SU346867A1 - METHOD FOR PRODUCING DERIVATIVES OF BENZOMORFAN - Google Patents

Description

The invention relates to the field of obtaining new derivatives of 6,7-benzomorfan, which can be applied in the pharmaceutical industry.

There is a known method for the preparation of benzomorphic derivatives, the axis n-1th in the substitution reaction of 6,7-benzomorphans are reactive with their halides.

The use of new bepsomorphans and halides in the known method resulted in the preparation of new compounds representing chain pharmaceutical preparations.

The proposed method for producing benzomorphane derivatives of the general formula

.R.

NCHSN2-p 5

R., h „- About

RI

where R is hydrogen, Ci-Cz-alkoxygruppa or hydroxyl group;

An RI and R2-Ci-C3 alkyl group;

Ra is hydrogen, halogen. A C-C3-alkoxy group, a Ci-C3 alkyl group, a Ci-C3 alkyl alkyl group, a nitrocorn group, a trifluoromethyl group, an amino group, a hydroxyl group;

which is a 6,7-benzomorphan derivative of the general formula

where R, RI and Ra have the above meanings, are reacted with a reactive halide of the general formula

C- (CHn) -v

I. P l.

where Rs, R and p are as defined above;

X is a halogen atom;

Y is an oxygen atom or ethylenedioxy group, followed by hydrolysis in the case when Y is an ethylenedioxy group derived from an ethylene dioxy derivative.

The reaction is carried out in the presence of a base, for example, sodium carbonate, nli calpe, sodium bicarbonate, sodium or potassium hydroxide, pyridine or triethylamine, in an inert organic solvent, for example hexane benzene, toluene, xylene, chloroform, dimethylformamide, methanol, ethanol, isonylpropyl alcohol . The reaction takes place at a temperature ranging from 20 to 200 ° C (preferably 60-150 ° C). The desired product is isolated in a known manner. Example 1. 2Oxy-2- 7- (l-fluorobenzoyl) nropyl-5, 9-dimethyl-6,7-beisomorphane. A. 2-Oxy-2- 4 - {p-fluorophenyl) -4,4-ethylenedioxybutyl-5, 9 - dnmethyl-6,7 - benzomorfan. To a mixture of 1.08 g of 2-hydroxy-5,9-dimethyl-6,7-benzomorphan, 0.6 g of sodium bicarbonate and 15 ml of dimethylformamide, 1.43 g of 4 - (/ g-fluorfein) -4 was added, 4-ethylenedioxy-1-bromobutane. The resulting mixture was stirred for 4 hours at a temperature of 130-145 ° C, the solvent was removed with increased. pressure and water added to the residue. This mixture was kept in a refrigerator until a precipitate formed with T. ill. 174-179C. After recrystallization from ztirate acetate, pure crystals of 2-hydroxy-2-4 (fluorophenyl) -4,4-ethylenedioxybutyl — 5.9 days old-6, 7-benzomorphane with m.p. 180-183 ° C. Infrared spectrum: v, narafin: 1605, 1582, 1500, - 1210, 1147, 1043, 830. Calculated for CsoHsaNOs,%: C 73.38; H 7.59; N 3.29. Found,%: C 73.51; H 67.62; N 3.25. B. 2-Oxy-2- - (“- fluorobenzoyl) - propyl 5, 9-dimethyl - 6.7 - beisomorphane. A mixture of 2.4 g of 2-hydroxy-2-4 - ("- fluorophenyl) -4,4 - ethyldioxybutyl - 5.9 - dimethyl-6,7 - benzomorphane, 20 L-1L of methanol, 10 ml of water and 1.5 ml of concentrated hydrochloric acid was heated under reflux for 1 hour. After concentration under reduced pressure, the reaction mixture was basified with an aqueous ammonia solution and extracted with ether. The ether extract was washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate and filtered. The filtrate was stripped dry and the raw material was not added. After non-recrystallization from ethyl acetate, it was prepared 2-hydroxy-2-y-lfluorobenzoyl) -nroyl-5,9-dimethyl-6,7-benzo-morphane with t. Nl. 166-1-69 ° C. 2600 (broad), 1690, 1598, 1582, 1222, 840, 769. Calc. For C2.iH28NOoF,%: C 75.56; H 7.40; N 3.67. Found,%; C 75.48; H 7.43; N 3.81. This product was dissolved in chloroform and gaseous hydrogen chloride was added to the solution. After removing the solvent, the residue was crystallized from a mixture of acetone and methanol; The resulting hydrochloride had so nl. 213-215 ° C. vSapin: 2580, 2550, 1690, 1620, 1599, 1584, 1504, 1210, 1204, 1148, 831. Found; C 68.98; H 7.19; N 3.63; C1 8.27. Example 2. (and-fluorobenzoyl) -pronyl, 9-dimethyl-6,7-benzomorfai. A. 2- (l-fluorophenyl), 4-ethylenedioxyutyl-5,9-dimethyl-6,7-benzomorfan. A mixture of 3 g, 9-dimethyl-6,7-benzomorfan, 1.68 g of sodium bicarbonate, 4.29 g of 4- (l-fluorophenyl) -4,4-ethnenedioxn-1-chlorobutane and 30 ml of ethanol was heated under reflux with stirring for 6 hours. During the concentration of this mixture under reduced pressure, most of the ethanol was removed, followed by the addition of water to the residue. The resulting mixture was extracted several times with water saturated with sodium chloride, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and the residue was distilled under reduced pressure. Got 4.75 g of (l-fluorophenyl) -4,4-ethylenedioxybutyl-5, 9 - dimethyl-6,7 - benzomorphane with t. Knn. PO-9 ° C (0.8 mm Hg. Art.). V paraffin: 1605, 1508, 1217, 1150, 1040, 835. B. (rt-fluorobenzoyl) -propyl -5.9 - dimethyl-6, 7-bepzo.morphan. To a mixture of 4.7 g of 2- 4- (lfluorophenyl) -4,4-ethylenedioxybutyl-5,9 - dimethyl-6, 7-benzomorfana, 50 ml of methanol and 30 ml of water was added 5 ml of concentrated hydrochloric acid. This mixture was heated under reflux with a refrigerator for 1 hour, concentrated under reduced pressure, the residue was basified with aqueous ammonia solution and extracted with ethn.m. The ethereal extract was washed with water, saturated with sodium chloride, dried over anhydrous sodium sulphate and filtered. The extract was concentrated and the resulting yellow residue was distilled under reduced pressure. 1.5 g of 2- - {pfluorobenzoyl) -propyl-5,9-dimethyl-6,7-benzo-morphane were obtained with t. 140-150 ° C (0.5 mm Hg. Art.). V paraffin: 1690, 1601, 1510, 1220, 835, 760, 720. The solution of (l-fluorobenzoyl) -nronyl-5.9 dimethyl-6, 7-benzomorfana in the ether was acidified with gaseous hydrochlorides of m. The precipitate formed was filtered and the ether was washed. After non-recrystallization from a mixture of ether and acetone, (l-fluorobenzoyl) propyl-5,9-dimethyl-6,7-benzomorphane hydrochloride was obtained or benzomorphane with t. 162-166 ° C. V paraffin: 2350 (nn of rock), 1680, 1600, 1508, 832, 760, 750, 720. Calculated for Co4H29NOClF,%: C 71.72; H 7.27; N 3.48; CI 8.82. Found,%: C 71.42; H 7.40; N 3.39; C1 8.77. Example 3. 2-Hydroxy-2-7 - ("- fluorobenzoyl) propyl-5-.methyl-9-ethyl-6,7-benzomorphan. L. 2-Oxy-2- (l-fluorophenyl) -4,4-ethylenedioxybutyl-5-methyl-9-ethyl-6.7-benzomorphan. According to the procedure of Example 1, A, by the reaction of 2.31 g of 2-hydroxy-5-methyl-9-ethyl-6, 7-benzomorphan with 2.56 g of 4- (l-fluorobenzoyl) -4,4-ethylenedioxy-1- chlorbutane received 2-hydroxy-2-4 - (/ g-fluorophenyl) -4,4-ethylenedioxybutyl-5-methyl-9-ethyl-6,7-benzomorphane with m.p. 161 - 167 ° C. After recrystallization from ethyl acetate, the melting point increased to 170-171 ° C.

V paraffin: 1615, 1605, 1579, 835, 794.

Calculated for CsTHa.tNOaF,%: C 73.77; H 7.80; N 3.19.

Naidio: C 73.58; H 7.78; K 3.52.

B. 2-Oxy-2-7 - ("- fluorobenzoyl) -propyl-5methyl-9-ethyl-6, 7-benzomorphap. In accordance with the procedure of Example 1, B 2-hydroxy-2-4 - (difluorophenyl) -4,4-ethylenedioxybutyl-5 - methyl-9 - ethyl - 6.7 - beisomorph was converted to 2-hydroxy-2-7 hydrochloride (p-fluorobenzoyl) -propyl-5-methyl-9-ethyl-6, 7-benzomorpha a with so on. pl. 160-165 ° C.

vnaplJ, HH: 1692, 1620, 1597, 1582, 1500, 838. Calculated for C25H3iNO2ClF,%: C 69.82, H 67.23; N 3.24.

Found,%: C 69.78; H 7.29; N 3.29.

Example 4. 2-Oxy-2- 7- (l-chlorobenzoyl) propyl-5, 9-dimethyl-6,7-benzomorfan.

A. 2-Oxy-2- (p-chlorfepyl) -4,4-ethylenedioxybutyl-5,9-dimethyl - 6,7 - benzomorfan. A mixture of 2.17 g of 2-hydroxy-5,9-dimethyl-6,7-beisomorphane, 1.26 g of patric bicarbonate, 30 ml of dimethylformamide and 3.29 g of 4- (g-chlorophenyl) -4,4 ethylenedioxy-1- chlorbutan was stirred for 3 hours at a temperature. The solvent was removed under reduced pressure, and water was added to the resulting residue. The resulting precipitate was separated by filtration and recrystallized from a mixture of ether and methanol. Got 2-hydroxy-2-4 - (/ gchlorophenyl-4, 4-etilepdioxybutyl - 5.9 - dnmethyl-6, 7-benzomorfan with T. pl. 169-170 ° C.

 2650 (broad), 1620, 1603, 1585, 1495, 1225, 1047, 830.

Calculated for C26H32NOC1,%: C, 70.65; H 7.30; N 3.17; C1 8.02.

Found,%: C 70.65; H 7.27; N 3.14; C1 8.23.

B. 2-Oxy-2- Y- (rt-chlorobenzoyl) propyl-5,9 dimethyl-6, 7-benzomorphap. To a mixture of 3.65 g of 2-hydroxy-2-4 - (-chlorphenyl) -4,4 - ethylenedioxybutyl-5, 9 - dimethyl - 6.7 - benzomorphane, 50 ml of methanol and 30 ml of water were added 5 ml of concentrated hydrochloric acid. acid. This mixture was heated under reflux for 1 hour and then concentrated under reduced pressure. The resulting residue was basified with an excess of aqueous ammonia solution and extracted with ether. The organic solution was washed with water, dried over anhydrous sodium sulphate and filtered. The filtrate was concentrated to a solid, from which, after recrystallization from a mixture of ether and acetone, 2-hydroxy-2-Y- (d-chlorobenzoyl) -propyl -5.9 dimethyl-6, 7-benzomorfats with m.p. 179-181 ° C.

 2600 (broad), 1690, 1625, 1590, 1495, 1235, 1216, 1083, 766.

Calculated for C24H28NO2C1,%: C, 72.44; H 7.09; N 3.52; C1 8.91.

Found,%: C 72.17; H 7.25; N 3.89; C1 8.86.

The free base was converted to the hydrochloride by treatment with anhydrous gaseous hydrogen chloride. The precipitate was separated by filtration and washed with ether. After recrystallization from a mixture of methanol and acetone, 2-hydroxy-2-7- (chlorobenzoyl) -propyl-5,9-dimethyl-6.7-benzomorphane hydrochloride was obtained from 191-192 ° C.

 2550, 1685, 1616, 1590, 1570, 1505. 1230, 1081, 810, 757.

Calculated for C24H29NO2C1,%: C, 66.36; H 6.73; N 3.22; C1 16.32.

Found,%; C, 65.86; H 6.96; N 3.52;

C1 16,73.

25

Example 5. 2-Hydroxy-2-7 - ("- methoxybenzoyl) -npropyl-5,9-dimethyl-6,7-benzomorfan.

A. 2-Oxy-2-4 - ("-methoxyphen-4,4-ethylenedioxybutyl-4, 9 - dimethyl-6,7 - benzomorfan.

1.2 g of sodium bicarbonate and 2.7 g of 4- (g-methoxyphenyl) -4,4 - ethylenedioxy were added to a solution of 2.17 g of 2-hydroxy-5,9-dimethyl-6,7-benzomorphane in 30 ml of dimethylformamide -1 - chlorbutane. This mixture was stirred for 2 hours at

temperature of 120-140 ° C. After evaporation of the solvent under reduced pressure, water was added to the residue. The mixture was kept in a refrigerator until a precipitate formed which was separated. H was recrystallized from ethyl acetate.

Got 2-hydroxy-2 - 4 - (p - methoxyphenyl) 4, 4-ethylenedioxybutyl-5,9-dimethyl-6,7-benzomorfan with so pl. 156-158.5 ° C.

V paraffin 2650 (wide), 1615, 1580, 1515,

1500, 1245, 1050, 830.

Calculated for C27H35NO4,%: C, 74.11; H 8.06; N 3.20.

Found,%: C 73.74; H 8.20; N 3.60.

B. 2-Oxy-2- 7 - (p-methoxybenzoyl) -propyl-5, 9-dimethyl-6,7-benzo.morfan. To a mixture of 2.0 g of 2-hydroxy-2-4 - (/ g-methoxyphenyl) -4,4-ethylene-oxobutyl-5, 9 - dimethyl-6,7 - benzomorphane, 20 ml of methanol and 10 ml of water were added 1, 5 ml of concentrated hydrochloric acid.

The mixture was heated with stirring for 1 hour. The reaction mixture was concentrated under reduced pressure until methanol was removed and basified with aqueous ammonia solution. The resulting solution was extracted

chloroform. The extract was washed with water saturated with sodium chloride, dried over anhydrous sodium sulphate and filtered. After removal of the solvent, the crude product was obtained. As a result of recrystallized (d-methoxy-isoisoyl) -propyl-5,9-dimethyl - 6.7 beisomorphane with m.p. 148-152 ° C.

VnaplJiHH: 2650 (wide), 1680, 1600, 1570, 1500, 1255, 1160, 1020, 820, 760.

Calculated for CasHsiNOs,%: C, 76.30; H 7.94; N 3.56.

Found,%: C 76.16; H 7.88; N 3.42.

Example 6. 2-Hydroxy-2-7 - (/ g-methylbenzoyl) propyl-5, 9-dimethyl-6,7-benzomorphan.

A. 2-Oxy-2- 4 - (/ g-methylphenyl) -4,4-ethyl 11-dioxybutyl-5, 9-dimethyl-6,7 - bsisomorphane. In accordance with the procedure of Example 1, A, but using 2.17 g of 2-hydroxy-5,9-dimstil6, 7-benzomorphan, 1.2 g of sodium bicarbonate, 30 ml of dimethylformamide and 2.06 g of 4 - (/ g me-1-ylphenyl) -4,4-etilepdioksp-1-chlorobutane, obtained crude 2-hydroxy-2 - (l-methylphenyl) 4, 4-ethylenedioxybutyl-5,9-dimethyl-6,7-benzomorfan. After recrystallization of the crude product from ethyl acetate, pure crystals of 2-hydroxy-2-4 - (l-methylphenyl) -4.4 ethylenedioxybutyl-5, 9 - dimethyl - 6.7 - benzomorphane with m.p. 173-176 ° C.

 2650 (wide), 1615, 1580, 1505, 1240, 1050, 820.

Calculated for CrPccK,%: C, 76.92; H 8.37; N 3.32.

Found,%: C 76.84; H 8.55; N 3.82.

B. 2-Oxy-2- 7- (-methylbenzoyl) -propyl 5, 9-dimethyl-6,7-benzomorfan. In accordance with the procedure of example 1, B, but using 2.5 g of hydroxy-2-4 - (p - methylphenyl) - 4,4 - ethylenedioxybutyl-5,9-dimethyl-6,7-benzomorfana, a crude compound was obtained, after recrystallization of which from ethyl acetate gave pure crystals of 2-hydroxy-2-7 - ((g-methoxybenzoyl) -propyl-5,9-dimethyl-6,7-benzomorphane with m.p. 157.5-164.5 ° C.

Paragraph: 2600 (wide), 1683, 161, 1580, 1498, 1233, 800, 765.

Calculated for С25Пз1КЮ2,%: С 79.53; H 8.28; N 3.71.

Found,%: C 79.45; H 8.29; N 3.80.

Example 7. 2-Hydroxy-2-y- (/ g-trifluoromethyl. Benzoyl) -prepp-5,9-dimethyl - 6,7 - benzomorfan.

A mixture of 1.19 g of 2-hydroxy-5,9-dimethyl-6,7-benzo-morphane, 0.6 g of sodium bicarbonate, 1.77 g of 4- (g-trifluoromethylphenyl) -4,4-ethylenedioxy-chlorobutane and 15 ml dimethylformamide was stirred for 3 hours at a temperature of 130-145 ° C. The resulting reaction mixture was concentrated under reduced pressure to remove most of the dimethylformamide. Water was added to the residue and extracted with ether. The ether extract was washed with water, dried over anhydrous sodium sulphate and filtered. The filtrate was treated with charcoal and concentrated under reduced pressure. The residual oil was dissolved in hot aqueous methanol and the solution was treated with hydrochloric acid to rp 1. After heating under reflux for 1 hour, the solution was treated with charcoal and filtered. The filtrate was concentrated under reduced pressure.

pressure, basified with aqueous ammonia and extracted with chloroform. The extract was washed with water, suction or above anhydrous sodium sulfate, filtered, and concentrated to an amorphous

the remainder.

This residue was chromatographed on a silica gel column with ethyl acetate to give the crude product. After recrystallization of the latter from ethyl acetate,

2-hydroxy-2- - (/ g - trifluoromethylbepzolyl) - propyl-5, 9-dimethyl-6,7-benzomorphan with t. Pl. , 5-120 ° C.

 1690, 1612, 1578, 1128, 1065, 1015, 830.

Calculated for C25H28X02Rz,%: C 69.59; H 6.54; N 3.25.

Paydepo,%: C 69.81; H 6.73; N 3.00. EXAMPLE 8. 2-hydroxy-2-7- (methoxybenzoyl) propyl-5-methyl-9-ethyl-6,7-beisomorphane.

A. 2-Oxy-2- (l-methoxyphenyl) -4,4 ethylenedioxybutyl-5-methyl-9-ethyl-6,7-beisomorphane. In accordance with the procedure of Example 5, A, by the reaction of 2.3 g of 2-hydroxy-5-methyl-9-ethyl-6, 7-benzomorphan with 2.7 g of 4- (-methoxyphenyl) -4,4-ethylenedioxy-1-chlorobutane 2-hydroxy-2-4 - (-methoxyphenyl) -4,4-ethylenedioxybutyl-5-methyl-9-ethyl-6, 7-benzomorphane with m.p. 140-142 ° C. one

V paraffin: 2650, 2550, 1613, 1580, 1510, 1497, 1252, 1053, 1038, 836.

Calculated for C28H37N04,%: C, 74.47; H 8.26; N 3.10. Found,%: C 74.69; H 8.24; N 3.23.

B. 2-hydroxy-2- 7 - ("- methoxybenzoyl) -propyl 5-methyl-9-ethyl-6, 7-benzomorphan. In accordance with the procedure of example 5, B from 2-hydroxy-2 4- (ha-methoxyphenyl) -4,4-ethylenedioxybutyl-5-methyl-9-ethyl-6, 7-benzomorfana was obtained a crude product, during recrystallization of which from a mixture methanol and acetone obtained pure crystals of 2-hydroxy-2 Y- ((g-methoxybenzoyl) -proyl-5-methyl-9-ethyl-6, 7-benzomorfana with t. nl. 148.5-150 ° C.

YI: 1675, 1612, 1598, 1570, 1510, 1504. Calcd for C25H34MW,%: C, 70.33; H 7.72; N 3.15. Found,%: C 70.14; H 7.77; N 3.14.

Example 9. 2-Oxy-2- b - ((g-fluorobepzoyl) butyl-5, 9-dimetpl-6,7-benzomorfai.

A mixture of 2.17 g of 2-hydroxy-5,9-dimethyl-6,7-benzomorfan, 1.26 g of sodium bicarbonate, 3.88 g

5- / g-fluorophenyl-5,5-ethylenedioxy-1-chloropentane and 30 ml of methylpharmamide were stirred

within 4 hours at a temperature of 125-130 ° C,

The mixture was then concentrated with reduced