WO2004094358A1 - Process for the manufacture of 3,5-bis(trifluoromethyl)acetophenone - Google Patents

Process for the manufacture of 3,5-bis(trifluoromethyl)acetophenone Download PDF

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Publication number
WO2004094358A1
WO2004094358A1 PCT/IT2003/000253 IT0300253W WO2004094358A1 WO 2004094358 A1 WO2004094358 A1 WO 2004094358A1 IT 0300253 W IT0300253 W IT 0300253W WO 2004094358 A1 WO2004094358 A1 WO 2004094358A1
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WO
WIPO (PCT)
Prior art keywords
trifluoromethyl
bis
process according
phenyl
hydroxyethane
Prior art date
Application number
PCT/IT2003/000253
Other languages
French (fr)
Inventor
Alessandro Nardello
Andrea Faccin
Marisa Pretto
Original Assignee
Miteni S.P.A.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Miteni S.P.A. filed Critical Miteni S.P.A.
Priority to PCT/IT2003/000253 priority Critical patent/WO2004094358A1/en
Priority to AU2003230220A priority patent/AU2003230220A1/en
Publication of WO2004094358A1 publication Critical patent/WO2004094358A1/en

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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
    • C07C45/27—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 3,5- bis(trifluoromethyl)acetophenone.
  • 3,5-bis(trifluoromethyl)acetophenone is a particularly versatile chemical compound and is especially known as a key intermediate in the synthesis of molecules with therapeutical activity.
  • WO02/24615 and WO02/50009 describe the manufacture of 3,5- bis(trifluoromethyl)acetophenone by reaction of 3,5- bis(trifluoromethyl)bromobenzene with acetic anhydride through the Grignard derivative.
  • the invention relates to a process for the manufacture of 3,5-bis(trifluoromethyl)acetophenone which comprises the oxidation of 3,5-bis(trifluoromethyl)phenyl-1-hydroxyethane by means of hydrogen peroxide in an inert solvent, in the presence of an oxidation catalyst.
  • the invention relates to a process for the manufacture of 3,5-bis(trifluoromethyl)acetophenone comprising
  • the starting 3,5-bis(trifluoromethyl)phenyl-1-hydroxyethane may be in the racemic form or as one of enantiomers thereof pure or in admixture with one another.
  • 3,5-bis(trifluoromethyl)phenyl-1-hydroxyethane may be in the racemic form or as one of enantiomers thereof pure or in admixture with one another.
  • 3,5-bis(trifluoromethyl)phenyl-1-hydroxyethane it will be meant any one of the above-mentioned products or mixtures.
  • inert suitable solvents which are not miscible with water are for example the halogenated solvents and include chloroform, dichloromethane, 1 ,2-dichloroethane, 1 ,2-dichloropropane, chlorobenzene, dichlorobenzene, 1 ,3-bis(trifluoromethyl)benzene, chloro- and dichloro-toluens, chloro-xylenes and the like, optionally in a mixture with one another or in admixture with non-halogenated inert solvents.
  • the halogenated solvents include chloroform, dichloromethane, 1 ,2-dichloroethane, 1 ,2-dichloropropane, chlorobenzene, dichlorobenzene, 1 ,3-bis(trifluoromethyl)benzene, chloro- and dichloro-toluens, chloro-xylenes and the like, optionally in a mixture with one another or in admi
  • the hydrogen peroxide is preferably used in aqueous solution at a concentration between 25% and 60% w/w, advantageously between 30% and 35% w/w and is used in a great excess to the product to be oxidized, for example in an excess greater than 100%, advantageously in an excess greater than 250% to the stoichiometric amount of the product to be oxidized.
  • step (a) may be carried out both metering the hydrogen peroxide onto the organics and metering the organics onto the hydrogen peroxide wherein the catalyst has been dispersed.
  • a minimal amount of mineral acid is added to the aqueous solution of hydrogen peroxide, for example sulphuric acid or hydrochloric acid, in order to promote the activity of the catalyst.
  • phase transfer catalyst it is meant, according to the present invention, a compound which facilitates the transport of reagents to the interphase water-organic solvent to promote the reaction of step (a).
  • phase- transfer catalysts such as quaternary ammonium salts such as tetra-n- propylammonium-bromide and tetra-n-propylammonium-hydroxide or quaternary phosphonium salts such as tetra-phenyl-phosphonium chloride and bromide, are on the market; according to an advantageous aspect of the present invention, phase transfer catalyst is methyl-tri-n-octylammonium chloride, known under the trademark Aliquat 336.
  • phase transfer catalyst used is catalytic; by way of example, amounts between 1 and 10% w/w, preferably at a rate of about 2- 3% w/w to the reagent, may be used.
  • oxidation catalyst it is meant, according to the present invention, a compound which can promote the oxidation reaction of the alcohol to ketone.
  • selenium oxide, palladium acetate, hydrated ruthenium oxide may be used as an oxidation catalyst; sodium tungstate of formula NaW0 4 is a particularly advantageous oxidation catalyst.
  • the oxidation catalyst is added to the reaction as usually in amounts between 1 and 10% w/w, preferably at a rate of about 1-3% w/w to the product to be oxidized.
  • Step (a) of the reaction is preferably carried out at a temperature between 1 and 10% w/w, preferably at a rate of about 1-3% w/w to the product to be oxidized.
  • the duration of the reaction of step (a) is a function of parameters which affect it, such as the temperature and the possibility of interaction of the two phases of the reaction mixture.
  • phase transfer catalyst also through a vigorous stirring.
  • step (a) the reaction mixture is advantageously cooled to about 40°C to promote phase separation.
  • the separation of the two phases is carried out and 3,5-bis(trifluoromethyl)acetophenone is collected from the organic layer according to the operative methods well known to those skilled in the art, for example by evaporation of solvents and following vacuum rectification.
  • 3,5-bis(trifluoromethyl)phenyl-1-hydroxyethane may be produced according to any one of the synthesis described in the literature; according to a particularly preferred aspect of the present invention, 3,5- bis(trifluoromethyl)phenyl-1-hydroxyethane is prepared starting from 3,5- bis(trifluoromethyl)-1-bromobenzene by reaction with acetaldehyde through an organomagnesium derivative.
  • the invention relates to a process for the manufacture of 3,5-bis(trifluoromethyl)acetophenone starting from 3,5-bis(trifluoromethyl)phenyl-1-hydroxyethane wherein this last product is obtained from 3,5-bis(trifluoromethyl)-1-bromobenzene by reaction with magnesium or a derivative thereof to give an organomagnesium reagent and following reaction of this latter with acetaldehyde.
  • the product derived from this synthesis may be subjected to oxidation without any intermediate purification.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (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)acetophenone by oxidation of 3,5-bis(trifluoromethyl)phenyl-1-hydroxyethane by means of hydrogen peroxide in an inert solvent in the presence of an oxidation catalyst.

Description

"Process for the manufacture of 3,5- bis(trifluoromethyl)acetophenone" FIELD OF THE INVENTION
The present invention relates to a new process for the manufacture of 3,5- bis(trifluoromethyl)acetophenone. PRIOR ART
3,5-bis(trifluoromethyl)acetophenone is a particularly versatile chemical compound and is especially known as a key intermediate in the synthesis of molecules with therapeutical activity. WO02/24615 and WO02/50009 describe the manufacture of 3,5- bis(trifluoromethyl)acetophenone by reaction of 3,5- bis(trifluoromethyl)bromobenzene with acetic anhydride through the Grignard derivative.
In the literature there is no trace of the synthesis of 3,5- bis(trifluoromethyl)acetophenone starting from the corresponding alcohol that is starting from 3,5-bis(trifluoromethyl)phenyl-1-hydroxyethane, despite this latter is a widely available reactant in the industrial field. SUMMARY OF THE INVENTION
Therefore, the manufacture of 3,5-bis(trifluoromethyl)acetophenone starting from 3,5-bis(trifluoromethyl)phenyl-1-hydroxyethane has been carried out by an oxidation reaction which is industrially easy to carry out and gives excellent yields.
Therefore, according to one of its aspects, the invention relates to a process for the manufacture of 3,5-bis(trifluoromethyl)acetophenone which comprises the oxidation of 3,5-bis(trifluoromethyl)phenyl-1-hydroxyethane by means of hydrogen peroxide in an inert solvent, in the presence of an oxidation catalyst.
DETAILED DESCRIPTION OF THE INVENTION
More particularly, the invention relates to a process for the manufacture of 3,5-bis(trifluoromethyl)acetophenone comprising
(a) reacting 3,5-bis(trifluoromethyl)phenyl-1-hydroxyethane with hydrogen peroxide in an inert water-immiscible solvent, in the presence of a phase transfer catalyst and an oxidation catalyst at a temperature between the room temperature and the reflux temperature of the solvent; and optionally (b) isolating the product thus obtained.
The starting 3,5-bis(trifluoromethyl)phenyl-1-hydroxyethane may be in the racemic form or as one of enantiomers thereof pure or in admixture with one another. In the present description, unless otherwise specified, by the term
3,5-bis(trifluoromethyl)phenyl-1-hydroxyethane it will be meant any one of the above-mentioned products or mixtures.
According to the present invention, inert suitable solvents which are not miscible with water are for example the halogenated solvents and include chloroform, dichloromethane, 1 ,2-dichloroethane, 1 ,2-dichloropropane, chlorobenzene, dichlorobenzene, 1 ,3-bis(trifluoromethyl)benzene, chloro- and dichloro-toluens, chloro-xylenes and the like, optionally in a mixture with one another or in admixture with non-halogenated inert solvents.
The hydrogen peroxide is preferably used in aqueous solution at a concentration between 25% and 60% w/w, advantageously between 30% and 35% w/w and is used in a great excess to the product to be oxidized, for example in an excess greater than 100%, advantageously in an excess greater than 250% to the stoichiometric amount of the product to be oxidized.
In order to carry out the process of the present invention, the reaction of step (a) may be carried out both metering the hydrogen peroxide onto the organics and metering the organics onto the hydrogen peroxide wherein the catalyst has been dispersed.
Advantageously, a minimal amount of mineral acid is added to the aqueous solution of hydrogen peroxide, for example sulphuric acid or hydrochloric acid, in order to promote the activity of the catalyst.
As it is known, the solution of hydrogen peroxide forms two layers with the inert water-immiscible solvent.
By "phase transfer catalyst" it is meant, according to the present invention, a compound which facilitates the transport of reagents to the interphase water-organic solvent to promote the reaction of step (a). Many phase- transfer catalysts, such as quaternary ammonium salts such as tetra-n- propylammonium-bromide and tetra-n-propylammonium-hydroxide or quaternary phosphonium salts such as tetra-phenyl-phosphonium chloride and bromide, are on the market; according to an advantageous aspect of the present invention, phase transfer catalyst is methyl-tri-n-octylammonium chloride, known under the trademark Aliquat 336.
The amount of phase transfer catalyst used is catalytic; by way of example, amounts between 1 and 10% w/w, preferably at a rate of about 2- 3% w/w to the reagent, may be used.
By "oxidation catalyst" it is meant, according to the present invention, a compound which can promote the oxidation reaction of the alcohol to ketone.
For example, selenium oxide, palladium acetate, hydrated ruthenium oxide may be used as an oxidation catalyst; sodium tungstate of formula NaW04 is a particularly advantageous oxidation catalyst.
The oxidation catalyst is added to the reaction as usually in amounts between 1 and 10% w/w, preferably at a rate of about 1-3% w/w to the product to be oxidized. Step (a) of the reaction is preferably carried out at a temperature between
30°C and the reflux temperature of the solvent, advantageously lower than this latter.
The duration of the reaction of step (a) is a function of parameters which affect it, such as the temperature and the possibility of interaction of the two phases of the reaction mixture.
The interaction between the two phases is facilitated, as well as by using a phase transfer catalyst, also through a vigorous stirring.
The progress of the reaction may be verified by means of usual analyses, for example by means of gas-chromatography or thin-layer chromatography in order to verify the disappearance of the reagent and the formation of the desired product. When step (a) is finished, the reaction mixture is advantageously cooled to about 40°C to promote phase separation. The separation of the two phases is carried out and 3,5-bis(trifluoromethyl)acetophenone is collected from the organic layer according to the operative methods well known to those skilled in the art, for example by evaporation of solvents and following vacuum rectification.
3,5-bis(trifluoromethyl)phenyl-1-hydroxyethane may be produced according to any one of the synthesis described in the literature; according to a particularly preferred aspect of the present invention, 3,5- bis(trifluoromethyl)phenyl-1-hydroxyethane is prepared starting from 3,5- bis(trifluoromethyl)-1-bromobenzene by reaction with acetaldehyde through an organomagnesium derivative.
Therefore, according to another of its aspects, the invention relates to a process for the manufacture of 3,5-bis(trifluoromethyl)acetophenone starting from 3,5-bis(trifluoromethyl)phenyl-1-hydroxyethane wherein this last product is obtained from 3,5-bis(trifluoromethyl)-1-bromobenzene by reaction with magnesium or a derivative thereof to give an organomagnesium reagent and following reaction of this latter with acetaldehyde. The product derived from this synthesis, may be subjected to oxidation without any intermediate purification.
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 1,1 kg of 3,5-bis(trifluoromethyl)phenyl-1-hydroxyethane, 42,5 g of
Aliquat 366 and 2 I of 1 ,2 dichloroethane were charged into a 5 I reactor.
The reaction mixture was heated to 50°C, then 50,0 g of Na2W04-2H2O, previously dissolved in 1 ,25 I of 130 vol H2O2, acidified with sulphuric acid, was poured until the yellow coloration disappears. After 9 hours the reaction was complete, was cooled and then the organic layer (upper) was separated from the aqueous one (lower). The organic layer was washed 3 times with demineralized water (3 x 2 1) and once with 2 I of an aqueous solution of 1% sodium bisulfite. Most of the dichloroethane was removed by vacuum evaporation (200 mm Hg) and 1743,4 g of solvent was collected. Through the rectification of the residue, 990 g of 3,5- bis(trifluoromethyl)acetophenone was obtained. EXAMPLE 2
100 g of 3,5-bis(trifluoromethyl)phenyl-1-hydroxyethane and 2,3 g of Aliquat 366 were charged into a reactor together with 125 g of chlorobenzene and a solution of 1 g of sodium tungstate in 5 g of water.
The reaction mixture was heated to 60°C, then a solution of 80 g of 130 vol hydrogen peroxide in water, previously acidified at about pH 1 with sulphuric acid, was poured into it. The reaction mixture was heated to 70°C and was allowed to react for 15 hours. The heating and the stirring were stopped and the reaction mixture was allowed to settle; the organic layer (upper) was separated from the aqueous one (lower). The organic layer was washed with a solution of 15% sodium metabisulfite. The solvent was removed (boiling point = 95-97°C, atm) from the organic layer and the residue was rectified. 87,8 g of 3,5- bis(trifluoromethyl)acetophenone was thus obtained (boiling point =55-
58°C, 8-10 mmHg).

Claims

CLAIMS A process for the manufacture of 3,5-bis(trifluoromethyl)acetophenone comprising the oxidation of 3,5-bis(trifluoromethyl)phenyl-1-hydroxyethane by means of hydrogen peroxide in an inert solvent, in the presence of an oxidation catalyst. Process according to claim 1 comprising
(a) reacting 3,5-bis(trifluoromethyl)phenyl-1-hydroxyethane with hydrogen peroxide in an inert water-immiscible solvent, in the presence of a phase transfer catalyst and an oxidation catalyst at a temperature between the room temperature and the reflux temperature of the solvent; and optionally
(b) isolating the product thus obtained. Process according to claims 1 or 2, characterized in that 3,5- bis(trifluoromethyl)phenyl-1-hydroxyethane is in its racemic form or in the form of one of its enantiomers, pure or in admixture with one another. Process according to claims 1 or 2, characterized in that the inert water- immiscible solvent is a halogenated solvent. Process according to claim 4, characterized in that the halogenated solvent is selected from chloroform, dichloromethane, 1 ,2-dichloroethane, 1 ,2-dichloropropane, chlorobenzene, dichlorobenzene and 1 ,3- bis(trifluoromethyl)benzene, chloro- and dichloro-toluens, chloro-xylenes, optionally in admixture with one another or in a mixture with non- halogenated inert solvents. Process according to claims 1 or 2, characterized in that the hydrogen peroxide is in aqueous solution and is used in excess to 3,5- bis(trifluoromethyl)phenyl-1-hydroxyethane. Process according to claim 6, characterized in that the hydrogen peroxide solution has a concentration between 25% and 60% w/w. Process according to claim 2, characterized in that phase transfer catalyst is a quaternary ammonium salt. Process according to claims 1 or 2, characterized in that the oxidation catalyst is selected from selenium oxide, palladium acetate, hydrated ruthenium oxide and dihydrated sodium tungstate. 10. Process according to claim 9, characterized in that the oxidation catalyst is dihydrated sodium tungstate. 11. Process according to claims 1 or 2, characterized in that phase (a) of the reaction is carried out at a temperature between 30°C and the reflux temperature of the solvent. 12. Process according to claims 1 or 2, characterized in that 3,5- bis(trifluoromethyl)phenyl-1-hydroxyethane is obtained from 3,5- bis(trifluoromethyl)-1-bromobenzene by reaction with magnesium or a derivative thereof to give an organomagnesium reagent and subsequent reaction with acetaldehyde.
PCT/IT2003/000253 2003-04-23 2003-04-23 Process for the manufacture of 3,5-bis(trifluoromethyl)acetophenone WO2004094358A1 (en)

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PCT/IT2003/000253 WO2004094358A1 (en) 2003-04-23 2003-04-23 Process for the manufacture of 3,5-bis(trifluoromethyl)acetophenone
AU2003230220A AU2003230220A1 (en) 2003-04-23 2003-04-23 Process for the manufacture of 3,5-bis(trifluoromethyl)acetophenone

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Cited By (1)

* Cited by examiner, † Cited by third party
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

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BOGDAL, DARIUSZ ET AL: "Microwave -assisted oxidation of alcohols using aqueous hydrogen peroxide", SYNLETT (2000), (1), 143-145, XP008025982 *
MCBEE, EARL ET AL: "Preparation and polymerization of trifluoromethyl- and chloro-(trifluoromethyl)- substituted styrenes", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY., vol. 72, 1950, AMERICAN CHEMICAL SOCIETY, WASHINGTON, DC., US, pages 4053 - 4055, XP002266098, ISSN: 0002-7863 *
SATO, KAZUHIKO ET AL: "A Practical Method for Alcohol Oxidation with Aqueous Hydrogen Peroxide under Organic Solvent- and Halide - Free Conditions", BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN (1999), 72(10), 2287-2306, XP002266097 *

Cited By (2)

* Cited by examiner, † Cited by third party
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

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