DESC:FIELD
The present disclosure relates to a process for preparing 1-(4-chlorophenyl)-3-hydroxypyrazole.
BACKGROUND
Pyraclostrobin is a strobilurin fungicide having broad fungicidal activity. It has been widely used in controlling diseases on wheat, rice, peanut, grape, vegetables, potato, banana, lemon, coffee, fruit trees, walnut, tea tree, tobacco and ornamental plants, lawn and other field crops.
A method for the preparation of pyraclostrobin involves cyclization of 4-chlorophenylhydrazine with alkyl acrylate, the resulting 1-(4-chlorophenyl)-3-pyrazolidinone provides 1-(4-chlorophenyl)-3-hydroxypyrazole upon oxidation.
1-(4-Chlorophenyl)-3-hydroxypyrazole is an important intermediate in the synthesis of pyraclostrobin. However, in the prior art methods for the preparation of 1-(4-Chlorophenyl)-3-hydroxypyrazole, the yields and purity are low.
There is therefore, felt a need for developing a simple process for preparing 1-(4-chlorophenyl)-3-hydroxypyrazole with relatively high purity and a good yield.
OBJECTS
Some of the objects of the present disclosure, which at least one embodiment herein satisfies, are as follows.
It is an object of the present disclosure to ameliorate one or more problems of the prior art or to at least provide a useful alternative.
An object of the present disclosure is to provide a simple process for the preparation of 1-(4-Chlorophenyl)-3-hydroxypyrazole having comparatively high purity and good yield.
Other objects and advantages of the present disclosure will be more apparent from the following description, which is not intended to limit the scope of the present disclosure.
SUMMARY
The present disclosure relates to a process for preparing 1-(4-chlorophenyl)-3-hydroxypyrazole. The process involves cyclization of 4-chlorophenylhydrazine hydrochloride and alkyl acrylate by using at least one base and at least one first fluid medium to obtain 1-(4-chlorophenyl)-3-pyrazolidinone (pyrazolidinone). The so obtained 1-(4-Chlorophenyl)-3-pyrazolidinone is oxidized in the presence of at least one oxidizing agent and at least one second fluid medium to obtain 1-(4-chlorophenyl)-3-hydroxypyrazole. The alkyl acrylate can be methyl acrylate, ethyl acrylate, propyl acrylate and butyl acrylate. The base can be metal hydride and is at least one selected from the group consisting of lithium hydride, sodium hydride, potassium hydride and calcium hydride. The first fluid medium can be 1,2-dimethoxyethane (monoglyme), tetrahydrofuran (THF), diisopropyl ether (DIPE), Diethylene glycol dimethyl ether (diglyme) and methyl t-butyl ether (MTBE). The oxidizing agent can be air and oxygen and the second fluid medium can be aqueous base selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, and calcium hydroxide. The process of the present disclosure is simple and provides high yield and high purity of the product i.e. 1-(4-chlorophenyl)-3-hydroxypyrazole.
DETAILED DESCRIPTION
1-(4-Chlorophenyl)-3-hydroxypyrazole is an important intermediate in the synthesis of pyraclostrobin. The present disclosure envisages a simple process for preparing 1-(4-chlorophenyl)-3-hydroxypyrazole.
In an aspect of the present disclosure, there is provided a process for the preparation of 1-(4-chlorophenyl)-3-hydroxypyrazole.The process involves the following steps.
In a first step 4-chlorophenylhydrazine hydrochloride undergoes cyclization with alkyl acrylate using at least one base and at least one fluid medium to obtain 1-(4-chlorophenyl)-3-pyrazolidinone (pyrazolidinone).

Step-I: Cyclization of 4-chlorophenylhydrazinewith ethyl acrylate

The base can be metal hydride, which is at least one selected from the group consisting of lithium hydride, sodium hydride, potassium hydride and calcium hydride. In one embodiment of the present disclosure, the metal hydride is sodium hydride (NaH). NaH can be used in the form of dispersion in mineral oil containing 50% to 75% NaH.
The first fluid medium can be 1, 2-dimethoxyethane (monoglyme), tetrahydrofuran (THF), diisopropyl ether (DIPE), Diethylene glycol dimethyl ether (diglyme) and methyl t-butyl ether (MTBE). Typically, the first fluid medium can be 1, 2-dimethoxyethane (monoglyme).
The molar ratio of the amount of 4-chlorophenylhydrazine hydrochloride to the amount of metal hydride in the cyclization step can be in the range from 1:1 to 1:5. In an exemplary embodiment of the present disclosure, the molar ratio of the amount of 4-chlorophenylhydrazine hydrochloride to the amount of metal hydride is in the range 1:1 to 1:3.
The alkyl acrylate can be methyl acrylate, ethyl acrylate, propyl acrylate and butyl acrylate. In an exemplary embodiment the alkyl acrylate is ethyl acrylate. The addition of alkyl acrylate can be carried out slowly in order to control the reaction rate. In the process of the present disclosure, the step of addition of alkyl acrylate is carefully controlled to avoid a sudden rise in temperature of the reaction mixture (RM). Therefore, alkyl acrylate can be added slowly for a time period in the range of 1 to 5 hours. By controlled addition of alkyl acrylate the temperature of the reaction mixture is maintained in the range of 20 °C to 35 °C. This slow addition result in obtaining the product with high purity and high yield.
The cyclization is carried out under an inert atmosphere in a suitable reactor under stirring. In an exemplary embodiment, the first fluid medium is introduced in the reactor followed by the addition of the metal hydride to the reactor in portions over a period of 1 to 5 hours, at a temperature in the range of 20 °C to 35 °C. For the industrial scale batches, longer period may be employed. After the addition of metal hydride in the reactor, 4-chlorophenylhydrazine hydrochloride is added in the reactor, in portions over a period of 1 to 5 hours at a temperature in the range of 20 °C to 35°C to obtain a mixture.
The mixture containing metal hydride and 4-chlorophenylhydrazine hydrochloride in the first fluid medium is stirred under an inert atmosphere for a period in the range of 1 to 20 hours, at a temperature in the range of 20 °C to 35 °C. This step is followed by addition of alkyl acrylate under stirring over a time period in the range of 1 hour to 5 hours.
After completing the addition of alkyl acrylate to the reactor, the reaction mixture is maintained under stirring in an inert atmosphere at a temperature in the range of 10 ?C to 50 ?C for a time period in the range of 1 hr to 8 hrs. Typically, the time period is in the range of 3 hrs to 5 hrs. The reaction mixture of cyclization step can be monitored for the consumption 4-chlorophenylhydrazine hydrochloride using High Performance Liquid Chromatography (HPLC) or other suitable spectroscopic techniques.
The reaction mixture is slowly quenched with an acid such as acetic acid, at room temperature and the pH of the mixture is adjusted to a range of 5-6. The reaction mixture is equilibrated at room temperature for 30 min to confirm that the pH is in the range of 5-6.
The reaction mixture is concentrated by heating under reduced pressure to obtain a thick stirrable first slurry. The first distillate is collected and kept aside. Water is added to the first slurry at a temperature in the range of 50-60 °C and concentrated till the water starts distilling out from the reaction mixture to obtain a second slurry and a second distillate. The second slurry is stirred, cooled to room temperature, and filtered to obtain a cake which is washed with water (2×125 ml) and dried to obtain a mixture comprising 1-(4-Chlorophenyl)-3-pyrazolidinone as well as 1-(4-chlorophenyl)-3-hydroxypyrazole which can be directly used for the next step. The yield of the cyclization step is found to be in the range from 85 to 95%.
In a second step of the process of the present disclosure, 1-(4-Chlorophenyl)-3- pyrazolidinone is oxidized with an oxidizing agent in a second fluid medium to obtain 1-(4-chlorophenyl)-3-hydroxypyrazole.

Step-II: oxidation of 1-(4-Chlorophenyl)-3-pyrazolidinone
The oxidizing agent can be air or oxygen. The oxidation is carried out in the presence of an aqueous NaOH solution. In one exemplary embodiment, 1-(4-Chlorophenyl)-3-pyrazolidinone is oxidized with bubbled air in the presence of aqueous NaOH solution.
The second fluid medium can be an aqueous base selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, and calcium hydroxide. Other fluid mediums may be used for oxidizing 1-(4-Chlorophenyl)-3-pyrazolidinone.
The oxidation can be carried out at a temperature in the range of 50 ?C to 150 ?C typically, at a temperature in the range from 75 ?C to 85 ?C. The oxidation can be carried out for a time period in the range of 5 hrs to 50 hrs. The oxidation can be carried out under pressure of the oxidizing agent. In one exemplary embodiment, air pressure is 10 kg/cm2. The step of oxidation can be carried out in the presence of a catalyst. In one embodiment of the present disclosure, the catalyst is anthraquinone-2-sulfonic acid sodium salt or anthraquinone-2-sulfonic acid silver salt.
The yield in the oxidation step is in the range from 70 to 95%. The purity of 1-(4-Chlorophenyl)-3-hydroxypyrazole obtained by the process of the present disclosure is in the range of 90 to 99%.
The present disclosure is further described in the light of the following laboratory experiments which are set forth for illustration purpose only, and not to be construed for limiting the scope of the disclosure. The following experiments can be scaled up to industrial/commercial scale, and the results obtained can be extrapolated to industrial scale.
Experimental details:
Step-1: Preparation of 1-(4-Chlorophenyl)-3-pyrazolidinone (pyrazolidinone)in accordance with the process of the present disclosure:
Experiment 1:
Procedure: A 3L flanged reactor equipped with a teflon gate stirrer was charged with 1, 2dimethoxyethane (1000 ml, MC = 0.42%) under nitrogen (inert) atmosphere. Sodium hydride (84.5 g; purity 65.4%; 2.3 mole) was added in small portions to 1,2-dimethoxyethane, over 1 hr, while stirring. p-Chlorophenylhydrazine hydrochloride (179 g; 1 mole) was slowly added in small portions to the above mixture, over 2.5 hrs, at room temperature. The reaction mixture was maintained at room temperature for 10 hours under nitrogen atmosphere (inert atm). Ethyl acrylate (120 g; 1.2 moles) was slowly added under stirring to the above reaction mixture, through a dropping funnel over 3 hrs, maintaining the temperature between 28-30°C. The reaction was monitored by HPLC. After maintaining at room temperature for 4 hrs, the resultant mixture showed absence of the starting material (by HPLC). On completion, the reaction mixture was slowly quenched with acetic acid by adjusting the pH in the range of 5-6 at room temperature. The pH adjusted resultant mixture was equilibrated for 30 mins and the pH was confirmed in the range of 5-6. The pH adjusted resultant mixture was concentrated by heating under reduced pressure till thick stirrable first slurry and first distillate of 875 ml was obtained. Water, 625 ml, was added to the first slurry, at 60 °C. This slurry was concentrated till water started distilling out from the reaction mixture to obtain second slurry and second distillate of 125 ml. The second slurry was stirred, cooled to room temperature, and filtered to obtain a cake and a filtrate. The so obtained cake was washed with water (2×125 ml) and dried to obtain pyrazolidinone (186 g, HPLC purity = 75.86%) along with 3-hydroxypyrazole (20.74%). The filtrate was extracted with 1, 2-dichloroethane/MCB (2×200 ml) and the organic layer was separated, dried, and concentrated to obtain 12 gms of oily mass. The oily mass needs to be removed to avoid contamination in the product hence the extraction. The commercially available sodium hydride was coated with oil taking into consideration the safety aspect while handling the same.
The mixture of pyrazolidinone and 3-hydroxypyrazole as such was taken to the next reaction.
Yield on purity = 91.65%.

Experiment 2-4:
The preparation of 1-(4-Chlorophenyl)-3-pyrazolidinone of experiments 2 to 4 were carried out similarly as in experiment 1, except for varying the amount of sodium hydride, solvents and reaction time, which are summarized in Table-1 below.
Table 1:
Expt. No PCPH.HCl mole Ethyl acrylate mole/mole NaH mole/mole Solvent ml/mole Reaction conditions Yield on purity
1 1 1.2 2.3 Monoglyme,
1 lit/mole RT-4 hrs 91.65%
2 0.3 1.2 2.18 THF,
1 lit/mole RT-2 hrs 73%
3 0.3 1.2 2.16 DIPE,
1 lit/mole RT-4 hrs 73%
4 0.3 1.2 2.40 MTBE,
1 lit/mole RT-2 hrs 75%
The condensation of 4-chlorophenyl hydrazine hydrochloride with alkyl acrylates in the presence of NaH can be carried out in various solvents as represented in table 1. From table 1, it is observed that monoglyme is comparatively a better solvent for the process of preparation of 1-(4-Chlorophenyl)-3-pyrazolidinone, however cyclizatyion reaction using monoglyme requires more time than THF and MTBE.

Step-2: Preparation of 1-(4-Chlorophenyl)-3-hydroxypyrazole (3-Hydroxypyrazole):
Experiment 5: Comparative
The pyrazolidinone cake (153 g) and filtrate (380 ml) from example-1 (aqueous filtrate which contains sodium salt of 1-(4-chlorophenyl)-3-hydroxypyrazole & sodium salt of 1-(4-Chlorophenyl)-3-pyrazolidinone) were taken and mixed with 500 ml water. The solution was heated to 80°C and air was bubbled through it. The reaction mixture was monitored by HPLC. After 23 hrs, 32.7%pyrazolidinone was left unconverted in the reaction mixture. Hence, NaOH (lye, 0.2 mole) was added to the reaction mixture and air bubbled through the solution at 80°C for 37 hrs. The sample analysis by HPLC, even after 37 hrs of air bubbling showed 16 % pyrazolidinone content. The resultant mixture was quenched with 20 ml acetic acid (AcOH) at 70°C andthe pH was adjusted to 4. The pH adjusted resultant mixture was cooled to 25°C, filtered, the cake was washed with water (2 x 100 ml) and dried to obtain 119 g of 3-Hydroxypyrazole (78.03 % purity by HPLC).
The HPLC analysis is given in Table 2:
Table 2:
Sample Tempt /Hr 1.5 min to 4.9 min 7.00 min 12.96 min
Pyrazoli
dinone 3-Hydroxy
Pyrazole
Feed 4.2 63.15 32.5 %
RMS after 4 hours 80°C/4 hrs 6.6 57.2 36.02 %
RMS after 8 hours 80°C/8 hrs 7.8 48.8 42.2 %
RMS after 17 hours 80°C/17 hrs 7.7 37.4 53.8 %
RMS after 23 hours 80°C/23 hrs 5.8 32.7 61.02 %
Extra NaOH lye was added here to enhance the rate of oxidation.
RMS after 34 hours 80°C/34 hrs 21.9 9.8 60.7 %
RMS after 37 hours 80°C/37 hrs 16.71 12.9 67.34 %
Product 119 gms. 5.0 14.96 78.03 %
*RMS is reaction mixture
It is evident from the results summarized in table 2 that the conventional process for oxidation of 1-(4-Chlorophenyl)-3-pyrazolidinone to 1-(4-chlorophenyl)-3-hydroxypyrazole is sluggish & takes several hours to reaction completion.
Experiment 6: Preparation of 1-(4-Chlorophenyl)-3-hydroxypyrazole (3-Hydroxypyrazole) using a catalyst and unpressurized air:
Pyrazolidinone cake (50.4 g; HPLC purity = 57.51% & 38.14% 3-hydroxypyrazole), and anthraquinone-2-sulfonic acid sodium salt (silver salt; 1.64 g; 2 mole%) was added to 0.8 N NaOH aqueous solution (385 ml; 1.2 moles) heated to 80°C, under stirring, to form a thin slurry. Air was bubbled through the reaction mixture at 80 °C. The reaction mixture was monitored by HPLC. After 4 hrs the pyrazolidinone content was found to be<1%. The reaction was diluted with water (150 ml), quenched with 20 ml acetic acid at 65 °C and the pH was adjusted to 4. The reaction mixture was equilibrated for 30 mins at 65 °C and the pH was confirmed. The reaction mixture was cooled to 25 °C, filtered; the cake was washed with water (2 × 100 ml) and dried to obtain 40 g 3-Hydroxypyrazole (98.76 % purity by HPLC).
Experiment 7: Preparation of 1-(4-Chlorophenyl)-3-hydroxypyrazole (3-Hydroxypyrazole) using pressurized air:
In a 1 liter SS autoclave, 1.5N NaOH aq. solution (570 ml) was added. Pyrazolidinone (140 g, HPLC purity = 68%, 3-hydroxypyrazole = 38.84%; 0.708 mole) was added to this solution under stirring. The reactor was closed and pressurized with 10 kg/cm2 of air, and the reaction mixture was heated to 80°C for 4 hrs when HPLC showed absence of pyrazolidinone. The reaction mixture was transferred to an open glass reactor, acidified with AcOH at 75 °C to pH = 4. The reaction mixture was equilibrated for 30 mins at 75 °C and the pH was confirmed. The reaction mixture was cooled to 25 °C, filtered, the cake was washed with water (2 × 100 ml) and dried to obtain 120 g of 3-Hydroxypyrazole (yield on purity = 85.7%, purity by HPLC = 98.36 %).
Conventionally, the oxidation reaction, i.e. conversion of 1-(4-Chlorophenyl)-3-pyrazolidinone to 1-(4-chlorophenyl)-3-hydroxypyrazole, required several hours of air bubbling for completion of the reaction , however conversion of 1-(4-Chlorophenyl)-3-pyrazolidinone to 1-(4-chlorophenyl)-3-hydroxypyrazole takes place under air pressure in 4 hrs and/or the rate of the reaction can be enhanced by adding catalytic amount of silver salt to the reaction mass & passing air at atmospheric pressure.
TECHNICAL ADVANCES AND ECONOMICAL SIGNIFICANCE
The process of the present disclosure described herein above has several technical advantages including but not limited to the realization of a process for the synthesis of 1-(4-Chlorophenyl)-3-hydroxypyrazole (3-Hydroxypyrazole), that is simple; and provides high yield and high purity.
The foregoing description of the specific embodiments so fully reveals the general nature of the embodiments herein that others can, by applying current knowledge, readily modify and/or adapt for various applications such specific embodiments without departing from the generic concept, and, therefore, such adaptations and modifications should and are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments. It is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation. Therefore, while the embodiments herein have been described in terms of preferred embodiments, those skilled in the art will recognize that the embodiments herein can be practiced with modification within the spirit and scope of the embodiments as described herein.
Throughout this specification the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.
The use of the expression “at least” or “at least one” suggests the use of one or more elements or ingredients or quantities, as the use may be in the embodiment of the disclosure to achieve one or more of the desired objects or results.
Any discussion of documents, acts, materials, devices, articles or the like that has been included in this specification is solely for the purpose of providing a context for the disclosure. It is not to be taken as an admission that any or all of these matters form a part of the prior art base or were common general knowledge in the field relevant to the disclosure as it existed anywhere before the priority date of this application.
The numerical values mentioned for the various physical parameters, dimensions or quantities are only approximations and it is envisaged that the values higher/lower than the numerical values assigned to the parameters, dimensions or quantities fall within the scope of the disclosure, unless there is a statement in the specification specific to the contrary.
While considerable emphasis has been placed herein on the components and component parts of the preferred embodiments, it will be appreciated that many embodiments can be made and that many changes can be made in the preferred embodiments without departing from the principles of the disclosure. These and other changes in the preferred embodiment as well as other embodiments of the disclosure will be apparent to those skilled in the art from the disclosure herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the disclosure and not as a limitation.
,CLAIMS:WE CLAIM:
1. A process for preparing 1-(4-chlorophenyl)-3-hydroxypyrazole, said process comprising:
a. cyclizing 4-chlorophenylhydrazine hydrochloride and alkyl acrylate byusing at least one base and at least one first fluid medium to obtain 1-(4-chlorophenyl)-3-pyrazolidinone (pyrazolidinone); and
b. oxidizing 1-(4-Chlorophenyl)-3-pyrazolidinone in the presence of at least one oxidizing agent , and at least one second fluid medium to obtain 1-(4-chlorophenyl)-3-hydroxypyrazole.

2. The process as claimed in claim 1, wherein said base is at least one metal hydride selected from the group consisting of lithium hydride, sodium hydride, potassium hydride and calcium hydride.

3. The process as claimed in claim 1, wherein saidat least one first fluid medium is selected from the group consisting of 1,2-dimethoxyethane, tetrahydrofuran, diisopropyl ether and methyl ter-butyl ether.

4. The process as claimed in claim 1, wherein the molar ratio of said 4-chlorophenylhydrazine hydrochloride to said base is in the range of 1:1 to 1:5.

5. The process as claimed in claim 1, wherein said alkyl acrylate is selected from the group consisting of ethyl acrylate, propyl acrylate and butyl acrylate.

6. The process as claimed in claim 1, wherein the amount of alkyl acrylate is in the range of 1-1.1 to 1-1.3

7. The process as claimed in claim 1, wherein said oxidizing agent is pressurized air having pressure in the range of 8 kg/cm2 to 15 kg/cm2.

8. The process as claimed in claim 1, wherein said oxidizing agent is air and catalyst.

9. The process as claimed in claim 8, wherein said catalyst is anthraquinone-2-sulfonic acid metal salt.

10. The process as claimed in claim 1, wherein said at least one second fluid medium is an aqueous base selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide and calcium hydroxide.