FI81583B - FOERFARANDE FOER N-DEMETYLERING AV MORFINANALKALOIDER. - Google Patents

Abstract

1. Process for the preparation of compounds having the N-demethylmorphinane structure of the general formula (III) see diagramm : EP0168686,P8,F1 wherein Z is CH2 -CH2 or CH=CH, Y is an oxygen atom or a group R3 and R4 wherein R3 is a hydrogen atom, a hydroxy group, an acyloxy group having from 1 to 3 carbon atoms or a benzoyloxy group, its spatial configuration being alpha, R4 is a hydrogen atom, a halogen atom, a hydroxy group, an alkyl group having from 1 to 3 carbon atoms, an acyloxy group having from 1 to 3 carbon atoms, a benzoyloxy or azido group, its spatial configuration being beta, R2 is hydrogen atom, an acyloxy group having from 1 to 3 carbon atoms or a benzoyloxy group, R1 is a hydrogen atom, an alkyl group having from 1 to 5 carbon atoms, an aryl or aralkyl group, an acyl group having from 1 to 3 carbon atoms or a benzoyl group, with the proviso that when R3 is a hydrogen atom, a hydroxy group, an acyloxy or benzoyloxy group, R4 is a hydrogen atom or an alkyl group, and when R4 is a hydrogen atom, a halogen atom, a hydroxy group, an acyloxy, benzoyloxy or azido group, R3 is a hydrogen atom, by reaction of morphinane alkaloids of the general formula (I) see diagramm : EP0168686,P9,F2 in which Z, Y, R1 and R2 have the definitions given above, with phosgene or diphosgene at a temperature of from 0 to 1208C in a solvent, and subsequent hydrolysis of the resulting N-chlorocarbonyl-N-demethyl derivative of the general formula (II) see diagramm : EP0168686,P9,F3 in which Z, Y, R1 and R2 have the meanings given above, with a mineral acid, which process is characterized in that the reaction with phosgene or diphosgene is carried out in 1,2-dichloroethane in the presence of alkali metal carbonates or alkali metal hydrogen carbonates, and then, without isolation, the resulting N-chlorocarbonyl-N-demethyl derivative of the general formula (II) is heated with 5 % hydrochloric acid.

Description

1 815 0ό

The present invention relates to a process for the preparation of compounds of general formula (III) having a morphinan backbone.

5 N

for the preparation of N-demethylation of morphinan alkanolides of the general formula (I) 15 / v N-CH3} (I)

20 \ w) \ J

Replacement of the N-methyl group of morpholine alkaloids with other alkyl groups led to the discovery of pharmacologically and therapeutically important morphine antagonists as well as the separation of agonistic and antagonistic activity (Adv. In Biochem. Psychopharm. Vol. 8: Narcotic Antagonists, Rav. of the Future 9 (6), 443, 1984). Because morphane alkaloids (morphine, codeine, thebaine) can be obtained from natural sources (plants), most methods attempt to prepare secondary amines from the above N-methyl-tert-amines (the secondary amine can then be converted to the desired compound by N-alkylation). Suitably the N-methyl group is replaced by a readily hydrolysable functional group.

2 81 5 ο ό The N-demethylating agent is subject to the following requirements: it must be inexpensive, durable, easy to manufacture, sufficiently reactive to obtain good yields and non-toxic.

5 Bromocyanine (H.A. Hageman, Org. Reactions 7, 198, 1953), which has previously been widely used for N-demytylation of the morphinan backbone, has gradually been displaced in recent years to replace chloroformic acid esters. The biggest drawback of bromocyanine is its considerable toxicity. It is also readily degradable, so it can only be used as a freshly prepared product, and there are references in the literature to its explosiveness.

Acid (or alkaline) hydrolysis of the cyanamides formed in the Braun reaction may in some cases result in partial molecular degradation (or structural change) (AC Currien, GT Newbold, FS Spring. J. Chem. Soc. 4693, 1961) or reaction stops in the urea phase (KW Bentley, DG Hardy: J. Am. Chem. Soc. 89, 3281, 1967).

20 In contrast, chloroformic acid esters are easy to handle, less toxic and easy to purify by distillation. Previously used methyl, ethyl and phenyl esters gave very good yields (85-95%) in the N-demethylation reaction 25 (MM Abdel-Monem, PS Portoghese: J. Med Chem. 15, 208, 1972; GA Brine, KG Boldt, CK Hart, Fl Carrol: Organic Prep. Proced. Int. 8, 103, 1976; KC Rice, EL May: J. Heterocyclic Chem. 14, 665, 1977).

It was found that isolation of the urethane-30 derivatives obtained as intermediates is necessary and the urethane derivatives can then be directly converted by means of a base or hydrazine. Because the above hydrolyses take a relatively long time (24-48 hours) and decomposition and side reactions can occur during this time, it was later proposed to use chloro-3,81583-fatty acid 2,2,2-trichloroethyl ester (IJ Borowitz, V.) for 35 N-demethylation. Diakiw: J. Heterocyclic Chem. 12, 1123, 1975; JI DeGraw, JH Lawson, JL Crase, HL Johnson, M. Ellis, ET Uyeno, GH Loew, DS Berkowitz: J. Med Chem. 21, 415, 5 1978) and chloroformic acid vinyl ester.

The advantage of using trichlorethyl ester is that it is reactive and the urethanes formed can be easily decomposed with activated zinc powder. However, it is disadvantageous that the decomposition of urethanes formed from 14-acyloxymorphinanes results in 0-> N-acyl migration (DE-A-2 727 805), which makes direct preparation of the N-demethyl derivative impossible.

There are also examples in the literature where a zinc complex of an N-demethyl derivative is formed (N.P. 15 Peet: J. Pharm. Sci. 69, 1447, 1980). According to the literature, the most preferred N-demethylating agent so far is chloroformic acid vinyl ester (U.S. Patent Nos. 3,905,981, 4,141,897, 4,161,597). This compound is highly reactive due to the semi-clay nature of the electrons of the vinyl group, so using it, the reactions are quantitative.

If the vinyl urethanes are treated with an equivalent amount of acid (hydrochloric acid, hydrobromic acid), an addition takes place, and when the product is boiled in methanol, the secondary amine salt is formed. In other words, the decomposition of urethane takes place under very mild reaction conditions and the secondary amine is thus obtained in good yield and in very pure form.

If urethanes formed from 14-O-acylmorphinanes are treated with an acid, a salt of the 14-O-acyl-N-demethyl compound (hydrochloride, hydrobromide, etc.) is formed, i. in this case there is no O - »N-acyl migration. However, in addition to the advantages shown, it should be mentioned that the preparation of chloroformic acid vinyl ester may be difficult to solve (due to pyrolysis), which makes it necessary to further study N-methylation methods. Diphosgene was chosen for the study because it had been successfully used for N-demethylation of tropane alkaloids. Diphosgene or chloroformic acid tri-5 chloromethyl ester can be readily prepared by chlorination of chloroformic acid methyl ester (Ά. Efrati, I.

Feinstein, L. Wackerle, A. Goldman: J. Org. Chem. 45, 4059, 1980; K. Kurita, Y. Iwakura: Org. Synth. 59, 195, 1980).

10 While it behaves like phosgene in most reactions (1 mole of diphosgene gives 2 moles of phosgene), its boiling point is 128 eC, its vapor pressure at room temperature is low (10 mmHg), the highly toxic phosgene has recently become more and more ear-15. diphosgene. Diphosgene and phosgene react with tertiary amines in the same way as chloroformic acid esters, the methyl group is cleaved in the form of methyl chloride to form carbamoyl chloride and, in the case of diphosgene, also phosgene (H. Babad, A.D. Zeiler: Chem. 20 Rev. 73, 75, 1973).

Phosgene was proposed for the N-demethylation of tertiary amines analogously to the reaction described by Braun as early as 1947 (V.A. Rudenko. A.Y. Jakuboch, T.Y. Nikoforova: J. Gen. Chem. (USSR) 17, 2256, 1947; CA. 42 25 4918e).

Since phosgene can form complexes with tertiary amines in an amine-phosgene ratio of 1: 1 and 1: 2 and the latter decomposes to form a tertiary amine (H. Babad, AD Zeiler: Chem. Rev. 73, 75, 1973), 30 phosgenes should be used in excess. , because the use of excess amine also forms tetrasubstituted urea.

Banholzer et al. (GB Patents 1,166,798, 1,167,688 and R. Banhozer, A. Heusner, W. Schulz: Liebigs Ann. Chem. 2227, 1975) were the first to disclose N-demethylation of tropane-35 alkaloids with phosgene11a or li 5,81533 diphosgene. . By heating the resulting carbamoyl chloride (isolation is not necessary) with water, it is hydrolyzed to the secondary amine hydrochloride and carbon dioxide.

5 In view of the above, it seemed appropriate to study the N-demethylation of morphinan-based compounds with diphosgene, as the hydrolysis of carbamoyl chlorides is likely to take place under much milder conditions than the hydrolysis of urethanes or cyanamides.

Dihydrocodeinone was chosen as the model compound and was found to form the expected N-chlorocarbonyl-N-demethyldihydrocodeinone when treated with diphosgene in a solution containing 1,2-dichloroethane (or dichloromethane, chloroform, carbon tetrachloride, benzene, toluene).

The structure of the latter compound was also confirmed by the fact that a similar reaction took place between dihydrocodeinone and phosgene, on the one hand, when the chlorocarbonyl compound was boiled with ethanol to form the urethane described in the literature, N-ethoxycarbonyl-N-demethyldihydrocodeinone (6. Horväth, Gaäl, R. Bognär: Acta Chim. Acad. Sci. Hung. 82, 217, 197-4).

Anhydrous sodium carbonate catalyzes the formation of the N-chlorocarbon-25 carbonyl derivative, while anhydrous sodium carbonate can also be used to bind any amounts of acid. The N-chlorocarbonyl derivative is then heated with water to hydrolyze it to N-demethyl dihydrocodeinone chlorohydrate.

Diphosgene and phosgene can acylate hydroxy groups derived from alcohols or phenols to form hydrochloric acid, and hydrochloric acid binds a tertiary amine, so morphine derivatives containing hydroxyl groups should be protected by acylation.

During the hydrolysis of the carbamoyl chloride formed in the N-demethylation of 3-O-acetyldihydromorphinone 6,81583, deacetylation also took place and N-demethyldihydromorphinone chlorohydrate was formed. However, aqueous hydrolysis of 6-O-acetyl-N-chlorocarbonyl-N-demethylcodein-5 obtained from 6-O-acetylcodeine formed 6-O-acetyl-N-demethylcodeine and therefore morphine, codeine, ethylmorphine, dihydrocodeine, dihydroethylmorphine, dihydrohydrin was performed with hydrochloric acid at a concentration of 5%. The desired N-de-10 methyl compound was then isolated as a homogeneous product.

The method of the invention can be used for dihydrocodeinone, dihydromorphinone, codeine, dihydrocodeine, morphine, dihydromorphine, ethylmorphine, dihydroethylmorphine, deoxycodeine-E, dihydrodeoxycodeine-E, 14-hydroxydihydrocodeinone, 14-hydroxide for N-demethylation of hydroxydihydromorphinone, 3-O-benzylmorphine and azidomorphine.

The idea of the invention is based on the fact that by a method not previously used for compounds having a morphinan backbone, morphinan alkaloids of general formula (I) are reacted with diphosgene and converted to general formula (II) by N-chlorocarbonyl-N- to demethyl compounds 25 0 i ^ NC-Cl 30 / 7v \ \ / z (UM j (id R1'0 ^> ^ 0 - "^ Y 'which the latter compounds are then converted with water or 5% hydrochloric acid solution in good yield in general yield). to N-demethyl derivatives of formula (III) which are obtained in high purity.

Il 7 81583

The process according to the invention is characterized in that a morphinan alkali of the general formula (1) J n -ch 3 / 5u) 10 in which Rx 'is C 1-6 alkyl or acetyl and Y' is Y or acyl is reacted with diphosgene 1, In 2-dichloroethane at a temperature of 0 to 120 ° C in the presence of an alkali metal bicarbonate or an alkali metal bicarbonate, and without isolating the N-chlorocarbonyl-N-dimethyl derivative of general formula (II) formed

Ar-C-Cl

20 / i \ / H

(öWj (ii> R.'CK V '^ Y · 25 where Z, Y' and Rj 'have the same meaning as in the general formula (I), this is heated in water or in a 5% hydrochloric acid solution.

The steric position of R3 and R4 depends on the group Z as follows: when Z is CH2-CH2, the position of R3 is axial and the position of R4 is equatorial and when Z is CH-CH, the position of R3 is quasi-equatorial and the position of R4 is quasi-axial.

One of the important insights of the invention is that the appropriate N-chlorocarbonyl-N-demethyl derivatives can be hydrolyzed under mild and simple reaction conditions not previously known that no decomposition and adverse side reactions occur and no toxic parent compounds are formed during the process. wastewater.

Thus, the use of diphosgene is the most advantageous in comparison with the use of bromocyanide and chloroformic acid esters in terms of the hazards of the reagents, their difficulty of preparation and their cost and large-scale availability.

The use of diphosgene used according to the invention is considered to be more advantageous than the use of toxic phosgene, given that the phosgene formed in the reaction of diphosgene can be safely removed from the system by purging with nitrogen in a suitable scrubber.

The process according to the invention is suitable for the large-scale preparation of N-demethylmorphane derivatives which are important from a pharmacological and therapeutic point of view.

The invention is illustrated by the following examples, which do not limit the scope of the invention. Melting points were determined on a Koffler apparatus and are uncorrected. MERCK 5554 silica gel 60F254 plates were used for thin layer chromatography studies. Eluents: benzene: meth ani i = 8: 2; chloroform: methanol = 9: 1 and chloroform: acetone: ethyl-lamine * 5: 4: 1 (vol / vol). Ultraviolet light and Dragendorff reagent were used to detect spots. PMR spectra were performed on a BRUKER W200SY at 200 MHz. Chemical shifts (6) are in ppm. Mass spectra were performed on a VG-7035 (GC-MS-DS) electron-30 collision ionization method.

Examples 1. N-demethyldihydrocodeinone 3 g (19 mmol) of dihydrocodeinone are dissolved in 60 ml of 1,2-dichloroethane, 1 g (10 mmol) of sodium carbonate are added and then, with stirring at 0 [deg.] C., dropwise n 9 81583 19.8 g (12 mL, 100 mmol) of diphosgene. The mixture was stirred at 0 ° C for 30 minutes, allowed to warm to room temperature and then boiled with stirring for 10 hours. The mixture is washed thoroughly with nitrogen and the inorganic salt 5 is filtered off. The 1,2-dichloroethane solution is washed with ice-cold 5% hydrochloric acid (3 x 20 ml), then the organic phase is evaporated in vacuo. Add 100 ml of water to the residue and heat on a water bath for five hours. The mixture is cooled to below 10 ° C and made early (pH -9-10) with concentrated ammonium hydroxide. The mixture is extracted with chloroform (3 x 50 ml), the organic phase is washed with brine, dried over magnesium sulphate and evaporated.

Yield: 2.33 g (82%), m.p. 150-151 ° C (from ethyl acetate).

PMR (CDCl 3): 6.66 dd (H-1.2; 2H), 4.7 s (H-56; 1H); 3.9 s (0CH 3, 3H).

MS: m / e 285 (M +; 23%).

0.4% (13%) of dihydrocodeinone is recovered from a 5% hydrochloric acid solution by basifying the solution (concentrated ammonium hydroxide) and extracting with chloroform.

2. N-demethyldihydromorphinone 3.3 g (10 mmol) of 3-O-acetyldihydromorphinone are dissolved in 60 ml of 1,2-dichloroethane, 1 g (10 25 mmol) of sodium carbonate are added and then, with stirring at 0 DEG C., 19.8 g of g (12 mL, 100 mmol) of diphosgene. The mixture is stirred at 0 ° C for 30 minutes, then the mixture is allowed to warm to room temperature and boiled with stirring for 15 hours. The mixture is washed with nitrogen and the inorganic salt is filtered off. The mixture is washed with 5% hydrochloric acid (3 x 20 ml), then the organic phase is evaporated in vacuo. Add 100 ml of water to the residue and boil for eight hours. The mixture is cooled to below 10 eC. The hydrochloride of the product separates as crystals. It is filtered and washed with 35 cold water. Yield 2.15 g (70%) of the hydrochloride salt.

10 81 583

The base m.p. 300-303 ° C. The starting material is recovered from a 5% hydrochloric acid solution as described in Example 1.

3. N-demethylcodeine 15 3.41 g (10 mmol) of 6-O-acetylcodeine are dissolved in 81 ml of 1,2-dichloroethane, 1 g (10 mmol) of sodium carbonate are added and then, with stirring at 0 [deg.] C., 19.8 g of g (12 mL, 100 mmol) of diphosgene. The mixture is stirred at 0 ° C for 30 minutes, allowed to warm to room temperature and then boiled with stirring for 20 hours. The mixture is washed with nitrogen and the inorganic salt is filtered off. The residue is washed with 5% hydrochloric acid (3 x 20 ml) and evaporated. The residue is boiled in 5% hydrochloric acid for 5 hours, then cooled to below 10 ° C, whereupon the product separates as crystals, is filtered and washed with ice-cold water. The crystalline hydrochloride salt is dissolved in water, the solution is made alkaline with concentrated hydrochloric acid, extracted with chloroform, the chloroform solution is dried and evaporated. The base obtained is crystallized from acetone or ethyl acetate.

Yield: 2.3 g (80%), m.p. 185 eC.

PMR (CDCl 3): 6.65 dd (H-1.2; 2H); 5.7 m (H-8; 1H); 5.3 m (H-7; 1H); 4.9 d (H-5B; 1H); 4.2 m (H-6B; 1H); 3.8 s (OMe; 3H).

MS: m / e 285 (M < + >, 100%), 215 (50%).

4. N-Demethyldihydrocodeine 3.43 g (10 mmol) of 6-O-acetyldihydrocodeine are N-demethylated as described in Example 3. After acid hydrolysis, on cooling, the hydrochloride salt of the product does not separate from the solution and therefore the solution is made directly alkaline with concentrated ammonium hydroxide, the product is extracted into chloroform and crystallized from ethanol.

Yield: 1.9 g (66%), m.p. 194 eC.

PMR (CDCl 3): 6.7 dd (H-1.2; 2H); 4.6 d (H-56; 1H); 4.1 m (H-6B; 1H); 3.8 s (OMe; 3H).

li 11 81583 MS: m / e 287 (M +; 100 h).

5. N-Demethylmorpholine 3.7 g (10 mmol) of 3,6-di-O-acetylmorphine are dissolved in 100 ml of 1,2-dichloroethane, thus N-demethyldold 5 as described in Example 3. After cooling the hydrochloric acid solution, the pH is adjusted to nine with concentrated ammonium hydroxide. The product separates as crystals, is filtered and washed with cold water.

Yield: 2.1 g (77%); first batch 1.8 g; from the initial solution is obtained by extraction with a chloroform-isopropanol mixture (3: 1 by volume) a second crop of 0.3 g. Sp. 274-277 ° C.

PMR (DMSO-d 6): 6.4 dd (H-1.2; 2H); 5.6 m (H-8; 1H); 5.2 m (H-7; 1H); 4.7 dd (H-58; 1H); 4.1 m (H-68; 1H).

MS: m / e 271 (M% · 100%); 201 (51%).

6. N-Demethyldihydromorphine 3.71 g (10 mmol) of 3,6-di-O-acetyldihydromorphine are dissolved in 100 ml of 1,2-dichloroethane, then N-demethylolate as described in Example 5.

Yield: 1.65 g (60%), m.p. 262-266 ° C.

PMR (DMSO-d 6): 6.5 dd (H-1.2? 2H); 4.2 d (H-5B; 1H); 3.8 m (H-68; 1H).

MS: m / e 273 (M +; 100%); 228 (22%); 150 (45%).

7. N-Demethylmorphinyl-3-ethyl ether 3.55 g (10 mmol) of 6-O-acetylethylmorphline are N-demethylold as described in Example 3. As the solution cools, the hydrochloride of the product separates, is filtered and washed with cold water. The salt gives a base which is crystallized from ethanol.

Yield: 2.5 g (84%), m.p. 156-157 ° C.

8. N-Demethyl-1-hydromorpholine-3-ethyl-ether / 3.57 g (10 mmol) of 6-O-acetyl-dihydroethylmorphine to N-demethylold as described in Example 4. The hydrochloric acid solution is made alkaline and the product is obtained by extraction and crystallization from ethyl acetate.

i2 815S3

Yield: 2.32 g (77%), m.p. 128 - 131 eC.

PMR (CDCl 3): 6.6 dd (H-1.2; 2H); 4.5 d (H-58; 1H); 4.1 m (O-CH 2 -CH 3; 2H); 3.95 m (H-68; 1H); 1.4 t (O-CH 2 -CH 3; 3H).

MS: m / e 301 (M +; 100%).

9. N-demethyldecoxycodellin-E

1.42 g (5 nunol) of deoxycodein-1-E are dissolved in 50 ml of 1,2-dichloroethane. 0.5 g (5 nunol) of sodium carbonate is added to the solution and 6.0 ml (50 mmol) of diphosgene are added dropwise to the resulting suspension with stirring and cooling. After stirring for 30 minutes, cooling is stopped and the mixture is boiled with stirring for 15 hours. The cooled mixture is washed with nitrogen, the inorganic salt is filtered and the organic phase is washed with cold 5% hydrochloric acid (2 x 20 ml) and brine. The dichloroethane is evaporated off under vacuum, 60 ml of water are added to the residue and then heated on a water bath for eight hours. The mixture was allowed to cool, made alkaline (pH 10, concentrated NH 4 OH) and extracted with chloroform (3 x 30 mL). The extract is dried (magnesium sulfate) to give homogeneous N-demethyldeoxycodeine-E (0.6 g, 60%) by thin layer chromatography. The base does not crystallize, but when its ethanol solution is acidified with 48% hydrobromic acid, crystalline hydrobromide is obtained. Sp. 207-310 ° C (m.p. 311-312 ° C in the literature; R. L. Clark et al .: J. Am. Chem. Soc. 75, 4963, 1953).

10. N-demethyldihydrodeoxycodeine-E

1.4 mg (5 mmol) of dihydrodeoxycodeine-E are used as starting material in the process of Example 9.

Extraction with chloroform gives 0.45 g (33%) of crystalline N-demethyldihydrodeoxycodeine-E. Crystallized from ethyl acetate, m.p. is 91-92 ° C (according to the literature, m.p. 92-94 ° C; R. L. Clark et al .: J. Am. Chem. Soc. 75, 35 4963, 1953).

li

Claims (4)

A process for the preparation of compounds containing an N-demethylmorphinan backbone having the general formula 5 (III) 10 / - \ \ \ 0 / \ f (III) If wherein 15. is -CH2-CH2- or -CH-CH-, Y is oxygen or a group R 3 R 4, wherein R 3 is hydrogen and R 4 is hydroxy, and R x is hydrogen or C 1-6 alkyl, characterized in that the morphinan alkaloid of general formula (I) N-CH 2 (oW) «r» 25 \ - /> - / R 1'0 ^ wherein R 1 'is C 1-4 alkyl or acetyl, And Y' is Y or acetyloxy is reacted with diphosgene in 1.2-30 dichloroethane at a temperature 0 to 120 ° C in the presence of an alkali metal bicarbonate or an alkali metal hydrogen carbonate, and without isolating the formed N-chlorocarbonyl-N-demethyl derivative of the general formula (II) 35 14 S1 8 8 3 o Λ ^ -C-Cl (Pyx ^ y (II) in which Z, Y 'and Rx' have the same meaning as in the general formula (1), this is heated in water or in a 5% hydrochloric acid solution. Process according to Claim 1, characterized in that the molar ratio of morphinan alkali of general formula (I) to diphosgene is 1: 3 to 1:20, preferably 1:10, and the molar ratio of morphinan alkaloid of general formula (1) to alkali metal carbonate or alkali metal hydrogen carbonate is 1: 0.5-1: 2, preferably 1: 1. Process according to Claim 1, characterized in that the reaction with diphosgene is carried out at a temperature of from 20 to 120 ° C, preferably from 80 to 20 ° C. Process according to Claim 1, characterized in that alkali metal carbonate, preferably sodium carbonate or potassium carbonate, alkali metal hydrogen carbonate, preferably potassium hydrogen carbonate or sodium hydrogen carbonate, in particular sodium carbonate, is used as catalyst and / or acid-binding agent. is 81583