SK38794A3 - Method of preparation (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

Process for preparing (6R, 7R, 14S)-17-cyclopropylmethyl 7,8-dihydro-7-/(1s)-1-hydroxy-1,2,2-trimethylpropyl/ -6-0-methyl-6,14-ethano-17-normorphine of general formula I, used as a strong analgesic (Buprenorphine). Synthesis includes simultaneous cleavage of the essential functional group and hydrolysis of the cyane group by alkaline hydroxide, acylation of the occurring secondary amide by cyclopropyl carbonyl chloride with subsequent reduction of the occurring amide by a complex hydride, possibly direct alkylation of the secondary amide by cyclopropyl methyl halogenide, and final catalytic reduction of the endocyclic double bond.<IMAGE>

Description

Technical field

The invention relates to a process for the preparation of (6R, 7R, 14S) -17-cyclopropyl-1-methyl-7,8-dihydro-7 - [(IS) -1-hydroxy-1,22-trimethylpropyl] -6-O-methyl- 6,14-ethano-17-normortine, a compound of formula (I).

which is used as a strong analgesic (Buprenorphine).

BACKGROUND OF THE INVENTION

The known synthesis (CS pat. 277 222 Petrickova, Hajecek, Markovic) is based on the semisynthetic derivative of 7- [1-hydroxy-1,2,2-trimethylpropyl] -6,14-etheno-6,7,8,14-tetrahydrothebaine of the 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 formula ( III)

is hydrolyzed by treatment with 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)

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 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 of 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- normorphine 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 (O5

SUMMARY OF THE INVENTION

The process of the invention solves in a simpler manner the synthesis of (6R, 7R, 14S) -17-cyclopropylmethyl-7,8-dihydro-7 - [(1S) -1-hydroxy-1,2,2-trimethylpropyl] -6-O-methyl -6,14-ethano-17-normorphinin (I), which is used as a potent analgesic (Buprenorphine).

The proposed procedure addresses the task as follows:

Single-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 a 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 formula ( III) by treatment with an alkali hydroxide, e.g. sodium or potassium hydroxide in a multifunctional alcohol such as diethylene glycol in the temperature range of 150 ° C to 210 ° C hydrolyzes and, at the same time, selectively O-demethylated to give the compound 7,8-dihydro-7- [1-hydroxy-1,2,2- trimethylpropyl] -6-O-methyl-6,14 etheno-17-normorphine 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 ( VII)

whose reduction of hydrogen on a catalyst such as palladium on carbon in an internal solvent such as tetrahydrofuran, ethanol, methanol or ethyl acetate in the temperature range of 20 ° C to 80 ° C and a pressure range of 5-15 MPa produces the title compound (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 by either: the compound of formula (VIII) is converted into 17-cyclopropanecarbonyl-7,8-dihydro-7- [1-hydroxy-7- [1-hydroxy] amide by reaction with cyclopropylcarbonyl chloride in water and chlorinated aliphatic hydrocarbon, preferably methylene chloride or chloroform. -1,2,2-trimethylpropyl] -6-O-methyl-6,14-etheno-17-normorfin in 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. C 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 the above procedure 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.

EXAMPLES

Example 1: Preparation of the compound 7,8-dihydro-7- [1-hydroxy-1,2,2-trimethylpropyl] -6-O-methyl-6,14-etheno-17-normorphine 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 31 ice / water (1: 1). 77.0 g of ammonium chloride was added to the solution, 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 ⁺ H, C ₂₅ H ₃₃ NO ₄ , calcd. 411.2410, 73%)

354 ([MC ₄ H ₉ ] ⁺ , 17%), 311 ([MC ₆ H ₁₃ O] ⁺ , 15%),

101 ([C ₆ H ₁₃ O] ⁺ -, 12%)

IR: (cml)

3447

1631, 1602 (C-C)

UV: ([nm], A)

216, 1.053

290, 0.063

Example 2: Preparation of the amide of compound 17-cyclopropanecarbonyl-7,

8-Dihydro-7- [1-hydroxy-1,2,2-trimethylpropyl] -6-methyl-6,14-etheno-17-normorphine 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, a solution of 8.4 mL (0.09 M) of cyclopropylcarbonyl chloride in 60 mL of chloroform was added dropwise. After 2 hours, the organic phase was separated, the aqueous phase was extracted with 2 x 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 ⁺ H, C ₂₉ H ₃₇ NO ₅ , calcd. 479.2672, 100%)

422 ([M -C ₄ H ₉ ] ⁺ , 47%), 378 ([MC ₆ H 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 the solution was added dropwise

35.2 g of tartaric acid in 100 ml of water and 100 ml of tetrahydrofuran. 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 a white crystal of compound (VII) of 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-normorphine 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. stirred 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-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% H2O) was added, and the reaction mixture was reduced with hydrogen at 8 MPa and a temperature of 80 ° C for 6 h. The catalyst was then filtered off and the reaction mixture was concentrated to about 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. This substance is widely used as an effective analgesic in which non-addiction is expected.

Claims (3)

PATENT CLAIMS 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, 14- of ethano-17-normorphine (I) from 17-cyano-7- [1-hydroxy-1,2,2-trimethylpropyl] -6,14-etheno-6,7,8,14-tetrahydro-17-nortebaine 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-nor13-thebaine of formula (III) is reacted with an alkali hydroxide, e.g. sodium or potassium hydroxide in a multifunctional alcohol such as diethylene 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-normorphine of formula (VIII) is converted to 17-cyclopropylmethyl-7,8-dihydro-7- [1-hydroxy-1,2,2-trimethyl] propyl] -6- O-methyl-6,14-etheno-17-normalorfin of 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, within a temperature range of 20 ' C to 80 ° C and at a pressure of 5 to 15 MPa gives a compound of formula (I). 2. The process of claim 1, wherein the compound is converted to 7,8-dihydro-7- [1-hydroxy-1,2,2-trimethylpropyl]. - 6-O-methyl-6,14-etheno-17-normorphine of formula (VIII) is converted to amide by reaction with cyclopropylcarbonyl chloride, in water and chlorinated aliphatic hydrocarbon, methylene chloride or chloroform, in the temperature range 0 ° C to 30 ° C of compound 17-cyclopropanecarbonyl-7,8-dihydro-7- [1-hydroxy-1,2,2-trimethylpropyl] -6-O-methyl-6,14-etheno-17-normorphine of formula (IX), which is reduced 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). 3. The method of claim 1, wherein the compound is converted to 7,8-dihydro-7- [1-hydroxy-1,2,2-trimethylpropyl] -6-O-methyl-6,14-etheno-17. -normorphine of formula (VIII) is converted by alkylation with cyclopropylmethyl bromide or cyclopropylmethyl chloride in a dipolar aprotic solvent such as dimethylformamide in the temperature range of 20 ° C to 120 ° C to give 17-cyclopropylmethyl-7,8-dihydro-7- [1-hydroxy- 1,2,2-Trimethylpropyl] -6-O-methyl-6,14-etheno-17-normorphine of formula