Field of the invention:

The present invention relates to the improved process for the preparation of (R)-4-(2-(Halomethyl)-3-methylbutyl)-l-methoxy-2-(3-methoxypropoxy) benzene, compound of formula -1 and 3-amino-2,2-dimethylpropanamide compound of formula-12, useful intermediates 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 and its pharmaceutically acceptable salts.

Formula-1 Formula-12

la) X=Br

lb)X=C1

Background of the Invention:

The process for the preparation of renin inhibitors have been reported in US5559111. (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 and 3-amino-2,2-dimethylpropanamide are the most important intermediates used in the preparation of (2S,4S,5S,7S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy) phenyl] -octanamide and its pharmaceutically 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 hydrogen peroxide and lithium hydroxide 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 main disadvantage of the preceding step is that it takes a very long time i.e. around four days for completion of the reaction.

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 hydrogen peroxide and lithium hydroxide to provide 2(R)-isopropyl-3[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propionic acid. It was treated with sodium borohydride and iodine to provide (R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutan-l-o1.

An alternative process reported in Tetrahedron letters, Vo1. 46(2005), pages: 6337-6340 for the preparation of (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutan-1-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-methylbutan-l-o1 which is difficult to handle on a large scale industrial process and also provides impurities.

The said journal also provides a process for the preparation of 3-amino-2,2-dimethylpropanamide. The process comprising of reacting 2-cyanoacetamide with methyl iodide in presence of sodium methoxide provides 2-cyano-2-methylpropanamide. The obtained 2-cyano-2-methylpropanamide was treated with lithium aluminium hydride fo1lowed by treated with Carboobenzoxy Chloride(CbzC1) in the presence of triethyl amine provides benzyl 3-amino-2,2-dimethyl-3-oxopropylcarbamate. The obtained benzyl 3-amino-2,2-dimethyl-3-oxopropylcarbamate compound was treated with Pd(OH)2/C under hydrogen pressure provides 3-amino-2,2-dimethylpropanamide. But the said process reported very poor yields (20 %) and hence there is a need in the art for an alternative process with high purity and yield.

(R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutan-l-o1 is converted into (R)-4-(2-(Halomethyl)-3 -methylbutyl)-1 -methoxy-2-(3 -methoxypropoxy) benzene, compound of formula -1,wherein X is bromo or chloro derivative by utilizing the corresponding halogenating agent.

Since the prior art processes are time consuming, providing low yield and invo1ve very high cost of production, hence there is a need for a process which overcomes the above said problems and provides (R)-2-(4-methoxy-3 -(3 -methoxypropoxy) benzyl)-3-methylbutan-1 -o1 with higher purity and yield.

Brief Description of the Invention:

The present invention relates to the improved process for the preparation of (R)-4-(2-(halomethyl)-3 -methylbutyl)-1 -methoxy-2-(3 -methoxypropoxy)benzene, 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 and its pharmaceutically acceptable salts.

The first aspect of the present invention is to provide an improved process for the preparation of (R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutan-l -o1 compound of formula-11, comprises of reducing the (R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methyl butanoic acid compound of formula-10, with sodium
borohydride in the presence of boron trifluoro etherate in nitrogen atmosphere in the presence of ether so1vent preferably tetrahydrofuran to provide (R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutan-l-o1 compound of formula-11.

The second aspect of present invention pertains to an improved process for the
preparation of (R)-4-(2-(halomethyl)-3-methylbutyl)-1 -methoxy-2-(3-methoxy
propoxy)benzene, compound of formula-1, which comprises of;

a) Reacting 3-methoxypropan-l-o1 compound of formula-2 with methanesulfonyl chloride in the presence of base, gives 3-methoxypropyl methane sulfonate compound of formula-3,

b) condensation of compound of formula-3 with 3-hydroxy-4-methoxy benzaldehyde compound of formula-4, in the presence of base in a suitable so1vent gives 4-methoxy-3-(3-methoxypropoxy) benzaldehyde compound of formula-5,

c) reducing the 4-methoxy-3-(3-methoxypropoxy) benzaldehyde compound of formula-5 in the presence of suitable reducing agent, in a suitable so1vent gives (4-methoxy)-3-(3-methoxypropoxy)benzyl alcoho1 compound of formula-6,

d) compound of formula-6 on subsequent bromination in the presence of suitable so1vent provides 4-(bromomethyl)-1 -methoxy-2-(3-methoxypropoxy)benzene compound of formula-7,

e) compound of formula-7 undergoes condensation with (R)-3-(3-methylbutanoyl)-4-phenyloxazo1idin-2-one compound of formula-8 in the presence of suitable base in a suitable so1vent to give (R)-3-((R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutanoyl)-4-phenyloxazo1idin-2-one compound of formula-9,

f) compound of formula-9 undergoes hydro1ysis in the presence of a suitable base in a suitable so1vent to give (R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methyl
butanoic acid compound of formula-10,

g) compound of formula-10 on further reduction in the presence of suitable reducing
agent, in a suitable so1vent gives (R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-
methylbutan-1-o1 compound of formula-11,

h) treating compound of formula-11 with a suitable halogenating agent in a suitable so1vent provides (R)-4-(2-(halomethyl)-3-methylbutyl)-1 -methoxy-2-(3-methoxy propoxy) benzene, compound of formula-1.

The third aspect of the present invention pertains to a single pot process for the preparation of (4-methoxy)-3-(3-methoxypropoxy)benzyl alcoho1 compound of formula-6 from 3-methoxypropyl methane sulfonate compound of formula-3.

The fourth aspect of the present invention pertains to a process for the preparation of (R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutan-l-o1 compound of formula-11, which comprises of reducing the (R)-3-((R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutanoyl)-4-phenyloxazo1idin-2-one compound of formula-9 with a suitable reducing agent in a suitable so1vent to provide (R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutan-l-o1 compound of formula-11.

The fifth aspect of the present invention pertains to an improved process for the preparation of 3-amino-2,2-dimethylpropanamide compound of formula-12, which comprises of;

a) Reacting ethyl 2-cyanoacetate compound of formula-13 with methyl iodide in the presence of suitable base in a suitable so1vent to provide ethyl 2-cyano-2-methylpropanoate compound of formula-14,

b) compound of formula -14 on treatment with methano1ic ammonia provides 2-cyano-2-methylpropanamide compound of formula-15,

c) compound of formula-15 on reduction with a suitable reducing agent provides 3-amino-2,2-dimethylpropanamide compound of formula-12.

Detailed Description of 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 formamide, dimethyl sulfoxide; "ketone so1vents" like acetone, methyl ethyl ketone, methyl isobutyl ketone; "alcoho1ic so1vents" like methano1, ethano1, n-propano1, isopropano1, n-butano1 and isobutano1; "chloro so1vents" like methylene chloride, chloroform and ethylene dichloride; "nitrile so1vents" like acetonitrile and propionitrile; 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.

The reactions is carried out in the presence/or absence of a phase transfer catalyst which is selected from the group consisting of but not limited to tetra butyl ammonium bromide, tetra propyl ammonium bromide, tributyl benzyl ammonium bromide, tetra octyl ammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium hydrogen sulfate, benzyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, tetra butyl ammonium acetate, tetra butyl ammonium iodide, ethyl triphenyl phosphonium bromide, more preferably tetra butyl ammonium bromide or alkali iodides like sodium iodide, potassium iodide and lithium iodide.

The present invention relates to the improved process for the preparation of (R)-4-(2-(halomethyl)-3 -methylbutyl)-1 -methoxy-2-(3-methoxypropoxy) benzene, compound of formula -1, a useful intermediate in the synthesis of an orally active renin inhibitor and its pharmaceutically acceptable salts.

The first aspect of the present invention provides an improved process for the preparation of (R)-2-(4-methoxy-3 -(3 -methoxypropoxy)benzyl)-3 -methylbutan-1 -o1 compound of formula-11

Formula-11

which comprises of,

reducing the (R)-2-(4-methoxy-3 -(3 -methoxypropoxy)benzyl)-3 -methyl butanoic acid
compound of formula-10,

Formula-10 with sodium borohydride in the presence of boron trifluoro etherate in nitrogen atmosphere in ether so1vent preferably tetrahydrofuran to provide (R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutan-l-o1 compound of formula-11.

In the prior art the above reaction was carried out using sodium borohydride and iodine to provide (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutan-l-o1. The main disadvantage of prior art is that it takes a very long time i.e. around four days for completion of the reaction. Also lithium aluminium hydride was utilized in the place of sodium borohydride, which is difficult to handle on a large scale industrial process and also prove impurities. In our invention the reaction was completed within four to five hours and also the impurities were contro1led by the specific reagent used.

The second aspect of the present invention pertains to an improved process for the preparation of (R)-4-(2-(halomethyl)-3-methylbutyl)-l-methoxy-2-(3-methoxypropoxy) benzene, compound of formula-1 which comprises of;

a) Reacting 3 -methoxypropan-1 -o1 compound of formula-2

Formula-2 with methanesulfonyl chloride in the presence of a base in a suitable so1vent gives 3-methoxypropyl methanesulfonate compound of formula-3,

Formula-3

b) condensation of 3-methoxypropyl methanesulfonate compound of formula-3 with 3-hydroxy-4-methoxybenzaldehyde compound of formula-4,

Formula-4 in the presence of a suitable base in a suitable so1vent gives 4-methoxy-3-(3-methoxypropoxy)benzaldehyde compound of formula-5,

Formula-5
c) reduction of 4-methoxy-3-(3-methoxypropoxy)benzaldehyde compound of formula-5

in the presence of suitable reducing agent in a suitable so1vent gives (4-methoxy)-3-(3-methoxypropoxy)benzyl alcoho1 compound of formula-6,

Formula-6
d) which on subsequent bromination with a suitable brominating agent in a suitable
so1vent provides 4-(bromomethyl)-l-methoxy-2-(3-methoxypropoxy) benzene compound of formula-7,

Formula-7
e) 4-(bromomethyl)-l-methoxy-2-(3-methoxypropoxy) benzene compound of formula-7 ndergoes condensation with (R)-3-(3-methylbutanoyl)-4-phenyloxazo1idin-2-one compound of formula-8,

Formula-8
in the presence of suitable base in a suitable so1vent gives (R)-3-((R)-2-(4-methoxy-3-
(3 -methoxypropoxy)benzyl)-3 -methylbutanoyl)-4-phenyloxazo1idin-2-one compound
of formula-9,

Formula-9

f) compound of formula-9 undergoes hydro1ysis with a suitable base in presence of
peroxide in a suitable so1vent to give (R)-2-(4-methoxy-3-(3-
methoxypropoxy)benzyl)-3-methyl butanoic acid compound of formula-10,

Formula-10
g) reducing the compound of formula-10 with a suitable reducing agent, in a suitable
so1vent gives (R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutan-1 -o1 compound of formula-11,

Formula-11 h) treating the compound of formula-11 with a suitable halogenating agent in a suitable so1vent provides (R)-4-(2-(halomethyl)-3 -methylbutyl)-1 -methoxy-2-(3 -methoxy propoxy) benzene, compound of formula-1.

Formula-1 The reactions in the above process may where ever required, be carried out in the presence of a 'phase transfer catalyst' which are defined above. 3-methoxypropane-l-o1 compound of formula-2 is prepared by treating it with a potassium hydroxide to generate the anion. The anion reacts with methyl iodide to provide compound of formula-2. In the step a) invention provides, reacting 3-methoxypropane-l-o1 compound of formula-2 with methanesulfonyl chloride in the presence of suitable bases like inorganic bases such as 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 preferably triethyl amine and the suitable so1vent is selected from chloro so1vents; preferably methylene chloride to provide 3-methoxypropylmethanesulfonate compound of formula-3.

In the step b) invo1ves reacting 3-methoxypropylmethanesulfonate compound of formula-3 with 3-hydroxy-4-methoxybenzaldehyde compound of formula-4 in the presence of suitable base. The suitable base is selected from the group consisting of but is not limited to inorganic bases selected from alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates preferably potassium carbonate. When sodium carbonate was used in place of potassium carbonate then the impurity level slightly increases. Hence potassium carbonate was preferred. The so1vents were selected from the group consisting of but is not limited to ester so1vents, ether so1vents, hydrocarbon so1vents like to1uene, xylene, cyclohexane, hexane, heptane; and suitable non po1ar aprotic so1vent includes but is not limited to benzene, to1uene, xylene, tetrahydofuran, 2-methyltetrahydrofuran, preferably to1uene; and reflux about 6-10 hrs, 8-10 hrs and 9-10 hrs; preferably 8-10 hrs to provide 4-methoxy-3-(3-methoxypropoxy)benzaldehyde compound of formula-5. When the reaction was carried out using potassium carbonate using to1uene as a so1vent then the yield and purity of the product increased substantially.

In the step c) 4-methoxy-3-(3-methoxypropoxy)benzaldehyde compound of formula-5 is reduced in the presence of suitable reducing agents like DIBAL, sodium borohydride, lithium tri-sec-butylborohydride ("L-selectride"), sodium dihydro-bis-(2-methoxyethoxy)aluminate(Vitride), bis diisobutyl aluminium hydride, lithium aluminium hydride, and the like, preferably sodium borohydride; and 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 tetrahydrofuran to provide (4-methoxy-3-(3-methoxypropoxy) phenyl) methano1, compound of formula-6.

In the step d) (4-methoxy-3-(3-methoxypropoxy) phenyl) methano1 compound of formula-6 is treated with suitable brominating agent selected form N-bromo succinamide, phosphorus tribromide, carbon tetrabromide preferably phosphorus tribromide in a suitable chloro so1vents selected from methylene chloride, ethylene dichloride, carbon tetra chloride, chloroform preferably methylene chloride to provide 4-(bromo methyl)-1-methoxy-2-(3-methoxypropoxy) benzene compound of formula-7.

In the step e) invention provides, reacting 4-(brornomethyi)-l-methoxy-2-(3-methoxypropoxy) benzene compound of formula-7 with (R)-3-(3-methylbutanoyl)-4-phenyloxazo1idin-2-one compound of formula-8 in the presence of strong bases selected from n-butyl lithium, LiHMDS (lithium hexamethyldisilazane), lithium diisoproypyl amide, sodium tertiary butoxide and potassium tertiary butoxide preferably LiHMDS and so1vent includes but is not limited to ester so1vents, ether so1vents, hydrocarbon so1vents, po1ar aprotic so1vents, ketone so1vents, alcoho1ic so1vents, chloro so1vents, po1ar so1vents or mixtures thereof; preferably tetrahydrofuran to provide (R)-3-((R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3 -methylbutanoyl)-4-phenyloxazo1idin-2-one compound of formula-9. When (R)-3-(3-methylbutanoyl)-4-phenyloxazo1idin-2-one compound of formula-8 was used in the place of (R)-3-(3-methylbutanoyl)-4-benzyloxazo1idin-2-one which is known in the art it was observed that there was substantial increase in the enantiomeric excess of required isomer.

In the step f) hydro1ysis of (R)-3-((R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutanoyl)-4-phenyloxazo1idin-2-one compound of formula-9 is carried out with a suitable alkaline base 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; in the presence of suitable peroxide selected from hydrogen peroxide, per acids such as peracetic acid, trifluoro peracetic acid, perbenzoic acid, m-chloro perbenzoic acid and the like preferably lithium hydroxide in presence of hydrogen peroxide in a suitable po1ar aprotic so1vents like tetrahydrofuran and hydrated lithium hydroxide to provide (R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutanoic acid compound of formula-10.

In the step g) invo1ves reduction of (R)-2-(4-methoxy-3-(3-methoxy propoxy) benzyl)-3-methylbutanoic acid compound of formula-10. The use of lithium aluminum hydride was reported in the prior art for this reaction, which is difficult to handle. In the present invention the reaction is performed in the combination of boron trifluoride etherate or BF3-THF and sodium borohydride complex preferably sodium borohydride in presence of suitable catalyst like BF3.Et20 in tetrahydrofuran to provide (R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutan-l-o1 compound of formula-11. This reagent is easy to handle and hence useful for scaling up. The reaction, can be carried out using DIBAL-H, vitride, etc in the presence of the 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 tetrahydrofuran.

In the step h) invo1ves reacting (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutan-l-o1 compound of formula-11 with a suitable halogenating agent selected from carbon tetra chloride, oxalyl chloride, thionyl chloride, phosphorous pentachloride, n-chloro succinamide, Phosphorus tribromide, carbon tetrabromide, N-bromo succinamide in presence or absence of triphenyl phosphene 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 methylene chloride to provide (R)-4-(2-(halomethyl)-3-methylbutyl)-l-methoxy-2-(3-methoxypropoxy) benzene compound of formula-1.

The third aspect of the present invention pertains to an single pot process for the preparation of (4-methoxy)-3-(3-methoxypropoxy) benzyl alcoho1 compound of formula-6 which comprises of treating the 3-methoxypropyl methane sulfonate compound of formula-3 with 3-hydroxy-4-methoxybenzaldehyde compound of formula-4 in the presence of suitable base in a suitable so1vent and subsequently treating the product formed without iso1ating it, with a suitable reducing agent like sodium borohydride to provide (4-methoxy)-3-(3-methoxypropoxy)benzyl alcoho1 compound of formula-6.

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 preferably potassium carbonate and 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 to1uene

The fourth aspect of the present invention is to provide a process for the preparation of (R)-2-(4-methoxy-3 -(3 -methoxypropoxy)benzyl)-3 -methylbutan-1 -o1 compound of formula-11,

Formula-11 which comprises of, reducing the (R)-3-((R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutanoyl)-4-phenyloxazo1idin-2-one compound of formula-9

Formula-9
with a suitable reducing agent in a suitable so1vent at a suitable temperature provides
(R)-2-(4-methoxy-3 -(3 -methoxypropoxy)benzyl)-3 -methylbutan-1 -o1 compound of formula-11.

The suitable reducing agent is selected from the combination of boron trifluoride
etherate or BF3-THF and sodium borohydride complex preferably sodium borohydride in
presence of suitable catalyst like BFs.EtiO in a suitable so1vent selected from ether
so1vents, ester so1vents, ketone so1vents, po1ar aprotic so1vents, hydrocarbon so1vents or mixtures thereof; preferably tetrahydrofuran and the reaction is carried out at reflux
temperature of the so1vent used in the reaction.

The fifth aspect of the present invention pertains to an improved process for the preparation of 3-amino-2,2-dimethylpropanamide compound of formula-12, which comprises of; a) Reacting ethyl 2-cyanoacetate compound of formula-13

Formula-13

with methyl iodide in the presence of base in a suitable so1vent to provide ethyl 2-cyano-2-methylpropanoate compound of formula-14,

Formula-14
b) compound of formula -14 on treatment with methano1ic ammonia provides 2-cyano-2-methylpropanamide compound of formula-15

Formula-15
c) compound of formula-15 on reduction with raney nickel in the presence of ammonia in a suitable so1vent provides 3-amino-2,2-dimethylpropanamide compound of
formula-12.

Formula-12
Wherein in the step a) the suitable base is selected from inorganic bases like alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates or organic bases preferably potassium carbonate so1vent is selected from ester so1vents, ether so1vents, hydrocarbon so1vents, po1ar aprotic so1vents, ketone so1vents, alcoho1ic so1vents, chloro so1vents, po1ar so1vents or DMPU or mixtures thereof preferably dimethyl formamide. In the above reaction the methylation can be done by using dimethyl sulfate.

Wherein in step c) the reduction can be carried out by using vitride, DIBAL, Pd/C, vitride etc; and the suitable so1vent is selected from ester so1vents, ether so1vents, hydrocarbon so1vents, po1ar aprotic so1vents, ketone so1vents, alcoho1ic so1vents, chloro so1vents, po1ar so1vents; preferably methano1.

The present invention is schematically represented by the fo1lowing schemes

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-methoxypropan-1-o1.
735 grams of KOH was added to 1500 grams of 1,3-Propanedio1 at 80°C in portion wise for 1 hour and stirred for 1 hour. Then added 815 grams of methyl iodide drop wise for 12 hours and the mixture is stirred for 6 hours at 80°C. Coo1ed the reaction mixture to room temperature and extracted with chloroform. Separated the organic and aqueous layers; organic layer is dried with sodium sulphate and concentrated and then fractionally distilled to afford the title compound. Yield: 466 grams. Boiling point: 149°C.
Example-2: Preparation of 3-methoxypropyl methane sulfonate.

To the so1ution of 3-methoxypropan-l-o1 (100 gms) in methylene chloride (700 ml) added triethyl amine(168 gms) and coo1ed the reaction mixture to 0-5°C. Added methane sulfonyl chloride (153 gms) 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: 165 grams.

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

A mixture of 2000 ml to1uene, 100 grams 3-hydroxy-4-methoxybenzaldehyde, 136 grams of potassium carbonate and 150 grams of 3-methoxypropyl methanesulfonate was heated to reflux temperature. Stirred the reaction mixture for 10 hours at the same temperature. After completion of the reaction, the reaction mixture was coo1ed to room temperature. The reaction was quenched with water. Separated the both aqueous and organic layers. The organic layer was washed with water and dried with sodium sulphate. Distilled off the so1vent completely under reduced pressure to get the title compound.

Yield: 127 grams.

Example-4: Preparation of 4-Methoxy-3-(3-methoxy propoxy) benzyl alcoho1.

Added 11.87 grams of sodiumborohydride to 100 grams of 4-methoxy-3-(3-mehoxypropoxy)benzaldehyde in THF (1000 ml) at 0-5°C. The reaction mixture was allowed to coo1 to the 25-30°C and stirred for 7 hours at the same temperature. After completion of the reaction, the reaction was quenched with coo1 water and the PH was adjusted to 2 with 2N HC1. The reaction mixture was extracted with dichloromethane. The organic layer was dried with sodium sulphate and distilled under reduced pressure to get the title compound. Yield: 89 grams (88%).

Example-5: Preparation of 4-Methoxy-3-(3-methoxy propoxy) benzyl alcoho1.

A mixture of 2000 ml of to1uene, 100 grams of 3-hydroxy-4-methoxybenzaldehyde, 136 grams of potassium carbonate and 143.6 grams of 3-methoxypropyl methanesulfonate was heated to reflux temperature and stirred for 10 hours at the same temperature. After completion of the reaction, the reaction mixture was coo1ed to 25-30°C. Water was added to the reaction mixture and stirred for 30 minutes. Both the organic and aqueous layers were separated; organic layer was washed with sat. sodium bicarbonate and dried with sodium sulphate. 24.9 grams of sodium borohydride was added to the reaction mixture and fo1lowed by 50 ml of methano1 for about 60 minutes at 0-5°C. The reaction mixture was stirred for 7 hours at 25-30°C. After completion of the reaction, the reaction was quenched with ice coo1ed water with vigorous stirring and the PH of the reaction mixture was adjusted to 2 with 2N HC1. Both the organic and aqueous layers were separated and extracted the aqueous layer with methylene chloride. Both the organic layers were combined and washed with water. The organic layer was dried with sodium sulphate and distilled under reduced pressure to get the title compound. Yield: 114 grams.

Example-6: Preparation of 4-Methoxy-3-(3-methoxypropoxy) benzyl bromide

A so1ution of 145 ml of phosphorous tribromide in dichloromethane (350 ml) was added slowly to a mixture of (4-methoxy-3-(3-methoxypropoxy)benzyl alcoho1(70 grams) and dichloromethane(1050 ml) at 0-5°C about 2 hours. Stirred the reaction mixture for 10 minutes. After completion of the reaction, the reaction was quenched by pouring the reaction mixture slowly into ice co1d water with constant stirring. Seperated the both organic and aqueous layers. Washed the organic layer with water. The organic layer was dried with sodium sulphate. Distilled off the so1vent completely under reduced pressure to get the title compound. Yield: 71 grams.

Example-7: Preparation of (R)-3-(3-methylbutanoyl)-4-phenyloxazo1idin-2-one
Added a mixture of 250 ml of ethylene dichloride, 50 grams of 3-methylbutanoic acid, 8.0 grams of 4-dimethylamino pyridine and 80.17 grams of (R)-4-phenyloxazo1idin-2-one into a RB flask at ambient temperature and stirred for 30 minutes. Coo1ed the reaction mixture to 10-15°C and slowly added 107.4 grams of DCC in 30 minutes and stirred for 2 hours at the same temperature. Raised the temperature to 25-3 0°C and stirred for 12 hours. After completion of the reaction, filtered the byproduct and washed with ethylene dichloride. Then washed the filtrate with 2% hydrochloric acid and distilled off the so1vent completely under vacuum to get semi-so1id. Added cyclohexane to the semiso1id and distilled off completely under vacuum to get crystalline so1id, which is further treated with cyclohexane and stirred for 1.5 hour at RT. filter the so1id and wash the cake with cyclohexane and suck dry to get the title compound. Yield: 115 grams. Melting Point: 65-70°C.

Example-8: Preparation of (R)-3-((R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutanoyl)-4-phenyloxazo1idin-2-one.

A so1ution of (R)-3-(3-methylbutanoyl)-4-phenyloxazo1idin-2-one(51.9 grams) in tetrahydrofuran (150 ml) was added slowly to a mixture of tetrahydrofuran(150 ml) and lithium hexamethyl disilazide(LiHMDS) (350 ml) at -70°C under nitrogen atmosphere. Stirred the reaction mixture for 2 hours at the same temperature. Added a so1ution of 4-(bromomethyl)-l-methoxy-2-(3-methoxypropoxy)benzene (50 grams) in tetrahydrofuran (150 ml) to the above reaction mixture at -70°C. Raised the temperature to 0-5°C slowly.

The reaction mixture was stirred for 7 hours at the same temperature. After completion of the reaction, the reaction was quenched with 10% ammonium chloride so1ution and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride so1ution. Distilled off the so1vent completely from organic layer under reduced pressure to get the title compound. Yield: 80 grams, ee: 98.8%.

Example-9: Preparation of (R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyI)-3-methylbutanoic acid.

To 80 grams of (R)-3-((R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methyl butanoyl)-4-phenyloxazo1idin-2-one added 560 ml of tetrahydrofuran and 240 ml of water. Coo1ed the reaction mixture to 0-5°C and added 14.32 grams of lithium hydroxide mono hydrate to it. 30% hydrogen peroxide(69 ml) was added to the reaction mixture slowly at 0-5°C Raised the temperature of reaction mixture to 25-30°C and stirred for 7 hours at same temperature. After completion of the reaction, the reaction mixture was coo1ed to 0-5°C. 10% sodium sulphite so1ution (500 ml) was added to the reaction mixture and fo1lowed by 10% sodium bicarbonate so1ution (500 ml) was added and stirred the reaction mixture for 1 hour. The reaction mixture was extracted with ethyl acetate. Acidify the reaction mixture using 2N hydrochloric acid. Added methylene chloride to the reaction mixture and stirred for 20 minutes. Separated the both aqueous and organic layers and dried the organic layer with sodium sulphate. Distilled off the so1vent completely under reduce pressure to get the title compound. Yield: 25 grams.

Example-10: Preparation of (R)-2-[4-methoxy-3-(3-methoxypropoxy) benzyl]-3-methyl-butan-1-o1.

7.16 grams of sodium borohydride was added to the 0-5 °C pre coo1ed tetrahydrofuran (300 ml) under nitrogen atmosphere. A so1ution of (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutanoic acid (50 grams) disso1ved in tetrahydrofuran (200 ml) was added to the reaction mixture slowly. Stirred the reaction mixture for 1 hour at 0-5°C. Boron trifluoride etherate (BF3.Et20)(45.48 grams) was added to reaction mixture for about 45 minutes. Raised the temperature to 25-30°C. The reaction mixture was stirred for 5 hours at same temperature. After completion of the reaction, coo1ed the reaction mixture to 0-5 °C and added 50% hydrochloric acid so1ution (30 ml) to it. Added 500 ml of water and fo1lowed by 500 ml of methylene chloride to the reaction mixture. Separated the both aqueous and organic layers and the organic layer was washed with 10% sodium bicarbonate so1ution, fo1lowed by 10% sodium chloride so1ution. The organic layer was dried with sodium sulphate and distilled off the so1vent completely under reduced pressure to get the title compound. Yield: 36 grams.

Example-11: Preparation of Preparation of 2(R)-[4-Methoxy-3-(3-methoxypropoxy)-benzyl]-3-methyl-butano1

A so1ution of (R)-3-((R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methyl butanoyl)-4-phenyloxazo1idin-2-one(2 grams) disso1ved in tetrahydrofuran (10 ml) was added to the mixture of sodium borohydride (1.5 gm) and tetrahydrofuran (20 ml) at 0-5°C. Stirred the reaction mixure for 30 minutes at 10-15°C. Boron trifluoride etherate(BF3.Et20)(4.3 grams) was added to reaction mixture and heated to 60-65°C. The reaction mixture was stirred for 11 hours at same temperature. After completion of the reaction, coo1ed the reaction mixture to 0-5°C and quenched with 2N hydrochloric acid. The reaction mixture was extracted with ethyl acetate and washed with water. The organic layer was dried with sodium sulphate and distilled off the so1vent completely under reduced pressure to get the title compound. Yield: 1.3 grams

Example-12: Preparation of (R)-4-(2-(bromomethyl)-3-methylbutyl)-l-methoxy-2-(3-methoxypropoxy) benzene (Formula-la) 49 grams of triphenyl phosphine was added to the mixture of (R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutan-l-o1 (30 grams) and methylene chloride (450 ml) at -30 to -40°C. 35 grams of N-bromo succinamide was added to the reaction mixture at -30 to -40°C and stirred for 30 minutes at same temperature. The temperature of the reaction mixture was raised to 25-30°C and stirred for 5 hours at the same temperature. After completion of the reaction, the reaction mixture was quenched with sodium bicarbonate so1ution. Separated the both the organic and aqueous layers and the aqueous layer was extracted with methylene chloride. The organic layer was distilled off completely and the obtained residue was co-distilled with ethyl acetate. Cyclohexane was added to the obtained residue and stirred for 1 hour. The reaction mixture was filtered. Distilled off the so1vent completely from filtrate under reduced pressure. N-hexane was added to the obtained residue and stirred for 1 hour at 0-5°C. The reaction mixture was filtered, and the so1vent from the filtrate was distilled off completely. N-hexane and diethyl ether were added to the obtained residue and coo1ed to -20°C. The reaction mixture was stirred for 1 hour, filtered, washed with chilled N-hexane and dried to get the title compound as a so1id. Yield: 20 grams.

Example-13: Preparation of (R)-4-(2-(bromomethyl)-3-methylbutyl)-l-methoxy-2-(3-methoxypropoxy) benzene (Formula-la) 49 grams of triphenyl phosphine was added to the mixture of (R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutan-l-o1 (30 grams) and methylene chloride (450 ml) at -30 to -40°C. 35 grams of N-bromo succinamide was added to the reaction mixture at -30 to -40°C and stirred for 30 minutes at same temperature. The temperature of the reaction mixture was raised to 25-30°C and stirred for 5 hours at the same temperature. The reaction mixture was distilled off completely and the obtained residue was co-distilled with ethyl acetate. Cyclohexane was added to the obtained residue and stirred for 1 hour. The reaction mixture was filtered. Distilled off the so1vent completely from filtrate under reduced pressure. N-hexane was added to the obtained residue and stirred for 1 hour at 0-5 °C. The reaction mixture was filtered, and the so1vent from the filtrate was distilled off completely. N-hexane and diethyl ether were added to the obtained residue and coo1ed to -20°C. The reaction mixture was stirred for 1 hour, filtered, washed with chilled N-hexane and dried to get the title compound as a so1id. Yield: 22 grams.

Example-14: Preparation of (R)-4-(2-(chloromethyl)-3-methylbutyl)-l-methoxy-2-(3-methoxypropoxy) benzene (Formula-lb) 49 grams of triphenyl phosphine was added to the mixture of (R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutan-l-o1 (30 grams) and methylene chloride (450 ml) at -30 to -40°C. 26.5 grams of N-chloro succinamide was added to the reaction mixture at -30 to -40°C and stirred for 30 minutes at same temperature. The temperature of the reaction mixture was raised to 25-30°C and stirred for 5 hours at the same temperature. After completion of the reaction, the reaction mixture was quenched with sodium bicarbonate so1ution. Separated the both the organic and aqueous layers and the aqueous layer was extracted with methylene chloride. The organic layer was distilled off completely and the obtained residue was co-distilled with ethyl acetate. Cyclohexane was added to the obtained residue and stirred for 1 hour. The reaction mixture was filtered. Distilled off the so1vent completely from filtrate under reduced pressure. N-hexane was added to the obtained residue and stirred for 1 hour at 0-5°C. The reaction mixture was filtered, and the so1vent from the filtrate was distilled off completely. N-hexane and diethyl ether were added to the obtained residue and coo1ed to -20°C. The reaction mixture was stirred for 1 hour, filtered, washed with chilled N-hexane and dried to get the title compound as a so1id. Yield: 25 grams.

Example-15: Preparation of ethyl-2-cyano-2-methylpropanoate 376 grams of methyl iodide was added to a mixture of 244 grams of potassium carbonate, 300 ml of N,N-dimethylformamide and coo1ed the reaction mixture to 0-5°C. 100 grams of ethyl 2-cyano acetate was added to the reaction mixture at 0-5°C and stirred for 9 hours at the same temperature. After completion of the reaction, the reaction mixture was filtered and washed with methyl tert-butyl ether. Aqueous hydrochloric acid was added to the obtained filtrate. Separated the both organic and aqueous layers. Extracted the aqueous layer with methyl tert-butyl ether. Both the organic layers were combined, washed with brine so1ution and fo1lowed by sodium thio sulphate so1ution. Distilled off the so1vent completely from organic layer under reduced pressure to get the title compound. Yield: 106 grams.

Example-16: Preparation of 2-cyano-2-methylpropanamide.

1000 ml of methano1ic ammonia was added to 100 grams of ethyl 2-cyano-2-methylpropanoate and stirred the reaction mixture for 12 hours at 25-3 0°C. After the reaction was completed, the reaction mixture was distilled off completely under reduced pressure. Cyclohexane was added to the reaction mixture and stirred for 1 hour at 25-30°C. The reaction mixture was filtered, washed with cyclohexane. Dried the compound to get the title compound. Yield: 67.5 grams.

Example-17: Preparation of 3-amino-2,2-dimethylpropanamide

33 grams of Raney nickel was added to a mixture of 50 grams of 2-cyano-2-methylpropanamide and 750 ml of methano1ic ammonia and fo1lowed by 50 ml of methano1. 4 kg of hydrogen pressure was applied to the reaction mixture. The reaction mixture was stirred for 14 hours at 40-45°C. After the reaction was completed, the reaction mixture was filtered on hyflow bed and washed with methano1. Distilled off the reaction mixture completely to get the title compound as semi so1id. Yield: 41.5 grams.

We C1aim:

1. An improved process for the preparation of (R)-2-(4-methoxy-3-(3-methoxy propoxy)benzyl)-3-methylbutan-l-o1 compound of formula-11, comprises of, reducing the (R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methyl butanoic acid compound of formula-10, with a suitable reducing agent in nitrogen atmosphere in a suitable so1vent to provide (R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutan-1-o1 compound of formula-11.

2. An improved process for the preparation of (R)-2-(4-methoxy-3-(3-methoxy propoxy)benzyl)-3-methylbutan-l-o1 compound of formula-11, comprises of, reducing the (R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methyl butanoic acid compound of formula-10, with sodium borohydride in presence of boron trifluoro etherate in nitrogen atmosphere in ether so1vent, preferably tetrahydrofuran to provide (R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutan-l -o1 compound of formula-11.

3. An improved process for the preparation of (R)-4-(2-(halomethyl)-3-methylbutyl)-l-methoxy-2-(3-methoxypropoxy) benzene compound of formula-1, comprises of:

a) Reacting 3-methoxypropan-1 -o1 compound of formula-2, with methanesulfonyl chloride in the presence of a base in a suitable so1vent to provide 3-methoxy propyl methanesulfonate compound of formula-3,

b) condensing the 3-methoxypropyl methanesulfonate compound of formula-3 with 3-hydroxy-4-methoxybenzaldehyde compound of formula-4, in the presence of a suitable base in a suitable so1vent to provide 4-methoxy-3-(3-methoxy propoxy) benzaldehyde compound of formula-5,

c) reducing the 4-methoxy-3-(3-methoxypropoxy)benzaldehyde compound of formula-5 in presence of a suitable reducing agent in a suitable so1vent to provide (4-methoxy)-3-(3-methoxypropoxy)benzyl alcoho1 compound of formula-6,

d) reacting the 4-methoxy-3-(3-methoxypropoxy)benzyl alcoho1 compound of formula-6, with a suitable brominating agent in a suitable so1vent to provide 4-
(bromomethyl)-l-methoxy-2-(3-methoxypropoxy) benzene compound of formula-7,

e) condensing the 4-(bromomethyl)-l-methoxy-2-(3-methoxypropoxy) benzene compound of formula-7 with (R)-3-(3-methylbutanoyl)-4-phenyloxazo1idin-2-one compound of formula-8, in presence of a suitable base in a suitable so1vent to provide pure (R)-3-((R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methyl butanoyl)-4-phenyloxazo1idin-2-one compound of formula-9,

f) hydro1yzing the (R)-3-((R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutanoyl)-4-phenyloxazo1idin-2-one compound of formula-9, in a suitable base in presence of peroxide in a suitable so1vent to provide (R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methyl butanoic acid compound of formula-10,

g) reducing the compound of formula-10 with a suitable reducing agent in nitrogen atmosphere in a suitable so1vent to provide (R)-2-(4-methoxy-3-(3-methoxy propoxy)benzyl)-3-methylbutan-l-o1 compound of formula-11,

h) reacting the compound of formula-11 with a suitable halogenating agent in a suitable so1vent to provide (R)-4-(2-(halomethyl)-3-methylbutyl)-l-methoxy-2-(3-methoxypropoxy) benzene compound of formula-1.

4. The process according to claim 3, wherein,

in step-a) the suitable base is selected from inorganic bases such as 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 preferably triethyl amine; and the suitable so1vent is selected from chloro so1vents; preferably methylene chloride,

in step-b) the suitable base is selected from alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates preferably potassium carbonate; and the suitable so1vent is selected from ester so1vents, ether so1vents, hydrocarbon so1vents like to1uene, xylene, cyclohexane, hexane, heptane; and suitable non-po1ar aprotic so1vent includes but not limited to benzene, to1uene, xylene, tetrahydofuran, 2-methyltetrahydrofuran, preferably to1uene,

in step-c) the suitable reducing agent is selected from DIBAL, sodium borohydride, lithium tri-sec-butylborohydride ("L-selectride"), sodium dihydro-bis-(2-methoxy ethoxy)aluminate(Vitride), bis diisobutyl aluminium hydride, lithium aluminium hydride, preferably sodium borohydride; and 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 tetrahydrofuran,

in step-d) the suitable brominating agent is selected form N-bromo succinamide, phosphorus tribromide, carbon tetrabromide, preferably phosphorus tribromide; and the suitable so1vent is chloro so1vents selected from methylene chloride, ethylene dichloride, carbon terra chloride, chloroform preferably methylene chloride,

in step-e) the suitable base is selected from n-butyl lithium, LiHMDS (lithium hexamethyldisilazane), lithium diisoproypyl amide, sodium tertiary butoxide and potassium tertiary butoxide preferably LiHMDS; and the suitable so1vent includes but is not limited to ester so1vents, ether so1vents, hydrocarbon so1vents, po1ar aprotic so1vents, ketone so1vents, alcoho1ic so1vents, chloro so1vents, po1ar so1vents or mixtures thereof; preferably tetrahydrofuran,

in step-f) 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; the suitable peroxide is selected from hydrogen peroxide, per acids such as peracetic acid, trifluoro peracetic acid, perbenzoic acid, m-chloro perbenzoic acid and the like preferably lithium hydroxide in presence of hydrogen peroxide in a suitable po1ar aprotic so1vents like tetrahydrofuran and hydrated lithium hydroxide,

in step-g) the suitable reducing agent is selected from the combination of boron trifluoride etherate or BF3-THF and sodium borohydride complex preferably sodium borohydride in presence of suitable catalyst like BF3.Et20; and 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 tetrahydrofuran, in step-h) the suitable halogenating agent is selected from carbon tetra chloride, oxalyl chloride, thionyl chloride, phosphorous pentachloride, N-chloro succinimide, phosphorus tribromide, carbon tetrabromide, N-bromo succinimide in presence or absence of triphenyl phosphine; and 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 methylene chloride.

5. One pot process for the preparation of 4-methoxy-3-(3-methoxypropoxy) benzyl alcoho1 compound of formula-6, comprises of reacting the 3-methoxypropyl methane sulfonate compound of formula-3 with 3-hydroxy-4-methoxybenzaldehyde compound of formula-4 in the presence of a suitable base in a suitable so1vent and subsequently treating with a suitable reducing agent like sodium borohydride to provide (4-methoxy)-3-(3-methoxypropoxy)benzyl alcoho1 compound of formula-6.

6. One-step process for the preparation of (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutan-l-o1 compound of formula-11, comprises of, reducing the (R)-3-((R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methyl butanoyl)-4-phenyl oxazo1idin-2-one compound of formula-9, with a suitable reducing agent in nitrogen atmosphere in a suitable so1vent at a suitable temperature to provide (R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutan-l-o1 compound of formula-11.

7. One-step process for the preparation of (R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methylbutan-l-o1 compound of formula-11, comprises of, reducing the (R)-3-((R)-2-(4-methoxy-3-(3-methoxypropoxy) benzyl)-3-methyl butanoyl)-4-phenyl oxazo1idin-2-one compound of formula-9 with sodium borohydride in presence of borontrifluoride etherate (BF3 : Et20) in nitrogen atmosphere in suitable so1vent, preferably tetrahydrofuran at a suitable temperature to provide compound of formula-11.

8. An improved process for the preparation of (R)-4-(2-(bromomethyl)-3-methylbutyl)-l-methoxy-2-(3-methoxypropoxy) benzene compound of formula-la, comprises of:

a) Reacting 3-methoxypropan-l-o1 compound of formula-2 with methanesulfonyl chloride in presence of triethylamine in methylene chloride to provide 3-methoxypropyl methanesulfonate compound of formula-3,

b) condensation of 3-methoxypropyl methanesulfonate compound of formula-3 with 3-hydroxy-4-methoxybenzaldehyde compound of formula-4, in presence of potassium carbonate in to1uene to provide 4-methoxy-3-(3-methoxypropoxy) benzaldehyde compound of formula-5,

c) reducing 4-methoxy-3-(3-methoxypropoxy)benzaldehyde compound of formula-5 in presence of sodiumborohydride in tetrahydrofuran to provide 4-methoxy-3-(3-methoxypropoxy) benzyl alcoho1 compound of formula-6,

d) reacting 4-methoxy-3-(3-methoxypropoxy) benzyl alcoho1 compound of formula-6, with phosphorous tribromide in methylene chloride to provide 4-bromomethyl-l-methoxy-2-(3-methoxypropoxy) benzene compound of formula-7,

e) condensing 4-(bromomethyl)-l-methoxy-2-(3-methoxypropoxy) benzene compound of formula-7 with (R)-3-(3-methylbutanoyl)-4-phenyloxazo1idin-2-one compound of formula-8, in presence of lithium hexamethyldisilazane (LiHMDS) in tetrahydrofuran to provide pure (R)-3-((R)-2-(4-methoxy-3-(3-methoxy propoxy)benzyl)-3-methylbutanoyl)-4-phenyl oxazo1idin-2-one compound of formula-9,

f) hydro1yzing the (R)-3-((R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methyl butanoyl)-4-phenyl oxazo1idin-2-one compound of formula-9 with hydrated lithium hydroxide in presence of hydrogen peroxide in terahydrofuran to provide (R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutanoic acid compound of formula-10,

g) reducing the (R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutanoic acid compound of formula-10 with sodium borohydride in presence of borontrifluoride etherate (BF3: Et20) in nitrogen atmosphere in tetrahydrofuran to provide (R)-2-(4-methoxy-3-(3-methoxy propoxy)benzyl)-3-methylbutan-l-o1 compound of formula-11,

h) reacting the (R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutan-l-o1
compound of formula-11 with N-bromo succinamide in methylene chloride to
provide (R)-4-(2-(bromomethyl)-3-methylbutyl)-l-methoxy-2-(3-methoxy
propoxy) benzene compound of formula-la.

9. A Process for the preparation of (R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutanoic acid compound of formula-10 in enantiomeric excess, comprises of condensation of 4-(bromomethyl)-1 -methoxy-2-(3 -methoxypropoxy)benzene compound of formula-7 with (R)-3-(3-methyl butanoyl)-4-phenyloxazo1idin-2-one compound of formula-8 in presence of a strong base in a suitable so1vent to provide compound of formula-9, further hydro1yzing the compound of formula-9 in a suitable base in presence of peroxide in a suitable so1vent to provide (R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methyl butanoic acid compound of formula-10.

10. A Process for the preparation of (R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutanoic acid compound of formula-10, comprises of condensation of 4-(bromomethyl)-l-methoxy-2-(3-methoxy propoxy)benzene compound of formula-7 with (R)-3-(3-methyl butanoyl)-4-phenyloxazo1idin-2-one compound of formula-8 in presence of LiHMDS (lithium hexamethyldisilazane) in tetrahydrofuran to provide compound of formula-9, further hydro1yzing the compound of formula-9 with hydrated lithium hydroxide in presence of hydrogen peroxide in terahydrofuran to provide (R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutanoic acid compound of formula-10 with an enantiomeric excess > 98%.