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    • 专利摘要:
    This invention provides certain 5- substituted-10,11-dihydro-5H- dibenzo[a,d]cyclohepten-5,10-imines. The compounds have the formula: <IMAGE> where R<1> and R<2> are hydrogen or certain hydrocarbon radicals, and R<3> and R<4> and H, halogen, alkoxy, CF3S-, -CN, -COOH or OH.
    公开号:SU895288A3
    申请号:SU782665603
    申请日:1978-09-18
    公开日:1981-12-30
    发明作者:Стэнли Андерсон Пол；Элизабет Кристи Марсиа；Эдвард Эванс Бен；Каради Сандор
    申请人:Мерк Энд Ко,Инк (Фирма)；
    IPC主号:
    专利说明:

    38 The reduction of compounds of general formula II is hydrogenated at the moment of release during the interaction of the active metal, such as zinc, with an acid, such as acetic acid, when heated from 40 to. If R is not hydrogen, the new compounds are obtained by alkylation of compounds in which R is hydrogen, with a suitable reagent of the formula R-halogen, where halogen is chlorine, bromine or iodine. The reaction is usually carried out in an inert solvent, such as benzopigga topooop. However, an alkylated reagent can be used as a solvent, depending on its finite properties, in sufficient excess. It is preferable to carry out the reaction in the presence of an acid acceptor, for example, an inorganic carbonate, such as sodium carbonate, an organic base, such as pyridine, or a basic resin. Temperatures in the order of 5O-1OOC can be used for from 1O to 5 days. New compounds of general formula 1 can be converted to optical isomers by standard methods, such as the formation of diastereomeric pairs upon the formation of salts with an optically active acid, such as (-) di- | p-toluene-t-tartaric acid and, or ( +) - di-) t-toluene-1-tartaric acid, followed by fractional cristoplicapia and regeneration of the free base. The starting compounds and methods used to prepare the intermediates in the processes described above are given in the examples. Additive salts of imine compounds with acids are formed by mixing the solution of an imine solution with a solution of a pharmaceutically acceptable non-toxic acid, such as hydrochloric, fumaric maleic, succinic, acetic, citric, tartaric, phosphoric, and the like. According to the method of treatment, new imines are able to give the effect of relieving fear, without causing excessive sedation of sleep disorders, in dosages of about 0.0150 mg per kg of body weight, preferably 0.05-10 mg / kg of body weight, when taken 1-4 times in a day. In addition, new compounds are useful as muscle relaxates, anticonvulsants, as well as for the treatment of extrapyramidal disorders at comparable dosage levels. 8. PRI me R 1. 5-Motype-1O, 11-dihydro-5H-dibenzo (a, d) cyclohepten-5, 1O-41MIN and its oxapat. Stage A. Preparation of 1O- (1-p; iperyl) -5H-dibenzo (a, d) cyclohepten-5-one. A mixture of 71.3 g of 10-bromo-5H-dibenzo (o, s3) n1Klohepten-5-one, 5O mp piperidine, 1 l of tert-butanol and 33.6 g of potassium tert-butylate is stirred at reflux for 2 h and then at room temperature overnight. The mixture is filtered to dryness. The residue is mixed with water and decanted. Methanol is piped to the residue, the mixture is filtered, and 59.8 g of 1O- (1-piperidyl) -5H-ibenzo (c (, d) cyclohepten-5-one) is obtained, mp 103-105 ° C. Step B. Preparation of 5-hydroxy-5-methyp--10 - (- w peridyl) -5H-dibenzo (C, d) cycloheptene. A solution of 140 ml of a 1.8 molar solution of methyllithium in ether and 250 ml of ether at 5-10 ° C in an atmosphere nitrogen is treated dropwise with a solution of 59 g of 1O- (1-piperidyl) -5H-dibenzo (Q, c) cyclohepten-5-one in 250 ml of tetrahydrofuran. After 2 h, the mixture is poured into ice and kept until it melts. The mixture is thoroughly extracted with ether, the extract is dried with sodium sulfate, filtered t and concentrated to dryness, the residue is directly used in the next stage. Step C. Preparation of 5-methylene-10-oxo-10, 11-dihydro-5H-dibenzo (o, s3) cycloheptene. Carbinol obtained in stage B is dissolved in 500 ml of a 10N ethanol solution of hydrogen chloride and 30 ml of concentrated hydrochloric acid are heated at reflux overnight, the solvent is evaporated, and the residue is extracted with 500 ml of benzene. The extract is dried and concentrated to dryness. The residue is extracted with 30 ml of boiling hexane. When the extract is cooled, 18.5 g of solid particles precipitate, which, after recrystallization from hexane, yield 16.5 g of 5-methylene-10-oxo-10, 11-digndro-5H-dibenzo (o |, c) cycloheptene, t .pl. 84-86 ° C. Step D. Preparation of 10-hydroximino-5-methylene-10D1-dihydro-5H-dibenzo (a, d) sh1-cloheptene. A mixture of 16.5 g of oxo compound, obtained in stage C, 6.6 g of hydroxylamine hydrochloride, 8.2 g of sodium acetate and ZOO ml of methanol is heated at the boil with reverse hydrocodone for 5 hours. The solvent is evaporated and the residue is treated with 25O ml of water. The mixture is extracted three times with 150 MP ether, filtered and evaporated to obtain
    16.8 g of 1O-hydroximino-5-methylene-10, I-dihydro-5H-dibenzo (C1, d) w clopentene, etc. 156-16О.C.
    Step E. Preparation of 10-hydroxamino-5-methylene-10, 11-dihydro-5H- / shbenzo (0 |, d) cycloheptene.
    A mixture of 15.3 g of oxime obtained by staging In 500 ml of methanol, 12 g of sodium cyanoborgiarite in 45O ml of methanol is treated dropwise with 12 ml of 12N. a solution of hydrogen chloride in 50 mp of methanol over 5 hours, and then the mixture was stirred overnight at room temperature. The solvent is evaporated, the residue is mixed with 2OO ml. 1 n. hydrochloric acid solution, alkalinized with concentrated ammonia solution and extracted three times with 175 ml of ether. The combined extracts are dried with sodium sulfate, filtered and evaporated. The crystalline residue is washed with methanol to give 9.6 g of 10-hydroxamino-5-methylene-1O, 11-dihydro-5H-dibenzo (c (, J) cyclohepten, 1, mp 145-1.
    Step F, Preparation of 12-oxt-5-methyl-lO, ll-dihydro-5H-dibenzo (c, d) cyclopenten-5, 10-imine.
    A solution of 8.8 g of the hydroxamino compound obtained in Step E in 2OO ml of xylene is added dropwise to 80 ml of boiling xylene. After refluxing for one hour under reflux, the solvent is evaporated, the residue is prepared with 250 ml of water and 7 ml of hydrochloric acid, and the mixture is washed with 1OO ml of ether, and the washing liquid is washed. The aqueous phase is alkalinized with a concentrated aqueous solution of ammonia and extracted three times with 1OO ml of ether. The extract is dried with sodium sulfate, filtered and evaporated. The residue is recrystallized from cyclohexane to obtain 8.5 g of 12-hydroxy-5-methyl-10,11-di-hydro-5H-dibenzo (C1, d) cyclohepten-5, 1O-imine, m.p. 141-144 ° C.
    Step Q. Preparation of 5-methyl-10,11-dihydro-5H-dibenzo (CJ, d) cyclohepten-5,10-on and its oxapate.
    A mixture of 1.2 g of oxime prepared in stage F, 7 ml of acetic acid and 1.2 g of zinc dust is heated at 6070 ° for 3.5 hours. The mixture is filtered
    and the pellet is washed with 200 ml of ether and 50 MP of water. The filtrate is agglomerated with 5% sodium hydroxy acid pactEyprome and extracted with ether. The extract is dried with sodium sulfate, filtered and evaporated to dryness to obtain 1.1 g of product. It is dissolved in 20 ml of acetone and treated with 0.6 g of oxalic acid in 10 ml of acetone. After cooling overnight, 1.2 g of 5-methyl-10,11-dihydro-5H-diben30 (a, d) cyclohepten-5,1O-imine, m.p. 203-2O6 C (with decomp.), Which, after recrystallization from a mixture of methanol and acetone, has a mp. 215-217 C (s
    different)
    Example 2. 5-Ethyl-10,11-dihydro-5H-dibenzo (O, d) cyclohepten-5, 10-imin.
    Step A. Preparation of 5-ethylidon-10i-oxo-10,11-dihydro-5H-dibenzo (a, d V cyclohepten.
    To a stirred suspension of ethyltriphenyl phosphonium bromide 21 g, O, O57 mol in ether (400 ml) was added dropwise butyl lithium in hexane (48 ml, 1.3 mol). To the resulting solution was added a solution of 1- (5-keto-5H-dibenzo (a, s3) cyclohepten-1O-yl) -4-methylpiperazine (13.5 g, O, O44 mol) in togrogrofrofran (100 ml). The mixture is stirred and heated under reflux for 3.5 hours, 1 st water (30 (5 ml) is collected and poured into ice. The organic phase is separated and the aqueous phase is extracted with ether (ml). The combined organic solutions are concentrated under reduced pressure. Concentrate stirred with a mixture of 1N hydrochloric acid solution (ZOO ml and ether (300 ml). The ether phase is separated, the aqueous phase is extracted with ether, the combined ether solutions are dried over sodium sulfate, filtered, the filtrate is concentrated to 1OO ml. Triphenylphosphine oxide is removed yut filter In addition, the filtrate T is chromatographed on silica gel, which is eluted with chloroform, and 10.2 g (98%) of 5-Egilitsen-1O-oxo-1O, 11-dihydro-5H-dibenzo (O, d) -cycloheptene are obtained, t. 93-95 ° C.
    Following the procedure described in Example 1 (stages D - (j), but replacing 5-methylene-U-oxo-1O, 11-dihydrch-5H-dibenzo (C, d) diclohepten used in stage Ti, an equimolecular amount of 5-etipidene-10-oxo-10,11-dihydro- (O |, d) unKnorenTeHa, is obtained successively: 5-ethish1-1O-hydroximino-10,11 - -dihydro-5H-dibenzo (C1, 6 a) cyclohepten (yield 86%), i.e., 1.28-131 ° C.; 5-etitgaden-1O-hydroxamino-10,11 -dihydro-5H-dibenzo (a, d) 1pc heptene (yield 89%), t, Square 121-124 ° C; 5-these p-12-OXI - 10,11-di giro-5 H-dibenzo (O, d) cyclohepten-5-1O-imine (yield 21%), t. or 112-I6 C; 5-etip-10,11-dihydro-5H-dibenzo- (Q, d) cyclo hepten-5, (yield 9O%) and its hydroxapate, mp 240241 ° C. Using mainly the procedure described in Example 2, but replacing the ethyl bromide ethyltriphenylphosphonium used in stage A with an equimolecular amount of Wittig reagent Formulas (SiH5) a + CH2H Srg-9), where -CHJR is methyl, propyl or butyl, the compounds of the formula are obtained where is methyl, propyl (m.p. 293-299.5 ° C) as a compound with HCP CH and a radical of the formula Chsns1) ,,,,, Example 3, 3- (and 7) -Brom-5m thyl-1O, 11-dihydro-5H-dibenzo (c1, d) cylopetene-5,10-im. Stage A. Preparation of 3.1 O, 11-tribromo-5H-dibenzo (Q, d) 1 Schlohepten-5one. A solution of bromine (53 g, 0.33 mog) in glacial acetic acid (125 ml) is added dropwise to a stirred suspension of 3-bromo-5H-dibenzo (C (, c) cyclohepten-5-one (71.25 g, 0.25 mol) in glacial acetic acid (775 ml). After stirring the mixture at room temperature for several hours, the solids are collected, washed with glacial acetic acid and dried. The yield is 105.8 g ( 95%), mp 173-175t. Stage B. Preparation of 3,10-dibromo-5H-dibenzo (a, b) iicloheptin-5-one and 3, 11-dibryum-5H-dibenzo (a, d) nnKnoren ten-5-one. The product grown in stage A is added to Sodium hydroxide solution (28 g, 0.7 mol) in methanol (2 p) is stirred. The thick mixture is stirred at reflux for 1.25 hours. After cooling, the precipitate is collected, washed with methanol and then with water, dried and receive 81 g (90%) of a mixture of 3,1O-dibromo-5H-dibenzo (O, d) w clogepten-5-oia and 3,11-dibromo-5H-dibenzo (d, d) 1hcclohepten-5-one (t pl. 146-156 0. Stage C. Preparation of 3-bromo-1O- (4-methylpiperazinyl) -5H-dibenzo (C1, d) - cycle ogepten-5-one and 3-bromo-11 - (4-me - tilpiperazinyl) -5H-dibenzo (O, d) cyclohepte n-5-one. Potassium tert-butipate (6.8 g. O, Ob mop) are added to a stirred suspension of 3,10-dibromo-5H-dibenzo (a, b) cyclohepten-5-one and 3.1 l-dibrom-5H-dibenzo (a, c) cyclohepten-5-one (18.2 g, 0.05 MOTib) 4-methylpiperazine (10 ml) and dry tert-butyl alcohol (2OO ml) at room temperature and nitrogen atmosphere. The dark orange mixture is heated to boiling for 2 hours, then stirred at room temperature overnight. The mixture is drunk in about 800 ml of ice water and extracted with ether. The ether extract is washed with water, dried over anhydrous sodium sulfate, filtered and evaporated. A mixture of 3-bg) OM-10- (4-methylnperazinip) -5H-dibenzo (a, d) cyclohepten-5-one and 3-bromo-11- (4-methylpiperazyl) -5H-dibeise is obtained (a, d) cyclohepten-5-one in the form of a gum-like residue of a reddish-yellow color. The yield is 19, g (1OO% /. Step D- Preparation of 3-bromo-5-methyl-1O- (4-methylpiperazinyl) -5H-dibenzo (d, d) imKnorenTeH-5-OHa and 3-bromo-5 -methyl-11- (4-methylpiperazinyl) -5H-dibenzo (O, d) cyclohepten-5-ola. 85 ml of a 1.6 mol solution of methyl nitrite in ether are added dropwise to the stirred solution of the product obtained in step C ( 18 g, O, O47 mol), in ether (2OO ml) and tetrahydrofuran (60 ml), cooled on an ice bath under nitrogen atmosphere. Stirring is continued at room temperature for 3 hours. The mixture is cooled on ice and hydrolyzed by adding water to drop m. Pos After adding water and ether, the layers are separated, and the aqueous phase is re-extracted with ether. The combined ether extracts are washed with water, dried over anhydrous sodium phosphate and evaporated. The mixture is stirred with 3-bromo-5- -methyl-10- (4-methyl-piperazine) -5H-diabenzo (C |, d) Jikpogepten-5-opa and 3-bromo-5-metip-11 - (4-metip-piperazi "nip) -5H-dibenzo {a, 6) cyclohepten-5opa in as a glassy residue dark yellow. The yield is 18 g of Step E. Preparation of 3-bromo-5-methylene-10, 11-dihydro-5H-dibenzo (a, d) -1-chlohepten-10-one and 7-bromo-5-methylene -1O, 11- dihydro-5H-dibenzo (3, d) cyclohepten-10-one. A mixture of the product obtained in stage 1E (18 g, O, O45 mol) of 95% ethanop (8O mp) is stirred at room temperature for 30 minutes and at boiling point for 1 hour. The mixture consists of an oily brown phase (bottom) and the aqueous alcohol phase (above). The next stage is decanted, and the alcohol is distilled off under vacuum. The residual aqueous mixture is extracted with chloroform. The previously prepared brown maspo is dissolved in chloroform, and the combined chloroform phases are washed with water and dried over anhydrous magnesium sulphate. Evaporation of the filtered extract results in a crude product in the form of a glassy dark-yellow color. This chromium material is graphed on a silica gel column, eluting with toluene. Evaporation of the combined fractions results in a once-purified product of fine solids (8.5 g) in vice-May. After trituration with cyclohexane, one of the product isomers is obtained in the form of white solid particles. The yield is 2.6 g (mp 125-158 ° C). Two recrystallized from cyclohexane gave the product with m.p. 158-163 C. Evaporation of the first cyclohexane mother liquor allows to obtain another product isomer as a dark yellow oil. Rubbing successively three times in 10 ml of hexane leads to the formation of yellow solid particles with a yield of 3.3 g (mp. -75-83 C). Two recrystallizations from hexaia result in a product with m.p. 84-89 ° C. An isomer with a higher melting point (amp. Pl. 160-164 ° C) has the structural formula called 7-bromo-5-mustilene-1O, 11-dihydro-5H-dibenzo (C |, d) 1He. The other isomer, 3-bromo-5-methylene 1 O, 11-dihydro-5H-dibenzo (c 1, d) aikloepten-10-one (mp 84-91 C), has the structural formula O Stage F. Preparation 3 (and 7) -bromo-5-methyl-ICf, 11-dihydro-5H-dibenzo- (O, (J) cyclohepten-5,1O-imna. Using the procedure described in example 1 (D-Gi stages) jHO is used instead of 5-methylene -1O-oxo-1O, 11-d.hydro-5H-dibenzo (C1, d) cycloheptene ec - A bimolecular amount of the corresponding 3- and 7-bromo 111X) of the derivative is obtained successively the following compounds: Step G: 3 (and 7) -bromo-10-hydroximino-5-methylene-10, 11-yyhydro-5H-di-ben-3o (C3f, d) cycloheptene, m.p. respectively 171-175 and 179-18lC; Stages G .3 (and 7) -bromo-1O-hydro. amine-5-methylene-10,11-dihydro-5H-li-6eH3o (CI, d) cycloheptene, m.p. 149-153 and 136-13 9 C, respectively; Stage H: 3 (and 7) -brom-12-hydroxy-5- -methyl-10,11-dihydro-5H-dibenzo (a, d) cyclohepten-5, 1O-imine, t. pl. 175-180 and 187-189 ° С, respectively; stage i. hlrgidrat 3 (and 7) -bromo-5-meti l-10,1 l-dihydro-5H-dibenzo (C (, d) cyclohepten-5,1O-imine, i.e. above ZOO ° C. Similarly receive the following compounds: 3-bromo-5-methi-10,11-di giro-5 H-dibenzo (P, u) cyclohepten-5,1O-imine; 2-bromo-5-ethyl-10,11-dihydro -5H-dibenzo (01, d) cyclohepten-5,10-imine; 7-bromo-5-these l-10,11-di hydro-5H-dibenzo (0 | d) cyclohepten-5,10-im. Example 4. Salt of fumaric acid 1O, 11-dihydro-5,12-dimethyl-5H-dibenzo (Q, d) cyclohepten-5-imine, Step A. Preparation of 10,11-dihydro-12-ethoxycarbonyl-5-methyl- 5H-dibenzo (Q, d) cyclohepten-5,10-imine. A mixture of 1.15 g of 1O, 1 l-dihydro-5-methyl-5H-dibenzo (C, d) cyclo epten-5,10ymina, 1.0 g of anhydrous sodium carbonate, 1 ml of ethyl hlormur avi-.
    Acidic acid and 1O MP of dry benzop are stirred at reflux for 2 h. The mixture is flushed and the filtrate is evaporated under vacuum to give 1.45 g of white crystalline 10,11-dihydro-12-0toxycarbonyl-5-methyl-5H -dibenzo (c |) cyclohepten-5, 1O-41Mina, t. pl. 8О-83 С.
    Stage B. Preparation of 10,11-dihydro-5, 12-yimet L-5H-dibenzo (C |, 3) cyclichepten-5, 10-imine.
    The urethane solution obtained in step A in 15 ml of absolute ether is added dropwise to a suspension of 190 ml of lithium apium hydride in 15 ml of absolute ether with stirring under a nitrogen atmosphere. After 24 hours at room temperature, the mixture is cooled in an ice bath and hydrolyzed by adding dropwise a minimum amount of water containing a few drops of a 5% aqueous solution of sodium hydroxide. After dilution with ether, the mixture is filtered. The filtrate is evaporated in vacuo to give 1.1 g of the free base of the product as a colorless oil. The product is combined with a, yr of a similar material and dissolved in 25 ml of ethyl acetate. A warm solution of 1.2 g of fumaric acid in 12 ml of methanol is added. The fumaric acid crystallizing salt is collected and recrystallized from a mixture of methanol and ethyl acetate, which results in 2.1 g of the salt of fumaric acid 1O: 11-dihydro-5,12-dimethyl-5H. Benzo (c (, 5) cyclohepten-5,10 -imin, t. pl. 186-188s.
    Example 5. 12-Benzyl-10,11-di hydro-5-methy l-5 H-dibenzo- (c (, d) cyclohepten-5, 10-mi n.
    A mixture of 2.45 g of 10,11-dihydro-5-methyl-5H-dibenzo (o |, Y) cyclohepten-5,1 Oimin, 1.9 g of benzyl chloride, 3.2 g of anhydrous sodium carbonate and 50 ml of dry benzene are stirred at boiling point over 4 days. The mixture is filtered and the filtrate is evaporated under vacuum to obtain 3.1 products in the form of oily solid particles, m.p. 107lll c. The product is recrystallized twice from 95% ethanol and 1.85 g of white crystals of 12-benzyl-11, 1O-dihydro-5-methyl-5H-dibenzo (01 / s3) cyclohepten-5, 10-imine, t. Pl. 111114 S.
    Example 6. 12-Alg sp-10,11-dihydro-5-methyl-5H-dibenzo (a, c) cyclopenten-5, 10-im.
    A mixture of 2.45 g of 10,11-dihydro-5-methyl-5H-dibenzo (C | d) cyclohepten-5,10-imine, 1.8 g of alpyl bromide, 3, O g of anhydrous sodium carbonate and 50 ml of dry benzene are stirred at the boiling point for 20 hours. The mixture is filtered, the filtrate is evaporated under vacuum and 1.2 g of an oily free base are obtained. The expanded compound is dissolved in 5 ml of acetone and 0.75 g of fumaric acid in 75 ml of acetone is added to a warm solution. The crystallized salt is collected, perekristapsovuyu from acetone and get 1.45 g of white crystals of the salt of fumaric acid 12-allyl-10,11-dihydro-5-methi11-5H-dibenzo (C1 (O) cyclohepten-5,1O- imine, mp 180-18 2 ° C.
    Using the procedure of Example 6, but using instead of allyl bromide and 1O, 11-dihydro-5-methyl-5H-dibenzo (0 |, c} cyclohepten-5, 10-imine, a compound of the formula R-Ei 5-K -CH2-10, 11-dihydro-5H-dibenzo (01,6) cyclohepten-5,10-imine in the table, get, - 12-1 -10,11 -di hydro-5 N-dibenzo (O1, s3) cyclohepten- 5,10-imini, also privecennye in the table, according to the following scheme.
    / T: LH
    -SN
    NSt.pl. 132.5-135.5 ° C)
    Q N {m. 111-11z ° C hydroxapat)
    -CH -CHj
    -dH
    -SN
    -sn,
    - (CH) VJ (CH) 2 2-B
    -sn
    Example 7. Hporohydrate 5,10,12 -t rt metip-10,11 -di hydro-5H-di-benzo (I, 3) cyclohepten-5,1CM1min. Stage A. Preparation of 1O-amino-5-methylene-10, 11-dihydro-5H-dibenzo (O (, d) cycloheptene, To a stirred suspension of zinc dust (0.9 g, 0.138 mop) in 100 ml of acetic acid 10-hydroxamino-5-methylene-10,11-dihydro-5H-dibenzo {a, d) Schopohepten (10.42 mol) is added to an acid heated in an oil bath with an acid bath. The mixture was stirred in an oil bath for 2 hours, cooled and poured into 5OO ml of water. The mixture is alkalinized with concentrated ammonia solution, and then extracted with ether. The combined ether salts are washed with water, dried over sodium sulfate, filtered and evaporated to dryness under vacuum. The residue recrystallized from hexane and 7.8 g of product with m.p. 84.5-86.5 ° C. Stage B. The study of 10-isociano-5- -methylene-10,11-dihydro-5H-dibene (Q, ci) cyclo1-heptene. To a solution of 10-amino-5-metipen-10, 11-dihydro (C |, d) cycloheptene (8.1 g 36 mol) in chloroform (180 ml) to N (mp 115.5-117 ° C) H (v. 163-164 C)
    NSt.pl. 132.5-13 S.sV) H (i.e. 112-111,) NSt.pp. 111-113 C) base 3-B) 7-B bavilut granules of hydrhgis sodium (4.42 g, 0.11 mol), benziptriethylammonium chloride (O, 42 g, 1.8 mmol) and water (0.5 ml) . The mixture is stirred under a nitrogen atmosphere until the granules of sodium hydroxide are dissolved for about 4 hours), treated with anhydrous potassium carbonate, filtered and evaporated to dryness under vacuum. The resulting oil is dissolved in chloroform (180 ml), treated with an additional 1.5 g (37.5 mmol) of sodium hydroxide and 0.2 g of lO, bti mmol) benzyltriethylammonium chloride, and stirred overnight under a nitrogen atmosphere. The mixture is again dried over potassium carbonate, filtered and evaporated to dryness under vacuum. The resulting maspo is chromatographed on 120 g of sigacachep and eluted with dichpormethane. The combined fractions are evaporated to dryness under vacuum and the resulting solids are recrystallized from ether to give 4 g of solid particles (mp 96-98 ° C). Step C. Preparation of U-iso-Iono--1O-methyl-5-methylene-10.1 l of igidpo-5H-dibenzo (CI, (3) cycloheptene. Diisopropylamine (1.1 g, 1O, 9 mmol) in 25 ml of dry tetrahydrofuran is stirred in a bath with a mixture of dry pdend and acetone. In a nitrogen atmosphere, this solution is treated with a mixture of n-uchippiti and hexane (5.0 mp, 2.2 mol of solution), added dropwise during more than 10 minutes. a solution of 10-isocyano-1O, 11-dihydro-5H-dibenzo (O1, s) oicloheptene (2.4 g, 10.4 mmop) in 25 MP suhtoh) tetrahydrofuran is added dropwise (within 45 minutes to the solution Dinzopropipamida lithium. Received The bright red solution is stirred in the cold for 15 minutes and then treated with methyl iodide (4.56 g, 32 mmol) added in a single step. The mixture is stirred for 2 hours in the cold and 1 hour at room temperature. The solvent is removed under vacuum and the residue is chromatographed on 75 g of silica gel, eluted with chloro-chlorine. The combined fractions are evaporated under vacuum to give 2.2 g (86%) of solids. Recrystallization from ether gives the product with m.p. 146-147.5 p. Stage D. Preparation of 10-metip-10-eti lamino-5-methy pen-JD hporohydrate l-dihydro-5H-dibenzo (OI, d) cycloheptene 1 O isocyano-U-megyl-5-methylen-10,11-digitsoo -5H-aibenzo (C |, d) cycloheptene (1.8 g, 7.3 mmol) dissolved in dry ether (100 mp) is added dropwise to a suspension of lithium tetrahydroaluminate (0.53 g 14 mmop) in ether (40 ml) stirred under nitrogen. The mixture is heated under reflux for 1 cool and the excess hydride is decomposed by carefully adding 1.5 ml of ice water dropwise. The suspension is filtered and the solids are washed twice with ether. The combined ether extracts were evaporated in vacuo to give 1.8 g of oil. This oil, dissolved in 10 ml of absolute ethanol, is treated with a slight excess of 8N. a solution of hydrogen chloride in ethanol and cooled with aony4eHtieM 1.7 g (81%) of powder C. mp. 238-24О С (sec.). Stage E. Preparation of hydrochloride 5, 1O, 12-trimetip-GO, 11-dihydro-5H-dibenzo (O1 | NW) cyclohepten-5D-imine. 10-methi p-10-methylamino-5-methylene n-10,11-dihydro-5H-dibenzo (0 |,) cycloheptene (1.6 g, 6.4 mmol) is dissolved in dry tetrahydrofuran (40 ml ). To this solution, stirred at room temperature under an atmosphere of nitrogen, is added with i-buti sodium (Z.Omp, 2.2 mn solution in hexane) in a dropwise manner over 5 minutes. The mixture was stirred for 10 minutes, then treated with 3 MP of ice water. Tetrahydrch} uranium is removed under vacuum, and the residue is treated with ether. The ethereal solution is washed with water, dried over sodium sufate and evaporated under a vacuum. The residual maso is chromatographed on 120 g of sipicagep, epyuirut dichhpormetanom and 1-, 1,5-, 2-, 3- and 5% methanopes in dihpormetan. The combined product fractions are evaporated to dryness under vacuum, dissolved in 50 mp absolute ethanol and treated with a slight excess of 8N. solution of hydrogen chloride in ethanol. The solvent is removed under vacuum, and the solid residue is recrystallized from 20 mp of absolute ethanol to give 5,1OD 2-trimetip-1OD hydrochloride 1-dihydro-5H-dibenzo (O1, c) cyclohepten-5,1O-imine, t. square 295-296.5С. Similarly, Yu-alip-5,12-dimethyl-5, 10-diethyp-12-methy l-, 10-cyclopropip-5 D2-dimetip-10,11-dihydro (o |, s3) cyclohepten-5 , 10-imin. Example 8. Optical splitting. Racemic 5-methyp-1O, 11-dihydro-5H-dibenzo (C |, 9) cyclohepten-5Dimine (3.93 g, 0.0188 mol) and (-) di-P-toluip O-tartaric acid (6, 88 g, 0.0178 mol) is dissolved in 21 ml of acetone. A seed crystal is added to the solution, and after several hours of incubation at room temperature, the crystalline salt is collected. This product is repeatedly recrystallized from acetone to a constant rate of rotation. The syrup is suspended in cold water, mixed with an aqueous solution of sodium hydroxide, and the base is extracted with ether. The washed and dried ether extract was evaporated to dryness under reduced pressure to form (-) 5-methi l-10 D 1-dihydro-5H-dibenzo (a, cJ) -cyclohepten-5,10-imine in the form of a solid residue with mp . 71.5-73.5 C. The residual mother liquor obtained during the initial crystallization of the (-) isomer is evaporated to dryness under reduced pressure. A suspension of the glassy residue in a cold baud is mixed with an aqueous solution of sodium hydroxide, and the base is extracted with ether. The washed and dried ether extract is concentrated to optically impure (+) - base as a solid residue. This product (2.27 g, O, O SW mol) and) di-ts1iuip-1-tartaric acid (3.9 g, 0.0103 mol) is dissolved in 20 ml of acetone. After standing for several hours at room temperature, the crystalline salt is collected and repeatedly recrystallized from acetone to a constant rate of rotation. The salt is again converted to the base in the manner described above to give (+) 5-metip-1O, 11 - -dihydro-5H-dibenzo (a (, 3) cyclogepten-5, 10-imine, mp 72 -74 C. Example 9. The cleavage of (±) -5 -methyl-1O, 11-dihydro-5H-dibenzo (c1, c3) cyclohepten-5,10-them on. Levorotatory isomer. To a solution of 66.1 g (0.299 mop ) racemate 5-metip-10,11-DIHYDRO-5H-DIbenzo (C |, c) 1 Sclohepten-6,10-imine in 1 O7 ml of thermal acetone is added 115.4 g (0.299 mol) of di-jn-toluene m-acid dissolved in 163 ml of acetone. The solution is stirred until a homogeneous mixture is obtained, is held for 18 h at, then oh Wait in the refrigerator for up to 4 hours. The resulting batch is filtered, washed once with cold acetone, collected and kept at 50 ° C in a vacuum oven. The result is 82.97 compounds A as a white solid, p (2 5.9 ( in abs. ethyl alcohol) and mp 141-14bS (foam). The filtrate of the solid A is concentrated to dryness in a vacuum, and the solid B residue is used in the preparation of the degrading isomer. Sodium A is dissolved in 345 O mp boiling acetone, filtered, concentrated to 1500 ml, incubated for 18 hours at 25 ° C, then cooled in a refrigerator to 0 ° C for 4 hours. The precipitate is removed by filtration, washed once with cold acetone. collected-. sulphate in a vacuum oven. As a result, 45.5 g of C is obtained as a white solid, LQ Iggg -131.9 (in absolute ethanol), mp. 142-144C (foam). The digested cobalt C (.44.8 g, 0.0737 mol) is treated with 300 ml of 1O% sodium hydroxide and ZOO ml of sulfuric ether, and the mixture is transferred to dissolve the solid. The ether layer is separated, dried over 8 818 magnesium sulfate, filtered and evaporated to dryness in vacuo. The result is 16.0 g (silica GF, eluted with a mixture of metaiop: chloroform 1: 9) homogeneous colorless maspa. Crystallization from 4O mp cycpohexane yields 14.16 g (-) - 5-methyl-1O, 11-dihydro-5H-dibenzo (a, c3) cyclohepten-5, 1O-imine as a white solid substance, Co, 8 ( C 0.032 g / 2 MP of ethyl alcohol), so pl. 68.5-69.5 ° C, Right-rotating isomer. Residue B, obtained during the synthesis of the levorotatory isomer, is converted into the free base by mixing with AOO ml of 10% OO. sodium hydroxide and ZOO ml of sulfuric ether to dissolve the solid. The ether layer is dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. As a result, 37.9 g of orange maspa will break out. The oil is dissolved in 61 mp of thermal acetone and treated with a solution of 69.3 g (0.171 mol) of di-I-toluene-1-tartaric acid monohydrate in 98 ml of acetone. The solution is stirred until a homogeneous mass, maintained for 18 hours while being refrigerated at 0 ° C for 4 hours. The resulting salt is filtered off, washed once with cold acetone, collected and dried in a vacuum oven. 68.8 g D are obtained in the form of a white solid, 1 ° (in absolute alcohol ethyl alcohol) t. pl. 136-144 ° C (foam). The salt is dissolved in 2900 ml of boiling acetone, filtered, concentrated to 900 MP, incubated for 18 hours at 25 ° C and then kept in a refrigerator at 0 ° C for 4 hours. The precipitate is filtered, washed once with cold acetone, collected and dried when in a vacuum oven. In the result, 36.5 g of E are obtained in the form of a white solid, Ic} Il g | -l-132.0 ° (in absolute ethanol), m.p. 142144С (foam). Split E salt (36.5 g, 0.0601 mop) is treated with ZOO ml of 10% sodium hydroxide and ZOO ml of sulfuric ether, and the mixture is stirred until the solid salt is dissolved. The sulfuric ether is separated, dried over magnesium sulphate, filtered and evaporated to dryness in vacuo. As a result, 12.6 g (silica GF, eluted with a mixture of
    methypol alcohol and chloroform 1: 9) homogeneous colorless mask. 11.26 g of (+) 5-methyl-10,11-dihydro-5H-dibenzo (c1, c3) 11 piclohepten-5,10- $ mi in the form of a white solid substance, with J ° - "- 161.4 ° (, O38 g / 2 ml of ethyl alcohol) t, nn. 68.5-bE
    Example 11. (+) - 5-metip-10,11g -aigidro-5H-aibenzo (C1,13) cyclohepten-5- 10 amine sour maleate.
    Solution 1O, 05 g (0.0451 mol) (+) 5-megyl-10, 11-digiar-5H-iibenzo (C}, 3) cyclohepten-5,1O-imine in 25 ml of absolute ethanol is filtered and the filter is washed with absolute ethyl alcohol to obtain 4 O of filtrate. A solution of 5.27 g (0, O454 mol) of maleic acid in 20 ml of absolute ethyl alcohol20
    filtered in the same copba. The combined filtrates are mixed, seeded to crystallize, pry at room temperature for a short time, then: cool for 8 hours. 35 Crystalry is collected and dried. As a result, acidic maleate (+) - 5-metip-1O, 11-dihydro-5H-di6eH3o (CI, d) cyclohepten-5,10-imine is obtained with m.p. 208.5-210 cIaJ -t- 114 (0 30 0, O128 g / 2 ml of ethyl alcohol).
    h i New compounds 1 or their pharmaceutically acceptable soybeans can be used in medicine as a means c5} of fear, as muscle relaxants and for the treatment of exrapyramidal disorders of Parkinson's disease.
    权利要求:
    Claims (1)
    [1]
    The invention The method of obtaining 5-substituted 1O, 11-dihydro-5H-dibenzo (with |, (3) cyclohepten-5, 10-imines of the general formula J
    R1
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    同族专利:
    公开号 | 公开日
    PL121605B1|1982-05-31|
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    CY1283A|1985-07-05|
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    AT370103B|1983-03-10|
    PL112834B1|1980-11-29|
    IT1113279B|1986-01-20|
    HU180868B|1983-04-29|
    KE3501A|1985-02-22|
    CH637954A5|1983-08-31|
    FI782680A|1979-03-20|
    ES483285A1|1980-09-01|
    GB2004872B|1982-04-15|
    PL209632A1|1979-06-04|
    SU915800A3|1982-03-23|
    YU41432B|1987-06-30|
    PH15920A|1983-04-22|
    NO783017L|1979-03-20|
    FI65618C|1984-06-11|
    DK389978A|1979-03-20|
    GB2061947A|1981-05-20|
    DK153843B|1988-09-12|
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    JPS5463100A|1979-05-21|
    PT68544A|1978-10-01|
    DE2840786A1|1979-03-22|
    ES483288A1|1980-04-16|
    FR2403334B1|1982-11-19|
    SE437520B|1985-03-04|
    DK153843C|1989-01-23|
    ZA785291B|1980-04-30|
    ATA669778A|1982-07-15|
    NO151861C|1985-06-19|
    AR231544A1|1984-12-28|
    NL191488C|1995-08-04|
    ES483283A1|1980-04-16|
    SG9585G|1985-08-08|
    ES483286A1|1980-04-16|
    IE781866L|1979-03-19|
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    GB2061947B|1982-08-04|
    CA1129850A|1982-08-17|
    PL118478B1|1981-10-31|
    FR2403334A1|1979-04-13|
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    BE794904A|1972-02-04|1973-08-02|Roussel Uclaf|NEW DIBENZOCYCLOHEPTENE DERIVATIVES AND THEIR PREPARATION|
    BE829075A|1974-05-15|1975-11-14|9,10-DIHYDROANTHRACEN-9,10-IMINES SUBSTITUTES AND THEIR HETEROCYCLIC ANALOGUES |US4232158A|1979-06-04|1980-11-04|Merck & Co., Inc.|10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imines|
    US4477668A|1982-04-07|1984-10-16|Merck & Co., Inc.|Process for 5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine|
    GB8719199D0|1987-08-13|1987-09-23|Merck Sharp & Dohme|Chemical compounds|
    US5686614A|1995-04-11|1997-11-11|Neurogen Corporation|Preparation of chiral 5-aminocarbonyl-5H-dibenzo a,d!cyclohepten-5,10-imines by optical resolution|
    US5739337A|1996-03-08|1998-04-14|Neurogen Corporation|Process for preparing dibenzo-1-carboxamido-1,4-azabicyclo 3.2.1!octanes|
    WO2017093354A1|2015-11-30|2017-06-08|INSERM |Nmdar antagonists for the treatment of diseases associated with angiogenesis|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US83463977A| true| 1977-09-19|1977-09-19|
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