CN102432626B - Synthesis method of 4,5,6,7-tetrahydrothiophene[3,2-c] pyridine hydrochloride - Google Patents
Synthesis method of 4,5,6,7-tetrahydrothiophene[3,2-c] pyridine hydrochloride Download PDFInfo
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Abstract
The invention discloses a synthesis method of 4,5,6,7-tetrahydrothiophene[3,2-c] pyridine hydrochloride. The synthesis method is characterized by comprising the following steps of: adding water, formaldehyde and 2- thiophene ethylamine into a reaction bulb, raising the temperature to be between 50 DEG C and 55 DEG C, preserving heat for 20 to 30 hours, extracting a reaction liquid by using dichloroethane after reaction, mixing an organic layer, and washing by using a saturated salt solution; subjecting the organic layer to pressure reduction and drying by distillation to obtain imine, throwing the imine to the reaction bulb, adding ethanol hydrogen chloride, adding the water, raising the temperature to be between 65 DEG C and 75 DEG C, preserving heat, adding activated carbon, preserving heat and filtering; and cooling filtrate to be between 0 DEG C and 5 DEG C, preserving heat for 1 to 2 hours, filtering, drying a filter cake, and thus obtaining a finished product. In the synthesis method, the ethanol hydrogen chloride is directly adopted and subjected to cyclization to form salt and is recrystallized, the reaction step is few, the reaction condition is moderate, the process is simple, and the synthesis method is favorable for realizing industrialized production; raw materials are cheap and readily available, and the production cost is greatly reduced; and hydrogen chloride gas is not required to be used, no waste acid is generated, and pollution is low.
Description
Technical field
The present invention relates to a kind of clopidogrel intermediate 4,5,6, the synthetic method of 7-tetramethylene sulfide [3,2-c] pyridine hydrochloride.
Background technology
Clopidogrel is a kind of new and effective safe antiplatelet drug condensation.Clinical trials show in a large number, and it has good market outlook.
Clopidogrel intermediate 4 in prior art, 5, the synthetic method of 6,7-tetramethylene sulfide [3,2-c] pyridine hydrochloride, bibliographical information mainly contain following several method: one, taking 2 thiophene ethyl amine as raw material, through formaldehyde condensation, more logical hydrogen chloride gas one-tenth ring salify, this method step is few, but it is too many to prepare in hydrogenchloride spent acid, and environmental pollution is large; Two, taking thiophene as raw material, by directly synthetic 2 thiophene ethyl amine of 2 bromo ethamine, then obtain product with formaldehyde and hydrogenchloride, but this method yield is low, and has 25%, be not suitable for industrial production.
Summary of the invention
Technical problem to be solved by this invention is for the deficiencies in the prior art, provide that a kind of method is more reasonable, reactions steps is few, reaction conditions is gentle, technique is simple, be conducive to realize 4,5,6 of suitability for industrialized production, the synthetic method of 7-tetramethylene sulfide [3,2-c] pyridine hydrochloride.
Technical problem to be solved by this invention is to realize by following technical scheme.The present invention is a kind of synthetic method of 4,5,6,7-tetramethylene sulfide [3,2-c] pyridine hydrochloride, is characterized in, its step is as follows:
(1) preparation of imines: in reaction flask, add water, formaldehyde, 2 thiophene ethyl amine, is warming up to 50-55 DEG C, insulation 20-30h, after reaction finishes, reaction solution extracts with ethylene dichloride, merges organic layer, uses saturated common salt water washing; Organic layer evaporated under reduced pressure obtains imines;
The mass ratio of described water, formaldehyde and 2 thiophene ethyl amine is 200:50-60:120-130;
(2) imines is dropped in reaction flask, adding mass concentration is the ethanolic hydrogen chloride of 25-30 %, then adds water, is warming up to 65-75 DEG C, and insulation 4-8h, adds gac, and insulation 0.5-1h, filters; Filtrate is cooled to 0-5 DEG C, and insulation 1-2h, filters, and filter cake is dried and obtained 4,5,6,7-tetramethylene sulfide [3,2-c] pyridine hydrochloride;
The mass ratio of described imines, ethanolic hydrogen chloride, water and gac is 130-150:480-520:45-55:2-4.
In the step (1) of synthetic method of the present invention, the mass ratio of described water, formaldehyde and 2 thiophene ethyl amine is preferably 200:52:127.
In the step (2) of synthetic method of the present invention, the mass ratio of described imines, ethanolic hydrogen chloride, water and gac is preferably 139:500:50:3.
The synthetic route of the inventive method is as follows:
Compared with prior art, synthetic method of the present invention has the following advantages: it directly adopts ethanolic hydrogen chloride to become ring salify, recrystallization, and reactions steps is few, reaction conditions gentleness, technique is simple, is conducive to realize suitability for industrialized production; Raw material is cheap and easy to get, greatly reduces production cost; Without use hydrogen chloride gas, do not have spent acid produce, pollute little, meet country advocate environmental requirement.
Embodiment
Below further describe concrete technical scheme of the present invention, so that those skilled in the art understands the present invention further, and do not form the restriction to its right.
Embodiment 1, a kind of synthetic method of 4,5,6,7-tetramethylene sulfide [3,2-c] pyridine hydrochloride, its step is as follows:
(1) preparation of imines: in reaction flask, add water, formaldehyde, 2 thiophene ethyl amine, is warming up to 50 DEG C, insulation 20h, after reaction finishes, reaction solution extracts with ethylene dichloride, merges organic layer, uses saturated common salt water washing; Organic layer evaporated under reduced pressure obtains imines;
The mass ratio of described water, formaldehyde and 2 thiophene ethyl amine is 200:50:120;
(2) imines is dropped in reaction flask, adding mass concentration is the ethanolic hydrogen chloride of 25 %, then adds water, is warming up to 65 DEG C, and insulation 4h, adds gac, and insulation 0.5h, filters; Filtrate is cooled to 0 DEG C, and insulation 1h, filters, and filter cake is dried and obtained 4,5,6,7-tetramethylene sulfide [3,2-c] pyridine hydrochloride;
The mass ratio of described imines, ethanolic hydrogen chloride, water and gac is 130:480:45:2.
Embodiment 2, a kind of synthetic method of 4,5,6,7-tetramethylene sulfide [3,2-c] pyridine hydrochloride, its step is as follows:
(1) preparation of imines: in reaction flask, add water, formaldehyde, 2 thiophene ethyl amine, is warming up to 55 DEG C, insulation 30h, after reaction finishes, reaction solution extracts with ethylene dichloride, merges organic layer, uses saturated common salt water washing; Organic layer evaporated under reduced pressure obtains imines;
The mass ratio of described water, formaldehyde and 2 thiophene ethyl amine is 200:60:130;
(2) imines is dropped in reaction flask, adding mass concentration is the ethanolic hydrogen chloride of 30 %, then adds water, is warming up to 75 DEG C, and insulation 8h, adds gac, and insulation 1h, filters; Filtrate is cooled to 5 DEG C, and insulation 2h, filters, and filter cake is dried and obtained 4,5,6,7-tetramethylene sulfide [3,2-c] pyridine hydrochloride;
The mass ratio of described imines, ethanolic hydrogen chloride, water and gac is 150:520:55:4.
Embodiment 3, a kind of synthetic method experiment of 4,5,6,7-tetramethylene sulfide [3,2-c] pyridine hydrochloride, step is as follows:
(1) preparation of imines: in reaction flask, add 200g water, 52g formaldehyde, 127g2-thiophene ethamine, is warming up to 52 DEG C, insulation 25h, after reaction finishes, reaction solution extracts with ethylene dichloride, merges organic layer, uses saturated common salt water washing.Organic layer evaporated under reduced pressure obtains imines 139g, yield 100%;
(2) 139g imines is dropped in reaction flask, add 500g ethanolic hydrogen chloride (27%), then add 50g water, be warming up to 70 DEG C, insulation 5h, adds 3g gac, insulation 0.5h, filters, and filtrate is cooled to 0-5 DEG C, insulation 1h, filters, and filter cake is dried and obtained 4,5,6,7-tetramethylene sulfide [3,2-c] pyridine hydrochloride 165.5g, yield 94.3%.
Claims (1)
1. one kind 4,5,6, the synthetic method of 7-tetramethylene sulfide [3,2-c] pyridine hydrochloride, is characterized in that, its step is as follows:
(1) preparation of imines: in reaction flask, add 200g water, 52g formaldehyde, 127g2-thiophene ethamine, is warming up to 52 DEG C, insulation 25h, after reaction finishes, reaction solution extracts with ethylene dichloride, merges organic layer, uses saturated common salt water washing; Organic layer evaporated under reduced pressure obtains imines 139g;
(2) 139g imines is dropped in reaction flask, add the ethanolic hydrogen chloride of 500g27%, then add 50g water, be warming up to 70 DEG C, insulation 5h, adds 3g gac, insulation 0.5h, filters, and filtrate is cooled to 0-5 DEG C, insulation 1h, filters, and filter cake is dried and obtained 4,5,6,7-tetramethylene sulfide [3,2-c] pyridine hydrochloride 165.5g.
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| CN104557970B (en) * | 2015-01-19 | 2016-09-21 | 临海市利民化工有限公司 | A kind of preparation method of ticlopidine hydrochloride |
| CN112759575B (en) * | 2019-11-06 | 2022-06-07 | 武汉武药制药有限公司 | Preparation method of clopidogrel hydrogen sulfate and intermediate N- (2-thienylethyl) methylamine thereof |
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| US4906756A (en) * | 1988-05-10 | 1990-03-06 | Syntex (U.S.A.) Inc. | 2-(2-nitrovinyl)thiophene reduction and synthesis of thieno[3,2-c]pyridine derivatives |
| EP0573975A1 (en) * | 1992-06-08 | 1993-12-15 | Fuji Photo Film Co., Ltd. | 2-alkoxycarbonyl-5-o-chlorobenzyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine derivative and process for producing the same |
| US6858734B2 (en) * | 2003-04-23 | 2005-02-22 | Rhodia Pharma Solutions Inc. | Preparation of (S)-Clopidogrel and related compounds |
| CN101585842B (en) * | 2009-07-13 | 2011-07-20 | 北京赛科药业有限责任公司 | Research and control method of impurity B control method in clopidogrel |
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