CS277222B6 - Process for preparing buprenorphine - Google Patents

Abstract

Buprenorphine is a known high compound analgesic activity. Preparing new from 7α-2-hydroxy-3,3-dimethyl-2-butyl 6,14-endo- etheno- 6,7,8,14- tetrahydrothebaine at 6 degrees, successive by treatment with cyanogen bromide, alkali hydroxide, cyclopropylcarbonyl chloride, complex hydride, again alkali hydroxide, and finally hydrogen on the catalyst.

Description

The invention relates to a process for the preparation of buprenorphine, a compound of formula I

AND,

The compound of formula I is known and is used as a potent analgesic.

The following processes for the preparation of the compound of formula I are known from the literature, which are mostly protected by patents:

According to British patents (Bentley KW Brit, patent 1,136214, Brit, patent 902 659, Brit, patent 925 723, Brit, patent 937 214, Brit, patent 969 263 (thebaine is condensed with methyl vinyl ketone, the resulting product is catalytically hydrogenated to give The resulting alcohol is demethylated on a nitrogen atom, converted to the corresponding N-methylcyclopropylamine, which is finally O-demethylated.

The second process for the preparation of the compound of formula I according to the Indian patent (Indian IN 156 632) is again based on thebaine to which acrolein is added. The resulting aldehyde is reacted with methylmafnesium halide and the corresponding alcohol is oxidized to thevinone, which is again hydrogenated to a ketone identical to the above procedure.

The Chinese authors published (Shanghai Yike Daxue Xuebao 1986, 13 (4) 301-3) the preparation of buprenorphine from thebaine in four steps in high yield.

The essence of the process according to the invention lies in the fact that the compound of formula II.

is reacted with methylene chloride or the cyano derivative obtained with cyanogen bromide in a chlorinated hydrocarbon such as chloroform at temperatures between 0 ° C and 30 ° C, of formula III

III, is hydrolysed by the action of an alkali hydroxide, for example sodium or potassium hydroxide, in a multifunctional alcohol such as diethylene glycol in the temperature range of 150 to 180 ° C, the prepared base of formula IV

is converted by reaction with cyclopropylcarbonyl chloride in the presence of a tertiary amine such as triethylamine in a chlorinated aliphatic hydrocarbon, for example methylene chloride or chloroform, at a temperature in the range of 0 ° C to 25 ° C to an amide of formula V

which is reduced with a complex hydride in an organic solvent such as benzene, toluene, ether, tetrahydrofuran, the obtained compound of formula VI

VI, is then cleaved with an alkaline hydroxide, such as sodium or potassium hydroxide, in diethylene glycol at temperatures between 200 and 250 ° C to give the phenol of formula VII.

VII, which is finally reduced with hydrogen over a catalyst such as palladium on carbon or platinum in an inert solvent such as tetrahydrofuran, ethanol, or ethyl acetate.

The substances of formulas III and VII are new substances.

The advantage of the above process is the increase in the total production yield while reducing the production costs.

Due to the presence of an isolated double bond, the intermediates of formulas V and VI are more stable and, in addition, crystalline and are therefore more suitable for handling.

The following examples illustrate the possibility of preparing the above substances.

Example 1 a) N-cyano derivative (compound of formula III)

To 4 g of the alcohol of formula II in 10 ml of dried methylene chloride was added 1.4 g of cyanogen bromide in 6.8 ml of methyl chloride at room temperature. The resulting solution was stirred at room temperature for 8 hours. The solution then stood at the same temperature for 16 hours. After this time, the solution was evaporated on a rotary evaporator. The residue was crystallized from ethyl alcohol to give 3.8 g (92.5%) of white crystals of m.p. = 254 ° C to 258 ° C.

b) Base (compound of formula IV)

3.47 g of potassium hydroxide was dissolved in 42 ml of diethylene glycol under inert and at 100 ° C. To this solution was then added the N-cyano derivative of formula III (3 g). The reaction mixture was then heated to 170-175 ° C for 2.5 hours. After cooling to room temperature, the reaction mixture was poured into 300 ml of distilled water. The precipitate formed was filtered off with suction and air-dried. 2.48 (88%) of off-gray crystals of m.p. = 186 to 190 ° C, which were used in the next step without further purification.

c) N-cycloproovlamide (compound of formula V)

To a solution of 2.1 g of the compound of formula IV and 2.2 ml of triethylamine in 15 ml of dried methylene chloride was added dropwise 1.54 g of cyclopropylcarbonyl chloride in 12 ml of drying at 5 ° C over 45 minutes.

CS 277222 B6 4 methylene chloride. The resulting solution was warmed to room temperature and stirred for 6 hours. He stood at the same temperature for another 18 hours. It was then diluted to a volume of 60 ml with methylene chloride and extracted twice with distilled water, 3x with 6% hydrochloric acid, 3x with 25% potash, 1x with water, 1x with saturated sodium chloride solution. The organic layer was dried over sodium sulfate and evaporated to dryness on a rotary evaporator. 2.4 g of an oil (97.5%) are thus obtained, which crystallizes on standing, m.p. = 196-202 ° C. The product was chromatographically uniform and was used in the next reaction step without further purification.

d) N-cyclopropylmethylamine (compound of formula VI)

A solution of synhydride in toluene (6.95 g of a 78% solution of synhydride in toluene was diluted with 20 ml of toluene) was added dropwise to a solution of 2.4 g of the amide of formula V in 100 ml of sodium-dried toluene at room temperature. The resulting solution was then heated to 70-75 ° C for 6 hours. After this time, it was cooled to 5 DEG C. and the reaction mixture was carefully quenched with 15 ml of water, then a further 60 ml of 15% sodium hydroxide solution was added dropwise to this solution. The organic layer was separated and extracted with distilled water and saturated brine. The organic portion was dried over sodium sulfate and evaporated in vacuo. 2.21 g of an oil (95%) were obtained, which crystallized on standing, m.p. · = 145 to 153 ° C. The product was chromatographically uniform and was used in the next reaction step without further purification.

e) Phenol (compound of formula VII)

To 1.2 g of the amide of formula VI was added a solution of 3.6 g of potassium hydroxide in 15 ml of diethylene glycol under an inert solution. The mixture was heated to reflux at 220 ° C for 2.5 hours. The resulting solution was cooled to room temperature and poured into 25 ml of distilled water. To this solution was added 2.5 g of solid ammonium chloride with stirring. The resulting precipitate, which was filtered off with suction and air-dried, was dissolved in 20 ml of methylene chloride. The insoluble matter was filtered off. The filtrate was concentrated in vacuo and chromatographed on silica gel. After chromatography, a crystalline residue was obtained, which was crystallized from methanol. The desired product was obtained as white crystals of m.p. - 238-240 ° C, (0.29 g).

f) Buoranorphine (compound of formula 1)

0.207 g of the phenol of formula VII was dissolved in 20 ml of tetrahydrofuran. To the solution was added 300 mg of 5% palladium on carbon catalyst, and the mixture was hydrogenated at atmospheric pressure and room temperature until hydrogen consumption ceased. Then the catalyst was filtered off, the solution was concentrated on a vacuum rotary evaporator. The residue was crystallized from methanol to give 0.140 g of the desired product (67.6%) as white crystals of m.p. = 217 ° C to 220 ° C.

Example 2 a /

The reaction was carried out as in Example 1a. Dried chloroform was used as a solvent. The resulting solution was stirred at 0 ° C to 5 ° C for 8 hours. He then stood at this temperature for another 18 hours. After working up the reaction mixture and crystallizing, the desired product was obtained in 86.3% yield.

b /

The reaction was carried out analogously to Example 1b. Sodium hydroxide was used instead of potassium hydroxide. The reaction mixture was heated to 150 ° C to 155 ° C for 3.5 hours. After working up the reaction mixture, 78% of the desired product was obtained, which was also chromatographically uniform.

C/

The reaction was similar to Example 1c, except that the reaction was performed in chloroform and at 0 ° C to 5 ° C. The reaction time was increased to 52 hours. After decomposition of the reaction mixture, 86% of the desired product was obtained, which was also chromatographically uniform.

d /

The reduction according to Example Id was performed with lithium aluminum hydride in tetrahydrofuran at 5 ° C for 48 hours. After decomposition of the reaction mixture, 75% of the product was obtained as a viscous oil which was not chromatographically uniform.

E e / ’

The cleavage was performed as described in Example 1e, using sodium hydroxide instead of potassium hydroxide. The temperature and time were observed as in the first case. After chromatography, the yield dropped to 10%.

F/

The final reduction was again performed with hydrogen at atmospheric pressure as in Example If. However, platinum was used as a catalyst and ethyl acetate as the solvent. The result of the reaction was comparable to the first example.

Claims (1)

PATENT CLAIMS Process for the preparation of buprenorphine of formula I HIM- the cr (i), OH, characterized in that the compound of formula II OH (ii), is reacted with cyanogen bromide in a chlorinated hydrocarbon such as methylene chloride or chloroform at a temperature in the range of 0 ° C to 30 ° C, the N-cyano derivative of formula III obtained (III), is hydrolysed by the action of an alkali hydroxide, for example sodium hydroxide or diethylene glycol, in a base of formula IV potassium in a multifunctional alcohol such as a temperature range of 150 ° C to 180 ° C, prepared (IV) is converted by reaction with cyclopropylcarbonyl chloride in the presence of a tertiary amine, for example triethylamine, in a chlorinated hydrocarbon medium such as methyl chloride or chloroform, at a temperature in the range 0 ° C to 25 ° C, to an amide of formula V which is reduced with a complex hydride in an organic solvent such as benzene, toluene, ether, tetrahydrofuran, the obtained amine of formula VI ' then cleaved with an alkaline hydroxide, such as sodium or potassium hydroxide, in diethylene glycol, at a temperature in the range of 200 ° C to 220 ° C to give the phenol of formula VII (VII), which is finally reduced with hydrogen over a catalyst such as palladium on carbon or platinum in an inert organic solvent such as tetrahydrofuran, ethanol, or ethyl acetate.