DESC:FIELD
The present disclosure relates to a process for the preparation of Pinoxaden.
BACKGROUND
The background information herein below relates to the present disclosure but is not necessarily prior art.
8-(2,6-diethyl-p-tolyl)-1,2,4,5-tetrahydro-7-oxo-7H-pyrazolo[1,2-d][1,4,5]oxadiazepin -9-yl-2,2-dimethylpropionate, commonly known as Pinoxaden, is a phenylpyrazoline based herbicide. Pinoxaden upon application to weeds and unwanted plants gets absorbed through leaves and then transmitted to the meristematic tissues. Pinoxaden is known to inhibit acetyl-CoA carboxylase (ACC) in the weeds and unwanted plants, thereby blocking fatty acid synthesis, hindering cell division, resulting in destruction of the cell membrane lipid structure, which leads to weed death. Further, Pinoxaden acts systemically and at a fast speed, leading to the inhibition of growth of the sensitive weeds within 48 hours after application.
Many processes are known in the prior art for the synthesis of Pinoxaden. However, Pinoxaden obtained by the conventional methods has low purity and its purification process is cumbersome, time consuming and not environmentally friendly.
Further, conventional route for preparing Pinoxaden involves the use of noble metal such as palladium for C-C coupling reaction. The palladium catalyst in the form of PdCl2 in HCl, PDCl2 (TPP)2, tetrakis(triphenylphosphine)palladium and the like are known for catalyzing C-C coupling reaction. However, when the palladium catalyzed reaction is carried out for the synthesis of Pinoxaden, palladium is found in many streams of reactions. The palladium containing product when taken to next step, the palladium is found in the next step also and its further involvement in the subsequent steps leads to the final product, Pinoxaden, having lower purity and less yield.
There is, therefore, felt a need for a process for preparing Pinoxaden that mitigates the drawbacks mentioned hereinabove.
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.
Another object of the present disclosure is to provide a process for preparation of Pinoxaden having a relatively high purity and high yield.
Still another object of the present disclosure is to provide a simple and environmental friendly process for the preparation of Pinoxaden
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 Pinoxaden. The process comprises reacting 2,6-diethyl-4-methyl-aniline (DEMA) with NaNO2 in a first fluid medium at a first predetermined temperature for a first predetermined time period to obtain a reaction mixture. HBr is passed to the reaction mixture at a second predetermined temperature for a second predetermined time period followed by raising the temperature and maintaining at a temperature in the range of 30 °C to 50 °C for a time period in the range of 3 hours to 6 hours to obtain 2,6-diethyl-4-methyl bromo benzene. Separately, malononitrile is dissolved in a second fluid medium along with t-butanol and sodium hydride at a temperature in the range of 80 °C to 120 °C under stirring for a time period in the range of 1 hour to 5 hours to obtain a reaction mass followed by cooling the reaction mass to a temperature in the range of 15 °C to 25 °C to obtain a cooled reaction mass. The so obtained 2,6-diethyl-4-methyl bromo benzene and a palladium catalyst are added to the cooled reaction mass, wherein 2,6-diethyl-4-methyl bromo benzene is reacted with malononitrile at a third predetermined temperature for a third predetermined time period to obtain a product mass comprising 2,6-Diethyl-4-methyl-phenyl-malononitrile. The so obtained product mass comprising 2,6-Diethyl-4-methyl-phenyl-malononitrile is subjected to vacuum distillation to obtain palladium free 2,6-Diethyl-4-methyl-phenyl-malononitrile. The palladium free 2,6-Diethyl-4-methyl-phenyl-malononitrile is reacted with sulfuric acid at a fourth predetermined temperature for a fourth predetermined time period to obtain 2,6-Diethyl-4-methyl-phenyl-malonamide. The so obtained 2,6-Diethyl-4-methyl-phenyl-malonamide is reacted with 1,4,5-hexahydro-oxadiazepine in a third fluid medium by using a first base at a fifth predetermined temperature for a fifth predetermined time period to obtain 8-(2,6-Diethyl-4-methylphenyl)-1,2,4,5-tetrahydro-9-hydroxy-7H-pyrazolo[1,2-d][1,4,5]oxadiazepin-7-one (pyrazole-oxadiazepine). The pyrazole-oxadiazepine is reacted with pivaloyl chloride in a fourth fluid medium in the presence of a second base at a sixth predetermined temperature for a sixth predetermined time period to obtain Pinoxaden.
The present disclosure further relates to a process for preparing 1,4,5-hexahydro-oxadiazepine hydrochloride. The process comprises acetylating hydrazine, by adding hydrazine to ethyl acetate under stirring, at a temperature in the range of 25 °C to 35 °C to obtain mono acetyl hydrazine. The mono acetyl hydrazine is further acetylated, by slowly adding acetic anhydride to the mono acetyl hydrazine, at a temperature in the range of 25 °C to 35 °C to obtain N,N’-diacetylhydrazine. Separately, diethylene glycol is chlorinated using a chlorinating agent, in the presence of a catalyst in a halogenated fluid medium, at a temperature in the range of 50 °C to 90 °C to obtain 2,2’-dichlorodiethyl ether. 2,2’ dichlorodiethyl ether is reacted with N,N’-diacetylhydrazine, by using a phase transfer catalyst, a base and a nucleophillic catalyst in a fluid medium to obtain 4,5-diacetyl-hexahydro-1,4,5-oxadiazepine. 4,5-diacetyl-hexahydro-1,4,5-oxadiazepine is treated with a salt forming agent to obtain 1,4,5-hexahydro oxadiazepine hydrochloride.
DETAILED DESCRIPTION
Embodiments are provided so as to thoroughly and fully convey the scope of the present disclosure to the person skilled in the art. Numerous details are set forth, relating to specific components, and methods, to provide a complete understanding of embodiments of the present disclosure. It will be apparent to the person skilled in the art that the details provided in the embodiments should not be construed to limit the scope of the present disclosure. In some embodiments, known processes or well-known apparatus or structures, and well known techniques are not described in detail.
The terminology used, in the present disclosure, is only for the purpose of explaining a particular embodiment and such terminology shall not be considered to limit the scope of the present disclosure. As used in the present disclosure, the forms "a,” "an," and "the" may be intended to include the plural forms as well, unless the context clearly suggests otherwise. The terms "comprises," "comprising," “including,” and “having,” are open ended transitional phrases and therefore specify the presence of stated features, integers, steps, operations, elements, modules, units and/or components, but do not forbid the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof. The particular order of steps disclosed in the method and process of the present disclosure are not to be construed as necessarily requiring their performance as described or illustrated. It is also to be understood that additional or alternative steps may be employed.
The terms first, second, third, etc., should not be construed to limit the scope of the present disclosure as the aforementioned terms may be only used to distinguish one element, component, region, layer or section from another component, region, layer or section. Terms such as first, second, third etc., when used herein do not imply a specific sequence or order unless clearly suggested by the present disclosure.
Pinoxaden is a phenylpyrazoline based herbicide. Pinoxaden is known to inhibit acetyl-CoA carboxylase (ACC) in the weeds and unwanted plants, thereby blocking fatty acid synthesis. Pinoxaden acts systemically and at a fast speed, leading to death of sensitive weeds within 48 hours after application. Pinoxaden is represented by a following structure;

Pinoxaden
Chemical Name: 8-(2,6-diethyl-p-tolyl)-1,2,4,5-tetrahydro-7-oxo-7H-pyrazolo[1,2-d][1,4,5]oxadiazepin-9-yl-2,2-dimethylpropionate
CAS no.: 243973-20-8
The present disclosure provides a simple and efficient process for the preparation of Pinoxaden having a relatively high purity and in high yields.
In a first aspect, the present disclosure provides a process for preparing Pinoxaden.
The process for preparing Pinoxaden comprises the following steps:
(i) preparing 2,6-diethyl-4-methyl bromo benzene by;
a. reacting 2,6-diethyl-4-methyl-aniline (DEMA) with NaNO2 in a first fluid medium at a first predetermined temperature for a first predetermined time period to obtain a reaction mixture; and
b. passing HBr to the reaction mixture at a second predetermined temperature for a second predetermined time period followed by raising the temperature and maintaining at a temperature in the range of 30 °C to 50 °C for a time period in the range of 3 hours to 6 hours to obtain 2,6-diethyl-4-methyl bromo benzene;
(ii) preparing palladium free 2,6-Diethyl-4-methyl-phenyl-malononitrile by;
a. separately dissolving malononitrile in a second fluid medium along with t-butanol and sodium hydride at a temperature in the range of 80 °C to 120 °C under stirring for a time period in the range of 1 hour to 5 hours to obtain a reaction mass followed by cooling the reaction mass to a temperature in the range of 15 °C to 25 °C to obtain a cooled reaction mass;
b. adding 2,6-diethyl-4-methyl bromo benzene and a palladium catalyst to the cooled reaction mass, wherein 2,6-diethyl-4-methyl bromo benzene is reacted with malononitrile at a third predetermined temperature for a third predetermined time period to obtain a product mass comprising 2,6-Diethyl-4-methyl-phenyl-malononitrile; and
c. subjecting the so obtained product mass comprising 2,6-Diethyl-4-methyl-phenyl-malononitrile to vacuum distillation to obtain a palladium free 2,6-Diethyl-4-methyl-phenyl-malononitrile;
(iii) reacting the palladium free 2,6-Diethyl-4-methyl-phenyl-malononitrile with sulfuric acid at a fourth predetermined temperature for a fourth predetermined time period to obtain 2,6-Diethyl-4-methyl-phenyl-malonamide;
(iv) reacting 2,6-Diethyl-4-methyl-phenyl-malonamide with 1,4,5-hexahydro-oxadiazepine in a third fluid medium in the presence of a first base at a fifth predetermined temperature for a fifth predetermined time period to obtain 8-(2,6-Diethyl-4-methylphenyl)-1,2,4,5-tetrahydro-9-hydroxy-7H-pyrazolo[1,2-d][1,4,5]oxadiazepin-7-one (pyrazole-oxadiazepine); and
(v) reacting the pyrazole-oxadiazepine with pivaloyl chloride in a fourth fluid medium in the presence of a second base at a sixth predetermined temperature for a sixth predetermined time period to obtain Pinoxaden.
The process of preparing Pinoxaden in accordance of the present disclosure is described in detail herein below:
Step (i): Preparation of 2,6-diethyl-4-methyl bromo benzene
The schematic representation of the preparation of 2,6-diethyl-4-methyl bromo benzene in accordance with the present disclosure is given below as Scheme 1.
Scheme 1
In a first step, 2,6-diethyl-4-methyl-aniline (DEMA) is added in portions to a first fluid medium to obtain slurry. NaNO2 is added to the so obtained slurry and maintained at a first predetermined temperature for a first predetermined time period to obtain a reaction mixture.
The first fluid medium is selected from aqueous HBr, aqueous PTSA (p-Toluenesulfonic acid), t-butanol and a mixture thereof. In an exemplary embodiment of the present disclosure, the fluid medium is aqueous HBr. In an exemplary embodiment of the present disclosure, the fluid medium is a mixture of aqueous PTSA (p-Toluenesulfonic acid) and t-butanol
The first predetermined time period is in the range of 1 hour to 4 hours. In an exemplary embodiment of the present disclosure, the first predetermined time period is 2 hours.
The first predetermined temperature is in the range of -10 °C to 15 °C. In an exemplary embodiment of the present disclosure, the first predetermined temperature is -5 °C. In another exemplary embodiment of the present disclosure, the first predetermined temperature is 10 °C.
To the so obtained reaction mixture, HBr is passed at a second predetermined temperature for a second predetermined time period followed by raising the temperature and maintaining the same at a temperature in the range of 30 °C to 50 °C for a time period in the range of 3 hours to 6 hours to obtain 2,6-diethyl-4-methyl bromo benzene.
The second predetermined time period is in the range of 0.5 hour to 6 hours. The second predetermined temperature is in the range of 0 °C to 20 °C.
In an exemplary embodiment of the present disclosure, HBr is passed at 5 °C for 5.5 hours. In another exemplary embodiment of the present disclosure, aqueous HBr is added in portions for 45 minutes at 10 °C.
Step (ii): Preparation of 2,6-Diethyl-4-methyl-phenyl-malononitrile
The schematic representation of the preparation of 2,6-Diethyl-4-methyl-phenyl-malononitrile in accordance with the present disclosure is given below as Scheme 2.

Scheme 2
Separately, malononitrile is dissolved in a second fluid medium along with t-butanol and sodium hydride at a temperature in the range of 80 °C to 120 °C under stirring for a time period in the range of 1 hour to 5 hours to obtain a reaction mass followed by cooling to a temperature in the range of 15 °C to 25 °C to obtain a cooled reaction mass.
The second fluid medium is o-xylene.
The tert-butanol reacts with sodium hydride and is converted into sodium tert-butoxide which catalyzes the reaction. Excess of tert-butanol helps in dissolving the sodium tert-butoxide formed, in second fluid medium at elevated temperature.
2,6-diethyl-4-methyl bromo benzene and a palladium catalyst are added to the cooled reaction mass, wherein 2,6-diethyl-4-methyl bromo benzene is reacted with malononitrile at a third predetermined temperature for a third predetermined time period to obtain a product mass comprising 2,6-Diethyl-4-methyl-phenyl-malononitrile.
The palladium catalyst is selected from palladium dichloride, bis(triphenylphosphine)palladium(II) dichloride, tetrakis(triphenylphosphine)palladium and 1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II). In an exemplary embodiment of the present disclosure, the palladium catalyst is bis(triphenylphosphine)palladium(II) dichloride. In another exemplary embodiment of the present disclosure, the palladium catalyst is tetrakis(triphenylphosphine)palladium. In still another exemplary embodiment of the present disclosure, the palladium catalyst is1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II).
The third predetermined temperature is in the range of 80 °C to 160 °C. In an embodiment of the present disclosure, the third predetermined temperature is in the range of 100 °C to 150 ºC.
The third predetermined time period is in the range of 1 hour to 14 hours. In an exemplary embodiment of the present disclosure, the third predetermined time period is 4 hours. In another exemplary embodiment of the present disclosure, the third predetermined time period is 12 hours.
The so obtained product mass comprising 2,6-Diethyl-4-methyl-phenyl-malononitrile is subjected to vacuum distillation to obtain palladium free 2,6-Diethyl-4-methyl-phenyl-malononitrile.
A stabilizer is added to the product mass comprising 2,6-Diethyl-4-methyl-phenyl-malononitrile followed by carrying out the vacuum distillation at a temperature in the range of 120 °C to 160 ºC and at a vapor pressure in the range of 1 to 4 mm Hg to obtain the palladium free 2,6-Diethyl-4-methyl-phenyl-malononitrile.
The stabilizer is butylated hydroxyl toluene (BHT).
In order to make the product palladium free, the inventors of the present disclosure have developed a process and isolation technique wherein the palladium is removed in same step. Due to which further involvement of palladium in the subsequent steps is avoided. This process makes final product Pinoxaden palladium free containing less than 1 ppm palladium.
Step (iii): Preparation of 2,6-Diethyl-4-methyl-phenyl-malonamide
The schematic representation of the preparation of 2,6-Diethyl-4-methyl-phenyl-malonamide in accordance with the present disclosure is given below as Scheme 3.

Scheme 3
The palladium free 2,6-Diethyl-4-methyl-phenyl-malononitrile obtained in step (ii) is reacted with sulfuric acid at a fourth predetermined temperature for a fourth predetermined time period to obtain a reaction mixture. The reaction mixture is drowned in crushed ice to obtain a slurry comprising 2,6-Diethyl-4-methyl-phenyl-malonamide. The slurry is filtered and dried to obtain 2,6-Diethyl-4-methyl-phenyl-malonamide.
The fourth predetermined temperature is in the range of 40 °C to 80 °C. In an embodiment of the present disclosure, the fourth predetermined temperature is in the range of 40 °C to 55 ºC.
The fourth predetermined time period is in the range of 1 hour to 10 hours. In an embodiment of the present disclosure, the fourth predetermined time period is in the range of 2 to 8 hours.
Step (iv): preparation of pyrazole-oxadiazepine
The schematic representation of the preparation of pyrazole-oxadiazepine in accordance with the present disclosure is given below as Scheme 4.

Scheme 4
2,6-Diethyl-4-methyl-phenyl-malonamide obtained in step (iii) is reacted with 1,4,5-hexahydro-oxadiazepine in a third fluid medium by using a first base at a fifth predetermined temperature for a fifth predetermined time period to obtain pyrazole-oxadiazepine.
The third fluid medium is o-xylene.
1,4,5-hexahydro-oxadiazepine is used in the form of free base or mono-hydrochloride salt or di-hydrochloride salt or a mixture thereof. In an exemplary embodiment of the present disclosure, 1,4,5-hexahydro-oxadiazepine mono-hydrochloride salt is used. In another exemplary embodiment of the present disclosure, 1,4,5-hexahydro-oxadiazepine di-hydrochloride salt is used.
The first base is selected from sodium carbonate, potassium carbonate and triethyl amine. In an exemplary embodiment of the present disclosure, the first base is sodium carbonate. In another exemplary embodiment of the present disclosure, the first base is triethyl amine.
The fifth predetermined temperature is in the range of 100 °C to 160 °C. In an embodiment of the present disclosure, the fifth predetermined temperature is in the range of 130 °C to 150 ºC.
The fifth predetermined time period is in the range of 1 to 12 hours. In an exemplary embodiment of the present disclosure, the fifth predetermined time period is 4 hours.
Step (v): Pinoxaden preparation
The schematic representation of the preparation of Pinoxaden in accordance with the present disclosure is given below as Scheme 5.

Scheme 5
Pyrazole-oxadiazepine obtained in step (iv) is reacted with pivaloyl chloride in a fourth fluid medium by using a second base at a sixth predetermined temperature for a sixth predetermined time period to obtain Pinoxaden.
The fourth fluid medium is o-xylene.
The second base is selected from sodium carbonate, potassium carbonate and triethyl amine. In an exemplary embodiment of the present disclosure, the second base is sodium carbonate.
The sixth predetermined temperature is in the range of 0 °C to 10 °C. In an exemplary embodiment of the present disclosure, the sixth predetermined temperature is 5 ºC.
The sixth predetermined time period is in the range of 1 hour to 5 hours. In an exemplary embodiment of the present disclosure, the sixth predetermined time period is 3 hours.
In a second aspect, the present disclosure provides a process for preparing of 1,4,5-hexahydro-oxadiazepine hydrochloride.
The process for preparing 1,4,5-hexahydro oxadiazepine hydrochloride comprises the following steps:
a. acetylating hydrazine, by adding hydrazine to ethyl acetate under stirring, at a temperature in the range of 25 °C to 35 °C to obtain a mono acetyl hydrazine;
b. further acetylating the mono acetyl hydrazine, by slowly adding acetic anhydride to the mono acetyl hydrazine, at a temperature in the range of 25 °C to 35 °C to obtain N,N’-diacetylhydrazine;
c. separately, chlorinating diethylene glycol by using a chlorinating agent, in the presence of a catalyst in a halogenated fluid medium, at a temperature in the range of 50 °C to 90 °C to obtain 2,2’-dichlorodiethyl ether;
d. reacting 2,2’ dichlorodiethyl ether with N,N’-diacetylhydrazine by using a base in the presence of a phase transfer catalyst and a nucleophillic catalyst in a fluid medium to obtain 4,5-diacetyl-hexahydro-1,4,5-oxadiazepine; and
e. treating 4,5-diacetyl-hexahydro-1,4,5-oxadiazepine with a salt forming agent to obtain 1,4,5-hexahydro oxadiazepine hydrochloride.
The process of preparing 1,4,5-hexahydro oxadiazepine hydrochloride in accordance of the present disclosure is described in detail herein below:
Steps-a to b: Synthesis of diacetyl hydrazine from hydrazine
The schematic representation of the synthesis of N,N’-diacetylhydrazine in accordance with the present disclosure is given below as Scheme 4a.

Scheme 4a
In a first step hydrazine is acetylated, by reacting hydrazine with ethyl acetate under stirring, at a temperature in the range of 25 °C to 35 °C to obtain a solution comprising a mono acetyl hydrazine. The so obtained mono acetyl hydrazine in the solution, is further acetylated by slowly adding acetic anhydride to the solution, at a temperature in the range of 25 °C to 35 °C to obtain N,N’-diacetylhydrazine.
In an embodiment of the present disclosure, a molar ratio of hydrazine to ethyl acetate is in the range of 1:1 to 1:1.2, and a molar ratio of hydrazine to acetic anhydride is in the range of 1:0.95 to 1:1.05. In an exemplary embodiment of the present disclosure, the molar ratio of hydrazine to ethyl acetate is 1:1.2, and the molar ratio of hydrazine to acetic anhydride is 1:1.
Step c: Synthesis of 2,2’-dichlorodiethyl ether
The schematic representation of synthesis of 2,2’-dichlorodiethyl ether in accordance with the present disclosure is provided below in Scheme 4b.

Scheme 4b
Separately, in a second step, diethylene glycol is chlorinated by using a chlorinating agent, in the presence of a catalyst in a halogenated fluid medium, at a temperature in the range of 50 °C to 90 °C to obtain 2,2’-dichlorodiethyl ether.
In an embodiment of the present disclosure, the amount of halogenated fluid medium is in the range of 2 moles to 3 moles per mole of diethylene glycol. In an exemplary embodiment, the amount of halogenated fluid medium is 2.5 moles per mole of diethylene glycol.
In an embodiment of the present disclosure, the halogenated fluid medium is selected from ethylene dichloride (EDC), monochlorobenzene (MCB), toluene and dichloromethane (DMC). In an exemplary embodiment, the halogenated fluid medium is ethylene dichloride (EDC).
In an embodiment of the present disclosure, the catalyst is selected from dimethylformamide (DMF) and pyridine. In an exemplary embodiment, the catalyst is dimethylformamide (DMF).
In an embodiment of the present disclosure, the amount of catalyst is in the range of 0.05 mole% to 0.5 mole%, with respect to the amount of diethylene glycol.
In accordance with the present disclosure, a molar ratio of the diethylene glycol to the chlorinating agent is in the range of 1:2 to 1:2.1. In an exemplary embodiment, the molar ratio of the diethylene glycol to the chlorinating agent is 1:2.
In accordance with the present disclosure, the chlorinating agent is thionyl chloride (SOCl2).
The gases released from the reaction mixture during the reaction are absorbed in an alkali scrubber. Thus, making the process environmental friendly and efficient.
Step-d: Synthesis of 4,5-diacetyl-hexahydro-1,4,5-oxadizepine
The schematic representation of the synthesis of 4,5-diacetyl-hexahydro-1,4,5-oxadizepine in accordance with the present disclosure is given below as Scheme 4c.

Scheme 4c
2,2’ dichlorodiethyl ether is reacted with N,N’-diacetylhydrazine by using a base in the presence of a phase transfer catalyst and a nucleophilic catalyst in a fluid medium to obtain 4,5-diacetyl-hexahydro-1,4,5-oxadiazepine.
The fluid medium is selected from dimethyl sulphoxide (DMSO) and dimethyl formamide (DMF). In an exemplary embodiment, the fluid medium is dimethyl sulphoxide (DMSO).
In an embodiment of the present disclosure, the phase transfer catalyst is tetrabutyl ammonium bromide in an amount in the range of 1 mole% to 5 mole% with respect to the amount of N,N’-diacetylhydrazine. In an exemplary embodiment, the amount of the phase transfer catalyst is 2 mole% with respect to the amount of N,N’-diacetylhydrazine.
In an embodiment of the present disclosure, the base is selected from sodium carbonate (Na2CO3), and potassium carbonate (K2CO3). In an exemplary embodiment, the base is potassium carbonate (K2CO3).
In accordance with the present disclosure, the nucleophilic catalyst is potassium Iodide (KI) in an amount in the range of 1 mole% to 5 mole% with respect to the amount of N,N’-diacetylhydrazine. In an exemplary embodiment, the amount of the nucleophilic catalyst is 2 mole% with respect to the amount of N,N’-diacetylhydrazine.
Step-e: Synthesis of 1,4,5-hexahydro oxadiazepine hydrochloride
The schematic representation of the synthesis of 1,4,5-hexahydro oxadiazepine hydrochloride in accordance with an embodiment of the present disclosure is given below as Scheme 4d.

Scheme 4d
In this step, 4,5-diacetyl-hexahydro-1,4,5-oxadiazepine is dissolved in diethylene glycol and treated with a salt forming agent to obtain 1,4,5-hexahydro oxadiazepine hydrochloride salt.
In accordance with the present disclosure, the salt forming agent is hydrogen chloride (HCl).
In an embodiment of the present disclosure, the yield of 1,4,5–hexahydro oxadiazepine hydrochloride is in the range of 35% to 50%.
The process of the present disclosure is carried out at ambient temperatures. Thus, the process of the present disclosure is energy efficient.
The process of the present disclosure employs inexpensive and easily available reagents. Thus, the process of the present disclosure is economical.
The foregoing description of the embodiments has been provided for purposes of illustration and not intended to limit the scope of the present disclosure. Individual components of a particular embodiment are generally not limited to that particular embodiment, but, are interchangeable. Such variations are not to be regarded as a departure from the present disclosure, and all such modifications are considered to be within the scope of the present disclosure.
The present disclosure is further illustrated herein below with the help of the following experiments. The experiments used herein are intended merely to facilitate an understanding of the ways in which the embodiments herein may be practiced and to further enable those of skill in the art to practice the embodiments herein. Accordingly, the experiments should not be construed as limiting the scope of embodiments herein. These laboratory scale experiments can be scaled up to industrial/commercial scale and the results obtained can be extrapolated to industrial/commercial scale.
EXPERIMENTAL DETAILS:
EXPERIMENT 1: Preparation of palladium free 2,6-Diethyl-4-methyl-phenyl-malononitrile
Step (i) Preparation of 2,6-Diethyl-4-methyl Bromo Benzene
Example – 1A
492.5 g of 99.3 % pure 2,6-diethyl-4-methyl-aniline was added in portions to 1748 g of 48 % aqueous HBr at 25 °C to get a white color thick slurry with a complete salt formation. The slurry was cooled down to -5 °C and 530 g of aqueous NaNO2 solution (corresponding to 3.3 mole of NaNO2) was added to the slurry to obtain a reaction mixture. The reaction mixture was maintained at –5 °C for 2 hours. Then to this reaction mixture, dry HBr gas was passed for 5.5 hrs at 5 °C and the temperature was raised and maintained at 40 °C for 5.5 hours to obtain 2,6-diethyl-4-methyl bromo benzene after work up and fractionation (70 % yield and 99 % purity).
Example – 1B
164.15 g of 99.3 % 2,6-diethyl-4-methyl-aniline was added in portions to the mixture of 570 g of aqueous PTSA and 2000 ml t-butanol at 30 °C to obtain a thick slurry. The slurry was cooled down to 10 °C and 346 g of aqueous NaNO2 solution (corresponding to 2 mole of NaNO2) was added to the slurry to obtain a reaction mixture. The reaction mixture was maintained at 10 °C for 2 hours. Then to this reaction mixture, 409 g of aqueous HBr (49 %) was added in portions for 45 minutes at 10 °C and the temperature was maintained at 35 °C to obtain 2,6-diethyl-4-methyl bromo benzene after work up and fractionation (33 % yield).
Step (ii) Preparation of 2,6-Diethyl-4-methyl-phenyl-malononitrile
Example – 2A
2000 ml o-xylene,129 g of NaH and 370 g of t-butanol were mixed in a reactor under nitrogen atmosphere and 74 g of malononitrile was added to the reactor and stirred for 2 hours at 100 °C to obtain a reaction mass. The reaction mass was cooled to 20 °C and 227 g of 2,6-diethyl-4-methyl bromo benzene (99.9 %) (obtained in step (i)) and 3 gm Bis-triphenylphosphine palladium dichloride were added to the reaction mass followed by heating and stirring at 145 °C for 2 hours to obtain 2,6-Diethyl-4-methyl-phenyl-malononitrile (92 % yield and 99.5 % purity).
Example – 2B
250 ml o-xylene, 5.53 g of NaH and 12 g of t-butanol were mixed in a reactor under nitrogen atmosphere and 3.52 g of malononitrile was added to the reactor and stirred for 2 hours at 100 °C to obtain a reaction mass. The reaction mass was cooled to 20 °C and 12 g of 2,6-diethyl-4-methyl bromo benzene (94 % purity) (obtained in step (i)) and 1.16 gm tetrakis(triphenylphosphine) palladium were added to the reaction mass followed by heating and stirring at 145 °C for 4 hours to obtain 2,6-Diethyl-4-methyl-phenyl-malononitrile (87 % yield and 98 % purity).
Example – 2C
240 ml o-xylene, 6.7 g of NaH and 14 g of t-butanol were mixed in a reactor under nitrogen atmosphere and 4.18 g of malononitrile was added to the reactor and stirred for 2 hours at 100 °C to obtain a reaction mass. The reaction mass was cooled to 20 °C and 14.25 g of 2,6-diethyl-4-methyl bromo benzene (95.5 % ) (obtained in step (i)) and 1 gm of 1,1’-[Bis(diphenylphosphino)-ferrocene] dichloro Palladium (II) were added to the reaction mass followed by heating and stirring at 145 °C for 12 hours to get 2,6-Diethyl-4-methyl-phenyl-malononitrile conversion to 83 %.
Vacuum distillation of 2,6-Diethyl-4-methyl-phenyl-malononitrile to remove palladium
174 g of 2,6-diethyl-4-methyl-phenyl-malononitrile having 1248 ppm palladium was mixed with 1 mol % of butylated hydroxyl toluene (used as stabilizer) to obtain a mixture. The mixture was vacuum distilled at a temperature of 140 to 150 °C under a vapor pressure in the range of 1 to 2 mm Hg to obtain a palladium free 2,6-Diethyl-4-methyl-phenyl-malononitrile.
The distilled product was 95 wt % of the input and the palladium content was found to be less than 1 ppm. The distillation residue had all palladium as analyzed by ICP-MS. Hence, the vacuum distillation of crude 2,6-diethyl-4-methyl-phenyl malononitrile was made free of palladium.
Step (iii) Preparation of 2,6-Diethyl-4-methyl-phenyl-malonamide
Example – 3A
531.2 g of palladium free 2,6-Diethyl-4-methyl-phenyl-malononitrile obtained in step (ii) was added to a cold solution of 1750 g of 98 % sulphuric acid and 113 g water to obtain a mixture and the mixture was heated to 50 °C for 3 hours to obtain a reaction mixture. The reaction mixture was drowned in a crushed ice to obtain slurry comprising 2,6-Diethyl-4-methyl-phenyl-malonamide. The slurry was filtered and dried to obtain 2,6-Diethyl-4-methyl-phenyl-malonamide (95 % yield with 99 % purity).
EXPERIMENT 2: Preparation of 1,4,5 –hexahydro oxadiazepine hydrochloride from hydrazine and diethylene glycol
Step-I: - Synthesis of N, N’-diacetylhydrazine.
In a reactor, aqueous hydrazine (1255 g, 20 mole) was added to ethyl acetate (1936 g, 22 mole) under continuous stirring over 5 hours at 27 °C to obtain a mixture and the mixture was further maintained at 27 °C for 4 hours to obtain a clear solution containing mono acetyl hydrazine. Acetic anhydride (2040 g) was added to the so obtained clear solution over 2 hours at 30 °C to obtain a reaction mixture and the reaction mixture was stirred for 4 hours to obtain a slurry containing N,N’-diacetyl hydrazine. Chlorobenzene (200 ml/mole of N,N’-diacetyl hydrazine) was then added to the slurry and the diluted slurry was equilibrated at 30°C for 1 hour to obtain an equilibrated slurry. The equilibrated slurry was cooled to 0 °C under continuous stirring and was filtered to collect solids comprising crude N, N’-diacetylhydrazine and a first filtrate. The crude N, N’-diacetylhydrazine was washed with chilled monochlorobenzene (MCB) to obtain a residue and MCB wash. The residue was dried to obtain N, N’-diacetylhydrazine [Yield=1850 gm; purity (GLC) = 99.2%].
Step-II: - Synthesis of 2,2’-dichlorodiethyl ether
Diethylene glycol (530 g, 5 mole) was mixed with 1,2-dichloroethane (1000 ml, 200 ml/mole of DEG) followed by mixing dimethyl formamide (10 ml) to obtain a clear solution. The clear solution was heated to 70 °C to obtain a heated solution. Thionyl chloride (1190 g, or 2 mole of thionyl chloride per mole of diethylene glycol) was slowly added into the heated solution, over 10 hours to obtain a mixture and the mixture was maintained at 70 °C for 4 hours to obtain a reaction mixture comprising 2,2’-dichlorodiethyl ether. Sodium carbonate (25 g) was added to the reaction mixture under continuous stirring to obtain a slurry. The slurry comprising 2,2’-dichlorodiethyl ether was subjected to distillation to collect a fraction at 75 °C and at 40 mm Hg that contained 2,2’-dichlorodiethyl ether [Yield=602 gm (83%); purity (GLC)=98.5%].
Step-III: - Preparation of 4,5-diacetyl-hexhydro-1,4,5-oxadiazepine
Example III A: N, N’ diacetylhydrazine (292 g, 2.5 mole) was mixed with DMSO (3000 g/1200 g, mole) under continuous stirring in a reactor to obtain a clear solution. Potassium carbonate (690 g, 5 mole) and 2,2’-dichlorodiethyl ether (450 g, 3 mole) were added to the clear solution under continuous stirring to obtain a slurry. A mixture of tetrabutyl ammonium bromide (2 mole%) and potassium iodide (2 mole%) was added to the slurry to obtain a resultant mixture and the resultant mixture was heated to 75 °C to obtain a heated mixture. Potassium hydroxide (335 g, 5 mole) was added in portions to the heated mixture at 75 °C over 4 hours to obtain a slurry containing diacetyl oxadiazepine. After completion of the reaction, the heated mixture was cooled to 20 °C under continuous stirring for 1 hour to obtain a cooled product mixture. The cooled product mixture was filtered to obtain solids of diacetyl oxadiazepine and a filtrate. The solids of diacetyl oxadiazepine were washed with DMSO and dried. The filtrate and the DMSO wash were distilled at 130 °C under a reduced pressure of 5mm of Hg to obtain a concentrated mass of 4,5-diacetyl-1,4,5–hexahydro oxadiazepine [Yield=479 g].
Example III B: N,N’-Diacetylhydrazine (698 g, 6 moles) & 2,2’-dichlorodiethyl ether (948 g, 6.6 moles) were dissolved in 3 litres of DMF by heating to 75°C under stirring in a reactor. In another reactor charged 3 litres of DMF with potassium carbonate (1.656 kg, 12 moles), 20 g of TBAB (0.12 mole) & 38.6 g of potassium iodide (0.12 mole). This was heated to 100-105°C & distilled 180 ml of distillate under vacuum. Added the clear solution of N,N’-diacetylhydrazine and Dichlorodiethyl ether in DMF in 17 hours at 95-100°C/vacuum with simultaneous distillation. After completion of the reaction the reaction mass was cooled to 25°C and filtered the slurry. The cake was washed with DMF. The filtrate and wash was concentrated to get 1.137 kg of concentrated mass of diacetyl-hexahydro-oxadiazepine with GLC purity = 88%.
Step-IV: - Preparation of 1,4,5 –hexahydro-oxadiazepine hydrochloride.
The concentrated mass of 4,5-Diacetyl-1,4,5–hexahydro oxadiazepine (240 g, 1.25 mole) obtained in Example III A was mixed in diethylene glycol (312 ml, 250 ml, mole of 4,5-diacetyl-1,4,5-hexahydro-oxadiazepine) to form a slurry. The slurry was heated to 45 °C and dry HCl gas (3.5 mole, mole) was passed into the slurry at 45 °C for 12 hours, and was further maintained at 55 °C for 16 hours to obtain a product mixture. The product mixture was cooled to 0 °C followed by filteration to obtain a crude oxadiazepine hydrochloride salt. The crude oxadiazepine.HCl salt was suspended in 1 ml of isopropyl alcohol per gm of oxadiazepine.HCl, at 0 °C for 1 hour to obtain oxadiazepine slurry. The oxadiazepine slurry was filtered followed by drying under reduced pressure at 55°C to obtain 1,4,5-hexahydro oxadiazepine hydrochloride [Yield=85gm; yield on purity starting from N,N’-diacetyl hydrazine = 38%]
EXPERIMENT 3: Preparation of Pinoxaden
Step (iv) Preparation of palladium free pyrazole-oxadiazepine
Palladium free pyrazole-oxadiazepine was prepared by reacting palladium free 2,6-Diethyl-4-methyl-phenyl-malonamide obtained in step (iii) of experiment 1 (example 3A) and 1,4,5 –hexahydro oxadiazepine hydrochloride obtained in step (IV) of experiment 2.
Example - 4A
24.8 g 2,6-Diethyl-4-methyl-phenyl-malonamide obtained in step (iii) of experiment 1 in 300 ml o-xylene was added to a reactor followed by adding 20.5 g 1,4,5 –hexahydro oxadiazepine hydrochloride obtained in step (IV) of experiment 2 to obtain a reaction mixture. 11 g of Na2CO3 was added to the reaction mixture and refluxed at 145 °C for 10 hours to obtain a palladium free pyrazole-oxadiazepine (72 % yield with 99 % purity).
Example - 4B
249.5 g 2,6-Diethyl-4-methyl-phenyl-malonamide obtained in step (iii) of experiment 1 in 1500 ml o-xylene was added to a reactor followed by adding 209 g 1,4,5 –hexahydro oxadiazepine hydrochloride obtained in step (IV) of experiment 2 to obtain a reaction mixture. The reaction mixture was heated at 55 °C and the pressure was reduced to distill off moisture. 254 g of triethyl amine was added to the moisture free reaction mixture and refluxed at 145 °C for 2 hours to obtain a palladium free pyrazole-oxadiazepine (91.8 % yield with 98.7 % purity).
Example - 4C
2567 g 2,6-Diethyl-4-methyl-phenyl-malonamide in 16000 ml o-xylene was added to a reactor followed by adding 1504 g 1,4,5–hexahydro oxadiazepine di-hydrochloride to obtain a reaction mixture. The reaction mixture was heated at 55 °C and the pressure was reduced to distill off moisture. 2570 g of triethyl amine was added to the moisture free reaction mixture and refluxed at 150 °C for 4 hours to obtain a palladium free pyrazole-oxadiazepine (95 % yield with 98.7 % purity).
Step (v) Pinoxaden preparation
Example - 5A
1000 ml o-xylene was added to 80 g of pyrazole-oxadiazepine which was further mixed with 30 g sodium carbonate to obtain a reaction mass. The reaction mass was cooled to 5 °C to obtain a cooled mass. 32 g pivaloyl chloride was added to the cooled mass for 2 hours and stirred for 8 hours to obtain Pinoxaden (95 % yield with 97 % purity). The Pinoxaden obtained was having palladium content less than 1 ppm.
Preparation of Pinoxaden from 2,6-Diethyl-4-methyl-phenyl-malonamide without isolating pyrazole-oxadiazepine
1925 g 2,6-Diethyl-4-methyl-phenyl-malonamide in 12150 ml o-xylene was added to a reactor followed by adding 1128 g 1,4,5–hexahydro oxadiazepine hydrochloride to obtain a reaction mixture. The reaction mixture was heated at 55 °C under reduced pressure to distill off moisture. 2570 g of triethyl amine was added to the moisture free reaction mixture and refluxed at 150 °C for 4 hours to obtain a mixture containing pyrazole-oxadiazepine. The mixture was cooled to 5 °C and 962 g of pivaloyl chloride was added to it and stirred continuously to obtain a mass. The mass was acidified to pH 1 and filtered at 10 °C to obtain Pinoxaden (90 % yield with 98 % purity). The Pinoxaden obtained was having palladium content less than 1 ppm.
TECHNICAL ADVANCEMENTS
The present disclosure described herein above has several technical advantages including, but not limited to, the realization of;
- a simple and environmental friendly process for the preparation of Pinoxaden; and
- provides Pinoxaden having a comparatively high purity and in high yields.
The embodiments herein and the various features and advantageous details thereof are explained with reference to the non-limiting embodiments in the following description. Descriptions of well-known components and processing techniques are omitted so as to not unnecessarily obscure the embodiments herein. The examples used herein are intended merely to facilitate an understanding of ways in which the embodiments herein may be practiced and to further enable those of skill in the art to practice the embodiments herein. Accordingly, the examples should not be construed as limiting the scope of the embodiments herein.
The foregoing description of the specific embodiments so fully reveal 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.
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 Pinoxaden, said process comprising the following steps:
(i) preparing 2,6-diethyl-4-methyl bromo benzene by;
a. reacting 2,6-diethyl-4-methyl-aniline (DEMA) with NaNO2 in a first fluid medium at a first predetermined temperature for a first predetermined time period to obtain a reaction mixture; and
b. passing HBr to said reaction mixture at a second predetermined temperature for a second predetermined time period followed by raising the temperature and maintaining at a temperature in the range of 30 °C to 50 °C for a time period in the range of 3 hours to 6 hours to obtain 2,6-diethyl-4-methyl bromo benzene;
(ii) preparing palladium free 2,6-Diethyl-4-methyl-phenyl-malononitrile from 2,6-diethyl-4-methyl bromo benzene by;
a. separately dissolving malononitrile in a second fluid medium along with t-butanol and sodium hydride at a temperature in the range of 80 °C to 120 °C under stirring for a time period in the range of 1 hour to 5 hours to obtain a reaction mass followed by cooling the reaction mass to a temperature in the range of 15 °C to 25 °C to obtain a cooled reaction mass;
b. adding 2,6-diethyl-4-methyl bromo benzene and a palladium catalyst to said cooled reaction mass, wherein 2,6-diethyl-4-methyl bromo benzene is reacted with malononitrile at a third predetermined temperature for a third predetermined time period to obtain a product mass comprising 2,6-Diethyl-4-methyl-phenyl-malononitrile; and
c. subjecting the so obtained product mass comprising 2,6-Diethyl-4-methyl-phenyl-malononitrile to vacuum distillation to obtain a palladium free 2,6-Diethyl-4-methyl-phenyl-malononitrile;
(iii) reacting said palladium free 2,6-Diethyl-4-methyl-phenyl-malononitrile with sulfuric acid at a fourth predetermined temperature for a fourth predetermined time period to obtain 2,6-Diethyl-4-methyl-phenyl-malonamide;
(iv) reacting 2,6-Diethyl-4-methyl-phenyl-malonamide with 1,4,5-hexahydro-oxadiazepine in a third fluid medium by using a first base at a fifth predetermined temperature for a fifth predetermined time period to obtain 8-(2,6-Diethyl-4-methylphenyl)-1,2,4,5-tetrahydro-9-hydroxy-7H-pyrazolo[1,2-d][1,4,5]oxadiazepin-7-one (pyrazole-oxadiazepine); and
(v) reacting said pyrazole-oxadiazepine with pivaloyl chloride in a fourth fluid medium by using a second base at a sixth predetermined temperature for a sixth predetermined time period to obtain Pinoxaden.
2. The process as claimed in claim 1, wherein said first fluid medium is selected from aqueous HBr, aqueous PTSA (p-Toluenesulfonic acid), t-butanol and a mixture thereof.
3. The process as claimed in claim 1, wherein said first predetermined time period is in the range of 1 hour to 4 hours and said first predetermined temperature is in the range of -10 °C to 15 °C.
4. The process as claimed in claim 1, wherein said second predetermined time period is in the range of 0.5 hour to 6 hours and said second predetermined temperature is in the range of 0 °C to 20 °C.
5. The process as claimed in claim 1, wherein said vacuum distillation in step (ii) is carried out at a temperature in the range of 120 ºC to160 ºC and at a vapor pressure in the range of 1 to 4 mm Hg pressure to obtain said palladium free 2,6-Diethyl-4-methyl-phenyl-malononitrile.
6. The process as claimed in claim 5, wherein a stabilizer is added during said vacuum distillation.
7. The process as claimed in claim 6, wherein said stabilizer is butylated hydroxyl toluene (BHT).
8. The process as claimed in claim 1, wherein said second fluid medium, said third fluid medium and said fourth fluid medium is o-xylene.
9. The process as claimed in claim 1, wherein said palladium catalyst is selected from palladium dichloride, bis(triphenylphosphine)palladium(II) dichloride, tetrakis(triphenylphosphine)palladium and 1,1'-Bis(diphenylphosphino)ferrocene] dichloropalladium(II).
10. The process as claimed in claim 1, wherein said third predetermined temperature is in the range of 80 °C to 160 °C and said third predetermined time period is in the range of 1 hour to 14 hours.
11. The process as claimed in claim 1, wherein said fourth predetermined temperature is in the range of 40 °C to 80 °C and said fourth predetermined time period is in the range of 1 hour to 10 hours.
12. The process as claimed in claim 1, wherein 1,4,5-hexahydro-oxadiazepine used in step (iv) is in any form selected from free base, mono-hydrochloride salt, di-hydrochloride salt and a mixture thereof.
13. The process as claimed in claim 1, wherein said first base and said second base is independently selected from sodium carbonate, potassium carbonate and triethyl amine
14. The process as claimed in claim 1, wherein said fifth predetermined temperature is in the range of 100 °C to 160 °C and said fifth predetermined time period is in the range of 1 hour to 12 hours.
15. The process as claimed in claim 1, wherein said sixth predetermined temperature is in the range of 0 °C to 10 °C and said sixth predetermined time period is in the range of 1 hour to 5 hours.
16. A process for preparing 1,4,5-hexahydro-oxadiazepine hydrochloride, said process comprising the following steps:
a. acetylating hydrazine, by adding hydrazine to ethyl acetate under stirring, at a temperature in the range of 25 °C to 35 °C to obtain a mono acetyl hydrazine;
b. further acetylating said mono acetyl hydrazine, by slowly adding acetic anhydride to said mono acetyl hydrazine, at a temperature in the range of 25 °C to 35 °C to obtain N,N’-diacetylhydrazine;
c. separately, chlorinating diethylene glycol by using a chlorinating agent, in the presence of a catalyst in a halogenated fluid medium, at a temperature in the range of 50 °C to 90 °C to obtain 2,2’-dichlorodiethyl ether;
d. reacting 2,2’ dichlorodiethyl ether with N,N’-diacetylhydrazine by using a base in the presence of a phase transfer catalyst and a nucleophilic catalyst in a fluid medium to obtain 4,5-diacetyl-hexahydro-1,4,5-oxadiazepine; and
e. treating 4,5-diacetyl-hexahydro-1,4,5-oxadiazepine with a salt forming agent to obtain 1,4,5-hexahydro oxadiazepine hydrochloride.
17. The process as claimed in claim 16, wherein a molar ratio of the hydrazine to the ethyl acetate is in the range of 1:1 to 1:1.2, and a molar ratio of the hydrazine to the acetic anhydride is in the range of 1:0.95 to 1:1.05.
18. The process as claimed in claim 16, wherein said halogenated fluid medium is selected from ethylene dichloride (EDC), monochlorobenzene (MCB), and dichloromethane (DMC).
19. The process as claimed in claim 16, wherein said catalyst is selected from dimethylformamide (DMF) and pyridine, and wherein said catalyst is in an amount in the range of 2.5 mole% to 5 mole%, with respect to the amount of said diethylene glycol
20. The process as claimed in claim 16, wherein a molar ratio of said diethylene glycol to said chlorinating agent is in the range of 1:2 to 1:2.1.
21. The process as claimed in claim 16, wherein said chlorinating agent is thionyl chloride (SOCl2).
22. The process as claimed in claim 19, wherein said fluid medium is selected from dimethyl sulphoxide (DMSO) and dimethyl formamide (DMF).
23. The process as claimed in claim 16, wherein said phase transfer catalyst is tetrabutyl ammonium bromide in an amount in the range of 1 mole% to 5 mole% with respect to the amount of N,N’-diacetylhydrazine.
24. The process as claimed in claim 16, wherein said base is selected from sodium carbonate (Na2CO3), and potassium carbonate (K2CO3).
25. The process as claimed in claim 16, wherein said nucleophillic catalyst is potassium Iodide (KI) in an amount in the range of 1 mole% to 5 mole% with respect to the amount of N,N’-diacetylhydrazine.
26. The process as claimed in claim 16, wherein said salt forming agent is hydrogen chloride (HCl).
Dated this 11th day of October, 2021

_______________________________
MOHAN RAJKUMAR DEWAN, IN/PA – 25
of R.K.DEWAN & CO.
Authorized Agent of Applicant

TO,
THE CONTROLLER OF PATENTS
THE PATENT OFFICE, AT MUMBAI