A kind of preparation method of anti-platelet aggregation compounds
Technical field
The invention belongs to technical field of pharmaceutical chemistry, be specifically related to the synthetic method of a class anti-platelet aggregation compounds, relate in particular to the industrial process of this class 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.Its salt is met the moisture instability, and free alkali is separated out, and purifying has certain difficulty.And because the strongly-acid of its salt also can be subjected to certain restriction aspect preparation.Patent ZL200510016205.X provides a kind of new A DP receptor-blocking agent class antiplatelet formula I compound, when having excellent activity, 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 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).
Chemical structure:
Wherein R is methyl or 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, 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].
There is following shortcoming in the technical program:
1. need to buy clopidogrel be raw material to this synthetic method, and cost is higher, is not suitable for industrialized production.
2. operation steps is comparatively loaded down with trivial details, repeatedly reaction solution is carried out aftertreatment, if be used for industrialized production, not only wasting a large amount of reagent increases cost, does not also meet environmental requirement.
3. use a large amount of hydrazine hydrates, be unfavorable for labour protection.
Summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of method of preparation I compound of suitable industrialized production is provided, its purpose is to overcome the existing high shortcoming of synthetic method cost of material, when guaranteeing quality product, select the cheap raw material that is easy to get for use, thereby reduce production costs, be fit to large-scale industrialization production.
Technical scheme provided by the invention is as follows:
2-(2-chloro-phenyl-)-2-bromo-methyl acetate and 2-(thiophene-2-yl) ethamine reacts under the catalysis of acid binding agent, generates intermediate II.Intermediate II and hydrazine hydrate, acetone or propione reaction generate intermediate III.Intermediate III cyclization reaction production I compound.
Wherein R is methyl or ethyl.
With dissolvings such as 2-(2-chloro-phenyl-)-2-bromo-methyl acetate methylene dichloride, trichloromethane, toluene, dioxane.Add acid binding agents such as triethylamine, pyridine, salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus, sodium hydroxide or potassium hydroxide.Add 2-(thiophene-2-yl) ethamine stirring reaction again, generate intermediate II.With the solution of intermediate II, be warming up to 50~60 ℃ of mixed solutions that add hydrazine hydrate and acetone or propione, reaction makes intermediate III; Intermediate III is dissolved in organic acid or mineral acid, with formaldehyde the Pictet-Spengler reaction takes place, and makes formula I compound.
Wherein the concentration of hydrazine hydrate is 60-90%; The mol ratio of intermediate II, hydrazine hydrate and acetone or propione is 1: (1-1.2): (1-1.2).Organic acid that Pictet-Spengler reaction is used or mineral acid are wherein a kind of of formic acid, acetate, hydrochloric acid, sulfuric acid; Temperature of reaction is 30~100 ℃; The mol ratio of compound III, acid and formaldehyde is 1: (1-4): (1-2).
The present invention compared with prior art, its remarkable advantage is:
1. replace clopidogrel with starting raw material 2-cheap and easy to get (2-chloro-phenyl-)-2-bromo-methyl acetate and 2-(thiophene-2-yl) ethamine, greatly reduce production cost.
2. reaction conditions gentleness, simple and safe operation process is easy to realize suitability for industrialized production.Reaction times is short, need not heat, less demanding to equipment, and it is low to consume energy.Saved the energy, facility investment and running cost, effects of energy saving and emission reduction is obvious, meets the requirement of low-carbon economy.
3. significantly reduce the hydrazine hydrate usage quantity, be beneficial to labour protection.
4. constant product quality, the purity height, the productive rate height can reach the requirement of industrial amplification production.
Embodiment
The present invention can realize by following concrete technology:
Reference example: 2-(2-chloro-phenyl-)-2-[2-(thiophene-2-yl) ethamine] methyl acetate (II) synthetic
In the 250mL reaction flask, add 2-(2-chloro-phenyl-)-2-bromo-methyl acetate 26.4g (0.1mol) and 100mL methylene dichloride, start stirring, molten clear back adds 27.6g (0.2mol) Anhydrous potassium carbonate, adds 2-(thiophene-2-yl) ethamine 12.7g (0.1mol) in batches.After finishing, be warming up to back flow reaction 3 hours (the flaggy demonstration reacts completely).Stopped reaction filters.With small portion filtrate evaporate to dryness, get white solid product (HPLC:98.4%).
1H?NMR(DMSO-d
6,400MHz)δ:2.997~3.068(m,1H),3.107~3.177(m,1H),3.253~3.339(m,2H),3.725(s,3H),5.588(s,1H),6.903~6.909(d,1H),6.941~6.962(m,1H),7.364~7.379(q,1H),7.463~7.532(m,2H),7.599~7.622(q,1H),7.756~7.779(m,1H),10.456(bro,1H)。
Embodiment 1: intermediate III-1 synthetic
With the solution of gained intermediate II of last step, be warming up to 50 ℃, stir the mixed solution that adds 60% hydrazine hydrate 8.34g (0.1mol) and acetone 5.81g (0.1mol) down, in 50 ℃ of reaction 1h (the flaggy demonstration reacts completely).Stopped reaction, cooling has solid to generate.Filter, drying gets solid product 30.3g (HPLC:99.8%), yield 86.7%.The Rf=0.41[single-point, developping agent: ethyl acetate: sherwood oil (60-90 ℃)=1: 1].
Embodiment 2:Synthesizing of intermediate III-2
With the solution of gained intermediate II of last step, be warming up to 60 ℃, stir the mixed solution that adds 90% hydrazine hydrate 6.67g (0.12mol) and propione 10.3g (0.12mol) down, in 60 ℃ of reaction 0.5h (the flaggy demonstration reacts completely).Stopped reaction, cooling has solid to generate.Filter, drying gets solid product 33.4g (HPLC:99.0%), yield 87.4%.The Rf=0.45[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, add 3.5g (0.01mol) intermediate III-1, add 15% formic acid solution 10mL (0.04mol), stir adding 0.6g (0.02mol) formaldehyde down.Be warming up to 50 ℃ and continue reaction 0.5h (the flaggy demonstration reacts completely).Stopped reaction, with 3 * 10mL dichloromethane extraction, anhydrous sodium sulfate drying, solvent is to the greatest extent steamed in decompression, gets solid product 3.24g (HPLC:99.3%), yield 89.4%.M.p.169.0-170.6 ℃, Rf=0.37[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, add 3.8g (0.01mol) intermediate III-2, add 15% hydrochloric acid soln 8mL (0.03mol), stir adding 0.5g (0.015mol) formaldehyde down.Be warming up to 70 ℃ and continue reaction 0.5h (the flaggy demonstration reacts completely).Stopped reaction, with 3 * 10mL dichloromethane extraction, anhydrous sodium sulfate drying, solvent is to the greatest extent steamed in decompression, gets solid product 3.38g (HPLC:99.0%), yield 86.6%.M.p.168.5-170.1 ℃, Rf=0.40[single-point, developping agent: ethyl acetate: sherwood oil (60-90 ℃)=1: 1].