FI63028B - NOW FOERFARANDE FOER FRAMSTAELLNING AV SOM CEILING MODEL ANVAENDA N- (FURYL-METHYL) -BENSOMORFANER - Google Patents

Description

F5SF * 1 [b] (11, advertisement publication, n9ft JS * LBJ (11) UTLÄGGNINGSSKRIFT Ο ό UZ Ö C (45) Γαtentti · ΜΓ .:;.:, Y! J. 4 1903 'Ss v ^ (51) K ».Ik? /Int.a.3 C 07 D 405/06 ENGLISH —FINLAND (M) —Λμ · * ··· ^ 792993 (FI) (22) H ^ mhpUv_A ^, ^ 26.09.79 V 7 (23 ) AlkupUvt — GiUctotsdtg OU 09.73 (41) Translator JulklMkri - KMt offantllg 26.09.79

Patent and Registration Board ............,.

_ _, ___, (44) Date of departure and date of issue. - 31.12.82

Patent and registration authorities Antokin utbgd och «UkrikM pubkcund (32) (33) (31) Pyr * ·» * «uolk ·» »- B * gW prtortm 06.09.72

Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) P 22 ^ 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) (jb) Leitzinger Oy (5I +) Separated from application 2748/73 (publication 63027) -

Avdelad frän ansökan 2748/73 (utläggningsskrift 63027) ___

Patent Publications 57,409 and 57,758 and Patent Application 1963/73 describe novel compounds having the general formula CH 2 - (j-jJ-R 3 -n '' 0 c $ ~ '!

RO

wherein R is hydrogen, methyl or acetyl, R is hydrogen or alkyl of 1-3 carbon atoms, R 2 is hydrogen, methyl or ethyl and R "* is hydrogen or methyl ·

When R 2 is alkyl, there are stereoisomeric benzomorphans in which the above groups are in the cis- (α-benzomorphan series) or in the trans position (β-benzomorphan series).

2 63028

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

Quaternary ammonium compounds with the general formula yr5 m

Cp <R * 0 13 4 wherein R - R are as defined above, R is hydrogen, alkyl, aralkyl or acyl, Y is an oxygen or sulfur atom, R1 is methyl or ethyl and * is an anion of an inorganic or organic acid, is reduced by the formula To the compound of formula III - / R 2 R 2 1 where R - R have the same meaning as above and if necessary 4 the substituent R is converted into the substituent R.

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? 63028 in 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 reacts readily with quaternary ammonium derivatives of formula II, which can therefore be advantageously reduced with this less flammable hydride. Sodium borohydride 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 derivatives of the formula II can also take place with evolving hydrogen, which is 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, zinc can be amalgamated according to Clemmensen by treatment with mercuric chloride to increase 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.

Compounds of formula II in which Y represents a sulfur atom 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. Raney nickel is preferably added during the reaction in 4,63028 portions. 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 wider. In contrast to the ammonium derivative of the formula II, for example, the carboxylic acid amide cannot be reduced with sodium borohydride, evolving hydrogen, Raney nickel or catalytically, but with very specific complex hydrides. The thioamides required as starting compounds can be prepared, for example, by thionating the carboxylic acid amides with phosphorus pentasulfide. The preparation of carbonamide is apparent from the aforementioned patent application 1963/73.

Compounds of formula II in which Y represents a sulfur atom I

(imidothioester salts) can be prepared, e.g., by alkylation of the corresponding thioamides.

Compounds of formula II in which Y is an oxygen atom (imidoester salts) can be terminated by alkylation of the corresponding carbonamides with oxonium salts.

The following examples illustrate the invention.

Example 1 2-Furfuryl-2'-hydroxy-5,9a-dimethyl-6,7-benzomorphane methanesulphate a) 2- (2-thiofuroyl) '2' - (2-furoyloxy) -5,9a-dimethyl-6 , 7-benzomorphan 5 63028 10.1 g (0.025 mol) of 2- (2-furoyl) -2 '- (2-furoyloxy) -5,9α-dimethyl-6,7-benzomorphan are dissolved in 125 ml of absolute pyridine. 3.2 g of phosphorus pentasulfide are added to the solution and the mixture is refluxed with stirring for 3 hours, while preventing the ingress of moisture. The pyridine is removed in vacuo and the residue is shaken, 100 ml of methylene chloride and 100 ml of water. The aqueous phase is extracted once more with 50 ml of methylene chloride, the combined methylene chloride solutions are washed successively with 50 ml of 2N hydrochloric acid in the presence of ice and then 3 times with water, dried over sodium sulphate and evaporated in vacuo. The yellow residue (10 g) is 2- (2-thiofuroyl) -2 '- (2-furoyloxy) -5,9a-dimethyl-6,7-benzomorphane.

The reaction product is used for the alkylation described in the next reaction step.

b) 2- (2-thiofuroyl) -2 '- (2-furoyloxy) -5,9a-dimethyl-6,7-benzomorphane methiodide.

The thioamide prepared in the above reaction step is dissolved in 150 ml of absolute acetone, 17.8 g or 7.85 ml of methyl iodide are added to the solution, and the solution is boiled at reflux.

The yellow solution then turns yellow-red and after about 1 hour the reaction product begins to separate as crystals. Boil for a total of 2 hours, then allow to cool and gradually add 450 ml of absolute ether with stirring. The crystallization is allowed to complete by standing overnight, after which it is separated by suction avoiding the ingress of moisture, washed with absolute ether and dried in a vacuum desiccator with concentrated sulfuric acid until the weight remains constant. The total yield of reaction steps a) and b) is 11.0 g, i.e. 78% of theory; melting point 125-130 ° C. The sample recrystallized from acetone / ether also melts at 125-130 ° C.

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

To a suspension of 0.6 g of lithium aluminum hydride in 20 ml of absolute tetrahydrofuran is added, with stirring and ice-cooling, 2.82 g (0.005 mol) of 2- (2-thiofuroyl) -2- (2-furoyl-6,63028 oxy) -5, 9α-Dimethyl-6,7-benzomorphane-metiodide (reaction step above). The yellow color of the salt then disappears in the blink of an eye. After 15 minutes, the ice bath is removed and the reaction mixture is further stirred for 1 hour at room temperature. 2 ml of water are then added dropwise with stirring and 50 ml of saturated diammonium tartrate solution are added. Shake vigorously for some time and then carry out the separation in a separatory funnel. The tetrahydrofuran solution (upper layer) is evaporated in vacuo and the aqueous layer is extracted 3 times with 40 ml of chloroform. The residue of the tetrahydrofuran solution is dissolved in the combined chloroform extracts, washed with water, dried over sodium sulfate and evaporated in vacuo. The residue is dissolved in 5 ml of ethanol and, after the solution has been acidified with 0.5 g of methanesulphonic acid, absolute ether is added until the solution is slightly cloudy. The methanesulfonate crystallizes, which is stored overnight in a refrigerator to complete the crystallization. It is then filtered off with suction and washed with ethanol / ether, then with ether. After drying, 1.2 g of compound (61 S of theory) with a melting point of 163-165 ° C are obtained. The melting point rises to 165-168 ° C after recrystallization from ethanol / ether.

Example 2 2-Furfuryl-2'-hydroxy-5,9a-dimethyl-6,7-benzomorphane methanesulfonate 1 g of sodium borohydride is dissolved in 10 ml of water. The solution is diluted with 20 ml of ethanol, after which 2.82 g (0.005 mol) of 2- (2-thiofuroyl) -2 '- (2-furoyloxy) -5-9a-dimethyl-6,7-benzomorphane are added with stirring. -metoiodide (see Example 1, reaction step b). In this case, the temperature rises to 45 ° C and the yellow color of the salt disappears in the blink of an eye. Stir for a further 1 hour and then add, first dropwise, a total of 25 ml of 2N hydrochloric acid and boil for 15 minutes at reflux. Cool, add 25 ml of 2N ammonia and extract 3 times with 50 ml of chloroform. The combined chloroform solutions are washed with water, dried over sodium sulfate and evaporated in vacuo. The residue is crystallized according to Example 1c) as methanesulfonate. Yield 1.5 g or 76% of theory; melting point 164-167 ° C, after recrystallization from ethanol / ether 166-168 ° C.

7 63028

Example 3 2-Furfuryl-2'-hydroxy-5,9-α-dimethyl-6,7-benzomorphane 2.82 g (0.005 moles) of 2- (2-thiofuroyl) -2- (2-furoyloxy) -5 9α-Dimethyl-6,7-benzomorphane-metiodide (see Example 1, reaction step b) is added to a suspension of 10 g of Raney nickel in 100 ml of methanol and the reaction mixture is refluxed for 30 minutes. It is then cooled and filtered, through diatomaceous earth. The filtrate is evaporated in vacuo and, for complete cleavage of the 2'-furoyloxy group, the residue is boiled for 15 minutes in a mixture of 50 ml of methanol and 13.5 ml of 2N sodium hydroxide. It is then cooled, 25 ml of 2N ammonium chloride are added and the mixture is evaporated in vacuo. The residue, 50 ml of water and 50 ml of chloroform are shaken and the aqueous phase is extracted twice more with 25 ml of chloroform. The combined chloroform extracts are washed with water, dried over sodium sulfate and 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 eluent). The fractions containing pure substance are combined and evaporated in vacuo. The residue is crystallized from benzene / petroleum ether. Yield 0.2 g, melting point 103 ° C.

Example 4 2-Furfuryl-2'-hydroxy-5,9a-dimethyl-6,7-benzomorphane a) 2- (2-trifluoroyl) -2 '- (2-furoyloxy) -5,9a-dimethyl-6,7 -bentsomorfaani-etoetyylisulfaatti

According to Example 1, 2- (2-furoyl) -2 '- (2-furoyloxy) -5,9o-dimethyl-6,7-benzomorphane (4.0 g, 0.01 mol) is obtained via the corresponding thioamide, which is reacted in acetone with diethyl sulfate, the title compound as a non-crystallized syrup.

b) 2-Furfuryl-2'-hydroxy-5,9a-dimethyl-6,7-benzomorphane Starting from the reaction product of the above reaction step, 63028 is obtained with sodium borohydride by reduction of the title compound according to Example 2 in a total yield of 1.7 g or 57% of all reaction steps a) to b). of theory; melting point 97-98 ° C, after recrystallization from benzene / petroleum ether 103-105 ° C.

Example 5 2- (3-Methyl-furfuryl) -2'-hydroxy-5-ethyl-9a-methyl-6,7-benzomorphane Starting from 2'-hydroxy-5-ethyl-9a-methyl-6,7-benzomorphane ( 2.3 g of 0.01 mol) are obtained according to Example 1a) and b) 2- (3-methyl-furfuryl) -2 '- (3-methyl-3-furoyloxy) -5-ethyl-9a-methyl-6, 7-benzomorphane and hence 2- (3-methyl-2-thiofuroyl) -2 '- (3-methyl-2-furoyloxy) -5-ethyl-9a-methyl-6,7-benzomorphane. Alkylation according to Example 1b) with methyl iodide gives the corresponding methiodide as a non-crystallized syrup which is reduced according to Example 2 with sodium borohydride. The reduction product is crystallized from aqueous methanol. The total yield of the four synthetic steps is 0.25 g, or 7.7% of theory; melting point 178 ° C, unchanged on recrystallization from methanol.

Example 6 2- (3-Furylmethyl) -2'-hydroxy-5-ethyl-6,7-benzomorphane hydrochloride Starting from 2'-hydroxy-5-ethyl-6,7-benzomorphane (2.17 g, 0.01 moles) of 2- (3-furoyl) -2 '- (3-fluoryloxy) -5-ethyl-6,7-benzomorphane and 2- (3-thiofuroyl) -2' - (3-furoyloxy) -5- ethyl-6,7-benzomorphan. Alkylation with methyl iodide gives 4.2 g of the corresponding methiodide from the latter, which is reduced according to Example 2 with sodium borohydride. The reduction product is crystallized as the hydrochloride from ethanol / ether. The total yield of the four synthetic steps is 1.5 g, or 44% of theory; melting point 212 ° C, after recrystallization 223 ° C.

9 63028

Example 7 2- (2-methyl-3-furylmethyl) -2'-hydroxy-5,9a-dimethyl-6- [7-benzomorphane a) 2- (2-methyl-3-furoyl) -2'-hydroxy-5, 9a-Dimethyl-6,7-benzomorphan 43.4 g (0.2 mol) of 2'-hydroxy-5,9a-dimethyl-6,7-benzomorphan are dissolved in 1400 ml of methanol and 50 g of potassium carbonate in 80 ml of water are added to the solution with vigorous stirring. . 32 g (0.22 mol) of 2-methylfuran-3-carboxylic acid chloride are added to the suspension over 1 hour with stirring, followed by stirring for a further hour at room temperature. Evaporate and shake the residue together with 300 ml of chloroform and 150 ml of water. The aqueous phase is separated and extracted once more with 150 ml of chloroform. The chloroform extracts are combined and washed successively with 150 ml of 2N hydrochloric acid, 150 ml of water and 150 ml of sodium hydrogen carbonate. It is then dried over sodium sulfate and evaporated in vacuo. The residue is crystallized from toluene. Yield 58.5 g or 30% of theory; melting point 157-159 ° C.

b) 2- (2-methyl-3-furoyl) -2'-acetoxy-5,9a-dimethyl-6,7-benzomorphane 32.5 g (0.1 mol) of 2- (2-methyl-3-furoyl) - 2'-Hydroxy-5,9a-dimethyl-6,7-benzomorphane and 325 ml of acetic anhydride are heated on a boiling water bath for 2 hours. It is then evaporated in vacuo and the residue is shaken for 1 hour with ice water. The reaction product is then extracted 3 times with chloroform (200 ml and 2 times with 100 ml) and the combined chloroform extracts are washed with water. Dry over sodium sulfate, then evaporate the solution in vacuo. The reaction product remains as a syrup, which is further reacted in the next reaction step.

c) 2- (2-methyl-3-furoyl) -2'-acetoxy-5,9a-dimethyl-6,7-benzomorphane ethofluoroborate

The residue from the above reaction step in 100 ml of absolute methylene chloride and 19 g (0.1 mol) of triethyloxonium fluoroborate 103030 are stirred at room temperature for 24 hours to prevent the ingress of moisture. After evaporation in vacuo, the reaction product remains as a viscous residue, which, because of its decomposition, is expediently used in this form.

d) 2- (2-methyl-3-furylmethyl) -2'-hydroxy-5,9a-dimethyl-6,7-benzomorphane

The residue of the above reaction step is dissolved in 100% absolute ethanol, and 5.5 g (0.15 mol) of sodium borohydride are added portionwise to the solution with stirring and cooling. Stir overnight, then pour 300 any water and extract with ether. After evaporation of the ether extract, the residue is dissolved in 300 parts of methanol and 100 ml of 2N sodium hydroxide are added to the solution, followed by refluxing for 30 minutes. Most of the methanol is then removed in vacuo, 20 ml of 2N ammonium chloride are added to the residue and extracted with chloroform (200, 100, 100 ml). The combined extracts are washed with water, dried over aqueous isopropanol. Yield 22 g or 70.5% of theory. (total yield from reaction step b) to d). Melting point 138-140 ° C.

Example 8 2- (Furfuryl) -2'-hydroxy-5,9a-dimethyl-6,7-benzomorphane Starting from 2'-hydroxy-5,9a-dimethyl-6,7-benzomorphane (2.17 g, 0.01 moles) to give the title compound according to Example 7 in a total yield of reaction steps a) to d) of 65% of theory (crystallized from aqueous isopropanol); melting point 119-120 ° C.

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Claims (2)

A new process for the preparation of N- (furylmethyl) -benzomorphans having the general formula / "-O-" 1 -NRO wherein R is hydrogen, methyl or acetyl, R 1 - is hydrogen or alkyl, wherein 3 is 1 to 3 carbon atoms, R is hydrogen, methyl or ethyl and R is hydrogen or methyl, and acid addition salts thereof, characterized in that the quaternary ammonium salt having the formula YR5 {♦} -N u \ ___ y \ rj R ^ O 1 L 3 J 4 in which R to R are as defined above, R is a hydrogen atom, an alkyl, aralkyl or acyl group, Y is an oxygen or sulfur atom, R 1 is methyl or ethyl »and A 1 is an anion of an inorganic or organic acid, is reduced to a compound of formula III 12 63028 '/ C H2 ~ ff "1— r3 —J \ ~ R2 / yV 111 R ^ OR 14 where R - R have the same meaning as above and, if necessary, the substituent R4 is converted into the substituent R in a manner known per se. 13 63028 For the preparation of N- (furyl-methyl) -benzomorphaner in the form of a / / '' - O '' RO, R is a mixture of methyl or acetyl, R 1 - a mixture of alkyl or alkyl 2 3 1-3 cholesterol, R avser väte, methyl eller ethyl, R avser väte eller methyl, velvet deras syraadditionssalter, känneteck- nat därav, att quartrt ammoniumsalt med formuleln YK5 (*) R ^ O där R ^ · - R ^ Tiar förut angiven betydelse, R4 avser en väteatom, en alkyl-, aralkyl- eller acylgrupp, Y avser en syre- eller svavelatom, R ^ is methyl or ethyl and A is an anion or an organic or organic syrup, which is reduced to form III