FI63027B - NYTT FOERFARANDE FOER FRAMSTAELLNING AV SOM CEILEMEDEL ANVAENDA RACEMATISKA ELLER OPTISKT AKTIVA N- (FURYL- ELLER TIENYL-METHYL) -BENSOMORFANER - Google Patents

Description

R25r71 Μ (11) U LUTUSj ULSAISU n «η« Ta L J U; UTLÄCGNINGSSKRIFT 6 OU ^ ^ • 5® (4¾ ^ ~ ^ (51)> W ^ Ia% Q.3 'C IO? D 405/06, 409/06 ENGLISH —FINLAND (21)? «« Nttll * knuM - PKtmxMatoMg 2T ^ 8 / T3 (22) H * twmlip «ivt — AiMMtninpd ^ () 4.09-73 (23) Alkupilvt — GlkigtMudaf o4.09.73 (41) Tullut iulkl ** k * l - Hiv * off« ntlif 07.03.74

Patents and registries (44) NihUvtiuipwwn and others kiwL |

Patent · och regitterrtyrelten 'Aiwektn utU * d odi utUkrift · * pubUcurad 31.12.82 (32) (33) (31) Fmrduttjr ttuoikwi —e «(ird printout 06.09.72

Federal Republic of Germany-Förbundsrepubliken

Germany (DE) P 221 + 3703.2 (71) C.H. Boehringer Sohn, D-6507 Ingelheim am Rhein, Federal Republic of Germany Förbundsrepubliken Tyskland (DE) (72) Sven Liittke, Gau-Algesheim, Herbert Merz, Ingelheim / Rhein,

Adolf Langbein, Ingelheim / Rhein, Gerhard Walther, Ingelheim / Rhein, Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) (74) Leitzinger Oy (5I +) A new process for the preparation of racemic or optically active N- (furyl or thienyl methyl) benzomorphans - N-furfarande för framställning av som läkemedel använda racematiska eller optiskt aktiva N- (furyl- or thienyl-methyl) -benzomorphaner

Patent publications 57409 and 5775Θ and patent application 1963/73 describe new compounds with the general formula "r-Fjh" 5

- N

^ --- R1 j

RO

as well as their acid addition salts.

In formula I, R is hydrogen, methyl or acetyl, R 1 is hydrogen or alkyl of 1 to 3 carbon atoms, is hydrogen, methyl or ethyl, R 1 is hydrogen or methyl and X is an oxygen or sulfur atom.

If R is an alkyl group, there are stereoisomeric benzomorphans in which the above groups are in the cis- (α-benzomorphane series) or trans (β-benzomorphan series).

2 63027

It has now been found that the above-mentioned compounds of the formula I can be prepared in a simple manner by the following reduction method:

Reduce compounds of the formula / '· -ξ? - "' r 40 λ 12 wherein R is hydrogen, alkyl, aralkyl or acyl and R, R and X have the same meaning as above to give compounds of the formula ch2-X ~ TLr, / X ^

| - N

_ / \ r2 III

R40 wherein R * and X are as defined above, and optionally to prepare a compound of formula 1 wherein R is hydrogen, an alkyl or acyl group is removed from a compound of formula III wherein R1 is alkyl, aralkyl or acyl; and optionally - to prepare a compound of formula I wherein R is a methyl or acetyl group - methylating or acetylating a compound of formula III wherein R 1 is a hydrogen atom; and optionally the compounds of general formula I 63027 are converted into their physiologically acceptable acid addition salts.

The reduction can take place, for example, with complex hydrides. Particularly suitable and readily available is lithium aluminum hydride, which is used in calculated amount or preferably in excess. The reaction is carried out in inert solvents, e.g. ethers, preferably diethyl ether or tetrahydrofuran or dioxane. The reaction temperature can be varied within wide limits, preferably between 0 ° C and the boiling point of the solvent. Sodium borohydride, which is less effective, is used in calculated amount or preferably in excess. Of the many useful solvents, alcohols, especially methanol or ethanol, optionally mixed with water, are preferred. The reaction temperature, which can be varied within wide limits, is preferably between 20 ° C and the boiling point of the solvent or solvent mixture.

Further processing of the reduction charge and purification and crystallization of the reaction product are carried out using generally known methods.

The reduction of the thioamides of the formula II can also take place with evolving hydrogen formed in situ in a known manner, e.g. from base metals, preferably zinc or iron, and from acids such as hydrochloric acid, sulfuric acid and acetic acid. Optionally, according to Clemmensen, zinc can be amalgated by treatment with mercuric chloride to increase the reactivity. Using sodium, aluminum or other amalgams and water or alcohol can also work in an alkaline environment. Various solvents can be used for this type of reduction. The best ones are those that do not degrade the compounds used through adverse side reactions. Depending on the starting compound and the reaction conditions, e.g. alcohols, in particular ethanol and methanol, or tetrahydrofuran and dioxane, optionally mixed with water, can be used. It is recommended to work between room temperature and the reflux temperature of the solvent. Further processing of the reduction charge and purification and crystallization of the reaction product are carried out using generally known methods.

4,63027

The compounds of formula II can be desulfurized reductively using Raney nickel. Raney nickel is best used in large excess; the total amount is 10 to 100 times the amount of material to be desulfurized. It is preferred to add Raney nickel in portions during the reaction. Several solvents can be used, preferably alcohols, especially methanol and ethanol. During the reaction, hydrogen can be passed through the reaction mixture, but the removal of sulfur also takes place without hydrogen. Vigorous mixing is preferred.

Further processing of the reduction charge and purification and crystallization of the reaction product are carried out using generally known methods.

Finally, it is also possible to reduce the compounds of formula II electrochemically.

The new processes for the preparation of the compounds of the general formula I, in which the compounds of the formula II are reduced, have the advantage, for the preparation of these compounds, by reduction of the corresponding amides, that the reduction is substantially easier and therefore the choice of reducing agents is much greater. In contrast to the thioamide of formula II, for example the carboxylic acid amide cannot be reduced with sodium borohydride, evolving hydrogen,

Raney nickel or catalytic, but with very specific complex hydrides. The thioamides required as starting compounds can be prepared, for example, by thionation of carboxylic acid amides (compounds of formula II in which the sulfur atom has been replaced by oxygen) with the aid of phosphorus pentaeulfide. The preparation of carbonamide is apparent from the aforementioned patent application 1963/73.

The following examples illustrate the invention.

Example 1 2-Furfuryl-2'-hydroxy-5,9a-dimethyl-6,7-benzomorphane a) 2- (2-furoyl) -2 '- (2-furoyloxy) -5,9-dimethylmethyl- 6,7-ben ts ό πιό r fan 5 63027

To a suspension of 21.7 g of 2'-hydroxy-5,90i-dimethyl-6,7-benzomorphania (0.1 mol) in 217 ml of absolute methylene chloride and 40 ml of triethylamine are added dropwise with stirring and refluxing the solution. with 28.7 g (0.22 mol) of furan-2-carboxylic acid chloride in 109 ml of absolute methylene chloride.

The reaction mixture is then refluxed for a further 4 hours. It is then cooled and, in the presence of ice, washed twice with 100 ml of 2N hydrochloric acid and then three times with water. After drying over sodium sulfate, the methylene chloride solution is evaporated in vacuo. The residue crystallizes on trituration with 250 ml of hot ethanol. Stir until the solution cools and allow to stand overnight in the refrigerator. It is then filtered off with suction, washed with absolute ether and dried at 80 ° C. Yield 38.5 g = 95% of theory; mp 176-177 ° C. The sample recrystallized from ethanol melts at 177-178 ° C.

The amide need not be crystallized as described above before the next thionation. Generally, the residue obtained after evaporation of the methylene chloride solution is reacted without purification.

b) 2- (2-thiofuroyl) -2 '- (2-furoyloxy) -5,9a-dimethyl-6,7-benzomorphane 10.1 g (0.025 mol) of 2- (2-furoyl) -2'- (2-Furoyloxy-5,9a-dimethyl-6,7-benzomorphane is dissolved in 125 ml of absolute pyridine. 3.2 g of phosphorus pentasulphide are added to the solution and the mixture is refluxed with stirring for 3 hours to prevent moisture from entering. The pyridine is removed in vacuo and shake the residue with 100 ml of methylene chloride and 100 ml of water, extract the aqueous phase once more with 50 ml of methylene chloride, wash the combined methylene chloride solutions successively with 50 ml of 2N hydrochloric acid in the presence of ice and then three times with water, dry over sodium sulphate and evaporate. The yellow residue (10 g) is 2- (2-thiofuroyl) -2 '- (2-furoyloxy) -5,9a-dimethyl-6,7-benzomorphane.

o) 2-furfuryl-2'-hydroxy-5,9a-dimethyl-6,7-benzomorphane 63027 10 g of 2- (2-thiofuroyl) -2 '- (2-furoyloxy) -5,9a-dimethyl-6, 7-Benzomorphane (residue from the above reaction step) is dissolved in 150 ml of absolute tetrahydrofuran and a suspension of 1.9 g of lithium aluminum hydride in 50 ml of tetrahydrofuran is added dropwise to the solution with stirring and cooling. The reaction mixture is then allowed to warm to room temperature and refluxed for 2 hours. It is then cooled and 4 ml of water are added dropwise with stirring. Add 174 ml of saturated diammonium tartrate solution. Stir vigorously, then allow the phases to separate in a separatory funnel, separate the (upper) tetrahydrofuran layer and evaporate. The aqueous layer is changed 3 times with 50 ml of chloroform. The evaporation residue of the tetrahydrofuran phase is dissolved in the combined chloroform extracts and the solution is washed with 50 ml of water. After drying over sodium sulfate, the chloroform solution is evaporated in vacuo and the residue is crystallized from 25 ml of benzene. The crystals are filtered off with suction after standing overnight in a refrigerator and washed with a 1: 1 mixture of benzene and petroleum ether and finally with petroleum ether. The air-dried substance (6.5 g) melts at 104-106 ° C with decomposition. It contains 1 mole of crystal benzene, which can be removed by drying at 80 ° C for a longer vacuum. The dried substance then melts at 122 ° C. The total yield of reaction steps b) and c) is 69% of theory.

Example 2 2-Furfuryl-2'-hydroxy-5,9a-dimethyl-6,7-benzomorphan methanesulfonate a) 2- (2-thiofuroyl) -2 '- (2-furoyloxy) -5,9a-dimethyl -6,7-benzomorphan

According to Example Ib, 10.1 g (0.025 moles) of 2- (2-furoyl) -2 '- (2-furoyloxy) -5,9a-dimethyl-6,7-benzomorphane are reacted to give the title compound.

b) 2- (2-thiofuroyl) -21-hydroxy-5,9a-dimethyl-6,7-benzomorphane

The residue from the above reaction step (10.5 g) is dissolved in 150 ml of methanol, 37.5 ml of 2N sodium hydroxide are added to the solution, and the mixture is refluxed for 15 minutes. It is then acidified with 40 ml of 2N hydrochloric acid and the methanol is removed in vacuo. The residue, 100 ml of chloroform and 50 ml of 2N ammonia are shaken together.

After the organic layer is separated, the aqueous solution is extracted once more with 50 ml of chloroform. The combined chloroform solutions are washed with 50 ml of water, dried over sodium sulfate and evaporated in vacuo. The residue (10 g) is 2- (2-thiofuroyl) -2'-hydroxy-5,9a-dimethyl-6,7-benzomorphane.

c) 2-Furfuryl-2'-hydroxy-5,9a-dimethyl-6,7-benzomorphane methanesulfonate

According to Example 1e, 1.9 g of lithium aluminum hydride are reduced with 10 g of 2- (2-thiofuroyl) -2'-hydroxy-5,9a-dimethyl-6,7-benzomorphane (residue from the above reaction step). It is then further processed as described. The crude product can be purified by crystallization from benzene / petroleum ether according to Example 1e or by chromatographic treatment with alumina as follows:

40 g of alumina (activity III, neutral) in chloroform are slurried on a chromatography column. The basic residue is dissolved in 2 to 5 ml of chloroform and this solution is chromatographed on an alumina column. Chloroform is used as solvent and the eluate is collected in 10 ml fractions. The integrity and purity of the eluate fractions are examined by thin-layer chromatography (the substance sought is present in about the first 200 ml of eluate). Evaporate in vacuo and crystallize the residue as a metal sulfonate.

To this end, the evaporation residue of the eluate is dissolved in 5 ml of ethanol and the solution is acidified with 0.5 g of methanesulphonic acid. Absolute ether is added to the solution until it just clouds. 2-Furfuryl-2'-hydroxy-5,9a-dimethyl-6,7-benzomorphane methanesulfonate crystallizes out. To complete the reaction, allow to stand overnight in the refrigerator. It is then filtered off with suction, washed with ethanol / ether and finally with ether. Dry at 80 ° C to give 6.1 g of compound with a melting point of 163-165 ° C. The ethanol / ether recrystallized sample melts at 164-167 ° C. The total yield from reaction steps a) to c) is 64% of theory.

8 63027

Example 3 2-Furfuryl-21-hydroxy-5,9a-dimethyl-6,7-benzomorphane hydrobromide a) 2- (2-thiofuroyl) -2 '- (2-furoyloxy) -5,9a-dimethyl- 6,7-Benzomorphane H.05 g (0.01 mol) of 2- (2-furoyl) -2 '- (2-furoyloxy) -5,9a-dimethyl-6,7-benzomorphane is reacted to give the title compound. as described in Example Ib.

b) 2-Furfuryl-2 '- (2-furoyloxy) -5,9a-dimethyl-6,7-benzomorphane 2- (2-thiofuroyl) -2' - (2-furoyloxy) -5,9a-dimethyl-6 The 7-benzomorphane (from reaction step a above) is dissolved in 50 ml of ethanol, 50 ml of water and 100 ml of glacial acetic acid are added to the solution and heated to boiling. 10 g of zinc powder are added, followed by refluxing with stirring for 2 hours. Allow to cool slightly and suck off the still warm reaction mixture through a pad of diatomaceous earth. The filtrate is made concentrated with ammonia in the presence of ice and extracted with chloroform (3 times 100 ml). The combined chloroform extracts are washed with water and dried over sodium sulfate and evaporated in vacuo. The residue is crystallized from a mixture of 14 ml of methanol and 1 ml of water. The crystals are allowed to stand overnight in the refrigerator, after which they are separated by suction and washed with a small amount of cold methanol. Dry at 60 ° C to give 2.0 g of 2-furfuryl-2 '- (2-furoyloxy) -5,9a-dimethyl-6,7-benzomorphane, m.p. 109 ° C. The melting point rises to 130 ° C upon recrystallization from methanol.

c) 2-Furfuryl-2'-hydroxy-5,9o-dimethyl-6,7-benzomorphane hydrobromide 2.0 g 2-furfuryl-2 '- (2-furoyloxy) -5,9a-dimethyl-6 The 7-bentomorphane (see reaction step above) is dissolved in 50 ml of methanol, 12.5 ml of 2N sodium hydroxide are added to the solution and the reaction mixture is refluxed for 15 minutes. It is then cooled, 50 ml of 2N ammonium chloride are added and the mixture is evaporated in vacuo to remove methanol. The evaporated residue is extracted 3 times with 30 ml of chloroform and the combined extracts are washed with water, dried over sodium sulfate and evaporated in vacuo. The residue is dissolved in 5 ml of ethanol and the solution is acidified with 60% hydrobromic acid. Add absolute ether until the solution becomes cloudy, whereupon the hydrobromide precipitates. To complete the crystallization, allow to stand for 3 days in the refrigerator. It is then filtered off with suction and washed with ethanol / ether and lastly with ether. The crystals are dried at 80 ° C to give 2.5 g of product, melting point 197 ° C. The yield of steps a) to c) is 66% of theory.

Example * + 2-Furfuryl-2'-hydroxy-5,9a-dimethyl-6,7-benzomorphane a) 2- (2-thiofuroyl) -2, - (2-furoyloxy-5,9a-dimethyl-6,7 -benzomorphane • +.05 g (0.01 mol) of 2- (2-furoyl) -2- (2-furoyloxy) -5,9a-dimethyl-6,7-benzomorphane is thionated according to Example Ib) .

b) 2-Furyl-2'-hydroxy-5,9a-dimethyl-6,7-benzomorphan Shake 2.5 g of zinc chips, 0.125 g of HgCl2, 2.5 ml of water and 0.1 ml of concentrated hydrochloric acid. minutes. The solution is then decanted. The amalgamated zinc chips are washed with water and added to a solution of 2- (2-thiofuroyl) -2 '- (2-furoyloxy) -5,9o-dimethyl-6,7-benzomorphane (see reaction step above) in 30 ml of ethanol. . 12.5 ml of concentrated hydrochloric acid and 2.5 ml of water are added, followed by boiling at reflux for 1 hour. After cooling, dilute with 100 ml of water, add 50 ml of concentrated ammonia and extract first with 100 ml and then once more with 50 ml of chloroform. The combined extracts are washed with water, dried over sodium sulfate and evaporated in vacuo. The residue is purified according to Example 2c) by chromatography on alumina and the purified base is crystallized from benzene / petroleum ether. 1.9 g of 2-furfuryl-2'-hydroxy-5,9a-dimethyl-6,7-benzomorphane with a melting point of 104-105 ° C (1 mol of crystal benzene) are obtained. The total yield of reaction steps a) and b) is 50.5% of theory.

... f ,. V

Example 5 2-Furfuryl-2'-hydroxy-5,9-dimethyl-6,7-benzomorphane 63027 a) 2- (2-thiofuroyl) -2 '- (2-furoyloxy) -5,9a-dimethyl-6 , 7-benzomorphan 4.05 g (0.01 mol) of 2- (2-furoyl) -2 '- (2-furoyloxy) -5,9a-dimethyl-6,7-benzomorphane are thionated with phosphorus pentasulfide according to Example Ib) .

b) 2-Furfuryl-2'-hydroxy-5,9a-dimethyl-6,7-benzomorphane 2- (2-thiofuroyl) -2 '- (2-furoyloxy) -5,9a-dimethyl-6,7- b ents omorphan (see previous reaction step) is dissolved in 250 ml of methanol and the solution is refluxed for> +5 minutes, after the addition of 5 g of Raney nickel in contact with methanol. Add another 5 g of Raney nickel and boil for a further 45 minutes.

It is then cooled and the solution is filtered off with suction through diatomaceous earth. The filtrate is evaporated in vacuo. For purification, the crude product is chromatographed using a column 50 cm long and 5 cm in diameter and a mixture containing 1900 ml of chloroform, 100 ml of methanol and 2 ml of concentrated ammonia. 20 ml of eluate fractions are collected and examined by thin-layer chromatography. (silica gel plates, same flux). The fractions containing pure substance are combined and evaporated in vacuo. The residue is crystallized from benzene / petroleum ether. The total yield of reaction steps a) and b) is 0.3 g, melting point 102-103 ° C.

Example 6 2- (2-Methyl-3-furylmethyl) -2'-hydroxy-5,9a-dimethyl-6,7-benzomorphane methanesulfonate Starting from 2'-hydroxy-5,9a * dimethyl-6,7- Benzomorphane (2.17 g), (0.01 mol) and 2-methyl-3-furoyl chloride (3.2 g) are obtained as described in Example 1 in a total yield of 3.1 g, i.e. 76% of theory. The melting point of 255-256 ° C rises to 268-270 ° C upon recrystallization from ethanol / ether.

... f · f- 11 63027

Example 7 2- (3-Furylmethyl) -2'-hydroxy-5,9a-dimethyl-6,7-benzomorphane hydrochloride Starting from 2'-hydroxy-5,9a-dimethyl-6,7-benzomorphane (2 , 17 g, 0.01 mol) and 3-furoyl chloride (2.9 g), the title compound is obtained according to Example 1 in a total yield of 2.3 g or 69% of theory; melting point 248 ° C from ethanol / ether after recrystallization 252 ° C.

Example 8 2-Tenyl-2'-hydroxy-5,9-dimethyl-6,7-benzomorphane hydrochloride Starting from 2'-hydroxy-5,9a-dimethyl-6,7-benzomorphane (2.17 g, O .01 moles) and 2-thenoyl chloride (3.2 g) give the title compound according to Example 2 in a total yield of 2.4 g, i.e. 68.5% of theory, melting point 255-257 ° C from ethanol / ether after recrystallization 258-259 ° C.

Example 9 2- (3-Methyl-furfuryl) -2'-hydroxy-5,9α-dimethyl-6,7-benzomorphan methanesulfonate Starting from 2'-hydroxy-5,9a-dimethyl-6,7-benzomorphane (2 , 17 g, 0.01 mol) and 3-methyl-2-furoyl chloride (3.2 g) according to Example 3 give the title compound in a total yield of 2.3 g, i.e. 56.5% of theory: melting point: 202-203 ° C.

Example 10 2- (2-Methyl-3-furylmethyl) -2'-hydroxy-5,9β-dimethyl-6,7-benzomorphane methanesulfonate Starting from 2'-hydroxy-5,9 8-dime ;. y 1 i-6,7-Bent somor f Aert ΐ ί 63027 (2.17 g, 0.01 mol) and 2-methyl-3-furoyl chloride (3.2 g) give the title compound according to Example 1 in a total yield of 3.1 g i.e. 76% of theory; melting point 213-214 ° C, after recrystallization from ethanol / ether 209 ° C.

Example 11 2- (2-Methyl-3-furylmethyl) -2'-hydroxy-5-methyl-6,7-benzomorphane hydrochloride Starting from 2'-hydroxy-5-methyl-6,7-benzomorphane (2, 05 g, 0.01 mol) and 2-methyl-3-furoyl chloride (3.2 g) give the title compound of Example 1 in a total yield of 1.7 g or 51% of theory; melting point 212 ° C, after recrystallization from ethanol / ether 218 ° C.

Example 12 2-Furfuryl-2'-hydroxy-5-methyl-9a-ethyl-6,7-benzomorphane Starting from 2'-hydroxy-5-methyl-9a-ethyl-6,7-benzomorphane (2.32 g, O , 01 moles) and 2-furoyl chloride (2.9 g) give the title compound according to Example 1 in a total yield of 1.2 g, i.e. 45 S of theory; melting point 173 ° C, after recrystallization from aqueous ethanol 182 ° C.

Example 13 2-Furfuryl-2-methoxy-5,9a-dimethyl-6,7-benzomorphane hydrochloride Starting from 2'-methoxy-5,9-dimethyl-6,7-benzomorphane ( 2.32 g, 0.01 mol) and 2-furoyl chloride (2.9 g) are obtained according to Example 4 in a total yield of 1.4 g, i.e. 40% of theory; melting point 206 ° C, after crystallization from ethanol / ether 210 ° C.

Example 14 63027 (-) - 2-Furfuryl-2'-hydroxy-5,9α-dimethyl-6,7-benzomorphane methanesulfonate Starting from (-) - 2'-hydroxy-5,9a-dimethyl-6,7-benzomorphane (2.17 g, 0.01 mol) and 2-furoyl chloride (2.9 g) give the title compound according to Example 2 in a total yield of 2.8 g or 71% of theory; melting point 205-206 ° C.

Example 15 (-) - 2- (3-Thienylmethyl) -2'-hydroxy-5,9a-dimethyl-6,7-benzomorphane methanesulfonate Starting from (-) - 21-hydroxy-5,9a-dimethyl-6 1,7-Benzomorphans (2.17 g, 0.01 mol) and 3-thenoyl chloride (3.2 g) give the title compound according to Example 1 in a total yield of 3.1 g, i.e. 73 S of theory; melting point 205-206 ° C, unchanged on recrystallization from ethanol / ether.

Claims (1)

A new process for the preparation of racemic or optically active N- (furyl or thienylmethyl) -benzomorphans of the general formula - N 1 - R 2 1 RO wherein R is hydrogen or methyl or acetyl, R 1 is hydrogen or alkyl, 2 to 3 having 1 to 3 carbon atoms, R is hydrogen, methyl or ethyl, R is hydrogen or methyl and X is an oxygen or sulfur atom, and acid addition salts thereof, characterized in that the compound of formula S - N / “ (wherein R *, R 1, R 3 and X are as defined above and R 1 is a hydrogen atom, an alkyl, aralkyl or ayl group, is reduced to a compound of formula 63027 ch 2 - N / / 2 111 R40 in which R * - R 1 have the same meaning as above, and optionally for the preparation of a compound of formula I in which R is hydrogen, from a compound of formula III in which R represents an alkyl, aralkyl or acyl group, removing an alkyl or acyl group, and optionally - a ka to prepare a compound of formula I wherein R is a methyl or acetyl group - methylating or acetylating a compound of formula III 4 wherein R is a hydrogen atom; and optionally converting the compounds of the general formula I into their physiologically acceptable acid addition salts. 16 63027 Paten tkrav Nytt förfarande för framställning av som läkemedel använda racema-tiska ell optiscti aktiva N- (furyl- eller thieny1-methyl-1) -benzo-morphaner, vilkas allmänna formeln är en -i r3 / r— N / - R2 RO där R avser väte eller methyl, R * avser väte eller alkyl med 1-3 2 3 kolatomer, R är väte, methyl eller ethyl, R avser väte eller methyl or X är en syre- eller svavelatom, velvet deras syraadditions- salter, kännetecknat därav, att en förening, Väre formulel är, / H> 'r4o 12 3 4 där R, R, R och X har förut angiven betydelse och R avser en väteatom, en alkyl-, aralkyl- eller acylgrupp, reduceras til en förening med formeln,, ·, 'l *