Title of Invention

"METHOD OF PREPARING 1-ACETYL-1-CHLOROCYCLOPROPANE"

Abstract

A method of preparing 1-acetyl-l-chlorocyclopropane which comprises (a) providing 3, 5-dichloro-2-pentanone; (b) providing a phase transfer catalyst selected from the group consisting of tetraalkylammonium halides and aryltrialkylammonium halides; (c) providing an aqueous solution of a base selected from the group consisting of bases whose conjugate acids have a pKa value in water of from 8 to 15; (d) admixing 3,5-dichloro-2-pentanone, the phase transfer catalyst and the aqueous solution of the base at a temperature above room temperature in the absence of an organic solvent; and (e) separating the 1-acetyl-l-chlorocyclopropane.

Full Text

The present invention relates to the preparation of 1-acetyl-l-chloro-cyclopropane from 3,5-dichloro-2-pentanone. It is known that treatment of 3,5-dichloro-2-pentanone with a base with heating will, provide 1 -acetyl- 1-chlorocyclopropane. However, it is generally acknowledged that such a procedure does not provide acceptable yields. SUMMARY OF THE INVENTION The present invention provides a method of preparing 1-acetyl-l -chlorocyclopropane which comprises: (a) providing 3,5-dichloro-2-pentanone; (b) providing a phase transfer catalyst; (c) providing an aqueous solution of a base selected from the group consisting of bases whose conjugate acids have a pKa value in water of from about 8 to about 15; (d) admixing 3,5-dichloro-2-pentanone, the phase transfer catalyst and the solution at a temperature above room temperature in the absence of an organic solvent; and (e) separating the 1 -acetyl-1 -chlorocyclopropane. DETAILED DESCRIPTION OF THE INTVENTION The method of the present invention may be carried out in a batch manner or continuously. The bases used in the method of the present invention include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium phosphate and potassium phosphate. Sodium metal bases are generally preferred. Hydroxide anion bases are preferred. Sodium hydroxide is most preferred. In order to achieve complete conversion of 3,5-dichloro-2-pentanone, the preparation is generally effected with at least a molar equivalent of base relative to the amount of 3,5-dichloro-2-pentanone. Preferably from about 1.1 to about 1.5 molar equivalents of base, more preferably from about 1.1 to about 1.2 molar equivalents of base, are used per mole of 3,5-dichloro-2-pentanone. The concentration of base is generally from about 5% to about 50% by weight of sodium hydroxide, preferably from about 10% to about 30% by weight, more preferably from about 20% to about 25%. A continuous process will generally use the latter range or base concentrations when the base is sodium hydroxide. The method of the present invention may be carried out in the presence or absence of an organic solvent. When the method of the invention is carried out using hydroxides as base in the absence of an organic solvent, the product must be removed from the reaction mixture within a relatively short time or the excess base in the reaction mixture must be neutralized tp rrrinimize the decomposition of the product if there is excess base. However when weaker bases such as carbonates or phosphates are used even in the absence of an organic solvent, the product can remain in the reaction mixture for extended periods of time. In the presence of an excess of hydroxide base and without organic solvent, the product is generally removed immediately after completion of the reaction is detected, e.g., by liquid chromatography (LC) or gas chromatography (GC) analysis. The reaction takes generally from about 0.1 to about 600 minutes after the completion of admixing. Generally in the absence of solvent, when from about 1 to about 3 mole percent of catalyst and from about 1 to about 1.5 molar equivalents of hydroxide base (20-25% concentration) are used, the reaction is complete in a time from about 0.1 to about 5 minutes after completion of admixing. When a solvent is added, the reaction is completed from about 0.2 to about 5 minutes after completion of admixing. When a hydroxide base is substituted by a carbonate or phosphate anion base, the reaction takes from about 15 to about 120 minutes. When organic solvent is used, the latter reaction time may be extended to a time from about 30 to about 300 minutes. In the absence of solvent, and when hydroxide bases are used, the reaction is generally stopped from about 1 minute to about 15 minutes after completion of the reaction is determined. When carbonates or phosphates are used, notwithstanding the use of organic solvent, Ihe.reaction may,be stopped from :about| to.about 120 ;rmnutes after die determination of the completion of the 'reaction. - ••••; • The present invention also provides a method of preparing 1-acetyl-l-chlorocyclopropane which comprises (a) providing 3,5-dichloro-2-pentanone; : (b) providing a phase transfer catalyst; (c) providing an aqueous solution of a base selected from the group consisting of bases whose conjugate acids have a pKa value in water of from about 8 to about 15; (d) admixing 3.,5-dichloro-2-pentanone, the phase transfer catalyst and the aqueous solution of a base at a temperature above room temperature in the presence of an organic solvent which organic solvent is substantially immiscible in water and which solvent is substantially impervious to the reaction conditions of the method; and (e) separating the 1-acetyl-l-chlorocyclopropane, The presence of an organic solvent considerably slows down the decomposition of the product by the excess base. This therefore allows the reaction to be carried out for extended length of time. Thus when the reaction is carried out in the presence of an organic solvent, at the end of the admixing, the reaction is heated until the reaction is complete as determined, e.g., by GC or LC. The excess base is then neutralized with acid and the product separated from the reaction mixture by fractional distillation. Suitable solvents include monohalobenzenes,'dihalobenzenes, e.g., 1,2-dichlorobenzene, dialkyl ethers wherein the alkyl groups of the ether may the same or different and which alkyl groups are from Cl to C12, preferably from Cl to C8; and alkylaryl ethers. Solvents which are suitable for the method of the present invention include those solvents having a miscibility in water of from about 0 grams solvent per 100 rnL water at 25°C (room temperature) to about 3 g/100-mL water; preferably from about 0.01 g/100 mL water to about 1 g/100 rnL water. The reaction may be preferably ran in the presence of an organic solvent in which 3,5-dichloro-2-pentanone is soluble. A phase transfer catalyst is necessary for this process since thejreactions carried out in'the absence of phase transfer catalyst give poor yields even under otherwise optimal reaction conditions. The phase transfer catalyst may be any catalyst suited for that purpose known to one of skill in the art. Water-irascible and water-immiscible catalysts may be employed. Generally tetraallcylaniiaoniurn halides and aryltriaLkylammordum halides are used. Preferably the phase transfer catalyst is selected from the group consisting of tetrabutylammonimn halides and methyltrialkylammoiiiuni halides. Most preferably the phase transfer catalyst is nietliyltiioctylammonium chloride and/or methyltributylanimoniuni chloride. The amount of the catalyst may vary widely. Generally from about 0.1 to about 10 mole percent is used. Preferably from about 1 to about 5 mole% is used. By the term mole% is meant the stoichiometric amount of the catalyst as a percent of the 3,5-dichloro-2-pentanone inmoles. For example, if 1 mol of 3,5-dichloro-2-pentanone were reacted, then about 0.03 moles (3 mole%) of catalyst might be used. The weight: weight ratio of 3,5-dichloropentanone to phase transfer catalyst is generally from about 10:1 to about 100:1, preferably about 10:1 to about 30:1 and more preferably about 12:1 to about 16:1. The solvent is generally chosen so that the boiling point of the solvent at atmospheric pressure is different than that of the boiling temperature of 1 -acetyl-1-chlorocyclopropane at atmospheric pressure so that the product can be separated from the solvent by fractional distillation. A preferred solvent is 1,2-dichloro-benzene. The temperature of the reaction has a significant effect on the performance of the reaction. When hydroxides are used as base, the yield is higher when the reactants are brought into contact with each other at higher temperatures. At lower temperatures, side reactions increase causing the yield of the desired product to decrease stibstantially. When weaker bases such as carbonates and phosphates are used, the reaction is very slow at lower temperatures and therefore the reaction is preferably carried out under reflux conditions to achieve reasonable rate of reaction. In the case where the reaction is run above room temperature, the reactants may optionally be heated to a temperature of from about 50°C to about 100°C at atmospheric pressure. If such pre-heating is done, the optimal j temperature is from about8Q°C to abput 100°C. ....... The preparation may also be run continuously. Persons of ordinary skill in the art will understand that the preparation may be run in any suitable vessel that will allow the continuous removal of the product and separation of any byproducts. Generally, the mixture is made by admixing the reactants in the absence of an organic solvent in a flow reactor. There is allowed thereafter a short mixhig time, generally from about 0.1 minutes to about 60 minutes, preferably from about 0.2 minutes to abotrt 10 minutes, most preferably from about 0.5 minutes to about 2 minutes before the product is separated, hi a separation step, the admixture is then delivered to a steam distillation apparatus wherein 1-acetyl-l-chlorocyclo-propane is azeotropically distilled with water and then condensed. The remaining salts and phase transfer catalyst are captured in the water of the steam distillation apparatus. The reaction may be optionally run continuously in the presence of organic solvent. The product is then fractionally distilled away from the organic solvent after the initial.azeotropic distillation. EXAMPLES Example 1: A 3-neck round-bottomed flask equipped with a reflux condenser and a magnetic stir bar was charged with aq. NaOH (38.5 g, 23%, 0.221 moles) and heated to 95 °C. A mixture of 3,5-dichloro-2-pentanone (28.5 g, 98% pure, 0.18 moles) and methyltrioctylammonium chloride (in the commercial form of Aliquat 336, 2.0 g, 0.005 moles) heated to 90 °C in an addition funnel, was rapidly added to it hi less than 5 seconds. The stirring was then started and the reaction mixture Was stirred at 95 °C for 3 minutes. The flask was then plunged into ice-water bath. A weighed amount of internal standard (para-xylene) was added to it and stirred for 5 minutes while tightly closed. The layers were then allowed to separate and the organic layer was injected on GC. The yield was calculated using the predetermined response factor between 1-acetyl-l-chlorocyclopropane and para-xylene and was found to be 84.6% based on 3,5-dichloro-2-pentanone. Example 2: A 3-neck round-bottomed flask equipped with a reflux condenser and a magnetic stir bar was charged with aq. NaOH (47.0 g, 23%, 0.27 moles) and heated to 95 DC. A mixture of 3,5-dichloro-2-pentanone (28.5 in61es) heated to 90 "C'M^anaddMo^ funnel, was rapidly added to it in less than 5 seconds. The stirring was then started and the reaction mixture was stirred at 95 °C for 2 minutes. The reaction was then quenched by addition of aqueous hydrochloric acid (28.0 g, 9.8%, 0.075 moles). The product was then distilled out of the reaction mixture as an azeotrope with water at atmospheric pressure. A weighed amount of internal standard (para-xylene) was added to the distillate and stirred tightly closed. The layers were then allowed to separate and the organic layer was injected on GC. The yield was calculated using the predetermined response factor between 1-aceryl-l-chloro-cyclopropane and/>#ra-xylene. The yield was found to be 83.0% based on 3,5-dichloro-2-pentanone. Example 3: A 3-neck round-bottomed flask equipped with a reflux condenser and a magnetic stir bar was charged with aq. NaOH (32.4 g, 25%, 0.20 moles), 1,2-dichlorobenzene (20.1 g) and methyltrioctylammonium chloride (in the commercial form of Aliquat 336,1.0 g, 0.0025 moles) and heated to 90 °C. 3,5-dichloro-2-pentanone (28.5 g, 98% pure, 0.18 moles) was then added to it from an addition funnel over 3 hours. After the addition was over, the reaction mixture was cooked at 90 °C for 1 hour and then cooled to room temperature. The yield was determined using para-xylene as internal standard as in Example 1 and was found to be 84% based on 3,5-dichloro-2-pentanone. Example 4: A 3-neck round-bottomed flask equipped with a reflux condenser and a magnetic stir bar was charged with aq. potassium carbonate (62.1 g, 47%, 0.21 moles) and heated to 95 °C. A mixture of 3,5-dichloro-2-pentanone (28.5 g, 98% pure, 0.18 moles) and methyltributylammoniuin chloride (2.06 g, 75% aq. solution, 0.0066 moles) heated to 90 °C in an addition funnel, was rapidly added to it in less than 5 seconds. The stirring was then started and the reaction mixture was stirred at 95 °C for 15 minutes. The flask was then plunged into ice-water bath. A weighed amount of internal standard (para-xylene) was added to it and stirred for 5 minutes while tightly closed. The layers were then allowed to separate and the organic layer fwas injected on GC. The yield was calculated rising the predetermined response factor between 1-acetyl-l-chlorocyclopropane and par-a-xylene and was found tobe$2.9%based on 3,5-dichlpro-2-pentanone. About , :il;5% 3,5-dicMoro-2-pentanone was ibundto be unreacted. Example 5: A 3-neck round-bottomed flask equipped with a reflux condenser and a magnetic stir bar was charged with aq. potassium phosphate (58.4 g, 0.275 . • moles), water (58.4 g) and heated to 100 °C. A mixture of 3,5-dichloro-2- pentanone (28.5 g, 98% pure, 0.18 moles) and methyltrioctylairnnonium chloride (in the commercial form of Aliquat 336, 2.08 g, 0.0051 moles) heated to 100 °C in an addition funnel, was rapidly added to it in less than 5 seconds. The stirring was then started and the reaction mixture was stirred at 100 °C for 20 minutes. The flask was then plunged into ice-water bath and diluted with 40 g water to dissolve all solids. The yield was determined as in Example 1 and was found to be 85.1% based on 3,5-dichloro-2-pentanone. Example 6: A stream containing a mixture of 3,5-dichloro-2-pentanone (640 g/min., 95.5% pure, 3.94 moles/min) and methyltrioctylammonium chloride (in the commercial form of Aliquat 336,46.3 g/min, 0.114 moles/min) preheated to 89 °C and a stream of aq. sodium hydroxide (23% solution, 999 g/min, 5.74 v moles/min) preheated to 92 °C was fed simultaneously into an one inch diameter, 3 meter long tube packed with static mixers. The mean residence time for the reaction mixture inside the tube reactor was estimated to be about 1 tnin. The reaction mixture mat came out the other end of the tube reactor was directly introduced into a steam distillation column. The product distilled over as an azeotrope with water while the salts, catalyst and impurities left the steam distillation column from the bottom. The yield of the product formed in the tube reactor was determined as follows: Initially the system was allowed to achieve a steady state under the above-mentioned flow rates. Then the reaction mixture that came out the other end of the tube reactor was diverted into a collection pot (instead of sending to the steam-distillation column) containing some cold water for a short time while at the same time noting down the amount of 3,5-dichloro-2-pentanone that entered the tube reactor in that time period. The amount of product .in the collection pot was determined as in Example 1 and the yield of the product t was found to be 82% based on 3,5-dichloro-2-pentanone. Example 7: Three 3 liter jacketed cylindrical glass reactors were connected in series via dip tubes in such a way that the after a certain level is reached in the reactor, the pump between the reactors would pump the reactor contents via the dip tubes into the next reactor so that the level remained constant based on the position of the dip tubes. The second and the third reactors were fitted with a distillation head and condenser to distill out the product during the run. To begin file run, the first reactor jacket temperature was set to 106-107 °C and a stirred mixture of 335-dichloro-2-pentanone (98.8% pure) and 75% aqueous methyl- « tribxitylamnionixun chloride (MTBC1) with a weight ratio of 15 : 1 was pumped in at a rate of 2.0 ml/min and at the same time a 47% aq. potassium carbonate solution was pumped into the same reactor at a rate of 3.6 ml/min. Under these conditions the mole ratio of 3,5-dichloro-2-pentanone : potassium carbonate : MTBC1 entering the first reactor was 1.0:1.1: 0.033. When the level in the first reactor reached 972 ml, the pump between reactor 1 and reactor 2 was started to pump the slurry into the second reactor. The level in the first reactor was maintained at around 972 ml by the position of the dip tube leading to the purnp. hi this way the three reactors were filled after a certain time. The jacket temperatures of the second and third reactors were kept about 15 °C higher than that of the first reactor. As the slurry came over in the second and third reactors the product was distilled overhead as an azeo'trope with water. Most of the product was distilled over from reactor 2, any remaining product was recovered in the distillation from reactor 3. The yield of 1-acetyl-l-chlorocyclopropane was found to be 86% based on 3,5-dichloro-2-pentanone. -. * Although the invention has been described in detail in the foregoing for the purpose of illustration, it is to be tmderstood that such detail is solely for that purpose and that variations can be made therein by those skilled in the art without departing from the spirit and scope of the invention except as it may be limited by the claims. WeGlaim: ORIGINAL 1. A method of preparing 1 -acetyl-1 -chlorocyclopropane which comprises (a) providing 3,5-dichloro-2-pentanone; (b) providing a phase transfer catalyst selected from the group consisting of tetraalkylammonium halides and aryltrialkylammonium halides in an amount of 0,1 to 10 mole percent; (c) providing an aqueous solution of a base selected from the group consisting of bases whose conjugate acids have a pKa value in water of from 8 to 15; (d) admixing 3,5-dichloro-2-pentanone, the phase transfer catalyst and the aqueous solution of the base at a temperature above room temperature, in the absence of an organic solvent; and ' (e) separating the 1-acetyl-1-chlorocyclopropane. wherein, the aqueous solution contains 1.1 to 1.5 molar equivalent of base relative to the amount of 3,5-dichloro-2-pent-anone. 2. The method as claimed in Claim 1 wherein the base is sodium hyciroxide or potassium hydroxide. 3. The method as claimed in Claims 1 and 2 wherein the aqueous solution of base is an aqueous solution comprising from 5 % to 50 % by weight of sodium hydroxide. 4. The method as claimed in Claims 1 to 3 wherein the aqueous solution of base is an aqueous solution comprising from 10 % to 30 % by weight of sodium hydroxide. 5. The method as ctaimed in Claims 1 to 4 wherein the aqueous solution of base is an aqueous solution comprising from 20 % to 25 % by weight of sodium hydroxide. 6. The method as claimed in Claims 1 to 5 wherein the phase transfer catalyst is a tetrabutylammonium halide and/or a methyltrialkylammonium halide. 7. The method as claimed in Claims 1 to 6 wherein the phase transfer catalyst is methyltrioctylammonium chloride and/or methyltributylammonium chloride. 8. The method as claimed in Claims 1 to 7 carried out as a continuous process. 9. The method as claimed in Claim 8 wherein 3,5-dichloro-2-pentanone and the catalyst are introduced either separately or as a mixture into a flow of aqueous solution of base. 10. The method as claimed in Claim 8 or Claim 9 wherein the 3,5-dichloro-2-pentanone and/or the catalyst and/or the aqueous solution of base are preheated to a temperature of from 70°C to 100°C before introduction into a reactor. 11. The method as claimed in Claim 10 wherein in the separating step (e) the admixture from step (d) is introduced into a steam distillation apparatus. 12. The method as claimed in Claims 1 to 11 wherein the ratio by weight of the 3,5-dichloro-2- pentanone to the phase transfer catalyst is from 10:1 to 100:1. 13. The method as claimed in Clarni 12 wherein the ratio is from 10:1 to 30:1. 14. The method as claimed in Claim 12 wherein the ratio is from 12:1 to 16:1. I 15. The method as claimed in Claims 1 to 7 that is carried out as a batch process. 16. The method as claimed in Claim 15 wherein the mixing time is from 0.1 minutes to 600 minutes. 17, The method as claimed in Claim 1 wherein the is carried out as a batch process, the mixing time is from 0.1 minutes to 600 minutes and the base is sodium Carbonate, potassium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide or potassium hydroxide. Dated this 28.09.200.6 O (1 [PAYAJ^XALRA] OF REMFRY &ISAGAR ATTORNEY FOR THE APPHCANT[S]

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5652-delnp-2006-Abstract-(14-05-2012).pdf

5652-delnp-2006-Abstract-(17-12-2012).pdf

5652-delnp-2006-abstract.pdf

5652-delnp-2006-Claims-(08-08-2013).pdf

5652-delnp-2006-Claims-(14-05-2012).pdf

5652-delnp-2006-Claims-(17-12-2012).pdf

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5652-delnp-2006-Correspondence Others-(12-08-2013).pdf

5652-delnp-2006-Correspondence Others-(14-05-2012).pdf

5652-delnp-2006-Correspondence Others-(17-02-2014).pdf

5652-delnp-2006-Correspondence Others-(17-12-2012).pdf

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5652-delnp-2006-Correspondence-Others-(08-08-2013).pdf

5652-delnp-2006-Correspondence-Others-(10-06-2013).pdf

5652-delnp-2006-correspondence-others.pdf

5652-delnp-2006-Description (Complete)-(14-05-2012).pdf

5652-delnp-2006-description (complete).pdf

5652-delnp-2006-form-1.pdf

5652-delnp-2006-form-13-(17-12-2012).pdf

5652-delnp-2006-form-18-(04-04-2008).pdf

5652-delnp-2006-form-2.pdf

5652-delnp-2006-Form-3-(12-08-2013).pdf

5652-delnp-2006-Form-3-(14-05-2012).pdf

5652-delnp-2006-Form-3-(17-02-2014).pdf

5652-delnp-2006-Form-3-(17-12-2012).pdf

5652-delnp-2006-Form-3-(22-05-2012).pdf

5652-delnp-2006-form-3.pdf

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5652-delnp-2006-GPA-(14-05-2012).pdf

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5652-delnp-2006-pct-notification.pdf

5652-delnp-2006-pct-request.pdf

5652-delnp-2006-pct-searcch report.pdf

5652-delnp-2006-Petition-137-(14-05-2012).pdf

Examination Report.pdf