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.