US3659023A - Method of inducing anesthesia with 2-bromo-1 1 2 3 3-pentafluoropropane - Google Patents

Abstract

2-BROMO-1,1,2,3,3-PENTAFLUOROPROPANE IS EMPLOYED AS AN ANESTHETIC AGENT BY ADMINISTRATION BY INHALATION.

Description

United States Patent U.S. Cl. 424-350 1 Claim ABSTRACT on THE DISCLOSURE 2-bromo-1,l,2,3,3-pentafluoropropane is employed as an anesthetic agent by administration by inhalation.

CROSS REFERENCES TO RELATED APPLICATIONS This is a continuation of co-pending application Ser. No. 858,206, filed Mar. 10, 1969, now abandoned, which in turn is a division of application Ser. No. 664,604, filed Aug. 31, 1967, now U.S. Pat. 3,480,683. Application Ser. No. 664,604 is a continuation-in-part of application Ser. No. 538,523, filed Feb. 2, 1966, now U.S. Pat. 3,362,874.

This invention relates to a novel bromopentafluoropropane. More particularly, this invention relates to a monobromopentafluoropropane having a bromine atom substituted on the number two carbon atom, namely, 2- bromo 1,1,2,3,3 pentafluoropropane.

It is known that certain halogenated alkanes are useful inhalation anesthetics. Chloroform and halothane are well-known examples of such compounds which are derivatives of the lower alkanes, methane and ethane, respectively. More recently, it has also been disclosed .that certain halogenated fluoropropanes are useful inhalation anesthetics. Thus, Dishart, U.S. Pat. 3,034,959, discloses the inhalation anesthetic use of 3 bromo-1,1, 2,2 tetrafluoropropane and Belgian Pats. 663,478 and 668,605 disclose the inhalation anesthetic use of 3- bromo-3-chloro-1,1,2,2-pentafluoropropane.

Position isomers of the monobromopentafluoroproipane of the present invention also are known. Thus, 3-bromo- 1,1,1,2,2 pentafluoropropane is disclosed by McBee et al., 77 J. Am. Chem. Soc. 3149 (1955); 3-bromo-l,l,l, 3,3-pentafiuoropropane is disclosed by Muray, British Pat. 908,110; 2 bromo l,1,1,2,3 pentafluoropropan'e is disclosed by Rausch et al., 28 J. Org. Chem. 494 (1963); and 1- and 3-bromo 1,1,2,2,3 pentafluoropropanes are disclosed in a dissertation by Beck, Reactivities of Aliphatic Fluorides, The Ohio State University (1959).

Two of the above position isomers of the monobromopentafluoropropane of the present invention have been further disclosed as having inhalation anesthetic properties. Thus, Raventos, British Pat. 913,143, discloses the inhalation anesthetic properties of 3 bromo 1,l,1,3,3- pentafluoropropane and Burns et al., 17 Anaesthesia 337-343 (1962), disclose the inhalation anesthetic properties of 3-br0mo-1,l,1,2,2-pentafiuoropropane.

It has now been found that the novel monobromopentafluoropropane as defined herein is a useful inhalation anesthetic which has an inhalation margin of safety in mice which is not only substantially higher than the margin of safety of the abovementioned position iso- ICC mers disclosed by Raventos and Burns et al., but is also substantially higher than the margin of safety of the inhalation anesthetics in current use, namely, ether, chloroform, and halothane. As such, the novel compound of this invention holds good promise as an effective and useful agent for inducing anesthesia in man.

The novel monobromopentafiuoropropane of this in-. vention also is stable to soda lime as distinguished from the position isomer of Raventos, 3-bromo 1,1,1,3,3- pentafluoropropane, which is not stable to soda lime. This property of the novel compound of the present invention makes it useful in conventional re-circulation apparatus which employs soda lime for the absorption of carbon dioxide from the patient undergoing anesthesia.

The novel inhalation anesthetic compound of the pres ent invention also has been found to be nonflammable in air and noneX'plosi-ve in oxygen at ambient temperatures. Its lower flammability limit in oxygen of about 9% by volume is well above the useful concentrations for inhalation anesthesia in man which is not more than about 5% by volume. Moreover, the flammability margin of safety of the novel compound of this invention is sub.- stantially greater than the margin of safety of the position isomer of Burns et al., 3-bromo 1,1,1,2,2 pentafluoropropane.

The novel 2 bromo 1,1,2,3,3 pentafluoropropane of the present invention is a clear liquid at normal room temperature and has a boiling point of 60.2- C. at 736 mm. Hg. It can be conveniently stored in containers normally used for conventional anesthetics of comparable boiling point, e.g., halothane. It can be administered by apparatus or machines designed for the vaporization of liquid anesthetics and admixtures thereof with oxygen, air or other gaseous mixtures containing oxygen in amounts capable of supporting respiration.

For use in anesthesia, the 2 bromo 1,1,2,3,3 pentafluoropropane should be free of toxic impurities which may be present according to the particular process used for its manufacture. This compound can, however, be used in admixture with pharmaceutically acceptable diluents and stabilizers, e.g., thymol, or one or more of the known inhalation anesthetics, e.g., nitrous oxide, ether, halothane, chloroform, cyclopropane, methoxyfiuorane, and the like.

The novel monobromopentafluoropropane defined here- .in can be conveniently prepared by elimination of a .Mar. 10, 1969, now U.S. Pat. 3,458,584.

A preferred method .of preparation of the novel .monobromopentafluoropropane of this invention comprises the employment of a mixture of a metal oxide, for example, lead dioxide, and sulfur tetrafluoride for the selective addition of fluorine to the double bond of the 2 bromo 1,3,3 trifluoropropene in an autoclave at a temperature of about C. for about five hours.

Although the above methods of preparation and reaction conditions are specifically described, it will be understood that the novel monobromopentafiuoropropane of this invention is not limited to this specific method of preparation. For example, other methods of fluorine. addition to the double bond in 2 bromo 1,3,3 trifluoropropene may be employed to prepare the novel anesthetic agent 2 bromo 1,1,2,3,3 pentafiuoropropane. Thus, elemental fluorine, high valency metallic fluorides (such as, for example, cobalt trifluoride, silver difiuoride, antimony pentafluoride, manganese trifluoride and cerium tetrafiuoride), xenon tetrafluoride or a mixture of lead dioxide and anhydrous hydrogen fluoride and the like can be used to fluorinate the intermediate 2-bromo-l,3,3- trifluoropropenes.

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

EXAMPLE 1 1,1,3,3-tetrafluoropropan-2-ol (1) Hydrogen at the rate of one-half liter per minute was bubbled through 1,3-dichloro-l,l,3,3-tetrafluoroacetone at "4 C. The mixture of vapors passed through a Pyrex tube (45 cm. x 1.9 cm. LD.) containing 2% palladium on carbon granules (4-12 mesh) and heated to 200 C. The reaction products were condensed in a trap cooled by Dry Ice. A 750:1 ratio by weight of dichlorotetrafluoroacetone to palladium is optimum.

In a typical run 1250 grams (6.28 moles) of dichlorotetrafiuoroacetone was vaporized with hydrogen during 22 hoursand the mixture passed over 85 grams of palladium-carbon catalyst. Fractional distillation of the reaction products gave 704 grams (5.33 moles, 85% of theory) of crude alcohol (I) B.P. 106-109" C., suitable for use in the next step.

Alternatively, the alcohol 1) can be prepared by reduction of 1,1,3,3-tetraliuoroacetone with sodium borohydride. The alcohol (I) obtained in this manner had B.P. l0709 C., 12 1.333. The identity of the alcohols prepared in these two ways was confirmed by infrared spectra.

EXAMPLE 2 1,1,3,3-tetrafluoro-2-propyl-p-toluenesulfonate (II) A mixture of crude 1,1,3,3-tetrafluoropropan-2-ol (I) (315 g., 2.4 moles), p-toluenesulfonyl chloride (460 g., 2.4 moles) and 600 ml. of water was stirred as N sodium hydroxide (514 ml., 2.57 moles) was added during 1.5 hours, and the temperature was maintained between 25 C.-40" C. Stirring was continued for 16 hours. The lower layer of crude ester (II) was separated, stirred, evachated to between 25-40 mm. Hg and heated to 125 C.

until volatile impurities ceased to be removed. Five hundred eighty-three grams (2.04 moles, 85% of theory) of crude ester (II) suitable for use in subsequent steps was obtained. Crystallization from ligroin gave ester (11),

MP. 31" C., a 1.466. v

Analysis.-Calculated for C H F4O S (percent): C, 41.91; H, 3.52; S, 11.20. Found (percent): C, 42.13; H, 3.63; S, 10.95.

EXAMPLE 3 2-bromo-1,1,3,3-tetrafiuoropropane (III) a mixture of III, 1,4-dioxane and water, from which the III was purified by successive washings with water and aqueous 60% sulfuric acid. It was neutralized by a wash with cold dilute aqueous sodium hydroxide. The crude bromide (III) amounted to 314 grams (81.5% of theory). Fractional distillation gave 256 grams of bromide (III),

.b .82.6-82.8 C. Pure (99.9% by G.L.C.) bromide log P=8.1590

Its 60 mo. nuclear magnetic resonance (NMR) and infrared spectra confirmed the CI-lF -CH Br-CI-IF structure.

EXAMPLE 4 Cisand trans-Z bromo-1,3,3-trifluoropropenes (IV) A mixture of 2-bromo-1,1,3,3-tetrafluoropropane (III) (368 g., 1.88 moles) and low-moisture (about 2% water) soda lime (180 g.) was heated to boiling under total reflux for about sixteen hours. Gas liquid chromatographic, infrared, and proton nuclear magnetic resonance analyses of the liquid reaction product showed essentially complete conversion to a mixture of cisand trans-2-bromo-1,3,3- trifiuoropropenes (IV). The ratio of the cisand transpropene isomers produced was about 13:1. The predominant propene has a longer retention time than either the other propene or the starting propane on a column packed with 20% diisodecylphthalate on Chromasorb P at C. to C. Fractional distillation of the propene mixture did not aiford an efiicient separation, and the cisand trans-propene isomers distilled concurrently, b 1 77.5-78.0 C. (290 g., 1.66 moles, 88% yield). The last fraction collected afforded the purest product, b 78.0 C., d 1.8429, 113 1.3961, and is 99.4% the predominant propene and 0.54% the other propene.

EXAMPLE 5 Z-bromo-1,l,2,3,3-pentafluoropropane (V) A 300 ml. Hoke high pressure (5,000 p.s.i.) cylinder equipped with a 2,600 to 3,000 p.s.i. rupture disc assembly and a Hoke M327A needle valve was charged with 48.6 grams of PbO After pressure checking the system at p.'s.i.', the contents were thoroughly vacuum degassed while the cylinder was heated externally. Next, 23.6 grams of 2-bromo-1,3,3-trifluoropropene (IV) were distilled in on a high vacuum system after which the vessel was allowed to warm to ambient temperature. This warming procedure is believed to be desirable since the olefin can then act as a reaction medium and heat sink for the exothermic reaction of PbO' and SF, carried out in the next step. The vessel was then precooled to 196 C. and 38 ml. SF, (73 g., at 78 C.) were distilled in, after which the vessel was allowed to warm very slowly to ambient temperature by placing it in a cold Dewar flask. The next morning the cylinder was placed in a rocking furnace, warmed to 100 C., and rocked for five hours. After cooling, the volatile contents were removed under vacuum through traps at 78 C. and 196 C. placed in series. The -78 C. trap usually contained 24 to 26 grams of product which analyzed from 75 to 95% 2-bromo-1,1,2,3,3-pentafluoropropane by gas chromatography. Extraction of this product with dilute aqueous alkaline sodium sulfite, drying of the washed product, and fractional distillation gave 2-bromo-1,1,2,3,3-penta'- fluoropropane; b 60.2" C., (1 1.86, having a purity of 99.9% as determined by gas-liquid chromatography. The molecular structure CH'F CFBrCI-IF was confirmed by proton nuclear magnetic resonance and infrared spectra.

EXAMPLE 6 Inhalation of the vapor of 2-bromo-1,1,2,3,3-pentaflu oropropane admixed with air in the manner described by Robbins, 86 J. Pharmacol. Exper. Therap. 197-204 (1946), produced anesthesia in white mice. The minimum concentration by volume percent required to produce full anesthesia (loss of negative righting reflex) in 50% of the test animals in five minutes, AC and the minimum concentration by volume percent required to kill 50% of the test mice in five minutes, LC are given in Table I, be

low. The inhalation margin of safety asmeasured in mice by the ratio LC /AC is also given in Table I. For purposes of comparison, similar data which were obtained under the same conditions as for the above compound are given for three inhalation anesthetics in current use, namely, ether, chloroform and halothane, and for the position isomers 3-bromo-1,1,1,2,2-pentafiuoropropane and 3-bromo-l,1,1,3,3-pentafiuoropropane disclosed by Burns et al., and Raventos, respectively, as having inhalation anesthetic properties. The number of mice used with the different anesthetic agents varied from 25 to 92 for determining each of the AC and LC doses.

TABLE I.-INH ALATION ANESTHESIA IN MICE Compound A050 L050 Lose/AC5 CHF CFIBrCHFg 0. 73 3. 67 5. 0 CF3CF2CH3BI 1.71 5. 58 3. 3 CF3CFz-CF2BI 1. 62 5. 84 3. 6

ther 3. 69 12. 0 3. 2 chloroform O. 94 2. 56 2. 7 Halothane O. 78 2. 62 3. 4

Surgical anesthesia (stage 111, plane 2) was induced in two dogs with about 3% by volume of 2-bromo-1,1,2,3,3- pentafluoropropane in oxygen and maintained for 30 to 60 minutes with about 1.5% to 2.5% by volume of this anesthetic agent in oxygen. For purposes of comparison, surgical anesthesia was induced in four dogs with 2% to 4% by volume halothane in oxygen and maintained for 60 minutes with 1% to 2% by volume of halothane in oxygen.

The anesthetic agent was administered via an endotracheal catheter with inflation cuffs in a non-rebreathing system subsequent to initial anesthesia with sodium methohexital and pretreatment with atropine sulfate and heparm.

Heart rate and myocardial responses were determined from EKG records. Spontaneous respiratory rate and respiratory minute volume were maintained by means of a pressure change transducer and a wet-test meter, respectively. The arterial blood pressure was monitored, and blood samples were withdrawn for determinations of blood gases and pH.

Anesthesia with 2-bromo-l,1,2,3,3-pentafiuoropropane in two dogs was equivalent to halothane anesthesia. Both compounds produced a fall in diastolic blood pressure below 70 mm. Hg, and a decrease in heart rate. However, normal spontaneous respiratory rate and minute volume and normal pCO values were observed in anesthesias with both compounds. The EKG records were also normal with the exception of T-wave inversion during anesthesia with both compounds.

EXAMPLE 8 The soda lime stability of the novel inhalation anesthetic of the present invention was determined essentially according to the procedure of Glover and Hodgson, 16 Anesthesia 19-23 (1961). The liquid anesthetic (0.65 ml.) and soda lime (0.50 g., 8-12 mesh, 15%20% by weight of water) were sealed in a glass ampule and heated at 70 C. for three hours and then analyzed by gas-liquid partition chromatography. For purposes of comparison, a liquid anesthetic blank was treated in the same way in the absence of soda lime. The chromatographic results are given in Table II, below, in which R.T. is retention time in minutes from air and Area percent is 100 times the ratio of the area under a peak to the total area under TABLE II.SODALIll/IE STABILITY OF ANESTHETICS Blank Soda lime treated Area Area, Area, perperper- Oompound R.T. cent R.T. cent R.T cent CHFzOFB1CHFz 7. 5 99. 9 0. 43 0. 50 7. 5 99. 5 Halot'nane 7. 2 99. 9 4. 2 0. 20 7. 2 99. 8

The remarkable soda lime stability of the novel monobromopentafluoropropane of this invention is shown by the high correspondence between the 99.9+ and 99.5 Area percents after 7.5 minutes of retention time in the blank sample and the soda lime treated sample, respectively.

EXAMPLE 9 The flammability of gaseous mixtures of the novel inhalation anesthetic of the present invention and air or oxygen was determined at room temperature and atmospheric pressure by visualization of the downward propagation of a flame in a glass bottle having a cylindrical portion 2.3 inches ID. x 3.5 inches in height. The bottle was flushed with pure oxygen or air, a known quanity of liquid anesthetic was added rapidly, and the bottle was closed with a ground glass stopper. The bottle was then rotated and shaken until the liquid anesthetic was completely vaporized and uniformly mixed with oxygen or air. The stopper was then removed and immediately a burning stick inserted in the bottle 1.5 to 2.0 inches below the bottle mouth.

The concentration by volume percent of the gaseous anesthetic in oxygen or air was calculated by well-known computation means employing the known volume of the stoppered bottle (i.e., the volume of the contained oxygen or air), the known volume of the added liquid anesthetic, the known densities and molecular weights and application of the ideal gas law to compute the gaseous volume of the anesthetic sample.

The lower flammability limits in oxygen, LFIO and in air, LFlAir, as determined by the above procedure are given in Table III, below. These flammability limits are stated as a range of two concentrations by volume percent; downward flame propagation was observed at the higher concentration but not at the lower concentration of the anesthetic in the gaseous mixture. The median anesthetic concentration for mice, AC as determined in Example 6, above, is also given in Table III. The ratio, LFlOg/ AC herein referred to as the flammability margin of safety, is also given in Table III. For purposes of comparison, similar data which were obtained under the same conditions as for the above compound are given for the position isomer 3-bromo-1,1,l,2,2-pentafluoropropane, which has been previously disclosed as having inhalation anesthetic properties.

TABLE III.FLAMMABILITY OF ANESTHETICS L 10 Compound LFlOz LFlAir AC5; 5.0. 1 CHF2-OFBrCHFz 8.9-9.6 Nonflammable 0.71 1 CF2CFtCHzBr 11.0-11.6 do 1.71 6.2

As will be readily apparent to those skilled .in the art, other examples of the herein-defined invention can be devised after reading the foregoing specification and claim appended hereto by various modifications and adaptations without departing from the spirit and scope of the invention. All such modifications and adaptations are ineluded within the scope of the invention as defined in the appended claim.

What is claimed is:

1. The method of inducing anesthesia in animals which comprises administering by inhalation to said animals an eifective amount of 2-bromo-1,1,2,3,3-pentafluoropropane for inducing anesthesia.

References Cited UNITED STATES PATENTS Downing et a1. 260 653. McBee et a]. 260653 Sucking et a1. 2606-53 Muray et a1. 260-653 Regan 260'-653 Regan 424350 Regan 42A--350 JEROME D. GOLDBERG, Primary Examiner