CZ279819B6 - Process for preparing 3,14 beta-dihydroxy-17-cycloa lkyl methylmorphinans - Google Patents

Abstract

A process for preparing 3,14 beta-dihydroxy-17-cycloalkyl methylmorphinan of general formula I, above all Butorphanol, which is an effective analgesic. Synthesis includes single-stage alkylation of 3,14β-dihydroxy morphinan or 14β-hydroxy-3-methoxy morphinan by the relevant cycloalkyl methyl halogenide or acylation by cycloalkane carbonyl halogenide with subsequent reduction of the carbonyl group by the action of complex hydrides and possible cleavage of the essential functional group by the action of a complex aluminium halogenide - dialkyl sulphate.<IMAGE>

Description

Technical field

The present invention relates to a process for the preparation of 3,14β-dihydroxy-17-cycloalkylmethylmorphinans of the general formula I

wherein R is cyclopropyl or cyclobutyl. These compounds are potent analgesics which are believed to be non-addictive and have an antagonistic morphine effect.

BACKGROUND OF THE INVENTION

Compounds of Formula I ZOU (US Pat. No. 3,819,635), thebaine alkaloid (Moural J., c. Farm. 1, 32, 23 (1983)).

were prepared by total synthesis or semi - synthesis from natural Hájíček J. and Trojánek J .: Czech Known Synthesis (US Pat.

139,534 and US Pat. No. 14 is based on 14β-hydroxy-3-methoxy-

819,635, U.S. Pat. file no.

058 531) in its final phase

(II)

NH which is reacted with a cycloalkanecarboxylic acid chloride or anhydride of formula III

RCOOH (III) wherein R is the same as formula I. The obtained intermediate of formula IV

-1GB 279608 B6

COR (IV) is reduced by complex hydrides to the product of formula (V)

N- CH, R (A)

This is isolated from the reaction mixture in the form of a base or a salt with an inorganic or organic acid. Finally, cleavage of the ether functional group of formula (V) with hydrobromic acid, boron bromide, pyridine hydrochloride or NaSC ₂ H ₅ to give a compound of formula (I) or a pharmaceutically acceptable acid salt thereof.

SUMMARY OF THE INVENTION

The aim of our work was to find a viable and economically advantageous way of synthesis of the semisynthetic morphinated alkaloid Butorphanol (I, R = cyclobutyl), ie 3,148β-dihydroxy-17-cyclobutylmethylmorphinan. The proposed procedure solves the task in three modifications. A process for the preparation of 3,14β-dihydroxy-17-cycloalkylmethylmorphinates of formula (I)

_N-CH2 R (I)

Wherein R denotes cyclopropyl or cyclobutyl, characterized in that the compound of formula VI

(VI) wherein R 1 is hydrogen or methyl, alkylates a cycloalkylmethyl halide or acylates a three or four carbon ring cycloalkanecarbonyl halide,

a) in the case of alkylation, when R 1 is hydrogen, a compound of formula I is formed,

b) in the case of alkylation, when R _p is methyl, the resulting intermediate of formula V is formed

N- CH, R (V) wherein R is as defined above, demethylates by treatment with an aluminum halide-dialkylsulfide complex to form a compound of formula (I),

c) when acylated with a cycloalkane halide, a compound of formula VII is formed

N- COR where R and R _p are as defined above, (VII)

Which is reduced by the action of complex hydrides when R _x is hydrogen to form a compound of formula I, and when v _χ is methyl, the resulting intermediate of formula V

wherein R is as defined above, demethylates by treatment with an aluminum halide-dialkyl sulfide complex to give the desired compound of formula (I).

The indisputable advantage of alkylation is the reduction in the number of reaction steps while increasing the yield in both cases described (R 1 is hydrogen or methyl). However, in the case of the more difficult availability of a cycloalkylmethyl halide, acylation is also an operationally convenient and economically advantageous method of preparation.

The advantage of this process over the known synthesis (U.S. Pat. No. 3,819,635, U.S. Pat. No. 4,139,534 and U.S. Pat. No. 4,058,531) is also the use of a non-toxic and substantially cheaper O-demethylating agent (especially then at the last or one of the final stages of the synthesis of the pharmacologically active substance), while achieving at least the same yield as the prior art / using bortribromide, or achieving significantly higher yields compared to using hydrobromic acid, pyridine hydrochloride and NaSC ₂ H ₅ . Easier and safer handling of the complex (in this case aluminum chloride-dimethylsulfide) is also important for larger scale operations than with boron bromide, which has so far been the only reagent to provide satisfactory yields.

In the process for the preparation of the 3,14β-dihydroxy-17-cycloalkylmethylmorphinates according to the invention, in the first step the starting compound of formula VI is alkylated with a cycloalkylmethyl halide or acylated with a cycloalkanecarboxylic acid halide in an inert organic solvent. In the case of acylation, the carbonyl group is reduced with complex hydrides. In the case where R _x in formula VI is methyl, demethylation of the resulting compound of formula V by aluminum halide-dialkylsulfide complex at -30 ° C in anhydrous inert organic solvents, preferably the AlCl ₃ -dimethylsulfide complex in dichloromethane or toluene, may follow room temperature.

The details of the production method according to the invention follow from the following examples.

-4GB 279608 B6

DETAILED DESCRIPTION OF THE INVENTION

Example 1 (-) - 17-Cyclobutylmethyl-14β-hydroxy-3-methoxymorphinan (V, R = cyclobutyl)

To 1.0 g (3.7 mmol) of (-) - 14β-hydroxy-3-methoxymorphinan II in 25 mL of dry dimethylformamide and in the presence of 0.5 g (6 mmol) of crushed and dried sodium bicarbonate was stirred and under a nitrogen atmosphere. 1.08 g (44 mmol) of cyclobutylmethyl bromide was added The reaction mixture was stirred at 90-95 ° C for 5 hours The bicarbonate was filtered off and the filtrate was then added dropwise with stirring to 600 ml of distilled water. After drying with sodium sulfate, the chloroform solution was concentrated to a pale yellow oily product ((V), R = cyclobutyl) (1.1 g; i.e., 88%) to give crystalline hydrochloride, m.p.

Example 2 (-) - 17-Cyclobutanecarbonyl-143-hydroxy-3-methoxymorphinan (VII,

R = cyclobutyl, R (methyl),

To 5.0 g (18 mmol) of (-) - 140-hydroxy-3-methoxymorphinan (II) dissolved in 60 ml of dichloromethane was added 2.6 g (26 mmol) of triethylamine. At 0-5 ° C, a solution of 2.5 g (21 mmol) of cyclobutanecarbonyl chloride in 10 mL of dichloromethane was added dropwise over 30 minutes. After one hour reaction at 10 ^e C, the reaction mixture was successively shaken with water, 6% aqueous HC1, 25% aqueous K ₂ CO ₃ · ^ θΡ® ^and water. The organic phase was dried over sodium sulfate and the dichloromethane was distilled off. 6.1 g (i.e. 94%) of an oily product were obtained, which on standing gave a crystalline substance with a melting point of 140 ° C.

Example 3 (-) - 17-Cyclobutyl-14β-hydroxy-3-methoxymorphinan (V, R = cyclobutyl)

To 1.0 g (26 mmol) of LiAlH ₄ in a dry nitrogen-filled flask was first added dropwise 10 ml of dry tetrahydrofuran, followed by a solution of 6.0 g of (-) - 17 'cyclobutanecarbonyl' 14β-hydroxy-3 'methoxymorphinan ( 18 mmol) ((VII), R = cyclobutyl, R (4-methyl)) dissolved in 30 mL of tetrahydrofuran. The reaction mixture refluxed during the dropwise addition. Excess LiAlH ₄ was quenched by dropwise addition of 10 mL of tetrahydrofuran, undiluted with 1 mL of water under nitrogen. The resulting precipitate was filtered off with suction, washed with dichloromethane and then the dichloromethane layer was concentrated to a residue (5.7 g). The residue was chromatographed on ten times silica gel and crystallized from ethanol. The yield was

4.6 g (i.e. 80%).

-5GB 279608 B6

Example 4 (-) - 17-Cyclobutylmethyl-3,14β-dihydroxymorphinan (I, R = cyclobutyl)

To 1.0 g (39 mmol) of (-) - 3,14P-dihydroxymorphinan (VI, where R 1 is hydrogen) in 25 ml of dry dimethylformamide and in the presence of 0.5 g (6 mmol) of triturated and dried sodium bicarbonate, 0.96 g (3.9 mmol) of cyclobutylmethyl bromide was added under stirring and under nitrogen. The reaction mixture was stirred at 90-95 ° C for 5 hours. The bicarbonate was filtered off and the filtrate was added dropwise to 600 ml of distilled water with stirring. The resulting precipitate was extracted (3 x 100 mL) with chloroform. After drying over sodium sulfate, the chloroform solution was evaporated to dryness in vacuo. After crystallization of the crude product from acetone, 0.7 g (88.5%) of compound I is obtained, wherein R is cyclobutyl. Melting point 222 ° C.

Example 5 (-) - 17-cyclobutylmethyl-3,14β-dihydroxymorphinan (I, R = cyclobutyl)

15.6 g (0.117 mol) of aluminum chloride was dissolved in 100 ml of dichloromethane and 54.2 ml (0.741 mol) of dimethylsulfide. To this mixture was added dropwise a solution of 4.0 g (11.7 mmol) of (-) - 17-cyclobutylmethyl-14β-hydroxy-3-methoxymorphinan (V, R = cyclobutyl) in 80 ml at room temperature over 1 hour. of dichloromethane. After the dropwise addition, the reaction mixture was stirred at room temperature for 1 hour and then a solution of 18.1 g (0.12 mol) of tartaric acid in 150 ml of distilled water was added dropwise with cooling. The resulting phases were separated and the aqueous phase was basified with aqueous ammonia to pH 8.5 with cooling. The resulting light gray precipitate was then extracted (3 x 150 mL) with chloroform and, after drying over sodium sulfate, evaporated to dryness in vacuo. Crystallization of the crude product from acetone gave 3.25 g (85%) of (I, R = cyclobutyl). Melting point 222 ° C.

Industrial applicability

The invention is useful in the pharmaceutical industry in the manufacture of the substance Butorphanol. This substance is widely used as an effective analgesic, which is believed to be non-addictive as well as antagonistic to the morphine effect.

Claims (1)

PATENT CLAIMS A process for the preparation of 3,14β-dihydroxy-17-cycloalkylmethylmorphinates of formula I (I) wherein R is cyclopropyl or cyclobutyl, characterized in that the compound of formula VI R, O (VI) wherein R 1 is hydrogen or methyl, alkylates with a cycloalkylmethyl halide or acylates a cycloalkanecarbonyl halide with three or four carbon atoms in each ring, a) in the case of alkylation, when R1 is hydrogen, a compound of formula I is formed, b) in the case of alkylation, when R1 is methyl, the resulting intermediate of formula V (V) formed Wherein R is as defined above, demethylates by treatment with an aluminum halide-dialkylsulfide complex to form a compound of formula (I), c) when acylated with a cycloalkanecarbonyl halide, a compound of formula VII (VII) is formed wherein R and Rj are as defined above, which is reduced by treatment with complex hydrides when R 1 is hydrogen to form a compound of formula I, d) when Rj. is methyl, the resulting intermediate of formula (V) is formed N- C1-4 R (V) wherein R is as defined above, -methylated by treatment with an aluminum halide-dialkyl sulfide complex to form a compound of formula I.