Field of the Invention:

The present invention relates to the novel process for the preparation of (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutan-l-o1, compound of formula -1, a useful intermediate in the synthesis 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 or its salts thereof.

Formula-1

Renin is the first enzyme in the renin-angiotensin-aldosterone system which plays a ro1e in blood pressure contro1. 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 tubules of the kidneys to increase reabsorption of sodium, with water fo1lowing thereby increasing plasma vo1ume and blood pressure. (2S,4S,5S,7S)-N-(2-Carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl]-octanamide binds to the S3bp binding pocket of renin, essential for its activity. Binding to this pocket prevents the conversion of angiotensinogen to angiotensin I.

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-methoxypropoxy)phenyl]-octanamide and its pharmaceutically acceptable salts are potent in these class of drugs. It is a very complex mo1ecule having a number of chiral centers. Hence it invo1ves the synthesis and the condensation of complex, stereo specific intermediates for effective synthesis of the final drug substance of the required structure. (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutan-l-o1 is one of the most important intermediate used in 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 and its harmaceutically acceptable salts. The reported process comprises of reacting the 3-hydroxy-4-methoxy-benzyl alcoho1 with l-bromo-3-methoxy-propane in presence of potassium carbonate in acetone to provide 4-methoxy-3-(3-methoxypropyloxy)-benzyl alcoho1. It was further reacted with trimethyl bromosilane to provide 4-methoxy-3-(3-methoxypropyloxy)-benzyl bromide. In the subsequent step 4(R)-benzyl-3-isovaleroyl-oxazo1idin-2-one was taken and reacted with lithium hexamethyl-disilazide to provide a lithiated compound which was in-situ reacted with 4-methoxy-3-(3-methoxypropyloxy)-benzyl bromide to provide 4(R)-benzyl-3-{2(R)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propionyl}-oxazo1idine-2-one which was further treated with lithium hydroxide in presence of hydrogen peroxide to provide 2(R)-isopropyl-3[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propionic acid. The propionic acid derivative was treated with sodium borohydride and iodine to provide (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutan-l-o1. The process invo1ves numerous steps which are time consuming, providing low yield and inflating the cost of production.

Helvetica chimica acta-Vo1. 86(2003) provides a process for the preparation of (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutan-l-o1 which comprises of reacting 3-hydroxy-4-methoxybenzaldehyde with 1,3-dibromopropane to provide 3-(3-bromopropoxy)-4-methoxybenzaldehyde. Which on further reaction with sodium methoxide provided 4-methoxy-3-(3-methoxypropoxy)benzaldehyde. The obtained compound was reduced with sodium borohydride to provide 4-methoxy-3-(3-methoxypropoxy)benzene methano1. It was reacted with trimethyl bromosilane to provide 4-methoxy-3-(3-methoxypropoxy)benzyl bromide. This was further reacted with lithiated (R)-4-benzyl-3-(3-methylbutanoyl)oxazo1idin-2-one, which was prepared by reacting lithium hexamethyl-disilazide with (R)-4-benzyl-3-(3-methylbutanoyl)oxazo1idin-2-one to provide 4(R)-benzyl-3- {2(R)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propionyl}-oxazo1idine-2-one. It was treated with lithium hydroxide in presence of hydrogen peroxide to provide 2(R)-isopropyl-3[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propionic acid. The obtained compound was treated with sodium borohydride in presence of iodine to provide (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutan-1-o1.

Tetrahedron letters, vo1ume 46(2005), Pages: 6337-6340, reported the process for the preparation of (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutan-l-o1. The said article reports the usage of lithium aluminium hydride instead of sodium borohydride in the conversion of 2(R)-isopropyl-3[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propionic acid to (R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methyl butan-1-o1.

The main disadvantage of the above processes is that 4-methoxy-3-(3-methoxypropoxy) benzyl bromide which is formed as an intermediate is highly unstable and was found to decompose during short contact with the surface metallic materials such as a spatula or metal stirrer, hence decreasing the yield.

Hence there is a need in the art for a process which overcomes the above said problems and provides (R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutan-l-o1 with higher purity and yield.

Brief Description of the Invention:

The first aspect of the present invention is to provide a novel process for the preparation of (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutan-l-o1 compound of formula-1, which comprises of,

a) Reacting 3-methoxypropylmethanesulfonate compound of formula-2 with 3-hydroxy-4-methoxybenzaldehyde compound of formula-3 in the presence of suitable base in a suitable so1vent to provide 4-methoxy-3-(3-methoxypropoxy)benzaldehyde compound of formula-4,

b) reacting the 4-methoxy-3-(3-methoxypropoxy)benzaldehyde compound of formula-4 with (R)-3-(3-methylbutanoyl)-4-phenyloxazo1idin-2-one compound of formula-5 in the presence of titanium tetrachloride or titanium(IV) isopropoxide or mixtures thereof and a base in a suitable so1vent to provide (4R)-3-((2S)-2-(hydroxy(4-
ethoxy-3-(3-methoxypropoxy) phenyl) methyl)-3-methylbutanoyl)-4-
phenyloxazo1idin-2-one compound of formula-6,

c) hydrogeno1ysis of compound of formula-6 with a suitable hydrogen source in the presence of suitable acid, in a suitable so1vent to provide (R)-3-((R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutanoyl)-4-phenyloxazo1idin-2-one compound of formula-7,

d) alkaline peroxide mediated hydro1ysis of compound of formula-7 in a suitable so1vent to provide (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutanoic acid compound of formula-8,

e) reducing the compound of formula-8 with suitable reducing agent, in a suitable so1vent to provide (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutan-l-o1 compound of formula-1.

The second aspect of the present invention is to provide a process for the preparation of (4R)-3-((2S)-2-(hydroxy(4-methoxy-3-(3-methoxypropoxy)phenyl) methyl)-3-methylbutanoyl)-4-phenyloxazo1idin-2-one compound of formula-6, which comprises of reacting the 4-methoxy-3-(3-methoxypropoxy)benzaldehyde compound of formula-4 with (R)-3-(3-methylbutanoyl)-4-phenyloxazo1idin-2-one compound of formula-5 in presence of titanium tetrachloride or titanium(IV) isopropoxide or mixtures thereof and a base in a suitable so1vent to provide (4R)-3-((2S)-2-(hydroxy(4-methoxy-3-(3-methoxypropoxy)phenyl)methyl)-3-methylbutanoyl)-4-phenyloxazo1idin-2-one compound of formula-6.

The third aspect of the present invention is to provide a process for the preparation of (R)-3-((R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methyl butanoyl)-4-phenyloxazo1idin-2-one compound of formula-7, which comprises of hydrogeno1ysis of (4R)-3-((2S)-2-(hydroxy(4-methoxy-3-(3-methoxypropoxy)phenyl) methyl)-3-methylbutanoyl)-4-phenyloxazo1idin-2-one compound of formula-6 with suitable reducing agent in the presence of suitable acid, in a suitable so1vent to provide (R)-3-((R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutanoyl)-4-phenyl oxazo1idin-2-one compound of formula-7.

The fourth aspect of the present invention is to provide a novel process for the preparation of (R)-3-((R)-2-(4-methoxy-3 -(3 -methoxypropoxy)benzyl)-3 -methyl butanoyl)-4-phenyloxazo1idin-2-one compound of formula-7, which comprises of

a) reacting the 4-methoxy-3-(3-methoxypropoxy)benzaldehyde compound of formula-4 with (R)-3-(3-methylbutanoyl)-4-phenyloxazo1idin-2-one compound of formula-5 in presence of titanium tetrachloride or titanium(IV) isopropoxide or mixtures thereof and a base in a suitable so1vent to provide (4R)-3-((2S)-2-(hydroxy(4-methoxy-3-(3-methoxypropoxy)phenyl)methyl)-3-methylbutanoyl)-4-phenyloxazo1idin-2-one compound of formula-6,

b) hydrogeno1ysis of the compound of formula-6 with a suitable hydrogen source in the presence of suitable acid, in a suitable so1vent to provide (R)-3-((R)-2-(4-methoxy-3-(3 -methoxypropoxy)benzyl)-3 -methylbutanoyl)-4-phenyloxazo1idin-2-one compound of formula-7.

The fifth aspect of the present invention is to provide the novel (4R)-3-((2S)-2-(hydroxy(4-methoxy-3 -(3 -methoxypropoxy)phenyl)methyl)-3 -methylbutanoyl)-4-phenyloxazo1idin-2-one compound of formula-6. The novel compound of formula-6 is useful as an intermediate in the preparation of (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3 -methylbutan-1 –o1compound of formula-1.

The sixth aspect of the present invention is to provide a novel amine salts of (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutanoic acid compound of general formula-9. These novel amine salts are useful in the preparation of highly pure (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutanoic acid compound of formula-8.

The seventh aspect of the present invention is to provide a process for the preparation of novel amine salts of (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutanoic acid compound of general formula-9, which comprise of treating the (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutanoic acid compound of formula-8 with suitable amines in a suitable so1vent to provide the corresponding amine salts compound of formula-9.

Detailed Description of the Invention:

As used herein the present invention the term "suitable so1vents" refers to so1vents selected from "ester so1vents" like ethyl acetate, methyl acetate, isopropyl acetate; "ether so1vents" like tetrahydrofuran, diethyl ether, methyl tert-butyl ether; "hydrocarbon so1vents" like to1uene, hexane, heptane and cyclohexane; "po1ar aprotic so1vents" like dimethyl acetamide, dimethyl sulfoxide, acetonitrile; "ketone so1vents" like acetone, methyl ethyl ketone, methyl isobutyl ketone; and "alcoho1ic so1vents" like methano1, ethano1, n-propano1, isopropano1, n-butano1 and isobutano1; "chloro so1vents" like methylene chloride, chloroform and ethylene dichloride; po1ar so1vents like water; and mixtures thereof.

As used herein the present invention the term "suitable bases" refers to the bases selected from inorganic bases like alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and 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, N-methyl morpho1ine, piperidine, pyridine and their mixtures there of.

As used herein the present invention the term "suitable acids" refers to the acids selected from hydrochloric acid, hydrobromic acid, acetic acid, benzenesulfonic acid, camphbursulfonic acid, ethanesulfonic acid, fumaric acid, maleic acid, methane sulfonic acid, oxalicacid, phosphoric acid and sulfuric acid.

The first aspect of present invention provides a novel process for the preparation of (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutan-l-o1 compound of general formula-1, which comprises of; a) Reacting the 3-methoxypropylmethanesulfonate compound of formula-2

with 3-hydroxy-4-methoxybenzaldehyde compound of formula-3
Formula-3 in the presence of suitable base and in a suitable so1vent to provide 4-methoxy-3-(3-methoxypropoxy)benzaldehyde compound of formula-4,

Formula-4

b) reacting the compound of formula-4 with (R)-3-(3-methylbutanoyl)-4-phenyl
oxazo1idin-2-one compound of formula-5

Formula-5 in presence of titanium tetrachloride or titanium(IV) isopropoxide or mixtures thereof and a base in a suitable so1vent to provide (4R)-3-((2S)-2-(hydroxy(4-methoxy-3-(3-methoxypropoxy)phenyl)methyl)-3-methylbutanoyl)-4-phenyloxazo1idin-2-one compound of formula-6,

Formula-6

c) hydrogeno1ysis of the compound of formula-6 with a suitable hydrogen source in the presence of acid in a suitable so1vent to provide (R)-3-((R)-2-(4-methoxy-3-(3-
methoxypropoxy)benzyl)-3-methylbutanoyl)-4-phenyloxazo1idin-2-one compound of
formula-7,

Formula-7

d) hydro1ysis of compound of formula-7 with a suitable base in the presence of peroxide in a suitable so1vent to provide (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3- methylbutanoic acid compound of formula-8,

Formula-8

e) reducing the compound of formula-8 with a suitable reducing agent in a suitable
so1vent to provide (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutan-
1 -o1 compound of formula-1.

Formula-1 Wherein the step a) the reaction between 3-methoxypropyl methanesulfonate, compound of formula-2 and 3-hydroxy-4-methoxybenzaldehyde compound of formula-3 is carried out in presence of a suitable bases, preferably inorganic base such as alkali metal carbonates like sodium carbonate, potassium carbonate; in a suitable so1vents , preferably hydrocarbon so1vents selected from to1uene, xylene, cyclohexane, hexane, heptane; and at a suitable temperature;

Wherein the step b) the reaction of 4-methoxy-3-(3-methoxypropoxy) benzaldehyde compound of formula-4 with (R)-3-(3-methylbutanoyl)-4-phenyloxazo1idin-2-one compound of formula-5 take place in presence of titanium tetrachloride or titanium(IV) isopropoxide or mixtures thereof and a suitable base is preferably organic base such as diisopropy ethyl amine in a suitable so1vent selected from ester so1vents, ether so1vents, hydrocarbon so1vents, po1ar aprotic so1vents, ketone so1vents, alcoho1ic so1vents, chloro so1vents, po1ar so1vents or mixtures thereof; preferably chloro so1vents.

The reaction of 4-methoxy-3-(3-methoxypropoxy) benzaldehyde compound of formula-4 with (R)-3-(3-methylbutanoyl)-4-phenyloxazo1idin-2-one compound of formula-5 also takes place when the reagents like lithium diisopropyl amine(LDA), Lithium hexamethyldisilazide(LiHMDS), n-butyl lithium are utilized in the place of titanium tetrachloride or titanium(IV) isopropoxide or mixtures thereof.

Wherein in the step c), hydrogeno1ysis of (4R)-3-((2S)-2-(hydroxy (4-methoxy-3-(3-methoxypropoxy)phenyl)methyl)-3-methylbutanoyl)-4-phenyloxazo1idin-2-one compound of formula-6 is carried out by reacting it with palladium on carbon in presence of suitable acid selected from hydrochloric acid, hydrobromic acid, acetic acid, benzenesulfonic acid, camphoursulfonic acid, ethanesulfonic acid, fumaric acid, maleic acid, methane sulfonic acid, oxalicacid, phosphoric acid and sulfuric acid in presence of hydrogen.

The hydrogeno1ysis can also be carried out by using the suitable reducing agents. 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/ A1203, Pd/MgO, Pd/CaC03> Pd/ BaS04, PdO, Pd Black, PdCl2> Rh/C, Ru/C, Re/C, PtC>2, Rh/C, Ru02; or hydride reagents like sodium borohydride, sodium cyanoborohydride, lithium aluminium hydride and vitride etc in the presence or absence of hydrogen.

Wherein in the step d) alkaline peroxide mediated hydro1ysis of (R)-3-((R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutanoyl)-4-phenyloxazo1idin-2-one, compound of formula-7 is carried out in the presence of suitable base such as inorganic bases like alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates or organic bases like triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, N-methyl morpho1ine, piperidine and pyridine in the presence of peroxides like hydrogen peroxide, per acids such as peracetic acid, trifluoro peracetic acid, perbenzoic acid, m-chloro perbenzoic acid and the and the like; the suitable so1vent is selected from ester so1vents, ether so1vents, hydrocarbon so1vents, po1ar aprotic so1vents, ketone so1vents, alcoho1ic so1vents, chloro so1vents, po1ar so1vents or mixtures thereof; preferably lithium hydroxide in presence of hydrogen peroxide in tetrahydrofuran.

Wherein the step e) the conversion of (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methyl butanoic acid compound of formula-8 into (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutan-l-o1 compound of formula-1 is carried out by the conventional methods.

The second aspect of the present invention provides a process for the preparation of (4R)-3-((2S)-2-(hydroxy(4-methoxy-3-(3-methoxypropoxy) phenyl)methyl)-3-methyl butanoyl)-4-phenyloxazo1idin-2-one compound of formula-6.

Formula-6

which comprises of reacting the 4-methoxy-3-(3-methoxypropoxy)benzaldehyde compound of formula-4,

Formula-4 with (R)-3-(3-methylbutanoyl)-4-phenyloxazo1idin-2-one compound of formula-5

Formula-5 in presence of titanium tetrachloride or titanium(IV) isopropoxide or mixtures thereof and a base in a suitable so1vent to provide (4R)-3-((2S)-2-(hydroxy(4-methoxy-3-(3-methoxypropoxy)phenyl)methyl)-3-methylbutanoyl)-4-phenyloxazo1idin-2-one compound of formula-6.

The reaction of 4-methoxy-3-(3-methoxypropoxy) benzaldehyde compound of formula-4 with (R)-3-(3-methylbutanoyl)-4-phenyloxazo1idin-2-one compound of formula-5 take place in presence of titanium tetrachloride or titanium(IV) isopropoxide or mixtures thereof and a suitable base is selected from organic bases preferably diisopropy ethyl amine in a suitable so1vent selected from ester so1vents, ether so1vents, hydrocarbon so1vents, po1ar aprotic so1vents, ketone so1vents, alcoho1ic so1vents, chloro so1vents, po1ar so1vents or mixtures thereof; preferably chloro so1vents.

The reaction also takes place when the reagents like lithium diisopropyl amine (LDA), Lithium hexamethyldisilazide (LiHMDS), n-butyl lithium are utilized in the place of titanium tetrachloride or titanium (IV) isopropoxide or mixtures thereof.

The third aspect of the present invention provides a process for the preparation of (R)-3-((R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutanoyl)-4-phenyl oxazo1idin-2-one compound of formula-7

Formula-7 which comprises of hydrogeno1ysis of (4R)-3-((2S)-2-(hydroxy(4-methoxy-3-(3-methoxypropoxy)phenyl)methyl)-3-methylbutanoyl)-4-phenyloxazo1idin-2-one compound of formula-6

Formula-6 with a suitable hydrogen source in the presence of suitable acid in a suitable so1vent to provide (R)-3-((R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutanoyl)-4-phenyloxazo1idin -2-one compound of formula-7.

The hydrogeno1ysis of (4R)-3-((2S)-2-(hydroxy(4-methoxy-3-(3-methoxy propoxy)phenyl)methyl)-3-methylbutanoyl)-4-phenyloxazo1idin-2-one compound of formula-6 is carried out by reacting it with palladium on carbon in presence of suitable acid selected from hydrochloric acid, hydrobromic acid, acetic acid, benzenesulfonic acid, camphoursulfonic acid, ethanesulfonic acid, fumaric acid, maleic acid, methane sulfonic acid, oxalic acid, phosphoric acid and sulfuric acid in the presence of hydrogen;

The hydrogeno1ysis can also be carried out by using the suitable reducing agents. 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/ A1203, Pd/MgO, Pd/CaC03) Pd/ BaS04, PdO, Pd Black, PdCl2) Rh/C, Ru/C, Re/C, PtC>2, Rh/C, RuC«2, hydride reagents like sodium borohydride, sodium cyanoborohydride, lithium aluminium hydride and vitride etc. in presence or absence of hydrogen.

The fourth aspect of the present invention provides a novel process for the preparation of (R)-3-((R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methyl butanoyl)-4-phenyloxazo1idin-2-one compound of formula-7 which comprises of

a) Reacting the 4-methoxy-3-(3-methoxypropoxy)benzaldehyde compound of formula-4

Formula-4 with (R)-3-(3-methylbutanoyl)-4-phenyloxazo1idin-2-one compound of formula-5

Formula-5 in presence of a titanium tetrachloride or titanium(IV) isopropoxide or mixtures thereof, and a suitable base in a suitable so1vent provides (4R)-3-((2S)-2-(hydroxy(4-methoxy-3-(3-methoxypropoxy)phenyl)methyl)-3-methylbutanoyl)-4-phenyl oxazo1idin-2-one compound of formula-6.

Formula-6

b) hydrogeno1ysis of compound of formula-6 with a suitable hydrogen source in the
presence of suitable acid in a suitable so1vent to provide (R)-3-((R)-2-(4-methoxy-3-
(3-methoxypropoxy)benzyl)-3-methylbutanoyl)-4-phenyloxazo1idin-2-one compound
of formula-7.

Wherein in the step a) the reaction of 4-methoxy-3-(3-methoxypropoxy) benzaldehyde compound of formula-4 with (R)-3-(3-methylbutanoyl)-4-phenyl oxazo1idin-2-one compound of formula-5 take place in presence of titanium tetrachloride or titanium(IV) isopropoxide or mixtures thereof and a suitable base is selected from organic bases preferably diisopropy ethyl amine in a suitable so1vent selected from ester so1vents, ether so1vents, hydrocarbon so1vents, po1ar aprotic so1vents, ketone so1vents, alcoho1ic so1vents, chloro so1vents, po1ar so1vents or mixtures thereof; preferably chloro so1vents.

The reaction also takes place when the reagents like lithium diisopropyl amine (LDA), Lithium hexamethyldisilazide (LiHMDS), n-butyl lithium are utilized in the place of titanium tetrachloride or titanium (IV) isopropoxide or mixtures thereof.

Wherein in the step b) hydrogeno1ysis of (4R)-3-((2S)-2-(hydroxy(4-methoxy-3-(3-methoxypropoxy)phenyl)methyl)-3-methylbutanoyl)-4-phenyloxazo1idin-2-one compound of formula-6 is carried out by reacting it with palladium on carbon in presence of suitable acid selected from hydrochloric acid, hydrobromic acid, acetic acid, benzenesulfonic acid, camphoursulfonic acid, ethanesulfonic acid, fumaric acid, maleic acid, methane sulfonic acid, oxalic acid, phosphoric acid and sulfuric acid in presence of hydrogen.

The hydrogeno1ysis can also be carried out by using the suitable reducing agents. 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/ A1203, Pd/MgO, Pd/CaC03) Pd/ BaS04, PdO, Pd Black, PdCl2; Rh/C, Ru/C, Re/C, PtO2, Rh/C, RuO2, hydride reagents like sodium borohydride, sodium cyanoborohydride, lithium aluminium hydride and vitride etc. in presence or absence of hydrogen.

The fifth aspect of the present invention provides (4R)-3-((2S)-2-(hydroxy(4-methoxy-3-(3-rnethoxypropoxy)phenyl)methyl)-3-methylbutanoyl)-4-phenyloxazo1idin-2-one compound represented by the fo1lowing structural formula-6,

Formula-6 The novel compound of formula-6 of the present invention is useful as an intermediate in the preparation of (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutan-1-o1 compound of formula-1.

The sixth aspect of the present invention provides a novel amine salts of (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutanoic acid compound of general formula-9,

Formula-9 The novel amine salts compound of general formula-9 are useful in the preparation of highly pure (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutanoic acid compound of formula-8.

The term "Organic amine" refers to the amine selected from methyl amine, ethyl amine, di methyl amine, tri methyl amine, diethyl amine, tri ethyl amine n-propyl amine, isopropyl amine, n-butyl amine, tertiary butyl amine, (+/-)-sec-butyl amine, octyl amine, 2-ethyl hexylamine, benzyl amine, a-methyl-benzylamine, phenyl ethylamine, dibenzylamine, N-methylbenzylamine, N,N-dimethylbenzylamine, N,N-diethyl benzyl amine, N-ethyl-N-methylbenzylamine, tribenzyl amine, cyclopentylamine, cyclohexyl amine, cycloheptylamine, N-methylcyclopentylamine, N-ethylcyclohexyl amine, N-ethyl cycloheptylamine, dicyclohexylamine, N,N-dimethylcyclo pentylamine, N,N-dimethyl cyclohexylamine, N,N-diethylcycloheptylamine and the like.

The seventh aspect of the present invention provides a process for the preparation of novel amine salts of (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutanoic acid compound of general formula-9 which comprises of reacting the (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutanoic acid compound of formula-8 with a suitable amine as discussed above, in a suitable so1vent selected from ester so1vents, ether so1vents, hydrocarbon so1vents, po1ar aprotic so1vents, ketone so1vents, alcoho1ic so1vents, chloro so1vents, po1ar so1vents or mixtures thereof, at a suitable temperature provides the corresponding amine salt of compound of general formula-9.

The obtained amine salts, compound of general formula-9 are useful in the preparation of highly pure (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutanoic acid compound of formula-8 as well as compound of formula-1.

The intermediate compounds and salts prepared in the above aspect of the present invention are used in the preparation of highly pure (2S,4S,5S,7S)-N-(2-Carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy) phenyl]-octanamide and its pharmaceutically acceptable salts.

The present invention is schematically represented a fo1lows.

Scheme-1:

Scheme-2:

Scheme-3:

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 3-methoxypropyl methanesulfonate.

To the so1ution of 3-methoxypropan-l-o1 (100 grams) in methylene chloride (700 ml) added triethyl amine(168 grams) and coo1ed the reaction mixture to 0-5°C. Added methane sulfonyl chloride (153 grams) to the reaction mixture at 0-5°C. Stirred the reaction mixture for 6 hours at same temperature. Water (500 ml) was added to the reaction mixture and stirred for 30 minutes at 25-30°C. Separated the both aqueous and organic layers. The organic layer was washed with 5% sodium bicarbonate so1ution and fo1lowed by washed with water. Distilled off the so1vent completely from the organic layer under reduced pressure to get the title compound. Yield: 185 grams

Example-2: Preparation of 4-methoxy-3-(3-methoxypropoxy) benzaldehyde.

To a so1ution of 3-hydroxy-4-methoxybenzaldehyde (100 grams), to1uene (2000 ml) and potassium carbonate (136 grams), added 3-methoxypropylmethane sulfonate (143.6 grams) and then heated the reaction mixture to reflux temperature. After completion of the reaction, coo1ed the reaction mixture to 25-30°C, added water and stirred for 30 minutes. Both organic and aqueous layers were separated. Washed the organic layer with 5% sodium bicarbonate so1ution. Distilled off the so1vent completely from organic layer under reduced pressure to get the title compound. Yield: 130 grams.

Example-3: Preparation of (4R)-3-(2S)-2-(hydroxy(4-methoxy-3-(3-methoxy propoxy)phenyl) methyl)-3-methylbutanoyl)-4-phenyloxazo1idin-2-one.

To 77 grams of titanium tetrachloride added 1200 ml of methylene chloride under nitrogen atmosphere. Coo1ed the reaction mixture to 0-5°C, and added 40.5 grams of titanium IV isopropoxide at the same temperature. To the above reaction mixture added a
so1ution of (R)-3-(3-methylbutanoyl)-4-phenyloxazo1idin-2-one (100 grams) disso1ved in methylene chloride (200 ml) at 0-5°C and stirred for 30 minutes at same temperature. Then added a so1ution of N-ethyl diisopropylamine (DIPEA)(115 grams) at 0-5°C and stirred for 30 minutes at the same temperature. Coo1ed the reaction mixture to -25 to -30°C and then added a mixture of 4-methoxy-3-(3-methoxypropoxy) benzaldehyde (91 grams) disso1ved in methylene chloride(100 ml) and stirred at the same temperature. After completion of the reaction, added a mixture of acetic acid(100 ml) in methylene chloride (100 ml) at -25 to-30°C. Then raised the temperature to 0-5°C and added 2N so1ution of sulfuric acid (200 ml) to the reaction mixture. Stirred the reaction mixture for 1 hour. Separated the both organic and aqueous layers. The organic layer was washed twice water and distilled off the so1vent completely under reduced pressure to get the title compound. Yield: 175 grams.

Example-4: Preparation of (R)-3-((R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutanoyl)-4-phenyloxazo1idin-2-one.

To a mixture of 60 grams of wet Pd/C and 300 ml of acetic acid added a so1ution of (4R)-3-(2S)-2-(hydroxy(4-methoxy-3-(3-methoxypropoxy)phenyl)methyl)-3-methyl butanoyl)-4-phenyloxazo1idin-2-one (100 grams) in acetic acid (300 ml) at 25-30°C.

Applying 4.0 Kgs/cm hydrogen pressure to the reaction mixture. Heated the reaction mixture to 60-70°C and stirred. After completion of the reaction, the reaction mixture

was coo1ed to 25-30°C. Filtered the reaction mixture and washed twice with 100 ml
acetic acid. Added 350 ml of water to the filtrate and extracted with methylene chloride.

Washed the organic layer with water and 5% sodium bicarbonate so1ution. The so1vent
from the organic layer was completely distilled off under reduced pressure to get the title
compound.

Yield: 90 grams.

Example-5: Preparation of (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyI)-3-
methylbutanoic acid.

90 ml of 30% hydrogen peroxide was added to 0-5°C pre coo1ed tetrahydrofuran (500 ml). 200 ml of water was added to the reaction mixture. Aqueous lithium hydroxide

so1ution (18.5 grams in 100 ml of water) was added to the reaction mixture at 0-5°C and stirred for 15 minutes. A so1ution of (R)-3-((R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutanoyl)-4-phenyloxazo1idin-2-one (100 grams) in tetrahydrofuran (200 ml) was added to the above reaction mixture at 0-5°C. Raised the temperature to 25-30°C and stirred the reaction mixture. After completion of the reaction, coo1ed the reaction mixture to 0-5°C. Added 15% sodium bicarbonate so1ution fo1lowed by 15% sodium sulphite so1ution to the reaction mixture at same temperature. Added ethyl acetate (650 ml) to the reaction mixture and stirred for 10 minutes. Separated the organic and aqueous layers. The aqueous layer was coo1ed to 0-10°C and acidified with 2N hydrochloric acid and extracted with methylene chloride. Separated the both aqueous and organic layers. Distilled off the so1vent completely from the organic layer under reduced pressure to get the title compound. Yield: 52 grams.

Example-6: Preparation of S-phenylethanamine salt of (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutanoic acid.

To a so1ution of (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutanoicacid (l00grams) compound of formula-9 in mixture of acetonitrile (200 ml) and cyclohexane (400 ml) was added S-phenylethylamine (39 grams) at 25-30°C. The reaction mixture was stirred for 30 minutes and coo1ed to 0-10°C. Stirred the reaction mixture for 60 minutes at 0-10°C, filtered the obtained so1id and washed with mixture of acetonitrile (20 ml) and cyclohexane (20 ml). The material was dried for 3hrs at 40-45°C. The dried material was disso1ved in dichloromethane (200 ml) and then water (200 ml) was added. Reaction mixture was stirred for 10 min at 30°C, and coo1ed to 0-10°C. The pH of the reaction mixture was adjusted to 1.5 by adding 50% HC1 (70 ml) so1ution at 0-10°C.

Temperature of the reaction mixture was raised to 15-25°C. Both the organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined and washed with 10% NaCl so1ution, distilled of the so1vent completely under reduced pressure to get the title compound. Yield: 102 grams.

Example-7: Preparation of tert.Butyl amine salt of (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methy!butanoic acid.

To a so1ution of (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutanoicacid (l00grams) compound of formula-9 in mixture of acetonitrile (200 ml) and cyclohexane (400 ml) was added tert.Butyl amine (39 grams) at 25-30°C. The reaction mixture was stirred for 30 minutes and coo1ed to 0-10°C. Stirred the reaction mixture for 60 minutes at 0-10°C, filtered the obtained so1id and washed with mixture of acetonitrile (20 ml) and cyclohexane (20 ml). The material was dried for 3hrs at 40-45°C. The dried material was disso1ved in dichloromethane (200 ml) and then water (200 ml) was added. Reaction mixture was stirred for 10 min at 30°C, and coo1ed to 0-10°C. The pH of the reaction mixture was adjusted to 1.5 by adding 50% HC1 (70 ml) so1ution at 0-10°C. Temperature of the reaction mixture was raised to 15-25°C. Both the organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined and washed with 10% NaCl so1ution, distilled of the so1vent completely under reduced pressure to get the title compound. Yield: 90 grams.

We Claim:

1. A novel process for the preparation of (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutan-l-o1 compound of formula-1, comprises of,

a) Reacting the 3-methoxypropylmethanesulfonate compound of formula-2,

Formula-2

with 3-hydroxy-4-methoxybenzaldehyde compound of formula-3,

Formula-3

in presence of a suitable base and a suitable so1vent to provide 4-methoxy-3-(3-methoxypropoxy)benzaldehyde compound of formula-4,

Formula-4

b) reacting the compound of formula-4 with (R)-3-(3-methylbutanoyl)-4-phenyl
oxazo1idin-2-one compound of formula-5,

Formula-5

in presence of titanium tetrachloride or titanium(IV) isopropoxide or mixtures thereof, and a base in a suitable so1vent to provide (4R)-3-((2S)-2-(hydroxy(4-methoxy-3-(3-methoxypropoxy)phenyl)methyl)-3-methylbutanoyl)-4-phenyl oxazo1idin-2-one compound of formula-6,

Formula-6

c) hydrogeno1ysis of compound of formula-6 with a suitable hydrogen source in the
presence of a acid in a suitable so1vent to provide (R)-3-((R)-2-(4-methoxy-3-(3-
methoxypropoxy)benzyl)-3-methylbutanoyl)-4-phenyloxazo1idin-2-one
compound of formula-7,

Formula-7

d) hydro1yzing the compound of formula-7 with a suitable base in presence of
peroxide in a suitable so1vent to provide (R)-2-(4-methoxy-3-(3-methoxypropoxy)
benzyl)-3-methylbutanoic acid compound of formula-8,

Formula-8

e) reducing the compound of formula-8 with a suitable reducing agent in a suitable
so1vent to provide (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methyl
butan-1-o1 compound of formula-1.

Formula-1

2. A process according to claim 1, wherein,

in step-a) the suitable base is selected from alkali metal carbonates like sodium carbonate, potassium carbonate; and the suitable so1vent is preferably hydrocarbon so1vents selected from to1uene, xylene, cyclohexane, hexane and heptane,

in step-b) the suitable base is selected from diisopropyl ethyl amine or triethyl amine and suitable so1vent is selected from ester so1vents, ether so1vents, hydrocarbon so1vents, po1ar aprotic so1vents, ketone so1vents, alcoho1ic so1vents, chloro so1vents, po1ar so1vents or mixtures thereof; preferably chloro so1vents,

in step-c) the hydrogeno1ysis step is carried out by using reducing agent selected from Pd/C, Raney nickel, Pt02, Pd black, PdCl2 , PdO, Pd/BaS04, Pd/Al203, Rh/C, Ru/C, Ru02, and hydrogen gas or other reducing agents such as sodium borohydride, Lithium aluminium hydride or vitride thereof; the suitable acid is selected from hydrochloric acid, hydrobromic acid, acetic acid, benzenesulfonic acid, camphorsulfonic acid, ethanesulfonic acid, fumaric acid, maleic acid, methane sulfonic acid, oxalicacid, phosphoric acid and sulfuric acid in presence of hydrogen,

in step-d) the suitable base is selected from inorganic bases like alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates or organic bases like triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, N-methyl morpho1ine, piperidine and pyridine; and the peroxides like hydrogen peroxide, per acids such as peracetic acid, trifluoro peracetic acid, perbenzoic acid, m-chloro perbenzoic acid and the like; the suitable so1vent is selected from ester so1vents, ether so1vents, hydrocarbon so1vents, po1ar aprotic so1vents, ketone so1vents, alcoho1ic so1vents, chloro so1vents, po1ar so1vents or mixtures thereof; preferably lithium hydroxide in presence of hydrogen peroxide in tetrahydrofuran.

3. A compound having the fo1lowing structural formula:

wherein, P = H (formula-6), or

P = benzyl (formula-6a).

4. A process for the preparation of (4R)-3-((2S)-2-(hydroxy(4-methoxy-3-(3-methoxy propoxy) phenyl)methyl)-3-methyl butanoyl)-4-phenyloxazo1idin-2-one compound of formula-6, comprises of reacting the 4-methoxy-3-(3-methoxypropoxy)benzaldehyde compound of formula-4, with (R)-3-(3-methylbutanoyl)-4-phenyloxazo1idin-2-one compound of formula-5 in presence of titanium tetrachloride or titanium(IV) isopropoxide or mixtures thereof, and a base in a suitable so1vent to provide (4R)-3-((2S)-2-(hydroxy(4-methoxy-3-(3-methoxypropoxy)phenyl)methyl)-3-methyl butanoyl)-4-phenyloxazo1idin-2-one compound of formula-6.

5. A process for the preparation of (4R)-3-((2S)-2-(hydroxy(4-methoxy-3-(3-methoxypropoxy) phenyl)methyl)-3-methyl butanoyl)-4-phenyloxazo1idin-2-one compound of formula-6, comprises of reacting the 4-methoxy-3-(3-methoxypropoxy)benzaldehyde compound of formula-4, with (R)-3-(3-methylbutanoyl)-4-phenyloxazo1idin-2-one compound of formula-5 with the mixture of titanium tetrachloride and titanium(IV) isopropoxide, in presence of organic base selected from triethyl amine or diisopropyl ethylamine in methylene chloride.

6. A process for the preparation of (R)-3-((R)-2-(4-methoxy-3-(3-methoxy propoxy) benzyl)-3-methylbutanoyl)-4-phenyl oxazo1idin-2-one compound of formula-7, comprises of hydrogeno1ysis of (4R)-3-((2S)-2-(hydroxy(4-methoxy-3-(3-methoxy propoxy)phenyl)methyl)-3-methylbutanoyl)-4-phenyloxazo1idin-2-one compound of formula-6, by using palladium on carbon and hydrogen gas in presence of an organic or mineral acid to provide (R)-3-((R)-2-(4-methoxy-3-(3-methoxypropoxy)ben2yl)-3-methylbutanoyl)-4-phenyl oxazo1idin -2-one compound of formula-7.

7. A novel process for the preparation of (R)-3-((R)-2-(4-methoxy-3-(3-methoxy propoxy)benzyl)-3-methylbutanoyl)-4-phenyloxazo1idin-2-one compound of formula-7, comprises of:

a) Reacting the 4-methoxy-3-(3-methoxypropoxy)benzaldehyde compound of formula-4 with (R)-3-(3-methylbutanoyl)-4-phenyloxazo1idin-2-one compound of formula-5 in presence of a titanium tetrachloride or titanium(IV) isopropoxide or mixtures thereof, and a suitable base in a suitable so1vent to provide (4R)-3-((2S)-2-(hydroxy(4-methoxy-3-(3-methoxypropoxy)phenyl)methyl)-3-methylbutanoyl)-4-phenyl oxazo1idin-2-one compound of formula-6,

b) hydrogeno1ysis of compound of formula-6 with a suitable hydrogen source in the presence of suitable acid in a suitable so1vent to provide (R)-3-((R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutanoyl)-4-phenyloxazo1idin-2-one compound of
formula-7.

8. Novel amine salts of intermediate compound of general formula-9,

Formula-9

wherein, the "Organic amine" is selected from methyl amine, ethyl amine, di methyl amine, tri methyl amine, diethyl amine, tri ethyl amine n-propyl amine, isopropyl amine, n-butyl amine, tertiary butyl amine, (+/-)-sec-butyl amine, octyl amine, 2-ethyl hexylamine, benzyl amine, a-methyl-benzylamine, phenyl ethylamine, dibenzylamine, N-methylbenzylamine, N,N-dimethylbenzylamine, N,N-diethyl benzyl amine, N-ethyl-N-methylbenzylamine, tribenzyl amine, cyclopentylamine, cyclohexyl amine, cycloheptylamine, N-methylcyclopentylamine, N-ethylcyclohexyl amine, N-ethyl cycloheptylamine, dicyclohexylamine, N,N-dimethylcyclo pentylamine, N,N-dimethyl cyclohexylamine, N,N-diethylcycloheptylamine and the like.

9. A process for the preparation of novel amine salts of (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutanoic acid compound of general formula-9, comprises of reacting the (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutanoic acid compound of formula-8 with a suitable amine in a suitable so1vent selected from ester so1vents, ether so1vents, hydrocarbon so1vents, po1ar aprotic so1vents, ketone so1vents, alcoho1ic so1vents, chloro so1vents, po1ar so1vents or mixtures thereof, at a suitable temperature to provide the corresponding amine salt of compound of general formula-9.

10. A process for the preparation of highly pure (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutanoic acid compound of formula-8, comprises of reacting the amine salt of (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutanoic acid compound of general formula-9 with a suitable acid in a suitable so1vent to provide the highly pure compound of formula-8.