The present invention provides a one pot process for preparation of hydroxypyrazole compound of formula 1,

wherein R is C1-C3 alkyl.

BACKGROUND OF THE INVENTION
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 by reaction of ethoxymethylenemalonic acid diethyl ester with aqueous ammonia solution to form monoamide derivative. Then 35% methylhydrazine added dropwise by maintaining the reaction temperature at 5°C to the monoamide derivative. After complete addition, mixture is heated and stirred at 60°C for 4 hours, followed by neutralization with concentrated hydrochloric acid to produce 1-methyl-5-hydroxypyrazole-4-carboxylic acid ethyl ester and isomer 1-methyl-3-hydroxypyrazole-4-carboxylic acid ethyl ester (1.8%).
The isolated 1-methyl-5-hydroxypyrazole-4-carboxylic acid ethyl ester is decarboxylated using 49% aqueous sodium hydroxide solution to obtain 1-methyl-5-hydroxypyrazole.
It has been observed that an abrupt increase in temperature from 5°C to 60°C during the addition of monomethyl hydrazine to monoamide, derivative results in large amount of undesired isomer i.e., 1-methyl-3-hydroxypyrazole-4-carboxylic acid ethyl ester (1.8%). Also, the decarboxylation using base leads to the formation of impurities, resulting in lower yield and purity of the final product.
The inventors of the present invention have found that the preparation of hydroxypyrazoles from alkoxymethylenemalonic acid dialkyl ester if carried out in one pot with sequential and controlled increase of temperature in cyclization step results in good yields, lesser chemical operations, thereby increasing the yield of the product.

OBJECT OF THE INVENTION
The object of the present invention is to provide an alternative and cost-effective process for preparation of compound of formula 1,

wherein R is C1-C3 alkyl

SUMMARY OF THE INVENTION
In an aspect, the present invention provides a one pot 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 an aqueous ammonia to obtain a compound of formula 3;

b) contacting the compound of formula 3 with monoalkyl hydrazine to obtain a compound of formula 4; and

c) decarboxylating the compound of formula 4 with an acid to obtain the compound of formula 1, wherein the process is carried out without isolating any intermediate at any stage.

In another aspect, the present invention provides a process for preparation of a compound of formula 1,

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

wherein R is C1-C3 alkyl,
with an aqueous ammonia to obtain a compound of formula 3,

b) adding monoalkyl hydrazine to the compound of formula 3 at a temperature of 30 to 40ºC to obtain a reaction mixture,
c) sequentially and periodically heating reaction mixture of step b) to obtain a compound of formula 4, and

d) decarboxylating the compound of formula 4 to obtain the compound of formula 1.
In another aspect, the present invention provides a one pot 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 an aqueous ammonia to obtain a compound of formula 3;

b) adding monoalkyl hydrazine to the compound of formula 3 at a temperature of 30 to 40ºC to obtain a reaction mixture,
c) sequentially and periodically heating reaction mixture of step b) to obtain a compound of formula 4 and

d) decarboxylating the compound of formula 4 with an acid to obtain the compound of formula 1,

DETAILED DESCRIPTION OF THE INVENTION
As used herein, the C1-C3 alkyl refer to methyl, ethyl, n-propyl, 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 20-25% aqueous ammonia solution at 25-30°C to obtain a mixture containing mono amide compound of formula 3.
In another embodiment, the present invention provides a process wherein, de-ionised water is added to the reaction mixture containing mono amide compound of formula 3 prior to the addition of monoalkyl hydrazine.
As used herein, the monoalkyl hydrazine is monomethyl hydrazine. The monomethyl hydrazine used herein has purity greater than 98%, preferably greater than 99%.
In an embodiment of the present invention, the monomethyl hydrazine is used in the form of 30 to 40% aqueous solution.
The mixture containing mono amide compound of formula 3 was contacted with 35% aqueous monomethylhydrazine while maintaining the reaction temperature at 30-50°C to produce a compound of formula I.
In a preferred embodiment, the addition of 35% aqueous monomethylhydrazine to the above mixture was carried out dropwise by maintaining the temperature in the range of 30-40°C.
In an embodiment, the sequential and periodical heating is carried out at a temperature range of 35 to 55ºC.
In another embodiment, the sequential and periodical heating is carried out by raising 3 to 5ºC of temperature every one hour.
In another embodiment, the sequential and periodical heating is carried out by raising 3 to 5ºC of temperature every one hour.
In another embodiment, the sequential and periodical heating is carried out by heating the reaction mixture to a temperature of 35-40ºC for an hour, then to a temperature of 42-45ºC for another hour, and finally to a temperature of 47-55ºC for an hour.
In another embodiment, the present invention provides a process wherein sequential and periodical heating is carried out by first heating the reaction mixture to a temperature of 40°C and stirring at the same temperature for an hour, then heating to a temperature of 45°C and stirring at the same temperature for another hour and finally heating at a temperature of 50°C and stirring at the same temperature for an hour.
This slow addition of monomethylhydrazine while maintaining the reaction temperature at 30-40°C and gradual increase in temperature during reaction helps in high selectivity and low isomer formation.
The decarboxylation of compound of formula 4 is carried out using acid at a temperature of 85 to 100°C for 4 to 7 hours.
As used herein, the acid is selected from a group consisting of hydrochloric acid, sulfuric acid and acetic acid or the like.
In an embodiment, the present invention provides a process wherein, the decarboxylation is carried out using concentrated hydrochloric acid followed by heating the reaction mixture to a temperature of 85°C to 100°C for 5 hours.
In an embodiment, the present invention involves minimal use of the acid. The acid is used in range of 1 to 2 times (weight by weight) of the compound of formula 4.
In another embodiment, the present invention provides a process wherein, the step of decarboxylation is followed by neutralization to adjust pH in the range of 4.5 to 6. This particular range of pH results in maximum isolation of product and also results in minimzing impurities.
The neutralization is carried out at a temperature of 25-35°C. The neutralization is carried out using an aqueous base such as sodium hydroxide or potasium hydroxide.
In another embodiment, the present invention provides a process for isolation of the compound of formula 1 by azetropic distillation of its solution in an appropiate solvent.
As used herein, an appropiate solvent for azeotropic distillation is 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 50°C, under reduced pressure (50 to 150mbar) to obtain residual bottom mixture. An appropiate 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 salt (sodium chloride) from the process and filtrate was concentrated at 50°C under reduced pressure to make product concentration in the mixture around 25%. The concentrated mixture was gradually cooled to 10°C in 8.0 hours to get pure compound of formula I.
The compound of formula 1 is obtained with good yield, purity and selectivity.
The compound of formula 4 is obtained with good yield, purity and selectivity.
In an embodiment, the process of present invention results in less than 0.05% of isomeric impurity i.e., 1-methyl-3-hydroxypyrazole.
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.
The completion of the reaction may be monitored by high pressure liquid chromatography (HPLC).
The compound of formula 2 which is used herein as starting material can be prepared by any of the methods known in the art or can be obtained commercially.
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 in one pot.
Ethoxymethylenemalonic acid diethyl ester (100g) was charged into a four-necked flask equipped with a mechanical stirrer, a thermometer, a condenser and aqueous ammonia solution (25%, 40g) was added dropwise at 25-30°C to obtain a mixture containing ethyl-2-carbamoyl-3-ethoxyprop-2-enoate (monoamide).
To the above mixture, water (150g) was charged followed by dropwise addition of aqueous monomethylhydrazine (35%, 59.1g) while maintaining the reaction temperature at 30-40°C. After completion of the dropwise addition, the mixture was first heated to 40°C and was stirred for 1.0 hour at 40°C, then was heated to 45°C and was again stirred 1 hour at 45°C and finally was heated to 50°C and was stirred for 1.0 hour at 50°C. The reaction was monitored by HPLC. To the above mixture concentrated hydrochloric acid solution (160g) was added and the reaction mixture was heated to 95°C for 5 hours. The mixture was then cooled to 25°C and neutralized to adjust pH to 5 by adding 105g of 50% aqueous sodium hydroxide solution at 25-35°C. The water present in the mixture was removed by distillation of the mixture at 50°C, under reduced pressure (50 to 150mbar) to obtain residual bottom mixture. 1,4-dioxane (600g) was added to the residual bottom mixture and azeotropic distillation was carried out at 50°C under reduced pressure till water content was less than 0.1%.
The mixture was then filtered and filtrate was concentrated at 50°C under reduced pressure. The concentrated mixture was gradually cooled to 10°C in 8.0 hours to get pure 1-methyl-5-hydroxypyrazole in good yield and free of 3-isomer.
Example: 2- Preparation of 1-methyl-5-hydroxypyrazole in one pot
Ethoxymethylenemalonic acid diethyl ester (100g) was charged into a four-necked flask equipped with a mechanical stirrer, a thermometer, a condenser and aqueous ammonia solution (25%, 40g) was added dropwise at 25-30°C to obtain a mixture containing ethyl-2-carbamoyl-3-ethoxyprop-2-enoate (monoamide).
To the above mixture water (130g) was charged followed by dropwise addition of aqueous monomethylhydrazine (35%, 59.5g) while maintaining the reaction temperature at 30-40°C. After completion of the dropwise addition, the mixture was first heated to 40°C and was stirred for 1.0 hour at 40°C, then was heated to 45°C and was stirred the mixture for 1 hour at 45°C and finally was heated to 50°C and was stirred for 1.0 hour at 50°C. The reaction was monitored by HPLC. To the above mixture concentrated. hydrochloric acid solution (160g) was added and the reaction mixture was heated to 95°C for 5 hours. The mixture was then cooled to 25°C and neutralized to adjust pH to 5.5 by adding 105g 50% aqueous sodium hydroxide solution at 25-35°C.
The water present in the mixture was removed by distillation of the mixture at 50°C, under reduced pressure to obtain residual bottom mixture. Toluene (820g) was added to the residual bottom mixture and azeotropic distillation was carried out at 50°C under reduced pressure till water content was less than 0.1%.
The above process of azeotropic distillation was also carried out using tetrahydrofuran, methyltetrahydrofuran, cyclohexane and 1,4-dioxane to bring the water content to less than 0.1%.
The mixture was then filtered to remove salts from the process and filtrate was concentrated at 50°C under reduced pressure. The concentrated mixture was gradually cooled to 10°C in 6.0 hours to get pure 1-methyl-5-hydroxypyrazole isomer in good yield and free of 3-isomer.

Example: 3- Preparation of 1-methyl-5-hydroxypyrazole in two steps.
Step 1: Preparation of 1-methyl-5-hydroxypyrazole-4-carboxylic acid ethyl ester
Ethoxymethylenemalonic acid diethyl ester (198g) was charged into a four-necked flask equipped with a mechanical stirrer, a thermometer, a condenser and aqueous ammonia solution (25%, 125g) was added dropwise at 25-30°C to obtain a mixture containing ethyl-2-carbamoyl-3-ethoxyprop-2-enoate (monoamide).
De-ionized water (50g) was added to the reaction mixture followed by dropwise addition of aqueous monomethylhydrazine (35%, 120g) while maintaining the reaction temperature at 30-40°C. After completion of the addition, the mixture was first heated to 40°C and stirred for an hour at 40°C, then heated to 45°C and stirred the mixture for an hour at 45°C and finally heated to 50°C and stirred for an hour at 50°C.
After completion of the reaction, the mixture was cooled to 25°C and deionized water (250g) was added to it. To the above mixture concentrated hydrochloric acid solution (194g) was added while maintaining the reaction temperature between 25 to 30°C and to adjust pH to 2 to obtain 1-methyl-5-hydroxypyrazole-4-carboxylic acid ethyl ester in good yield and purity.
Step 2: Preparation of 1-methyl-5-hydroxypyrazole
To step 1 product (148g), concentrated hydrochloric acid (180g) was added and the reaction mixture was heated to 95°C for 5 hours. The mixture was then cooled to 25-35°C and neutralized to adjust reaction mixture pH to 5 by adding aqueous sodium hydroxide solution (50%,142g) at 25-35°C.
The 70-80% water present in the mixture was removed by distillation of the mixture at 50°C, under reduced pressure (50 to 150mbar) to obtain residual bottom mixture. 1,4-dioxane (1260g) was added to the residual bottom mixture and azeotropic distillation was carried out at 50°C under reduced pressure till water content was less than 0.1%.
The mixture was then filtered to remove salt (NaCl) from the process and filtrate was concentrated at 50°C under reduced pressure to make product concentration in the mixture around 25%. The concentrated mixture was gradually cooled to 10°C in 8.0 hours to get 1-methyl-5-hydroxypyrazole in good yield, puirty and free of 3-isomer.
Example: 4 - Preparation of 1-methyl-5-hydroxypyrazole in two steps.
Step 1: Preparation of 1-methyl-5-hydroxypyrazole-4-carboxylic acid ethyl ester
Ethoxymethylenemalonic acid diethyl ester (100g) was charged into a four-necked flask equipped with a mechanical stirrer, a thermometer, a condenser and aqueous ammonia solution (25%, 62g) was added dropwise at 25-30°C to obtain a mixture containing ethyl-2-carbamoyl-3-ethoxyprop-2-enoate (monoamide).
De-ionized water (25g) was added to the reaction mixture followed by dropwise addition of aqueous monomethylhydrazine (35%, 61g) while maintaining the reaction temperature at 30-40°C. After completion of the addition, the mixture was first heated to 40°C and stirred for an hour at 40°C, then heated to 45°C and stirred the mixture for an hour at 45°C and finally heated to 50°C and stirred for an hour at 50°C.
After completion of the reaction, the mixture was cooled to 25°C and deionized water (130g) was added to it. To the above mixture concentrated hydrochloric acid solution (97g) was added while maintaining the reaction temperature between 25 to 30°C and to adjust pH to 2 to obtain 1-methyl-5-hydroxypyrazole-4-carboxylic acid ethyl ester. in good yield and purity.
Step 2: Preparation of 1-methyl-5-hydroxypyrazole
To step 1 product (74g), added concentrated hydrochloric acid (86g) and the reaction mixture was heated to 95°C for 5 hours. The mixture was then cooled to 25-35°C and neutralized to adjust reaction mixture pH to 5 by adding aqueous sodium hydroxide solution (50%, 72.25g) at 25-35°C.
The 80-85% water present in the mixture was removed by distillation of the mixture at 50°C, under reduced pressure (50 to 150mbar) to obtain residual bottom mixture Tetrahydrofuran (800g) was added to the residual bottom mixture and azeotropic distillation was carried out at 50°C under reduced pressure till water content was less than 0.1%.
The mixture was then filtered to remove salt (NaCl) from the process and filtrate was concentrated at 50°C under reduced pressure to make product concentration in the mixture around 15%.
The concentrated mixture was gradually cooled to 10°C in 8.0 hours to get 1-methyl-5-hydroxypyrazole in good yield, purity and free of 3-isomer.

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 an aqueous ammonia to obtain a compound of formula 3;

b) adding monoalkyl hydrazine to the compound of formula 3 at a temperature of 30 to 40ºC to obtain a reaction mixture;
c) sequentially and periodically heating reaction mixture of step b) to obtain a compound of formula 4; and

d) decarboxylating the compound of formula 4 with an acid to obtain the compound of formula 1.
2. The process as claimed in claim 1, wherein the step a) to step d) are carried out in one pot without isolating any intermediate in-between.
3. The process as claimed in claim 1, wherein the reaction of compound of formula 2 with an aqueous ammonia is carried out at a temperature of 25-30°C.
4. The process as claimed in claim 1, wherein the sequential and periodical heating is carried out at a temperature range of 35 to 55ºC.
5. The process as claimed in claim 4, wherein the sequential and periodical heating is carried out by raising 3 to 5ºC of temperature every one hour.
6. The process as claimed in claim 1, wherein the decarboxylation is carried out at a temperature range of 85 to 100°C.
7. The process as claimed in claim 1, wherein the decarboxylation is followed by neutralization to adjust pH range of 4.5 to 6.
8. The process as claimed in claim 1, wherein the compound of formula 1 is obtained with less than 0.05% of 1-methyl-3-hydroxypyrazole.
9. The process as claimed in claim 1, wherein the monoalkyl hydrazine used is in the form of 30 to 40% aqueous solution.
10. The process as claimed in claim 1, wherein the compound of formula 1 is azeotropically distilled using a solvent selected from a group consisting of tetrahydrofuran, methyltetrahydrofuran, toluene, cyclohexane and 1,4-dioxane to obtain pure compound of formula I having less than 0.1% of water.