NO762989L - - Google Patents

Description

"Analogy method for the production of physiological

isk active connectionl*'',

This invention relates to a new halogenated ether which possesses anesthetic action and which is virtually free of unwanted side effects when administered to warm-blooded animals by inhalation.

According to the invention, the new compound 2-chloro-1,2,2-trifluoroethyl-difluoromethyl ether with the formula CHF20CHFCC1F2 is thus provided.

The structure of the compound is confirmed by the following physical data:

Proton magnetic resonance spectrum (in carbon tetrachloride using tetramethylsilane as internal reference)

The compound has a boiling point of 56°C at normal atmospheric pressure.

According to a further feature of the invention, a method for the production of 2-chloro-1,2,2-trifluoroethyl-difluoromethyl ether is provided, which comprises: (a) chlorination of difluoromethyl-1,2,2-trifluoroethyl ether

(CHF2OCHFCHF2); or

(b) fluorination of methyl 2,2,2-trichloroethyl ether (CH 3 O CH 2 CC 3 );

or

(c) reductive partial dechlorination of difluoromethyl-1,2-dichloro-1,2,2-trifluoroethyl ether (CHF'2OCFCiCF2Cl).

The chlorination process can conveniently be carried out at laboratory temperature using gaseous chlorine under the influence of ultraviolet radiation.

The fluorination process can conveniently be carried out using a fluorinating agent of a high-valence metal, e.g. cobalt(III) fluoride id, at elevated temperature, e.g. at 60°C.

The reductive, partial dechlorination process can be carried out

using hydrogen and a catalyst, e.g. a palladium catalyst, and it can be carried out at a temperature between 170 and 190°C, at which temperature the second chlorine atom is not substantially removed. Alternatively, the method can be carried out using a complex metal hydride, e.g. lithium aluminum hydride or sodium borohydride, or in the absence of a solvent or in a suitable solvent, e.g. dimethyl sulfoxide, or an ether such as dibutyl ether or diglyme.

The compound CHL?2OCHFCHF2 used as starting material is a known compound (Tetrahedron, 197.1, 2J7, 4533 - 4551).

The compound CH^OCR^CCl^ used as starting material is a known compound (Bulletin de la Société Chimique de France, 1967, 1520-1532).

The compound CHF20CFC1CF2C1 used as starting material can be obtained from tetrafluoroethylene by means of the following

c

series of reactions:

CF2=CF2+ Na0CH3> C!!30-CF = CF'2

+ Cl2 > CH3O-CFC1-CF2Cl

<+>Cl2> CHC100-CFC1-CF Cl

+ SbF3CHF20-CFC1-CF2F1

The new compound according to the invention can be incorporated into anesthetic preparations together with oxygen and possibly together with one or more other physiologically acceptable materials, the proportion of anesthetic agent in the preparation being such that when the preparation is administered by inhalation to a warm-blooded animal, it produces and/or maintains anaesthesia, and the proportion of oxygen in the preparation is such that when the preparation is administered by inhalation to a warm-blooded animal, respiration is maintained.

It should be understood that the 2-chloro-1,2,2-trifluoroethyl difluoromethyl ether must be free of toxic contaminants when used in an anesthetic preparation.

The oxygen present in the preparation must be pure oxygen, or it can be in the form of air, i.e. in a mixture with nitrogen and smaller amounts of other gases.

The other physiologically acceptable materials as appropriate

may be present in the preparation, e.g. be one or more substances selected from other anesthetic agents for inhalation, e.g. halothane, nitrous oxide, diethyl ether, divinyl ether, trifluoroethyl vinyl ether, cyclopropane, trichloroethylene, chloroform, enflurane, fluroxene, methoxyflurane, teflurane and 1-chloro-2,2,2-trifluoroethyl-difluoromethyl-ether;

pharmaceutically inert gases, e.g. nitrogen, chemically inert gases such as those present in air, e.g. neon and argon, and carbon dioxide and water vapor; and pharmaceutically acceptable stabilizers which may be present to protect one or more of the other components in the preparation from the effects of light, oxidation and/or attack by acid or base. As a suitable stabilizer, e.g. a volatile stabilizer is used which is physiologically acceptable, e.g. ethanol, or a non-volatile stabilizer which is not carried along during evaporation to a significant extent, e.g. thymol.

The preparation will usually contain between 0.25 and 3.5% by volume

of the 2-chloro-1,2,2-trifluoroethyl-difluoromethyl ether.

The preparation can be administered to warm-blooded animals, including humans, to achieve anesthesia by conventional technique. The preparation can be preformed and administered as such, or alternatively 2-chloro-1,2,2-trifluoroethyl-difluoromethyl-ether and oxygen, both of which can be together with other physiologically acceptable materials, can be administered separately, the preparation being formed either immediately before or during administration. E.g. the preparation may be used in apparatus or machines designed for the vaporization of liquid anesthetic agents, and the mixture thereof with oxygen or with air or other gaseous mixtures containing oxygen, in a quantity sufficient to sustain respiration.

The compound according to the invention can be filled onto an anesthesia device for inhalation.

When providing anesthesia in a warm-blooded animal, it is administered. to the animal an anesthetically effective amount of 2-chloro-1,2,2-trifluoroethyl-difluoromethyl ether together with sufficient oxygen to maintain respiration.

The following examples shall serve to illustrate the invention. nelsen further:

Example 1

Chlorine gas was in an amount of 40 ml per minute for 4 hours bubbled through 40 ml (57 g) of difluoromethyl-1,2,2-trifluoroethyl ether (CHF2OCHFCHF2) under ultraviolet irradiation. Unreacted chlorine passed from the reaction vessel through a vertical air cooler and a dephlegmator - which was kept at -78°C with trichlorethylene / solid carbon dioxide, which condensed any organic components in the outlet gases. The reaction mixture was then distilled into a cold trap, dried over a molecular sieve and finally separated into its. components on a preparative gas-liquid chromatogram using a 30-foot column containing 20% diethylhexyl sebacate on a Celite support.

2-Chloro-1,2,2-trifluoroethyl-difluoromethyl-ether- was obtained i

a dividend of approx. 6% based on difluoromethyl-1,2,2-trifluoroethyl ether.

Example 2

methyl 2,2,2-trichloroethyl ether (56 ml) was added over 5 hours to a reactor containing cobalt(III) fluoride (2000 g) which was stirred and kept at 60°C. Nitrogen was then blown through the stirred reactor contents for one hour, the material entrained by the nitrogen being condensed and collected in a trap which was

kept at, -75°C. The contents of the trap were washed with water and dried over a molecular sieve, and 45 g of material was formed.

The combined product from ten such reactions was distilled fractionally, and the desired fraction was further purified by gas chromatography using a 9 m x 1.3 cm column containing 20% by weight of a polyethylene glycol (Carbowax M") on a support of "Celite 2-chloro-1,2,2-trifluoroethyl-difluoromethyl ether (120 g) was thus obtained.

Example 3

1,2-Dichloro-1,2,2-trifluoroethyl-difluoromethyl ether was introduced into a stream of hydrogen at a flow rate of 750 ml per minute through a tube (50 cm x 2.5 cm) containing a 5 % pall-adium-on-charcoal catalyst heated to a temperature between 170 and 190°C, and off-gassing leaving the tube was passed into a vessel cooled with solid carbon dioxide.The collected liquid was again passed through the tube - in a stream of hydrogen, and the exhaust gases were again collected. The liquid thus obtained was distilled

fractionated, and one thus obtained di fluoro ty.1-2-chloro-1,2,2-trifluoroethyl ether, b.p. 56°C.

The difluoromethyl-1,2,2-trifluoro-1,2-dichloroethyl ether used as starting material was obtained as follows: : Chlorine gas was introduced into methyl 1,2-dichloro-1,2,2-trifluoroethyl- ether (68 g) which was in a 50 ml radiation cell equipped with a cooler and a trap with low carbon dioxide, and which was irradiated by means of a Hanovia medium pressure lamp. An exothermic reaction took place, and the internal temperature rose to 50°C. When the weight of the reaction mixture had increased to 99 g, which indicates that two hydrogen atoms had been replaced by two chlorine atoms, the reaction was stopped, and the reaction mixture was fractionally distilled. Dichloromethyl-1,2-dichloro-1,2,2-trifluoroethyl ether was thus obtained, b.p. 127°C.

The above material (48 g) was added slowly to antimony trifluoride (35.8 g) which was stirred at 90°C, and the reaction product which distilled from the reaction mixture was collected in a vessel cooled by solid carbon dioxide. The product was fractionally distilled and thus obtained difluoromethyl-1,2-dichloro-1,2,2-trifluoroethyl ether, b.p. 61 - 61.5°C.

Example 4

A group of 6 mice is placed in a; chamber with a volume of 10 liters containing a solid mixture of sodium hydroxide and calcium hydroxide, and a mixture of 2-chloro-1,2,2-trifluoroethyl-difluoromethyl ether and oxygen, with a known percentage content, is released into the chamber. A reservoir bag containing the known mixture is used to maintain atmospheric pressure since the mixture is inhaled by the mice and since exhaled carbon dioxide is absorbed by the sodium hydroxide-calcium hydroxide mixture. After 30 minutes, the concentration of 2-chloro-1,2,2-trifluoroethyl-difluoromethyl ether in the chamber is determined by gas chromatography.

The experiment is repeated using different mixtures of 2-chloro-1,2,2-trifluoroethyl difluoromethyl ether and oxygen, and AC^-q, i.e. the volume concentration of 2-chloro-1,2,2-trifluoroethyl -difluoromethyl ether, which anesthetizes 3 mice out of 6 after 30 minutes of treatment, is found to be 0.9%. LC^-q, i.e. the volume concentration of 2-chloro-1,2,2-trifluoroethyl-difluoromethyl ether which kills 3 mice out of 6 after 30 minutes of treatment, is found to be 4.2%. The compound's therapeutic ratio is therefore 4.2/0.9, i.e. 4.7. Under 'similar conditions, the hC^^, LC^q°g therapeutic ratios for halothane are respectively 0.85%, 3.4% and 4.0-

Example 5

A mixture of 2-chloro-1,2,2-trifluoroethyl-difluoromethyl ether (3% v/v) and air (97% v/v) was administered to a cat over a period of 10 minutes. Induction of anesthesia and subsequent reconstitution from anesthesia was smooth and rapid.

Example 6

A cat was anesthetized by injection of a 2.5% weight/volume solution of thiopentone trium in water into a cephalic vein in a dose corresponding to 20 mg per kg of body weight. Anesthesia was then maintained by administration of a mixture of 2-chloro-1,2,2-trifluoroethyl-difluoromethyl ether (1% v/v) and oxygen (99% v/v) which was stored in a large nylon sack. Anesthesia was maintained in this way for 40 minutes. Average arterial pressure and heart rate during this period were both significantly higher than under corresponding anesthesia with halothane.

Claims (1)

Analogous method for the preparation of the physiologically active compound 2-chloro-1,2,2,-trifluoroethyl-difluoromethyl-ether with the formula CHF2 0CHFCC1F2 , characterized by : a) chlorination of difluoromethyl-1,2,2-trifluoroethyl ether (CHF2 OCHFCHF2 ); or b) fluorination of methyl 1-2,2,2-trichloroethyl ether (CH3 0CH2 CC13 ); or c) reductive partial dechlorination of difluoromethyl-1,2-dichloro-1,2,2-trifluoroethyl ether (CHF2 0CFC1CF2 C1).