Field of the Invention:

The present invention relates to a 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 compound of formula-1 or its salt thereof.

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:

The process for the preparation of renin inhibitors have been reported in US 5559111. (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 and its pharmaceutically acceptable salts are potent in these class of drugs. It is very complex molecule having a number of chiral centers. Hence it involves the synthesis and condensation of complex, stereo specific intermediates for effective synthesis of the final drug substance of the required structure.

US 6730798 disclosed a process for the preparation of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methylnon-4-enoic acid ester. The disclosed process involves condensation of (R)-4-(2-(chloromethyl)-3-methylbutyl)-l-methoxy-2-(3-methoxypropoxy)benzene with (S,E)-5-chloro-2-isopropylpent-4-enoic acid ester compound to provide (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy) benzyl)-8-methylnon-4-enoic acid ester, which is isolated using diethyl ether and purified by flash chromatography.

US 7132569 disclosed a process for the preparation of aliskiren hemifumarate. The disclosed process involves condensation of (R)-4-(2-(chloromethyl)-3-methylbutyl)-l-methoxy-2-(3-methoxy propoxy) benzene with (S,E)-5-chloro-2-isopropyl-N,N-dimethylpent-4-enamide to provide (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-N,N,8-trimethyl non-4-enamide, which is isolated using diisopropyl ether and purified by flash chromatography using ethylacetate-hexane (2:1). It was converted into its corresponding bromo lactone, which is isolated using diisopropyl ether and further purified by thin layer chromatography to provide pure bromo lactone compoud. The bromo lactone on azidation provided azido lactone derivative, which is isolated using diisopropyl ether and further purified by flash chromatography to provide the azido lactone as an oil. Further, condensation of the azido lactone with 3-amino-2,2-dimethyl propanamide provides (2S,4S,5S,7S)-N-(3-amino-2,2-dimethyl-3-oxopropyl)-5-azido-4-hydroxy-2-isopropyl-7-(4-methoxy-3-(3-methoxy propoxy) benzyl)-8-methyl nonanamide, which is isolated using ethylacetate and further purified by thin layer chromatography. The said compound was reduced to provide aliskiren and then converted into its hemifumarate salt.

The above processes involve chromatographic purification in each step. The use of chromatographic purification makes the process cumbersome, time consuming, uneconomical and difficult to handle on large scale. It also leads to the generation of lot of spent solvents and solid waste which are difficult to dispose which may lead to the pollution of the environment. Hence it becomes imperative to avoid chromatographic purification for the process to be more effective.

Henceforth, there is a need to develop an improved process which can reliably be carried out in an industrial scale, in a cost efficient manner and to provide highly pure intermediates, which in turn results in a highly pure aliskiren hemifumarate. Advantages of the present Invention:

• Provides the crystalline form of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy) benzyl)-8-methylnon-4-enoic acid tertiary butyl amine salt.

• Provides the solid crystalline form of (3S,5S)-5-((lS,3S)-l-azido-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentyl)-3-isopropyldihydrofuran-2(3H)-one.

• Avoids chromatographic purification, which is costly and difficult to handle on large scale.

• Uses simple, milder and non-toxic reagents making it eco-friendly process Brief description of the invention:

The first aspect of the present invention is to provide an improved process for the preparation of aliskiren hemifumarate compound of formula-la, which comprises of the following steps:

a) Condensing the (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methyl non-4-enoic acid compound of formula-4 and/or its amine salt with a suitable amine hydrochloride salt compound of general formula-7 in the presence of a suitable condensing agent in a suitable solvent to provide (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methyl-4-nonene amide derivative compound of general formula-8,

b) treating the compound of general formula-8 with a suitable halogenating agent in the presence of aqueous acid in a suitable solvent to provide (3S,5S)-5-((lR,3S)-l-halo-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentyl)-3-isopropyldihydro furan-2(3H)-one compound of general formula-10, which is isolated using an ether solvent to provide pure compound of general formula-10,

c) treating the compound of general formula-10 with a suitable alkali metal azide in a suitable solvent to provide (3S,5S)-5-((lS,3S)-l-azido-3-(4-methoxy-3-(3-methoxypropoxy) benzyl)-4-methylpentyl)-3-isopropyldihydrofuran-2(3H)-one compound of formula-11, which is isolated using an ether solvent to provide pure compound of formula-11,

d) condensing the compound of formula-11 with 3-amino-2,2-dimethyl propanamide compound of formula-12 in the presence of a proton donor in a suitable solvent to provide (2S,4S,5S,7S)-N-(3-amino-2,2-dimethyl-3-oxopropyl)-5-azido-4-hydroxy-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methylnonanamide compound of formula-13, which is further purified from hydrocarbon solvent to provide pure compound of formula-13,

e) reducing the compound of formula-13 with a suitable reducing agent in a suitable solvent to provide aliskiren compound of formula-1,

f) treating the compound of formula-1 with fumaric acid in a suitable solvent to provide aliskiren hemifumarate compound of formula-1 a.

The second aspect of the present invention is to provide an improved process for the preparation of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methyl non-4-enoic acid compound of formula-4 and its amine salt, which comprises of treating (R)-4-(2-(chloromethyl)-3-methylbutyl)-l-methoxy-2-(3-methoxypropoxy) benzene compound of formula-2 with magnesium turnings in the presence of alkenyl halides in a suitable solvent, followed by condensation with (S,E)-5-chloro-2-isopropylpent-4-enoic acid compound of formula-3 and/or its amine salt, in the presence of N-methyl pyrrolidone and a suitable metal complex, in a suitable solvent to provide (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy) benzyl)-8-methylnon-4-enoic acid compound of formula-4, which is isolated using an ester solvent to provide pure compound of formula-4, which is further converted into its amine salt.

The third aspect of the present invention is to provide a process for the preparation of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methylnon-4-enoic acid compound of formula-4 and its amine salt, which comprises of following steps:

a) Treating the (R)-4-(2-(chloromethyl)-3-methylbutyl)-l-methoxy-2-(3-methoxypropoxy) benzene compound of formula-2 with magnesium turnings in the presence of alkenyl halides in a suitable solvent, followed by condensation with (S,E)-5-chloro-2-isopropylpent-4-enoic acid ester compound of general formula-5, in the presence of N-methyl pyrrolidone and a suitable metal complex, in a suitable solvent provides (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methylnon-4-enoic acid ester compound of general formula-6, which is isolated using an ester solvent to provide pure compound of general formula-6,

b) hydrolyzing the compound of general formula-6 in the presence of an acid or a base in a suitable solvent provides compound of formula-4,

c) further, the compound of formula-4 is converted into its amine salt.

The fourth aspect of the present invention is to provide an improved process for the preparation of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methyl-4-nonene amide derivative compound of general formula-8, which comprises of treating the (R)-4-(2-(chloromethyl)-3-methylbutyl)-l-methoxy-2-(3-methoxypropoxy) benzene compound of formula-2 with magnesium turnings in the presence of alkenyl halides in a suitable solvent, followed by condensation with (S,E)-5-chloro-2-isopropyl-pent-4-ene amide derivative compound of general formula-9 in the presence of N-methyl pyrrolidone and a suitable metal complex, in a suitable solvent to provide compound of general formula-8, which is isolated using an ester solvent to provide pure compound of general formula-8.

The fifth aspect of the present invention is to provide one pot process for the preparation of aliskiren compound of formula-1.

The sixth aspect of the present invention is to provide one pot process for the preparation(3S,5S)-5-((lR,3S)-l-halo-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methyl pentyl)-3-isopropyl dihydrofuran-2(3H)-one compound of general formula-10.

The seventh aspect of the present invention provides a novel crystalline form of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methylnon-4-enoic acid tertiary butyl amine salt compound of formula-4a (herein designated as crystalline form-M) as well as process for its preparation.

The eighth aspect of the present invention provides a novel crystalline form of (3S,5S)-5-((lS,3S)-l-azido-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentyl)-3-isopropyldihydro furan-2(3H)-one compound of formula-11 (herein designated as crystalline form-S) as well as process for its preparation.

The ninth aspect of the present invention provides a process for the preparation of (R)-4-(2-(chloromethyl)-3-methylbutyl)-1 -methoxy-2-(3-methoxypropoxy)benzene compound of formula-2.

Brief Description of the drawings:

Figure 1: Illustrates the PXRD pattern of crystalline form-M of (2S,7R,E)-2-isopropyl-7-(4- methoxy-3-(3-methoxypropoxy)benzyl)-8-methylnon-4-enoic acid tertiary butyl amine salt compound of formula-4a.

Figure 2: Illustrates the DSC thermogram of crystalline form-M of compound of formula-4a.

Figure 3: Illustrates the PXRD pattern of crystalline form-S of (3S,5S)-5-((lS,3S)-l-azido-3-(4- methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentyl)-3-isopropyldihydrofuran-2(3H)-one compound of formula-11.

Figure 4: Illustrates the DSC thermogram of crystalline form-S of compound of formula-11.

Detailed Description of Invention:

The suitable solvents, wherever necessary, used in the present invention are selected from "ester solvents" like ethyl acetate, methyl acetate, isopropyl acetate; "ether solvents" like tetrahydrofuran, diethyl ether, methyl tert-butyl ether; "hydrocarbon solvents" like toluene, hexane, heptane and cyclohexane; "polar aprotic solvents" like dimethyl acetamide, dimethyl sulfoxide, acetonitrile; "ketone solvents" like acetone, methyl ethyl ketone, methyl isobutyl ketone; and "alcoholic solvents" like methanol, ethanol, n-propanol, isopropanol, n-butanol and isobutanol; "chloro solvents" like dichloromethane, chloroform and dichloroethane, carbon tetrachloride and chloroform; polar solvents like water; and also mixtures thereof.

The term "acid" herein the present invention is selected from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or organic acids such as acetic acid, trifluoroacetic acid, methane sulfonic acid, para toluene sulfonic acid, ortho phosphoric acid, oxalic acid and tartaric acid.

The term "base" herein the present invention is selected from inorganic bases like alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkali metal alkoxides such as sodium tert-butoxide, potassium tert-butoxide; alkali metal carbonates like sodium carbonate, potassium carbonate; alkali metal bicarbonates like sodium bicarbonate and potassium bicarbonate; and organic bases like triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, piperidine, dimethyl amino pyridine and pyridine.

As used herein, the term "alkyl" refers to straight chain or branched hydrocarbon groups, generally having specified number of carbon atoms, preferably alkyl group having 1 to 12 carbon atoms. Examples of alkyl groups include, without limitation, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, t-butyl and the like.

As used herein, the term "cycloalkyl" refers to saturated monocyclic and bicyclic hydrocarbon rings, generally having a specified number of carbon atoms that comprise the ring i.e C3.7 cycloalkyl refers to a cycloalkyl group having 3,4,5,6 and 7 carbon atoms as ring members.

As used herein, the term "aryl-C1-6 alkyl" refers to an aryl group attached to the substrate through an alkyl group containing one to six carbon atoms. The term "aryl" refers to monovalent or divalent aromatic groups respectively including 5 and 6 membered monocyclic aromatic groups that contain zero to four heteroatom independently selected from nitrogen, oxygen and sulfur. The aryl groups may be attached to the substrate at any ring atom, unless such attachment would violate valence requirements. Aryl groups may include one or more non hydrogen substituents unless such substitution would violate valence requirements.

The suitable condensing agent is selected from carbodiimides such as N,N -diisopropylcarbodiimide (DIC), l-ethyl-3-(3-dimethyl aminopropyl)carbodiimide (EDC), N,N'-dicyclohexyl carbodiimide (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), di phenylphosphoroazidate (DPPA), P2O5, 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-l,2,3-triazole-4-carboxylate (HOCt), N-hydroxy succinamide (HOSu), (2-(lH-benzotriazol-l-yl)-l,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 suitable reducing agent is selected from heterogeneous catalysts containing from about 0.1% to about 20% by weight of transition metals such as Ni, Pd, Pt, Rh, Re, Ru and Ir, including oxides and combination thereof, raney nickel, palladium catalyst such as Pd/C, Pd/SrC03, Pd/ Al2O3, Pd/MgO, Pd/CaC03, Pd/ BaS04, PdO, Pd Black, PdCl2, Rh/C, Ru/C, Re/C, Pt02, Rh/C, RUO2; or hydride reagents like sodium borohydride, sodium cyanoborohydride, lithium aluminium hydride and vitride etc in the presence or absence of hydrogen.

The first aspect of the present invention is to provide an improved process for the preparation of aliskiren hemifumarate compound of formula-la, which comprises of the following steps:

a) Condensing the (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-
methyl non-4-enoic acid compound of formula-4 and/or its amine salt with a suitable amine hydrochloride salt compound of general formula-7 in the presence of a suitable condensing agent in a suitable solvent provides (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methyl-4-nonene amide derivative compound of general formula-8,

b) treating the compound of general formula-8 with a suitable halogenating agent in the presence of aqueous acid in a suitable solvent provides (3S,5S)-5-((lR,3S)-l-halo-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentyl)-3-isopropyldihydrofuran-2(3H)-one compound of general formula-10, which is isolated using an ether solvent to provide pure compound of general formula-10,

c) treating the compound of general formula-10 with a suitable alkali metal azide in a suitable solvent provides (3S,5S)-5-((lS,3S)-l-azido-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentyl)-3-isopropyldihydrofuran-2(3H)-one compound of formula-11, which is isolated using an ether solvent to provide pure compound of formula-11,

d) condensing the compound of formula-11 with 3-amino-2,2-dimethyl propanamide compound of formula-12 in the presence of a proton donor in a suitable solvent to provide (2S,4S,5S,7S)-N-(3-amino-2,2-dimethyl-3-oxopropyl)-5-azido-4-hydroxy-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy) benzyl)-8-methylnonanamide compound of formula-13, which is purified from hydrocarbon solvent to provide pure compound of formula-13,

e) reducing the compound of formula-13 with a suitable reducing agent in a suitable solvent to provide aliskiren compound of formula-1,

f) treating the compound of formula-1 with fumaric acid in a suitable solvent to provide aliskiren hemifumarate compound of formula-la.

wherein, in step a) the condensation may be alternatively carried out by converting the compound of formula-4 into its acid chloride using a suitable chlorinating agent selected from oxalyl chloride, phosphoryl chloride, thionyl chloride, phosphorous trichloride, phosphorous penta chloride and pivolyl chloride; and followed by reaction with the suitable amine hydrochloride salt compound of general formula-7 to provide compound of general formula-8,

In the step b) the suitable halogenating agent is selected from elemental bromine, iodine, N-bromo, N-chloro, N-iodo carboxamide, dicarboxamides, N-bromo, N-chloro, N-iodo phthalimide, N-chloro, N-bromo, N-iodo succinamide, tertiary butyl hypochlorite, N-halogenated sulfonamides and imide.

In US 7132569, it is illustrated that bromo derivative of compound of formula-10 is isolated using diisopropylether-hexane and further purified by thin layer chromatography using diethylether-hexane (2:1), which is a tedious process.

In the present invention the compound of formula-10 is isolated using diisopropyl ether which provided the pure compound of formula-10 with out using chromatographic purification. Further it provided the compound with a purity of 95.85%.

In step c) the suitable alkali metal azide is lithium azide or sodium azide to provide compound of formula-11. In US 7132569, the compound of formula-11 was obtained as an oil and further purified by flash chromatography using ethylacetate-hexane (1:3) to provide compound of formula-11 with a purity of 93.8% by HPLC.

Whereas, in the present invention the compound of formula-11 is directly isolated using diisopropyl ether as a solid, with out the need for purification by flash chromatography and also obtained the compound with a purity of 96.6% by HPLC.

In step d) a proton donor used is 2-hydroxy pyridine. In US 7132569, the compound obtained in this step was purified by chromatographic purification using ethylacetate-hexane (4:1) to provide compound of formula-13 with a purity of 88.5% by HPLC. Whereas, in the present invention, the said compound is purified by recrystallization using cyclohexane solvent to provide highly pure compound of formula-13 with a purity of 91.44% by HPLC.

Henceforth, the process of the present invention is more advantageous over the prior art processes, which avoids the frequent use of chromatography techniques.

Further a preferred embodiment of the present aspect is to provide an improved process for the preparation of aliskiren hemifumarate compound of formula-la, which comprises of the following steps:

a) Treating the (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methyl non-4-enoic acid tertiary butyl amine salt compound of formula-4a with hydrochloric acid to provide (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy) benzyl)-8-methyl non-4-enoic acid compound of formula-4, which on condensation with dimethyl amine hydrochloride compound of formula-7a in the presence of dicyclohexyl carbodiimide in combination with HOBT, in the presence triethylamine in dichloroethane provides (2S,7R,E)-2-isopropyl-7-(4-methoxy-3 -(3 -methoxy propoxy)benzyl)-N,N,8-trimethylnon-4-enamide compound of formula-8a,

b) treating the compound of formula-8a with N-bromo succinamide, in the presence of aqueous ortho phosphoric acid in tetrahydrofuran provides (3S,5S)-5-((lR,3S)-l-bromo-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentyl)-3-isopropyldihydrofuran-2(3H)- one compound of formula-10a, which is isolated using diisopropyl ether to provide pure compound of formula-10a,

c) treating the compound of formula-10a with sodium azide in tripropylene glycol or
diethylene glycol provides (3S,5S)-5-((lS,3S)-l-azido-3-(4-methoxy-3-(3-methoxy
propoxy)benzyl)-4-methylpentyl)-3 -isopropyldihydrofuran-2(3 H)-one compound of
formula-11, which is isolated using diisopropyl ether provides pure compound of formula-11,

d) condensing the compound of formula-11 with 3-amino-2,2-dimethyl propanamide compound of formula-12 in the presence of 2-hydroxy pyridine in triethylamine to provide (2S,4S,5S,7S)-N-(3-amino-2,2-dimethyl-3-oxopropyl)-5-azido-4-hydroxy-2-isopropyl-7-(4-methoxy-3-(3-methoxy propoxy)benzyl)-8-methylnonanamide compound of formula-13, which is further purified from cyclohexane provides pure compound of formula-13,

e) reducing the compound of formula-13 with Pd/C in the presence or absence of ethanolamine under hydrogen pressure in isopropyl alcohol to provide aliskiren compound of formula-1,

f) treating the compound of formula-1 with fumaric acid in ethanol provides aliskiren hemifumarate compound of formula-la.

The second aspect of the present invention is to provide an improved process for the preparation of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methyl non-4-enoic acid compound of formula-4 and its amine salt, which comprises of treating (R)-4-(2-(chloromethyl)-3-methylbutyl)-1 -methoxy-2-(3-methoxypropoxy)benzene compound of formula-2 with magnesium turnings in the presence of alkenyl halides in a suitable solvent, followed by condensation with (S,E)-5-chloro-2-isopropylpent-4-enoic acid compound of formula-3 and/or its amine salt, in the presence of N-methyl pyrrolidone and a suitable metal complex, in a suitable solvent provides (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methylnon-4-enoic acid compound of formula-4, which is further isolating using ester solvent provides pure compound of formula-4. Further it is converted into its amine salt.

Further in a preferred embodiment of the present aspect is to provide an improved process for the preparation of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy) benzyl)-8-methylnon-4-enoic acid compound of formula-4 and its tertiary butyl amine salt compound of formula-4a, which comprises of treating the (R)-4-(2-(chloromethyl)-3-methylbutyl)-l-methoxy-2-(3-methoxy propoxy) benzene compound of formula-2 with magnesium turnings in the presence of 1,2-dibromo ethane in tetrahydrofuran followed by condensation with (S,E)-5-chloro-2-isopropylpent-4-enoic acid compound of formula-3 in the presence of iron acetyl acetonate and N-methyl pyrrolidone in tetrahydrofuran provides (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methylnon-4-enoicacid compound of formula-4, which is further treated with tertiary butylamine in a mixture of methyl tertiary butyl ether and acetonitrile provides (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxy propoxy)benzyl)-8-methylnon-4-enoic acid tertiary butyl amine salt compound of formula-4a.

Further in a preferred embodiment of the present aspect provides an improved process for the preparation of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxy propoxy)benzyl)-8-methylnon-4-enoic acid compound of formula-4 and its tertiary butyl amine salt compound of formula-4a, which comprises of treating the (R)-4-(2-(chloromethyl)-3-methylbutyl)-l-methoxy-2-(3-methoxypropoxy) benzene compound of formula-2 with magnesium turnings in the presence of 1,2-dibromo ethane in tetrahydrofuran followed by condensation with the (S,E)-5-chloro-2-isopropylpent-4-enoic acid tertiary butyl amine salt compound of formula-3a, in the presence of iron acetyl acetonate and N-methyl pyrrolidone in tetrahydrofuran provides (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methylnon-4-enoic acid compound of formula-4, which is further treated with tertiary butylamine in a mixture of methyl tertiary butyl ether and acetonitrile provides (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methylnon-4-enoic acid tertiary butyl amine salt compound of formula-4a.

The third aspect of the present invention is to provide a process for the preparation of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methylnon-4-enoic acid compound of formula-4 and its amine salt, which comprises of the following steps:

a) Treating the (R)-4-(2-(chloromethyl)-3-methylbutyl)-l-methoxy-2-(3-methoxy propoxy) benzene compound of formula-2 with magnesium turnings in the presence of alkenyl halides in a suitable solvent, followed by condensation with (S,E)-5-chloro-2-isopropylpent-4-enoic acid ester compound of general formula-5 in the presence of N-methyl pyrrolidone and a suitable metal complex, in a suitable solvent to provide (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy) benzyl)-8-methylnon-4-enoic acid ester compound of general formula-6, which is isolated using an ester solvent to provide pure compound of general formula-6.

b) hydrolyzing the compound of general formula-6 in the presence of an acid or a base in a suitable solvent provides compound of formula-4,

c) further, the compound of formula-4 is converted into its amine salt.
Wherein, the alkenyl halides used is 1,2-dibromo ethane; and the suitable metal complex is iron complex such as iron acetyl acetonate.

In US 6730798, the compound of formula-6 was isolated using diethyl ether, which was further purified by flash chromatography using diethylether- hexane (1:4). Whereas, in the present invention the compound of formula-6 is directly isolated using ethyl acetate and thus avoiding chromatographic purification. Hence the present invention is more advantageous.

Further in the above aspect, the compound of general formula-5 is prepared directly from (S,E)-5-chloro-2-isopropylpent-4-enoic acid (S)-phenyl ethanamine salt compound of formula-3b, by treating with a suitable alcohol in the presence of acid to provide compound of general formula-5 (or) by converting it into its corresponding free acid and then treating it with an alcohol in the presence of an acid to provide compound of general formula-5.

A preferred embodiment of the present aspect, provides a process for the preparation of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methylnon-4-enoic acid compound of formula-4 and its tertiary butyl amine salt compound of formula-4a, which comprises of following steps:

a) Treating the (R)-4-(2-(chloromethyl)-3-methylbutyl)-l-methoxy-2-(3-methoxy propoxy) benzene compound of formula-2 with magnesium turnings in the presence of 1,2-dibromo ethane in tetrahydrofuran, followed by condensation with (S,E)-methyl 5-chloro-2-isopropylpent-4-enoic acid methyl ester compound of formula-5a in the presence of iron acetyl acetonate and N-methyl pyrrolidone in tetrahydrofuran provides (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methylnon-4-enoic acid methyl ester compound of formula-6a, which is isolated using an ethyl acetate provides pure compound of formula-6a,

b) hydrolyzing the compound of formula-6a with aqueous lithium hydroxide in a mixture of tetrahydrofuran and methanol provides compound of formula-4.

c) further, the compound of formula-4 reacts with tertiary butyl amine in a mixture of methyl tertiary butyl ether and acetonitrile provides (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxy propoxy)benzyl)-8-methylnon-4-enoic acid tertiary butyl amine salt compound of formula-4a.

In a preferred embodiment of the present aspect is to provide a process for the preparation of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methyl non-4-enoic acid compound of formula-4 and its tertiary butyl amine salt compound of formula-4a, which comprises of following steps:

a) Treating the (R)-4-(2-(chloromethyl)-3-methylbutyl)-l-methoxy-2-(3-methoxypropoxy) benzene compound of formula-2 with magnesium turnings in the presence of 1,2-dibromo ethane in tetrahydrofuran, followed by condensation with (S,E)-ethyl 5-chloro-2-isopropylpent-4-enoic acid ethyl ester compound of formula-5b in the presence of iron acetyl acetonate and N-methyl pyrrolidone in tetrahydrofuran provides (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methylnon-4-enoic acid ethyl ester compound of formula-6b,

b) hydrolyzing the compound of formula-6b in the presence of aqueous lithium hydroxide in a mixture of tetrahydrofuran and methanol provides compound of formula-4,

c) further, the compound of formula-4 reacts with tertiary butylamine in a mixture of methyl tertiary butyl ether and acetonitrile provides (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxy propoxy)benzyl)-8-methylnon-4-enoic acid tertiary butyl amine salt compound of formula-4a.

The fourth aspect of the present invention is to provide an improved process for the preparation of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methyl-4-nonene amide derivative compound of general formula-8, which comprises of treating the (R)-4-(2-(chloromethyl)-3-methylbutyl)-l-methoxy-2-(3-methoxy propoxy)benzene compound of formula-2 with magnesium turnings in the presence of alkenyl halides in a suitable solvent, followed by condensation with (S,E)-5-chloro-2-isopropyl-pent-4-enamide derivative compound of general formula-9 in the presence of N-methyl pyrrolidone and a suitable metal complex, in a suitable solvent to provide compound of general formula-8, which is isolated using an ester solvent provides pure compound of formula-8.
In the above aspect the alkenyl halides used is 1,2-dibromo ethane; and the suitable metal complex is iron complex such as iron acetyl acetonate. In US 7132569, the compound of formula-8 was isolated using diethyl ether, which is further purified by flash chromatography using diethylether- hexane (1:4).

Whereas, in the present invention the said compound is isolated using ethyl acetate and thus avoiding chromatographic purification. Hence the present invention is more advantageous.

In a preferred embodiment of the present aspect is to provide an improved process for the preparation of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-N,N,8-trimethyl non-4-enamide compound of formula-8a, which comprises of treating the (R)-4-(2-(chloromethyl)-3 -methylbutyl)-1 -methoxy-2-(3 -methoxypropoxy)benzene compound of formula-2 with magnesium turnings in the presence of 1,2-dibromo ethane, followed by its condensation with (S,E)-5-chloro-2-isopropyl-N,N-dimethylpent-4-enamide compound of formula-9a in the presence of iron acetyl acetonate and N-methyl pyrrolidone provides compound of formula-8a, which is isolated using ethyl acetate to provide pure compound of formula-8a.

The fifth aspect of the present invention is to provide one pot process for the preparation
of aliskiren compound of formula-1, which comprises of following steps:

a) Treating the (3S,5S)-5-((lR,3S)-l-halo-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4- methyl pentyl)-3-isopropyldihydrofuran-2(3H)-one compound of general formula-10 with a suitable alkali metal azide in a suitable solvent provides (3S,5S)-5-((lS,3S)-l-azido-3-(4- methoxy-3-(3-methoxypropoxy)benzyl)-4-methyl pentyl)-3-isopropyldihydro furan-2(3H)- one compound of formula-11,

b) condensing the compound of formula-11, in-situ with 3-amino-2,2-dimethyl propanamide compound of formula-12 in the presence of a proton donor in a suitable solvent provides (2S,4S,5S,7S)-N-(3-amino-2,2-dimethyl-3-oxopropyl)-5-azido-4-hydroxy-2-isopropyl-7-(4-methoxy-3-(3 -methoxypropoxy)benzyl)-8-methylnonanamide compound of formula-13,

c) reducing the compound of formula-13 in-situ with a suitable reducing agent, optionally in the presence of ethanolamine in a suitable solvent provides aliskiren compound of formula-1.

Wherein, in step a) the suitable solvent used is l,3-Dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone (herein after referred as DMPU); the suitable alkali metal azide used is sodium azide, in step b) proton donor used is 2-hydroxy pyridine.

In a preferred embodiment of the present aspect is to provide one pot process for the preparation of aliskiren compound of formula-1, which comprises of following steps of:

a) Treating the (3S,5S)-5-((lR,3S)-l-bromo-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methyl pentyl)-3-isopropyldihydrofuran-2(3H)-one compound of formula-10a with sodium azide in DMPU provides (3S,5S)-5-((lS,3S)-l-azido-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentyl)-3-isopropyl dihydrofuran-2(3H)-one compound of formula-11,

b) condensing the compound of formula-11 in-situ with 3-amino-2,2-dimethyl propanamide compound of formula-12 in the presence of 2-hydroxy pyridine in triethylamine provides (2S,4S,5S,7S)-N-(3-amino-2,2-dimethyl-3-oxopropyl)-5-azido-4-hydroxy-2-isopropyl-7-(4-methoxy-3-(3-methoxy propoxy)benzyl)-8-methylnonanamide compound of formula-13,

c) reducing the compound of formula-13 in-situ with Pd-C in the presence of hydrogen pressure and in the presence of ethanolamine in isopropyl alcohol to provide aliskiren compound of formula-1.

The sixth aspect of the present invention is to provide one pot process for the preparation compound of general formula-10, which comprises of following steps:

a) Treating the (R)-4-(2-(chloromethyl)-3-methylbutyl)-l-methoxy-2-(3-methoxy propoxy) benzene compound of formula-2 with magnesium turnings in the presence of alkenyl halides in a suitable solvent, followed by condensing it with (S,E)-5-chloro-2-isopropyl-pent-4-enamide derivative compound of general formula-9 in the presence of N-methyl pyrrolidone and a suitable metal complex in a suitable solvent provides (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxy propoxy)benzyl)-8-methyl-4-nonene amide derivative compound of general formula-8,

b) treating the compound of general formula-8 with a suitable halogenating agent in the presence of aqueous acid in a suitable solvent provides (3S,5S)-5-((lR,3S)-l-halo-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentyl)-3-isopropyldihydrofuran-2(3H)-one compound of general formula-10, which is isolated using an ether solvent provides pure compound of general formula-10.

Wherein, in step a) alkenyl halides used is 1,2-dibromo ethane; the suitable metal
complex used is iron acetyl acetonate,

In step b) the suitable halogenating agent is selected from elemental bromine, iodine, N-
bromo, N-chloro, N-iodo carboxamide, dicarboxamides, N-bromo, N-chloro, N-iodo phthalimide, N-chloro, N-bromo, N-iodo succinamide, tertiary butyl hypochlorite, N- halogenated sulfonamides and imide; preferably N-bromo succinamide.
In a preferred embodiment of the present aspect is to provide one pot process for the
preparation of (3 S,5 S)-5-(( 1 R,3 S)-1 -bromo-3 -(4-methoxy-3 -(3- methoxypropoxy)benzyl)-4- methylpentyl)-3-isopropyldihydrofuran-2(3H)-one compound of formula-10a, which comprises of folio wing steps:

a) Treating the (R)-4-(2-(chloromethyl)-3-methylbutyl)-l-methoxy-2-(3-methoxypropoxy) benzene compound of formula-2 with magnesium turnings in the presence of 1,2-dibromo ethane in isopropyl alcohol, followed by condensing it with (S,E)-5-chloro-2-isopropyl-N,N-dimethylpent-4-enamide compound of formula-9a in the presence of iron acetyl acetonate and N-methyl pyrrolidone provides (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-N,N,8-trimethylnon-4-enamide compound of formula-8a,

b) treating the compound of formula-8a with N-bromo succinamide in the presence of aqueous ortho phosphoric acid in tetrahydrofuran provides compound of formula-10a, which is isolated using diisopropyl ether provides pure compound of formula-10a.
In the above fourth and sixth aspects, the (S,E)-5-chloro-2-isopropyl-pent-4-ene amide derivative compound of general formula-9 was prepared by reacting the (S,E)-5-chloro-2-isopropylpent-4-enoic acid compound of formula-3 with a suitable amine hydrochloride compound of general formula-7 in the presence of suitable condensing agent in a suitable solvent (or) by converting the compound of formula-3 into its acid chloride and followed by condensing it with compound of general formula-7 provides compound of general formula-9.

The seventh aspect of the present invention provides a novel crystalline form of (2S,
7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methylnon-4-enoic acid tertiary butyl amine salt compound of formula-4a (herein designated as crystalline form-M). The crystalline form-M of compound of formula-4a, which is characterized by its powder XRD having peaks at about 8.4, 11.8, 19.8 and 20.1 ± 0.2 degrees two-theta and substantially as shown in figure-1; or by its DSC thermogram showing endotherm at about 143.17°C as shown in figure-2.

The eighth aspect of the present invention provides a novel crystalline form of (3S,5S)-5-((lS,3S)-l-azido-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentyl)-3-isopropyl dihydro furan-2(3H)-one compound of formula-11 (herein designated as crystalline form-S). The crystalline form-S of compound of formula-11, which is characterized by its powder XRD having peaks at about 6.1, 9.3, 10.1, 15.4, 18.5 and 20.8 ± 0.2 degrees two-theta and substantially as shown in figure-3; or by its DSC thermogram showing endotherm at about 62.8°C as shown in figure-4.

The ninth aspect of the present invention provides the process for preparation of (R)-4-(2-(chloromethyl)-3-methyibutyl)-l-methoxy-2-(3-methoxypropoxy)benzene compound of formula-2, which comprises of following steps:

a) Condensing the 4-methoxy-3-(3-methoxypropoxy)benzaldehyde compound of formula-14 with isovelarate under suitable conditions provides 2-(hydroxy(4-methoxy-3-(3-methoxy propoxy)phenyl)methyl)-3-methylbutanoic acid ester compound of formula-15,

wherein, R is same as defined above,

b) hydrolyzing the compound of formula-15 in the presence of an acid or a base to provide (E)-2-(4-methoxy-3-(3-methoxypropoxy)benzylidene)-3-methylbutanoic acid compound of formula-16,

c) treating the compound of formula-16 with a chiral auxiliary in a suitable solvent to provide compound of formula-17,

wherein, Aux* is a chiral auxiliary selected from 4-phenyloxazolidin-2-one or phenyl ethylamine,

d) reducing the compound of formula-17 with a suitable reducing agent in a suitable solvent provides compound of formula-18,

e) hydrolyzing the compound of formula-18 with an acid or base in a suitable solvent provides (R)-2-(4-methoxy-3 -(3 -methoxypropoxy)benzyl)-3 -methylbutanoic acid compound of formula-19,

f) reducing the compound of formula-19 with a suitable reducing agent in a suitable solvent provides (R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutan-1 -ol compound of formula-20,

g) reacting the compound of formula-20 with a suitable chlorinating agent in a suitable solvent to provide compound of formula-2.

Wherein, in step h) the suitable chlorinating agent is selected from phosphoryl chloride, phosphorous trichloride, phosphorous pentachloride, thionyl chloride and oxalyl chloride.

The compounds of formula-4, 4a, 6 and 8 of the present invention were analyzed by HPLC using the following conditions:

Apparatus: A liquid chromatographic system is to be equipped with variable wavelength UV-detector; Column : Chiral pak-IC, 250 x 4.6 mm, 5 μm or equivalent; Flow rate : 1.0 mL/minute; Wavelength : 230 nm; Column temperature : 15°C; Injection volume: 20 uL; Run time : 50 minutes; Diluent: mobile phase n-hexane: IPA: Ethanol: TFA: DEA (90:05:05:0.1:0.1 v/v); Elution : Isocratic; Sample conc: 1.0 mg/ml

Aliskiren hemifumarate was analyzed by HPLC using the following conditions:

Apparatus: A liquid chromatographic system is to be equipped with variable wavelength UV-detector; Column : Symmetry C18, 250 x 4.6 mm, 5 μm or equivalent; Flow rate : 1.0 ml/minute; Wavelength : 230 nm; Column temperature : 45°C; Injection volume: 10 μL; Run time : 53 minutes; Diluent: watenacetonitrile (50:50 v/v); Elution : Gradient; Sample cone: 2.0 mg/ml; mobile phase-A: Buffer:acetonitrile (70:30 v/v); mobile phase-B: acetonitrile: water (90:10 v/v); Buffer: 0.02M potassium dihydrogen phosphate and 0.03M 1-octane sulphonic acid mono hydrate in 1000 ml of water, adjust pH to 2.0 with diluted orthophosphoric acid. Filtered this solution through 0.45um Nylon membrane filter paper and sonicate to degas it.

The compounds of formula-10,11 and 13 of the present invention were analyzed by HPLC using the following conditions:

Apparatus: A liquid chromatographic system is to be equipped with variable wavelength UV-detector; Column : Kromasil 100 C1 8, 150 x 4.6 mm, 5 μm or equivalent; Flow rate : 1.0 mL/minute; Wavelength : 230 nm; Column temperature : 20°C; Injection volume: 20 uL; Run time : 50 minutes; Diluent: water:acetonitrile (50:50 v/v); Elution : Gradient; Sample conc: 1.0 mg/ml; mobile phase-A: 0.1% orthophosphoric acid: acetonitrile (50:50 v/v); mobile phase-B: acetonitrile: water (9:1 v/v);

The present invention is represented schematically as follows:

The process described in the present invention is 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 (S,E)-ethyl 5-chloro-2-isopropylpent-4-enoate (Formula-5b)

Purified water (1250 ml) and dichloromethane (1000 ml) were added to (S,E)-5-chloro-2-isopropyl pent-4-enoic acid phenyl ethanamine salt (250 gm) and cooled to 10-15°C. pH of the reaction mixture was adjusted to 1.8 with 50% aqueous hydrochloric acid. The reaction mixture temperature was raised to 25-30°C and both the organic and aqueous layers were separated. Extracted the aqueous layer with dichloromethane. Both the dichloro methane layers were combined and distilled off the solvent completely to get residue. Ethanol (1000 ml) was added to the obtained residue and cooled to 0-5°C.
Sulfuric acid (832 gm) was added to the reaction mixture at 0-5°C and then heated to 70-80°C. Stirred the reaction mixture for 16 hours at 70-80°C. After completion of the reaction, poured the reaction mixture into chilled water and extracted the product with dichloromethane. Both the dichloromethane and aqueous layers were separated. The dichloromethane layer was washed with 5% sodium bicarbonate solution and then distilled off the solvent completely under reduced pressure to get the title compound. Yield: 147.0 grams Example-2: Preparation of (S,E)-ethyl 5-chloro-2-isopropylpent-4-enoate (FormuIa-5b)

Sulfuric acid (16.5 gm) was added to a solution of (S,E)-5-chloro-2-isopropylpent-4-enoic acid phenyl ethanamine salt (10.0 gm) in ethanol (50 ml) at 0-5°C over a period of 2 hours. The reaction mixture was heated to 75-80°C and stirred for 10 hours at 75-80°C.
After completion of the reaction, the reaction mixture was poured into chilled water and extracted the product with dichloromethane. Both the dichloromethane and aqueous layers were separated. The dichloro methane layer was washed with 5% sodium bicarbonate solution and then distilled off the solvent under reduced pressure to get the title compound. Yield: 7.0 grams Example-3: Preparation of (S,E)-methyl 5-chloro-2-isopropylpent-4-enoate (Formula-5a)

Sulfuric acid (3.3 gm) was added to a solution of (S,E)-5-chloro-2-isopropylpent-4-enoic acid phenyl ethanamine salt (10.0 gm) in methanol (50 ml) at 0-5°C over a period of 15 minutes. The reaction mixture was heated to 65-70°C and stirred for 10 hours at 75-80°C.
After completion of the reaction, the reaction mixture was poured into chilled water and extracted the product with dichloromethane. Both the dichloromethane and aqueous layers were separated. The dichloro methane layer was washed with 5% sodium bicarbonate solution and then distilled off the solvent under reduced pressure to get the title compound. Yield: 5.5 grams.

Example-4: Preparation of (2S,7R,E)-ethyl 2-isopropyl-7-(4-methoxy-3-(3-methoxy propoxy) benzyl)-8-methylnon-4-enoate (FormuIa-6b)

A mixture of magnesium turnings (27.4 gm) and tetrahydrofuran (480 ml) was heated to 63-68°C under nitrogen atmosphere. 1,2-dibromoethane (17.9 gm) was added to the reaction mixture and stirred for 10 minutes. (R)-4-(2-(chloromethyl)-3-methylbutyl)-l-methoxy-2-(3-methoxypropoxy)benzene compound of formula-2 (120 gm) and 1,2-dibromoethane (35.8 gm) were dissolved in tetrahydrofuran (480 ml) and added slowly to the above reaction mixture at 63-68°C over a period of 1 hour. The reaction mixture was stirred for 3 hours at 63-68°C. After completion of the reaction, the reaction mixture was cooled to 0-5 °C and the mixture of (S,E)-ethyl 5-chloro-2-isopropylpent-4-enoate compound of formula-5b (70 gm), N-methyl pyrrolidone (18.8 gm) and Fe(AcAc)3 (6.7 gm) in tetrahydrofuran (480 ml) was slowly added to the reaction mixture at 0-5°C over a period of 1 hour and stirred for 11/2 hour at 0-5°C. After completion of the reaction, the reaction mixture was quenched with aqueous HC1 and extracted the product into ethyl acetate. Both the ethyl acetate and aqueous layers were separated. The ethyl acetate layer was washed with saturated sodium chloride solution and then distilled off the solvent completely under reduced pressure to get the title compound. Yield: 166.0 grams.

Example-5: Preparation of (2S,7R,E)-methyl 2-isopropyl-7-(4-methoxy-3-(3-methoxy propoxy) benzyl)-8-methylnon-4-enoate (Formula-6a)

A mixture of magnesium turnings (1.8 gm) and tetrahydrofuran (32 ml) was heated to 63-68°C under nitrogen atmosphere. 1,2-dibromoethane (1.2 gm) was added to the reaction mixture and stirred for 10 minutes. (R)-4-(2-(chloromethyl)-3-methylbutyl)-l-methoxy-2-(3-methoxypropoxy) benzene compound of formula-2 (8.0 gm) and 1,2-dibromoethane (2.4 gm) were dissolved in tetrahydrofuran (32 ml) and added slowly to the above reaction mixture at 63-68°C. Stirred the reaction mixture for 4 hours at the same temperature. After completion of the reaction, the reaction mixture was cooled to 0-5°C and the mixture of (S,E)-methyl 5-chloro-2-isopropylpent-4-enoate compound of formula-5a (4.3 gm), N-methyl pyrrolidone (1.2 gm) and Fe(AcAc)3 (0.4 gm) dissolved in tetrahydrofuran (32 ml) was slowly added to the reaction mixture at 0-5°C and stirred for 1 hour at the same temperature. After completion of the reaction, quenched the reaction mixture with aqueous HC1 and extracted the product in ethyl acetate. The ethyl acetate layer was washed with saturated sodium chloride solution and then distilled off the solvent completely under reduced pressure to get the title compound. Yield: 9.2 grams.

Example-6: Preparation of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy) benzyl)-8-methyl non-4-enoic acid (Formula-4)

A mixture of magnesium turnings (4.9 gm) and tetrahydrofuran (80 ml) was heated to 63-68°C under nitrogen atmosphere. 1,2-dibromoethane (3.2 gm) was added to the reaction mixture and stirred for 10 minutes. (R)-4-(2-(chloromethyl)-3-methylbutyl)-l-methoxy-2-(3-methoxy propoxy) benzene compound of formula-2 (21.4 gm) and 1,2-dibromoethane (6.4 gm) were dissolved in tetrahydrofuran (80 ml) and added slowly to the above reaction mixture at 63-68°C. Stirred the reaction mixture for 4 hours at the same temperature. After completion of the reaction, the reaction mixture was cooled to 0-5°C and the mixture of (S,E)-5-chloro-2-isopropylpent-4-enoic acid compound of formula-3 (6.0 gm), N-methyl pyrrolidone (1.57 gm) and Fe(AcAc)3 (0.56 gm) taken in tetrahydrofuran (80 ml) was slowly added to the reaction mixture at 0-5°C and stirred for 1 hour at the same temperature. After completion of the reaction, quenched the reaction mixture with aqueous HC1 and extracted the product in ethyl acetate. The ethyl acetate layer was washed with saturated sodium chloride solution and then distilled off the solvent completely under reduced pressure to get the title compound. Yield: 23.04 grams.

Example-7: Preparation of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy) benzyl) -8-methyl non-4-enoic acid tertbutyl amine salt (Formula-4a)

A mixture of magnesium turnings (2.28 gm) and tetrahydrofuran (40 ml) was heated to 63-68°C under nitrogen atmosphere. 1,2-dibromoethane (1.5 gm) was added to the reaction mixture and stirred for 10 minutes. (R)-4-(2-(chloromethyl)-3-methylbutyl)-l-methoxy-2-(3-methoxypropoxy) benzene compound of formula-2 (10 gm) and 1,2-dibromoethane (3.0 gm) were dissolved in tetrahydrofuran (40 ml) and added slowly to the above reaction mixture at 63-68°C. Stirred the reaction mixture for 4 hrs at the same temperature. After completion of the reaction, the reaction mixture was cooled to 0-5°C and the mixture of (S,E)-5-chloro-2-isopropylpent-4-enoic acid tertiary butyl amine salt compound of formula-3a (8.73 gm), N-methyl pyrrolidone (1.57 gm) and Fe(AcAc)3 (0.56 gm) taken in tetrahydrofuran (40 ml) was added slowly to the reaction mixture at 0-5°C and stirred for 1 hour at the same temperature. After completion of the reaction, quenched the reaction mass with aqueous HC1 and extracted the product in ethyl acetate.
The ethyl acetate layer was washed with saturated sodium chloride solution and then distilled off the solvent completely under reduced pressure to get the title compound.
Yield: 2.0 grams.

ExampIe-8: Preparation of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy) benzyl) -8-methyl non-4-enoic acid tert.butyl amine salt (Formula-4a)

Lithium hydroxide (78 gm), followed by water (400 ml) were added to a mixture of
(2S,7R,E)-ethyl 2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methylnon-4- enoate compound of formula-6b (160 gm), tetrahydrofuran (600 ml) and methanol (400 ml). The reaction mixture was heated to 65-70°C and then stirred for 26 hours at 65-70°C. After completion of the reaction, distilled off the solvent completely under reduced pressure to obtained residue. Water was added to the reaction mixture. Extracted the product with pet.ether and both the pet.ether and aquoeus layers were separated. Extracted the aqueous layer with acetonitrile and both the acetonitrile layer and aqueous layers were separated. Both the petether and acetonitrile layers were combined and cooled to 0-5°C. Tertiary butyl amine (27 ml) was added to the reaction mixture at 0-5°C and stirred for 1/2 hour at 0-5°C. Distilled off the solvent completely under reduced pressure and isolated the product in acetonitrile. Filtered the solid, washed with acetonitrile and then dried to get the title compound. Yield: 87.0 grams; Purity by HPLC: 95.90%

Example-9: Preparation of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy) benzyl) -8-methyl non-4-enoic acid tert.butyl amine salt (compound of formula-4a)

2N potassium hydroxide (150 ml) and water (260 ml) were added to a solution of (2S,7R,E)-methyl 2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methyl-non-4-enoate compound of formula-6a (65 gm) in dioxane (780 ml) and heated to reflux and then stirred for 24 hours at the same temperature. After completion of the reaction, distilled off the solvent completely under reduced pressure. Water was added to the reaction mixture and then repeatedly washed the reaction mixture with methyl tertiary butyl ether. Acetonitrile was added to the reaction mixture. Adjusted the pH to 3.0-4.0 by using aqueous hydrochloric acid at 0-5°C and then saturated with sodium chloride and separated the organic layer from aqueous layer. Tertiary butyl amine was added to the organic layer at 0-5°C and then distilled off the solvent completely. Isolated the compound in acetonitrile and dried to get the title compound. Yield: 37.2 grams; purity by HPLC: 98.57 %.

Example-10: Preparation of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy) benzyl) -N,N,8-trimethylnon-4-enamide (formula-8a)

A mixture of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methylnon-4-enoic acid tertiary butyl amine salt compound of formula-4a (75 gm), dichloroethane (300 ml) and water (300 ml) was cooled to 0-5°C. Adjusted the pH to 2.5 with 10% hydrochloric acid and separated the organic layer and kept a side. Dimethyl amine hydrochloride salt compound of formula-7a (22 gm) was added to dichloro ethane (150 ml) and cooled to 0-5°C. To this mixture HOBT (1.6 gm) and triethyl amine (22.8 gm) were added followed by the above organic layer at 0-5 °C and stirred the reaction mixture for 45 minutes at 0-5. A solution of DCC (32 gm) in dichloro ethane (150 ml) was added to the reaction mixture at 0-5°C over a period of 1 hr, then the temperature of the reaction mixture was raised to 25-30°C and stirred the reaction mixture for 12 hrs at 25-30°C. Cooled the reaction mixture to 0-5°C and stirred the reaction mixture 1/2 hour. Filtered the reaction mixture, washed the filtrate with 5% HC1 and 5% sodium bicarbonate followed by saturated sodium chloride solution and distilled off the solvent completely from the organic layer to get the title compound as a residue. Yield: 67.0 grams; Purity by HPLC: 90%.

Example-11: Preparation of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy) benzyl)-N,N,8-trimethylnon-4-enamide (FormuIa-8a)

A mixture of magnesium turnings (11.5 gm) and tetrahydrofuran (200 ml) was heated to 63-68°C under nitrogen atmosphere. 1,2-dibromoethane (7.5 gm) was added to the reaction mixture and stirred for 10 minutes. (R)-4-(2-(chloromethyl)-3-methylbutyl)-l-methoxy-2-(3-methoxypropoxy)benzene compound of formula-2 (50 gm) and 1,2-dibromoethane (7.5 gm) were dissolved in tetrahydrofuran (200 ml) and added slowly to the above reaction mixture at 63-68°C. Stirred the reaction mixture for 4 hours at the same temperature. After completion of the reaction, the reaction mixture was cooled to 0-5°C and the mixture of (S,E)-5-chloro-2-isopropyl-N,N-dimethylpent-4-enamide compound of formula-9a (26.1 gm), N-methyl pyrrolidone (7.9 gm) and Fe(AcAc)3 (2.8 gm) in tetrahydrofuran (200 ml) was slowly added to the reaction mixture at 0-5 °C and stirred for 1 hour at the same temperature. After completion of the reaction, quenched the reaction mass with aqueous HC1 and extracted the product in ethyl acetate. The ethyl acetate layer was washed with saturated sodium chloride solution and then distilled off the solvent completely under reduced pressure to obtained a residue.

Tetrahydrofuran (330 ml) and water (5.28 ml) were added to the above obtained residue and cooled to 0-5°C. 88% orthophosphoric acid (7.92 ml) was slowly added to the reaction mixture at 0-5°C and then added NBS (21.67 gm) in 3 equal lots at 0-5°C. Stirred the reaction mixture for 45 minutes at 0-5°C. After completion of the reaction, the reaction mixture was quenched with aqueous sodium metabisulfite and n-heptane was added to it. Both the organic layer and aqueous layers were separated and the aqeous layer was extracted with methyl tertiary butyl ether. Both the organic layers were combined and washed with 10% HC1, 5% sodium bicarbonate followed by sodiumchloride solution. Distilled off the solvent from the organic layer and co-distilled with pet.ether. Product was further purified from diisopropyl ether. Filtered the solid, washed with diisopropyl ether and then dried to get the title compound. Yield: 25.08 grams; Purity by HPLC: 92.75%

Example-12: Preparation of (3S,5S)-5-((lR,3S)-l-bromo-3-(4-methoxy-3-(3-methoxy propoxy) benzyI)-4-methylpentyl)-3-isopropyldihydrofuran-2(3H)-one(Formula-10a)

A mixture of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-N,N,8-trimethyl non-4-enamide compound of formula-8a (150 gm), tetrahydrofuran (750 ml) and water (15 ml) was cooled to 0-5°C. 44% orthophosphoric acid (48 ml) was added slowly to the reaction mixture at 0-5 °C over a period 15 minutes. N-Bromo succinamide (60 gm) was added to the reaction mixture at 0-5°C and stirred for 1 hour at 0-5°C. After completion of the reaction, the reaction mixture was quenched with aqueous sodium metabisulfite and n-heptane was added to it. Both the organic layer and aqueous layers were separated and the aqeous layer was extracted with methyl tertiary butyl ether. Both the organic layers were combined and washed with 10% HC1, 5% sodium bicarbonate followed by sodiumchloride solution. Distilled off the solvent from the organic layer and co-distilled with pet.ether. Product was further purified from diisopropyl ether. Filtered the solid, washed with diisopropyl ether and then dried to get the title compound. Yield: 111.0 grams; M.R: 48-51 °C; Purity by HPLC: 97.61% Example-13: Preparation of (3S,5S)-5-((lS,3S)-l-azido-3-(4-methoxy-3-(3-methoxy propoxy) benzyl)-4-methylpentyl)-3-isopropyldihydrofuran-2(3H)-one(Formula-ll)

A mixture of (3S,5S)-5-((lR,3S)-l-bromo-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methyl pentyl)-3-isopropyldi-hydrofuran-2(3H)-one compound of formula-10a (100 gm), sodium azide (62 gm) and polyethylene glycol (700 ml) was heated to 80-85°C and stirred for 20 hours at 80-85°C. After completion of the reaction, the reaction mixture was quenched with water and the product was extracted with methyl tert.butyl ether. The methyl tert.butyl ether layer was washed with 5% sodium bicarbonate followed by 10% sodium chloride solution and dried with sodium sulfate. Distilled off the solvent and isolated the title compound in diisopropyl ether to get pure title compound as a solid.
Yield: 46.0 grams; M.R: 59.5-61.5°C; Purity by HPLC: 96.64%

Example-14: Preparation of (3S,5S)-5-((lS,3S)-l-azido-3-(4-methoxy-3-(3-methoxy propoxy)benzyl)-4-methylpentyl)-3-isopropyldihydrofuran-2(3H)-one(Formula-ll)

A mixture of (3S,5S)-5-((lR,3S)-l-bromo-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methyl pentyl)-3-isopropyldi-hydrofuran-2(3H)-one compound of formula-10a (10 gm), sodium azide (6.2 gm) and tripropylene glycol (70 ml) was heated to 80-85°C and stirred the reaction mixture for 20 hours at 80-85°C. After completion of the reaction, the reaction mixture was quenched with water and the product was extracted with methyl tert.butyl ether. The methyl tert. butyl ether layer was washed with 5% sodium bicarbonate followed by 10% sodium chloride solution and dried with sodium sulfate. Distilled off the solvent and isolated the title compound in diisopropyl ether to get pure title compound as a solid. Yield: 8.8 grams; M.R: 59-60.8°C; Purity by HPLC: 93%

Example-15: Preparation of (2S,4S,5S,7S)-N-(3-amino-2,2-dimethyl-3-oxopropyl)-5-azido-4-hydroxy-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyI)-8-methyl nonanamide (Formula-13)

A mixture of (3S,5S)-5-((lS,3S)-l-azido-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methyl pentyl)-3-isopropyldihydrofuran-2(3H)-one compound of formula-11 (45 gm), 3-Amino-2,2-dimethylpropanamide compound of formula-12 (34 gm), 2-hydroxy pyridine (10.2 gm) and triethylamine (51 ml) was heated to 85-90°C and stirred for 16 hours at 85-90°C. After completion of the reaction, the reaction mixture was cooled to 25-30°C and the reaction mixture was quenched with 5% aqueous sodium bicarbonate solution. Extracted the product with ethyl acetate. Ethyl acetate layer was washed with 10% hydrochloric acid, 5% aqueous sodium bicarbonate followed by sodium chloride solution and dried with sodium sulfate. Distilled off the solvent completely to get the title compound as a residue and purified by repeated with cyclohexane. Yield: 56.0 grams; HPLC purity: 91.4%

Example-16: Preparation of (2S,4S,5S,7S)-5-amino-N-(3-amino-2,2-dimethyI-3-oxopropyl)-4-hydroxy-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methyl nonanamide (Formula-1)

Ethanol amine (37.3 ml) was added to a solution of (2S,4S,5S,7S)-N-(3-amino-2,2-dimethyl-3 -oxopropyl)-5 -azido-4-hydroxy-2-isopropyl-7-(4-methoxy-3 -(3 -methoxypropoxy)benzyl)-8-methyl nonanamide compound of formula-13 (55 gm) in isopropyl alcohol (550 ml). To the mixture 10% Pd/C (37.3 gm) was added and applied hydrogen pressure for 3 hours. After completion of the reaction, the reaction mixture was filtered through hyflow bed and washed the bed with isoprypyl alcohol and distilled off the solvent from the filtrate under reduced pressure. Methyl tertiary butyl ether was added to the obtained residue and stirred for 10 minutes. Separated the ethanol amine layer and organic layer from the reaction mixture, washed the organic layer with saturated sodium chloride and then distilled off the solvent to get the title compound. Yield: 60.0 grams; purity by HPLC: 93.93%.

Example-17: Preparation of (2S,4S,5S,7S)-5-amino-N-(3-amino-2,2-dimethyl-3-oxopropyl)-4-hydroxy-2-isopropyI-7-(4-methoxy-3-(3-methoxypropoxy)benzyI)-8-methyl nonanamide (Formula-1)

Ethanol amine (1.23 ml) was added to a solution (2S,4S,5S,7S)-N-(3-amino-2,2-dimethyl-3 -oxopropyl)-5 -azido-4-hydroxy-2-isopropyl-7-(4-methoxy-3 -(3 -methoxypropoxy)benzyl)-8-methyl nonanamide compound of formula-13 (8.0 gm) in isopropyl alcohol (40 ml). To the mixture 10% Pd/C (1.23 gm) was added and applied hydrogen pressure for 3 hrs. After completion of the reaction, the reaction mixture was filtered through hyflow bed and washed the bed with isopropyl alcohol and then distilled off isopropyl alcohol from the filtrate. Water and followed by methyl tert.butyl ether were added to the obtained residue and stirred for 10 minutes. Adjusted the pH to 3.0 with aqueous hydrochloric acid and separated the methyl tert.butyl ether layer. The aqueous layer was washed repeatedly with methyl tertbutyl ether and added dichloromethane into the aqueous layer. Adjusted the pH to 9.5 with aqueous sodium carbonate solution, then separated both the organic layer and aqueous layers. The organic layer was washed with water and then distilled off the solvent completely to get the title compound. Yield: 7.0 gm; purity by HPLC: 95.0%.

Example-18: One pot process for the preparation of (2S,4S,5S,7S)-5-amino-N-(3-amino-2,2-dimethyl-3-oxopropyl)-4-hydroxy-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy) benzyl)-8-methylnonanamide (Formula-1)

A mixture of (3S,5S)-5-((lR,3S)-l-bromo-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-
4-methyl pentyl)-3-isopropyl dihydrofuran-2(3H)-one compound of formula-10a (10 gm), sodium azide (3.9 gm) and DMPU (80 ml) was heated to 75-80°C and then stirred for 4 hours at 75-80°C. After completion of the reaction, the reaction mixture was quenched with water and the product was extracted with methyl tert.butyl ether. The methyl tert.butyl ether layer was washed with sodium bicarbonate solution followed by brine solution. Distilled off the solvent completely to get (3S,5S)-5-((lS,3S)-l-azido-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentyl)-3-iso-propyldihydrofuran-2(3H)-one compound of formula-11 as a residue. 3-amino-2,2-dimethyl propanamide compound fo formula-12 (8.8 gm), 2-hydroxy pyridine (2gm) and triethyl amine (10 ml) were added to the above residue and heated to 85-90°C and then stirred for 15 hours at 85-90°C. After completion of the reaction, the reaction mixture was cooled to 25-30°C and quenched with 5% aqueous sodium bicarbonate solution. Extracted the product with ethyl acetate and the ethyl acetate layer was washed with 5% aqueous sodium bicarbonate followed by brine solution. Distilled off the solvent completely under reduced pressure to get the (2S,4S,5S,7S)-N-(3-amino-2,2-dimethyl-3-oxopropyl)-5-azido-4-hydroxy-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methyl nonanamide compound of formula-13 as a residue. The above residue was dissolved in isopropyl alcohol (100 ml), added Pd/C (5 gm) and applied hydrogen pressure for 3 hours. After completion of the reaction, the reaction mixture was filtered through hyflow bed and washed the bed with isopropyl alcohol. Distilled off isopropyl alcohol from the filtrate, water and methyl tert.butyl ether were added to the reaction mixture and stirred for 10 minutes. Adjusted the pH of the reaction mixture to 3.0 with aqueous HC1 and separated the methyl tertbutyl ether layer. The aqueous layer was washed repeatedly with methyl tert.butyl ether and added dichloromethane into the aqueous layer. Adjusted the pH to 9.5 with aqueous sodium carbonate solution, then separated both the organic layer and aqueous layers. The organic layer was washed with water. Distilled off the solvent completely to get the title compound. Yield: 4.0 grams; Purity by HPLC: 90%. Example-19: Procedure for the preparation of Aliskiren hemifumarte amorphous form
Aliskiren free base (50 gm) was dissolved in ethanol (150 ml) and stirred for 10 minutes. To this solution fumaric acid (5.2 gm) was added and stirred for 10 minutes at 25-30°C. Filtered the reaction mixture and distilled off the solvent from the filtrate under reduced pressure and then co-distilled with dichloromethane to obtaine the residue, n-pentane was added to the obtained residue, isolated the product in n-pentane and then dried to get aliskiren hemifumarate. Yield: 51.0 grams; purity by HPLC: 99%.

Example-20: Process for the preparation of Aliskiren hemifumarte crystalline form-A

Aliskiren free base (50.0 gm) was dissolved in ethanol (150 ml) and stirred for 10 minutes. To this solution fumaric acid (5.2 gm) was added and stirred for 10 minutes at 25-30°C. Filtered the reaction mixture, distilled off the solvent from the filtrate under reduced pressure and then co-distilled with dichloromethane and n-pentane. Acetonitrile was added to the obtained residue and stirred for lhour at 25-30°C. Filtered the obtained solid, washed with acetonitrile and then dried to get the crystalline form-A of aliskiren hemifumarate. Yield: 45.0 grams; purity by HPLC: 99.5%. Example-21: Process for the preparation of Aliskiren hemifumarte amorphous form Aliskiren hemifumarate (40.0 gm) was dissolved in dichloromethane (160 ml) and stirred for 10 minutes. Distilled off the solvent completely under reduced pressure and co-distilled with n-pentane. The product was isolated in n-pentane (40 ml) at 15°C and then dried to get the aliskiren hemifumarate amorphous form. Yield: 33.0 gm; purity by HPLC: 99.35%.

Example-21: Preparation of (2S,4S,5S,7S)-5-amino-N-(3-amino-2,2-dimethyI-3-
oxopropyl)-4-hydroxy-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methyl nonanamide

(2S,4S,5S,7S)-N-(3-amino-2,2-dimethyl-3-oxopropyl)-5-azido-4-hydroxy-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methylnonanamide (35 gm) was dissolved in a mixture of methyl tert.butyl ether (175 ml) and methanol (3.5 ml). 5% Pd/C (2.0 gm) and ethanol amine (3.2 ml) were added to th reaction mixture and hydrogen gas bubbling was applied for 2-3 hrs for completion of the reaction. Filtered the reaction mixture through hyflow bed and washed the bed with methyl tertbutyl ether (100 ml). Cooled the filtrate to 0-10°C, added methylene chloride (35 ml) and water (35 ml) to it at the same temperature. Separated the organic layer and the aqueous layer was extracted with methylene chloride (35 ml) at 0-10°C. Washed the organic layer with saturated sodium chloride solution and distilled off the solvent at below 40°C. Isopropyl alcohol was added to the residue and distilled off the solvent completely under reduced pressure at below 45°C. The obtained residue was washed with cyclohexane to get the pure title compound.
Yield: 33.4 gm; Purity by HPLC: 96 %

We Claim:

1. A crystalline form-M of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy) benzyl)-8-methylnon-4-enoic acid tertiary butylamine salt compound of formula-4a characterized by,

a) its powder X-ray diffractogram having peaks at about 8.4, 11.8, 19.8 and 20.1 ± 0.2 degrees two-theta as illustrated in figure-1, (or)

b) its DSC thermogram showing endotherm at 143.17°C as illustrated in figure-2.

2. A crystalline form-S of (3S,5S)-5-((lS,3S)-l-azido-3-(4-methoxy-3-(3-methoxypropoxy) benzyl)-4-methylpentyl)-3-isopropyldihydrofuran-2(3H)-one compound of formula-11 characterized by,

a) its powder X-ray diffractogram having peaks at about 6.1, 9.3,10.1, 15.4,18.5 and 20.8 ± 0.2 degrees two-theta as illustrated in figure-3, (or)

b) its DSC thermogram showing endotherm at 62.8°C as illustrated in figure-4.

3. A process for the preparation of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-
methoxypropoxy) benzyl)-8-methylnon-4-enoic acid compound of formula-4 and its amine salt, comprising of:

a) Treating the (R)-4-(2-(chloromethyl)-3-methylbutyl)-l-methoxy-2-(3-methoxypropoxy) benzene compound of formula-2 with magnesium turnings in a suitable solvent in the presence of 1,2-dibromoethane provides corresponding Grignard reagent,
Grignard reagent

b) reacting (S,E)-5-chloro-2-isopropylpent-4-enoic acid compound of formula-3 or its amine salt with Grignard reagent obtained in step a) in the presence of suitable metal complex and N-methylpyrrolidone in a suitable solvent to provide compound of formula-4,

c) extracting and isolating the compound of formula-4, obtained in step-b), using ethyl acetate to provide pure compound of formula-4,

d) optionally converting the compound of formula-4 into its amine salt by treating the compound of formula-4 with a suitable amine in a suitable solvent.

4. A process for the preparation of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-
methoxypropoxy)benzyl)-8-methyl-4-nonene amide compound of general formula-8,
comprising of:

a) Treating the (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methylnon-4-enoic acid tertiary butyl amine salt compound of formula-4a with an acid in a suitable solvent to provide (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy) benzyl)-8-methylnon-4-enoic acid,

b) condensing (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)- 8-methylnon-4-enoic acid with a suitable amine hydrochloride compound of general formula-7, in the presence of a suitable condensing agent and a suitable base in a suitable solvent to provide compound of general formula-8.

5. A process for the preparation of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-
methoxypropoxy) benzyl)-8-methylnon-4-enoic acid compound of formula-4 or its amine
salt, comprising of:

a) Treating the (R)-4-(2-(chloromethyl)-3-methylbutyl)-l-methoxy-2-(3-methoxypropoxy) benzene compound of formula-2 with magnesium turnings in the presence of 1,2-dibromoethane in tetrahydrofuran to provide corresponding Grignard reagent,

b) reacting the (S,E)-5-chloro-2-isopropylpent-4-enoic acid ester compound of general formula-5 with Grignard reagent obtained in step a) in the presence of N-methylpyrrolidone and a suitable metal complex in a suitable solvent to provide (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methyl non-4-enoic acid ester compound of general formula-6,

c) extracting and isolating the compound of general formula-6 using ethyl acetate to provide pure compound of general formula-6,

d) hydrolyzing the compound of general formula-6 in the presence of an acid or a base in a suitable solvent to provide (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy) benzyl)-8-methyl non-4-enoic acid compound of formula-4,

e) optionally converting the compound of formula-4 into its amine salt by treating the compound of formula-4 with a suitable amine in a suitable solvent.

6. A process for the preparation of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-
methoxypropoxy)benzyl)-8-methyl-4-nonene amide compound of general formula-8,
comprising of:

a) Treating the (R)-4-(2-(chloromethyl)-3-methylbutyl)-l-methoxy-2-(3-methoxypropoxy) benzene compound of formula-2 with magnesium turnings in the presence of 1,2-dibromoethane in a suitable solvent to provide its corresponding Grignard reagent,

b) reacting the (S,E)-5-chloro-2-isopropyl-pent-4-ene amide derivative compound of general formula-9 with Grignard reagent obtained in step a) in the presence of a suitable metal complex and N-methylpyrrolidone in a suitable solvent to provide compound of general formula-8,

c) extracting and isolating the compound of general formula-8 using ethyl acetate to provide pure compound of general formula-8.

7. A process for the preparation of aliskiren hemifumarate compound of formula-la, comprising of:

a) Condensing the (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methyl non-4-enoic acid compound of formula-4 or its amine salt with a suitable amine hydrochloride compound of general formula-7 in the presence of a suitable condensing agent in a suitable solvent to provide compound of general formula-8,

b) treating the compound of general formula-8 with a suitable halogenating agent in the presence of aqueous acid in a suitable solvent to provide compound of general formula- 10,

c) isolating the compound of general formula-10 using ether solvent to provide pure compound of general formula-10,

d) treating the compound of general formula-10 with a suitable alkali metal azide in a suitable solvent to provide (3S,5S)-5-((lS,3S)-l-azido-3-(4-methoxy-3-(3-methoxy propoxy)benzyl)-4-methylpentyl)-3 -isopropyldihydrofuran-2(3H)-one compound of formula-11,

e) isolating the compound of formula-11 using ether solvent to provide pure solid compound of formula-11,

f) condensing the compound of formula-11 obtained in step e), with 3-amino-2,2-dimethyl propanamide compound of formula-12 in the presence of a proton donor in a suitable solvent to provide (2S,4S,5S,7S)-N-(3-amino-2,2-dimethyl-3-oxopropyl)-5-azido-4-hydroxy-2-isopropyl-7-(4-methoxy-3 -(3 -methoxypropoxy)benzyl)-8-methylnonanamide compound of formula-13,

g) optionally purifying the compound of formula-13 from a suitable hydrocarbon solvent to provide pure compound of formula-13,

h) reducing the compound of formula-13 with a suitable reducing agent in a suitable
solvent to provide aliskiren compound of formula-1,

i) treating the compound of formula-1 with fumaric acid in a suitable solvent to provide
aliskiren hemifumarate compound of formula-la.

8. A process for the preparation of aliskiren hemifumarate compound of formula-la, comprising of:

a) Treating the (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methylnon-4-enoic acid tertiary butyl amine salt compound of formula-4a with hydrochloric acid in a mixture of water and dichloroethane to provide (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methyl non-4-enoic acid compound of formula-4,

b) reacting the compound of formula-4 with dimethyl amine hydrochloride compound of formula-7a in the presence of dicyclohexyl carbodiimide and 1-hydroxybenzotriazole in the presence of triethylamine in dichloroethane to provide (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-N,N,8-trimethylnon-4-enamide compound of formula-8a,

c) reacting the compound of formula-8a with N-bromo succinamide, in the presence of aqueous ortho phosphoric acid in tetrahydrofuran to provide (3S,5S)-5-((lR,3S)-l-bromo-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentyl)-3-isopropyl dihydrofuran-2(3H)-one compound of formula-lOa,

d) isolating the compound of formula-10a using diisopropyl ether to provide pure compound of formula-1 Oa,

e) reacting the compound of formula-10a with sodium azide in tripropylene glycol or diethylene glycol to provide (3S,5S)-5-((lS,3S)-l-azido-3-(4-methoxy-3-(3-methoxy propoxy)benzyl)-4-methylpentyl)-3 -isopropyldihydrofuran-2(3H)-one compound of formula-11,

f) isolating the compound of formula-11 using diisopropyl ether to provide pure solid compound of formula-11,

g) condensing the compound of formula-11 with 3-amino-2,2-dimethyl propanamide compound of formula-12 in the presence of 2-hydroxy pyridine in triethylamine to provide (2S,4S,5S,7S)-N-(3-amino-2,2-dimethyl-3-oxopropyl)-5-azido-4-hydroxy-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methylnonanamide compound of formula-13,

h) purifying the compound of formula-13 from cyclohexane to provide pure compound of
formula-13,

i) reducing the compound of formula-13 with Pd/C in the presence of ethanolamine under hydrogen pressure in isopropyl alcohol to provide aliskiren compound of formula-1,

j) treating the compound of formula-1 with fumaric acid in ethanol to provide aliskiren
hemifumarate compound of formula-la.

9. One pot process for the preparation of aliskiren compound of formula-1, which comprising of:

a) Reacting the compound of formula-lOa with sodium azide in l,3-Dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone (DMPU) to provide (3S,5S)-5-((lS,3S)-l-azido-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentyl)-3-isopropyl dihydrofuran-2(3 H)-one compound of formula-11,

b) condensing the compound of formula-11 in-situ with 3-amino-2,2-dimethyl propanamide compound of formula-12 in the presence of 2-hydroxy pyridine in triethylamine to provide (2S,4S,5S,7S)-N-(3-amino-2,2-dimethyl-3-oxopropyl)-5-azido-4-hydroxy-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methylnonanamide compound^ of formula-13,

c) reducing the compound of formula-13 in-situ with Pd/C in presence of ethanolamine under hydrogen pressure in isopropyl alcohol to provide aliskiren compound of formula-1.

10. A process for the preparation of solid (3S,5S)-5-((lS,3S)-l-azido-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentyl)-3-isopropyldihydrofuran-2(3H)-one compound of formula-11, comprising of:

a) Dissolving the compound of formula-11 in diisopropyl ether at 25-30°C,

b) cooling the reaction mixture to 0-5°C,

c) stirring the reaction mixture for 2 hours at 0-5 °C,

d) filtering the precipitated solid and washing with diisopropyl ether,

e) drying the solid to get pure compound of formula-11.