FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"PROCESS FOR PREPARATION OF HIGHER DERIVATIVES OF B-
KETOESTER"
2. APPLICANT:
(a) NAME: Omkar Speciality Chemicals Limited
(b) NATIONALITY: Indian Company incorporated under the
Companies Act, 1956
(c) ADDRESS: B-34, MIDC, Badlapur (East), Dist -Thane-421503,
Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner
in which it is to be formed.

TECHNICAL FIELD:
This invention relates to preparing higher derivatives of p-ketoester. These derivatives find application in synthesis of heterocycles, cholesterol reducing drugs and are an important building block for the synthesis of many drug molecules.
BACKGROUND AND PRIOR ART:
Numerous methods appear in literature for the preparation of p-ketoesters. In Blaise reaction, (3-ketoester is obtained via zinc mediated reaction of nitriles with a-haloester as shown in scheme 1. Scheme I

Many other preparative processes are also described in US221333, US2367632, US2407942, J. Am. Chem. Soc, 63, 2252 (1941); 63, 3156(1941).
DE2412784 describes preparation of β-ketoesters using d'mikyi carbonates and base in benzene and hexamethyl phosphorotriamide to achieve the product in better yield. However this method is also not suitable for commercialization as both solvents are toxic and cannot be used commercially.
It has been proposed to produce p-ketoesters by reacting aceto acetic esters with acid chlorides via magnesium alcoholates, followed by hydrolytic dissociations in British Patent specification No. 1000709 and US3142692. Unfortunately, this method has number of difficulties in practice, for example magnesium alcoholates used in the process should be of high activity and purity. Secondly preparation of magnesium alcoholate uses carbon tetra chloride as a solvent. Commercially use of carbon tetrachloride is restricted due to its toxic nature.
Accordingly p-ketoesters have also been prepared by reacting an acyl chloride with sodium salt of alkyl acetoacetate. However when an acyl chloride is reacted with sodium

salt of alkyl acetoacetate, acyl radical attaches to keto oxygen as well as to carbon resulting in diacylated product. The acylation of metal ketones has been studied extensively in the literature. In one such investigation, reaction of m- or p- nitro benzoyl chloride with the copper (11) chelate of acetyl acetone, it was found that on shaking the reactants in CHCI3 for 12-24 hrs at room temperature, a triketone was obtained together with a precipitate of cupric chloride. The triketone is further converted to p-diketone by treatment with aq. ammonia followed by acidification with HCI.
US5194671 describes formation of calcium chelate of aceto carboxylic acid ester where addition of aceto carboxylic acid ester to calcium hydroxide or oxide is carried in presence of methylene dichloride. During this process thick unstirrable mass of calcium chelate of aceto carboxylic acid ester is formed, vigorous stirring has to be maintained to avoid lumps formation; practically it is not feasible to maintain such a high speed on commercial scale. Secondly heat and mass transfer suffers which will ultimately affect the reaction rate.
Therefore, there is a need in the art to provide a process which overcomes the above difficulties like heat and mass transfer to give good output and feasible at commercial scale.
Thus the object of present invention is to provide a process for preparation of β-ketoester derivatives in good yield in a safe, simple and economic way starting from easily available raw materials.
SUMMARY OF INVENTION:
The present invention discloses safe, simple and economic way of producing P-ketoester derivatives of general formula (I)


In which, R1 is selected from an alkyl group containing C1-C18 carbon atoms or an aromatic ring. R2 is selected from an alkyl group containing C1-C18, an alkenyl group or phenyl group.
Accordingly-ketoester derivatives are obtained by reacting diketone chelate of general formula (11) with acyl chloride of general formula (III) followed by hydrolysis.

wherein, Ri is selected from an Alkyl group with C1-C8 carbon atoms or phenyl or benzyl group

wherein, R is an Alkyl group with C1-C8 carbon atoms.
DETAILED DESCRIPTION OF THE INVENTION:
Accordingly, the present invention provides a method for synthesizing compound of general formula (I). These compounds find wide application as organic building blocks, in synthesis of drug intermediate and heterocycles.
In the preferred embodiment, the process of present invention comprises of reacting diketone chelate of general formula (II) with acyl chloride of general formula (III) followed by hydrolysis. The important step of the present invention lies in the formation of diketone chelate in situ by the action of metal compounds which can be selected from the group consisting of halides, hydroxides, acetates, nitrates, oxalates, amides, sulfide and the like compounds of metals including but not limited to lithium, sodium,

potassium, magnesium, calcium, strontium, barium, zinc, aluminium, chromium, molybdenum, iron, nickel, cobalt, on compound of general formula (IV) where, R, is alkyl group with C1-C8 carbon atoms or phenyl or benzyl group.

Diketone chelate which is formed are generally believed to be complex coordination compounds in which a coordinate linkage is established between the metal compound and enol form and the oxygen atom of the remaining carbonyl group of compound of general formula (IV). The metal atom thereby becomes part of one or more six membered rings. After completion of alkylation of Diketone chelate, hydrolysis is carried to yield targeted β-ketoester derivative.
According to the preferred embodiment, a method for synthesizing compound of general formula (I) comprising following steps:
a) Charging an organic solvent in reactor A followed by adding a compound capable of forming chelate with compound of general formula (IV) at a temperature range of-5-25°C preferably between 0-20°C more preferably between 5-15°C;

b) Preparing mixture of aceto acetic acid ester and acyl chloride in another reactor B
followed by lowering the temperature in the range -5-25°C preferably between 0-
20°C more preferably between 5-15°C;
c) Adding reaction mixture of reactor B into reactor A at the rate of 100-500 mL/min
under stirring to obtain p-ketoester derivatives of general formula (I);

d) hydrolyzing β-ketoester derivative of general formula (T) at temperature range of 0-50°C preferably between 10-30°C more preferably between 15-25°C with diluted mineral acids;
e) Adjusting the pH of reaction mixture by liquor ammonia at a temperature range of -5 - 15°C more preferably between 0-10°C and isolating the targeted compound by conventional techniques after neutralizing with acetic acid.
The solvent used for the purpose of the present invention may be selected from the group consisting of methylene dichloride, ethylene dichloride, chloroform, toluene, xylenes, tetrahydrofuran, methyl tetrahydrofuran, Diisopropyl ether, cyclohexane, C3-C10 alkanes, dimethyl ketone, methyl iso butyl ketone, methyl ethyl ketone, cyclohexanone and like.
The aceto acetic acid ester and acyl chloride is always present in molar ratio of 1,0-1.5 more preferably between 1.05-1.3.
The dilute mineral acids are selected from the group consisting of hydrochloric acid, sulphuric acid, and nitric acid with strength of 10-20%.
In the process of the present invention, product is isolated at pH of 7 by neutralizing with acetic acid. The product is isolated by using commonly known techniques available in the art such as extraction/evaporation, purification by fractional distillation.
Thus the present invention results in improved yield of β-ketoester derivatives of general formula (I).
The present invention will be more specifically explained in the following examples. However, it should be understood that the following examples are intended to illustrate the present invention and cannot limit the scope of the present invention in any manner.

Example 1
688L toluene and 100kg calcium hydroxide were charged in a reactor A and temperature was lowered to 5-15°C. In reactor B mixture of 100kg methyl aceto acetate and 106kg iso-butyryl chloride was prepared at 15-25°C and dosed to reactor A at the rate of 100-500mL/min after complete addition reaction mixture was added to 180L cone, hydrochloric acid in 400L water and stirred for 1 h. Basic pH of reaction mixture was adjusted by liquor ammonia and reaction was further stirred for Ih at 0-10°C. Reaction mixture was neutralized (pH = 7) by acetic acid. Layers were separated, toluene was recovered. Pure product obtained after distillation was 100kg. Yield: 80.6% Purity: NLT 98.0%
Example 2
Under same condition as in Example 1, mixture of 112kg ethyl aceto acetate, 106kg iso-butyryl chloride in 688L toluene was reacted with calcium hydroxide. Subsequent reaction time after had been dosed in was 5hr to adjust alkaline pH. Ethyl iso-butyryl acetate obtained was 95Kg. Yield: 70.0% Purity: NLT 98.0%
Example 3
Under same condition as in example 1, mixture of 100kg methyl aceto acetate, 140kg benzoyl chloride in 688L toluene was reacted with 100kg calcium hydroxide. Subsequent reaction time after had been dosed in was 8hr to adjust alkaline pH. Methyl benzoyl acetate obtained was 120Kg. Yield: 78.2% Purity: NLT 98.0%.

WE CLAIM,
1. A process for producing P-ketoester derivatives of general formula (I)

Wherein, R1 alkyl group containing C1-C8 carbon atoms or aromatic ring, R2 is alkyl group containing C1-C18 carbon atoms, alkenyl group or aromatic ring, comprising
a) Charging an organic solvent in reactor A followed by adding a compound capable of forming chelate with compound of general formula (IV) at a temperature range of -5-25°C preferably between 0-20°C more preferably between 5-15oC ;

b) preparing mixture of aceto acetic acid ester and acyl chloride in another reactor B followed by lowering the temperature in the range of -5-25°C preferably between 0-20°C more preferably between 5-15°C;
c) Adding reaction mixture of reactor B into reaction mixture of reactor A at the rate of 100-500 mL/min under stirring to obtain P-ketoester derivatives of general formula (1);
d) Hydrolyzing p-ketoester derivative of general formula (I) at temperature range of 0-50°C preferably between 10-30°C more preferably between 15-25°C with dilute mineral acids;
e) Adjusting the pH of reaction mixture by liquor ammonia at a temperature range of-5 - 15°C more preferably between 0-10°C and
f) Isolating the targeted compound by conventional techniques after neutralizing
with acetic acid.

2. The process according to claim 1, wherein, the solvent is selected from the
group consisting of methylene dichloride, ethylene dichloride, chloroform,
toluene, xylenes, tetrahydrofuran, methyl tetrahydrofuran, Diisopropyl ether,
cyclohexane, C3-C10 alkanes dimethyl ketone, methyl iso butyl ketone, methyl
ethyl ketone or cyclohexanone.
3. The process according to claim 1, wherein, the molar ratio of aceto acetic acid ester and acyl chloride is in the range of 1.0-1.5 more preferably between 1.05-1.3.
4. The process according to claim 1, wherein, the dilute mineral acids are selected from the group consisting of hydrochloric acid, sulphuric acid, nitric acid with a strength of 10-20%.
5. The process according to any one of the preceding claims, wherein, the product is isolated at pH of 7.
6. The process according to any one of the preceding claims, wherein, the pH is maintained using acetic acid.
7. The process according to claim 1, wherein, the conventional techniques are selected from extraction/evaporation, purification by fractional distillation.