SK278432B6 - Preparation method of 3,14beta-dihydroxy-17- -cycloalkylmethylmorphinanes - Google Patents

Abstract

This patent is dealing with the procedure closed to the preparation of 3,14beta dihydroxy-17- -cycloalkylmethylmorphinanes with a general formula (I), acceptable when talking about operational and economical aspects, this procedure is especially related to Butorfanol which is an effective analgesic. The synthesis includes one step alkylation of 3,14beta- dihydorxymorphinane or 14beta-hydroxy-3- -metoxymorphinane with the appropriate cycloalkylmethyl halogenide or acylation with cyclocarbonylhalogenide and the subsequent reduction of the carbonyl group based on the influence of complex hydrides or splitting of ethereal functional group based on the influence of the complex aluminium halogenide - dialkylsulphide.

Description

Technical field

The invention relates to a process for the preparation of 3,14C-dihydroxy-17-cycloalkylmethylmorphinans of formula (I), reduced by complex hydrides to the product of formula (V)

(V) wherein R is cyclopropyl or cyclobutyl. These compounds are potent analgesics which are believed to be non-addictive and at the same time to have an antagonistic morphine effect.

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, borontribromide, pyridine hydrochloride or NaSC ₂ IIs is carried out to give a compound of formula (I) or a pharmaceutically acceptable acid salt thereof.

BACKGROUND OF THE INVENTION

Compounds of formula (I) were prepared by total synthesis (US Pat. No. 3,819,635) or by semi-synthesis of 25 from the natural alkaloid thebaine (Mouralova J., Hajicek J. and Trojanek J .: Czechoslovak. Farm. 1, 32, 23 ( 1983)).

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) in its final phase is based on the 14-B-hydroxy-3-methoxy-30 morphinan of formula (II). .

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), i. 3,14B-dihydroxy-17-cyklobutylmetylmorfinanu). The proposed procedure solves the problem in three modifications. A process for the preparation of 3,14-dihydroxy-17-cycloalkylmethylmorphinates of formula (I),

(II)

wherein R is cyclopropyl or cyclobutyl by reacting a compound of formula (VI) which is reacted with a cycloalkanecarboxylic acid chloride or anhydride of formula (III),

RCOOH (III) wherein R is the same as in formula (I). Intermediate (IV) obtained

(VI) wherein R 1 is hydrogen or methyl, alkylated with a cycloalkylmethyl halide or acylated with a cycloalkanecarbonyl halide each having three or four carbon atoms in the cycle,

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 R1 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;

of formula (V) by the action of an aluminum halide-dialkylsulftd complex at 0-30 ° C in anhydrous inert organic solvents, preferably the AlCl ₃ -dimethylsulfide complex in dichloromethane or toluene at room temperature.

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

wherein R and R] is defined as above, which is reduced with complex hydrides, where R is hydrogen to give a compound of formula (I), and in the case where R ₁ is methyl, the resulting intermediate of formula (V),

wherein R is as defined above, demethylates 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 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 the use of a nontoxic and substantially cheaper O-demethylating agent (especially in the last or most recent). in one of the final stages of the synthesis of the pharmacologically active substance), while at least the same yield as from the previously known borontribromide synthesis or attaining significantly higher yields compared to hydrobromic acid, pyridine hydrochloride and NaSC ₂ H ₅ . Also easier and safer to handle the complex (in this case aluminum chloride-dimethylsulfide) than to borontribromide, which, as the only one of the reagents used so far, has yielded satisfactory yields, is also important for operational use to a greater extent.

In a process for the preparation of the 3,14B-dihydroxy-17-cycloalkylmethylmorphinans of 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.

When R 1 in formula (VI) is methyl, demethylation of the resulting compound of general formula may follow

DETAILED DESCRIPTION OF THE INVENTION

Example 1: (-) - 17-Cyclobutylmethyl-14B-hydroxy-3-methoxymorphone ((V), R = cyclobutyl)

To 1.0 g (3.7 mmol) of (-) - 14B-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 stirring. 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 while stirring. The white precipitate formed was extracted (3 x 100 mL) with chloroform. The chloroform solution, after drying with sodium sulfate, was concentrated to a pale yellow oily product ((V), δ = cyclobutyl) (1.1 g, i.e. 88%), which gave crystalline hydrochloride. The hydrochloride melts at 132 ° C.

Example 2: (-) - 17-Cyclobutanecarbonyl-14B-hydroxy-3-methoxymorphinan ((VII), R = cyclobutyl, Rj = methyl)

To 5.0 g (18 mmol) of (-) - 14B-hydroxy-3-methoxymorphman (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 an hour reaction at 10 ° C, the reaction mixture was successively shaken with water, 6% aqueous HCl, 25% aqueous K ₂ CO _3, and water again. The organic phase was dried over sodium sulfate and the dichloromethane was distilled off. 6.1 g (ie 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-14B-hydroxy-3-methoxymorphone ((V), R = cyclobutyl)

To 1.0 g (26 mmol) of L1 AlH4 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-14B-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 resulting precipitate was suction filtered, washed with dichloromethane and the dichloromethane layer was then 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 (ie 80%).

Example 4: (-) - 17-Cyclobutyimethyl-3,14B-dihydroxymorphinan ((I), R = cyclobutyl)

To 1.0 g (39 mmol) of (-) - 3,14B-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 cyclo-5-butylmethyl 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. The chloroform solution was evaporated to dryness in vacuo after drying over sodium sulfate. 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-Cyclobutyl Imets 1-3,14B-dihydroxymorphan ((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 dimethylsulphide. To this mixture was added dropwise a solution of 4.0 g (11.7 mmol) of (-) - 17-cyclobutylmethyl-3,14B-hydroxy-3-methoxy-morphman ((V), R) at room temperature over 1 hour. = cyclobutyl) in 80 ml of dichloromethane. After the dropwise addition, the reaction mixture was stirred at room temperature for 1 25 hours 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 light gray precipitate formed was then extracted (3 x 150 ml) with chloroform and evaporated to dryness in vacuo over sodium sulphate. 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 a wide application as an effective analgesic in which non-addiction is assumed and at the same time an antagonistic morphine effect.

wherein R 1 represents hydrogen or methyl, alkylated with a cycloalkylmethyl halide or acylated with a cycloalkanecarbonyl halide with three or four carbon atoms in each cycle,

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 R1 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 form a compound of formula (I),

(c) where acylating a cycloalkanecarbonyl halide produces a compound of formula (VII),

Claims (1)

PATENT CLAIMS A process for the preparation of 3,14B-dihydroxy-17-cycloalkylmethylmorphinans of formula (I) wherein R and R 1 are: is 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 R 1 is methyl, the resulting intermediate of formula (V), (I) H _and C-H (V) wherein R is cyclopropyl or cyclobutyl, wherein the compound of formula 60 vše- (VI), wherein R is defined as above, complex halide demethylated aluminum-dialkyl sulfide to form a compound of formula (I).