NO161915B - PROCEDURE FOR N-DEMETHYLING OF MORPHINAN ALKALOIDS. - 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

The present invention relates to a new process for the preparation of compounds with an N-demethylmorphine skeleton of general formula (III)

in which

Z denotes CH2~CH2 or CH=CH,

Y is an oxygen atom or R and R4 in which R3 denotes a

hydrogen atom, and R^ denotes hydrogen,

R 1 is a hydrogen atom or a C 1-3 alkyl group.

Replacement of the N-methyl group in morphine alkaloids with another alkyl group led to the discovery of morphine antagonists which are significant from a pharmacological and therapeutic point of view, as well as separation of the agonistic and antagonistic effects (Adv. in Biochem. Psychopharm. volume 8 : Narcotlc Antagonists (Raven Press, New York 1974);

E. F. Hahn: Drugs of the Future 9( 6), 443 (1984)).

As the morphinan alkaloids (morphine, codeine, thebaine) can be obtained from natural plant sources, most methods have involved trying to produce secondary amines from the above-mentioned N-methyl-t-amines. (The secondary amine can be converted to the desired compound later by N-alkylation). It is appropriate to replace the N-methyl group with an easily hydrolyzable functional group.

The requirements for the N-demethylating agent are as follows: it must be cheap, stable, easy to manufacture, it must exhibit sufficient reactivity and ensure good yields and must not be toxic.

Cyan bromide, which was formerly widely used for N-demethylation of the morphinan skeleton (H.A. Hageman: Org. Reactions 1_, 198 (1953)), has been gradually displaced by chloroformate esters during the last few years. The biggest disadvantage of cyanogen bromide is that it is relatively toxic, due to its volatile nature it is appropriate to prepare this fresh before use, and on the other hand, several authors have described its explosive nature.

The acid (or alkaline) hydrolysis of the cyanamides formed by the von Braun reaction may lead to a partial cleavage (or conversion) of the molecule in certain cases (A. C. Currie, G. T. Newbold, F. S. Spring: J. Chem. Soc. 4693 (1961)), or the reaction stops in the urea phase (K.W. Bentley, D.G. Hardy: J. Am. Chem. Soc. 89, 3281 (1967)).

In contrast, the chloroformic acid esters can be easily processed, they are less toxic compounds, and purification of these can easily be carried out by distillation. methyl, ethyl

and the phenylesters that were first used gave excellent yields (85-95%) in the course of the N-demethylation

(M.M. Abdel-Monem, P.S. Portoghese: J. Med. Chem. !L5, 208

(1972); GO. Brine, K.G. Boldt, C.K. Hart, F.I. Carroll: Organic Prep. Procedure Int. 8, 103 (1976); K.C. Rice,

E.L. May: J. Heterocyclic Chem. 14, 665 (1977)).

It was found that isolation of the urethane intermediates is necessary and these can be directly converted by a base or a hydrazine. Since the above-mentioned hydrolysis is relatively long-lasting (24 to 48 hours) and since during this time cleavage and side reactions can take place, in recent times chloroformic acid-2,2,2-trichloroethyl ester

(I.J. Borowitz, V. Diakiw: J. Heterocyclic Chem. 12, 1123

(1975); J.I. DeGraw, J.H. Lawson, J.L. Crase, H.L. Johnson, M. Ellis, E.T. Uyeno, G.H. Loew, D.S. Berkowitz: J. Med. Chem. _21, 415 (1978)) and the chloroformic acid vinyl ester became

proposed for N-demethylerNone.

The advantage of the trichloroethyl ester is that it is reactive and that the formed urethanes can be easily split with activated zinc powder. However, it is a disadvantage that the cleavage of the urethanes obtained from the 14-acyloxymorphinans is accompanied by 0—>N-acyl migration (German publication no. 2 727 805) which does not enable a direct preparation of the N-demethyl derivative.

In the literature there are also examples in which a zinc complex of the N-demethyl derivative is formed (N.P. Peet: J. Pharm. Sei. 69, 1447 (1980)). According to the literature, the chloroformic acid vinyl ester is the best N-demethylating agent (US Patent 3,905,981, 4,141,897, 4,161,597). This agent is highly reactive due to the electron-withdrawing character of the vinyl group so that it ensures quantitative turnover.

If the vinyl urethanes are treated with an equivalent amount of acid (hydrochloric acid, hydrogen bromide), addition takes place, and when boiled with methanol, a salt of the secondary amine is formed. Cleavage of the urethane thus takes place under very mild reaction conditions so that the secondary amine can be obtained in good yield and in high purity.

If the urethanes formed from 14-0-acylmorphinans are treated with an acid, the salt (hydrochloride, hydrobromide, etc.) of the 14-'0-acyl-N-demethyl compound is formed, i.e. that in this case no 0-^N takes place -acyl migration. In addition to the advantages stated above, however, it should be noted that the production of the chloroformic acid vinyl ester is problematic (due to pyrolysis), which makes it necessary to study further N-demethylation methods. Diphosgene was chosen because this has been successfully used for N-demethylation of the tropane alkaloids. The disphosgene or chloroformate trichloromethyl ester can be readily prepared by chlorination of chloroformate methyl ester (A. Efrati, I. Feinstein, L. Wackerle, A. Goldman: J. Org. Chem. 45, 4059 (1980)? K. Kurita, Y. Iwakura: Org. Synth. J59, 195,

(1980)).

As diphosgene behaves in most reactions similar to phosgene (1 mol of diphosgene gives off 2 mol of phosgene), its boiling point is 128°C, its voltage is low (10 mmHg) at room temperature, recently the highly toxic phosgene more and more being replaced with dysphosgene. The disphosgene and phosgene react with tertiary amines in a similar manner to the chloroformate esters, the methyl group is split off in the form of methyl chloride, and carbamoyl chloride is formed, and in the case of disphosgene, phosgene is also formed (H. Babad, A.D. Zeiler: Chem. Rev. 73f 75 (1973) ).

Phosgene was proposed for the N-demethylation of tertiary amines as analogous to the reaction according to Braun as early as 1947 (V.A. Rudenko, A.Y. Jakubovich, T.Y. Nikoforova: J. Gen. Chem. (USSR) 17, 2256 (1947); CA. 4_2, 4918e ).

Since phosgene together with tertiary amines can form complexes in an amine-phosgene ratio of 1:1 and 1:2 and since by splitting the latter a tertiary amine is formed

(H. Babad, A.D. Zeiler: Chem. Rev. 73, 75 (1973)), the use of an excess of phosgene is suitable because tetrasubstituted urea is also formed if the amine is used in excess.

Banholzer et al. (in British patent specification 1 166 798 and

1,167,688 and R. Banholzer, A. Heusner, W. Schulz: Liebig's Ann. Chem. 2227 (1975)) were the first to describe N-demethylation of alkaloids with a tropane skeleton with phosgene and diphosgene. During heating of the obtained carbamoyl chloride (isolation is not necessary) with water, this hydrolyzes to secondary amine chloride hydrate and carbon dioxide.

On the basis of the above indications it seemed appropriate to investigate the N-demethylation of compounds with a morphinane skeleton with diphosgene as the hydrolysis of the carbamoyl chlorides would probably take place under much milder conditions than of the urethanes or cyanamides.

As a model compound, dihydrocodeinone was chosen, and it was found that it emits the expected N-chlorocarbonyl-N-demethyl-dihydrocodeinone with diphosgene in a solution containing 1,2-dichloroethane (or dichloromethane,

chloroform, carbon tetrachloride, benzene, toluene).

The structure of the latter was also confirmed by the fact that the dihydrocodeinone exhibited a similar reaction with phosgene, and on the other hand, boiling the chloro-carbonyl compound with ethanol produced the urethane described in the literature, N-ethoxycarbonyl-N-demethyl -dihydrocodeinone, (G. Horvåth, P. Kerekes, Gy. GaSl,

R. Book year: Acta Chim. Acad. Pollock. Hung. 8_2, 217 (1974)).

Anhydrous sodium carbonate catalyzes the formation of the N-chlorocarbonyl derivative, in addition to the fact that it is also appropriate to use anhydrous sodium carbonate to bind possible traces of acid. The N-chlorocarbonyl derivative is then heated with water and can be hydrolysed to N-demethyldihydro, codeinone chlorohydrate.

Hydroxy groups originating from alcohols or phenols can be acylated by dysphosgene and phosgene during the formation of hydrochloric acid, and hydrochloric acid binds the tertiary amine, which is why it is appropriate to protect the morphine derivatives containing a hydroxyl group by acylation.

During the course of the hydrolysis of the carbamoyl chloride formed by N-demethylation of 3-O-acetyl-dihydromorphinone, a deacetylation also took place, and N-demethyl-dihydromorphinone chlorohydrate was formed. However, in the aqueous hydrolysis of 6-0-acetyl-N-chlorocarbonyl-N-demethylcodeine obtained from 6-0-acetylcodeine, 6-0-acetyl-N-demethylcodeine was formed, therefore the hydrolysis in the case of morphine, codeine, ethylmorphine, dihydrocodeine, dihydroethylmorphine, dihydromorphine, was performed with hydrochloric acid at a concentration of 5%. The appropriate N-demethyl compound was thus isolated as a uniform product.

The present method is suitable for N-demethylation of dihydrocodeinone, dihydromorphinone, codeine, dihydrocodeine, morphine, dihydromorphine, ethylmorphine, dihydroethylmorphine, desoxycodein-E, dihydrodesoxycodein-E, 14-hydroxy-dihydrocodeinone, 14-hydroxycodeinone, 14-hydroxy-dihydromorphinone, 3 -0-benzylmorphine, azidomorphine.

The method according to the invention is characterized by the fact that morphine alkaloids of general formula (I)

in

where R is or an acetyl group, and Y is Y or an acetyl group, is reacted with phosgene or diphosgene in a solvent at temperatures of from 0 to 120°C in the presence of alkali carbonates/alkali hydrocarbonates, after which the formed N-chlorocarbonyl-N -demethyl derivative of general formula (II)

in which Z, Y<1> and R^ are as defined above, without insulation is heated with water or a dilute, inorganic acid.

One of the important features of the invention is the recognition that the suitable N-chlorocarbonyl-N-demethyl derivative can be hydrolysed under mild and simple reaction conditions, i.e. that no cleavages and harmful side effects occur, and no toxic mother liquors are formed during the manufacturing process and waste fluids.

The use of phosgene and diphosgene is most advantageous compared to cyanide bromide and the chloroformate esters in terms of the reagents' degree of danger, difficulties associated with their manufacture, price and their availability for processes on an industrial scale.

In the method according to the invention, the use of diphosgene is considered more advantageous in relation to the toxic phosgene when one takes into account that the phosgene formed during the course of the reaction of phosgene can be safely removed from the system by washing with nitrogen in a suitable washer.

The method according to the invention is suitable for the economic production of the N-demethylmorphinan derivatives which are important from a pharmacological and therapeutic point of view.

The invention is further illustrated in the following examples. Melting points were determined on a Koffler apparatus and the data are uncorrected. For thin-layer chromatographic investigations, Merck 5554 silica gel 60F254 foils were used. Eluents: benzenermethanol =

8:2; chloroform:methanol = 9:1, and chloroform:acetone:ethylamine = 5:4:1 (v/v). The spots were detected in UV light and with

a Dragendorff reagent. PMR spectra were taken on a Bruker W200SY apparatus at 200 MHz. The chemical shifts are indicated in S (ppm). The mass spectra were performed on an apparatus of the type VG-703 5 (GC-MS-DS) with the electron impact ionization method.

Example 1

N-demethyl-dihydrocodeinone

3 g (10 mmol) of dihydrocodeinone was dissolved in 60 ml of 1,2-dichloroethane, 1 g (10 mmol) of sodium carbonate was added, and with stirring at a temperature of 0°C, 19.8 g (12 ml, 100 mmol) diphosgene added drop by drop. The mixture was stirred at 0°C for 30 minutes, then allowed to warm to room temperature and boiled with stirring for 10 hours. The mixture was washed thoroughly with nitrogen, the inorganic salt was filtered off. The solution containing 1,2 dichloroethane was washed with 3 x 20 ml of 5% hydrochloric acid (ice-cold), after which the organic phase was evaporated in vacuo. 100 ml of water was added to the residue which was heated on a water bath for 5 hours. The solution was cooled to below 10°C and made alkaline (pH value = 9-10) with concentrated ammonium hydroxide. After extraction with 3 x 50 ml chloroform, the organic phase was washed with salt water and dried over magnesium sulfate. Yield: 2.33 g (82%), mp: 150-151°C (ethyl acetate)

PMR (CDCl 3 ): 6.66 dd (H-1.2; 2H); 4.7 s (H-5P; 1H); 3.9 p

(OHCH3?3H).

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

0.4 g (13%) of dihydrocodeinone can be recovered from the 5% hydrochloric acid solution by making it alkaline (concentrated ammonium hydroxide) and extracting (chloroform).

Example 2

N- d erne thy1- d ihydromorph inon

3.3 g (10 mmol) of 3-O-acetyl-dihydromorphinone was dissolved in 60 ml of 1,2-dichloroethane, 1 g (10 mmol) of sodium carbonate was added, and with stirring at 0°C, 19.8 g ( 12 ml,

100 mmol) diphosgene added dropwise. The mixture was stirred at 0°C for 30 minutes, then allowed to warm to room temperature and boiled with stirring for 15 hours. The mixture was washed with nitrogen, the inorganic salt was filtered off. This was washed with 3 x 20 ml of 5% hydrochloric acid, after which the organic phase was evaporated in vacuo. 100 ml of water was added to the residue which was boiled for 8 hours. The mixture

was cooled to below 10°C, and the hydrochloride of the product was separated in crystalline form. This was filtered and washed with cold water. Yield: 2.15 g (70%) of chlorohydrate.

Melting point of the base recovered from this: 300-303°C. The starting compound was recovered from the 5% hydrochloric acid solution as described in Example 1.

Example 3

N-demethylcodeine

3.41 g (10 mmol) of 6-O-acetylcodeine was dissolved in 80 ml of 1,2-dichloroethane, 1 g (10 mmol) of sodium carbonate was added, and while stirring at 0°C, 19.8 g (12 ml, 100 mmol) diphosgene added dropwise. The mixture was stirred at 0°C for 30 minutes and then allowed to warm to room temperature and was stirred and boiled for 20 hours. The mixture was flushed with nitrogen and the inorganic salt was filtered off. The residue was washed with 3 x 20 ml of 5% hydrochloric acid and then evaporated. The residue was boiled with 5% hydrochloric acid for 5 hours. The solution was then cooled to below 10°C, the product separated in crystalline form and was filtered off and washed with ice water. The crystalline chlorohydrate was dissolved in water, made alkaline with concentrated ammonium hydroxide, extracted with chloroform, whereupon the chloroform phase was dried and evaporated. The base thus obtained was crystallized from acetone or ethyl acetate.

Yield: 2.3 g (80%), m.p. 185°C.

PMR (CDCl 3 ): 6.65 dd (H-1.2; 2H); 5.7 m (H-8; 1H);

5.3 m (H-7; 1H); 4.9d (H-53; 1H); 4.2 m

(H-63; 1H); 3.8 s (OMe; 3H).

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

Example 4

N-demethyl-dihydrocodeine

3.43 g (10 mmol) of 6-0-acetyl-dihydrocodeine was N-demethylated as described in example 3. After acid hydrolysis while cooling, the hydrochloride salt was not separated from the solution, which is why it was directly made alkaline with conc.

triturated ammonium hydroxide, whereupon the product was obtained by chloroform extn. and crystallized from ethanol. Yield: 1.9 g (66%), m.p. 194°C.

PMR (CDCl 3 ): 6.7 dd (H-1,2; 2H); 4.6d (H-53; 1H); 4.1 m

(H-63; 1H); 3.8 s (OMe; 3H)

MS: m/e 287 (M<+>; 100%).

Example 5

N-demethylmorph in

3.7 g (10 mmol) of 3,6-di-0-acetylmorphine was dissolved in 100 ml of 1,2-dichloroethane and was then N-demethylated as described in example 3. After cooling the hydrochloric acid solution, the pH value was adjusted to 9 with concentrated ammonium hydroxide. The product separated in crystalline form and was filtered and washed with cold water. Yield: 2.1 g (77%); obtaining first 1.8 g and then 0.3 g from the alkaline solution using chloroform-isopropanol (3:1, v/v) by extraction. Temp. 274-277°C.

PMR (DMSO-dg): 6.4 dd (H-1,2; 2H); 5.6 m (H-8; 1H); 5.2 m (H-7; 1H); 4.7 dd (H-53? 1H); 4.1 m

(H-63; 1H)

MS: m/e 271 (M<+>; 100%); 201 (51%).

Example 6

N-demethyl-dihydromorphine

3.71 g (10 mmol) of 3,6-di-O-acetyl-dihydromorphine was dissolved in 100 ml of 1,2-dichloroethane and was N-demethylated as described in example 5.

Yield: 1.65 g (60%), m.p. 262-266°C.

PMR (DMS0-d6); 6.5 dd (H-1,2; 2H); 4.2d (H-53; 1H);

3.8 m (H-63; 1H)

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

Example 7

N-demethylmorphln-3-ethylethene

3.55 g (10 mmol) of 6-0-acetyl-ethylmorphine was N-demethylated as described in example 3. During cooling,

the chloral hydrate was separated from the product, which was filtered and washed with cold water. From this the base was recovered and crystallized from ethanol.

Yield: 2.5 g (84%), m.p. 156-157°C.

Example 8

N-demethyl-dihydromorphln-3-ethyl ether

3.57 g (10 mmol) of 6-0-acetyl-dihydroethylmorphine was N-demethylated as described in example 4. The product was obtained by making the hydrochloric acid solution alkaline followed by extraction, after which the product was crystallized from ethyl acetate.

Yield: 2.32 g (77%), m.p. 128-131°C.

PMR (CDCl 3 ): 6.6 dd (H-1.2; 2H); 4.5 d (H-53; 1H); 4.1 m (O-CH 2 -CH 3 ; 2H); 3.95 m (H-63; 1H); 1.4 h

(0-CH2-CH3; 3H)

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

Example 9

N- demethyl- desoxycodein- E

1.42 g (5 mmol) of desoxycodein-E was dissolved in 50 ml of 1,2-dichloroethane. 0.5 g (5 mmol) sodium carbonate was added, and to the resulting suspension 6.0 ml (50 mmol) diphosgene was added dropwise while stirring and while cooling. After 30 minutes of stirring, the cooling was stopped, after which the mixture was boiled for 15 hours with stirring. After cooling, the mixture was flushed with nitrogen, and the inorganic salt was then filtered, and the organic phase was washed with 2 x 20 mL of cold 5% hydrochloric acid and brine. The dichloroethane was evaporated in vacuo to the residue, 60 ml of water was added, and the mixture was heated on a water bath for 8 hours. After cooling, the mixture was made alkaline (pH 10; conc. NH 3 OH) and was extracted with 3 x 30 ml chloroform. After drying the chloroform (magnesium sulfate), 0.6 g (60%) of N-demethyl-desoxycodein-E was obtained which was homogeneous according to thin layer chromatography. The base did not crystallize out, but when an alcoholic solution of it was acidified with

48% hydrogen bromide, crystalline hydrobromide can be obtained. Melting point: 307-310°C (literature melting point: 311-312°C, R.L. Clark et al.: J. Am. Chem. Soc. 75, 4963 (1953)).

Example 10

N- demethyl- dihydrodesoxycodein- E

1.4 mg (5 mmol) of dihydrodesoxycodein-E was used as starting compound and was processed as described in example 9. After extraction with chloroform, 0.45 g (33%) of crystalline N-demethyl-dihydrodesoxycodein-E was obtained. After the product was crystallized from ethyl acetate, the melting point was 91-92°C (literature melting point: 92-94°C? R.L. Clark et al.: J. Am. Chem. Soc. 25, 4963 (1953)).

Claims (3)

1. Process for the preparation of compounds with N-demethylmorphine skeleton of general formula (III) in which Z denotes CH2~CH2 or -'CH=CH, Y is an oxygen atom or R and R4 in which R3 denotes a hydrogen atom, and R^ denotes hydrogen, Rj^ is a hydrogen atom or a C^_3~alkyl group, characterized in that morphine alkaloids of general formula (I) i i where R^ is R^ or an acetyl group, and Y is Y or an acetyl group, is reacted with phosgene or diphosgene in a solvent at temperatures of from 0 to 120°C in the presence of alkali carbonates/alkali hydrocarbonates, after which the formed N- chlorocarbonyl-N-demethyl derivative of general formula (II) in which Z, Y<1> and R| is as defined above, without insulation is heated with water or a diluted, inorganic acid. 2. Method according to claim 1, characterized in that the molar ratio between morphine alkaloids of general formula (I) and phosgene/diphosgene is 1:3 - 1:20, suitably 1:10, and that the molar ratio between the morphine alkaloids of general formula (I) and alkali -carbonates/alkali hydrocarbonates is 1:0.5 - 1:2, suitably 1:1. 3. Method according to claim 1, characterized in that the reaction with phosgene/diphosgene is carried out at a temperature of 20-120°C, suitably 80°C.