• 专利附录
  • 专利说明
  • 权利要求
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    • 专利摘要:
    METHOD OF OBTAINING N-
    公开号:SU1148559A3
    申请号:SU813318201
    申请日:1981-08-07
    公开日:1985-03-30
    发明作者:Перро Жак；Томине Мишель
    申请人:Сосьете Дъэтюд Сьянтифик Э Эндюстриель Де Лъиль-Де-Франс (Фирма)；
    IPC主号:
    专利说明:

    4:30
    cl
    SP
    The invention relates to the production of new protrusions of one pyrrolidine series, which can be used in medicine, in particular for the treatment of migraine. . The amide bond formation reaction is known for the condensation of the corresponding amine and CiJ acid anhydrides. The aim of the invention is to develop a method of obtaining new compounds with valuable pharmacological properties. The goal is achieved by the fact that with the implementation of the method of obtaining N -. (1-all l-2-gplplolidinsh methyl) -2-metoc-4-amido-5 -methylsulfonylbenzamide 2-methoxy-A-amino-5-methylsulfamylbenzic acid is reacted with ethyl chloroformate at 10–20 C in the presence of triethylamine in an organic solvent followed by treatment of the resulting compound with N-allyl-2-aminomethyl-pyrrolide-diridine. The original 2-methoxy-4-amino-5-methylsulfamylbenzoic. the acid is obtained by reacting 2-methoxy-4-acetaminobenzoic acid methyl ester with sulfuric acid, in the presence of acetic acid and acetic anhydride, the resulting 2-methoxy-4-acetamino-5-sulfo benzoic acid methyl ester / is reacted with methanol at room temperature, The methyl 2-methoxy-4-amino-5-sulfobenzoic acid methyl ester is treated with phosphorus pentachloride in the presence of a solvent, and then with methylamine, followed by hydrolysis of the resulting compound with caustic sodium. PRI me R 1. one). Metsch1-2-methoxy-4-acetamino-5-sulf. Benzoate. . 45 liters of acetic acid are loaded into a reactor with a capacity of 100 liters, shuffle and 22.5 kg of methyl 2-methoxy-4-adhetamine benzoate are added, then another 30 liters of acetic anhydride is charged. Over 15 minutes, 5.730 liters of sulfuric acid (d 1.84) are added. The temperature rises spontaneously to. The ester is dissolved. Then TehmepaTypy is gradually increased to 70C. Wednesday 9 immediately cooled to and. dehydrated by squeezing centrifuge. The product is washed twice (each time with 8 liters of acetone), then dried in a dry cake at. Properties of the obtained product: weight 24.5 kg, yield 81.5%, t-, front. (decomp.), sulfur content of 10.56% (theoretical content of 10.57), white crystals. 2). Methyl 2-methoxy-4-amino-5-sulfobenzoate. 75 liters of methanol are loaded into a reactor with a capacity of 100 liters, mixed, and 24.5 kg of finely divided methyl 2-labels Ci-4-acet finp-5-sulfobenzoate is added. The sulfonic acid is dissolved. Shortly thereafter, the deacetylized: derivative is crystallized. The reaction mixture is left at room temperature for 24 hours with stirring to complete the precipitation. The product is dehydrated in a centrifuge, washed twice (each time with 6 l of methyl alcohol) and dried in a ventilated dryer with .. Properties of the obtained product: weight 20.5 kg, yield 98%, t. Sh1. / decomp.), the sulfur content is 12.10% (theoretical content is .12.26%). 3). Methyl 2-methoxy-4-amino-5-methoxy sulfamyl benzoate. a) 33.5 l of acetonitrile are loaded into a reactor with a capacity of 100 l, stirred, 16.8 kg of methyl 2-methoxy-4-amino-5-sulfobenzoate are added, then 17.5 are added in several doses over approximately t5 min. kg of phosphorus pentachloride. The reaction medium is gradually heated to reflux temperature (approximately 80-85 ° C); The reaction starts at a temperature of approximately, with a large amount of gas evolving. After 2 h, the temperature reaches 80s, at this level it is maintained for 1.5 hours. Then the solution is cooled to. c) 95 l of an aqueous solution containing 35% methylamine is loaded into a reactor with a capacity of 200 l, mixed. and cooled to. Then slowly, in several stages, the previous solution (sulfochloride) is poured in, the temperature is maintained at -10-15 ° C, the solution is added for 4 hours, after which the temperature rises
    shay up to. The solution is diluted with 300 l of labor and filtered through 2 kg of carbon black from charcoal. The filtrate is acidified by stirring. 70 liters of hydrochloric acid (d 1.18). The product gradually crystallizes. It is left for 120 hours, then dehydrated, washed with water and dried in a drying oven at 50 ° C. Yield 15 kg.
    4), 2-Methoxy-4-amino-5-methylsulfamylbenzoic acid, 22 liters of water and 22 liters of sodium hydroxide solution are loaded into a 100-liter reactor and mixed with 15 kg of the previous product. The reaction medium heats up to complete reflux for 20 hours. During the first few hours, the large amount of methylamine is observed. The reaction medium is cooled before and poured into the sump. Add 12 liters of water. The solution is stirred and acidified with 17 liters of hydrochloric acid (d 4.18) to pH 1, while cooling the solution. The acid crystallizes, it is dehydrated at, washed with water and dried in a drying oven at. The purified acid has the following properties: weight 12,100 kg, so pl. , A1 theoretical 215.4, obtained 212J sulfur content: theoretical 12.31%, obtained 12.23%.
    40 liters of water and 2,600 kg of sodium bicarbonate are loaded into a sump, mixed, and 12,100 kg of 2-methoxy-4-amino-5-methylsulfonyl benzoic acid are added in several steps. The dissolution of the acid is accompanied by a strong peyou formation. A small amount of insoluble gelatinous substance remains, which is separated by filtration under vacuum. The filtrate is acidified with 5.6 liters of hydrochloric acid. I.
    The product is crystallized, dehydrated, washed with water and dried in a drying oven at. Purified acid has the following properties: weight 11.9 kg, so pl. 202c, A1 theoretical 215.4, obtained 215, sulfur content: theoretical 12, -31%, obtained 12.37%.
    five). N- (1-allyl-2-pyrrolidinylmethyl) -2-metxy-4-amino-5-methylsulfamylbenzamide.
    85594
    In a reactor with a capacity of 100 liters, 10 liters of permuted water are mixed, stirred and 5300 cm of triethylamine and 10 kg of 2-methoxy-45-amino-5-methylsulfonyl benzoic are added. acid. The suspension is heated to approximately 45 ° C to dissolve all the substances, then cooled with brine before and introduced.
    10 25 liters of acetone.
    Slowly (within 15 minutes), 3,670 cm of ethyl chloroformate are poured in, ensuring that the temperature does not exceed, and stirred for
    15 30 min at this temperature. Then, slowly (within 30 minutes), 6.4 Kf K-allyl-2-aminomethylpyrrolidine is poured in (the temperature should not exceed 15 ° С).
    2D The temperature is raised to and the reaction mixture is stirred at this temperature. Acetone is distilled off at ordinary pressure, then under vacuum, the trace, so that the temperature
    5 in the mass did not exceed 60 ° C.
    55 liters of water are added, the reaction medium is acidified to pH 3 (47 liters of chemically pure hydrochloric acid) and 1 kg of activated gas is added.
    Q soot 3S. The solution is filtered. The filtrate is made alkaline with 5 L of ammuck with vigorous stirring. Add 10 kg of ice and continue stirring for 1 hour.
    5 First, the benzamide, which crystallizes in liquid form, is left overnight. Then it is dehydrated at 20 ° C, washed through with water and dried in a drying oven at 60 ° C. The resulting product has the following properties: weight 9 kg, yield 61%, so pl. 166-167 6.
    In a reactor with a capacity of 50 liters, 9 kg of nonieHHoro benzamide in 18 liters of absolute ethanol is dissolved at boiling. The solution is filtered with 1 kg of carbon black from charcoal in a pressure filter. The filtrate 0 is washed with 2 l of boiling alcohol, then cooled to. Benzamide crystallizes. It is dehydrated, washed with cold alcohol and dried in a drying oven at. A product is obtained which has the following properties: white crystals, weight 8 kg, yield after re-crystallization 89%.
    five
    Since the chromatographic study shows broad spots, two more crystallizations from ethyl alcohol are carried out in order to obtain a purified product with the following properties: white crystals, weight 6 kg, yield after repeated crystallization 67%.
    By the described method receive benzamid with a total yield of 41%. Analysis of the benzamide obtained gives the following results: t. Pl. 168.5169 ° С, titer 99.82, .H, jO 0.1%, C,%: theoretical 53.38,. Obtained 53.13, .N%: theoretical 6.85, obtained 6.88, N %: theoretical 14.65, obtained 14.65, S,%: theoretical 8.58, obtained 8.54.
    Chromatographic study shows the presence of a secondary spot (0.2-0.5%).
    In a pharmacological study of benzamide, the acute toxicity of the compound is first determined. The lethal dose (LDjj) of benzamide mg / kg) with various routes of administration for males Nfijimeft was:
    IV 44
    Intraperitoneally184
    Subcutaneously. 204 Orally administered 3600
    The effect of benzamide on the central nervous system, in particular the neuroleptic effect, was investigated. Tests have shown that the compound exhibits a very weak depressive effect, namely, it slightly reduces the spontaneous mobility of the infant, even at high doses (Table 1), and does not increase the duration of the hypnosis caused by barbiturates (Table 2).
    Unlike conventional neuroleptics, the compound does not cause catalepsy in rats even at a dose of 200 mg / kg subcutaneously and does not counteract stereotypical movements of rats, for example, apomorphine or amphetaine.
    Benzamide does not have an anticonvulsant action if convulsions are caused by electric shock, a chemical agent (pentetrazole, nicotine) or a sound stimulus.
    148559.
    The analgesic effect of benzamide at a single dose is mild compared with the pain caused by a mechanical, chemical 5 or thermal stimulus in a mouse.
    The effect of benzamide on the cardiovascular system was studied on a dog anesthetized with chlorazol. The following results were obtained. ♦ The compound causes a decrease in blood pressure in proportion to the dose taken.
    Pressure change,%
    21 32 36 48 54 59 58
    The compound does not cause a change in the hypotonic response to acetylcholine or to the excitation of the vagus nerve. Benzamide does not have an anti-chlorinergic effect, which is confirmed by experience in an isolated ileum with a yardstick test.
    The compound lowers the hypertonic reaction caused by blocking the carotid arteries with catecholamines (adrenaline and noradrenaline) and small doses of nicotine (Table 3), lowers the hypertonic response to serotonin in a dog, anesthetized and then treated with ganglion blocking means, chlorozonone, and stabilizing the dog, anesthetized and then treated with ganglion-blocking agent, chloro-monone, and stabilizing the dog, anesthetized and then treated with a ganglion blocking means, stabilizes the serotonin in anesthetized reaction with serotonin, anesthetized and then treated with a ganglion blocking agent, chloro-monone, and stabilizing with a means of chlorotonamide to stabilize the dog.
    As can be seen from the table. 4, benzamid counteracts hypertonic action of serotonin. The results of studies of other interactions with serotonin have shown that benzamide inhibits the contraction of an isolated rat uterus, serotonin ryzovannaya (dose of about 5 to 0.2 mg / l), shows a protective effect against the effect of serotonin, causing stomach sound in rats (effective dose of cocTaBiiH "i- trench
    7
    3 MG / CG when administered subcutaneously) reduces the swelling of the paw in a rat that received a 0.01 mg intraperitoneal injection of serotonin (an effective dose of 4-6 mg / kg is administered intraperitoneally and 200 mg / kg when administered orally).
    In addition, the effect of benzamide with histamine on the arterial pressure of the anesthetized dog and the isolated ileum of the guinea pig was investigated. Established the absence of antihistamine properties.
    48559 "
    Thus, the resulting benzamid has valuable pharmacological properties. In particular, it can be used to treat 5 migraines, in which there are
    vasomotor disorders caused by adrenergic and serotonergic transmissions (the latter intermediate transmission may also
    10 to act through other mechanisms). The correctness of this hypothesis is shown by clinical studies.
    Table 1
    Introduction Suppression
    Winter and Flataker Method
    26% with a dose of 80 mg / kg
    20% at a dose of 300 mg / kg
    Dose,
    Mg / kg
    Intraperitoneally
    Note.
    Activography method
    22Z at a dose of 80 mg / kg
    25% with a dose of 300 mg / kg
    table 2
    The duration of hypnosis in treated and control mice
    1.6
    Nentobarbital 60 mg / kg Intraperitoneally is used as a barbiturate. effect observed at maximum dose
    1148559
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    权利要求:
    Claims (2)
    [1]
    METHOD FOR PRODUCING S- (1-AL- £ LIL-2-pyrrolidinylmethyl) -2-METHOXY-4-AMIN0-5-methylsulfamylbenzamide, characterized in that.
    [2]
    2-Methoxy-4-amino-5-methylsulfamylbenzoic acid is reacted with ethyl chloroformate at 10-20 ° C in the presence of triethylamine in an organic solvent, followed by treatment of the resulting compound with Y-allyl-2-aminomethyl-pyrrolidine.
    eo yu
    1 1148559 2
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    引用文献:
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    FR1525M|1961-07-25|1962-11-16|Ile De France|New antiemetic drugs.|
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    US3766178A|1967-04-03|1973-10-16|Ile De France|Substituted 2-arylalkyloxy benzamides|
    GB1364231A|1968-12-23|1974-08-21|Robins Co Inc A H|N-/1-substituted-3-pyrrolidinyl/benzamides and thiobenzamides|
    US3862139A|1972-06-23|1975-01-21|Delmar Chem|Heterocyclic benzamide compounds|
    FR2244760B1|1973-09-25|1980-06-27|Ile De France|
    CH605793A5|1974-03-05|1978-10-13|Ile De France|
    FR2294698B1|1974-12-18|1979-03-16|Synthelabo|
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    US4186135A|1976-08-04|1980-01-29|Societe D'etudes Scientifiques Et Industrielles De L'ile-De-France|Substituted 2,3-alkylene bis benzamides and derivatives and method of preparation|
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    US4210660A|1978-12-20|1980-07-01|Yamanouchi Pharmaceutical Co., Ltd.|Benzamide derivatives|
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