Title of Invention

A PROCESS FOR THE PREPARATION OF FUNGICIDE TEBUCONAZOLE 1-(4-CHLOROPHENYL) -4,4-DIMETHYL-3-(1H-1,2,4-TRIAZOL-1-YLMETHYL)PENTAN-3-OL

Abstract

The process for the production of tebuconazole starting from reaction of l-(4-chlorophenyl)-4,4 dimethyl pentan-3-one (alkyl ketone) with mixture of dimethyl sulphide and dimethyl sulphate in the presence of catalyst and potassium hydroxide, wherein the reaction mass is heated and cooked over a appropriate period to complete the reaction, wherein the mass is dissolved in water to remove salts, to separate organic layer and dimethyl sulphide is distilled out to get 2-(4-chlorophenylethyi)-2-tert.-butyi-oxirane. The residue (oxirane) is further reacted with 1,2,4 triazole in solvent medium of dimethyl sulpho oxide in the presence of sodium hydroxide and water, heated and cooked for a suitable time to get crude tebuconazole. dimethyl sulpho oxide is distilled and solid residue is dissolved in toluene, washed with water, cooled to crystallize, filtered and dried under reduced pressure. The yield of the product is 85% based on alkyl ketone with a purity of 98%.

Full Text

F0RM2 THE PATENTS ACT, 1970 (39 of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10; rule 13) 1. Title of the invention. - A PROCESS FOR THE PREPARATION OF FUNGICIDE TEBUCONAZOLE l-(4-chIorophenyl)-4,4-dimethyI-3-(lH-l,2,4-triazo[-l-ylmethyl)pentan-3-o! 2. Applicant(s) (a) NAME: (b) NATIONALITY: (c) ADDRESS: SINGH, Avtar An Indian Citizen Director (Operations & Business Development) Punjab Chemicals and Crop Protection Limited, Oberoi Chambers Bldg. No. II, PIotNo.-645/646, New Link Road, Andheri (W) Mumbai-400053, Maharashtra- India. 3. PREAMBLE TO THE DESCRIPTION The following specification particularly describes the invention and the manner in which it is to be performed: FIELD OF APPLICATION This invention relates to a process for the preparation of the fungicide tebuconazole corresponding to the formula. PRIOR ART Tebuconazole namely l-(4-chlorophenyl)-4,4-dimethyl-3-(lH-l?2,4-triazol-l-ylmethyl)pentan-3-ol is a systemic fungicide with protective, curative and eradicant action. Rapidly absorbed into the vegetative parts of the plant, with translocation principally acropetally. Inhibits ergosterol biosynthesis. It is commonly used in cereals, rust species, powdery mildew, tea and grapes. US PATENT NO. 4,723,984 describes a process for preparation of tebuconazole comprising reaction between l-(4-chlorophenyl)-4.4_dimethyl pentan-3-one with mixture of dimethyl sulphides and dimethyl Sulphate in the presence of sodium methylate in solvent medium such as absolute ac;etonitrile and ethyl acetate is used to separate organic and aquous phase and the residue (oxirane) is obtained by distillation. The residue is further reacted with 1,2,4 triazole in the presence of ethanol, heated to 150° C over a period of 20 hours to get crude tebuconazole and organic solvent such as ether is used to crystallize tebuconazole. 2 17 APR 2009 Due to use of absolute acetonitrile which is toxic and hazardous, it is not safe to carry out the process. Besides the use of sodium methylate which generates static charge during feeding requires static charge arrestor. Further there is use of another solvent ethyl acetate and the loss of solvent during recovery will make the product costly. Additionally the residue (oxirane) is distilled before reacting with 1,2,4 triazole and thus increasing the time of reaction. Also maintaining temp, of reaction at 150 C for 20 hours with in solvent medium such as ethanol is not safe because it requires primary, secondary and tertiary condensers to avoid losses. Also the use of ether as solvent makes the process hazardous due to very low flash point and recovery of ether envisages higher losses of ether solvent. Thus there is need to provide a process which takes care of the above mentioned drawbacks and at the same time provides high yield of tebuconazole without using hazardous chemicals. OBJECTS OF INVENTION An object of the invention is to provide a process for the preparation of the fungicide tebuconazole that is very easy to carryout. Another object of the invention is to provide for the preparation of the fungicide tebuconazole, which gives good yields and is economical. 3 17 APR 2009 Another object of the invention is to provide a process for the preparation of fungicide which reduces the reaction time. Another object of the invention is to provide a process for the preparation of the fungicide which eliminates hazardous reagent and is safe to carry out. DESCRIPTION OF INVENTION The present process of preparation of l-(4-chlorophenyl)-4,4-dimethyl-3-(lH-1.2,4-triazol-1 -ylmethyl)pentan-3-ol comprises reaction of 3 -(4-chlorophenyl)-4,4-dimethyl pentan-3-one (alkyl ketone) with mixture of dimethyl sulphide and dimethyl sulphate in the presence of catalyst and potassium hydroxide, followed by addition of water to separate organic and aqueous layer, followed by distillation of dimethyl sulphide from organic phase to obtain 2-(4-chlorophenylethyl)-2-tert.-butyl-oxirane> followed by addition of 1.2,4 triazole to yield tebuconazole and used exclusively as fungicide. According to the invention the use of toxic reagent acetonitrile is eliminated and the reaction is safe to carry out. According to the invention the use of potassium hydroxide is preferred over Sodium methylate because of its higher reactivity, cheap and very safe to handle. According to the invention with the use of potassium hydroxide, the yield of intermediate oxirane was achieved more than that of sodium methylate. According to the invention a catalyst is used to reduce the time of reaction and makes the product more economical. According to the invention dimethyl sulphide is regenerated, recovered and recycled to reduce the consumption of dimethyl sulphide and making the product economical. 4 17 APR 2009 According to the invention oxirane is not distilled and the reaction time is less. According to the invention ethanol is replaced with dimethyl sulpho oxide to reduce time, temperatures of reaction and to increase the purity of the product. According to the invention use of aromatic solvent toluene, the homogeneity of the reaction mixture is improved to help better crystallization and improving quality and yield of the product. The following experimental examples are illustrative of the invention but not limitative of the scope thereof. EXAMPLE! To a stirred mass of 1.83 parts by wt. of dimethyl sulphide was added 0.91 parts by wt. of dimethyl sulphate between temp, at 32-36° C and the mixture was cooked over a period of 4 hours' To this mixture 0.015 parts by wt. of catalyst; 1.0 part by wt. of l-(4-chlorophenyl)-4,4 dimethyl pentan-3-one (alkyl ketone) and 0.60 parts by wt. of potassium hydroxide were added. The reaction mass was heated to 40-42° C and cooked over a period of 18 hours. The reaction was completed when alkyl ketone was absent by GC method. To this mixture 4.5 parts by wt. of water were added and allowed to settle for separation of organic and aqueous layer. Aqueous layer containing salt was sent to ETP and organic layer containing 2-(4-chlorophenylethyl)-2-tert-butyl-oxirane and dimethyl sulphide was further processed to distill out dimethyl sulphide between 45-75° C at atmospheric pressure and residue (oxirane) was obtained. The residue(oxirane) was further added to a mixture of 0.34 parts by wt. of 1,2,4 triazole; 2.19 parts by wt. of dimethyl sulpho oxide (DMSO); 0.04 parts by wt. of sodium hydroxide and 0.066 parts by wt. of water at a temperature between 78-80° C. 5 17 APR 2009 The mass was heated to 120° C and cooked over a period of 2 hours. The reaction was completed when the oxirane content was below 1.5% by GC method. DMSO was distilled out under reduced pressure between 80-85° C to get crude tebuconazole which was further dissolved in 2.50 parts by wt. of toluene and washed four times with water to purify the mass. The washed mass was cooled to 0-5° C to crystallize, filtered and dried under reduced pressure between 55-60°C. EXAMPLE-2 To a stirred mass of 1.87 parts by wt. of dimethyl sulphide was added 0.94 parts by wt. of dimethyl sulphate between temp, at 32-36° C and the mixture was cooked over a period of 4 hours To this mixture 0.018 parts by wt. of catalyst; 1.0 part by wt. of 1-(4-chlorophenyl)-4,4 dimethyl pentan-3-one (alkyl ketone) and 0.65 parts by wt. of potassium hydroxide were added. The reaction mass was heated to 40-42° C and cooked over a period of 18 hours. The reaction was completed when alkyl ketone was absent by GC method. To this mixture 5.0 parts by wt. of water were added and allowed to settle for separation of organic and aqueous layer. Aqueous layer containing salt was sent to ETP and organic layer containing 2-(4-chlorophenylethyl)-2-tert.-butyl-oxirane and dimethyl sulphide was further processed to distill out dimethyl sulphide between 45-75° C at atmospheric pressure and residue (oxirane) was obtained. The residue(oxirane) was further added to a mixture of 0.36 parts by wt. of 1,2,4 triazole; 2.30 parts by wt. of dimethyl sulpho oxide (DMSO); 0.05 parts by wt. of sodium hydroxide and 0.075 parts by wt. of water at a temp, between 78-80° C. The mass was heated to 120° C and cooked over a period of 2 hours. The reaction was completed when the oxirane content was below 1.5% by GC method. DMSO was distilled out under reduced pressure between 80-85° C to get crude tebuconazole which was further dissolved in 2.75 parts by wt, of toluene and washed four times 6 17 APR 2009 with water to purify the mass. The washed mass was cooled to 0-5° C to crystallize, filtered and dried under reduced pressure between 55-60°C. 7 17 APR 2009 We Claim 1. A process for preparation of tebuconazole comprising reacting mixture of dimethyl sulphide and dimethyl sulphate with l-(4-chlorophenyl)-4,4-dimethyl pentan-3-ones in presence of catalyst and potassium hydroxide, followed by addition of water to separate organic and aqueous layer, followed by distillation of dimethyl sulphide from organic phase to obtain 2-(4-chlorophenylethyl)-2-tert.-butyl-oxirane, followed by addition of 1,2,4 triazole to yield tebuconazole. 2. A process as claimed in claim 1, wherein 1.83-1.87 parts by wt. of dimethyl sulphide and 0.91-0.94 parts by wt. of dimethyl sulphate are mixed 3. A process as claimed in claim 2, wherein the mixture of dimethyl sulphide and dimethyl sulphate is prepared at a temperature between 32-36°C 4. A process as claimed in claim 1, wherein 1.0 part by wt of l-(4-chlorophenyl)-4.4-dimethyl pentan-3-one is reacted with the mixture of dimethyl sulphide and dimethyl sulphate in the presence of catalyst and potassium hydroxide 5. A process as claimed in claim 4 wherein catalyst is used in amount of 0.015 - 0.017 parts by wt. 6. A process as claimed in claim 4 wherein potassium hydroxide is used in amount 0.60-0.65 parts by wt. 7. A process as claimed in claim 4 wherein the reaction is carried out at temperature between 40°C-42° C. 8. A process as claimed in claim 1, wherein the mass is cooked over a period of 18 hours. 1 7 APR 2009 9. A process as claimed in claim 19 wherein 4.5 - 5.0 parts by wt. of water is added in reaction mass containing dimethyl sulphide and 2-(4-chlorophenylethyl)-2-tert.butyl-oxirane to dissolve salt and organic phase is separated, which is further processed to obtain dimethyl sulphide and residue (oxirane). 10. A process as claimed in claim 1, wherein dimethyl sulphide is distilled out preferably at temperature between 45-75°C. 11. A process as claimed in claim 1, wherein residue (oxirane) is further reacted with 0.34 - 0.36 parts by wt. of 1,2,4 triazole in the presence of 2.19 - 2.30 parts by wt of dimethyl sulpho oxide, 0.04 - 0.05 parts by wt of sodium hydroxide and 0.066-0.075 parts by wt. of water preferably at a temperature between 78-80° C. 12. A process as claimed in claim 1, wherein the reaction is carried out at a temperature preferably between 78-80°C. i 13. A process as claimed in claim 1, wherein the reaction mass is further heated to 120° C and cooked over a period of 2 hours. 14. A process as claimed in claim 1, wherein dimethyl sulpho oxide is distilled under reduced pressure preferably between temperature 80-85°C. 15. A process as claimed in claim 1. wherein 2.50 - 2.75 parts by wt- of toluene is added to dissolve crude tebuconazole. 16. A process as claimed in claim 1, wherein crude tebuconazole in toluene is washed four times with water. 17. A process as claimed in claim 1, wherein tebuconazole is crystallized at temperature preferably between 0-5° C. 9 17 APR 2009 18. A process as claimed in claim 1, wherein wet tebuconazole is dried under reduced pressure at a temperature preferably between 55-60°C 19. A process as claimed in any preceding claim wherein the yield of tebuconazole is 85% based on with l-(4-chlorophenyl)-4,4-dimethyl pentane- 3-ones.

Documents:

1011-mum-2009-abstract.doc

1011-mum-2009-abstract.pdf

1011-MUM-2009-CLAIMS(AMENDED)-(7-3-2013).pdf

1011-MUM-2009-CLAIMS(AMENDED)-(8-10-2012).pdf

1011-MUM-2009-CLAIMS(MARKED COPY)-(7-3-2013).pdf

1011-MUM-2009-CLAIMS(MARKED COPY)-(8-10-2012).pdf

1011-mum-2009-claims.doc

1011-mum-2009-claims.pdf

1011-MUM-2009-CORRESPONDENCE(13-1-2014).pdf

1011-MUM-2009-CORRESPONDENCE(24-6-2009).pdf

1011-mum-2009-correspondence.pdf

1011-mum-2009-description(complete).doc

1011-mum-2009-description(complete).pdf

1011-mum-2009-form 1.pdf

1011-MUM-2009-FORM 18(24-6-2009).pdf

1011-mum-2009-form 2(title page).pdf

1011-mum-2009-form 2.doc

1011-mum-2009-form 2.pdf

1011-mum-2009-form 3.pdf

1011-MUM-2009-POWER OF ATTORNEY(24-6-2009).pdf

1011-MUM-2009-REPLY TO EXAMINATION REPORT(8-10-2012).pdf

1011-MUM-2009-REPLY TO HEARING(7-3-2013).pdf