- Improved method for preparing dabigatran etexilate intermediate
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The invention belongs to the field of medical intermediate synthetic methods, and relates to an improved method for preparing a dabigatran etexilate intermediate, in particular, a synthetic method of3-[[[2-[[(4-amidinophenyl)amino]methyl]-1H-benzimidazole-5-yl]carbonyl](pyridine-2-yl)amino] ethyl propionate p-toluene sulfonate 1. According to the method, use of a large amount of solvents and hydrogen chloride is avoided, the reaction process is stable, the dosage of reactants is easy to control, on one hand, impurities generated by side reactions are reduced, and subsequent synthesized dabigatran etexilate is easier to purify; on the other hand, wastes caused by release of saturated hydrogen chloride gas are greatly reduced, the environmental pollution is reduced, meanwhile the steps aresimple and easy to control, and the method is suitable for large-scale production.
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- Preparation method of non-peptide type thrombin inhibitor dabigatran
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The invention discloses a preparation method of a non-peptide type thrombin inhibitor dabigatran and belongs to the technical field of medicine chemistry. The technical scheme is characterized by providing the preparation method of the non-peptide type thrombin inhibitor dabigatran; and a synthesis route is as follows: a formula is shown in the description. The preparation method has the advantages of moderate reaction conditions, relatively high yield and low cost and is suitable for industrial production.
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- Preparation process of Pradaxa
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The invention discloses a preparation process of Pradaxa. After obtaining a compound 3 with the structural formula as shown in the description, an alkali liquor is added to separate out the compound 3; micro-molecule alcohol is used for refining; under the action of a reaction solvent and an organic alkali, the compound 3 and hexyl chloroformate conduct a condensation reaction to obtain a compound2 with the structural formula as shown in the description; an acid liquor is used for washing, and vacuum concentration is performed till the product is dry; an organic solvent is used for refining;and the compound 2 and methanesulfonic acid are salified to obtain Pradaxa. Through the continuous operation that solid-liquid separation is performed after the alkali liquor is added to separate outthe compound 3, the problems that lots of acid is evaporated to corrode equipment due to vacuum concentration and many degradation impurities are produced by heating are solved. The pickling process is adopted to control specific impurities in a reaction liquid of the compound 2. At last, an appropriate methanesulfonic acid charge ratio and an appropriate charging temperature are adopted to guarantee correct product crystal forms.
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Paragraph 0072; 0073
(2018/03/06)
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- Identification, synthesis, and strategy for the reduction of potential impurities observed in dabigatran etexilate mesylate processes
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Synthetic impurities that are present in dabigatran etexilate mesylate were studied, and possible pathways by which these impurities are formed during the manufacturing process were examined. The impurities were monitored by high-performance liquid chromatography, and their structures were determined by mass spectrometry and 1H and 13C NMR. Potential causes for the formation of these impurities are discussed, and strategies to minimize their formation are also described.
- Zheng, Yong-Yong,Shen, Cheng-Wu,Zhu, Mei-Yu,Zhou, Yi-Meng,Li, Jian-Qi
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p. 744 - 750
(2014/07/08)
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- AN IMPROVED PROCESS FOR PREPARATION OF DABIGATRAN ETEXILATE AND PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF
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The present invention provides an improved process for preparation of dabigatran etexilate and pharmaceutically acceptable acid addition salts thereof, particularly mesylate salt. The present invention also provides novel salts of intermediates of Dabigatran etexilate and their polymorphs.
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- IMPROVED PROCESS FOR THE PREPARATION OF 4-(BENZIMIDAZOLYLMETHYLAMINO)-BENZAMIDES AND THE SALTS THEREOF
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The invention relates to a process for preparing an optionally substituted 4-benzimidazol- 2-ylmethylamino)-benzamidine, characterised in that (a) an optionally correspondingly substituted diaminobenzene is condensed with 2 [4- (1,2,4-oxadiazol-5-on-3-yl)-phenylamino]-acetic acid, (b) i) the product thus obtained is hydrogenated and ii) optionally the amidino group is carbonylated, without isolating the intermediate product of the hydrogenation beforehand; as well as a process for preparing a salt of an optionally substituted 4(benzimidazol-2-ylmethylamino)-benzamidine, wherein (a) an optionally correspondingly substituted diaminobenzene is condensed with 2-[4-(1,2,4-oxadiazol-5-on-3-yl)-phenylamino]-acetic acid, (b) the product thus obtained is hydrogenated, and (c) i) optionally the amidino group is carbonylated and ii) without prior isolation of the intermediate product of the carbonylation the desired salt is isolated.
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Page/Page column 25
(2010/11/27)
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- Process for the preparation of 4-(benzimidazolylmethylamino)-benzamidines
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Production of optionally substituted 4-(benzimidazol-2-ylmethylamino)-benzamidines (I) involves: (a) condensing an optionally substituted diaminobenzene (II) with 2-(4-(1,2,4-oxadiazol-5-on-3-yl)-phenylamino)-acetic acid (III); (b) hydrogenating the product (IV); and (c) optionally carbonylating the amidino group. The intermediates (III), 2-(4-(1,2,4-oxadiazol-5-on-3-yl)-aniline (V) and benzimidazole derivatives (IV') are new compounds. Independent claims are included for the following new intermediates: 2-(4-(1,2,4-oxadiazol-5-on-3-yl)-phenylamino)-acetic acid of formula (III), 2-(4-(1,2,4-oxadiazol-5-on-3-yl)-phenylaminomethyl)-benzimidazoles of formula (IV') and 2-(4-(1,2,4-oxadiazol-5-on-3-yl)-aniline of formula (V). R 1> : alkyl or cycloalkyl; R 2> : alkyl (optionally substituted (os) by cycloalkyl-(1-3C) alkyl, where the 1-3C alkyl is os by COOH or a group convertible in vivo to COOH); or NR 21>R 22>; R 21> : alkyl (os by COOH, alkoxycarbonyl, COOCH 2Ph, CONHSO 2T, CONHSO 2Ph, 'trifluorosulfonylamino' (sic), trifluorosulfonylaminocarbonyl' (sic), or 1H-tetrazolyl); 2-4C alkyl substituted (but not on the alpha -C adjacent to the N) by OH, -O-T-Ph, -NH-T-COOH, -NH-T-COOT, -N(T)-T-COOH or -N(T)-T-COOT; or piperidinyl (os by T); R 22> : H; alkyl; cycloalkyl (os by T); 3-6C alkenyl or 3-6C alkynyl (both with the unsaturated part not bonded directly to N); phenyl (os by F, Cl, Br, T or OT); or benzyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, thienyl or imidazolyl (all os by T); or NR 21>R 22> : 5-7 membered cycloalkyleneimino (os by COOH or (1-4C) alkoxycarbonyl and optionally fused with a benzene ring); T : 1-3C alkyl; alkyl groups have 1-6C and cycloalkyl groups 3-7C unless specified otherwise. [Image] ACTIVITY : Anticoagulant. MECHANISM OF ACTION : Thrombin inhibitor.
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Page/Page column 10
(2010/02/15)
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