CZ16393A3 - Process for preparing 3,14 beta-dihydroxy-17-cycloalkyl 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

A process for the preparation of 3,143-dihydroxy-17-cycloalkylmethylmorphinates

Technical field

The invention relates to a process for the preparation of -alkylmethylmorphinans of general interest

3,143-dihydroxy-17-cyclosporide of formula

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 the formula were prepared by total synthesis (US Pat. No. 3,819,635), or by semi-synthesis from the natural alkaloid thebaine (Mouralova J., Hajicek J. and Trojanek J.: Czechoslovak. Farm. 1, 32, 23 ( 1983)). The known synthesis (US Pat. No. 3,819,635, US Pat. No. 4,139,534 and US Pat. No. 4,058,531) in its final phase starts from 14β-hydroxy-3-methoxymorphinan of formula (II).

OH (II) which is reacted with a cycloalkanecarboxylic acid chloride or anhydride of the formula III-f

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

is reduced by complex hydrides to the product of formula (V-f)

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 function of the formula -FV-ením by treatment with hydrobromic acid, boron bromide, pyridine hydrochloride, or NaSC 2 H 5 affords a compound of formula fTsf or a pharmaceutically acceptable acid salt thereof.

SUMMARY OF THE INVENTION

The aim of our work was to find a viable and economically viable synthesis route for the 1-synthetic morphinan alkaloid Butorphanol (-CI-), R = cyclobutyl), ie 3,14B-dihydroxy-17-cyclobutylmethylmorphinan. The proposed procedure solves the task in three modifications. A process for the preparation of 3,14B-dihydroxy-17cycloalkylmethylmorphinates of general formula

wherein R is cyclopropyl or cyclobutyl, a compound of formula WiSf consisting of

(VI)

wherein R 1 is hydrogen or methyl, alkylates a cycloalkylmethylalcohol, or acylates a C 3 -C 4 cycloalkanecarbonyl halide,

a) in the case of alkylation, when R 1 is hydrogen, a compound of the formula z / I 2 is formed,

b) in the case of alkylation, when R 1 is methyl, the resulting intermediate of the formula • ('V-y' (V)

wherein R is as defined above, demethylated by treatment with an aluminum halide-dialkylsulfide complex to form a compound of formula (Ί /,

c) in the case when acylated cykloalkanha1ogenidem _of producing the compound of formula fVllf

N-COR (VII) wherein R and R 1 are as defined above, which is reduced by treatment with complex hydrides when R 1 is hydrogen to form a compound of formula (d), and when R 1 is me t? Yi, the resulting intermediate of formula J / Vf

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

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 the more difficult availability of a cycloalkylmethyl halide, acylation is also a viable 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 nontoxic and substantially cheaper O-demethylation agent (especially then the last or one of the final steps of the synthesis of pharmacologically active substance) while achieving at least the same yield as in the hitherto known syntheses _of using hortribromid, or achieve substantially higher yield compared to using the action of hydrobromic acid, pyridine hydrochloride, and NaSC2Hs. Easier and safer handling of the complex (in this case aluminum chloride-dimethylsulfide) than important with boron bromide, which has so far been the only reagent utilized to provide satisfactory yields, is important for larger scale operations.

When carrying out process 3143-dihydroxy-17-cykloalkylmet ^ ylmorfinanů invention, in a first step, the starting compound of the formula / (V Italians Lu cykloa1ky1methy1- ha1ogenidem _a halide or acylated cykloalkankarboxy1ové acid in an inert organic solvent. In the case of acylation followed by reduction of the carbonyl group complex hydrides.

When R 1 in formula (VL) is methyl, the resulting compound of formula (I) may be demethylated by the action of an aluminum halide-dialkylsulfide complex at 0-3 ° C in anhydrous inert organic solvents, preferably the AlCl 3 -dimethylsulfide complex in dichloromethane or toluene. for fuxk-o-fyv temperature at f-AtoA ',

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

DETAILED DESCRIPTION OF THE INVENTION

Example 1:

( ^_ ) -17-Methyl-1-β-hydroxy-3-methoxymorphinan (/ VY,

R = cyclobutyl1)

To 1.0 g (3.7 mmol) of (-) - 14? -Hydroxy-3-methoxy-morphinan in 25 ml of dry dimethylformamide and in the presence of 0.5? (6 mmol) of triturated and dried sodium bicarbonate was stirred and under a nitrogen atmosphere, 1.0 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 60 ml of distilled water. The white precipitate formed was extracted with chloroform (3 x 10 ml). The chloroform solution was dried over sodium sulfate, concentrated to a pale yellow oily product ((V), R = cyclobutyl) (l .mu.g; tj.8ej%) _of which gives the crystalline hydrochloride. Melting point of hydrochloride 132 ° C.

Example 2:

(-) - 17-Cyclobutanecarbonyl-143-hydroxy-3-methoxymorphinan ((VII), R = cyclobutyl, R 1 = methyl)

To 5.0 g (1 mmol) of (-) - 14β-hydroxy-3-methoxymorphinan (II), dissolved in 60 ml of dichloromethane, was added 2.2 g (26 mmol) of triethylamine. A solution of 2.5 g (21 mmol) of cyclobutanecarbonyl chloride in 10 ml of dichloromethane was added dropwise over 30 minutes at 0-5 ° C. After an hour reaction at 10 ° C, the reaction mixture was shaken successively 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 .mu.g (i.e. 9%) of an oily product was obtained which on standing gave a crystalline substance with a melting point of 14 [deg.] C.

Example 3:

(-) - 17-Cyclobutyl-143-hydroxy-3-methoxy-morphinan ((V),

R = cyclobutyl)

To 1.0 g (26 mmol) of L1AIH4 in a nitrogen-filled dry flask was first added dropwise 10 ml of dry tetrahydrofuran, followed by a solution of N, (-) - 17-cyclobutanecarbonyl-143-hydroxy-3-methoxymorphinan (18 mmol) (( VII), R = cyclobutyl, R 1 = methyl dissolved in 3 µl of tetrahydrofuran. The reaction mixture refluxed during the dropwise addition of excess LiAlH 4 was added dropwise by dropwise addition of 10 ml of tetrahydrofuran, diluted with water under nitrogen. and the dichloromethane layer was then concentrated to a residue (5.7 g) and the residue was chromatographed on silica gel (10X) and crystallized from ethanol to yield 4.6% (80%).

Example 4:

(-) - 17-Cyclobutylmethyl-1,3,143-dihydroxymorphinan ((I),

R = cyclobutyl1)

K 1.0 ^; (39 mmol) of (-) - 3,14β-dihydroxymorphinan (N -Vl-γ, where R 1 is hydrogen) in 2 µl of dry dimethylformamide and in the presence of 0.5 µg (6 mmol) of ground and dried sodium bicarbonate was stirred and under 0.9 µg (3.9 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 dropped into 600/1 L of distilled water with stirring. The precipitate formed was extracted (3 x 100 µl) 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% (88.5%) of compound X '', where R is cyclobutyl, is obtained. Melting point 222-4.

Example 5:

( ^- ) -17-cyclobutylmethyl-3,14β-dihydroxymorphinan ((I),

R = cyclobut 1)

15.6 g (0.117 mol) of aluminum chloride was dissolved in iodomethane of dichloroethane and 54 .mu.M (741 mol) of dimethylsulfide. To this mixture was pekvj-oic teplotyJv dropwise over 1 hour a solution of 4, Og (11.7 mmol) of (-) - 17-cyklobutylmet _{<1-14βhydroxy} hydroxy-3-ME1-ioxy-morphinan (= V R = cyclobutyl ) in 8 [mu] l of dichloromethane. After dropwise addition, the reaction mixture was stirred at room temperature.

A solution of 18 .mu.l (0.12 mol) of tartaric acid in 150 .mu.l 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 15 (ml ml)) with chloroform and evaporated to dryness in vacuo over sodium sulfate to give 3.2 g (8%) of the crude product after crystallization of the acetone (8%). (R = cyclobutyl), m.p.

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-cycloalkylmethylmorphinans of the general formula (I) in which R represents cyclopropyl or cyclobutyl, the compound of the formula (VI) in which R is denoted by t. hydrogen or methyl, alkylated with a cycloalkylmethylalkyl halide or acylated with a cycloalkanecarbonyl halide of three or four carbon atoms in each ring, and / in the case of alkylation when R ^ represents hydrogen, a compound of the formula ¢ 1) is formed; the resulting intermediate of formula -fV (wherein R is as defined above) demethylates by treatment with an aluminum halide-dialkylsulfide complex to form a compound of formula (c) when acylated with cycloalkanecarbonyl and a halide produces a compound of formula (VII) wherein R and R 1 have as defined above, which is reduced by the action of complex hydrides when R 1 is hydrogen to form a compound of formula d / v when Ri is methyl. the resulting intermediate of formula (V) wherein R is as defined above, the demelic acid is treated with an aluminum halide-dialkylsulfide complex to form a compound of formula