Description: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”
The present application is an improvement or modification over the invention claimed in the complete specifications of the main patent application IN202211035954 filed on 23-06-2022.

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

The following specification particular 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,

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.
Indian patent publication No. 202211035954 granted to the same applicant discloses a process for preparation of 1-methyl-5-hydroxypyrazole by simultaneously hydrolysis and decarboxylation of 1-methyl-5-hydroxypyrazole-4-carboxylic acid ethyl ester using an acid resin. The present invention is an improvement over the said invention.
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,

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,

Formula I
wherein R is C1-C3 alkyl group,
comprising the steps of:
a) hydrolyzing and decarboxylating a compound of formula 2,

Formula 2
wherein R is C1-C3 alkyl group,
using perfluoropolymers of supra-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 and isopropyl. Preferably alkyl is methyl or ethyl.
In an embodiment, the hydrolysis and decarboxylation of compound of formula 2 is carried out using perfluoroploymers of supra-acid to form a compound of formula 1.
In an embodiment, the hydrolysis and decarboxylation of compound of formula 2 is carried out simultaneously.
In preffered embodiment, the simultaneously hydrolysis and decarboxylation of compound of formula 2 is carried out at a temperature of 90 to 100°C to form compound of formula 1.

As used here, ‘perfluoropolymers of supra acid’ selected from a group consisting of Nafion supra acid series such as Nafion NR40, Nafion NR50, Nafion NR60, Aquivion PFSA resin such as Aquivion® D72-25BS, Aquivion® PW98, Aquivion® E87-05 and 3M ionomer series such as 3M 800, 3M 729 and 3M 825 or a like.
In an embodiment, the hydrolysis and decarboxylation of compound of formula 2 is carried out in presence of a mixture of water and organic solvent selected from a group consisting of 1,4-dioxane, tetrahydrofuran, methyltetrahydrofuran, toluene, ethers like a group consisting of dimethyl ether of diethylene glycol (diglyme), polyethylene glycol, polypropylene glycol, polytetramethylene glycol or polytetramethylene ether glycol, anisole, 1,2-dimethoxybenzene, 1,3-dimethoxybenzene and 1-4-dimethoxybenzene.
In another embodiment, the weight % of the perfluoropolymers of supra-acid w.r.t compound formula II ranges from about 1 to 10 and most preferably 4-7.
In another embodiment, the mole ratio of the solvent w.r.t compound formula II is from about 5 to 15 and more preferably 7 to 10.
In another embodiment, reaction is carried out using 2-10% of water with respect to organic solvent.
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.
After hydrolysis and decarboxylation of compound of formula 2, the reaction mixture is cooled to 25-35°C, filtered, washed with appropriate solvent to recover unreacted reagents and combined filtrate containing product. The recovered unreacted reagents is reused in subsequent batches without any processing, this makes the process more advantageous.
Then water and ethanol present in the combined filtrate is removed by distillation at 50-55°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.
In an embodiment, the compound of formula 2 can be prepared by any known method in the literature.
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 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 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: Preparation of 1-methyl-5-hydroxypyrazole
1-Methyl-5-hydroxypyrazole-4-carboxylic acid ethyl ester (74.7g, 0.44mol), 1,4-dioxane (300g), Nafion-50 (3.7g, 5 wt%) and water (16g, 0.88mol) were charged into a reactor. The reaction mixture was heated to 95°C. After reaction completion, the reaction mixture was cooled to 25-35°C, filtered, washed with 1,4-dioxane (50g) to recover solid acidic Nafion 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: 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), Nafion 40 dry (1.9g, 5% w.r.t ester) and water (8g, 0.44mol) were added. The reaction mixture was heated to 95°C. After reaction completion, the reaction mixture was cooled to 25-35°C, filtered, washed with 1,4-dioxane (25g) to obtain solid acidic Nafion 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), Nafion 60 dry (1.9g, 5% w.r.to ester) and water (8g, 0.44mol) were added. The reaction mixture was heated to 95°C. After reaction completion, the reaction mixture was cooled to 25-35°C, filtered, washed with 1,4-dioxane (25g) to obtain solid acidic Nafion 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
1-Methyl-5-hydroxypyrazole-4-carboxylic acid ethyl ester (74.7g, 0.44mol), 1,4-dioxane (300g), Aquivion® PW98 (3.7g, 5 wt%) and water (16g, 0.88mol) were charged into a reactor. The reaction mixture was heated to 95°C. After reaction completion, the reaction mixture was cooled to 25-35°C, filtered, washed with 1,4-dioxane (50g) to recover solid acidic Aquivion 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%. , Claims:WE CLAIM
1. A process for preparation of a compound of formula 1,

Formula I
wherein R is C1-C3 alkyl group,
comprising the steps of:
a) hydrolyzing and decarboxylating a compound of formula 2,

Formula 2
wherein R is C1-C3 alkyl group,
using perfluoropolymers of supra-acid to obtain the compound of formula 1.
2. The process as claimed in claim 1, wherein the reaction is carried out at a temperature of 90 to 100°C.
3. The process as claimed in claim 1, wherein the perfluoropolymers of supra-acid is selected from a group consisting of Nafion supra acid series such as Nafion NR40, Nafion NR50, Nafion NR60, Aquivion PFSA resin such as Aquivion® D72-25BS, Aquivion® PW98, Aquivion® E87-05 and 3M ionomer series such as 3M 800, 3M 729 and 3M 825.
4. The process as claimed in claim 1, wherein the reaction is carried out in the presence of a mixture of water and an organic solvent selected from a group consisting of 1,4-dioxane, tetrahydrofuran, methyltetrahydrofuran, toluene, ethers a group consisting of dimethyl ether of diethylene glycol (diglyme), polyethylene glycol, polypropylene glycol, polytetramethylene glycol or polytetramethylene ether glycol, anisole, 1,2-dimethoxybenzene, 1,3-dimethoxybenzene and 1-4-dimethoxybenzene.
5. The process as claimed in claim 1, wherein the reaction is carried out using 2-10% of water with respect to organic solvent.

Dated this 27th Day of September 2023.