MXPA99006614A - Method of preparing monofluoromethyl ethers - Google Patents

Abstract

A method of preparing fluoromethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether (sevoflurane) and structurally related monofluormethyl ethers in which the monochloromethyl ether precursor thereof is reacted with a sterically hindered tertiary amine hydrofluoride salt.

Description

METHOD OF PREPARATION OF MONOFLUOROMETILO ETHERIES FIELD OF THE INVENTION The present invention is directed to a method of preparing monofluoromethyl ethers, and in particular, fluoromethyl 2,2,2-trifluoro-1- (trifluoroethyl) ethyl ether (sevoflurane) in which the yields of the desired products are improved on prior art methods.

BACKGROUND OF THE INVENTION In recent years, fluorinated ethers have been discovered which have useful anesthetic properties via inhalation. These anesthetics include desflurane (CF3CHFOCHF2), isoflurane (CF? CHC10CHF :), enflurane (HC1FCCF20CHF2), and sevoflurane ((CF) 2CH0CH2F). Sevoflurane is an advantageous inhalation anesthetic because of its attack or rapid onset of anesthesia and rapid recovery, which are convenient features of today's inhalation anesthetics. Sevoflurane is administered by the inhalation route to Ref .: 30773 warm-blooded, high-air-consuming animals, in an amount from about 1% to 51 by volume in a mixture with oxygen or an oxygen-containing gas mixture in enough to support breathing. U.S. Patent Nos. 3,683,092 and 3,689,571 disclose the use of sevoflurane as an inhalation anesthetic and its synthesis by reaction of chloromethyl 2,2,2-trifluoro-1- (trifluoromethyl) ethyl ether with excess potassium fluoride in a high-purity solvent. boiling point, sulfolane, at 120 ° C to replace the chloro group chlorine with fluorine. These patents also describe a method for producing sevoflurane by reaction of hexafluoroisopropanol with dimethyl sulfate and a solution of sodium hydroxide, and a subsequent fluorination of the resulting 2,2,2-trifluoro-1- (trifluoromethyl) ethyl ether with bromine trifluoride. . U.S. Patent 4,328,376 describes the separation of sevoflurane from an olefin by-product produced in a process similar to that described in US Patent 3,689,571. Other synthetic routes for sevoflurane are found in the following patent publications: US Patent 3,897,502 - fluorination of methyl 2,2,2,2-trifluoro-1- (trifluoromethyl) ethyl ether with 20% fluorine in argon; Patents 4,250,334 and 4,469,898 - Fluoromethylation of hexafluoroisopropanol using hydrogen fluoride, formaldehyde and sulfuric acid or other dehydrating agents; U.S. Patent 4,874,901 - reaction of chloromethyl 2, 2, 2-tr? Fluoro-1- (tpfluoromethyl) ethyl ether with pure potassium fluoride under conditions of high temperature and pressure; and the international PCT application WO 97 25303 - reaction of hexafluoroisopropanol with bis (fluoromethyl) ether. Okazaki, et. to the. in J. Fluopne Chem. 1974, 4 (4), 387 describes an electrochemical fluorination that gives a fluoromethyl ether. German Patent No. 25 20 962 describes a synthesis of fluoromethyl ethers from chloroethyl ethers with hydrogen fluoride at 125 ° -149 ° C in the presence of chromium oxyfluoride. Bensoam, et. to the. in Tetrahedrom Lett. 1979, 4,353 describes a synthesis of fluoromethyl ethers by exchange of halogen with tetraalkyl-phosphorphosphorans. Finally, German Patent No. 28 23 969 describes a process for the preparation of oraganofluor compounds, including monofluoromethyl ethers, by reaction of corresponding organochlorides or bromides with selected amine fluorhydrates. Triethylamine hydrofluoride and pipeline hydrofluoride are specific examples of fluoroplants used for the preparation of such organofluorine compounds, which are typically produced in yields of from about 40 to 80%.

DESCRIPTION OF THE INVENTION According to the present invention, there is provided a synthesis of certain monofluoromethyl ethers, in particular sevoflurane, which is characterized by improving yields in previously known methods.

BRIEF DESCRIPTION OF THE INVENTION In accordance with the present invention, there is provided a method for the fluorination of certain monochloromethyl ethers with spherically hindered tertiary amine hydrofluoride salts to produce the corresponding monofluoromethyl ethers. More particularly, the invention is directed to a method for producing fluoromethyl 2, 2, 2-tr? Fluoro-1- (tpfluoromethyl) ethyl ether (sevoflurane - (CF?) ^ CHOCH? F) which comprises reacting the chloromethyl 2,2,2-tpfluoro-1- (trifluoromethyl) ethyl with diisopropylethylamine hydridohydrate.

DETAILED DESCRIPTION OF THE INVENTION The present invention is generally directed to a method for the fluorination of monochloromethyl ethers with spherically hindered tertiary amine hydrofluoride salts to give the corresponding monofluoromethyl ethers. The monochloromethyl ether starting materials of the present invention are known compounds and are represented by the general formula: I Rr -c- I wherein A is fluoro lower alkyl, fluorine or chlorine and Rx and R2 are independently selected from hydrogen, lower alkyl, branched lower alkyl, fluoro lower alkyl, fluorine and chlorine with the proviso that at least one of A, Ri or R is fluoro lower alkyl, lower alkyl or branched lower alkyl. Fluorination of the above monochloromethyl ethers with spherically hindered tertiary amine hydrofluoride salts gives monofluromethyl ethers represented by the formula: A I i R2 where A, Ri or R2 are defined as above. In a preferred embodiment, the present invention is directed to a method for producing fluoromethyl 2,2,2-trifluoro-1- (trifluoromethyl) ethyl ether (sevoflurane) by reaction of chloromethyl 2,2,2-trifluoro-1 ether - (trifluoromethyl) ethyl with a spherically hindered tertiary amine hydrofluoride salt. Preferred spherically-freed tertiary amines useful in the method of the present invention are selected from those represented by the formula: I X - I wherein X, Y, and Z are lower alkyl groups, at least one of which is a branched lower alkyl or cycloalkyl group. Examples of representative branched or lower cycloalkyl groups present in compounds of the above formula include isopropyl, tertbutyl, neopentyl, cyclohexyl and the like. In a preferred embodiment of the invention, the hindered tertiary amine is diisopropylethylamine. The term "lower alkyl" as used herein means saturated alkyl groups containing from 1 to 6 carbon atoms and must be straight chain unless specifically stated otherwise. The term "fluoro lower alkyl" as used herein means saturated alkyl groups containing from 1 to 6 carbon atoms and which are substituted by at least one fluorine. A preferred lower alkyl fluoro group is trifluoromethyl. The spherically hindered tertiary amine hydrofluoride salt used in the reaction of the present invention is currently formed in situ as well as will be recognized by those skilled in the art of fluorocarbon chemistry. While the reactant of the reaction described therein is referred to herein as the hydrofluoride salt, it is the use of the spherically hindered tertiary amines described which provides the improved yields of the object synthesis. The hydridohydrate salts of the exposed amines can be formed in situ by combining anhydrous hydrogen fluoride with about one molar equivalent of the spherically hindered tertiary amine, for example, diisopropylethylamine. Alternatively, a previously prepared, spherically hindered tris-hydrogen-tertiary amine fluoride complex can be added to the reaction mixture and treated with two molar equivalents of the free tertiary amine to form three molar equivalents of the salt of tertiary amine hydrofluoride spherically hindered in situ. In accordance with the present invention, the spherically hindered tertiary amine hydrofluoride salt is combined with the monochloroethyl ether precursor, and the resulting mixture heated for an appropriate sufficient time to cause the formation of the monofluoromethyl ether product.

The conversion of monochloromethyl ethers to monofluoromethyl ethers by heating with a spherically hindered tertiary amine hydrofluoride salt of the present invention can be conducted in the absence of a solvent, or in the presence of a solvent, for example, an inert solvent of boiling at elevated temperature such as l-methyl-2-pyrrolidinone, sulfolane or the like. In a preferred embodiment of the invention, the reaction is conducted without additional solvent using an excess of the monochloromethyl ether reagent which also works well as the solvent. The conversion of monochloromethyl ethers to monofluoromethyl ethers according to the present invention can be conducted at elevated temperatures, in the range of 50 ° -100 ° C, at atmospheric pressure or in a sealed vessel under pressure. In a preferred embodiment of the invention, the reaction is conducted at the reflux temperature of monochloromethyl ether. The use of spherically hindered tertiary amine hydrofluoride salts for the conversion of monochloromethyl ethers to monofluoromethyl ethers in the present invention is a substantial advantage over prior use of triethylamine hydrofluoride and piperidine hydrofluoride, as described in the German Patent No. 28 23 969. The yields of the obtained product desired in the present invention are consistently superior to those obtained using the tertiary amine hydrofluoride salts previously described, as evidenced in the Examples provided therein subsequently. It has been shown, in contrast to the amine fluorohydrate salts of the prior art, that those of the present invention are not alkylated to a degree in the reaction. The alkylation of the less hindered amine hydrofluoride salts of the prior art to form a quaternary ammonium salt as a reaction by-product has not been previously described in the literature. The consistently higher yields obtained using the spherically hindered tertiary amines in the method of the invention are the result of avoiding this lateral reaction not described above. The following additional examples illustrate the invention disclosed, it being understood that this in no way intends the specifications given therein to be limited thereto.

EXAMPLE 1 Preparation of fluoroethyl 2,2,2-tpfluoro-1- (trifluoromethyl) ethyl ether with diisopropylethylamine hydrofluoroate.

In an efficient smoking hood, liquid hydrogen fluoride (85.1 g, 4.25 mol) is transferred into a one liter Teflon reaction vessel cooled in a cold dry ice / acetone bath. The vessel was fixed with a dry ice condenser, thermocouple, and a funnel was added and a portion of chloromethyl 2,2,2-tpfluoro-l- (trifluoromethyl) ethyl ether (80.1 g) was added. A solution of diisopropylethylamine (249.0 g, 1.93 mol) in 2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl chloroethyl ether (271.0 g) was slowly added while maintaining the internal temperature in the range of - 5 to 10 ° C. After the addition was complete, the mixture was transferred to a 2 liter glass flask and the Teflon® vessel was rinsed with a solution of diisopropylethylamine (307.0 g, 2.38 mol) in chloromethyl 2, 2, 2- ether. tr? fluoro-1- (tpfluoromethyl) ethyl which was also transferred to the glass flask. An additional 850 g of chloromethyl 2, 2, 2-tpfluoro-l- (trifluoromethyl) ethyl ether was added to the reaction bottle to yield the total of 1381.1 g (6.38 mol). This mixture was heated to reflux for 16 hours. After cooling to room temperature, water (700 L) was added to the reaction mixture and, after vigorously shaking, the resulting layers were separated. The lower organic layer was further washed with 700 L of dilute hydrochloric acid (35 mL of 12 N HCl in 665 mL of water). The organic layer (1259.7 g) was analyzed by NMR and gas chromatography and was shown to consist of 63.6% fluoromethyl ether 2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl (sevoflurane) and . 4% 2, 2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether recovered, giving a yield of 95% sevoflurane based on the consumption of the starting material.

EXAMPLE 2 Preparation of fluoromethyl 2,2,2-trifluoro-1- (trifluoromethyl) ethyl ether with triethylamine hydrohydrate.

Triethylamine (5.0 g, 49.4 mmol) was added to a solution of triethylamine tris hydrogen fluoride (4.0 g, 24.8 mmol) in chloromethyl 2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether (32.28 g, 149.1 mmol). This mixture was heated to reflux for 16 hours, during which time the solids separated. The precipitate consists of triethylamine hydrochloride and the undesired quaternary salt, 1,1,1,3,3,3-hexafluoroisopropoxymethyl) tetylammonium chloride, formed by the reaction of chloromethyl 2, 2, 2-tr? Fluoro ether -1- (trifluoromethyl) ethyl with triethylamine. After cooling to room temperature, water (500 mL) was added to the reaction mixture and then stirred vigorously to dissolve all solids, the lower organic layer was separated. The organic layer (27.98 g) was analyzed by NMR and gas chromatography and was found to consist of 42.3% fluoromethyl 2, 2, 2-tr? Fluoro-1- (tpfluoromethyl) ethyl ether (sevoflurane) and 57.5% Chloromethyl 2,2, 2-tr? fluoro-1- (trifluoroethyl) ethyl ether recovered. This corresponds to a 79% yield of sevoflurane based on the consumption of the starting material.

EXAMPLE 3 Preparation of fluoromethyl 1,1,2,3,3,3-hexafluoropropyl ether with diisopropylethylamine hydridohydrate.

Diisopropylethylamine (56 mL, 320 mmol) was added to a solution of chloromethyl 1,1,2,3,3,3-hexafluoropropyl ether (98.8 g, 440 mmol, 96% purity) and a fluoride complex was previously prepared of tris-hydrogen diisopropylethylamine (30.7 g, 160 mmol) by reaction of diisopropylethylamine with three molar equivalents of anhydrous hydrogen fluoride. The mixture was refluxed under N2 for 12 hours. Upon cooling, the mixture solidified. Water (100 L) was added with rapid stirring. The lower organic layer was dried over CaCl2, to give 83 g of a dark liquid. NMR analyzes showed that this liquid is composed of 88% fluoromethyl ether 1, 1, 2, 3, 3, 3-hexafluoropropyl, 8% fluoromethyl ether 1, 2, 3, 3, 3-hexafluoropropyl recovered, and 4% dichloroethyl 1,1,2,3,3,3-hexafluoropropyl ether, an impurity present in the starting chloromethyl ether. The distillation yielded 64 g of 1, 1, 2, 3, 3, 3, 3-hexafluoropropyl fluoromethyl ether as a clear, colorless liquid (mp 68 ° C) in a yield of 78% based on the amount of consumption of the starting material. The use of triethylamine hydrofluoride under other identical forms of reaction conditions gives a significantly low yield (52%) of the desired fluoromethyl ether.

EXAMPLE 4 Preparation of fluoromethyl 1,2,2,2-tetrafluoroethyl diisopropylethylamine ether using hydrofluoride.

Diisopropylethylamine (6.97 mL, 40.0 mmol) was added to a solution of chloromethyl 1,2,2,2-tetrafluoroethyl ether (9.99 g, 60.0 mmol) and tris-hydrogen fluoride of diisopropylethylamine (3.78 g, 20.0 mmol), previously prepared by diisopropylethylamine reaction with three molar equivalents of anhydrous hydrogen fluoride. The mixture was heated to reflux under N for 10 hours. Upon cooling, the mixture was a well dispersed slurry. It was added stirring water cooled with ice (10 mL) with rapid stirring. The organic layer was dried by movement over CaCl2, to give 8.44 g of a yellowish liquid. NMR analysis showed that this liquid consists of 73% fluoromethyl 1,2,2,2-tetrafluoroethyl ether, 18% recovered chloromethyl 1,2,2,2-tetrafluoroethyl ether and 7% diisopropylethylamine hydrochloride. These correspond to a yield of 81% of the desired fluoromethyl ether based on the consumption of the partition material. The use of triethylamine hydrofluoride under other forms of identical reaction conditions gives a significantly low yield (35%) of the desired fluoromethyl ether. It is noted that in relation to this date, the best method known by the applicant, to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following

Claims (7)

1. A method for the preparation of a monofluoromethyl ether represented by the formula: A I I 2 characterized in that A is fluoro lower alkyl, fluorine or chlorine and Ri and R2 are independently selected from the group consisting of hydrogen, lower alkyl, branched lower alkyl, fluoro lower alkyl, fluorine or chlorine with the proviso that at least one of A, Ri or R2 is fluoro lower alkyl, lower alkyl or branched lower alkyl, by the reaction of the corresponding monochloromethyl ether with a spherically hindered tertiary amine hydrofluoride salt.

2. A method according to claim 1, characterized in that the spherically hindered tertiary amine is represented by the formula: X-N wherein X, Y, and Z are independently selected from the group consisting of lower alkyl, branched lower alkyl, and lower alkyl cycloalkyl, with the proviso that at least one of them consists of a branched lower alkyl or cycloalkyl group .

3. A method according to claim 2, characterized in that X is an ethyl group and each of Y and Z is an isopropyl group.

4. A method according to claim 1, characterized in that said monofluoromethyl ether is the fluoromethyl 2,2,2-trifluoro-1- (trifluoromethyl) ethyl ether, said monochloromethyl ether is the chloromethyl 2, 2, 2-trifluoromethyl ether -l- (trifluoromethyl) ethyl and said spherically hindered tertiary amine hydrofluoride salt is the diisopropylethylamine hydrofluoride salt.

5. A method according to claim 1, characterized in that said reaction is carried out in the presence of a solvent.

6. The method according to claim 5, characterized in that the reaction is carried out at the reflux temperature of the reaction mixture.

7. A method according to claim 1, characterized in that the reaction is carried out using an excess of the chloromethyl ether starting material relative to the amount of the diisopropylethylamine hydrofluoride salt, in the absence of the added solvent.