WO2004094353A1 - Process for the manufacture of 3,5-bis(trifluoromethyl)phenyl-1-hydroxyethane and derivative thereof - Google Patents
Process for the manufacture of 3,5-bis(trifluoromethyl)phenyl-1-hydroxyethane and derivative thereof Download PDFInfo
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- WO2004094353A1 WO2004094353A1 PCT/IT2003/000254 IT0300254W WO2004094353A1 WO 2004094353 A1 WO2004094353 A1 WO 2004094353A1 IT 0300254 W IT0300254 W IT 0300254W WO 2004094353 A1 WO2004094353 A1 WO 2004094353A1
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- trifluoromethyl
- process according
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- hydroxyethane
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
- C07C29/38—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones
- C07C29/40—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones with compounds containing carbon-to-metal bonds
-
- 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
- C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
- C07C45/29—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups
- C07C45/294—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups with hydrogen peroxide
Definitions
- the present invention relates to a new process for the manufacture of hexafluoro-xylene derivatives, particularly 3,5-bis(trifluoromethyl)phenyl-1- hydroxyethane.
- 3,5-Bis(trifluorornethyl)phenyl-1 -hydroxyethane is a particularly versatile chemical compound and is especially known as a key intermediate in the synthesis of molecules with therapeutical activity.
- WO94/19323 and WO01/44200 describe the manufacture of 3,5- bis(trifluoromethyl)phenyl-1 -hydroxyethane by reaction of 3,5- bis(trifluoromethyl)benzaldehyde with methylmagnesium bromide.
- the invention relates to a process for the manufacture of 3.5-bis(trifluoromethyl)phenyl-1- hydroxyethane comprising:
- inert suitable solvents are for example aliphatic ethers, aromatic hydrocarbons and mixtures thereof, such as diethyl ether, THF, methyl-THF, toluene, o,m,p-xylenes, o,m,p-hexafluoroxylenes for example 1 ,3-bis(trifluoromethyl)xylene, isobutyl-ether, dimethoxyethane
- step (a) may be carried out according to any one of the known conditions in the art of manufacture of organomagnesium adducts (as reported for example in Organic Syntheses, vol. 1 , p. 550; Chem. Ber. 1996,
- the reaction (a) is carried out in anhydrous conditions in order to avoid the hydrolysis of the organomagnesium adduct. Furthermore, according to a preferred aspect, the reaction is carried out in a stream of an inert gas for example in a nitrogen or helium stream.
- an excess of magnesium for example a molar excess between 3 and 10%, advantageously a molar excess of magnesium between about 4 and 6% is used.
- Step (a) of the reaction may be carried out at a temperature between the room temperature and the reflux temperature of the solvent used.
- Step (a) does not usually need an activation, because the addition of the
- 3,5-bis(trifluoromethyl)-1-bromobenzene reagent to the reaction mixture promotes a self-initiation; however, if necessary or desired, it is possible to add an usual activator, such as bromine, iodine, 1 ,2-dibromoethane or
- Step (a) becomes complete within a few hours; all the reagent is converted usually within 2-5 hours; the progress may be verified by means of usual analyses, for example by means of gas-chromatography or thin-layer chromatography.
- step (a) is finished, the reaction mixture is advantageously cooled and the pure or previously diluted with the solvent of reaction acetaldehyde is added.
- the acetaldehyde is preferably added in a stoichiometric amount to the starting bromoderivative, optionally in a slight excess to offset possible losses by evaporation.
- the reaction of step (b) is carried out at a temperature lower than the boiling point of acetaldehyde itself, that is lower than 21 °C, for example at a temperature between 0 and 15°C, preferably between 0 and 5°C.
- the reaction of step (b) may be also carried out metering the Grignard reactant prepared in step (a) onto pure or dispersed in the reaction solvent acetaldehyde.
- Step (b) is complete within a few hours, is cooled and metered onto a diluted acid, such as aqueous sulphuric acid, hydrochloric acid, hydrobromic acid verifying that the reaction mixture temperature does not increase excessively.
- a diluted acid such as aqueous sulphuric acid, hydrochloric acid, hydrobromic acid verifying that the reaction mixture temperature does not increase excessively.
- the reaction with the aqueous diluted acid may be also carried out metering the same onto the organic layer.
- step (b) When step (b) is completed, the aqueous layer is removed and 3,5- bis(trifluoromethyl)phenyl-1 -hydroxyethane is isolated from the organic layer according to the usual procedures, for example by evaporating the solvents and collecting the residue; the product thus obtained may be, if necessary, purified according to the conventional methods.
- the yields of the process of the present invention depend on the operative procedures used but they are generally suitable to the industrial application of the process of the invention.
- 3,5-bis(trifluoromethyl)phenyl-1 -hydroxyethane thus obtained may be used as a synthesis intermediate in its racemic form or may be subjected to the well known procedures for the resolution of two enantiomers thereof, for example by kinetic resolution (as reported for example in
- 3,5-bis(trifluoromethyl)phenyl-1- hydroxyethane in the racemic form or as one of pure enantiomers thereof or in a mixture with one another, may be used for example to prepare 3,5- bis(trifluoromethyl)-acetophenone by a simple oxidation reaction.
- the invention relates to the use of 3,5-bis(trifluoromethyl)phenyl-1 -hydroxyethane as a reagent for the manufacture of 3,5-bis(trifluoromethyl)acetophenone.
- the product may be used both in its racemic form or in the form of one of its enantiomers either pure or in admixture with one another.
- the invention relates to a process as described in steps (a) and (b) and (c) hereinbefore, which further comprises the oxidation of the product obtained from step (c) to 3,5- bis(trifluoromethyl)acetophenone.
- the oxidation may be carried out according to the conventional procedures for the oxidation of alcohols to ketones, well known to those skilled in the art, advantageously by means of hydrogen peroxide in an inert solvent and in the presence of an oxidation catalyst.
- the following experimental part describes some preferred embodiments of the process of the present invention for an illustrative purpose and without limiting it in any way.
- the reaction mixture was cooled to 15°C by means of an ice bath.
- the reaction was exothermic.
- the organomagnesium adduct was then hydrolyzed with 924,5 g of 15% H 2 SO 4 .
- the hydrolysis was carried out cooling the system by means of an ice-water bath. The layers were allowed to separate, the aqueous layer (lower) was then washed 2 times with 150 ml of ether which was combined to the organic layer (upper).
- reaction started, at reflux temperature, 95,0 g of 3,5-bis(trifluoromethyl)-1- bromobenzene was metered, then the reaction mixture was allowed to react for about 3 h, always at reflux temperature.
- the reaction mixture was cooled to 0-5°C and 15 g of acetaldehyde was added into 15 g of a 1/1 mixture of anhydrous tetrahydrofuran and diethyl ether setting the rate of metering so as not to exceed 10°C internally and was allowed to react for 1 hour at 5-10°C.
- the unreacted magnesium was filtered off and the reaction was poured into 250 g of 10% hydrochloric acid cooled in an ice bath.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a process for the manufacture of 3,5-bis (trifluoromethyl)phenyl-1-hydroxyethane starting from 3,5-bis(trifluoromethyl)-1-bromobenzene comprising the formation of an organomagnesium derivative and subsequent reaction with acetaldehyde.
Description
"Process for the manufacture of 3.5-bis(trifluoromethyl)phenyl- 1 -hydroxyethane and derivative thereof FIELD OF THE INVENTION
The present invention relates to a new process for the manufacture of hexafluoro-xylene derivatives, particularly 3,5-bis(trifluoromethyl)phenyl-1- hydroxyethane. PRIOR ART
3,5-Bis(trifluorornethyl)phenyl-1 -hydroxyethane is a particularly versatile chemical compound and is especially known as a key intermediate in the synthesis of molecules with therapeutical activity.
WO94/19323 and WO01/44200 describe the manufacture of 3,5- bis(trifluoromethyl)phenyl-1 -hydroxyethane by reaction of 3,5- bis(trifluoromethyl)benzaldehyde with methylmagnesium bromide.
However, the reduction starting from 3,5-bis(trifluoromethyl)acetophenone, as described for example in WO94/19323, using sodium borohydride in methanol, is the most used process for the manufacture of 3,5- bis(trifluoromethyl)phenyl-1 -hydroxyethane. The starting 3,5- bis(trifluoromethyl)acetophenone is usually synthesized from 3,5- bis(trifluoromethyl)-1-bromobenzene, as described for example in US6395898, by reaction with acetic anhydride in the presence of magnesium.
SUMMARY OF THE INVENTION
It has now been found that it is possible to prepare 3,5- bis(trifluoromethyl)phenyl-1 -hydroxyethane starting directly from 3,5- bis(trifluoromethyl)-1-bromobenzene by a one-pot reaction which is industrially easy to realize and gives excellent yields. DETAILED DESCRIPTION OF THE INVENTION
Therefore, according to one of its aspects, the invention relates to a process for the manufacture of 3.5-bis(trifluoromethyl)phenyl-1- hydroxyethane comprising:
(a) reacting the 3,5- bis(trifluoromethyl)-1-
bromobenzene reagent with magnesium, in an inert solvent;
(b) reacting the reaction mixture with acetaidehyde; and optionally
(c) isolating the product thus obtained.
According to the present invention, inert suitable solvents are for example aliphatic ethers, aromatic hydrocarbons and mixtures thereof, such as diethyl ether, THF, methyl-THF, toluene, o,m,p-xylenes, o,m,p-hexafluoroxylenes for example 1 ,3-bis(trifluoromethyl)xylene, isobutyl-ether, dimethoxyethane
(DME), diethoxyethane, diglyme, butyl-diglyme, ethyl-diglyme, triglyme, and the like, optionally in admixture with one another. The reaction of step (a) may be carried out according to any one of the known conditions in the art of manufacture of organomagnesium adducts (as reported for example in Organic Syntheses, vol. 1 , p. 550; Chem. Ber. 1996,
129:233-235 and references thereof); according to an advantageous aspect, the reaction (a) is carried out in anhydrous conditions in order to avoid the hydrolysis of the organomagnesium adduct. Furthermore, according to a preferred aspect, the reaction is carried out in a stream of an inert gas for example in a nitrogen or helium stream.
Generally an excess of magnesium is used, for example a molar excess between 3 and 10%, advantageously a molar excess of magnesium between about 4 and 6% is used.
Step (a) of the reaction may be carried out at a temperature between the room temperature and the reflux temperature of the solvent used.-
Step (a) does not usually need an activation, because the addition of the
3,5-bis(trifluoromethyl)-1-bromobenzene reagent to the reaction mixture promotes a self-initiation; however, if necessary or desired, it is possible to add an usual activator, such as bromine, iodine, 1 ,2-dibromoethane or
Vitride®, in order to initiate the reaction.
Step (a) becomes complete within a few hours; all the reagent is converted usually within 2-5 hours; the progress may be verified by means of usual analyses, for example by means of gas-chromatography or thin-layer chromatography.
When step (a) is finished, the reaction mixture is advantageously cooled and the pure or previously diluted with the solvent of reaction acetaldehyde is added.
The acetaldehyde is preferably added in a stoichiometric amount to the starting bromoderivative, optionally in a slight excess to offset possible losses by evaporation.
According to an embodiment of the present invention, the reaction of step (b) is carried out at a temperature lower than the boiling point of acetaldehyde itself, that is lower than 21 °C, for example at a temperature between 0 and 15°C, preferably between 0 and 5°C.
According to another embodiment of the present invention, the reaction of step (b) may be also carried out metering the Grignard reactant prepared in step (a) onto pure or dispersed in the reaction solvent acetaldehyde.
Step (b) is complete within a few hours, is cooled and metered onto a diluted acid, such as aqueous sulphuric acid, hydrochloric acid, hydrobromic acid verifying that the reaction mixture temperature does not increase excessively.
According to another embodiment of the present invention, the reaction with the aqueous diluted acid may be also carried out metering the same onto the organic layer.
When step (b) is completed, the aqueous layer is removed and 3,5- bis(trifluoromethyl)phenyl-1 -hydroxyethane is isolated from the organic layer according to the usual procedures, for example by evaporating the solvents and collecting the residue; the product thus obtained may be, if necessary, purified according to the conventional methods.
The yields of the process of the present invention depend on the operative procedures used but they are generally suitable to the industrial application of the process of the invention.
3,5-bis(trifluoromethyl)phenyl-1 -hydroxyethane thus obtained may be used as a synthesis intermediate in its racemic form or may be subjected to the well known procedures for the resolution of two enantiomers
thereof, for example by kinetic resolution (as reported for example in
FERREIRA E.M. et al. J. Am. Chem. Soc, 2001, 123:7725).
As a synthesis intermediate, 3,5-bis(trifluoromethyl)phenyl-1- hydroxyethane, in the racemic form or as one of pure enantiomers thereof or in a mixture with one another, may be used for example to prepare 3,5- bis(trifluoromethyl)-acetophenone by a simple oxidation reaction.
Therefore, according to another of its aspects, the invention relates to the use of 3,5-bis(trifluoromethyl)phenyl-1 -hydroxyethane as a reagent for the manufacture of 3,5-bis(trifluoromethyl)acetophenone. For this purpose the product may be used both in its racemic form or in the form of one of its enantiomers either pure or in admixture with one another.
According to another of its aspects, the invention relates to a process as described in steps (a) and (b) and (c) hereinbefore, which further comprises the oxidation of the product obtained from step (c) to 3,5- bis(trifluoromethyl)acetophenone.
The oxidation may be carried out according to the conventional procedures for the oxidation of alcohols to ketones, well known to those skilled in the art, advantageously by means of hydrogen peroxide in an inert solvent and in the presence of an oxidation catalyst. The following experimental part describes some preferred embodiments of the process of the present invention for an illustrative purpose and without limiting it in any way.
EXAMPLE 1
44,1 g of Mg (1 ,814 mol) and 350 ml of anhydrous diethyl ether were charged into a 3 I four-necked flask fitted with mechanical stirrer, thermometer, Allihn condenser and a 250 ml addition funnel; the mixture was heated to the reflux temperature and 500,6 g of 3,5-bis(trifluoromethyl)-1- bromobenzene (1 ,7085 mol), dissolved in 500 ml of anhydrous diethyl ether, was percolated within 2 hours. The start of the reaction was visible through the turbidity of the reaction mass, which became black within few minutes. When the pouring was finished the reflux was kept for 40 minutes.
The reaction mixture was cooled to 15°C by means of an ice bath. 82,0 g of acetaldehyde (1 ,8615 mol), dissolved in 150 ml of ether, was then poured within 2 hours, keeping the internal temperature <21 °C. The reaction was exothermic. When the pouring was finished the system was then allowed to stir for 30' and at room temperature. The organomagnesium adduct was then hydrolyzed with 924,5 g of 15% H2SO4. The hydrolysis was carried out cooling the system by means of an ice-water bath. The layers were allowed to separate, the aqueous layer (lower) was then washed 2 times with 150 ml of ether which was combined to the organic layer (upper). The organic layer was washed 2 times with demineralized water (2 x 800 ml), then the solvent was evaporated obtaining 383,9 g of residue corresponding to 3,5- bis(trifluoromethyl)-1 -hydroxyethane. EXAMPLE 2 161,5 g of a 1/1 mixture of anhydrous tetrahydrofuran and diethyl ether and then 9,1 g of elementary magnesium (0,374 mol) and 5,0 g of 3,5- bis(trifluoromethyl)-1-bromobenzene were charged into a reactor. After the , reaction started, at reflux temperature, 95,0 g of 3,5-bis(trifluoromethyl)-1- bromobenzene was metered, then the reaction mixture was allowed to react for about 3 h, always at reflux temperature. The reaction mixture was cooled to 0-5°C and 15 g of acetaldehyde was added into 15 g of a 1/1 mixture of anhydrous tetrahydrofuran and diethyl ether setting the rate of metering so as not to exceed 10°C internally and was allowed to react for 1 hour at 5-10°C. The unreacted magnesium was filtered off and the reaction was poured into 250 g of 10% hydrochloric acid cooled in an ice bath. The reaction mixture was left under stirring at room temperature for 1 hour and the two layers were separated. The product was isolated from the organic layer by evaporation of the solvents, thus obtaining 78,2 g of 3,5-bis(trifluoromethyl)-1- hydroxyethane.
Claims
1. A process for the manufacture of 3,5-bis(trifluoromethyl)phenyl-1- hydroxyethane comprising
(a) reacting the 3,5-bis(trifluoromethyl)-1-bromobenzene reagent with magnesium, in an inert solvent;
(b) reacting the reaction mixture with acetaldehyde; and optionally
(c) isolating the product thus obtained.
2. Process according to claim 1 , characterized in that the inert solvent is selected from diethyl ether, THF, methyl-THF, toluene, o,m,p-xylenes, o,m,p-hexafluoroxylene, isobutyl-ether, dimethoxyethane (DME), diethoxyethane, diglyme, butyl-diglyme, ethyl-diglyme, triglyme and mixtures thereof.
3. Process according to claim 1 , characterized in that step (a) is carried out in anhydrous conditions.
4. Process according to claim 1 , characterized in that the magnesium is used in excess to 3,5-bis(trifluoromethyl)-1-bromobenzene. 5. Process according to claim 1 , characterized in that acetaldehyde is added in a stoichiometric amount or in a slight excess to 3,
5-bis(trifluoromethyl)-
1-bromobenzene.
6. Process according to claim 1 , characterized in that the reaction temperature of step (b) is lower than or equal to 21 °C.
7. Process according to claim 6, characterized in that the reaction . temperature of step (b) is between 0°C and 15°C.
8. Process according to claim 1 , characterized in that at the end of step (b) the reaction is treated with diluted mineral acids.
9. Process according to claim 1 , characterized in that the product of step (c) is subjected to an oxidation to give 3,5-bis(trifluoromethyl)acetophenone.
10. Use of 3,5-bis(trifluoromethyl)phenyl-1-hydroxyethane, in its racemic form or in the form of one of its enantiomers or as mixtures containing different ratios of the two enantiomers, for the manufacture of 3,5- bis(trifluoromethyl)acetophenone.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2003230221A AU2003230221A1 (en) | 2003-04-23 | 2003-04-23 | Process for the manufacture of 3,5-bis(trifluoromethyl)phenyl-1-hydroxyethane and derivative thereof |
| PCT/IT2003/000254 WO2004094353A1 (en) | 2003-04-23 | 2003-04-23 | Process for the manufacture of 3,5-bis(trifluoromethyl)phenyl-1-hydroxyethane and derivative thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IT2003/000254 WO2004094353A1 (en) | 2003-04-23 | 2003-04-23 | Process for the manufacture of 3,5-bis(trifluoromethyl)phenyl-1-hydroxyethane and derivative thereof |
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| Publication Number | Publication Date |
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| WO2004094353A1 true WO2004094353A1 (en) | 2004-11-04 |
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| PCT/IT2003/000254 WO2004094353A1 (en) | 2003-04-23 | 2003-04-23 | Process for the manufacture of 3,5-bis(trifluoromethyl)phenyl-1-hydroxyethane and derivative thereof |
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| AU (1) | AU2003230221A1 (en) |
| WO (1) | WO2004094353A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106278846A (en) * | 2016-08-17 | 2017-01-04 | 沧州普瑞东方科技有限公司 | A kind of method of synthesis 3,5 bis trifluoromethyl 1-Phenylethanone .s |
| WO2022078796A1 (en) * | 2020-10-12 | 2022-04-21 | Basf Se | PROCESS FOR THE PREPARATION OF α-ALKYL-2-(TRIFLUOROMETHYL)-BENZYL ALCOHOLS |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111302916A (en) * | 2020-03-18 | 2020-06-19 | 湖南复瑞生物医药技术有限责任公司 | Preparation method of 3, 5-bis (trifluoromethyl) acetophenone |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003043575A2 (en) * | 2001-11-19 | 2003-05-30 | Merck & Co., Inc. | Process for the synthesis of (r)-1-(3,5-bis(trifluoromethyl)-phenyl)ethan-1-ol and esters thereof by dynamic kinetic resolution |
-
2003
- 2003-04-23 AU AU2003230221A patent/AU2003230221A1/en not_active Abandoned
- 2003-04-23 WO PCT/IT2003/000254 patent/WO2004094353A1/en not_active Application Discontinuation
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003043575A2 (en) * | 2001-11-19 | 2003-05-30 | Merck & Co., Inc. | Process for the synthesis of (r)-1-(3,5-bis(trifluoromethyl)-phenyl)ethan-1-ol and esters thereof by dynamic kinetic resolution |
Non-Patent Citations (3)
| Title |
|---|
| DOAMARAL J R ET AL: "ANTIMALARIAL ACTIVITY OF GUANYLHYDRAZONE SALTS OF AROMATIC KETONES. I. PRIMARY SEARCH FOR ACTIVE SUBSTITUENT PATTERNS", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 12, no. 1, January 1969 (1969-01-01), pages 21 - 25, XP001106497, ISSN: 0022-2623 * |
| KELLY, DAVID P. ET AL., AUST. J. CHEM., vol. 31, 1978, pages 1209 - 1221, XP001091352 * |
| MCBEE, EARL ET AL., J. AM. CHEM. SOC., vol. 72, 1950, pages 4053 - 4055, XP002265674 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106278846A (en) * | 2016-08-17 | 2017-01-04 | 沧州普瑞东方科技有限公司 | A kind of method of synthesis 3,5 bis trifluoromethyl 1-Phenylethanone .s |
| CN106278846B (en) * | 2016-08-17 | 2018-09-21 | 沧州普瑞东方科技有限公司 | A method of synthesis 3,5- bis trifluoromethyl acetophenones |
| WO2022078796A1 (en) * | 2020-10-12 | 2022-04-21 | Basf Se | PROCESS FOR THE PREPARATION OF α-ALKYL-2-(TRIFLUOROMETHYL)-BENZYL ALCOHOLS |
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| AU2003230221A1 (en) | 2004-11-19 |
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