CN101781311A - Novel preparation method of platelet aggregation inhibition compound - Google Patents
Novel preparation method of platelet aggregation inhibition compound Download PDFInfo
- Publication number
- CN101781311A CN101781311A CN 201010122906 CN201010122906A CN101781311A CN 101781311 A CN101781311 A CN 101781311A CN 201010122906 CN201010122906 CN 201010122906 CN 201010122906 A CN201010122906 A CN 201010122906A CN 101781311 A CN101781311 A CN 101781311A
- Authority
- CN
- China
- Prior art keywords
- compound
- preparation
- reaction
- acetone
- hydrazine hydrate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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, interventional therapy 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 the 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.Adenosine diphosphate (ADP) (ADP) is the important agonist that platelet activation, buildup effect amplify, and suppressing the thrombocyte effect by 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 inhibitor class antiplatelet drug of a present clinical line, because it is the extremely weak oily matter of alkalescence, needs and strong acid ability salify.Chance moisture instability can make free alkali separate out again, and purifying has certain difficulty.And because its strongly-acid also can be subjected to 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:
The chemistry of two kinds of compounds is by name:
(S)-and α, α-[2-chloro-phenyl--2-(4,5,6, the 7-tetramethylene sulfide 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-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(diethyl) methene base] acethydrazide (when R is an ethyl).
The synthetic method of this compound of putting down in writing among the patent ZL200510016205.X is as follows:
In the reaction flask that stirring, condenser, thermometer are housed, add clopidogrel 38g, dehydrated alcohol 30mL, stir down slowly heating, make the reaction raw materials dissolving, add 45.6g hydrazine hydrate (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 adds 50mL distilled water and 30mL methylene dichloride in resistates, fully stirs, and tells organic layer, and water layer merges organic layer with 3 * 30mL dichloromethane extraction, uses the anhydrous sodium sulphate 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, condenser, thermometer 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 ℃): ethyl acetate=1: 1].
Summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of novel method for preparing Compound I is provided, its purpose is to overcome the shortcoming of original synthetic method, and the step that simplifies the operation shortens the production cycle, finally reduces production costs.
Technical scheme provided by the invention is as follows:
S-(+)-2-(2-Chlorophenyl)-2-(4,5,6,7-tetrahydrothieno[3,2-c] pyridine-5-yl) 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, hydrolysate 2-(2-chloro-phenyl-)-2-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) the method synthetic compound I that " cooks different foods in one pot " of acetate (II) and Vinyl chloroformate, hydrazine hydrate and acetone or propione.
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 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 bicarbonate, saleratus, sodium hydroxide, the potassium hydroxide.Cold condition 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, 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 be prepared, intermediate 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 61.6% only 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 by following concrete technology:
Reference example: 2-(2-chloro-phenyl-)-2-(4,5,6, the 7-tetramethylene sulfide 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, moltenly add 15mL 30% aqueous sodium hydroxide solution after clear 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 distilled water, and ice-water bath stirs down, slowly adds Glacial acetic acid, 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)-and α, α-[2-chloro-phenyl--2-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(dimethyl) methene base] acethydrazide
In the 250mL reaction flask that stirring, condenser, thermometer are housed, step reaction product 15.4g and 50mL dioxane in the adding stir molten clear.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%) 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: ethyl acetate: sherwood oil (60-90 ℃)=1: 1].
Embodiment 2:(S)-and α, α-[2-chloro-phenyl--2-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(dimethyl) methene base] acethydrazide
In the 250mL reaction flask that stirring, condenser, thermometer are housed, step reaction product 15.4g and 50mL dioxane in the adding stir molten clear.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 (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: ethyl acetate: sherwood oil (60-90 ℃)=1: 1].
Embodiment 3:(S)-and α, α-[2-chloro-phenyl--2-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(dimethyl) methene base] acethydrazide
In the 250mL reaction flask that stirring, condenser, thermometer are housed, step reaction product 15.4g and 60mL dioxane in the adding stir molten clear.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 (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: ethyl acetate: sherwood oil (60-90 ℃)=1: 1].
Embodiment 4:(S)-and α, α-[2-chloro-phenyl--2-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also)]-N '-[(diethyl) methene base] acethydrazide
In the 250mL reaction flask that stirring, condenser, thermometer are housed, step reaction product 15.4g and 70mL dioxane in the adding stir molten clear.Be cooled to 10 ℃, add the 10.6g anhydrous sodium carbonate, 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 (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 tetrahydrofuran (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 (ethyl acetate): v (sherwood oil (60-90 ℃))=1: 1].
Claims (6)
1. novel preparation method suc as formula the I compound is characterized in that technical process and reaction conditions carry out in the following manner:
Wherein R is methyl or ethyl.
The method synthetic compound I that 2-(2-chloro-phenyl-)-2-(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-5-yl also) acetate (II), Vinyl chloroformate, hydrazine hydrate 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, add acid binding agent, low temperature drips Vinyl chloroformate down, reacted 0.5-1 hour, heat up, in 20～30 ℃ of mixed solutions that add hydrazine hydrate and acetone or propione, reaction for some time makes Compound I.
3. the preparation method of a Compound I as claimed in claim 2, it is characterized in that: described acid binding agent is one or both in salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus, sodium hydroxide, the potassium hydroxide.
4. the preparation method of a Compound I as claimed in claim 2, it is characterized in that: described cold condition is 7～12 ℃.
5. the preparation method of a Compound I as claimed in claim 2, it is characterized in that: described reaction for some time is 1-2 hour.
6. the preparation method of a Compound I as claimed in claim 2, it is characterized in that: the mol ratio of described Compound I I, Vinyl chloroformate, acid binding agent, hydrazine hydrate, acetone or propione is 1: (1-1.3): (1-3): (0.9-1.1): (0.9-1.1).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010101229062A CN101781311B (en) | 2010-03-12 | 2010-03-12 | Novel preparation method of platelet aggregation inhibition compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010101229062A CN101781311B (en) | 2010-03-12 | 2010-03-12 | Novel preparation method of platelet aggregation inhibition compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101781311A true CN101781311A (en) | 2010-07-21 |
| CN101781311B CN101781311B (en) | 2012-07-25 |
Family
ID=42521474
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2010101229062A Active CN101781311B (en) | 2010-03-12 | 2010-03-12 | Novel preparation method of platelet aggregation inhibition compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101781311B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102010424A (en) * | 2010-11-16 | 2011-04-13 | 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 |
| CN102010423A (en) * | 2010-11-16 | 2011-04-13 | 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 |
| CN102796093A (en) * | 2012-08-23 | 2012-11-28 | 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 |
-
2010
- 2010-03-12 CN CN2010101229062A patent/CN101781311B/en active Active
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 |
|---|
| 《Chinese chemical letters》 20081231 Die Cheng等人 Synthesis and activity evaluation of some novel derivatives of 4,5,6,7-tetrahydrothieno [3,2-c]-pyridine 689-692 1-6 第19卷, 第6期 2 * |
| 《Chinese chemical letters》 20081231 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 1075-1079 1-6 第19卷, 第9期 2 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102010424A (en) * | 2010-11-16 | 2011-04-13 | 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 |
| CN102010423A (en) * | 2010-11-16 | 2011-04-13 | 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 |
| 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 |
| CN102796093A (en) * | 2012-08-23 | 2012-11-28 | 天津药物研究院 | Thiomorpholine-containing pyrrole derivatives and their preparation method and use |
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101781311B (en) | 2012-07-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2683566C1 (en) | Derivative with articulated rings and method for preparation thereof, intermediate compound, pharmaceutical composition and application thereof | |
| CN106243031B (en) | A kind of Ah handkerchief replaces the preparation method of Buddhist nun | |
| EP3181557B1 (en) | Carboxylic acid compound, method for preparation thereof, and use thereof | |
| RU2715229C2 (en) | Quinoline compounds, methods for production thereof and use thereof as medicinal agent which inhibits urate transporter | |
| JP2013532162A5 (en) | Fused pyrimidines and triazines and their use for the treatment and / or prevention of cardiovascular disorders | |
| WO2009056070A1 (en) | Ligustrazine aromatic acid ether derivative, its preparation method, pharmaceutical composition, and application | |
| WO2007015744A1 (en) | Disubstituted thienyl compounds and their use as pharmaceuticals | |
| EP2141148A1 (en) | Indole derivative having cpla2 inhibitory activity, use of the same and method for producing the same | |
| CN107286156A (en) | New URAT1 inhibitor and its in application pharmaceutically | |
| CN111518031B (en) | Hydroxamic acid-containing compound and preparation method and application thereof | |
| CN101781311B (en) | Novel preparation method of platelet aggregation inhibition compound | |
| CN101910144A (en) | Para-hydroxybenzene acrylic acid derivatives and uses thereof | |
| CN102702191A (en) | Synthesis method of vinpocetine | |
| CN110862372B (en) | Synthesis of clopidogrel intermediate (S) -2- (2-thiophenoethylamine) - (2-chlorophenyl) -methyl acetate | |
| CN104987310A (en) | Synthesis process of levosimendan | |
| CN101265250A (en) | Substituted flavonoids and preparation method, application and pharmaceutical composition thereof | |
| CN107602400A (en) | A kind of method for accelerating mefenamic acid generated time | |
| CN101812072B (en) | Method for preparing anti-platelet aggregation compounds | |
| CN101735222B (en) | Pyrrole-nitrogen heterocyclic tropone compound and application thereof as protein-tyrosine-phosphatase 1 B inhibitor | |
| CN112979577A (en) | Preparation method of oxadiazole derivative | |
| CN101434533B (en) | Novel preparation of sofalcone | |
| CN107311939B (en) | Preparation method of substituted pyrimidone derivative | |
| CN106588888A (en) | High-purity L-sunitinib malate preparation method | |
| CN101812073B (en) | Method for preparing acethydrazide derivatives | |
| CN103130785A (en) | Preparation method of iloperidone |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |