SE417821B - PROCEDURE FOR PREPARING N- (FURYL OR TIENYL-METHYL) -BENZOMORPHANES AND -MORPHINANES - Google Patents

Description

7312111 alkyl of 1- to 1 carbon atoms or a 1,4-butylene chain, R; represents hydrogen, methyl or ethyl and X represents an oxygen or sulfur atom.

When B1 and / or R2 are alkyl groups, stereoisomeric benzomorphans are obtained, in which the other groups are arranged in the cis-Qx-benzomorphan) or trans position (C6-benzomorphan).

It has now been found that the above compounds of formula I and Ia can be prepared by the following reduction procedure in a simple manner: a) Reduction of compounds of formula u II wherein H4 represents hydrogen, alkyl, aralkyl or acyl and E1, R2 and X have to compounds of the formula III in which B1 - R4 and X have the meaning given above and optionally - for the preparation of a compound of the formula Ia - dealkylation or deacylation of a compound of the formula III, in which R does not represent hydrogen and optionally - for the preparation of a compound of formula I, wherein R represents a methyl or acetyl group, methylation or acetylation of a compound of formula III, wherein R represents a hydrogen atom. i b) Reduction of quaternary ammonium compounds of the general formula F _ I __ ï fl s <+> 3 w -Ü-R 'IV_ ~ R2 ~~ -. . wherein R 1 - Ru and X have the meaning given above, Y represents oxygen or sulfur, R 5 a lower alkyl group having 1 to 4 carbon atoms and A (') an anion of an inorganic or organic acid, to compounds of formula III and optionally - for the preparation of a compound of formula Ia - dealkylation or deacylation of a compound of formula III, wherein Ru does not represent hydrogen and optionally - for the preparation of a compound of formula I, wherein R represents a methyl or ethyl group - methylation or acetylation of a compound of formula III, wherein R represents a hydrogen atom.

The reduction can e.g. happen with complex hydrides. Particularly suitable and easy to obtain is lithium aluminum hydride, which is used in a calculated amount or preferably in excess. The reaction is carried out in inert solvents, for example ether, preferably diethyl ether or tetrahydrofuran or dioxane. The reaction temperature is variable within wide limits, preferably temperatures between 0 ° C and the boiling point of the solvent are used. Sodium borohydride, which reacts only with difficulty with the thioamide of formula II, reacts broadly with quaternary ammonium derivatives of formula IV, which can thereby be advantageously reduced with this less flammable hydride. fl an uses sodium borohydride in the calculated amount or preferably in excess. Of the many useful solvents, alcohols, especially methanol or ethanol, optionally mixing with water, are preferred. The reaction temperature, which can vary widely, is preferably between 20 ° C and the boiling temperature of the solvent or solvent mixture.

The processing of the reduction approaches as well as the purification and crystallization of the reaction products take place using known methods.

The reduction of thioamides of formula II and the derivatives of formula IV can also take place with atomic hydrogen, which is generated in a known manner in situ, e.g. of base metals, preferably zinc or iron and acids such as hydrochloric acid, sulfuric acid or acetic acid. According to Clemmensen, the zinc may be amalgamated by treatment with mercury II chloride, in order to increase the reducing power. Using sodium, aluminum or other amalgam and water or alcohol, you can also work in an alkaline environment. For such reduction, various solvents are useful.

Preference is given to those which do not decompose the compounds used by undesired side reactions. Depending on the starting compounds and reaction conditions, it is possible to use alcohols, in particular ethanol and methanol or tetrahydrofuran and dioxane, optionally mixed with water. It is advisable to work between room temperature and the reflux temperature of the solvent.

The processing of the reduction approach as well as purification and crystallization. - .. m-e. 7312111-3 - 4. tion of the reaction product takes place using generally known methods.

Compounds of formula II and compounds of formula IV, wherein Y represents a sulfur atom, can be reductively desulfurized using Raney nickel. Raney nickel is preferably used in a large excess, approximately 10 to 100-fold by weight, based on the substance intended for desulphurisation. It is advantageous to add the Raney nickel portionwise during the course of the reaction. A variety of solvents can be used, preferably alcohols, especially methanol and ethanol. During the reaction, hydrogen can be passed through the reaction mixture, but the desulfurization also takes place without hydrogen. Vigorous stirring is beneficial.

The processing of the reduction approach as well as the purification and crystallization of the reaction product takes place using generally known methods. Finally, it is also possible to reduce compounds of formula II and IV electrochemically.

The new processes for the preparation of compounds of formula I by reduction of compounds of formula II and IV have, in addition to the preparation of these compounds by reduction of corresponding amides, the advantage that the reduction is considerably easier and consequently the choice of reducing agent is much greater. For example, carbonic acid amides are reduced in contrast to thioamides of formula II resp. ammonium derivatives of formula IV not with sodium borohydride, êt ° märt hydrogen.

Raney nickel or catalytic, but only with very special complex hydrides. The thioamides necessary as starting compounds can be prepared, for example, by thionation of carboxylic acid amides (compounds of formula II, in which the sulfur atom can be replaced by oxygen), with phosphorus pentasulfide. The preparation of the carboxylic acid amide is described in Swedish patents 363630, 363826, 408462 and 405121.

Compounds of formula IV, wherein Y represents a sulfur atom, (imidothioester salts) can be prepared, for example, by alkylation of the corresponding thioamide of formula II.

Compounds of formula IV, wherein Y represents an oxygen atom (imidoester salts) are available by alkylation of the corresponding carbonamide with oxonium salts. The invention is further illustrated by the following examples, in which the temperatures refer to degrees Celsius.

Example 1 (Process a) 9-Furfuryl-9'-hydroxy-5,9n-dimethylo, 7-benzomorphane a) 2- (2-furoyl) -2 '- (β-furoyloxy) -5,91-dimethyl-5 .7-Benzomorphan II a suspension of 21.7 g of 2'-hydroxy-5,9w-dimethyl-6,7-benzomorphan (0.1 mol) in 217 ml of absolute methylene chloride and 10 ml of triethylamine were added dropwise with stirring and refluxing. a solution of 28.7 g (0,22m01É 7312111-3 furan-2-carboxylic acid chloride in 109 ml of absolute methylene chloride. Then the reaction mixture was boiled for a further 4 hours under reflux. It was then cooled and washed in the presence of ice twice with 100 each. After drying with sodium sulphate, the methylene chloride solution was evaporated in vacuo. The residue was crystallized by digestion with 250 ml of hot ethanol. The mixture was stirred until cold and allowed to stand overnight in a refrigerator. , was washed with absolute ether and dried at 800 ° C.

Yield: 38.5 g = 95 of the theoretical value; mp 176 - 177 °.

A sample recrystallized from ethanol melted at 177-1780.

The described crystallization of the amide is not necessary for the subsequent ionization. In general, the remainder of the methylene chloride solution is reacted without further purification. b) 2- (2-thiofuroyl) -2 '- (2-furoyloxy) -5,9a-dimethyl-6,7-benzomorphane 10.1 g (0.025 mol) 2- (2-furoyl) -2' - ( 2-Furoyloxy) -5,9N-dimethyl-6,7-benzomorphane was dissolved in 125 ml of absolute pyridine. The solution was boiled after the addition of 3.2 g of phosphorus pentasulfide while stirring and shutting off moisture for three hours under reflux. The pyridine was removed in vacuo and the residue was shaken with 100 ml of methylene chloride and 100 ml of water. The aqueous phase was extracted once more with 50 ml of methylene chloride, the combined methylene chloride solutions were washed successively with 50 ml of 2N HCl in the presence of ice, then three times with water, dried over sodium sulphate and evaporated in vacuo. The yellow residue (10 g) consisted of 2- (2-thiofuroyl) -2 '- (2-furoyloxy) -5,9 fi-dimethyl-6,7-benzomorphan. c) 2-Furfuryl-2'-hydroxy-5,9n-dimethyl-6,7-benzomorphane 10 g 2- (2-thiofuroyl) -2 '- (2-furoyloxy) -5,9 fi-dimethyl-6,7 The henomorphan (the residue from the previous reaction step) was dissolved in 150 ml of absolute tetrahydrofuran and the solution was added dropwise with stirring and cooling in a suspension of 1.9 g of L1AlH2 in 50 ml of tetrahydrofuran. The reaction mixture was then allowed to warm to room temperature and then refluxed for 2 hours. The mixture was then cooled and added dropwise with 4 ml of water with stirring. 175 ml of saturated diammonium tartrate solution were added. After vigorous mixing, the phases were allowed to separate in a separatory funnel, the (upper) tetrahydrofuran layer was separated and evaporated. The aqueous layer was extracted three times with 50 ml of chloroform each. With the combined chloroform extracts, the evaporation residue of the tetrahydrofuran phase was dissolved and the solution was washed with 50 ml of water. After drying the chloroform solution with sodium sulfate, it was evaporated in vacuo and the residue was crystallized from 25 ml of benzene.

The crystallisate was filtered off with suction after standing overnight in a refrigerator and washed with a mixture of benzene and petroleum ether 1: 1 and finally with 6 6 petroleum ether. The air-dried substance (6.5 g) melted at 10 DEG-10 DEG C. during sonication. It contained 1 moi of crystalline benzene, which could be removed by prolonged drying at 80 ° in vacuo. The dried substance then melted at 222 °. The total yield of reaction steps b) and c) was 69% of the theoretical value.

Example Gel 2. (Process a) 2-Furfuryl-2'-hydroxy-5,90-dimethyl-6,7-benzomorphane methanesulfonate a) 2- (2-thiofuroyl) -2 '- (2-furoyloxy) -5, 9m-Dimethyl-6,7-benzomorphane 10.1 g (0.025 mol) of 2- (2-furoyl) -2 '- (2-furoyloxy) -5,9a-dimethyl-6,7-benzomorphane were reacted as described in Example 1 under b) to the title compound. b) 2- (2-thiofuroyl) -2'-hydroxy-5,90-dimethyl-6,7-benzomorphane The residue from the previous reaction step (10.5 g) was dissolved with 150 ml of methanol, the solution was added with 57.5 ml 2 n NaOH and the mixture was refluxed for 15 minutes. Then acidified with Ä0 ml of 2 n H01 and the methanol was removed in vacuo. The residue was shaken with 100 ml of chloroform and 50 ml of 2 n ammonia. When the organic layer was separated, the aqueous solution was extracted once more with 50 ml of chloroform. The combined chloroform solutions were washed with 50 ml of water, dried over sodium sulfate and evaporated in vacuo. the residue (10 g) consisted of 2- (2-thiofuroyl) -2'-hydroxy-5,4-dimethyl-6,7-benzomorphan. c) 2-Furfuryl-2'-hydroxy-5,9w-dimethyl-6,7-benzomorphane-methanesulfonate 10 g 2- (2-thiofuroyl) -2'-hydroxy-5,9W-dimethyl-6,7-benzomorphan (the residue from the previous reaction step) was reduced analogously to Example 1c) using 1.9 g of LiAlH 4. The mixture was then processed as described therein. The crude product can be purified by crystallization from benzene / betroleum ether analogously to Example 1 c) or by chromatography on alumina as follows: In a chromatography column, 40 g of alumina (activity III, neutral) were suspended in chloroform. The base residue was dissolved with 25 ml of chloroform and this solution was chromatographed on the alumina column. Chloroform was used as the solvent and the eluate was collected in 10 ml fractions. The eluate fractions were tested by thin layer chromatography for uniformity and purity. The desired substance was found in approximately 200 ml of the eluate). It was evaporated in vacuo and the residue crystallized as methanesulfonate. _; To this end, the evaporation residue of the eluate was dissolved with 5 ml of ethanol and the solution was acidified with 0.5 g of methanesulfonic acid. The solution was added to a fine cloud with absolute ether. 2-Furfuryl-2'-hydroxy-5,9o-dimethyl-6,7-benzomorphane-methanesulfonate was crystallized. To complete the crystallization, the mixture was allowed to stand overnight in a refrigerator. 7 73121 11 -3 It was then filtered off with suction, washed with ethanol / ether and finally with ether.

After drying at 800 DEG C., 6.3 g of substance with a melting point of 163 DEG-165 DEG C. were obtained. A sample recrystallized from ethanol / ether melted at 164-1670.

The total yield, calculated on the reaction steps a) - c) amounted to 6Ä% of the theoretical value.

Example 5 (Process a) 2-Furfuryl-2'-hydroxy-5, quaedimethyl-6,7-benzomorphan hydrobromide a) 2- (2-thiofuroyl) -2 '- (2-furoyloxy) -5,90-dimethyl -6,7-Benzomorphane ,05 g (0,01 mol) of 2- (2-furoyl) -2 '- (2-furoyloxy) -5,90-dimethyl-6,7-benzomorphane were reacted as described in Example 1 under b) to the title association. b) 2-Furfuryl-2 '- (2-furoyloxy) -5,9n-dimethyl-6,7-benzomorphan 2- (2-thiofuroyl) -2' - (2-furoyloxy) -5,9d-dimethyl-6 Benzomorphane (from previous reaction step a) was dissolved in 50 ml of ethanol, the solution was added with 50 ml of water and 100 ml of glacial acetic acid and heated to boiling. After adding 10 g of zinc dust, it was boiled with stirring for 2 hours under reflux. The mixture was cooled slightly and the still hot reaction mixture was filtered off over a kieselguhr layer. The filtrate was made ammoniacal in the presence of ice with concentrated ammonia and extracted with chloroform (3 times with 100 ml each). The combined chloroform extracts were washed with water, dried over sodium sulfate and evaporated in vacuo. The residue was crystallized from 14 ml of methanol and 1 ml of water.

When the crystallizate was refrigerated overnight, it was filtered off with suction and washed with a small amount of cold methanol. Drying at 60 ° gave 2.0 g of 2-furfuryl-2 '- (2-furoyloxy) -5,9Cedimethyl-6,7-benzomorphane, m.p. 1090, which was raised on recrystallization from methanol to 130 °. c) 2-Furfuryl-2'-hydroxy-5,90> dimethyl-6,7-benzomorphan hydrobromide 2.0 g 2-furfuryl-2 '- (2-furoyloxy) -5,90-dimethyl-6,7 -benzomorphan (see previous reaction step) was dissolved in 50 ml of methanol, the solution was added with 12.5 ml of 2 n NaOH and the reaction mixture was refluxed for 15 minutes. It was then cooled, added with 50 ml of 2N ammonium chloride and evaporated in vacuo until the methanol was removed. The evaporated solution was extracted three times with 30 ml of chloroform each, and the combined extracts were washed with water, dried over sodium sulfate and evaporated in vacuo. The residue was dissolved with 5 ml of ethanol and the solution was acidified with 60% hydrobromic acid. After adding absolute ether to turbidity, the hydrobromide crystallized. To complete the crystallization, the mixture was allowed to stand in a refrigerator for 3 days. It was then filtered off, washed with ethanol / ether and finally with ether. The crystallized material dried at 80 °. 2.5 g, melting point 197 °. The yield over steps e) - e) amounted to 66 e of the theoretical value. ' 7312111-z Example Gel 4 (Process a) 2-Furfuryl-2'-hydroxy-5,9a-dimethyl-6,7-benzomorphane a) 2- (2-thiofuroyl) -2 '- (2-furoyloxy) -5,90- dimethyl-6,7-benzomorphane 4.05 g (0.01 mol) of 2- (2-furoyl) -2 '- (2-furoyloxy) -5,9c = dimethyl-6,7-benzomorphane were ionized as described in Example 1 under b). b) 2-furfuryl-2'-hydroxy-5,9A-dimethyl-6,7-benzomorphane 2.5 g; The zinc pan was shaken for 5 minutes with 0.125 g of Hgciá, 2.5 ml of water and 0.1 ml of concentrated H01. Then the solution was decanted. The amalgamated zinc pads were washed with water and added to a solution of 2- (2-thiofuroyl) -2 '- (2-furoyloxy) -5,9a-dimethyl-6,7-benzomorphan (see previous reaction step) in 30 ml of ethanol. After adding 12.5 ml of concentrated hydrochloric acid and 2.5 ml of water, the mixture was refluxed for 1 hour. After cooling, it was diluted with 100 ml of water, added with 50 ml of concentrated ammonia and extracted first with 100 ml, then again with 50 ml of chloroform. The combined extracts were washed with water; dried over sodium sulfate and evaporated in vacuo. The residue was purified analogously to Example 2 c), by chromatography on alumina and the purified base was crystallized from benzene / hetroleum ether.

1.9 g of 2-furfuryl-2'-hydroxy-5,9-dimethyl-6,7-benzomorphane with a melting point of 104 DEG-105 DEG (1 mol of crystalline benzene) were obtained. The total yield over reaction steps a) and b) was 50.5% of the theoretical value.

Example Gel 5. (Process a) 2-Furfuryl-2'-hydroxy-5,9 fi-dimethyl-6,7-benzomorphane a) 2- (2-thiofuroyl) -2 '- (2-furoyloxy) -5,9 fi dimethyl-6,7-benzomorphane 4.05 g (0.01 mol) of 2- (2-furoyl) -2 '- (2-furoyloxy) -5,9G-dimethyl-6,7-benzomorphane were thioned as described in Example 1 under b) with phosphorus pentasulfide. '' B) 2-Furfuryl-2'-hydroxy-5, Q-dimethyl-6,7-benzomorphan 2- (2-thiofuroyl) -2 '~ (2-furoyloxy) -5,9-dimethyl-6,7-benzomorphan ( cf. the previous reaction step) was dissolved in 250 ml of methanol and the solution was boiled after the addition of 5 g of methanol-moistened Raney nickel for 45 minutes under reflux. Then 5 g of Raney nickel were added again and boiled again for 45 minutes. Finally, the mixture was cooled and the solution was filtered off with kieselguhr. The filtrate was evaporated in vacuo.

For purification, the crude product was chromatographed on 300 g of silica gel using a column of 50 mm in length and 5 mm in diameter and a mixture of 1900 ml of chloroform, 100 ml of methanol and 2 ml of concentrated ammonia.

Eluate fractions of 25 ml were collected and examined by thin layer chromatography (silica gel plates, co-eluent). The fractions with pure substance were combined and evaporated in vacuo. The residue was crystallized from benzene / betroleum ether. Total yield over reaction steps a) 9 b12 = (0.3 g, melting point 102 DEG-105 DEG.

Example 6 (Process a) 2- (2-Methyl-5-furylmethyl) -2'-hydroxy-5,90-dimethyl-6,7-benzomorphane methanesulfonate Starting from 2.17 g (0.0l mol) 2'-hydroxy-5,9o-dimethyl-6,7--benzomorphane and 5.2 g of 2-methyl-5-furoyl chloride, in the manner described in Example 1, the title compound 1 was obtained in a total yield of 5.1 g = = 76% of the theoretical value. The melting point of 255 - 2560 was raised by recrystallization from ethanol / ether to 268 - 270 °.

Example 7 (Process a) 2- (5-furylmethyl) -2'-hydroxyl-5,9: -dimethyl-6,7-benzemorphane hydrochloride Starting from 2.17 g (0.0l mol) of 2'-hydroxy- 5.9 m-dimethyl-6,7--benzomorphane and 2.9 g of 5-furoyl chloride were obtained, analogously to Example 1, the title compound 1 gave a total yield of 2.5 g = 69% of theory; melting point 248 °, after recrystallization from ethylene / ether 252 °.

Example 8 (Process a) 2-Tenyl-2'-hydroxy-5,9a-dimethyl-6,7-benzomorphane hydrochloride Starting from 2.17 g (0.0l mol) of 2'-hydroxy-5,9- In addition to Example 2, the title compound 1 obtained a total yield of 2.4 g = 68.5% of the theoretical value, of d-methyl-6,7-benzomorphane and 5.2 g of 2-tenoyl chloride; melting point 255 - 257 °, after recrystallization from ethanol / ether 258 - - 259 °.

Example 9 (Process a) 2- (5-methyl-furfuryl) -2'-hydroxy-5,9o-dimethyl-6,7-benzomorphane-methanesulfonate Starting from 2.17 g (0.01 mol) of 2 ' -hydroxy-5,9Q-dimethyl-6,7--benzomorphane and 5.2 g of 5-methyl-2-furoyl chloride, in analogy to Example 5 the title compound 1, a total yield of 2.5 g = 56.5% of the theoretical the value; melting point 202 - 2o3 °.

Example 10 (Process a) (+) - N-furfuryl-5-hydroxy-morphinane Starting from 2.45 g (0.0l mol) of (+) - 5-hydroxy-morphinane and 2.9 g of 2-furoyl chloride were obtained analogous to Example 5 the title compound 1 a total yield of 1.4 g = 45% of the theoretical value; melting point 204 - 205 °, after recrystallization 205 - 206 °.

Example 11 (Process a) 2- (2-methyl-5-furylmethyl) -2'-hydroxy-5,9ß-dimethyl-6,7-benzomorphane-methanesulfonate _ Starting from 2.17 g (0.0l 2) -Nydri-exi-B, 9,3-alkylmethyl-6,7-benzomorphane and 5.2 g of 2-methyl-5-phenylyl chloride were obtained analogously to Example 1 the title compound in a tetalut yield of 3.1 cs = 76 ïšlav the 1290- 7312111-3 10 rhetorical value; melting point 213 - 2140, after recrystallization from ethanol / ether 2090.

Example Gel 12 (Method a) 2- (2-methyl-3-furylmethyl) -2'-hydroxy-5-methyl-6,7-benzomorphane hydrochloride Starting from 2.05 g (0.0l mol) of 2'-hydroxy -5-methyl-6,7-benzomorphane and 3.2 g of 2-methyl-3-furoyl chloride were obtained analogously to Example 1 of the title compound in a total yield of 1.7 g = 1.5% of the theoretical value; mp 212 °, after recrystallization from ethanol / ether 2180.

Example 13 (Process a) 2-Furfuryl-2'-hydroxy-5-methyl-9a-ethyl-6,7-benzomorphane Starting from 2.32 g (0.0l mol) of 2'-hydroxy-5-methyl-9a -ethyl-6,7- -benzomorphan and 2.9 g of 2-furoyl chloride were obtained analogously to Example 1 of the title compound in a total yield of 1.2 g = 55% of the theoretical value; melting point 1730, after recrystallization from aqueous methanoi 182 °.

Example 14 (Process a) 2-Furfuryl-2-methoxy-5,9m-dimethyl-6,7-benzomorphan hydrochloride Starting from 2.32 g (0.01 mol) of 2'-methoxy-5,90-dimethyl-6, 7-Benzomorphan and 2.9 g of 2% uryl chloride chloride are analogous to Example 4 of the title compound in a total yield of 1.4 g = 40 of the theoretical value; melting point 206 °, after recrystallization from ethanol / ether 200 °.

Example Gel 15 (Method a) (-) - 2-Furfuryl-2'-hydroxy-5,9A-dimethyl-6,7-benzomorphane methanesulfonate Starting from 2.17 g (0.01 mol) (-) - 2 ' -hydroxy-5,90-dimethyl-6,7--benzomorphane and 2.9 g of 2-phenylyl chloride, in analogy to Example 2 the title compound 1, a total yield of 2.8 g = 71% of theory was obtained; melting point 205 - 2o6 °.

Example Gel 16 (Method a) (-) - 2- (3-Thienylmethyl) -2'-hydroxy-5,93-dimethyl-6,7-benzomorphane methanesulfonate Starting from 2.17 g (0.01 mol) (-) - 2'-hydroxy-5,9 fi-dimethyl-6,7--benzomorphane and 3.2 g of 3-tenoyl chloride were obtained analogously to Example 1 the title compound in a total yield of 3.1 g = 73% of the theoretical the value; mp 205 - 2060, unchanged after recrystallization from ethanol / ether.

Example Gel 17 (Process b) 2-Furfuryl-2'-hydroxy-5,9: -dimethyl-6,7-benzomorphane methanesulfonate a) 2- (2-thiofuroyl) -2 '- (2-furoyloxy) -5, 9u-Dimethyl-6,7-benzomorphane 10.1 (0.025 mol) of 2- (2-furoyl) -2 '- (2-furoyloxy) -5,9w-dimethyl-6,7-benzomorphan was thioned as described in Example 1 under b) with phosphorus pentasulfide. The reaction product was used for the next reaction- .. ..._..._... _....>. - ..- «-_- ~ - ~ ._ '7312111-3' -1 | The alkylation described in steps. b) 2- (2-thiofuroyl) -2 '- (2-furoyloxy) -5,9-dimethyl-6,7-benzomorphan-methiodide The thioamide prepared in the previous reaction step was dissolved in 150 ml of absolute acetone and the solution was boiled after the addition of 17 .8 g = 7.85 ml of methyl iodide under reflux. The yellow solution then turned yellow-red and after about 1 hour the reaction product began to separate into crystalline form. The mixture was boiled for a total of 2 hours, then allowed to cool and slowly added with stirring with Ä50 ml of absolute ether.

When the crystallization was complete by standing overnight, it was filtered off with avoidance of humidity, washed with absolute ether and dried in a vacuum desiccator over concentrated sulfuric acid to a constant weight. Total yield over reaction steps a) and b) 11.0 g = 78% of theory! melting point 125 - 1500. A sample recrystallized from acetone / ether also melted at 125 - I50 °. c) 2-Furfuryl-2'-hydroxy-5,90-dimethyl-6,7-benzmorphane-methanesulfonate To a suspension of 0.6 g of LiAlH 4 in 20 ml of absolute tetrahydrofuran was added with stirring and ice-cooling 2.82 g ( 0.005 mol) 2- (2-thiofuroyl) -2 '- (2-furoyloxy) -5,9J-dimethyl-6,7-benzomorphan methoiodide (previous reaction steps). The yellow color of the salt disappeared instantly.

After 15 minutes, the ice bath was removed and the reaction mixture was stirred for an additional hour at room temperature. Then, with further stirring, 2 ml of water were added dropwise and the mixture was then added with 50 ml of saturated diammonium tartrate solution. Shake vigorously for a while and then separate the mixture into a separatory funnel. The tetrahydrofuran solution (upper layer) was evaporated in vacuo, the aqueous layer was dried three times with 40 ml of chloroform each. To the combined chloroform extracts, the evaporation residue of the tetrahydrofuran solution was dissolved, washed with water, dried over sodium sulfate and evaporated in vacuo. the residue was dissolved with 5 ml of ethanol and the solution was added, after acidification with 0.5 g of methanesulfonic acid, with absolute ether to cloudy. The methanesulfonate crystallized, which was kept in a refrigerator overnight to complete the crystallization. It was then filtered off with suction and washed with ethanol / ether, then with ether. After drying, 1.2 g of substance (61% of theory) with a melting point of 163 DEG-165 DEG C. were obtained, which was raised to 165 DEG-168 DEG C. after recrystallization from ethanol / ether.

Example 18 (Method b) 2-Furfuryl-2'-hydroxy-5,9m-dimethyl-6,7-benzomorphane methanesulfonate 1 g of sodium borohydride was dissolved in 10 ml of water and after dilution with 20 ml of ethanol, the solution was added with stirring with 2 82 g (0.005 '1212 mol) of 2- (2-thiofuroyl) -2' - (2-furoyloxy) -5,90-dimethyl-6,7-benzomorphan methiodide (see Example 17, reaction step b)). The temperature then rose to Ä5 ° and the yellow color of the salt disappeared immediately. The mixture was stirred for a further hour and then added, first dropwise, with a total of 25 ml of 2 N HCl and boiled for 15 minutes under reflux. The mixture was then cooled, added with 25 ml of 2 n ammonia and extracted three times with 50 ml of chloroform each. The combined chloroform solutions were washed with water, dried over sodium sulfate and evaporated in vacuo. The residue was crystallized as described in Example 17 under c) as methanesulfonate. Yield 1.5 g = 76% of theory; mp 164 - 167 °, after conversion from ethanol / ether 166 - 168 °.

Example Gel 19 (Method b) 2-Furfuryl-2'-hydroxy-5,9-dimethyl-6,7-benzomorphane 2.82 g (0.85 moi) α- (ε-thiofuroyn-α'-ε-furoyloxy) -5,9n-Dimethyl-6,7-benzomorphan-methiodide (see Example 17, reaction step b)) was added to a suspension of 10 g of Raney nickel in 100 ml of methanol and the reaction mixture was refluxed for 30 minutes. The mixture was then cooled and filtered over kieselguhr. The filtrate was evaporated in vacuo and the residue was boiled to complete decomposition of the 2'-furoyloxy grouping for 15 minutes in 50 ml of methanol and 12.5 ml of 2N NaOH. Then the mixture was cooled, added with 25 ml of 2 n ammonium chloride and evaporated in vacuo. The residue was shaken with 50 ml of water and 50 ml of chloroform and the aqueous phase was extracted twice more with 25 ml of chloroform each. The combined chloroform extracts were washed with water, dried over sodium sulfate and evaporated in vacuo. The residue was purified analogously to Example 5 by chromatography on silica gel and crystallized from benzene / betroleum ether. Yield 0.2 g, melting point 105 °.

Example Gel 20 (Method b) 2-Furfuryl-2'-hydroxy-5,9-dimethyl-6,7-benzomorphane a) 2- (2-thiofuroyl) -2 '- (2-furoyloxy) -5,9N-dimethyl -6,7-Benzomorphane-ethoethyl sulfate Analogously to Example 17, 4.0 g (0.01 mol) of 2- (2-furoyl) -2 '- (2-furoyloxy) -5,9q-dimethyl were obtained -6,7-benzomorphane over the corresponding thioamide which was reacted in acetone with diethyl sulfate, the title compound as a non-crystallizing syrup. b) 2-Furfuryl-2'-hydroxy-5,9, -dimethyl-6,7-benzomorphane Starting from the reaction product in the previous reaction step, the title compound was obtained by reduction with sodium borohydride analogously to Example 18 in a total yield over all reaction steps of a ) - b) of 1.7 g = 57% of the theoretical value; mp 97 - 980, after recrystallization from benzene / betroleum ether 103 - 105 °. Example 21 (Process b) 2- (3-Methyl-furfuryl) -2'-hydroxy-5-ethyl-9q-methyl-6,7-benzomigran Starting from 2.3 g (0.01 mol) 2'-Hydroxy-5-ethyl-9α-methyl-6,7-benzomorphane was obtained analogously to Examples 1 a) and b) 2- (3-methyl-furfuryl) -2 '- (3-methyl-2 -furoyloxy) -5-ethyl-9-methyl-6,7-benzomorphan and thereof 2- (3-methyl-2-thiofuroyl) -2 '- (3-methyl-2-furoyloxy) -5-ethyl-9d- methyl-6,6-benzomorphane.

The latter gave on alkylation with methyl iodide analogous to Example 17 b) the corresponding method iodide as a non-crystallizing syrup, which was reduced analogously to Example 18 with sodium borohydride. The reduction product was crystallized from aqueous methanol. Total yield over four synthesis steps 0.25 g = 7.7% of the theoretical value; melting point 178 °, unchanged after recrystallization from methanol.

Example 22 (Process b) (-) - N-furfuryl-3-hydroxy-morphinane Starting from P, N3 g (0.01 mol) of 3-hydroxy-morphinane were obtained analogously to Example 1a) and b) 2- (2 -furoyl) -3- (2-furoyloxy) -morphinane and thereof 2- (2-thiofuroyl) -3- (2-furoyloxy) -morphinane.

The latter gave on alkylation with methyl iodide analogously to Example 17 b) a non-crystallizing syrup which was reduced analogously to Example 18 with sodium borohydride. The reduction product was crystallized from acetone. Total yield over Ä synthesis step 1.4 g = 43 ß of the theoretical value; melting point 205 - 2060, resp. 207 ° after recrystallization from vinegar ester.

Example 2 § (process_b) 2- (5-furylmethyl) -2'-hydroxy-5-ethyl-6,7-benzomorphan hydrochloride Starting from 2.17 g (0.0l mol) of 2'-hydroxy-5-ethyl The benzomorphane was obtained analogously to Examples 1a) and b) E- (3-furoyl) -2'-§5-furoyloxy) -5-ethyl-6,16-benzomorphane and from there 2- (Z-thiofuroyl) -N-furoyloxy-5-ethyl-6,7-benzomorphan. The latter, when alkylated with methyl iodide, gave ü2 g of the corresponding methioiodide, which was reduced analogously to Example 18 with sodium borohydride. The reduction product crystallizes dose such as hydrochloride from ethanol / ether. Total yield over Ä synthesis step 1.5 g = ÄH% of the theoretical value; melting point 2120, after recrystallization 2230.

Example 24 (Process b) 2- (2-methyl-3-furylmethyl) -2'-hydroxy-5,90-dimethyl-6,7-benzomorphane a) 2- (2-methyl-3-furoyl) -2 ' Hydroxy-5,9'-Dimethyl-6,7-benzomorphane H 1 Hg (0.3 mol) f-hydroxyl-9,9-dimethyl-6,7-bunuomorphane was dissolved in 100 ml of methanol and the solution was added with vigorous stirring. with 50 g of potassium carbonate in 5 ml of water. To the suspension was added with stirring within 1 hour 32 g (0.2 mol) of e-methylfuran-β-carboxylic acid chloride and then stirred for a further 1 hour at room temperature. Then the mixture was evaporated and the residue was shaken with 300 ml of chloroform and 150 ml of water. The aqueous phase was separated and extracted once more with 150 ml of chloroform. The chloroform extracts were combined and washed successively with 150 ml of 2 n HO1, 150 ml of water and 150 ml of sodium bicarbonate. It was then dried over sodium sulphate and evaporated. in a vacuum. The residue was crystallized from toluene. Yield 58.5 g = 90 ß of the theoretical value; melting point 157 -159 °. b) 2- (2-methyl-3-furoyl) -2'-acetoxy-5,9n-dimethyl-6,7-benzomorphane 52.5 g (0.1 mol) 2- (2-methyl-3-furoyl ) -2'-Hydroxy-5,9-dimethyl- -6,7-benzomorphane was heated with 325 ml of acetic anhydride for 2 hours on a boiling water bath. Then 1 vacuum was evaporated and the residue was shaken for 1 hour with ice water. Then the reaction product was extracted three times with chloroform (200 ml and twice with 100 ml each) and the combined chloroform extracts were washed with water. After drying over sodium sulfate, the solution was evaporated in vacuo. The reaction product remained as a syrup, which was reacted again in the next reaction step. c) 2- (2-methyl-5-furoyl) -2'-acetoxy-5,9 * # dimethyl-6,7-benzomorphane etofluoroborate The residue from the previous reaction step was stirred in 100 ml of absolute methylene chloride with 19 g (0 , 1 mol) triethyl-oxonium fluoborate 2Ä hours under humidity exclusion at room temperature. After evaporation in vacuo, a tough residue remained of the reaction product, which, due to its decomposition ability, is conveniently further processed in this form. d) 2- (2-methyl-3-furylmethyl) -2'-hydroxy-5,5-dimethyl-6,7-benzomorphane The residue from the previous reaction step was dissolved in 100 ml of absolute ethanol and the solution was added portionwise with 5.5 g (0, 15 mol) sodium borohydride with stirring and cooling. The mixture was stirred overnight, then poured into 300 ml of water and extracted with ether. After evaporation of the ether extracts, the residue was dissolved in 300 ml of methanol and the solution was boiled after the addition of 100 ml of 2 n NaOH for 30 minutes under reflux.

Then the main amount of the methanol was removed in vacuo, the residue was added with 120 ml of 2 n ammonium chloride and extracted with chloroform (200, 100, 100 ml). The combined extracts were washed with water, dried over sodium sulfate and evaporated in vacuo. The residue was crystallized from aqueous isopropanol. Yield 221g = 70.5% of the theoretical value. (Total yield over reaction steps b) - d)). Melting point 138 - - 14o °.

Example 25 (Method b) 2- (Furfuryl) -2'-hydroxy-5, N-dimethyl-6,7-benzomorphane Starting from 21.7 g (0.01 mol) of 2'-hydroxy-5,9n-dimethyl- 6,7-Benzomorphane was obtained, analogously to Example 24, of the title compound in a total yield over reaction steps a) - d) of 65% of the theoretical value (crystallized from aqueous isopropanol melting point 119 DEG-110 DEG C.).

Claims (2)

Process for the preparation of N- (heteroaryl-methyl) -benzomorphans and -morphinanes of the general formula N / C fl z G19 ~ R2._ \\} (l - _ .I RO wherein R represents hydrogen, -methyl or acetyl, R 1 and R 2, which may be the same or different, represent hydrogen, alkyl of 1-4 carbon atoms or a 1,4-butylene chain, R 3 represents hydrogen, methyl or ethyl and X represents oxygen or sulfur and their acid addition salts, characterized in that a compound of the formula z ---- l- 4- RB NV N RZ- - _, II II Rl- - J H40 5 + is reduced, wherein Z represents a group of the formula - N- fi- or -k = Å - A ('), SY represents oxygen or sulfur, R5 represents lower alkyl having 1-4 carbon atoms, A (_) represents an anion of an inorganic or organic acid, and R1, H2, R 3 and X are as defined above and 'R 4 represents hydrogen, alkyl, aralkyl or acyl to a compound of the formula VIII wherein R 1 - R 4 and X are as defined above and - optionally - for the preparation of a compound of formula N / CH 2 -Q- RQ fvRg- .. \ R1: 1 no '- dealkylates or deaoylates a compound of formula III, wherein R4 represents alkyl, aralkyl or acyl and - optionally - for the preparation of a compound of formula I, wherein R represents methyl or acetyl, methylates or acetylates a compound of formula III wherein R represents hydrogen and optionally transfers the compounds of general formula I to their physiologically tolerable acid addition salts. 2. A process according to claim 1, characterized in that the reduction is carried out with complex metal hydrides, with atomic hydrogen, with Raney nickel or electrochemically. MENTIONED PUBLICATIONS; Sweden 363 630 (co7a 41 / oo), 363 826 (co7d 43 / za), 408 642 (co7D 221/28) Other publications: u ääågleší? Š? .Í6å.Fearson, DE, Survey of Organic Synthesis ", New York , Munck-Petersen, J. and østrup, G., Organic Chemical Synthesis, Kßvn, 1959, p. 410.