SU577983A3 - Method of preparing 2-tetra-hydrofurfuryl-6,7-benzomorphanes or their salts,racemates or optically-active antipodes - Google Patents

Description

a solvent at the boiling point of the reaction mixture, followed by isolation of the target product in a free form or as a salt, in the form of a racemate or an optically active antipode,

Preferred is the reduction with the use of complex hyacads of metals of high reducing ability, in particular with lithium aluminum gord. The hydride is used in a calculated amount or in a quantity of ке 1, preferably twice. The reaction is carried out in an inert solvent, for example diethyl ether, drizopropyl effe, or predominantly in: tetrahydro4 uranium. The process is carried out at a temperature of 50 ° C.

When restoring O-atsivnyh derivatives of the formula P, in Y is an oxygen atom, with complex metal ions, naphimer when reduced from aluminum by RIDOM lithium, varying with the reduction of the carbonyl group, the O-aa radical radical dissociates itself, and JB which R is a hydrogen atom. ,

The reduction of Gaoam Aav (a compound of the formula P, in which Y is a sulfur atom) occurs easier than the reduction of carbonamides. It can be co-hydrated with coco-hexnix or with hydrogen in the presence of nickel Ren, ” ,

Target food products were separated from the reaction mixture using conventional methods. If necessary, the resulting crude products can be purified using methods of oco & iX methods, such as column chromatography or them. crystallization i. in the form of founding L dl their salts.

Depending on the reaction conditions and reagents used, the reaction products obtained are either sternally homogeneous compounds or mixtures of racemic or optically active diasteras.

Due to their different chemical properties in physical properties, diastereomers can be separated by lime by means of methods, for example, fractional crystallization. Racemic compounds by conventional methods of splitting a racemate can be divided into appropriate optical antipodes,

Compounds of general formula I are isolated as a base or salt using mineral acids (hydrochloric, broMISTO, iodide, hydrofluoric, sulfuric, phosphoric, nitric acids) or orgasmic acids (acetic, propionic, oleic, valerian, pyvapine , Kapronova, Shavel A, Maponova, Ntarna, Maleinova, Fumarova, Dairy, Pyroviogra na, Vinnna, Limnna, Blochna, Beeoiva.

paraoxybenzoic, salipilova, tl-aminobenzoic, phthaloic, cinnamon, ascorbic, 8-chloro-otefilnn, methanesophone or ethanephosphonic).

Example (±) -2-Tetrahydro ({urfuryl-2-oxy-5,9-dimethyl-6,7-benzomorfan (racemic diastereomers I and I),

21.7 g (0.1 mol) of (±) -2-hydroxy-5,9-dimethyl-6, 7-benzomorphan is dissolved in 40 ml of methanol with heating and mixed with 25 g at room temperature, stirred vigorously. dissolved in 40 ml of potassium carbonate water. A fine mixture of part of the base and carbonate is released. While stirring vigorously, 22.2 g (0.165 mol) of tetrahydrofuran-2-carboxylic acid chloride are added dropwise to the suspension for 30 minutes and stirred for another 1 h. The mixture is then evaporated in vacuo and the residue is shaken with 150 ml of chloroform and 10 O ml of water . After the chloroform layer is separated in a separatory funnel, the aqueous phase is extracted once more with 50 ml of chloroform. The combined chloroform No. 1e extracts are successively washed with 1OO ml of 1 N, HCC and 100 ml of water, dried with sodium sulfate and, after adding 5 O ml of toluene, is evaporated to a vacuum, the residue consists of 2- (tetrygisto: 2--4URyl) -2-hydroxy- 5, e-dimethyl-b, 7-benzoorfan, which is used to reduce and.

The evaporation residue is dissolved in 2 5 O ml of absolute tefagydro4uran and the solution in flow 2O minutes, while stirring, is added dropwise to an ice-cooled suspension of 12 g of lithium aluminum hydride in 15O ml of absolute tetragon schieofuran. The ice bath is then removed, stirred an additional hour for 1 hour at room temperature and heated to reflux for 2 hours. The mixture is cooled and 50 / ml of water are mixed in drops, exchanging and cooling. Then, 1200 ml of the solution are used, the waste diammonn, - vst ||| “live in a separatory funnel and. After completion of a good wasp & danw phase (upper) tetrahydrof wound from a heavy aqueous layer. The tetrahischarfuran solution is removed under vacuum, the aqueous solution is extracted with 1OO ml of chloroform. The extract from the hlc form dissolves the residue from evaporation of the tetrahydro solution (uranium) and the solution is washed with water, dried with sodium sulfate and evaporated in vacuo. The crude mixture of diastereomers is obtained as a residue. Racemic diastereomers 1 and II are isolated as hydrochlorides. The mixture of diastereomers is dissolved in ethanol with the addition of concentrated hydrochloric acid. Now crystallization occurs. After standing for a night, suck off, rinse with ethanol with ether (1: 1) and then with npoo1 ether and air dry, and then with. The not very pure diastereomer I hydrochloride and the mother liquor 1. After recrystallization, a substance is obtained with a melting point of 294 ° C and a stock solution of 2, After evaporation of this solution, a crystallisate is obtained with a melting point of 287-288 ° C and a mother liquor 3 The latter, together with the exact solution 1, is evaporated in vacuo and the residue is crystallized from ethanol to obtain a substance with mp 287-288 ° C and a mother liquor 4. The crystallized crystals with mp 287-288 ° C are combined and recrystallized wate from ethanol. This gives a pure diastereomer hydrochloride 1 with so pl. Pl.294 ° to the mother liquor 5. The total yield of the pure substance with so pl. 294 ° C is about 11.3 g. Liastereomer 11 is recovered from. stock solutions 3.4 n 5 as follows. The mother solutions are boiled under vacuum and the residue is shaken with C 75 ml of chlorofarm, 75 ml of water and 10 ml of concentrated ammonia. After separation of the chloroform phase in a separatory funnel, the aqueous phase is extracted once more with 25 ml of chloroform. The combined chloroform extracts are washed with water, dried with sodium sulfate and evaporated in vacuo. The residue consists of a crude baseline of the second diastereomer. / It crystallizes from 10 ml of a mixture of toluene and gasoline (60-80 ° C) in a volume ratio of 7O:: ZO. After standing for a night, the mixture is sucked at room temperature, washed with a small amount of cold toluene (/) gasoline, and then gasoline, and dried at 8 ° C. Get a pure div | Eomer 11c m. pl. 166os.O.MayayM & K) PyoRp solution get a residue, where it is spilled, and both of the diaste eomersda; After the separation, a pure diastereomer hydrochloride of 1 tbsp. Is obtained. nrt 294 ° C and 9.3 g of diastereomer C (base) with so pl. 166 ° C, Example 2. (-) - 2- (D-tetrahydro (| ur furyl - (1P | 51, 9B) -2-hydroxy-5,9-dimethyl-6, 7-benzoforman and (-) - 2- {L-tetrahydrofurfuryl) - (, 5R, 9P) -2-hydroxy-5,9-dimvtil-6, 7 benzomorphan. To a suspension of 8.7 g (0.04 mol) (1R, 51, 9К) - (-) - 2 hydroxy-5,9-dimethyl-6,7-benzomorphan in 87 ml of absolute methylene chloride and 16 ml of triethylamine at room temperature, stirring and using a reflux condenser, add solution for 15 min. from 11.9 g {О, 88 .-., in - - mol) of tetrahydrofur-2-carboxylic acid tetrahydrofur-2-carboxylic acid in 40 ml of absolute methylene chloride. The reaction mixture is then heated for 2 hours under reflux. Then it is cooled, washed twice with 30 ml of water each time, dried with sodium sulfate and evaporated in vacuo. The residue consists of crude 2- (tetrahydro-2-furoyl) -2 - (tvtrahydro-2-furoyloxy) -5,9-dimethyl-6, 7-benzomorfana, which is used for the next reduction. Using 5.0 g of lithium aluminum hydride, the evaporation residue is reduced as in Example 1 and the reaction product described in this example is separated from the tetrahydrofuran phase and the chloroform extract from diammonium tartrate solution. It consists of a crude mixture of these compounds. In the separation of diastereomers, crystallized crystals are converted from methyl ethyl ketone. After cooling overnight at 2 ° C, suction is performed and washed with a small amount of cold methyl ethyl ketone. The mother liquor is maintained, the crystals are dried at 8 ° C. Get crystals with t., W1. 197 ° С, from which, after recrystallization from methanol and water (2: 1), 4.8 g of pure {-) - 2 -. (1) ntb1 agidrofurfurnl) - (1R, 5R, 91) -2-hydroxy-5 are obtained , 9-dimethyl-6,7-benzomorfan with t. Pl. 201. The second dias. Thermometer is obtained from the methylate ketone stock solution. The mother solution of methyl ethyl ketone is evaporated in vacuo, and the residue is crystallized from methyl ethyl ketone. After standing for g) at room temperature, 2 methyl ethyl ketone mother liquor and dried at room temperature are sucked off. It was recrystallized from methyl ethyl ketone, and a solution of 3 methyl ethyl ketone and crystallisate was obtained. The latter is composed of a mixture of both diameters of 1: 1, and can again be subjected to the description of the separation process. Royal solutions 2 and 3 obedivvut. N evaporated in vacuo. The remainder of the yitepKb ki consists of the dynastremore Egos; .cr. &Amp; sallize OUT mixture from toluene and bbyzv a () in a volume ratio of 7rg50 11slot one hundred overnight at a coma: teMtt aiype wash with gasoline. Poile drying at 8 ° C gives (-) - 2-f L-te1re1igarofur (| uryl) - (1, 51, 91) -2-oks-5,9-dnmethyl-6,7-benzomaran with m. Pl. 137 ° C. From the residue from the evaporation mother liquor, a substance with the same melting point is obtained by fistallization from 5O ml of toluene / bivone 9 above. output of the second diastereomer 3.4 g. Example 3. (-) B-tetrahydro- -., .. - - - J- -, ur (| urnl) - (, 51, 91) -2-hydroxy-5, & -m mtil-6, 7-bvnomomorphane and (-) - 2-t U-tetrahydrofurfurnl) - (1P, 5R, 9R) -2-oxy-5,9-dimvtil-6,7-bvneomorphan. 4.34 g (0.02 mol) of (1R, 5R, 9R) - (-) - 2 hydroxy-5,9-dimvgip-6,7-benaomorphan analogously to example 1, is converted to the corresponding gonfluorine 2- (tvtrahydro-2 -4) uroipa). As a residue from evaporation, 8.3 g of crude product is obtained, which is converted in the following way to the corresponding 2- (tetrahydro-2-thio: 4 uv) derivative. The residue is dissolved with 100 ml of absolute pyridine and the solution is refluxed for 3 hours with 2.6 g of phosphorus pentasulfide. It is then evaporated to a residue and shaken with iOO ml of methylene chloride and 100 ml of water. After separation in a separatory funnel, the aqueous phase is again extracted with SO ml hlc of methylene. The combined methylene chloride solutions are washed successively in the presence of ice with 30 ml of 2NHC {- and three times with 30 m of water. He eats drying sulphate of sodium and: hisrivanv in vacuum there are 5,2 g of crude: the feed 2 {silver 1-2 | uroyl). He is subjected to further interaction in the next step of reaction. The remainder of the solution of a solution of methylene chloride is bostavavdvayut similarly to Program 1 Prvmen Alvyuvvdrvda-lvtn. A reactive {product is purified by chromatography on a co-alumina oxide. Ochstenauk is obtained, however ethe not separated mixture of the indicated compounds. After separation, similarly to jepvu iy 2, 0.6 g of (-) - 2- (D-tetrovgrdrfur (} urvl) - 0.5 g of (-) - 2- (1. -tvtrvgvshch) b4ur4vgrip) - (1B, 5R , 9R) -2-oxv-5,9-dimvtil-6,7-bezomorphavs with m. Pl. 201 to 137 ° C. Similarly, the following compounds are obtained:. ,, -, /, () -2- (1 | -tetrahydro4urfUryl) - (15, 55, 9S) -2 -oxy-5,9-two-meter-6. "7-be1 | zomorfan with t. Sh1, 206 ° Cj o13 I-109.3 (methanol); (-b) -2- (-T) tetragi (fofur rvl) - (15, 55, 95) -2-oxn-5,9-dvmetvy-6,7-benzene (L) - | 27 ..- .. with JL 1), 2 ° C (c "lj methanol) J (-) - 2- tetragvofur ({urvl-2 -oia5B-5,9,9 -trvmetvl-6.7-6 hevomsffan with 184 ° С {(i:) -2-tetragvdrof rf1Urvl-2-hydroxy-5,9,9 -trvmetvl-6,7-benzomorphane, the racemic diastereomer I with m. (4) -2- tetrahydrofurfuryl-2-hydroxy-5-me tIII-9c1 ethyl-6,7-benzomorphan with tll 171 ° C (±) -2-tetrahydrofurfuryl-2-oxy-5-ethyl-9 1-metvl-6, 7- benzomorphan with a melting point of 170 ° C} (±) -2-tetrahydrofurfuryl-2-hydroxy-5, EL and aethyl-6,7-benzomorphan with melting point 239 ° С hydrochloride)} (1) -tetrahydrofurfuryl-2 -oxy-5-methyl6, 7-bvnzomorphan with t. PL, 171-172 ° C (meansupyonat); (±) -2-Tetrahydro4urfuryl-2 -oxy-5ethyl-6, 7-bvnzomorphan with mp. 150-151 ° C} (±) -2-tetrahydro || urfuryl-2-oxy-5-tl propnp-6, 7-benzomorfan with so pl. 152 ° Cj (±) -2-tetrahydrofuryl-2-methoxy-5, 9 (1-dimethyl-6,7-benzomorfan with mp 07-208 ° С (hydrochloride). Example 4. (±) -2-Tetragonpo (terp (| yyl-2-oxy-5, 9aC-dimethyl-6,7-benzomorphane (mixture of diastereomers). 2.17 g of (t) -2-acetoxy-5,9 cll-dimethyl 6, 7-benzomorophene solution is treated with by heating in 4O ml of methanol and at room temperature and vigorous stirring, the solution is mixed with 2.5 g of potassium carbonate, paci boiled in 10 ml of water. A fine-crystalline mixture of a portion of osshevans in carbonate is precipitated. With a further strong stirring, a drop is added to the suspension. mi 3.5 g hlsfangidrvda tetragi Bleach 49ran-2-carboxylic acid for 30 minutes and stir further for 1 hour. Then evaporate in vacuo and residue the residue by shaking with 15 ml of chloroform in 10 ml of water. After separating the chloroform layer in a separating iBopOHKe, extract once more with 2O ml of chloroform. The combined chloroform extracts are washed with 10 ml of 1 ml of HNSE in water MP, dried with sodium sulfate and after addition of 10 ml of toluene and evaporated in vacuo. The residue consists of 2- {tetrahvd |) 2-hydrochloric) -2 -aae TokCB-S 9ct -Dimetvl-6,7-benzomorfan krto (: yl is subjected to the following reduction of the residue. The residue from; Y {| FVO is dissolved in 25 ml of absolute tetrafrafuran in, stirring, the solution is added dropwise to an ice-cooled suspension of 1, O g of lithium aluminum hydride in 154 ml of absolute tetragonal oxide of 2O minutes, then remove the left bath and stir for 1 more at a room temperature, then boiled with an off-the-shelf fridge for 2 hours. Then c is cooled at the same time as it is cooled. 1 ml of water is added dropwise thereafter, 12O ml of saturated tartrate dammonv solution is added to the mixture, vortexed in a separating funnel and the (upper) tetrahydrofdgrang phase is removed from the heavy aqueous layer after sufficient settling. the aqueous solution is extracted with 10 ml of chloroform. The residue from evaporation of the tetrahydrofuran