Process for preparing CHF.sub.2 OCHFCF.sub.3 and CHF.sub.2 OCHClCF.sub.3 and novel intermediate compounds employed therein

Abstract

Process for preparing CHF.sub.2 OCHFCF.sub.3 through the use of novel intermediate compounds CHCl.sub.2 OCH.sub.2 COCl and CHCl.sub.2 OCHClCOCl.

Description

FIELD OF THE INVENTION

The present invention is directed to the field of inhalation anesthetics and particularly to methods of producing known volatile liquid inhalation anesthetics from inexpensive starting materials.

BACKGROUND OF THE INVENTION

Volatile liquid inhalation anesthetics are known in the art and include by way of example halothane, trichloroethylene, and halogenated ether derivatives including enflurane, fluroxene, methoxyflurane, isoflurane and 2-(difluoromethoxy)-1,1,1,2-tetra-fluoroethane.

The latter two inhalation anesthetics have received much attention because they provide a rapid rate of recovery and therefore are particularly suitable for administering to patients during outpatient surgery.

The most common method of preparing isoflurane (CHF.sub.2 OCHClCF.sub.3) is by the reaction of trifluoroethanol (CF.sub.3 CH.sub.2 OH) and chlorodifluoromethane (CF.sub.2 HCl) in the presence of an organic base to produce a compound of the formula CHF.sub.2 OCH.sub.2 CF.sub.3 which is then reacted with chlorine gas in the presence of light energy and optionally an organic solvent to thereby obtain isoflurane.

2-(difluoromethoxy)-1,1,1,2-tetrafluoroethane (hereinafter referred to as "CHF.sub.2 OCHFCF.sub.3 ") is most commonly produced by reacting isoflurane with a fluorinating agent such as BrF.sub.3. The production of CHF.sub.2 OCHFCF.sub.3 is largely dependent on the starting materials used to prepare isoflurane.

The starting material, trifluoroethanol, is both difficult to produce and expensive to obtain. Use of this starting material therefore significantly increases the cost of producing both isoflurane and CHF.sub.2 OCHFCF.sub.3.

It is therefore an object of the invention to provide methods of producing isoflurane and CHF.sub.2 OCHFCF.sub.3 from inexpensive starting materials.

It is a further object of the invention to employ novel intermediate compounds for the production of isoflurane and CHF.sub.2 OCHFCF.sub.3.

SUMMARY OF THE INVENTION

The present invention is generally directed to a process of preparing a compound of the formula CHF.sub.2 OCHFCF.sub.3 from the novel starting compound dichloromethoxy-.alpha.-chloroacetyl chloride (hereinafter referred to as "CHCl.sub.2 OCHClCOCl") and to a process in which both CHF.sub.2 OCHFCF.sub.3 and isoflurane (CHF.sub.2 OCHClCF.sub.3) are produced through the use of inexpensive starting materials and novel intermediates.

DETAILED DESCRIPTION OF THE INVENTION

The process of the present invention comprises reacting the novel compound CHCl.sub.2 OCHClCOCl with SF.sub.4 to produce the anesthetic CHF.sub.2 OCHFCF.sub.3. The reaction is conducted at elevated temperatures, preferably in the range of about 145.degree. to 155.degree. C. Isoflurane is also produced and can be converted by known methods into CHF.sub.2 OCHFCF.sub.3 or retained for use as an anesthetic.

CHCl.sub.2 OCHClCOCl may be prepared by reacting CH.sub.3 OCH.sub.2 COOH with a chlorinating agent such as SOCl.sub.2 or PCl.sub.5 to produce the corresponding acid chloride which in turn is reacted with chlorine gas in the presence of light energy either neat or in an organic solvent such as carbon tetrachloride, to produce CHCl.sub.2 OCH.sub.2 COCl as a first novel intermediate compound and CHCl.sub.2 OCHClCOCl as a second novel intermediate compound.

The yield of the first and second novel intermediates is temperature dependent. In general the reaction may be conducted at a temperature in the range of about -15.degree. C. to the boiling point of the solvent, or in the absence of a solvent, to about 50.degree. C.

An increased yield of the first novel intermediate is favored by lower temperatures in the above described temperature range, preferably about 0.degree. to 15.degree. C., most preferably about 10.degree. C. A higher yield of the first intermediate is desirable for the production of isoflurane (CHF.sub.2 OCHClCF.sub.3).

On the other hand, for the direct production of CHF.sub.2 OCHFCF.sub.3, increasing the yield of the second intermediate is desirable. Accordingly, the reaction of CH.sub.3 OCH.sub.2 COCl and chlorine gas in the presence of light energy is conducted at higher temperatures than 10.degree. C., preferably at least 20.degree. C.

The second intermediate compound may be reacted with SF.sub.4 at elevated temperatures in accordance with the invention to yield the desired compound CHF.sub.2 OCHFCF.sub.3.

The first intermediate compound may be reacted with SF.sub.4 at elevated temperatures to produce the isoflurane precursor CHF.sub.2 OCH.sub.2 CF.sub.3, which in turn is reacted with chlorine gas and light energy, optionally in the presence of an organic solvent, to yield isoflurane. The isoflurane thus produced may be converted to CHF.sub.2 OCHFCF.sub.3 by reaction with a fluorinating agent such as bromine trifluoride.

CHF.sub.2 OCHFCF.sub.3 is normally a clear, colorless, liquid having the following physical properties: boiling point 23.5.degree. C., molecular weight 168, estimated vapor pressure 660 mmHg at 20.degree. C., and a specific gravity of 1.44. IR shows a prominent peak at 4903 cm.sup.-1 and the .sup.1 H NMR shows a triplet at 6.5 ppm (J=70 Hz) and a doublet of quartets at 5.9 ppm (J.sub.gem =56 Hz, J.sub.vic =3 Hz). The compound is non-flammable, and stable to soda lime, rendering it particularly suitable as an inhalation anesthetic. Other characteristics and descriptions of CHF.sub.2 OCHFCF.sub.3 and anesthetic compositions containing the same are disclosed in U.S. Pat. No. 4,762,856, incorporated herein by reference.

EXAMPLE 1

Production of CHCl.sub.2 OCHClCOCl From Methoxy Acetyl Chloride

18.9 g of methoxy acetyl chloride (CH.sub.3 OCH.sub.2 COCl) and 200 ml of CCl.sub.4 were added to a 300 ml reactor fitted with an outer cooling jacket. The temperature of the reactor was maintained at -5.degree. to 5.degree. C. Chlorine gas was gradually added to the reactor through a gas dispersion tube at the rate of 0.002 liter/min (0.057 mg/min).

After approximately 16 hours, the chlorine gas flow was reduced to its lowest visual setting as evidenced by the presence of bubbles in the reaction solution and continued for 8 additional hours. The reaction mass was then warmed to room temperature and the CCl.sub.4 distilled off at ambient pressure. The resulting product (37.6 g) was transferred to a 50 ml flask and vacuum distilled to produce a fraction having the following characteristics:

bp.sub.52 mm =to 89.degree. C. (10.4 g) The .sup.1 H NMR showed a 7.4 ppm singlet for CHCl.sub.2 --O-- and a 4.6 ppm singlet for --O--CH.sub.2 COCl.

EXAMPLE 2

Production of CHCl.sub.2 OCH.sub.2 COCl From Methoxy Acetyl Chloride

20 g of methoxy acetyl chloride and 168 g of CCl.sub.4 were added to the same reactor described in Example 1. The temperature of the reactor was maintained at about 30.degree. C. Chlorine gas was gradually added to the reactor through a gas dispersion tube at approximately the same rate as described in Example 1 over approximately three hours.

The reaction mass was then allowed to warm to room temperature and the CCl.sub.4 was distilled off at ambient pressure. The resulting product was vacuum distilled to produce a fraction having the following characteristics:

bp.sub.(2.0-4.7 mm) =42.degree.-55.degree. C. (17.2 g) The .sup.1 H NMR showed a 7.7 ppm singlet for CHCl.sub.2 --O-- and a 5.9 ppm singlet for --O--CH.sub.2 COCl.

EXAMPLE 3

Reaction of CHCl.sub.2 OCHClCOCl with SF.sub.4

A stainless steel tube reactor containing 6.3 g (0.03 moles) of CHCl.sub.2 OCHClCOCl produced in Example 1 was cooled with liquid nitrogen and 13.3 g (0.06 moles) of SF.sub.4 was condensed into the stainless steel tube reactor. The reactor was warmed to room temperature and then heated to and maintained at a temperature of 145.degree.-155.degree. C. for 6 hours during which time the resulting pressure was from 600-650 psig.

The reactor was then cooled to room temperature and the resulting gaseous products were collected in a scrubber containing a 9% NaOH solution maintained at 10.degree. C. The reactor was then heated to 80.degree. C. and additional distillate collected in the NaOH scrubber. The scrubber was then heated to 100.degree. C. to yield an organic phase which was collected in a Dean-Stark trap cooled to 0.degree. C. Two cuts of 2.9 g and 0.5 g were collected in the trap. The cuts were analyzed by gas chromatography and found to have the following composition:

______________________________________Component Wt (g) Moles % Yield______________________________________CHF.sub.2 OCHFCF.sub.3 1.44 0.0086 29%isoflurane 1.47 0.0080 27%______________________________________

EXAMPLE 4

Reaction of CHCl.sub.2 OCH.sub.2 COCl With SF.sub.4

A stainless steel tube reactor containing 10.4 g (0.059 moles) of CHCl.sub.2 OCH.sub.2 COCl produced in Example 2 was cooled with liquid nitrogen and 14.6 g (0.07 moles) of SF.sub.4 was condensed into the tube reactor. The reactor was allowed to warm to room temperature and then gradually warmed to 132.degree. C. over the course of 21/2 hours. The pressure in the reactor increased from 95 to 505 psig.

Thereafter the temperature of the reactor was gradually raised to between 143.degree. to 163.degree. C. for about 1 hour causing the pressure in the reactor to increase to between 585 to 645 psi. The reactor was then maintained at a temperature between 145.degree. to 155.degree. C. for about 4 hours at an autogenous pressure of between 595 to 605 psig.

The reactor was then cooled to room temperature and the resulting gases were vented into a scrubber containing a solution of 50 g of 50% NaOH in 320 g of water at a temperature of -10.degree. C.

The resulting organic layer (8.7 g) was separated from the aqueous phase. Gas chromatography showed a retention time (3.97 min) similar to that of CF.sub.3 CH.sub.2 OCHF.sub.2. The product was separately tested in a mass spectrophotometer and .sup.1 H NMR and the above structure was confirmed. The yield of the product was 69%. The resulting product can be readily converted to isoflurane (CHF.sub.2 OCHClCF.sub.3) by reaction with chlorine gas in the presence of light energy.

Claims

1. A process for preparing a compound of the formula CHF.sub.2 OCHFCF.sub.3 comprising reacting a compound having the formula CHCl.sub.2 OCHClCOCl with SF.sub.4 at an elevated temperature.

2. The process of claim 1 wherein the reaction temperature is from about 145.degree. to 155.degree. C.

3. The process of claim 1 further comprising:

(a) reacting a compound having the formula CH.sub.3 OCH.sub.2 COCl in the presence of chlorine gas and light energy and in the presence or absence of an organic solvent at a temperature in the range of from about -15.degree. C. up to the boiling point of the solvent or, if no solvent is present, up to about 50.degree. C. to thereby produce a compound having the formula CHCl.sub.2 OCH.sub.2 COCl and a compound having the formula CHCl.sub.2 OCHClCOCl;

(b) reacting the compound CHCl.sub.2 OCHClCOCl with SF.sub.4 at an elevated temperature to produce a compound having the formula CHF.sub.2 OCHClCF.sub.3 and said compound CHF.sub.2 OCHFCF.sub.3 ; and

(c) separating said compound CHF.sub.2 OCHFCF.sub.3 from said compound CHF.sub.2 OCHClCF.sub.3.

4. The process of claim 3 further comprising reacting said compound CHF.sub.2 OCHClCF.sub.3 with a fluorinating agent to produce said compound CHF.sub.2 OCHFCF.sub.3.

5. The process of claim 3 wherein step (a) is conducted at a temperature from about 0.degree. to 15.degree. C. to thereby favor the formation of said compound CHCl.sub.2 OCH.sub.2 COCl.

6. The process of claim 5 wherein step (a) is conducted at a temperature of about 10.degree. C.

7. The process of claim 3 wherein step (a) is conducted at a temperature of at least 20.degree. C. to thereby favor the formation of said compound CHCl.sub.2 OCHClCOCl.

8. The process of claim 3 further comprising reacting the compound CHCl.sub.2 OCH.sub.2 COCl with SF.sub.4 to produce a compound having the formula CHF.sub.2 OCH.sub.2 CF.sub.3 and reacting said compound CHF.sub.2 OCH.sub.2 CF.sub.3 with chlorine gas in the presence of light energy to produce said compound CHF.sub.2 OCHClCF.sub.3.

9. The process of claim 8 further comprising reacting the compound CHCl.sub.2 OCH.sub.2 COCl with SF.sub.4 at approximately the temperature of liquid nitrogen, allowing the reactants to gradually warm to room temperature, gradually heating the reactants to a temperature of from about 143.degree. to 163.degree. C., maintaining the reactants at a temperature of from about 145.degree. to 155.degree. C., allowing the reactants to cool to room temperature, and separating the compound CHF.sub.2 OCH.sub.2 CF.sub.3 from the other reaction products.