FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention: "An improved process for the preparation of 5-hydroxy-3-oxo
pentanoic acid derivatives"
2. Applicant(s):
(a) NAME: ARCH PHARMALABS LIMITED
(b) NATIONALITY: An Indian Company
(c) ADDRESS: "H" Wing, 4th floor, Tex Centre. Off Saki Vihar Road, Chandivali,
Andheri (East), Mumbai-400 072, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

TECHNICAL FIELD OF THE INVENTION:
The present invention relates to a process for preparing 5-hydroxy -3-oxopentanoic acid derivatives of formula 1 which is a key intermediate for Atorvastatin comprising reaction of acetic acid ester of formula 11 with 3-hydroxy propionic acid derivative of formula III using alkali dialkyl amide like lithium diisopropyl amide, potassium diisopropyl amide, sodium diisopropyl amide preferably lithium diisopropyl amide, hereinafter referred as LDA, as a base which is prepared by using lithium metal as a source of lithium at ambient temperature overcoming deficiencies in the prior art for the preparation of said compound of formula I wherein n-butyl lithium is used as a source of lithium for preparing LDA which is used as a base for the preparation of 5-hydroxy -3-oxopentanoic acid derivatives. Prior art references for the preparation of LDA which can be used for the preparation of compound of formula 1 discloses the process comprising using n-butyl lithium as a source of lithium at temperature -40°C to 0°C. Preparation of LDA based on n-butyl lithium as a source of lithium may comprise cryogenic reaction conditions (US7132267, US7557238, US2008/248539), unsafe to use, hazardous expensive and utilizes pyrophoric n-Butyl Lithium. This invention provides a safe and economically viable process for preparing said compound of formula-I.

Wherein Rl represents any of an alky I group of 1 to 12 carbon atoms which can be straight chain or branched, an aryl group of 6 to 12 carbon atoms and an aralkyl group of 7 to 12 carbon atoms,
R.2 represents any of hydrogen, an alkyl group of 1 to 12 carbon atoms which may be straight chain or branched and 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, methylcyano group, a carboxyl group and alkoxycarbonyl
group.
R3 represents any of an alky) group of 1 to 12 carbon atoms, an aryl group of 6 to 12
carbon atoms and an aralkyl group of 7 to 12 carbon atoms; and R2 and R3 may be
joined to each other to form a ring.
BACKGROUND OF THE INVENTION;
A group of compounds called "statins" comprising lovastatin, simvastatin, mevastatin, pravastatin, atorvastatin, rosuvastatin, and cerivastatin and fluvastatin show antilipidemic activity and are widely known as HMG-COA reductase inhibitor. 5-hydroxy-3- oxo pentatonic acid derivative of formula I which is an important pharmaceutical intermediate, particularly an intermediate of an HMG-COA reductase inhibitor.
EP1577297A, discloses a process for the preparation of compound of formula I comprising reaction of 1,1-dimethylethyl acetate some times referred as tert butyl acetate in THF and (R)-ethyl-4-cyano-3-hydroxybutanoate at a temperature range of-50°C to 25°C in presence of lithium diisopropylamine prepared by mixing n-butyl lithium and diisopropylamine at -40°C using THF as solvent.
US2008/248539, (EP2066788A2) discloses a process for the preparation of compound of formula I comprising reaction of tert butyl acetate in THF and (R)-ethyI-4-cyano-3-hydroxybutanoate at a temperature -20°C in presence of lithium diisopropylamine which is prepared by adding solution of n-butyl lithium in hexane into solution of diisopropylamine in THF at -20°C.
US7557238 discloses the preparation of compound of formula I comprising reaction of tert butyl acetate in THF and (R)-ethyl-4-cyano-3-tert-butyIdiphenylsiIyloxy)-

butanoate at a temperature range of -75°C to -45°C in presence of lithium diisopropylamine which is prepared by adding a solution of n-butyl lithium in hexane into solution of diisopropylamine in THF at -5 to -10°C followed by the removal of tert-butyl diphenyl silyl group by hydrolysis.
USRE39333E (ItP]024139B1, EP1104750B1) discloses a process for the preparation of compound of formula I comprising reaction of acetic acid ester and 3-hydroxy propionic acid derivative at a temperature upto -20°C in presence of lithium diisopropylamine which is prepared by adding solution of diisopropylamine into solution of n-butyl lithium in hexane at 5°C.
The major drawback in prior art references for the preparation of compound of formula-1 using LDA as a base comprises using n-butyl lithium as a source of lithium which is unsafe, hazardous to use, pyrophoric in nature and require cryogenic reaction conditions for the preparation of l.DA.
In view of drawbacks of the prior art, il is desirable to develop a process for preparing a compound of formula I which does not require use of n-butyl lithium as a source of lithium for the preparation of LDA. Such a process should be safe, cheaper and practically suitable on production scale.
OBJECT OF THE INVENTION:
Main aspect of the present invention is to provide a process for the preparation of 5-hydroxy-3-oxopentanoic acid derivatives of formula I.
The object of the present invention in the above perspective, is to provide a production process by which 5-hydroxy-3-oxopcntanoic acid derivatives of formula I, a useful pharmaceutical intermediate for Atorvastatin can be prepared easily from readily available, inexpensive, safe starling material without using n-butyl lithium

which is unsafe and pyrophoric and without using extra ordinary cryogenic conditions as disclosed in the prior art.
Another aspect of the invention is to provide a process for the preparation of (5R)-l,l-dimethyl-6-cyano-5-hydroxy-3-oxo-hexoanate of formula-VI.
Another aspect of the present invention is to provide a process for the preparation of compound of formula I comprising reacting compounds of Formulae II and III using alkali metal dialkyl amide preferably lithium diisopropyl amide as a base which is prepared by using lithium metal as a source of lithium with diisopropyl amine at ambient temperature.
Advantages of the present invention:
1. Avoiding use of n-butyl lithium as a source of lithium which is unsafe, hazardous to use, pyrophoric in nature and requires cryogenic reaction conditions to prepare LDA which is used as a base to prepare a compound of formula-I.
2. Lithium metal is much safer to be used as it is available in wax coated cubes, less expensive than n-butyl lithium thereby reducing the cost of LDA which in turn also affect the cost of preparing compound of formula 1.
3. Process for making LDA avoids cryogenic conditions, thereby saves energy.
4. Process is suitable on production scale.
SUMMARY OF THE INVENTION:
The present invention relates to a process for the preparation of 5-hydroxy-3-oxo pentatonic acid derivative of formula 1 which is an important pharmaceutical intermediate, particularly an intermediate of an HMG-COA reductase inhibitor that can be prepared easily from readily available, inexpensive, less hazardous starting materials without using extra ordinary cryogenic reaction conditions as disclosed in the prior art.

The present invention relates to a process lor preparing 5-hydroxy -3-oxopentanoic acid derivatives comprising reacting acetic acid ester of formula II and a hydroxypropionic acid derivative of formula III in presence of an alkali metal dialkylamide as a base preferably lithium diisopropyl amide which is prepared by using lithium metal replacing, hazardous, pyrophoric, unsafe n-butyl lithium which may require cryogenic reaction conditions.

Wherein Rl represents any of an alkyl group of 1 to 12 branched or straight chain carbon atoms, an aryl group of 6 to 12 carbon atoms and an aralkyl group of 7 to 12 carbon atoms,
R2 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.

Wherein Rl represents any of an alkyl group of 1 to 12 branched or straight chain carbon atoms, an aryl group of 6 to 12 carbon atoms and an aralkyl group of 7 to 12 carbon atoms,


R2 represents any of hydrogen, an alkyl group of 1 to 12 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. R3 represents any of an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms and an aralkyl group of 7 to 12 carbon atoms; and R2 and R3 may be joined to each other to form a ring.
DETAILED DESCRIPTION OF THE INVENTION:
"Reference will now be made in detail to the preferred embodiments of the invention. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. In addition, and as will be appreciated by one of the skill in the art, the invention may be embodied as a method, system or process."
The present invention relates to a process for preparing 5-hydroxy-3-oxopentanoic acid derivative of formula I

Wherein Rl represents any of an alkyl group of branched or straight chain 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms and an aralkyl group of 7 to 12 carbon atoms,

R2 represents any of hydrogen, an alkyl group of 1 to 12 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; comprising reacting compound of formulae 11 and III

Wherein R1 represents any of an alkyl group of 1 to 12 branched or straight chain
carbon atoms, an aryl group of 6 to 12 carbon atoms and an aralkyl group of 7 to 12
carbon atoms,
R2 represents any of hydrogen, an alkyl group of 1 to 12 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.
R3 represents any of an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12
carbon atoms and an aralkyl group of 7 to 12 carbon atoms; and
in the presence of alkali metal amide of formula IV preferably lithium diisopropyl
amide of formula X , wherein;



R4 and R5 may be same or different and each represents any of an alkyl group of 1 to 12 branched or straight chain carbon atoms, an aryl group of 6 to 12 carbon atoms, an aralkyl group of 7 to 12 carbon atoms. Preferably R4 and R5 both are isopropyl.
M represents alkali metal such as Lithium, sodium or potassium. Preferably alkali metal is lithium. More preferably the base is lithium diisopropyl amide, hereinbefore and hereinafter referred as LDA.
In an embodiment dialkyl amide of formula IV is prepared by reacting an alkali metal such as lithium, sodium or potassium with dialkyl amine of formula V wherein R4 and R5 are as defined hereinbefore at ambient temperature in the presence of a catalyst such as isoprene, styrene, a-methyl styrene, anthracene and the like. The ambient temperature may be between about 10°C to about 50°C.

In a preferred embodiment Lithium disiopropylamide of formula X is prepared by reacting lithium metal with diisopropyl amine of formula IX at ambient temperature in presence of a catalyst such as isoprene, styrene, a-methyl styrene, and the like. The ambient temperature may be between about 10°C to about 50°C.


The present invention is now described in detail.
The acetic acid ester is represented by the general formula II:

Wherein Rl represents any of alkyl group of 1 to 12 branched or straight chain carbon atoms, an aryl group of 6 to 12 carbon atoms and an aralkyl group of 7 to 12 carbon atoms.
As specific examples, there can be mentioned methyl, ethyl, isopropyl, tert-butyl, n-octyl, phenyl, naphthyl, p-methoxy phenyl, benzyl and p-nitrobenzyl, among others. The preferred is tert-butyl.
The 3-hydroxy propionic acid derivative is represented by the general formula III:

R2 represents any of hydrogen, an alkyl group of 1 to 12 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

iralkyl group of 7 to 12 carbon atoms which may have a substituent, a cyano group, a cyanomethyl group, a carboxyl group and alkoxycarbonyl group. As specific examples, there can be mentioned methyl, ethyl, isopropyl, tert-butyl, chloromethyl, bromomethyl, cyanomethyl, benzyloxymethyl, trityloxymethyl, tert-butyldiphenylsyloxymethyl, dimethoxymethyl, l,3-dithian-2-yl, l,3-dithiola-2-yl, vinyl, 2-phenylvinyl, 2-phenylethyl, 2-carbobenzyloxyaminoethyl, phenyl, naphtyl, p-methoxyphenyl. benzyl, p-nitrobenzyl. cyano. carboxy and tert-butoxycarbonyl, among others. Preferred are methyl, ethyl, isopropyl, tert-butyl, chloromethyl, cyanomethyl, benzyloxymethyl, trityloxymethyl, tert-butyldiphenylsyloxymethyl, dimethoxymethyl, vinyl, 2-phenylethyl, phenyl, naphtyl, p-methoxyphenyl, benzyl, p-nitrobenzyl, among others. More preferred are chloromethyl, cyanomethyl, and benzyloxymethyl among others. Most preferred is cyano methyl.
As the substituents on the alkyl, alkenyl, aryl and aralkyi groups each represented by the above R2, there can be mentioned halogen, cyano, C7-19aralkyloxy, Cl-12 alkoxy, C6-12 aryl, nitro, siloxy, N-protected amino, Cl-12 alkyl thio, C6-12 arylthio and C7-12 arakylthio, among others. The number of substituents may be 0 to 3. The number of carbon atoms of the said alkoxycarbonyl group in the above R2 may be 2 to 13.
R3 represents any of an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms and an aralkyi group of 7 to 12 carbon atoms. Specifically can be mentioned as methyl, ethyl, isopropyl. tert-butyl, n-octyl, phenyl, naphthyl, p-methoxyphenyl, benzyl, p-nitrobenzyl etc.Preferred is methyl or ethyl. Most preferred is ethyl.
The alkali metal amide is represented by the general formula IV:


Here R4 and R5 may be the same or different and each represents any of an alkyl group of branched or straight chain 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, an aralkyl group of 7 to 12 carbon atoms. Specifically there can be mentioned methyl, ethyl, isopropyl, tert-butyl, n-octyl, phenyl, naphthyl, p-methoxyphenyl, benzyl and p-nitrobenzyl, trimethylsilyl, triethyl silyl and phenyldimethylsilyl among others. Preferred are methyl, ethyl, n-propyl, isopropyl, n-butyl, and tert-butyl. Most preferred is isopropyl.
M represents alkali metal. Specifically there can be mentioned lithium, potassium and sodium. Preferably alkali metal is lithium.
In an embodiment 5-hydroxy-3-oxopentanoic acid derivatives can be prepared comprising preparation of dialkyl amide comprising adding alkali metal and dialkyl amine and a catalyst in a suitable organic solvent system at ambient temperature to form alkali metal dialkyl amide. The catalyst can be isoprene, styrene, a-methyl styrene or antharacene and the like. Preferably the catalyst can be isoprene or styrene. The ambient temperature can be about I0°C to about 50°C. The organic solvent system can be aliphatic or aromatic hydrocarbon, carboxylic acid ester, halogenated hydrocarbon, ether or a mixture thereof. Preferably the solvent system may be hexane, cyclohexane, THF or a mixture thereof. The compound of formula II is added to a solution prepared hereinbefore containing alkalimetaldialkylamide at temperature up to -50°C. The mixture is stirred and to this is added a solution of compound of formula III.

In a preferred embodiment (5R)-l,l-dimethylethyl-6-cyano-5-hydroxy-3-oxo-hexanoate of formula VI can be prepared comprising preparation of alkalimetaldialkylamine of formula V comprising reaction of alkali metal and dialkylamine of formula IV wherein R4 and R5 are as defined hereinbefore in the presence of a catalyst in a suitable solvent system at ambient temperature to form alkalimetaldialkylamine of formula V. The catalyst can be isoprene, styrene, a-methyl styrene or antharacene. Preferably the catalyst can be isoprene or styrene. The ambient temperature can be about 10°C to about 50°C. The solvent system can be hydrocarbon, carboxylic acid ester, halogenated hydrocarbon and ether or a mixture thereof. Preferably the solvent system may be hexane, cyclohexane, THF or a mixture thereof. The compound of formula II wherein Rl is t-butyl is added to a solution prepared hereinbefore containing alkali metal dialkylamide at temperature up to -50°C. The mixture is stirred and to this is added a solution of compound of formula III wherein R2 is cyanomethyl and R3 is ethyl.

In a more preferred embodiment (5R)-l.l-dimethylethyl-6-cyano-5-hydroxy-3-oxo-hexanoate of formula VI can be prepared comprising preparation of lithium diisopropylamide of formula X comprising reaction of lithium metal and disopropylamine of formula IX in the presence of a catalyst in a suitable solvent system at ambient temperature to form lithium diisopropyl amide of formula X. The catalyst can be isoprene, styrene, a-methyl styrene or antharacene. Preferably the catalyst can be isoprene or styrene. The ambient temperature can be about 10°C to

about 50°C. The solvent system can be hydrocarbon, carboxylic acid ester, halogenated hydrocarbon and ether or a mixture thereof. Preferably the solvent system may be hexane, cyclohexane, THF or a mixture thereof. The compound of formula II wherein Rl is t-butyl is added to a solution prepared hereinbefore containing alkali metal dialkylamide at temperature up to -50°C. The mixture is stirred and to this is added a solution of compound of formula III wherein R2 is cyanomethyl and R3 is ethyl.

The process begins with the preparation of alkali metal amide preferably lithium diisopropyl amide (LDA).
The alkali metal dialkyl amide is not particularly restricted but includes lithium diisopropylamide, potassium diisopropylamide and sodium diisopropylamide. The preferred alkali metal dialkyl amide is lithium diisopropylamide hereinbefore and hereinafter referred as LDA. The said LDA is prepared insitu comprising addition of solution of a catalyst such as isoprene or styrene or a-methyl styrene or anthracene and the like in an organic solvent such as THF into the mixture comprising diisopropyl amine and lithium metal dispersed in a solvent system such as a mixture of THF and hexane in about an hour at a temperature of about 10°C to about 50°C,

preferably about 20uCt o about 50 C more preferably about 35°C to about 50UC. The amount of use of diisopropyl amine is about 1 to about 5 molar equivalents and more preferably about 1.5 to 4 molar equivalents, based on lithium metal used. The amount of use of isoprene or styrene or a-methyl styrene or anthracene is preferably about 0.5 to about 3 molar equivalents and more preferably about 0.5 to about 1.5 molar equivalents, based on lithium metal used.
The acetic acid ester is not particularly restricted but includes methyl acetate, ethyl acetate, tert-butyl acetate, phenyl acetate and benzyl acetate. Preferred is tert-butyl acetate. The amount of use of this acetic acid ester is about 1 to about 6 molar equivalents and preferably about 1.5 to about 4.5 molar equivalents, based on 3-hydroxypropionic acid derivative.
The 3-hydroxy propionic acid derivative is not particularly restricted but includes
methyl-3-hydroxy propionate, ethyl-3-hydroxybutanoate, ethyl-3-hydroxypentanoate,
ethyl 4-chloro-3-hydroxybutanoate, ethyl 4-bromo-3-hydroxybutanoate, ethyl- 4-
cyano-3-hydroxybutanoate, ethyl 4-benzyloxy-3-hydroxybutanoate, ethyl4-trityloxy-
3-hydroxybutanoate, ethyl 4-tert-butyldiphenyloxy-3-hydroxybutanoate, ethyl 3-
cyano-3-hydroxy propionate, methyl 4.4-dimcthoxy-3-hydroxy butanoateethyl-5-
phenyl-3 -hydroxyhexanoate, ethy 1-5 -carbobenzy loxyam ino-3 -hydroxyhexanoate,
phenyl-3-phenyl-3-hydroxypropionate, methyl-3-naphthyl-3-hydroxypropionate,
benzyl-4-phenyl-3-hydroxybutanoate ethyl 4-p-nitrophenyl-3-hydroxy butanoate and 3-hydroxybutyrolactone, among others. The most preferred is ethyl- 4-cyano-3-hydroxybutanoate.
Furthermore, in accordance with the present invention, an optically active 3-hydroxypropionic acid derivative can be used as starting material to give the corresponding objective compound without being sacrificed in optical purity. Therefore more preferred are optically active ethyl-3-hydroxybutanoate, ethyl-4-

chloro-3-hydroxybutanoate, ethyl-4-cyano-3-hydroxybutanoate, ethyl -4-benzyoxy-3-hydroxybutanoate and 3-hydroxybutyrolactone, among others. The most preferred is optically active ethyl-4-cyano-3-hydroxybutanoate.
The alkali metal amide preferably lithium amide is not particularly restricted but includes lithium dimethyl amide, lithium diethylamide, lithium diisopropyl amide, lithium di-tert-butylamide, lithium dicyclohexylamide, lithium diphenylamide, lithium dibenzylamide and lithium hexamethydisilazade, among others. These can be used alone or two or more of them in combination. The most preferred is lithium diisopropylamide. The amount of use of the lithium amide relative to 3-hydroxy propionic acid derivative is preferably 1 to 10 molar equivalents, more preferably 3 to 5 molar equivalents.
The solvent which can be used for this reaction may be an aprotic organic solvent. The organic solvent mentioned above includes hydrocarbon solvents such as benzene, toluene, n-hexane, cyclohexane etc., ether solvents such as diethyl ether, tetrahydrofuran, 1.4-dioxane, methyl tert butyl ether, dimethoxymethane, ethylene glycol dimethyl ether etc., halogen containing solvents such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloro ethane etc. These solvents may be used each alone or two or more of them in combination. Preferred are hydrocarbon solvents benzene, toluene, n-hexane, cyclohexane etc and ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane, methyl tert butyl ether dimethoxymethane and ethylene glycol dimethyl ether. Most preferred are hexane and tetrahydrofuran.
The reaction temperature for reaction between compound of formula II and compound of formula III to form a compound of formula I is performed at about -35°C to about -50°C preferably at about -40°C to about -45°C.

The invention can be further illustrated by the following non-limiting examples: Preparation of (5R)-1, l-dimethylethyl-6-cvano-5-hydroxy-3-oxo-hexanoate: Example 1:
Under the nitrogen gas, a solution composed of 357.Og (3.52 mol) isopropyl amine and 60 ml tetrahydrofuran was charged with freshly cut 20.88g (3.0 mol) lithium metal followed by addition of 300 ml hexane at ambient temperature (32°C). The contents were stirred well. This was added with drop wise addition of solution composed of 104.40g (1.53mol) isoprene and 200ml tetrahydrofuran over a time period of about one hour keeping the temperature in the range of 35-50°C. The reaction was them maintained for 3 hours to prepare lithium diisopropyl amide. The solution containing LDA is chilled to -45°C and solution composing 300g (2.58 mol) tert- butyl acetate and 80 ml tetrahydrofuran was added drop wise keeping the temperature -50°C to -45°C in about I to 2 hours. Contents were stirred at the same temperature for one and half hour followed by the drop wise addition of solution composed of lOOg (0.635 mol) ethyl-R-4-cyano butanoate and 84 ml tetrahydrofuran in about 1 to 2 hours keeping the temperature -40° to -35°C. Temperature is maintained and stirring was continued till the completion of reaction (3 to 5 hrs). Reaction mass was quenched by the slow addition of aqueous sulphuric acid composed of 224g con sulphuric acid and 1.3 liter water under stirring keeping temperature -10°C to 30°C. After standing the organic layer was separated, washed with saturated sodium chloride solution and dried over anhydrous sodium sulphate. The solvent was them distilled off under reduced pressure resulting into concentrated, which is further purified by treating with hexane. Finally hexane was distilled off under reduced pressure yielding 140g high quality product.
Example 2:
Under the nitrogen gas, a solution composed of 322.Og (3.18 mol) isopropyl amine and 60 ml tetrahydrofuran was charged with freshly cut 22.37 (3.24 mol) lithium metal followed by addition of 300 ml hexane at ambient temperature (32°C). The
17
2 8 AUG 2009

contents were stirred well. This was added with drop wise addition of solution composed of 104.15g (0.66mol) styrene and 200ml tetrahydrofuran over a time period of about one hour keeping the temperature in the range of 35-50°C. The reaction was them maintained for 3 hours to prepare lithium diisopropyl amide. The solution containing LDA is chilled to -45°C and solution composing 298g (2.54 mol) tert- butyl acetate and 80 ml tetrahydrofuran was added drop wise keeping the temperature -50°C to -45°C in about 1 to 2 hours. Contents were stirred at the same temperature for one and half hour followed by the drop wise addition of solution composed of lOOg (0.635 mol) ethyl-R-4-cyano butanoate and 84 ml tetrahydrofuran in about 1 to 2 hours keeping the temperature -40° to -35°C. Temperature is maintained and stirring was continued till the completion of reaction (3 to 5 hrs). Reaction mass was quenched by the slow addition of aqueous sulphuric acid composed of 224g con sulphuric acid and 1.3 liter water under stirring keeping temperature -10°C to 30°C. After standing the organic layer was separated, washed with saturated sodium chloride solution and dried over anhydrous sodium sulphate. The solvent was them distilled off under reduced pressure resulting into concentrated, which is further purified by treating with hexane. Finally hexane was distilled off under reduced pressure yielding 141g high quality product.

A Process for the preparation ot 5-hydroxy-3-oxo pentanoic acid derivatives of formula-1

Wherein;
Rl represents any of an alkyl group of branched or straight chain 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms and an aralkyl group of 7 to 12 carbon atoms;
R2 represents any of hydrogen, an alkyl group of 1 to 12 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; Comprising: a. reacting an alkali metal with dialkylamine of formula V, in the
presence of a catalyst at ambient temperature in an organic solvent to obtain alkali metal dialkyl amide of formula IV; wherein M is a alkali metal and R4 and R5 as defined hereinbefore in the specification;


R4 and R5 may be the same or different and each represents any of an alkyl group of branched or straight chain 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, an aralkyl group of 7 to 12 carbon atoms. Specifically there can be mentioned methyl, ethyl, isopropyl, tert-butyl. n-octyl. phenyl, naphthyl, p-methoxyphenyl, benzyl and p-nitrobenzyl, trimethylsilyl, triethyl silyl and phenyldimethylsilyl among others. Preferred are methyl, ethyl, n-propyl, isopropyl, n-butyl, and tert-butyl. Most preferred is isopropyl;
M represents alkali metal. Specifically there can be mentioned lithium, potassium and sodium. Preferably alkali metal is lithium b. to a reaction mass of (a) is added compound of formula-II wherein Rl
is as defined hereinbefore in the specification, at temperature upto -
50°C;
Wherein;
Rl represents any of alkyl group of 1 to 12 branched or straight
chain carbon atoms, an aryl group of 6 to 12 carbon atoms and an
aralkyl group of 7 to 12 carbon atoms, to a reaction mass of (b) is added a compound of formula-Ill wherein R2 and R3 as defined hereinbefore in the specification to obtain a compound of formula I


Wherein;
R2 represents any of hydrogen, an alkyl group of 1 to 12 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, a
cyanomethyl group, a carboxyl group and alkoxycarbonyl group. As
specific examples, there can be mentioned methyl, ethyl, isopropyl,
tert-butyl, chloromethyl, bromomethyl, cyanomethyl,
benzyloxymethyl, trityloxymethyl, tert-butyldiphenylsyloxymethyl, dimethoxymethyl, l,3-dithian-2-yl, l,3-dithiola-2-yl, vinyl, 2-phenylvinyl, 2-phenylethyl, 2-carbobenzyloxyaminoethyl, phenyl, naphtyl, p-methoxyphenyl. benzyl, p-nitrobenzyl, cyano, carboxy and tert-butoxycarbonyl, among others. Preferred are methyl, ethyl, isopropyl, tert-butyl, chloromethyl, cyanomethyl, benzyloxymethyl, trityloxymethyl, tert-butyldiphenylsyloxymethyl, dimethoxymethyl, vinyl, 2-phenylethyl, phenyl, naphtyl, p-methoxyphenyl, benzyl, p-nitrobenzyl, among others. More preferred are chloromethyl, cyanomethyl, and benzyloxymethyl among others. Most preferred is cyano methyl.
As the substituents on the alkyl. alkenyl, aryl and aralkyl groups each represented by the above R2, there can be mentioned halogen, cyano, C7-19aralkyloxy, Cl-12 alkoxy. C6-12 aryl, nitro, siloxy, N-protected amino, Cl-12 alkyl thio, C6-12 arylthio and C7-12 arakylthio, among others. The number of substituents may be 0 to 3. The number of carbon atoms of the said alkoxycarbonyl group in the above R2 may be 2 to 13;
R3 represents any of an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms and an aralkyl group of 7 to 12 carbon

atoms. Specifically can be mentioned as methyl, ethyl, isopropyl, tert-butyl. n-octyl, phenyl, naphthyl, p-methoxyphenyl, benzyl, p-nitrobenzyl etc. Preferred is methyl or ethyl. Most preferred is ethyl.
2. A process of claim 1 wherein the alkali metal can be sodium, potassium or lithium.
3. A process of claim 2 wherein alkali metal is lithium
4. A process of claim 1 wherein organic solvent is hydrocarbon, carboxylic acid ester, ether, halogenated hydrocarbon or a mixture thereof.
5. A process of any claim 4 wherein organic solvent is hexane, cyclohexane, THF or a mixture thereof.
6. A process of claim 1 wherein dialkylamine is diisopropyl amine
7. A process of claim 1 wherein catalyst is selected from the group of isoprene, styrene, a-methyl styrene or anthracene.
8. A process of claim 1 wherein ambient temperature is about 10°C to about 50°C.
9. A process for the preparation of (5R)-l,l-dimethylethyl~6-cyano-5-hydroxy-3-oxo-hexaonate of Formula-VI;

Comprising a.reacting an alkali metal with dialkylamine of formula V in the presence of a catalyst at ambient temperature in an organic solvent to obtain alkali metal dialkyl amide of formula IV;
?~>
18 AUG 2009

Wherein;
M is an alkali metal;
R4 and R5 as defined hereinbefore in the first claim.
to a reaction mass of (a) is added compound of formula-VII at temperature up to -50°C;

to a reaction mass of (b) is added a compound of formula-VIII to obtain a compound of formula-VI

10. A process of claim 9 wherein the alkali metal can be sodium, potassium or lithium.
11. A process of claim 10 wherein alkali metal is lithium.
12. A process of claim 9 wherein organic solvent is hydrocarbon, carboxylic acid ester, ether, halogenated hydrocarbon or a mixture thereof.
13. A process of claim 12 wherein organic solvent is hexane, cyclohexane, THF or a mixture thereof.
14. A process of claim 9 wherein dialkylamine is diisopropyl amine
15. A process of claim 9 wherein catalyst is isoprene, styrene, a-methyl styrene or anthracene.
16. A process of claim 9 wherein ambient temperature is about 10°C to about 50°C.
17. A process for the preparation of (5R)-l,l-dimethylethyl-6-cyano-5-hydroxy-3-oxo-hexaonate of formula-VI


comprising; a. reacting lithium metal with diisopropyl amine of formula IX in the
presence of a catalyst at ambient temperature in an organic solvent to obtain lithium diisopropylamide of formula X;

b. to a reaction mass of (a) is added compound of formula-VII at temperature up to -50°C;

c. to a reaction mass of (b) is added a compound of formula-VI11 to obtain a compound of formula-VI

19.

A process of claim 17 wherein organic solvent is hydrocarbon, carboxylic acid ester, ether, halogenated hydrocarbon or a mixture thereof A process of claim 17 wherein organic solvent is hexane, cyclohexane, THF or a mixture thereof.

20. A process of claim 17 wherein catalyst is isoprene, styrene, a-methyl styrene or anthracene
21. A process of claim 17 wherein ambient temperature is about 10°C to about 50°C.