- Continuous synthesis method of succinate (by machine translation)
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The invention discloses a method for continuously synthesizing succinic acid, which is designed according to 3D printing technology, and sequentially combines the chlorination, hydrolysis, condensation, salt forming and refining steps of 4 -acetylamino -2, 3 -dihydrobenzofuran -7 - methyl formate into each reaction chamber to realize the continuous synthesis of drugs. To the method, tedious manual operation is not needed, chemical synthesis is carried out rapidly, the yield of a synthetic route is improved in a flowing chemical manner, and the safety problem caused by manual operation is avoided. The method provided by the invention can greatly reduce the cost generated in the aspects of drug storage, transportation and the like, thereby improving the medicine supply efficiency and stability, and bringing great economic and social benefits for the development of the pharmaceutical industry. (by machine translation)
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Paragraph 0033-0035; 0039-0041; 0045-0047; 0051-0053; 0057
(2020/09/16)
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- PROCESSES FOR THE PREPARATION OF HIGHLY PURE PRUCALOPRIDE SUCCINATE AND ITS INTERMEDIATES
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Provided herein are purification processes for the preparation of highly pure prucalopride succinate salt. Provided also herein are improved, commercially viable and industrially advantageous processes for the preparation of Prucalopride and its intermediate compounds, for example, methyl 4-acetylamino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylate and alkyl 4-[[(4-amino-5-chloro-2,3-dihydro-7-benzofuranyl)carbonyl]-amino]-1-piperidinecarboxylate.
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Page/Page column 25
(2017/09/05)
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- Synthetic method for prucalopride succinate intermediate 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid
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The invention belongs to the technical field of medicines, and relates to a synthetic method for a prucalopride succinate intermediate 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid. The final product 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid is obtained by using p-aminosalicylic acid as a starting raw material, successively performing esterification, acylation, and twice halogenation to obtain 4-acetylamino-3-bromo-5-chloro-2-hydroxybenzoic acid methyl ester, then performing substitution reaction on 1,2-dibromoethane and the 4-acetylamino-3-bromo-5-chloro-2-hydroxybenzoic acid methyl ester to obtain 4-acetylamino-3-bromo-2-(2-bromoethoxy)-5-chlorobenzoic acid methyl ester, and successively performing cyclization and hydrolyzation. According to the invention, the raw materials are easy to get, the operation is simple and mild, the production period is short, the purity is high, the safety is good, the costs are low, and the synthetic method is suitable for industrialized production.
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- Method for preparing prucalopride intermediate
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The invention belongs to the field of medicine synthesis, and particularly relates to a method for preparing a prucalopride intermediate. The method comprises the following steps: performing acylation and demethylation reactions on 2-methoxy-4-acetylamino-5-chloro methyl benzoate (I) serving as an initial raw material at 0-20 DEG C under the action of a proper amount of an acylating agent and lewis acid to obtain an intermediate (II); adding an alkaline reagent into the intermediate (II), and performing cyclization reaction at 0-20 DEG C in a polar solvent to obtain an intermediate (III); adding hydrazine hydrate and absolute ethyl alcohol to the intermediate (III), and performing reduction reaction at 70-80 DEG C to obtain an intermediate (IV); performing hydrolysis reaction on the intermediate (IV) at 90-100 DEG C under the action of a sodium hydroxide solution to obtain sodium salt of an intermediate (V), and acidizing with hydrochloric acid to obtain the intermediate (IV). The synthesizing route has mild reaction condition, low production cost and high yield, and is suitable for industrial production.
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Paragraph 0024; 0029
(2017/02/09)
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- Synthesis and structure-activity relationship of 3-substituted benzamide, benzo[b]furan-7-carboxamide, 2,3-dihydrobenzo[b]furan-7- carboxamide, and indole-5-carboxamide derivatives as selective serotonin 5- HT4 receptor agonists
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The title compounds (6-9) were prepared and evaluated for serotonin 5- HT4 agonistic activity in in vitro tests. Introducing a propyl or allyl group at the 3-position of benzamide caused only a slight enhancement of agonistic activity. Construction of the benzo[b']furan skeleton and 2,3- dihydrobenzo[b]furan skeleton caused a significant enhancement of the activity. 4-Amino-N-[2-(1-azabicyclo[3.3.0]octan-5-yl)ethyl]-5-chloro-2- methylbenzo[b]furan-7-carboxamide (7b) hemifumarate was as potent as cisapride. 4-Amino-N-[2-(1-azabicyclo[3.3.0]octan-5-yl)ethyl]-5-chloro-2,3- dihydro-2-methylbenzo[b]furan-7-carboxamide (8a) hemifumarate, 4-amino-N-[2- (1-azabicyclo [3.3.0]octan-5-yl)ethyl]5-chloro-2,3-dihydro-2- ethylbenzo[b]furan-7-carboxamide (8c) hemifumarate, and 4-amino-N-]2-(1- azabicyclo[3.3.0]octan-5-yl]-5-chloro-2,3-dihydro-2,3-dimethylhenzo[b]furan- 7-carboxamide (8d) hemifumarate were more potent than cisapride. Furthermore, 8a hemifumarate was free from dopamine D1, D2, serotonin 5-HT1, 5-HT2 and muscarine M1, M2 receptor binding activity in the in vitro tests. On the other hand, construction of the indole skeleton caused a remarkable decrease in activity.
- Kakigami, Takuji,Usui, Toshinao,Tsukamoto, Katsura,Kataoka, Tadashi
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