FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
[See section 10, rule 13]
A Novel Process for Desalination of Lisinopril
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 describes the invention and the manner in which it is to be performed.

TITLE
A NOVEL PROCESS FOR DESALINATION OF LISINOPRIL
FILED OF THE INVENTION
The present invention relates to a novel process for desalination of (N2-[(S)-1-Carboxy-3-phenylpropyl]-L-lysyl-L-proline) of formula I (herein after called as Lisinopril), which is a very useful antihypertensive agent.

In particular, there is provided a novel process for removing the salts from Lisinopril of formula I by partitioning the product using n-butanol and water system at specific pH.
BACKGROUND OF THE INVENTION
Lisinopril is a drug of the angiotensin converting enzyme (ACE) inhibitor class that is primarily used in the treatment of hypertension, congestive heart failure, heart attack and also in preventing renal and retinal complication of diabetes.

Lisinopril can readily be synthesized by hydrolyzing an N2- (1(S)-
ethoxycarbonyl-3-phenylpropyl)-N6-(trifluoroacetyl)-L-lysyl-L-proline of
formula II (herein after called as Lisinopril ester)

using an alkali in the presence of water and neutralizing all the alkaline components in the hydrolysis mixture using an acid. This process generates large amount of inorganic salts (sodium chloride and sodium trifluoroacetate) which are removed by conventional methods such as precipitating the salts or using ion exchange resin.
EP168769 and Journal of Organic Chemistry, 1988, 53, 836-844 discloses a process for preparation of Lisinopril by hydrolyzing Lisinopril ester wherein the generated salts are removed by treatment on ion exchange column, concentrating the elute and crystallizing the Lisinopril as a dihydrate using ethanol and water.
This process, however, is not only complicated in operation but also poor in productivity since it is necessary to remove a large amount of salts by ion exchange treatment, causes the elute very dilute, so that large scale equipment is

required and a long period and a large quantity of heat energy is needed for the concentration of the elute.
US 6,271,393 and Trans IChemE, 2002, 80(A), 201-208 discloses the process to hydrolyze Lisinopril ester by using NaOH and water. Reaction mixture was acidified with hydrochloric acid to get the pH 2.8±0.5 and was further basified to get pH 6. In this process lot of salt was generated which was precipitated using antisolvent such as ethanol and finally filtered.
However, the product obtained using this method has sulphated ash more than the accepted value. To get the acceptable limit of sulphated ash the process of Lisinopril purification using ethanol and water is repeated which causes a great loss in yield of Lisinopril. Also the reproducibility of this process is very low.
JP 253497 describes the process for preparation of Lisinorpil by hydrolyzing Lisinorpil ester using tetrabutyl ammonium hydroxide and neutralizing the hydrolysis mixture with trifluoroacetic acid. Tetrabutylammonium trifluoroacetate is formed as a salt which is removed by using mixed solvent system such as ethanol and water.
However, the process is not suitable for large scale preparation because special reagents such as tetrabutylammonium hydroxide and trifluoroacetic acid are used which are expensive.
Thus, all prior art processes for desalination of Lisinopril have various disadvantages. The processes are complicated, inefficient and expensive. Desalination is carried out using water miscible alcohols such as ethanol and the salts remain in the product due to its moisture content and hence need repetitive treatment to remove the salts which results in the great loss of final product.

Hence there is a need to be developed simple, efficient and cost effective process for the desalination of Lisinopril to obtain Lisinopril in good yield and high purity.
Inventors of the present invention have surprisingly found out that the salts generated during the hydrolysis of Lisinopril ester of formula II are removed by partitioning the product using n-butanol and water at specific pH. This process provides simple and efficient system to remove the salts and affords Lisinopril of formula I with high purity and good yield. Also the process is economically advantageous on a large scale.
It has been appeared that none of the prior art processes report the partitioning method for removal of the salts from Lisinopril of formula I.
OBJECT OF THE INVENTION
An object of the present invention is to provide a novel process for the desalination of Lisinopril of formula I
Another object of the present invention is to provide a simple, easy and efficient system for the desalination of Lisinopril of formula I
Yet another object of the present invention is to provide a commercially viable process for the desalination of Lisinopril of formula I
Yet another object of the present invention is to provide a novel process to isolate Lisinopril of formula I with good yield and high quality by avoiding further purification

SUMMARY OF THE INVENTION
According to the present invention there is provided a novel process for desalination of Lisinopril of formula f

Formula I
In particular, there is provided a novel process for removing the salts from Lisinopril of formula I by partitioning the product using n-butanol and water system at specific pH.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a novel process for desalination of Lisinopril of formula I, which is a very useful antihypertensive agent.


In particular, there is provided a novel process for removing the salts from the reaction mixture of Lisinopril of formula I by partitioning the product between n-butanol and water system at specific pH.
In the process of the present invention Lisinopril of formula I is prepared by hydrolyzing Lisinopril ester of formula II

Formula II
using NaOH and water. After hydrolysis, disodium salt of Lisinopril and sodium trifluoroacetate is formed. pH of reaction mixture is then adjusted to 3.0, when Lisinopril hydrochloride is formed along with 2 moles of sodium chloride and one mole of sodium trifluoroacetate. The product Lisinopril hydrochloride is then taken out from the mixture using an appropriate n-butanol and water mixture.
Thus, the desalination process of the present invention comprises the steps of
i) adjusting the pH of reaction mixture, obtained by the hydrolysis of Lisinopril
ester of formula II, using an inorganic acid
ii) adding n-butanol to the reaction mixture obtained in step i
iii) separating aqueous layer containing the salts to obtain the product, which is
free from the salts in n-butanol layer.

The process of the present invention for removal of salts, generated by hydrolysis of Lisinopril ester of formula II, from Lisinorpil of formula I is as deoicted in Figure 1.


Lisinopril ester of formula II is prepared by reductive amination of 2-oxo-4-phenyl ethyl butyrate with the dipeptide using the process as described in Journal of Organic Chemistry, 1988, 53, 836-844 which is incorporated herein by reference. Lisinopril ester obtained after isolation of the reaction mass is in the form of oily mass. This oily mass is then treated with methyl-tert-buty\ ether and subsequently purified with isopropyl ether using the process as described in our co-pending Indian Patent application 870/MUM/2008 which is incorporated herein by reference, to get pure crystalline solid of Lisinopril ester of formula II.
An aspect of the present invention is to provide simple, easy and efficient system for removal of salts from Lisinopril of formula I. This system involves the mixture of n-butanol and water. The product Lisinopril hydrochloride is partitioned between n-butanol and water layer. In this process the product is obtained in the n-butanol layer while the salt is remained in the water layer.
Since Lisinopril of formula I is also soluble in water, the inventors of the present invention found out that the selection of solvent plays a vital role in the removal of the salts efficiently. The present inventors selected n-butanol as a solvent since n-butanol has only 10% solubility in water and gets partitioned with water, unlike the other alcohols such as ethanol, methanol or isopropanol which are completely miscible with water. It has been found out that the ratio of n-butanol to water (to get two distinct layers) makes this system effective for removal of salts from the reaction mixture. It minimizes the loss of product to the aqueous layer, avoids contamination of the salts in the product and affords the final product that passes quality standards required by formulation. Thus the ratio of n-butanol to water during extraction at pH 3 is crucial factor of the invention.
In an aspect of the present invention the process of desalination of Lisinopril of formula I is carried out at specific pH. n-Butanol is added to the reaction

mixture at pH 3.0. After separation, the pH of the n-butanol layer is adjusted to 5-6 with aqueous ammonia and concentrated.
After removal of salts from the reaction mixture, the n-butanol concentrate is converted to Lisinopril dihydrate by using water and alcohol such as isopropyl alcohol at 40-45°C.
It has been observed that the product obtained using prior art processes contains 10-20 % of moisture content and hence the product is contaminated with the salt. The reason is very clear since salt is being precipitated using water miscible alcohols such as ethanol and hence there is a complete chance of salt movement to mother liquor in soluble form which precipitates along with Lisinopril. The Lisinopril obtained by such processes needs further and repeated purification to get the acceptable limit of sulphated ash.
The process of the present invention avoids the further and repeated purification and affords Lisinopril of formula I which passes the quality standards, laid down by EP/BP pharmacopoeia, without any further purification. The Lisinopril dihydrate obtained by the present process is with sulphated Ash < 0.1% and HPLC purity > 99.65%.
In an embodiment of the present invention, n-butanol and water ratio used for partitioning the product is selectively 1: 1.55
In another embodiment of the present invention, the product is partitioned between n-butanol and water system at pH ranging from 3.0 to 3.2, more preferably at pH 3.0

In another embodiment of the present invention, the desalination of Lisinopril of formula I is carried out at temperature ranging from 10° C to 30° C, preferably at 15° C to 20° C.
In yet another embodiment of the present invention pH of the n-butanol layer is adjusted from 5 to 6 preferably from 5 to 5.3.
The detail of the invention provided in the following example is given by the way of illustration only and should not be construed to limit the scope of the present invention.
Example:
(N2-[(S)-l-Carboxy-3-phenylpropylJ-L-lysyI-L-proline)
Lisinopril ester (200 gm, HPLC purity NLT 95%) was charged with aqueous NaOH solution (43%, 48.7 gm) in a four neck round bottom flask and was heated at 40-45° C for 4 hrs. At 15-20° C, pH was adjusted to 3.0 with 15% HC1. n-butanol (415 ml) was added to reaction mass, stirred. The n-butanol layer was then separated and aqueous layer was further extracted with 207.5 ml and 132 ml of n-butanol. pH of combined organic layer was adjusted to 5.0-5.3 by aqueous ammonia. n-Butanol was distilled out at 45-46°C under vacuum to get the volume of the reaction mass up to 500 ml. Reaction mass was diluted with n-butanol (400 ml) and then filtered the salt (ammonium chloride). The salt was washed with n-butanol (100 ml). n-Butanol was distilled out completely at 45-46° C under vacuum. Thick brownish oil was obtained. DM water was added to it and heated at 40-45° C to get clear solution and again pH was adjusted to 5.2-5.3 by aqueous ammonia at 40-45° C. Water was distilled out completely from the reaction mass at 40-45° C under vacuum. DM water (95 ml) was added to it

and stirred it to get clear solution followed by 832 ml of isopropyl alcohol addition. The reaction mass was seeded with 2.0 gm of pure Lisinopril at 40-45° C and maintained at same temperature for 10-14 hrs. After that allowed it to cool at ambient temperature and stirred for 2.0 hrs at this temperature. Product was filtered and washed with IP A (2 x 415 ml). Product was unloaded and was dried at 40-45° under vacuum till moisture content comes in between 8.0 -9.5%. Yield-122 gm (73%); HPLC purity > 99.65%; Sulphated ash < 0.1 %
The advantages of process of the present invention are,
1. The process provides simple, easy and efficient system to remove the salts from Lisinopril
2. The process minimizes the loss of Lisinopril
3. The process affords Lisinopril with high purity and good yield
4. The process affords Lisinopril that passes the quality standards laid down by EP/BP pharmacopeia without any further purification
5. The process is economically advantageous on a larger scale

We claim,
1. A novel process for desalination of Lisinopril (N2-[(S)-l-Carboxy-3-phenylpropyl]-L- lysyl-L-proline) of formula I by partitioning the product between n-butanol and water system at specific pH

Formula I
2 . The process as claimed in claim 1, wherein the desalination process comprises the steps of

Formula II
ii) adding n-butanol to the reaction mixture obtained in step i
j) adjusting the pH of reaction mixture, obtained by the hydrolysis of Lisinopril ester of formula II, using an inorganic acid

hi) separating aqueous layer containing the salts to obtain the product, which is free from the salts in n-butanol layer.
3. The process as claimed in claim 1 or 2, wherein the product is partitioned between n-butanol and water system at pH ranging from 3.0 to 3.2 , more preferably at pH 3.0
4. The process as claimed in claim 3, wherein pH is adjusted by using an inorganic acid, preferably hydrochloric acid
5. The process as claimed in claim 1 or 2, wherein n-butanol and water ratio used is selectively 1: 1.55
6. The process as claimed in claim 1 or 2, wherein the desalination of Lisinopril of formula I is carried out at temperature ranging from 10° C to 30° C, preferably
at 15° C to 20° C.