FORM-2
THE PATENTS ACT, 1970 (39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION [See section 10, rule 13]
Improved process for preparation of L-valine benzyl ester p-toluene sulfonate
APPLICANT:
CALYX CHEMICALS AND PHARMACEUTICALS LTD. 2, Marwah's Complex, Sakivihar Road, Sakinaka, Andheri (E), Mumbai-400 072, Maharashtra, India
Indian Company incorporated under the Companies Act 1956
The following specification particularly describes the nature of this invention and the manner in which it is to be performed:

FIELD OF INVENTION
The present invention provides an improved and commercially viable process for preparation of L-valine benzyl ester p-toluenesulfonate. The present invention in particular provides an improved process for preparation of L-valine benzyl ester p-toluenesulfonate comprising simple and efficient process of isolation of L-valine benzyl ester p-toluenesulfonate from the reaction mixture by using an anti-solvent.
BACKGROUND OF INVENTION
L-valine benzyl ester p-toluenesulfonate of formula (I)

has wide application in chemical industries for example for preparation of pharmaceuticals. It is used as intermediate for drugs like Valsartan or a pharmaceutical acceptable salt. According to its application there is a commercial need for L-valine benzyl ester p-toluenesulfonate in large quantity.
US5362912 discloses a method for preparation of L-valine benzyl ester p-toluenesulfonate by reacting L-valine and benzyl alcohol in presence of p-toluene sulfonic acid monohydrate in toluene. The mixture was heated to reflux and then cooled and was poured into ethyl ether thereby precipitating the product. The amount of ethyl ether used is very high.

EP985658 discloses a process for preparation of L-valine benzyl ester p-toluenesulfonate by reacting L-valine and benzyl alcohol in presence of p-toluene sulfonic acid in toluene at 100-150 °C and crystallizing the product out of reaction mixture by cooling the reaction mixture to 60-90 °C and inoculating seed of crystals of L-valine benzyl ester p-toluenesulfonate followed by further cooling the solution to 0-10 °C. The volume of toluene solution used is as high as 35 volumes.
The prior art mentioned above suffers from a major drawback that the inoculating seed of crystals of L-valine benzyl ester p-toluenesulfonate is required for crystallization for which availability of good quality seed is needed. Experience has shown that only good quality is needed to have efficient crystallization and also, it is difficult to guess the perfect timing as to when seed is to be added to the reaction mixture to initiate crystallization. It is observed that the seed needs to be at equilibrium before seed is added otherwise it gets dissolve. Thus, it is arresting operational simplicity and affecting commercial production. Other drawbacks include use of solvents in high volume, numerous operations which makes the process tedious and cumbersome, also according to the prior art the crystallization step takes place at temperature as low as 0 °C to 10 °C.
Hence, there remains a need to provide an alternative to prior art process which overcomes the above drawbacks and is cost effective, feasible and industrially viable with high yield and purity, which is subject matter of the present invention.
OBJECT OF INVENTION
1. It is an object of the present invention to provide an improved, simple and cost-effective process for preparation of L-valine benzyl ester p-toluenesulfonate.

2. It is another object of the present invention to provide simple and efficient process for isolation of L-valine benzyl ester p-toluenesulfonate from reaction mixture.
3. It is another object of the present invention to provide a process for preparation of L-valine benzyl ester p-toluenesulfonate with reduced parameters and utility simplification.
4. It is yet another object of the present invention to provide commercially feasible process for the preparation of L-valine benzyl ester p-toluenesulfonate with good yield and purity.
SUMMARY OF INVENTION
According to an aspect of the present invention, there is provided an improved process for preparation of L-valine benzyl ester p-toluenesulfonate comprising the steps of,
a) reacting L-valine with benzyl alcohol in presence of p-toluenesulfonic acid monohydrate in toluene at temperature ranging from 100°C to 150°C for 10 to 20 hours
b) optionally, distilling out 0.5 to 3 volumes of toluene with respect to L-valine
c) cooling the reaction mixture to 60-90°C and adding an anti-solvent selected from cycloalkanes or branched aliphatic ether
d) cooling the mixture to 20-25 °C for 4 to 7 hours and then optionally cooling further to 10-15°C for 0.5 to 3 hours
e) filtering and washing the solid with toluene or with mixture of toluene and an anti-solvent.

According to another aspect of the present invention, there is provided an improved process for isolation of L-valine benzyl ester p-toluenesulfonate from the reaction mixture by using an anti-solvent selected from cycloalkane or branched aliphatic ether.
In particular, the present invention provides an improved process for isolation of L-valine benzyl ester p-toluenesulfonate from the reaction mixture by using an anti-solvent, comprising the steps of,
a) optionally, distilling out 0.5 to 3 volumes of toluene
b) cooling the reaction mixture to 60-90°C and adding an anti-solvent selected from cycloalkanes or branched aliphatic ether
c) cooling the mixture to 20-25°C for 4 to 7 hours and then optionally cooling further to 10-15°C for 0.5 to 3 hours
d) filtering and washing the solid with toluene or with mixture of toluene and an anti-solvent.
DETAILED DESCRIPTION OF INVENTION
The present invention relates to an improved and commercially viable process for preparation of L-valine benzyl ester p-toluenesulfonate of formula I with high purity and yield.


The present invention in particular relates to an improved process for isolation of L-valine benzyl ester p-toluenesulfonate from the reaction mixture by using an anti-solvent selected from cycloalkanes or branched aliphatic ether.
The process of the present invention for the preparation of L-valine benzyl ester p-toluenesulfonate is as shown in the Scheme I below

In an aspect of the present invention there is provided an improved process for preparation of L-valine benzyl ester p-toluenesulfonate comprising the steps of,
a) reacting L-valine with benzyl alcohol in presence of p-toluenesulfonic acid monohydrate in toluene at temperature ranging from 100°C to 150°C for 10 to 20 hours
b) optionally, distilling out 0.5 to 3 volumes of toluene with respect to L-valine
c) cooling the reaction mixture to 60-90°C and adding an anti-solvent selected from a cycloalkanes or branched aliphatic ether
d) cooling the mixture to 20-25 °C for 4 to 7 hours and then optionally cooling further to 10-15°C for 0.5 to 3 hours
e) filtering and washing the solid with toluene or with mixture of toluene and an anti-solvent.

According to an embodiment of the present invention the amount of toluene used in step a) of the reaction is in the range of 5 to 12 volumes with respect to L-valine, preferably 7 to 11 volumes.
Thus, the reaction of the present invention does not require high volumes of reaction solvent as required by prior art process. The process disclosed in EP9856588 uses the volume of toluene as high as 35 volumes.
According to another embodiment of the present invention, the molar ratio of the benzyl alcohol used in step a) with respect to L-valine is in range of 0.5 to 4, preferably 1 to 3.
The molar ratio of the p-toluenesulfonic acid monohydrate used in step a) with respect to L-valine is in range of 0.5 to 3, preferably 1 to 2.5.
According to another embodiment of the present invention, anti-solvent used in step c) and e) is selected from cycloalkanes like cyclopentane, cyclohexane or cycloheptane, preferably cyclohexane is used.
According to yet another embodiment of the present invention, anti-solvent used in step c) and e) is selected from the branched aliphatic ether, preferably isopropyl ether is used.
According to another aspect of the present invention, there is provided an improved process for isolation of L-valine benzyl ester p-toluenesulfonate from the reaction mixture by using an anti-solvent selected from cycloalkanes or branched aliphatic ether.

In particular, the present invention provides an improved process for isolation of L-valine benzyl ester p-toluenesulfonate from the reaction mixture by using an anti-solvent, comprising the steps of,
a) optionally, distilling out 0.5 to 3 volumes of toluene
b) cooling the reaction mixture to 60-90°C and adding an anti-solvent selected
from cycloalkanes or branched aliphatic ether
c) cooling the mixture to 20-25 °C for 4 to 7 hours and then optionally cooling
further to 10-15°C for 0.5 to 3 hours
d) filtering and washing the solid with toluene or with mixture of toluene and an
anti-solvent.
Improved isolation process of the present invention, as discussed above, avoids the inoculation of seeds of final compound. It is observed that good quality crystal seeds needed to have efficient crystallization and also seeds need to be at equilibrium before addition otherwise it get dissolved. It is also difficult to guess the perfect timing as to when seed is to be added to the reaction mixture to initiate crystallization. The process further avoids the crystallization at lower temperatures such as 0-10°C.
Thus, isolation process of the present invention is simple, cost-effective and improves the yield and purity of the final compound as compared to prior art process.
The details of the invention provided in the following examples are given by the way of illustration only and should not be construed to limit the scope of the present invention.

EXAMPLES
Exaraple-1:
To 50 g (0.43 moles) of L-valine was added 138.5 g (1.28 moles) of benzyl alcohol, 97.44 g (0.513 moles) of para toluene sulphonic acid monohydrate and 500 ml of toluene. This reaction mixture was heated to reflux using dean-stark at 116-120 °C. The reaction mixture was maintained at reflux temperature for 10-12 h. Approximately 1 -2 V toluene was distilled out. The reaction mixture was cooled to 75-80 °C and 50 ml of cyclohexane was added to it. The resulting solution was cooled to 20-25 °C within 4-5 h, then to 10-15 °C within 1-2 h. The resulting crystals were collected by filtration, washed with chilled mixture of toluene and cyclohexane (100 ml, 1:1). The solid cake obtained was dried at 50-55 °C for 10-12 h yielding 140 gm of L-valine benzyl ester tosylate. Yield: 86% HPLC purity: 99.69%.
Example -2:
To 50 g (0.43 moles) of L-valine was added 138.5 g (1.28 moles) of benzyl alcohol, 97.44 g (0.513 moles) of para toluene sulphonic acid monohydrate and 500 ml of toluene. This reaction mixture was heated to reflux and removed the water through dean-stark at 116-120 °C. The reaction mixture was maintained at reflux temperature for 10-12 h. Approximately 1-2 V toluene was distilled out at reflux temperature. The reaction mixture was then cooled to 75-80 °C and 50 ml of isopropyl ether was added to it. The resulting solution was cooled to 20-25 °C within 4-5 h, further cooled to 10-15 °C. The resulting crystals were collected by filtration, washed with chilled mixture of toluene and isopropyl ether (100 ml,l:l). The solid cake obtained was dried at 50-55 °C for 10-12 h giving 145 gm of L-valine benzyl ester tosylate. Yield: 89.53% HPLC purity: 99.37%.

Example -3:
To 50 g (0.43 moles) of L-valine was added 138.5 g (1.28 moles) of benzyl alcohol, 97.44 g (0.51 moles) of para toluene sulphonic acid monohydrate and 375 ml (7.5 V) of toluene. This reaction mixture was heated to reflux and the water was removed through dean-stark at 116-120 °C. The reaction mixture was maintained at reflux temperature for 10-12 h. Approximately 1-2 V of toluene was distilled out at reflux temperature. The reaction mixture was cooled to 75-80 °C and 50 ml of isopropyl ether was added to it. The resulting solution was cooled to 20-25 °C for 3-4 h, filtered, washed with chilled 50 ml of toluene and dried at 50-55 °C for 10-12 h resulting in 141 gm of L-valine benzyl ester tosylate. Yield: 87 % HPLC purity: 98.7%
Example -4:
To 50 g (0.43 moles) of L-valine was added 138.5 g (1.28 moles) of benzyl alcohol, 97.44 g (0.513 moles) of para toluene sulphonic acid monohydrate and 350 ml (7.0V) of toluene. This reaction mixture was heated to reflux and removed the water through dean-stark at 116-120 °C. The reaction mixture was maintained at reflux temperature for 10-12 h. Approximately 1-2 V of toluene was distilled out at reflux temperature, reaction mixture was cooled to 75-80 °C. 50 ml of cyclohexane was added at 75-80 °C and the mixture was then cooled to 20-25 °C, mixture was further cooled to 10-15 °C. The mixture was filtered followed by washing with chilled 50 ml of toluene and subsequent drying at 50-55 °C for 10-12h yielding 145 gm of L-valine benzyl ester tosylate. Yield: 89.53% HPLC purity: 97.33%.

Example -5:
To 50 g (0.43 moles) of L-valine was added 138.5 g (1.28 moles) of benzyl alcohol, 97.44 g (0.513 moles) of para toluene sulphonic acid monohydrate and 350 ml (7.0V) of toluene. This reaction mixture was heated to reflux and the water was removed through dean-stark at 116-120 °C. The reaction mixture was maintained for 10-12 h at reflux temperature. Approximately 1-2 V of toluene was distilled out. The reaction mixture was cooled to 75-80 °C and 50 ml of isopropyl ether was added to it. The reaction solution was then cooled to 20-25 °C within 3-4 h, and further cooled to 10-15 °C within 1-2 h. The solid obtained was collected by filtration, washed with chilled 50 ml of toluene and dried at 50-55 °C yielding 150 gm of L-valine benzyl ester tosylate. Yield: 92.6% HPLC purity: 97.0%.
Example-6:
To 50g (0.43 moles) of L-valine was added 138.5 g (1.28 moles) of benzyl alcohol, 97.44 g (0.513 moles) of para toluene sulphonic acid monohydrate and 500 ml (10 V) of toluene. This reaction mixture was heated to reflux and the water was removed through dean-stark at 116-120 °C. The reaction mixture was maintained for 10-12 h at reflux temperature. The reaction mixture was cooled to 75-80 °C and 50 ml of cyclohexane was added. The resulting solution was cooled to 20-25 °C within 4-5 h, then to 10-15 °C within 1-2 h. The solid was collected by filtration, washed with a mixture of toluene and cyclohexane (100 ml, 1:1). The solid cake obtained was dried at 50-55 °C for 10-12 h yielding 140 gm of L-valine benzyl ester tosylate. Yield: 86% HPLC purity: 99.69%.

We claim
1. An improved process for preparation of L-valine benzyl ester p-toluenesulfonate
comprising the steps of,
a) reacting L-valine with benzyl alcohol in presence of p-toluenesulfonic acid monohydrate in toluene at temperature ranging from 100°C to 150°C for 10 to 20 hours
b) optionally, distilling out 0.5 to 3 volumes of toluene with respect to L-valine
c) cooling the reaction mixture to 60-90°C and adding an anti-solvent selected from cycloalkanes or branched aliphatic ether
d) cooling the mixture to 20-25°C for 4 to 7 hours and then optionally cooling further to 10-15°C for 0.5 to 3 hours
e) filtering and washing the solid with toluene or with mixture of toluene and an anti-solvent

2. An improved process for isolation of L-valine benzyl ester p-toluenesulfonate from the reaction mixture by using an anti-solvent selected from cycloalkanes or branched aliphatic ether
3. The process as claimed in claim 2, wherein isolation of L-valine benzyl ester p-toluenesulfonate comprises the steps of,

a) optionally, distilling out 0.5 to 3 volumes of toluene
b) cooling the reaction mixture to 60-90°C and adding an anti-solvent selected
from cycloalkanes or branched aliphatic ether
c) cooling the mixture to 20-25°C for 4 to 7 hours and then optionally cooling
further to 10-15°C for 0.5 to 3 hours

d) filtering and washing the solid with toluene or with mixture of toluene and an anti-solvent
4. The process as claimed in claim 1, wherein the amount of toluene used in step a) is in the range of 5 to 12 volumes with respect to L-valine, preferably 7 to 11 volumes
5. The process as claimed in claim 1, wherein the molar ratio of the benzyl alcohol used in step a) with respect to L-valine is in range of 0.5 to 4, preferably 1 to 3
6. The process as claimed in claim 1, wherein the molar ratio of the p-toluenesulfonic acid monohydrate used in step a) with respect to L-valine is in range of 0.5 to 3, preferably 1 to 2.5
7. The process as claimed in claim 1, 2 or 3, wherein anti-solvent used is cycloalkane
like cyclopentane, cyclohexane or cycloheptane, preferably cyclohexane is used
8. The process as claimed in claim 1, 2 or 3, wherein anti-solvent used is branched
aliphatic ether, preferably isopropyl ether is used.