SK13394A3 - Method of preparation of 3,14 beta-dihydroxy-17- -cycloalkylmethylmorphinans - 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

SUMMARY OF THE INVENTION

The aim of the work was to find a viable and economically advantageous way of synthesis of the semisynthetic morphinan alkaloid Butorphanol ((I), R = cyclobutyl), ie. 3,14p-dihydroxy-17-cyclo-butylmetylmorfínanu). The proposed procedure solves the problem in three modifications. Process for the preparation of 3,14β-dihydroxy-17-cycloalkylmethylmorphinans of general formula (I)

(I) wherein R is cyclopropyl or cyclobutyl, characterized in that the compound of formula (VI)

(VI) wherein R R is hydrogen or methyl, alkylates with a cycloalkylmethyl halide or acylates a cycloalkanecarbonyl halide with three or four carbon atoms in each cycle,

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

b) in the case of alkylation, when R 1 is methyl, the resulting intermediate of formula (V) is 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 cycloalkane halide, a compound of formula (VII) is formed

where R and R 1 is as defined above, which is reduced by the action of complex hydrides when R1 is hydrogen to form a compound of formula (I), and when R prípade is methyl, the resulting intermediate of formula (V) is formed

(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 (R1 is hydrogen or methyl). However, in the case of a more difficult availability of a cycloalkylmethyl halide, acylation is also an operationally convenient and economically advantageous preparation method.

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 that such a non-toxic and substantially cheaper O-demethylating agent is used (especially in or at least one of the final steps of the synthesis of a pharmacologically active substance), while achieving at least the same yield as the hitherto known synthesis using borontribromide, or achieving significantly higher yields compared to the action of hydrobromic acid, pyridine hydrochloride and NaSC2H4. Also easier and safer to handle the complex (in this case aluminum chloride-dimethylsulfide) than to borontribromide, which has so far provided only satisfactory yields, is also important for larger scale operations.

In carrying out the process for the preparation of the 3,14β-dihydroxy-17-cycloalkylmethylmorphinans according to the invention, in the first step the 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.

When R R in formula (VI) is methyl, the resulting compound of formula (V) may be demethylated by an aluminum halide-dialkyl sulfide complex at 0-30 ° C in anhydrous inert organic solvents, preferably AlCl ,- dimethylsulfide in dichloromethane or toluene at room temperature.

The details of the preparation process according to the invention follow from the following examples.

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 were stirred and under 1.08 g (44 mmol) of cyclobutylmethyl bromide was added under nitrogen atmosphere. The reaction mixture was stirred at 90-95 ° C for 5 hours. The bicarbonate was filtered off and the filtrate was then added dropwise to 600 ml of distilled water with stirring. The white precipitate formed was extracted (3 x 100 mL) with chloroform. After drying with sodium sulfate, the chloroform solution was concentrated to a pale yellow oil ((V), δ = cyclobutyl) (1.1 g, i.e., 88%) to give crystalline hydrochloride. The hydrochloride melts at 132 ° C.

Example 2:

(-) - 17-Cyclobutanecarbonyl-14β-hydroxy-3-methoxymorphinan ((VII), R = cyclobutyl, R 6 = methyl)

To 5.0 g (18 mmol) of (-) - 14β-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 reaction for 1 hour at 10 ° C, the reaction mixture was successively shaken with water, 6% aqueous HCl, 25% aqueous K 2 CO 3 and again with 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 1:

(-) - 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 and then a solution of 6.0 g of (-) - 17-cyclobutanecarbonyl-14β-hydroxy-3-methoxymorphinan (18 mmol). ((VII), R = cyclobutyl), R (= 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 diluted with 1 mL of water under nitrogen. The 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 (t-80%).

Example 4:

(-) - 17-Cyclobutylimethyl-3,14β-dihydroxymorphinan ((I),

R = cyclobutyl)

To 1.0 g (39 mmol) of (-) - 3,14β-dihydroxymorphinan ((VI), where R 1 is hydrogen) in 25 ml of dry dimethylformamide and in the presence of 0.5 g of 6 mmol) of ground and dried sodium bicarbonate, 0.96 g (3.9 mmol) of cyclobutylmethyl bromide was added under stirring and under a nitrogen atmosphere. 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 precipitate formed was extracted (3 x 100 mL) with chloroform. After drying over sodium sulfate, the chloroform solution was evaporated to dryness in vacuo. Crystallization of the crude product from acetone gave 0.70 g (88.5%) of (I) wherein R 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-3,143-hydroxy-3-methoxy-morphinan ((V), R = cyclobutyl) in room temperature at room temperature over 1 hour. 80 ml 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 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). 222 ° C.

Industrial usability

The invention is useful in the pharmaceutical industry in the manufacture of the substance Butorphanol. This substance has wide application as an effective analgesic, which is believed to be non-addictive and at the same time to have an antagonistic morphine effect.

Claims (1)

PATENT CLAIMS Method of Preparation 3 14β-dihydroxy-17-cycloalkylmethylmorphinans (I), wherein R is cyclopropyl or cyclobutyl, characterized in that the compound of formula (VI) is: OH (VI) 1 in which R 1 represents hydrogen or methyl, alkylates with a cycloalkylmethyl halide or acylates a cycloalkanecarbonyl halide with three or four carbon atoms in each cycle, a) in the case of alkylation, when R 6 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) wherein R is as defined above is demethylated 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): is as defined above, which is reduced by treatment with complex hydrides when R R is hydrogen to form a compound of formula (I), d) when R 1 is methyl, the resulting intermediate of formula (V) wherein R is as defined above is demethylated by treatment with an aluminum halide dialkylsulfide to give a compound of formula (I).