FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
COMPLETE SPECIFICATION.
(See section 10]
1. Title of the invention: "A process for the preparation of montelukast acid and it's sodium salt"
2. Macleods Pharmaceuticals Ltd., an Indian Company, having its Registered Office at 304 - Atlanta Arcade, Opp. Leela Hotel, Marol Church Road, Andheri (East), Mumbai - 400 059, Maharashta, India.
3. The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed.


Field of the Invention
The present invention relates to a process for the preparation of montelukast sodium salt. The process includes (a) reacting 2-(2-(3-(S)-(3-(7-chloro-2-quinolinyl)-ethenyl) phenyl)-3-hydroxypropyl)- phenyl-2-propanol of Formula II with diphenyl chloro phosphate to get a compound of Formula III; (b) condensing the compound of Formula III with alkyl ester of l-(mercaptomethyl) cyclopropane acetic acid of Formula IV to get [R- (E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl]-3-[2-(l- hydroxy- 1-methylethyl) phenyl] propyl] thio] methyl] cyclopropaneacetic acid alkyl ester of Formula V; (c) hydrolyzing the compound of Formula V to montelukast sodium of Formula I.
Background of the Invention
Formula I
Chemically, montelukast sodium is sodium [R- (E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl]-3-[2-(l-hydroxy-1-methylethyl) phenyl] propyl] thio] methyl] cyclopropaneacetate having the structural Formula I, and is known from U.S. Patent No. 5,565,473.

1

Montelukast sodium is a leukotriene antagonist, and is thus useful as an anti-asthmatic,
anti-allergic, anti-inflammatory and cytoprotective agent. Montelukast sodium is
currently indicated for the treatment of asthma and allergic rhinitis.
U.S. Patent No. 5,565,473 discloses a process for preparing montelukast sodium by
reacting 2-(2-(2-(3 (S)-(3-(2-(7-chloro-2-quinolinyl)-ethenyl) phenyl)-3-
(methanesulfonyloxy) propyl) phenyl)-2-propoxy) tetra hydro pyran with methyl 1-(acetylthiomethyl) cyclopropane acetate in presence of hydrazine, cesium carbonate in acetonitrile as solvent to get methyl ester of montelukast in pyran protected form, which is further reacted with pyridinium p-toluene sulfonate, sodium hydroxide in a mixture of methanol and tetrahydrofuran as a solvent to afford montelukast sodium of Formula (I).
U.S. Patent No. 5,614,632 discloses a process for preparing montelukast sodium by reacting dilithium dianion of 1-(mercaptomethyl) cyclopropaneacetic acid with 2-(2-(3 (S)-(3-(2-(7-chloro-2-quinolinyl) ethenyl) phenyl)-3-methanesulfonyloxypropyl) phenyl)-2-propanol compound to afford montelukast. It is further converted to its corresponding sodium salt via dicyclohexyl amine salt.
U.S. Patent application US 20050256156 discloses a process for preparing pharmaceutically acceptable salt of montelukast by (a) activating the 2-(2-(3 (S)-(3-(2-(7-chloro-2-quinolinyl) ethenyl) phenyl)-3-((a-hydroxy) propyl) phenyl)-2-propanol with a benzylsulfonyl or mesyl group; (b) reacting the product of step a with 1-(mercaptomethyl) cyclopropaneacetic acid alkyl ester in a solvent and in the presence of a cosolvent and a base; and (c) hydrolyzing the product of step b to obtain a pharmaceutically acceptable salt of montelukast.
U.S. Patent application US 20050234241 discloses a process for preparing montelukast by the mesylation of 2-(2-(3 (S)-(3-(2-(7-chloro-2-quinolinyl) ethenyl) phenyl)-3-hydroxypropyl) phenyl)-2-propanol using methane sulfonyl chloride and condensation of the resulting mesylate with a compound of formula (VI)
2

CH2X
CH,SH CI'

CH2X
\^

HO H3C'

CH,

Formula VI

Formula VII

where X=CN or CONH2 or mixture of compound of formula (VI) wherein X=CN and compound of formula (VI) wherein X=CONH2 to give a compound of formula (VII) where X=CN or CONH2. This compound is hydrolyzed to afford Montelukast, and it is isolated in the form of an amine salt, which is then converted into sodium salt of Montelukast in a conventional method.
U.S. Patent application US 20050245569 discloses a process for preparing montelukast sodium by using intermediate compound of Formula VIII.
SH

^^

HO
HaC

CHa

Formula VIII

3

U.S. Patent application US 20050107612 discloses a process for the preparation of montelukast or a salt thereof by reacting 2-[l-[l R-3- [2-(7-chloroquinoline-2-yl) vinyl [phenyl]-3-[2-methoxy carbonyl phenyl] propyl sulfonyl methyl] cyclopropyl] acetic acid or a salt thereof with methyl magnesium chloride or methyl magnesium bromide in an organic solvent.
U.S. Patent application US 20060194839 discloses a process for preparing montelukast sodium by using [R- (E)]-2-[3-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl]-3-(2-benzyloxy-methyl) propyl) thiomethyl-cyclopropaneacetic acid intermediate.
PCT application WO 2006008751 discloses a process for the preparation of montelukast free acid by reacting methyl 2-[(3S)-[3-[(2E)-(7-chloro quinolin-2-yl) ethenyl] phenyl]-3-halopropyl] benzoate with 1 -(mercapto methyl) cyclopropane acetic acid in the presence of alkali hydrides or alkoxides to get 2-[l-[l(R)-[3-[2-(7-chloroquinoline-2-yl) ethenyl] phenyl]-3-[2-(methoxycarbonyl) phenyl] propyl sulfonyl methyl] cyclopropane acetic acid, which on reaction with grignard reagent yield montelukast free acid.
The above prior art procedures involve more number of steps, which include a series of protections and deprotections of diol intermediate, usage of hazardous and costly raw materials such as n-butyl lithium, hydrazine, pyridinium p-toluenesulfonate, grignard reagent. The processes of the prior art references involve tedious workup to isolate the required product and thus results in excess time cycle, which in turn rendering the process more costly and less eco friendly thus the process is not amenable for commercial scale up.
4

Summary Of The Invention
In light of the above drawbacks in the prior art processes, there is a need for the development of a simple, convenient and efficient process for the preparation of montelukast sodium salt, which is convenient to operate on an industrial scale.
The first aspect of the present invention is to provide a process for the preparation of montelukast sodium salt of Formula I

Formula I
comprising:
(a) reacting 2-(2-(3-(S)-(3-(7-chloro-2-quinolinyl)-ethenyl) phenyl)-3-
hydroxypropyl)- phenyl-2-propanol of Formula II

Formula 11 with diphenyl chloro phosphate to get a compound of Formula III;
5

Formula III
(b) condensing the compound of Formula III with alkyl ester of l-(mercaptomethyl) cyclopropane acetic acid of Formula IV, wherein R is alkyl or substituted alkyl of Ci to C4 carbon atoms in straight or branched chain form,
SH
COOR Formula IV
to get [R- (E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl]-3-[2-(l-hydroxy-1-methylethyl) phenyl] propyl] thio] methyl] cyclopropaneacetic acid alkyl ester of Formula V;

6


Formula V
(c) hydrolyzing the compound of formula V to montelukast sodium of Formula I.
Formula III
The second aspect of the present invention is to provide a compound of Formula III


7

Detailed Description of the Invention
The 2-(2-(3-(S)-(3-(7-chloro-2-quinolinyl)-ethenyl) phenyl)-3-hydroxypropyl)- phenyl-2-propanol of Formula II may be prepared by any of the methods known in the art including those described in U.S. Patent Nos. 5,565,473; 5,614,632 and WO 95/18107.
The reaction of 2-(2-(3-(S)-(3-(7-chloro-2-quinolinyl)-ethenyl) phenyl)-3-hydroxypropyl)- phenyl-2-propanol of Formula II with diphenyl chloro phosphate may be carried out in chlorinated hydrocarbons solvent in the presence of base.
Examples of chlorinated hydrocarbons solvent include dichloromethane, dichloroethane, chloroform, carbon tetra chloride or mixture(s) thereof.
Examples of bases include organic base such as trimethylamine, triethylamine, tributylamine, triisopropylamine, diisopropylethylamine, pyridine, morpholine, DBU (1,8-diazabicyclo- [5. 4. 0]-undec-7-ene), DBN (1,5-diazabicyclo- [4.3.0] non-5-ene), 4-dimethylaminopyridine or mixture(s) thereof.
The base may be used in an amount of 1.0-6.0 molar equivalents of compound of Formula II.
The reaction of 2-(2-(3-(S)-(3-(7-chloro-2-quinolinyl)-ethenyl) phenyl)-3-hydroxypropyl)- phenyl-2-propanol of Formula II with diphenyl chloro phosphate may be carried out at a temperature in the range of about -70°C to about -10°C for about 0.5 hour to about 3 hours
8

The 2-(2-(3 (S)-(3-(7-chloro-2-quinolinyl)-ethenyl) phenyl)-3-phosphoryloxypropyl) phenyl-2-propanol of Formula III may be extracted with halogenated hydrocarbons solvent such as dichloromethane, dichloroethane, carbon tetra chloride or mixture(s) thereof.
The 2-(2-(3 (S)-(3-(7-chloro-2-quinolinyl)-ethenyl) phenyl)-3-phosphoryloxypropyl) phenyl-2-propanol of Formula III may be isolated from the organic layer after washing the organic layer with aqueous hydrochloride solution / aqueous sodium bicarbonate solution / sodium chloride solution and concentrating under reduced pressure and stirring with a mixture of hydrocarbon solvents and alkyl acetate solvents at a temperature in the range of about 0°C to about 30°C.
Examples of hydrocarbon solvents include n-hexane, hexanes, heptanes, toluene, xylene, or mixture(s) thereof.
Examples of alkyl acetate solvents include methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate, amyl acetate or mixture(s) thereof.
The isolation of compound of Formula III may be accomplished by cooling, filtration or a combination thereof.
The compound of Formula III may be dried under reduced pressure at a temperature in the range of about 10°C to about 30°C.
The compound of Formula III obtained from step a, may be further reacted with alkyl ester of 1 -(mercaptomethyl) cyclopropane acetic acid of Formula IV in organic solvent in the presence of an inorganic base at a temperature in the range of about 0°C to about 30°C for about 3 hours to about 24 hours.
9

The alkyl ester of 1 -(mercaptomethyl) cyclopropane acetic acid of Formula IV may be prepared by methods known in the art.
The alkyl ester of 1-(mercaptomethyl) cyclopropane acetic acid of Formula IV may be prepared by reacting 1-(mercaptomethyl) cyclopropane acetic acid with thionyl chloride in alkanol solvent at a temperature in the range of about 0°C to about 65°C.
Examples of alkanol solvent include methanol, ethanol, n-propanol, iso propanol, butanol or iso butanol.
Examples of organic solvent include dimethylsulfoxide, N, N-dimethylformamide or tetrahydrofuran.
Examples of inorganic base include alkali metal carbonate, alkali metal bicarbonate, alkali metal hydroxide and mixtures thereof.
Examples of alkali metal carbonate include lithium carbonate, sodium carbonate or potassium carbonate.
Examples of alkali metal bicarbonate include sodium bicarbonate or potassium bicarbonate.
Examples of alkali metal hydroxide include sodium hydroxide or potassium hydroxide.
The [R- (E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl]-3-[2-(l- hydroxy-1-methylethyl) phenyl] propyl] thio] methyl] cyclopropaneacetic acid alkyl ester of Formula V may be extracted with alkyl acetate solvents such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate or amyl acetate.
10

The [R- (E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl]-3-[2-(l- hydroxy-1-methylethyl) phenyl] propyl] thio] methyl] cyclopropaneacetic acid alkyl ester of Formula V may be isolated from the organic layer after washing the organic layer with sodium chloride solution and concentrating under reduced pressure
The [R- (E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl]-3-[2-(l- hydroxy-1-methylethyl) phenyl] propyl] thio] methyl] cyclopropaneacetic acid alkyl ester of Formula V may be reacted with alkali metal hydroxide in organic solvent to get montelukast sodium of Formula I.
The reaction of [R- (E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl]-3-[2-(l-hydroxy-1 -methylethyl) phenyl] propyl] thio] methyl] cyclopropaneacetic acid alkyl ester of Formula V with alkali metal hydroxide may be carried out at a temperature in the range of about 0°C to about 30°C for about 1 hour to about 55 hours.
Example of alkali metal hydroxide includes sodium hydroxide.
Examples of organic solvent include methanol, ethanol, n-propanol, iso propanol, butanol, diethyl ether, tetrahydrofuran or mixture(s) thereof.
The isolation of montelukast sodium of Formula I may be accomplished by crystallization with hydrocarbon solvents.
Examples of hydrocarbon solvents include hexanes, heptanes, toluene, xylene, or mixture(s) thereof.
The isolation of montelukast sodium of Formula I may be accomplished by cooling, filtration or a combination thereof.
The montelukast sodium of Formula I may be dried under reduced pressure at a temperature in the range of about 25°C to about 30°C.
11

The schematic diagram for the process of preparing montelukast sodium of Formula I is provided below:



Diphenyl chloro phosphate

Formula II

Formula III

Formula IV


NaOH


Formula

Formula V

12

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLES:
Example 1: Preparation of methyl ester of l-(mercaptomethyl) cyclopropane acetic acid
Thionyl chloride (7.4 ml) was added to solution of 1-(mercaptomethyl) cyclopropane acetic acid (10.0 gm) in methanol (100 ml) at 0-5°C. The reaction mixture thus obtained was stirred at 60-65°C for 2 hours and concentrated under reduced pressure to get methyl ester of 1-(mercaptomethyl) cyclopropane acetic acid. Yield: 9.0 gm
Example 2: Preparation of 2-(2-(3 (S)-(3-(7-chloro-2-quinolinyl)-ethenyl) phenyl)-3-phosphoryloxypropyl) phenyl-2-propanol
4-Dimethylaminopyridine (5.3 gm) was added to solution of 2-(2-(3 (S)-(3-(7-chloro-2-quinolinyl)-ethenyl) phenyl)-3-hydroxypropyl) phenyl-2-propanol (5 gm) in dichloromethane (50 ml) at 25°C. The resulting reaction mixture was stirred for 30 minutes, cooled to -70°C and diphenyl chloro phosphate (7.5 ml) was added and reaction mixture was further stirred for 2 hours at -65°C to -70°C. The resulting reaction mixture was treated with water (25 ml) and extracted with dichloromethane (20 ml). The organic layer was washed by aqueous hydrochloride solution (0.5 M, 20 ml), sodium bicarbonate solution (5 %, 20 ml) and sodium chloride solution (saturated). The organic layer was
13

dried and concentrated under reduced pressure to get oily residue. The oily residue was dissolved in ethyl acetate (25 ml), diluted with hexane (200 ml) and then stirred for 12 hours at 25-30°C. The resulting solids were filtered and dried at 30°C under reduced pressure to get yellow colored compound. Yield: 7.3 gm
Example 3: Preparation of [R- (E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl]-3-[2-(l-hydroxy-l-methylethyl) phenyl] propyl] thio] methyl] cyclopropaneacetic acid methyl ester.
Sodium hydroxide solution (47 %, 1.56 gm) was added to solution of methyl ester of 1-(mercaptomethyl) cyclopropane acetic acid (2.97 gm) in N, N-dimethylformamide (25 ml) at 25°C under inert atmosphere. The reaction mixture thus obtained was stirred for 30 minutes at 25°C and solution of 2-(2-(3 (S)-(3-(7-chloro-2-quinolinyl)-ethenyl) phenyl)-3-phosphoryloxypropyl) phenyl-2-propanol (25%, 22 ml) in tetrahydrofuran was added and resulting reaction mixture was stirred for 12 hours at 20°C. The reaction mixture was treated with sodium chloride solution (5%, 100 ml) and extracted by ethyl acetate (100 ml). The organic layer was washed two times with water (50 ml each), dried over sodium sulphate and concentrated under reduced pressure to get [R- (E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl]-3-[2-(l -hydroxy-1-methylethyl) phenyl] propyl] thio] methyl] cyclopropaneacetic acid methyl ester. Yield: 3.0 gm
14

Example 4: Preparation of [R- (E))-l-[[[l-l3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl]-3-[2-(l-hydroxy-l-methylethyl) phenyl] propyl] thio] methyl] cyclopropaneacetic acid sodium salt
Sodium hydroxide solution (10 %, 2.5 gm) was added to solution of [R- (E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl]-3-[2-(l-hydroxy-l-methylethyl) phenyl] propyl] thio] methyl] cyclopropaneacetic acid methyl ester (2.9 gm) in methanol (7.6 ml) at 25-30°C. The resulting turbid solution was diluted with tetrahydrofuran (0.5 ml) and stirred for 50 hours at 25-30°C. The resulting reaction mixture was concentrated under reduced pressure to get oily residue. The residue was diluted with ethyl acetate (20 ml) and water (10 ml) and organic layer separated. The organic layer was washed by sodium chloride solution (5%, 5 ml) and diluted with heptane (20 ml). The resulting heavy liquid was separated, stripped with ethanol and evaporated to get R- (E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl]-3-[2-(l -hydroxy- 1-methylethyl) phenyl] propyl] thio] methyl] cyclopropaneacetic acid sodium salt. Yield: 1.3 gm
15

WE CLAIM:
1. A process for the preparation of montelukast sodium salt of Formula I

Formula I comprising:
(a) reacting 2-(2-(3-(S)-(3-(7-chloro-2-quinolinyl)-ethenyl) phenyl)-3-hydroxypropyl)- phenyl-2-propanol of Formula II


Formula II

16

with diphenyl chloro phosphate to get a compound of Formula III;

Formula III
(b) condensing the compound of Formula III with alkyl ester of 1-(mercaptomethyl) cyclopropane acetic acid of Formula IV, wherein R is alkyl or substituted alkyl of Ci to C4 carbon atoms in straight or branched chain form,
/ SH
N COOR
Formula IV
to get [R- (E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl]-3-[2-(l-hydroxy-1-methylethyl) phenyl] propyl] thio] methyl] cyclopropaneacetic acid alkyl ester of Formula V;
17


Formula V
(c) hydrolyzing the compound of formula V to montelukast sodium of Formula I.
2. The process according to claim 1, wherein reaction of 2-(2-(3-(S)-(3-(7-chloro-2-quinolinyl)-ethenyl) phenyl)-3-hydroxypropyl)- phenyl-2-propanol of Formula II with diphenyl chloro phosphate is carried out in chlorinated hydrocarbons solvent such as dichloromethane, dichloroethane, chloroform and carbon tetra chloride in the presence of base such as trimethylamine, triethylamine, tributylamine, triisopropylamine, diisopropylethylamine, pyridine, morpholine, DBU (1,8-diazabicyclo- [5. 4. 0]-undec-7-ene), DBN (1,5-diazabicyclo- [4.3.0] non-5-ene) and 4-dimethylaminopyridine..
3. The process according to claims 1 or 2, wherein reaction of 2-(2-(3-(S)-(3-(7-chloro-2-quinolinyl)-ethenyl) phenyl)-3-hydroxypropyl)- phenyl-2-propanol of Formula II with diphenyl chloro phosphate is carried out at a temperature in the range of about -70°C to about -10°C for about 0.5 hour to about 3 hours.
18

4. The process according to claim 1, wherein compound of Formula III obtained from step a, is further reacted with alkyl ester of 1 -(mercaptomethyl) cyclopropane acetic acid of Formula IV in organic solvent such as dimethylsulfoxide, N, N-dimethylformamide and tetrahydrofuran in the presence of an inorganic base such as alkali metal carbonate, alkali metal bicarbonate and alkali metal hydroxide.
5. The process according to claim 1, wherein compound of Formula III obtained from step a, is further reacted with alkyl ester of 1 -(mercaptomethyl) cyclopropane acetic acid of Formula IV at a temperature in the range of about 0°C to about 30°C for about 3 hours to about 24 hours.
6. The process according to claim 1, wherein [R- (E)]-l-[[[l-[3-[2-(7-chloro-2-
quinolinyl) ethenyl] phenyl]-3-[2-(l- hydroxy-1-methylethyl) phenyl] propyl] thio]
methyl] cyclopropaneacetic acid alkyl ester of Formula V is hydrolyzed into montelukast
sodium of Formula I by sodium hydroxide in organic solvent such as methanol, ethanol,
n-propanol, iso propanol, butanol, diethyl ether, tetrahydrofuran or mixture(s) thereof.
7. The process according to claims 6, wherein reaction of R- (E)]-l-[[[l-[3-[2-(7-chloro-
2-quinolinyl) ethenyl] phenyl]-3-[2-(l- hydroxy-1-methylethyl) phenyl] propyl] thio]
methyl] cyclopropaneacetic acid alkyl ester of Formula V with sodium hydroxide is
carried out at a temperature in the range of about 0°C to about 30°C for about 1 hour to
about 55 hours.
19

Formula III
used for the preparation of montelukast sodium salt of Formula I
Formula I
8. The process according to claim 6, wherein isolation of montelukast sodium of Formula I is accomplished by crystallization with hydrocarbon solvents such as hexanes, heptanes, toluene, xylene, cooling, filtration or a combination thereof.
9. A compound of Formula III


20


10. A compound of Formula III

Formula 111

21

ABSTRACT
The present invention relates to a process for the preparation of montelukast sodium salt. The process includes (a) reacting 2-(2-(3-(S)-(3-(7-chloro-2-quinolinyl)-ethenyl) phenyl)-3-hydroxypropyl)- phenyl-2-propanol of Formula II with diphenyl chloro phosphate to get a compound of Formula III; (b) condensing the compound of Formula III with alkyl ester of 1-(mercaptomethyl) cyclopropane acetic acid of Formula IV to get [R- (E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl]-3-[2-(1- hydroxy-1-methylethyl) phenyl] propyl] thio] methyl] cyclopropaneacetic acid alkyl ester of Formula V; (c) hydrolyzing the compound of Formula V to montelukast sodium of Formula I.
Dated this 26th day of September, 2007

To
The Controller of Patents The patent Office, At Mumbai

22
FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
PROVISIONAL SPECIFICATION.
(See section 10]
1. Title of the invention: "A novel process for the preparation of Valacyclovir hydrochloride"
2. Macleods Pharmaceuticals Ltd., an Indian Company, having its Registered Office at 304 - Atlanta Arcade, Opp. Leela Hotel, Marol Church Road, Andheri (East), Mumbai - 400 059, Maharashta, India.
3. The following specification describes the invention.

A NOVEL PROCESS FOR THE PREPARATION OF VALACYCLOVIR HYDROCHLORIDE
The present invention relates to a novel process for the preparation of valacyclovir hydrochloride. The process includes a) coupling an N-Phthalimido-L-valine with acyclovir to form a protected valacyclovir b) deprotecting the protected valacyclovir to form valacyclovir or a pharmaceutically acceptable salt thereof.
Chemically, valacyclovir hydrochloride is 2-((2-Amino-l, 6-dihydro-6-oxo-9H-purin-9-yl) methoxy) ethyl L-valinate hydrochloride having the structural Formula I, and is known from U.S. Patent No. 4,957,924.


H2N N
.HC1

Formula I

1

A first aspect of the present invention is to provide a novel process for the preparation of valacyclovir hydrochloride comprising the steps of:
a) coupling an N-Phthalimido-L-valine with acyclovir to form a protected valacyclovir
b) deprotecting the protected valacyclovir to form valacyclovir or a pharmaceutically acceptable salt thereof
A second aspect of the present invention is to provide a protected valacyclovir of compound of Formula II.

Wherein A represents hydrogen atom, an alkyl group of C| to Cio carbon atoms, an alkoxy group of Ci to Cio carbon atoms or halogen group.
A third aspect of the present invention is to provide a protected valacyclovir of compound of Formula II used for the preparation of valacyclovir hydrochloride
2

A fourth aspect of the present invention is provide a process of preparing valacyclovir hydrochloride as described in scheme I: O

Wherein A represents hydrogen atom, an alkyl group of Ci to Cio carbon atoms, an alkoxy group of Ci to Cio carbon atoms or halogen group.
3

4