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 hydroxypyrazole compounds 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, in which 1-methyl-5-hydroxypyrazole-4-carboxylic acid ethyl ester is hydrolysed and decarboxylated using 49% of aqueous sodium hydroxide solution to obtain 1-methyl-5-hydroxypyrazole.
Japan Patent Pub. No. S58140073A 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.
Thus, the conventional means of simultaneous hydrolysis and decarboxylation by use of bases like metal hydroxides or by use of mineral acids such as hydrochloric acid are very tedious as these acid or bases could not be recycled after the reaction completion. Further the effluents generation necessitates the step of removing them from reaction mixture. The discharge of these effluents also makes the process less environment friendly.
The present invention provides an alternative, environment friendly with minimum effluent generation and cost-effective process for preparation of hydroxypyrazole compounds.

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) hydrolyzing and decarboxylating a compound of formula 4,

wherein R is C1-C3 alkyl group,
using an acidic resin 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 simultaneous hydrolysis and decarboxylation of compound of formula 4 is carried out using acidic resin at a temperature of 85 to 100°C for 40 to 45 hours to form compound of formula 1.
In another embodiment, acidic resins are selected from a group consisting of DIAION acidic series such as DIAION PK2201, PK28, RCP145H; DOWEX UPCORE series such as Mono C-600, MC-575; DOWEX MARATHON series such as C, C-10, MSC, Amberlyte IR120, Amberlyte IR100; Acidic amberlyst series such as Amberlyst 15 dry, Amberlyst 35 dry, Amberlyst 17 dry, Amberlyst 45, 46, 19, and salts sulphate thereof.
In an embodiment, the sulphate salt of acidic resins are preffered.
In an embodiment, the simultaneous hydrolysis and decarboxylation of compound of formula 4 is carried out using acidic resin in presence of a mixture of water and organic solvent selected from a group consisting of 1,4-dioxane, tetrahydrofuran, methyltetrahydrofuran and toluene.
In another embodiment, reaction was carried out using 2-10% of water with respect to organic solvent.
In a preferred embodiment, the acidic resins are used in the form of sulfonic acid salt.
The acidic resins used in the present invention are available in various forms like wet or dry grannular (spherical or cylindrical shaped), solid, powder or gel etc.
The acid resin used as catalyst are strongly acidic, cation exchanger and have various advantages such as it can be recycled multiple times without any reprocessing which makes the process more economically viable. The effluent discharge of acidic resin is minimum in the environment due to its high recyclability.
The use of acidic resins eliminates the necessary step of pH adjustment, extraction, removal of inorganic by products and aqueous waste which are essential in conventional means of acidic and basic hydrolysis and decarboxylation.
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 and 1,4-dioxane or the like.
In an embodiment, after simultaneous hydrolysis and decarboxylation of compound of formula 4, the reaction mixture is cooled to 25-35°C, filtered, washed with appropriate solvent to recover solid acidic resin and combined filtrate containing product.
Then water and ethanol present in the combined filtrate is removed by distillation at 50°C, under reduced pressure (50 to 150mbar) till water content reached to less than 0.1% and finally the combined 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 filteration to get pure compound of formula I.
The recovered acidic resin is reused in subsequent batches without any processing, this makes the process more advantageous.

In an embodiment, the compound of formula 4 is prepared by one pot process 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 the compound of formula 4;

wherein R is C1-C3 alkyl group.
In an embodiment, the present invention provides a process wherein, the compound of formula 2 is reacted with 20-25% of 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, water is added to the reaction mixture containing mono amide compound of formula 3 prior to the addition of monoalkyl hydrazine. The monoalkyl hydrazine is then added while maintaining the reaction temperature at 30-40°C. After that, the reaction mixture is heated at 40°C to 50°C till completion to obtain a compound of formula 4.
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 an embodiment, after completion of the reaction of mono amide compound of formula 3 with monoalkyl hydrazine, the mixture was cooled to 25°C and added deionized water into it. To the above mixture mineral acid is added while maintaining the reaction temperature between 25 to 30°C and adjusted pH to 1.8 to 2.0.
As used herein, the mineral acid is selected from a group consisting of hydrochloric acid, sulfuric acid and acetic acid or the like.
In another embodiment, the reaction mass containing the compound of formula 4 is further cooled to 10°C and solid product is filtered and dried to obtain the compound of formula 4. The isolated compound of formula 4 is converted to compound of formula 1.
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.
In an embodiment, the reaction of compound of formula 3 and monomethylhydrazine is carried out in aqueous medium without using any organic solvent.
In an embodiment, the compound of formula 1 is obtained with a purity greater than 98%, preferably greater than 99%.
In another embodiment, the compound of formula 1 is obtained with a yield greater than 90%, preferably greater than 95%.
In an embodiment, the process of present invention results in less than 0.05% of isomeric impurity i.e., 1-alkyl-3-hydroxypyrazole.
In still another embodiment, the compound of formula 1 obtained in the process is substantially free of isomeric impurity i.e., 1-alkyl-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 chouromatography (HPLC).
The compound of formula 4 which is used herein as starting material can be prepared by any of the methods known in the art or as disclosed in present invention 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 examples are given by way of illustration and therefore should not be construed to limit the scope of the present invention.

EXAMPLES
Example 1:
Step 1: Preparation of 1-methyl-5-hydroxypyrazole-4-carboxylic acid ethyl ester
Ethoxymethylenemalonic acid diethyl ester (100g, 0.46mol) was charged into a four-necked flask equipped with a mechanical stirrer, a thermometer, and a condenser. 25% of aqueous ammonia solution (63g, 0.92mol) was charged 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 35% aqueous monomethylhydrazine (61g, 0.46mol) while maintaining the reaction temperature at 30-40°C. After completion of the addition, the mixture was heated to 40°C to 50°C till the reaction completion.
After completion of the reaction, the mixture was cooled to 25°C and water (125g) was added into it. To the above mixture concentrated hydrochloric acid solution (98g) was added drop wise while maintaining the reaction temperature between 25 to 30°C and pH was adjusted to 2.
The reaction mass was analysed for completion, cooled to 10°C, stirred for 1 hour, followed by filtration and drying to get 1-methyl-5-hydroxypyrazole-4-carboxylic acid ethyl ester (74.7g) as solid product.
Yield: 95.1%; Purity: 98.1%
Step 2: Preparation of 1-methyl-5-hydroxypyrazole
1-Methyl-5-hydroxypyrazole-4-carboxylic acid ethyl ester (74.7g, 0.44mol), 1,4-dioxane (300g), 3.7g amberlyst 15 dry (5mol%) and water (16g, 0.88mol) were charged into a reactor. The reaction mixture was heated to 95°C for 40-45 hours. After reaction completion, the reaction mixture was cooled to 25-35°C, filtered, washed with 1,4-dioxane (50g) to recover solid acidic amberlyst resin and filtrate containing product.
The water and ethanol were distilled out from filtrate at 50-55°C under reduced pressure (50 to 150mbar) till water content reached to less than 0.1%. The filtrate was concentrated to 18-20% under reduced pressure at 50°C. The concentrated mixture was gradually cooled from 50°C to 10°C in 6-8.0 hours, filtered and washed with cooled 1,4-dioxane to get pure 1-methyl-5-hydroxypyrazole solid product (41g) after drying.
Yield: 95%; Purity (by HPLC): 99.6%.
Example 2:
Step 1: Preparation of 1-methyl-5-hydroxypyrazole-4-carboxylic acid ethyl ester
Ethoxymethylenemalonic acid diethyl ester (50g, 0.23mol) was charged into a four-necked flask equipped with a mechanical stirrer, a thermometer and a condenser. 25% aqueous ammonia solution (31.5g, 0.46mol) was charged 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 35% aqueous monomethylhydrazine (30.5g, 0.23mol) 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, then heated to 45°C and stirred for an hour, finally heated to mixture at 50°C and stirred for another hour.
After completion of the reaction, the mixture was cooled to 25°C and deionized water (65g) was added into it. To the above mixture concentrated hydrochloric acid solution (50g) was added while maintaining the reaction temperature between 25 to 30°C and pH was adjusted to 1.8-2.
The reaction mass was analysed by HPLC, the reaction mass was cooled to 10°C and solid product was filtered and dried to obtain 1-methyl-5-hydroxypyrazole-4-carboxylic acid ethyl ester (37.3g).
Yield: 95.2%; Purity: 98.6%
Step 2: Preparation of 1-methyl-5-hydroxypyrazole
To 1-methyl-5-hydroxypyrazole-4-carboxylic acid ethyl ester (step 1 product, 37.3g, 0.22mol), 1,4-dioxane (150g), 1.9g amberlyst 35 dry (5% w.r.t ester) and water (8g, 0.44mol) were added. The reaction mixture was heated to 95°C for 40-45 hours. After reaction completion, the reaction mixture was cooled to 25-35°C, filtered, washed with 1,4-dioxane (25g) to obtain solid acidic amberlyst resin and filtrate containing product was combined.
Then water and ethanol present in the combined filtrate were removed by distillation at 50°C, under reduced pressure (50 to 150mbar) till water content reached to less than 0.1%. and finally, 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 from 50°C to 10°C in 6-8.0 hours, filtered and washed with cooled 1,4-dioxane to get pure 1-methyl-5-hydroxypyrazole.
Yield: 95%, Purity (by HPLC): 99.8%.
Example 3: Preparation of 1-methyl-5-hydroxypyrazole
To 1-methyl-5-hydroxypyrazole-4-carboxylic acid ethyl ester (step 1 product, 37.3g, 0.22mol), 1,4-dioxane (150g), amberlyst 17 dry (1.9g, 5% w.r.to ester) and water (8g, 0.44mol) were added. The reaction mixture was heated to 95°C for 40-45 hours. After reaction completion, the reaction mixture was cooled to 25-35°C, filtered, washed with 1,4-dioxane (25g) to obtain solid acidic amberlyst resin and filtrate containing product was combined.
Then water and ethanol present in the combined filtrate were removed by distillation at 50°C, under reduced pressure (50 to 150mbar) till water content reached to less than 0.1%. and finally, 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 from 50°C to 10°C in 6-8.0 hours, filtered and washed with cooled 1,4-dioxane to get pure 1-methyl-5-hydroxypyrazole.
Yield: 94%, Purity (by HPLC): 99.56%.
Example 4: Preparation of 1-methyl-5-hydroxypyrazole
To 1-methyl-5-hydroxypyrazole-4-carboxylic acid ethyl ester (step 1 product, 50g, 0.29mol), 1,4-dioxane (200g), amberlyte IR120 (2.5g, 5% w.r.to ester) and water (10.7g, 0.59mol) were added. The reaction mixture was heated to 95°C for 40-45 hours. After reaction completion, the reaction mixture was cooled to 25-35°C, filtered, washed with 1,4-dioxane (33.5g) to obtain solid acidic amberlyst resin and filtrate containing product was combined.
Then water and ethanol present in the combined filtrate were removed by distillation at 50°C, under reduced pressure (50 to 150mbar) till water content reached to less than 0.1%. and finally, 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 from 50°C to 10°C in 6-8.0 hours, filtered and washed with cooled 1,4-dioxane to get pure 1-methyl-5-hydroxypyrazole (27.4g) after drying.
Yield: 94.8%, Purity (by HPLC): 99.66%.
Example 5: Preparation of 1-methyl-5-hydroxypyrazole
To 1-methyl-5-hydroxypyrazole-4-carboxylic acid ethyl ester (step 1 product, 100g, 0.59mol), 1,4-dioxane (400g), amberlyte IR100 (5.0g, 5% w.r.to ester) and water (21.4g, 1.19mol) were added. The reaction mixture was heated to 95°C for 40-45 hours. After reaction completion, the reaction mixture was cooled to 25-35°C, filtered, washed with 1,4-dioxane (67g) to obtain solid acidic amberlyst resin and filtrate containing product was combined.
Then water and ethanol present in the combined filtrate were removed by distillation at 50°C, under reduced pressure (50 to 150mbar) till water content reached to less than 0.1%. and finally, 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 from 50°C to 10°C in 6-8.0 hours, filtered and washed with cooled 1,4-dioxane to get pure 1-methyl-5-hydroxypyrazole.
Yield: 95.2%, Purity (by HPLC): 99.46%.

,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) hydrolyzing and decarboxylating a compound of formula 4,

wherein R is C1-C3 alkyl group,
using an acidic resin to obtain the compound of formula 1.
2. The process as claimed in claim 1, wherein the acidic resins comprises DIAION acidic series selected from DIAION PK2201, PK28, RCP145H; DOWEX UPCORE series selected from Mono C-600, MC-575; DOWEX MARATHON series selected from C, C-10, MSC, Amberlyte IR120, Amberlyte IR100; Acidic amberlyst series selected from Amberlyst 15 dry, Amberlyst 35 dry, Amberlyst 17 dry, Amberlyst 45, 46, 19 and salts thereof.
3. The process as claimed in claim 1, wherein the hydrolysis and decarboxylation of the compound of formula 4 is carried out in presence of a mixture of water and organic solvent selected from a group consisting of 1,4-dioxane, tetrahydrofuran, methyltetrahydrofuran and toluene.
4. The process as claimed in claim 3, wherein reaction is carried out using 2-10% of water with respect to organic solvent.
5. The process as claimed in claim 1, wherein the reaction is carried out at a temperature of 85 to 100°C.
6. The process as claimed in claim 1, wherein the compound of formula 1 is isolated by azetropic distillation of its solution in an solvent selected from a group consisting of tetrahydrofuran, methyltetrahydrofuran, toluene and 1,4-dioxane.
7. The process as claimed in claim 2, the acidic resin is recycled and reused.
8. The process as claimed in claim 1, wherein the compound of formula 4 is prepared by one pot process 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 the compound of formula 4;

wherein R is C1-C3 alkyl group.
9. The process as claimed in claim 5, wherein the contacting of compound of formula 2 with the aqueous ammonia is carried out at a temperature range from 25-30°C.
10. The process as claimed in claim 5, wherein the contacting of the compound of formula 3 with monoalkyl hydrazine is carried out at a temperature range from 30-50°C.

Dated this 23rd Day of June 2022.