SK278715B6 - Method for preparation of (6r,7r,14s)-17-cyclopropylmethyl-7,8- -dihydro-7-£(1s)-1-hydroxy-1,2,2-trimethylpropyl|-6-0-methyl- -6,14-ethano-17-normorphine - Google Patents

Abstract

This patent describes a solution, suitable from economical point of view, closed to the synthesis of (6R,7R,14S)-17- -cyclopropylmethyl-7,8-dihydro-7-[(1S-)-1-hydroxy-1,2,2- -trimethylpropyl]-6-0-methyl-6,14-ethanol-17-normorphine (I) used as the strong analgesic (Buperomorphine). The above mentioned synthesis is provided based on the selective cracking of ethereal functional group and hydrolysis of a cyano group with the use of alkaline hydroxide and acylation of created secondary amine with the use of cyclopropyl carbonyl chloride and with the use of the subsequent reduction of the created amide with complex hydride or with the use of a direct acylation of the secondary amine, while cyclopropylmethylhalogenide is used for these purposes and the final catalytic reduction of endocyclic double bond is provided.

Description

The invention relates to a process for the preparation of (6R, 7R, 14S) -17-cyclopropylmethyl-7,8-dihydro-7 - [(1S) -1-hydroxy-1,2,2-trimethylpropyl] -6-O- of methyl-6,14-ethano-17-normorphine, a compound of formula (I), is converted by reaction with cyclopropylcarbonyl chloride in the presence of triethylamine to the amide of 17-cyclopropanecarbonyl-1- 7- [hydroxy-1,2,2-trimethylpropyl] -6 14-etheno-6,7,8,14-tetrahydro-17-northebain of formula (V)

which is used as a strong analgesic (Buprenorphine).

BACKGROUND OF THE INVENTION

Known synthesis (CS pat. 277 222 Petŕíčková, Háječek, Markovič) is based on the semisynthetic derivative 7- [1-hydroxy-1,2,2-trimethylpropyl] -6,14-etheno-6,7,8,14- tetrahydrothebaine of formula (II),

which reacts with cyanogen bromide in a chlorinated hydrocarbon, the obtained cyano derivative of 17-cyano-7- [1-hydroxy-1,2,2-trimethylpropyl] -6,14-etheno-6,7,8,14-tetrahydro-17-nortebaine of the formula (III),

is hydrolyzed by treatment with an alkali hydroxide in diethylene glycol, the prepared base of compound 7- [1-hydroxy-1,2,2-trimethylpropyl] -6,14-etheno-6,7,8,14-tetrahydro-17-nortebaine of formula (IV) which reduced with a complex hydride in an organic solvent, the obtained compound 17-cyclopropylmethyl-7- [1-hydroxy-1,2,2-trimethylpropyl] -6,14-etheno-6,7,8,14-tetrahydro-17-northebain formula (VI),

is then cleaved with an alkali hydroxide in diethylene glycol to give 17-cyclopropylmethyl-7,8-dihydro-7- [1-hydroxy-1,2,2-trimethylpropyl] -6-O-methyl-6,14-etheno-17 -normorfm of formula (VII),

which is finally reduced by hydrogen on the catalyst, e.g. on palladium on carbon in an internal solvent to give compound (I).

SUMMARY OF THE INVENTION

The process of the invention solves in a simpler manner the synthesis of (6R, 7R, 14S) -17-cyclopropylmethyl 1-7,8-dihydro-7 - [(1S) -1-hydroxy-1,2,2-trimethylpropyl] -6-0II JU lllľ

B6

And methyl-6,14-ethano-17-normorphine (I), which is used as a strong analgesic (Buprenorphine).

The proposed procedure addresses the task as follows:

One-step hydrolysis of the cyano group with simultaneous selective cleavage of the ether functionality on the C3 carbon of the compound of formula (III) to give the compound of formula (VIII).

Conversion of a compound of formula (VIII) to a compound of formula (VII).

Final reduction of the compound of formula (VII) with hydrogen on the catalyst to give compound (I).

Compound (VIII) is converted to compound (VII) by either acylating a compound of formula (VIII) with cyclopropylcarbonyl chloride to an amide of formula (IX) followed by reducing the amide to a compound of formula (VII), or by direct alkylating the compound of formula (VIII) with cyclopropylmethylbromide to a compound of (VII).

The process according to the invention is characterized in that the compound 17-cyano-7- [1-hydroxy-1,2,2-trimethylpropyl-6,14-etheno-6,7,8,14-tetrahydro-17-nortebaine of the formula (III) by treatment with an alkali hydroxide, e.g. sodium or potassium hydroxide in a multifunctional alcohol such as diethylene glycol hydrolyzes at a temperature between 150 ° C - 210 ° C and at the same time selectively methylates to give the compound 7,8-dihydro-7- [1-hydroxy-1,2,2- trimethylpropyl] -6-O-methyl-6,14-etheno-17-nor-morphine of formula (VIII),

which is converted to the compound 17-Cyclopropylmethyl-7,8-dihydro-7- [1-hydroxy-1,2,2-trimethylpropyl] -6-O-methyl-6,14-etheno-17-normorphine of formula (Vil) .

whose reduction of hydrogen on a catalyst such as palladium on carbon in an internal solvent such as tetrahydrofuran, ethanol, methanol or ethyl acetate between 20 ° C and 80 ° C and a pressure range of 5-15 MPa gives the title compound (I).

The compound 17-cyclopropylmethyl-7,8-dihydro-7- [1-hydroxy-1,2,2-trimethylpropyl] -6-O-methyl-6,14-etheno-17-normorphine of formula (VII) is prepared either A compound of formula (VIII) is converted into the amide of 17-cyclopropanecarbonyl-7,8-dihydro-7 in a temperature range of 0 ° C to 30 ° C by treatment with cyclopropylcarbonyl chloride, in water and chlorinated aliphatic hydrocarbon, preferably methylene chloride or chloroform. - [1-hydroxy-1,2,2-trimethylpropyl] -6-O-methyl-6,14-etheno17-normorphine of formula (IX)

and this is reduced with a complex hydride in an organic solvent such as benzene, toluene, ether, tetrahydrofuran to compound (VII), or the compound of formula (VIII) is directly alkylated with cyclopropylmethyl bromide or cyclopropylmethyl chloride in a dipolar aprotic solvent such as dimethylformamide. to 120 ° C to compound (VII).

Compounds of formulas (VIII) and (IX) are novel and their physical chemical characteristics are listed below.

The advantage of this process over the known synthesis of CS pat. 277222 is a significant increase in total production yield by shortening the entire synthesis by one and two steps, respectively. The details of the process according to the invention are illustrated by the following examples.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Preparation of a compound of compound 7,8-dihydro-7- [1-hydroxy-1,2,2-trimethylpropyl] -6-O-methyl-6,14-etheno-17-normorfin of formula (VIII)

81.2 g (1.45 M) of potassium hydroxide was dissolved in 800 ml of diethylene glycol at 150 ° C. To this solution was added 70.0 g (0.16 M) of the cyanoderivative (III) and the reaction mixture was heated to 200 ° C for 16 hours. The reaction mixture was then cooled to 20 ° C and poured into 3 L of ice-water (1: 1). To the solution was added 77.0 g ammonium chloride, and the mixture was stirred at 5 ° C for 1 hour. The resulting precipitate was aspirated, washed with water and dried. The precipitate was crystallized from metynol and 35.6 g (53.9%) of white crystals of compound (VIII) with a melting point = 295.3 ° C - 296.7 ° C were obtained.

MS: (m / z, rel. Int.)

411.2420 (M ⁺ ', C25H33NO4, calcd. 411.2410, 73%) 354 ([M-C4H9] ^+, 17%), 311 ([M-C 6 H ₁₃ O] ^+, 15%), 101 ([C ₆ H ₁₃ O] ⁺ -, 12%)

IR: (cm ^-1 ) 3447 (OH) 1631, 1602 (C = C) UV: ([nm], λ) 216.1.053 290, 0.063

Example 2

17-Cyclopropanecarbonyl-7,8-dihydro-7- [1-hydroxy-1,2,2-trimethyl-propyl] -6-O-methyl-6,14-octeno-17-normorphine amide preparation of formula (IX)

25.0 g (0.06 M) of norderiv (VIII) was dissolved in 200 ml of dimethylformamide, to which was added 200 ml of chloroform, 200 ml of water and 27 ml of ammonia. With vigorous stirring was added to this mixture

I dropwise solution of 8.4 ml (0.09 M) of cyclopropylcarbonyl chloride in 60 ml of chloroform. After 2 hours, the organic phase was separated, the aqueous phase was extracted twice

100 ml of chloroform. The organic phases were combined and concentrated to about 50 ml. The solution was slowly added dropwise to 350 mL of ice-water (1: 1). The resulting precipitate was stirred for 1 hour and then aspirated, washed with water and dried. 28.1 g (96.4%) of a light gray precipitate of compound (IX) with a melting point = 147.0-148.1 ° C were obtained.

MS: (m / z, rel. Int.)

498.2675 (M < ⁺ &^gt;,&^gt; 29-37-5, calcd. 479.2672, 100%) 422 ([M-C4H9] ⁺ , 47%), 378 ([M-C6H ₁₃ O] ⁺ , 10%)

101 ([C ₆ H ₁₃ O] ⁺ , 12%), 69 ([C ₃ H ₅ CO] ⁺ , 20% UV: ([nm], A)

216 nm (1,192) 290 nm (0.081)

Example 3 Preparation of 17-cyclopropylmethyl-dihydro-7- [1-hydroxy-1,2,2-trimethyl-propyl] -6-O-methyl-6,14-etheno-17-normorphine of formula (VII)

8.4 g LiAlH ₄ (0.22 M) was poured into the reaction flask under argon. 80 ml tetrahydrofuran (dried) was slowly added dropwise to the hydride via a dropping funnel. A solution of 22.0 g (0.045 M) of the amide (IX) in 80 ml of tetrahydrofuran was then added dropwise to the suspension so that the mixture slowly refluxed. The reaction mixture was stirred for 1 hour and then a solution of 35.2 g of tartaric acid in 100 ml of water and 100 ml of tetrahydrofuran was added dropwise. Finally, the reaction mixture was extracted with ether (2 x 200 mL). The organics were combined, concentrated and the residue was crystallized from methanol. 17.3 g (81%) of white crystal of compound (VII) with a melting point = 237.5 - 239.0 ° C were obtained.

Example 4

Preparation of 17-cyclopropylmethyl-7,8-dihydro-7- [1-hydroxy-1,2,2-trimethyl-propyl] -6-O-methyl-6,14-etheno-17-normorfin of formula (VII) )

1.0 g (2.4 mM) of norderiv (VIII) was dissolved in 35 ml of dimethylformamide, to this solution was added 2.0 g of anhydrous sodium carbonate and slowly added dropwise 0.25 ml (2.6 mM) of cyclopropylmethyl bromide. The reaction mixture was heated to 80 ° C and stirred at 80 ° C for 4 hours. The reaction mixture was then cooled to 20 ° C and added dropwise to 150 ml of water cooled to 0 ° C. The resulting precipitate was 1 hour. and then aspirated. 0.85 g (87.2%) of a white precipitate of compound (VII) with a melting point = 237.7 - 239.0 ° C was obtained.

Example 5

Preparation of (6R, 7R, 14S) -17-Cyclopropylmethyl-7,8-dihydro-7 - [(1S) -1-hydroxy-1,2,2-trimethylpropyl] -6-O-methyl-6,14- ethano-17-normorphine (I)

10.8 g (23.2 mM) of compound (VII) was dissolved in 250 ml of ethanol, 8.65 g of 3% Pd / C (containing 50% H ₂ O) was added, and the reaction mixture was reduced with hydrogen under pressure 8 MPa and 80 ° C for 6 h. The catalyst was then filtered off and the reaction mixture was concentrated to ca. 50 ml. White crystals of compound (I) - 9.3 g (86.0%), m.p. = 209-210 ° C, crystallized from the solution.

Industrial usability

The invention is useful in the pharmaceutical industry in the manufacture of the substance buprenorphine, which has a broad application as an effective analgesic, which is believed to be non-addictive.

Claims (3)

A process for the preparation of (6R, 7R, 14S) -17-cyclopropylmethyl-7,8-dihydro-7 - [(1S) -1-hydroxy-1,2,2-trimethylpropyl] -6-O-methyl -6,14-ethano-17-normorphine (I) (I) from 17-cyano-7- [1-hydroxy-1,2,2-trimethylpropyl] -6,14-etheno-6,7,8, 14-tetrahydro-17-nortcbain 25 of formula (III), characterized in that the compound 17-cyano-7- [1-hydroxy-1,2,2-trimethylpropyl] -6,14-etheno-6,7,8,14-tetrahydro-17 -nortebaine of formula (III) is reacted with an alkali hydroxide, e.g. sodium or potassium hydroxide in a multifunctional alcohol such as dictylene glycol, in the temperature range of 150 ° C to 210 ° C, prepared compound 7,8-dihydro-7- [1-hydroxy-1,2,2-trimethylpropyl] -6-O- methyl-6,14-etheno-17-normorfin of formula (VIII) (V) is converted to 17-cyclopropylmethyl-7,8-dihydro-7- [1-hydroxy-1,2,2-trimethylpropyl] -6 -O-methyl-6,14-etheno-17-normorphine of the formula (VII) wherein by reduction with hydrogen on a catalyst such as palladium on carbon in an internal organic solvent such as tetrahydrofuran, ethanol, methanol or ethyl acetate over a temperature range 20 ° C to 80 ° C at 5 to 15 MPa gives the compound of formula (I). a solvent such as dimethylformamide in the temperature range of 20 ° C to 120 ° C to provide 17-cyclopropylmethyl 1-7,8-dihydro-7- [1-hydroxy-1,2,2-trimethylpropyl] -6-O-methyl -6,14-etheno-17-normorphine of formula (VII). ^H » ^c tu, The method of claim 1, wherein the conversion of 7,8-dihydro-7- [1-hydroxy-1,2,2-trimethylpropyl] -6-O-methyl-6,14-etcno The -17-normorphine of formula (VIII) is converted to the amide of 17-cyclopropanecarbonyl-7,8-dihydro-7 by treatment with cyclopropylcarbonyl chloride, in water and chlorinated aliphatic hydrocarbon, methylene chloride or chloroform, in the temperature range of 0 ° C to 30 ° C. - [1-hydroxy-1,2,2-trimethylpropyl] -6-O-methyl-6,14-etheno-17-normor-fin of formula (IX), The end of the document which is reduced with a complex hydride in an organic solvent such as benzene, toluene, ether, tetrahydrofuran to give 17-cyclopropylmethyl-7,8-dihydro-7- [1-hydroxy-1,2,2-trimethylpropyl] - 6-O-methyl-6,14-etheno-17-normorphine of formula (VII). A process according to claim 1, wherein the conversion of 7,8-dihydro-7- [1-hydroxy-1,2,2-trimethylpropyl] -6-O-methyl-6,14-etheno The -17-normorphine of formula (VIII) is converted by alkylation with cyclopropylmethyl bromide or cyclopropylmethyl chloride in a dipolar aprotic