DE1138026B - Process for the preparation of 3-bromo-1, 1, 2, 2-tetrafluoropropane which is effective for inhalation anesthesia - Google Patents

Description

Process for the production of 3-bromo-1 which is effective for inhalation anesthesia, 1, 2,2-tetrnfluoropropane The invention relates to a process for the preparation of 3-bromo-1,1,2,2-tetrafluoropropane, which is used as an inhalation anesthetic in a mixture with Oxygen or air and optionally nitrous oxide can be used.

It is known that a number of organic fluorine compounds has anesthetic properties. Although some of these connections are not have the undesirable properties of common inhalation anesthetics almost all of them have other undesirable properties, such as high toxicity, hydrolytic Instability, reactivity with soda lime, insufficient effectiveness in reasonable Concentrations and insufficient anesthesia width.

Most produce undesirable physiological side effects.

To date, only one organic fluorine compound is considered suitable for clinical use as an inhalation anesthetic has been viewed. At this The compound is 2-bromo-2-chloro-1,1,1-trifluoroethane. This connection is a relatively new, very strong and non-flammable anesthetic. The effective concentration varies from about 10 / g to less than 3.5 ° / 0.010 with sufficient anesthesia for surgical procedures within 5 to 7 minutes with concentrations of 2 to 2.5 O / o and with concentrations of 0.8 to 1 0/0 is maintained. The connection is offered in stores with the note, that it leaves little room for error and strong hypotension Cardiac arrest can occur when the patient suddenly becomes relatively high Exposing concentrations. Therefore careful and proper handling is essential required. The compound is only intended to be used in vaporizers that go through allow accurate calibration concentrations that are in fractions of 0.1 0 / o above a clinical range of 0.5 to 3.50 /, and under the control of a trained person Anesthetists can be changed. It is stated that usually during a short but distinct stage of excitation occurs after the induction of anesthesia, if medication is not given beforehand; a degradation develops the respiratory exchange, which usually persists.

Hypotension of varying degrees according to the depth of the Anesthesia is common.

Generally one is required for major surgery Muscle relaxation is only achieved at depths of anesthesia in which there is greater hypotension can occur.

3-bromo-l, l, 2,2-tetrafluoropropane is a new in- halation anesthetic effective compound obtained by reacting the p-toluenesulfonic acid ester of l-hydroxy-2,2,3,3-tetrafluoropropane is produced with potassium bromide in a manner known per se.

It has been found that 3-bromo-1,1,2,2-tetrafiuorpropane of the formula HCF2CF2CH2Br is particularly suitable for use as an inhalation anesthetic, as this compound smoothly and easily produces a deep anesthetic and its vapors in concentration within the anesthetic area a pleasant and not have an irritating odor. The compound is made of soda lime among the in one Conditions applied to anesthesia device not affected. In rigorous Experiments with a strongly alkaline solution split off some hydrogen fluoride. When shaking the compound with 10 of the above sodium hydroxide solution in the closed Tube at 80 "C for 20 hours, 50% of the compound is recovered unchanged. In concentrations that produce sufficient anesthesia for surgical purposes, the compound does not cause convulsions in mice and dogs.

The anesthetic width, defined as the difference between the mean concentration of the anesthetic causing respiratory arrest and the mean concentration required to maintain anesthesia in the second level of the third stage in humans, is at 3-bromo-1,1,2,2- tetrafluoropropane surprisingly and particularly large compared to 2-bromo-2-chloro-1,1,1-trifluoroethane, as the comparison shows: Average Average, to concentrate on upright Respiratory arrest leading to maintenance of anesthesia anesthesia width Anesthetic concentration at (second level of the third continuous administration stage) ("wo) *) (C / c) *) (Olo concentration) AB A-3 3 bromine-1 1, 2,2-tetrafluoropropane ....> 5 | 1 | > 4 2-bromo-2-chloro-1,1,1-trifluoroethane 2 1 1 *) The percentages relate to the composition of the breathing atmosphere.This comparison shows that the average concentration leading to respiratory failure, expressed as a percentage of the breathing atmosphere, is 21/2 times greater in the compound prepared according to the invention than that of 2-bromo-2- chlorine-l, l, l-trifluoroethane. On the other hand, the average concentration required to maintain the anesthesia in the second level of the third stage is the same for both compounds.

It follows that in the case of the prepared according to the invention Link a margin of 40 /, between concentration leading to the breath stopping and anesthetic concentration, on the other hand with the known compound only 10 /, leeway owns.

In addition, one achieves with the one produced according to the invention Connection has other advantages that cannot be reproduced in terms of numbers.

So 2-bromo-2-chloro-1,1,1-trifluoroethane leads under certain circumstances to strong Hypotension with cardiac arrest, when suddenly the patient is suddenly relatively high Concentrations administered. In contrast, there are those produced according to the invention Connection practically hardly any hypotension. Likewise, the use of the known harbors Compound the risk of cardiac arrhythmias, which in the inventively produced Connection does not occur. Muscle relaxation is generally required for surgical procedures necessary. It is well known that the muscles of the extremities and relax initially only last the muscles of the abdomen and chest. With the familiar connection this necessary muscle relaxation can only be achieved at depths of anesthesia where increased hypotension may occur. In contrast, the one produced according to the invention has Compound the very special advantage that sufficient muscle relaxation is achieved in humans as early as the first level of the third stage.

In the following example, the contents are given in parts of the room, if nothing else is done.

Example 142.8 g (0.5 mol) of paratoluenesulphonic acid ester are heated of 1-hydroxy -2,2,3,3-tetrafluoropropane with 59.5 g (0.5 mol) of potassium bromide and 150 milliliters of diethylene glycol for 2 hours with a temperature rise to 1900 C. Another 12 grams of potassium bromide is added added and keeps the reaction mass at about 190 ° C. for a further 6 hours. A total of 90 g of distillate are distilled from the reaction mass away. This is washed twice with water, dried over anhydrous magnesium sulfate, subjects the product to fractional distillation and passes it through columns of activated alumina. The 3-bromo-1,1,2,2-tetrafluoropropane thus obtained has a boiling point of 74 ° C at 760 mm Hg pressure, a density d20 of 1.81 and a refractive index n25 of 1.3558; the bromine content is 40.30 /, (calculated 41.01 0 /,).

Cleaning To establish the anesthetic connection, the Impurities reduced to less than 10 parts per million parts, determined by gas chromatography, by effective fractional distillation and passage by columns of activated by heating in an air oven at 200 "C for four hours Aluminum oxide.

Preparation of the p-toluenesulfonic acid ester of 1-hydroxy-2,2,3,3-tetrafluoropropane The compound is prepared according to the procedure of Thiers, J. Amer. chem. Soc., B. 75, p. 5978 (1953), using 1-hydroxy-2,2,3,3-tetrafluoropropane, obtained according to the procedure described in U.S. Patent 2,559,628 will. The physical properties and results of chemical analysis of the Product are as follows: F. 14 to 16 "C; boiling point 131" C at 3 mm Hg; nB = 1.4600.

Analysis (C ,, H ,, F, O, S).

Calculated. . . C 41.96, H 3.5, F 26.6, S found ... C41.9, H3.6, F26.0, S 11.00 / ,.

Claims (1)

PATENT CLAIM: Process for the production of inhalation anesthetic effective 3-bromo-l, l, 2,2-tetrafluoropropane, characterized in that the p-Toluenesulfonic acid ester of 1-hydroxy-2,2,3,3-tetrafluoropropane with potassium bromide implemented in a manner known per se.