TITLE OF THE INVENTION

An improved process for the preparation of methyl 3-(methyIamino)-3-5 oxopropanoate.

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of methyl 3-(methylamino)-3-oxopropanoate having the structural Formula I.

10

O O

H3C^ XX /CH3

Fomuila I

BACKGROUND OF THE INVENTION

The process for the preparation of methyl 3-(methylamino)-3-oxopropanoate is 15 disclosed in CN 101085747A, the process discloses an invention consists of four step process where step b product is an acid which is further isolated to convert to step c product. Thionyl chloride is used Dimethyl amide compound of step 4 is removed by fractional distillation.

20 Alternatively, S. M. McElvain Laboratory of Organic Chemistry’s J. Am. Chem. SOC. 1991, 113, 1164-1 173 discloses the preparation of ethyl 3-(methylamino)-3-oxopropanoate. Although the alternative process described by Samuel H Gellman et. al. avoids the use of reagents like thionyl chloride, the product differs from the actual product related to this process.

25

As already explained, to date the prior art failed to provide efficient methods for obtaining methyl 3-(methylamino)-3-oxopropanoate in high purity and with high yields. The lack of efficient manufacturing processes increases the cost of the drugs
like Paroxetine Hydrochloride salt and the pharmaceutical compositions containing it, which has already resulted in expensive medications. In view of the pharmaceutical value of the compound of formula T, it is thus desirable to develop an efficient and safe process for the preparation of methyl 3-(methylamino)-3-oxopropanoate in high purity and high yield, which can be easily applied at an industrial scale with low energy requirements and costs.

Therefore, the present invention overcomes the drawbacks of the prior art by providing process with less number of steps which are simple, efficient, high yield preparation process.

OBJECTS OF THE INVENTION

The principal object of this invention is to develop an improved preparation process for the preparation of methyl 3-(methylamino)-3-oxopropanoate. with high yield and purity.

SUMMARY OF THE INVENTION

The present invention provides a cost effective, novel and an efficient process for the preparation of methyl 3-(melhylamino)-3-oxopropanoate compound of Formula I with higher yields and better purity.

In one embodiment, the present invention provides an improved process for the preparation of methyl 3-(methylamino)-3-oxopropanoate having the structural Formula I,

O O

H3C^ X JL, /CH3

Formula I

which comprises:

a) hydrolyzing compound of Formula TV
^ X X ^

xh3

Formula IV

in presence of hydrolyzing agent and alcoholic solvent to obtain compound of Formula III;

O O

^ X X

H3cOO K

Formula III

b) amidation of compound of Formula III to obtain compound of Formula II;

O O

H3C^ iL A. /K

NH —

Formula II

c) insitue reacting compound of Formula II with sodium carbonate, dimethylsulfate/diethyl sulfate in solvent to obtain compound of formula-I.

O O

H3C^ A /CH3

NH '"o'" 3

Formula I

DETAILED DESCRIPTION OF THE INVENTION

Accordingly, the present invention provides a Lhree-slep process for the preparation of of methyl 3-(methylamino)-3-qxopropanoateof compound of Formula I, as shown.in the Scheme-I given below.
o O KOH, McOH o O sq„% HH,CH I" 2 |

—— ^cAAdK . „ '

rellux Stage-b _ , ,,

diethyl malonate Stage a L Formula II J

Formula IV Formula III NajCO,

Stage-c DMS

Acetone

o o

methyl 3-(methyIamino)-3-oxopropanoate

Formula I

Scheme-I

5 In step-a, the compound of Formula IV is hydrolyzed with hydrolyzing agent in presence of solvent to obtain compound of Formula III as per the literature.1

The bases used in the hydrolysis reaction is selected from inorganic agents such as potassium hydroxide, sodium hydroxide, calcium hydroxide, ammonium 10 hydroxide and the like; Preferably potassium hydroxide.

The reaction temperature may range from 20-50 °C and preferably at a temperature in the range from 20-60 °C. The duration of the reaction may range from 10-16 hours, preferably for a period of 12 hours.

15

The polar protic solvent used in the reaction is selected from methanol, ethanol, iso-propyl alcohol, butanol, hexanol, and the like; Preferably methanol.

In step-b, the compound of Formula III is treated with 40% aq. 20 Methylamine/methanolic methylamine in presence of aqueous media to obtain compound of Formula II.

*

The amidation reagent used is selected from aqueous Methylamine or methanolicmethyl amine. Preferably using 40% aq.methylamine.

The solvent used is selected from toluene, xylene, tetramethyl oxolane or tetra hydro furan and the like. Preferably using toluene.

5

The duration of the reaction may range from 20 hours to 52 hours, preferably for a period of 24 hours.

In step-c, the compound of Formula II is esterified with dimethyl sulphate or 10 diethyl sulphate presence of polar solvent to obtain compound of Formula 1.

The reducing agent used is selected from dimethyl sulphate, diethyl sulfhate and the like. Preferably using dimethyl sulphate.

15 The polar aprotic solvent used is selected from acetone, methyl ethyl ketone, tetrahydrofuran, 1,4-dioxane and the like. Preferably using acetone.

The bases used is selected from sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate and the like. Preferably using sodium 20 carbonate.

The reaction temperature may range from 20 -50 °C and preferably at a temperature in the range from 20-40 °C. The duration of the reaction may range from 1 -14 hours, preferably for a period of 1 2 hours.

25

EXPERIMENTAL PORTION

Thedetails ofthe invention aregiven in theexample provided below, which is given to illustrate the invention only and therefore should not be construed to limit the 30 scope of the invention.
Example-l: Process for preparation of methyl 3-(methylamino)-3-oxopropanoale of formula-I

Step-a:

To a solution of diethyl malonate (400 grams, 2.49 mol, 1.0 eq) in commercial methanol (1600 mL), potassium hydroxide pellets (140 grams) at room temperature added commercial methanol (1600 mL) over a period of 1 to 2 hours. During addition, a white crystalline precipitate forms, reaction mixture was stirred at 25-30 °C for 2 hours. After the mixture has stood overnight, it is heated to boiling on the steam bath. Precipitation of the potassium ethyl malonate is completed by cooling the filtrate in an ice bath. The salt is collected by suction filtration, washed with a small amount of methanol, and dried under reduced pressure at room temperature. An additional amount of the potassium salt is obtained by concentrating the mother liquors on the steam bath to about 100-125 ml to afford stage-a product as white crystalline precipitate (200 grams, 50-80%) and the formula III used for stage-b without further purification.

Stcp-b:

To crystalline precipitate product of step-a (50 grams, 0.293 mol, 1.0 eq) added 40% aq. Methyl amine (50 m.L), followed by stirring for 48 hours in closed conditions. After completion of the reaction added toluene (500 mL) and removed water by azeotropically. After completion of water removal, toluene layer evaporated under reduced pressure.

Step-c:

The above obtained solid is re-dissolved in water (50 mL), acetone (150 mL) and added Na2C03 (31 grams, 0.292 moles). After dissolving the sodium carbonate, added dimethyl sulphate (55 grams, 0.436 moles) slowly below 50 °C and stirred for 12-16 hours. After completion of the reaction, filtered the solid and washed with acetone (50 mL). The filtrate was evaporated under reduced pressure to afford the compound of Formula-I i,e. methyl 3-(methylamino)-3-oxopropanoate (38 grams,
crude, yield 100%). The crude compound distilled further to get the required purity.