CS266942B1 - Process for the preparation of N-ethoxycarbonylorkodeinone - Google Patents

Abstract

The solution relates to the production of N-ethoxycarbonylnorcodeinone by oxidation of N-ethoxycarbonylnorcodeinone with alkali metal or ammonium dichromate in a two-phase system of immiscible liquids in the presence of phase transfer catalysts, which are tetrasubstituted ammonium salts, where one substituent can be an alkyl with 4 to 18 carbon atoms, or benzyl or phenyl, the remaining substituents are alkyls with 1 to 4 carbon atoms and the anion can be a fluorine atom, a hydrogen sulfate group or a methanesulfonyloxy group, preferably tetrabutylammonium hydrogen sulfate. The reaction is carried out in an organic phase-aqueous phase system, where the organic phase is formed by chlorinated alkanes with 1 or 2 carbon atoms and 1 to 4 chlorine atoms, e.g. dichloromethane, 1,2-dichloroethane or chloroform or lower aromatic hydrocarbons e.g. benzene or toluene and the aqueous phase is formed by 10 to 35 wt. sulfuric acid. The oxidation is carried out in the range of 0 to 40 °C with stirring. The reaction proceeds rapidly and in good yields. Without phase transfer catalysts, the product is obtained under the same conditions in a yield of only 8% in 24 hours.

Description

oxidation of N-ethoxycarbonylnorcodeine of formula II,

an alkali metal or ammonium dichromate in the presence of phase transfer catalysts which are tetrasubstituted ammonium salts of formula III,

R r_N - R ¹ (III)

R wherein R is alkyl of 1 to 4 carbon atoms, R ¹ is alkyl of 1 to 18 carbon atoms, benzyl or phenyl and X is fluorine, bisulfate or methanesulfonyloxy, preferably tetrabutylammonium bisulfate.

The compound of formula I is an important intermediate in the partial syntheses of a number of pharmaceutically valuable substances, especially potent analgesics or morphine narcotics antagonists with morphinan structure such as butorphanol, naloxone or naltrexone, starting from natural alkaloids of the morphinan family such as codeine, thebaine or morphine. .

Previously, the oxidation of an allyl-type secondary hydroxyl group in the starting material of formula II was performed with active manganese dioxide in chloroform (e.g., Schwartz MA, Wallace RA: J. Med. Chem. 24, 1565 [1981], or Rice KC, May EL: J Heterocycl. Chem. 14, 665 [1977]). However, carrying out this oxidation process on a large scale encounters considerable difficulties, on the one hand, due to the need to work with a large amount of oxidizing agent and with a solid heterophase,

CS 266 942 B1 on the one hand with considerable volumes of solvent. In another method of oxidation with Jones reagent (Lawson J. A., DeGraw J. I., Anbar M .: J. Heterocycl. Chem. 13, 593 [1976]) it is necessary to chromatograph the crude reaction mixture on a large amount of silica gel. In addition, reproducing this procedure found that the product partially decomposed on the column and yields fell below 65%.

These disadvantages are eliminated by a method of producing N-ethoxykarbonylnorkodeinonu formula I by oxidation of N-ethoxykarbonylnorkodeinu formula II according to the invention whose principle consists in that the oxidation is carried dichromate alkali metal or ammonium, in the presence of tetrasubstituted ammonium salts of formula III wherein R, R ¹ and X mean the same as previously stated, in a system of two immiscible liquids organic phase - aqueous phase, where organic phase means lower chlorinated alkanes with 1 or 2 carbon atoms and 1 to 4 chlorine atoms, eg dichloromethane, 1,2-dichloroethane or chloroform or lower aromatic hydrocarbons, e.g. benzene or toluene, and the aqueous phase means 10 to 35% by weight, sulfuric acid, with the addition of phase transfer catalysts in an amount of 10 to 30 mol%. The reaction is carried out at temperatures in the range of 0 to 40 ° C, preferably at room temperature and does not require any special equipment other than vigorous stirring. However, the oxidation is strictly conditioned by the presence of phase transfer catalysts. Indeed, it has been found experimentally that without the addition of these catalysts the reaction proceeds almost (only 8% of the oxidation product of formula I is formed in 24 hours), while yields above 80% are obtained in 15 to 60 minutes, allowing the process according to the invention to be carried out. easily and economically even on a technical scale. The details and advantages of the method according to the invention result from exemplary embodiments which illustrate but do not limit it.

Example 1

To a solution of 44.7 g (0.126 mol) of N-ethoxycarbonylnorcodeine in 450 ml of 1,2-dichloroethane was added a solution of 16.67 g (0.056 mol) of crystalline sodium dichromate and 15 g (0.044 mol) of tetra-n-butylammonium bisulfate in 850 ml of 20% sulfuric acid and the mixture was stirred vigorously at room temperature for 30 minutes. After completion of the reaction, the organic phase is separated off and the aqueous phase is shaken three times with 100 ml of 1,2-dichloroethane each time. The combined organic portions are extracted twice with 100 ml of water, once with 100 ml of 10% sodium bicarbonate solution, three times with 100 ml of water each time, dried over anhydrous sodium sulfate and the 1,2-dichloroethane is distilled off in vacuo. The residue is dissolved in 100 ml of benzene and filtered through a column of 150 g of silica gel using 1500 ml of benzene as eluent. After distilling off the benzene in vacuo, 39.2 g (88%) of n-ethoxycarbonylnorcodeinone are obtained in the form of a foam. The product is chromatographically uniform by thin layer chromatography on silica gel GF ₂₅ 4 in a toluene-acetone-ethanol-conc. ammonia 50:50:

CS 266 942 Bl

7.5: 2.5 (detection in ultraviolet radiation at 254 nm and then with Dragendorff's reagent).

Example 2

To a solution of 35.7 g (0.1 mol) of N-ethoxycarbonylnorcodeine in 460 ml of benzene was added a solution of 12.6 g (0.05 mol) of ammonium dichromate and 5.6 g (0.02 mol) of benzyltriethylammonium methanesulfonate in 700 ml. 15% sulfuric acid and the mixture was stirred vigorously for 60 minutes at 30 ° C. The progress of the oxidation was monitored by thin layer chromatography. After completion of the reaction, the two phases were separated, the aqueous phase was shaken three times with 80 ml of benzene, the benzene extracts were combined and attached to a separate benzene layer; The benzene fractions were shaken twice with 80 ml of water, once with 80 ml of saturated sodium bicarbonate solution and three times with 80 ml of water and dried over anhydrous sodium sulfate. Elution was performed with 1200 ml of benzene. After distilling off the benzene in vacuo to give 30.17 g (85%) of N-ethoxykarbonylnorkodeinonu as a foam, which was by thin layer chromatography on silica gel GF ₂₅ 4 uniform in the system toluene-acetone-ethanol terminus. ammonia 50: 50: 7.5; 2.5 (detection in ultraviolet light at 254 nm and then with Dragendorff's reagent).

Claims (2)

OBJECT OF THE INVENTION A process for the preparation of N-ethoxycarbonylnorcodeinone of formula I, oxidation of N-ethoxycarbonylnorcodeine of formula Π, characterized in that the compound of formula II is oxidized with an alkali metal or ammonium dichromate, preferably sodium dichromate in an acidic medium in a system of two immiscible liquids in the presence of phase transfer catalysts which are tetrasubstituted ammonium salts of formula III, R R — N ⁺ - R ¹ AND R (III) in which R represents lower alkyl having 1 to 4 carbon atoms, R ¹ is alkyl having 4 to 18 carbon atoms, benzyl or phenyl and X represents a fluorine atom, a bisulfate group or methanesulfonyloxy group, preferably tetrabutylammonium bisulfate, at a temperature of 0 up to 40 ° C with stirring. 2. The process according to claim 1, characterized in that the two-phase system of immiscible liquids consists of an organic phase, which means lower chlorinated alkanes having 1 or 2 carbon atoms and 1 to 4 chlorine atoms, e.g. dichloromethane, 1,2-dichloroethane or chloroform, or lower aromatic hydrocarbons, for example benzene or toluene, on the one hand, by the aqueous phase, which means 10 to 35% by weight, sulfuric acid.