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-SUBSTITUTED HYDROXYPYRAZOLES”
The present application is a modification over the invention claimed in the complete specifications of the main patent application IN202211016574 filed on 24-03-2022.

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-substituted hydroxypyrazole compounds of formula 1,

wherein “R” refers to alkyl or aryl group.

BACKGROUND OF THE INVENTION
N-substituted 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. 61189271 discloses a process for preparation of 1-methyl-5-hydroxypyrazole by reaction of a solution of methyl 3-methoxyacrylate in methanol with methyl hydrazine. The process is complicated and results in reduced yield.
Japan Publication No. 2003137871 discloses a process for preparation of 1-methyl-5-hydroxypyrazole by reaction of methyl 3,3-dimethoxypropionate with methylhydrazine in the presence of methanol solution of sodium methylate. The process involve use of sodium methylate as a catalyst, the additional use of catalyst in the process increase the cost of production during commercial scaleups.
Indian Patent Application No. 202211016574 belongs to the present applicant and discloses a process for preparation of 1-methyl-5-hydroxypyrazole by reacting ethyl 5-hydroxy-1-methyl-1H-pyrazole-4-carboxylate with ammonium chloride and water.

There is a need to develop an alternate commercially and economically viable process for large scale production of N-subsitututed hydroxypyrazole with high purity and yield. In addition, the process avoids the use of any catalyst within the process.
The present invention provides an alternative, environment friendly and cost-effective process for preparation of N-substituted hydroxypyrazole compounds.

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

wherein “R” refers to alkyl or aryl group.

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

wherein “R” refers to alkyl or aryl group;
comprising the steps of:
a) reacting a compound of formula 2 with compound of formula 3,

Formula 2
wherein “R1” and “R2” refers to alkyl group;

Formula 3
wherein “R” refers to alkyl or aryl group;
using an acid to obtain a compound of formula 1, wherein reaction is carried out in an absence of any catalyst.

DETAILED DESCRIPTION OF THE INVENTION
As used herein, “R” refers to alkyl or aryl group and also include substituted and unsubstituted alkyl and aryl group. The alkyl refers C1-C3 alkyl, selected from methyl, ethyl, propyl, isopropyl; and aryl refers to phenyl, pyridine, pyrazole or like and substituted aryl refers to aryl substituted with alkyl, halogen, cyano, nitro, amino, amide or a like.
As used herein, the “R1” and “R2” refers C1-C3 alkyl group and may be selected from methyl, ethyl, propyl, isopropyl.
In an embodiment, the present invention provides a process for preparation of compound of formula 1. The compound of formula 1 is selected from a group comprising N-methyl-5-hydroxypyrazole, N-ethyl-5-hydroxypyrazole N-isopropyl-5-hydroxypyrazole and N-phenyl-5-hydroxypyrazole or a like.
In an embodiment, the compound of formula 2 is selected from a group comprising methyl 3,3-dimethoxypropanoate, ethyl 3,3-diethoxypropanoate, methyl 3,3-diethoxypropanoate and ethyl 3,3-dimethoxypropanoate or a like.
In an embodiment, the compound of formula 3 is selected from a group comprising methylhydrazine, ethylhydrazine, (propan-2-yl)hydrazine and phenylhydrazine or a like.
In an embodiment, the reaction of compound of formula 2 and compound of formula 3 is carried out using an acid to form a compound of formula 1.
As used herein, the acid is selected from a group consisting of inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and organic acids such as acetic acid and p-toluenesulfonic acid.
In an embodiment, the reaction of compound of formula 2 and compound of formula 3 is carried out using an acid at a temperature selected in the range from 40-110°C to obtain a compound of formula 1.
In another embodiment, the reaction of compound of formula 2 and compound of formula 3 using an acid is carried out in presence of solvent.
As used herein, the solvent is selected from a group comprising alcohol such as methanol, ethanol, and propanol; hydrocarbon solvents such as hexane, toluene, benzene and halogenated solvents such as dichloroethane, chloroform, carbon tetrachloride etc, aprotic polar solvents such as tetrahydrofuran, N,N-dimethylformamide, 1,4-dioxane and acetonitrile or a like.
In another embodiment, the reaction of compound of formula 2 and compound of formula 3 using an acid is carried out in the absence of any catalyst.
In an embodiment, the reaction of compound of formula 2 and compound of formula 3 is carried out using an acid is carried out in a time period selected in the range from 4 to 6 hours to form a compound of formula 1.
In an embodiment, the compound of formula 3 is used in pure form with 98% assay or aqueous form or solution form. The aqueous compound of formula 3 used in the present invention, wherein aqueous is present in the range of 30 to 45 wt%, or in the range of 35 to 40 wt%.
In another embodiment, the molar ratio of compound of formula 3 to compound of formula 2 is in the range from 0.9 to 2.0.
In an embodiment, the present invention provides a process wherein, the compound of formula 2 is reacted with 35-40% of aqueous compound of formula 3 at 40-110°C to obtain a compound of formula 1.
In preferred embodiment, the present invention provides a process for preparation of N-isopropyl-5-hydroxypyrazole by reacting methyl 3,3-dimethoxypropionate with ethylhydrazine using hydrochloric acid at 40-110°C.
In another embodiment, the present invention provides a process wherein, compound of formula 3 added into a compound of formula 2 while maintaining the reaction temperature at 10-40°C. After that, the reaction mixture is heated at 40°C to 110°C till completion to obtain a compound of formula 1.
In another embodiment, the present invention provides a process for isolation of the compound of formula 1 by adjusting pH of the reaction mass using a base at 20-50°C. The pH may be adjusted in the range of 4.0 to 7.0 more preferably from 4.8 to 5.2 using an base.
As used herein, a base selected from a group consisting of inorganic base such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate or like and organic base such as sodium methoxide, poatssium methoxide, sodium ethoxide and potassium methoxide or a like.
In an embodiment, after pH adjustment, reaction mass was distilled using a solvent.
As used herein, the solvent for distillation is selected from a group consisting of tetrahydrofuran, methyltetrahydrofuran, toluene and 1,4-dioxane or the like.
After distillation, the reaction mass is filtered to remove inorganic salts, followed by concentrating filtrate at 50°C under reduced pressure to make product concentration in the mixture around 15-30% or 20-30%. The concentrated mixture was gradually cooled followed by filteration to get pure compound of formula 1.
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 70%, preferably greater than 80%.
In an embodiment, the process of present invention results in less than 0.05% of isomeric impurity i.e., N-sustituted-3-hydroxypyrazole.
In an embodiment, the compound of formula 1 is obtained with a purity greater than 98%, more specifically between 98 to 99.9% and isomeric impurity less than 0.05%, more specifically between 0.00001 to 0.047%.
In another embodiment, the compound of formula 1 obtained in the process is substantially free of isomeric impurity i.e., N-substituted-3-hydroxypyrazole (3-isomer).
In preferred embodiment, the present invention provides a process for preparation of N-phenyl-5-hydroxypyrazole by reacting ethyl 3,3-diethoxypropionate with ethylhydrazine using hydrochloric acid at 40-110°C, wherein isomeric impurity is less than 0.05%.
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 N-methyl-5-hydroxypyrazole
Methyl 3,3-dimethoxypropionate (10g, 0.07mol), methanol (60g,1.9mol) were added into the reactor and then dropwise added a solution of 30-35% aqueous hydrochloric acid (11g, 0.11mol) and 35% aqueous methylhydrazine (13.9g, 0.11mol) in the reaction solution at 20-40°C in a controlled manner. After addition, the reaction was heated at 60-70°C for 4-6 hours. After reaction completion, cooled the mass at 25-30°C, followed by pH adjustment to neutral using 48% sodium hydroxide. Charged methyl tetrahydrofuran (200g) into the reaction mass and distilled it at 50-55oC under vacuum.
Filtered the reaction mass, concentrated the mother liquor to adjust concentration of product to 20-25%, cooled and filtered to get pure N-methyl-5-hydroxypyrazole.
Purity: 99.5%, Yield: 83%
Example 2: Preparation of N-isopropyl-5-hydroxypyrazole
Methyl 3,3-dimethoxypropionate (10g, 0.07mol), methanol (60g,1.9mol) were added into the reactor and then dropwise added a solution of 30-35% aqueous hydrochloric acid (11g, 0.11mol) and aqueous isopropyl hydrazine (24, 0.11mol) in the reaction solution at 20-40°C in a controlled manner. After addition, the reaction was heated at 60-70°C for 4-6 hours.
After reaction completion, cooled the mass at 25-30°C, followed by pH adjustment to neutral using 48% sodium hydroxide. Charged methyl tetrahydrofuran (200g) into the reaction mass and distilled it at 50-55oC under vacuum.
Filtered the reaction mass, concentrated the mother liquor to adjust concentration of product to 20-25%, cooled and filtered to get pure N-isopropyl-5-hydroxypyrazole.
Purity: 99.2%, Yield: 68%
Example 3: Preparation of N-phenyl-5-hydroxypyrazole
Methyl 3,3-dimethoxypropionate (10g, 0.07mol), methanol (60g,1.9mol) were added into the reactor and then dropwise added a solution of 30-35% aqueous hydrochloric acid (11g, 0.11mol) and aqueous phenyl hydrazine (34g, 0.11mol) in the reaction solution at 20-40°C in a controlled manner. After addition, the reaction was heated at 60-70°C for 4-6 hours. After reaction completion, cooled the mass at 25-30°C and pH adjusted using 48% potassium hydroxide to neutral and then added methyl tetrahydrofuran (200g) and distilled it at 50-55oC under vacuum.
Filtered the reaction mass, concentrated the mother liquor to adjust concentration of product to 20-25%, cooled and filtered to get pure N-phenyl-5-hydroxypyrazole.
Purity: 99.1%, Yield: 60%
Example 4: Preparation of N-methyl-5-hydroxypyrazole
Ethyl 3,3-diethoxypropionate (10g, 0.05mol), 1,4-dioxane (60g,13.6mol) were added into the reactor and then dropwise added a solution of 30-35% aqueous hydrochloric acid (8g, 0.08mol) and 35% aqueous monomethyl hydrazine (10g, 0.08mol) in the reaction solution at 20-40°C in a controlled manner. After addition, the reaction was heated at 90-100°C for 4-6 hours. After reaction completion, cooled the mass at 25-30°C and pH adjusted using 48% sodium hydroxide to neutral and then added methyl tetrahydrofuran (100g) and distilled it at 50-55oC under vacuum.
Filtered the reaction mass, concentrated the mother liquor to adjust concentration of product to 20-25%, cooled and filtered to get pure N-phenyl-5-hydroxypyrazole.
Purity: 98.7%, Yield: 77%.
, Claims:WE CLAIM
1. A process for preparation of a compound of formula 1,

“R” refers to alkyl or aryl group;
comprising the steps of:
b) reacting a compound of formula 2 with a compound of formula 3,

Formula 2
wherein “R1” and “R2” refers to alkyl group;

Formula 3
“R” refers to alkyl or aryl group;
using an acid to obtain the compound of formula 1;
wherein reaction is carried out in absence of any catalyst.
2. The process as claimed in claim 1, wherein the reaction is carried out at a temperature of 40-110°C.
3. The process as claimed in claim 1, wherein the acid is selected from a group consisting of inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and organic acids such as acetic acid and p-toluenesulfonic acid.
4. The process as claimed in claim 1, wherein the reaction is carried out in a solvent selected from alcohols such as methanol, ethanol, and propanol; hydrocarbon solvents such as hexane, toluene, benzene; halogenated solvents such as dichloroethane, chloroform, carbon tetrachloride; aprotic polar solvents such as tetrahydrofuran, methyl tetrahydrofuran, N,N-dimethylformamide, 1,4-dioxane and acetonitrile.
5. The process as claimed in claim 1, wherein the compound of formula 1, has purity of greater than 98%.
6. The process as claimed in claim 1, wherein the compound of formula 1 has isomeric impurity less than 0.05%.
7. The process as claimed in claim 1, wherein the compound of formula I is isolated using a solvent.
8. The process as claimed in claim 7, wherein the solvent is selected from a group consisting of tetrahydrofuran, methyltetrahydrofuran, toluene and 1,4-dioxane.
Dated this 24th Day of January 2024.
.