DD235639A5 - PROCESS FOR THE N-DEMETHYLATION 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

16 488 55

Process for the N-demethylation of morphinan alkaloids

Field of application of the invention:

The invention relates to a process for the preparation of Morphinan alkaloids of the general formula (III) with Morphinan structure by N-demethylating Morphinanalkaloiden of the general formula (I).

Characteristic of the known technical solutions:

The replacement of the N-methyl group of morphine alkaloids with another alkyl group resulted from a pharmacological and therapeutic point of view in the discovery of major morphine antagonists as well as the separation of agonist and antagonist activity (Adv., Biochem., Psychopharm., Vol 8: Narcotic Antagonists / Raven Press, New York ); EF »Cock: Drugs of the Future 9/6 / , 443/1984 /).

Since the morphine alkaloids (morphine "codeine _t tainain) are available from natural (plant) sources, most of the processes seek to produce secondary amines from the above N-methyl tertiary araines. (The secondary amine can be further converted to the desired compound by N-alkylation.) It is convenient.

25.IQ85- 2S23-.S

the N-methyl group in the other to be replaced by a readily hydrolyzable functional group.

The requirements of the N-demethylating agent are the following: it should be cheap, stable, easy to produce, have sufficient reactivity, good yields and not be toxic. The earlier to. N-demethylation of the morphine structure commonly used cyanogen bromide (H. A. Hageman: Org. Reactions 7, 198/1953 /) has been displaced in recent years more and more of the Chloramiesensäureestern. The biggest disadvantage of cyanogen bromide is that it is very toxic, because of its (instability must be freshly prepared before consumption, on the other hand, several authors mention its explosiveness.

The acidic (or alkaline) hydrolysis of the cyanamides formed in the reaction by Braun may, in certain cases, lead to the partial decomposition (or reaction) of the molecule (AC Currie, GT Newbold, FS Spring: O. Chem. Soc. 4693/1961 / ), or else it stops the reaction in the urea phase (KW Bentley, DG Hardy: 3rd era, Chem. Soc., 89, 3281/1967). In contrast, the chloroamic acid esters can be easily treated, they are less toxic compounds and their purification can easily be done by distillation. The methyl, ethyl and phenyl esters used at the beginning gave excellent yields (85-95 %) in N-demethylation (MM Abdel-Monem, PS Portoghese: 0. Med. Chem. Ij5, 208/1972 / Hart, FI Carroll: Organic Prep Proced, Int. £, 103/1976 /; KX Rice, EL May: 3rd Heterocyclic Chem., 14, 665/1977 /).

It has been found that isolating the ether-mediurethane derivatives is not necessary, they can be further reacted directly by a caustic or hydrazine

The above hydrolyses are quite tedious (24-48 hours) and decay and also side reactions can already take place during this time. Later, for N-demethylation, chloroformic acid-2,2-trichloroethyl ester (1.3 × Borowitz, V Diakiw: 3 Heterocyclic Chem. 12, 1123/1975; DI De Graw, DH Lawson, 3rd L Crase, HL "Johnson, M. Ellis, ET Uyeno, GH Loew, DS Berkowitz: 0. Med. Chem. 2_1, 415 / 1978 /) and vinyl chloroformate.

The advantage of Trichloräthylesters is that it is reactive and the resulting urethanes can be easily cleaved by activated zinc powder, However, a disadvantage is that the cleavage of the urethanes obtained by the 14-acyloxy-morphinanes by Acylwandern 0 - ^ N takes place; , φΕ ~ Ο $ 2,727,805 ), which does not allow direct preparation of the N-oemethyl derivative.

There is also an example in the literature where the zinc complex of the N-demethyl derivative is formed (N- * P. Peet: 3. Pharm. Sei, 69, 1447/1980 /). According to previous indications in the technical literature, the vinyl chloroformate is the most ideal N-demethylating active substance (US Pat. Nos. 3,905,981, 4,141,897 and 4,161,597). This substance is very reactive due to the electron-attracting effect of the vinyl group, thereby ensuring quantitative reactions.

When the vinylurethanes are treated with an equivalent acid (hydrochloric acid, hydrogen bromide), an addition proceeds, and boiling with methanol produces the salt of the secondary amine. The splitting of the urethane is thus carried out under very mild reaction conditions, and cjs can be obtained the secondary amine in good yield and high purity.

The urethanes formed from 14-0-acyl-morphinans are treated with acid, and the salt (hydrochloric acid, hydrogen-bromide-containing) of the compound 14-0-acyl-N-demethyl is formed, in which case it does not occur

0> N Acyl migration. In addition to the mentioned advantages must

however, it is to be noted that the problem of vinyl chloroformate production is difficult to solve (due to pyrolysis), which necessitated the study of further N-demethylation methods. Diphosgene was chosen because it was successfully used for N-demethylating tropane alkaloids , The diphosgene or trichloromethyl chloroformate can be readily prepared by the chlorination of methyl chloroformate (A. Efrati I. Feinsein, L. Wackerle, A. Goldman: 3. Org. Chem. 45, 4059/1980 /; K. Kurita, Y. Iwakura: Org. Synth. 59, 195/1980 /).

Since it behaves similarly in most reactions such as (a mole diphosgene provides 2 moles of phosgene), its boiling point is 128 ⁰ C is its Tension (10 mmHg) is niadrig at room temperature, it has recently been striving the highly toxic phosgene by diphosgene to replace. The diphosgene and the phosgene react with tertiary amines similar to chloroformates »the methyl group is split off in the form of methyl chloride and carbamoyl chloride is formed in diphosgene also produces phsogen (H. Babad, AD Zeiler: Chem. Rev. 73_, 75/1973 /). The phosgene was probed for N-demethylation of tertiary amines as analogous to the Braun reaction as early as 1947 (VA Rudenko, AY Oakubovich, TY Nikiforova: O. Gen. Chem. (USSR) 17 , 2256/1947 /; CA. 42, 4918e).

Since the phosgene with tertiary amines amine-phosgene complexes in the ratio 1: 1 and 1: 2 form, and the disintegration of the latter, a tertiary amine is formed (H. Babad, A.D.

Zeiler: Chem. Rev. 73_, 75/1973 /), the use of phosgene excess is expedient because tetrasubstituted urea forms when the amine is in excess.

Banholzer et al. GB-PS 1 166 798 and 1 167 688 and R. Banholzer, A. Heusner, W. Schluß: Liebigs Ann. Chem. 2227/1975 /) mentioned as first the N-demethylation of alkaloids / with tropane structure with phosgene and diphosgene. The resulting carbamoyl chloride (need not be isolated) is hydrolyzed with water heated to secondary amine chlorohydrate and carbon dioxide. \

Accordingly, N-demethylation of compounds having morphine anion structure with diphosgene has been studied since hydrolysis of the carbamoyl chlorides is then possible under significantly milder conditions than that of the urethanes or cyanamides.

As a model compound, dihydrocodeinone was chosen and found to provide the expected N-chlorocarbonyl-N-demethyl-dihydro-codeinone with diphosgene in a solution containing 1,2-dichloroethane (or dichloromethane, chloroform, carbon tetrachloride, benzene, toluene).

The structure of this compound was also confirmed by the fact that the dihydrocodeinone had a similar reaction with phosgene, on the other hand that when the chlorocarbonyl compound was boiled with ethanol, the urethane described in the trade, N-ethoxycarbonyl-N-demethyl -dihydrokodeinone (G, Horväth, P. Kerekes, Gy. Gaal, R. Bognär: Acta Chim. Acad. Sei. Hung. 82, 217/1974 /). The formation of the N-chlorocarbonyl derivative is catalyzed by anhydrous sodium carbonate. It is also useful because of the formation of traces of acid.

moderately, to use anhydrous sodium carbonate. Furthermore, the N-chlorocarbonyl derivative can be hydrolyzed with water to give N-demethyldihydrocodeinone hydrochloride hydrolyzed «

The diphosgene and phosgene acylate the alcoholic and phenolic hydroxy groups during the formation of hydrochloric acid, and the hydrochloric acid binds the tertiary amine, therefore, it is convenient to protect the hydroxyl group-containing morphine derivatives by acylation.

For example, in hydrolyzing the carbamoyl chloride resulting from the N-demethylation of 3-O-acetyl-dihydromorphinone, deacetylation also occurred to give N-demethyl-dihydromorphinone hydrochloride. However, upon aqueous hydrolysis of the 6-O-acetyl-N-chlorocarbonyl-N-deraethyl-codein derived from 6-O-acetyl-codein, 6-O-acetyl-N-demethyl-codein was formed, therefore morphine became codeine , Ethylmorphin, Dihydrocodein, Dihydroäthylmorphin, Oihydromorphine carried out the hydrolysis with 5% hydrochloric acid. Thereby, the corresponding N-demethyl compound was isolated as a unitary product.

Object of the invention: ^l

The present process is for the N-demethylation of dihydrocodeinone , dihydromorphinone, codeine, dihydrocodein, morphine , dihydromorphine, ethylmorphine, dihydroethylmorphine, deoxycodein-E , dihydrodeoxy-codein-E, 14-hydroxy-dihydro-codeinone, 14-hydroxy-codeinone / 14- Hydroxy-dihydromorphinone, 3-0-benzyl- _# orphin, azidomorphine suitable.

Explanation of the essence of the invention:

The essence of the invention is that rait one in the circle of compounds with Morphinan structure not yet used method Morphinanalkaloide the general formula (I) with phosgene or diphosgene to N-chlorocarbonyl-N-demethyl compounds of the general formula (II ) and the latter can be converted into N-demethyl derivatives of the general formula (III) in good yield after reaction with water or thin mineral acid.

In the general formula ^ (I), (II), (HI), the substituents have the following meanings:

Z is CH ₂ -CH ₂ or CH = CH, Y is an oxygen atom or R-, and R _{4 is} where

R ₃ is a hydrogen atom, a hydroxyl group f is an acyloxy group having 1 to 3 carbon atoms or a benzoyloxy group, wherein Rj is located in dU- Raumstellung,

R 1 is a hydrogen, halogen, hydroxyl, acyloxy group of 1 to 3 carbon atoms, an alkyl group of 1 to 3 carbon atoms, a benzoyloxy or an azido group, where R is located in a β-position R ₂ is a hydrogen atom, an acyloxy group having 1 to 3 carbon atoms,

ν or a benzoyloxy group

R 1 represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an aryl or aralkyl group, an acyl group

with 1 to 3 carbon atoms or a benzoyl group

with the restriction that

when R _{3 represents} a hydrogen atom, a hydroxyl group, acyloxy or benzoyloxy group,

R _{4 is} a hydrogen atom or an alkyl group, and

when R4 is a hydrogen atom, a halogen atom, a hydroxyl group, an alkyl, acyloxy, benzoyl, or azido group, R ₃ represents a hydrogen atom.

The spatial position of the groups R ₃ and R ₄ is as follows, depending on the meaning of the group Z:

when Z is CH ₂ -CH ₂ , then the spatial position of the group R _{3 is} axial and the spatial position of the group R _{4 is} equatorial; if Z is CH = CH, then the spatial position of the group R _{3 is} quasi-equatorial and that of the group R _{4 is} quasi-axial.

The invention is based on an important finding that the corresponding N-chlorocarbonyl-N ^ demethyl derivatives can be abhydrolysed under the mildest and simplest reaction conditions known hitherto, ie disintegration and harmful side reactions do not take place, no toxic mother liquors are formed during processing and sewage.

The use of phosgene and diphosgene is most advantageous for industrial scale processes, as compared to cyanogen bromide and chloroformate esters, both in terms of the severity of the reagents, the difficulty of their preparation, their price, and their affordability.

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In the method of the invention, the use of diphosgene compared to the toxic phosgene is considered to be more advantageous taking into account that the phosgene formed in the reaction of diphosgene can be safely removed from the system by purging with nitrogen through a suitable scrubber.

The process of the present invention is useful for economically producing the pharmacologically and therapeutically important N-demethyl-morphinan derivatives in industrial scale.

The present invention will be further illustrated by way of example with examples without being limited to the examples.

The melting points were determined in a Koffler apparatus, the data are not corrected. For the thin layer chromatography studies MERCK 5554 silica gel 60F__. Sheets used. Eluent: benzene; methanol = 8: 2; Chloroform = 9: 1, or chloroform: acetone: ethylamine = 5: 4: 1. / V / v /. The stains were detected with UV light and a Dragendorff reagent. PMR images were taken in a BRUKER W200SY type apparatus at 200 MHz. "Chemical shifts were reported in > f ( ppm). Mass spectra were prepared by electron impact ionization in apparatus VG-7035 / GC-MS-DS /.

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Embodiments; Example 1: N-demethyl-dihydrokodeinon

3 g (10 mM) Dihydrokodeinon are dissolved in 60 ml of 1,2-dichloroethane, 1 g (10 mM) of sodium carbonate is added and stirring at 8 ⁰ C 19.8 g (12 ml, 100 mM) are added dropwise diphosgene. The mixture is stirred at ⁰ ° C. for 30 minutes, then allowed to warm to room temperature and refluxed for 10 hours with stirring. It is purged with nitrogen, the inorganic salt is filtered off. With 3 χ 20 ml of 5% hydrochloric acid (ice cold), the solution containing 1,2-dichloroethane is washed, then the organic phase in! Vacuum evaporated. To the residue is added 100 ml of water, then heated on a water bath for 5 hours. It is then cooled and alkalized under 10 ⁰ C with concentrated ammonium hydroxide (pH = 9-10). After extraction with chloroform (3 × 50 ml), the organic phase is washed with brine and dried over magnesium sulfate. Yield: 2.33 g (82 %) m.p .: 15O-151 ° C (ethyl acetate) PMR (CDCl ₃ ): 6.66 dd (H-1.2; 2H); 4.7 sec (H-5β, IH);

3.9 S (OCH ₃ ; 3H)

MS: m / e 285 (M ⁺ , 23 %)

From the 5% hydrochloric acid solution can be recovered by alkalizing (concentrated ammonium hydroxide) and extraction (chloroform) 0.4 g (13 % ( dihydrocodeinone).

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Example 2: N-demethyl-dihydro-morphinone

3.3 g (10 mM) of 3-O-acetyl-dihydromorphinone are dissolved in 60 ml of 1,2-dichloroethane, 1 g (10 mM) of sodium carbonate is added and 19.8 g (12 ml, 100 mM) are added with stirring. Diphosgene added dropwise at ⁰ ° C. The mixture is stirred at ⁰ ° C. for 30 minutes, then allowed to warm to room temperature and refluxed for 15 hours with stirring. It is purged with nitrogen, the inorganic salt is filtered off. It is washed with 3 χ 20 ml of 5% hydrochloric acid, then the organic phase is evaporated in vacuo. To the residue is added 100 ml of water and boiled for 8 hours. It is cooled below 10 ⁰ C, the chlorohydrate of the product is deposited in crystalline form. It is filtered and washed with cold water.

Yield: 2.15 g (70 %); Hydrochloride melting point of the recovered therefrom Base: 300-303 ⁰ C. The starting material is recovered solution as in Example 1 from the solution of 5% hydrochloric acids.

Example 3: N-demethyl-codein

3.41 g (10 mM) of 6-O-acetyl-codeine are dissolved in 80 ml of 1,2-dichloroethane, 1 g (10 mM) of sodium carbonate is added, and 19.8 g (12 ml, 100 mM) are added with stirring. Diphosgene added dropwise at ⁰ ° C. The mixture is stirred for 30 minutes at 0 C, then allowed to warm to room temperature and stirred and boiled for 20 hours. It is purged with nitrogen, the inorganic salt is filtered off. The organic phase is washed with 3 × 20 ml of 5% hydrochloric acid and then evaporated. The residue

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is boiled with 60 ml of 5 % hydrochloric acid for 5 hours. It is cooled below 10 ° C., the product is separated off in crystals, filtered off and washed with ice-water. The crystalline hydrochloride is dissolved in water, alkalized with concentrated ammonium hydroxide and extracted with chloroform. The chloroform-containing phase is dried and evaporated. The base thus obtained is crystallized from acetone or ethyl acetate. Yield: 2.3 g (80 %) mp: 1S5 ° C PMR (CDCl ₃ ): 6.65 dd (HI, 2; 2H); 5.7 m (H-8; IH);

5.3 ra (H-7; IH); 4.9 d (H-5β, IH);

4.2 m (H-6β, IH); 3.8 s (OMe; 3H). MS: m / e 285 (M ⁺ , 100 %) , 215 (50 %)

Example 4: N-demethyldihydrocodein

3.34 g (10 mM) of 6-O-acetyl-dihydro-codein are N-demethylated as described in Example 3. After the acidic hydrolysis, the hydrochloric acid salt of the product does not precipitate out of the solution by cooling, therefore it is obtained by extraction with chloroform, extracted directly with concentrated ammonium hydroxide, and crystallized from ethanol.

Yield: 1.9 g (66%) Schrap .: 194 ⁰ C PMR _(CDCl3): 6.7 dd (HI, 2, 2H); 4.6 d (H-5β, IH);

4.1 m (H-6β, IH); 3.8 S (OMe; 3H) MS: m / e 287 (M ⁺ , 100 %)

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Example 5; N-desmethyl morphine

3.7 g (10 μM) of 3,6-di-O-acetyl-morphine are dissolved in 100 ml of 1,2-dichloroethane and N-demethylated as described in Example 3. After cooling the hydrochloric acid solution, the pH is adjusted to 9 with concentrated ammonium hydroxide. The product separates out in crystalline form, it is filtered off and washed with cold water. Yield: 2.1 g (77 %); first generation 1.8 g; from the alkaline solution chloroform-isopropanol (3: 1, v / v) applying by extraction 0.3 g second generation. M .: 274-277 ⁰ C

PMR (DMSO-d ₆ ): 6.4 dd (H-1,2; 2H); 5.6 m (H-8; IH);

5.2 m (H-7; IH); 4.7 dd (H-5β, IH);

4.1m (H-6: IH) MS: m / e 271 (M ⁺ , 100 %); 201 (51 %)

Example 6: N-demethyl-dihydromorphine

3.71 g (10 mM) of 3,6-di-O-acetyl-dihydromorphine are dissolved in 100 ml of 1,2-dichloroethane and demethylated as described in Example 5.

Yield: 1.65 g (60%), m.p .: 262-266 ⁰ C PMR (0MS0-d _6): 6.5 dd (Hl, 2; 23); 4.2 d (H-5: IH);

3.8m (H-6β; IH) m / e 273 (M ⁺ ; 100 %) ; 228 (22 %) ; 150 (45 %) .

Example 7: N-desmethyl morphine-3-ethyl ether

3.55 g (10 mM) of 6-O-acetyl-ethylmorphine are N-demethylated as described in Example 3. The chlorohydrate of the product separates by cooling, filtered and washed with cold water. From this, the base is recovered and crystallized from ethanol. Yield: 2.5 g (84%) Schrap .: 156-157 ⁰ C.

Example 8: N-demethyl dihydromorphine-3-ethyl ether

3.57 g (10 mM) of 6-O-acetyl-dihydroethylmorphine are N-demethylated as in Example 4. From the hydrochloric acid solution, the product is obtained by alkalization and extraction and crystallized from ethyl acetate. Yield: 2.32 g (77%) M.p .: 128-131 C ⁰ PMR _(CDCl3): 6.6 dd (H-1,2;> 2 H); 4.5 d (H-5β, IH);

4.1m (O-CH ₂ -CH ₃ ; -2H); 3.95 m (H-6S; IH);

1.4 t (O-CH ₂ -CH ₃ ; 3H) MS: m / e 301 (M ⁺ , 100 %) .

Example 9: N-demethyl-deoxy-codeine-E

1.42 g (5 mM) of deoxykodein-E are dissolved in 50 ml of 1,2-dichloroethane. 0.5 g (5 mM) of sodium carbonate is added, and 6.0 ml (50 mM) of diphosgene are added dropwise to the resulting suspension with stirring by cooling. After stirring for 30 minutes, the cooling is stopped, then the mixture is boiled for 15 hours with stirring. After cooling, it is purged with nitrogen, the inorganic salt is filtered off and the organic phase is washed with 2 × 20 ml

washed cold 5% hydrochloric acid and salt water. "The dichloroethane is evaporated in vacuo and the residue 60 ml of water are added. The solution is heated on a water bath for 8 hours. After cooling, it is alkalized (pH = 10, concentrated.NH40H) and extracted with 3 × 30 ml of chloroform. After drying the chloroform phase (magnesium sulfate), the N-demethyl-deoxy-codeine-E (0.6 g, 60 %) is obtained by vacuum evaporation , which is homogeneous by thin-layer chromatography. The base does not become crystalline, but when its alcoholic solution is acidified with 48% hydrogen bromide, crystalline hydrobromide is obtained.

Melting point: 307-310 ⁰ C. (melting point according to the literature: 311-312 ⁰ C, RL Clark et al .: G.Am.Chem Soc 75, 4963/1953 /..). >

Example 10: N-demethyl-dihydrodesoxykodein-E

1.4 g (5.mM) of dihydro-deoxycodeine-E are used as in Example 9 and, after extraction with chloroform, 0.45 g (33 %) of crystalline N-demethyl-dihydro-deoxy-codeine-E are obtained. Crystallized from ethyl acetate, the melting point 91-92 ⁰ C (melting point in the literature: 92-94 ⁰ C, RL Clark et al.: D. Am. Chem. Soc., 75, 4963/1953 /).

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Claims (7)

claims 1. A process for the preparation of compounds having N-dimethyl · raorphinan structure of the general formula (III), wherein Z is CH ₂ -CH ₂ or CH = CH, -Y is an oxygen atom or the group R ₃ and R ₄ , wherein
Rz represents a hydrogen atom, a hydroxyl group / an acyloxy group having 1 to 3 carbon atoms or a benzoyloxy group, wherein the substituent is located in the cO space position, R 1 is a hydrogen atom, halogen atom, a hydroxyl group, an alkyl group having 1 to 3 carbon atoms, an acyloxy group having 1 to 3 carbon atoms, a benzoyloxy or azido group, wherein R ^ is arranged in .beta.-position, R _{2 is} a hydrogen atom, an acyloxy group is 1 is up to 3 carbon atoms or a benzoyloxy group, R 1 is hydrogen, an alkyl group having 1 to 5 carbon atoms, an aryl or aralkyl group, an acyl group having 1 to 3 carbon atoms or a benzoyl group, on condition that
when R 1 represents a hydrogen atom, a hydroxyl group, Acyloxy or benzoyloxy group, R ^ is a hydrogen atom or an alkyl group, and - 17 - when R _{4 represents} a hydrogen atom, a halogen atom, a hydroxyl group, an acyloxy, benzoyloxy or azido group, R _{3 represents} a hydrogen atom, of morphinan alkaloids of the general formula (I), wherein Z, Y, R ^ and R _{2 are} as defined above, characterized in that the morphine alkaloids of the general formula (I) wherein Z, Y, R ^, R ₂ , R ₃ and R _{4 are} as defined above, are reacted with phosgene or diphosgene at a temperature of from ^{0 to} 120 ^° C. in a solvent in the presence of alkali metal carbonates / alkali metal hydrocarbonates, then without isolating the resulting N-chlorocarbonyl-N-demethyl derivatives of the general formula (II) wherein Z, Y, Rt, R ₂ , and R _{2 are} as defined for the compounds of the general formula (I), with water or mineral acid. 2. The method according to claim 1, characterized in that the molar ratio of Morphinanalkaloide of the general formula (I) and of phosgene / diphosgene 1: 3 - 1:20, suitably 1:10 and that of Morphinan alkaloids of the general formula (I) and. the alkali metal carbonates / alkali hydrocarbonate 1: 0.5 - 1: 2, advantageously 1: 1. 3. The method according to claim 1, characterized in that for N-demethylation phosgene / diphosgene, diphosgene useful is used. 4. The method according to claim 1, characterized in that the reaction with diphosgene at a temperature of 30-120 ° C, advantageously at 80 ° C, takes place. 5. The method according to claim 1, characterized in that halogenated hydrocarbons as solvents, dichloro • '- 18 - methane, 1,2-dichloroethane, chloroform, carbon tetrachloride, aromatic hydrocarbons, benzene, toluene, ether, diethyl ether, tetrahydrofuran, dioxane, ketones, acetone, 2-sutanone, preferably 1,2-dichloroethane. Process according to Claim 1, characterized in that the catalyst or Acid binder alkali metal carbonates, preferably sodium carbonate, potassium carbonate, alkali metal hydroxycarbonates, preferably sodium hydrogen carbonate, potassium hydrogen carbonate, expedient sodium carbonate is used. 7. The method according to claim 1, characterized in that the hydrolysis of corresponding N-chlorocarbonyl derivatives of the general formula (II) is carried out in water, when the molecule contains no ester group, and in thin mineral acids, preferably in hydrochloric acid, carried out, when the molecule contains an ester group. - For this purpose 1 formula sheet -