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

“PROCESS FOR THE PREPARATION OF HYDROXY PYRAZOLES”
The present application is an improvement over the invention claimed in the complete specifications of the main granted patent IN327684 filed on 30/09/2015.

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 the preparation of hydroxy pyrazoles of formula I.

Formula I
wherein R represents a hydrogen atom, an alkyl group, an aryl, heteroaryl ring, and wherein X represents halogen, hydrogen, n represents an integer from 1-3.

BACKGROUND OF THE INVENTION
The present invention provides a process for the preparation of hydroxy pyrazole compounds which are important intermediates for production of pharmaceutical and agrochemical products.
The US Patent Application No. 20160151337 describes a process for the preparation of 5-hydroxy-1-methyl-3-trifluoromethyl pyrazole by reaction a solution of ethyl 4,4,4-trifluoroacetylacetate in ethanol, methylhydrazine and HCl and then mixture was heated to reflux for 16 hours to yield the desired compound having yield 75%.
The Japanese Patent Application No. 2007/031342 describes a process for the preparation of 5-hydroxy-1-methyl-3-trifluoromethyl pyrazole by condensation of 4,4,4-trifluoroethyl acetoacetate and methyl hydrazine in the presence of acetic acid.
The US Patent No. 11299463 describes a process for the preparation of hydroxy pyrazoles by reacting ethyl-4,4,4-trifluroacetoacetate and monomethyl hydrazine solution in a microreactor. The process involves use of 100% monomethyl hydrazine solution, which is very difficult to handle and not easily available. Also, the use of microreactor involves significant chances of solid formation leading to chocking in reactor during the process.
Indian Patent No. 327684 granted to the present applicant discloses a process for preparation of 5-hydroxy-1-methyl-3-trifluoromethyl pyrazole by condensing ethyl 4,4,4-trifluoroacetoacetate with monomethyl hydrazine to obtain desired product with yield of 72%.
It has been observed that the step of condensation results in the formation of an impurities that mandates extensive distillation and results in considerable loss of yield.
Therefore, there is a need in the art to evolve a very pure, high efficiency and time-saving method for the preparation of hydroxy pyrazoles.
The inventors of the present invention have come up with a facile, timesaving, energy efficient and environment friendly process for the preparation of hydroxy pyrazoles.

OBJECT OF THE INVENTION
The object of the present invention provides a simple, safe, and commercially viable process for preparation of hydroxy pyrazoles of Formula I in good yield and purity.

SUMMARY OF THE INVENTION
In an aspect, present invention provides a process for the preparation of hydroxy pyrazoles of formula I,

Formula I
wherein R represents a hydrogen atom, an alkyl group, an aryl, heteroaryl ring, and wherein X represents halogen, hydrogen, n represents an integer from 1-3,
comprising the step of condensing a compound of Formula II with methyl hydrazine to obtain compound of formula I;

Formula II
wherein Xn and R, are represented as above;
wherein the condensation is carried in a continuous mode.

DETAILED DESCRIPTION OF DRAWINGS
Figure 1 and figure 2 describes the reactor setup used in the preparation of the present invention.
As referred in figure 1 (continuous flow reactor), a mixture of raw material and acid feed ‘S1’ and other reagent feed ‘S2’ are fed to polytetrafluoroethylene (PTFE) flow reactor ‘F1’. The outlet of the flow rector ‘F1’ is fed to PTFE flow reactor ‘F2’. The reaction outflow is collected in collection vessel ‘C1’. The ‘C1’ is connected to ‘R1’ for crystallization. The ‘R1’ is connected to ‘T1’ for filtrate collection and also connected to ‘D1’ for drying, which is further connected to ‘P1’ to get final product.
As referred in figure 2 (continuous stirred tank reactor), installed C1, C2 and C3 reactors in series. The solution ‘S1’, ‘S2’ and ‘S3’ were dosed into ‘C1’. The reaction stream transfer between ‘C1’ to ‘C3’ and then transfers to collection vessel ‘V1’ via insulated PTEF transfer lines. Finally, the product stream directed to reactor ‘R1’ for crystallization and filtration. The ‘R1’ is connected to ‘T1’ for filtrate collection and also connected to ‘D1’ for drying, which is further connected to ‘P1’ to get final product.

DETAILED DESCRIPTION OF THE INVENTION
As used herein, “alkyl” may be selected from a group comprising methyl, ethyl, propyl, isopropyl or the like.
As used herein, aryl and heteroaryl ring includes, benzene, pyridine, pyran, furan, thiophene, pyrrole and imidazole.
As used herein, aryl, heteroaryl ring may be further substituted with a group selected from C1-C6 alkyl, C1-C6 alkoxy, nitro, fluoro, chloro, bromo, -CX3 (where X= F, Cl, Br, H), and cyano.
As used herein, “substantially free of impurities” refers to the product having GC area%: 0.05% to 1.0% of impurity-I and impurity-II, preferably 0.01 to 0.1% of impurity-I and impurity-II.
As used herein, the compounds of Formula II may be prepared by any method known in the art, for example JP 2007/031342. The compound of Formula III may be obtained from commercial source.
In an embodiment, the present invention provides a process for the preparation of hydroxy pyrazoles of formula I,

Formula I
wherein R represents a hydrogen atom, an alkyl group, an aryl, heteroaryl ring, and wherein X represents halogen, hydrogen, n represents an integer from 1-3,
comprising the step of condensing a compound of Formula II with compound of formula III to obtain compound of formula I;

Formula II
wherein Xn and R, are represented as above;

Formula III
wherein R represented as above.
wherein the condensation is carried out in continuous mode.
The process of the present invention is carried out in a continuous mode. The process is carried out under continuous either in a flow reactor or in continuous stirred tank reactor (CSTR).
In an embodiment, the present invention is carried out in a continuous flow reactor and in batch reactor, preferably in a continuous flow reactor or a continuous stirred tank reactor (CSTR).
The process of the present invention is carried out in a continuous mode. In continuous mode, the feed of mixtures is continuously supplied to a reactor, and pure hydroxy pyrazoles is continuously separated.
In another embodiment, the present invention provides a process for preparation of hydroxy pyrazoles of formula I, comprising the step of condensing a compound of Formula II with compound of formula III, wherein the condensation is carried in a batch mode, and wherein the molar concentration of compound of formula III w.r.t compound of formula II is the range from 1.2 to 1.4 mole equivalents, most preferably 1.4 mole equivalents to maintain the pH in the range from 4.0 to 7.5, more preferably 6.0 to 7.2 to give 80 to 85% of the compound of formula I with a purity of more than 95%.
In another embodiment, the molar concentration of compound of formula III w.r.t compound of formula II is the range from 1.2 to 1.4 mole equivalents, most preferably 1.4 mole equivalents.
In another embodiment, the pH of the process of the present invention is in the range from 4.0 to 7.5.
In an embodiment, the present invention is carried out in the presence of an acid.
The ‘acid’ is an “alkanoic acid” selected from formic acid, acetic acid and trifluoroacetic acid or the like. The molar ratio of alkanoic acid w.r.t compound of formula II is used in the range from 0.25 to 1.25 mole equivalents, preferably 0.75 to 1.0 mole equivalents and most preferably 1.0 mole equivalent.
In an embodiment, the process of the present invention is carried out in the absence of any solvent.
In preferred embodiment, the process of the present invention is carried out in the presence of an acid and in absence of solvent.
In an embodiment, the condensation of formula II and methyl hydrazine is carried out at a temperature of 5°C to 95°C. Most preferably condensation is carried out at 70 to 90°C.
In another embodiment, the compound of formula II and acid are added slowly using dosing pump in the reactor.
In preferred embodiment, the condensation of compound of Formula II and methyl hydrazine is carried out in the presence of an acid at a temperature 90°C.
In a specific embodiment, the present invention provides a process for preparation of 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol (MTP), comprising the step of condensing ethyl 4,4,4-trifluoroacetoacetate and methyl hydrazine using formic acid.
In another specific embodiment, the process is carried out in a continuous flow reactor.
In yet another specific embodiment, the process is carried out in a CSTR.
In another embodiment of the present invention, the process provides a compound of formula I, substantially free of impurities, the impurities are in the range of 0 to 0.2%, preferably 0 to 0.05%.
In another embodiment of the present invention, the process provides compound of formula I, substantially free of Impurity-I and Impurity-II

Impurity-I

Impurity-II
In preferred embodiment of the present invention, the process provides 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol, substantially free of impurities.
In preferred embodiment of the present invention, the process provides 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol, substantially free of 5-ethoxy-1-methyl-3-(trifluoromethyl)-1H-pyrazole impurity.
In another preferred embodiment of the present invention, the process provides 5-hydroxy-1-methyl-3-trifluoromethyl pyrazole, substantially free of 3-hydroxy-1-methyl-5-(trifluoromethyl)pyrazole impurity.
In another embodiment, the continuous flow reactor system used in this study is shown in Figure-1. The reactor system comprises of feed streams S1 and S2. The feed S1 comprising a mixture of compound of formula I and formic acid and the feed S2 comprising 35-45% aqueous monomethyl hydrazine solution were fed to flow reactor F1 through static mixer at 5-10°C with 5-25 minutes residence time, preferably 10 minutes residence time. The outlet of the flow rector F1 was fed to flow reactor F2 at 70-90°C with 25-45 minutes residence time, preferably 30 minutes residence time. The reaction outflow was collected in collection vessel C1 at 60-70°C, which was send to R1 for crystallization, filtration followed by drying in D1 and filtrate collection in T1 and then finally get pure product in P1.
In another embodiment, the continuous flow reactor system (CSTR) used in this study is shown in Figure-2. The CSTR installed C1, C2 and C3 in series. The solution S1, S2 and S3 were dosed into C1 vessel and the reaction stream transfer between CSTRs (C1-C3 and V1) were enabled by gravity via insulated PTEF transfer lines. Finally, the product stream was directed to reactor R1 for crystallization and filtration and the wet cake was further transferred to D1 for drying. The pure product was obtained in P1 with good yield and higher purity.
The present invention for preparation of compound of formula I have following advantages over the known methods:
1. The use of flow reactors prevents effluent and improves yield significantly.
2. The mode of addition of reactant and reagent used in the reaction positively affects the product selectivity. The present inventors observed an improvement in the selectivity with slow and continuous addition of reagents to the reaction mixture.
3. The use of continuous flow reactor for the reaction to get 100% conversion, minimizes the impurity and thereby increases the selectivity towards the desired product significantly.
4. The inventor of the present invention found during experimentation, that the reaction carried out at 70-90°C is an ideal condition for keeping the mass as liquid for easy handling.
5. The process of present invention is safe at commercial scale.
6. The specific concentration of reagents ensures optimal basicity required for improving the yield and purity of the product.
The purity of isolated compound of formula I is greater than 90% and preferably greater than 95% and more preferably greater than 99%.
The yield of compound of formula I is greater than 85% and preferably greater than 90%.
The reactant and reagent used in the present invention may be prepared by any method known in the literature or can be obtained commercially.
The compound of Formula I is isolated by any method known in the art, for example, chemical separation, extraction, acid-base neutralization, distillation, evaporation, column chromatography and filtration or a mixture thereof.
The completion of the reaction may be monitored by any one of chromatographic techniques such as thin layer chromatography (TLC), high pressure liquid chromatography (HPLC), ultra-pressure liquid chromatography (UPLC), Gas chromatography (GC), liquid chromatography (LC) and alike.
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 5-hydroxy-1-methyl-3-trifluoromethyl pyrazole using continuous flow reactor.
In a flow reactor shown in figure 1, a solution S1 containing ethyl-4,4,4-trifluoro acetoacetate (1.0 eq., 95-99%) and formic acid (1eq., 85-100%) and aqueous monomethyl hydrazine solution (1.1 eq., 35-45%) of S2 were flowed through a static mixer to flow rector F1 at 5-10°C with 9-10 mins residence time and followed to flow reactor F2 at 70-90°C with a residence time of 30 mins. The output was collected in collection vessel (C1) at 65-70°C and transferred into reactor R1 for crystallization and filtration. The reaction stream was separated, aqueous layer collected in T1, and wet cake collected in D1 for drying and pure product collected as P1. Yield: 92-94%; Purity by GC: >99.5 %
Example 2: Preparation of 5-hydroxy-1-methyl-3-trifluoromethyl pyrazole using CSTR.
In a CSTR shown in figure 2, the temperatures of the CSTRs (C1-C3) were achieved to the specified ranges. All the three pumps were started simultaneously. A solution S1 of ethyl-4,4,4-trifluoro acetoacetate (1.0 eq.) was dosed at 5.0 mL/min and second solution S2 containing aqueous formic acid (1.0 eq.) at 1.4 mL/min and the outflow of the above mixture send to C1. Simultaneously started dosing solution S3 of 35-40% monomethyl hydrazine solution into reactor C1 at 3.0 mL/mins. The overflow of C1 connected to C2 and the overflow of C2 connected to C3 approximately after 90 minutes, the reaction was monitored by GC analysis at overflow C3 for the absence of ethyl-4,4,4-trifluoro acetoacetate. The overflow of C3 collected in vessel V1 at 60-70°C and transferred to R1 for crystallization followed by filtration and drying in D1 at temperature of 60-70°C under vacuum 30-60 mmHg and aqueous layer or filtrate collected in T1.
The pure crystalline white to off-white product was obtained as P1.
Yield: 90-93%; Purity by GC: >99.5 %

SRF LIMITED NO. OF SHEETS: 02
APPLICATION NO. ………………. SHEET NO. 01

Figure 1: Continuous process using flow reactor

SRF LIMITED NO. OF SHEETS: 02
APPLICATION NO. ………………. SHEET NO. 02

Figure 2: Continuous process using CSTR

, Claims:WE CLAIM:
1. A process for the preparation of hydroxy pyrazoles of formula I,

Formula I
wherein R represents a hydrogen atom, an alkyl group, an aryl, heteroaryl ring, and wherein X represents halogen, hydrogen, n represents an integer from 1-3,
comprising the step of condensing a compound of Formula II with methyl hydrazine to obtain compound of formula I,

Formula II
wherein Xn and R, are represented as above;
wherein the condensation is carried in a continuous mode.
2. The process as claimed in claim 1, wherein the reaction is carried out in the presence of an acid.
3. The process as claimed in claim 2, wherein the acid is selected from the group consisting of term “alkanoic acid” is selected from formic acid, acetic acid and trifluoroacetic acid.
4. The process as claimed in claim 1, wherein the reaction is carried out in the absence of any solvent.
5. The process as claimed in claim 1, wherein the reaction is carried out at a temperature of range from 5°C to 95°C.
6. The process as claimed in claim 1, wherein the compound of formula I is substantially free of impurities,

Impurity-I;

Impurity-II
7. The process as claimed in claim 1, wherein the purity of compound of formula I is greater than 99% and yield is greater than 90%.
8. The process as claimed in claim 1, wherein the flow process of the present invention is illustrated in figure 1and figure 2.

Dated this 1st day of February 2023.