WO2001044152A1 - Process for the production of trifluoromethylacetophenones - Google Patents
Process for the production of trifluoromethylacetophenones Download PDFInfo
- Publication number
- WO2001044152A1 WO2001044152A1 PCT/EP2000/010596 EP0010596W WO0144152A1 WO 2001044152 A1 WO2001044152 A1 WO 2001044152A1 EP 0010596 W EP0010596 W EP 0010596W WO 0144152 A1 WO0144152 A1 WO 0144152A1
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- WO
- WIPO (PCT)
- Prior art keywords
- general formula
- group
- aromatic ring
- process according
- acidification
- Prior art date
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Classifications
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- 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.
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- 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
(a) reacting a trifluoromethylbenzoyl halide of the general formula II
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
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
(a) reacting a trifluoromethylbenzoyl halide of the general formula II
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
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.
Priority Applications (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IL14971300A IL149713A0 (en) | 1999-12-14 | 2000-10-27 | Process for the production of trifluormethylacetophenones |
| JP2001545242A JP2003517029A (en) | 1999-12-14 | 2000-10-27 | Method for producing trifluoromethylacetophenone |
| AU13889/01A AU1388901A (en) | 1999-12-14 | 2000-10-27 | Process for the production of trifluoromethylacetophenones |
| MXPA02005873A MXPA02005873A (en) | 1999-12-14 | 2000-10-27 | Process for the production of trifluoromethylacetophenones. |
| BR0016320-1A BR0016320A (en) | 1999-12-14 | 2000-10-27 | Process for the production of trifluoromethylacetophenones |
| EP00975941A EP1240127A1 (en) | 1999-12-14 | 2000-10-27 | Process for the production of trifluoromethylacetophenones |
| KR1020027006569A KR20020056943A (en) | 1999-12-14 | 2000-10-27 | Process for the production of trifluoromethylacetophenones |
| HK03105240.4A HK1052926A1 (en) | 1999-12-14 | 2003-07-21 | Process for the production of trifluoromethylacetophenones |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9929562.8A GB9929562D0 (en) | 1999-12-14 | 1999-12-14 | Organic compounds |
| GB9929562.8 | 1999-12-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2001044152A1 true WO2001044152A1 (en) | 2001-06-21 |
Family
ID=10866309
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP2000/010596 WO2001044152A1 (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 |
|---|---|---|---|---|
| TWI455919B (en) * | 2008-04-09 | 2014-10-11 | Du Pont | Method for preparing 3-trifluoromethyl chalcones |
| 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 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5969188A (en) * | 1999-01-05 | 1999-10-19 | Nipa Hardwicke, Inc. | Process for producing trifluoromethylacetophenones |
| WO1999054272A1 (en) * | 1998-04-18 | 1999-10-28 | Avecia Limited | Process for the preparation of 2-hydroxyalkyl halophenones |
-
1999
- 1999-12-14 GB GBGB9929562.8A patent/GB9929562D0/en not_active Ceased
-
2000
- 2000-10-27 KR KR1020027006569A patent/KR20020056943A/en not_active Application Discontinuation
- 2000-10-27 WO PCT/EP2000/010596 patent/WO2001044152A1/en not_active Application Discontinuation
- 2000-10-27 MX MXPA02005873A patent/MXPA02005873A/en unknown
- 2000-10-27 CN CN00816915A patent/CN1409697A/en active Pending
- 2000-10-27 IL IL14971300A patent/IL149713A0/en unknown
- 2000-10-27 AU AU13889/01A patent/AU1388901A/en not_active Abandoned
- 2000-10-27 EP EP00975941A patent/EP1240127A1/en not_active Withdrawn
- 2000-10-27 JP JP2001545242A patent/JP2003517029A/en active Pending
- 2000-10-27 BR BR0016320-1A patent/BR0016320A/en not_active Application Discontinuation
-
2003
- 2003-07-21 HK HK03105240.4A patent/HK1052926A1/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999054272A1 (en) * | 1998-04-18 | 1999-10-28 | Avecia Limited | Process for the preparation of 2-hydroxyalkyl halophenones |
| US5969188A (en) * | 1999-01-05 | 1999-10-19 | Nipa Hardwicke, Inc. | Process for producing trifluoromethylacetophenones |
Non-Patent Citations (1)
| Title |
|---|
| MARTIN, R. ET AL: "Simple and efficient preparation of ketones from morpholine amides", SYNLETT (1997), (12), 1414-1416, XP002165265 * |
Also Published As
| Publication number | Publication date |
|---|---|
| GB9929562D0 (en) | 2000-02-09 |
| BR0016320A (en) | 2002-08-27 |
| JP2003517029A (en) | 2003-05-20 |
| AU1388901A (en) | 2001-06-25 |
| KR20020056943A (en) | 2002-07-10 |
| HK1052926A1 (en) | 2003-10-03 |
| MXPA02005873A (en) | 2003-01-28 |
| IL149713A0 (en) | 2002-11-10 |
| CN1409697A (en) | 2003-04-09 |
| EP1240127A1 (en) | 2002-09-18 |
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