FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"PROCESS FOR PREPARATION OF PYRAZOLE DERIVATIVE"
2. APPLICANT:
(a) NAME: M/S. INDOCO REMEDIES LIMITED.
(b) NATIONALITY: Indian Company incorporated under the Indian
Companies ACT, 1956.
(c) ADDRESS: Indoco House, 166 C. S. T. Road, Santacruz (East),
Mumbai - 400 098. Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF INVENTION:
The present invention provides a process for preparation of 3 — amino pyrazole derivatives represented by Formula -I,

Formula -1
Where R1 = H, C1 - C4 alkyl group or benzyl group or phenyl group; R2 =C-1 - C6 alkyl group or benzyl group.
BACKGROUND AND PRIOR ART:
The compound 3 - ammo pyrazote derivative of Formula - I is a useful active intermediate for the preparation of pharmaceutical compounds used for treatment of hyperuricemia and chronic gout, antiurolithic viz. Allopurinol, an inhibitor of smooth muscle cell growth particularly vascular re-narrowing after percutaneous transluminal coronary angioplasty, membrane proliferative nephris, arterioscleotic diseases, hypertension, or diabetes mellitus.
The prior art discloses various methods for the preparation of the base moiety of pyrazole derivative of Formula - II
Formula - II Where R1 =H & R2 is as described above.
The preparation of ethyl 3-amino-lH-pyrazole-4-carboxylate is disclosed in US Patent No US 2,868,803 wherein the process involves cyclization of ethoxy-methylene-cyanoacetic

acid ethyl ester with hydrazine hydrate in presence of alcohol at reflux condition for 6 hours to afford ethyl 3-amino-lH-pyrazole-4-carboxylate as represented in scheme -1.

Scheme -I
The starting ethoxy-methylene-cayanoacetic acid ethyl ester was prepared according to the process described in the Journal, J. Amer. Chem. Soc, 74(19), 4889 - 4891 (1952), wherein the reaction of ethyl orthoformate with ethyl cyanoacetate is carried out at reflux to afford oily product which is distilled under vacuum to isolate pure intermediate compound..
Another method for preparation of ethyl 3-amino-lH-pyrazole-4-carboxylate is reported in the Journal, Bulletin of the Chemical Society of Japan, 50(4), 957 - 960 (1977). The process disclosed involves reaction of amidrazone derivatives and ethyl 2-cyano-3-ethoxyacrylate in ethanol to give intermediate N-(2-cyano-2-ethoxycarbonylvinyl) amidrazone derivative, which is cyclised by refluxing in toluene to give ethyl 3-amino-lH-pyrazole-4-carboxylate. The method is as reported in scheme - II.

Scheme - II

The US patent US 4,468,353 disclosed a process for preparation of intermediate alkoxymethylene compounds used for preparing 3-amino-lH-pyrazole-4-carboxylic acid ethyl ester. Wherein the ethoxy-methylene-cayanoacetic acid ethyl ester is prepared by reacting ethyl cyanoacetate with orthoformic acid triethyl ester in the presence of acetic anhydride at 130°C to 150°C. The method is as reported in scheme - III.

The drawbacks of the prior art are:
1. the intermediate compound requires high vacuum distillation to isolate pure
compound;
2. requires the use of acetic anhydride for the reaction which is to be removed under
vacuum to isolate pure intermediate;
3. requires high temperature of 130°C for the prepai-ation of the intermediate;
4. requires the use of solvent for reaction with hydrazine hydrate and during the
cyclisation of the intermediate.
Therefore there remains a need for an improved process which ameliorates the problems of the prior art processes and is industrially rugged and useful.
The present invention provides an improved process for the preparation of 3 - amino pyrazole derivatives in which the intermediate formed is solid and does not require high vacuum distillation of the intermediate and the reaction with hydrazine hydrate is carried out in water at lower temperature which makes the process rigid and operator friendly, therefore industrially useful.
OBJECT OF THE INVENTION:
The object of the present invention is to provide a rigid and robust synthetic process for the preparation of 3 - amino pyrazole derivatives of Formula -I.

Another object of the present invention is to provide a process for the preparation of 3 -
amino pyrazole derivatives of Formula - I, using economical and environment friendly
solvent.
Another objective of the present invention is to prepare 3 - amino pyrazole derivatives of
Formula -I having high purity.
SUMMARY OF THE INVENTION:
In accordance with'the above objectives, the present invention provides a process for the preparation of 3 -amino pyrazole derivative of Formula-I;

Formula -I
Where R1 = H, C\ - C4 alkyl group or benzyl group or phenyl group; R2 = C1 - C6 alkyl group or benzyl group; comprising of reacting the compound of Formula - III, with hydrazine hydrate.

Formula - III Where R2 is as defined above.
1. The process for the preparation of 3 - amino pyrazole derivative comprising the steps of;
i. reacting ester of cyano acetic acid with morpholine in presence of triethylorthoformate and diluent to give the intermediate compound of Formula -III;


Formula - III
ii. reacting the compound of Formula - III with hydrazine hydrate in presence of water to yield 3 - amino pyrazole derivative of Formula -1.
DESCRIPTION OF THE INVENTION:
The present invention describes the process of preparation of pyrazole derivative of Formula -I
Formula -I
Where R1 - H, C2 - C & alkyl benzyl group or phenyl group; R2 = C1 - C6 alkyl group or benzyl group.
In one of the embodiment of the present invention, the ester of cyano acetic acid is reacted with morpholine in presence of triethylorthoformate and diluent to yield the intermediate compound of Formula - III. The ester of cyanoacetic acid for the reaction is selected from alkyl ester having C1 - C6 carbon atoms or benzyl ester. The preferred ester for the reaction is alkyl ester. The most preferred ester is ethyl cyanoacetate. The reaction is carried out in presence of diluent selected from C1 - C4 linear or branched alcohol; wherein the preferred diluent used is isopropyl alcohol. The reaction is carried out at temperature of 60 - 90°C, wherein the preferred temperature of the reaction is 70 - 90°C and the most preferred temperature of the reaction is 85 - 90°C. The reaction is maintained at reflux for 3 - 5 hours for the completion, cooled to 25 - 30°C and further to

0 - 10°C. Stirred and filtered the solid to recover the intermediate compound of Formula - III. The reaction sequence is as given below in scheme - IV;

Formula - III Scheme - IV
In another embodiment of the present invention the intermediate compound of Formula -III is reacted with Hydrazine hydrate in presence of polar solvent at temperature of 15 -60°C to isolate the pyrazole derivative of Formula - II. The preferred temperature of reaction is 15 - 30°C for 1 hour, 25 - 30°C for 3 hours and 40 - 45°C for 2 hours. The gradual raising of temperature help to get the completion of the reaction without formation of unwanted impurities. The reaction is further cooled to 25 - 30°C and subsequently to 0 - 5°C and filtered to isolate the pyrazole derivative of Formula - II. The reaction sequence is as given below in scheme - V

Formula - III Formula - II
Scheme - V
In another embodiment compound of Formula - II (R2 = - C2H5) is reacted with an alkylating agent in presence of a base and suitable solvent to afford N - substituted pyrazole derivative of Formula - IV;


Formula - IV
The alkylating agent used is selected from alkyl halide, alkyl sulfate, and benzyl halide. The suitable base used for the alkylation reaction is sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, or sodium hydride. The suitable solvent for alkylation is selected from water, C1 - C4 alcohol and dimethyl formamide.
Further details of the process of the present invention will be apparent from the examples presented below. The examples presented are purely illustrative and are not limited to the particular embodiments illustrated herein but include the permutations, which are obvious as set forth in the description.
EXAMPLES:
Example 1: Preparation of Ethyl 2 - cyano - 3 - morpholinoacrylate:
Charged in a flask ethyl cyanoacetate (220gm, 1.95moles), triethyl orthoformate (314gm, 2.12 moles), morpholine (306.5gm, 3.52moles) and isopropyl alcohol (35 ml). Stirred and raised the temperature to reflux and maintained for 3 hours. The solid product crystallized out during the reaction was cooled to 25 - 30°C and further chilled to 0 -.5°C and stirred for 1 hour The crystalline solid was filtered and washed with chilled isopropyl alcohol. Dried the product till constant weight. Dry wt = 325gm. (79.48 %)
Example 2: Preparation of ethyl 3 - amino - 1H- pyrazole - 4 - carboxylate:
Charged ethyl 2 - cyano - 3- morpholinoacrylate (250gm, 1.19 moles) to water ( 600mL) maintaining temperature at 15 - 20°C. Charged under stirring hydrazine hydrate (80 % technical, 74gm, 1.18 moles) to the reaction solution. The mixture was stirred at 15 - 20°C one hour, at 25 - 30°C for 3 hours and 40 - 45°C for 2 hours. After completion of the reaction, the reaction mass was cooled to 25 - 30°C and further chilled to 0 - 5°C.

Filtered the solid product and washed with chilled water to isolate ethyl 3 - amino - 1H-pyrazole - 4 - carboxylate. Dried the product till constant weight at 50 - 55°C. Dry wt = 170gm. (92.14%)
Example 3: Preparation of ethyl 3 - amino - 1 - benzyl - 1H - pyrazole - 4 -carboxylate:
Charged in the flask containing dimethylformamide (500 ml), sodium methoxide (91.8gm, 1.7 moles), ethyl 3 - amino- 1H- pyrazole - 4 - carboxylate (250gm, 1.61 moles), benzyl chloride (208.72 ml, 1.65 moles) and stifred. Raised the temperature of the reaction mixture to reflux and maintained 3 hours. After completion of the reaction, concentrated the reaction mass completely under reduced pressure. To the residual mass charged water and stirred. The product was extracted in dichloromethane (3 X 200 ml) separated the organic layer and distilled the solvent. The residual mass was taken in acetone to isolate the required product ethyl 3 - amino --1 - benzyl - 1H- pyrazole - 4 -carboxylate. The compound was filtered and dried at 50 - 55°C till constant weight. Drywt = 316gm(80%).

We claim;
1. A process for the preparation of 3 - amino pyrazole derivative of Formula -1

Formula -I
Where R1 = H, C1 - C4 alkyl group or benzyl group or phenyl group; R2 = C1 - C6 alkyl group or benzyl group;
comprising a step of reacting the compound of Formula - III, with hydrazine hydrate.

Formula - III
2. The process for the preparation of 3 - amino pyrazole derivative as claimed in claim 1 comprising of;
i. reacting ester of cyano acetic acid with morpholine in presence of triethylorthoformate and diluent to give the intermediate compound of Formula -III;
Formula - III
ii. reacting the compound of Formula - III with hydrazine hydrate in presence of water to yield 3 - amino pyrazole derivative of Formula -I.

3. The process as claimed in claim 2 (i), wherein the ester of cyano acetic acid is
selected from
Methyl, ethyl, propyl, isopropyl or benzyl ester of cyanoacetic acid.
4. The process as claimed in claim 3; wherein the preferred ester of cyano acetic acid is ethyl ester.
5. The process as claimed in claim 2 (i), wherein the diluent used is selected from CI -C4 linear or branched chain alcohol.
6. The process as claimed in claim 5; wherein the preferred diluent selected is isopropyl alcohol.
7. The process as claimed in claim 2(i); wherein the reaction is carried out at temperature of 60 - 90°C.
8. The process as claimed in claim 7; wherein the preferred temperature of the reaction is 85-90°C.