CS251792B2 - Method of compouns preparation with n-demethylmorphinane skeleton - 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 process for the preparation of compounds of formula III

(111) t with a morphinan skeleton by removing the methyl group from the moofinane alkaloids of formula I

(I) The replacement of the methyl group on the nitrogen atom of the moofinan alkaloids with another, alkyl group has led to the discovery of moofin antagonists important from a pharmacological and therapeutic point of view, as well as the separation of agonist and antagonist action: Adv. in Biochem. Psychqpharm. Volume 8: Oacacotic Annaggonits, Paven Press, Oew York, 1974; E. F. Hahn: Drugs of the Future 9/6 /, 443, 1984.

251792 ’

Although morphinan alkaloids (morphine, codeine, thebaine) can be obtained from natural (plant) sources, the aim of most of the process is to prepare secondary amines from the above-mentioned N-methyl-tertiary amines. (The secondary amine can then be processed to the desired compound by N-alkylation.) It is desirable to replace the methyl group on the nitrogen atom with a more easily hydrolyzable functional group.

The requirements for the N-demethylating agent are as follows: The N-demethylating agent should be inexpensive, stable, easy to prepare, have sufficient reactivity, provide good yields and not be toxic.

Bromocyanate, formerly widely used for N-demethylation of morphinan skeleton /Н.А. Hageman; Org. Reactions 7, 198, 1935] has been progressively displaced by chlorofluoric acid esters over the past few years. The biggest drawback of cyanogen bromide is that it is quite toxic, because of its pre-emptive character it is advisable to prepare it freshly before use; some authors also draw attention to its explosiveness.

Acidic (or alkaline) hydrolysis of the cyanamides formed in the von Braun reaction may, in some cases, lead to partial decomposition (or transformation) of the molecule. Currie, G. T. Newbold, F.S. Spring: J. Chem. Soc. No. 4,693, 1961, or the reaction is stopped in the urea phase / K.W. Bentley, D.G. Hardy, J. Am. Chem. Soc. 89, 3281 (1967)].

In contrast, chloroformic acid esters are easier to work with, are less toxic and can be purified by distillation. The methyl esters, ethyl esters and phenyl esters already used gave excellent results (85-95% yields) from the demethylation of the nitrogen atom from the beginning. Abdel-Monem, P.S. Portoghese: J. Med: Chem. 15, 208 (1972); G.A. Brine, K.G. Boldt, C.K. Hart, F.I. Carroll: Organic Prep. Proced. Int. 8, p. 103, 1976; K.C. Rice, E.L. May: J. Heterocyclic Chem. 14, 665 (1977)].

It has been found that the isolation of urethane derivatives as intermediates is not necessary, they can be further converted directly with base or hydrazine. Since the above hydrolyses are rather lengthy (24-48 hours), at which time decomposition and side reactions may already occur, 2,2,2-trichloroethyl chloroformate (I.J) has been proposed for N-demethylation. Browitz, V. Diakiw: J. Heterocyclic Chem. 12, pp. 1,123 (1975); HER. DeGraw, J.H. Lawson, J.L. Crase, H.L. Jonson, M. Ellis, E.T. Uyeno, G.H. Loew, D.S. Berkowitz, J. Med. Chem. 21, p. 415, 1978) and vinyl chloroformate.

The trichloroester has the advantage that it is reactive and that the formed urethanes can readily decompose with the activated zinc powder. However, it is a disadvantage that the decomposition of urethanes obtained from 14-acyloxymorphinans is accompanied by O-N acyl migration (German Published Application No. 2,727,805), which does not allow the direct preparation of the N-demethyl derivative.

Examples have been found in the literature where zinc complexes of the N-demethyl derivative / N.P are formed. Peet: J. Pharm. Sci. 69, 1447 (1980)]. According to literature data, chloroformic acid vinyl ester is considered to be the most perfect N-demethylating agent: U.S. Pat. Nos. 3,905,981, 4,141,897, 4,161,597]. This reagent is very reactive for the ability of the vinyl group to bind electrons, thereby ensuring a quantitative reaction.

When vinylurethanes are treated with an equivalent amount of acid (hydrochloric acid, hydrobromic acid), addition occurs, boiling with methanol to form the secondary amine salt. Under very mild reaction conditions, the urethane decomposes and the secondary amine can be obtained in very good yield and high purity.

When urethanes formed from 14-O-acylmorphinans are treated with acid, salt / hydrochloride, hydrobromide and the like 14-O-acyl-N-demethylated compound are formed, in which case no O ---> N acyl migration.

However, in addition to these advantages, it should be noted that the preparation of vinilettirt clic acid is difficult (due to pyrolysis) and therefore other N-dimethylation methods need to be investigated. Difossene was chosen for this purpose since it has already been successfully used for the N-deemeylation of propane alkaloids. The diploginine or trichloroethylether of herring acid may be readily prepared by L, Waahkele, A. Synth. £ 9, 195, c. Efraai, I. Feenstein, Goldman, J.

1980 /.

Ors. Chem. / 5, p. 4,059, 1980; K. Kurt, Y. Iwakura: Org.

Most reactions behaves like fossen / mol íeden dioosgenu its boiling te ^p is 1 Lot ² to 8 ° C, is a low tension jeto ^kA / 1.33 kPa / diossgen in releasing two moles Foceno ^y /, at net: .nnčti is novvji very toxic fossene is increasingly replaced by dioss ^^ i ^^ m. Difossen and fossen react with the cyanines, the methyl group cleaving off in the case of the fossen / δ gene. Babad, AD

Since the tertiary amines, like the chloro-esters, are in the form of meetl chloride, a carbameol-chlooid is formed. · Rev. £ 3,757 (1973).

Fossen was designed for the N-deirmeyylation of tertiary amines as an analog of the von reaction

Braun already in 1947 /V.A. Rudeko, A.Y. Jakubovich,

17,

YOU. NikUrova: J. Gen. Chem. (USSR), p.2566, 1947, C.A. 42, 4,918e /.

1: 1 / Н.

Since fossene can form with tertiary amines and 1: 2, while decomposing the amine-fossene complexes Babad, A.D. Zeeler, Chem. Roar. In the case where the tertiary amine (1: 2) ammonium phosgene ratio is formed in the complexes, an excess of phosphorus is appropriate since the amine is in excess to form a tetra substituted urea.

Banholzer

A. Heuuner, W.

et al. (British Patent Nos. 1,166,798 and 1,167,688 and R. Banhhozer Schnuz: Liebigs Ann. Chem. 2,227, 1975] first described the N-dimethylation of alkaloids with tropane skeleton phosgene and dioosgene. By heating the obtained (isolation) it is not necessary / to hydrolyze to secondary amine chlorlydrate and carbameol chloride carbon dioxide.

On the basis of the above, it appears appropriate to test the N-demylation of compounds with a hypophosphite skeleton by dissolution, since the hydrolysis of carbameol chloride is likely to proceed under much milder conditions than urethanes or cyanamides.

The dihydrocodeion was chosen as a model compound and was found to provide the expected N-chlorocarbonyl-N-diethyl-dihydrocodiinone with diosgene in a solution containing 1,2-dichloroethane (or dichloromethane, chloroform, carbon tetrachloride, benzene, toluene).

The structure of the N-chlorocarbonyl-N-dimethyldihydrocolinoinine was confirmed by the fact that the dihydrocodeinone exhibits a similar reaction with fossene, on the other hand, by boiling the clorocarbonyl compound with ethanol, the urethane described in the standard, N-Ethyloxycarbone di-N-ethoxycarbone di-N-ethoxycarbone diethyl ether. Horvath, P. Kerekes, Gy. Gaai, R. Bognar: Acta Chim. Acad. Sci. Hug.

82, pp. 217 (1974)].

Anhydrous sodium carbonate catalyses the formation of an N-chlorocarbonyl derivative, while the use of anhydrous sodium carbonate is also suitable for binding traces of acid. Then, the N-chlorocarbonyl derivative is heated with water and can be hydrolyzed to N-dimethyldilyl codeinone.

Hydroxy groups ραιΐΐάβΐίοί from alcohols or phenols can be acylated with diossgene and phosgene during the formation of hydrochloric acid and hydrochloric acid binds the tertiary amine, making it suitable for protecting moofin derivatives containing this hydroxyl group by acylation.

For example, during the hydrolysis of carbamoyl chloride formed by N-demethylation of 3-O-acetylhydromorphinone, desacetylation occurs and N-demethyldihydromorphinone chlorohydrate is formed.

AND

However, water hydrolysis of 6-O-acetyl-N-chlorocarbonyl-N-demethylcodeine obtained from 6-O-acelyl codeine produces 6-O-acetyl-N-demethylcodeine and therefore, in the case of morphine, codeine, ethylmorphine, dihydrocodeine, dihydroethylmorphine, dihydromorphine hadrolysis performed with 5% hydrochloric acid. Thus the N-demethyl compound is isolated as a uniform product.

The method of the invention is useful for removing a methyl group from a nitrogen atom of dihydrocodeinone, dihydromorphinone, codeine, dihydrocodeine, morphine, dihydromorphine, ethylmorphine, dihydroethylmorphine, desoxycodeine-E, dihydrodesoxycodeine-E, 14-hydroxydihydrocodeinone, 14-hydroxycodeinone, 14-hydroxycodeinone, 14-hydroxycodeinone, O-benzylmorphine and azidomorphine.

SUMMARY OF THE INVENTION The present invention is based on the fact that the morphinan alkaloids of the formula I are reacted with phosgene or diphosgene in a manner which has not yet been completely used in the morphinan skeleton compound and are converted to the N-chlorocarbonyl-N-demethyl compounds of the formula II.

(II) which are converted by treatment with water or dilute mineral acid in good yield and in high purity to the N-demethylated derivatives of the general formula III.

In formulas I, II and III, the symbols have the following meanings:

Z is -CHg-CHg or -CH = CH-

Y is oxygen or a radical Rg, and R _4, wherein

R 8 represents a hydrogen atom, a hydroxyl group, an acyloxy group having 1 to 3 atoms or a benzoyloxy group and its steric position is alpha,

R ₄ represents a hydrogen atom, halogen atom, hydroxyl group, an acyloxy group having 1 to 3 carbon atoms, alkyl of 1-3 carbon atoms, a benzyloxy group or an azido group and the steric position is beta,

R ₂ is hydrogen, acyloxy having 1-3 carbon atoms or benzoyloxy,

R 8 is hydrogen, C 1 -C 5 alkyl, aryl or aralkyl, C 1 -C 3 acyl or benzoyl, provided that when

R 8 represents a hydrogen atom, a hydroxyl group, an acyloxy group or a benzoyloxy group

R @ ₄ is hydrogen or alkyl;

R ₄ is hydrogen, halogen, hydroxy, alkyl, acyloxy, benzoyloxy group or an azido group, means

R ₃ is hydrogen.

The steric position of the Rg and R ₄ groups, depending on the meaning of the Z group, is as follows: If the Z group is -CHg-CHg, the steric position of the Rg group is axial and the R ₄ group is equatorial if Z is -CH = CH-, the steric position of the Rg group is quasi-equatorial and the R ₄ group is quasi-axial.

An important principle of the process according to the invention is the finding that suitable N-chlorocarbonyl-N-demethyl derivatives can be hydrolyzed under mild and very simple reaction conditions,

No decomposition and no undesirable side reactions occur, with no toxic leach liquors or toxic effluents.

The use of phosgene and diphosgene is most preferred with respect to cyanogen bromide and chloroformic acid esters with respect to the hazards of the reactants, the difficulty of their preparation, their cost, and their availability on an industrial scale.

In the process according to the invention, the use of nifusgene is considered to be more advantageous with regard to toxic phosgene, taking into account that the phosgene formed during the diphosgene reaction can be safely removed from the system by flushing with nitrogen in a suitable scrubber. The process according to the invention is suitable for the economical preparation on a large scale of N-demethylmoofinan derivatives important in pharmacological and therapeutic terms.

The invention is illustrated by the following examples, which are not intended to limit the invention. Melting points were determined in each apparatus and were not adjusted. For chrumatourrf0i thin layer film is used Merck Silica ^{gel 60F254} 5554 * ^u as t ^l e ^{s h} UCN environment, a system ^b enzen: ^P in Omer 8: ^2; ehloroUrem * '^ ^{, J} ': meano! 9: 1; chloroform: acetone: ethylamine in a ratio of 5: 4: 1 (ob / te / volume). The spots are identified under ultra-light and Dragendooff reagent. PMR spectra are recorded in a Bruker W200SY instrument at 200 MHz. The chemical shift is indicated in (ppm).

Impact electron ionization apparatuses are used for the htm spectra.

type VG-7035 (GC-MS-DS) using the method

Example 1 ml of 1,2-dichloroethane, 1 g (10 mM) was added dropwise and 19.8 g (12 ml, 100 mM) of diphosgene was added dropwise.

C a

10) concentrated ammonium hydroxide. After extraction, the organic phase is washed with brine and dried (MgSO4), m.p. 150 DEG-151 DEG C. (ethyl acetate).

N-DDeetytdihydrucodeinone

The mixture is stirred at 30 ° C for 30 minutes, then allowed to warm to room temperature and boiled with stirring for 10 hours. The mixture was purged with nitrogen and the inorganic salt was washed with nitrogen. The solution containing 1,2-nichlurethane was washed three times with 20 ml of 5% hydrochloric acid each (ice cold) and then the organic phase was evaporated in vacuo. Add 100 ml of water to the residue and heat in a water bath for five hours. It is then cooled to below 10 DEG C. (alkalinized) to pH 9 to chlorine (3 times with 50 ml each) of magnesium. Yield: 2.33 g (82%).

PMR / CDC1 ₃ / 6.66 dd // - 1.2;

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

2H /; 4.7 s H-5-beta; 1Н /; 3.9 s / OCH3; 3H /

From a 5% hydrochloric acid solution, 0.4 g (13%) of dihynrokudtinone can be obtained by alkalization (with concentrated ammonium hydroxide) and extraction (chlorophyll).

Example 2

N-DDeetytdihydromeuinone

3.3 g (10 mM) of 3-O-acttyldhhydroeorfinut in 60 ml of 1,2-nehlurttat are dissolved, 1 g (10 ml of sodium carbonate) is added and 19.8 g of sodium carbonate are added dropwise at 0 DEG C. with stirring. The mixture is stirred at 0 ° C for 30 minutes, then allowed to warm to ambient temperature and boiled under stirring for 15 hours. ΟοΙ ^ / ^ / ^ _v ^ RíZtok is washed thrice with 20 ml of 5% hydrochloric acid and then the organic and

phase is evaporated in vacuo. Add 100 ml of water and boil for 8 hours. It is cooled to below 10 ° C and the product chlorohydrate is separated in crystalline form. Filter and wash. with cold water. Yield: 2.15 g (70% of theory) of chlorohydrate. The melting point obtained from the chlorohydrate is 300 to 303 ° C. The material was obtained from a solution in 5% hydrochloric acid as described in Example 1.

Example 3

N-Demethylcodeine

Dissolve 3.41 g (10 mM) of 6-O-acetyl codeine in 80 ml of 1,2-dichloroethane, add g (10 mM) of sodium carbonate and add dropwise at 0 ° C to 19.8 g / 12 ml. , 100 mM / diphosgene. The mixture was stirred at 0 ° C for 30 minutes, then allowed to warm to room temperature and stirred and boiled for 20 hours. The mixture was purged with nitrogen and the inorganic salt was filtered off. The residue is washed three times with 20 ml of 5% hydrochloric acid each and then evaporated. The residue was boiled with 5% hydrochloric acid for five hours. Cool to below 10 ° C, separate the product in crystalline form, filter and wash with ice water. The crystalline chlorohydrate was dissolved in water, basified with concentrated ammonium hydroxide, extracted with chloroform, and the chloroform phase was dried and evaporated. The base thus obtained is recrystallized from acetone or ethyl acetate. Yield: 2.3 g (80% of theory);

PMR / CDC1 ₃ / 6.65 dd / H 1.2; 2H /; 5.7 m / N-8 ,; 1H /; 5.3 m / N-7; 1H /; 4.9 d / N-5-beta; 1H /; 4.2 m / N-6-beta; 1Н /; 3.8 s / ОМе; ЗН /.

MS: m / e 285 / M &^lt; ⁺ &^gt;; 100% / 215/50% /

Example 4

N-Demethyldihydrocodeine

Following the procedure of Example 3, N-demethylated 3.43 g (10 mM) of 6-O-acetyldihydrocodeine.

After acid hydrolysis, the hydrochloride acid addition salt of the product is not separated from the solution by cooling, therefore the mixture is directly basified with concentrated ammonium hydroxide, the product is obtained by extraction with chloroform and recrystallized from ethanol. Yield: 1.9 g (66% of theory);

PMR / CDC1 ₃ / 6,7 dd / Н-1,2; 2H /; 4.6 d / N-5-beta; 1H /; 4.1 m / N-6-beta; 1H /; 3.8 s / OMe; ЗН /

MS: m / e 287 / M &^lt; ⁺ &^gt;; 100% /

Example 5

N-Demethylmorphine

3.7 g (10 mM) of 3,6-di-O-acetylmorphine are dissolved in 100 ml of 1,2-dichloroethane and then the methyl group is removed from the nitrogen atom as described in Example 3. After cooling the solution in hydrochloric acid, the The pH was adjusted to 9 with concentrated ammonium hydroxide solution. The product is collected in crystalline form, filtered off and washed with cold water. Yield 2.1 g (77%); first generation 1.8 g; from the alkaline solution using chloroform-isopropanol (3: 1, v / v) extraction, 0.3 g of a second generation is obtained. Melting point 274-277 ° C.

PMR (DMSO-d6) 6.4 dd / N-1.2; 2Н /; 5.6 m / N-8; 1H /; 5.2 m / N-7; 1H /; 4.7 dd / N-5-beta; 1Н /; 4.1 m / N-6-beta; 1Н /

MS: m / e 271 / M &^lt; ⁺ &^gt;; 100% /; 201/50% /

Example

N-Demethyldihydromorphine

3.71 g (10 mM) of 3,6-ii-acetyldihydroooophin are dissolved in 100 ml of 1,2-dichloroethane and N-iernomylated as described in Example 5. Yield 1.65 g (60%), m.p. mp 262-266 ° C.

PMR (DMSO-d 6): 6.5 id (H-1.2); 2H /; 4.2 d / H-5-beta; 1H /; 3.8 m / H-6-beta; 1И /.

MO: o / e 273 / M *; 100 ·% /; 228 (22%); 150 (45%).

Example 7

N-Demotytmerrin-Zzetylether

In the manner described in Example 3, 3.55 g (10 mM) of 6-O-acetylethyloorphine was N -emoeylated. By cooling, the chloro-chlorate of the product is separated, which is filtered off and washed with ice water. The base is recovered and recrystallized from ethanel. Yield is 2.5 g / 84% /, melting point is 156 ^and 157 ° C.

Example 8

N-methyldihydroloorphine-3-ethyletter

As described in Example 4, 3.57 g (10 mM) of 6-O-acetyliityirrttyloorphines were N-isothylated. By alkalization, the product is extracted from the solution in hydrochloric acid and crystallized from ethyl acetate. Yield is 2.32 g / 77% /, melting point 128-13 ¹ ° C.

PMR / CDD13 ₃ : 6.6 dd / H-1.2; 2H; 4.5 d / i-5-beta; 1H /; 4.1 m / OCl2; 2H /; 3.95 m / H-6-beta; 1Н /; 1.4 t / OC2 -C2; 3H

MO: ^m / e 301 / M ^{< + >;} 100% /

Example '9

N-Demethyldesoxycodeine-E

1.42 g (5 mM) of detrxycodeins-E in 50 ml are added. 0.5 g (5 mM) of sodium sulfite is added and 6.0 ml (50 mM) of diphosphates are added to the suspension while stirring and cooling. . After 30 minutes, stop stirring and cooling and boil the mixture with stirring for 15 hours. After cooling, the mixture was purged with nitrogen, the inorganic salt was decomposed, and the organic phase was washed twice with 20 ml of cold 5% hydrochloric acid each time and brine. Evaporate was removed in vacuo, 60 ml of water was added to the residue, and the mixture was heated on a water bath for 8 hours.

Mon. cooling was basified (to pH 10 with concentrated ammonium hydroxide) and extracted three times with 30 ml of chloroform each. After drying with chloroform (magnesium sulphate), N-dernetilicrykriein-E (0.6 g 60%) is obtained, which is homogeneous in terms of thin layer chromium-yoga. i ..? '· nevykcrsttaujt / but when an alcoholic solution of ^ ^ ί γβ 48% hydrobromic acidic: o., yielding Cr stalický ^{hyd y} yy ^b rroi ^d. Having ^a melting ^point is from ³⁰⁷ to ³ ° C 10 ^ / ^ TE OTA ^th n ^{e d} i ^t according to ^y era.tsr ³ is from 11 to ³¹² ° C, RL Clark et al: ^J. AM. Ctem. Ooc. ^35, p. 4963, 1953].

Example 10

N-eemotyldihyirodtsoxykrdein-E

1.4 mg (5 mM) of dihydroxybenzoic acid E are used as starting materials and the procedure is as described in Example 9. After extraction with chloroform, 0.45 g (33% of fluorine) of crystalline N-demoeylhyiroitoxycodeine-E is obtained. After recrystallization from ethyl acetate, the melting point is 91-92 °; according to the literature, the melting point is 92-94 ° C; R.L. Clark et al. J. Adm. Chem. Soc. 75, 4963 (1953)].

Claims (6)

OBJECT OF THE INVENTION A process for the preparation of a compound of formula III with N-demethylmorphinan (III) wherein it is A group of formula Z-CH₂-CH₂-or -CH = CHY oxygen atom or a radical Rg, and R _4, wherein means R 8 is hydrogen, hydroxyl, C 1 -C 3 acyloxy or benzoyloxy and its steric position is alpha, R4 is a hydrogen atom, a halogen atom, a hydroxyl group, an alkyl group, an acyloxy group having from 1 to 3 carbon atoms, a benzoyloxy group or an azido group and its steric position is beta, R 8 is hydrogen, C 1 -C 3 acyloxy or benzoyloxy; R 8 is hydrogen, C 1 -C 5 alkyl, aryl or aralkyl, C 1 -C 3 acyl, benzoyl, provided that when it is znamená R 8 represents a hydrogen atom, a hydroxyl group, an acyloxy group or a benzoyloxy group R 4 is a hydrogen atom or an alkyl group and when it is R 4 is hydrogen, halogen, hydroxyl, acyloxy, benzoyloxy. or azido, means · Rg is hydrogen, from morphinan alkaloids of the formula I, wherein Z, Y, Rg and Rg are as defined above, characterized in that a polymorphic alkaloid of the formula I * (I) wherein Z, Y, R1 is reacted; R ₂ , R 8 and R 4 are as defined above, with phosgene or diphosgene in a molar ratio of 1:10 in a solvent at 0 to 120 ° C in the presence of alkali carbonates or alkaline hydrogen-gelatinates, whereupon N-chlorocarbonyl-N- is formed without isolation demtyl derivative of the general formula II (11) wherein Z, Y, R _1, R ₂ , R _{3 and} R ₄ are as defined above, heating with water or a dilute mineral acid 2. Process according to claim 1, characterized in that the N-demethylation reaction is carried out at a ratio of morphinan alkaloids of the formula I to alkali carbonates or alkali hydrogen carbonates of from 1: 0.5 to 1: 2, preferably 1: 1. 3. Process according to claim 1, characterized in that the reaction with phosgene or diphosgene is carried out at a temperature of 20 to 120 ° C, preferably at a temperature of 80 ° C. 4. The process of claim 1 wherein the N-demethylation reaction is carried out in the presence of halogenated hydrocarbons, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, aromatic hydrocarbons, benzene, toluene, ethers, diethyl ether, tetrahydrofuran, dioxane, ketones, acetone, 2-butanone as solvents, preferably γ. presence of 1,2-dichloroethane as solvent. 5. Process according to claim 1, characterized in that the N-demethylation reaction is carried out in the presence of alkali carbonates, preferably potassium carbonate, alkali hadrogen carbonates, preferably sodium bicarbonate or potassium bicarbonate as catalysts and acid binding agents, preferably in the presence of carbonate. sodium. 6. A process according to claim 1, wherein the hydrolysis of the appropriate N-chlorocarbonyl derivatives of formula (II), wherein the individual symbols are as defined in point 1, is carried out in water when the molecule does not contain an ester group and a dilute mineral acid. preferably in dilute hydrochloric acid when the molecule contains an ester group.