CN101781311B - Novel preparation method of platelet aggregation inhibition compound - Google Patents
Novel preparation method of platelet aggregation inhibition compound Download PDFInfo
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- CN101781311B CN101781311B CN2010101229062A CN201010122906A CN101781311B CN 101781311 B CN101781311 B CN 101781311B CN 2010101229062 A CN2010101229062 A CN 2010101229062A CN 201010122906 A CN201010122906 A CN 201010122906A CN 101781311 B CN101781311 B CN 101781311B
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- 0 *C(*)=NNC(C(c(cccc1)c1Cl)N(CC1)Cc2c1[s]cc2)=O Chemical compound *C(*)=NNC(C(c(cccc1)c1Cl)N(CC1)Cc2c1[s]cc2)=O 0.000 description 1
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Abstract
The invention belongs to the technical field of pharmaceutical chemistry, and particularly provides a novel preparation method of a compound for preparing platelet aggregation inhibitors with a general formula (I). The preparation route adopts a one-pot method, and the intermediate directly enters the next reaction without being purified or separated. The method can prepare the target compound I in one step. Compared with the synthesis techniques provided in the prior literature, the invention increases the yield, simplifies the operation steps and shortens the production cycle, thereby finally reducing the production cost and meeting the requirements for green synthesis techniques. In the compound I, R is a methyl or ethyl group.
Description
Technical field
The invention belongs to technical field of pharmaceutical chemistry, relate in particular to a kind of novel preparation method of anti-platelet aggregation compounds.
Background technology
Thrombosis can cause the heart, brain, pulmonary circulation illness such as Acute Myocardial Infarction, apoplexy, pulmonary infarction, is threatening human beings'health and life, also is common complication and the inaccessible again factor of intervention property postangioplasty in the surgical operation.Though the thromboembolism treatment of carrying out in recent years, PCI even operative treatment make acute myocardial infarction and treatment of cerebral obtain the progress that attracts people's attention; Patient's salvage success rate improves greatly; Quality of life has also had tangible improvement, but the cardiovascular and cerebrovascular disease disability rate is after all up to 30%.Therefore the drug development of prevention and treatment cardiovascular and cerebrovascular disease becomes the focus of paying close attention in recent years and studying.Cause thrombotic factor a lot, as thrombocyte stagnate in the lip-deep adhesion of vessel wall and gathering, the blood flow stasis of blood of damage, the activation of thrombin impels the formation of zymoplasm, antiplasmin activity is low inferior, can both impel thrombosis.Thrombocyte is thrombotic essential material in these factors, thus suppress hematoblastic accumulate in the prevention of thrombus disease and treat in play an important role.ADP (ADP) is the important agonist that platelet activation, buildup effect amplify, and suppressing the thrombocyte effect through the blocking-up adp receptor has become the important means that stops pathologic thrombosis (coronary heart disease, cerebro-vascular diseases, pulmonary infarction, thrombophlebitis etc.) and myocardial infarction, unstable angina pectoris, peripheral vascular disease, congestive heart failure etc.
Clopidogrel is the adp receptor suppressor factor class antiplatelet drug of a present clinical line, because it is the extremely weak oily matter of alkalescence, needs and strong acid ability salify.The chance moisture is unstable, and free alkali is separated out, and purifying has certain difficulty.And because its strongly-acid also can receive certain restriction aspect preparation.Patent ZL200510016205.X provides a kind of new adp receptor retarding agent class antiplatelet compound I, having the good bioactive while, has more superior physico-chemical property compared to clopidogrel.Because its free alkali itself is solid, the stability of its salt is also better, is easy to purifying and preparation.
Chemical structure:
Wherein R is methyl or ethyl.
The chemistry of two kinds of compounds is by name:
(S)-and α, α-[2-chloro-phenyl--2-(4,5,6, the 7-THTP is [3,2-c] pyridine-5-yl also)]-N '-[(dimethyl-) methene base] acethydrazide (when R is a methyl);
(S)-and α, α-[2-chloro-phenyl--2-(4,5,6, the 7-THTP is [3,2-c] pyridine-5-yl also)]-N '-[(diethylammonium) methene base] acethydrazide (when R is an ethyl).
The compound method of this compound of putting down in writing among the patent ZL200510016205.X is following:
In the reaction flask that stirring, condensing surface, TM are housed, add clopidogrel 38g, absolute ethyl alcohol 30mL, stir down slowly heating; Make the reaction raw materials dissolving, add 45.6g Hydrazine Hydrate 80 (80%), continue to be heated to backflow; Insulation reaction 4 hours, (the flaggy demonstration reacts completely).Solvent is to the greatest extent steamed in decompression then, steams and finishes, and in resistates, adds 50mL zero(ppm) water and 30mL methylene dichloride, fully stirs, and tells organic layer, and water layer merges organic layer with 3 * 30mL dichloromethane extraction, uses the SODIUM SULPHATE ANHYDROUS 99PCT thorough drying.Methylene dichloride is to the greatest extent steamed in decompression, gets white solid 23.4g.(HPLC：97.16)，m.p.139.0～139.3℃。
In the reaction flask that stirring, condensing surface, TM are housed, add hydrazides thing 4g, anhydrous methanol 40mL, start stirring, heating makes its dissolving.Continue to be heated to 40 ℃, drip 0.79g acetone, finish, insulation reaction 3 hours (the flaggy demonstration reacts completely).Stopped reaction, cooling has solid to generate.Filter, anhydrous methanol 3 * 2mL washing, drying gets solid product (HPLC:99.8%).M.p.169.1～170.8 ℃, Rf=0.3 [single-point, developping agent: sherwood oil (60-90 ℃): ETHYLE ACETATE=1: 1].
Summary of the invention
The present invention is directed to the deficiency of prior art, a kind of novel method for preparing compound I is provided, its purpose is to overcome the shortcoming of original compound method, and the step that simplifies the operation shortens the production cycle, finally reduces production costs.
Technical scheme provided by the invention is following:
S-(+)-2-(2-Chlorophenyl)-2-(4,5,6,7-tetrahydrothieno [3,2-c] pyrid ine-5-y1) acetic acid methyl ester (clopidogrel) can be by document EP 465358; EP342118; EP420706; US4847265; J Org Chem, 1968,33 (6): the preparation of 2565-2566 method, the IR of product,
1H NMR,
13C NMR, MS, the ultimate analysis value, optically-active is consistent with reference substance.
The hydrolysis reaction yield of clopidogrel is high, the method synthetic compound I that hydrolysate 2-(2-chloro-phenyl-)-2-(4,5,6, the 7-THTP is [3,2-c] pyridine-5-yl also) acetate (II) and Vinyl chloroformate, Hydrazine Hydrate 80 and acetone or propione " are cooked different foods in one pot ".
Wherein R is methyl or ethyl.
Concrete grammar adds acid binding agent for II is dissolved in the dioxane, and low temperature drips Vinyl chloroformate down, reacts 0.5-1 hour, and reaction finishes, and heats up, and in 20～30 ℃ of mixed solutions that add Hydrazine Hydrate 80 and acetone or propione, reaction for some time makes compound I.
Wherein acid binding agent is one or both in salt of wormwood, yellow soda ash, sodium hydrogencarbonate, saleratus, sodium hydroxide, the Pottasium Hydroxide.Coldcondition is 7～12 ℃, and the reaction times is 1-2 hour.The mol ratio of compound I I, Vinyl chloroformate, acid binding agent, Hydrazine Hydrate 80, acetone or propione is 1: (1-1.3): (1-3): (0.9-1.1): (0.9-1.1).
The present invention compared with prior art, its remarkable advantage is:
A. adopt the method for " cooking different foods in one pot " to prepare, midbody directly carries out next step reaction without purifies and separates.Simplified operation steps, shortened reaction time, reduced the consumption of solvent, thereby reduced production costs.
B. the yield of the first step is merely 61.6% in the former document, and total recovery can reach more than 77% among the present invention, when further reducing cost, has reached the requirement of green synthesis process.
Embodiment
The present invention can realize through following concrete technology:
Reference implementation example: 2-(2-chloro-phenyl-)-2-(4,5,6, the 7-THTP is [3,2-c] pyridine-5-yl also) acetate (II)
In the 250mL reaction flask, add 20g clopidogrel and 60mL methyl alcohol, start to stir and be warming up to backflow, add 15mL 30% aqueous sodium hydroxide solution after dissolving clearly in batches.After finishing, continue reaction 0.5 hour (the flaggy demonstration reacts completely).Stopped reaction, decompression steam methyl alcohol to the greatest extent, add 60mL zero(ppm) water, and ice-water bath stirs down, slowly adds Glacial acetic acid min. 99.5, and adjust pH is 4-5.Continue to stir, have a large amount of white solids to generate, filter drying.Get white solid product 18g (HPLC:99.1%), yield 94.3%.
1H?NMR(DMSO-d
6，400MHz)δ：2.775～2.871(m，4H)，3.572～3.684(q，2H)，4.714(s，1H)，6.758～6.771(d，1H)，7.246～7.258(d，1H)，7.329～7.404(m，2H)，7.472～7.495(m，1H)，7.607～7.630(m，1H)。
Embodiment 1: (S)-α, α-[2-chloro-phenyl--2-(4,5,6, the 7-THTP is [3,2-c] pyridine-5-yl also)]-N '-[(dimethyl-) methene base] acethydrazide
In the 250mL reaction flask that stirring, condensing surface, TM are housed, step reaction product 15.4g and 50mL dioxane in the adding stir and dissolve clearly.Be cooled to 7 ℃, add 2.0g sodium hydroxide, and Vinyl chloroformate 5.4g slowly is added dropwise to reaction system, dropwise, rise to 15 ℃ and continue reaction 0.5h (the flaggy demonstration reacts completely).Be warming up to 20 ℃.With 2.9g Hydrazine Hydrate 80 (80%) and 2.6g acetone mixing, slowly be added dropwise to reaction system, finish insulation reaction 1 hour (the flaggy demonstration reacts completely).Stopped reaction, cooling has solid to generate.Filter, the anhydrous methanol washing, drying gets solid product 14.2g (HPLC:99.7%), yield 78.4%.M.p.169.3-170.7 ℃, Rf=0.35 [single-point, developping agent: ETHYLE ACETATE: sherwood oil (60-90 ℃)=1: 1].
Embodiment 2: (S)-α, α-[2-chloro-phenyl--2-(4,5,6, the 7-THTP is [3,2-c] pyridine-5-yl also)]-N '-[(dimethyl-) methene base] acethydrazide
In the 250mL reaction flask that stirring, condensing surface, TM are housed, step reaction product 15.4g and 50mL dioxane in the adding stir and dissolve clearly.Be cooled to 10 ℃, add the 13.8g Anhydrous potassium carbonate, and Vinyl chloroformate 6.0g slowly is added dropwise to reaction system, dropwise, rise to 15 ℃ and continue reaction 0.5h (the flaggy demonstration reacts completely), be warming up to 23 ℃.With 2.8g Hydrazine Hydrate 80 (90%) and 2.9g acetone mixing, slowly be added dropwise to reaction system, finish insulation reaction 1.5 hours (the flaggy demonstration reacts completely).Stopped reaction, cooling has solid to generate.Filter, absolute ethanol washing, drying gets solid product 14.1g (HPLC:99.5%), yield 77.8%.M.p.169.2-170.8 ℃, Rf=0.35 [single-point, developping agent: ETHYLE ACETATE: sherwood oil (60-90 ℃)=1: 1].
Embodiment 3: (S)-α, α-[2-chloro-phenyl--2-(4,5,6, the 7-THTP is [3,2-c] pyridine-5-yl also)]-N '-[(dimethyl-) methene base] acethydrazide
In the 250mL reaction flask that stirring, condensing surface, TM are housed, step reaction product 15.4g and 60mL dioxane in the adding stir and dissolve clearly.Be cooled to 12 ℃, add the 15.0g saleratus, and Vinyl chloroformate 7.1g slowly is added dropwise to reaction system, dropwise, rise to 15 ℃ and continue reaction 1h (the flaggy demonstration reacts completely), be warming up to 26 ℃.With 3.2g Hydrazine Hydrate 80 (85%) and 3.2g acetone mixing, slowly be added dropwise to reaction system, finish insulation reaction 2 hours (the flaggy demonstration reacts completely).Stopped reaction, cooling has solid to generate.Filter, washing with acetone, drying gets solid product 14.2g (HPLC:99.6%), yield 78.4%.M.p.169.0-170.5 ℃, Rf=0.36 [single-point, developping agent: ETHYLE ACETATE: sherwood oil (60-90 ℃)=1: 1].
Embodiment 4: (S)-α, α-[2-chloro-phenyl--2-(4,5,6, the 7-THTP is [3,2-c] pyridine-5-yl also)]-N '-[(diethylammonium) methene base] acethydrazide
In the 250mL reaction flask that stirring, condensing surface, TM are housed, step reaction product 15.4g and 70mL dioxane in the adding stir and dissolve clearly.Be cooled to 10 ℃, add the 10.6g soda ash light, and Vinyl chloroformate 6.5g slowly is added dropwise to reaction system, dropwise, rise to 15 ℃ and continue reaction 1h (the flaggy demonstration reacts completely), be warming up to 30 ℃.With 3.0g Hydrazine Hydrate 80 (85%) and 4.3g3-pentanone mixing, slowly be added dropwise to reaction system, finish insulation reaction 1.5 hours (the flaggy demonstration reacts completely).Stopped reaction, cooling has solid to generate.Filter, the THF washing, drying gets solid product 15.1g (HPLC:99.5%), yield 77.4%.M.p.173.8-175.2 ℃, Rf=0.38 [single-point, developping agent: v (ETHYLE ACETATE): v (sherwood oil (60-90 ℃))=1: 1].
Claims (4)
1. the preparation method suc as formula the I compound is characterized in that technical process and reaction conditions are undertaken by following mode:
Wherein R is methyl or ethyl
The method synthetic compound I that 2-(2-chloro-phenyl-)-2-(4,5,6, the 7-THTP is [3,2-c] pyridine-5-yl also) acetate (II), Vinyl chloroformate, Hydrazine Hydrate 80 and acetone or propione " are cooked different foods in one pot ",
2. the preparation method of a compound I as claimed in claim 1; It is characterized in that: II is dissolved in the dioxane, adds acid binding agent, 7～12 ℃ drip Vinyl chloroformate; Reacted 0.5-1 hour; Heat up,, react and made compound I in 1-2 hour in 20～30 ℃ of mixed solutions that add Hydrazine Hydrate 80s and acetone or propione.
3. the preparation method of a compound I as claimed in claim 2, it is characterized in that: said acid binding agent is one or both in salt of wormwood, yellow soda ash, sodium hydrogencarbonate, saleratus, sodium hydroxide, the Pottasium Hydroxide.
4. the preparation method of a compound I as claimed in claim 2, it is characterized in that: the mol ratio of said compound I I, Vinyl chloroformate, acid binding agent, Hydrazine Hydrate 80, acetone or propione is 1: (1-1.3): (1-3): (0.9-1.1): (0.9-1.1).
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| CN2010101229062A CN101781311B (en) | 2010-03-12 | 2010-03-12 | Novel preparation method of platelet aggregation inhibition compound |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102010424B (en) * | 2010-11-16 | 2012-05-30 | 天津药物研究院 | Crystal form III of (S)-alpha, alpha-[(2-chlorphenyl)-(4,5,6,7-thiophane[3,2-c]pyridine-5-yl)-N'-(dimethyl)methylene] acethydrazide and preparation method thereof |
| CN102010423B (en) * | 2010-11-16 | 2012-06-27 | 天津药物研究院 | Crystal form II of (S)-alpha, alpha-[(2-chlorphenyl)-(4,5,6,7-tetrahydrothieno [3,2-c] pyridine-5-yl)]-N'-(dimethyl) methylene) acethydrazide and preparation method |
| CN102796093B (en) * | 2012-08-23 | 2015-06-24 | 天津药物研究院 | Thiomorpholine-containing pyrrole derivatives and their preparation method and use |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1683373A (en) * | 2005-02-23 | 2005-10-19 | 天津药物研究院 | Thiophenopyridine substituted acetyl hyarazine derivative |
| CN101260112A (en) * | 2008-04-11 | 2008-09-10 | 天津药物研究院 | Acethydrazide derivatives containing thieno[3.2-c]pyridine, preparation method and use thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1683373A (en) * | 2005-02-23 | 2005-10-19 | 天津药物研究院 | Thiophenopyridine substituted acetyl hyarazine derivative |
| CN101260112A (en) * | 2008-04-11 | 2008-09-10 | 天津药物研究院 | Acethydrazide derivatives containing thieno[3.2-c]pyridine, preparation method and use thereof |
Non-Patent Citations (2)
| Title |
|---|
| Die Cheng等人.Synthesis and activity evaluation of some novel derivatives of 4,5,6,7-tetrahydrothieno [3,2-c]-pyridine.《Chinese chemical letters》.2008,第19卷(第6期),689-692. * |
| Die Cheng等人.Synthesis, activity evaluation and 3D-QSAR study of some novel derivatives of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine.《Chinese chemical letters》.2008,第19卷(第9期),1075-1079. * |
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