FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patent Rules, 2006
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. TITLE OF THE INVENTION: AN IMPROVED PROCESS FOR THE
PREPARATION OF BETA-KETO ESTERS OF FORMULA .
2. APPLICANT:
(a) NAME: ARCH PHARMALABS LIMITED
(b) NATIONALITY: INDIAN
(c) ADDRESS: ARCH PHARMALABS LIMITED,
541-A, ARCH HOUSE, MAROL-MAROSHI ROAD, ANDHERI (EAST), MUMBAI-400059
PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

TITLE:
An improved process for the preparation of beta-keto esters of formula I

wherein R is straight or branched chain alkyl group, R,represents any of hydrogen, an alkyl group of 1 to 12 branched or straight chain carbon atoms which may have a substitucnt, an alkenyl group of 2 to 12 carbon atoms which may have substitucnt, an aryl group of 6 to 12 carbon atoms which may have a substitucnt, an aralkyl group of 7 to 12 carbon atoms which may have a substituent, a cyano group, methylcyano group, a carboxyl group and alkoxycarbonyl group, hydroxy group, R2 is a hydroxy group or keto group, R3 is independently hydrogen, straight or branched chain alkyl group,
FIELD OF TECHNOLOGY:
The instant invention relates to an improved process for the preparation of compound of formula I by cross Claisen condensation comprising using lithium metal amine chemically represented as LiNH2 of formula II as lithium source over conventionally used n-butyl lithium, lithium diisopropylamide referred as LDA, lithium hexamethyldisilazane referred as LiHMDS. Inventive feature of the instant invention is the preparation of enolates of formula III using lithium amine of formula II as base made from cheap and readily available raw materials viz. liquid ammonia and lithium metal followed by its reaction with another ester molecule different from that used for enolate generation. None of the conventional method for the preparation of 5-hydroxy- pentanoic acid derivatives of formula IV discloses use of LiNH2 of formula II as base for the said reaction step.

wherein R is straight or branched chain alkyl group, Represents any of hydrogen, an alkyl group of 1 to 12 branched or straight chain carbon atoms which may have a substituent, an alkenyl group of 2 to 12 carbon atoms which may have substituent, an aryl group of 6 to 12 carbon atoms which may have a substituent, an aralkyl group of 7 to 12 carbon atoms which may have a substituent, a cyano group, methylcyano group, a carboxyl group and alkoxycarbonyl group, hydroxy group, R2 is a hydroxy group or keto group, R3 is independently hydrogen, straight or branched chain alkyl group,


wherein K is straight or branched chain alkyl group, R3 is independently hydrogen, straight or branched chain alky) group,R5 is hydrogen or has the general formula II1A, M is alkali metal


R3 is independently hydrogen, straight or branched chain M is alkali metal

wherein R is straight or branched chain alkyl group, R, represents any of hydrogen, an alky] group of 1 to 12 branched or straight chain carbon atoms which may have a substituent, an alkenyl group of 2 to 12 carbon atoms which may have substituent, an aryl group of 6 to 12 carbon atoms which may have a substituent, an aralkyl group of 7 to 12 carbon atoms which may have a substituent, a cyano group, methylcyano group, a carboxyl group and alkoxycarbonyl group

BACKGROUND OF THE INVENTION:
5-hydroxy- pentanoic acid derivatives of formula IV is a useful pharmaceutical intermediate used for the preparation of many pharmaceutical medicaments. Compound of formula IV is conventionally manufactured by a cross Claisen type reaction between acetic acid derivatives (strictly speaking, the enolate of acetic acid derivative) and substituted hydroxy propanoate using lithium bases selected from the group cited hereinbefore.

EP1577297A, discloses a process for the preparation of beta keo ester comprising reaction of acetic acid derivative in THF with 3-hydroxy propionic acid derivative at a temperature range of about -50°C to about 25°C in the presence of lithium diisopropylamine prepared by reaction comprising n-butyl lithium and diisopropylamine at -40°C using THF as a solvent.
US2008/248539, discloses a process for the preparation of beta keo ester comprising reaction of acetic acid derivative in THF with 3-hydroxy propionic acid derivative at a temperature about -20°C in the presence of lithium diisopropylamine which is prepared by adding solution of n-butyl lithium in hexane into solution of diisopropylamine in THF at about -20°C.
US7557238 discloses a process for the preparation of beta keo ester comprising reaction of acetic derivative in THF with 3-hydroxy propionic acid derivative at a temperature range of about -75°C to about -45°C in the presence of lithium diisopropylamine which is prepared by adding a solution of n-butyl lithium in hexane into solution of diisopropylamine in THF at about -5 to about -10°C followed by the removal of tert-butyl diphenyl silyl group by hydrolysis.
USRE39333E discloses a process for the preparation of beta keo ester comprising reaction of acetic acid ester with 3-hydroxy propionic acid derivative at a temperature upto -20°C in the presence of lithium diisopropylamine which is prepared by adding solution of diisopropylamine into solution of n-butyl lithium in hexane at 5°C.
IN2009CH00540 discloses a process for the preparation of beta keo ester comprising reaction of trimethyl silyl (TMS)-protected intermediate substituted 3-hydroxy propionic acid derivative with acetic acid derivative using HMDS-Li as a base followed by hydrolyzing the silylated product.
IN2009-MU1975 discloses a process for the preparation of beta keo ester comprising the reaction of substituted 3-hydroxy propionic acid derivative with acetic acid derivative using in-situ generated lithium diispropylamine as a base obtained by the reaction of lithium metal as lithium source and diisopropylamine.
WO2005026107 discloses a process for the preparation of beta keo ester comprising the reaction of substituted 3-hydroxy propionic acid derivative with

acetic acid derivative using lithium diisopropylamide followed by removal of the tert-butyldiphenylsilyl protecting group.
WO2011048425 (hereinafter refered as '425) discloses a continuous noncryogenic process for the preparation of beta keo ester comprising rapid reaction of lithium hexamethyldisilazane with acetic acid derivative in THF through a stainless steel capillary tube at temperature <0°C to afford l-(l,l-dimethylethoxy)ethanol lithium salt. The intermediate obtained is further immediately reacted with a flow of Et 3-hydroxy propionic acid derivative in another stainless steel capillary tube at 55°C (preferably over a time frame of minutes or seconds, so that rate of reaction of enolate with its reaction partner will be faster than the rate of its decomposition, thereby avoiding the self condensation that results into the formation of impurity abbreviated by TBAA of formula VII as shown below).

Inventive feature of the said '425 patent application is to use non cryogenic conditions (such as temperature like -40°C) for both synthesis and use of ester enolates. In the said application the applicant has mentioned name of lithium amide as a base. The mention of lithium amide as a base is merely to broaden the scope of the invention as neither in any example nor in the table disclosing reaction results based on different bases the said lithium amide has been used.
'425 in an example disclosing reaction quench/workup on the page no 14 does not disclose the isolated yield of the product. It discloses 72% content in crude product as determined by proton NMR analysis.
Inventors of the instant invention have conducted an experiment based on the process disclosed in '425 comprising using enolate at non cryogenic reaction. The reaction comprises lithium amide to react with acetic acid derivative generating the enolate at room temperature. It has been observed that the reaction results in the formation of about 50% TBAA dimer due to self condensation. This in a very vivid manner indicates that lithium amide is not suitable for such reaction, therefore, not in the scope of the invention of '425.

US6340767 discloses a process for the preparation of compound of formula III comprising reaction of ethyl 4-benzyloxy-3-hydroxybutyrate with acetic acid derivative in the presence of grignard reagent tert butyl magnesium chloride using THF as a solvent at 0-5°C, followed by drop wise addition of lithium diisopropylamide solution (made by reaction of diisopropyl amine and n-butyl lithium in hexane) over a period of time and the resulting mixture continued to stir at 5-20°C for 16 h. Product obtained after the work-up is further subjected to column chromatography yielding 57% as red oil without indicating the purity of the material.
US5155251 discloses a process for the preparation of beta keo ester comprising reaction of lithium diisopropyl amide with acetic acid derivative in THF thereby generating enolate at a temperature of -50°C, followed by its reaction with (3-hydroxy propionic acid derivative resulting into the formation of compound of formula V. The product is not isolated. A sample is purified by column chromatography.
Drawbacks in prior art references for the preparation of beta keo ester using LDA as a base comprises using n-butyl lithium as a source of lithium which is unsafe, hazardous to use, pyrophoric in nature. Secondly use of THF as a solvent as used in most of the prior arts is not favorable at plant level as it possesses risk of peroxide formation that leads to the risk of explosion. One more limitation in using THF is its solubility in water that creates the problems during the work-up of the reaction thereby affecting the yield of the product. Use of expensive chemicals like Grignard reagent, diisopropyl amine, silylating agent etc., all these not only increase the cost of process but also increase the unit operations like preparation of Grignard reagent, LDA preparation from lithium and diisopropyl amine, preaparation of silylated intermediates and removal of silyl group etc.
In view of drawbacks of the prior art, it is desirable to develop an economical and industrially safe process for preparing a compound formula I particularly compound of formula V using cheap and easily available raw materials, high yielding with good purity. The inventors of the present invention disclose herein a process for the preparation of compound of formula I by cross Claisen condensation comprising using lithium metal amine chemically represented as LiNH2 of formula II as lithium source over conventionally used industrially unsafe

n-butyl lithium, lithium diisopropylamide referred as LDA, lithium hexamethyldisilazane referred as LiHMDS. The most advantageous feature of the reaction under the instant invention is the use of cheap and readily available raw materials lithium metal and liquid ammonia.
OBJECT OF THE INVENTION:
First aspect of the instant invention is to provide an economical and industrially safe process for the preparation of compound of formula I by cross Claisen condensation using lithium metal amine chemically represented as LiNH2 of formula II as lithium source over conventionally used n-butyl lithium, lithium diisopropylamide referred as LDA, lithium hexamethyldisilazane referred as LiHMDS.
Second aspect of the instant invention is to provide an economical and industrially safe process for the preparation of compound of formula V by cross Claisen condensation using lithium metal amine chemically represented as LiNH2 of formula II as lithium source over conventionally used n-butyl lithium, lithium diisopropylamide referred as LDA, lithium hexamethyldisilazane referred as LiHMDS.
Third aspect of the instant invention is to provide an economical and industrially safe process for the preparation of compound of formula I comprising the reaction between the acetic acid derivative of formulae A' and 3-hydroxy propionic acid derivative of formula B' using lithium amine of formula II which itself is prepared by the reaction of lithium metal and liquid ammonia in the presence of an electron carrier.
Forth aspect of the invention is to provide a process for the preparation of compound of formula I comprising the steps:
i) preparation of Li-ammonia complex comprising reaction of lithium metal with ammonia in a solvent;
ii) adding ester of formula A' to the reaction mass of step i) in the presence of an electron carrier;



iii) adding the compound of formula B' to the reaction mass of step ii;
R1epresents any of hydrogen, an alkyl group of 1 to 12 branched or straight chain carbon atoms which may have a substituent, an alkenyl group of 2 to 12 carbon atoms which may have substituent, an aryl group of 6 to 12 carbon atoms which may have a substituent, an aralkyl group of 7 to 12 carbon atoms which may have a substituent, a cyano group, methylcyano group, a carboxyl group and alkoxycarbonyl groupR2 represents any of hydrogen, an alkyl group of 1 to 12 branched or straight chain carbon atoms
iv) isolating the compound of formula I by the standard methods of work up.
Fifth aspect of the invention is to provide a process for the preparation of compound of formula V comprising the reaction between ethyl 3-hydroxypentanoate and tert butyl acetate using lithium amide chemically represented by LiNH2 which itself is made by reaction of cheap and readily available Lithium metal and liquid ammonia in the presence of an electron carrier.
Sixth aspect of the invention is to provide a process comprising the steps:
i) preparation of Li-ammonia complex comprising reaction of lithium metal with ammonia in a solvent;

iii) adding ethyl 3-hydroxypentanoate of formula B;

ii) adding tert butyl acetate of formula A; in the presence of electron carrier

iv) isolating the compound of formula V by the standard methods of work up.
One more aspect of the invention is to prepare a compound of formula IV wherein R is tert-butyl and Rl is optionally substituted alkyl preferably ethyl.
One more aspect of the invention is to prepare a compound of formula IV wherein R is tert-butyl and Rl is cyanomethyl.
Beta ketoester, the subject matter of the invention is racemic or stereo specific.
SUMMARY OF THE INVENTION:
The instant invention relates to a process for preparing a compound formula I particularly compound of formula V comprising using cheap and easily available raw materials with high yield and higher purity. The process comprises the reaction of acetic acid derivative of formula A' and 3-hydroxy propionic acid derivative of formula B'B in a solvent and lithium amine of formula II as lithium source over conventionally used n-butyl lithium, lithium diisopropylamide referred as LDA, lithium hexamethyldisilazane referred as LiHMDS particularly process for the preparation of compound of formula V comprising the reaction of A and B using LiNH2 of formula II as shown herein below.

DETAILED DESCREPTION OF THE INVENTION:
Disclosed herein is an improved process for the preparation of compound of formula I comprising the reaction of compounds of formulae A' and B' in a solvent and lithium amine as lithium source over conventionally used n-butyl lithium, lithium diisopropylamide referred as LDA, lithium hexamethyldisilazane referred as LiHMDS. Inventive feature of the invention lies is the preparation of lithium amine of formula II which acts as lithium source which comprises the reaction of lithium metal with liquid ammonia using a solvent in presence of an electron carrier. General embodiment of the process for the preparation of compound of formula I comprising the steps:

i) preparation of Li-ammonia complex comprising.reaction of lithium metal with ammonia in a solvent;

iii) adding the 3-hydroxy propionic acid derivative of formula B' to the reaction mixture of step ii);

ii) adding acetic acid derivative of formula A' to the lithium ammonia complex obtained in step i) in the presence of an electron carrier;
R, represents any of hydrogen, an alkyl group of 1 to 12 bhanched or straight chain carbon atoms which may have a substituent, an alkenyl group of 2 to 12 carbon atoms which may nave substituent, an aryl group of 6 to 12 carbon atoms which may have a substituent, an aralkyl group of 7 to 12 carfoon atoms which may have a substituent, a cyano group, methylcyano group, a carboxyl group and alkoxycarbonyl groupR2 represents any of hydrogen, an alkyl group of 1 to 12 branched or straight chain carbon atoms
iv) isolating the compound of formula I from the reaction mixture by standard methods of work up
Electron carrier used in the preparation of lithium amine of formula II is olefinic compounds or inorganic metal salts selected from the group comprising isoprene, styrene and the like and ferric chloride, ferric nitrate, cobalt chloride and the like. Preferably electron carrier is olefinic compound.
Solvent used for the preparation of lithium amine of formula II and for further reaction is selected from the group comprising ethereal solvents and non aromatic hydrocarbons. Ether solvent is selected from the group comprising cyclic and acyclic ethers and mixtures thereof.
In a specific embodiment of the invention disclosed herein is a process for the preparation of compound of formula V comprises the steps:

i) preparation of Li-ammonia complex comprising contacting lithium metal with ammonia in a methyl tert butyl ether;

iii) adding ethyl 3-hydroxypentanoate of formula B into the reaction mixture of step ii);

ii) adding tert butyl acetate of formula A into the reaction mixture of step i) in the presence of isoprene;
iv) isolating the compound of formula V from the reaction mass by standard methods of work up.
The following example will illustrate the entire invention:
Example: 400 ml methyl tert butyl ether is charge with 15 g of lithium metal at ambient temperature. Liquid ammonia is then charged at a temperature of-10 to -15°C. This reaction mass is then added with the solution of isoprene 104 g in 50 ml methyl tert butyl ether and stirring is continued for another half an hour. Tert butyl acetate (296 g) is then further added to the above content at -10 to -15°C under the stirring followed by the addition of ethyl 3-hydroxypentanoate (lOOg) under the same condition. Reaction is monitored on HPLC till the completion if complies, the reaction is quenched by the addition of aqueous sulphuric acid. The compound of formula V is then extracted with tert butyl acetate which upon distillation yields crude compound of formula V (140g) which is then purified by using Hexane if required.

CLAIMS:
1. A process for the preparation of compound of formula I

wherein R is straight or branched chain alkyl group, R1represents any of hydrogen, an alkyl group of 1 to 12 branched or straight chain carbon atoms which may have a substituent, an alkenyl group of 2 to 12 carbon atoms which may have substituent, an aryl group of 6 to 12 carbon atoms which may have a substituent, an aralkyl group of 7 to 12 carbon atoms which may have a substituent, a cyano group, methylcyano group, a carboxyl group and alkoxycarbonyl group, hydroxy group, R2 is a hydroxy group or keto group, R3 is independently hydrogen, straight or branched chain alkyl group,
comprising the steps:
i) preparation of lithium-ammonia complex comprising contacting lithium metal with ammonia in a solvent
ii) adding acetic acid derivative of formula A' to lithium-ammonia complex obtained in step i) in the presence of an electron carrier;

iii)adding 3-hydroxy propionic acid derivative of formula B' to the reaction mixture of step ii;

R, represents any of hydrogen, an alkyl group of 1 to 12 branched or straight chain carbon atoms which may have a substituent, an alkenyl group of 2 to 12 carbon atoms which may have substituent, an aryl group of 6 to 12 carbon atoms which may have a substituent, an aralkyl group of 7 to 12 carbon atoms which may have a substituent, a cyano group, methylcyano group, a carboxyl group and alkoxycarbonyl groupR2 represents any of hydrogen, an alkyl group of 1 to 12 branched or straight chain carbon atoms
iv) isolating the compound of formula I by the standard methods of work up.

2. The process of claim 1 wherein solvent for step i for the preparation of lithium-ammonia complex is selected from the group comprising cyclic and acyclic ethers, non aromatic hydrocarbons and the mixture thereof.
3. The process of claim 2 wherein solvent is methyl tert butyl ether.
4. The process of claim 1 step I wherein electron carrier used for the preparation of lithium-ammonia complex is selected from the group comprising olefinic compounds and inorganic metal salts selected from the group comprising isoprene, styrene and the like and ferric chloride, ferric nitrate, cobalt chloride and the like.
5. The process of claim 4 wherein electron carrier used for the preparation of lithium-ammonia complex is isoprene or styrene.
6. A process for the preparation of compound of formula V

comprising steps:
i) preparation of Li-ammonia complex comprising contacting lithium metal with ammonia in a methyl tert butyl ether;

iii) adding ethyl 3-hydroxypentanoate of formula B into the reaction mixture of step ii);

ii) adding tert butyl acetate of formula A into the reaction mixture of step i) in the presence of isoprene;
iv) isolating the compound or formula V from the reaction mass by standard methods of work up.