ESAGOES Tyropod Fifty

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. For example, the present compound can an immersion-type water cooled ultraviolet lamp be admixed with suitable proportions of known through a Pyrex sleeve. The reaction flask was sur anesthetics such as nitrous oxide, ethyl ether, mounted by a cold water condensor, and this conden cyclopropane, halothane, ethyl vinyl ether and the like 30 sor was surmounted by a Dry Ice cooled condensor anesthetic adjuncts. In nitrous oxide, the lower flamma connected to a Dry Ice cooled trap which permitted the bility limit of fluoromethyl 1,1,1,3,3,3-hexafluoro-2- release of hydrogen chloride. The product was washed propyl ether is 10 percent by volume whereas the lower with ice cold water, cold dilute aqueous sodium flammability limit of the analagous chloromethyl hydroxide solution, and cold water. It was separated, 1,1,1,3,3,3-hexafluoro-2-propyl ether of U.S. Pat. No. 35 dried by azeotropic distillation, and fractionally 3,476,860 in nitrous oxide is 6 percent by volume. The distilled to recover 1,1,1,3,3,3-hexafluoro-2-propyl significance of this advantage is apparent since the use methyl ether (1,171 grams), biso 50.2 to 51.0 C, of of nitrous oxide along with oxygen is known to 99.9 percent purity by GLC. Subsequently, a generally have an adverse effect upon the flammability chloromethyl 1,1,1,3,3,3-hexafluoro-2-propyl ether of organic compounds. 40 fraction (1,346 grams), biso 77.0 to 77.2°C, of 99.9 The fluorinated ether of this invention can also be in percent purity by GLC was obtained. jected directly into the body by means of a catheter or shunt see, e.g., Folkman et al., Science, Vol. 154, EXAMPLE 3 pages 148-9 (1966) or can be prepared in an emul Fluoromethy 1,1,1,3,3,3-Hexafluoro-2-propyl sion form of the oil-in-water type and injected into the 45 animal to evolve satisfactory anesthesia (see, e.g., Ether. Krantz et al., Anesth. and Analg., Vol. 41, pages 257-62 A solution of chloromethyl 1,1,1,3,3,3-hexafluoro-2- (1962 and U.S. Patent No. 3,216,897). The anesthetic propyl ether (754 grams, 3.49 moles) in dry agent enters the central nervous system via the circula tetrahydrothiophene 1, 1-dioxide (2,000 ml) and dry, tory blood and leaves the body in the exhaled air in a 50 powdered potassium fluoride (203 grams, 3.49 moles) manner analagous to the inhalation route of adminis were stirred and heated to 30 C in a creased flask tration. Still other methods of administration will be ap fitted with a fractional distillation assembly. A distillate parent to those skilled in the art. (200 ml), bas 56.0 to 62 C, was collected during 5 The following examples will further illustrate the hours. Then the reaction mixture was cooled to room present invention although the invention is not limited 55 temperature, dry potassium fluoride (100 grams, 1.74 to these specific examples. All parts and percentages moles) was added, and the cycle of operations was re set forth herein are on a weight basis unless otherwise peated three times at temperatures between 138 to specified. 185 to give distillates (100 ml, 100 ml and 50 ml), b 58 to 61° C, 55.5° to 57 C, and 54.2° to 55.9° C, EXAMPLE 60 respectively. From this portionwise addition of potassi Chloromethyl 1,1,1,3,3,3-Hexafluoro-2-propyl um fluoride (503 grams total, 8.7 moles) there was ob Ether, tained distillates totalling 672 grams, be 54.2 to 62.0 Chlorine gas (165 grams, 2.32 moles) was bubbled into C, which by GLC analysis was about 92 percent 1,1,1,3,3,3-hexafluoro-propyl methyl ether (420 fluoromethyl and 6.8 percent chloromethyl 1,1,1,3,3,3- grams, 2.32 moles) during four hours. After 5 minutes, 65 hexafluoro-2-propyl ethers. The combined distillates the reaction was initiated by illumination with a sun were dried over anhydrous calcium sulfate (33 grams) lamp through a Pyrex reaction flask for about five and filtered. 3,689,571 5 6 Fractional distillation of 659 grams gave a forerun and then allowed to dry overnight in room air, m.p. (46 grams), bis 53.5 to 57.0 C, and then 99.6 percent 52.5°C, yield of 52 percent by weight based on hex pure fluoromethyl 1,1,1,3,3,3-hexafluoro-2-propyl afluoro-2-propanol. After one recrystallization from ether (505 grams), bis 57.0 to 57.7° C. There carbon tetrachloride, this compound had m.p. 54.6°C remained 94 grams of undistilled substance. and micro b.p. 154.5°C at 753 torr. The proton NMR The fluoromethyl ether fraction (31 1 grams), bas spectrum of this compound in CC (0.10 g/ml.) 57.5° to 57.7 C, was 99.9 percent pure by GLC and showed a singlet (6 at 4.27 ppm) and a septet (8 = 3,60 had a density of 1.505 at 23°C. ppm, J = 6Hz) in an area ratio of 2:1. The chemical shifts (8) are given relative to internal tetramethyl EXAMPLE 4 10 silane. A tentative structure for this compound is Fluoromethyl 1,1,1,3,3,3-Hexafluoro-2-propyl (CFa),CH-O-CH. O. The latter compound (m.p. Ether. Bromine trifluoride (14.5 ml, 0.34 mole) was 54.6°C) and anhydrous hydrogen fluoride in a 1:1.33 added portionwise during 2 hours to 1,1,1,3,3,3-hex weight ratio were heated in a steel autoclave for 2 afluoro-2-propyl methyl ether (45 ml, 0.34 mole) with hours at 90 -1 10°C, then for 4 hours at 150-180°C stirring in a Pyrex flask fitted with a reflux condenser 15 and then cooled. After removal of hydrogen fluoride, and a Teflon syringe and needle. A vigorous exother the remaining liquid, water-immiscible product (40. mic reaction occurred at about 20°C and higher. The percent by weight based on the compound m.p. reaction temperature was maintained between 20 and 54.6°C) was found by proton nuclear magnetic and gas 50° C with the aid of a water bath. A proton NMR spec liquid chromatographic analyses to be about 90 per trum of the product indicated the conversion of the cent fluoromethyl 1,1,1,3,3,3-hexafluoro-2-propyl methyl ether to the corresponding fluoromethyl ether ether. was substantially complete. The product was washed with aqueous sodium sulfite, aqueous sodium hydrox EXAMPLE 7 ide, and water to decolorize and neutralize. The 25 The fluoromethyl 1,1,1,3,3,3-hexafluoro-2-propyl washed product (61 grams) was dried over anhydrous ether of this invention was shown to have useful calcium chloride and shown by GLC analysis to be 97.5 anesthetic properties in mice essentially according to percent fluoromethyl 1,1,1,3,3,3-hexafluoro-2-propyl the procedure described by Robbins, J. Pharmacol. ether. Exptl. Therap, Vol. 86, pages 197-204 (1946). The 5 30 minute median anesthetic concentration, ACso, and the EXAMPLE 5 5 minute median lethal concentration, LCs, were Fluoromethyl 1,1,1,3,3,3-Hexafluoro-2-propyl determined by a log-probit plot of the data as described Ether. 1,1,1,3,3,3-hexafluoro-2-propyl methyl ether by Miller and Tainter, Proc. Soc. Exptl. Biol. Med., Vol. 57, pages 261-64 (1944). The number of test mice (622 grams, 3.41 moles) was stirred in a reactor fitted 35 used was 30 for each of the ACso and LCso concentra with an additional funnel containing bromine tions. Fluoromethyl 1,1,1,3,3,3-hexafluoro-2-propyl trifluoride (301 grams, 2.20 moles) and a cold water ether was found to have an ACso of 1.42 volume per condenser connected to an ice-cooled trap. The BrFa . cent and an LCso of 8.38 volume percent, or an was added portionwise, and the temperature of the anesthetic margin of safety (LCso/ACso) of 5.9 in mice. reactants adjusted between 25 and 50°C so that the 40 Identical tests with several anesthetics in general use reaction progressed at a rapid but controllable rate. gave the following results: When the reaction was complete, water was cautiously halothane, LCs/AC = 2.74/0.78 = 3.5; added to decompose any BrF3 which remained. The diethyl ether, LCs/ACso = 13.6/3.83 = 3.5; reaction product was freed of hydrogen fluoride and 45 fluroxene, LCs/ACs = 11.6/3.5 F3.3; bromine by successive washings with water, sodium methoxyflurane, LCso/ACso-2.52/0.56-4.5. sulfite solution and water. The washed product was dried by freezing out water at -20°C. The dried EXAMPLE 8 product weighed 541 grams and was 98.3 percent In order to demonstrate the unexpected and unobvi fluoromethyl 1,1,1,3,3,3Hexafluoro-2-propyl methyl 50 ous outstanding anesthetic properties of the ether and 1.7 percent the starting methyl ether by gas fluoromethyl 1,1,1,3,3,3-hexafluoro-2-propyl ether liquid chromatography. In addition, the trap contained compared to the corresponding properties of various of 92 grams of about a 1:1 mixture of these fluoromethyl its isomers and analagous compounds, the following and methyl ethers. Fractional distillation of the 541 tests were conducted. grams of product gave purified fluoromethyl 55 Dogs and rats anesthetized 3 hours daily, 5 days per 1,1,1,3,3,3-hexafluoro-2-propyl ether: 343 grams of week for 2 weeks, with fluoromethyl 1,1,1,3,3,3-hex better than 99.9 percent purity, bis 58.1-58.2°C, d'4 afluoro-2-propyl ether in oxygen showed no signs of 1.505; and 95 grams of better than 99.0 percent purity. toxicity. Anesthesia proceeded smoothly and rapidly, the anesthetic state was unmarked by convulsive move EXAMPLE 6 60 ments or electro-encephalographic abnormalities, and Fluoromethyl 1,1,1,3,3,3-Hexafluoro-2-propyl recovery occurred within two minutes. On the other Ether. 1,1,1,3,3,3-hexafluoro-2-propanol, paraformal hand, chloromethyl 1,1,1,3,3,3-hexafluoro-2-propyl dehyde and anhydrous hydrogen fluoride in a, respec ether produced severe toxic signs and death in rats and tively, 1:2:4 molar ratio were stirred at about 9°C. In dogs anesthetized 3 hours daily on 5 consecutive days. about 30 minutes, the homogeneous mixture began to 65 In rnice, recovery time was undesirably prolonged to 18 deposit a crystalline product. After about 2 hours, this to 20 minutes following only 10 minutes of anesthesia product was collected by filtration, washed with water, with CF(CFCL)CHOCHCL and in mice 3,689, 57 7 8 anesthetized with (CF),CHOCHFC, opisthotonus was The lower flammability limit in oxygen, LFLO, of observed during induction. In dogs, (CF),CHOCHF, the gaseous anesthetic is defined as the concentration produced anesthesia marked by convulsive movements by volume percent of the anesthetic in the gaseous mix and electro-encephalographic abnormalities. The com ture at which downward flame propagation was ob pound (CHF)CFOCHF, caused loss of righting reflex 5 served. - - - in mice but produced only hypnosis and clonic convul The concentration by volume percent of the gaseous sive activity but little analgesia in dogs. anesthetic in oxygen was calculated by well-known computation means employing the known volumes, EXAMPLE 9 densities and molecular weights, and application of the In still another comparison between fluoromethyl O ideal gas law. 1,1,1,3,3,3-hexafluoro-2-propyl ether and several close In this test, the LFLO, for fluoromethyl 1,1,1,3,3,3- analogs administered to dogs via the inhalation route, hexafluoro-2-propyl ether was 11.8 and the ratio the following results were obtained. LFLO/ACso (using the ACso from Example 7, above) ANESTHETIC COMPARISON IN DOGS Induction monw Maintenance Number of Concentration Time, Concentration, Recovery time, Compound test dogs wol. percent minutes vol. percent minutes Results 8------5-8 5 4-5 5-25------No significant side effects after single or repeated exposures. CHF-o-o-c F3 CF B 3------3. 20 0.2-0. 5 No recovery. Spontaneous leg movements during an Cardiac failure. esthesia, severe respiratory and cardiac CH.C-0--0 FC depression. CF3 B dog, 4 ex- 15 2-3 20-30------EEG seizure discharges and convulsive posures movements during anesthesia. CHF cl-o-c-c E3 CF H 2------3. 15 0.5-i, 0 No recoveries--- Spontaneous cardiac arrhythmias, high amplitude EEG spiking and convul CHF-0--0 Fs sive movements during anesthesia. CF2Cl - Anesthesia maintained for 2-3 hours in each dog. --- ...------EXAMPLE 10 was 8.3. By way of comparison, the LFLO, for the The flammabilityis of gaseous mixtures of E3methyl /ACsohexafluoro-2-propyl ratio W. 2E ether was 6.0 and iits fluoromethyl 1,1,1,3,3,3-hexafluoro-2-propyl ether 2 Aavso w and oxygen were determined at room temperature and Various other examples and modifications or adapta atmospheric pressure by visualization of the downward 40 tions of the foregoing examples can be devised by the propagation of a flame in a glass bottle having a cylin person skilled in the art after reading the foregoing drical portion 2.3 inches i.d. x 3.5 inches in height. The specification and the appended claims without depart bottle was flushed with pure oxygen, a known quantity ing from the spirit and scope of the invention. All such of the liquid anesthetic was added rapidly, and the bot further examples, modifications and adaptations are in tle was closed with a ground glass stopper. The bottle 45 cluded within the scope of the invention. was then rotated and SE i the Rid anesthetic What is claimed is: was completely vaporized and uniformly mixed with 1. Fluoromethyl 1,1,1,3,3,3-hexafluoro-2-propyl oxygen. The stopper was then removed and immediate ether. ly a burning stick was inserted in the bottle 1.5 to 2.0 inches------below the bottle mouth. SO

55

65 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3, 689, 571. Dated September 5, 1972 Inventor(s) Bernard M. Regan and John C. Longstreet It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below: In the specification, col. 7, in the table under Example 9, the first listed structural formula should appear as follows:

H

chroic,CF3

Signed and sealed this 6th day of August 1974.

(SEAL) Attest: McCOY M. GIBSON, JR. C, MARSHALL, DANN Attesting Officer Commissioner of Patents