DE1171929B - Process for the production of D- and L-morphmands - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

PATENT LETTERING

Boarding school Class: C 07 d

Number:

File number:

Filing date

German class: 12 ρ-14

S 71867 IVd / 12 ρ

December 29, 1960

June 11, 1964

December 23, 1964

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The patent specification corresponds to the patent specification

The invention relates to a process for the preparation of D- and L-morphinane derivatives of the general formula

Process for the production of
ü- and L-morphinane derivatives

in which R is lower alkyl groups, R _{1 is} a hydrogen atom, alkyl, aralkyl or acyl groups and R ₂ and R _{3 are} hydrogen atoms, hydroxy, lower alkyl, alkoxy or ethylenedioxy groups and the ring C of the morphinane structure can be unsaturated, and is characterized in that one morphinane derivatives of the general formula

30 -NR ₁

In which R _{1 has} the meaning given and can also represent the cyano group, with compounds of the general formula

R ₄ X

in which R _{4 is} optionally substituted phenyl, naphthyl, pyridyl or quinolyl radicals and X is halogen atoms, reacts in the presence of basic solvents and copper powder at temperatures between 100 and 200 ⁰ C, the reaction products obtained optionally in a manner known per se with hydrochloric acid and Treated amalgamated zinc and the ethers obtained of the 4-hydroxymorphinane derivatives with alkali or alkaline earth metals in liquid ammonia at temperatures from -33 to -70 ⁰ C converts.

Patented for:

Shionogi & Co., Ltd., Osaka (Japan)

Representative:

Dipl.-Chem. Dr. phil. H. Wittek, patent attorney,

Heidelberg-Schlierbach, Im Grund 20

Named as inventor:
Yoshiro Sawa, Ashiya-shi, Hyogo,
Shin Maeda, Amagasaki-shi, Hyogo,
Naoki Tsuji, Takaishi-cho, Osaka (Japan)

Claimed priority:

Japan dated December 29, 1959 (41 351

and 41 352)

The compounds prepared according to the process are used as intermediates for the preparation of Medicinal products and can also be used as sedatives, analgesics and antitussive agents Find use.

Many compounds have already been made whose structure is closely related to that of morphine is related and have sedative and analgesic properties, but not pathological habituation and not cause depressive mania. Among these compounds are many that do not have any substituents have in the 4-position of the morphinane structure.

According to the method according to the invention, from the naturally occurring morphine alkaloids, z. B. thebaine derivatives, such effective morphinane derivatives unsubstituted in the 4-position can be obtained.

When reacting the morphinane derivative with an aryl halide can be used as a basic solvent Pyridine or similar bases or solvents containing an inorganic base are preferred Pyridine containing alkali carbonate can be used.

Examples of the aryl halides used are phenyl halides, methylphenyl halides, methoxyphenyl halides, Naphthyl halides, pyridyl halides, quinolyl halides, etc., chlorides, bromides and iodides.

409 766/331

The reduction is carried with alkali metals or alkaline earth metals such as lithium, sodium or calcium, in liquid ammonia at temperatures of -33 to - at about -50 ⁰ C, carried out 70 ^c C, preferably. In the liquid ammonia, suitable non-polar solvents, such as ether, dioxane, tetrahydrofuran or toluene, can optionally be present as solubilizing agents.

The ether of the 4-hydroxymorphinane derivative can be used to split off substituents on ring C of the morphinane structure treated with hydrochloric acid and amalgamated zinc.

The following examples illustrate in more detail the implementation of the invention Procedure.

E.g. 1 1

a) 47.01 g of LS.o-dimethoxy ^ -oxy-N-methyl-5,8-didehydro-morphinan (dihydro-thebaine-Φ), which is obtained from thebaine according to the method of KW B e η 11 ey and co-workers in The Journal of the Chemical Society, 1952, pp. 958 to 966, is dissolved in 240 ml of pyridine. 31.10 g of potassium carbonate, 4.7 g of copper in powder form and 47.1 g of bromobenzene are added to this solution and the mixture is stirred under reflux at 150 to 155 ° C. for 15 hours. After the completion of the reaction, the inorganic substances are removed by filtration and the solvent is distilled off under reduced pressure. After adding a little water to this residue, the mixture is distilled again to remove volatile substances. The residue is then extracted with benzene and purified by chromatography on clay. After recrystallization from 2-propanol to obtain 36.12 g of L-3,6-dimethoxy-4 - phenoxy - N - methyl - 5,8 - didehydro - morphinan in a 61.8 ° / _O by weight yield; M.p. = 137 ° C. [<x] ³ _D ° = + 34.1 ° (0.973% in ethanol). Picrate: F. = 187 to 188 ⁰ C (decomposition).

b) A piece of sodium is added to 600 ml of liquid ammonia, and it is cooled to -50 to -6O ⁰ C. A mixture of 15 g of L-Sjö-dimethoxy ^ -phenoxy-N-methyl-S ^ -didehydromorphinan and 150 ml of anhydrous toluene is slowly added dropwise to this solution over a period of about 50 minutes. During the dropwise addition, the sodium is gradually decomposed. In the presence of excess sodium, the mixture is stirred for one hour, after which the remaining sodium is decomposed by adding ammonium chloride. After the ammonia has evaporated, the residue is extracted with toluene, after a little water has been added, and the extracts are washed with 1N NaOH. After removing the solvent, the residue was purified by chromatography on clay. After recrystallization from petroleum ether, 10.31 g of L-3,6-dimethoxy-N-methyl-5,8-didehydromorphinane are obtained in a yield of 90%; M.p. = 85 to 87 ⁰ C. [(xYo ⁵ = -24.9 ° (2 ⁰ I ₀ in ethanol).

B e i s ρ i e 1 2

According to the procedure given in Example 1 under a), L-3,6-dimethyl-4-phenoxy-N-methyl-5,8-didehydromorphinan is obtained manufactured.

A piece of lithium is placed in 100 ml of liquid ammonia and the solution is cooled to -50 to -55 ° C. A mixture of 2.0 g of LS.S-dimethoxy ^ -phenoxy-N-methyl-S ^ -didehydromorphinan and 20 ml of anhydrous toluene is slowly added dropwise to the solution over a period of about 20 minutes. During the dropwise addition , the lithium is gradually removed. In the presence of an excess of lithium, the mixture is stirred for one hour. The unused lithium is then decomposed by adding ammonium chloride. The lithium consumption is 0.25 g. After the ammonia has evaporated, the residue is extracted with benzene after adding a little water. The benzene solution is purified by chromatography on clay. After recrystallization from petroleum ether to obtain 1.23 g of L-3,6-dimethoxy-N-methyl-5,8-didehydro-morphinan with mp = 86-87 ⁰ C.

B e i s ρ i e 1 3

According to the procedure given in Example 1 under a), L-3,6-dimethyl-4-phenoxy-N-methyl-5,8-didehydromorphinan is obtained manufactured.

A piece of calcium is added to 100 ml of liquid ammonia and it is cooled to -55 ° C. to this solution is a mixture of 2.0 g of L-3,6-dimethoxy ^ -phenoxy-N-methyl-S ^ -didehydro-morphinan and 20 ml of anhydrous toluene slowly added dropwise. During the dropwise addition, will Calcium gradually decomposes. In the presence of an excess of calcium, the mixture becomes during Stirred for one hour and the rest of the calcium decomposed by the addition of ammonium chloride. After Evaporation of the ammonia, the residue is extracted with benzene after adding a little water. After recrystallization from petroleum ether, 1.23 g of L ^ .o-dimethoxy-N-methyl-S ^ -didehydromorphinane are obtained; F. = 86 to 87 ° C.

B e i s ρ i e 1 4

a) A mixture of 12.52 g of L-3,6-dimethoxy-4-oxy-N-methyl-5,8-didehydromorphinan, 8.88 g of 4-nitro-1-bromobenzene, 6.0 g of potassium carbonate , 1.3 g of copper powder and 40 ml of pyridine is heated under reflux for 10 hours at 15O ⁰ C. The further work-up is carried out in a manner analogous to that in Example 1. 9.9 g of L-3,6-dimethoxy-4- (4-nitro-phenoxy) -N-methyl-5,8-didehydromorphinan with F. = 97 to 108 ⁰ C (after recrystallization from ether). [oc]% ° = -17.7 ° (0.990% in ethanol).

b) 1.50 g of L-3,6-dimethoxy-4- (4-nitro-phenoxy) -N-methyl-5,8-didehydromorphinan are dissolved in 15 ml of anhydrous toluene and in 80 ml of liquid ammonia, which contains sodium, at -55 to - 60 ° C reduced. The further work-up is carried out in a manner analogous to that in Example 1. 0.177 g is obtained L-S.ö-Dimethoxy-N-methyl-SjS-didehydro-morphinan, which is identical to the product obtained in Example 1.

Example

a) A mixture of 12.55 g of L-3,6-dimethoxy-4-oxy-N-methy] -5,8-didehydromorphinan, 7.53 g of 4-bromotoluene, 6.2 g of potassium carbonate, 1, 3 g of copper powder and 40 ml of pyridine is heated under reflux for 15 hours at 150 ⁰ C. The further work-up is carried out in a manner analogous to that in Example I; 8.47 g of L-3,6-dimethoxy-4- (4-methylphenoxy) -N -methyl- 5,8 -didehydro-mor-

phinane; F. = 159 to 16O ⁰ C (after recrystallization from 99% ethanol). [<κ] ² ° = + 36.4 ° (1.094% in ethanol).

b) 1.00 g of L-3,6-dimethoxy-4- (4-methyl-phenoxy) -N-methyl-5,8-didehydromorphinan is dissolved in 20 ml of anhydrous toluene and in liquid ammonia which contains sodium , at -50 to - 55 ⁰ C reduced. Further work-up is carried out in a manner analogous to that in Example 1. 0.75 g of L-3,6-dimethoxy-N-methyl-5,8-didehydromorphinan, which is identical to the product obtained in Example 1, is obtained.

P e i s ρ i e 1 6

a) A mixture of 12.52 g of L-3,6-dimethoxy-4-oxy-N-methyl-5,8-didehydromorphinan, 8.32 g of 4-bromanisole, 6.2 g of potassium carbonate, 1.3 g of copper powder and 40 ml of pyridine is heated under reflux for 15 hours at 150 ⁰ C. Working up is carried out in a manner analogous to that in Example 1. 6.18 g of L - 3,6 - dimethoxy - 4 - (4 - methoxy - phenoxy) N-methyl-5,8-didehydromorphinan are obtained; F. = 128 to 129 ° C (after recrystallization from ether). [κ] ¹ * = + 27.1 ° (1.019% in ethanol).

b) 0.954 g of L-3,6-dimethoxy-4- (4-methoxy-phenoxy) -N-methyl-5,8-didehydromorphinan are dissolved in 17 ml of anhydrous toluene and in 80 ml of liquid ammonia which contains sodium , reduced at -55 to -60 ^{° C.} The further work-up is carried out in a manner analogous to that in Example 1; 0.72 g of L - 3,6 - dimethoxy - N - methyl - 5,8 - didehydromorphinan, which is identical to the product obtained in Example 1, are obtained.

Example 7

a) 3 a mixture of 12.52 g of L-3,6-dimethoxy-4-oxy-N-methyl-5,8-didehydromorphinan, 9.1 g of 2-bromonaphthalene, 6.2 g of potassium carbonate, 1.3 g of copper in powder form and 40 ml of pyridine are refluxed at 150 ° C. for 15 hours. The further work-up is carried out in a manner analogous to that in example i. 9.64 g of l-3,6-dimethoxy-4- (2-naphthyloxy) -N-methyl-5,8-didehydromorphinan are obtained; F. = 204 to 205.5 ⁰ C (after recrystallization from ethyl acetate). [<x] ² _D ⁹ = + 28.0 ° (1.05% in chloroform).

b) 1.00 g of L - 3,6 - dimethoxy - 4 - (2 - naphthyloxy) -N-methyl-5,8-didehydromorphinan is dissolved in 30 ml of anhydrous toluene and in 100 ml of liquid ammonia, which contains sodium reduced at -55 to -60 ⁰ C. Further work-up is carried out in a manner analogous to that in Example 1. 0.48 g of LS ^ -dimethoxy-N-methyl-SjS-didehydromorphinan, which is identical to the product obtained in Example 1, is obtained.

Examples

a) A mixture of 12.52 g of L-3,6-dimethoxy-4-oxy-N-methyl-5.8-didehydromorphinan, 7.0 g of 2-bromopyridine, 6.2 g of potassium carbonate, 1.3 g of copper powder and 40 ml of pyridine is heated under reflux for 15 hours at 150 ⁰ C. The further work-up is carried out in a manner analogous to that in Example 1. 6.63 g of L-3,6-dimethoxy-4- (2-pyridyloxy) -N-methyl-5,8-didehydromorphinan are obtained; F. = 153 to 154 ° C (after recrystallization from ethyl acetate). [«] S ⁴ = + 14.7 ° (1.066% in ethanol).

b) 1.00 g of L-3,6-dimethoxy-4 - (2-pyridyloxy) -N-methyl-5,8-didehydromorphinan is dissolved in 15 ml of anhydrous toluene and in 70 ml of liquid Ammonia reduced at -50 to -55 ° C. The other Working up is carried out in an analogous manner to Example 1. This gives 0.58 g of L-S ^ -dimethoxy-N-methyl-S ^ -didehydro-morphinan, which is identical to the product prepared in Example 1.

Example 9

a) A mixture of 12.52 g of L-3,6-dimethoxy-4-oxy-N-methyl-5,8-didehydro-morphinan, 9.16 g of 4-bromoquinoline, 6.2 g of potassium carbonate, 1.3 g of copper in powder form and * 40 ml of pyridine are refluxed for 15 hours. The further work-up is carried out in a manner analogous to that in Example 1. 5.6 g of L-3,6-dimethoxy-4- (4-quinolyloxy) -N-methyl-5,8-didehydromorphinan are obtained. The melting point of Dimethiodids is 226-227 ⁰ C (with decomposition). [<x] l ° = -12.5 ° (0.624% in H ₂ O).

b) The L-3,6-dimethoxy-4- (4-quinolyloxy) -N-methyl-5,8-didehydro-morphinan is dissolved in 30 ml of anhydrous toluene and in 100 ml of liquid ammonia, which contains sodium, at - 55 to -6O ⁰ C reduced. The further work-up is carried out in a manner analogous to that in Example 1. 0.51 g of L-3,6-dimethoxy-N-methyl-5,8-didehydromorphinan are obtained.

Example 10

a) A mixture of 1.0 g of L-3,6-dimethoxy-4-oxy-N-methyl-5-dehydromorphinan (dihydro-thebainon-enol-methyl-ether), 1.0 g of bromobenzene, 1, 0 g of potassium carbonate, 1.0 g of copper powder and 40 ml of pyridine is heated for 15 hours at 115 to 12O ⁰ C under reflux. The further work-up is carried out in a manner analogous to that in Example 1. 0.30 g of LS ^ -dimethoxy ^ -phenoxy-N-methyl-5-dehydromorphinane are obtained; F. = 106 to 107 ⁰ C (after recrystallization from petroleum ether). [oc] f = -55.4 ° (2.069% in ethanol).

b) 1.0 g of L-3,6-dimethoxy-4-phenoxy-N-methyl-5-dehydromorphinan is dissolved in 400 ml of liquid ammonia, which contains sodium, at -50 to -60 ° C

. reduced. The further working up is carried out in an analogous manner as in Example 1. This gives 0.699 g of L-3,6-dimethoxy - N - methyl - 5 - dehydro - morphinan with F. = 103.5 to 104.5 ⁰ C (recrystallized from petroleum ether ). [«] *> = -70.5 ° (1.039% in ethanol).

Example 11

According to the given in Example 1 under a)

Working method is L-S ^ -Dimethyl ^ -phenoxy-N-methyl-5,8-didehydro-morphinan manufactured.

a) 3.0 g of L-3,6-dimethoxy-4-phenoxy-N-methyl-5,8-didehydro-morphinan are added to 25 ml of concen- trated hydrochloric acid ^y. The Mir schung is vigorously stirred while warming on a water bath. Half of the amalgamated zinc, which has been prepared from 20 g of zinc, is gradually added to this mixture over the course of one hour. 5 ml of concentrated hydrochloric acid are added and the mixture is stirred for one hour. The other half of the amalgamated zinc is then added and the mixture is stirred for a further 3 hours with the addition of 5 5 ml portions of concentrated hydrochloric acid. After cooling, the reaction mixture is made alkaline with sodium hydroxide and extracted with benzene. The crude product is purified by chromatography on clay and yields 1.24 g

LS-methoxy-1-phenoxy-N-methyl-morphinan; F. = 92 to 93 ° C. [«] £ = -6.7 ° (2% in ethanol).

b) 2.34 g of LS-methoxy ^ -phenoxy-N-methyl-morphinan are dissolved in 10 ml of anhydrous ether and reduced by the addition of sodium in 100 ml liquid ammonia at -55 to -60 ⁰ C. The further work-up is carried out in a manner analogous to that in Example 1. 1.702 g of L-3-methoxy-N-methyl-morphinan are obtained; F. = 106 to 108 ° C. [<χ] ί ° = -45.9 ° (2% in ethanol).

Example 12

a) A mixture of 5.74 g of D-3-methoxy-4-oxy-N-methyl-morphinan, 6.28 g of bromobenzene, 3.14 g of potassium carbonate, 1.0 g of copper in powder form and 40 ml of pyridine is used during Heated under reflux for 15 hours. The further work-up is carried out as in Example 1. 3.76 g of D-3-methoxy-4-phenoxy-N-methyl-morphinane are obtained; M.p. = 94 ° C. Picrat: F. = 215 to 216 ⁰ C.

b) 0.97 g of DS-methoxy ^ -phenoxy-N-methyl-morphinan are dissolved in 50 ml of anhydrous ether, and containing 500 ml of liquid ammonia in which sodium, at -55 to - 60 ⁰ C reduced. The further work-up is carried out in a manner similar to that in Example 1. 0.688 g of D-3-methoxy-N-methylmorphinane are obtained; F. = 109 to 111 ° C (recrystallized from ether). [oi) i ° = + 48.1 ° (0.915% in ethanol).

B e i s ρ i e 1 13

a) A mixture of 2 g of L-3-methoxy-4-oxy-6 «-oxy-N-methyl-morphinan, 3.1 g of bromobenzene, 1.8 g of potassium carbonate, 0.2 g of copper in powder form and 20 ml of pyridine are refluxed for 8 hours heated. The further work-up takes place in a manner analogous to that in Example 1. 1.72 g of L-3-methoxy-4-phenoxy-6o: -oxy-N-methyl-morphman are obtained as an oily substance. Hydroiodide: m.p. = 237-238 ° C.

b) 0.95 g of LS-methoxy ^ -phenoxy-oa-oxy-N-methyl-morphinan are dissolved in 10 ml of anhydrous toluene and reduced with 100 ml of liquid ammonia containing sodium. Working up is carried out in an analogous manner to Example 1. This gives 0.57 g of L-3-methoxy-6a-oxy-N-methy] -morphines; F. = 134 to 135 ⁰ C (recrystallized from ether), [λ] * ² = -31.3 ° (2.049% in ethanol).

Example 14

a) A mixture of 2 g of D-3-ethoxy-4-oxy-N-methyl-morphinan, 3 g bromobenzene, 1.8 g potassium carbonate, 0.3 g copper in powder form and 30 ml pyridine is refluxed for 10 hours. The further processing takes place in an analogous manner as in Example 1. 1.9 g of D-3-ethoxy-4-phenoxy-N-methyl-morphinan are obtained as a colorless oily substance. Phosphate: F. = 234 to 235 ° C (recrystallized of water). [a] £ = + 8.4 ° (1.090% in ethanol).

b) 0.42 g of D-S-ethoxy ^ -phenoxy-N-methyl-morphinan are dissolved in 15 ml of anhydrous toluene and in 50 ml of liquid ammonia, which is sodium contains, reduced at -40 to -50 ° C. The other Working up is carried out in a manner analogous to that in Example 1. 0.30 g of D-3-ethoxy-N-methyl-morphinan is obtained as an oily substance. Phosphate: m.p. = 227 to 228 ° C.

Example 15

a) A mixture of 2 g of D-3-methoxy-4-oxymorphinane, 3.2 g of bromobenzene, 2 g of potassium carbonate, 0.3 g of copper in powder form and 30 ml of pyridine is refluxed for 10 hours. Working up is carried out in a manner analogous to that in Example 1. 1.7 g of DS-methoxy ^ -phenoxy-morphinan are obtained in the form of an oily substance. Hydrobromide: F. = 105 ⁰ C (recrystallized from water).

b) 0.7 g of D-3-methoxy-4-phenoxymorphinan are dissolved in 14 ml of anhydrous toluene and in 80 ml liquid ammonia, which contains sodium, reduced. The work-up is carried out in an analogous manner to in Example 1. 0.53 g of D-3-methoxymorphinane is obtained in the form of an oily substance. Hydrobromide: F. = 285 ° C (recrystallized from water). [«] *" = + 11.5 ° (1.203% in ethanol).

. B e i s ρ i e 1 16

a) A mixture of 2 g of D-3-methoxy-4-oxy-N-cyano-morphinan, 3g of bromobenzene, 1.8g of potassium / carbonate, 0.3 g of copper in powder form and 30 ml of pyridine is taken for 10 hours Heated to reflux. The further work-up is carried out in a manner analogous to that in Example 1. 1.5 g of D-3-methoxy-4-phenoxy-N-cyano-morphinan are obtained in the form of an oily substance which has a. has strong absorption band ascribed to the cyano group at 2220 cm " ¹ .

b) 0.5 g DS-methoxy ^ -phenoxy-N-cyano-morphinan are dissolved in 15 ml of anhydrous toluene and containing 50 ml of liquid ammonia in which sodium, at - 50 ⁰ C reduced. The further work-up is carried out in a manner analogous to that in Example 1. 0.227 g of D-3-methoxymorphinane is obtained, since the cyano group in the N position has been split off at the same time.

B e i s ρ i el 17

a) A mixture of 1 g of D-3-methoxy-4-oxy-N-ethyl-morphinane, 1.5 g of bromobenzene, Ig potassium carbonate, 0.1 g of copper in powder form and 20 ml of pyridine is refluxed for 10 hours. Working up is carried out in a manner analogous to that in Example 1. 0.7 g of D-3-methoxy-4-phenoxy-N-ethyl-morphinane are obtained in the form of an oily substance. Hydrobromide: F. = 257 to 260 ° C, with decomposition (recrystallized from water), [oc [S *

= + 32.6 ° (1.140% in ethanol).

b) 1.07 g of D-3-methoxy-4-phenoxy-N-ethyl-morphinan are dissolved in 15 ml of anhydrous toluene and reduced in liquid ammonia which contains sodium. Further work-up is carried out in a manner analogous to that in Example 1. 0.76 g of D-3-methoxy-N-ethyl-morphinane is obtained in the form of an oily substance. Hydrobromide: m.p. = 225 to 227 ° C (recrystallized from water). [«] £ = + 66.8 ° (1.175% in H ₂ O).

B e i s ρ i e 1 18

a) A mixture of 2.3 g of D-3-methoxy-4-oxy-N-phenethyl-morphinan, 3 g of bromobenzene, 1.8 g of potassium carbonate, 0.3 g of copper in powder form and 40 ml of pyridine is used for 15 hours heated to reflux. The further work-up is carried out in a manner analogous to that in Example 1. 1.9 g of n-3-methoxy-4-phenoxy-N-phenethyl-morphinane are obtained; F. = 140 to 142 ° C (recrystallized from ethanol). [<x] l ° = -85.6 ° (0.548% in ethanol).

b) 0.727 g of D - 3 - methoxy - 4 - phenoxy - N - phenethylmorphinane are dissolved in 15 ml of anhydrous toluene and reduced in 60 ml of liquid ammonia containing sodium. Further processing takes place in

in a manner analogous to Example 1. 0.58 g of D-3-methoxy-N-phenethyl-morphinan is obtained in the form of an oily substance. Oxalate: F. = 204 to 205 ⁰ C, with decomposition (recrystallized from water).

Example 19

a) A mixture of 1.3 g of D-3-methoxy-4-oxy-N-phenacetyl-morphinan, 1.5 g of bromobenzene. 0.9 g of potassium carbonate, 0.2 g of copper in powder form and ■ 20 ml of pyridine is refluxed for 10 hours. Further work-up is carried out in an analogous manner to Example I. 0.9 g of D-3-methoxy-4-phenoxy-N-phenacetyl-morphinan is obtained as an oily substance which has a strong absorption band at 1630 cm " ¹ , which is ascribed to the carbonyl group .

b) 0.439 g of D-S-methoxy ^ -phenoxy-N-phenacetylmorphinan are dissolved in 15 ml of anhydrous toluene and in 50 ml of liquid ammonia containing sodium, reduced. The further work-up is carried out in a manner analogous to Example 1. 0.317 g of ao is obtained D- 3 -Methoxy- N -phenacetylmorphinan as an oily substance.

Claims (1)

Claim: Process for the preparation of D- and L-morphinane derivatives the general formula RO 35 10 atom, alkyl, aralkyl or acyl groups and R ₂ and R ₃ mean hydrogen atoms, hydroxy, lower alkyl, alkoxy or ethylenedioxy groups and the ring C of the morphinane structure can be unsaturated, characterized in that one morphinane derivatives of the general formula NR ₁ in which R is lower alkyl groups, R _{1 is} a hydrogen 40 in which R _{1 has} the meaning given and can also represent the cyano group, with compounds of the general formula R ₄ X in which R _{4 is} optionally substituted phenyl, naphthyl, pyridyl or quinolyl radicals and X is halogen atoms, reacts in the presence of basic solvents and copper powder at temperatures between 100 and 20O ⁰ C, the reaction products obtained optionally in a manner known per se with hydrochloric acid and Treated amalgamated zinc and the ethers obtained from the 4-hydroxymorphinan derivatives with alkali or alkaline earth metals in liquid ammonia at temperatures from -33 to -70 ° C. 409 766/331