EP1240127A1 - Process for the production of trifluoromethylacetophenones - Google Patents
Process for the production of trifluoromethylacetophenonesInfo
- Publication number
- EP1240127A1 EP1240127A1 EP00975941A EP00975941A EP1240127A1 EP 1240127 A1 EP1240127 A1 EP 1240127A1 EP 00975941 A EP00975941 A EP 00975941A EP 00975941 A EP00975941 A EP 00975941A EP 1240127 A1 EP1240127 A1 EP 1240127A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- general formula
- group
- aromatic ring
- process according
- acidification
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 238000000034 method Methods 0.000 title claims abstract description 23
- LBWMQVOHFPLVBY-UHFFFAOYSA-N 3,3,3-trifluoro-1-phenylpropan-1-one Chemical class FC(F)(F)CC(=O)C1=CC=CC=C1 LBWMQVOHFPLVBY-UHFFFAOYSA-N 0.000 title claims abstract description 11
- 238000004519 manufacturing process Methods 0.000 title description 3
- -1 trifluoromethylbenzoyl halide Chemical class 0.000 claims abstract description 19
- 230000020477 pH reduction Effects 0.000 claims abstract description 10
- 125000003118 aryl group Chemical group 0.000 claims abstract description 9
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims abstract description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 6
- 239000007818 Grignard reagent Substances 0.000 claims abstract description 5
- 239000002253 acid Substances 0.000 claims abstract description 4
- 238000002360 preparation method Methods 0.000 claims abstract description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 3
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims abstract description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract description 3
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 3
- 239000000460 chlorine Substances 0.000 claims abstract description 3
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 3
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 3
- 239000011737 fluorine Substances 0.000 claims abstract description 3
- 125000005843 halogen group Chemical group 0.000 claims abstract description 3
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 3
- 239000001301 oxygen Substances 0.000 claims abstract description 3
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 3
- 125000004434 sulfur atom Chemical group 0.000 claims abstract description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- ABXGMGUHGLQMAW-UHFFFAOYSA-N 1-[3-(trifluoromethyl)phenyl]ethanone Chemical compound CC(=O)C1=CC=CC(C(F)(F)F)=C1 ABXGMGUHGLQMAW-UHFFFAOYSA-N 0.000 claims description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- RUJYJCANMOTJMO-UHFFFAOYSA-N 3-(trifluoromethyl)benzoyl chloride Chemical group FC(F)(F)C1=CC=CC(C(Cl)=O)=C1 RUJYJCANMOTJMO-UHFFFAOYSA-N 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 235000019270 ammonium chloride Nutrition 0.000 claims description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 2
- 239000000920 calcium hydroxide Substances 0.000 claims description 2
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 2
- BRPQOXSCLDDYGP-UHFFFAOYSA-N calcium oxide Chemical compound [O-2].[Ca+2] BRPQOXSCLDDYGP-UHFFFAOYSA-N 0.000 claims description 2
- 239000000292 calcium oxide Substances 0.000 claims description 2
- ODINCKMPIJJUCX-UHFFFAOYSA-N calcium oxide Inorganic materials [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 claims description 2
- 239000011787 zinc oxide Substances 0.000 claims description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000007792 addition Methods 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 238000003756 stirring Methods 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- YWQNAFUPXWKYRS-UHFFFAOYSA-N morpholin-4-yl-[3-(trifluoromethyl)phenyl]methanone Chemical compound FC(F)(F)C1=CC=CC(C(=O)N2CCOCC2)=C1 YWQNAFUPXWKYRS-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- XOBKSJJDNFUZPF-UHFFFAOYSA-N Methoxyethane Chemical compound CCOC XOBKSJJDNFUZPF-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 239000005857 Trifloxystrobin Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229960004132 diethyl ether Drugs 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000000855 fungicidal effect Effects 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229940050176 methyl chloride Drugs 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 239000011369 resultant mixture Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- ONCZDRURRATYFI-TVJDWZFNSA-N trifloxystrobin Chemical compound CO\N=C(\C(=O)OC)C1=CC=CC=C1CO\N=C(/C)C1=CC=CC(C(F)(F)F)=C1 ONCZDRURRATYFI-TVJDWZFNSA-N 0.000 description 1
Classifications
-
- 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
- C07C45/004—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reaction with organometalhalides
-
- 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
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
Definitions
- the present invention relates to a method for preparation of trifluoromethylacetophenones, specifically, 3-trifluoromethylacetophenone.
- the present invention provides a process for producing the trifluoromethylacetophenones in high yield and purity and employs readily available starting materials. Furthermore, the described process has advantages with respect to environmental protection.
- the process of the present invention comprises the two steps of (a) reacting a trifluoromethylbenzoyl halide with a cyclic secondary amine in the presence of aqueous base to form a cycloalkyl-trifluoromethylbenzamide and (b) addition of a methyl Grignard reagent to said benzamide followed by acidification with aqueous acetic acid to form the product.
- a trifluoromethylbenzoyl halide with a cyclic secondary amine in the presence of aqueous base to form a cycloalkyl-trifluoromethylbenzamide
- a methyl Grignard reagent to said benzamide followed by acidification with aqueous acetic acid to form the product.
- the present invention provides a process for the preparation of trifluoromethylacetophenones of the general formula I
- Hal is a halogen atom selected from the group consisting of fluorine, chlorine, bromine, and iodine, with a cyclic secondary amine of the general formula
- A is C 3 -C 7 -alkylene bridge which may be interrupted by a oxygen or sulfur atom in the presence of an aqueous base, used as an acid acceptor, resulting in the formation of a cycloalkyl-trifluoromethylbenzamide of the general formula IV
- the process is used to produce 3-trifluoromethylacetophenone.
- the cyclic secondary amine of formula III specifically contributes to the high yield and purity of the trifluoromethylacetophenone so produced.
- the cyclic secondary amine typically denotes pyrrolidine, piperidine either unsubstituted or substituted in 2, 3 or 4 position by lower alkyl like methyl or ethyl, or preferably is morpholine or thiomorpholine.
- the reactions of both steps (a) and (b) are typically carried out at moderate temperatures, ranging from about room temperature (+20°C to 25°C) to about +60°C.
- the trifluoromethylbenzoyl halide reactants are known. Particularly useful in the practice of the present invention is 3-trifluoromethylbenzoyl chloride.
- the bases useful as an acid acceptor are sodium hydroxide, potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium hydroxide, zinc oxide, calcium oxide and mixtures thereof in aqueous solution at concentrations of about 5-70%.
- the cyclic amine may be any of those within the above-defined formula III and mixtures of one or more thereof, but are not limited to given examples.
- Particularly useful in the process of the present invention are piperidine and morpholine.
- the process of the invention is carried out in an inert solvent such as an ether like diethylether, ethylmethylether, tert.butyl-methylether, tetrahydrofuran, dioxane and the like.
- Grignard reagents used for the present invention are the Grignard reagents which employ methyl as the alkyl substituent. Typical are l-Mg-CH 3 , Br-Mg-CH 3 and CI-Mg-CH 3 .
- Acidification is preferably accomplished with acetic acid.
- acidification reagents such as hydrochloric acid, sulfuric acid and ammonium chloride may also be employed in the process of the present invention.
- the high purity products of the present invention facilitate the handling as intermediates for the production of the important agricultural fungicide trifloxystrobin.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention provides a novel process for the preparation of trifluoromethylacetophenones of general formula (I), wherein the position of the CF3-group on the aromatic ring may be in the 2- or 3-position relative to the acetyl, which process comprises (a) reacting a trifluoromethylbenzoyl halide of general formula (II), wherein the position of the CF3-group on the aromatic ring may be in the 2- or 3-position relative to the acetyl and Hal is a halogen atom selected from the group consisting of fluorine, chlorine, bromine, and iodine, with a cyclic secondary amine of general formula (III), wherein A is C3-C7-alkylene bridge which may be interrupted by a oxygen or sulfur atom in the presence of an aqueous base, used as an acid acceptor, resulting in the formation of a cycloalkyl-trifluoromethylbenzamide of general formula (IV), wherein the position of the CF3-group on the aromatic ring and A are as defined above, and (b) adding a methyl Grignard reagent to said cycloalkyl-trifluoromethylbenzamide followed by acidification with an aqueous acidification reagent to form the trifluoromethylacetophenone of formula (I).
Description
Process for the production of trifluromethylacetophenones
The present invention relates to a method for preparation of trifluoromethylacetophenones, specifically, 3-trifluoromethylacetophenone.
Several processes have been used to produce 3-trifluoromethylacetophenone in the past; however, all of them are not properly suited for a large scale industrial production process which should be a simple and efficient process to provide trifluoromethylacetophenones in high yield and high purity starting with readily commercially available reagents.
The present invention provides a process for producing the trifluoromethylacetophenones in high yield and purity and employs readily available starting materials. Furthermore, the described process has advantages with respect to environmental protection.
The process of the present invention comprises the two steps of (a) reacting a trifluoromethylbenzoyl halide with a cyclic secondary amine in the presence of aqueous base to form a cycloalkyl-trifluoromethylbenzamide and (b) addition of a methyl Grignard reagent to said benzamide followed by acidification with aqueous acetic acid to form the product. The use of cyclic amines has the advantage of reducing wastes by recycling of the amines.
The present invention provides a process for the preparation of trifluoromethylacetophenones of the general formula I
wherein the position of the CF3-group on the aromatic ring may be in the 2- or 3- position relative to the acetyl, which process comprises
(a) reacting a trifluoromethylbenzoyl halide of the general formula II
wherein the position of the CF3-group on the aromatic ring may be in the 2- or 3- position relative to the acetyl and Hal is a halogen atom selected from the group consisting of fluorine, chlorine, bromine, and iodine, with a cyclic secondary amine of the general formula
HN ( III )
wherein A is C3-C7-alkylene bridge which may be interrupted by a oxygen or sulfur atom in the presence of an aqueous base, used as an acid acceptor, resulting in the formation of a cycloalkyl-trifluoromethylbenzamide of the general formula IV
wherein the position of the CF3-group on the aromatic ring and A are as defined above, and (b) adding a methyl Grignard reagent to said cycloalkyl-trifluoromethylbenzamide followed by acidification with an aqueous acidification reagent to form the trifluoromethylacetophe- none of formula I.
In a preferred embodiment of the present invention the process is used to produce 3-trifluoromethylacetophenone.
The cyclic secondary amine of formula III specifically contributes to the high yield and purity of the trifluoromethylacetophenone so produced.
The cyclic secondary amine typically denotes pyrrolidine, piperidine either unsubstituted or substituted in 2, 3 or 4 position by lower alkyl like methyl or ethyl, or preferably is morpholine or thiomorpholine.
The reactions of both steps (a) and (b) are typically carried out at moderate temperatures, ranging from about room temperature (+20°C to 25°C) to about +60°C. The trifluoromethylbenzoyl halide reactants are known. Particularly useful in the practice of the present invention is 3-trifluoromethylbenzoyl chloride. Examples of the bases useful as an acid acceptor, are sodium hydroxide, potassium hydroxide, potassium carbonate, potassium
bicarbonate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium hydroxide, zinc oxide, calcium oxide and mixtures thereof in aqueous solution at concentrations of about 5-70%. The cyclic amine may be any of those within the above-defined formula III and mixtures of one or more thereof, but are not limited to given examples. Particularly useful in the process of the present invention are piperidine and morpholine. With preference the process of the invention is carried out in an inert solvent such as an ether like diethylether, ethylmethylether, tert.butyl-methylether, tetrahydrofuran, dioxane and the like.
Grignard reagents used for the present invention are the Grignard reagents which employ methyl as the alkyl substituent. Typical are l-Mg-CH3 , Br-Mg-CH3 and CI-Mg-CH3 .
Acidification is preferably accomplished with acetic acid. However other acidification reagents such as hydrochloric acid, sulfuric acid and ammonium chloride may also be employed in the process of the present invention.
The high purity products of the present invention facilitate the handling as intermediates for the production of the important agricultural fungicide trifloxystrobin.
The following examples illustrate the present invention. They are not to be construed to limit the scope of the claims in any way.
EXAMPLE 1 :
88 g of water and 45 g of morpholine are added to a 750 ml flask equipped with a stirrer, two addition funnels, condenser, and heating mantle. To this mixture is simultaneously added with stirring 104.3 g (0.5 mole) of 3-trifluoromethylbenzoyl chloride and 40.8 g of 50% aqueous NaOH. The pH during these additions is maintained between 9-10. The temperature during these additions is maintained between +40°C and +55°C. After completion of the additions, the mixture is heated for 30 minutes to +55°C to +60°C with stirring. After addition of 75 g of toluene the lower aqueous layer is discarded. Additional toluene and water is added to the flask with stirring. After standing again for a few minutes the lower aqueous layer again is removed. The solvent of the upper organic layer is
evaporated under vacuum. After complete removal of the toluene from the organic layer 4-(3-trifluoromethylbenzoyl)-morpholine is isolated and is used in Example 2.
EXAMPLE 2:
310 g of tetrahydrofuran, 18 g of magnesium chips and a few crystals of iodine is added to a 1 liter flask equipped with a stirrer, condenser, dry nitrogen atmosphere, and a subsurface addition tube. The mixture is heated to +50°C with gentle stirring. To this mixture is added 41.1 g of methyl chloride by subsurface addition, maintaining the temperature between +50°C and + 60°C. The resultant methyl magnesium Grignard reagent is cooled to +30°C. To this Grignard solution is added with stirring 4-(3-trifluoromethylbenzoyl)-morpholine (as prepared in Example 1 ) dissolved in tetrahydrofuran over a period of one to two hours. After complete addition the mixture is heated to a temperature between +35°C and +40°C and stirred for 18 hours.
To another 1 liter flask, similarly equipped, is added 90 g of acetic acid and 205 g of water. With stirring, the above Grignard mixture is added to this second flask. The resultant mixture is then allowed to separate. The lower aqueous layer is removed, and the upper organic layer is then washed several times with saturated brine. The organic layer is then heated under vacuum to remove tetrahydrofuran. After removal of the solvent, the product mixture is distilled under vacuum yielding 98% pure 3-trifluoromethylacetophenone.
Claims
1 . A process for the preparation of trifluoromethylacetophenones of the general formula I
wherein the position of the CF3-group on the aromatic ring may be in the 2- or 3- position relative to the acetyl, which process comprises
(a) reacting a trifluoromethylbenzoyl halide of the general formula II
wherein the position of the CF3-group on the aromatic ring may be in the 2- or 3- position relative to the acetyl and Hal is a halogen atom selected from the group consisting of fluorine, chlorine, bromine, and iodine, with a cyclic secondary amine of the general formula
HN A ( III )
wherein A is C3-C7-alkylene bridge which may be interrupted by a oxygen or sulfur atom in the presence of an aqueous base, used as an acid acceptor, resulting in the formation of a cycloalkyl-trifluoromethylbenzamide of the general formula IV
wherein the position of the CF3-group on the aromatic ring and A are as defined above, and (b) adding a methyl Grignard reagent to said cycloalkyl-trifluoromethylbenzamide followed by acidification with an aqueous acidification reagent to form the trifluoromethylaceto- phenone of formula I.
2. A process according to claim 1 wherein the trifluoromethylbenzoyl halide is 3-trifluoromethylbenzoyl chloride.
3. A process according to claim 1 wherein the cyclic amine is morpholine or thiomorpholine.
4. A process according to claim 1 wherein 3-trifluoromethylacetophenone is produced.
5. A process according to claim 1 wherein the base is selected from sodium hydroxide, potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium hydroxide, zinc oxide or calcium oxide or a mixture thereof.
6. A process according to claim 1 wherein the acidification reagent is acetic acid, hydrochloric acid, sulfuric acid or ammonium chloride or a mixture thereof.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9929562 | 1999-12-14 | ||
| GBGB9929562.8A GB9929562D0 (en) | 1999-12-14 | 1999-12-14 | Organic compounds |
| PCT/EP2000/010596 WO2001044152A1 (en) | 1999-12-14 | 2000-10-27 | Process for the production of trifluoromethylacetophenones |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1240127A1 true EP1240127A1 (en) | 2002-09-18 |
Family
ID=10866309
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP00975941A Withdrawn EP1240127A1 (en) | 1999-12-14 | 2000-10-27 | Process for the production of trifluoromethylacetophenones |
Country Status (11)
| Country | Link |
|---|---|
| EP (1) | EP1240127A1 (en) |
| JP (1) | JP2003517029A (en) |
| KR (1) | KR20020056943A (en) |
| CN (1) | CN1409697A (en) |
| AU (1) | AU1388901A (en) |
| BR (1) | BR0016320A (en) |
| GB (1) | GB9929562D0 (en) |
| HK (1) | HK1052926A1 (en) |
| IL (1) | IL149713A0 (en) |
| MX (1) | MXPA02005873A (en) |
| WO (1) | WO2001044152A1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI518076B (en) * | 2008-04-09 | 2016-01-21 | 杜邦股份有限公司 | Method for preparing heterocyclic compound |
| JP5211876B2 (en) * | 2008-06-11 | 2013-06-12 | セントラル硝子株式会社 | Method for producing high purity 2'-trifluoromethylpropiophenone |
| CN104478792B (en) * | 2014-12-26 | 2016-10-05 | 西华大学 | A kind of compound with bacteriostatic activity and the preparation method and application of water solublity liquor thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9808447D0 (en) * | 1998-04-18 | 1998-06-17 | Zeneca Ltd | Process |
| US5969188A (en) * | 1999-01-05 | 1999-10-19 | Nipa Hardwicke, Inc. | Process for producing trifluoromethylacetophenones |
-
1999
- 1999-12-14 GB GBGB9929562.8A patent/GB9929562D0/en not_active Ceased
-
2000
- 2000-10-27 MX MXPA02005873A patent/MXPA02005873A/en unknown
- 2000-10-27 BR BR0016320-1A patent/BR0016320A/en not_active Application Discontinuation
- 2000-10-27 EP EP00975941A patent/EP1240127A1/en not_active Withdrawn
- 2000-10-27 AU AU13889/01A patent/AU1388901A/en not_active Abandoned
- 2000-10-27 WO PCT/EP2000/010596 patent/WO2001044152A1/en not_active Ceased
- 2000-10-27 JP JP2001545242A patent/JP2003517029A/en active Pending
- 2000-10-27 KR KR1020027006569A patent/KR20020056943A/en not_active Withdrawn
- 2000-10-27 CN CN00816915A patent/CN1409697A/en active Pending
- 2000-10-27 IL IL14971300A patent/IL149713A0/en unknown
- 2000-10-27 HK HK03105240.4A patent/HK1052926A1/en unknown
Non-Patent Citations (1)
| Title |
|---|
| See references of WO0144152A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1409697A (en) | 2003-04-09 |
| KR20020056943A (en) | 2002-07-10 |
| MXPA02005873A (en) | 2003-01-28 |
| JP2003517029A (en) | 2003-05-20 |
| HK1052926A1 (en) | 2003-10-03 |
| AU1388901A (en) | 2001-06-25 |
| GB9929562D0 (en) | 2000-02-09 |
| WO2001044152A1 (en) | 2001-06-21 |
| BR0016320A (en) | 2002-08-27 |
| IL149713A0 (en) | 2002-11-10 |
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