United States Patent 15 3,689,571 Regan et al. (45) Sept. 5, 1972 54 FLUORINATED ETHER 56) References Cited (72) Inventors: Bernard M. Regan; John C. Long- UNITED STATES PATENTs street, both of Chicago, Ill. 3,476,860 1 1/1969 Croix et al..........260/614 FX (73) Assignee: Baxter Laboratories, Inc., Morton 3,346,448 10/1967 Gilbert et al........... 260/614 F Grove, Ill. 22 Filed: July 31, 1970 OTHER PUBLICATIONS Mitsch et al., J. Heterocyclic Chem., Vol. 2, (1965) 21 Appl. No.: 60,132 pp. 152- 156 Related U.S. Application Data 63 Continuation-in-parts of Ser. No. 771,365, Oct. Primary Examiner-Howard T. Mars 28, 1968, abandoned. Attorney-Scott J. Meyer (52) U.S. C. ............................... 260/614 F, 424/342 57 ABSTRACT ESAGOES Tyropod1,1,1,3,3,3-hexafluoro-2-propyl ether, usefulfifty as an anesthetic agent. 1 Claim, No Drawings 3,689,571 1. 2 FLUORNATED ETHER are formed with the present fluoromethyl 1,1,1,3,3,3- hexafluoro-2-propylether. CROSS-REFERENCE TO RELATED APPLICATION The outstanding utility of the fluoromethyl This is a continuation-in-part of co-pending applica 1,1,1,3,3,3-hexafluoro-2-propyl ether of the present in tion Ser. No. 771,365, filed Oct. 28, 1968 and now 5 vention is further highlighted by comparison with abandoned. isomers of that compound which do not have this utili This invention relates to the fluorinated ether, ty. For example, the compound CHsOCF(CF), was fluoromethyl 1,1,1,3,3,3-hexafluoro-2-propyl ether, found to be non-anesthetic up to 8 percent by volume having the structure CHF-O-CH(CF)2. in oxygen, which means that it would burn at its In recent years, several fluorinated ethers have been 10 anesthetic concentration since its lower flammability found to have useful anesthetic properties, notably limit is about 7 percent to 8 percent. Another isomer, methoxyflurane, CHOCFCH; fluroxene, CFCHOC the trifluoromethyl 2,2,3,3-tetrafluoropropyl ether of H = CH, roflurane; CHOCFCHBrF; and ethrane, Aldridge and Shepherd, J. Org, Chem., Vol. 29, pages CHFOCFCHCIF. 11-15 (1964), has been shown to cause violent convul With the recent availability of various polyhalo 15 sions and deaths in mice at a concentration as low as isopropanols, which serve as excellent starting materi 0.5 percent. Yet another isomer, CHFOCHCFCF is als for the corresponding methyl ethers, certain non-anesthetic up to its lethal concentration and anesthetic halogenated isopropyl methyl ethers have produces convulsions in mice. In still another com been developed. U.S. Pat. No. 3,476,860 describes a parison, it has been found that the isomeric (CHF),C group of halogenated derivatives of fluorinated F-O-CHF, is a weak anesthetic in which deep isopropyl methyl ethers of which two compounds, anesthesia is not obtained and abnormal EEG (electro namely, CF(CF,Cl). CHOCHCl and (CF),CHOCH, encephalographic) and convulsantactivity is observed. Cl, were stated to be anesthetic. That patent also All of the foregoing comparisons between the novel describes the preparation of several other related com 25 fluorinated ether of this invention and several isomeric pounds, for example, (CF),CHOCHF, and (CF)CH ethers further supports the unobvious and unexpected OCHFC. utility of the present invention. Surprisingly and unexpectedly, it has now been The fluoromethyl 1,1,1,3,3,3-hexafluoro-2-propyl found that the present fluoromethyl 1,1,1,3,3,3-hex ether of this invention is a volatile liquid, is non afluoro-2-propyl ether, which was not mentioned in 30 flammable in air at ambient temperatures and has a U.S. Pat. No. 3,476,860, is an outstanding anesthetic lower flammability limit in oxygen of about 11.8 agent. On the other hand, the foregoing two specific volume percent, which is about three times its compounds suggested as anesthetic agents in said anesthetic maintenance concentration in dogs. patent, and several of the other related compounds Fluoromethyl 1,1,1,3,3,3-hexafluor-2-propyl ether is described in said patent, have now been found upon 35 prepared by several methods. In one method, the further testing to have undesirable properties which chloromethyl 1,1,1,3,3,3-hexafluoro-2-propyl ether is mitigate against their use as clinically useful first prepared by the free radical chlorination of anesthetics. 1,1,1,3,3,3-hexafluoro-2-propyl methyl ether and, That is, it has now been found that when ad more preferably, by a photo induced reaction between ministered to dogs in repeated doses for long periods of 40 about 0.5 to about 1 mole of chlorine per mole of the time, the compounds having a chlorinated methyl hexafluoro-2-propyl methyl ether and a temperature of group, for example, (CF)CHOCHCl, are unstable from about 20 C. to about 65° C. The chlorine is then and toxic to the animal, while that compound having a replaced with fluorine in the methyl group. In this difluorinated methyl group, for example, (CFa),CH replacement reaction, the chloromethyl ether is OCHF, is convulsant. The monochlorinated com 45 reacted with from about 1 to about 3 molar equivalents pound, (CF),CHOCHFCl, also produces opisthotonus of dry potassium fluoride in the presence of a mutual in mice. On the other hand, the present fluoromethyl solvent, for example, an organic solvent such as 1,1,1,3,3,3-hexafluoro-2-propyl ether exhibits out tetrahydrothiophene 1, 1-dioxide, under essentially an standing anesthetic properties over repeated and long hydrous conditions and a temperature of from about term dosage administration in dogs. Consequently, the SO 80 C to about 180 C. present compound has an unexpected and unobvious Another method of preparation of the present utility not exhibited by those compounds mentioned in anesthetic compound involves the reaction of the cor U.S. Pat. No. 3,476,860. responding methyl ether and bromine trifluoride in ac Although the present inventors are not to be bound cordance with a general procedure disclosed by Yu by theory, it is believed that the instability and toxicity 55 minov et. al., Zh. Obshch. Khim., Vol. 37, pages of the chlorinated ether, (CF)CHOCHCl, is due to 375-80 (1967); Chem. Abstracts, Vol. 67, No. 43,357x. the hydrolysis or breakdown of this compound to the In this reaction, fluoromethyl 1,1,1,3,3,3hexafluoro-2- reaction products formaldehyde, hydrochloric acid and propyl ether is prepared from 1,1,1,3,3,3-hexafluoro-2- hexafluoroisopropanol. This toxicity is believed to be propyl methyl ether and from about 0.5 to about 1.0 due primarily to the formation of the formaldehyde and 60 molar equivalent of bromine trifluoride, preferably hydrochloric acid since upon intravenous administra about two-thirds of a molar equivalent, by refluxing at . tion of hexafluoroisopropanol to dogs, the latter com about 20 C to about 50 C. pound by itself was not found to be toxic. These reac Still another method of preparation of the present tion products have been found to be formed during anesthetic ether involves the reaction of 1,3- long term dosage administration of the anesthetic, 65 polyfluoro-2-propanol, formaldehyde and hydrogen (CF)CHOCHCl, in an amount of about 170 times fluoride in accordance with a general procedure the amount that the corresponding reaction products described by Weinmayr, U.S. Pat. No. 2,992,276. 3,689,571 3 4 Surprisingly and unexpectedly, the compound of the minutes. Thereafter, the exothermic reaction was al present invention cannot be prepared by the halogen lowed to proceed autogeneously under partial reflux replacement methods described in examples 3 and 4 of (hydrogen chloride emitted) employing a Dry Ice con U.S. Pat. No. 3,476,860, which involve the reaction of densor. The reaction product was washed successively the corresponding chlorinated ether and antimony 5 with cold water, a small amount of aqueous sodium trifluoride. That is, the fluoromethyl 1,1,1,3,3,3-hex bisulfite and cold water made slightly alkaline with afluoro-2-propyl ether cannot be prepared by the reac sodium hydroxide. The washed product weighed 478 tion of (CF),CHOCH2Cl and antimony trifluoride as is grams. It was dried by azeotropic distillation and then taught in said patent for the preparation of the cor fractionally distilled at 747 mm. Hg. A forerun of 79 responding (CF)CHOCHF, and (CF)CHOCHFC). 10 grams, b 65-77.2 C, was first obtained. The next 281 In general, the anesthetic compound of this invention grams, b 77.2-77.3 C, was chloromethyl 1,1,1,3,3,3- is administered by the inhalation route to warm hexafluoro-2-propyl ether of 99.8 percent purity by . blooded, air breathing animals in an amount of from about 1 percent to about 5 percent by volume in admix gas liquid chromatography (GLC) and with a density of ture with from about 99 percent to about 95 percent by 5 23 C of about 1.517. The CHC-O-CH(CF) struc volume of oxygen or a gaseous mixture containing ox ture was confirmed by a proton nuclear magnetic ygen in sufficient amount to support respiration. resonance (NMR) spectrum. Although specific methods of administration of the EXAMPLE 2 fluoromethyl 1,1,1,3,3,3-hexafluoro-2-propyl ether as an anesthetic agent are described herein, it will be un 20 Chloromethyl 1,1,1,3,3,3-Hexafluoro-2-propyl derstood that this compound is not limited to any par Ether. ticular method of administration. Thus, the fluorinated Dry chlorine gas (685 grams, 9.66 moles) was bubbled ether of this invention can be admixed with one or at an average rate of 31 grams per hour into methyl more other anesthetic agents in order to achieve ad 1,1,1,3,3,3-hexafluoro-2-propyl methyl ether (2712 vantages in administration, degree of relaxation, safety 25 grams, 14.9 moles) at 20 to 25°C with illumination by and the like.