IL32586A - 1,3-polyhalo-2-propyl methyl and halomethyl ethers and their preparation - Google Patents

Description

Novel 1,3-polyhalo-2-propyl methyl and halomethyl ethers and their preparation BAXTER LABORATORIES, C. 30879 trifluoromethyl 1, 1, 3, 3-tetrafluoro-2 -propyl ether trichloro methyl 1, 1, 3, 3-tetrafluoro-2-propyl ether chlorodifluoromethyl 1, 1, 3, 3~tetrafluoro-2 -propyl ether bromodifluoromethyl 1, 1, 3, 3-tetrafluoro-2 -propyI ether dichlorofluoromethyl 1, 1, 3, 3-tetrafluoro-2-propyl ether bromodichloromethyl 1, 1, 3, 3 -tetrafluoro-2 -propyl ether bromochlorofluoromethyl 1, 1, 3, 3-tetrafluoro-2 -propyl ether .

The above 66 preferred halomethyl ethers of this invention can be prepared from any of six appropriate 1, 3-polyhalo-2 -propahols of which three are commercially available: 1, 1, 1, 3, 3, 3-hexafluoro-, 1- chloro- l, 1, 3, 3, 3 ^pentafluoro- and 1, 3-dichloro- l, 1, 3, 3 -tetrafluoro- 2- propanols. A fourth, 1, 1, 3, 3 -tetrafluoro-2 -propanol, can be prepared as described in U. S. Patent 3, 362, 874. A fifth, 1, 1, 1, 3, 3-pentafluoro-2 -propanol, can be prepared by reduction of chloropenta-fluoroacetone with hydrogen employing a palladium on carbon catalyst.

The sixth, the novel 1-chloro- l, 1, 3, 3-tetrafluoro-2 -propanol, can 1-be prepared by reduction of/chloro- 1, 1, 3, 3-tetrafluoroacetone with sodium borohydride as specifically described hereinafter (Example 21).

The novel halomethyl ethers of this invention can be prepared from the foregoing six alcohols by several methods. In the preferred method, these six alcohols are converted to the corresponding novel methyl ethers by reaction with dimethyl sulfate and aqueous sodium hydroxide essentially as described by Gilbert and Veldhius in U. S.

Patents 3, 346, 448 and 3, 352, 928. The preparations of the novel 1, 1, 1, 3, 3-pentafluoro-2 -propyl, 1 -chloro- l, 1, 3, 3-tetrafluoro-2 -propyl and 1, 3-dichloro- l, 1, 3, 3-tetrafluoro-2 -propyl methyl ethers Four of the above described six methyl ethers were reacted with from about 0. 65 to about 3 molar equivalents of chlorine initiated o o by light at temperatures of from about 20 C to about 130 C to give successively the corresponding chloromethyl, dichloromethyl and trichloromethyl ethers. Thus, the preparation of chloro-, dichloro- and trichloromethyl 1, 1, 1, 3, 3, 3 -hexafluoro-2 -propyl ethers (the last is ' claime (Examples 1, 2, 3, 4, 5 and 6); chloromethyl 1, 1, 1, 3, 3-pentafluoro- 2-propyl ether (Example 16); chloro- and dichloromethyl 1 -chloro- 1, 1, 3, 3, 3-pentafluoro-2 -propyl ethers (Examples 18 and 19); and chloro- and dichl romethyl 1, 1, 3, 3-tetrafluoro-2 -propyl ethers (Example 20) are specifically described hereinafter. Other chloro-, dichloro- and trichloromethyl ethers of the general formula can be prepared in a like manner.

Reaction of methyl 1, 1, 1, 3, 3, 3-hexafluoro-2 -propyl ether and bromine in ultraviolet light produced bromomethyl 1, 1, 1, 3, 3, 3 -hexafluoro- 2 ^-propyl ether, which was also produced by the interaction of chloromethyl 1, 1, 1, 3, 3, 3 -hexafluoro-2 -propyl ether and excess potassium bromide in tetrahydrothiophene 1, 1 -dioxide at about p 100 0 (Example 14). Other bromomethyl ethers of the general for- mula can be prepared by analogous procedures. .

Fluoromethyl 1, 1, 1, 3, 3, '3 -hexafluoro-2 -propyl ether was prepared from the analogous chloromethyl ether and potassium fluoride in tetrahydrothiophene 1, 1 -dioxide at about 100°C (Examples 7 and 8).

Other fluoromethyl ethers of the general formula can be prepared in this manner.

Chlorofluoromethyl and difluoromethyl 1, 1, 1, 3, 3, 3 -hexa¬ fluoro-2 - ro l ether re re ared from the analo ous dichlorom h l ether and potassium fluoride in tetrahydrothiophene 1, 1-dioxide o at about 125 C (Example 9). . The chlorofluoromethyl ether was also prepared from fluoromethyl 1, 1, 1, 3, 3, 3 -hexafluoro-2 -propyl ether and about one molar equivalent of chlorine in a reaction initiated / by light (Example 10). The difluoromethyl ether was also prepared · from the analogous dichloromethyl ether, antimony trifluoride and a small amount of either antimony pentafluoride or antimony penta- chloride at about 50°C (Examples 11- and 12).; Other chlorofluoromethyl and difluoromethyl ethers of the general formula can be prepared by similar procedures.. ; . ·' Chlorodifluoromethyl 1/1, 1, 3, 3, 3-hexafluoro-2 -propyl ether (not was prepared from the analogous trichloromethyl ether, antimony trifluoride and a little antimony peritachloride at about 50°C (Example 13). Other chlorodiflupromethyl ethers of the general formula can be prepared analogously. , - Trifluoromethyl ethers of the general formula can be pre¬ pared from the analogous trichloro methyl or chlorodifluoromethyl ethers and antimony pentafluoride. at about 50°C; ' Dichlorofluoromethyl .ethers of the. general. formula can be prepared by reaction between fluoromethyl or chlorofluoromethyl ethers of the general formula and from about 2 to about 1 molar equivalents, respectively, of chlorine initiated by light.

, The bromofluoromethyl, bro mo difluoro methyl, bromochloro-fluoro methyl, biro mo chloro methyl and bro mo dichlo omethyl ethers of the general formula can be prepared from the appropriate fluoromethyl, difluoromethyl, chlorofluoromethyl, chloromethyl irradiatin including difluoro methyl 2 -propyl ether, mixtures, of difluoro Still another procedure for the preparation of difluoromethyl and dichloromethyl ethers of the general formula is the reaction between formate esters and sulfur tetrafluoride [e. g. , see Hasek. et al, , J. Am, Chem. Soc. , Vol. 82, pp. 543-51 (1960)] or phos phorous pentachlpride [e. g. , see Gross et al. , Chem. Ber. , Vol. 49, pp. 544-50 (1961), Chem. Abs. , Vol. 55, p. 12284g] , respectively.

The trifluoromethyl ethers of the general formula can be prepared, e. g. , by a general method such as described by Aldrich and Sheppard, J. Org. Chem. , Vol. 29, pp. 11 - 15 (1964) from suitable 1, 3-polyhalo-2 -propanols, carbonyl fluoride, sulfur tetrafluoride and hydrogen fluoride, viz. , Alternatively, trifluoromethyl, difluoromethyl and fluoro-methyl ethers of the general formula can be prepared by reaction between an appropriate methyl ether and cobaltic fluoride, essentially by a method as described by Clayton et al. , J. Chem. Soc. , 1965, - 32586/2 3.S .S .R. Otdel. Khim. Nauk . I960 pp . 231;-6 (Chem. Abs . , Vol. 54 , p. 20871e ) . .

Other polyhaloacetones useful as intermediates for 1;his invention can be prepared by chlorination (e .g. , as described by McBee and Burton, J. Am. Chem. Soc , Vol. 74, pp. 3902-4 (1952) and Lovelace et al.. , "Aliphatic Fluorine Compounds", Reinhold, 1958, pp. 184-5) of several known fluorinated acetones : 1,. 1,.3-trifluoroacetone, 1, 1, 1, 3-tetrafluoroacetone, 1, 1, 3, 3-tetra- , fluoroacetone, 3-chloro- l -trifluoroacetone and 1-chloro- l, 1, 3-tri- . fluoroacetonei .

Alternatively, some of these polyhaloacetone intermediates can be prepared by chlorination 0f fluorinated aceto- acetic ethers followed by acid hydrolysis [ e. g. , the methods of Hill et al. , loc. cit. and of McBee et al. , J. Am. Chem. Soc. , Vol. 75, pp. 4091-2 (1953)] or by hydrogen replacement of chlorine or bromine in polyhaloacetones employing trialkyl phosphites and subsequent acid hydrolysis (e. g. , the method of Middleton and Lindsey, loc. cit. ).

In order to generally illustrate the present invention in more detail, the most preferred methods of preparing the most preferred compounds of this invention, viz. , chloromethyl 1, 3 -hexafluoro-2 - propyl ether, fluoromethyl 1, 3-hexafluoro-2 -propyl ether, chloro- fluoromethyl 1, 3-hexafluoro-2-propyl ether and difluoromethyl 1, 3- hexafluoro-2 -propyl ether, and the useful general anesthetic properties of these compounds are set forth as follows : Chloromethyl 1, 1, 1, 3, 3, 3-hexafluoro-2 -propyl ether is hexafluoro -2 -propyl methyl ether and, more preferably, by a photo- induced reaction between about 0. 5 to about 1 mole of chlorine per mole of the he afluoro -2 -propyl methyl ether at a temperature of from about 20°C to about 65°C. The reaction mixture is washed with an aqueous alkaline solution, separated, dried and fractionally distilled to give the desired chloromethyl ether, boiling at 77. 5°C at 760 mm. Hg pressure and having a density of about 1. 517 at o . 23 C. Other similar such free radical reactions induced by light, heat and peroxide catalysis and other similar such methods of recovery can also be employed in the like manner to prepare the novel chloromethyl ether.

Fluoromethyl 1, 1 - 1, 3, 3, 3 -hexafluoro- -propyl ether is preferably prepared by the fluorination of 1, 1, 1, 3,. 3, 3 -hexafluoro-2 -propyl methyl ether with bromine trifluoride. Most preferably, -the ether is reacted with from' about 0. 5 to about 1. 5 molar equivalents of bromine trifluoride at a temperature of from about 20°C to about 50°C.

Chlorofluoro methyl 1, 1, 1, 3, 3, 3 -hexafluoro-2 -propyl ether is preferably prepared by the free radical chlorination of fluoro¬ methyl 1, 1, 1, 3, 3, 3 -hexafluoro-2 -propyl ether and, more preferably, by a photo-induced reaction between about 0. 5 to about 1 mole of chlorine per mole of the fluoromethyl ether at a temperature of from about 20°C to about 70°C.

Difluoro methyl 1, 1, 1, 3, 3, 3 -hexafluoro-2 -propyl ether is preferably prepared by the free radical , chlorination of 1, 1, 1, 3, 3, 3 - hexafluoro- 2 -propyl methyl ether in the manner described above for the chloromethyl 1, 1, 1, 3, 3, 3 -hexafluoro-2 -propyl ether except that about 1. 5 to about 2 moles of chlorine are used per mole of the hexa-fluoro- 2 -propyl methyl ether in order to prepare the dichloromethyl 1, 1, 1, 3, 3, 3-hexafluoro-2 -propyl ether, followed by replacement of the chlorine with fluorine. Most preferably, in the replacement reaction the dichloromethyl ether is reacted with from about 2 to about 5 molar equivalents of potassium fluoride in the presence of a suitable (mutual) solvent, for example, an organic solvent such as tetrahydrothiophene 1, 1 -dioxide, at a temperature of from about 80°C to abou 150°C, or with from about 2 / 3 to about one molar equivalent of antimony trifluoride and a small amount (ca. 0. 01 to 0. 1 mole) of antimony pentafluoride or antimony pentachloride at" a o ° temperature of from about 25 C to about 85 C.

Chloromethyl 1, 1, 1, 3, 3, 3 -hexafluoro-2 -propyl ether is a volatile liquid, is nonflammable in air at ambient temperatures and has a lower flammability limit in oxygen of about ten volume percent, which is well above the ordinary concentration required for anesthesia of less than about four volume percent.

Fluoromethyl 1, 1, , 3, 3, 3 -hexafluoro-2 -propyl ether is a volatile liquid, is nonflammable in air at ambient temperatures and has a lower flammability limit in oxygen of about 11. 8 volume percent, . which is well above the ordinary concentration required for anesthesia of less than about six volume percent.

The difluoromethyl and chlorofluoromethyl 1, 1, 1, 3, 3, 3-hexafluoro -2 -propyl ethers also are volatile liquids and are nonflammable in either air or oxygen at ambient temperatures.

In order to show the importance of the chemical structure of the novel halomethyl 1, 3-polyhalo-2 -propyl ethers of this invention for their useful anesthetic properties, comparisons were made between the preferred chloromethyl, fluoromethyl, chlorofluoromethyl and difluoromethyl 1, 1, 1, 3, 3, 3-hexafluoro^2-propyl ethers of the present invention and known halomethyl fluoroalkyl ethers heretofore tested as anesthetics and the known anesthetic methyl hexaflupro^2 -propyl ether, and between the fluoromethyl 1, 1, 1, 3, 3, 3 -hexafluoro-r 2 -propyl ether of this invention and the known isomeric heptafluorinated methyl n-propyl ether.

Thus, chloromethyl ethers are known generally to have a high degree of chemical reactivity inimical to inhalant anesthetic use.

They have received little investigation as inhalant anesthetics.

Only two such compounds, chloromethyl 1, 1, 2, 2 -tetrafluoroethyl ether and chloromethyl 2 - chloro- 1, 1, 2 -trifluoroethyl ether, are previously reported to have been tested as inhalant anesthetics; These two chloromethyl ethers were shown to have a high degree of chemical stability by Park et al. , J. Am. Chem. Soc'y, , Vol. 74, pp. 2292 -4 (1952). Subsequently, they were tested as inhalant anesthetics in the dog by Van Posnak and Artusio, Toxicol, and Applied Pharmacol. , Vol. 2 , pp. 374-8 (1960). The test results were described by these investigators as discouraging of utility. The two dogs anesthetized with the former chloromethyl ether died 24 and with the latter chloromethyl ether was not satisfactory as it was marked by twitching, shivering and jerking movements. The unsatisfactory anesthesia obtained with chloromethyl 2 ?-chloro-l, 1, 2 -trifluoro ethyl ether can be attributed to the chloromethyl moiety of this ether, since the corresponding methyl ether, 2 -chloro- l, 1, 2 -trifluoro ethyl methyl ether, was shown to be a "usable surgical anesthetic'1 in dogs ("Two dogs received this agent, and satisfactory anesthesia was obtained in both", p. 375. "Good Surgical Anesthesia" Table 1, p. 376^ "Satisfactory surgical anesthesia can be secured with . . . 1, 1, 2 'trifluoro -2 -chloroethyl methyl ether", p. 378) by these investigators 'in the, same report. These reports of Park et al. and Van Posnak and Artusio were discouraging of anesthetic utility of even stable chloromethyl ethers. Surprisingly, the chloromethyl 1, 1, 1, 3, 3, 3-hexafluoro-2-propyl ether of this invention has been found to have outstanding utility as an anesthetic agent.

The mouse anesthetic and flammability test data for the novel chloromethyl, fluoromethyl, chlorofluoro methyl and difluoromethyl 1, 1, 1, 3, 3, 3 -^hexafluoro-2 propyl ethers and the known methyl 1, 1, 1, 3, 3, 3 -hexafluoro-2 -propyl ether were compared. These comparisons show surprisingly that the halo methyl ethers have better anesthetic margins of safety (LC^Q/ CgQ) than shown by the corresponding methyl ether (6. 3 for the chloromethyl ether, 5, 9 for the fluoromethyl ether, 5. 9 for the chlorpfluoromethyl ether and 5.2- for the difluoromethyl ether vs. 4. 4 for the methyl ether). Moreover,, the chlorpfluoromethyl arid difluoromethyl ethers are nonflammable and the flammability margins of safety in oxygen (2. 7). The differences in flammability margins of safety are impor¬ tant to the utility of the respective compounds. Induction and main¬ tenance of deep surgical anesthesia in man with any of these five anesthetics in :oxygen is expected* to require about three to five-fold higher concentrations than the concentration required to anesthetize 50% of the test mice (AC-. Q). Consequently, if one compares the LFLO with 3 to 5 times the C^ Q for these five compounds it becomes apparent that 3 to 5 times the ACgg for the methyl ether is dangerously above the LFLC^, whereas 3 to 5 times the ACQ Q for. the chloromethyl, fluoromethyl, chlorofluoro methyl and difluoro methyl ethers is still safely below their LFLOg 's.

In an anesthetic comparison between the hovel fluoromethyl 1, 1, 1, 3, 3, 3 -hexafluoro-2 -propyl ether of this invention and the isomeric heptafluorinated methyl propyl ether, it was found that the fluoromethyl ether of this invention has an A- ^ of 1. 42 volume percent, an LC^ Q of 8: 38 volume percent and, therefore, a high margin of safety (LC^/ AC5 Q) of 5. 9 in mice. Contrarywise, the trifluoromethyl 2, 2, 3, 3 -tetrafluoroprppyl ether of Aldrich and Sheppard loc. cit. has been shown to cause violent convulsions and deaths in mice at a concentration as low as 0. 5%.

Also, in considering the potential use of polyfluorinated . ethers as anesthetic agents, it is of interest to note that the hexa- fluorodiethyl ether (Indoklon) is known to be a convulsive agent.

Krantz et al. , J . Am. Med. Assn. , Vol. 166, pp. 1555 - 62 (1958).

*Based on generar experience with known halogen- containing anesthetics, e. g. , methoxyflurane, · ΐ1υοΓθΧθηβ and halothane.

"New Drugs", 1967 Edition, Amer. Med. Assn. , Chicago, 111. , In further support of the importance of the chemical structure of the novel halomethyl 1, 3-polyhalo-2 -propyl ethers of the present invention for their useful anesthetic properties, comparisons were made with other halomethyl 1, 3 -polyhalo-2 -propyl ethers containing insufficient hydrogens and excess halogens as defined by the above general formula for said novel halomethyl ethers of this invention. Thus, trichloromethyl 1, 1, 1 , 3, 3, 3 -hexafluoro-2 -propyl ether (b. p. 104. 5°C) was foun of 1. 61 and a margin of safety scular rigidity accompanied anesthesia and tonic and clonic convulsions occurred at near lethal concentrations of this compound. Chlorodifluoromethyl 1, 1, 1, 3, 3, 3 -hexafluoro-2 -propyl ether (b. p. 46°C) and chloromethyl 1, 1, 3, 3 -tetrafluoro-2 -propyl ether (b. p. 122°C) were found to be non-anesthetic and had LC^ Q ' S of 1. 82 and 1. 09, respectively.

Therefore, these three compounds were unsuitable for use as general anesthetics.

In addition to the above, it is seen from the published art that most other known halomethyl ethers which have been tested as anesthetics by other investigators have been found to he non-useful for that purpose. Table I, below, summarizes this published art.

TABLE I Previously Reported Halomethyl Ether Anesthetic Candidates Compound * - Reported Anesthetic. Results ', ' .■ ' ; ■■ " CH2F -0-CHFCl Unsatisfactory anesthesia in the dog, , apnea and deatha CH2Cl-0-CF2 -CHF2 Initially satisfactory anesthesia in. dogs, but deaths followed 24 and 48 ·.· hours latera CH2Cl-0-CF2CHFCl Unsatisfactory anesthesia in the dog . with twitching, shivering and jerking movements3.

CF 2 CI - O - CF 2 CHF CI 80 % - • Unsatisfactory 'anesthesia in the dog CFCl2 -0-CF2 -CHF2 20% with rigidity, twitching' and shivering3- CHF2 -0-CF2CHFCl Satisfactory anesthesia in dogs*3 , CHF2 -0-CH2CF3 Convulsant, anesthetic0 CF2Cl-0-CF2CFCl2 Convulsant, delayed death CCl3-0-CF2 -CFCl2 Anesthetic, convulsantc aVan Posnak and Artusio, Toxicol, and Appl. . Pharma. -, ■ Vol. - 2, pp. 374-8 (1960) .* : ' bVirtue et ali , Can. Anaes. Soc. J. , . Vpl. 13, pp. 233-41 (1966) cKrantz and RudOj "The Fluorinated Anesthetics"; Chap. 10, pp. 535 - Handbuch Experimental Pharmacol. , Vol. 20, 1966. Animal not \ specified.

In summary, only one of the previously reported halomethyl ethers was found to produce satisfactory anesthesia.

Surprisingly, it has now been found that the halomethyl. 1, 3-polyhalo-2 -propyl ethers of the present invention are particularly useful as inhalant anesthetics in warm-blooded, air-breathing mam mals. These novel. anesthetic compounds can be administered by conventional methods in gaseous admixture with oxygen in amounts suitable to induce and maintain anesthesia and to support respiration.

For example, chloromethyl 1, 1, 1, 3, 3, 3 -hexafluoro -2 -propyl ether has been shown to induce and maintain surgical depth of anes¬ thesia in rabbits, dogs and cats quite satisfactorily. Anesthesia a was smooth with satisfactory analgesia and muscle relation.

Electrocardiograms of dogs showed no aberrant cardiac arrhythmias during anesthesia. Recovery from anesthesia was uneventful; de¬ layed deaths or delayed signs of toxicity due to the anesthetic did not occur. Periods of surgical anesthesia were maintained for up to four hours.

Fluoromethyl, chlorofluoro methyl and difluoromethyl 1, -1, 1, 3., 3, 3÷ hexafluoro -2 -propyl ethers have also been shown to induce and maintain surgical depth of anesthesia in dogs quite satisfactorily. Anesthesia was smooth and electrocardiograms showed no aberrant cardiac arrhythmias. Periods of surgical anesthesia were maintained for one hour.

Although specific methods of administration of the halomethyl 1, 3-polyhalo-2 -propyl ethers are described herein, it will be under¬ stood that these novel halomethyl ethers are not limited to any particular method of administration. Thus, the halomethyl ethers can be admixed with one or more other anesthetic agents in order to achieve advantages in administration, degree of relaxation, safety and the like. For example, the halomethyl ethers can be admixed with suitable proportions of known anesthetics such as nitrous oxide, ethyl ether, cyclopropane, halothane, ethyl vinyl ether and the like agents of this invention can also be injected directly into the body . by means of a catheter or a shunt [ see, e. g. , Folkman et al. , Science, Vol. 154, pp. 148 -9 (1966)] or can be prepared in an emulsion form of the oil-in— water type and injected into the animal to evoke satisfactory anesthesia [ see, e. g. , Krantz et al. , Anesth. and Analg. , Vol. 41, pp. 257-62 (1962) and U. S. Patent 3, 216, 897] .

The anesthetic agent enters the central nervous system via the circulatory blood and leaves' the body in the exhale'd air in a man¬ ner analogous to the inhalation route of administration. Still other methods of administration will be apparent to those skilled in the art.

Some of the halomethyl 1, 3-polyhalo-2 -propyl ethers of this invention have relatively high boiling points (i. e. , above about 125°C) at atmospheric pressure and thus low vapor pressures (i. e. , below about 10 mm. Hg) at ambient temperatures. In such instances it will be advantageous to administer the anesthetic other than by inhalation, e. g. , intravenously as, described above.

Some of such halomethyl ethers of this invention which are preferably administered intravenously by one or both of the above methods are: bromochloro, trichloro, and bromodichloromethyl 3- ,l,^-pentafluoro-2 -propyl ethers; bromochloromethyl 1 -chloro- 3- ■- · . ' ■ . . , l, 6-pentafluoro-2 -propyl ether; dichloro, bromochloro, bromochloro- fluoro, trichloro and bromodichloromethyl 1, 1, 3, 3 -tetrafluoro-2 - propyl ethers; chloro, bromo, bromofluoro, . dichloro, bromochloro, bromochlorofluoro, trichloro and bromodichloromethyl 1-chloro- 1, 1, 3, 3-tetrafluoro-2 -propyl ethers; and chloro, bromo,. chlorofluoro, bromoflouro, dichloro and bromochloromethyl 1, 3-dichloro- 1, 3 - tetrafluoro- 2 -propyl ethers.

The following examples will further illustrate the present invention although the invention is not limited to these specific examples. All parts and percentages set forth herein are on a weight basis unless otherwise specified.

EXAMPLE 1 Chloromethyl 1, 1, 1, 3,, 3, 3-Hexafluoro-2 -propyl Ether.

Chlorine gas (165 grams, 2. 32 moles) was bubbled into 1, 1, 1, 3, 3, 3-hexafluoro-2 -propyl methyl ether (420 grams, 2. 32 moles) during four hours. After five minutes, the reaction was initiated by illumination with a. sun lamp through a Pyrex reaction flask for about five minutes. Thereafter, the exothermic reaction was allowed to proceed autogeneously under partial reflux (hydrogen chloride e emitted) employing a Dry Ice condenser. The reaction product was washed successively with cold water, a small amount of aqueous sodium bisulfite and cold water made slightly alkaline with sodium hydroxide. The washed product weighed 478 grams. It was dried by azeotropic distillation and then fractionally distilled at 747 mm.

Hg. A forerun of 79 grams, b 65°- 77. 2°Q was first obtained. The next 281 grams, b 77. 2°- 77. 3°C, was chloromethyl 1, 1, 1, 3, 3, 3- hexafluoro- 2 -propyl ether of 99. 8% purity by gas liquid chromato¬ graphy (GLC) and with a density at 23°C of about 1. 517'. The CH^Cl-O-CHiCFg^ -structure was confirmed by a proton nuclear magnetic resonance (NMR) spectrum.

EXAMPLE 2 Chloromethyl 1, 1, 1, 3, 3, 3 -Hexafluoro-2 -propyl Ether. Dry chlorine gas (685 grams, 9. 66 moles) was bubbled at an average rate of 31 grams per hour into 1, 1, 1, 3, 3, 3 -hexafluoro-2 -propyl methyl ether (2712 grams, 14. 9 moles) at 20° to 25°C with illumination by an immersion-type water cooled ultraviolet lamp through a Pyrex e sleeve. The reaction flask was surmounted by a cold water condenser, e e and this condenser was surmounted by a Dry Ice cooled condens< r connected to a Dry Ice cooled trap which permitted the release of hydrogen chloride. . The product was washed with ice cold water, cold dilute aqueous sodium hydroxide solution,, and cold water. It was separated, dried by azeotropic distillation, and fractionally dis tilled to recover 1, 1, 1, 3, 3, 3 -hexafluoro-2 -^.propyl methyl ether (1171 grams), b75'¾ 50. 2° to 51. 0°C, of 99. 9% purity by GLC. Subsequently, a chloromethyl 1, 1, 1, 3, 3, 3 -hexafluoro-2 -propyl ether fraction (1346 grams), b75 Q 77. 0° to 77. 2°C, of 99. 9% purity by GLC was obtained.

EXAMPLE 3 Chloromethyl 1, 1, 1, 3, 3, 3 -Hexafluoro-2 -propyl Ether.

Chlorine gas (820 grams, 11. 6 moles) was bubbled at a rate of 50 grams per hour into 1, 1, 1, 3, 3, 3 -hexafluoro-2 -propyl methyl o o ether (3250 grams, 17. 85 moles) at 23 to 25 C with illumination as in Example 2. As in Example 2, the product was washed, separated, and then dried by azeotropic distillation.

Fractional distillation gave recovered hexafluoro-2 -propyl ° ° O o fraction (102 grams), 50. 4 to 76. 9 C, and then chloromethyl 1, 1, 1, 3, 3, 3 -hexafluoro -2 -propyl ether (1733 grams), b>747 76. 9Q to 77. 3°C, of 99; 9% purity by GLC. There remained 404 grams of undistilled substance.

EXAMPLE 4 Dichloromethyl 1, 1, 1, 3, 3, 3 -Hexafluoro -2 -propyl . Ether.

Chlorine gas (590 grams, 8. 3. moles) was bubbled into 1, 1, 1, 3, 3, 3- hexafluoro -2 -propyl methyl ether (728 grams, 4. 0 moles) during . 12 hours. After five minutes the reaction was initiated'by illumi¬ nation with a sun lamp through a Pyrex reaction flask for about five minutes. Thereafter, the exothermic reaction was allowed to proceed autogeneously under partial reflux (hydrogen chloride e emitted) employing a Dry Ice condenser. The reaction product was washed successively with water, a small amount of aqueous sodium bisulfite and water made slightly alkaline with sodium hydroxide. The washed product weighed 980 grams. It was dried by azeotropic distillation and then fractionally distilled at 746-750 mm. Hg, Foreruns of 145 grams, b 70°- 77. 4°C, substantially chloromethyl 1, 1, 1,3, 3, 3 -hexafluoro -2 -propyl ether, and 127 grams o o b 90. 2 -92. 1 . C were obtained. The next 499 grams fraction, b o o 92. 1 -95. 5 C, was substantially dichloromethyl. 1, 1, 1, 3, 3, 3 - hexafluoro- 2 -propyl ether;, a sample of 96. 6% purity by GLC and containing also 3. 2% of trichloromethyl 1, 1, 1, 3, 3, 3-hexafluoro- o . 2 -propyl ether has a density at 23 C of about 1. 635. The CHCLj structure was confirmed by a proton NMR. spec trum.

EXAMPLE 5 Chloromethyl and Dichloromethyl 1, 1, 1, 3, 3, -Hexafluoro- 2 -propyl Ethers. Dry chlorine gas ( 1042 grams, 14. 7 moles) was bubbled at a rate of 42 grams per hour into hexafluoro -2 -propyl methyl ether (1590 grams, 8. 8 moles) at 22° to 25°C with illumination by an immersed water-cooled ultraviolet lamp as in Example 2. The product was washed and dried over anhydrous calcium sulfate.

Fractional distillation gave chloromethyl 1, 1, 1, 3, 3, 3- o o hexafluoro -2 -propyl ether (562 grams), ^743- 747 77. 1 to 77. 3 C, of 99. 9% purity by GLC and dichloromethyl 1, 1, 1, 3, 3, 3 -hexafluoro- 2 -propyl ether ( .8·■ 28■ g=>rams), » b 4 - 4 92. 8° to 93. 3°C of 98% purity by GLC.

EXAMPLE 6 Chloromethyl, Dichloromethyl and Trichloromethyl 1, 1,- 1, 3, 3, 3- (The last compound is not claimed ) Hexafluoro -2 -propyl Ethers. / Dry chlorine gas (1025 grams, 14. 6 moles) was bubbled into hexafluoro -2 -propyl methyl ether (161 1 grams, 8. 9 moles) during 26 hours at temperatures of 22° to 25°C with illumination by an immersed water-cooled ultraviolet lamp. The product (2098 grams) was washed and dried over anhydrous, calcium sulfate. ' ' .. ' 1 Fractional distillation gave a forerun (914 grams), b,-^ . 73. 2° to 93. 4°C, most of which (604 grams), b. p. 76. 8° to 77. 7°C, 93. 0°C, was dichloromethyl 1, 1, 1, 3, 3, 3-hexafluoro-2 -prppyl ether of 98. 8% purity by GLC. Subsequently, a fraction (50. 5 grams), b737 103. 5° to 103. 7°C, with a density of 1. 673 at 23°C was tri- . chloromethyl 1, 1, 1, 3, 3, 3- hexafluoro- 2 -propyl ether of 98. 9% purity by GLC. The CCl¾-0-CH(CF ) structure was confirmed by a pro- 3 2 ton NMR spectrum.

EXAMPLE 7: Fluoromethyl 1, 1, 1, 3, 3, 3-Hexafluoro-2 -propyl Ether. , Chloromethyl 1, 1, 1, 3, 3, 3 -hexafluoro -2 -propyl ether (114 grams, 0. 525 mole), potassium fluoride (61 grams, 1. 05 moles), and tetra- hydrothiophene 1, 1-dioxide (500 grams) were stirred and heated to 80° to 95°C for 3 hours while a product (42 grams) . of b. p. 58° to 60°C was collected by fractional distillation. Then more potassium fluoride (29. 5 grams, 0. 51 mole) was added. Stirring and heating from 100° to 150°C distilled out more product (14 grams) of b. p. o o that . 58 to 60 C. Proton NMR and GLC analyses showed/the total pro¬ duct (56 grams) was about 85% fluoromethyl 1, 1, 1/3, 3, 3-hexafluoro-2 -propyl ether.

A second run carried out in the same manner as above except using more potassium fluoride (121 grams, 2. 08 moles) gave more product (69 grams) of b. p. 58° to 60°C, The combined products (125 grams) were washed with water and dried over anhydrous calcium sulfate. o Fractional distillation gave a forerun (23 grams), b^g 53. 5 to 57. 0°C, and then fluoromethyl 1, 1, 1, 3, 3, 3 -hexafluoro -2 -propyl ether (54 grams), b 57. 0° to 58. 0°C of 98. 0% purity by GLC. The CH^F-O-CHiCFg^ structure was confirmed by a proton NMR spectrum.

Subsequent fractions (20 grams) had b-^g 58. 0° to 65. 0°C and there remained 16 grams of undistilled substance.

EXAMPLE 8 Fluoromethyl 1, 1, 1, 3, 3, 3-Hexafluoro-2 -propyl Ether. A solution of chloromethyl 1, 1, 1, 3, 3, 3-hexafluoro-2 -propyl ether (754 grams, 3. 49 moles) in dry tetrahydrothiophene 1, l dioxide (2000 ml) and dry, powdered potassium fluoride (203 grams, 3. 49 moles) were stirred and heated to 130°C in a creased flask fitted with a fractional distillation assembly. A distillate (200 ml), ^748 ° °^> was c°Hec'':ed d ring five hours. Then the reaction mixture was colled to room temperature, dry potassium fluoride (100 grams, 1. 74 moles) was added, and the cycle of o operations was repeated three times at temperatures between 138 o o to 185 C to give distillates (100 ml, 100 ml and 50 ml), b746 58 to 61°C, 55. 5° to 57°C, and 54. 2° to 55. 9 C, respectively. From this portionwise addition of potassium fluoride (503 grams total, 8. 7 moles) there was obtained distillates totalling 672 grams, b746 54. 2° to 62. 0°C, which by GLC analysis was about 92% fluoro¬ methyl and 6. 8% chloromethyl 1, 1, 1, 3,- 3, 3-hexafluoro-2 -propyl ethers. The combined distillates were dried over anhydrous calcium sulfate (33 grams) and filtered.

Fractional distillation of 659 grams gave a forerun (46 grams), b745 53, 5° to 57. 0°C, and then 99. 6% pure fluoromethyl 1, 1, 1, 3, 3, 3^ ° ° remained 94 grams of undistilled substance.

The fluoromethyl ether fraction (311 grams), b^-. 57. 5° to 57. 7°C, was 99. 9% pure by GLC and had a density of 1. 505 at 23°C.

EXAMPLE 9 Chlo rofluoro methyl and Difluoromethyl 1, 1, 1, 3, 3, 3-Hexa- fluoro -2 -propyl Ethers. A solution of dichloromethyl 1, 1, 1, 3, 3, 3- hexafluoro- 2 -propyl ether (165 grams, 0. 66 mole) in anhydrous tetrahydrothiophene 1, 1 -dioxide (500 ml) and dry, powdered potassium fluoride (26 grams, 0. 45 mole) were stirred and heated to 125°C in a creased flask fitted with a fractional distillation assembly. When o the temperature of the distillate reached about 62 C, it was collected (15 ml), b^,- 62° to 74°C. Then the reaction mixture was cooled to below 80°C, the same amount of potassium fluoride as above (26 grams, 0. 45 mole) was added, and the cycle of operations was o o repeated three times at temperatures between 130 and 140 C to give distillates (25 ml, 10 ml, and 20 ml), b? 3 ? 64° to 74°C, 42° o o o to 44 C, and 42 to 70 C, respectively. From this portionwise addition of potassium fluoride (104 grams total, 1. 79 moles) there was obtained distilled products totalling 116 grams, b 42° to 74°C, which were combined, washed with water, dried over calcium chloride and analyzed by GLC and proton NMR spectroscopy. These analyses showed that the product (113 grams) was about 93% a mix¬ ture of chlorofluoromethyl, difluoromethyl and dichloromethyl 1, 1, 1, 3, 3, 3-hexafluoro-2 -propyl ethers in 5 :3 :2 molar ratios, re¬ spectively.

Fractional distillation of 105 grams gave a forerun (7 grams), D737 38. 8° to 40. 6°C, followed by a fraction (14 grams), b737 40. 6° to 43. 0°C, which was 94. 2% difluoromethyl 1, 1,-1, 3, 3, 3-hexafluoro -2 - propyl ether by GLC. Next, an intermediate fraction (17 grams), b737 43. 0° to 66. 5°C, was obtained, followed by fractions (31 grams), b737 66. 5° to 68. 2°C, of chlorofluoro methyl 1, 1, 1, 3, 3, 3-hexafluoro -2 -propyl ether of 96. 5% purity by GLC of which 16 grams, b? 3 ? 67. 3° to 67. 6°C was of 97. 8% purity. There remained 32 grams of undistilled substance.

' EXAMPLE 10 Chlorofluoromethyl 1, 1, 1, 3, 3, 3-Hexafluoro-2 -propyl Ether.

Dry chlorine gas (121 grams, 1. 71 moles) was bubbled at a rate of about 40 grams per hour into fluoromethyl 1, 1, 1, 3/ 3, 3-hexafluoro-2 -propyl ether (342 grams, 1. 71 moles) with illumination by a sun lamp through a. Pyrex flask fitted with a cold water condensor sur¬ mounted by a Dry Ice condensor followed by a Dry Ice trap. The . o "'- 0 ' · ■ ■"· temperature of the reaction mixture rose from about 60 to 70 C during chlorination. The product (396 grams) was washed and dried over anhydrous calcium sulfate.

Fractional distillation gave a forerun (24 grams), b734_ 51. 2° to 62. 0°C, and then fractions of chlorofluoromethyl 1, 1, 1, 3, 3, 3- hexafluoro- 2 -propyl ether; (80 grams), t>734 ^° to 5° , of 94. 4% purity by GLC; (174 grams), b? 34 67. 5° to 67. 8°C, of 95. 4% purity; and (63 grams), b734 67. 8° to 68. 3°C of 85. 0% purity. The 174 gram fraction had a density of 1. 573 at 23°C. Purification of the product can be improved by gas-liquid chromatography..

The CHFCl-0-CH(CF ) structure was confirmed by a proton EXAMPLE 11 Difluoromethyl 1, 1, 1, 3, 3, 3-Hexafluoro-2 -propyl Ether. Dichloromethyl 1, 1, 1, 3, 3, 3-hexafluoro-2 -propyl ether (460 grams, 1. 83 moles), °γ^ρ 92. l°-95. 5°C, antimony trifluoride (292 grams, 1. 63 moles) and antimony pentachloride (5. 0 ml, 0. 04 mole) were stirred together and heated to total reflux under a cold water con-densor for about 30 hours during which time the temperature of the vapor, just above the liquid phase, dropped from 85°C to 45°C.

The desired product was distilled from the reaction mixture, and the distillate was washed successively with cold 20% hydrochloric acid, cold water and then slightly alkaline water to remove residual antimony halides and acidic ΐηιρμΓΪίϊεΞ . The weight of the washed product was 304 grams. It was dried over calcium chloride and fractionally distilled at 739-745 mm. Hg. A forerun of 15 grams, b 40. 5°-41. 0°C, was collected. The next 248 grams, b?45 41. 0°-41. 5°C, was substantially difluoromethyl 1, 1, 1, 3, 3, 3-hexafluoro-2 -propyl ether; samples of 96- 97% purity by GLC and containing also about 3% chlorodifluoromethyl 1, 1, 1, 3, 3, 3-hexafluoro-2 -propyl ether, had a density at 23°C of about 1. 547. The CHF2 -0-CH(CF3)2 structure was confirmed by a proton NMR spectrum.

EXAMPLE 12 Difluoromethyl 1, 1, 1,3, 3, 3-Hexafluoro-2 -propyl Ether.

Dichloromethyl 1, 1, 1, 3, 3, 3-hexafluoro-2 -propyl ether (747 grams, 2. 98 moles), 93. 4° to 93. 5°C, antimony trifluoride (530 grams, 2. 98 moles), and antimony pentafluoride (22 ml, 0. 3 mole) were, stirred together at room temperature. Immediately an exothermic reaction occurred and the mixture refluxed at about 45 C. When the reaction subsided, the mixture was heated to reflux for 4 hours and then distilled. The distillate (610 grams) was washed successively with cold aqueous 20% hydrochloric acid and cold water. It then was al dried over anhydrous ciacium sulfate.

Fractional distillation gave difluoromethyl 1, 1, 1, 3, 3, 3- hexafluoro- 2 -propyl ether (518 grams), 41. 1°C, of greater than 99. 9% purity by GLC.

Similarly, dichloromethyl hexafluoro- 2 -propyl ether (635 grams, 2. 53 moles), antimony trifluoride (400 grams, 2. 24 moles), and antimony pentafluoride (55 grams, 0. 25 mole) were caused to react. The distillate was washed as above to give 382 grams, which were then dried. .Fractional distillation gave difluoromethyl 1, 1, 1, 3, 3, 3- hexafluoro- 2 -propyl ether (244 grams), b 41. 3° to 41. 4°C.

EXAMPLE 13 Chloro difluoromethyl 1, 1, 1, 3, 3, 3 -Hexafluoro -2 -propyl Ether.(not cla Trichloromethyl 1, 1, 1, 3, 3, 3-hexafluoro-2 -propyl ether (108 grams, 0. 38 moles), b 107°C, antimony trifluoride (84 grams, 0. 48 moles), 759 and antimony pentachloride (5 grams, 0. 017 moles) were stirred and heated to boiling under reflux for six hours during which time the reflux temperature dropped to 45°C. The desired product was dis¬ tilled from the reaction mixture, and the distillate was washed suc¬ cessively with cold 20% hydrochloric aeid and cold water, and then dried in the cold over anhydrous calcium chloride. Fractional distillation gave 35. 6 grams of chloro difluoromethyl 1, 1, 1, 3, 3, 3- hexafluoro-2 -propyl ether, b?49 45. 2°-45. 8°C, with a density . at 23°C of about 1. 554 and a purity of 99. 1% by GLC. The CF2Cl-0-CH(CF3)2 structure was confirmed by a proton NMR spectrum.

EXAMPLE 14 Bromomethyl 1, 1, 1, 3, 3, 3-Hexafluoro-2 -propyl Ether. (a) Chloromethyl 1, 1, 1, 3, 3, 3 -hexafluoro -2 -propyl ether (152 grams, 0. 73 mole), potassium bromide (340 grams, 2. 86 moles), and wet (about 3% water) tetrahydrothiophene 1, 1 -dioxide (500 grams) were stirred and heated to 80° to 120°C for 3 hours under reflux.

Then product (89 grams) was collected by distillation, washed with cold water, and dried over anhydrous calcium chloride.

Fractional distillation gave mostly recovered chloromethyl ether containing hexafluoro- 2 -propanol in the fraction (32 ml), b-^-y 58° to 87. 4°C. The fraction, b?47 87. 4° to 90. 1°C, and the distillation residue (32 grams total) were bromomethyl 1, 1, 1, 3, 3, 3 -hexafluoro -2 -propyl ether of about 88% purity by GLC. (b) The photo-induced reaction between bromine and 1, 1, 1, 3, 3, 3 hexafluoro -2 -propyl methyl ether was slow and incomplete at about 50°C. A small amount (6 ml) of bromomethyl 1, 1, 1, 3, 3, 3 -hexafluoro- 2 -propyl ether b. p. 88°C prepared in this way was 87. 6 %pure by GLC. The structure was confirmed by a proton NMR spectrum. Its identity to the bromomethyl ether of (a) was shown by GLC retention times.

These preparations were combined and purified by preparative GLC to ive 99. 7% ure bromometh l 1 3 -hexafluoro -2 - ro l ether, b 90. 6°C (micro), density 1. 757 at 24°C. The CHnBr-0-CH(CF ) 743 2 3 structure was confirmed by a proton NMR spectrum.

EXAMPLE 15 Methyl 1, 1, 1, 3, 3-Pentafluoro-2 -propyl Ether. 1, 1, 1, 3, 3- pentafluoro-2 -propanol was prepared by the vapor phase reduction of chloropentafluoroacetone with hydrogen employing a heated 2% palladium on carbon granules (4- 12 mesh) catalyst. By this procedure, hydrogen at the rate of one liter per minute and the vapor of chloro¬ pentafluoroacetone at the rate of 1. 5 grams per minute were mixed and passed through a Pyrex tube (45 cm. x 1. 9 cm. i. d. ) containing the catalyst and heated to 180°C. The reaction products were con¬ densed in a trap cooled by Dry Ice.

In a typical run 480 grams (2. 63 moles) of chloropentafluoro¬ acetone were vaporized with hydrogen during 5. 5 hours, and the mixture passed over 85 grams of palladium- carbon catalyst. Frac¬ tional distillation of the 358 grams of reaction products gave 258 grams (1. 72 moles, 65% of theory) of 1, 3 -pentafluoro-2 -propanol, b. p. o 81 C. The structure of the alcohol, CF -CH(OH)-CHF , was con- 3 2 * firmed by proton NMR and infrared analyses.

Elemental analyses for CgHgFgO calc' d: C, 24. 01%; H, 2. 04%. Found: C, 23. 99%; H, 2. 18%.

Crude pentafluoro-2 -propanol (362 grams) of about 85% purity (approximately 2. 04 moles) by GLC, the chief . impurity being water, was added to water (500 ml), cooled to 10°C, and diluted with 5 N aqueous sodium hydroxide (420 ml, 2. 1 moles). With vigorous stirring, dimethyl sulfate (259 grams, 2. 05 moles) was added during 2 hours while maintaining the reaction temperature below 10°C.

Then the mixture was warmed to reflux temperature for 4 hours.

The product (332 grams) was separated from the aqueous layer and washed with cold water. The washed product was dried by azeotropic distillation. Fractional distillation then gave methyl 1, 1, 1, 3, 3-pentafluoro -2 -propyl ether (292 grams), b^^^ 59. 7° to 59. 8°C.

In a similar run this pentafluoro-2 -propanol (33 grams of about 95% purity by GLC) gave the corresponding methyl ether (27 grams), 1. 344 at proton NMR spectrum.

EXAMPLE 16 Chloromethyl 1, 1, 1, 3, 3 -Pentafluoro-2 -propyl Ether. Dry chlorine gas (84. 5 grams, 1. 19 moles) was bubbled at a rate of 28 grams per hour into .methyl 1, 1, 1, 3, 3-pentafluoro-2 -propyl ether (292 grams, 1. 78 moles) at 60° to 85°C with illumination by a sun lamp as iii Example 2. The product (329 grams) was washed and then dried over anhydrous calcium sulfate.

Fractional distillation gave first recovered methyl pentafluoro-2 -propyl ether (62 grams), b744 59..7° to 60. 3°Q and then intermediate fractions (58 grams), b^' 60. 3° to 97. 5°C. Substantially pure fractions of chloromethyl 1, 1, 1, 3, 3 -pentafluoro-2 -propyl ether (13 grams), b 97. 5° to 98. 1°C, (136 grams), b^ 98. 1° to 98. 3°C, and (38 grams), b 98. 3° to 99. 3°C, ere obtained next. -. 1° ° n f 1 0 a boiling material remained undistilled.. ■ EXAMPLE 17 1 -ChIoro- l, 1, 3, 3, 3-pentafluoro-2 -propyl Methyl Ether.

Chloropentafluoro-2 -propanol (908 grams, 4. 92 moles) was added to water (1000 ml), cooled to 10°C, and diluted with 5 N aqueous sodium hydroxide (1040 ml, 5. 2 moles). Dimethyl sulfate (632 grams, . 0 moles) was then added with vigorous stirring while maintaining the reaction temperature below 10°C. Then the mixture was warmed to reflux for 3 hours, cooled, and the product separated from the aqueous .layer and washed with cold water.

Fractional distillation gave 1-chloro- l, 1, 3, 3, 3-pentafluoro- 2 -propyl methyl ether (675 grams), b^^^ 78. 1° to 79. 4°C, a portion (77 grams), b? 47 79. 4°C, of which was 99. 9% pure by GLC. . .

EXAMPLE 18 Chloromethyl 1 -Chloro- l, 1, 3, 3, 3 -pentafluoro-2 -propyl Ether.

Dry chlorine gas (86. 5 grams^ 1. 22 moles) was bubbled at a rate of grams per hour into 1-chloro- l, 1, 3, 3, 3-pentafluorb-2 -propyl methyl ether (242 grams, 1. 22 moles) at 80° to 110°C with illumi¬ nation by sun lamp through a Pyrex reaction flask .which was surmounted e by a series of cold water and Dry Ice cooled condensers and a Dry Ice cooled trap. The product (281 grams) was washed successively with cold water, cold dilute sodium hydroxide, and cold water. The washed product was separated and dried by azeotropic distillation.

Fractional, distillation gave a forerun (67 grams), ?8. 1° to 107. 7°C,followed by substantially pure, fractions of chloromethyl 1-chloro- l, 1, 3, 3, 3-pentafluoro-2-propyl ether (125 grams), b 748 107. 7° to 107. 8°C, and (47 grams), b?48 107, 8° to 108. 2°C. The .

C and was 99. 7% was confirmed by Some (33 grams) high boiling material remained undistilled.

EXAMPLE 19 · . "■ ' - . 1-Chloro- l, 1, 3, 3, 3-pentafluoro-2 -propyl Di chloromethyl Ether. Dry chlorine gas (355 grams, 5. 0 moles) was bubbled at a rate of about 48 grams per hour into 1-chloro- l, 1, 3, 3, 3-pentafluoro- 2 -propyl methyl ether (598 grams, 3. 0 moles) at 80° to 112°C with illumination by a sun lamp as in the previous example. The product (766 grams) was washed and dried over anhydrous calcium sulfate.

Fractional distillation gave a forerun (55 grams), b-^^ 45. 1° to 107. 4°C, then fractions (215 grams), b747_740 107. 4° to 108. 7°C, containing about 94% of the corresponding chloromethyl ether of the previous example. Next, intermediate fractions (115 grams) b^Q 108. 7° to 121. 9°C, were . obtained. The desired dichloromethyl ether (283 grams), b? 3 g 121. 9° to 123°C, of about 97% purity -was obtained next. A fraction of this,- b 122. 3° to 122. 5°C, of 98% purity had a density of 1. 600 at 23°C. There remained undistilled 53 grams of higher boiling material. The CHCl2 -0-CH(CF_3)CF2Cl structure was confirmed by a proton NMR spectrum.

EXAMPLE 20 Chloromethyl and Dichloromethyl 1, 1, 3, 3 -Tetrafluoro -2 - propyl Ethers. Dry chlorine gas (170 grams, 2. 4 moles) was bubbled at a rate of 28 grams per hour into methyl 1, 1, 3, 3 -tetrafluoro -2 - propyl ether (175 grams, 1. 2 moles) at 85° to 130°C with illumination by a sun lamp as in Example 2. The product (253 grams) was washed and dried over anhydrous calcium sulfate. Proton NMR and GLC analyses showed that the dried product (245 grams) was about 23% chloromethyl and about 60% dichloromethyl 1, 1, 3, 3-tetrafluoro-2 - propyl ethers.

Fractional distillation gave chloromethyl 1, 1, 3, 3-tetrafluoro - 2 -propyl ether (54. 5 grams), b. p. 112° to 129°C, of about 78% purity by GLC. , Further purification by preparative GLC gave this chloro¬ methyl ether of 99. 6% purity, micro b. p. 120. 8°C at 734 mm. Hg and density 1. 468 at 24°C. The CH2Cl-0-CH(CHF2)2 structure was confirmed by a proton NMR spectrum.

Fractional distillation also gave dichloromethyl 1, 1, 3, 3- o ° tetrafluoro- 2 -propyl ether (127 grams), b75 Q 135. 1 - 140. 5 C, of about 82% purity by GLC. Further purification by preparative GLC . o gave this dichloromethyl ether of 99. 870 purity, micro b. p. 140. 1 C at 742 mm. Hg and .density 1. 552 at 24°C. The CHCl -0-CH(CHF ) 2 2 ώ structure was confirmed by a proton NMR spectrum.

EXAMPLE 21 l -Chloro- l, 1, 3, 3 -tetrafluoro- 2 -propanol. 1 -chloro- 1, 1, 3, 3- tetrafluoroacetone (454 grams, 2. 76 moles) was added during two hours to a stirred mixture of dry sodium borohydride (33 grams, 0. 87 mole) and dry diethyleneglycol dimethyl ether (420 ml) as the o o temperature was maintained between 30 and 45 C with external cooling.

The reaction mixture was stirred about 16 hours and then poured into a mixture of water (300 ml), ice (230 grams) and con¬ centrated hydrochloric acid (75 ml), whence some hydrogen evolved and solids precipitated. The mixture was filtered, the two liquid layers separated, and the lower layer washed with about 50 ml of 1 N sulfuric acid. Distillation of the combined upper aqueous layers gave only a small amount (12 grams ) of water immiscible product, ^7 4 95. 7° to 97. 4°C, which was added to the lower layer (761 grams).

Distillation of the combined water immiscible layers gave wet o o chlorotetrafluoro-2 -propanol (374 grams), b74_. 92. 0 to 1 10 C, with a density of about 1. 464.

The wet alcohol was added to concentrated sulfuric acid (271 grams) and this mixture fractionally distilled to obtain dehy¬ drated 1 - chloro- l, 1, 3, 3-tetrafluoro-2 -propanol (305. 6 grams), o ° b-740 96. 5 to 101. 5 C, with a density of about 1. 570. The purest o o fraction (161. 8 grams), 100. 6 to 101. 5 C and density of 1. 583, was 99. 86% pure by GLC. The CF2 Cl-CH(OH)-CHF2 structure was confirmed by a proton NMR spectrum.

EXAMPLE 22 1 -Chloro- l, 1, 3, 3-tetrafluoro-2 -propyl Methyl Ether. 1 - chloro - 1, 1, 3, 3 -tetrafluoro- 2 -propanol (290 grams, 1. 75 moles) and water 100 ml were stirred and cooled to below 10°C as dimethyl sulfate (221 grams, 1. 75 moles) and 5 N sodium hydroxide (350 ml, 1. 75 moles) were added simultaneously during one hour.

Then the reaction mixture was stirred at room temperature about five hours, separated, and the lower organic layer washed and dried over anhydrous calcium sulfate. The yield of product was 246 grams.

Fractional distillation gave 1 -chloro- l, 1, 3, 3-tetrafluoro-2-propyl methyl ether (205 grams), b?43 89. 2° to 89. 9°C, of 99. 88% purity by GLC and with density of 1. 4055 at 23°C. The structure was confirmed by a proton NMR spectrum.

EXAMPLE 23 1, 3-Dichloro- l, 1, 3, 3-tetrafluoro-2 -propyl Methyl Ether. 1, 3-dichloro- l, 1, 3, 3 -tetrafluoro -2 -propanol (454 grams, 2. 26 moles) and water (500 ml) were stirred and cooled to below 10°C as di-methylsulfate (286 grams, 2. 26 moles) and 10 N sodium hydroxide (230 ml, 2. 3 moles) were added simultaneously during two hours.

Then the reaction mixture was stirred at room temperature for about five hours, separated, and the lower organic layer washed and dried over anhydrous calcium sulfate; yield 439 grams.

Fractional distillation gave 1, 3-dichloro- l, 1, 3, 3-tetra-fluoro -2 -propyl methyl ether (188 grams), b743 109. 3° to 109. 6°C, of 100% purity by GLC and with a density of 1. 486 at 23°C and more ether of 97% purity (177 grams), b?43 108. 0° to 109. 3°C.

The CH3-0-CH(CF2Cl)2 structure was confirmed by a proton NMR spectrum.

EXAMPLE 24 The chloromethyl 1, 1, 1, 3, 3, 3 -hexafluoro-2 -propyl ether of this invention was shown to have useful anesthetic properties in mice essentially according to the procedure described by Robbins, J. Pharmacol. Exptl. Therap. , Vol. 86, pp. 197-204 (1946). The five minute median anesthetic concentration, and the five minute median lethal concentration, LC^Q, were determined by a log-probit plot of the data as described by Miller and Tainter, Proc.

Soc. Exptl. Biol. Med. , Vol. 57, pp. 261-64 (1944). The number of test mice used was 30 for each of the and LC-.Q concentrations. Chloromethyl 1, 1, 1, 3, 3, 3 -hexafluoro-2 -propyl ether was found to have an of 4.94 volume percent. Consequently, it has a relatively high anesthetic margin of safety (LC^Q AC^Q) of 6.3. Identical tests with several anesthetics in general use gave the following results: halothane, LC50/AC50 = 2.74/0.78 = 3.5; diethyl ether, LC50/AC50 - 13.6/3.83 = fluoroxene, - 11.6/3.5 = 3.3; methoxyflurane, LC50/AC50 = 2.52/0.56 = 4.5.

EXAMPLE 25 Two mature male New Zealand white rabbits were anesthetized by chloromethyl 1, 1, 1, 3, 3, 3 -hexafluoro-2 -propyl ether vapor admixed with oxygen. The anesthetic mixture was formed in a conventional anesthetic machine and delivered by a way of a face mask. A semi-closed technique and soda-lime absorption of carbon dioxide were employed. About 2.5 to 3.5 volume percent of this chloromethyl and maintained a moderately deep plane of surgical anesthesia with satisfactory analgesia and muscle relaxation. The course of anesthesia was generally smooth. After one hour, the face mask was removed, and recovery of righting reflex occurred in 7 to 10 minutes. Thereafter, observations of one rabbit for one week and of the other for one month did not show any signs of toxicity or other illness, and these animals were deemed useful for other experimental purposes.

EXAMPLE 26 Four mongrel dogs were anesthetized by chloromethyl 1, 1, 1, 3, 3, 3-hexafluoro-2 -propyl ether vapor admixed with oxygen. The anesthetic mixture was formed in a conventional anesthetic machine and delivered by way of an endotracheal tube with inflation cuffs. An open, non-rebreathing technique was employed. About 3 to 4 volume percent of this chloromethyl ether in oxygen induced surgical anesthesia in about five minutes. A moderate depth of surgical anesthesia was then maintained for 55 minutes with about 0. 5 to 2 volume percent of this chloromethyl ether. Anesthesia, was smooth and electrocardiograms showed no aberrant cardiac arrhythmias in any of the four dogs.

Another four mongrel dogs were anesthetized by the vapor of the chloromethyl ether of this invention admixed with oxygen in the same manner as stated above except that a closed rebreathing system with soda-lime absorption of carbon dioxide was employed.

The concentrations of the chloromethyl ether for induction and maintenance of anesthesia and the to al time and de th of sur ical anesthesia were the same as above. Again, anesthesia was smooth and electrocardiograms showed no aberrant cardiac arrhythmias.

EXAMPLE 27 Each of four mongrel dogs (two males and two females each weighing 8 to 12 kg) was anesthetized seven times with chloromethyl 1, 1, 1, 3, 3, 3-hexafluoro-2 -propyl ether admixed with oxygen for a total of 19 to 22 hours of anesthesia during 11 to 12 weeks.

Induction of anesthesia was accomplished by face mask administration of 4% by volume chloromethyl 1, 1, 1, 3, 3, 3-hexafluoro-2 -propyl ether in oxygen or by intravenous administration of sodium thiamylal or succinylcholine. Induction by the chloromethyl ether was rapid (5 to 10 minutes) and unusually smooth.

Maintenance of Stage III anesthesia in each dog was accomplished with 1. 5 to 3. 0% by volume chloromethyl 1, 1, 1, 3, 3, 3-hexafluoro-2 -propyl ether in oxygen for 1 to 5 hour periods. Skeletal muscle relaxation and analgesia appeared excellent.

Recovery from anesthesia in each dog occurred within 15 to 25 minutes when the dogs were able to stand. Occasional vomiting, but no other adverse effects occurred during recovery. Each dog was observed for 9 weeks following the seventh anesthetic procedure, and there were no adverse effects apparent at any time resulting from these repeated exposures to chloromethyl 1, 1, 1, 3, 3, 3-hexafluoro-2 -propyl ether.

EXAMPLE 28 Each of four adult, domestic cats (three males and one female) Induction of anesthesia was accomplished by face mask administration of 4% by volume chloro methyl 1, 1, 1, 3, 3, 3 -hexafluoro-2 -propyl ether in oxygen or by intravenous administration of sodium thiamylal. Induction by this chloromethyl ether was exceptionally smooth and occurred within 10 minutes. Conditions for maintenance of anesthesia, and depth and quality of anesthesia were about the same as for dogs in Example 27. Recovery from anesthesia in each cat occurred within 15 to 20 minutes, and was uneventful.

Each cat was observed for 12 weeks after the third anesthetic procedure, and no adverse effects were apparent at any time resulting from these multiple exposures to chloromethyl 1, 1 , 1, 3, 3, 3-hexa-fluoro -2 -propyl ether.

EXAMPLE 29 The difluoromethyl 1, 1, 1, 3, 3, 3-hexafluoro-2 -propyl ether of this invention was shown to have useful anesthetic properties in mice according to the procedure described in Example 24. Employing this procedure, the difluoromethyl ether was found to have an CgQ of 2. 55 volume percent and an of 13. 3 volume percent, or an anesthetic margin of safety (LC_. „/AC_. ,J of 5. 2. & J 50 50 EXAMPLE 30 Four mongrel dogs were anesthetized by difluoromethyl 1, 1, 1, 3, 3, 3-hexafluoro-2 -propyl ether vapor admixed with oxygen by the open, non-rebreathing technique described in Example 26.

About 5 to 8 volume percent of this difluoromethyl ether in oxygen of surgical anesthesia was maintained for 55 minutes with about 3 to 8 volume percent of this difluoro methyl ether. Anesthesia was smooth and electrocardiograms showed no aberrant cardiac arrhythmias in any of the four dogs.

EXAMPLE 31 The fluoromethyl 1, 1 , 1 , 3, 3, 3 -hexafluoro-2 -propyl ether of this invention was shown to have useful anesthetic properties in mice according to the procedure described in Example 24.

Employing this procedure, the fluoromethyl ether was found to have an of 8. 38 volume percent, or an anesthetic margin of safety of 5. 9.

EXAMPLE 32 Three mongrel dogs were anesthetized by fluoromethyl 1 , 3 -hexafluoro- 2 -propyl ether vapor admixed with oxygen by the open non-rebreathing technique described in Example 26. Surgical anes thesia was induced in three minutes with about 6 volume percent, and a moderate depth of surgical anesthesia was maintained for 57 minutes with about 1. 5 to 4 volume percent of this fluoromethyl ether. Anesthesia was smooth and electrocardiograms showed no aberrant cardiac arrhythmias in any of the three dogs.

EXAMPLE 33 The chlorofluoromethyl 1, 1, 1, 3, 3, 3 -hexafluoro-2 -propyl ether of this invention was shown to have useful anesthetic properties have an AC^ Q of 0. 94 volume percent and an LC^ Q of 5. 55 volume percent, or an anesthetic margin of safety (LC^ Q / AC^ Q) of 5. 9.

EXAMPLE 34 Two mongrel dogs were anesthetized by chlorofluoro methyl 1, 3 -hexafluoro-2 -propyl ether vapor admixed with oxygen by the open non-rebreathing technique described in Example 26. Surgical anesthesia was induced in five minutes with about 3 to 5 volume percent, and a moderate depth of surgical anesthesia was maintained for 65 minutes with about 0. 5 to 2 volume percent of this chlorofluoro^-methyl ether. Anesthesia was smooth and electrocardiograms showed no aberrant cardiac arrhythmias in either of the two dogs.

EXAMPLE 35 In a manner similar to the procedure employed in Example 24, the bromomethyl 1, 3-hexafluoro-2 -propyl ether, the dichloromethyl 1, 3 -hexafluoro^2 -propyl ether, the chloromethyl 1 -rphloro- l, 3-pentafluoro- 2 -propyl ether, the dichloromethyl 1-chloro- l, 3-penta-fluoro- 2 -^propyl ether, the chloromethyl 1, 3 -pentafluoro-2-propyl ether and the dichloromethyl 1, 1, 3, 3-tetrafluoro-2 ~propyl ether were found to have useful anesthetic properties in mice as judged by their anesthetic concentrations and margins of safety.

EXAMPLE 36 In order to demonstrate the importance of the halogens in the halomethyl moiety of the novel halomethyl 1, 3-polyhalo-^2- comparison in flammability was made between the halogenated chloro- methyl, fluoromethyl, chlorofluoromethyl and difluoromethyl 1, 1, 1, 3, 3, 3 - hexafluoro -2 -propyl ethers and the methyl 1, 1, 1, 3, 3, 3 -hexafluoro-2 - propyl ether disclosed as an anesthetic agent in U. S. Patent 3, 346, 448.

The flammability of gaseous mixtures of the anesthetic compounds and oxygen w as determined at room temperature and atmospheric pre- sure by visualization of the downward propagation of a flame in a glass bottle having a cylindrical portion 2. 3 inches i. d. x 3. 5 inches in height. The bottle was flushed with pure oxygen, a known quantity of liquid anesthetic added rapidly, and the bottle closed with a ground glass stopper. The bottle was then rotated and shaken until the liquid anes ¬ thetic was completely vaporized and uniformly mixed with oxygen.

P The stopfer was then removed and immediately a burning stick was inserted in the bottle 1. 5 to 2. 0 inches below the bottle mouth.

The lower flammability limit in oxygen, LF LC^ , of the gaseous anesthetic is defined as the concentration by volume percent of the anesthetic in the gaseous mixture at which downward flame propagation was observed.

The concentration by volume percent of the gaseous anesthetic in oxygen was calculated by well-known computation means employing the known volumes, densities and molecular weights, and application of the ideal gas law .

The median anesthetic concentrations for mice, AC^ Q, and the median lethal concentrations for mice, LC^, as determined according to the procedure of Example 24, the lower flammability limit in oxygen, LF LC>2, and the flammability margin of safety, LF LO^ / AC^ Q, for these anesthetic compounds are set forth in Table II, below .

TABLE II Anesthetic and Flammability Comparisons of Some Methyl and Halomethyl 1, 3-Polyfluoro-2 -Propyl Ethers than SC25°, the saturation concentration at 25°C. in volume percent.

The results set forth in the above table show that the novel halomethyl hexafluoro- 2 -propyl ethers of the present invention have substantially greater flammability margins of safety than shown by the corresponding methyl hexafluoro-2 -propyl ether in gaseous mix¬ ture with oxygen.

The above table also shows that the preferred chloromethyl, fluoro methyl, difluoromethyl and chlorofluoromethyl ethers of this invention have better inhalation anesthetic margins of safety than the corresponding methyl ether and that the chloromethyl ether, in particular, has three times the anesthetic potency of the methyl ether.

Various other examples and modifications or adaptations of the foregoing examples can be devised by the person skilled in the without departing from the spirit and scope of the present invention.

Thus, other mutual solvents for the reactants, for example, aceto- nitrile, dimethylformamide, dimethylsulfoxide, dimethyleneglycol dimethylether, and N-methylpyrrolidine can be used in place of dioxide tetrahydrothiophene 1, 1 -disoiiie in the above examples to produce substantially equivalent results in the preparation of the novel compounds of this invention. All such further examples, modifications and adap^- tations are included within the scope of this invention. 32586/3 49 -

Claims (1)

1. CLAIMS methyl and ethers of the wherein I is or bromine and Y is fluorine or and wherein at most one X is at mos 2 are at least one I is at least 1 of X or Y is and 1 X is P when 2 and 2 are ethers according to Claim which there are at least two fluorine on each terminal carbon of the isopropyl moiety of the Methyl Methyl Methyl yl methyl Chloromethyl 1 1 Chlorofluoromethyl ether Compounds of Claim as listed herein or as in any one of Examples 1 to 14 to 22 and 2 k method fo the preparation of compounds of I in Claim wherein a is converted ether into the corresponding methyl by reactiontith dimethyl sulfate and aqueous alkali metal if desired 50 one more hydrogen atoms of the methyl group is or are replaced by chlorine or bromine by A method for the preparation of the compound according to Claim comprising the free radical chlorination of methyl method for the preparation of the compound according to Claim comprising the reaction between chlorine and methyl ether a ratio of about to 1 mole of the former per mole of the at a temperature of from about to about A method for the preparation the compound according to Claim comprisin replacement of the chlorine with fluorine in the methyl group of the corresponding dichloromethyl method according to Claim comprising reacting dichloromethyl ether with from about 2 to about 5 molar equivalents of potassium fluoride in a mutual solvent at a temperature of from about to about or from about to about one molar equivalent of antimony and a small amount of antimon pentafluoride or antimony pentachloride at a temperature of from about to about A method for the preparation of the compound according to Claim comprising the fluorination of methyl ether with bromine 51 A method according to Claim comprising ether with from about to about molar equivalents of bromine trifluoride at a temperature from about to abou for the preparation of the compound according to Claim comprising the free radical of fluoromethyl A method for the preparation of the compound according to Claim the reaction of chlorine propyl ether at a ratio of about to 1 mole of the former per mole of the at a temperature of from about to about Inhalant anesthetic compositions comprising any of the compounds of any of Claims 1 to 10 in which at least one A is other than in gaseous admixture with oxygen in amoun s suitable to maintain anesthesia and support 1 A method of inducing anesthesia in than human comprising administering to the animal effective amount of a compound according to any of Claims 1 to 10 in which least one is other than or a composition according to Ciaim For the Applicants insufficientOCRQuality