CN103450219B - A kind of hydrobromic acid prasugrel acetic acid compound and method for making thereof - Google Patents
A kind of hydrobromic acid prasugrel acetic acid compound and method for making thereof Download PDFInfo
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- CN103450219B CN103450219B CN201310389263.1A CN201310389263A CN103450219B CN 103450219 B CN103450219 B CN 103450219B CN 201310389263 A CN201310389263 A CN 201310389263A CN 103450219 B CN103450219 B CN 103450219B
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- acetic acid
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Abstract
The present invention relates to a kind of synthetic method of hydrobromic acid prasugrel acetic acid compound, take prasugrel as intermediate, by prasugrel and water mix and blend, obtain suspension liquid, then with Hydrogen bromide and acetic acid reaction, add organic solvent, separate out solid, dry, to obtain final product, or, take prasugrel hydrobromide as intermediate, by prasugrel hydrobromide and water mix and blend, suspension liquid, then and acetic acid reaction, add organic solvent, separate out solid, dry, to obtain final product.The present invention adopts water as solvent, more environmental protection, energy-conservation, and step of the present invention is simple, and the product purity obtained is high, and production cost is low, can suitability for industrialized production.
Description
Technical field
The present invention relates to a kind of hydrobromic acid prasugrel acetic acid compound and preparation method thereof, belong to medical art.
Background technology
Cardiovascular disorder becomes ascendant trend year by year, is one of serious disease causing the mankind disabled and dead at present.The appearance of Adenosine Diphosphate Receptor Antagonists is an important milestone of Antiplatelet therapy; it can reduce high-risk patient generation cardiovascular event risk; the control Percutaneous coronary interventions person distal vessels that happens suddenly is blocked, and significantly reduces myocardial infarction, cerebral apoplexy, lung or venothrombotic incidence and mortality ratio.
After a thiophene chlorine amine and clopidogrel, the platelet adp receptor blocker prasugrel of new generation developed jointly by Japanese Sankyo company and EliLilly company of the U.S., can anticoagulant more quickly and efficiently, it is a kind of Thienopyridines medicine, itself and percutaneous coronary intervention are combined, probably becomes the best therapy for the treatment of acute coronary syndrome.
Prasugrel (prasugrel) is a novel antiplatelet drug, within 2009, successively ratify listing in European Union and FDA, same clopidogrel (clopidogrel) is similar, prasugrel is by suppressing adenosine diphosphate (ADP) (adenosinediphosphate, the ADP) platelet aggregation of inducing thus playing antiplatelet effects.But the antiplatelet effects of prasugrel is stronger than clopidogrel, onset is faster, more effectively can reduce the cardiovascular event incidence of Acute Coronary Syndrome Patients.Prasugrel is a new oral effective Thienopyridines medicine, is the prodrug of a non-activity, irreversibly need could suppress the P on thrombocyte after cytochrome P 450 Enzyme metabolic conversion to active metabolite
2y
12adenosine diphosphate (ADP) acceptor.Clinical study proves, prasugrel has anticoagulant effect more better than current mainstream medicine clopidogrel, compared with the latter, take the heart of patient onste of new drug, apoplexy, because of the integrated risk of deaths from heart disease low by 20%, and instant effect, good effect, has good resistance and bioavailability, and toxicity is also lower.
Prasugrel is as a kind of potent adenosine diphosphate receptor antagonists, and in water, solubleness is less, in the impact of excipient substance with under preventing, is unfavorable for the preparation of pharmaceutical preparation and is not easy to stripping in pharmaceutical preparation.
Hydrobromic acid prasugrel acetic acid compound, its chemical name is 5-[(1RS)-2-cyclopropyl-1-(2-fluorophenyl)-2-oxygen ethyl]-4,5,6,7-tetramethylene sulfide [3,2-c] pyridine-2-acyl acetic acid ester hydrobromate acetic acid compounds, and molecular formula is C
22h
25fNO
5sBr, molecular weight is 514.41, and structural formula is:
Hydrobromic acid prasugrel acetic acid compound is the derived products of prasugrel, activeconstituents or prasugrel, but the solvability in water comparatively prasugrel improves greatly, so significant effect is played to the raising of the bioavailability of pharmaceutical preparation, significantly increase clinical efficacy.
The original synthetic route of mainly Japanese Sankyo company in the synthetic route prior art of prasugrel; with adjacent fluorine bromobenzyl for starting raw material; 1-cyclopropyl-2-(2-fluorophenyl is obtained with cyclopropylniitrile condensation after being made into Grignard reagent) ethyl ketone; then by its α position bromo; again with 2-thienone and piperidines generation substitution reaction, products therefrom obtains prasugrel after acetylize.The a lot of patent of current China has all related to the synthetic route of prasugrel and intermediate thereof, but the synthetic route of hydrobromic acid prasugrel acetic acid compound does not also find the patent of being correlated with.Although be referred to the preparation method of prasugrel salt in such as CN101255169B, and the synthetic method of unexposed hydrobromic acid prasugrel acetic acid compound, in the method prasugrel and acid at ambient temperature the reaction times long, cause impurity bigger than normal.CN102342921A discloses the pharmaceutical composition of prasugrel hydrobromide acetate compound, has related to relevant formulation patent, has not also mentioned synthetic route and the technique of this compound.
Summary of the invention
Little in order to solve prasugrel solubleness in water, the problem that bioavailability is low, the invention provides a kind of derivative of prasugrel and the synthetic method of hydrobromic acid prasugrel acetic acid compound, is namely intermediate with prasugrel, obtains with Hydrogen bromide and acetic acid reaction; Or, take prasugrel hydrobromide as intermediate, obtain with acetic acid reaction.The solvability of hydrobromic acid prasugrel acetic acid compound in water comparatively prasugrel improves greatly, thus improves bioavailability, adds clinical efficacy.
The object of the present invention is to provide a kind of synthetic method of hydrobromic acid prasugrel acetic acid compound, take prasugrel as intermediate, by prasugrel and water mix and blend, obtain suspension liquid, then with Hydrogen bromide and acetic acid reaction, add organic solvent, separate out solid, dry, to obtain final product.Or, take prasugrel hydrobromide as intermediate, by prasugrel hydrobromide and water mix and blend, obtain suspension liquid, then with acetic acid reaction, add organic solvent, separate out solid, dry, to obtain final product.The present invention adopts water as solvent, instead of organic solvent, more environmental protection, energy-conservation, and step of the present invention is simple, and the product purity obtained is high, and production cost is low, can suitability for industrialized production.
Technical scheme provided by the invention is as follows:
Hydrobromic acid prasugrel acetic acid compound compound shown in a kind of formula (I),
Molecular formula is C
22h
25fNO
5sBr, molecular weight is 514.41, and its synthesis step is:
(1) by prasugrel and water mix and blend, suspension liquid is obtained;
(2) in above-mentioned suspension liquid, drip the solution of Hydrogen bromide and acetic acid preparation, stirring and dissolving, heat up, reaction, then concentrating under reduced pressure becomes enriched material;
(3) in enriched material, add organic dissolution agent, preferred acetone, stirring and dissolving, place, separate out solid, dry, obtain the finished product hydrobromic acid prasugrel acetic acid compound.
As the present invention one preferred embodiment, in above-mentioned synthesis step (1), the weight ratio of prasugrel and water is 1:15.
As the present invention one preferred embodiment, in above-mentioned synthesis step (2), Hydrogen bromide is the hydrobromic acid aqueous solution of 40%, and prasugrel and 40% hydrobromic acid aqueous solution, acetic acid feed intake in w:w:v=1:0.54:10 ratio.
As the present invention one preferred embodiment, above-mentioned synthesis step is warmed up to 40 DEG C in (2), and react 10 minutes, then 35 DEG C are evaporated to dry.
As the present invention one preferred embodiment, in above-mentioned synthesis step (3), acetone and prasugrel add in v:w=5:1 ratio.
As the present invention one preferred embodiment, 60 DEG C of vacuum-dryings in above-mentioned synthesis step (3).
Preferred, the concrete synthesis step of hydrobromic acid prasugrel acetic acid compound of the present invention is:
(1) by prasugrel and water 1:15 mix and blend by weight, suspension liquid is obtained;
(2) in prasugrel suspension liquid, drip the hydrobromic acid aqueous solution of 40% and the solution of acetic acid preparation, in prasugrel: 40% hydrobromic acid aqueous solution: acetic acid (w:w:v)=1:0.54:10 ratio adds, stirring and dissolving is warmed up to 40 DEG C, react 10 minutes, then 35 DEG C are evaporated to dry;
(3) in enriched material, add acetone, in acetone: prasugrel (v:w)=5:1 ratio adds, stirring and dissolving, and placement is spent the night, separate out solid, 60 DEG C of vacuum-dryings, obtain the finished product hydrobromic acid prasugrel acetic acid compound.
Another technical scheme provided by the invention is as follows:
Hydrobromic acid prasugrel acetic acid compound compound shown in a kind of formula (I),
Molecular formula is C
22h
25fNO
5sBr, molecular weight is 514.41, and its synthesis step is:
(1) by prasugrel hydrobromide and water mix and blend, suspension liquid is obtained;
(2) in above-mentioned suspension liquid, drip acetic acid, stirring and dissolving, heat up, reaction, then concentrating under reduced pressure becomes enriched material;
(3) in enriched material, add organic dissolution agent (preferred acetone), stirring and dissolving, place, separate out solid, dry, obtain the finished product hydrobromic acid prasugrel acetic acid compound.
As the present invention one preferred embodiment, in above-mentioned synthesis step (1), the weight ratio of prasugrel hydrobromide and water is 1:15.
As the present invention one preferred embodiment, in above-mentioned synthesis step (2), prasugrel hydrobromide and acetic acid feed intake in w:v=1:8.5 ratio.
As the present invention one preferred embodiment, above-mentioned synthesis step is warmed up to 40 DEG C in (2), and react 10 minutes, then 35 DEG C are evaporated to dry.
As the present invention one preferred embodiment, in above-mentioned synthesis step (3), acetone and prasugrel hydrobromide add in v:w=5:1 ratio.
As the present invention one preferred embodiment, 60 DEG C of vacuum-dryings in above-mentioned synthesis step (3).
Preferred, the concrete synthesis step of hydrobromic acid prasugrel acetic acid compound of the present invention is:
(1) by prasugrel hydrobromide and water 1:15 mix and blend by weight, suspension liquid is obtained;
(2) in above-mentioned suspension liquid, drip acetic acid, in prasugrel hydrobromide: acetic acid (w:v)=1:8.5 ratio adds, stirring and dissolving is warmed up to 40 DEG C, and react 10 minutes, then 35 DEG C are evaporated to dry;
(3) in enriched material, add acetone, in acetone: prasugrel hydrobromide (v:w)=5:1 ratio adds, stirring and dissolving, and placement is spent the night, separate out solid, 60 DEG C of vacuum-dryings, obtain the finished product hydrobromic acid prasugrel acetic acid compound.
Embodiment
The preparation of embodiment 1 hydrobromic acid prasugrel acetic acid compound
(1) in reaction flask, add 10g by prasugrel and 150g water, mix and blend, obtains suspension liquid;
(2) in prasugrel suspension liquid, drip the hydrobromic acid aqueous solution 5.4g of 40% and the solution of acetic acid 100ml preparation, stirring and dissolving, is warmed up to 40 DEG C, and start timing, react 10 minutes, then 35 DEG C are evaporated to dry;
(3) in enriched material, add 50ml acetone, stirring and dissolving, placement is spent the night, and separates out solid, and 60 DEG C of vacuum-drying 4 hours, obtain the finished product hydrobromic acid prasugrel acetic acid compound 12.4g, yield is 90.0%, purity 99.9%.
The preparation of embodiment 2 hydrobromic acid prasugrel acetic acid compound
(1) in reaction flask, add 121.6g by prasugrel hydrobromide and 1824g water, mix and blend, obtains suspension liquid;
(2) in prasugrel hydrobromide suspension liquid, drip the solution that acetic acid 1033.6ml prepares, stirring and dissolving, is warmed up to 40 DEG C, and start timing, react 10 minutes, then 35 DEG C are evaporated to dry;
(3) in enriched material, add 608ml acetone, stirring and dissolving, placement is spent the night, and separates out solid, and 60 DEG C of vacuum-drying 4 hours, obtain the finished product hydrobromic acid prasugrel acetic acid compound 127.0g, yield is 92.2%, purity 99.9%.
The preparation of comparative example 1 hydrobromic acid prasugrel acetic acid compound
Test by the method for embodiment in CN101255169B 1, prasugrel 25g is dissolved in acetonitrile/ethanol (volume ratio 1/1) organic solvent and is mixed with organic solution, drip in this organic solution containing 40% hydrobromic aqueous solution 8ml and acetic acid 150ml, room temperature reaction 5-6 hour, till reacting completely.Filtering-depositing after concentrated, obtains hydrobromic acid prasugrel acetic acid compound crude product.With ethyl alcohol recrystallization, obtain hydrobromic acid prasugrel acetic acid compound 29.03g, yield 84.3%, purity 99.2%.
Embodiment 3 structural identification
1, ultimate analysis C
22h
25fNO
5sBr
Theoretical value: C:51.37%; H:4.90%; F:3.70%; N:2.72%; O:15.55%; S:6.23%; Br:15.53%.
Measured value: C:51.35%; H:4.92%; F:3.71%; N:2.70%; O:15.54%; S:6.22%; Br:15.54%.
2, nuclear-magnetism POP data
1HNMR(CDCl
3)δ:7.05-7.44(m,4H),6.26(s,1H),4.82(s,1H),3.47-3.59(m,2H),2.77-2.94(m,4H),2.27-2.29(m,1H),2.27(s,3H),1.01-1.06(m,2H),0.82-0.88(m,2H)。
MS-ESI(m/z):374［M+H］
+。
Claims (2)
1. a preparation method for hydrobromic acid prasugrel acetic acid compound compound as follows,
Molecular formula: C
22h
25fNO
5sBr, molecular weight: 514.41, is characterized in that:
(1) by prasugrel and water 1:15 mix and blend by weight, suspension liquid is obtained;
(2) in prasugrel suspension liquid, drip the hydrobromic acid aqueous solution of 40% and the solution of acetic acid preparation, in prasugrel: 40% hydrobromic acid aqueous solution: acetic acid is with weight: weight: volume=1:0.54:10 ratio adds, stirring and dissolving, be warmed up to 40 DEG C, react 10 minutes, then 35 DEG C are evaporated to dry;
(3) in enriched material, add acetone, in acetone: prasugrel is with volume: weight=5:1 ratio adds, stirring and dissolving, and placement is spent the night, separate out solid, 60 DEG C of vacuum-dryings, obtain the finished product hydrobromic acid prasugrel acetic acid compound.
2. a preparation method for hydrobromic acid prasugrel acetic acid compound compound as follows,
Molecular formula: C
22h
25fNO
5sBr, molecular weight: 514.41, is characterized in that:
(1) by prasugrel hydrobromide and water 1:15 mix and blend by weight, suspension liquid is obtained;
(2) in above-mentioned suspension liquid, drip acetic acid, in prasugrel hydrobromide: acetic acid is with weight: volume=1:8.5 ratio adds, stirring and dissolving is warmed up to 40 DEG C, and react 10 minutes, then 35 DEG C are evaporated to dry;
(3) in enriched material, add acetone, in acetone: prasugrel hydrobromide is with volume: weight=5:1 ratio adds, stirring and dissolving, and placement is spent the night, separate out solid, 60 DEG C of vacuum-dryings, obtain the finished product hydrobromic acid prasugrel acetic acid compound.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102342921A (en) * | 2010-08-01 | 2012-02-08 | 江苏正大天晴药业股份有限公司 | Pharmaceutical composition of prasugrel hydrobromide acetate compound |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102342921A (en) * | 2010-08-01 | 2012-02-08 | 江苏正大天晴药业股份有限公司 | Pharmaceutical composition of prasugrel hydrobromide acetate compound |
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Granted publication date: 20160323 Termination date: 20160830 |