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    • 专利摘要:
    1. METHOD FOR OBTAINING 3,4-DIHIDRO-5H-2,3-VENZODIAZEPINE DERIVATIVES of general formula 1 with st. CHCH B. NH / where R means a substituted one or two halo C2-C4 alkoxy radicals phenyl group, furyl or thienyl group; R is a hydrogen atom or a C, -C-alkyl group; R2. -Alkoxy- or C -C-cycloalkoxy radical; Rj is a C-C-alkoxy radical; characterized in that the 5H-2,3-benzodiazepine derivative of the general formula I1 XHi SL where R, R, R, and R. have the indicated C values, is reduced in an inert organic solvent using an inorganic or organic complex metal hydride, followed by an extracting product. in free state or in the form of a pharmaceutically acceptable acid additive salt. 2. The method according to claim 1, characterized in that sodium borohydride or dihydro-bis- is used as the reducing agent.
    公开号:SU1151206A3
    申请号:SU823404160
    申请日:1982-03-12
    公开日:1985-04-15
    发明作者:Кереши Ене；Ланг Тибор；Андраши Ференц；Секели Йожеф；Хамори Тамаш；Балог Тибор；Ила Лайош；Гольдшмидт Каталин；Шинегер Элеонора；Моравчик Имре
    申请人:Эдьт Дьедьсерведьесети Дьяр (Инопредприятие)；
    IPC主号:
    专利说明:

    31 nervous system, for example, suppressive spontaneous motor activity (SMA), analgesic, potentiating anesthesia. Compounds are identified based on elemental analysis (maximum deviation from the calculated values is + 0.3%), IR, NMR-H and / or mass spectra. The IR and NMR spectra show that during salt formation a proton is bound to the N-3 atom. Example 1. Preparation of 1- (3,4-dimethoxyphensh1) -4-methyl-5-ethyl-7, 8-dimethoxy-3, 4-dihydro 5H-2,3-benzodiazepine hydrochloride. A mixture of 100 g (0.26 mol) of 1- (3,3 dimethoxyphenyl) -4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine, 30 g (0.8 mol) of sodium borohydride and 150 ml of pyridine in a 5-liter round-bottomed flask in a 80UO C water bath are stirred for an hour. The resulting solution contains the minimum amount of sodium borohydride granules. The heating is stopped. After 20 minutes, 150 ml of water are added; strong evolution of hydrogen is observed and the internal temperature drops to. 1400 ml of water are added to the reaction mixture, then a solution of 260 ml of concentrated hydrochloric acid and 600 ml of water is added dropwise at 8-15 ° C over a period of 2 hours, washed 4 times with 50 ml of ice-cold water and leave. 111.34 g. Of the title compound are obtained. The yield is 99.4%. The crude product is slightly yellow and decomposes at 216-220 ° C. The gross form is C22HjjgN204. HC1. After recrystallization from isopropanol or anhydrous ethanol m.p. increases to 222-224 ° C. The yield from recrystallization can be increased by adding ethyl acetate, acetone or diethyl ether. The compound recrystallized from water contains 3 mol of water of crystallization; decomposition temperature 222-224C. If you use the appropriate amount of hydrochloride instead of the 5H-2,3-benzodiazepine base, then the target compound is obtained in the same way as the starting material. 064 Example 2. Preparation of 1- (3,4-dimethoxyphenyl) -4-methyl-5-ethyl-7,8-dimethoxy-3, 4-dihydro-5H-2,3-benzodiazepine. 42.1 g (0.1 mol) of the compound obtained according to example 1 are suspended in 400 ml of water or dissolved in hot water. 8 g of potassium carbonate is added to the suspension or solution in portions. The target compound is released when carbon dioxide is released; the product contains 1 mol of water of crystallization1. The product which is separated out is filtered off, washed 5 times with 15 ml of water each time to free from chlorides and air-dried. 34 g of the desired compound are obtained. I. The yield is 85%. The white crude product shrinks at 75 ° C, and coagulum containing bubbles is formed at 105115 ° C. It is advisable to carry out recrystallization from alcohol (methanol, anhydrous ethanol, isopropanol) after removing the water of crystallization. The pure title compound melts at 120-122 ° C. 5-troformula C22H28 204. The compound can also be isolated using other bases, such as sodium carbonate, sodium bicarbonate, ammonium hydroxide, triethylamine or pyridine. The yield of the product can be increased by obtaining the solution obtained in example 1 with chloroform or dichloromethane by extracting with an aqueous solution of one of the Bbmie bases or exchanging methanol, anhydrous ethanol or isopropanol and using organic bases as a medium (for example, triethylamine pyridine). Example 3. Preparation of 1- (3-chlorofensh1) -4-methyl-7,8-dimethoxy 3, 4-dihydro-5H-2,3-benzodiazepine. In a 750 ml globular flask with a capacity of 750 ml, equipped with a stirrer, a dropping funnel and a reflux condenser, 9.87 g (0.03 mol) of 1 - (3-chlorophene) -4-methyl-7,8-dimethoxy-5H-2 , 3-benzodiazepine, 25 ml of pyridine and 4.5 g (0.12 mol) of sodium borohydride. While stirring for 4 hours, the reaction mixture is heated in a water bath at 95-100 ° C. The resulting yellow solution contains a portion of
    sodium brghydride unchanged. 25 ml of water are added dropwise to the solution while cooling with water for 30 minutes. The reaction mixture is cooled with ice-cooled water. A mixture of 56 ml (0.7 mol) of concentrated hydrochloric acid and 118 ml of water is added dropwise within an hour. After adding 60 ml of the above mixture, precipitation begins, which later forms yellow lumps. The cooling is stopped, the mixture is stirred for another 30 minutes at room temperature. Most of the lumpy soft sediment dissolves. A solution of 20 g (0.5 mol) of sodium hydroxide in 60 ml of water is added dropwise to the mixture over 15 minutes. The separated crude target compound is first soft, later becoming hard. The lumps are filtered off, washed 4 times with 20 ml of water each and dried at 50-60 ° C. 9.6 g of the title compound are obtained. The output of 96.5%, so pl. 116120 0. In case the reaction mixture after alkalization is treated by extraction (e.g., chlorine form), the desired product is obtained in a similarly high yield. After recrystallization of the crude product from 30 ml of isopropanol, 8.5 g of the pure desired product are obtained. The yield is 85.5% The product is white and melts at 121-123 0. The gross formulas (N HC1) are melted at 216-218 ° С ( from isopropanol or a mixture of isopropanol with ethyl acetate) Other solvents can be used as the reaction medium instead of pyridine (for example, methanol, primary amines, acetic acid, or mixtures obtained with dichloromethane or dichloroethane). h Example 4, Preparation of 1- (3,4-dimethoxyphenyl) -4-methyl-5-7,8-dimethoxy-3, 4-dihydro-5H-2,3-benzodiazepine. A 70% benzene solution of 90 ml (0.6 mol) of NaAlH, (СОНjCH OCHj) 2 is dissolved in 90 ml of benzene. With stirring, the solution is added to a solution of 114.6 g (0.3 mol) of 1- (3,4-dimethoxyphenyl) -4-metsh-5-ethyl-7, 8-dkmethoxy-5H-2,3 -benzodiazepine in 1500 ml of benzo The internal temperature rises to 33-35 C. The reaction temperature
    the mixture r for 30 minutes rises to the boiling point of benzene (the gassing stops). The mixture is again cooled to 20 ° C. 450 ml of a 20% sodium hydroxide solution are added dropwise (in the case of using compounds containing phenolic hydroxyl groups, an aqueous solution of sodium carbonate). A light yellow two-phase mixture is obtained. The phases are separated from each other. The benzene layer is extracted 4 times with 350 ml of water, dried over anhydrous magnesium sulphate and concentrated. The residue (120 g) is recrystallized from 100 ml of methanol. 106.5 g of the expected compound are obtained, m.p. 1 18-120 C. Gross formula C jIljjN O. Yield 91.5%. After recrystallization from isopropanol, the melting point rises to 121-123 ° C. Example 5. Preparation of 1- (3,4-dimethoxyphenyl) -4methyl-5-ethyl-7, 8-diM-tox-2,4-diHYDRO-5H-2, 3-benzodiazepine hydrobromide. To a solution of 3.84 g (0.01 mol) of the compound obtained in Example 4 in 25 ml of isopropanol was added dropwise 1.1 ml of a 48% solution of hydrogen bromide (or containing 0.01 mol of hydrogen bromide saturated with gaseous hydrogen bromide isopropanol). The reaction mixture is cooled, the separated product is filtered and washed with a small amount of isopropanol. 4.15 g of the expected compound are obtained. Yield 90%. Gross formula. HBg, The product melts at 210-213 ° C (with decomposition). After recrystallization from isopropanol, the decomposition temperature rises to 214-215 s. Salt formation can also be carried out using a crude base. As the reaction medium, instead of isopropanol, it is also possible to use ethyl acetate, a mixture of isopropanol and acetone, or a mixture of isopropanol and diethyl ether. Example 6. Obtaining 1- (3,4-dimethoxyphenyl) -4-metnp-5-ztil-7, 8-dimethoxy-3, 4-dihydro-5H-2,3-benzodiazepine. To a solution of 3.82 g (0.01 mol) of 1- (3,4-dimethoxyphenyl) -4-metsh1-5-ethnp-7, 8-dimethoxy-5H-2,3-benzodiazepine in 38 ml of glacial acetic acid 3 g of sodium borohydride in 10 ml of water are added dropwise for 2 hours at 3-8 ° C, after which the reaction mixture is stirred for 5 hours at 20-25 ° C. After concentration under reduced pressure, the residue (18 g) dissolves almost completely in 30 ml of water. 40 ml of a 40% sodium hydroxide solution are added to the solution. The resulting soft precipitate product crystallizes after cooling. 3.1 g of the expected compound are obtained. The product shrinks at. Purification of the product was carried out as described in Example 2. 2.29 g of the title compound were obtained, melting at 120-122 °. Gross formula C ... EXAMPLE 7 Purification of compounds of general formula J due to their easily crystallizable salts. Having a low melting point and / or contaminated with starting materials. Compounds of general formula J, along with column chromatography, can be purified due to the formation of rhodic acid, -toluenesulfonic acid or perchloric acid, their salts. Rhodanate of the compound obtained according to example 2 (€ 2 HSCN) melts at 214-216 0 with decomposition (this salt is obtained by introducing into the interaction of a pure or cf base with ammonium rodanide and perecrist Licking from water or 90% isopropanol). p-Toluenesulfone of the compound obtained according to Example 2 (NjO-C-iHgOjS) is melted at 1 68 at {this salt is obtained in acetone as medium). Prechlorate of the compound obtained according to Example 2. (CjiH2eN204HC104) 215-217 0 with decomposition (this salt is obtained in isopropanol as a medium and recrystallized from 90% isochropanol). Of the above salts, the base can be isolated in the manner described in Example 2. Examples 8-18. Compounds are prepared as in Examples 1-7. The composition of the compounds is given in table.1. Investigate the pharmaceutical activity of new compounds. The compounds of general formula j and the known compound 1- (3,4 dimethoxyphenyl) -4-methoxy-5-ethyl-7, 8-dimethoxy-5H-2,3-benzodiazepine (tofisopam) are administered orally to mice and the potentiation of anesthesia caused by hexabarbitol sodium (50 mg / kg intravenous). The results are compared with the control (treated animals with hexabarbital sodium only). The effect of some compounds of general formula T on the general behavior of animals is observed. The results of anesthesia potentiation are presented in Table 2; results, Fighting Mice-test are presented in table 3.
    13 2-Hpriphenyl
    Ethyl
    CHjG
    Dhs
    50% ethanol as solvent, Ethanol or anhydrous ethanol as solvent.
    10; continued table. one
    Continuation of table 1
    II
    12 Table 2
    1151206
    13
    Fighting
    Connection
    Dose, mg / kg orally
    50
    11 13 17 100 100
    14
    1151206 Continuation of the table. 3
    Suppression, Z
    Relative strength
    1.24 1.00 1.00
    权利要求:
    Claims (2)
    [1]
    1. METHOD FOR PRODUCING 3,4-DIHYDR0-5H-2, 3-BENZODIAZEPINE DERIVATIVES of General Formula 1 wherein K is a phenyl group, a furyl or thienyl group substituted by one or two halides of C 2 -C 4 alkoxy radicals;
    R 2 is a hydrogen atom or a C ^ -C 7 alkyl group;
    R 2 “With l- C ^ -alkoxy- or C 4 -C 7 -cycloalkoxyradicap;
    R 3 is C 7 ~ C 4 alkoxy radical; characterized in that the 5H-2,3-benzodiazepine derivative of the general formula II wherein R 7 , R Z , R 3 and R 4 have the indicated meanings, is reduced in an inert organic solvent using an inorganic or organic complex metal hydride followed by isolation of the target product in a free state or in the form of a pharmaceutically acceptable acid addition salt.
    [2]
    2. The method according to π. 1, n and a with the fact that in the builder apply
    SU 151206 distinguished sodium dihydro-bis .- (2-methoxy-ethoxy) aluminate as a quality.
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    引用文献:
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    HU81620A|HU186760B|1981-03-12|1981-03-12|Process for preparing 3,4-dihydro-5h-2,3-aenzodiazepine derivatives|
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