficuhy.

Brief description of the Invention:

The first aspect of the present invention relates to a novel crystalline form of tert-butyl (3S,5S,6S,8S)-8-(3-amino-2,2-dimethyl-3-oxopropylcarbamoyl)-6-hydroxy-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-2,9-dimethyldecan-5-ylcarbamate compound of formula-17 and its process for preparation.

The second aspect of the present invention relates to a novel crystalline form of 3-amino-2,2-dimethylpropanamide compound of formula-16 and its process for preparation.

The third aspect of the present invention provides an improved process for the preparation of (2S,4S)-4-substituted-2-isopropyl-4-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)butanal compound of general formula-B, comprising of oxidizing the (3S,5S)-5-((1S,3S)-1-substituted-3 -(hydroxymethyl)-4-methylpentyl)-3 -isopropyldihydrofuran-2(3 H)-one compound of general formula-A with a suitable oxidizing agent in a suitable solvent.

The fourth aspect of the present invention provides one pot process for the preparation of (2S,4S,5S,7S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl]-octanamide hemifumarate compound of formula-la, comprising of:

a) N-deprotecting tert-butyl (3S,5S,6S,8S)-8-(3-amino-2,2-dimethyl-3-oxopropyl carbamoyl)-6-hydroxy-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-2,9-dimethyldecan-5-ylcarbamate compound of formula-17 with hydrochloric acid gas in a suitable solvent, followed by treating with a suitable base to provide (2S,4S,5S,7S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy) phenyl]-octanamide compound of formula-1,

b) reacting the compound of formula-1 in-situ with fumaric acid in a suitable solvent to provide compound of formula-la.

The fifth aspect of the present invention provides an improved process for the preparation of 3-amino-2,2-dimethylpropanamide compound of formula-16, comprising of:

a) Dimethylating ethyl 2-cyanoacetate compound of fomiula-22 with methyl iodide in presence of a suitable base in a suitable solvent at room temperature for a period of 4-5 hours provides ethyl 2-cyano-2-methylpropanoate compound of formula-23,

b) amidating the compound of formula-23 with ammonia in a suitable solvent at room temperature for a period of 2-3 hours provides 2-cyano-2-methylpropanamide compound of formula-24,

c) reducing the compound of formula-24 in-situ with Raney nickel in presence of ammonia in a suitable solvent under hydrogen pressure of 4 kg at a temperature below 60°C, preferably at room temperature for a period of 4-5 hours provides compound of formula-16.

The sixth aspect of the present invention provides an improved process for the preparation of (2S,4S,5S,7S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl]-octanamide hemifumarate compound of formula-la, comprising of:

a) Reacting 3-methylbutanoic acid compound of formula-2 with (4S)-4-benzyloxazolidin-2-one compound of formula-3 in presence of a suitable condensing agent in a suitable solvent to provide (4S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one compound of formula-4,

b) reacting the compound of formula-4 with (2E)-l,4-dibromobut-2-ene compound of formula-5 in presence of lithiimihexamethyldisilazide in a suitable solvent to provide (2S,7S,4E)-1,8-bis((4S)-4-benzyl-2-oxooxazolidin-3-yl)-2,7-diisopropyloct-4-ene-1,8-dione compound of formula-6,

c) halolactonizing the compound of formula-6 with N-bromosuccinamide in a suitable solvent to provide (4S)-4-benzyl-3-((2S,4R)-4-bromo-2-isopropyl-4-((2S,4S)-4-isopropyl -5-oxotetrahydro furan -2-yl)butanoyl)oxazolidin-2-one compound of formula-7,

d) azidating the compound of formula-7 with sodium azide in presence of tricaprylmethyl ammonium chloride in a suitable solvent to provide (4S)-3-((2S,4S)-4-azido-2-isopropyl-4-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)butanoyl)-4-benzyloxazolidin-2-one compound of formula-8.

e) hydrolyzing the compound of formula-8 with Uthium hydroxide in presence of hydrogen peroxide having below 7.5% by volume w.r.to compound of formula-8 in a suitable solvent, optionally isolating the compound with a suitable hydrocarbon solvent to provide (2S,4S)-4-azido-2-isopropyl-4-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)butanoic acid compound of formula-9 as a solid,

f) optionally, purifying the compound of formula-9 by converting it into its amine addition salts compound of general formula-21, followed by treating with a suitable acid,

g) reacting the compound of formula-9 with alkyl chloroformate in a suitable solvent, followed by reducing with sodium borohydride in a suitable solvent to provide (3S,5S)-5-((1 S,3 S)-1 -azido-3 -(hydroxymethyl)-4-methylpentyl)-3 -isopropyldihydrofuran-2(3H)-one compound of formula-10,

h) oxidizing the compound of formula-10 with a suitable oxidizing agent in a suitable solvent to provide (2S,4S)-4-azido-2-isopropyl-4-((2S,4S)-4-isopropyl-5-oxotetrahydro furan-2-yl)butanal compound of formula-11,

i) reacting the compound of formula-11 with 4-bromo-1-methoxy-2-(3-methoxypropoxy) benzene compound of formula-12 in the presence of alkyl magnesium halide and a suitable base in a suitable solvent to provide (3R,5S)-5-((1S,3S)-1-azido-3-(hydroxy(4-methoxy-3 -(3 -methoxypropoxy)phenyl)methyl)-4-methylpentyl)-3 -isopropyldihydro fiiran-2(3H)-one compound of formula-13,

j) reacting the compound of formula-13 with acetic anhydride in presence of a suitable base in a suitable solvent, followed by reducing with a suitable metal catalyst in a suitable solvent under hydrogen pressure to provide (3R,5S)-5-((1S,3S)-1-amino-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentyl)-3-isopropyldihydrofuran-2(3H)-one compound of formula-14,

k) protecting the amino group of compound of formula-14 with ditertiary butyl dicarbonate in presence of a suitable base in a suitable solvent to provide tert-butyl (1S,3S)-1-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)-3-(4-methoxy-3-(3-methoxypropoxy) benzyl)-4-methylpentylcarbamate compound of formula-15,

1) reacting the compound of formula-15 with 3-amino-2,2-dimethylpropanamide compound of formula-16 in presence of a suitable base in a suitable solvent, optionally isolating the compound with a suitable ether solvent to provide compound of formula-17 as a solid,

m) N-deprotecting tert-butyl (3S,5S,6S,8S)-8-(3-ammo-2,2-dimethyl-3-oxopropyl carbamoyI)-6-hydroxy-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-2,9-dimethyldecan-5-ylcarbamate compound of formula-17 with hydrochloric acid gas in a suitable solvent, followed by treating with a suitable base to provide (2S,4S,5S,7S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy) phenylj-octanamide compound of formula-1,

n) reacting the compound of formula-1 in-situ with flimaric acid in a suitable solvent to provide compound of formula-la.

The seventh aspect of the present invention is to provide an alternative process for the preparation of (2S,4S,5S,7S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3 -(3 -methoxypropoxy)phenyl]-octananiide hemifumarate compound of formula-la, comprising of:

a) Reducing the (3S,5S)-5-((1S,3S)-1-azido-3-(hydroxymethyl)-4-methylpentyl)-3-isopropyldihydrofuran-2(3H)-one compound of formula-10 obtained in step-g) of sixth aspect of the present invention with a suitable metal catalyst in presence of ethanolamine in a suitable solvent imder hydrogen pressure, followed by protecting with ditertiarybutyl dicarbonate in absence of a base in a suitable solvent, optionally isolating the compound with a suitable ether solvent to provide tert-butyl (1S,3S)-3-(hydroxymethyl)-1-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)-4-methylpentylcarbamate compound of formula-18 as a solid,

b) oxidizing the compound of formula-18 with a suitable oxidizing agent in a suitable solvent to provide tert-butyl (1S,3S)-3-formyl-1-((2S,4S)-4-isopropyl-5-oxotetrahydro fiiran-2-yl)-4-methylpentyl carbamate compound of formula-19,

c) reacting the compound of formula-19 with 4-bromo-1-methoxy-2-(3-methoxypropoxy) benzene compound of formula-12 in presence of alkyl magnesium halide and a suitable base in a suitable solvent to provide tert-butyl (1S,3S)-3-(hydroxy(4-methoxy-3-(3-methoxypropoxy)phenyl)methyl)-1-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)-4-methylpentylcarbamate compound of formula-20,

d) reducing the compound of formula-20 with a suitable metal catalyst in a suitable solvent under hydrogen pressure to provide tert-butyl (1S,3S)-1-((2S,4S)-4-isopropyl-5- oxotetrahydrofuran-2-yl)-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentyl carbamate compound of formula-15, e) converting the compound of formula-15 into (2S,4S,5S,7S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy) phenyl]-octanamide hemifumarate compound of formula-la by carrying out the steps-1) to n) of sixth aspect of the present invention.

The eighth aspect of the present invention relates to novel amine salts of (2S,4S)-4-azido-2-isopropyl-4-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)butanoic acid compound of general formula-21 and their process for preparation.

The ninth aspect of the present invention is to provide pure (2S,4S,5S,7S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxy propoxy)phenyl]-octanamide hemifumarate compound of formula-la.

Brief description of the drawings:

Figure-1: Illustrates the X-Ray powder diffraction pattern of crystalline form-M of tert-butyl (3S,5S,6S,8S)-8-(3-amino-2,2-dimethyl-3-oxopropylcarbamoyl)-6-hydroxy-3-(4-methoxy-3-(3- methoxypropoxy)benzyI)-2,9-dimethyldecan-5-ylcarbamate compound of formula-17.

Figure-2: Illustrates X-Ray powder diffraction pattern of crystalline form-N of 3-amino-2,2- dimethylpropanamide compound of formula-16.

Figure-3: Illustrates the DSC thermogram of crystalline form-M of tert-butyl (3S,5S,6S,8S)-8- (3-amino-2,2-dimethyl-3-oxopropylcarbamoyl)-6-hydroxy-3-(4-methoxy-3-(3-methoxypropoxy) benzyl)-2,9-dimethyldecan-5-ylcarbamate compound of formula-17.

Detailed description of the Invention:

As used herein the present invention, the term "suitable solvent" wherever necessary, is selected from "ester solvents" like ethyl acetate, methyl acetate, isopropyl acetate and the like; "ether solvents" like tetrahydrofliran, diethyl ether, diisopropyl ether, methyl tertiary butyl ether and the like; "hydrocarbon solvents" like toluene, n-pentane, hexane, heptane, petroleum ether, cyclohexane and the like; "polar aprotic solvents" like dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide, acetonitrile, N,N'-dimethylpropylene urea (DMPU), triethylamine and the like; "ketone solvents" like acetone, propanone, methyethyl ketone, methyl isobutyl ketone and the like; "alcoholic solvents" like methanol, ethanol, n-propanol, isopropanol, n-butanol, diglycol, isobutanol and the like; "chloro solvents" like dichloromethane, chloroform, carbon tetrachloride, dichloroethane and the like; and "polar solvents" like water; and also mixtures thereof.

The term "suitable base" used herein the present invention is selected from inorganic bases like alkali metal, and alkaline earth metal alkoxides, hydroxides, carbonates and bicarbonates such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, sodixim carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like; and ammonia, and organic bases like triethylamine, tributyl amine, dimethyl aniline, N-methylpiperidine, N-methyl pyrrolidine, N-methyl morpholine, diisopropyl methylamine, diisopropyl amine, diisopropyl ethylamine, cyclohexyldimethyl amine, piperidine, dimethyl amino pyridine, pyridine, 2-hydroxy pyridine and the like; alkyl and aryl lithium such as methyl lithium, n-butyl lithium, s-butyl lithium, t-butyl lithium, phenyl lithium and the like, and also mixtures thereof

The term "suitable coupling agent" herein the present invention is selected from carbodiimides such as N,Nl-diisopropylcarbodiimide (DIC), l-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), N,Nl-dicyclohexylcarbodiimide (DCC); alkyl or aryl chloroformates such as ethyl chloroformates, benzyl chloroformates, para-nitrophenyl chloroformates; 3-hydroxy-3,4-dihydro-l,2,3-benzotriazin-4-one, diethyl phosphoraro cyanidate (DEPC), diphenyl phosphoroazidate (DPPA), P205, 3-(diethoxyphosphoryloxy)-l,2,3-benzotriazine-4(3H)-one (DEPBT), N,N'-carbonyl diimidazole. The carbodiimides can be used optionally in combination with 1-hydroxybenzotriazole (HOBt), l-hydroxy-7-azatriazole (HOAt), l-hydroxy-lH-1,2,3-triazole-4-carboxylate (HOCt), N-hydroxy succinamide (HOSu), (2-(lH-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoro borate (TBTU), dimethylamino pyridine (DMAP). The alkyl or aryl chloroformates can be used optionally in combination with a base.

The term "suitable metal catalyst" herein the present mvention is selected from, but are not limited to Pd, Pt, Pd-C, Pt-C, Ru-C, Rh-C, palladium hydroxide [Pd(0H)2], palladium acetate [Pd(OAc)2], palladium chloride [PdCb], tetrakis(triphenylphosphine)palladium (0) [Pd(PPh3)4], Bis(triphenylphosphine)palladium(II)dichloride [Pd(PPh3)2Cl2], tris(dibenzylideneacetone) dipalladium [Pd2(dba)3], palladium thiomethyl phenylglutaramide, palladium on metal oxide, palladium on zeolites, platinum oxide, rhodium on aliunina and Raney nickel.

The first aspect of the present invention relates to a novel crystalline form of tert-butyl (3S,5S,6S,8S)-8-(3-amino-2,2-dimethyl-3-oxopropylcarbamoyl)-6-hydroxy-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-2,9-dimethyldecan-5-yIcarbamate compound of formula-17, herein designated as crystalline form-M. Further, the crystalline form-M in accordance with the present invention is characterized by its powder XRD pattern having peaks at about 4.3, 8.6, 9.1, 16.7 and 21.7± 0.2 degrees two-theta and substantially as shown in figure-1; by its DSC thermogram showing endotherm at about 143.01°C as shown in figure-3.

The first aspect of the present invention also provides a process for the preparation of crystalline form-M of tert-butyl (3S,5S,6S,8S)-8-(3-amino-2,2-dimethyl-3-oxopropylcarbamoyl)-6-hydroxy-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-2,9-dimethyldecan-5-ylcarbamate compound of formula-17, comprising of:

a) Adding a suitable ether solvent, preferably methyl tertiary butyl ether to tert-butyl (3S,5S,6S,8S)-8-(3-amino-2,2-dimethyl-3-oxopropylcarbamoyl)-6-hydroxy-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-2,9-dimethyldecan-5-ylcarbamate compound of formula-17 at room temperature,

b) stirring the reaction mixture,

c) filtering the solid and drying to get crystalline form-M of compound of formula-17.

The second aspect of the present invention relates to a novel crystalline form of 3-amino-2,2-dimethylpropanamide compound of formula-16, herein designated as crystalline form-N. Further, the crystalline form-N in accordance with the present invention is characterized by its powder XRD pattern having peaks at about 14.4, 16.8, 17.6, 20.2, 20.7, 28.7, 30.0, 30.5 and 38.3± 0.2 degrees two-theta and substantially as shown in figure-2.

The second aspect of the present invention also provides a process for the preparation of crystalline form-N of 3-amino-2,2-dimethylpropanamide compound of formula-16, comprising of:

a) Adding a suitable hydrocarbon solvent, preferably cyclohexane to 3-amino-2,2-dimethyl propanamide compound of formula-16,

b) cooling the reaction mixture to room temperature,

c) stirring the reaction mixture,

d) filtering the solid and then dried to get crystalline form-N of compound of formula-16.

The third aspect of the present invention is to provide an improved process for the preparation of (2S,4S)-4-substituted-2-isopropyl-4-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)butanal compound of general formula-B,

Wherein, R= -N3; Formula-11,

R= -NH-BOC; Formula-19 comprising of oxidizing the (3S,5S)-5-((1S,3S)-1-substituted-3-(hydroxymethyl)-4-methyI pentyl)-3-isopropyldihydrofuran-2(3H)-one compound of general formula-A

Wherein, R= -N3; Formula-10

R= -NH-BOC; Formula-18 with a suitable oxidizing agent in a suitable solvent.

Wherein, the suitable oxidizing agent is selected from oxalyl chloride in combination with dimethyl sulfoxide, and trichloroisocyanuric acid in combination with TEMPO and the like; and the suitable solvent is chloro solvent, preferably dichloromethane.

The fourth aspect of the present invention provides one pot process for the preparation of (2S,4S,5S,7S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl]-octanamide hemifimiarate compound of formula-la, comprising of:

a) N-deprotecting tert-butyl (3S,5S,6S,8S)-8-(3-amino-2,2-dimethyl-3-oxopropyl carbamoyl)-6-hydroxy-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-2,9-dimethyldecan-5-ylcarbamate compound of formula-17 with hydrochloric acid gas in a suitable solvent, followed by treating with a suitable base to provide (2S,4S,5S,7S)-N-(2-carbamoyl-2- methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy) phenyl]-octanamide compound of formula-1, b) reacting the compound of formula-1 in-situ with fumaric acid in a suitable solvent to provide compound of formula-la. Wherein, in step-a) the suitable solvent is chloro solvent, preferably dichloromethane; and the suitable base is inorganic base, preferably sodium carbonate, in step-b) the suitable solvent is chloro solvent, preferably dichloromethane.

US 2008306299 disclosed a process for the preparation of 3-amino-2,2-dimethyl propanamide compound of formula-16. The disclosed process involves the reaction of 2-cyano-2-methyl propanoate with ammonia in methanol provides 2-cyano-2-methyl propanamide, further the obtained compound in-situ reduced with Raney nickel under hydrogen pressure at a temperature of 60-150°C. The reduction at higher temperatures may lead to the formation of impurities. Hence always ambient conditions are preferable, i.e. 25-35°C. Hence the present invention is more advantageous over the prior reported processes.

The sixth aspect of the present invention provides an improved process for the preparation of (2S,4S,5S,7S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl]-octanamide hemifumarate compound of formula-la, comprising of:

a) Reacting 3-methylbutanoic acid compound of forraula-2 with (4S)-4-benzyloxazolidin-2-one compound of formuIa-3 in presence of a suitable condensing agent in a suitable solvent to provide (4S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one compound of formula-4,

b) reacting the compound of formula-4 with (2E)-l,4-dibromobut-2-ene compound of formula-5 in presence of lithium hexamethyl disilazide in a suitable solvent provides (2S,7S,4E)-1,8-bis((4S)-4-benzyl-2-oxooxazolidin-3-yl)-2,7-diisopropyloct-4-ene-1,8-dione compound of formula-6,

c) halolactonizing the compound of formula-6 with N-bromo succinamide in a suitable solvent provides (4S)-4-benzyl-3-((2S,4R)-4-bromo-2-isopropyl-4-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)butanoyl)oxazolidin-2-one compound of formula-7,

d) azidating the compound of formula-7 with sodium azide in presence of tricaprylmethyl ammonium chloride in a suitable solvent provides (4S)-3-((2S,4S)-4-azido-2-isopropyl-4-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)butanoyl)-4-benzyloxazolidin-2-one compound of formula-S,

e) hydrolyzing the compound of formula-8 with lithium hydroxide in presence of hydrogen peroxide having below 7.5% by volume in a suitable solvent, optionally isolating the compound with a suitable hydrocarbon solvent to provide (2S,4S)-4-azido-2-isopropyl-4-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)butanoic acid compound of formula-9 as a solid,

f) optionally, purifying the compound of formula-9 by converting it into its amine addition salt compound of general formula-21, followed by treating with a suitable acid,

g) reacting the compound of formula-9 with alkyl chloroformate in a suitable solvent, followed by reducing with sodium borohydride in a suitable solvent to provide (3S,5S)-5-((1S,3S)-1-azido-3-(hydroxymethyl)-4-methylpentyl)-3-isopropyldihydrofuran-2(3H)-one compound of formula-10,

h) oxidizing the compound of formula-10 with a suitable oxidizing agent in a suitable solvent to provide (2S,4S)-4-azido-2-isopropyl-4-((2S,4S)-4-isopropyl-5-oxotetrahydro fiiran-2-yl)butanal compound of formula-11,

i) reacting the compound of formula-11 with 4-bromo-1-methoxy-2-(3-methoxypropoxy) benzene compound of formula-12 in the presence of alkyl magnesium halide and a suitable base in a suitable solvent provides (3R,5S)-5-((1S,3S)-1-azido-3-(hydroxy(4-methoxy-3-(3-methoxypropoxy)phenyl)methyl)-4-methylpentyl)-3-isopropyldihydro furan-2(3H)-one compound of formula-13,

j) reacting the compound of formula-13 with acetic anhydride in presence of a suitable base in a suitable solvent, followed by reducing with a suitable metal catalyst in a suitable solvent under hydrogen pressure provides (3R,5S)-5-((1S,3S)-1-amino-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentyl)-3-isopropyldihydrofuran-2(3H)-one compound of formula-14,

k) protecting the amino group of compound of formula-14 with ditertiary butyl dicarbonate in presence of a suitable base in a suitable solvent provides tert-butyl (1S,3S)-1-((2S,4S)-

4-isopropyl-5-oxotetrahydrofuran-2-yl)-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentylcarbamate compound of formula-15,

1) reacting the compound of formula-15 with 3-amino-2,2-dimethylpropanamide compound of formula-16 in presence of a suitable base in a suitable solvent, optionally isolating the compound with a suitable ether solvent to provide compound of formula-17 as a solid, m) N-deprotecting tert-butyl (3S,5S,6S,8S)-8-(3-amino-2,2-dimethyl-3-oxopropyl carbamoyl)-6-hydroxy-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-2,9-dimethyldecan-5-ylcarbamate compound of formula-17 with hydrochloric acid gas in a suitable solvent, followed by treating with a suitable base to provide (2S,4S,5S,7S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy) phenylj-octanamide compound of formula-1, n) reacting the compound of formula-1 in-situ with fumaric acid in a suitable solvent to provide compound of formula-la.

Wherein, in step-a) the suitable condensing agent is selected from carbodiimides optionally in combination with HOBt, HO At, HOCt, HOSu, TBTU and DMAP; alkyl or aryl chloroformates optionally in combination with a base; 3-hydroxy-3,4-dihydro-1,2,3-benzotriazin-4-one, DEPC, DPP A, P2O5, DEPBT and GDI, preferably DCC in combination with DMAP; and the suitable solvent is chloro solvent, preferably dichloromethane,

in step-b) the suitable solvent selected from polar aprotic solvent, ether solvent or mixtures thereof, preferably a mixture of DMPU and tetrahydrofuran,

in step-c) the suitable solvent is selected from chloro solvent, polar solvents or mixtures thereof, preferably mixture of water and dichloromethane,

in step-d) the suitable solvent is selected from hydrocarbon solvent, polar solvent or mixtures thereof, preferably mixture of water and toluene,

in step-e) the suitable solvent is selected from ether solvent, polar solvent or mixtures thereof, preferably mixture of water and tetrahydrofuran; the suitable hydrocarbon solvent is selected from toluene, n-pentane, hexane, heptane, petroleum ether, cyclohexane and the like, preferably petroleum ether,

in step-f) the suitable acid is inorganic acid such as hydrochloric acid, hydrobromic acid etc, preferably hydrochloric acid.

in step-g) alkyl chloroformate is selected from ethyl chloroformate, methyl chloroformate and the like; the suitable solvent is chloro solvent, preferably dichloromethane; and the suitable solvent for reduction is ether solvent, preferably tetrahydrofuran,

in step-h) the suitable oxidizing agent and suitable solvent are same as defined in third aspect of the present invention,

in step-i) alkyl magnesium halide is n-butyl magnesium chloride (or) n-butyl magnesium bromide; and the suitable base is organic bases selected from alkyl lithium and aryl lithium, preferably n-butyl lithium; and the suitable solvent is ether solvent, preferably tetrahydrofuran,

in step-j) the suitable base is organic base, preferably a mixture of dimethyl aminopyridine and triethyl amine; the suitable solvent is chloro solvent, preferably dichloromethane; the suitable metal catalyst selected from, but are not limited to Pd, Pt, Pd-C, Pt-C, Ru-C, Rh-C, Pd(0H)2, Pd(0Ac)2, PdCl2, platinum oxide, rhodium on alumina and Raney nickel, preferably Pd-C,

in step-k) the suitable base is organic base, preferably triethylamine; the suitable solvent is chloro solvent, preferably dichloromethane,

in step-1) the suitable base is organic base, preferably 2-hydroxy pyridine; the suitable solvent is polar aprotic solvent, preferably triethylamine; and the suitable ether solvent is selected from tetrahydrofuran, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, preferably methyl tertiary butyl ether,

in step-m) the suitable base is inorganic base, preferably sodium carbonate;

in step-m) and step-n) the suitable solvent is chloro solvent, preferably dichloromethane,

The reaction of compound of formula-4 with compound of formula-5 was described in US 5606078, which was carried out at a temperature of 0°C for a period of 18 hours with a yield of 38%. Whereas, in the present invention the step-(b) of sixth aspect was carried out at a temperature of 0-5°C for a period of 6-8 hours with enhanced yield of 70%.

The azidation of compound of formula-7 with sodium azide to provide compound of formula-8 as described in US 5606078 which was carried out at a temperature of 76°C for a period of 48 hours. Whereas, in the present invention the step-(d) of sixth aspect was carried out at a temperature of 80-85°C for a period of 14-18 hours.

The usage of hydrogen peroxide by 7.5 to 12.5 % by volume for hydrolysis of compound of formula-8 was described in US 5606078. Whereas, in the present invention the step-(e) of sixth aspect was utihzing hydrogen peroxide below 7.5% by volume, preferably 6.5% by volume. Hence based on the above results the present invention is more advantageous over the prior reported processes.

The seventh aspect of the present invention is to provide an alternative process for the preparation of (2S,4S,5 S,7S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl]-octanamide hemifumarate compound of formula-la, comprising of:

a) Reducing the (3S,5S)-5-((1S,3S)-1-azido-3-(hydroxymethyl)-4-methylpentyl)-3-isopropyldihydrofuran-2(3H)-one compound of formula-10 obtained in step-g) of sixth aspect of the present invention with a suitable metal catalyst in presence of ethanolamine in a suitable solvent under hydrogen pressure, followed by protecting with ditertiarybutyl dicarbonate in absence of a base in a suitable solvent, optionally isolating the compound with a suitable ether solvent to provide tert-butyl (1S,3S)-3-(hydroxymethyl)-1-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)-4-methylpentylcarbamate compound of formula-18 as asohd,

b) oxidizing the compound of formula-18 with a suitable oxidizing agent in a suitable solvent to provide tert-butyl (1S,3S)-3-formyl-1-((2S,4S)-4-isopropyl-5-oxotetrahydro furan-2-yl)-4-methylpentylcarbamate compound of formula-19,

c) reacting the compound of formula-19 with 4-bromo-1-methoxy-2-(3-methoxypropoxy) benzene compound of formula-12 in presence of alkyl magnesium halide and a suitable base in a suitable solvent to provide tert-butyl (1S,3S)-3-(hydroxy(4-methoxy-3-(3-methoxypropoxy)phenyl)methyl)-1-((2S,4S)-4-isopropyl-5-oxotetra hydrofuran-2-yl)-4-methylpentylcarbamate compound of formula-20,

d) reducing the compound of formula-20 with a suitable metal catalyst in a suitable solvent under hydrogen pressure to provide tert-butyl (1S,3S)-1-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentyl carbamate compound of formula-15,

e) converting the compound of formula-15 into (2S,4S,5S,7S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy) phenyl]-octanamide hemifumarate compound of formula-la by carrying out the step-1 to step-n of sixth aspect of the present invention. Wherein, in step-a) the suitable solvent is ester solvent, preferably ethyl acetate; the suitable ether solvent is selected from tetrahydrofuran, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, preferably methyl tertiary butyl ether, in step-b) the suitable oxidizing agent and suitable solvent are same as defined in third aspect of the present invention, in step-c) alkyl magnesium halide is n-butyl magnesium chloride (or) n-butyl magnesium bromide (or) isopropyl magnesium chloride; the suitable base is organic base selected from alkyl or aryl lithium, preferably n-butyl lithium; the suitable solvent is ether solvent, preferably tetrahydrofuran, in step-d) the suitable solvent is alcoholic solvent, preferably ethanol.

The suitable metal catalyst used in step-a) and step-d) are same as defined in step-j) of sixth aspect of the present invention.

The reduction of compound of formula-10 as per the process described in US 5606078 was carried out at room temperature for a period of 24 hours. Further the protection of amino group of obtained compound was carried in presence of ethyldiisopropylamine in ethyl acetate at room temperature overnight. Whereas, in the present invention the reduction was carried out only in 5 hours at room temperature by using ethanolamine as a catalyst. Further, the protection of amino group of obtained compound was carried out in absence of a base only in 1 -2 hours.

The obtained compound of formula-la of the present invention can be converted into crystalline form-A of compound of formula-la by isolating the compound from acetonitrile.

The crystalline form-A of compound of formula-la obtained in the present invention can be converted into amorphous form of compound of formula-la using a suitable hydrocarbon solvent selected from cyclohexane, heptane, n-hexane and n-pentane, preferably n-pentane.

Compound of formula-12 of the present invention is commercially available and also can be prepared by the known methods.

The eighth aspect of the present invention relates to novel amine salts of (2S,4S)-4-azido-2-isopropyl-4-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)butanoic acid compound of general formula-21.

Wherein, R-NH2 is selected from methyl amine, tertiary butyl amine and cyclohexylamine.

Further, the eighth aspect of the present invention also provides a process for the preparation of novel amine salts of (2S,4S)-4-azido-2-isopropyl-4-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)butanoic acid compound of general formula-21, comprising of reacting (2S,4S)-4-azido-2-isopropyl-4-((2S,4S)-4-isopropyl-5-oxotetrahydrofiiran-2-yl)butanoic acid compound of formula-9 with a suitable amine in a suitable solvent.

Wherein, the suitable amine is primary amine selected from methyl amine, tertiary butyl amine and cyclohexyl amine; and the suitable solvent is hydrocarbon solvent selected from toluene, n-pentane, hexane, heptane, petroleum ether and cyclohexane, preferably toluene and cyclohexane.

The ninth aspect of the present invention provides a process for the preparation of pure (2S,4S,5S,7S)-N-(2-carbamoyl-2-methylpropyI)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl]-octanamide hemifumarate compound of formula-la, comprising of:

a) N-deprotecting tert-butyl (3S,5S,6S,8S)-8-(3-amino-2,2-dimethyl-3-oxopropyl carbamoyl)-6-hydroxy-3-(4-methoxy-3-(3-methoxypropoxy)benzyI)-2,9-dimethyldecan-5-ylcarbamate compound of formula-17 with hydrochloric acid gas in dichloromethane, followed by treating with potassium carbonate to provide (2S,4S,5S,7S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxy propoxy)phenyl]-octanamide compound of formula-1,

b) extracting the product into ethyl acetate,

c) washing the ethyl acetate layer with sodium carbonate solution,

d) adding a solution of fumaric acid in methanol,

e) isolating the compound from acetonitrile to provide pure compound of formula-1 a.

The following are the details of impurity-D (Aliskiren acid impurity) mentioned in terms of % area, observed in (2S,4S,5S,7S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7- diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl]-octanamide hemifiimarate compound of formula-la before and after base washings, preferably sodium carbonate washings Impurity Before sodium After sodium After acetonitrile carbonate washings carbonate washings isolation Impurity-D (Aliskiren 0.25% 0.11% 0.03% acid impurity)

The amount of impurity-D observed after isolation from acetonitrile without sodium carbonate washings is 0.22 % area.

Differential scanning calorimetric (DSC) analysis was performed with QIO V9.6 Build 290 calorimeter. Samples of about 2 to 3 milligrams, held in a closed pan, were analyzed at a heating rate of 10° per minute.

(2S,4S,5S,7S)-N-(2-carbamoyl-2-methylpropyl)-5-ammo-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl]-octanamide hemifiimarate compound of formula-la obtained by the present invention was analyzed by HPLC under the following conditions; Apparatus: A liquid chromatograph equipped with UV detector; Column: Symmetry shield RP 18, 250 X 4.6mm, 5^m or equivalent; Flow rate: 1.0 ml/mm; Wavelength: 230 nm; Column temperature: 45°C; Injection volimie: 10 ^iL; Run time: 53 min; Diluent: Acetonitrile:water (50:50)v/v; Mobile phase: Buffer: Acetonitrile (70:30) v/v; Mobile phase-B: Acetonitrile:water (90:10) v/v.

PXRD analysis of (2S,4S,5S,7S)-N-(2-carbamoyl-2-methylpropyI)-5-amino-4-hydroxy- 2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl]-octanamide hemifiimarate compound of formula-la and its related compound was carried out using BRUKER/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min.

The particle size distribution of (2S,4S,5S,7S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl]-octanamide hemifiimarate compound of formula-la is measured under the following conditions: Instrument: Malvern Mastersizer 2000; Measuring range: 0.02 to 2000 ^im; Wet sampler: Hydro 2000S; Dispersant: liquid paraffin; Absorption index: 0.1; Refractive Index of dispersant: 1.468; Refractive index of particle: 1.50.

The present invention is schematically represented as follows: Scheme-I:

The possible impurities observed in the synthesis of (2S,4S,5S,7S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyI-8-[4-methoxy-3-(3-methoxypropoxy)phenyl] octanamide hemifiimarate compound of formula-la along with some enantiomeric impurities are represented with their structures as follows:

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention. Examples: Example-1: Preparation of (4S)-4-benzyl-3-(3-methylbutanoyl)oxazolidm-2-one (Formula-4)

A mixture of 3-methylbutanoic acid compound of formula-2 (72 g), dimethylaminopyridine (10 g),(4S)-4-benzyloxazolidin-2-one compound of formula-3 (100 g) and dichloromethane (400 ml) was stirred until to get clear solution, and then added dicyclohexylcarbodiimide (145 g). The reaction mixture was stirred for 10 hours at 10-15°C, and then 8 hours at 25-3 0°C. After completion of the reaction, the reaction mixture was washed with dichloromethane and then treated with 5% hydrochloric acid solution followed by 10% sodium bicarbonate solution. The reaction mixture was further washed with sodium chloride solution and the solvent was completely distilled off to get a residue. Further the residue was isolated using petroleum ether (400 ml) to get title compound as a solid. Yield: 120 g; MR: 49-50°C, [a]D^^= (+) 52 to (+) 56° (C=l% in CHCI3).

Example-2: Alternative process for the preparation of (4S)-4-benzyl-3-(3-methyIbutanoyl) oxazolidin-2-one (Formula-4)

The obtained residue of compound of formula-4 in example-1 was isolated from petroleum ether (380 ml) and dichloromethane (20 ml) to get title compound as a solid. Yield: 120 g; MR: 49-50°C; [a]D"= (+) 52 to (+) 56° (C=l% in CHCI3).

Example-3: Preparation of (2S,7S,4E)-l,8-bis((4S)-4-benzyl-2-oxooxazolidin-3-yI)-2,7-diiso propyloct-4-ene-l,8-dione (Formula-6)

A solution of lithium hexamethyldisilazide (417 ml) was cooled to 0-5°C under nitrogen atmosphere and a solution of (4S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one compound of formula-4 (100 g) and tetrahydrofiiran (300 ml) was added to it at 0-5°C. The reaction mixture was stirred for 2 hours at 0-5°C. DMPU (87 ml), followed by a solution of (2E)-l,4-dibromobut-2-ene compound of formula-5 (36.9 g) and tetrahydrofiiran (100 ml) were added to the reaction mixture and then stirred for 8 hours at 0-5°C. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution and then extracted with methyl tertiary butyl ether. The methyl tertiary butyl ether layer was washed with saturated sodium chloride solution and then distilled off the solvent to get a residue. The residue on cooling gets solidified, filtered the solid and then dried to get title compound.
Yield: 75 g; MR: 110-113 °C; [a]D^^= (+) 48 to (+) 58° (C=l% in CHCI3).

ExampIe-4: Alternative process for the preparation of (2S,7S,4E)-l,8-bis((4S)-4-benzyI-2- oxooxazolidin-3-yl)-2,7-diisopropyloct-4-ene-l,8-dione(FormuIa-6)

A solution of lithium hexamethyldisilazide (350 ml) was cooled to -25 to -20°C under nitrogen atmosphere and a solution of (4S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one compound of formula-4 (100 g) and tetrahydrofuran (300 ml) was added to it at -25 to -20°C. The reaction mixture was stirred for 2 hours at -25 to -20°C. DMPU (87 ml), followed by a solution of (2E)-l,4-dibromobut-2-ene compound of formula-5 (45 g) and tetrahydrofuran (100 ml) were added to the reaction mixture and then stirred for 5 hours at -25 to -20°C. Again a solution of (2E)-l,4-dibromobut-2-ene compound of formula-5 (12.3 g) and tetrahydrofuran (25 ml) was added to the reaction mixture and stirred for 6 hours at -25 to -20°C. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution and then extracted with methyl tertiary butyl ether. The methyl tertiary butyl ether layer was washed with saturated sodium chloride solution and then distilled off the solvent to get a residue. The obtained residue was isolated using methanol solution to get title compound as a solid. Yield: 60 g; MR: 110-113°C; [a]D^^= (+) 48 to (+) 58° (C=l% in CHCI3).

Example-5: Alternative process for the preparation of (2S,7S,4E)-l,8-bis((4S)-4-benzyl-2-oxooxazolidin-3-yI)-2,7-diisopropyloct-4-ene-l,8-dione (FormuIa-6)

A solution of lithiimi hexamethyldisilazide (350 ml) was cooled to -5 to 0°C under nitrogen atmosphere and a solution of (4S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one compound of formula-4 (100 g) and toluene (700 ml) was added to it at -25 to -20°C. The reaction mixture was stirred for 2 hours at -5 to 0°C. DMPU (116 ml), followed by a solution of (2E)-l,4-dibromobut-2-ene compound of formula-5 (41 g) and toluene (300 ml) were added to the reaction mixture and then stirred for 18 hours at -5 to 0°C. After completion of the reaction, the reaction mixture was quenched with saturated sodium chloride solution. Both the toluene and aqueous layers were separated and the toluene layer was distilled off completely to get residue. The obtained residue was isolated fi^om methanol (500 ml) to get title compound as a solid. Yield: 60 g; MR: 110-113°C; [ajo^^ (+) 48 to (+) 58° (C=l% in CHCI3).

Example-6: Preparation of (4S)-4-benzyl-3-((2S,4R)-4-bromo-2-isopropyl-4-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)butanoyl)oxazolidin-2-one (Formula-7)

A mixture of compound of formula-6 (100 g), N-bromosuccinamide (34 g), dichloromethane (500 ml) and water (125 ml) was heated to 30-35°C and stirred for 6 hours at 30-35°C. After completion of the reaction, the solvent from the reaction mixture was distilled off completely to get a residue. The residue was isolated from isopropanol (250 ml) and water (8 ml) to get title compound as a solid.

Yield: 55 g; MR: 91-93°C; [a]D^^= (+) 33 to (+) 39° (C=l% in CHCI3). The said compound can be isolated from methanol, ethanol and aqueous mixtures. Example-7: Preparation of (4S)-3-((2S,4S)-4-azido-2-isopropyl-4-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)butanoyl)-4-benzyloxazolidin-2-one(Forniula-8)

A solution of sodium azide (38.3 g) and water (75 ml) was added to a mixture of (4S)-4-benzyl-3-((2S,4R)-4-bromo-2-isopropyl-4-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)butanoyl) oxazolidin-2-one compound of formula-7 (75 g), tricapryl methyl ammonium chloride (2.95 g) and toluene (675 ml), the reaction reaction mixture was heated to 80-85°C and stirred for 18 hours at same temperature. After completion of the reaction, the reaction mixture was cooled to 25-3 0°C and both the toluene and aqueous layers were separated. The toluene layer was washed with water followed by sodium chloride solution and the solvent from the toluene layer was distilled off completely to get a residue. The obtained residue was fiirther dissolved in methyl tertiary butyl ether (200 ml) and precipitated as a solid by adding n-hexane (200 ml). Filtered the solid and then dried to get title compound. Yield: 39 g; MR; 103-105°C; [a]D"= (+) 36.01 ± 2 (C=l% in CHCI3)

ExampIe-8: (2S,4S)-4-azido-2-isopropyI-4-((2S,4S)-4-isopropyI-5-oxotetrahydrofuran-2-yI) butanoic acid (Formula-9)

30% Hydrogen peroxide (21.5 ml) followed by a solution of (4S)-3-((2S,4S)-4-azido-2-isopropyl-4-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)butanoyl)-4-benzyIoxazolidin-2-one compound of formula-8 (50 g) and tetrahydrofiiran (250 ml) were added to a solution of lithium hydroxide (6.6 g) and water (50 ml) at 0-5°C. The temperature of the reaction mixture was raised to 25-30°C and stirred for 3 hours at the same temperature. After completion of the reaction, the reaction mixture was cooled to 0-5°C and added 10% sodium sulphite solution. The reaction mixture was acidified with 50% hydrochloric acid solution and then product was extracted with ethyl acetate. The solvent from ethyl acetate layer was distilled off completely and added dichloromethane and water to it. Now the reaction mixture was basified with 20% sodium carbonate solution. Both the dichloromethane and aqueous layers were separated, the aqueous layer was acidified with 50% hydrochloric acid solution and the product was extracted into ethyl acetate. Distilled off the solvent from ethyl acetate layer and then co-distilled with toluene to obtain a residue. The obtained residue was isolated from petroleum ether (200 ml) to get title compound as a solid. Yield: 29 g; MR: 56-58°C; [a]D^^= (-) 22 to (-) 27° (C=l%. in DCM).

Example-9: Alternative process for the preparation of (2S,4S)-4-azido-2-isopropyl-4-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)butanoicacid (Formula-9) 30% Hydrogen peroxide (21.5 ml) followed by a solution of (4S)-3-((2S,4S)-4-azido-2-isopropyl-4-((2S,4S)-4-isopropyl-5-oxotetrahydrofiiran-2-yl)butanoyl)-4-benzyloxazolidin-2-one compound of formula-8 (50 g) and tetrahydrofuran (125 ml) were added to a pre cooled solution of lithium hydroxide (6.6 g) and water (50 ml) at 0-5°C and stirred for 30 minutes at 0-5°C. The temperature of the reaction mixture was raised to 20-25°C and stirred for 6 hours at the same temperature. After completion of the reaction, the reaction mixture was cooled to 0-5°C and added 10% sodium sulphite solution followed by water and then dichloromethane. Both the dichloromethane and aqueous layers were separated. The aqueous layer was acidified with 50% hydrochloric acid solution and then extracted with ethyl acetate. Both ethyl acetate and aqueous layers were separated and the solvent from ethyl acetate layer was distilled off completely to get a residue. Cyclohexane was added to the obtained residue and heated to reflux temperature. The reaction mixture was stirred for 3 hours at reflux temperature and the solvent was completely distilled off to get residue. The obtained residue was isolated from petroleum ether (200 ml) to get title compound as a solid. Yield: 28.5 g; MR: 56-58°C

Example-10: Alternative process for the preparation of (2S,4S)-4-azido-2-isopropyl-4-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)butanoic acid (Formula-9)

30% Hydrogen peroxide (21.5 ml) followed by a solution of (4S)-3-((2S,4S)-4-azido-2-isopropyl-4-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)butanoyl)-4-benzyloxazoIidin-2-one compound of formula-8 (50 g) and tetrahydrofuran (75 ml) were added to a pre cooled solution of lithium hydroxide (6.6 g) and water (50 ml) at 0-5°C. The temperature of the reaction mixture was raised to 25-30°C and stirred for 6 hours at the same temperature. After completion of the reaction, the reaction mixture was cooled to 0-5°C and added 10% sodium sulphite solution followed by water. Dichloromethane was added to the reaction mixture and acidified with 50% hydrochloric acid solution. Both dichloromethane and aqueous layers were separated, the aqueous layer was extracted with ethyl acetate. Distilled off the solvent completely from ethyl acetate layer and then co-distilled with toluene.

a) Preparation of (2S,4S)-4-azido-2-isopropyl-4-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran- 2-yI)butanoic acid (Formula-9) through methyl amine salt compound of formula-21a:

Toluene (20 ml) was added to the reaction mixture and the reaction mixture was cooled to 25-30°C. Methylamine (17 ml) was added to the reaction mixture and stirred for 1 V^ hour at 25-30°C. Filtered the solid and washed with toluene. Dissolved the obtained solid in water (250 ml) and dichloromethane (200 ml). The reaction mixture was cooled to 0-5°C and then acidified with hydrochloric acid. Both dichloromethane and aqueous layers were separated and the solvent from dichloromethane layer was distilled off completely to get residue. The obtained residue was isolated from petroleum ether to get title compound as a solid. Yield: 28.5 g; MR: 56-58°C

b) Preparation of (2S,4S)-4-azido-2-isopropyl-4-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran- 2-yl)butanoic acid (Formula-9) through tertiary butyl amine salt (Formula-21b)

Process described in a) was repeated with and tertiary butyl amine (17 ml) instead of methyl amine in toluene (25 ml).Yield: 28.5 g; MR: 56-58°C

c) Preparation of (2S,4S)-4-azido-2-isopropyl-4-((2S,4S)-4-isopropyl-5-oxotetrahydro furan-2-yl)butanoic acid (Formula-9) through cyclohexyl amine salt (Formula-21c)

Process described in a) was repeated with and cyclohexyl amine (17 ml) instead of methyl amine in toluene (250 ml).YieId: 28.5 g; MR: 56-58°C

Example-11: Preparation of (3S,5S)-5-((1S,3S)-1-azido-3-(hydroxymethyI)-4-methylpentyl)-3-isopropyIdihydro furan-2(3H)-one (Formula-10)

Triethylamine (2.8 ml) followed by ethyl chloroformate (1.3 ml) were added to a mixture of (2S,4S)-4-azido-2-isopropyl-4-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)butanoic acid compound of formula-9 (4 g) and dichloromethane (20 ml) at -15 to -10°C and stirred for 30 minutes at -15 to -10°C. After completion of the reaction, water was added to the reaction mixture and both dichloromethane and aqueous layers were separated. The dichloromethane layer was washed with 1% hydrochloric acid solution followed by water and the solvent from dichloromethane layer was distilled off completely and the obtained residue was cooled to 25-30°C. Tetrahydrofuran (20 ml) was added to the residue and then cooled to -15 to -10°C. Sodium borohydride (0.56 g) followed by methanol (0.75 ml) were added to the reaction mixture at -15 to -10°C and stirred for 3 hours at -15 to -10°C. After completion of the reaction, the reaction mixture was quenched with 5% aqueous hydrochloric acid solution and the product was extracted with dichloromethane. The dichloromethane layer was washed with 5% aquoeus sodium carbonate solution followed by sodium chloride solution and then distilled off the solvent to get title compound as a residue. Yield: 3.5 g

ExainpIe-12: Preparation of (2S,4S)-4-azido-2-isopropyl-4-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yI)butanal (Formula-11)

A solution of (3S,5S)-5-((1S,3S)-1-azido-3-(hydroxymethyl)-4-methylpentyl)-3-isopropyldihydrofuran-2(3H)-one compound of formula-10 (12 g) and dichloromethane (48 ml) was added to a mixture of 2,2,6,6-tetramethylpiperidinyloxide (0.015 g), potassium bromide (0.499 g), dichloromethane (72 ml) at -15 to -5°C. p" of sodium hypochlorite solution (32 ml) was adjusted to 9.1 using 10% sodium bicarbonate solution and added to the reaction mixture at -15 to -5°C and stirred for 15 minutes. After completion of the reaction, the reaction mixture was quenched with 10% sodium thiosulfate solution. Both dichloromethane and aqueous layers were separated and the dichloromethane layer was washed with water followed by sodium chloride solution and then distilled off the solvent to get title compound as a residue. Yield: 11.9 g. Exainple-13: Preparation of (2S,4S)-4-azido-2-isopropyl-4-((2S,4S)-4-isopropyl-5-oxotetra hydrofuran-2-yl)butanal (FormuIa-11)

A solution of dimethylsulfoxide (3.5 g) and dichloromethane (5 ml) was added to a solution of oxalyl chloride (3.4 g) and dichloromethane (15 ml) at -75 to -70°C and stirred for 45 minutes at -75 to -70°C. A solution of (3S,5S)-5-((1S,3S)-1-azido-3-(hydroxymethyl)-4-methylpentyl)-3-isopropyldihydrofiiran-2(3H)-one compound of formula-10 (5 g) and dichloromethane (10 ml) was added to the reaction mixture and stirred for 45 minutes at -75 to -70°C. Triethyl amine (8.4 g) was added to the reaction mixture at -75 to -70°C and stirred for 3 hours at the same temperature. After completion of the reaction, the reaction mixture was quenched with sodium thiosulfate solution. Both dichloromethane and aqueous layers were separated, the dichloromethane layer was washed with sodium bicarbonate solution followed by sodium chloride solution and then distilled off the solvent to get title compound as a residue. Yield: 5.0 g.

Example-14: Preparation of (2S,4S)-4-azido-2-isopropyl-4-((2S,4S)-4-isopropyl-5-oxotetra hydrofuran-2-yl)butanaI (FormuIa-11)

A solution of Trichloroisocyanuric acid (1.8 g), potassium bromide (0.084 g) and dichloromethane (10 ml) was cooled to 0-5°C. A solution of (3S,5S)-5-((1S,3S)-1-azido-3-(hydroxymethyl)-4-methylpentyl)-3-isopropyldihydrofuran-2(3H)-one compound of fonnula-10 (2.0 g), dichloromethane (10 ml) and 2,2,6,6-tetramethylpiperidinyloxide (0.033 g) was added to the reaction mixture and stirred for 45 minutes at 0-5°C. After completion of the reaction, the reaction mixture was filtered and filtrate was washed with dichloromethane, followed by 5% sodium bicarbonate, water and sodium chloride solution. Distilled off the solvent fi-om the filtrate under reduced pressure to get title compound. Yield: 1.85 g

Example-15: Preparation of (3R,5S)-5-((1S,3S)-1-azido-3-(hydroxy(4-methoxy-3-(3-methoxy propoxy)phenyI)methyl)-4-methylpentyl)-3-isopropyldihydrofuran-2(3H)-one (Formula-13)

A solution of n-butyl magnesium chloride (8.9 ml) and tetrahydrofuran (7.4 ml) was cooled to 0-5°C and IN n-butyl lithium (5.2 ml) was added to it at 0-5°C. The reaction mixture was stirred for lYi hours at 0-5°C. A solution of 4-bromo-1-methoxy-2-(3-methoxy propoxy)benzene compound of formula-12 (2.0 g) and tetrahydrofuran (7.4 ml) was added to the reaction mixture and stirred for 1 Yz hour at 0-5°C. The reaction mixture was cooled to -80 to -70°C. A pre cooled solution of (2S,4S)-4-azido-2-isopropyl-4-((2S,4S)-4-isopropyl-5-oxotetrahydrofiiran-2-yl)butanal compound of formula-11 (2.0 g) and tetrahydrofuran (7.4 ml) at -80 to -70°C was added to the reaction mixture at -80 to -70°C and stirred for 5-6 hours at the same temperature. After completion of the reaction, the reaction mixture was quenched with 10% acetic acid solution and the product was extracted with toluene. The solvent from the toluene layer was distilled off completely to get title compound. Yield: 0.2 g. £xample-16: Preparation of (3R,5S)-5-((1S,3S)-1-amino-3-(4-methoxy-3-(3-methoxy propoxy)benzyl)-4-methylpentyl)-3-isopropyIdihydrofuran-2(3H)-one(Formula-15)

Preparation of (3R,5S)-5-((1S,3S)-1-amino-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentyl)-3-isopropyldihydrofuran-2(3H)-one compound of formula-15 from (3R,5S)-5-((1 S,3 S)-1 -azido-3-(hydroxy(4-methoxy-3-(3-methoxypropoxy)phenyl)methyl)-4-methylpentyl)-3-isopropyldihydrofuran-2(3H)-one compound of formula-13 proceeding through (3R,5S)-5-((1 S,3 S)-1 -amino-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentyl)-3-isopropyl dihydrofuran-2(3H)-one compound of formula-14 was carried out as per the process described in Journal of medicinal chemistry, 2007, 50 (20), 4832-4844.

Example-17: Preparation of tert-butyl (3S,5S,6S,8S)-8-(3-ainino-2,2-dimethyl-3-oxopropyl carbamoyl)-6-hydroxy-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-2,9-dimethyldecan-5- ylcarbamate (Formula-17)

A mixture of tert-butyl (1S,3S)-1-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentylcarbamate compound of formula-15 (100 g), 3-amino-2,2-dimethyl propanamide compound of formula-16 (65 g), 2-hydroxy pyridine (17.5 g) and triethylamine (100 ml) was heated to 60-65°C and stirred for 60 hours at 60-65°C. After completion of the reaction, distilled off the solvent completely and the reaction mixture was cooled to 25-30°C. Dichloromethane followed by 10% hydrochloric acid were added to the reaction mixture and both dichloromethane and aqueous layers were separated. The dichloromethane layer was washed with 10% hydrochloric acid followed by 10% sodium bicarbonate solution and 10% sodium chloride solution. The solvent from dichloromethane layer was distilled off completely and then co-distilled with methyl tertiary butyl ether. Methyl tertiary butyl ether (500 ml) was added to the obtained residue and stirred for 45 minutes at 25-30°C. Filtered the solid and then dried to get title compound as a solid. Yield: 100 g; MR: 142-145°C The PXRD and DSC of the obtained compound are shown in figure-1 and figure-3 respectively. IR data: 3445, 3340, 1706 and 1170 cm"^

Example-18: Preparation of (2S,4S,5S,7S)-N-(2-carbamoyl-2-methylpropyl)-5-aniino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyI]-octanamide hemifumarate (Formula-la)

Tert-butyl (3S,5S,6S,8S)-8-(3-amino-2,2-dimethyl-3-oxopropylcarbamoyl)-6-hydroxy-3-(4-methoxy-3 -(3 -methoxypropoxy)benzyl)-2,9-dimethyldecan-5-ylcarbamate compound of formula-17 (250 g) was dissolved in dichloromethane (2500 ml) and the reaction mixture was cooled to -15 to -9°C. Hydrochloric acid gas was passed into the reaction mixture at -15 to -9°C and stirred for 1 '/2 hour at the same temperature. Nitrogen gas was purged into the reaction mixture. Both the dichloromethane and aqueous layers were separated and the solvent from dichloromethane layer was distilled off completely to get a residue. The obtained residue was dissolved in ethyl acetate and washed with 10% sodium carbonate solution, followed by water at 5-15°C. A solution of Fumaric acid (23 g) and methanol (750 ml) was added to the organic layer at 5-15° and stirred for 30 minutes at the same temperature. Filtered the reaction mixture, distilled off the solvent completely from the filtrate and then co-distilled with acetonitrile. Acetonitrile (3000 ml) was added to the wet compound at 25-30°C and stirred for 4 hours at 25-30°C. Filtered the solid, washed with acetonitrile and them dried to get title compound. Yield: 200 g; Purity by HPLC: 99.82 %; Impurity-D: 0.03 % by HPLC. Particle Size Distribution: D(O.l) is 10.66 nm; D(0.5) is 90.77 urn; D(0.9) is 234.72 ^m. PXRD of the obtained compound is matching with crystalline form-A of (2S,4S,5S,7S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxy propoxy)phenyl]-octanamide hemifimiarate which is disclosed in WO2008061622. Example-19: Preparation of amorphous form of (2S,4S,5S,7S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy) phenyl]-octanamide hemifumarate (Formula-la)

The wet solid of crystalline form-A of (2S,4S,5S,7S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl]-octanamide hemifumarate compound of formula-la obtained in previous example was dissolved in dichloromethane (125 ml). Filtered the reaction mixture and distilled off the solvent completely from filtrate to get a residue, n-pentane (125 ml) was added to the obtained residue and stirred for 15 minutes. Filtered the solid and then dried to get title compound.

Yield: 13.8 g; MR: 100-105°C; Particle Size Distribution: D(O.l) is 15.03 urn; D(0.5) is 120.14 ^m;D(0.9) is 261.65 ^m

The same experimentation can be carried out with n-hexane, cyclohexane and heptane. PXRD of the obtained compound is matching with amorphous form of (2S,4S,5S,7S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxy propoxy)phenyl]-octanamide hemifumarate which is disclosed in WO2008061622. Example-20: Preparation of tert-butyl (1S,3S)-3-(hydroxymethyI)-1-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)-4-methylpentylcarbamate (Formula-18)

Ethanolamine (1.8 ml) followed by Pd-C (7.2 g) were added to a solution of (3S,5S)-5-((1S,3S)-1-azido-3-(hydroxymethyl)-4-methylpentyl)-3-isopropyldihydrofuran-2(3H)-one compound of formula-10 (18 g) and ethyl acetate (180 ml) at room temperatiire. Hydrogen gas was passed into the reaction mixture at room temperature for 2 hours. After completion of the reaction, filtered the unwanted solid and added ditertiarybutyldicarbonate (18 g) to the filtrate at 25-30°C and stirred for 2 hours. After completion of the reaction, the solvent from reaction mixture was distilled off completely and then co-distilled with methyl tertiary butyl ether to get title compound as a residue. Methyl tertiary butyl ether (36 ml) was added to the obtained residue and the reaction mixture was cooled to 0-5 °C. The reaction mixture was stirred for 1 hour at 0-5°C. Filtered the solid and then dried to get title compound. Tield: 16g;MR: 124-129°C.

Example-21: Preparation of tert-butyl (1S,3S)-3-formyl-1-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)-4-methylpentyIcarbamate (Formula-19)

Preparation of tert-butyl (1S,3S)-3-formyl-1-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)-4-methylpentylcarbamate was carried out in analogous manner to example-12 using tert-butyl (1 S,3 S)-3 -(hydroxymethyl)-1 -((2 S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)-4-methyl pentylcarbamate compound of formula-18 (15 g) instead of (3S,5S)-5-((1S,3S)-1-azido-3-(hydroxymethyl)-4-methylpentyl)-3-isopropyldihydrofuran-2(3H)-one compound of formula-10. The obtained residue was isolated from n-pentane (30 ml). Yield: 12 g.

Example-22: Preparation of tert-butyl (1S,3S)-3-formyI-1-((2S,4S)-4-isopropyI-5-oxotetraliydrofuran-2-yl)-4-methylpentyIcarbamate(Formula-19)

Preparation of tert-butyl (1S,3S)-3-formyl-1-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)-4-methylpentylcarbamate was carried out in analogous manner to example-13 using tert-butyl (1 S,3 S)-3 -(hydroxymethyl)-1 -((2 S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)-4-methyl pentylcarbamate compound of formula-18 (5 g) instead of (3S,5S)-5-((1S,3S)-1-azido-3-(hydroxymethyl)-4-methylpentyl)-3-isopropyldihydrofuran-2(3H)-one compound of formula-10. The obtained residue was isolated from petroleum ether to get title compound as a solid. Yield: 4.2 g;

Example-23: Preparation of tert-butyl (1S,3S)-3-formyl-1-((2S,4S)-4-isopropyl-5-oxotetra hydrofuran-2-yl)-4-methyIpentylcarbamate(Formula-19)

Preparation of tert-butyl (1S,3S)-3-formyl-1-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)-4-methylpentylcarbamate was carried out in analogous manner to example-13 using tert-butyl (1 S,3 S)-3-(hydroxymethyl)-1 -((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)-4-methyl pentylcarbamate compound of formula-18 (2 g) instead of (3S,5S)-5-((1S,3S)-1-azido-3-(hydroxymethyl)-4-methylpentyl)-3-isopropyldihydrofuran-2(3H)-one compound of formula-10. Yield: 1.85 g.

ExampIe-24: Preparation of tert-butyl (1S,3S)-3-(hydroxy(4-methoxy-3-(3-inethoxy propoxy)phenyl)methyl)-1-((2S,4S)-4-isopropyI-5-oxotetrahydrofuran-2-yl)-4-methylpentyI carbamate (Formula-20)

A solution of 4-bromo-1-methoxy-2-(3-methoxypropoxy)benzene compound of formula-12 (2.0 g) and tetrahydrofiiran (12.5 ml) was cooled to -75 ro -80°C and then added n-butyl lithium (5.7 ml).Isopropyl magnesium chloride (4.0 ml) was added to the reaction mixture at -75 to -80°C and stirred for 20 minutes. The temperature of the reaction mixture was raised to 25-30°C and stirred for 2 hours at 25-30°C. Now the reaction mixture was cooled to -30 to -30°C and a solution of Tert-butyl (1S,3S)-3-formyl-1-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)-4-methylpentyl carbamate compound of formula-19 (2.6 g) and teatrahydrofiiran (12.5 ml) was added to it. The reaction mixture was stirred for 5 hours at -15 to -20°C and then quenched with 10% hydrochloric acid solution. Both the tetrahydrofiiran and aqueous layers were separated and the tetrahydrofiiran layer was washed with water and then distilled off the solvent to get the title compound as a residue. Yield: 2.2 g.

Example-25: Preparation of tert-butyl (1S,3S)-1-((2S,4S)-4-isopropyl-5-oxotetrahydro furan-2-yl)-3-(4-methoxy-3-(3-methoxypropoxy)benzyI)-4-methyIpentyIcarbamate (Formula-15)

Tert-butyl (1S,3S)-3-(hydroxy(4-methoxy-3-(3-methoxypropoxy)phenyl)methyl)-1- ((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)-4-methylpentylcarbamatecompound of formula-20 (2.0 g) was dissolved in ethanol (20 ml). A slurry of palladium-carbon was prepared from palladium carbon (2.0 g) with water and added to the reaction mixture, followed by acetic acid (10 ml). Hydrogen gas was passed into the reaction mixture and heated to 65-75°C. After completion of the reaction, filtered the reaction mixture through hyflow bed and washed with ethanol. Distilled off the solvent from the filtrate and methyl tertiary butyl ether was added to it. Petroleum ether was added to the reaction mixture and stirred for 60 minutes at 25-30°C. The reaction mixture was cooled to 0-5°C. Filtered the reaction mixture, washed with petroleum ether and then dried to get title compound as a solid. Yield: 1.6 g Example-26: Preparation of Ethyl 2-cyano-2-methyIpropanoate (Formula-23)

Methyl iodide (762.2 grams) was added to dimethyl formamide (750 ml) pre-cooled at 0-10°C, followed by potassium carbonate (1069.0 grams) and Ethyl 2-cyano acetate compound of formula- 22 (250 grams) at 0-20°C. Temperature of the reaction mixture was raised to 20-25°C and stirred for 5 hours. After completion of the reaction, methyl tertiary butyl ether was added to the reaction mixture and stirred for 15 minutes at 20-25°C. Filtered the reaction mixture, water was added to the obtained filtrate and p" was adjusted to below 2.0 using 10% aqueous hydrochloric acid solution. Both organic and aqueous layers were separated. Organic layer was washed with 10% sodium thiosulfate solution followed by water. Distilled off the solvent completely from the organic layer to get the title compound as a residue. Yield: 293.0 g; purity by GC: 93.41% Example-27: Preparation of 2-cyano-2-niethylpropananiide (Formula-24)

Ethyl 2-cyano-2-methylpropanoate compound of formula-23 (75 g) was added to methanolic ammonia solution (prepared by passing ammonia gas into pre-cooled methanol solution (750 ml) at 10-15°C until assay gets about 10%) and the reaction mixture was stirred for 3 hours at 25-30°C. The reaction mixture containing 2-cyano-2-methylpropanamide compound of formula-23 was taken to next step without isolation. Example-28: Preparation of 3-amino-2,2-dimethylpropanamide (Formula-16)

The reaction mixture obtained in example-27 containing 2-cyano-2-methylpropanamide compound of formula-24 was taken into stainless steel vessel. A mixture of Raney nickel (39.4 g) and methanol (37.5 ml) was added to the reaction mixture. Hydrogen gas having a pressure of 4 kg was passed into the reaction mixture and stirred for 5 hours at 25-30°C. Filtered the reaction mixture through hy-flow bed, distilled off the solvent completely from the filtrate and the reaction mixture was cooled to 25-30°C. Isopropyl alcohol was added to the reaction mixture, heated the reaction mixture to 45-50°C and stirred for 15 minutes at 45-50°C. FiUered the reaction mixture through hy-flow bed and distilled off the solvent completely from the filtrate and then co-distilled with cyclohexane. Cyclohexane (150 ml) was added to the reaction mixture and stirred for 1 hour at 25-3 0°C. FiUered the solid and then dried to get title compound as a solid. Yield: 47 g; MR: 71-75°C; Purity by GC: 99.54%. The PXRD of the obtained compound is shown in figure-2. IR data: 3391 and 1658 cm''.

We Claim:

1. A crystalline form-M of tert-butyl (3S,5S,6S,8S)-8-(3-amino-2,2-dimethyl-3-oxopropyl carbamoyl)-6-hydroxy-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-2,9-dimethyldecan-5- ylcarbamate compound of formula-17 characterized by

a) its powder X-ray diffractogram having peaks at about 4.3, 8.6, 9.1, 16.7 and 21.7± 0.2 degrees two-theta as illustrated in figure-1,

b) its DSC thermogram showing endotherm at 143.01°C as illustrated in figure-3.

2. A crystalline form-N of 3-amino-2,2-dimethylpropanamide compound of formula-16 characterized by its X-ray powder diffractogram having peaks at about 14.4, 16.8, 17.6, 20.2, 20.7, 8.7, 30.0, 30.5 and 38.3± 0.2 degrees two-theta as illustrated in figure-2.

3. An improved process for the preparation of (2S,4S)-4-substituted-2-isopropyl-4-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)butanal compound of general formula-B,
Where in, R= -N3; Formula-11; R= -NH-BOC; Formula-19 comprising of oxidizing the (3S,5S)-5-((1S,3S)-1-substituted-3-(hydroxymethyl)-4-methyl pentyl)-3-isopropyldihydrofuran-2(3H)-one compound of general formula-A

Wherein, R= -N3; Formula-10; R= -NH-BOC; Formula-18 with oxlayl chloride in combination with dimethyl sulfoxide, and/or trichloro isocyanuric acid in presence of TEMPO in a suitable solvent. 4. One pot process for the preparation of (2S,4S,5S,7S)-N-(2-carbamoyl-2-methylpropyl)-5- amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl]-octanamide hemifiimarate compound of formula-la, comprising of:

a) N-deprotecting the compound of formula-17 with hydrochloric acid gas in a suitable chloro solvent preferably dichloromethane, followed by treating with a suitable inorganic base, preferably sodium carbonate to provide (2S,4S,5S,7S)-N-(2-carbamoyl-2-methyl propyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy) phenyl]-octanamide compound of formula-1, b) reacting the compound of formula-1 in-situ with fumaric acid in a suitable chloro solvent, preferably dichloromethane to provide compound of formula-la. 5. An improved process for the preparation of (2S,4S,5S,7S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl]-octanamide hemifumarate compound of formula-la, comprising of:

a) Reacting 3-methylbutanoic acid compound of formula-2 with (4S)-4-benzyloxazolidin-2-one compound of formula-3 in presence of a suitable condensing agent selected from carbodiimides optionally in combination with HOBt, HOAt, HOCt, HOSu, TBTU and DMAP; alkyl or aryl chloroformates optionally in combination with a base; 3-hydroxy-3,4-dihydro-l,2,3-benzotriazin-4-one, DEPC, DPP A, P2O5, DEPBT and GDI, preferably DCC in combination with DMAP in a suitable solvent, provides (4S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one compound of formula-4,

b) reacting the compound of formula-4 with (2E)-l,4-dibromobut-2-ene compound of formula-5 in presence of lithium hexamethyldisilazide in a suitable solvent selected from ether solvent, polar aprotic solvent and mixture thereof, provides (2S,7S,4E)-1,8-bis((4S)-4-benzyl-2-oxooxazolidin-3-yl)-2,7-diisopropyloct-4-ene-1,8-dione compound of formula-6,

c) halolactonizing the compound of formula-6 with N-bromo succinamide in a suitable solvent selected from chloro solvent, polar solvent and mixture thereof, provides (4S)-4-benzyl-3-((2S,4R)-4-bromo-2-isopropyl-4-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)butanoyl)oxazolidin-2-one compound of formula-7,

d) azidating the compound of formula-7 with sodium azide in presence of tricaprylmethyl ammonium chloride in a suitable solvent selected from hydrocarbon solvent, polar solvent and mixture thereof, provides (4S)-3-((2S,4S)-4-azido-2-isopropyl-4-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)butanoyl)-4-benzyloxazolidin-2-one compound of formula-8,

e) hydrolyzing the compound of formula-8 with lithium hydroxide in presence of hydrogen peroxide having below 7.5% by volume w.r.to the compound of formula-8 in a suitable solvent selected from ether solvent, polar solvent and mixture thereof, optionally isolating the compound using hydrocarbon solvent, preferably petroleum ether provides (2S,4S)-4-azido-2-isopropyl-4-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)butanoic acid compound of formula-9 as a solid,

f) optionally, purifying the compound of formula-9 by converting it into its amine addition salt compound of general formula-21, followed by treating with a suitable acid,

g) reacting the compound of formula-9 with alkyl chloroformate such as ethyl chloroformate or methyl chloro formate in a suitable chloro solvent preferably dichloromethane, followed by reducing with sodium borohydride in a suitable ether solvent, preferably tetrahydrofiiran provides (3S,5S)-5-((1S,3S)-1-azido-3-(hydroxyl methyl)-4-methylpentyl)-3-isopropyldihydrofiiran-2(3H)-one compound of formula-10,

h) oxidizing the compound of formula-10 with a suitable oxidizing agent selected from oxlayl chloride in combination with dimethyl sulfoxide, and/or trichloroisocyanuric acid in presence of TEMPO in a suitable solvent to provide (2S,4S)-4-azido-2-isopropyl-4-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)butanal compound of formula-11,

i) reacting the compound of formula-11 with 4-bromo-1-methoxy-2-(3-methoxypropoxy) benzene compound of formula-12 in the presence of alkyl magnesium halide such as n-butyl magnesium bromide or n-butyl magnesium chloride and a suitable base selected from alkyl lithium and aryl lithium, preferably n-butyl lithium in a suitable ether solvent, preferably tetrahydrofiiran provides (3R,5S)-5-((1S,3S)-1-azido-3-(hydroxy(4-methoxy-3-(3-methoxypropoxy)phenyl)methyl)-4-methylpentyl)-3-isopropyldihydro furan-2(3H)-one compound of formula-13,

j) reacting the compound of formula-13 with acetic anhydride in presence of a suitable base selected from organic base, preferably a mixture of dimethylamino pyridine and triethylamine, followed by reducing with a suitable metal catalyst selected from Pd, Pt, Pd-C, Pt-C, Ru-C, Rh-C, Pd(0H)2, Pd(OAc)2, PdCla, platinum oxide, rhodium on alvmiina and Raney-Ni, preferably Pd-C in a suitable alcoholic solvent, preferably ethanol under hydrogen pressure to provide (3R,5S)-5-((1S,3S)-1-amino-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentyl)-3-isopropyldihydrofuran-2(3H)-one compound of formula-14,

k) protecting the amino group of compound of formula-14 with ditertiary butyl dicarbonate in presence of a suitable organic base, preferably triethylamine in a suitable chloro solvent, preferably dichloromethane provides tert-butyl (1S,3S)-1-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentyl carbamate compound of formula-15,

1) reacting the compound of formula-15 with 3-amino-2,2-dimethylpropanamide compound of formula-16 in presence of a suitable organic base, preferably 2-hydroxypyridine in a suitable polar aprotic solvent, preferably triethylamine, optionally isolating the compound using a suitable ether solvent, preferably methyl tertiary butyl ether provides compound of formula-17 as a solid,

m) N-deprotecting the obtained compound of formula-17 with hydrochloric acid gas in a suitable chloro solvent, preferably dichloromethane, followed by treating with a suitable inorganic base, preferably sodium carbonate provides (2S,4S,5S,7S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy) phenylj-octanamide compound of formula-1,

n) reacting the compound of formula-1 in-situ with fumaric acid in a suitable chloro solvent preferably dichloromethane to provide compound of formula-la.

6. A process for preparation of crystalline form-N of 3-amino-2,2-dimethylpropanamide compound of formula-16, comprising of:

a) Reducing the 2-cyano-2-methylpropanamide compound of formula-23 with Raney-Ni in presence of ammonia in a suitable alcoholic solvent under hydrogen pressure of 4 kg at a temperature of below 60°C, preferably at room temperature for a period of 4-5 hours to provide 3-amino-2,2-dimethylpropanamide compound of formula-16,

b) isolating the compound obtained from step-a) from cyclohexane to provide crystalline form-N of 3-amino-2,2-dimethylpropanamide compound of formula-16.

7. A process for preparation of 2-cyano-2-methylprpoanamide compound of fonnula-23, comprising of:

a) Dimethylating Ethyl 2-cyanoacetate compound of formula-21 with methyl iodide in presence of potassium carbonate in dimethylformamide at room temperature for a period of 4-5 hours to provide Ethyl 2-cyano-2-methylpropanoate compound of formula-22,

b) amidating the compound of formula-22 with ammonia in methanol at a room temperature for a period of 2-3 hours to provide compound of formula-23.

8. A process for preparation of tert-butyl (1S,3S)-3-(hydroxymethyl)-1-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)-4-methylpentyI carbamate compound of formula-18, comprising of reducing the (3S,5S)-5-((1S,3S)-1-azido-3-(hydroxymethyl)-4-methylpentyl)-3-isopropyl dihydrofuran-2(3H)-one compound of formula-10 with Pd-C in presence ethanolamine in ethyl acetate under hydrogen pressure at room temperature for a period of 4-5 hours, followed by protecting with ditertiarybutyl dicarbonate in absence of a base in ethyl acetate at room temperature for a period of 1-2 hours to provide compound of formula-18.

9. A process for preparation of pure compound of formula-1 a, comprising of:

a) N-deprotecting tert-butyl (3S,5S,6S,8S)-8-(3-amino-2,2-dimethyl-3-oxopropyl carbamoyl)-6-hydroxy-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-2,9-dimethyldecan-5-ylcarbamate compound of formula-17 with hydrochloric acid gas in dichloromethane, followed by treating with potassium carbonate to provide (2S,4S,5S,7S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxy propoxy)phenyl]-octanamide compound of formula-1,

b) extracting the product into ethyl acetate,

c) washing the ethyl acetate layer with sodium carbonate solution,

d) adding a solution of fumaric acid in methanol,

e) isolating the compound from acetonitrile to provide pure compound of formula-1 a.

10. A compound of general formula-21

Wherein, R-NH2 is selected from methyl amine, tertiary butyl amine and cyclohexylamine.