DESC:FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
THE PATENT RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)

“PROCESS FOR PREPARATION OF N-ALKYL HYDROXYPYRAZOLES”

SRF LIMITED, AN INDIAN COMPANY,
SECTOR 45, BLOCK-C, UNICREST BUILDING,
GURGAON – 122003,
HARYANA (INDIA)

The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention provides a process for preparation of N-alkyl hydroxypyrazoles compound of formula 1,

wherein R is C1-C3 alkyl.

BACKGROUND OF THE INVENTION
N-alkyl hydroxypyrazole compounds are useful as intermediates for agricultural chemicals, particularly herbicides. These compounds are also very useful precursors for preparation of pharmaceuticals. Several methods are known in the art for the preparation of these compounds.
Japan Patent No. 4641667B2 discloses a process for preparation of 1-methyl-5-hydroxypyrazole involving the reaction of ethoxymethylenemalonic acid diethyl ester with aqueous ammonia solution to form monoamide derivative which upon reaction with methylhydrazine and subsequent neutralization with concentrated hydrochloric acid gives 1-methyl-5-hydroxypyrazole-4-carboxylic acid ethyl ester along with 1-methyl-3-hydroxypyrazole-4-carboxylic acid ethyl ester. 1-Methyl-5-hydroxypyrazole-4-carboxylic acid ethyl ester is hydrolysed and decarboxylated using an aqueous sodium hydroxide solution to obtain 1-methyl-5-hydroxypyrazole.
Japan Patent App. No. JPS58140073A discloses a process for preparation of 1-methyl-5-hydroxypyrazole by hydrolysis and decarboxylation of 1-methyl-5-hydroxypyrazole-4-carboxylic acid ethyl ester using a mineral acid such as hydrochloric acid. The 1-methyl-5-hydroxypyrazole-4-carboxylic acid ethyl ester is prepared by cyclization of ethoxymethylenemalonic acid di-ethyl ester with monomethyl hydrazine in presence of an organic solvent such as methanol.
The present invention provides an alternative, environment friendly with minimum effluent generation and cost-effective process for preparation of 1-methyl-5-hydroxypyrazole.

OBJECT OF THE INVENTION
The object of the present invention is to provide an alternative, environment friendly with minimum effluent generation and cost-effective process for preparation of a compound of formula 1,

wherein R is C1-C3 alkyl.

SUMMARY OF THE INVENTION
In an aspect, the present invention provides a process for preparation of a compound of formula 1,

wherein R is C1-C3 alkyl group,
comprising the steps of:
a) contacting a compound of formula 2,

wherein R is C1-C3 alkyl group
with ammonium chloride and sodium hydroxide to obtain a compound of formula 3;

b) contacting the compound of formula 3 with monoalkyl hydrazine;
c) adding hydrochloric acid followed by in-situ hydrolysis of the intermediate of formula 4,

in water and in presence of ammonium chloride generated in-situ to obtain the compound of formula 1.

DETAILED DESCRIPTION OF THE INVENTION
As used herein, the C1-C3 alkyl refers to methyl, ethyl, n-propyl and isopropyl. Preferably alkyl is methyl or ethyl.
In an embodiment, the present invention provides a process wherein, the compound of formula 2 is reacted with ammonium chloride and sodium hydroxide at 20-30°C to obtain mono amide compound of formula 3. The reaction step is carried out using 20 to 60% of an aqueous sodium hydroxide.
In an embodiment, the reaction mixture thus obtained is filtered to remove sodium chloride and washed further with a solvent to obtain a filtrate. The compound of formula 3 is isolated before using in next step.
In another embodiment, the reaction of the compound of formula 3 with monoalkyl hydrazine is carried out through sequential and periodical heating at a temperature range of 35 to 55ºC.
In another embodiment, the reaction of the compound of formula 3 and monomethylhydrazine is carried out in a solvent selected from a group consisting of 1,4-dioxane; methyltetrahydrofuran and tetrahydrofuran or the like.
In another embodiment, aqueous monomethyl hydrazine is used in a concentration range of 30 to 40%.
In another embodiment, the reaction of the compound of formula 3 and monomethylhydrazine is followed by addition of dry hydrochloric acid to convert ammonia liberated in the reaction to ammonium chloride. The acid is used in range of 1 to 2 times (weight by weight) of the compound of formula 3 to adjust the pH to 1.8-2.0.
The step of hydrolysis is carried out in situ in water in presence of ammonium chloride generated in the previous step-b at a temperature of 85°C to 100°C in a solvent selected from a group consisting of 1,4-dioxane, methyl tetrahydrofuran and water or the like.
In another embodiment, the present invention provides a process for isolation of the compound of formula 1 by azeotropic distillation of its solution in an appropriate solvent selected from a group consisting of tetrahydrofuran, methyltetrahydrofuran, toluene, cyclohexane and 1,4-dioxane or the like.
The water present in the mixture was removed by distillation of the mixture at 90-100°C, under reduced pressure (50 to 150mbar) to obtain residual bottom mixture. An appropriate solvent for azeotropic distillation was added to the residual bottom mixture and azeotropic distillation was carried out at 50°C under reduced pressure till water content is less than 0.1%.
The mixture was then filtered to remove ammonium chloride and filtrate was concentrated at 50°C under reduced pressure to make product concentration in the mixture around 18-20%. The concentrated mixture was gradually cooled to 10°C followed by filtration to get pure compound of formula 1.
In another embodiment, the present invention provides a process for preparation of 1-methyl-5-hydroxypyrazole comprising the steps of:
a) contacting ethoxymethylenemalonic acid diethyl ester with ammonium chloride and sodium hydroxide to obtain a reaction mixture comprising ethyl-2-carbamoyl-3-ethoxyprop-2-enoate;
b) filtering the reaction mixture of step a) and adding monomethyl hydrazine to the filtrate to obtain ethyl 5-hydroxy-1-methyl-1H-pyrazole-4-carboxylate;
c) adding hydrochloric acid followed by in-situ hydrolysis of the intermediate ethyl 5-hydroxy-1-methyl-1H-pyrazole-4-carboxylate in water in presence of ammonium chloride generated in-situ to obtain 1-methyl-5-hydroxypyrazole.
The compound of formula 1 is obtained with a purity greater than 98%, preferably greater than 99%.
The compound of formula 1 is obtained with a yield greater than 85%, preferably greater than 90%.
The effluents generated in the present invention such as water, sodium chloride, ethanol and ammonium chloride can be recovered easily by filtration and reused in the process.
In an embodiment, the process of present invention results in 0.001 to 0.05% of isomeric impurity i.e., 1-methyl-3-hydroxypyrazole.
In another embodiment, the process of present invention provides a compound of formula 1 with a purity greater than 98%, yield greater than 85% and isomeric impurity i.e., 1-methyl-3-hydroxypyrazole (3-isomer) in a range of 0.001 to 0.05%.
In another embodiment, the process of present invention results in less than 0.01% of isomer, 1-methyl-3-hydroxypyrazole (3-isomer). In still another embodiment, the compound of formula 1 obtained in the process is substantially free of isomeric impurity i.e., 1-methyl-3-hydroxypyrazole (3-isomer).
The isolation is carried out using any of the process consisting of extraction, distillation, filtration, decantation, washing, drying or a combination thereof.
Unless stated to the contrary, any of the words “comprising”, “comprises” and includes mean “including without limitation” and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it.
Embodiments of the invention are not mutually exclusive but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth in the appended claims.
The following example is given by way of illustration and therefore should not be construed to limit the scope of the present invention.

EXAMPLES
Example: 1- Preparation of 1-methyl-5-hydroxypyrazole.
Ethoxymethylenemalonic acid diethyl ester (50g, 0.232mol) and ammonium chloride (18.6 g, 0.35mol) was added into a reactor. An aqueous NaOH (40%; 29g, 0.29mol) was added dropwise at 20-30°C. After completion of the reaction, the precipitated sodium chloride was filtered and washed with 1,4-dioxane (28g) to obtain a filtrate containing ethyl-2-carbamoyl-3-ethoxyprop-2-enoate (monoamide).
To the above filtrate a solution of an aqueous monomethylhydrazine (35%; 32g, 0.24mol) was charged while sequentially and periodically heating at a temperature range of 35 to 55ºC. After achieving the desired conversion by HPLC, 1,4-Dioxane (28g) was added to the reaction mixture followed by slow addition of dry hydrochloric acid gas (13g) to adjust pH 1.8-2.0. The reaction mixture was heated to 95-100°C for 40-45 hours.
After completion of the reaction, water and ethanol present in the mixture were removed by distillation at 90-100°C, to obtain residual bottom mixture. 1,4-Dioxane (100g) was added to the residual bottom mixture and azeotropic distillation was carried out at 50 °C under reduced pressure till water content less than 0.1%. The reaction mixture was then filtered to remove ammonium chloride (recycled in next batch) from the process and filtrate was concentrated at 50°C under reduced pressure to make product concentration in the mixture around 18-20%. The concentrated mixture was gradually cooled to 10°C in 6.0 hours, filtered, washed with cool 1,4-dioxane to get pure 1-methyl-5-hydroxypyrazole.
Yield: 90%; Purity (by HPLC): 99.5%

Example: 2- Preparation of 1-methyl-5-hydroxypyrazole.
Ethoxymethylenemalonic acid diethyl ester (100g, 0.464mol) and ammonium chloride (37.2 g, 0.70mol; recycled from the Example 1) were added into a reactor. An aqueous sodium hydroxide (40%; 58g, 0.58mol) was added dropwise at 20-30°C. After completion of the reaction, the precipitated sodium chloride was filtered and washed with 1,4-dioxane (56g) to obtain a filtrate containing ethyl-2-carbamoyl-3-ethoxyprop-2-enoate (monoamide).
To the above filtrate, a solution of aqueous monomethylhydrazine (35%; 64g, 0.48mol) was added while sequentially and periodically heating at a temperature range of 35 to 55ºC. The reaction was monitored by HPLC. After completion of the reaction, 1,4-dioxane (56g) was added to the reaction mixture followed by slow addition of dry hydrochloric acid gas (26g) to adjust pH to 1.8-2.0. The reaction mixture was heated to 95-100°C for 40-45 hours.
After completion of reaction, water and ethanol present in the mixture were removed by distillation at 90-100°C, to obtain residual bottom mixture. 1,4-dioxane (200g) was added to the residual bottom mixture and azeotropic distillation was carried out at 50°C under reduced pressure till water content less than 0.1%. The reaction mixture was then filtered to remove ammonium chloride (recycled in next batch) from the process and filtrate was concentrated at 55°C under reduced pressure to make product concentration in the mixture around 18-20%. The concentrated mixture was gradually cooled to 12°C in 5.0 hours, filtered, washed with cool 1,4-dioxane to get pure 1-methyl-5-hydroxypyrazole.
Yield: 91%; Purity (by HPLC): 99.7%
,CLAIMS:WE CLAIM:
1. A process for preparation of a compound of formula 1,

wherein R is C1-C3 alkyl group,
comprising the steps of:
a) contacting a compound of formula 2,

wherein R is C1-C3 alkyl group,
with ammonium chloride and sodium hydroxide to obtain a compound of formula 3;

b) contacting the compound of formula 3 with monoalkyl hydrazine;

c) adding hydrochloric acid followed by in-situ hydrolysis of the intermediate of formula 4,

in water and in presence of ammonium chloride generated in-situ to obtain the compound of formula 1.
2. The process as claimed in claim 1, wherein the step of contacting the compound of formula 2 with ammonium chloride and sodium hydroxide is carried out at a temperature of 20-30°C.
3. The process as claimed in claim 1, wherein the step of contacting the compound of formula 3 with monoalkyl hydrazine is carried out through sequential and periodical heating at a temperature range of 35 to 55ºC.
4. The process as claimed in claim 1, wherein the step of contacting the compound of formula 3 with monoalkyl hydrazine is carried out in a solvent selected from a group consisting of 1,4-dioxane; methyltetrahydrofuran and tetrahydrofuran.
5. The process as claimed in claim 1, wherein the reaction of the compound of formula 3 with monoalkyl hydrazine is followed by addition of dry hydrochloric acid to convert ammonia liberated in the reaction to ammonium chloride.
6. The process as claimed in claim 1, wherein the hydrolysis is carried out in presence of a solvent selected from a group consisting of 1,4-dioxane, methyl tetrahydrofuran and water.

7. The process for preparation of 1-methyl-5-hydroxypyrazole as claimed in claim 1, comprising the steps of:
a) contacting ethoxymethylenemalonic acid diethyl ester with ammonium chloride and sodium hydroxide to obtain a reaction mixture comprising ethyl-2-carbamoyl-3-ethoxyprop-2-enoate;
b) filtering the reaction mixture of step a) and adding monomethyl hydrazine to the filtrate to obtain ethyl 5-hydroxy-1-methyl-1H-pyrazole-4-carboxylate;
c) adding hydrochloric acid followed by in-situ hydrolysis of the intermediate ethyl 5-hydroxy-1-methyl-1H-pyrazole-4-carboxylate in water in presence of ammonium chloride generated in-situ to obtain 1-methyl-5-hydroxypyrazole.
8. The process as claimed in claim 1, wherein the compound of formula 1 is obtained with a purity greater than 98%, yield greater than 85% and isomeric impurity i.e., 1-methyl-3-hydroxypyrazole (3-isomer) in a range of 0.001 to 0.05%.

Dated this 24th March 2022.
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