US3080430A - Fluorine-containing compounds - Google Patents

Description

States This invention relates to novel fluorine-containing compounds, particularly to 3-chloro-1,1,2,2-tetrafiuoropropane and 3-bromo-1,1,2,2-tetrafluoropropane.

The compounds of this invention and a process for making them are disclosed but not claimed in my copending application Serial No. 808,900, filed April 27, 1959, now Patent No. 3,017,421, patented January 16, 1962, which discloses and claims polyfluoroalkyl chloro sulfonates, bis(polyfiuoroaikyl)sulfates and their preparation from polyfluoroalkanols. Inhalation anesthetic mixtures containing the 3-bromo-1,1,2,2-tetrafluoropropane of this invention as an anesthetic are disclosed and claimed by Kenneth T Dishart in his copending application Serial No. 834,941, filed August 20, 1959, now abandoned and replaced by application Serial No. 95,501, filed March 14, 1961, and patented May 15, 1962, asPatent No. 3,034,959.

It is known that a number of organic fluorine compounds have anesthetic properties. While some of these do not have the undesirable properties of the common inhalation anesthetics, nearly all of them have other undesirable properties, such as high toxicity, hydrolytic instability, reactivity with soda-lime, insufiicient eilectiveness in reasonable concentrations, insufiicient margin of safety, and most producing undesirable physiological side effects. B. H. Robbins in J. Pharmacology and Experimental Therapeutics, 86, 197-204 (1946), reports the results of tests with some 46 fluorine compounds. Of these, only 18 were considered to show sufficient promise to Warrant testing on other than mice, and only 4 produced results such that it was felt that further invesigations thereof were indicated.

One organic fluorine compound has been accepted as being suitable for clinical use as an inhalation anesthetic. Such compound is 2-bromo-2-chloro-1,1,l-trifluoroethane which is sold under the trade name Fluothane. Such compound is a comparatively new, very potent, nonflammable anesthetic. The efiective concentration varies from about 1% to less than 3.5% with surgical anesthesia being induced within 5 to 7 minutes with concentrations of 2% to 2.5% and maintained with concentrations of 0.8% to 1%. It is sold with the caution that it does not permit a wide margin of error, and sudden exposure to relatively high concentrations can lead to profound hypotension with cardiac arrest, whereby the accurate and proper ad ministration of it is mandatory and it should be used only in Vaporizers that have been calibrated accurately to permit concentrations that may be altered in fractions of 0.1 percent over a clinical range of 0.5 percent to 3.5 percent and under the control of a trained anesthetist. It is pointed out that during induction 2. short but definite excitement period is usually present unless premedication is administered, a diminution of respiratory exchange develops and usually persists, and hypotension of variable degree is common, according to the depth of anesthesia. In general, muscle relaxation adequate for major surgical procedures is obtained only at anesthetic levels where a hypotension of some severity may occur.

It is an object of this invention to provide novel fluorinecontaining compounds. A particular object is to provide 3-chloro-1,1,2,2-tetrafiuoropropane and 3-bromo-1,l,2,2- tetrafiuoropropane, which have new and unusual properties. Other objects are to advance the art. objects will appear hereinafter.

Still other atet 2 i The above and other objects may be accomplished in accordance with this invention which comprises compounds of the formula HCF CF CH X wherein X is a halogen having an atomic weight between 35 and 80, i.e. 3-chloro-1,1,2,2-tetrafluoropropane having the formula HCF CF CI-I Cl and 3-bromo-1,1,2,2-tetrafiuoropropane having the formula HCF CF Cl-I Br.

The compounds of this invention are new compounds which are useful for a wide variety of purposes. They are useful as solvents, heat exchange media, hydraulic fluids, dielectrics, fire extinguishing agents, intermediates for the manufacture of other fluorine-containing compounds, and the like. The 3-bromo-1,1,2,2-tetrafiuoropropane is particularly valuable as an inhalation anesthetic, and has unexpected-1y unique properties for that purpose as disclosed more fully by Dishart in Patent No. 3,034,959.

The compounds of this invention are nonexplosive and nonflammable in air, and are stable solvents for oils and greases but have little effect on elastomers, plastics, insulation materials and metals. A selective solvent action adapts them for removing oil, grease, and dirt from such objects and equipment as motor stators, electrical controls, optical and precision instruments, gages, and aircraft instruments, without harm to metal or plastic parts. The compounds are preferably used as solvents in closed systems or well ventilated areas. The compounds are also useful as solvent media for the polymerization of pertluoroolefins, for example, tetrafluoroethylene.

The bromoand chlorofluoropropanes of this invention may be used as low boiling dielectric media to provide, for example, insulation and cooling simultaneously through evaporation in equipment fitted with a reflux condenser. The dielectric constants are:

Dielectric Constant, 8,000 cycles pre sec. at 25 0.

Compound S-bromo-1,1,2,2-tetralluoropropane In comparison, petroleum oil that is widely used as a dielectric has a dielectric constant of about 2, and highly chlorinated aromatic hydrocarbons that provide advantages over petroleum oil as dielectrics have a dielectric constant of 5 to 6.

The compounds are effective fire extinguishing agents. For example, a vigorous gasoline fire in an open dish was readily made to subside and to go out by impinging a fine stream of either the bromoor the chlorofluoropropane onto the burning gasoline. The fire of 'a wellburning paper and wood-chip mixture was soon smothered and put out with a stream of either compound. A temporary fire-proofing effect was provided, as the woodchips absorbed the fire extinguishing compound and could not be immediately reignited.

It has been found that the 3-brorno-l,1,2,2-tetrafiuoropropane of this invention is especially well adapted for use as an inhalation anesthetic because it smoothly and readily induces a deep anesthesia and its vapors, in concentrations within the anesthetic range, have a pleasant and non-irritating odor. This compound is nonfiammable and its vapors, mixed with oxygen in the proportions used for anesthesia, is not flammable or explosive. In concentrations that produce anesthesia satisfactory for surgical purposes, the compound does not cause convulsions in mice and dogs. It may be administered by various machine techniques with a wide margin of safety and has been observed to produce no pronounced change in respiratory rate or blood pressure in dogs until very deep levels of anesthesia were reached and maintained.

tion of from about 6% to about 7% by volume in oxy-' gen or air induces a surgical depth of anesthesia in dogs. Such level is readily maintained with concentrations of from about 4% to about by volume. Concentrations in excess of 8% have been used without fatality. At a given level of anesthesia in dogs, blood pressure depression is generally low.

The compounds of this invention may be considered to be members of series of compounds, the members of which differ firom the adjacent members by a -CF group, which series may be represented by the formulae H(-CF CH CI and H(CF CH Br wherein n represents an integer. Not all members of each series are known. Of those that are known, none, other than the 3-bromcl,l,2,2-tetrafiuoropropane of this invention, has been found suitable as an inhalation anesthetic. For example,

the compounds of the formula H(CF CH CI and H(CF CH Br cause convulsions in mice when used in inhalation anesthetic mixtures. The compounds in which n is 6 or higher have too low a vapor pressure at ordinary room temperatures to function as inhalation anesthetics. 2-bromo-1,l-difiuoroethane (n=1) having the formula HCF CI-I Br is unsuitable as an inhalation anesthetic because, when it was so used on dogs, it rendered them rigid, produced convulsions and resulted in cardiac arrhythmia as disclosed by Robbins in J. Pharmacology and Experimental Therapeutics, 86, pp. 197-204 (1946), see particularly page 202.

Robbins (10c. cit.) tested 2-chloro-1,1 difiuorcethane (11:1) having the formula HCF CH CI as an inhalation anesthetic on mice and found that it had an AD 50 value (the dose in volume percent in an air atmosphere required to induce anesthesia in 50% of the mice upon ten minutes exposure) of 2.15% and an FD value (the dose in volume percent that caused death in 50% of the mice in ten minutes) of 7.5 (page 198), but did not consider it to show .sufiicient promise to warrant testing it with dogs or other animals. On the other hand, as shown by Dishart in Patent No. 3,034,959, 3-bromo-1,1,2,2-tetrafiuoropropane has an AD 50- value in mice of 0.5%. Thus, the anesthetic dose (AD) of HCF CH CI is more than 4 times that for 3-bromo-1,1,2,2-tetrafiuoropropane.

A convenient method for preparing the compounds of 'this invention is to form a p-toluenesulfonic acid ester of 2,2,3,3-tetrafluoro-1-propanol following the procedure of Tiers et a1. (JACS, 75, 5978 (1953)) and then to react the resultant ester with the appropriate potassium halide to yield 3-bromo-( or 3-chloro-) l,1,2,2-tetrafiuoropropane following the procedure of Faurote et al. (IACS, 78, 4999 (1956)). Another method of preparation is to react the sodium derivative of 2,2,3,3-tetrafluoro-1- propancl with sulfuryl chloride and to convert the resultant chl-oro-sulfonate or sulfate ester to the required chloroor bromo-tetrailuor=opropane by reaction With lithium halide. A direct method for preparing the 3- chloro-l,1,2,2-tetratfiuoropropane is to feed 2,2,3,3-tetrafluoro-l-propanol to a refluxing mixture of thionyl chloride and pyridine, continue the refluxing, and then distill the 3-chloro-1,1,2,24etrafiuoropropane from the reaction mixture.

In order to more clearlyillustrate the preparation of the compounds of this invention, the following examples are given in which the proportions are by weight except where it is specifically indicated otherwise.

EXAMPLE 1 Preparation of 2,2,3,3-Tetrafluoropropyl Chlorosulfonate Sulfuryl chloride (168.5 g., 1.25 mol), dissolved in 2,2,3,3-tetrafiuoro-1prop anol (132 g., 1 mol), was added dropwise at 45 C.65 C. to a solution prepared by reacting sodium wire (23 g., 1 mol) with 2,2,3,3-tetrafluoro-1- propanol (330 g., 2.5 mol) At the end of one-half hours stirring, the solution was acidic. The reaction mixture was filtered to remove sodium chloride, and the filtrate was distilled. The fraction distilling at 142 C. to 145 C. (127.5 g.) was the desired 2,2,3,3-tetrafiuoropropyl chlorosulfonate and had an index of refraction (11 of 1.3710.

Analysis.-Calculated for C H O SF CI: C, 15.61; S, 13.87; Cl, 15.39. Found: C, 15.55; S, 13.5; C1, 15.25.

Conversion to 3 -Chlor0-1 ,1 ,2,2 -Tetraflu0r0pr0pane Lithium chloride (25.4 g., 0.6 mol) was heated in 75 nil. of diethylene glycol to 125 C. in a flask fitted with a Water separator-condenser unit. 2,2,3,3 tetrafluoropropyl chlorosulfonate (58 g., 0.25 mol) was added drop- Wise While stirring the reaction mixture. The product began to distill at the start of addition and continued to distill throughout the reaction. The pot temperature was raised to 170 C. before cooling. The crude distillate, collecting in the water separator, Weighed 33 g. After being washed with ice water, drying over anhydrous MgSO and distilling, 3 -chloro-1,1,2,2 -tetrafluoropropane was obtained in 61% yield (23 g.). By further fractional distillation and passage through columns of alumina activated by heating in an air oven at 200 C. for four days, a high quality compound was provided. Its physical properties and the result of chemical analysis are: M.P. -110 C., B.P. at 760 mm. 55 C., sp. gr. 20/4=1.43, n 1.3218; calculated chlorine content 23.58%, found 23.4% C1.

EXAMPLE 2 Preparation of Bis(2,2,3,3-Tetrafluoropr0pyl)Sulfate Sodium Wire (23 g., 1 mol) was reacted at C.-95 C. in excess 2,2,3,3-tetrafiuoro-1-propanol (330 g., 2.5 mol). To this solution, sulfuryl chloride (67.5 g., 0.5 mol), dissolved in 2,2,3,3-tetrafluoro-l-propanol (132 g., 1 mol), was added slowly at 70 C.- C. A white precipitate of sodium chloride formed. After'standing for about 48 hours at room temperature, the strongly acidic mixture was filtered to remove the salt. The filtrate was distilled at 107 C.112 C. to remove unreacted fluoro-alkanol. The residue from the first distillation consisted of two immiscible phases which were then fractionally distilled under vacuum. The desired bis(2,2,3,3-tetratluoropropy1)sulfate distills at C. to 91 C./6 mm. (61.5 g.); n 1.3498.

Analysis. Calculated for C H O SF C, 22.1; H, 1.84; F, 46.62; S, 9.81. Found: C, 22.7; H, 2.1; F, 45.1; S, 9.9.

Conversion to 3-Br0m0-1,1,2,2-Tetrafluoropr0pane Lithium bromide (14.5 g., 0.167 mol) and bis(2,2,3,3- tetrafiuoropropyhsulfate (27.5 g., 0.083 mol) were heated in 50 ml. diethylene glycol in a flask fitted with a water separator-condenser unit. The product began to distill when the mixture reached C. and continued to come over as the reaction temperature rose. The pot temperature was raised to C. before cooling. The crude distillate, collecting in the water separator, weighed 15.5 g. After being washed twice with ice water, drying over anhydrous MgSO fractionally distilling, and passing through columns of alumina as in Example 1, pure 3- bromo-l,1,2,2-tetrafluoropropane was obtained. Its physical properties and the result of chemical analysis are: M.P. 70 C., HP. at 760 mm. 74 C., sp. gr. 20/4=1.81, 11 1.3558; calculated bromine content 41.01%, found 40.3% bromine.

EXAMPLE '3 Preparation of 2,2,3,3-Tetrafluoropropyl p-Toluenesulfonate overnight. The resultant mass was then poured into a mixture of ice and sodium bicarbonate. The ester crystallized and Was collected by filtration. The ester was then dissolved in methanol, dried over anhydrous magnesium sulfate and filtered. The methanol was removed from the filtered solution by distillation at atmospheric pressure, and 142 g. of the desired ester collected as distillate at 124 C. to 126 C. at 2 mm. mercury pressure. The ester melts at 14 C. to 16 C., has n =L4600 and sp. gr. 20/4=1.397.

Analysis.Calculated for C H F O S: C, 42.15; H, 3.5; F, 26.6; S, 11.2. Found: C, 41.9; H, 3.6; F, 26.0; S, 11.2.

Conversion to 3-Br0m0-1,1,2,2-Tetrafluoropropane By the procedure of Tiers et al. (IACS, 75, 5979, (1953)), 142.8 g. (0.5 mol) of the above 2,2,3,3-tetrafiuoropropyl p-toluenesulfonate, 43.4 g. (0.5 mol) of lithium bromide and 150 ml. of diethylene glycol were heated together with a rise of temperature to 190 C. over a period of 2 hours. An additional 9 g. portion of lithium bromide was added and the mass kept at about 190 C. for another 6 hours. A total of 90 g. of product distilled from the reaction mass and was collected. The product was washed twice with water, dried over anhydrous magnesium sulfate, fractionally distilled, and passed through columns of activated alumina. The final product had a boiling point of 74 C. at 760 mm., sp. gr. 20/4 of 1.81, and refractive index 11;, of 1.3558.

thetic.

It will be understood that the foregoing examples are given for illustrative purposes solely and that this invention is not limited to the specific embodiments described therein. On the other hand, it will be apparent to those skilled in the art that variations and modifications can be made therein, particularly in the materials, proportions and conditions employed without departing from the spirit and scope of this invention.

From all of the above, it will be apparent that this invention provides novel compounds which are valuable for a variety of purposes. Particularly, the 3-bromo- 1,1,2,2-tetrafiuoropropane has unexpectedly unique propert-ies whereby it is outstanding as an inhalation anes- Therefore, this invention constitutes a valuable advance in and contribution to the art.

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A fluorine-containing compound having [the formula HCF CF CH X wherein X represents a halogen atom having an atomic weight between and 80.

2. 3-chloro-l,1,2,2-tetrafiuoropropane.

3. 3-bromo-1,1,2,2-tetrafluoropropane.

References Cited in the file of this patent Henne et al.: J.A.C.S., 59, 2363 (1943). Tarrant et al.: J.A.C.S., vol. 77, pp. 27837 (page 2785 particularly relied on), 1955.

Claims (1)

1. A FLUORINE-CINTAINING COMPOUND HAVING THE FORMULA HCF2CF2CH2X WHEREIN X REPRESENTS A HALOGEN ATOM HAVING AN ATOMIC WEIGHT BETWEEN 35 AND 80.