SU577982A3 - Method of preparing 2-tetra-hydrofurfuryl-6,7-benzomorphanes or salts thereof - Google Patents

Description

577 3 basic ogeit, for example, carbonate loading. The process is carried out at a temperature of from -10-C at the boiling point of the solvent or solvent mixture. Depending on the reaction conditions and reagents, the resulting reaction products are either steric, homogeneous compounds or mixtures of racemic or optically active diastereoisomers. The process uses the calculated amount of the alkylating agent of formula 1P or, preferably, an excess of it, working in the presence of an acid binding agent. such as, for example, triethylamine, dicyclohexyethylamine, sodium carbonate, potassium carbonate, and calcium oxide, or, preferably, sodium bicarbonate. Although it is possible to work without solvents, carrying out the process in inert solvents such as chloroform, toluene, ethanol, nitromethane, tetrahydro4 uranium, methyl sulfide, and preferably "imethylformamide," is more appropriate. Mixtures of the solvents given can also be used. An excess of alkylating agents, for example, excess tetrahydrofurfuryl bromide may also be used as a solvent. The reaction temperature can be varied over a wide range, with the lower limit being set by a too slow rate of reaction, and the upper limit - by the occurrence of side reactions. It is advisable to work at temperatures between 50 and 150 °, preferably about 10 ° C. The compounds of general formula D are bases and can be converted in a usual manner into physiologically tolerable salts. Acids suitable for salt formation are, for example, mineral acids, such as hydrochloric acid, or organic acids, such as acetic acid. Example 1. Methanolulfonate (-) - 2- (D -tetrahydrofurfuryl) 1R, 5R, 9R) -2-ixy-5, 9-dimetip-6,7 gbenzomorfana. 2.17 g (O, O1 mole) {1R, 5R, 9R) - (-) - 2-oxy-5,0-dimethyl-6,7-benzomorphane, 1.26 g sodium bicarbonate and 1.82 g ( O, OH mol) bromide B - (-) - tetragyarofurfuryl in a mixture of 15 ml of dimethylformamkde and 25 m of tetragoformu boil for 75 hours under reflux, stirred, evaporated in vacuo and the residue is shaken with 35 ml of chloroform and 35 ml of water. The aqueous solution is extracted twice with 15 ml of chloroform. The combined chloroform extracts are washed with 30 ml of water, dried with sodium sulfate and evaporated in vacuo. The product is dissolved in 25 ml of chloroform and the solution is purified chromatographically on a column with 50 g of aluminum oxide (degree of activity III, neutral chloro (}) form. Eluted with a mixture of chloroform) and methanol 09: 1. After alumina by thin-layer chromatography the fractions containing the desired product were combined with the pure substance and evaporated in vacuo. The evaporation residue is crystallized from a mixture of 10 ml of methanol and 6 ml of water. After aging at a temperature of 10 hours. the crystallized is filtered and washed with a small amount of aqueous methanol, dried at a temperature of 80 ° C. Poluchshot 2.3 g (76.5% of theory) of the crystalline base with t. Pl. 197 ° C, which rises upon recrystallization from aqueous methanol to 210 ° C, oll -108.5 ° C (s 1, methanol). To transfer to the methanesulfonate, adding 0.47 g of methanesulfonic acid, 1.55 g (O, OO5 mol) of the crystalline base is dissolved in 8 ml of ethanol and the solution is mixed with absolute ether before being cloudy (40 ml). After soaking for several days at 2 ° C, the salt is isolated in the form of coarse crystals. The crystallisate is filtered off, washed with ethanol / / ether (1: 1), with ether and dried at 50 ° C. Obtain 1.4 g (7O, 5% theory) of a product with so pl. 70 °, Example 2. (+) - 2 (1, -tetrahydrofgur4uryl) - (15, 5S, 9 3) -2-hydroxy-5,9-dimethyl-6, 7-benzomorfan. From 2.17 g (0.01 mol) (13, 5S, 9S) - (+) - 2 -oxy-5,9-dimetip-6,7-6 vnzomorphanana, 1.26 g sodium bicarbonate and 1.82 g (0.031 mole) L - (+) - tetrahydro bromide (| urfuryl, as described in Example 1), 2.2 g (72.5% of theory) of the indicated compound is obtained from aqueous methanol with t, mp, 199 °, which, after recrystallization from aqueous methanol rises to 20 °,, 3 (from 1, methanol). Example 3. (-) - 2- (1-tetrahydro-4furyl) - (1H, 51, 91) - (-) - 2-hydroxy-5, 9-dimegyp-6, 7-benzom6rfak. From 2.17 g (0.01 mol): (IT, 5R, 91) - (-) - 2-hydroxy-5,9-dimethyl-6,7-benzomorfana, 1.26 g of bicarbonate, sodium and Ij82 g (O, O11 mol) of bromide L. (+) - No. trahydrofurfgurshi is similar in Example 1, 2.3 g (76.5% of theory) of this compound is obtained with a melting point of 133 ° C, which, when recrystallized from aqueous methanol, rises to 1370, from about -98.5 ° (from 1 , methanol.) Example 4, (+) - 2- (1) -tetrahydro1 | UR4Uryl) - (&, 55, 95) -2-hydroxy-5,9-dimethyl-6, 7-benzomorfan}. From 2.17 (0, O1 mole) (IS, 5S, 95) - (+) - 2-hydroxy-5, 9-dimethyl-6,7-benzomorphane, 1.26 g of sodium bicarbonate and 1.82 g (, 0, O11 mop) bromide) - (-) - tetragilrofurfril

as in Example 1, from water hydrogen) of methanol, 2.1 g (00.5% of theory) of the abovementioned compound with t, nn are obtained. 133, which after recrystallization rises to 137 °, Y. 98.2.

Example 5, (-) - 2- (D-tetrahydro.: {| Urfuryl) - (IR, 5R, OR) -2-hydroxy-5,9-cimethyl-6, 7-benomorphane and (-) - 2- (L-tetrahydrofur4uryl) - (1R, 5R, 9R) -2 -keyi-S, 9-dimethyl-6, 7-belaomo x |) an,

21.7 g (O, 1 mol) (iR, 5R, EL) - (-) - 2 -oke-5,9-dimethyl-6,7-benzomorfana, 1 2.6 g sodium bicarbonate, 18.2 g (0, 11 mol) of bromide (t / -tetrahydrofurfuryl and 2 g of potassium iodide in 200 ml of dimethylformamide, while stirring for 18 hours, heated to 100 °, cooled, and mixed with 40O ml of water for 30 minutes with stirring. temperature is then filtered, washed with several portions of water, filtered at 8 ° C, dried to constant weight.

21.0 g of a mixture of the indicated di-stereoisomers are obtained. The mother liquor is kept

For separation of diastereoiomers, cetallisate is recrystallized from 22 O ml of methyl ethyl ketone. It is cooled for 10 hours at 2, sucked off and washed with a large amount of cold methyethylcatone. The mother liquor is kept, C7 crystals are kept at a temperature of 80 °. Obtain 11.7 g of crystals with so pl. 197 °, from which, after recrystallization from 27O ml of methanol and 135 ml of water, 1O is obtained, 6 g of pure (-) - 2- (3) -tetrahydro4ur4uril) - (11g, SR.SR) -2 oxy-5, E-dimvtil -6,7-benzomorfan 1 with so pl. 2O1 °.

The second D 1ac1 hereoisomer is prepared from mother solutions of dimethylformamide and 4-ethyl ethyl ketoe. The mother solution of dimethylformamide is evaporated in vacuo and the residue is crystallized from 5O mi-dnimethylformamide and 200m water. Stand 2 6 at room temperature, oTcactraatot washed with water and dried at 80 °, obtained 4.1 g of the second diastereoisomer. An additional amount of the substance was isolated from the methyl ethyl ketone stock solution. It is evaporated and the residue is crystallized from ZO ml of methyl ethyl ketone, settled overnight at room temperature, sucked off, get a stock solution of 2 methyl ethyl ketone and 4.4 g of crystallisate dried at a temperature of 80 ° C. Crystallizate is recrystallized from 35 ml of methyl ethyl ketone. a solution of 3 methyl ethyl ketoia and 1.4 g of cetalpizate. The crystal is composed of a mixture of both diastereoisomers at 1: 1 and again can be divided above

in a way. Magneshl solutions 2 and 3 combine fflior and liquid in vacuum in a vacuum. Vaccine from urination, as separated from the uterine solution of dimethylformamide secondary cryetal; And then (4.1 g), it is of the isatoric diastereoisomer. Together, they are crystallized from a mixture of trluol e with gasoline (60-80 °) in a volume ratio of 70:30. After standing for 10 hours at room temperature, they are filtered off with suction, washed with gasoline, and dried at 80 °. 6.5 g of (-) - 2- {U-tetrahydrO (| ur (1 rn)) - (IR, 5R, OT) -2-oxy-5, 9-dimetip-6,7-benzomorfana} are obtained. 137 °. From the residue from the evaporation of the mother liquor by cryetallization from 50 ml of toluene / gasoline mixture, another 2.7 g of the substance is obtained with the same g, pp. Output of the second diatereomer -.

Example 6. Methanelauner (-) - 2-tetrahydrofur1 | ) -oxy-5,9-9-trimetip-6, 7-benzomorfan.,

From 1D6 g (O, OO5 mol) () -2 -oxy-5, 9.9 - tri1. Hetil-6,7-benzomorphan and 0.91 g of bromide D () -tetrahydrofururil, as in Example 1, the above compound is obtained with m.p. 182 °, which, after recrystallization of the CZ, does not change the ethanol / ether. One of the two optically acted in} {dynastereomers is obtained. The second can be isolated from the mother liquor solutions.

Example 7, (1g) -2-tetrahydrofur4uryl-2-oxy-5.9o (, - aimethyl-6,7-benzomor 4 | an (racemic dietaroisomers 1 and P).

21.7 g {0.1 mol) (±) -2-oxy-5.9-dimeth-6, 7-benzomorophene, 13.7 g sodium bicarbonate, 19.9 g (0.12 mol) bromide (i ) -tetrahydrofurfril and 2 g of potassium iodide are mixed in 2OO ml of dimethylformamide, heated to 100 ° C for 18 hours. It is cooled, mixed with 4OO ml of water, sucked off and the residue is repeatedly washed. With water, sucked off, dried at 80 ° C. 25.4 g of krnetallisate are obtained, consisting of both racemic diastereon isomers J-C

; The racemic diastereon isomers were isolated in the form of hydrochlorides as follows. In addition, 7.3 ml of concentrated hydrochloric acid was added, the mixture of dihydroisomers was dissolved in 1OO ml of ethanol. They stand for 1Oh, the precipitate is filtered off, washed with a mixture of ethol / ether 1: 1, dried with ether in air, and the dates at 8O-CH3. This gives 13.5 g of gproprochloride of the diatereoisomer 1 and the mother liquor 1. After recrystallization from 350 ml of ethanol, 8.1 pure Veshave with a m.p. 294 ° C and mother liquor 2. After evaporation of the mother liquor 2 to 1OO ml, 2.0 g of a second crystallisag are obtained with a mp. 287-288 and mother liquor 3. 1 (x; the solution together with the mother liquor 1 is evaporated in a vacuum, and the residue is crystallized from 50 ml of ethanol, and another 1.3 g of the substance is taken up with mp. 287-288 ° and the mother liquor solution 4. Crystallized with 287-288 ° C, combined (4.1 g) and recrystallized from 40 ml of ethanol. Another 2.9 g of pure hydrochloride diastereoigomer 1 is obtained with a melting point of 294 ° C and the mother liquor 5 , The total yield of the pure substance with mp 294 ° C is 11.0 g. The diastereoisomer II is isolated from mother liquors 3,4 and 5. The mother liquors are evaporated in vacuo and the residue is shaken from 75 MP chlorine (, 76 ml of water and 10 ml of horses, ammonia. After separating the chloroform phase B in a separate funnel, the aqueous phase is extracted once more with 25 ml of chloroform. The combined chloroform extracts are washed with water, cyiiie.T sodium sulfate and evaporated in vacuo. The residue consists of a raw diastereoisomer3 II base, which is redrawn from 100 ml of a mixture of toluene and gasoline (60-80 °) in a volume ratio of 70: 30 DL, and standing. 10 hours at room temperature, sucked off, washed with a small amount of cold toluene / gasoline mixture, gasoline and dried at 8 ° C. Get 1O, 6 pure diastereoisomer II with t. Pl. 166 ° C By evaporation of the mother liquor, 3.5 g of residue is obtained, consisting of a mixture of both diastereon isomers, which can again be subjected to the described separation. Analogously to Example 7, 11.0 g of hydrochloride (i) -2-tetrahydrofur4uryl-2 -oxy-5.91-dcmethyl-6,7-benzomorphane (di-stereoisomer 1) and 10.6 g of (1) -2-tetrahyd are obtained. ro {ur4uryl-2-oxy-5,9o1-dimegyl-6,7-benaomorphane (diastereoisomer 11). By resolving the racemate as optical antipodes from the diastereoisomer 1, the compounds described in examples 1 and 2 and from the diastereoisomer i, the compounds described in examples 3 and 4 are obtained. Example 8. (i) -2-heterrahydrofur4y,: ogrnl-2 -OKCB-S, 9 ° C-dimethyl-6,7-benzomorfan (racemic diastereoisomer T). 2.17 g (O, O1 mol) 2-oxv-5,90 1-dime-6,7-beise {fan, 1.26 sodium bicarbonate and 2.82 g (O, O 11 mol) of tetrahydrofurfuryl ether para-toluene-sulfonic acids are stirred and mixed for 6 hours in a mixture of 2 O ml of dimethylformamide and 25 ml of tetrahydrofuran. The mixture was not cooled, the mixture was blended, and the filtrate in vacuo at a temperature of approximately 5 ° C was separated from the heterohydrofuran. After the addition of 4O ml of urban water, as described in Example 7, the mixture of cyastereoisomers is crystallized, separated, and 1.0 g of diastereoisomer hydrochloride 1 is obtained, c. . For conversion, the hydrochloride is dissolved in 10 ml of an ode and 1N ammonia is added dropwise. Set at 1Oh at room temperature, the base is filtered off, washed with water, filtered and recrystallized from 2O ml of methanol and 7 ml of water. Get about 75 g of substance with m. pl. 17576 ° C, which after recrystallization from aqueous methanol does not change. Example 9. Methanesupiphonat (i) tetrahydrofu | efurep-2 / -oxy-5,9,9-trimetrSH, 7-benzomorfana. (racemic diastereoses 1). From 1.16 g (0, OO5 mol) (±) -2-oxy5, 9,9-trimethyl-6,7-benzomorphan and O, 91 g 0,0055 mol) fomida (±) -tragarofururil analogously to example 1 teach said compound with t. pl. 207-21 O, which, after recrystallization from a mixture of eti90L / EFR, rises to 21 ° C. One of both radimetic diastereoisomers, L, is obtained. The second can be isolated from the mother liquors. I Example 1O. (i) -2-te1rshgidroigr4uril-2-hydroxy-5-methyl-E (31-ethyl-6,7-bvnzomorphan. A mixture of 2.31 g (O, 01 mol) (±) -2-oxy-5 -haethyl-9 ° C-etip-6, 7-beisomorphism 1.3 g sodium bicarbonate, 1.97 g (O, O12 mol) bromide (;) - hydrohydrofur (} uril and 0.2 g sodium iodide with 15 ml of dimethylformamide and 25 ml of tegrahydro4 urav, stirred, boiled under reflux for 6O hours. The reaction product is isolated, as in Example 1, purified by chromatography on 75 g of alumina and crystallized from aqueous methanop. Yield 1.2 g. after recrystallisation from 20 ml of methanol and 5 ml of water. Bacterium is one of the racemic diastereoisomers. The diastereoisomer can be isolated from mother liquors. Example (i). (i) -2-tetrahydro (| urfuryl-2-oxy-5-ethyl-9L, -met1sh-6,7-benzo - morphane .. From 2.31 g (0.61 mol) (±) -. 2-hydroxy-5 ethyl-9cC-metip-6, 7-benzomorfana and 1.97 g (O, O12 mol) of bromide (1 :) -tetrahydrofur (} urn analogously to Example 1O, 1.3 g of the above compound are obtained with m. p. 17EP, which, when re-installed from the MP of methanol and 1 O mp of water, does not change. The crystallized substance thus obtained is one of the two racemic diastereoisomers formed during the reaction. The second dynastereomer can be isolated from m & h exact solutions.