WO2020240392A1

WO2020240392A1 - Process for preparation of pyroxasulfone

Info

Publication number: WO2020240392A1
Application number: PCT/IB2020/054914
Authority: WO
Inventors: Anuj Kumar Mittal; Maneesh Kumar Sharma; Abhishek Jain; Mitthu Lal GURJAR; Sumit Srivastava; KVS Ram Rao; Venkata Srinivas Pullela; Bhavik Satish SHAH
Original assignee: Pi Industries Limited
Priority date: 2019-05-24
Filing date: 2020-05-23
Publication date: 2020-12-03

Abstract

The present invention discloses a process for the preparation of Pyroxasulfone of Formula (I) or salt thereof. Particularly, the present invention discloses an improved process for the preparation of hydroxycarbonimidic dibromide compound of Formula (III) or salt thereof, wherein bromine anion is recycled by using a suitable oxidizing agent. Moreover, the present invention relates to a continuous flow process for preparing of compound of Formula (I) or salt thereof.

Description

PROCESS FOR PREPARATION OF

PYROXASULFONE FIELD OF THE INVENTION: The present invention relates to a process for the preparation of Pyroxasulfone of Formula (I) or salt thereof. Particularly, the present invention relates to an improved process for the preparation of hydroxycarbonimidicdibromide, compound of Formula (III) or salt thereof, wherein bromide anion is recycled by using a suitable oxidizing agent.Moreover, the present invention relates to a continuous flow process for preparing of compound of Formula (I) or salt thereof.

BACKGROUND OF THE INVENTION: Pyroxasulfone belongs to isoxazoline class of herbicides, which inhibits fatty acid synthesis. Pyroxasulfone herbicide is classified in Group 15 of WSSA. It is chemically known as 3-[5- (difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-ylmethylsulfonyl]-4,5- dihydro-5,5-dimethylisoxazole, compound of Formula (I) and represent as:

Pyroxasulfone or salt thereof is disclosed in U.S. Patent No. 7,238,689, which is assigned to Ihara Chemical Industry Co. Ltd. Dibromo formimine of formula (III) is a key building block for the preparation of compound of formula (III), is disclosed in U.S. Patent No.6,207,863. The presently know methods for preparing hydroxycarbonimidicdibromide, compound of Formula (III)or salt thereof generate significant levels of effluent as by-products such as sodium bromide and hydrogen bromide, which impacts on product yield as well as cost. Therefore, there is a need to develop an effective process for the preparation of compound of Formula (I) or its intermediate hydroxycarbonimidicdibromide, compound of Formula (III) or salt thereof, wherein by-products can be recycled to reduce effluent and improvement in the yield, without impacting purity of hydroxycarbonimidicdibromide. SUMMARY OF THE INVENTION: The present invention provides an improved process for the preparation of Pyroxasulfone of Formula (I) or salt thereof;

wherein, the process comprising the steps of:

a) reacting glyoxalic acid with hydroxy amine sulphate to obtain 2-(hydroxyimino)acetic acid compound of Formula (II)or salt thereof, in a suitable solvent at a suitable pH;

b) reacting 2-(hydroxyimino)acetic acid with bromine in a suitable solvent at a suitable pH; c) recycling of bromine anion by addition of a suitable oxidizing agent;

d) optionally, isolating the compound of Formula (III) or salt thereof;

e) convertingthe compound of Formula (III) or salt thereof, to Pyroxasulfone of Formula (I) or salt thereof. Yet another objective of the present invention is to provide a continuous flow process for preparing the compound of Formula (I) or salt thereof by compound of Formula V (1- methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol)

as a starting material and with intermediates thereof of Formula VI, Formula VII, Formula VIII, or Formula X. A further objective of the present invention is to provide a continuous flow process for preparing the compound of Formula IX (5,5-dimethyl-4,5-dihydroisoxazol-3-yl carbamimidothioate)

by a multistep process using glyoxalic acid as a starting material and preparation of intermediate thereof. The present invention relates to a new method for the preparation of compound of Formula (I) or salt thereof said method comprises an integrated continuous flow process for reactions wherein a succession of integrated flow reactors are used to perform a series of reaction steps to yield the final product. In one aspect the process is a multistep synthesis of compound of Formula (I) or salt thereof in a continuous flow without isolation of intermediates produced during the flow. The purity of Pyroxasulfoneof Formula (I) or salt thereof obtained according to the present invention is more than 99 %, measured by HPLC. DETAILED DESCRIPTION OF THE INVENTION: DEFINITIONS: The foregoing definitions provided herein for the terminologies used in the present disclosure are for illustrative purpose only and in no manner limit the scope of the present invention disclosed in the present disclosure. As used herein, the terms "comprises", "comprising", "includes", "including",“consisting” or any other variation thereof, are intended to cover a non-exclusive inclusion, subject to any limitation explicitly indicated. For example, a process or method that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such process or method. Further, unless expressly stated to the contrary, "or" refers to an inclusive“or” and not to an exclusive“or”. For example, a condition A“or” B is satisfied by any one of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B is true (or present). Also, the indefinite articles "a" and "an" preceding an element or component of the present invention are intended to be nonrestrictive regarding the number of instances (i.e. occurrences) of the element or component. Therefore "a" or "an" should be read to include one or at least one, and the singular word form of the element or component also includes the plural unless the number is obviously meant to be singular. All amounts are percent by weight (“% wt”), unless otherwise noted. All ranges are inclusive. As used throughout the specification, the following abbreviations are applied: g=gram; and °C = Centigrade. The numerical values mentioned in the description and the foregoing claims though might form a critical part of the present invention of the present disclosure, any deviation from such numerical values shall still fall within the scope of the present disclosure if that deviation follows the same scientific principle as that of the present invention disclosed in the present disclosure. The present invention is directed to an improved process for the preparation of Pyroxasulfone of Formula (I) or salt thereof;

wherein, the process comprising the steps of:

a) reacting glyoxalic acid with hydroxy amine sulphate to obtain 2-(hydroxyimino)acetic acid (Formula II) or salt thereof, in a suitable solvent at a suitable pH;

b) reacting 2-(hydroxyimino)acetic acid with bromine in a suitable solvent at a suitable pH;

c) recycling of bromine anion by addition of a suitable oxidizing agent;

d) optionally, isolating the compound of Formula (III) or salt thereof;

e) converting the compound of Formula (III) or salt thereof, to Pyroxasulfone of Formula (I) or salt thereof. The step (a) and (b) comprising reacting glyoxalic acid with hydroxy amine sulphate to obtain 2-(hydroxyimino)acetic acid compound of Formula (II) or salt thereof,in a suitable solvent at a suitable pH,followed by reacting with bromine in a suitable solvent at a suitable pH, wherein the suitable solvent is a polar solvent and suitable pH is in the range of about 8 to 14, preferably in the range of about 10 to 14. The bromination reaction is carried out at temperature of about 5°C to 35°C. The amount of bromine used is in the range of about 0.25 to 3 mole equivalents, based on the amount of 2-(hydroxyimino)acetic acid or salt thereof, preferably the amount of bromine is in the range of about 0.25 to 2.0 mole equivalents. The step (c) comprises recycling bromine anionby addition of a suitableoxidizing agent, wherein the oxidizing agent is selected from the group comprising of fluorine; chlorine; hydrogen peroxide; nitric acid or nitrate compounds; sulfuric acid; peroxydisulfuric acid; peroxymonosulfuric acid; chlorite, chlorate, perchlorate and other analogus of halogen compounds; hypochlorite and other hypohalite compounds such as sodium hypochlorite; hexavalent chromium compounds such as chromic and dichromic acids, chromium trioxide, pyridinium chlorochromate, chromate/dichromate compounds; permanganate compounds such as potassium permanganate; sodium perborate; nitrous oxide, nitrogen dioxide, dinitrogen tetroxide; potassium nitrate; sodium bismuthate and mixture thereof. The addition of a suitable oxidizing agentin the reaction mixture is carried out at temperature of about 5°C to 35°C. The step (d) optionally comprises the isolation of the compound of Formula (III) or salt thereof, wherein the isolation may be carried out by any conventional method, such as by filtration or solvent extraction. After the completion of the reaction, traces of bromine were decomposed by the addition of a solution of sodium sulphite to the reaction mixture. The step (e) comprises the conversion of compound of Formula (III) or salt thereof to Pyroxasulfone or salt thereofby process as described in U.S. Patent No.7,238,689. In an embodiment of the present invention, there is provided an integrated, continuous flow method for the preparation of compound of Formula (I) or salt thereof

comprising the steps of

A. reacting a compound of Formula V (1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol)

with formaldehyde in presence of a base to obtain a compound of Formula VI (4- (hydroxymethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-olate) or salt thereof;

B. reacting the compound of Formula VI or salt thereof with chlorodifluoromethane in a suitable solvent in presence of a base to obtain a compound of Formula VII (5- (difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methanol;

C. reacting the compound of Formula VII (5-(difluoromethoxy)-1-methyl-3- (trifluoromethyl)-1H-pyrazol-4-yl)methanol) with chlorinating agent to obtain a compound of Formula VIII (3-(((5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H- pyrazol-4-yl)methyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole)

D. reacting the compound of Formula VIII (4-(chloromethyl)-5-(difluoromethoxy)-1-methyl- 3-(trifluoromethyl)-1H-pyrazole) with 5,5-dimethyl-4,5-dihydroisoxazol-3-yl carbamimidothioate (Formula IX)

to obtain a compound of Formula X (3-(((5-(difluoromethoxy)-1-methyl-3- (trifluoromethyl)-1H- pyrazol-4-yl)methyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole)

E. reacting the compound of Formula X (3-(((5-(difluoromethoxy)-1-methyl-3- (trifluoromethyl)-1H-pyrazol-4-yl)methyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole) with sodium tungstate and a reducing agent to obtain the compound of Formula (I) or salt thereof,

wherein said process is performed using continuous flow reaction conditions. An aspect of the present invention provides an integrated, continuous flow method for step A. for the preparation of 4-(hydroxymethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-olate preferably potassium 4-(hydroxymethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-olate (Formula VI) by reacting with a solution of formaldehyde, a base preferably potassium hydroxide in a suitable solvent preferably a polar solvent, and 1-methyl-3-(trifluoromethyl)- 1H-pyrazol-5-ol (Formula V). The residence time of the mixture in the reactor is typically anywhere between 30 seconds and 20 minutes, preferably about 30 seconds to 05 minutes, and more preferably about 01 minute depending on the temperature. The temperature in the reactor is typically anywhere between 10°C and 100°C, preferably between 20°C and 80°C and even more preferably between 20°C and 50°C, specifically 40°C.

Optionally, all flow reactors may be connected with batch equipment to get the right purity before introducing the flow in the next following continuous reaction step. In another aspect of the present invention, an integrated continuous flow method is provided for step B. for the preparation of (5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H- pyrazol-4-yl)methanol (Formula VII) by reacting with potassium salt of 4-(hydroxymethyl)- 1-methyl-3-(trifluoromethyl)-1H- pyrazol-5-olate (Formula VI) with chlorodifluoromethane in a suitable solvent (preferably chlorinated solvent or polar aprotic solvent) in the presence of a base. The residence time of the mixture in the reactor is typically anywhere between 30 seconds and 20 minutes, preferably about 30 seconds to 05 minutes, and more preferably about 05 minutes depending on the temperature. The temperature in the reactor is typically anywhere between 10°C and 100°C, preferably between 20°C and 80°C and even more preferably between 20°C and 50°C, specifically 25°C.

In a further aspect of the present invention, an integrated continuous flow method is provided for step C. for the preparation of 4-(chloromethyl)-5-(difluoromethoxy)-1-methyl-3- (trifluoromethyl)-1H-pyrazole (Formula VIII) by reacting with a chlorinating agent selected from thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, dichlorosuccinimide, calcium hypochlorite, sodium chlorite, carbon tetrachloride, hydrochloric acid or chlorine preferably thionyl chloride and (5-(difluoromethoxy)-1-methyl- 3-(trifluoromethyl)-1H-pyrazol-4-yl)methanol (Formula VII). The residence time of the mixture in the reactor is typically anywhere between 30 seconds and 20 minutes, preferably about 30 seconds to 05 minutes, and more preferably about 02 minutes depending on the temperature. The temperature in the reactor is typically anywhere between 10°C and 100°C, preferably between 20°C and 80°C and even more preferably between 20°C and 50°C, specifically 20°C.

In yet another aspect of the present invention, an integrated, continuous flow method is provided for step D. for the preparation of compound of Formula X (3-(((5- (difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)thio)-5,5-dimethyl- 4,5-dihydroisoxazole) by reacting with a solution of 5,5-dimethyl-4,5-dihydroisoxazol-3-yl carbamimidothioate (Formula IX) and 4-(chloromethyl)-5-(difluoromethoxy)-1-methyl-3- (trifluoromethyl)-1H-pyrazole (Formula VIII) in presence of a base preferably sodium hydroxide and a suitable solvent preferably polar protic solvent. The residence time of the mixture in the reactor is typically anywhere between 30 seconds and 20 minutes, preferably about 30 seconds to 05 minutes, and more preferably about 05 minutes depending on the temperature. The temperature in the reactor is typically anywhere between 10°C and 100°C, preferably 100°C.

Suitable solvent refers to polar protic or polar aprotic or non-polar solvent, preferably selected from the group comprising of, acetonitrile, water, alcohol or chlorinated solvents or a mixture thereof, wherein alcohol is selected from tert-amyl alcohol, benzyl alcohol, 1,4- butanediol, 1,2,4-butanetriol, n-butanol, 2-butanol, tert-butyl alcohol, denatured alcohol, di(propylene glycol) methyl ether, diethylene glycol, ethanol, ethylene glycol, 2- ethylhexanol, furfuryl alcohol, methanol,2-(2-methoxyethoxy)ethanol, 2-methyl-1-butanol, 2-methyl-1-pentanol, neopentyl alcohol, 2-pentanol, 1,3 propanediol, n-proponol, and propylene glycol; chlorinated solvent is selected from carbon tetrachloride, dichloromethane, chloroform, methyl chloride, chloroethane, hexachloroethane, pentachloroethane, 1,1,1,2- tetrachloroethane, 1,1,2,2-tetrachloroethane, 1,1,2-trichloroethane, 1,1,1-trichloroethane, 1,2- dichloroethane, 1,1-dichloroethane, chloroethane, tetrachloroethene, trichloroethylene, 1,2- dichloroethene, and 1,1-dichloroethene. It is preferred that the solvent is a polar solvent such as water. Other solvent that can also employ in the present invention is selected from the group the comprising of, bromoform, carbon tetrabromide, ethylene dibromide, toluene, xylene, benzotrifluorideor a mixture thereof. pH of the reaction mixture may be maintained by using a suitable base, wherein the base is selected from organic base or inorganic base. Organic base is selected from the group comprising of, but not limited to, alkyl ammonium hydroxide such as tetramethyl ammonium hydroxide, tetraethyl ammonium hydroxide, tetrapropyl ammonium hydroxide, tetrabutyl ammonium hydroxide, trimethyl-2-hydroxyethyl ammonium hydroxide (Choline), triethyl-2-hydroxy ethyl ammonium hydroxide, ethyltrimethyl ammonium hydroxide; alkyl amine such as trimethylamine, triethylamine, tributylamine, tripentylamine, monoethanolamine, diethylamine; pyridine, 4- dimethylaminopyridine, 2,4-lutidine, 2,6-lutidine, collidine, alpha-picoline, beta-picoline, gamma.-picoline, quinoline, isoquinoline, aniline, diemthylaniline, N, N-dimethylaniline, diethylaniline, benzidine, acetanilide, toluidine, and mixtures thereof. Inorganic base is selected from the group comprising of, but not limited to, alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, bisulfates, acetate, methoxide, ethoxide, phosphate, sulfite, sulfate preferably selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium bisulfate, potassium bisulfate, sodium acetate, potassium acetate, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, trisodium phosphate, tripotassium phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, sodium hydrogen sulfide, sodium sulfate, and mixtures thereof. Preferably, the base is selected from triethylamine, pyridine, potassium hydroxide, sodium hydroxide, and sodium carbonate. In a further aspect of the present invention, an integrated continuous flow method is provided for step E. for the preparation of compound of Formula I or salt thereof by reacting with sodium tungstate, and a oxidizing agent preferably hydrogen peroxide, and 3-(((5- (difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)thio)-5,5-dimethyl- 4,5-dihydroisoxazole (Formula IX). The residence time of the mixture in the reactor is typically anywhere between 30 seconds and 20 minutes, preferably about 30 seconds to 05 minutes, and more preferably about 10 minutes depending on the temperature. The temperature in the reactor is typically anywhere between 10°C and 100°C, preferably 100°C.

The purity of Pyroxasulfone or salt thereof of Formula (I) obtained according to the present invention process is more than 95%, measured by HPLC. All the reactions in steps A. to E. as described above are performed in flow reactors connected to each other in such a way to provide an integrated system. There are many configurations of such connected reactor system, that a person skilled in the art is aware of. The oxidizing agent refers to a reactant that removes electrons from other reactants during a redox reaction. Suitable oxidizing agent is selected from but not limited to, hydrogen peroxide or metachloroperbenzoic acid preferablyhydrogen peroxide. In an embodiment, provided herein the compound of Formula I, Formula VI, Formula VII, Formula VIII, or Formula X having HPLC purity of at least 95% is obtained by the process as described above. The improved process as disclosed in the present invention is used to prepare Pyroxasulfone of Formula (I) by reacting glyoxalic acid with hydroxy amine sulphate to obtain 2- (hydroxyimino)acetic acid of Formula (II) or salt thereof, in the presence of an organic base or inorganic baseto maintain the pH of the reaction mixture. The reaction mixture was further reacted with bromine in a suitable solvent at a suitable pH and recycling of bromine anionis carried out by addition of a suitable oxidizing agent such as chlorine to obtainhydroxycarbonimidic dibromide compound of Formula (III). Hydroxycarbonimidicdibromide is reacted with isobutylene gas in the presence of a suitable base at a suitable pH to produce compound of Formula (IV) as shown below, which is further utilized in the preparation of Pyroxasulfone of Formula (I) or salt thereof as described in U.S. Patent No.7,238,689.

In a further aspect of the present invention, 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol (Formula V) is one of the important starting material useful for the synthesis of compounds of Formula I, Formula VI, Formula VII, Formula VIII, or Formula X or agrochemically acceptable salt thereof.

Translating reactions into continuous-flow system is aiding more efficient, safer, and automated reactions. The ability of continuous-flow system to rapidly heat and cool reactions, micromix solutions, and improve reaction homogeneity affords opportunities to explore novel transformations while being environmentally conscious and creative. The injected fluid flows into reactor coils where the specific transformation is subjected to a range of conditions. For example, the fluid entering the reactor coil can be rapidly heated or cooled to mediate an effective transformation. In the context of the present invention, the term“without isolation” means that the product referred is not isolated as a solid, for example it is not isolated from the reaction mass and dried to form a solid. Thus,“without isolation” may mean that the product remains in solution and is then used directly in the next synthetic step. The residence time of the fluid within the system is determined by the internal diameter and length of the reactor coil. Mixers and unions connect reactor coils together and allow the addition of new reagents to the continuous-flow stream. The solution can be flowed through packed bed reactors to ensure efficient mixing, or to provide exposure to immobilized reagents for synthetic transformations. A continuous-flow system allows the possibility of in-line purification and reagent introduction at set points in the continuous-flow sequence. Another embodiment of the present invention provides a process for the preparation of an intermediate compound of Formula IX (5,5-dimethyl-4,5-dihydroisoxazol-3-yl carbamimidothioate) comprising the steps of:

1) reacting glyoxalic acid with hydroxyamino sulfate in presence of a base and/or a buffering agent to obtain hydroxyimino acetic acid;

2) reacting hydroxyimino acetic acid with chlorinating agent to obtain hydroxycarbodimic dichloride;

3) reacting hydroxycarbodimic dichloride with isobutylene and a base to obtain 3- chloro-5,5-dimethyl-4,5-dihydroisoxazole;

4) reacting 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole with thiourea in acidic medium to obtain 5,5-dimethyl-4,5-dihydroisoxazol-3-yl carbamimidothioate.

wherein said process is performed using continuous flow reaction conditions. The operation temperature in the reactor is typically anywhere between 5°C and 80°C, preferably between 5°C and 40°C more preferably 15°C and 20°C for step 2), preferably between 10°C and 70°C more preferably 40°C for step 3) and preferably between 10°C and 40°C more preferably 25°C and 40°C for step 4). Another aspect of the present invention provides a process for the preparation of an intermediate compound of Formula IX (5,5-dimethyl-4,5-dihydroisoxazol-3-yl carbamimidothioate) by a multistep process, including a process of reacting glyoxalic acid with hydroxyamino sulfate in presence of a base preferably sodium hydroxide and/or buffering agent preferably potassium hydrogen phosphate to obtain hydroxyimino acetic acid and hydroxyimino acetic acid which is further reacted with a chlorinating agent preferably chlorine at a suitable temperature of about 5-40°C preferably about 15-20°C to obtain hydroxycarbodimic dichloride. Hydroxycarbodimic dichloride was reacted with isobutylene and a base preferably potassium carbonate at a suitable temperature of about 10-70°C preferably about 40°C to obtain 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole. 3-chloro-5,5- dimethyl-4,5-dihydroisoxazole was then reacted with thiourea in acidic medium preferably hydrogen bromide or hydrogen chloride at a suitable temperature of about 10 to 40°C preferably about 25°C to 40°C to obtain compound of Formula IX (5,5-dimethyl-4,5- dihydroisoxazol-3-yl carbamimidothioate).

Yet another aspect of the present invention, provides the subsequent conversion of 5,5- dimethyl-4,5-dihydroisoxazol-3-yl carbamimidothioate (Formula IX) to Formula X (3-(((5- (difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)thio)-5,5-dimethyl- 4,5-dihydroisoxazole). The purity of compound of Formula (IX) or salt thereof is more than 95 %, as measured by HPLC. In an embodiment, provided herein is the compound of Formula IX having HPLC purity of at least 95% or atleast 98% obtained by the process as described above. The continuous flow process of the present invention has many advantages over the batch process as follows:- 1. Minimizes handling of intermediates, toxic and corrosive reagents and solvents.

2. Reduces solvent load, minimizes effluents and waste generation.

3. Dramatically reduced reaction times, less down streaming processing and increases process efficiency. The other advantages of this continuous reactor system are:

• The temperature used in each module of the reactor can be adapted at the kinetic rate of reaction.

• Overall reaction time is reduced from about hours to about minutes.

• Avoids the use and handling of toxic reagents.

• Avoids the isolation of intermediates at each stage and tedious workup procedure. • Improve yield and purity. The continuous flow reactions are performed in flow reactors connected to each other in such a way to provide an integrated system. There are many configurations of such connected reactor system, that a person skilled in the art is aware of. The compounds in continuous flow reaction may be prepared according to the following examples. The following examples are presented to illustrate further aspects of the present invention, but are not intended to limit the scope of the invention in any aspect. Examples Example 1:

50% aqueous solution of glyoxylic acid (74.05 g) was slowly added to a solution of 41.05% hydroxylamine sulphate in water at 0-5 °C for 1h. 25% sodium hydroxide (164 g) solution was added to the reaction mixture at 10-15 °C in 1 h. pH was adjusted to 10 to 14 by means of addition of 13% sodium carbonate (100 g). The obtained oxime solution was added to a solution of water (50 g) and liquid bromine (96 g) at 10-15 °C in 1 h. Chlorine gas (36 g) was purged into the reaction mixture at 10-15 °Cfor 4 h. After completion of reaction, a solution of 17% sodium sulphite (50 g) was added to the reaction mixture.n-butyl acetate (176 g) solvent was added. The organic and aqueous layers were separated to obtainhydroxycarbonimidicdibromide.

Yield: 95%

HPLC Purity: 90% Example 2:

50% aqueous solution of glyoxylic acid (74.05 g) was slowly added to a solution of 17.38% hydroxylamine sulphate in water at 0-5 °C for 1h. 25% sodium hydroxide (164 g) solution was added to the reaction mixture at 10-15 °C in 1 h. pH was adjusted to 10 to 14 by means of addition of 13% sodium carbonate (100 g). The obtained oxime solution was added to a solution of water (50 g) and liquid bromine (96 g) at 10-15 °C in 1 h. Chlorine gas (36 g) was purged into the reaction mixture at 10-15 °C for 4 h. After completion of reaction, a solution of 17% sodium sulphite (50 g) was added to the reaction mixture. n-butyl acetate (176 g) solvent was added. The organic and aqueous layers were separated to obtainhydroxycarbonimidicdibromide.

Yield: 96%

HPLC Purity: 92% Example 3:

50% aqueous solution of glyoxylic acid (74.05 g) was slowly added to a solution of 17.38% hydroxylamine sulphate in water at 0-5 °C for 1h. 25% sodium hydroxide (164 g) solution was added to the reaction mixture at 10-15 °C in 1 h. pH was adjusted to 10 to 14 by means of addition of 13% sodium carbonate (100 g).

The obtained oxime solution was added to a solution of water (50 g) and liquid bromine (96 g) at 10-15 °C in 1 h. Chlorine gas (36 g) was purged into the reaction mixture at 10-15 °C for 4 h. After completion of reaction, a solution of 17% sodium sulphite (50 g) was added to the reaction mixture. n-butyl acetate (150 g) solvent was added. The organic and aqueous layers were separated to obtain hydroxycarbonimidicdibromide.

Yield: 94%

HPLC Purity: 89% Example 4:

The obtained oxime solution was added to a solution of water (50 g) and liquid bromine (96 g) at 10-15 °C in 1 h.50% hydrogen peroxide (30 g) was added to the reaction mixture at 10- 15 °C for 4 h. After completion of reaction, a solution of 17% sodium sulphite (50 g) was added to the reaction mixture. n-butyl acetate (176 g) solvent was added. The organic and aqueous layer were separated to obtain hydroxycarbonimidic dibromide.

Yield: 90%

HPLC Purity: 93% Example 5:

To an aqueous stream of 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol (Formula V) and potassium hydroxide (2.5 M in water) were combined through a T-piece with an aqueous stream of formaldehyde solution (12.5 M in water). The resulting reaction stream was directed toward a 40ml flow reactor, with the residence time of 1 min and an operating temperature of 40°C. The resulting potassium 4-(hydroxymethyl)-1-methyl-3- (trifluoromethyl)-1H-pyrazol-5-olate was combined with difluorochloromethane gas in an acetonitrile solution directed towards another flow reactor, with residence time of 5 min and operating room temperature 25°C to yield (5-(difluoromethoxy)-1-methyl-3- (trifluoromethyl)-1H-pyrazol-4-yl)methanol (conversion by HPLC 95%). Example 6:

To an organic stream of (5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4- yl)methanol was combined with thionyl chloride (10M in acetonitrile) in flow reactor with residence time of 2 min and an operating temperature of 20°C to yield 4-(chloromethyl)-5- (difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole (conversion by HPLC > 98%). Example 7:

To an organic stream of 3-(((5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol- 4-yl)methyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole (0.45 M) was combined through a T- piece with an aqueous solution of 5,5-dimethyl-4,5-dihydroisoxazol-3-yl carbamimidothioate (1.0M) with residence time of 5 min and an operating temperature of 100°C in a flow reactor to yield 3-(((5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4- yl)methyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole (conversion by HPLC > 85%). Example 8:

To an organic solution of 3-(((5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol- 4-yl)methyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole and sodium tungstate was combined through a T-mixture with an aqueous solution of hydrogen peroxide with the residence time of 10 min and operating temperature 100°C in flow reactor to yield compound of Formula I. Example 9:

Synthesis of 5,5-dimethyl-4,5-dihydroisoxazol-3-yl carbamimidothioate

To an aqueous solution of hydroxylamine sulfate (2M in water), glyoxalic acid (5M in water) was added at 25-30°C. The reaction mixture was directed towards a 24ml flow reactor, operating at 25-30°C. Sodium hydroxide (7M solution) and potassium hydrogen phosphate (3M solution) were added to the reaction mixture. After, the completion of the reaction, the reaction mixture was converted to hydroxyimino acetic acid at pH 7 (Conversion by HPLC > 82%). A stream of chlorine gas was combined through T-piece with an aqueous stream of hydroxyimino acetic acid. The resulted reaction stream was directed towards a 24ml flow with a static mixture (MoC–PFA) reactor, operating at 15-20°C and converted to hydroxycarbonimidic dichloride (Conversion by GC > 87%). Hydroxycarbonimidic dichloride in the aqueous solvent was extracted into n-butyl acetate solvent. Hydroxycarbonimidic dichloride in n-butyl acetate was reacted with isobutylene gas in n- butyl acetate with potassium carbonate as base at 40 °C to ensure full conversion to 3-chloro- 5,5-dimethyl-4,5-dihydroisoxazole (Conversion by GC > 87%). The reaction mass was filtered and the filtrate containing 3-chloro-5,5-dimethyl-4,5- dihydroisoxazole was transferred to the another reactor having a solution of thio-urea and hydrogen bromide solution at 25-40°C to ensure full conversion to 5,5-dimethyl-4,5- dihydroisoxazol-3-yl carbamimidothioate (Conversion by GC > 45%).

Claims

Claims:

1. An improved process for the preparation of Pyroxasulfone of Formula (I) or salts thereof;

wherein, the process comprising the steps of: a) reacting glyoxalic acid with hydroxy amine sulphate to obtain 2-(hydroxyimino)acetic acid compound of Formula (II) or salts thereof, in a suitable solvent at a suitable pH;

c) recycling of unreacted bromine anion by addition of a suitable oxidizing agent;

d) optionally, isolating the compound of Formula (III) or salts thereof;

e) converting the compound of Formula (III) or salts thereof, to Pyroxasulfone or salts thereof.

2. The process according to claim 1, wherein the oxidizing agent is selected from the group comprising of fluorine, chlorine, hydrogen peroxide, nitric acid, sulfuric acid, peroxydisulfuric acid, peroxymonosulfuric acid, chlorite, chlorate, perchlorate, hypochlorite, sodium hypochlorite, chromium trioxide, pyridiniumchlorochromate, potassium permanganate, sodium perborate, nitrous oxide, nitrogen dioxide, dinitrogen tetroxide, potassium nitrate, sodium bismuthate and mixture thereof.

3. The process according to claim 1, wherein the solvent is a polar solvent.

4. The process according to claim 1, wherein the solvent is selected from the group comprising of water, alcohol, chlorinated solvent or a mixture thereof.

5. The process according to claim 4, wherein the solvent is water.

6. The process according to claim 1, wherein the amount of the bromine used is in the range of 0.25 to 3 mole equivalents, based on the amount of 2-(hydroxyimino)acetic acid.

7. The process according to claim 1, wherein the base is selected from organic or inorganic base.

8. The process according to claim 1, wherein the pH of the reaction is maintained in the range of 8 to 14.

9. A process of preparing a compound of Formula (I) or salt thereof:

comprising the steps of:

A. reacting a compound of Formula V (1-methyl-3-(trifluoromethyl)-1H-pyrazol-5- ol)

B. reacting the compound of Formula VI or salt thereof with chlorodifluoromethane in a suitable solvent in presence of a base to obtain a compound of Formula VII (5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methanol;

C. reacting the compound of Formula VII (5-(difluoromethoxy)-1-methyl-3- (trifluoromethyl)-1H-pyrazol-4-yl)methanol) with chlorinating agent to obtain a compound of Formula VIII (3-(((5-(difluoromethoxy)-1-methyl-3- (trifluoromethyl)-1H-pyrazol-4-yl)methyl)thio)-5,5-dimethyl-4,5- dihydroisoxazole)

D. reacting the compound of Formula VIII (4-(chloromethyl)-5-(difluoromethoxy)-1- methyl-3-(trifluoromethyl)-1H-pyrazole) with 5,5-dimethyl-4,5-dihydroisoxazol- 3-yl carbamimidothioate (Formula IX)

to obtain a compound of Formula X (3-(((5-(difluoromethoxy)-1-methyl-3- (trifluoromethyl)-1H-pyrazol-4-yl)methyl)thio)-5,5-dimethyl-4,5- dihydroisoxazole)

E. reacting the compound of Formula X (3-(((5-(difluoromethoxy)-1-methyl-3- (trifluoromethyl)-1H-pyrazol-4-yl)methyl)thio)-5,5-dimethyl-4,5- dihydroisoxazole) with sodium tungstate and an oxidizing agent to obtain the compound of Formula (I) or salt thereof;

wherein said process is performed using continuous flow reaction conditions.

10. The process as claimed in claim 9, wherein the base is an organic or inorganic base, preferably an inorganic base and more preferably selected from potassium hydroxide, sodium hydroxide, sodium carbonate, and/or potassium carbonate.

11. The process as claimed in claim 9, wherein the solvent is selected from polar protic or polar aprotic or non-polar solvent, preferably selected from acetonitrile, water, alcohol or chlorinated solvents or a mixture thereof.

12. The process as claimed in claim 9, wherein the chlorinating agent is selected from thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, dichlorosuccinimide, calcium hypochlorite, sodium chlorite, carbon tetrachloride, hydrochloric acid or chlorine.

13. The process as claimed in claim 9, wherein the reducing agent is selected from hydrogen peroxide or meta chloroperbenzoic acid.

14. The process as claimed in claim 9, wherein the residence time of said mixture in the reactor in step A. or step B. or step C., is typically anywhere between 30 seconds and 20 minutes, preferably about 30 seconds to 05 minutes depending on the temperature.

15. The process as claimed in claim 13, wherein the operation temperature in the reactor is typically anywhere between 10°C and 100°C, preferably between 20°C and 80°C and even more preferably between 20°C and 50°C.

16. The process as claimed in claim 9, wherein the residence time of said mixture in the reactor in step D or step E, is typically anywhere between 30 seconds and 20 minutes, preferably about 02 minutes to 10 minutes depending on the temperature.

17. The process as claimed in claim 16, wherein the operation temperature in the reactor is typically anywhere between 10°C and 100°C, preferably between 20°C and 100°C.

18. The process as claimed in claim 9, wherein purity of compound of Formula (I) or salt thereof is more than 95 %, as measured by HPLC.

19. The process for the preparation of an intermediate compound of Formula IX (5,5- dimethyl-4,5-dihydroisoxazol-3-yl carbamimidothioate) comprising the steps of: 1) reacting glyoxalic acid with hydroxyamino sulfate in presence of a base and/or a buffering agent to obtain hydroxyimino acetic acid;

2) reacting hydroxyimino acetic acid reacted with chlorinating agent to obtain hydroxycarbodimic dichloride;

wherein said process is performed using continuous flow reaction conditions.

20. The process as claimed in claim 19, wherein the operation temperature in the reactor is typically anywhere between 5°C and 80°C, preferably between 5°C and 40°C more preferably 15°C and 20°C for step 2), preferably between 10°C and 70°C more preferably 40°C for step 3) and preferably between 10°C and 40°C more preferably 25°C and 40°C for step 4).

21. The process as claimed in claim 19, wherein subsequently 5,5-dimethyl-4,5- dihydroisoxazol-3-yl carbamimidothioate (Formula IX) is converted into Formula X (3-(((5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4- yl)methyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole).

22. The process as claimed in claim 19, wherein the base is an organic or inorganic base, preferably an inorganic base and more preferably selected from potassium hydroxide, sodium hydroxide, sodium carbonate, and/or potassium carbonate.

23. The process as claimed in claim 19, wherein the chlorinating agent is selected from thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, dichlorosuccinimide, calcium hypochlorite, sodium chlorite, carbon tetrachloride, hydrochloric acid or chlorine.

24. The process as claimed in claim 19, wherein purity of compound of Formula (IX) or salt thereof is more than 95 %, as measured by HPLC.