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    • 专利摘要:
    New 2,9-dioxatricyclo[4,3,1,03,7] decane derivatives are disclosed which are substituted by an amino methyl group in the C3 position, and which exhibit sedative, especially sleep improving properties, and which have the formula <IMAGE> (I) wherein R1 represents an amino group ONE OF R2 and R3 is hydrogen and the other represents hydroxy acyloxy or carbamyloxy or R2 and R3 jointly represent oxygen ONE OF R4 and R5 is hydrogen and the other represents alkyloxy or aralkyloxy Y AND Y' EACH REPRESENT HYDROGEN OR JOINTLY FORM A BOND AND THEIR PHARMACOLOGICALLY ACCEPTABLE SALTS, AS WELL AS PHARMACEUTICAL FORMULATIONS THEREOF.
    公开号:SU791242A3
    申请号:SU772455502
    申请日:1977-02-21
    公开日:1980-12-23
    发明作者:Тис Виллиброрд；Азаи Акийи；Давид Самуэль
    申请人:Кали-Хеми Фарма,Гмбх (Фирма)；
    IPC主号:
    专利说明:

    cyclo (4, 3.1 C of cisana of formula (1), possessing biological activity).
    This is achieved by the fact that 2,9-dioxatricyclo-4,3,1,0 5 1 of the formula
    where X is iodine, bromine or chlorine; R is hydrogen,
     hydroxy or acetoxy and K4. and RS have the above values,
    subjected to: interaction with the amine of the formula.
    , n ft,, (i
    (Where R has the above meanings: when heated in an organic solvent medium and, if desired, bond 10; 11 hydrogenate and / or a compound of formula 41), where RJ is an oxy group and
     hydrogen, acylated or oxidized to a compound of formula (1), wherein
     R.- form oxygen, and the desired product is isolated in free form or as a salt.
    Preferably, the process is carried out at the boiling point of the reaction medium in the presence of a base, for example potassium bicarbonate or sodium.
    The process is preferably carried out in an environment of an aprotic solvent, such as dimethylformamide, or dimethyl sulfoxide or hexamethylphosphoric triamide.
    Salts of compounds of formula (1) are obtained by reacting compounds of formula (1) with an acid, mainly maleic or tartaric, in an environment of an organic solvent, such as methanol, ethanol, ethanol, ethyl ether, or mixtures thereof.
    In tab. 1-6 magnitudes of rotation are determined for salts in water and for individual substances in methanol.
    Example 1, Preparation of 3-piperidinomethyl-4 fb-oxy-8-methoxy-10-..-methylene-2,9-dioxatricyclo 4, 3,1, (G-decane (v) from 3-iodomethyl-4 (b -acetoxy-8-methoxy-10-methylene-2, 9-dioxatrcyclo 14,3,1, O chekana (y).
    190 g (V) together with 250 g of bicarbonate are suspended in 500 ml of piperidine. The mixture is heated for 4 hours at 150 ° C in an oil bath, under reflux and with vigorous stirring, then cooled to room temperature. Add 1.5 l
    ether, the mixture is dissolved in 1 l of water, then mixed with 200 ml of a 40% sodium hydroxide solution and shaken. After separation of the ether phase, the aqueous phase is extracted 3 more times with f 500 ml of ether. The combined ether extracts are dried over sodium sulfate and clarified with activated charcoal. Suction is filtered over a Teorit suction filter and washed with ether, the filtrate is evaporated at 50 ° C in a water jet vacuum and then under a vacuum oil pump in a rotary evaporator, 180 g of an oily product of formula (IV) are obtained. It is used without further purification to prepare the compound of formula (0)
     eleven
    Mol.v. 295.38; V + 41.6 ° (in methanol). 20 Analogously to Example 1, the compounds obtained are partially presented in Table. one.
    3. Morpholinomethyl-4 p -oxy-8-methoxy-10-methylene-2, 9-dioxatricyclo, 3,1,0 5 eecane (VI)
    3- (4-Methyl-1-piperazinylmethyl) -4 P -oxy-8-methoxy-10-methylene-2,9-dioxatricyclo 4,3,1, and aecane (VI I)
    3-Pyrrolidinomethyl-4p) -oxy-B-methoxy-10-methylene-2, 9-dioxatricylo 4,3, 1, (VIII)
    3-Pyrrolidinomethyl-4 (b-oxy-8 O methoxy-10-methylene-2, 9-dioxatricyclo
    5, 3,1,0 tsezan (IX)
    3- (4-Phenyl-1-piperazinylmethyl) -4, P-hydroxy-3-methoxy-10-methylene-2, 9-dioxate tricycloG4, 3,1, 0 cekane (X)
    3- (4-Okoethyl-1-piperazinylmethyl) -4 p -oxy-8-methoxy-10-methylene-2.90-dioxatricyclo 4,3,1,0 cicone (XI)
    3- (N, N, N-Triethylethylenediaminemethyl) -415-oxy-8-methoxy-10-J letilen-4, 9-dioxatricyclo f4, 3,1, SG decane (XII)
    3- (N-Benzyl-N-methylaminomethyl) 5 -4 p, -oxy-3-methoxy-10-methylene-2, 9-dioxatricyclo 4, 3,1,0 cans
    (Xiii)
    3- (N, N-Dibenzylaminomethyl) -4 (L-oxy-8-methoxy-10-methylene-2, 9-dioxatri0 cyclo 4,3,1, (XIV)
    3-g xamethylaminomethyl-4 p-hydroxy-8-methoxy-10-methylene-2, 9-dioxatricylo 4, 3, 1, o decane (XV)
    3- (1-Indolino1) -4 | L-oxy-8g-methoxy-10-methylene-2,9-dioxatri cyclo {; 4,3,1, (XVI)
    3-Piperidinomethyl-4-oxo-8-methoxy-10-methylene-2,9-dioxatricocyclo-4, 3,1, (XVI I)
    . . 3- (N, N-Diethylaminoethyl) -4 / 3-ok0 si-8-methoxy-10-methylene-2,9-dioxatricyclo 4, 3, 1, (G Decane (XVIII)
    (2-Pyridyl) -1-piperazinylmethylZ-4 | 1-hydroxy-8-methoxy-10-gietilen-2, 9-dioxatricyclo 4,3,1, about pecan 5 (XIX). Example 2 Preparation of 3-morpholinomethyl-4 p) oxy-3-methoxy-10-methylene-2, 9-dioxatricyclo 4,3,1, (g} decane (VI) from compound (V) 38 g of the compound of formula (V) with 50 g of sodium iodide are suspended in 100 ml of morpholine. The mixture is heated under reflux for 3 hours and then cooled to room temperature. After evaporation of the solvent, the mixture is mixed with 200 ml of 2N hydrochloric acid , then with a small amount of methanol to dissolve. The reaction solution is extracted twice with ether of 100 ml. The aqueous phase is mixed with 200 ml of 2N sodium hydroxide solution, saturated with chlorine. sodium ether and then extracted 5 times with ether (100 ml1. The ether extract is dried over sodium sulfate, clarified with activated 5 / gl and sucked off on a suction filter through Teorit. Co-centrate in vacuo, get 17.92 oily product, 61 % of C, 5K2, N05 mol. v. 297.35 theory; d- +42 (in methanol jj Example 3. By; 3-4- (2 Pyridyl) -1-piperazinylmethyl -4 fi -oxy-8-methoxy-10 - methylene-2, 0-dioxatricyclo 4, 3,1.0 decane (XI X) from the compound of the formula V 38 g of the compound of the formula V together with 39 g of 1- (2-pyridyl) -piperazine and 50 g of sodium bicarbonate are suspended in 100 ml of dimethylformamide and s Then the mixture is heated under reflux for 8 hours and then suction filtered on a suction filter through a Teorite screen and washed with methanol, and the filtrate is concentrated in vacuo. The residue after evaporation is dissolved in 200 ml of methanol and 8 g of hydroxynatry in 10 ml of water are mixed with the solution, then left for 10 minutes at room temperature, neutralized with dilute hydrochloric acid and the solvent is evaporated, the residue is alkalinized 2n. sodium hydroxide solution and extracted with chloroform. The combined ether extracts are treated with sodium sulfate and clarified with activated carbon, sucked off on a suction filter through a Theorite. Purified by chromatography on silica gel with eluent (50% ether in hexane). After concentrating the eluate and grinding the residue in methanol, the product crystallizes. Suction is carried out and washed with methanol to obtain 29.0 g of a white crystalline product, 77.7% of theory. Gi 27 3 ° 4Mol. at. 373.45; m.p. 130-132 ° C. d-J 0 ° (in methanol). Example 4. Preparation of 3- (, -diethylaminomethyl) -4p) -oxy-8-labels of C10-methylene-2,9-dioxatricylo 4.3 = 1.0} cisane (XX) from the compound of formula (V) 38 g of a compound of formula (V) along with 50 g of sodium bicarbonate and a suspension of 200 ml of diethylamine. The mixture in the refractory tube is kept for 6 hours with an oil bath, then cooled to room temperature and mixed with 4 g of hydroxide. in 10 ml of water and 100 ml of methanol. Stand 10 minutes at room temperature, 6 MLTI of acetic acid was added to the mixture. The solvent is evaporated, mixed with 10 ml of ether, the mixture is dissolved in 100 ml of water, mixed with 40 ml of 30% sodium hydroxide solution and shaken. After separation of the ether phase, the aqueous phase is extracted three times with 100 ml of ether. The combined ether phases are dried over sodium sulfate and clarified with activated charcoal. Suction is filtered over a Teorit suction filter, washed with ether, the filtrate is evaporated first at 50 ° C in a water jet vacuum pump and then at 100 ° C in an oil pump vacuum in a rotary evaporator, 32 g of an oily product are obtained. “About Mol.v. 283.37; CA +48 (in methanol). Analogously to example 4, the following substances are obtained: 3- (N, N-diethylaminomethyl) -4-oxo-8-methoxy-10-methyl-2, 9-dioxatricyclo 4, 3, 1, O cane (XXI) from 3-iodomethyl -4-oxo-8-methoxy-10-methylene-2, 9-dioxatricyclo 4.3,3.0 decane (XX) C 5 aM04 Mol.v. 281.34. 3- (N, N-diethylaminomethyl) -4 f-hydroxy-8-methoxy-10-methylene-2, 9-dioxatricyclo 4, 3, 1, C decane (XXII) of 3-iodomethyl-4-hydroxy-8- methoxy-10-methylene-2, 9-dioxatricyclo 4,3,1,0 decane (XXII). C, 5H: g5 0 Mol.v. 283, .36. Example 5. Preparation of 3-piperidinomethyl-4 f} -oxy-8-methoxy-1 0-methyl-2, 9-dioxatricyclo 4,3,1, O decane from (IV). The hydrogenation apparatus is purged for 10 minutes with nitrogen and 10 minutes with hydrogen. Then it is filled with hydrogen. In a hydrogenation flask, 100 g of wet Rene nickel is rinsed with methanol and, with stirring and with a slight excess pressure, is preliminarily hydrogenated for about 2 minutes at room temperature. After a solution of 180 g of a compound of formula IV in 250 MP of methanol is introduced into the hydrogenation flask, the solution is washed with 20 g of sodium hydroxide, dissolved in a small amount of water and cooled to room temperature, then diluted 5-fold with methanol and cooled to room temperature. Under stirring and slight pressure: the mixture is hydrogenated with 30 at room temperature. I consider the hydrogen absorption to be starchy, the mixture is filtered on a suction filter through a Theorite and washed with methanol. 30 ml of acetic acid are added and evaporated at, cooled to room temperature, the residue is treated with ether and triturated with 250 MP silica gel (particle size 0.2-0.5 mm). After evaporation of the solvent and the residue, the solution is dissolved in n-hexane and concentrated at. The residue is filtered with 500 g of silica gel in a column (particle size 0.20, 5 mm), first with 1 l of n-teksane, then with 1.5% diethylamine in n-hexane. The filtrate is evaporated and 150 g of an oily product of the formula 11 C Bd7M04 ,,, „Mol. 297,399; td-l O (in methanol). The compounds shown in Table 2 are prepared analogously. 2 .. 3-Morpholinomethyl-4 fb-hydroxy-8-methoxy-10-methyl-2, 9-dioxatricylo-4, 3,1, (g5cecan (XXI 11), 3- (4-Methyl-1-piperazinylmethyl) -4 | b-oxy-8-metsksi-10-methyl-2, 9-di oxatricyclo 4, 3,1, SG cecanum (XXIV.) 3-Pyrrolidinomethyl-4 pj -OKCH-8ct -methoxy-10 d, -methyl-2,9-diox-atricyclo 4,3,1, O-Udecane (XXV) 3- (4-Phenyl-1-piperazinylmethyl) -4P) -oxy-8 methoxy-10-ethyl-2, 9-dioxatricyclo 4,3,1, Cr1decane (XXV I 3- (4-Hydroxyethyl-1-piperazinylmethyl -4 f-hydroxy-8-methoxy-10-74ethyl-2, .9.-DioxatricocyloG4, 3,1, Cr decane (XXVI 3.- (N, m, N-Ip-ethylethylenediaminomethyl) -4 fb -keyi-3-methoxy-10-methyl-2, 9-dioxatricyclo 4,3,1,0 Lecan (XXVI11) 3- (M-Benzyl-M -methylaminomethyl) -4 {b-hydroxy-8-methoxy-1igmethyl-2, 9-dioxatricylo 4, 3,1, (G decane (XXIX 3- (N, N-Dibutylaminomethyl) -4 | b) OXI-- 8- methoxy-10-methyl-2,9-dioxa tricyclo 4, 3, 1, C decane (XXX) 3-Hexamethyleneimine-4 f -oxy-8-methoxy-10-methyl-2, 9-dioxatricyclo 4, 3, 1 , 0 decane (XXX)) 3- (t-Indolinomethyl) -4 p-hydroxy-8-m-tox-10-methyl-2,9-dioxatrycyclo 4,3,1,0 lecan (XXXI I) 3 (2- Pyridyl) -1-piperazinylme p-oxy-8-methox11-10-methyl-2, -dioxatricyclo 4,3,1, (G decane (XXXI 3-Pyrrolidinomethyl-4-oxy-8-meto-10-methyl- 2,9-dioxatricyclo, 3,1, dean (XXXIV) 3-Piperidinomethyl-4 | 1 -oxy-8-meth oxy-10-methyl-2,9-dioxatricyclo 4,3,1, СG7decane (XXXV) 3- (N,;: -Dnbu hylaminomethyl-4 p -oxy-8-methoxy-10- methyl-2, 9-dioxa tricyclo 4, 3, 1, SG decane (XXXVI) 3- (N, M Diethylaminomethyl) -4 -oxy-8-methoxy-10-methyl-2, 9-dioxa tricyclo 4,3, 1, G decane (XXXVII). Prm e p- 6. Preparation of 3- (M-methylaminomethyl) -4)% -oxy-8-methoxy-, -, -10-methyl-2,9-dioxatricyclo 4,3 , l, ffj. Decane monohydrate (XXXVI II) 16.9 g of 3- (M-benzyl-K-methylaminomethyl) - / 4 -oxy-8-methoxy-10-methyl-2, 9-dioxatricyclo 4,3, 1, o decane is dissolved in ethanol, hydrogenated with hydrogen using 5.0 g of palladium oxide. The duration of the hydrogenation is 2 hours. After the termination of the absorption of hydrogen, the mixture is filtered on a suction filter through Teorit and washed with ethanol. The filtrate is evaporated, 11 g of debenzylated compound are crystallized from a mixture of chloroform with ether (84% of theory). The crystals are washed with ether and dried n. Mol.v. 261.30; m.p. 161-164 С, W -25 ° (ъ methanol). Example. Preparation of 3-piperidinomethyl-4 | b-phenylcarbamoyloxy-8-methoxy-10-methyl-2, 9-dioxatricyclo L4, 3.1.0 1 cecanane (XXXIX). i 5.0 g of the compound of formula (V) is dissolved in 10 ml of methylene chloride,. mixed with 3 ml of phenyl isocyanate and 680 mg of phenylmercury acetate as a catalyst, the mixture is heated under reflux for 1-2 hours. 5 MP of methanol are added and the mixture is evaporated. The residue is dissolved in ether and treated with sodium sulfate and activated carbon. The mixture is filtered, washed with ether, and evaporated to give 6.27 g of crystalline phenyl-cobamate (90% of theory). CaiH t Oj-d Mol. 416.52; m.p. 81-86 C. Similarly, the substances are presented in Table. 3. 3-Hexamethyleneimine-4 p, -ethylcarbamoyloxy-8-meter-10-methylene 2, 9-dioxatricyclo 4,3,1, CG decane (XU) 3- 4- (p-chlorobenzhydri i) -1-piperazinylmethyl - 4-ethylcarbamoyl-8-methoxy-10-methylene-2, 9-dioxatricylo 4,3, l, CfJdekan (XLI) 3- ("-methyl-1-piperazinylmethyl) -4 (i-phenylcarbamoyloxy-8-methoxy-1p -methylene-2, 9-dioxatricyclo 4, 3,1,0 decane (XLII) (2-Ethylcarbamoyloxyethyl) -1-piperazinylmethyl-4 4 -ethylcarbamoyl-6-hydroxy-8-methoxy-DO-methyl-2, 9-dioxatricyclo-4, 3.1, 0 decane (XL I II) 3- 4-Pyridyl-2- (1-piperazinylmethyl) -4 | i-ethylcarbamoyloxy-8-methoxy-10-methylene-2, 9-dioxatricyclo 4,3,1, (ekan (x L IV) 3- (4-Methyl-1-piperazinylmethyl) -4 p -ethylcarbamoyloxy-8-methoxy-10-methylene-2, 9-dioxatricyclo 4,3,1, Oj decane (XL IV) 3- (N, N, N-Triethylenediaminomethyl) -4 (1-ethylcarbamoyl-8-methoxy-10-methyl-2, 9-di-satricyclo 4,3,1,0 decane (XLVI) 3-Pyrrolidinomethyl-4 (J-isopropyl carbamoyloxy-8 methoxy-10-methylene-2, 9-dioxatricyclo 4,3,1, (XLVII). 3-Piperidinomethyl-4d-allylcarba yloxy-8-methoxy-10-methyl-2,9 dioxo tricyclo 4, 3,1, 0 5decane (XLVIIl) 3-Pnperidinomethyl-4 d -isopropylcarbamoyloxy-8-methoxy-10-methyl-2, 9-dioxatricyclo 4,3,1, O cepane (XLIX) 3-Piperidinomethyl-4 (L-ethylcarbam-iloxy-8 -methoxy-10-met ylene-2,9-dioxatricyclo 4, 3, 1, Cr / decane (L) 3-Piperidinomethyl-4 (b-isopropylcarbamoyloxy-8-methoxy-10-methylene-2, 9-dioxatricyclo 4,3,1; 0 decane (LI), N-diethylaminoethyl-4fi-ally carbamoyloxy-8-methoxy-10-methylene-2, 9-dioxatricyclo 4,3,1, CG decane (LII) 3-Piperidinomethyl-4 f-allylcarba moyloxy-8-methoxy -10-methylene-2, 9-dioxatricyclo 4,3,1, O ecan {L I) For example 8. Preparation of 3-mor folinomethyl-p-benzoyloxy-B-methoxy-10-methyl-2, 9 -dioxatricyclo 4.3, 1.0 cecane (LIV) 3.73 g of the compound of formula (V) are dissolved in 15 ml of pyridine, mixed with 7.05 g of basic anhydride and boiled for 2 hours reverse refrigeration Chloroform is added and the mixture is stirred with 2N. soda solution. The organic phase is washed with water and the aqueous phases are separately extracted twice with chloroform. The organic extracts are treated with sodium sulfate and activated carbon and filtered on a suction filter through Teorit. The filtrate is evaporated, the residue is chromatographed on silica gel with 50% ether in n-hexane as an eluting step. After evaporation of the eluate, 2.9 benzoate is crystallized from isopropanol, which is 57% of theory. Mol at. 403.45; m.p. 120-121 ° C; djjj + 60 ° (in methanol). Analogously to example 8, receive: Pyridyl-2) -1-piperazinylmethyl-4-benzo "Lexi-8-methoxy-10 methylene-2, 9-dioxatricyclo 4,3,1, Cr can (LV) Mol.v. 477.54. 3- (4-Methyl-1-piperazinylmethyl) -4 (b-benzoyloxy-8-methoxy-10-methylene-2, 9-dioxatricyclo 4,3,1, (LVI) C ,, H5, Mol. 116 , 09; mp. 99-102 C. 3- 1- (2-Benzoyl-oxy-methyl) -1-piper Einyl methyl J-4 ft-benzoyloxy-8-label-10-methyl-2, 9-dioxatricyclo 4,3,1 Decane (LVII) Mol., C. 550.63 Example: Preparation of 3-hexamethylenemenomethyl-4 ft-acetoxy-8-methoxy-1, 0-methyl-2,9-dioxacrylate 4, 3,1.0 decane (LVlll) from 3-hexamethyleneimine-4P-hydroxy-8-methoxy-10-methyl-2, 9-dioxatricido 4,3, 1,0 ecan. Cg 3-hexamethylenimine-4p-oxy-8-methoxy-1 0-methyl- 2, 9-dioxatricyclo-4,3,1,0 decane is dissolved in 6 MP acetic anhyd The ida and the mixture are left for 30 minutes at room temperature. After the addition of chloroform, the mixture is shaken with 2N soda solution. The organic phase is washed once with water. Both aqueous phases are extracted twice with chloroform. The combined organic extracts are treated with sodium sulfate and activated carbon. The residue after suction and evaporation is purified by chromatography on alumina using 50% ntm ether in n. reKcaffe, then ether and finally 10% methanol in the air. After evaporation of the eluate, 2.2 g of oily acetate are obtained, which is 67.8% of theory. g. About Mol. at. 337.44-, A to-C QB methanol). Example 10. Preparation of 3-hexamethylenimino-4E-E-propionyloxy-8-methoxy-10-methyl-2, 9-dioxatricyclo 4, 3, 1.0 decane (L1X). 2.74 g of 3-hexamethyleneiminomethyl-4) -oxy-8-methoxy-10-methyl-2,9 dioxatricylo 4,3,1, 0 cecanum is dissolved in b ml of prprionic anhydride and given for 30 minutes at room temperature. After the addition of chloroform, the mixture is shaken with 2N. soda solution. The organic phase is treated with sodium sulfate and activated carbon. After filtration and evaporation of the organic phase, 950 mg of propionate is obtained, which is crystallized from isopropanol, which constitutes 29.4% of theory. C23H "N05 on. Mol. 367.47; m.p. 52-54 C / (methanol). Analogously to example 10, the following substances are obtained. - (p-Chlorobenzhydryl) -1-piperazinylmethyl -4 &amp; -propionyloxy-8-methoxy-10-methylene-2, 9-dioxatricyclo 4, 3, 1, au (LX). Mol.v. 552.78. PRI / m ER 11. Obtaining 3-piperidinomethyl-4 p -oxy-8-methoxy-10-methyl-2, 9-dioxatricylo 4,3,1,0 decanhydrochloride (LX1). 5 g of compound i) is dissolved in 50 ml of ether. Dry HC1 gas is passed through the solution until a precipitate forms. After removal of the ether; by decantation, the precipitate is treated with non-HC2 ether and triturated. After suction, washing with ether and drying, 5.4 g of crystalline hydrochloride are obtained, which is 97% of theory. C.H2gNCeo
    Mol.v. 333.86 m.p. 182-188 C, fd. - 18 (in methanol).
    T get taxed substances listed in Table. four.
    Z-Pyrrolidinomethyl-4 E-hydroxy-8-methoxy-10-methyl-2, 9-dioxytricyclo 4, 3, 1, Cr hydrochloride (LXII)
    3-Morpholinomethyl-4 | b-Oxy-8-labels .0-methyl-2, 9-dioxatricylo 4,3, 1, CrJaeK and hydrochloride (LX I t)
    3 - (4 -Fe or l -1 - pi perraz and nyl methyl) -4 -oxy-8-methoxy-10-methyl-2,9-di oxatricyclo-4,3,1, Сгудекандгидрохлорид (L X I V)
    3-Hexamethyleneimine-4 {L-oxy-8-methoxn-10-ethylene-2, 9-dioxatricyclo 4,3,1, (to au hydrochloride (LXV)
    3-Piperidinomethyl-4 f-phenylcarbamoyloxy-in-methoxy-10-mfl, 2, 9-dioxatricyclo-4,3,1, O-hydrochloride (LXVI)
    3-Hexamethyleneimine-4 (-oxy-8-methoxy-10-methyl-2, 9-dioxatricylo-4,3,1, ai hydrochloride (LXVI1)
    3-G1-endolinomethyl-4 p -oxy-8-methoxy-10-methylene-2, 9-dioxatricylo 4, 3,1, Operiy hydrochloride (LXVI II)
    3-l-Indolinomethyl-4-oxy-8methoxy-10-methyl-2, 9-dioxatricyclo t, 3,1, O eekanhydrochloride (LXIX)
    3-G4- (p-chlorobenzhydryl) -1-piperazinylmethyl-4 | b-methyl-carbamoyloxy-8-methoxy-10-methylene-2, 9-dioxatricyclo 4,3,1, O 7decandy hydrochloride {LXX)
    Example 12. Preparation of 3-pyrrolidinomethyl-4 p -oxy-3-methoxy-S -. methylene-2, 9-dioxatricyclo 4,3,1,0 danhydromalealeinate (LXX /).
    3.3 g of the compound of formula (IV) are dissolved in 20 ml of ether and mixed with a solution of 1.4 g of maleic acid in ether. After removal of the solvent by decantation, the residue is treated with ether and triturated. The mixture is filtered off with suction, washed with ether and dried, yielding 4.4 g of maleate (IV), which is 90.2% of theory,
    qqHj-.NOgMol .v. 397.43; m.p. 155-157 С, And + 8 ° (in methanol).
    The compounds listed in Table 2 are prepared analogously. five.
    3- (4-Methyl-1-piperazinylmethyl) p -oxy-8-methoxy-10-methyl-2,9-dioxatricylo 4, 3,1, SG1-akandigidromalealeinat (LXXIl)
    3-Pyrrolidinomethyl-4 f-hydroxy-8-methoxy-10-methyl-2, 9-dioxane 4, ZL, 0 1 de-canhydromaleate (LXXI I I)
    3- 4- (p-Chlorobenzhydryl) -l-piperidazinylmethyl J.-4-ethylcarbamyloxy-8-methoxy-1Q-methyl-2, 9-dioxatricylo 4, 3,1, SG-cekandigidromeleinate-hiathe (3-dioxatricyclo-4, 3,1, SG-c-methylen-2, 9-dioxatricyclo-4, 3.1
    3-G4-Methyl-1-piperazinylmethyl-4fb-phenylcarbamoyl and Loxy-8-methoxy-10-methylene-2, 9-dioxatricyclo 4,3,1, O ekandigidromaleinat (LXXV)
    3-G4- (2-pxyethyl) -1-piperazinylmethyl-4 f -oxy-8-methoxy-10-methyl-2, 9-dioxatricyclo 4,3,1, CG decandihydromaleinate (LXXVI).
    PRI me R 13. Getting 3-piperidinomethyl-4 f-hydroxy-8-methoxy-10-methyl-2, 9-dioxatricylo 4,3,1,0 decanhydrotartrate (LXXVII)
    150 g of the compound of formula (ij) are dissolved in 150 ml of ethanol, mixed with 75.0 g of α-tartaric acid, 0 is dissolved in 525.35 ml of ethanol at.
    When the solution is evaporated at 60 ° C, the hydrostartarate crystallizes out. The crystals are evaporated, treated with ether, sucked off on a suction filter, and washed with ether. Dry under vacuum at 50 ° C to obtain 203.6 g of the product of white crystalline hydrotartrate of the general formula CO) i, which is 91% of theory.
    SAMO, and
    Mol.v. 44-7.46; m.p. 178 seconds (to
    A coffer); d. water). Analogously, the following compounds are obtained, given in Table. 6,
    3- 4- (p-Chlorobenzhydryl) -1-piperazinylmethyl-4 p -oxy-8-methoxy-10-methylene-2, 9-dioxatricycloG4.3, 1.0 cecane dehydro-tartrate (LXXVI II) 3 4- (p-Chlorobenzhydryl A) -1-pipe 0 razinylmethyl-4 () - ethylcarbamoyloxy-8-methoxy-10-methylene-2, 9-dioxatricyclo 4,3,1, O ekandigidrotartrat (LXXIX)
    3- 4- (p-Chlorobenzhydryl) -1-pipa razinylmethyl -4 f-propionyloxy-8-methoxy-10-methylene-2, 9-dioxatricyclo G4, 3.1, O 7-decanedihydrotartrate (LXXX)
    (2-Pyridyl) -1-piperazinylmethyl -4 1-benzoyloxy-8-methoxy-10. -methylene-2, 9-dioxatricyclo 4,3,1,0 decantrihydrotartrate (LXXXl)
    3- (4-Methyl-1-piperazinylmethyl) -4- |% -benZoyloxy-8-methoxy-10-methylene-2, 9-dioxatricyclo 4,3,1, Odecane 5 dihydrotartrate (LXXXI I)
    3-14- (2-ethylcarbamoyloxyethyl) -1-piperazinylmethyl -4 | b-ethylcarbamoyloxy-8-methoxy-10-methyl-2, 9-dioxatri0 cycloG4, 3,1, o} decanhydroarthartrate (LXXXIII)
    3- (N, N, 1h-triethylethylenediaminomethyl) -, p-ethylcarbamoyloxy-8-methoxy-10-ethyl, 2, 9-dioxatricylo 4.3, 5 1.0 decantihydrotartrate (LXXX IV)
    3-piperidinomethyl-4 d. -oxy-8-labels si-ID-methyl-2, 9 - dioxatricyclo, 3.1, SGZcekanhydride (LXXXV)
    3-piperidinomethyl-4-eopropylcarbamoyloxy-8-methoxy-10-methyl-: g, 9-dioxatricyclo G4, 3,1,0 decanhydrotartrate (LXXXVI)
    3-N, M., 7-diethylaminomethyl-4c (: - ox-8-methoxy-10-methylene-2,9-dioxatricyclo G4, 3,1, Cr 7 decanhydroarthrate (LXXXV I)
    3-piperidinomethyl-4-allylcarbamoyloxy-8-methoxy-10-methyl-2, 9-dioxatricyclo f4, 3,1, SG decanhydroarthrate {LXXXVIII)
    3-N, M-Diethylaminomethyl-4o (; - allylcarbamoyloxy-8-methoxy-10-letylen-2, 9-dioxatricyclo f4, 3, 1, CH Dekangidrotartrate (LXXXiX)
    3-N, N-diethylaminomethyl-4-oxo-8-methoxy-10-methylene-2, 9-dioxane 4,3,1,05seconyl hydrotartrate (CS),
    3-morpholinomethyl 4 p -oxy-8-methoxy-10-methyl-2, E-dioxatricyclo 4.3, 1, 0 decanhydroarthritis (XCI)
    , 3-pyrrolidinomethyl-4 fb-hydroxy-8-methoxy-10-methylene-2, 9-dioxatricylo 4, 3,1,., Kanhydrotartartrate (XC1 I)
    3-piperidinomethyl-4o (.- hydroxy-8-methoxy-10-methyl-2, 9-dioxatricylo 4,3,1, (G decanhydrotartrate (XC I 11)
    3-N, N-Dibutylaminomethyl-4 f-hydroxy-8-methoxy-10-methyl-2, 9-dioxatricylo 4, 3, 1, O-decanhydrotartrate. (XC1 V)
    Example 14. Preparation of 3-aminomethyl-4b-oxy-8-methoxy-10-methylene-2, 9-dioxatricyclo 4,3,1, oVjdecane (XCIV)
    a) Preparation of 3-azidomethyl-4 fb-acetoxy-8-methoxy-10-methylene-2, 9-dioxatricylo 4, 3, 1, 0 decane (XCV) from. 3-iodomethyl-4 p-acetoxy-8-methoxy -10-methylene-2, 9-dioxatricyclo 4/3, 1 0 decane (V),
    14 g of the compound of the formula (VIM) are dissolved in 100 ml of triamide hexamethylphosphoric acid and mixed with 30 g of sodium azide. With vigorous stirring, heat for 4 hours at. 600 ml of ether are added to the solution and the organic phase is washed 5 times with 150 ml of water each time. The combined aqueous phases are shaken with ether. Then the combined organic phases are dried over sodium sulfate. Filtered and washed with ether, the filtrate is concentrated in a rotary evaporator at 50 ° C. 11.5 g of product are obtained in the form of a colorless oil.
    .-,Ltd.
    Mol.v. 295.33, - I.Pr-57SV Methanol
    b) Preparation of 3-azidomethyl-4 P-oxy-8-methoxy-10-1-methylene-2, 9-dioxatricylo f4, 3, 1, O decane (XCVI) from 3 azidomethyl-4 p-acetoxy-8-methoxy 10 methylene -2, 9-dioxatricylo 4.3, 1.0 decan ..
     10.55 g of 3-azidomethyl-4 ji-acetoxy-8-methoxy-10-methylene-2, 9-dioxatricylo 4, 3,1, 0} decane is dissolved in 250 ml of ether and mixed with a solution of 1.5 g of hydroxide sodium in 70 ml of methanol.
    The solution is stirred for 1 h at room temperature, then adjusted to pH 7 with glacial acetic acid, evaporated in a water jet pump vacuum. The residue is taken up in water and the aqueous phase is salted out with ammonium sulfate dung and extracted with ether. The combined organic phases are dried over sodium sulfate, filtered and evaporated in a rotary evaporator at 50 s. 7.9 g of product are obtained in the form of a colorless oil, which
    S corresponds to 87.2% of theories.
    WITH,, "
    Mol at. 253.26; (in methanol)
    c) Preparation of 3-aminomethyl-4 p-hydroxy-8-methoxy-10-methylene -2, 9-dioxatri cyclo 4, 3,1, CG decane (XCVII) from 3-azidomethyl-4 p) oxy-8- methoxy-10-y methylene-2,9-dioxatricyclo 4,3,1,0J decane.
    17.7 g of 3-azidometh1-4 | L-oxy-8-methoxy-10-methylene-2, 9-dioxatricyclo 4, 3, 1, 0 decane is dissolved in 700 ml of methanol and mixed with 35 ml of 80% hydrazine hydrate a. Then 1 g of Rene nickel is added and the mixture is held at room temperature in
    0 for an hour. The catalyst is sucked off through asbestos and the filtrate is evaporated in a water jet vacuum pump at. The residue is dissolved in benzene, filtered and, after distillation, the solvent is recrystallized from ether. 15.3 g of product are obtained in the form of colorless crystals, which is 94.6% of the theory. C Hjyno
    Mol at. 227.62, mp. 108-109s;
    0 CdJ -37 (in methanol).
    Example 15. Obtaining 3-aminomethyl-4 (b-oxy-8-methoxy-10-methyl-2, 9-dioxatricylo 4,3,1, 0 decane.
    five
    but). Preparation of 3-iodomethyl-4 ft-oxy-8-methoxy-10-methylene-2, 9-dioxatricylo 4,3,1, decane (CHC VI 1 O from 3-iodomethyl-4 P-acetoxy-8-methoxy-10 -methylene-2, 9-dioxatricyclo 4.3,
    0
    1.0 dean (V).
    38 g of a compound of formula (VIII) in 250 ml of methanol are mixed with 4 g of sodium hydroxide in 50 ml of methanol and stirred for 30 minutes at room temperature.
    5 temperature. 500 ml of water are added, the mixture is neutralized with glacial acetic acid, mixed with ammonium sulfate to saturation and extracted with ether. Dry over sodium sulfate, filter, and wash with ether, combined
    0 The organic phases are evaporated in vacuo at 50 ° C. 36.64 g of product are obtained in the form of a colorless oil, which is 94.5% of theory. q, H, .3
    five
    Mol.v. 338.15; G 1} | h-13 (e methanol).
    b) Preparation of 3-iodomethyl-4 / i-hydroxy-8-methoxy-10-methyl-2, 9-dioxatricylo 14, 3, 1.03 decane (XCIX) from 3-iodomethyl-4 p) -oxy-8- methoxy-10-methylene-2, 9-dioxatricyclo f4.3, l, o jfleKaHa.
    75 g of 3-iodomethyl-4 L-oxy-8-methoxy-10-methylene-2, 9-dioxatricylo {4.3, i, O decane in 250 ml of ethanol is mixed with 6 g of platinum oxide (IV) in 100 MP of ethanol and hydrogenated at room temperature (5 l hydrogen absorption). The catalyst is sucked off, the solution is evaporated in a rotary evaporator at 50 ° C. The residue is purified on silica gel with a mixture of hexane and ether and recrystallized from a mixture of n-hexane and ether. The yield is 69.9 g, which is 92.8% of theory. C H,
    Mol.v. 340,166; T.Sh1., 92-93 0, -k-35.3 in methanol /. ,
    c) Preparation of 3-iodomethyl-4 f-acetoxy-8-methoxy-10-methyl-2, 9-dioxatricylo 4, 3,1, CG ecan (c).
    20 g of 3-iodomethyl-4 p -oxy-8-methoxy-10-methyl-2, 9-dioxatricylo 4, 3, 1 0 decane is dissolved in 20 ml of pyridine and 10 ml of acetic anhydride and incubated for one hour at room temperature. temperature Then the reaction mixture is evaporated several times to dryness with ethanol. Purified through silica gel with a mixture of n-hexane and ether, 15.4 g of substance are obtained, which is 68.5% of theory.
    Mol at. 33.1-2; T. pl. 120-123s, 8 ° (in methanol).
    ) Preparation of 3-azidomethyl-4 p-acetoxy-8-methoxy-10-methyl-2, 9-dioxatricyclo 4, 3, 1, and cane (C1)
    15.4 g of 3-iodomethyl-4P-acetoxy-8-methoxy-10-methyl-2, 9-dioxatricylo 4, 3.1.1 T of decane is dissolved and 100 ml of triamide hexamethylphosphoric acid and mixed with 31 g of sodium azide i pu. The mixture is stirred for one hour at 100 ° C. 600 ml of ether are added and shaken 5 times with 150 ml of water. The aqueous phases are agitated 2 times with ether and the combined organic phases are dried over sodium sulfate, filtered and concentrated in vacuo at 50 ° C. 12 g of a colorless oil product are obtained (which corresponds to 100% of theory)
     -S „oh
    Mol at. 297.32; IG + W CB methanol).
    e) Preparation of 3-azidomethyl-4 / L-oxy-8-methoxy-10-methyl-2, 9-dioxatricylo 4, 3, 1, SGUdecane (SI).
    To 12 g of 3-azidomethyl-4 p-acetoxy-8-methoxy-10-methyl-2, 9-dioxatricyclo 4, 3, 1, decane in 200 ml of ether, 1.5 g of sodium hydroxide in 20 ml of methanol are added. The solution is stirred for 10 minutes at room temperature, then poured into 200 ml of ice water, neutralized with glacial acetic acid and mixed with gmmmonium sulfate until saturation. The mixture is extracted with ether, the combined organic phases are dried over sodium sulfate, filtered and concentrated in vacuo. 10.7 g of product are obtained in the form of a colorless oil, which corresponds to 100% of theory.
     Ah al
    Mol at. 255.28; (in methanol,
    e) Preparation of 3-amine-methyl 4-p) -oxy-8-methoxy-10-methyl-2, 9-dioxatricico G4.3, 1, about 7-decane (CIII)
    10.6 g of 3-azidomethyl-4 1) -oxy-8-methoxy-10-methyl-2, 9-dioxatricylo 4,3,1,0 decane in 200 ml of methanol is mixed with 32 ml of 80% hydrazine hydrate. Add 1 g of Rene nickel
    in 100 ml of methanol is stirred for 1 h at room temperature. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo. The residue is dissolved in water, the solution is made alkaline with sodium hydroxide and distilled off by distillation of ether. The combined ether phases are dried over sodium sulfate, filtered and concentrated in vacuo at. 9.1 g of product are obtained in the form of a colorless oil, which
    is 94.3% of theory.
    CiAoNO ,,
    Mol.v. 229.28; ) -9 (in methanol. EXAMPLE 16. Preparation of pN, N-dimethyl-IvI-inomethyl-4 of p -oxy-8-methoxy-10-methyl-2, 9-dioxatricylo 4,3, 1, o ekana (- Civ)
    800 mg of 3-aminomethyl-4 p.-Hydroxy-8-methoxy-10-methyl-2, 9-dioxatricylo 4, 3, 1.0 decane in 5 ml of methanop. mixed with. 5 ml of 37% formalin solution and mix Yumin at room temperature. Renee nickel staple is added at the tip and is hydrated at room temperature. By
    the end of the hydrogen uptake is filtered off from the catalyst and evaporated to dryness in vacuo. Purified by chromatography on silica gel using a mixture of chloroform and methanol. Get
    780 mg of product, which is 86.9% of QT theory.
    Mol.v. 267 .W1. 85-86 C,
    fdl -32.5 CB methanol).
    Example 17. Preparation of 3-tl, -azabicyclo SZ, 2., 2) nonanyl-methyl-4P -oxy.-8-methoxy-10-methyl-2, 9-dioxatricyclo 4,3,1, O-anhydro-tartrate (CV) ..
    . 7.6 g of a compound of formula V, together with 10 g of sodium bicarbonate, are suspended in 100 ml of dimethylformamide, then mixed with 7.5 g of Z.-aeabicyclo (3.2.2) nonane. The mixture is boiled for 6 hours at 170 ° С with an oiled bath, then
    cooled to room temperature.
    The mixture is evaporated, the residue is mixed with 40 ml of water and 8 ml of 30% sodium hydroxide solution, then extracted 3 times with 20 ml of ether. After evaporation, the ether extracts are obtained. 5.8 g of 3- 1-aabicyclo (3,2,2) nonanyl-methyl-4 p -oxy-8-methoxy-10-methylene-2, 9-dioxatricyclo-G4, 3,1.0 decane (C IX )
    5.3 g of the compound of formula (C IX) are dissolved in methanol, 4 g of Rene nickel are added and 0.8 g of sodium hydroxide is hydrogenated. After termination of the absorption of hydrogen, the mixture is sucked off on a suction filter through Teorit and washed with methanol.
    1.2 ml of acetic acid is added to the filtrate and evaporated, the residue is dissolved in ether and purified by chromatography on silica gel (particle size 0.2-0.5 mm).
    Elute N. the hexane with 1.5% diethylamine. The eluate is evaporated, to obtain 4.4 g of crystalline 3- 1-azabicyclo (3, 2, 2) nonansh13-methyl-4 f -oxy-8-methoxy-10-methyl-2, 9-dioxatricylo 4,3,1, (l5cekana.
    4-g of the compound of formula (C IV) is dissolved in 8 ml of ethanol. The mixture is mixed with 1.94 g of L (+) - tartaric acid, which is dissolved in 13.6 ml of ethanol. After evaporation of the solvent, and drying, 5.7 g of crystalline (CV) are obtained.
    Mol.v. 487.55, - mp. 73-81 С, ШУ +7,7 (8 methanol).
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    41
    Formula
    the invention
    权利要求:
    Claims (4)
    [1]
    1. The method of obtaining derivatives of 2, 9-dioxatricylo-4, 3,1,0 | decane
    general formula
    eleven
    where the remainder of the amine of the formula g N j. where Rg and Kg are the same or different, alkyl with 1-6 carbon atoms or benzyl,
    or R is an amine residue of the formula
    single
     - communication.
    -N R
    Where
    ten
    Il-and double bridge with the number of carbon atoms 1 - 2 in the case of a single bridge and 2. carbon atoms on each bridge in the case of a double bridge, or an oxygen atom, or imino group of the formula, where
    R is alkyl with 1-4 carbon atoms, (Jtu -OXY-, (Jt-acyloxy- or (-carbamoyloxy-alkyl residue with 1-4 carbon atoms, phenyl, pyridyl, or Gsshobenzhydryl,
    or R -1-indolinyl, K2 is hydrogen, and Kt is an oxy group, an acyloxy group with an alkyl residue with 1–4 carbon atoms or a phenyl residue, or a carbamoyloxy group with a hydroxy residue with 1–4 carbon atoms or a plyl residue, or a phenyl residue, or both R, -j and R together represent oxygen, one of Rg is hydrogen, another alkoxy group with the number of carbon atoms from 1 to 4, 10, 11 - the double bond can be hydrogenated, or their salts, differing
    79124242
    the fact that 2 j 9-dioxatricyclo 4, 3, 1, Dean of the general formula
    to
    where X is iodine, bromine or chlorine; R is hydrogen, R is hydroxy or acetoxy and R. Rj are as defined above,
    interacted with a 1 formula
    0
    HR (ml,
    where R. has the indicated values, when heated and, if desired, the bond 10.11 is hydrogenated and / or the compound of formula (I), where R ,, is a hydroxy group and
    5 K is an atom of VO; (Oroda, is acylated or oxidized to a compound of formula (I), where
    R 2 and R -, - form oxygen, and the target product is released in the free
    0 as a salt.
    [2]
    2. A method according to claim 1, characterized in that the amination process is carried out in an aprotic environment
    solvent, for example, dimethyl form 5 amide or dimethyl sulfoxide or triamide hexamethylphosphoric acid.
    [3]
    3. A method according to claim 1, characterized in that the heating is carried out at the boiling point of the reaction medium.
    [4]
    4. Method POP1, characterized in that the process is carried out in the presence of a base, for example potassium bicarbonate or sodium;
    five
    Sources of information taken into account in the examination
    1. Patent of the USSR No. 460623, cl. C 07 D 311/04, 02.22.72.
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    同族专利:
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    JPS5748073B2|1982-10-14|
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    MX5194E|1983-04-22|
    NO147341B|1982-12-13|
    CH638211A5|1983-09-15|
    ZA77847B|1978-09-27|
    GR62077B|1979-02-20|
    CA1098528A|1981-03-31|
    CS208651B2|1981-09-15|
    IE44774B1|1982-03-24|
    DE2607106C2|1986-01-16|
    IL51441D0|1977-04-29|
    AU512172B2|1980-09-25|
    AU2233977A|1978-08-24|
    SE432765B|1984-04-16|
    HU178020B|1982-02-28|
    JPS52102299A|1977-08-27|
    NZ183327A|1979-03-28|
    DE2607106A1|1977-09-01|
    IE44774L|1977-08-21|
    FR2341581A1|1977-09-16|
    NO820154L|1977-08-23|
    PT66206A|1977-03-01|
    AT357550B|1980-07-10|
    PL115308B1|1981-03-31|
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    ATA112277A|1979-12-15|
    FI770316A|1977-08-22|
    NL7701091A|1977-08-23|
    US4163055A|1979-07-31|
    IL51441A|1981-07-31|
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    YU47677A|1982-06-30|
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    US4242341A|1980-12-30|
    BE851681A|1977-08-22|
    NO147341C|1983-03-23|
    PH16259A|1983-08-19|
    NO770545L|1977-08-23|
    PL196122A1|1978-04-24|
    DK73077A|1977-08-22|
    ES455940A1|1978-03-01|
    引用文献:
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    DE2027890C3|1970-06-06|1979-02-01|Kali Chemie Ag|8-alkoxy or benzyloxy-3-methyl-10-methylene-2,9-dioxatricyclo- -decan-4-ones and 8-alkoxy or 8-benzyloxy-3,10-dimethyl -2,9dioxatricyclo- -decan-4-ones|
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    DE2306118C3|1973-02-08|1980-10-16|Kali-Chemie Pharma Gmbh, 3000 Hannover|S-methyl-10-methylene ^ -dioxatricyclo [43,1,037I decane and 3,10-dimethyl2,9-dioxatricyclo [43,1,03 · 7! decane and processes for their production|
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    DE3335826A1|1983-10-01|1985-04-18|Kali-Chemie Pharma Gmbh, 3000 Hannover|NEW N-3, 8 )) - UNDECANE -5-YL) -TRYPTAMINE DERIVATIVES|
    EP0350145A3|1988-04-28|1990-07-04|Yamanouchi Pharmaceutical Co. Ltd.|Pyridylthiazolidine carboxamide derivatives and their intermediates and production of both|
    US7226886B2|2005-09-15|2007-06-05|Chevron Phillips Chemical Company, L.P.|Polymerization catalysts and process for producing bimodal polymers in a single reactor|
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    申请号 | 申请日 | 专利标题
    DE2607106A|DE2607106C2|1976-02-21|1976-02-21|2,9-Dioxatricyclo [4,3,1,0 → 3 → →, → → 7 →] decane and process for their preparation|
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