WO2010058421A2 - Procédé de synthèse de 2,4-dichloro-5-fluoro-acétophénone (dcfa) - Google Patents

Procédé de synthèse de 2,4-dichloro-5-fluoro-acétophénone (dcfa) Download PDF

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WO2010058421A2
WO2010058421A2 PCT/IN2009/000652 IN2009000652W WO2010058421A2 WO 2010058421 A2 WO2010058421 A2 WO 2010058421A2 IN 2009000652 W IN2009000652 W IN 2009000652W WO 2010058421 A2 WO2010058421 A2 WO 2010058421A2
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mother liquor
temperature
dcfa
purified crystals
mixture
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WO2010058421A3 (fr
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Sisir Mandal
Narendra Patil
Inamdur Suleman
Vinod More
Prashant Puri
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Aditya Birla Science & Technology Co. Ltd.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
    • C07C45/46—Friedel-Crafts reactions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/78—Separation; Purification; Stabilisation; Use of additives
    • C07C45/81—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation

Definitions

  • the invention relates to a process for synthesis of 2, 4-dichloro-5-fluoroacetophenone (DCFA).
  • DCFA 2,4-dichloro-5-fluoroacetophenone
  • PNCB paranitrochlorobenzene
  • DCFA is usually prepared from paranitrochlorobenzene(PNCB) by the process steps involving chlorination of paranitrochlorobenzene to form dichloronitrobenzene, treatment of dichloronitrobenzene with potassium fluoride to form a fluorinated product, heating the fluorinated product in an environment of chlorine gas resulting in dichlorofluorobenzene and finally acylation of dichlorofluorobenzene by an acylating agent.
  • PNCB paranitrochlorobenzene
  • the overall yield of DCFA, during the process, is largely determined by the yield of the intermediate compounds, and in particular, by the yield of the fluorinated product obtained by the potassium fluoride treatment.
  • the yield of the fluorinated product obtained by the potassium fluoride treatment, during the conventional process, has been found to be low thereby considerably impacting the yield of 2, 4-dichloro-5-fluoroacetophenone (DCFA). It has been a practice, during the conventional process to use potassium fluoride in excess of the stoichiometric quantities, to facilitate the production of the fluorinated intermediate product. When large excess of potassium fluoride is utilized for the process, the cost is increased as well as the separation and purification of the final product (DCFA) becomes cumbersome.
  • One object of the invention is to provide a process for high yield synthesis of 2, 4-dichloro- 5-fluoro acetophenone (DCFA)
  • Another object of the invention is to provide a process for synthesis o f DCFA wherein the fluorination step is carried out by highly active potassium fluoride
  • Yet another object of the invention is to provide a process wherein the synthesis of DCFA is carried out by using potassium fluoride obtained from potassium chloride.
  • a further object of the invention is to minimize the losses during procedures for purification of DCFA.
  • DCFA 2,4-dichloro-5-fluoro acetophenone
  • the process comprising first reacting 3,4-dichloronitrobenzene with potassium fluoride having bulk density in the range of 0.2 to 1.0, to form a fluorinated intermediate product, then reacting the intermediate product with chlorine to form dichlorofluorobenzene and finally acylating dichlorofluorobenzene using an acylating agent followed by purification and enrichment of DCFA by melt crystallization from the mother liquor.
  • the invention provides a process for synthesis of 2,4-dichloro-5-fluoro acetophenone (DCFA)
  • the invention provides a process for synthesis of 2,4-dichloro-5-fluoro acetophenone (DCFA), the process comprising first reacting 3,4-dichloronitrobenzene with potassium fluoride having bulk density in the range of 0.2 to 1.3, to form a fluorinated intermediate product, then reacting the intermediate product with chlorine to form dichlorofluorobenzene and finally acylating dichlorofluorobenzene using an acylating agent to form a mixture containing DCFA along with impurities, followed by purification and enrichment of DCFA in the mixture by melt crystallization.
  • DCFA 2,4-dichloro-5-fluoro acetophenone
  • the invention provides a process for synthesis of 2,4-dichloro-5- fluoro acetophenone (DCFA), the process comprising first reacting 3,4-dichloronitrobenzene with potassium fluoride having bulk density in the range of 0.2 to 1.3, to form a fluorinated intermediate product, then reacting the intermediate product with chlorine to form dichlorofluorobenzene and finally acylating dichlorofluorobenzene using an acylating agent to form a mixture containing DCFA along with impurities, followed by purification and enrichment of DCFA in the mixture by melt crystallization wherein the potassium fluoride has a bulk density in the range of 0.2 to 0.5.
  • DCFA 2,4-dichloro-5- fluoro acetophenone
  • the invention provides a process for synthesis of 2,4-dichloro-5- fluoro acetophenone (DCFA), the process comprising first reacting 3,4-dichloronitrobenzene with potassium fluoride having bulk density in the range of 0.2 to 1.3, to form a fluorinated intermediate product, then reacting the intermediate product with chlorine to form dichlorofluorobenzene and finally acylating dichlorofluorobenzene using an acylating agent to form a mixture containing DCFA along with impurities, followed by purification and enrichment of DCFA in the mixture by melt crystallization wherein potassium fluoride is used in the first reaction in an amount not greater than 20% in excess of the stoichiometric amount of potassium fluoride required for the reaction
  • DCFA 2,4-dichloro-5- fluoro acetophenone
  • the invention provides a process for synthesis of 2,4-dichloro-5- fluoro acetophenone (DCFA), the process comprising first reacting 3,4-dichloronitrobenzene with potassium fluoride having bulk density in the range of 0.2 to 1.3, to form a fluorinated intermediate product, then reacting the intermediate product with chlorine to form dichlorofluorobenzene and finally acylating dichlorofluorobenzene using an acylating agent to form a mixture containing DCFA along with impurities, followed by purification and enrichment of DCFA in the mixture by melt crystallization wherein potassium fluoride I iS synthesized from potassium chloride generated in the first reaction
  • DCFA 2,4-dichloro-5- fluoro acetophenone
  • the invention provides a process for synthesis of 2,4-dichloro-5- fluoro acetophenone (DCFA), the process comprising first reacting 3,4-dichloronitrobenzene with potassium fluoride having bulk density in the range of 0.2 to 1.3, to form a fluorinated intermediate product, then reacting the intermediate product with chlorine to form dichlorofluorobenzene and finally acylating dichlorofluorobenzene using an acylating agent to form a mixture containing DCFA along with impurities, followed by purification and enrichment of DCFA in the mixture by melt crystallization wherein the melt crystallization is carried out, in a first crystallisation stage comprising charging the mixture in a crystallizer, cooling the mixture in the crystalliser, seeding the cold mixture by pure crystalline DCFA to form first purified crystals and a first mother liquor, melting the first purified crystals at a temperature above a predetermined temperature, reducing the temperature of the melt to form second purified crystals and
  • DCFA
  • the invention provides a process for synthesis of 2,4-dichloro-5- fluoro acetophenone (DCFA), the process comprising first reacting 3,4-dichloronitrobenzene with potassium fluoride having bulk density in the range of 0.2 to 1.3, to form a fluorinated intermediate product, then reacting the intermediate product with chlorine to form dichlorofluorobenzene and finally acylating dichlorofluorobenzene using an acylating agent to form a mixture containing DCFA along with impurities, followed by purification and enrichment of DCFA in the mixture by melt crystallization wherein the melt crystallization is carried out, in a first crystallisation stage comprising charging the mixture in a crystallizer, cooling the mixture in the crystallizer at a temperature in the range of about O 0 C to -30 0 C, seeding the cold mixture by pure crystalline DCFA to form first purified crystals and a first mother liquor, melting the first purified crystals at a temperature above a pre
  • the invention provides a process for synthesis of 2,4-dichloro-5- fiuoro acetophenone (DCFA), the process comprising first reacting 3,4-dichloronitrobenzene with potassium fluoride having bulk density in the range of 0.2 to 1.3, to form a fluorinated intermediate product, then reacting the intermediate product with chlorine to form dichlorofluorobenzene and finally acylating dichlorofiuorobenzene using an acylating agent to form a mixture containing DCFA along with impurities, followed by purification and enrichment of DCFA in the mixture by melt crystallization wherein the melt crystallization is carried out, in a first crystallisation stage comprising charging the mixture in a crystallizer, cooling the mixture in the crystallizer at a temperature in the range of about - 12 0 C to -15 0 C, seeding the cold mixture by pure crystalline DCFA to form first purified crystals and a first mother liquor, melting the first purified crystals at a temperature
  • the invention provides a process for synthesis of 2,4-dichloro-5- fluoro acetophenone (DCFA), the process comprising first reacting 3,4-dichloronitrobenzene with potassium fluoride having bulk density in the range of 0.2 to 1.3, to form a fluorinated intermediate product, then reacting the intermediate product with chlorine to form dichlorofluorobenzene and finally acylating dichlorofluorobenzene using an acylating agent to form a mixture containing DCFA along with impurities, followed by purification and enrichment of DCFA in the mixture by melt crystallization wherein the melt crystallization is carried out, in a first crystallisation stage comprising charging the mixture in a crystallizer, cooling the mixture in the crystalliser, seeding the cold mixture by pure crystalline DCFA to form first purified crystals and a first mother liquor, melting the first purified crystals at a temperature above 20 0 C, reducing the temperature of the melt to form second purified crystals and a
  • the invention provides a process for synthesis of 2,4-dichloro-5- fluoro acetophenone (DCFA), the process comprising first reacting 3,4-dichloronitrobenzene with potassium fluoride having bulk density in the range of 0.2 to 1.3, to form a fluorinated intermediate product, then reacting the intermediate product with chlorine to form dichlorofluorobenzene and finally acylating dichlorofluorobenzene using an acylating agent to form a mixture containing DCFA along with impurities, followed by purification and enrichment of DCFA in the mixture by melt crystallization wherein the melt crystallization is carried out, in a first crystallisation stage comprising charging the mixture in a crystallizer, cooling the mixture in the crystalliser, seeding the cold mixture by pure crystalline DCFA to form first purified crystals and a first mother liquor, melting the first purified crystals at a temperature above a predetermined temperature, reducing the temperature of the melt to -8 0 C or less to
  • the invention provides a process for synthesis of 2,4-dichloro-5- fluoro acetophenone (DCFA), the process comprising first reacting 3,4- dichloronitrobenzene with potassium fluoride having bulk density in the range of 0.2 to 1.3, to form a fluorinated intermediate product, then reacting the intermediate product with chlorine to form dichlorofluorobenzene and finally acylating dichlorofluorobenzene using an acylating agent to form a mixture containing DCFA along with impurities, followed by purification and enrichment of DCFA in the mixture by melt crystallization wherein the melt crystallization is carried out, in a first crystallisation stage comprising charging the mixture in a crystallizer, cooling the mixture in the crystalliser, seeding the cold mixture by pure crystalline DCFA to form first purified crystals and a first mother liquor, melting the first purified crystals at a temperature above a predetermined temperature, reducing the temperature of the melt to form second purified crystals and a
  • the invention provides a process for synthesis of 2,4-dichloro-5- fluoro acetophenone (DCFA), the process comprising first reacting 3,4- dichloronitrobenzene with potassium fluoride having bulk density in the range of 0.2 to 1.3, to form a fluorinated intermediate product, then reacting the intermediate product with chlorine to form dichlorofluorobenzene and finally acylating dichlorofluorobenzene using an acylating agent to form a mixture containing DCFA along with impurities, followed by purification and enrichment of DCFA in the mixture by melt crystallization wherein the melt crystallization is carried out, in a first crystallisation stage comprising charging the mixture in a crystallizer, cooling the mixture in the crystalliser, seeding the cold mixture by pure crystalline DCFA to form first purified crystals and a first mother liquor, melting the first purified crystals at a temperature above a predetermined temperature, reducing the temperature of the melt to form second purified crystals and a
  • the fluorinated intermediate product in the process of the invention is prepared by the procedure as illustrated in examples 1 to 8. Further, the acylation of DCFB is carried out by the procedure illustrated in examples 9 to 13.
  • the invention provides a process for obtaining DCFA in high purity and yield.
  • the process of the invention uses potassium fluoride having a bulk density in the range of 0.2 to 1.3.
  • potassium fluoride used in the process of the invention has a bulk density in the range of 0.2 to 0.5. More advantageously, the density of potassium fluoride is 0.5 g/cc.
  • the potassium fluoride used in the process of the invention is obtained either from potassium fluoride that is commercially available or from potassium fluoride that is generated from the potassium chloride by-product formed during the potassium fluoride treatment.
  • the potassium fluoride has a moisture content in the range of 200 to 3000 ppm. More advantageously, the moisture content of potassium fluoride is less than 600 ppm.
  • the process of fluorination is advantageously carried out in the presence of a phase transfer catalyst. More advantageously, the phase transfer catalyst concentration is in the range of 0.1 to 10 % w/w. Still more advantageously, the phase transfer catalyst concentration is 3%.
  • the fluorination is usually carried out in DMSO solvent, onium salt could be chosen from quaternary ammonium salt, quaternary phosphonium salt ,quaternary phosphazenium salt and amidophosphonium salts.
  • onium salts are triethy dodecyl ammonium halide, trimethyl dodecyl halides, ethylmethyl dodecyl halides.
  • the hydrocarbon radical of the onium group can vary from Cl - C22 or a mxture thereof.
  • the tetraalkylphosphonium salt of the present invention has a- branched alkyl chain containing 9 or more carbon atoms in total.
  • the branched alkyl chain containing 9 or more carbon atoms in total is preferably a branched alkyl chain containing 9 to 100 carbon atoms in total, more preferably a branched alkyl chain containing 12 to 50 carbon atoms in total, further preferably a branched alkyl chain containing 16 to 36 carbon atoms in total. If the tetraalkylphosphonium salt has a branched alkyl chain containing less than 9 carbon atoms in total, On the other hand
  • branched alkyl chain containing 9 or more carbon atoms in total include, for example, 2-butyloctyl group, 2-hexyldecyl group, 2-octyldodecyl group, 2- decyltetradecyl group, 2-dodecylhexadecyl group, 2-tetradecyloctadecyl group, 2- hexadecylicosyl group, 3,5,5-trimethylhexyl group, 3,7-dimethyloctyl group, 3,7,11,15- tetramethylhexadecyl group and so forth.
  • branched alkyl chains branching at the 2-position such as 2-butyloctyl group, 2-hexyldecyl group, 2-octyldodecyl group, 2- decyltetradecyl group, 2-dodecylhexadecyl group, 2-tetradecyloctadecyl group and 2- hexadecylicosyl group.
  • 2-Hexadecylicosyl group is more preferred.
  • the alkyl group may have an unsaturated bond (double bond or triple bond) or a substituent such as an ester group, an amide group, an ether group or a phenylene group as a partial structure.
  • phosphonium compounds are tetrapenyl phosphonium halide, ethyltriphenyl phosphonium halides or a mixture there of.
  • amidophosphonium are tetrakis ( dimethylamido)phosphonium halide, diethyl dimethylamidophosphonium halide etc.
  • Another group of catalyst can be chosen from guanidinium salt of the type, hexamethyl guanidinium halide, pentaethy methyl guanidinium halide, hexaethylguanidinium halides or with mixed substituents.
  • the anion A- of the phase transfer catalyst can be chosen from halides, carbonates, sulphates, nitrate, acetates, phenolates, sulfides etc.
  • the DCNB: DMSO ratio is in the range of 1 :0.3 to 1:5. More advantageously, the ratio is 1 :0.6.
  • the acylation of dichlorofluorobenzene in the process of the invention is usually carried out by acetyl chloride.
  • a DCFB: acetylchloride ratio (by w/w) of 1 :0.4 to 1:1 is maintained during the acylation. More advantageously, the DCFB: acetyl chloride ratio is 1 :0.55.
  • DCFB: AlCl 3 ratio (by w/w) is advantageously maintained in the range of 1 :1.5 to 1:2.2. More advantageously, the DCFB: AlCl 3 ratio is maintained at 1 :1.8.
  • the acetylation temperature is advantageously maintained in the range of 80 deg C to 130 0 C. More advantageously, the acetylation temperature is maintained in the range of 90-115 0 C, Still more advantageously, the acetylation temperature is maintained in the range of 110-115° C.
  • the activation temperature during addition of acetyl chloride can vary from 10 0 C to 50 0 C, preferably in the range of 20 0 C to 40 0 C, more preferably in the range of 25-35 0 C.
  • the AlCl 3 built up in quenching water can vary from 8% AlCl 3 solution to 12 % AlCl 3 solution.
  • the crude DCFA product prepared by the process of the invention can be extracted with halogenated solvents like ethylene dichloride , chlorobenzene.
  • the concentration of the solvent may vary from 0 - 50% with respect to the starting material.
  • the process of the invention also involve purification of a mixture containing DCFA and impurities, by melt crystallization.
  • the melt crystallization can include various crystallization stages involving introduction of impure DCFA into a crystallizer, cooling, seeding, separation of purified crystals and the mother liquor and slowly increasing the temperature of the purified crystals to sweating temperature.
  • the mother liquor adhered to the purified crystals are sweated off.
  • Fresh DCFA crystals are formed from the mother liquor collected after each stage of crystallization and the crystals are separated from the fresh mother liquor formed during each time and sweated off to obtain highly pure DCFA crystals.
  • the purified crystals are sweated off at a temperature in the range of 30 to 40 0 C.
  • the melt crystallization is continued for enrichment of purified DCFA crystals till the desired yield of DCFA is obtained.
  • Advantageously DCFA is obtained in a yield greater than 95%.
  • Example 1 FIuorination of 3,4-dichloronitrobenzene (3,4-DCNB):
  • the reaction mixture was filtered to remove KCl and unreacted KF and was washed twice by 50ml DMSO. DMSO was recovered by distillation under reduced pressure to give brown colored 3-chloro, 4-fluoro nitrobenzene crude product as syrupy liquid (yield 129.7 g).
  • the composition by GC % area is as follows.
  • the reaction mixture was filtered to remove KCl and unreacted KF and was washed twice by 50ml DMSO.
  • DMSO was recovered by distillation under reduced pressure to give brown colored 3-chloro, 4-fluoro nitrobenzene crude product as syrupy liquid (yield 127.39 g).
  • the composition by GC % area is as follows.
  • Example 7 Synthesis of 4-fluoro-3-chloro nitrobenzene from 3, 4-dichloronitobenzene on a plant scale using DMSO as solvent
  • the synthesis was carried out in a stainless steel reactor SS 316 was provided having diameter of 300 mm, height of 450 mm and possessing pitched blades diameter of 110 mm.
  • the stainless steel reactor was also provided with variable speed motor and mechanical seal.
  • Into the stainless steel reactor 6 kg of 3, 4- DCNB of specific gravity 1.45 was added and melted at a temperature of 42 0 C.
  • 4- DCNB, 3 liters of toluene and 4.2 kg of DMSO (DMSO level less than 0.65% of 3, 4- DCNB and water content less than 2000ppm) were added to obtain a reaction mass.
  • the reaction mass was refluxed at a temperature of 120 0 C followed by the application of vacuum of around 300 mm to 500 mm of Hg to remove moisture present in 3, 4- DCNB azeotropically. The vacuum was continued till the required moisture level of the reaction mass was less than 500 ppm. After removal of moisture from the reaction mass, 1.99 kg of spray dried potassium fluoride (bulk density less than 0.6) and 120 grams of catalyst (TBAB) were added and mixed properly at a temperature of 130 0 C to 140 0 C to obtain a reaction mixture. The moisture was again removed from the reaction mixture by vacuum distillation till the required moisture level of the reaction mixture was less than 350 ppm and finally distilling out the toluene completely from the reaction mixture.
  • the reaction mixture was further heated to a temperature of 170 0 C to 185 0 C for 3 to 5 hrs.
  • the sample reaction mixture was taken at every hour and checked on G.C for conversion of 3, 4- DCNB to 4-fluoro-3-chloro nitrobenzene. Heating of the reaction was stopped when about 96% or more of 3, 4- DCNB is converted to 4-fluoro-3-chloro nitrobenzene.
  • Example 8 Synthesis of 4-fluoro-3-chloro nitrobenzene from 3, 4- dichloronitobennzene on a plant scale using DMSO and acetone as solvents.
  • the synthesis was carried out in a stainless steel reactor SS 316 was provided having diameter of 300 mm, height of 450 mm and possessing pitched blades diameter of 110 mm.
  • the stainless steel reactor was also provided with variable speed motor and mechanical seal.
  • 4- DCNB of specific gravity 1.45 was melted at a temperature of 42 0 C.
  • 4- DCNB, 3 liters of toluene and 4.2 kg of DMSO (DMSO level less than 0.65% of 3, 4- DCNB and water content less than 2000ppm) were added to obtain the reaction mass.
  • the reaction mass was refluxed at a temperature of 120 0 C followed by the application of vacuum around 300 mm to 500 mm of Hg to remove moisture present in 3, 4- DCNB azeotropically. The vacuum was continued till the required moisture level of the reaction mass was less than 500 ppm.
  • the reaction mass of 3, 4- DCNB and DMSO mixture was carefully filled in an air tight container and kept under nitrogen pressure.
  • 2 kg of KF and 1.5 liters of acetone was taken and mixed to obtain a second reaction mass.
  • the second reaction mass was heated at a temperature of 90 0 C to remove acetone.
  • vacuum of around 730 mm of Hg was applied to the second reaction mass. The second reaction mass was heated till it was completely dry and heating was continued for one hour.
  • the reaction mass of 3, 4- DCNB and DMSO mixture was added to the second reaction followed by addition of 120 grams of catalyst (TBAB) to obtain a reaction mixture.
  • the reaction mixture was heated to a temperature of 130 0 C to 140 0 C.
  • the moisture is again removed from the reaction mixture by vacuum distillation till the required moisture level of the reaction mixture was less than 350 ppm and finally distilling out the toluene completely from the reaction mixture.
  • the reaction mixture was further heated to a temperature of 170 0 C to 185 0 C for 3 to 5 hrs.
  • the sample reaction mixture was taken at every hour and checked on G.C for conversion of 3, 4- DCNB to 4-fluoro-3-chloro nitrobenzene. Heating of the reaction mixture was stopped when about 95% or more of 3, 4- DCNB is converted to 4-fluoro-3-chloro nitrobenzene.
  • reaction mixture was quenched using 1 kg ice and 500 ml water maintaining the temperature below 5O 0 C.
  • the aqueous layer thus obtained was extracted with 200 ml of DCM thrice and combined all the extracts for evaporation. After the evaporation of DCM, 294.5g of brown product was obtained with the following composition.
  • Example 11 Preparation of 2, 4-dichloro-5-fluoro acetophenone (DCFA) from 2, 4- dichloro Fluorobenzene (DCFB) using 15% excess of Acetyl Chloride
  • DCFB 250 g, 1.51 mol
  • AlCB 297 g, 2.22 mol
  • the suspension was stirred at room temperature.
  • Acetyl chloride 135.4 g, 1.73 mol was added drop wise within two hours by maintaining the temperature 30-35 0 C. After complete addition of acetyl chloride the mixture was quickly heated to 110-120 0 C for 5-6 hrs.
  • reaction kinetics was monitored by taking samples every two hrs. After the reaction was stopped the crude reaction mixture was cooled to ambient temperature. Then the reaction mixture was quenched using 1 kg ice and 500 ml water maintaining the temperature below 5O 0 C. The aqueous layer thus obtained was extracted with 200 ml of DCM thrice and combined all the extracts for evaporation. After the evaporation of DCM, 297.2g of brown product was obtained with the following composition.
  • reaction mixture was quenched using 1 kg ice and 500 ml water maintaining the temperature below 5O 0 C.
  • the aqueous layer thus obtained was extracted with 200 ml of DCM thrice and combined all the extracts for evaporation. After the evaporation of DCM, 298.8g of brown product was obtained with the following composition.
  • reaction mixture was quenched using 1 kg ice and 500 ml water maintaining the temperature below 5O 0 C.
  • the aqueous layer thus obtained was extracted with 200 ml of DCM thrice and combined all the extracts for evaporation. After the evaporation of DCM, 291.39g of brown product was obtained with the following composition.
  • DCFA synthesized by example 4 was subjected to melt crystallization.
  • the first eutectic mixture comprising DCFB is distilled followed by a part of the distillate being added to the next batch of the feed and another part being used as raw material in the acylation step.
  • the second eutectic mixture comprising a composition similar to the feed (crude mixture) is added to the next batch of feed.
  • the product then obtained contains DCFA with 99% purity.
  • the product obtained is partially recycled and enhances the yield.
  • a portion (about 20%) is subjected to elevated temperatures and thus decomposition and subsequent loss of DCFA is minimized. The process results in increase in yield of DCFA by about 6-8%.
  • a crude product mixture containing DCFA 63gm, DCFB 26gm, DCFA isomer 5gm, higher boiler 5gm and tar lgm was charged in a lab scale crystallizer at temperature 30 0 C in such a way that the inner tube is dipped significantly into the crude product mixture.
  • the temperature of the liquid was slowly reduced to temperature below 4 C by circulating cool liquid and seeding was done with pure DCFA crystalline powder (0.5gm). Finally, the temperature was reduced to temperature -15 0 C and mixture was kept for 7 hours at -15 C for formation of significant amounts of crystal. The residual liquid was drained out after crystal formation was nearly complete. The crystals thus obtained were melted at temperature above 20 0 C and stored for recycle in the second batch.
  • Example 16 Purification of crude DCFA product in an SS crystallizer
  • a crude mixture containing 73gm DCFA, 5gm DCFA-isomer, 18gm DCFB, 2gm high boiler and tar 2gm was charged in a SS crystallizer .
  • the temperature of the liquid was brought down to 25 0 C by circulating cool liquid slowly and further seeding with DCFA crystals at the cooled temperature. After seeding, the temperature was slowly reduced to -15 0 C for 8hrs. Then the mother liquor was drained out at -15 0 C and the crystallizer was slowly heated to temperature about 33-34 0 C for sweating (3 0 C temperature raise every one hour). Finally the product with purity of 99.2%, containing DCFB 0.8% or less was obtained.
  • the process of the invention results in high yield synthesis of DCFA from PNCB.
  • DCFA synthesized during the process is isolated and purified by melt crystallization from the mother liquor resulting in continuous enrichment of DCFA in the crystals that are repeatedly formed and by continuous removal of impurities.
  • the process of invention provides DCFA having high purity. Owing to the use of potassium fluoride in near stoichiometric quantities (not greater than 20% in excess of the stoichiometric quantitity), residual potassium fluoride is minimized and thereby contamination of the product is reduced. This enables easier separation and purification of DCFA. Further, DMSO used during the potassium fluoride treatment can be recovered and reused with reduced water content. Furthermore, the reaction waste is reduced and process efficiency is increased leading to overall reduction in the cost. During the process of the invention, the decomposition of DCFA is avoided. Further, the purification procedures as followed in the method of the invention is simple, cheaper and high yield producing, compared to purification procedures conventionally followed.

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Abstract

La présente invention concerne un procédé de synthèse de la 2,4-dichloro-5-fluoro-acétophénone (DCFA) qui consiste à faire réagir du 3,4-dichloronitrobenzène avec du fluorure de potassium ayant une densité apparente comprise entre 0,2 et 1,3 pour former un intermédiaire fluoré, puis faire réagir cet intermédiaire avec du chlore pour former du dichlorofluorobenzène, et enfin acyler le dichlorofluorobenzène avec un agent acylant pour former un mélange contenant de la DCFA et des impuretés, lequel mélange est purifié et enrichi en DCFA par cristallisation à l'état fondu.
PCT/IN2009/000652 2008-11-18 2009-11-17 Procédé de synthèse de 2,4-dichloro-5-fluoro-acétophénone (dcfa) WO2010058421A2 (fr)

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IN2433MU2008 2008-11-18
IN2433/MUM/2008 2008-11-18
IN1671/MUM/2009 2009-07-20
IN1671MU2009 2009-07-20

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CN102796003A (zh) * 2012-07-11 2012-11-28 常州大学 2-氟-4,5-二氯硝基苯的制备方法
CN104496772A (zh) * 2014-12-26 2015-04-08 浙江林江化工股份有限公司 2,4-二氯-5-氟苯乙酮母液的纯化方法
WO2022099439A1 (fr) * 2020-11-10 2022-05-19 杭州臻挚生物科技有限公司 Procédé de préparation d'acide 2,4,5-trifluorophénylacétique
CN115650831A (zh) * 2022-12-26 2023-01-31 山东国邦药业有限公司 一种2,4-二氯-5-氟苯乙酮的合成方法

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EP0088423A2 (fr) * 1982-03-08 1983-09-14 Daikin Kogyo Co., Ltd. Fluorocétones ainsi que leurs produits cycliques de condensation
EP0309789A1 (fr) * 1987-09-08 1989-04-05 Sterling Winthrop Inc. Acides oxo-4 quinoléinecarboxyliques-3 utiles comme agents antibactériens et leur préparation
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102796003A (zh) * 2012-07-11 2012-11-28 常州大学 2-氟-4,5-二氯硝基苯的制备方法
CN104496772A (zh) * 2014-12-26 2015-04-08 浙江林江化工股份有限公司 2,4-二氯-5-氟苯乙酮母液的纯化方法
WO2022099439A1 (fr) * 2020-11-10 2022-05-19 杭州臻挚生物科技有限公司 Procédé de préparation d'acide 2,4,5-trifluorophénylacétique
CN115650831A (zh) * 2022-12-26 2023-01-31 山东国邦药业有限公司 一种2,4-二氯-5-氟苯乙酮的合成方法

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