HU199482B - Process for production of derivatives of n-dimethil-14-hydroxi-dihydromorphine - Google Patents

Abstract

The present invention relates to a novel process (I) in the formula R, is hydrogen, allyl, cyclopropyl methyl, cyclobutylmethyl or 3,3-dimethyl -allyl - N-demethyl-14-hydroxy-dihydromorphine derivatives to produce, in such a way that a) from the 16-hydroxy-dihydrocodeine to the 6th and the 6th Temporary protection of HO groups 14 N-demethyl-14-hydroxy-dihydrocodeine obtained by bromocyanate N-demethylation or one of them with the corresponding alkyl or allyl halide by reaction or cycloalkanylation and N-substituted-N-demethyl-14-hydroxy formed by reduction - dihydrocode -analogon with boron tribromide O-demethylated, or in the meaning of R, methyl in the corresponding cycloalkanecarboxylic acid halides by acylation followed by by reduction, or b) 14-hydroxy-dihydromorphine is 3, 6, and 6; With temporary protection of 14 HO groups bromocyanate N-demethylated, if desired N-demethyl-14-hydroxy-dihydromorphine was obtained with an appropriate alkyl or allyl halide reacted.

Description

The present invention relates to a novel process for the preparation of an N-demethyl antagonist and agonist of formula (I) wherein R 1 is hydrogen, allyl, cyclopropylmethyl, cyclobutylmethyl, or 3,3-dimethylallyl. 14-hydroxydihydromorphine derivatives.

Among the N-substituted-N-demethyl-14-hydroxydihydromorphine derivatives having the morphine antagonist agonist formula (I), several pharmacologically important compounds are known, e.g. α-Naloxol (R 1 = HH ₂ CH = CH ₂ ), α-Naltrexol (R 1 = CH ₂ C ₃ H ₅ ) and

Nalbuphin (R, = CH ₂ C ₄ H ₇ ). The above dihydromorphines can be prepared by reduction of the corresponding ketones (N-alkyl-N-demethyloxymorphone) with sodium borohydride [British Patent

I. 119.270; U. Weiss, S. J. Daumj. There are numerous references in the literature that the above reaction is non-stereoselective, with formation of 5-10% dihydroisomorphine epimer [E. F. Hahn,

J. Fishman, J. Med. Chem. 40, 31 (1975); T. R. Bürke, K. C. Rice, C. B. Pert: Heterocydes 23 99 (1985)]. In our own studies, the epimer by-product can only be removed from the target compound by multiple recrystallization or column chromatography. No selectivity was observed in the sodium borodhydride reduction using different solvents (methanol, ethanol, dioxane, tetrahydrofuran), and epimers were formed in the lithium aluminum hydride and aluminum isopropylate reduction. The present invention is based on the discovery that stereo-unit N-demethyl-14-hydroxydihydromorphine derivatives of general formula (I)

a) O-demethylation of the corresponding N-demethyl-14-hydroxydihydrocodeine, which is prepared from 14-hydroxydihydrocodeine. This latter starting material can be obtained by catalytic hydrogenation of 14-hydroxycodeine (Pd-C) of known stereochemistry in a quantitative yield (A. C. Currie, J. Gillon, G. T. Newbold, J. S. Spring: J. Chem. Soc. 1960, 773).

First, the 6,14-bis (O-acetyl) derivative of 14-hydroxycodeine was prepared, followed by the formation of the corresponding cyanamide derivative with bromocyano in chloroform, which was refluxed with 10% hydrochloric acid to give the expected N-demethyl derivative. established. By its N-alkylation or allyl in a solution of ethanol or dimethylformamide with the corresponding alkyl or allyl halides can yield a variety of N-substituted-N-demethyl-14-hydroxydihydrocodeine derivatives. The cyclopropylmethyl or cyclobutylmethyl group can be formed by N-acylation of N-demethyl-14-hydroxycodeine (with cyclopropanecarboxylic acid chloride or cyclobutanecarboxylic acid chloride and subsequent reduction of the amide (lithium aluminum hydride). 2-Formula (I)

N-demethyl-14-hydroxydihydromorphine derivatives were obtained by O-demethylation of the corresponding dihydrocodeines (boron tribromide chloroform); on the other hand

b) preparing N-demethyl-14-hydroxydihydromorphine; followed by N-alkylation or allylation thereof to yield the N-substituted compounds. N-demethylation of 14-hydroxy-dihydromorphine is carried out with bromocyanine.

Acetic anhydride was used to prepare the 3,6,14-tris (O-acetyl) derivative of 14-hydroxydihydromorphine, followed by bromyanane to give the cyanamide derivative, which was converted to N-demethyl-14-hydroxydihydromorphine by 10% hydrochloric acid hydrolysis.

Thus, according to the invention, the process is carried out by:

a) N-demethyl-14-hydroxydihydrocodeine obtained from N-demethylation of brominated cis-protected 14-hydroxy dihydrocodeine is optionally reacted with alkyl halides, if desired, and then reduced and N-alkyl or allyl N is formed. -demethyl-14-hydroxy dihydrocodeine analogs or »

-NH- is O-demethylated with boron tribromide, or

b) N-demethylation of the transiently protected 14-hydroxy-dihydromorphine with bromine, optionally reacting the resulting N-demethyl-14-hydroxy-dihydromorphine with an alkyl or allyl halide of the meaning R.

When R 1 represents a cycloalkylmethyl group, it may be formed by the corresponding cycloalkanecarboxylic acid halide acylation according to process a) followed by reduction.

The N-demethyl-14-hydroxydihydromorphine derivatives of the formula (I) thus prepared -

R 1 is hydrogen, allyl, cyclopropylmethyl, cyclobutylmethyl or 3,3-dimethylallyl, a group of morphine antagonists or a "mixed morphine antagonist and agonist".

The invention is further illustrated by the following examples, which are not limited to the examples.

Melting points were determined on a Koffler apparatus and data were not corrected. For thin layer chromatography, Merck 5554 silica gel 60 F ₂₅₄ films were used. Solvents: benzene methanol: 8-2; chloroform-methanol: 9-1; chloroform-acetone-diethylamine: 5-4-1 (v / v). The stains are UV light. and with Dragendorff's reagent. The PMR recordings were made on a BRUKER W 200 SY 200 MHz device. Chemical shifts are reported in δ (ppm). Mass spectra were performed on a VG-7035 (GC-MS-DS) using electron impact ionization. Relative intensities are given in brackets after the mass numbers.

-2HU 199482 B

EXAMPLES

1.) N-cyano-N-demethyl-6,14-bis (O-acetyl) -14-hydroxydihydrocodeine.

7.5 g (18.7 mmol) of 6,14-bis (O-acetyl) -14-hydroxydihydrocodeine in 70 mL of abs. dissolved in chloroform and a solution of bromocyanate (4.6 g, 43.4 mmol) in chloroform (25 mL) was added. After refluxing for 8 hours, a solution of bromine cyanide (23.6 mmol) (2.5 g) in chloroform (20 mL) was added and refluxed for a further 8 hours. The solution was then evaporated to dryness in vacuo and the residue dissolved in chloroform (150 mL). The chloroform solution was washed with 5% hydrochloric acid, distilled water and dried over magnesium sulfate. Concentration in vacuo afforded 7.3 g (95%) of product which was homogeneous on a thin layer.

After recrystallization (chloroform-ethanol), the melting point is 222-24 ° C.

PMR: (CDCl 3) 6.75-6.65 dd (H-1.2; 2H),

5.4 m (Η-6β; 1H), 4.8 m (Η-9α; 1H), 4.6 d (Η-5β; 1H), 3.85 s (Me; 3H), 2.25 s (14 -OAc; 3H), 1.8 s (6-OAc; 3H).

MS: m / e 412 (M ⁺ ; 100), 310 (89), 241 (46).

2.) N-Demethyl-14-hydroxydihydrocodeine

N-cyano-N-demethyl-6,14-bis (O-acetyl) -14-hydroxydihydrocodeine (6.0 g) was suspended in 60 ml of 10% hydrochloric acid and heated at reflux under nitrogen for 16 hours. The crystallizing chlorohydrate was cold filtered and washed with cold watermark. 4.2 g of chlorohydrate are obtained, which are dissolved in water and the base is precipitated with 25% ammonia solution. 3.5 g of base are obtained which are homogeneous by TLC. Crystallized from alcohol, m.p. 212-14 ° C.

PMR _(DMSO-d6): 6.7 to 6.5 d (H = 1.2, 2H);

4.4 d (Η-5βί 1H), 3.8 s (OCH ₃ ; 3H)

MS: m / e 303 (M ⁺ ; 100), 286 (56), 216 (29).

3.) N-Allyl-N-demethyl-14-hydroxydihydrocodeine

1.5 g of N-demethyl-14-hydroxydihydrocodeine (5 mmol) are suspended in 50 ml of ethanol, 0.7 g of sodium bicarbonate and 0.52 ml (6.0 mmol) of allyl bromide are added and the mixture is stirred for 70 hours. ° C. The inorganic salt is filtered off, the filtrate is evaporated, the residue is dissolved in 60 ml of chloroform, the filtrate is evaporated and the residue is crystallized from alcohol (1.2 g, 70.6%) m.p. 140 -42 ° C.

PMR (CDCl ₃ ): 6.7-6.6 dd (H-1.2; 2H), 5.8 m and 5.2 m (allyl protons; 3 H), 4.7 d (Η-5β; 1 H), 3.8 s (Me; 3 H)

MS: m / e 343 (M +; 86), 302 (24).

4.) N- (cyclopropylmethyl) -N-demethyl-14-hydroxydihydrocodeine

1.5 g (5 mmol) of N-demethyl-14-hydroxydihydrocodeine in 30 ml of abs. Dissolve in dimethylformamide, add 1.0 g of sodium bicarbonate and 0.8 g (6.0 mmol) of cyclopropylmethyl bromide. Stir at 80 ° C for 20 hours. The inorganic salt was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in water (100 mL) and extracted with chloroform (3 x 30 mL). The combined chloroform phases were washed with brine and dried over magnesium sulfate. The residue obtained after evaporation is crystallized from ethanol: 0.8 g, m.p. 143-45 ° C PMR (CDCl ₃ ): 6.65-6.55 dd (H-1.2; 2H),

4.6 d (Η-5β; 1H), 4.23 m (Η-6β; 1H), 3.85 s (-OMe; 3H), 1.8-0.2 m (cyclopropane protons)

MS: m / e 375 (M +; 10), 149 (57).

5.) N-3,3- (Dimethylallyl) -N-demethyl-14-hydroxydihydrocodeine

Starting from 1.5 g (5 mmol) of N-demethyl-14-hydroxydihydrocodeine, the same procedure as in the previous example was followed using 0.8 mL (7 mmol) of 3,3-dimethylallyl bromide. The product was subjected to column chromatography as described in the previous example to obtain 0.88 g (48%) of a homogeneous material which was a colorless oil.

PMR (CDCl ₃ ): 6.7-6.6 dd (H-1.2; 2H), 5.2 m

I-CH, CH = ^; 1 H), 4.6 d (Η-5β; 1H), 4.2 m (Η-6β; 1H), 3.9 s (-OMe; 3H), 1.7-1.6 s (= C ( Me) ₂ ; 6H)

MS: m / e 371 (M +; 51), 303 (45).

6.) N- (Cyclopropanecarbonyl) -N-demethyl-14-hydroxydihydrocodeine

N-Demethyl-14-hydroxydihydrocodeine (3.0 g, 10 mmol) was dissolved in dry dichloromethane (80 mL). Dry triethylamine (30 ml) was added, followed by slow addition of cyclopropanecarbonyl chloride (1.1 ml, 12.6 mmol) under ice-cooling.

The reaction mixture was refluxed for 4 hours. At the end of the reaction, the precipitated triethylamine chlorohydrate is filtered off and the filtrate is concentrated in vacuo.

The residue was dissolved in chloroform (100 mL) and washed with 5% hydrochloric acid (3 x 30 mL) and brine. After drying and evaporation, 3.6 g of a colorless oil (97%) are obtained, which are homogeneous by TLC.

PMR (CDCl ₃ ): 6.7-6.6 dd (H-1.2; 2H), 4.6 d (Η-5β; 1H), 4.2 m (Η-6β; 1H), 3, 85 s (-OMe; 3H), 1.2-0.7 m (cyclopropane protons)

MS: m / e 371 (M +; 8).

7.) N- (cyclopropylmethyl) -N-demethyl-14-hydroxydihydrocodeine

3.0 g of N- (cyclopropanecarbonyl) -N-demethyl-14-hydroxydihydrocodeine (8.1 mmol) in 100 ml of abs. lithium aluminum hydride (0.7 g, 18.4 mmol) was added.

-3HU 199482 B

After refluxing for 10 hours, ethyl acetate (10 mL) was added dropwise to the solution under ice-cooling followed by saturated ammonium chloride solution (100 mL). The inorganic salt was filtered off and washed with warm tetrahydrofuran. The tetrahydrofuran solution was separated and evaporated in vacuo.

The residue and the aqueous phase were extracted with chloroform and crystallized from ethanol: 1.7 g; mp 144-45 ° C.

The PMR and MS spectra were as described in Example 4.

8.) N-Allyl-N-demethyl-14-hydroxydihydro-morphine ((1) R 1 = CH ₂ CH = CH ₂ )

A solution of 1.2 ml of boron tribromide (12 mmol) in 50 ml of dry chloroform was cooled to 0 ° C while stirring and purging with nitrogen, 2.0 g (5.8 mmol) of N-allyl-N-demethyl-14-hydroxy 30 ml of a solution of chlorohydrocodeine in chloroform is added dropwise over 20 minutes and then stirred at 0-5 ° C for an additional 60 minutes.

The solution is then poured onto 100 g of ice and the pH of the aqueous phase is adjusted to 8.5-9.0 (cc. NH ₄ OH). The chloroform layer was separated and the aqueous layer was extracted with chloroform (3 x 20 mL). The combined organic layers were washed with brine, dried (magnesium sulfate) and evaporated. The residue was crystallized from methanol: 1.2 g (62%) of product, m.p. 200-202 ° C.

PMR (CDCl ₃ ): 6.6-6.5 dd (H-1.2; 2H), 5.3-4.85 m (allyl protons), 4.60 d (Η-5β; 1H), 4.4-4.1 m (Η-6β; 1H)

MS: m / e 329 (M +; 100), 288 (28).

9.) N- (cyclopropylmethyl) -N-demethyl-14-hydroxydihydromorphine ((I) R 1 = CH ₂ C ₃ H ₅ )

1.8 g of N- (cyclopropylmethyl) -N-demethyl-14-hydroxydihydrocodeine (5 mmol) are O-demethylated with 1.2 ml (12 mmol) of boron tribromide in a

Example 8. After extraction with chloroform, the product is crystallized from acetone: 1.45 g (85%), m.p. 169-71 ° C.

PMR (CDCl 3): 6.6-6.5 dd (H-1.2; 2H), 4.6 d (Η-5β; 1H), 4.3 (Η-6β; 1H), 1.8- 0.5 m (cyclopropane protons)

MS: m / e 343 (M ⁺ ; 35), 302 (17).

10) 3,6,14-tris (O-acetyl) -14-hydroxy-dihydromorphine

14-Hydroxydihydromorphine (5.0 g, 16.5 mmol) was stirred with 100 ml of freshly distilled acetic anhydride at 100 ° C for 2 hours. The acetic anhydride was evaporated in vacuo (~ 3 KPa) 4 and ice was added to the residue. After external cooling, it was made basic (with 25% ammonia solution, pH = 9) and the precipitated crystalline material was filtered off and washed with cold water. 5.8 g (83%) of crude product are obtained, which is TLC and

PMR says clean. It can be crystallized from alcohol (m.p. 186-88 ° C), but the loss of crystallization is high because part of the material is deacetylated during boiling in alcohol.

PMR (CDCl 3): 6.8-6.65 dd (H-1.2; 2H),

5.8 m (Η-6β; 1H), 4.8 d (Η-5β; 1H), 4.2 d

I (Η-9α; 1H), 2.35 s (-N-Me; 3H), 2.3s (3-OAc; 3H), 2.15 s (14-OAc; 3H), 1.95 s ( 6-OAc; 3H), ₁₅ MS: m / e 429 (M ⁺ ; 48), 387 (100).

11.) N-Cyano-N-demethyl-3,6,14-tris (0-acetyl) -14-hydroxydihydromorphine

3,6,14-Tris (O-acetyl) -14-hydroxydihydromorphine (3.0 g, 7 mmol) was dissolved in dry chloroform (40 mL) and a solution of bromo cyano (14 mmol) (1.5 g) in chloroform (20 mL) was added.

After stirring for 8 hours at 60 ° C and then adding another 1.5 g of bromocyan (in 20 ml of chloroform), another stirring for 8 hours is followed at 60 ° C. The solution was then evaporated in vacuo to dryness and the residue was taken up in 100 ml of chloroform

3θ dissolved. The chloroform layer was washed with water, 1% hydrochloric acid and brine and dried over magnesium sulfate. After evaporation, the resulting crystalline material was crystallized from alcohol: 2.6 g (86.4%); m.p. 196-98 ° C.

PMR (CDCl 3): 6.9-6.75 dd (H-1.2; 2H), 5.85 m (Η-6β; 1H), 4.8 m (Η-9α; 1H), 4.7 d (Η-5β; 1H), 2.3s (3-OAc; 3H), 2.2 s (14-OAc; 3H), 1.9 s (6-OAc; 3H)

MS: m / e 440 (M ⁺ ; 8), 398 (79), 296 (100).

12.) N-Demethyl-14-hydroxy-dihydromorphine (R. = H)

2.0 g of the cyanamide ⁴⁵ derivative prepared in the previous example are suspended in 25 ml of 10% hydrochloric acid and heated to reflux under nitrogen. Upon cooling the solution, ₅₀ hydrates of N-demethyl-14-hydroxydihydromorphine chlorine are precipitated. Filter and wash with cold water. Melting point: 334 ° C (decomposes at 320 ° C).

The chlorohydrate was dissolved in water, basified (pH 9: 25; 25% ammonia solution) and the base crystallized.

257-59 ° C.

PMR _(DMSO-d6): 6.7-6.6 (dd, H = 1.2, 2H);

4.6 d (Η-5β; 1H), 4.1 m (Η-6β; 1H) ⁶⁰ 13.) N-Allyl-N-demethyl-14-hydroxydihydromorphine

I ((I) R 1 = CH ₂ CH = CH ₂ )

0.6 g (2 mmol) of N-demethyl-14-hydroxydiod65 hydromorphine in 15 mL of abs. Dimethylformamide-4HU 199482Β was added and 0.4 g (5 mmol) of sodium bicarbonate and 0.3 ml (3 mmol) of allyl bromide were added. After stirring for 20 hours at 60 ° C, the solvent was evaporated in vacuo (~ 1 KPa). The residue was poured into water and extracted with chloroform. After evaporation of the chloroform phase, the oil was purified by column chromatography to give 0.4 g of product which was identical in every respect (m.p. PMR, MS, TLC) to the compound obtained in Example 8.

Claims (2)

1) Process of formula (I): wherein R 1 is hydrogen, allyl, cyclopropylmethyl, cyclobutylmethyl or 3,3-dimethylallyl - For the preparation of N-demethyl-14-hydroxydihydromorphine derivatives, characterized in that the. 6) and 14 of 14-hydroxy dihydrocodeine N-demethyl-14-hydroxydihydrocodeine, obtained by bromine cyanide N-demethylation by the temporary protection of HO groups, or a Of which the N-substituted-N-demethyl-14-hydroxydihydrocodeine analogue formed by reaction with the corresponding alkyl or allyl halide or by cycloalkanoylation and subsequent reduction is O-demethylated, or b. ) 14-hydroxy-dihydromorphine 3-, 6- and 14- In addition to HO-groups transition defending N demetitezzük cyanogen bromide and, if desired, the resulting _{N-demethyl-14-hydroxy-15-di} hidromorfint with an appropriate alkyl or aliilhalogeniddel. Process a) according to claim 1, characterized in that the cycloalkylmethyl group represented by R 20 cycloalkanecarboxylic acid halide and acylation followed by reduction.