United States Patent (19) 11 4,346,246 Terrell et al. 45) Aug. 24, 1982

54 PROCESS FOR ADJUSTING THE HALOGEN 58 Field of Search ...... 568/683, 684 CONTENT OF HALOGENATED ALIPHATIC (56) References Cited ETHERS U.S. PATENT DOCUMENTS (75) Inventors: Ross C. Terrell, Clark; Kirsten Hansen, Berkeley Heights, both of 4,149,018 6/1979 Bell et al...... 568/684 N.J. Primary Examiner-Howard T. Mars Assignee: Airco, Inc., Montvale, N.J. Attorney, Agent, or Firm-Roger M. Rathbun; Larry R. (73) Cassett 21 Appl. No.: 149,360 (57) ABSTRACT 22 Filed: May 13, 1980 Process for adjusting the halogen content of haloge nated aliphatic ethers, by selective replacement of a Related U.S. Application Data halide substituent on the ether with a hydrogen. The (63) Continuation of Ser. No. 19,953, Mar. 12, 1979, aban process is particularly useful for the production of cer doned. tain inhalant anesthetics. (51) Int. Cl...... C07C 41/01; CO7C 41/24 52) U.S. C...... 568/684; 568/683 9 Claims, No Drawings 4,346,246 1 2 PROCESS FOR ADJUSTING THE HALOGEN where B is OH or OR. CONTENT OF HALOGENATED ALPHATIC Second, dehydrohalogenation may occur. In this ETHERS * , reaction, hydrogen and halogen are removed from adja This is a continuation of application Ser. No. 19,953, cent carbon atoms to form a double bond: filed Mar. 12, 1979, now abandoned. INTRODUCTION This invention relates to processes for adjusting the 10 Ro---R - B se ro---R halogen content of halogenated aliphatic ethers, by R. R. R. R. selective reduction, i.e., replacement of a halide substit uent on the ether with a hydrogen. More specifically, This type of reaction is described in U.S. Pat. No. the invention is concerned with new processes, and 2,803,666, where this reaction occurs: with improvements in existing processes, for the pro 15 duction of certain halogenated aliphatic ethers that are useful as inhalant-anesthetics. (CCl3CHC),O + C2H5OH + KOH Ce BACKGROUND CCl2FCCIOCCl=CCl2. The halogenated ether, 1,2-trifluoro-2-chloroethyl 20 It is also described by Corley et al. in 78 JACS 3489 at difluoromethyl ether, CHF2OCF2CHFC, is a valuable 3491 and 3492, as for example in this preparation: inhalantanesthetic, enflurane, made and sold under the trademark ETHRANE by Airco, Inc., Montvale, N.J. 07645. It is referred to hereafter as enflurane. The presently-employed process for manufacturing 25 this anesthetic material generates a number of by-pro duct streams, each characterized by having more chlo Third, selective reduction may take place, in accor rine in the molecule than does the desired anesthetic dance with the present invention. In this reaction the product. One such by-product stream contains the con halogen is replaced by hydrogen, as in the examples of pound of CF2HOCF2CFCI2, which is very difficult to 30 this application. remove from the desired product by distillation or other In order for the reduction reaction to work, the ether separating technique, and of course it represents a yield must not undergo a hydrolysis or nucleophilic displace loss for the presently-employed process. . ment reaction or dehydrohalogenation reaction, which Other by-product streams are produced in the pre is faster than the reduction. In addition, any ether sently-employed process as "bottoms” from the vacuum 35 formed by the reduction reaction must not undergo stills. These bottoms contain the following components further reactions, especially dehydrohalogenation. in varying proportions: . .'', ...... In order for selective reduction to take place, rather CHCIOCF2CHFC than hydrolysis or nucleophilic displacement or dehy CCl3OCF2CHFC drohalogenation, certain conditions must be met. The CCHOCF2CHFC1 reactions of the halogenated ethers have been little ... CC12HOCF2CFC2 explored and have been considered highly unpredict CCIH2OCF2CFCl2 able. The present invention is remarkable in that only AtCCl3OCF2CFCI2 the present time, these materials... - are useless by-pro certain halogenated ethers can be selectively reduced, ducts that reduce the efficiency of the currently 45 and in that the reduction is selective. employed process. . . SUMMARY OF THE INVENTION Another important halogenated etheranesthetic is It has now been discovered that selective replace 1-chloro-2-trifluoro difluoromethyl ether, ment of a chlorine or bromine substituent on certain CF3CHCIOCHF2, isoflurane, made and sold under the 50 halogenated aliphatic ethers, with hydrogen, can be trademark FORANE by Airco, Inc. It is referred to accomplished by reacting one of the certain substituted hereafter as isoflurane. In the process for manufacturing ethers with an alkanol and a base, preferably but not this anesthetic, care must be exercised to avoid by-pro necessarily in the presence of a catalyst. The halogen duct formation, and the process now in use achieves replaced may be bonded to a terminal carbon or to an low conversions to the desired product. Representative 55 inner carbon. by-products produced include CF3CCl2OCHF2, which The process of the invention can be concisely de has been considered to be useless in the past. scribed as a process for replacing a halogen substituent The selective reduction of halogenated aliphatic with hydrogen in a halogenated aliphatic ether of the ethers is extremely difficult to accomplish because of methyl-ethyl or ethyl-ethyl type, comprising reacting the different responses exhibited by ethers of this kind 60 with a primary or secondary alkanol and an inorganic to a given reactant or to given reactants. Thus, there are base a halogenated aliphatic ether of the formula: three important reactions that halogenated aliphatic (a) CX3OCY2CZ3 ethers may undergo in the presence of a base. where - First, a hydrolysis or nucleophilic displacement reac tion may occur. This is a reaction in which the halogen 65, andCX3 is CF3, CH3, CH2F, CF2CL, CF2Br, or CHF2; atom is replaced by OH, OR, or other nucleophilic CZ3CY2 is CF3CCL2, CF3CCIBr, CF3CBr2, group, as represented by the equation: ". . CFCl2CF2, CFCl2CFCl, CFCl2CFBr, CFBrC1CF, CFCIBrCFC), CFBrCICFBr, 4,346,246 3 4. CCl3CF2, CFBr2CF2, CFBr2CFC1, CFBr2CFBr, chlorine or one bromine is selectively replaced with CCl2BrCF2, CCIBr2CF2 or CBr3CF2 hydrogen. This is a rather remarkable reaction because O it occurs despite the presence on the same molecule of (b) CX3CY2OCY2CX3 -CF3 or where at least one of the CX3CY2 groups is selected from the following: F F --C- or F-C- X X

10 groups, where X is chlorine or bromine. It is also a very valuable reaction because it is specific and permits the and the other CX3CY2 group may be the same or may conversion of previously useless by-products to valu be selected from the following: able products, and also offers a new tool for synthesis. The two primary areas of immediate commercial CF3CFC1, CF3CFBr, CH3CH2, CHFCH2, 15 interest relate to the preparation of the two inhalant CHF2CF2, CFCICF2, CF2ClCFC), CF2ClCFBr, anesthetics mentioned above, as follows. CF2BrCF2, CF2BrCFC), CF2BrCFBr, CHFBrCF2, CHCl2CF2, CHClBrCF2 or Preparation of Enflurane Anesthetic, CHBr2CF2. CHFOCFCHFC1 20 The halogenated ether CF2HOCF2CFCl2 is a partic THE PRIOR ART ularly undesirable by-product of the presently No prior art is known that discloses or suggest the employed process for the preparation of enfluraneanes present process. thetic. It is readily reduced to enflurane in good yield by In Fluorine Chemistry Reviews, by Metille and Burton, the process of the present invention, as follows: p. 354, the authors describe the dehalogenation of CF3I. 25 to CF3H, using KOH in a solvent of high dielectric constant, specifically referring to ethanol. The use of CHFOCFCFCl2 + CH3OH + NaOH - Ge the reaction to dehalogenate CF3CF2I to CF3CF2H is also discussed. () The source article referred to by Metille and Burton 30 CHFOCF2CHFC -- NaCl + CH2O is Banus et al., J. Chem. Soc. 1951, pp. 60-64. This (enflurane anesthetic) publication states that it is known that the C-I bond in CF3I can undergo homolytic fission but that, apart from Using this reaction, a product stream from the pre decomposition, CF3Cl, CF2Cl2 and CHF2Cl "do not sently-employed process for producing enflurane, that show reactions involving the homolytic or heterolytic 35 contains this by-product I, can be upgraded by reacting fission of the carbon-chlorine bond." The publication in the product stream itself to convert the by-product to general stresses that the iodo compounds are unique as enflurane, in situ. The enflurane itself, that is present in compared to the corresponding bromo or chloro com the product stream, is not affected by the reaction. pounds. It would not, therefore, suggest the use of the In addition, the other halogenated ether by-products same type of reaction even for brominated, chlorinated, mentioned above, that are produced as "bottoms," can or fluorinated alkanes, let alone ethers. be further processed by distillation and chlorination to Young, U.S. Pat. No. 3,391,204, in his Example 11, obtain a mixture containing a high proportion of the describes the reaction: ether CHCl2OCF2CFCl2. Fluorination of this ether leads to I above, which can then be reacted in accor CuCl 45 dance with the invention to produce more enflurane, CF2CICF2Cl + TEA se CFCCF2H thus materially improving overall process yield and economics. where TEA represents triethanolamine. It should be noted that when the alkanol employed is Examples 12 and 13 describe generally similar methanol, 1.5 moles are required per mole of ether, so dehalogenations. Young says that alcohol may be pres 50 that the equations above and below, that employ metha ent, but characterizes the alcohol as an "inert' solvent, nol, are not balanced. The reason is that methanol un and his reaction did not operate on ethers, but rather on dergoes the Cannizzaro reaction. When other suitable halogenated alkanes. alkanols are employed which do not give a Cannizzaro In German Pat. No. 2,554,884, partial dechlorination reaction, the reaction requires one mole of the alkanol of F2CHOCFCICF2Cl, an ether, was accomplished by 55 the use of hydrogen and a catalyst of either palladium or to one mole of reactant ether. a complex metallic hydride. Preparation of Isoflurane Anesthetic, Some reactions involving halogenated alkanes are to CF3CHClOCHF2 be found in the literature. U.S. Pat. Nos. 3,527,813 and In the isoflurane manufacturing process, 3,535,388 describe the introduction of chlorine and of 60 CF3CH2OCHF2 is chlorinated to give fluorine into halogenated alkanes. CF3CHCIOCHF2, isoflurane. However, the chlorina DETAILED DESCRIPTION OF THE tion must be done at low conversions in order to avoid INVENTION formation of large amounts of the by-product CF3CCl2OCHF2. However, this by-product can now The present invention involves the discovery that 65 when a halogenated aliphatic ether initial compound, be reduced to isoflurane as follows: selected from a limited class of halogenated ethers as defined above, is reacted with an alkanol and a base, one 4,346,246 6 catalyst, more particularly, a copper-containing catalyst such as metallic (elementary) copper or a copper salt of GENERAL an inorganic or organic acid, e.g., copper chloride, Only a limited number of halogenated ethers are bromide, nitrate, acetate, propionate, etc.; or corre susceptible to selective reduction in accordance with 5 sponding salts of silver, cobalt, tin, manganese, nickel, the invention. iron, molybdenum, chromium, antimony, vanadium and As to those of the formula CX3OCY2CZ3, as defined the like, or the said varivalent metals in elementary above, those ethers that are suitable for use in the pres form, or alloys thereof with each other or with other ent invention were selected from a very large number of metals. Preferably a copper-containing catalyst, specifi halogenated ethers of the methyl-ethyl type, based upon 10. cally elementary copper in powder form, or a copper several rules. These rules eliminate those halogenated salt, is employed. In general, the use of a catalyst com methyl-ethyl type ethers that would not be suitable by prising, for example, one or more of the metals identi reason of side reactions, either initially or after reduc fied above, or the inorganic or organic salts thereof, tion. These rules are: tends to produce higher conversions, shorter induction 1. No OCY2CZ3 group can have the configuration O 15 periods, and lower operating temperatures. CH-CX' where X" is Br or Cl, since these com Preferred catalysts include not only the finely divided pounds would probably eliminate HX" to give metals, metal salts, but also the amines, the mixtures -O-C=C in the presence of base. thereof with metal powders and metal salts. The most (CFOCHFCF2Br and CFOCHFCF2Cl may be preferred catalysts are mixtures of copper chloride with exceptions to this rule, but are not within the scope of 20 triethanolamine. Other suitable amines that may be the invention). used, depending on the particular reaction, include: 2. No OCY2CZ3 group shall have more than one hydro gen on the 9 carbon unless CY2 is CH2 or CF2; i.e. where two of the Z= H, then CY2 must be CH2 or Methylamine(monomethylamine) Hexamethylenetetramine 25 Dimethylamine Ammonium chloride CF2. Otherwise the halogenated ether compounds Diethylamine Benzyl trimethyl ammonium would not only be unstable to base but some of them Triethylamine methoxide would decompose spontaneously. Isopropylamine Ethylene diamine 3. Within the OCY2CZ3 group, there must be either two Di-n-propylamine Triethylene tetramine chlorines, two bromines, or one bromine and one Piperidine N,N,N-trimethyl ethylene 30 Morpholine diamine chlorine on one of the carbon atoms, otherwise the Monoethanolamine N,N-diethylene diamine compound will not be reduced. Diethanolamine 1,2-cyclohexylene dinitrilo The first two rules eliminate those halogenated ethers Hydrazine acetic acid that are unstable in the reaction mixture of this inven Aniline 3-dimethylamino propylamine tion. The third rule confines those ethers that have Pyridine Ethylenediamine tetraacetic acid survived the screening by rules 1 and 2 to those that 35 Diazo bicyclo (2,2,2) octane would be reduced, and in addition, eliminates reduced N-(2-amino ethyl morpholine) compounds that would not be stable in the presence of the base in the reaction mixture. The application of cl CONDITIONS OF REACTION these rules, of course, severely limits the number of The alkanol and base should be employed in excess halogenated ethers that are available for use in the selec 40 over the theoretical amount required to effect the de tive reduction process of the invention. sired reduction of the ether. The alkanol may function The same considerations can be applied in identifying both as a reactant and solvent and may be present in those halogenated ethers of the ethyl-ethyl type that are substantial excess for that reason. The limits are those suitable for use in practising the invention. .. established by the practical considerations of reaction The alkanol reactant is a primary or secondary alco 45 kinetics, ease of recovery of the product, and conserva hol, preferably a 1 to 4 carbon alkanol (i.e., a lower tion of energy. alkanol), but alkanols of any known chain length up to The temperature of the reaction is dependent upon about 12 carbons are useful and can be expected to be the particular reactants employed and may range, for effective, although even higher alcohols are operative. example, from about 0° C. to about 100-120° C. or Water soluble alcohols are preferred. The alkanol may 50 higher and, preferably, from about 20° C. to about 80' be substituted but preferably is not, as a matter of eco C. The temperature and/or pressure advantageously nomics. While methanol and ethanol are generally pre are such that the reaction mass is in a liquid state during ferred because of availability and cost, isopropanol and the course of the reaction. The reaction is exothermic, sec-butanol are useful and also are readily available. and once initiated, may require cooling, depending The base may be: an alkali metal dissolved in the 55 upon the equipment available and other conditions. alkanol; an alkali metal or alkaline earth metal hydrox The time of the reaction is not important since one ide, dry or in aqueous or alcoholic solution; or any may prefer to carry out the reaction for a relatively strongly basic material that does not interfere with the short period of time with a relatively low conversion desired reaction. Sodium hydroxide, sodium methylate, rate, rather than to make the reaction go substantially to potassium hydroxide, lithium hydroxide and calcium 60 completion. In general, the time of the reaction depends hydroxide, are examples of suitable basic materials. upon the particular reactants employed, the tempera Ammonia and sodium carbonate are useful in many ture of the reaction, the efficacy of the catalyst or cata reactions. lyst system (if employed), and other influencing factors. Catalysts are generally not essential but are useful for Generally, just a few hours up to about thirty, is ade many individual reactions in improving reactions rates, 65 quate to produce a suitable yield. yields or both. The catalyst, in finely divided or other The pressure used is dependent primarily upon the suitable state, may be a metal-containing (advanta particular reactants employed. The reaction may be geously, in most cases, a varivalent metal-containing) carried out at atmospheric pressure. The pressure em 4,346,246 7 8 ployed seems to have no material effect on the course of Example 2C the reaction. The product may be isolated by any suitable means Enflurane Preparation with a Catalyst System from the reaction mass. Ordinarily, the product is insol A mixture of CHF2OCF2CFCl2 (22 g, 0.1 mole), uble and is precipitated by a water-wash, which re 5 methanol (50 ml), 50% aqueous sodium hydroxide solu moves any water-soluble reaction products and by-pro tion (24 g, 0.3 mole), ethanolamine (6 g), and copper ducts. metal (1 g), was refluxed for 24 hours. The reaction To explain the invention further, several demonstra mixture was washed with water to give 10.9 g of water tions of it are reported in the following examples. All insoluble product, which was analyzed by gas chroma temperatures are in C., and all parts and percentages by 10. tography and shown to be 90% CHF2OCF2CHFC1. weight, as is, unless expressly stated to be otherwise. There was no unchanged starting material present. When this procedure was repeated, but with the use EXAMPLE 1. of 75 ml. of methanol rather than 50 ml, the water Production of Isoflurane Anesthetic insoluble product recovered amounted to 10.6 g., which 15 is considered to be an insignificant difference. CuCl EXAMPLE 3 CF3CCl2OCHF2 - NaOH -- CH3OH se Different Reactant Ether CF3CHClOCHF2 (isoflurane anesthetic) 20 Example 3A A mixture of CF3CCl2OCHCl2 (44g, 0.2 mole), 50% Small Scale Preparation aqueous sodium hydroxide solution (20 g, 0.25 mole), CuCl methanol (100 ml), CuCl2 (1 g), and triethanolamine (l CF2CIOCF2CFCl2 + NaOH -- CH3OH Ge. g), was refluxed for five hours and poured into water. 25 The water-insoluble layer was analyzed by gas chroma CF2COCF2CHFC1 (Product 3) tography and found to contain 16% unreacted CF3CCl2OCHF2, 25% methanol, and 54% A mixture of CF2ClOCF2CFCl2 (25.3 g, 0.1 mole), CF3CHCIOCHF2 (isoflurane anesthetic). methanol (50 ml), 50% aqueous sodium hydroxide solu 30 tion (16 g, 0.2 mole), triethanolamine (1 g), and CuCl2 (1 EXAMPLE 2 g), was refluxed for nineteen hours. The reaction mix Different Reactant Ether, With Catalysts ture was poured into water and 19 g of water-insoluble Example 2A product recovered. This was analyzed by gas chroma tography and shown to be about 91% Production of Enflurane 35 CF2COCF2CHFC1 (Product 3). Product 3 is useful as a solvent and degreasing agent. CHF2OCF2CFCl2 (Material 2) + NaOH -- CH3OH - E. S. Example 3B 40 Larger Scale Preparation CHF2OCF2CHFC1 (enflurane anesthetic) This reaction was repeated on a larger scale, and with a more detailed characterization of the product, as foll A mixture of CHF2OCF2CHCl2 (44 g, 0.2 mole), lows: 50% aqueous sodium hydroxide (20g, 0.25 mole) meth A mixture of CF2ClOCF2CFCl2 (253 g, 1 mole), anol (100 ml), CuCl2 (1 g), and triethanolamine (1 g), 45 methanol (750 ml), 50% aqueous sodium hydroxide (120 was refluxed for seven hours and then poured into wa g, 1.5 mole), CuCl2 (10 g), and triethanolamine (10 g), ter. The water-insoluble product recovered (34 g) was was refluxed for 24 hours. At the end of this time, 85% analyzed by gas chromatography and found to be 77% of the sodium hydroxide had reacted as shown by titra unreacted CHF2OCF2CFCl2 (Material 2) and 18% tion. The reaction mixture was distilled to recover 280 CHF2OCF2CHFC1 (enflurane). 50 g of product, b.p. 53-64, which was washed with Material 2 can be separated as a "bottom' in a still water to give 204 g. containing 69% from the enflurane product, for recycling through the CF2ClOCF2CHFCl (Product 3) and 27% unreacted process. The enflurane distillate, in purified form, is CF2COCF2CFCl2. This was redistilled to recover in useful as an inhalant anesthetic. purified form CF2CIOCF2CHFCl (Product 3), b.p. 64, Example 2B 55 which was identified by its NMR spectrum. Purification of Enflurane EXAMPLE 4 A reaction product containing enflurane together Different Reactant Ether with about 5% of Material 2 was purified as follows. 60 A mixture of CHF2OCF2CHFC (95.6 g) and CuCl CHF2OCF2CFCl2 (4.4 g), methanol (15 ml), copper (1 CFCC12OCF2C1 + NaOH + CH3OH > g), ethanolamine (6 g), and sodium hydroxide pellets (8 CF3CHCIOCF2Cl (Product 4) g), was refluxed for five hours and then washed with water. The water insoluble product (88.9 g) was shown 65 A mixture of CF3CC12OCF2Cl (50 g, 0.2 mole), by gas chromatography to be 99.7% pure methanol (100 ml), 50% aqueous sodium hydroxide CHF2OCF2CHFC1, with no CHF2OCF2CFCl2 pres solution (48 g, 0.6 mole), CuCl2 (2 g), and triethanol ent. amine (2 g), was refluxed for five hours. The reaction 4,346,246 10 mixture was washed with water to give 34 g. of water Thus, in the conversion of by-products from the man insoluble product material which was analyzed by gas ufacture of enflurane, the "bottoms' are chlorinated to chromatography and shown to be 79% obtain a mixture containing a high proportion of the CF3CHCIOCF2Cl (Product 4), which is useful as a compound, CHCl2OCF2CFCl2. Fluorination of this solvent and degreasing agent. 5 compound produces CF2HOCF2CFCI2, which can be In a different run, a reaction mixture of the same reduced by the process of the invention to enflurane, as composition, after refluxing for 68 hours, produced a in Example 2. major amount of Product 4. The process of this invention has the advantage of - In still another run, a reaction mixture of the same being highly specific, in the sense that few unwasted composition except for the sodium hydroxide, which 10 materials appear in the reaction mixture produced. was present in an amount of 24 g. (0.3 mole), produced Product recoveries and purifications are thus facilitated after 4 hours of reflux a product containing over 90% of and made less expensive. The many useless by-products Product 4. produced by the presently-employed process are either avoided completely because of the new synthesis tool EXAMPLE 5 15 that is available, or the quantity and number is reduced. Four Carbon Reactant Ether . . . The process provides new ways to synthesize valu able materials and, in addition, provides a way to con ...... : CuCl vert presently useless or unusual halogenated by-pro CFCCl2OCHCICF3+ NaOH + CH3OH se ducts into valuable intermediates. 20 While the invention has been disclosed herein by CF3CHCIOCHCICF3 (Product 5) reference to the details of preferred embodiments, it is to be understood that the disclosure is intended in an A mixture of CF3CCl2OCHCICF3 (15g, 0.053 mole), illustrative sense, and it is contemplated that modifica 50% aqueous sodium hydroxide solution (6.4 g, 0.08 tions may be made in the process within the spirit of the mole), methanol (50 ml), CuCl2 (0.1 g), and triethanol 25 invention and the scope of the appended claims. amine (0.1 g), was refluxed for four hours and poured We claim: into water. The water-insoluble product (10 g) was 1. A process for replacing a halogen substituent with analyzed by vapor phase chromatography and found to hydrogen in a halogenated aliphatic ether of the meth contain 48% CF3CHCIOCHCICF3 (Product 5), (dl. yl-ethyl or ethyl-ethyl type, comprising reacting a pri form), 38% CF3CHCIOCHCICF3 (meso form), and 8% 30 mary or secondary alkanol and an inorganic base se unreacted starting material. lected from the group consisting of alkali and alkaline Product 5 is useful as a solvent and degreasing agent. earth metal hydroxides and alkoxides, in the presence of a catalyst selected from the group consisting of copper, EXAMPLE 6 silver, cobalt, tin, manganese, nickel, iron, molybde Criticality of Ether Reactant 35 num, chromium, antimony, vanadium, the salts thereof, A mixture of CF3CHCIOCF2Cl (5.4g, 0.025 mole), an amine, and mixtures thereof, with a halogenated methanol (10 ml.), 50% aqueous sodium hydroxide (4 aliphatic ether of the formula: g., 0.05 mole), CuCl2 (0.25 g), and TEA (0.25 g), was (a) CX3OCY2CZ3 refluxed overnight. The water-insoluble product (2 g) where was subjected to NMR spectroscopy. The spectrum 40 CX3 is CF3, CH3, CH2F, CF2Cl, CF2Br, or CHF2; showed multipet centered (6 peaks) around 5.8 and two and CH3O singlets. None of the expected triplet for -OCHF2 was present. It is concluded that this starting ether does not undergo selective reduction in accor 45 dance with the invention. CCl3CF2, CFBr2CF2, CFBr2CFC), CFBr2CFBr, CCl2BrCF2, CCIBr2CF2 or CBr3CF2, or CONCLUSION (b) CX3CY2OCY2CX3 The invention provides a valuable, specific technique where at least one of the CX3CY2 groups is selected for selectively modifying the halogenation of a haloge 50 from the following: nated aliphatic ether, by a selective reduction process that substitutes a hydrogen substituent for a particular halogen substituent. The process thus makes possible the conversion of hitherto useless halogenated aliphatic ethers to materials that are either useful perse or that 55 CCl2BrCF2, CCIBr2CF2 or CBr3CF2; can be converted by further processing to directly use and the other CX3CY2 group may be the same or may ful materials. be selected from the following: The invention is of particular value in connection CF3CH2, CF3CHF, CF3CHCl, CFCHBr, with the production of enflurane anesthetic, since it not CF3CF2, CF3CFC), CF3CFBr, CH3CH2, only permits the conversion of a major by-product, CHFCH2, CHF2CF2, CFCICF2, CF2ClCFC), CHF2OCF2CFCl2, into the desired enflurane anesthetic CF2ClCFBr, CF2BrCF2, CF2BrCFC), product, as in Example 2, which is an important ad CF2BrCFBr, CHFBrCF2, CHCl2CF2, vance in the art in and of itself, but it also eliminates the CHCIBrCF2, or CHBrCF2. need that previously existed for separating this material 2. A process in accordance with claim 1 wherein the from the product stream containing the enflurane (a 65 aliphatic ether reactant is difficult task because of the many physical and chemical similarities between the compounds and the closeness of their boiling points). 4,346,246 11 12 5. A process in accordance with claim 1 wherein the and the reduced ether product is aliphatic ether reactant is CF3CHClOCHF2 3. A process in accordance with claim 1 wherein the and the reduced ether product is aliphatic ether reactant is

10 6. A process in accordance with claim 1 wherein the and the reduced ether product is aliphatic ether reactant is CF3CCOCHCICF3 CHFCCFOCHF. and the reduced ether product is 4. A process in accordance with claim 1 wherein the 15 aliphatic ether reactant is CFCHCIOCHCICF3. 7. A process in accordance with any one of claims 1, 2, 3, 4, 5, or 6, wherein the alkanol is a lower alkanol. 20 8. The process in accordance with claim 1, wherein and the reduced ether product is said alkali metal alkoxide comprises a sodium alkoxide. 9. A process in accordance with claim 1 or 8 wherein CHFCICFOCF2C1. said alkoxide comprises a methoxide. sk s 25

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