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    • 专利摘要:
    1. A method for the preparation of azepine derivatives of the general formula (. T1g, 1G (CH2) where IT) n 2 or gp 3 and 1, m 1 and g 3; C-C - alkyl, allyl, benzyl, unsubstituted or mono- or disubstituted by halogen, benzoyl, unsubstituted or mono- or disubstituted with halogen and / or methoxy group (C- | -St-alkoxy) carbonyl, benzyloxycarbonyl, and also if m p hydrogen atom. 2 and / or R2 and RJ do not simultaneously mean a hydrogen atom; R, is a hydrogen atom, carboxyl or (.-Alkoxy) carbonyl; R., Is a hydrogen atom or an amino group; X is an oxygen or sulfur atom of CH, V or -N - or a salt thereof, if R2 is carboxyl, characterized in that the compound of the general formula a (O l "H2Uv A el. (CHllnr X-CHj-COOtt with where R , m, n, and X have the indicated s. values and A - cyano or formyl, cyclization followed, if necessary, by hydrolysis and / or decarboxylation and separation of the target product in a free form or in the form of a salt. 1, characterized in that the reaction is carried out in a solvent medium. 3. The method according to claims 1 and 2, about 1 and 2, in that the reaction is carried out in the presence of a base. A method according to claims 1-3, characterized in that the reaction is carried out at a temperature from 0 ° C to the boiling point of the reaction mixture.
    公开号:SU1091858A3
    申请号:SU823388045
    申请日:1982-02-11
    公开日:1984-05-07
    发明作者:Заутер Роберт；Грис Герхарт；Грель Вольфганг；Гурнаус Рудольф；Эйселе Бернхард；Гаарманн Вальтер；Руппрехт Экард
    申请人:Др.Карл Томэ Гмбх (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to the preparation of new azepine-type compounds with pharmacological properties. The literature describes a method for the preparation of furan or thiophene condensed derivatives by the reaction of intramolecular aldol condensation of aromatic aldehydes, having appropriate substituents, or by adding aryl (thio) glycolic acid under the action of dilute alkalis. w pharmaco logical properties. The goal is achieved according to the method of obtaining azepine derivatives of the general formula (CH 2) 5 (CH 2) m p 2 5 or m 3 and m 1 and h 3 R-, - C — C, ap1t, allyl, benzyl unsubstituted or mono- or disubstituted with halogen, benzoyl, unsubstituted: or mono- or disubstituted with halogen and / or methoxy group (with -Cj-alkoxy) carbonyl5 benzyloxycarbonyl, also a hydrogen atom, if m n 2 and / or R2 and R, is not a hydrogen atom at the same time; ; RJ, is a hydrogen atom; 5 is carboco; and (C —C2-alkoxy) carbon; 1 | hydrogen atom or amino group oxygen or sulfur atom. or -and, or their salts; R2 is carboxyldc because the compounds of the general formula (CHglm Bi-W ICHsln where R p m S p and X have the indicated values of II and A are cyano or formyl, are cyclized, followed by hydrolysis and / or decarboxylation, if necessary The target product is boiled free or in the form of a salt, when Ry carbox: il. It is advisable to carry out the cycling in a solvent 5 such as methanol, ethanol, ether, dioxaH pyridine, triethylag-shn or their mixture in the presence of a base, for example, sodium carbonate s potassium hydroxide, sodium hydride, tert- potassium butylate, morpholine or diethylamine, or a water base, for example, a concentrated solution of potassium hydroxide, at a temperature from - ° C to the boiling point of the reaction mixture, the reaction is also carried out in a solvent, for example water, ethanol, ethanol and water, dioxane or ice acetic acid in the presence of acid ,, tgkoy. as hydrochloric, hydrobromic or sulfuric, or in the presence of a base e such as sodium hydroxide or potassium hydroxide. Example 1. Ethyl ester of b-benzyl-3, 6, Uzb-tetrahydro-4H-thieno (253rd) azepine-2-carboxylic acid. 85., 3 g (Oz298 mol) of 1-benzyl-4-chloro-5-formyl-25 3 hydrochloride; 6, 7-tetrahydro-1H-azepine 5 suspended in 350 ml of pyridine 3 is mixed with 43 g (Oj358 mol) of complex glycolic ester ethyglose ester at a room temperature: sodium temperature, 75 g are added dropwise during 1j5 h (O, 75 mole) of absolyut triethyl, pamine. By cooling with ice water, the terature of the reaction mixture is supported} below 35 ° C "The mixture is further stirred for 3 hours at room temperature and left to stand overnight, flowed with vigorous stirring and about: a1a building is slowly added with ice} t 80 cells of 48% water The second solution of the hydroxide is Kalik and additionally stirred for 2 hours with cooling, the price is ice. Thereafter, the reaction mixture is poured into ice water, and the resulting oil begins to crystallize after a period of time. The crystals are sucked off, washed with water and recrystallized from isopropanol alcohol. Output 68 g (7 F theory) 5, so pl. 65-66 C. Vygaisleno,%: C 68., 54J H 6.71 j N 4.44 S 10, 17. Found,%: C 68.76; H 6.92, N 4.42-S 10j05,
    31
    Similarly, methyl 6- (2-chloro-6-benzyl) -5.6, /, 8-tetragandpo-4H-thieno (2,3-d) azei-2-carboxylic acid is obtained.
    Calculated,%: C 60.80; And 5.40; SI 10.56, N A, G Found,%: C 60.67; H 5.33; CI 10.45, N 4.10.
    Example 2. Diethyl 5,6,7,8-tetpagidro-4H-thieno (2,3-d) azepine-2,6-dicarboxylic acid, diethyl ester of 5,6,7,8-tetrahydro-4H -thieno (3,2-e) azepine-2,5-dicarboxylic acid.
    92.5 g (0.4 mol) of an isomeric mixture of 4-chloro-5-formyl-2,3,6,7-tetrahydro-1H-1-azepinecarboxylic acid ethyl ester and 4-chloro-ethyl ester 3-formyl-2, 5,6,7-tetrahydro-1H-1-azepinecarboxylic acid is dissolved in 400 ml of pyridine. After adding 57.5 g (52.5 ml or 0.478 mol) of thioglycolic acid ethyl ester, is added dropwise with ice cooling and strong stirring 60 g (82.5 ml or 0.594 mol of triethylamine over 1.5 hours, and the temperature of the reaction mixture is kept below 25 C. Then I continue to stir for 4 hours and the mixture is left to stand overnight. The next day 1 is added dropwise a solution of 33.5 g (0.6 mol) of potassium hydroxide in 40 ml with strong agitation and cooling, the temperature should not exceed 10 C. Then additionally stir for 1 h, drink the reaction mixture into ice water, and extract with ethyl acetate containing ethyl acetate.
    The combined extracts were shaken three times with water and dried over sodium sulfate. After distillation, the solvent in vacuo gives a yellow oil, which is purified by chromatography on a silica gel column (1.5 l; toluene / acetone 19: 1). Yield 71.5 g (60% of theory).
    Calculated,%: C 56.55; H 6.44, N 4.71, S 10.78.
    Found,%: C 56.50; H 6.52; N 4.97; S 10.82.
    Similarly, a mixture of 6-benzyloxycarbonyl-5,6,7,7-tetrahydro-4H-thieno (2,3-y) azepine-2 carboxylic acid and 5-benzyl ethyl ester is obtained.
    oxcarbonyl-5,6,7,8-tetrahydro-4H-thieno (3,2-c) azepine-2-carboxylic acid.
    Yield 39.5% of theory, oil (2: 1 ratio of components).
    Calculated,%: C 63.49; H 5.89; N 3.90; S 8.92.
    Navde.no,%: C 63.68; H 5.87; N 3.83; S 9.03.
    Example 3. 6-Carbethoxy-5,6,7,8-tetrahydro-4H-thieno (2,3-d) azepine-2-carboxylic acid and 5-carbethoxy-5, 6,7,8-tetrahydro-4H- thieno (3,2-c) azepin-2-carboxylic acid
    10 g (0.034 mol) of a mixture of isomers consisting of 5,6,7,8-tetrahydro-4H-thieno (2,3-d) azepine-2,6-dicarboxylic acid diethyl ester and 5,6 diethyl ester , 7,8-tetrahydro-4H-thieno (3,2-e) azpin-2, 5-dicarboxylic acid is boiled for 4 hours under reflux in a solution of 2.8 g (0.05 mol) of potassium peroxide in 150 ml of absolute ethyl alcohol. The drips are evaporated in vacuo, the residue is taken up in water and extracted three times with ether. The ether extracts are removed and the aqueous phase is acidified with concentrated hydrochloric acid. Shake with ether several times, the combined ether phases are washed with water and dried over sodium sulfate. After distilling off the ether, 9.2 g of a yellowish oil remain.
    To separate the isomers, the mixture is subjected to chromatography on a silica gel column (capacity 1.3 liters; toluene / ice / acetic acid ratio 9: 1). The control over the separation of fractions is carried out by conducting thin layer chromatography. After combining the fractions containing only one isomer, the solvent is distilled off. Output (2,) - isomer, 1.05 g (11.6% of theory), so pl. 170-l7lc.
    Calculated,%: C 53.52; H 5.61; N, J5.20.
    Found,%: C 53.00; H 5.63; N 5.27.
    Yield (3,2-e) -isomer 3.05 g (33.9% of theory), mp; 135-137 ° C.
    Calculated,%: C 53.52; H 5.61, N 5.20; S 11.90.
    Found,%: C 53.60; H 5.74; N 5.28, S 12.20.
    Example 4  Ethyl ester 5,6, 7,8-tetrahydro-411-tie S1 noSg, 3-dj azepine - /: - carboxylic acid and ethyl ester 5,6,7,8-tetrahydro-4H-thieno (3,2- c) azepine-2-carboxylic acid.  82.5 g (0.275 mol) of a mixture of isomers consisting of 5,6,7,8-tetraparido-4H-thieno dethyl ester (2.  3-d) azepin-2 6-dicarboxylic acid and diethyl ester of 5,6,7,8-tetrahydro-4H-thieno (35 2-e) azepine-2,5-dicarboxylic acid with stirring at room temperature To the solution is added dropwise to a solution of 154 g (2.75 mol) of potassium hydroxide in 1.3 liters of absolute ethanol and subjected to reflux for 1 hour.  Then the ethanol formed is slowly distilled off.  A vacuum is created at the end of the distillation to remove the alcohol.  The dry residue consisting of a mixture of potassium salts of 5,6,758-tetrahydro-4H-thieno (2,3-d) azepine-2-carboxylic acid and 5,6,7,8-tetrahydro-4H-thieno (3,2- e azepin-2-carboxylic acid is suspended in 1.3 liters of absolute alcohol and hydrogen chloride is added, first at room temperature for 3 hours and then at reflux temperature for 1.5 hours.  The reaction mixture was left to stand for 48 hours and then the reaction was repeated as described.  Then it is cooled, the potassium chloride is sucked off and the filtrate is evaporated in vacuo.  The residue is dissolved in water and extracted twice with ether.  The aqueous phase is alkalinized with sodium carbonate and extracted three times with chloroform.  After washing the combined chloroform extracts 2 times with water and drying over sodium sulfate, they are evaporated in vacuo. The yield of the mixture of isomers 22. , 6 g (36% of theory).  To separate the isomers, 10 g of a mixture of numbers is subjected to chromatography on a silica gel column (capacity 1.9 L, chloroform / ethyl alcohol / ammonia ratio is 9: 1 j 3: 0,, 07.  The separation of the isomers is controlled by thin layer chromatography.  After the fractions containing only one isomer are combined, the solvent is distilled off.  Approx (2,3-d) -isomer 3.3 g .  (11.9% of theory).  Calculated,%; C 58.64; H 6.71 ;, N, 6.22; S 14.20.  8 Found: C 58.32, H 6.92 ,, N 6.39 ;, S 14.06, b. Yield (Ze2-c) -isomer 4.7 g (1638% of theory).  Calculated,%: m / e z25 HaE / tBHOj%: m / e 225 T. square  hydrochloride 252 ° C (decomposition).  Calculated,%: C 50.70-, H 6.17; N 5,, 29i Sat 13.35i S 12 ,. 0  Found,%: C 50.47, H 6.16; N 5.35; C1 13.54; S 12.25, Example 5.  6-Benzyl-5,6,7 5 8-tetrahydro-4H-thieno (2,3-d) azepine-2-carboxylic acid hydrochloride.  21.5 g (0.068 mol) of 6-benzyl-5 ethyl ester, b57 8-tetrahydro-4H-thieno (2,3-d 3ennH 2-carboxylic acid is heated over a steam bath, adding a solution of 50 ml of water in 100 ml of concentrated hydrochloric acid, while the substance gradually dissolves.  After 5 hours, 20 ml of concentrated hydrochloric acid is added again and the mixture is heated for 30 minutes.  The mixture is left to stand overnight, the precipitated product is filtered off with suction and recrystallized from ethanol.  Output 8.1 g (37% of theory), t. square  260 to 262 ° C (decomposition).  Calculated,%: C 59z34; H 5.605 N 4.33i Cl 10.95; S 9.90.  Found,%: C 59.40; H 5.76, N 4. 255 CB riJOj S 10.00.  Analogously to Example 1 (wherein the corresponding 4-chloro-5-formate compound is not always isolated as an intermediate product) and Examples 4 and 5 are prepared with the following compounds.  6-ethyl-5,6 ethyl ester hydrochloride, 7,8-tetrahydro-4H-thieno (2J 3-d) azepine-2-carboxylic acid.  Yield 22% of theory, t. square  about 198-199 S.  6-Ethyl-5,6,7,8-tetrahydro-4H-thieno (2,3-d) azepine-2-carboxylic acid hydrochloride.  Output.  51.3% of the theory5 tons, pl.  299 C (decomposition).  Included 5%: C 50.47 H 6.16; N 5.35; SI 13.54- S 12.25.  Nai: gene,%: C 50.70; H 6.26; N 5.34; cr 13.68; S 12,18.  6-Allyl-5,6,7,8-tetrahydro-4H-thieno (2,3-d) azepine-2-carboxylic acid ethyl ester hydrochloride.  Yield 31% of theory, t. square  196-197 ° C.  Calculated D: C 55,71; H 6.68, N 4 ,. 64; C1 11.74.  Found,%: C 55.70; H 6.75, N 4.63; C1 11.75.  Hydrochloride 6-allyl-5,6,7,8-hydro-4H-thieno (2,3-d) azepin-2-kap new acid.  The output of 44.4% of the theory of t. square  276 C (decomposition).  Calculated,%: C 52.65; N.  .  5.89; 5.12; CE 12.95; S 11.71.  Found,%: C 52.70; H 5.99; 5.06; C1 13.00; S 11.68.  Ethyl ester of 6-allyl-5, 6,7,8-tetragone 4H-thieno (2,3azepin-2-carboxylic acid.  Top 81% theory, brown oil.  Calculated,%: C 63.36; H 7.22; N 5.28.  Found,%: C 63.19; H 7.34; N 5.51.  6- (2-Chlorobenzyl) -5,6,7,8-hydro-4H-thieno (2,3-d) azepine-2-carcanoic acid ethyl ester hydrochloride.  Output 76.6% of theory t. square  191-192 ° C.  Calculated,%: C 55.96; H 5.48; N 3.62; C2 18.35- S 8.30.  Found,%: C 56.20; H 5.46; N 3.66, -C1 18.55; S 8.45.  6- (2-chlorobenzyl) -5,6,7,8-tetrahydro-4H-thieno hydrochloride (2-azazepine 2-carboxylic acid.  Out of 71.9% of theory, t. square  247-248 ° C.  Calculated,%: C. 53.64; H 4.78; N 3.91; CI 19.79; S 8.95.  Found,%: C 53.60, H 4.74; N 3.90; C2 19.65; S 8.76.  6- (4-chloro-benzyl) -5,6,7,8-tetrahydro-4H-tie but (2,3-d) azepine-2-carboxylic acid ethyl ester. 79% of theory, t. square  89-90 0.  Calculated,%: C, 61.79; H 5.76; N 4.00, SI 10.13; S 9.16.  Found,%: C 61.70; H 5.87; N 3, Cr 10.30 v S 9.15.  Hydrochloride 6- (4-chlorobenzyl) -5, 6,7,8-tetrahydrop Q-4H-tieno (2,3azepin-2-carboxylic acid.  Output 84.6 theory, t. square  253-254С (dilution).  Calculated,%: C 53.64; H 4.78; N 3.91, C1 19; 79; S 8.95.  Found,%: C 53.80; H 4.83; N 3.84; C 19.92-, S 8.98.  Sodium salt of 6-dodec-1-5,6,7 -tetrahydro-4H-thieno (2,3-d) azepine -2-carboxylic acid.  Output 36.2 theory, t.  silt   (decomposition) Calculated,%: C 65.08; H 8.84; N 3,61-, S 8,27.  88 Found: C 65.30; H 8.91; 3.45, S 8.22.  6- (5-chloro-2-methoxybenzoyl) -5,6,7,8-tetraido-4H-thieno (2,3-d) azepine-2-carboxylic acid ethyl ester.  Yield 21.6% of theory, t. square  192-193C.  Calculated,%: C 57.94; H 5.12N 3.56 j CI 9.00; S 8.14.  Found,%: C 58.30; H 5.18; N 3,61; Cr 9.11, S 8.16.  6- (5-Chloro-2-methoxybenzoyl) -5, 6,7,8-tetrahydro-4H-thieno (2,3-d) azepine-2-carboxylic acid.  Output 81.1% of theory, t. square  234-236 ° C.  Calculated,%: C 55.82; H 4.41; N 3.83-, S 8.76.  Found,%: C 56.00; H 4.58, N 3.90-, S 8.92.  5- (5-Chloro-2-methoxybenzosh1) -5,6,7,8-tetrahydro-4H-thieno (3,2-c) azepine-2-carboxylic acid ethyl ethyl epitome.  Vkod 26% theory, oil.  Calculated,%: C 57.93; H 5.12; N 3.56, S 8.14; CI 9.0tt.  Found,%: C 58.34; H 4.99; N 4.12-, S 7.76-, C1 9.37.  5- (5-Chloro-2 methoxybenzoyl) -5,6, 7,8, -tetrahydro-4H-thieno (3,2-e) azepine-2-carboxylic acid.  Yield 74% of theory, t.  square  215-216 ° C.  Calculated,%: C 55.82; H 4.41; N 3.83; CI 9.69; S 8.76.  Found,%: C 55.60; H 4.56; N 3.82-, C1 9.57, S 8.53.  5,6,7,8-tetrahydro-6-pr6pyl-4H-thieno (2,3-d) ethyl ester complex, azepine-2-carboxylic acid.  Yield 93% theory, oil.  T. square  hydrochloride 222-224 C.  Calculated,%: C 55.34; H 7.30; N 4.61, C1 11.67; S 10,55.  Found,%: C 55.52; H 7.17; N 4.48; cr 11.83; S 10.82.  5,6,7,8-tetrahydro-6-isopropyl-4H-thieno (2,3-d) azepine-2-carboxylic acid ethyl ester.  Yield 97% theory, oil.  T. square  hydrochloride 225-227 ° C.   Calculated,%: C 55.34; H 7.30; N 4.61; CI 11.67; S 10,55.  Found,%: C 55.35; H 7.24i N 4.59, C 11.77; S 10.77.  Ethyl ester 5,6,7,8, -tetrahydro-6-methyl-4H-thieno (2,3-d) azepine-2-carboxylic acid.  Vkod 42% of the theory, oil.  T.  square  hydrochloride 237-239 ° C.  Calculated,%: C 52.26; H 6.58; N 5.08; cr 12.86; S 11.62.  Found,%: C 52.36; H 6.51; N 5.21; cr 12.90; S 11.90.  Ethyl ester 5-ethyl-5, 6,7,8-tetrahydro-4H-thieno (3,2-e) azepine-2-carboxylic acid.  Yield 71.2% of theory, yellow oil.  Calculated,%: C, 61.63; H 7.56; N 5.53; S 12.65.  Found,%: C 61.45; H 7.39; N 5.77; S 12.89.  Methyl 6- (2-chloro-benzyl) -5,6,7,8-tetrahydro-4H-thieno (2,3-d) azepine-2-carboxylic acid methyl ester 63% of theory, t, pl.  91-92C.  Calculated,%: C, 60.80 - H, 5.40; Cl, 10.56; N 4.17.  Found,%: C 60.67j H 5.33; C1 10.45, N 4.10.  Example 6  3-Amino-6-benzyl-5,6,7,8-tetra hydro-4H-thieno (2,3-d) a3enHH-2-Kapboxylic acid ethyl ester.  4.9 g (0.020 mol) of 1-benzyl-4-chloro-5-cyano-2, 3,6,7-tetrahydro-1H azepine together with 2.5 g (0.021 mol) of ethyl thioglycolic acid ester and 2 , 2 g (0.021 mol) of sodium carbonate in 30 ml of ethanol are heated under reflux for 5 hours with stirring and then cooled, standing overnight. The next day, evaporated in vacuo and the residue is distributed in a mixture of chloroform and water.  The chloroform phase is washed three times with water, dried over sodium sulfate, and evaporated in vacuo.  The residue is triturated with isopropyl. alcohol, sucked off and recrystallized from isopropyl alcohol.  The output of 4.6 g (70% of theory), t. square  101-102 ° C.  Calculated,%: C 65.43; H 6, 71 ,; N 8.48-, S 9.70.  Found,%: C 65.60; H 6.33; N 8, 15; S 9.74.  In a similar manner, complex esters of 6-etch-3-amino-55.6 ester, 7.8-tetrahydro-4H-thieno (2,3-d) azepine-2-carboxylic acid are obtained.  Yield 89% of theory, light yellow oil.  Calculated: m / e 268.  Found: m / e 268.  Example 7  6-Bezyl-5,6,7,8-tetrahydro-4H thieno (2,3-d) azepine hydrochloride.  1 8 3.1 g (0.096 mol) of benzyl-5,6,7,8-tetrahydro-4H-thieno (2,3-d) hydrochloride, azepine-2-carboxylic acid is heated under reflux for 48 hours in 30 ml of concentrated hydrochloric acid.  After cooling as it is, it is concentrated under vacuum, mixed with water, alkalinized with 6 sodium hydroxide solution and shaken several times with ether.  The ether phases are washed again with water, dried over sodium sulfate and evaporated in vacuo. After re-evaporation of the benzene, the brown oil remains.  The resulting oil is dissolved in isopropyl alcohol, the hydrochloride is precipitated with isopropanol hydrochloric acid, and recrystallized from isopropyl alcohol.  Output 1.8 g (67% of theory), t. square  237-239 0.  Calculated,%; C, 64.38; H, 6.48; N, 5.01; CE 12.67-, S 11.46.  Found,%: C 64.20; H 6.60, N 4.88, cg 12; 70, S 11.70.  PRI me R 8.  Ethyl ester of 3-ag Shno-6-benzyl-5,6, 7,8-tetrahydro-4H-1-methylpyrrolo (2,3-d) a3epin-2 carboxylic acid.  1.24 g (0.003 mol) of 1-benzyl-4-chloro-5- and (iano-2,3,6, 7-tetrahydro-1H-azepine, together with 1.54 g (0.01 mol) of ethyl ethyl hydrochloride Sacrosin ester and 1.60 g (0.015 mol) of anhydrous soda in 10 ml of dimethylformamide are heated under stirring for 5 hours to 100 C.  After cooling, the reaction mixture was poured.  .  ice water and extracted several times with chloroform.  The combined chloroform extracts are washed 4 times with water, dried over sodium sulfate, and evaporated.  The residue is purified by chromatography on a silica gel column using a mixture of ethyl ethyl acetic acid and petroleum ether 9: 1: 3 as solvent.  Yield 0.8, g of oil (49% of theory).  Calculated: m / e 327 Found: m / e 327 Analysis of the hydrochloride Calculated,%: C 57.00; H 6.80; N 10.50.  Found,%: C 56.00; H 6.87N 10.43.  Example 9.  6-Benzyl-5,6,7,8-4H-1-methyl-propyl (2,3-d) azepine-2carboxylic acid ethyl ester hydrochloride.  11 8.6 g (0.03 mol) of 1-benzyl-4-chloro-5-formyl-2 hydrochloride 3,6,7-those rahydro-H-azepine are stirred for 1.5 hours at 40 ° C with 9 , 2 g (0.06 mol) of sacrosine ester hydrochloride and 12.7 g (0.12 mol of anhydrous soda in 90 ml of absolute dimethyl sulfoxide.  Then it is poured onto the SOA with ml of ice water and extracted twice with ethyl acetate.  The combined extracts are washed three times with water, dried over sodium sulfate and evaporated.  The red small residue thus obtained (5.8 g of 0.0175 mo is dissolved in 20 ml of absolute dimethylformamide and slowly added dropwise at 5-10 ° C under nitrogen atmosphere to a solution of 2.05 g (0.01775 mol) tert potassium butylate in 15 ml of absolute dimethylformamide.  After further stirring for 30 minutes at room temperature, the gel-like reaction solution is fed to ice water and extracted several times with ethyl acetate.  The combined organic phases are washed 4 times with water, dried over sodium sulfate and evaporated.  The residue is subjected to chromatographic purification on silica gel columns using a mixture of toluene and ethanol in the ratio 19: 1 as solvent.  Output 3.4 (36% of theory), t. square  20 C.  The product is dissolved in ethyl acetate and the hydrochloride is cooled with ethereal hydrochloric acid, filtered off with suction and recrystallized from a mixture of ethyl acetate and iso-propanol in a ratio of 9: 1.  T.  square  202-203 C (decomposition) Calculated,%: C 65.41 j H 7.22; CI 10.16-, N 8.03.  Found,%: C 65.40; H 7.20; CC 9.97, - N 8.09.  Example 10  6-Benzyloxycarbonyl-5,6, 7,8-tetrahydr6-4H-1-methylpyrrolo- (2,3-d) azepine-2-carboxylic acid ethyl ester. Prepared analogously to Example 9 from 4-chlorine-5- benzyl ester FORMIL-2,3 5 6,7-tetrahydro-1H-azepine-carboxylic acid and hydrochloride of the ethyl ester of reducine.  Yield 8% of theory, t. square  73-74 S.  8 Calculated,% C 67.00; H 6.79; 7.86.  N Found: C, 67.49; H, 6.77, 7.69.  Example 1 1.  6-Benzyl-5,6, 7,8-tetrahydro-4H-1-methylpyrrolo (2,3-d) a3ennH-2-Caparic acid.  To 3.1 g (0.01 mol) of 6-benzyl-5,6,7,8-tetrahydro-4H-1-methylpyrrolo ethyl ester (2, 3-d) azepin-2-carboxylic acid, add 10 ml 2 N.  the aqueous sodium hydroxide solution, the resulting mixture is dissolved in 80 ml of ethanol and heated to reflux temperature for 6 hours.  Then evaporated and the residue is subjected to chromatographic purification on silica gel, using as a solvent a mixture of chloroform with methanol in a ratio of 8.5: 1.5.  Yield 0.8 g (29% of theory), t. square  149-150s (decomposition).  Calculated,%: C 71.81; H 7.09; N 9.85.  Found,%: C 71.94 ,. H 6.88; N 10.09.  Example 12  6- (2-Chlorobenzyl) -5,6,7,8-tetrahydro-4H-1-methylpyrrolo (2,3-d) -azepine hydrochloride.  3.3 g (0.0095 mol) of 6- (2-chlorobenzyl) -5,6,7,8-tetrahydro-4H-1-methylpyrrolo (2, 3-d) azepine prepared analogously to example 11 by saponification -2-Carboxylic acid, sodium salt and 3.1 g (0.035 mol) of oxalic acid in 50 ml of propanol are heated under reflux for 8 hours.  Then evaporated, the residue is mixed with water and alkalinized 2 n.  soda lye.  After extraction with chloroform three times, the combined organic phases are washed with water, dried over sodium sulfate and evaporated.  The residue is subjected to chromatographic purification on a column, using as a solvent a mixture of toluene, ethyl acetate and ethanolic ammonia in a ratio of 9: 1: 0.05.  After evaporation of the solvent, the remaining yellowish oil is dissolved in absolute ether and HYDROCHLOR-1DH is precipitated with ethereal hydrochloric acid, which is sucked off and re-purified by reprecipitation with hot isopropanol with ether.  Output 1.9 g (64% of theory), t. square  179-180 ° C.  13 Calculated,%: C, 61.74; H 6.48; G2 22.78; N 9.00.  Found,%: C 61.67 - H 6.46, Wed 22.55, N 8.99.  Example 13  Oxalate 6-ben -5,6,7,8-tetrahydro-4H-1-methylpyrlo (2,3-d) a3enHHa.  Prepared analogously to example 12 of 6-benzyl-5,6,758-tetrahydro-AH-1-methylpyr ethyl (25 3-e) azepine-2-carboxylic acid ethyl ester by omyshenium and decarboxylation. 64% of theory, t.  square  182-183 Calculated,%: C 65.44; H 6.71; N 8.48.  Found,%: C 65.54; H 6.76; N 8.44.  Example 14  Oxalate 6- (4benzyl) -5,6,7,8-tetrahydro-4H-1-methylpyrrolo (2,3-d) azepine, Prepared analogously to example 12 from ethyl ester 6- (4-benzyl) -5, 6,7,8-tetrahydro-4H-1-m tilpyrrolo (2,) azepin-2-carboxylic acids by saponification and decarbox lysis.  Yield 29% of theory, t. mp 195-196 ° C.  Calculated,%: C 59.26; H 5.80 C 9.72; N 7.68.  Found,%: C 59.20; H 5.86-, C2 9.56, N 7.51.  Example 15  Oxalate 5,6,7-tetrahydro-4H-1-methylpyrrolo (2,3azepine.   5,6,7,8-Tetrahydro-4H-1-methylpyrrolo (2,3-azepine-2-carboxylic acid ethyl ester is prepared analogously to Example 12 by saponification and decarboxylation.  29% of theory, t.  square  180.  Calculated,%: C 54.99; H 6.71; N 11.66.  Found,%: C 55.18j H 6. , 75, N11.36.  Example 16  Ethyl 7-benzyl-55b, 7,8-tetrahydro-4H-thieno (253-d) azepin-2-acid carboxylic ester.  Prepared analogously to example 1 of 1-benzyl-3-chloro-4-forma-1-2 hydrochloride, 5,6,7-tetrahydro-1H-aza pina and complex thioglycol eff.  Yield 19% of theory, t. square  62-63 Calculated: m / e 315.  Found: m / e 315 Calculated,%: C 68.54; H 6.71, N 4.44; S 10.17.  8 Found,%: C 68.30; H 6.65 ,, N 4.53 S 10.22.  Example 17  6- (2-Chlorobenzyl) -5,6,7,8-tetragon butyl ester, cpo-4H-ypo (2,3-d) azepine-2-carboxylic acid.  To a suspension of 0.72 g (0.015 mol) of 50% sodium hydride and 10 ml of absolute dioxane with vigorous stirring at room temperature under a nitrogen atmosphere, 2.0 g (0.015 mol) of glycolic acid butyl is slowly added dropwise.  At the same time, the temperature of the highly foaming reaction mixture was kept below 30 ° C by cooling with ice water. After 155 hours of additional stirring at room temperature, a solution of 2.84 g (0.010 mol) of 1- (2-chlorobenz1) -4- was added dropwise chloro-5-formyl-2, 3,6,7-tetrahydro-1H-azepine in 20 ml of absolute dioxane, at which the reaction temperature rises from 20 to 33 C.  The mixture is then stirred for 2 hours at room temperature, poured onto 150 ml of ice-cold water, and extracted three times with ethyl acetate.  The combined organic phases are shaken three times with water, dried over sodium sulfate and evaporated.  The residue is subjected to chromatographic purification on silica gel using a mixture of chloroform and ethyl acetate in the ratio 93: 7 as a solvent.  Output 0, g (6% of theory), t.  square  2U ° C.  Calculated,%: C, 66.38; H 6.68; C2 9.80; N 3.87.  Found,%: C 66.31; H 6.50; C1 9.93; N 3s78.  Example 18  Butyl ester of 3-amino-6-benzsh1-5,6,7,8-tetrahydro-4H-phypo (253-d) -2-carboxylic acid.  To a suspension of 0.4 g (0.008 mol) of 50% sodium hydride and 5 ml of absolute dioxane are added dropwise 1.0 g (0.008 mol) of glycolic acid butyl ester dissolved in 8 ml of absolute dioxane, and stirred solution for 1 h at room temperature.  Then, while cooling with ice, a solution of 1.0 g (0.004 mol) of 1-benzyl-4-chloro-5-cyano-2, 3.6, 7-tetrahydro-1H-azepine in 15 ml of absolute 1B dioxane and again mix for 1 hour.  The reaction mixture is then poured into 80 ml of ice water and extracted three times with ethyl acetate.  The combined organic phases are shaken twice with water, dried over sodium sulfate, and evaporated.  The residue is subjected to chromatographic purification on a silica gel column using the solvent: toluene / ethyl acetate in a ratio of 7: 3.  Yield 0.2 g (14% of theory) t. square  20 ° C.  Calculated: m / e 342.  Found: m / e 342.  Example 19  6- (2-Chlorbenzyl-5,6,7,8-tetrahydro-4H-phypo (2,3-d) a pin-2-carboxylic acid.  Prepared analogously to Example 11 by saponification of 6- (2-chlorobenzyl) -5,6,7,8-tetrahydro-4H-phypo (2,3-d) azepine-2-carboxylic acid butyl ester with aqueous sodium yields. 65% theory lye in ethanol.  t. square  . 120 C (decomposition, start of specimen 200 C)  Calculated: m / e 305/307 (1 C1) Found: m / e 305/307 (1 C1) Calculated,%: C 62.85; H 5.27; C 11.60; N 4.58.  Found With 62.66-, H 5.35; 11.39; N 4.71.  C2 Example 20.  Hydrochloride 6-chlorobenzyl) -5,6,7,8-tetrahydro-4H-furo (2,3-e) azepine.  Prepared analogously to Example 12 from 6- (2-chlorobenzyl) -5,6,7,8-tetrahydro-4H-furo (2,3-d) azepine-2-carboxylic acid by decarboxylation.  35% yield of theory, t. square  20 Calculated: m / e 261/263 (1 C) Found: m / e 261/263 (1 CI).  Calculated,%: C 68.83; H 6.16; C 13.54; N 5.35.  Found,%: C 68.79-, H 6.33; CE 13.36; N 5.62.  Similarly to the examples given, the following compounds are prepared.  6- (2,6-dichlorobenzyl -5,6,7,8-tetrahydro-4H-tieno hydrochloride (2,3-d azepine).  T.  square  .  Dissolved,%: C 51.66; H 4.62; CI 30.50; N 4.02; S 9.19.  Found,%: C, 51.73; H, 4.48; Cg 30.60-, N.  4.00; S 9.14.  Hydrochloride 6- (2,4-dichlorobenzyl -5,6. 7,8-tetrahydro-4H-thieno (2,3-g. -N 181-182 C.  azepine.  T.  pl 8 Calculated,%: C 51.66; H 4.62; CI 30.50; N 4.02; S 9.19.  Found,%: C 51.90; H 4.47; C2 30.10; N 3.93; S 9.25.  6- (2-Chlorobenzyl) -5,6,7,8-tetrahydro-4H-1-methylpyrrolo (2,3-d) ethyl ester hydrochloride (azapine-2-carboxylic acid, tons). square  169-171 ° C.  Calculated,%: C 59.53; H 6.31; SI 18.50; N 7.31.  Found,%: C 59.47; H 6.34; C2 18.60, N 7.43. .  6-ethyl-5,6,7,8-tetrahydro-4H-1-methylpyrrolo (2,3-d) azethine-2-carboxylic acid hydrochloride ester hydrochloride.  T.  square  188 189 ° C.  Calculated,%: C 58.63; H 8.08; CI 12.36, N 9.77.  Found,%: C 58.40; H 8.12; C2 12.35, N 9.78.  Ethyl ester hydrochloride of 6- (4-chlorobenzyl) -5,6,7,8-tatrahydro-4H-1-methylpyrupoClO (2,3-d) azepine-2-carboxylic acid.  T.  square  185-186 ° C.  Calculated,%: C 59.53; H 6.31; CE 18.50; N 7.31.  Found,%: C 59.79; H 6.65; cr 18.10; N 7.14.  Ethyl ester hydrochloride 5,6,7,8-tetrahydro-4H-1-methylpyrrole (2, 3-d) azepine-2-carboxylic acid.  T. square  179-180 C.  Calculated,%: C 55.70; H 7.40; cr 13.70; N 10.83.  Found,%: C 55.84; H 7.28; CI 13.45; N 10.93.  6- (2-chlorobenzyl) -5,6, 7,8-tetrahydro-4H-thieno (2,3-d) azepine hydrochloride.  T.  square  195-197 ° C.  Calculated,%: C 57.33, H 5.45 N 4-, 46; C1 22.56, S 10.20.  Found,%: C 57.54; H 5.52; N 4.48, cr 22.50, S 10.32.  6-Allyl-5,6,7,8-tetrahydro-4H-thieno (2,3-d) azepine hydrochloride.  T. square  204-206 ° C.  Calculated,%: C 57.50; H 7.02; N 6.10; C2 15.43; S 13.95.  Found,%: C 57.40, H 6.94; N 6.13; cr 15.55, S 14.05.  6-ethyl-5,6,7,8-tetrahydro-4H-thieno (2,3-d) azepine hydrochloride.  T. square  231-234 ° C.  Calculated,%: C 55.16; H 7.41; N 6.43; CI 16.28; S 14.72.
    权利要求:
    Claims (4)
    [1]
    1. The method of obtaining azepine derivatives of the general formula a hydrogen atom, if rn = η = 2 and / or R ^ and Rj do not simultaneously mean a hydrogen atom;
    R 2 is a hydrogen atom, carboxyl or (C 1 -C ^ alkoxy) carbonyl;
    Rj is a hydrogen atom or an amino group;
    X is an oxygen or sulfur atom with "z or —N— or their salts, if R 2 is carboxyl, characterized in that the compound of the general formula
    J (CH 2 ) P / ^ X-CH 2 -COOH (CH 2 ) t (CH 2 ) η where R, m, η and X have the indicated meanings and A is cyano or formyl, cyclized with. subsequent, if necessary, hydrolysis and / or decarboxylation and vyschelivanie of the target product in free form or in the form of salt.
    where tn = η = 2, or m = 3 and ’= 1, m = 1 and η = 3;
    R ^ is C ^ -C ^ -alkyl, allyl, benzyl, unsubstituted or mono- or disubstituted by halogen, benzyl, unsubstituted or mono- or disubstituted by halogen and / or methoxy. (C ^ -C ^ -alkoxy) carbonyl, benzyloxycarbonyl, and
    [2]
    2. The method of pop. 1, the difference between the Ministry of Internal Affairs and the fact that the reaction in a solvent environment.
    [3]
    3. The method according to PP. 1 and 2, characterized in that the reaction is carried out in the presence of a base.
    [4]
    4. The method according to PP. 1 to 3, characterized in that the reaction is carried out at a temperature of from 0 ° C to the boiling point of the reaction mixture.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US3846446A|1971-10-01|1974-11-05|American Cyanamid Co|Substituted heterocyclic derivatives of azepine|
    US3758501A|1971-10-01|1973-09-11|M Weiss|Substituted heterocyclic derivatives of azepine|
    US3849441A|1971-10-01|1974-11-19|American Cyanamid Co|Substituted heterocyclic derivatives of azepine|US4520025A|1982-07-21|1985-05-28|William H. Rorer, Inc.|Bicyclic nitrogen heterocyclic ethers and thioethers, and their pharmaceutical uses|
    DE3230696A1|1982-08-18|1984-02-23|Dr. Karl Thomae Gmbh, 7950 Biberach|NEW THIENO-THIAZOLE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS|
    GB8800891D0|1988-01-15|1988-02-17|Lilly Industries Ltd|Pharmaceutical compounds|
    GB8909132D0|1989-04-21|1989-06-07|Lilly Industries Ltd|Pharmaceutical compounds|
    FR2652579B1|1989-10-02|1992-01-24|Sanofi Sa|DERIVATIVES OF 2-HYDROXY THIOPHENE AND FURANNE CONDENSED WITH A NITROGEN CYCLE, ON THE PREPARATION PROCESS AND THEIR THERAPEUTIC APPLICATION.|
    GB9025890D0|1990-11-28|1991-01-09|Lilly Industries Ltd|Pharmaceutical compounds|
    US5532240A|1991-12-26|1996-07-02|Yoshitomi Pharmaceutical Industries, Ltd.|Condensed thiophene compound and pharmaceutical use thereof|
    KR930703327A|1991-12-26|1993-11-29|고야 다다시|Condensed thiophene compounds and their medical uses|
    US5334596A|1993-05-11|1994-08-02|Merck & Co., Inc.|Fibrinogen receptor antagonists|
    DE4324580A1|1993-07-22|1995-01-26|Thomae Gmbh Dr K|Bicyclic heterocycles, pharmaceutical compositions containing them and methods for their preparation|
    US5696112A|1995-01-17|1997-12-09|American Cyanamid Company|Fused heterocyclic azepines as vasopressin antagonists|
    FR2733750B1|1995-05-03|1997-06-13|Synthelabo|DERIVATIVES OF GAMMA-OXO-ALPHA--5,6- DIHYDRO-4H-THIENOPYRROLE-5-BUTANOIQUE, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION|
    US5939417A|1998-10-19|1999-08-17|Cell Pathways Inc|1,3,6-trihydro-6-aza-3-oxapentalen-2-one derivatives for the treatment of neoplasia|
    DK1778243T3|2004-06-30|2013-02-04|Athersys Inc|Substituted azepine derivatives as serotonin receptor modulators|
    US7423056B2|2004-09-03|2008-09-09|Athersys, Inc.|Tricyclic heteroaryl piperazines, pyrrolidines and azetidines as serotonin receptor modulators|
    MX2008009178A|2006-01-19|2008-12-05|Athersys Inc|Thiophenyl and pyrrolyl azepines as serotonin 5-ht2c receptor ligands and uses thereof.|
    JP2016503808A|2012-12-21|2016-02-08|エイビーティー ホールディング カンパニー|Benzazepine and its use as serotonin 5-HT2c receptor ligand|
    WO2014159067A1|2013-03-13|2014-10-02|Abt Holding Company|Thienylindole azepines as serotonin 5-ht2c receptor ligands and uses thereof|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE19813105858|DE3105858A1|1981-02-18|1981-02-18|"NEW THIENO-AZEPINE, THEIR PRODUCTION AND USE AS A MEDICINAL PRODUCT"|
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