CN103467483A - Method for preparing hydrobromic acid prasugrel acetic acid compound - Google Patents
Method for preparing hydrobromic acid prasugrel acetic acid compound Download PDFInfo
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- CN103467483A CN103467483A CN2013103884809A CN201310388480A CN103467483A CN 103467483 A CN103467483 A CN 103467483A CN 2013103884809 A CN2013103884809 A CN 2013103884809A CN 201310388480 A CN201310388480 A CN 201310388480A CN 103467483 A CN103467483 A CN 103467483A
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- prasugrel
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- prasugrel hydrobromide
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- 0 *c1c(C(*(CC2)Cc3c2[o]c(OC(N)=O)c3)C(C2CC2)=O)cccc1 Chemical compound *c1c(C(*(CC2)Cc3c2[o]c(OC(N)=O)c3)C(C2CC2)=O)cccc1 0.000 description 1
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Abstract
The invention relates to a method for synthesizing a hydrobromic acid prasugrel acetic acid compound. The method comprises the following steps of taking the prasugrel as an intermediate, adding the prasugrel into a mixed solvent and stirring so as to obtain a turbid liquid, then reacting with the hydrobromic acid and acetic acid, adding an organic solvent, precipitating the solid, drying, and obtaining the hydrobromic acid prasugrel acetic acid compound; or taking the hydrobromic acid prasugrel as the intermediate, adding the hydrobromic acid prasugrel into the mixed solvent and stirring so as to obtain the turbid liquid, then reacting with the acetic acid, adding the organic solvent, precipitating the solid, drying, and obtaining the hydrobromic acid prasugrel acetic acid compound. According to the method, the mixed solvent is taken as the solvent, so that the method is more environment-friendly and energy-saving, has simple steps, can be used for preparing products with high purity, has low production cost, and can be used for industrial production.
Description
Technical field
The present invention relates to a kind of prasugrel hydrobromide acetic acid compound and preparation method thereof, belong to medical technical field.
Background technology
Cardiovascular disorder becomes ascendant trend year by year, is to cause at present one of disabled and dead serious disease of the mankind.The appearance of Adenosine Diphosphate Receptor Antagonists is an important milestone of Antiplatelet therapy; it can reduce high-risk patient Cardiovascular Events risk; control is blocked through the skin coronary intervention person distal vessels that happens suddenly, 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 of being developed jointly by Japanese Sankyo company and U.S. Eli Lilly company, anticoagulant more quickly and efficiently, it is a kind of Thienopyridines medicine, by it with through the combination of skin coronary intervention, probably become the best therapy for the treatment of acute coronary syndrome.
Prasugrel (prasugrel) is a novel antiplatelet drug, within 2009, in European Union and FDA, successively ratify listing, (clopidogrel) is similar for same clopidogrel, prasugrel passes through to suppress adenosine diphosphate (ADP) (adenosine diphosphate, ADP) thereby the platelet aggregation of inducing performance antiplatelet effects.But the antiplatelet effects of prasugrel is stronger than clopidogrel, and onset is faster, can more effectively 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, need could irreversibly suppress the P on thrombocyte to active metabolite through the cytochrome P 450 Enzyme metabolic conversion
2y
12the adenosine diphosphate (ADP) acceptor.Clinical study proves, prasugrel has than the better anticoagulant effect of current main flow medicine clopidogrel, with the latter, compare, take the heart of patient onste, apoplexy of new drug, will hang down 20% because of the integrated risk of deaths from heart disease, and instant effect, good effect, have 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, under the impact of excipient substance and preventing, is unfavorable for the preparation of pharmaceutical preparation and is not easy to stripping in pharmaceutical preparation.
Prasugrel hydrobromide 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 compound, molecular formula: C
22h
25fNO
5sBr, molecular weight: 514.41, structural formula is:
Prasugrel hydrobromide acetic acid compound is the derived products of prasugrel, activeconstituents or prasugrel, but the solvability in water improves greatly than prasugrel, like this raising of the bioavailability of pharmaceutical preparation is played to significant effect, increased greatly clinical efficacy.
It in the synthetic route prior art of prasugrel, is mainly the original synthetic route of Japanese Sankyo company; the adjacent fluorine bromobenzyl of take is starting raw material; obtain 1-cyclopropyl-2-(2-fluorophenyl with the cyclopropylniitrile condensation after being made into Grignard reagent) ethyl ketone; then by its α position bromo; with 2-thienone piperidines generation substitution reaction, products therefrom obtains prasugrel after acetylize again.The a lot of patents of China have all related to the synthetic route of prasugrel and intermediate thereof at present, but the synthetic route of prasugrel hydrobromide acetic acid compound is not also found relevant patent.Although for example in CN101255169B, mentioned the preparation method of prasugrel salt, and the synthetic method of unexposed prasugrel hydrobromide acetic acid compound, in the method prasugrel and acid at ambient temperature the reaction times long, cause impurity bigger than normal.Patent CN102342921A discloses the pharmaceutical composition of prasugrel hydrobromide acetic acid compound, has related to relevant preparation patent, does not also mention 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 derivative that the invention provides a kind of prasugrel is the synthetic method of prasugrel hydrobromide acetic acid compound, take prasugrel as intermediate, with Hydrogen bromide and acetic acid reaction, makes; Perhaps, take prasugrel hydrobromide as intermediate, make with acetic acid reaction.The solvability of prasugrel hydrobromide acetic acid compound in water improves greatly than prasugrel, thereby improved bioavailability, increased clinical efficacy.
The object of the present invention is to provide a kind of synthetic method of prasugrel hydrobromide acetic acid compound, take prasugrel as intermediate, prasugrel is added in mixed solvent and stirs, obtain suspension liquid, then, with Hydrogen bromide and acetic acid reaction, add organic solvent, separate out solid, drying, obtain.Perhaps, take prasugrel hydrobromide as intermediate, prasugrel hydrobromide is added in mixed solvent and stirs, obtain suspension liquid, then, with acetic acid reaction, add organic solvent, separate out solid, drying, obtain.The present invention adopts mixed solvent as solvent, has replaced organic solvent, and environmental protection more is energy-conservation, and step of the present invention is simple, and the product purity obtained is high, and production cost is low, but suitability for industrialized production.
Technical scheme provided by the invention is as follows:
Prasugrel hydrobromide acetic acid compound compound shown in a kind of formula (I),
Molecular formula: C
22h
25fNO
5sBr, molecular weight: 514.41, its synthesis step is:
(1) prasugrel is added in mixed solvent and stirs, obtain suspension liquid;
(2) drip the solution of Hydrogen bromide and acetic acid preparation in above-mentioned prasugrel suspension liquid, stirring and dissolving, heat up, and reaction, then be condensed into enriched material;
(3) add organic solvating agent in enriched material, preferred acetone, stirring and dissolving, place, and separates out solid, and drying, obtain the finished product prasugrel hydrobromide acetic acid compound.
As the present invention's one preferred embodiment, in above-mentioned synthesis step (1), mixed solvent is the solvent that water and organic solvent weight ratio 0.1-1:1-0.1 are mixed.Organic solvent is selected from one or more in acetonitrile, ethanol, methyl alcohol, tetrahydrofuran (THF), ethyl acetate, acetone, ether.
As the present invention's one preferred embodiment, in above-mentioned synthesis step (1), the weight ratio of prasugrel and mixed solvent is 1:10.
As the present invention's one preferred embodiment, the hydrobromic acid aqueous solution that in above-mentioned synthesis step (2), Hydrogen bromide is 40%, prasugrel and 40% hydrobromic acid aqueous solution, acetic acid are fed intake in the w:w:v=1:0.54:10 ratio.
As the present invention's one preferred embodiment, above-mentioned synthesis step is warmed up to 40 ℃ in (2), reacts 10 minutes, and then 35 ℃ are evaporated to dry.
As the present invention's one preferred embodiment, in above-mentioned synthesis step (3), acetone and prasugrel add in the v:w=5:1 ratio.
As the present invention's one preferred embodiment, 60 ℃ of vacuum-dryings in above-mentioned synthesis step (3).
Preferred, the concrete synthesis step of prasugrel hydrobromide acetic acid compound of the present invention is:
(1) by prasugrel and mixed solvent by weight the 1:10 mix and blend, obtain suspension liquid;
(2) to dripping 40% hydrobromic acid aqueous solution and the solution of acetic acid preparation in the prasugrel suspension liquid, in prasugrel: 40% hydrobromic acid aqueous solution: acetic acid (w:w:v)=1:0.54:10 ratio adds, and stirring and dissolving is warmed up to 40 ℃, react 10 minutes, then 35 ℃ are evaporated to dry;
(3) add acetone in enriched material, in acetone: prasugrel (v:w)=5:1 ratio adds, stirring and dissolving, and placement is spent the night, and separates out solid, and 60 ℃ of vacuum-dryings obtain the finished product prasugrel hydrobromide acetic acid compound.
Another technical scheme provided by the invention is as follows:
Prasugrel hydrobromide acetic acid compound compound shown in a kind of formula (I),
Molecular formula is C
22h
25fNO
5sBr, molecular weight is 514.41, its synthesis step is:
(1) prasugrel hydrobromide is added in mixed solvent and stirs, obtain suspension liquid;
(2) drip acetic acid in above-mentioned suspension liquid, stirring and dissolving, heat up, reaction, and then concentrating under reduced pressure becomes enriched material;
(3) add organic solvating agent in enriched material, preferred acetone, stirring and dissolving, place, and separates out solid, and drying, obtain the finished product prasugrel hydrobromide acetic acid compound.
As the present invention's one preferred embodiment, in above-mentioned synthesis step (1), the weight ratio of prasugrel hydrobromide and mixed solvent is 1:15.
As the present invention's one preferred embodiment, in above-mentioned synthesis step (2), prasugrel hydrobromide and acetic acid are fed intake in the w:v=1:8.5 ratio.
As the present invention's one preferred embodiment, above-mentioned synthesis step is warmed up to 40 ℃ in (2), reacts 10 minutes, and then 35 ℃ are evaporated to dry.
As the present invention's one preferred embodiment, in above-mentioned synthesis step (3), acetone and prasugrel hydrobromide add in the v:w=5:1 ratio.
As the present invention's one preferred embodiment, 60 ℃ of vacuum-dryings in above-mentioned synthesis step (3).
Preferred, the concrete synthesis step of prasugrel hydrobromide acetic acid compound of the present invention is:
(1) by prasugrel hydrobromide and mixed solvent by weight the 1:15 mix and blend, obtain suspension liquid;
(2) drip acetic acid in above-mentioned suspension liquid, in prasugrel hydrobromide: acetic acid (w:v)=1:8.5 ratio adds, and stirring and dissolving is warmed up to 40 ℃, reacts 10 minutes, and then 35 ℃ are evaporated to dry;
(3) add acetone in enriched material, in acetone: prasugrel hydrobromide (v:w)=5:1 ratio adds, stirring and dissolving, and placement is spent the night, and separates out solid, and 60 ℃ of vacuum-dryings obtain the finished product prasugrel hydrobromide acetic acid compound.
Embodiment
The preparation of embodiment 1 prasugrel hydrobromide acetic acid compound
(1) in reaction flask, add 10g by prasugrel and 50g water, 50g acetonitrile, mix and blend, obtain suspension liquid;
(2) to dripping 40% hydrobromic acid aqueous solution 5.4g and the solution of acetic acid 100ml preparation in the prasugrel suspension liquid, stirring and dissolving, be warmed up to 40 ℃, starts timing, reacts 10 minutes, and then 35 ℃ are evaporated to dry;
(3) add 50ml acetone in enriched material, stirring and dissolving, placement is spent the night, and separates out solid, and 60 ℃ of vacuum-drying 4 hours, obtain the finished product prasugrel hydrobromide acetic acid compound 12.1g, and yield is 87.9%, purity 99.9%.
The preparation of embodiment 2 prasugrel hydrobromide acetic acid compounds
(1) in reaction flask, add 121.7g by prasugrel hydrobromide and 100g water, 900g ethanol, mix and blend, obtain suspension liquid;
(2) drip the solution that acetic acid 1034.5ml prepares in the prasugrel hydrobromide suspension liquid, stirring and dissolving, be warmed up to 40 ℃, starts timing, reacts 10 minutes, and then 35 ℃ are evaporated to dry;
(3) add 608ml acetone in enriched material, stirring and dissolving, placement is spent the night, and separates out solid, and 60 ℃ of vacuum-drying 4 hours, obtain the finished product prasugrel hydrobromide acetic acid compound 128.3g, and yield is 93.2%, purity 99.9%.
The preparation of embodiment 3 prasugrel hydrobromide acetic acid compounds
(1) in reaction flask, add 100g by prasugrel and 900g water, 100g tetrahydrofuran (THF), mix and blend, obtain suspension liquid;
(2) to dripping 40% hydrobromic acid aqueous solution 54g and the solution of acetic acid 1000ml preparation in the prasugrel suspension liquid, stirring and dissolving, be warmed up to 40 ℃, starts timing, reacts 10 minutes, and then 35 ℃ are evaporated to dry;
(3) add 500ml acetone in enriched material, stirring and dissolving, placement is spent the night, and separates out solid, and 60 ℃ of vacuum-drying 4 hours, obtain the finished product prasugrel hydrobromide acetic acid compound 127.6g, and yield is 92.7%, purity 99.9%.
The preparation of Comparative Examples 1 prasugrel hydrobromide acetic acid compound
Method by embodiment in CN101255169B 1 is tested, prasugrel 25g is dissolved in acetonitrile/ethanol (volume ratio 1/1) organic solvent and is mixed with organic solution, in this organic solution, drip containing 40% hydrobromic aqueous solution 8ml and acetic acid 150ml, room temperature reaction 5-6 hour, until react completely.Filtering-depositing after concentrated, obtain prasugrel hydrobromide acetic acid compound crude product.Use ethyl alcohol recrystallization, obtain prasugrel hydrobromide acetic acid compound 29.03g, yield 84.3%, purity 99.2%.
Embodiment 4 structural identifications
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:51.33%; H:4.91%; F:3.74%; N:2.73%; O:15.50%; S:6.21%; Br:15.55%.
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 (5)
1. the prasugrel hydrobromide acetic acid compound compound shown in a formula (I),
Molecular formula: C
22h
25fNO
5sBr, molecular weight: 514.41, it is characterized in that, take prasugrel as intermediate, with Hydrogen bromide and acetic acid reaction, make; Perhaps, take prasugrel hydrobromide as intermediate, make with acetic acid reaction.
2. prasugrel hydrobromide acetic acid compound compound according to claim 1, its synthesis step is:
(1) prasugrel is added in mixed solvent and stirs, obtain suspension liquid;
(2) drip the solution of Hydrogen bromide and acetic acid preparation in above-mentioned prasugrel suspension liquid, stirring and dissolving, heat up, and reaction, then be condensed into enriched material;
(3) add organic solvating agent in enriched material, preferred acetone, stirring and dissolving, place, and separates out solid, and drying, obtain the finished product prasugrel hydrobromide acetic acid compound.
3. prasugrel hydrobromide acetic acid compound compound according to claim 1, its synthesis step is:
(1) prasugrel hydrobromide is added in mixed solvent and stirs, obtain suspension liquid;
(2) drip acetic acid in above-mentioned suspension liquid, stirring and dissolving, heat up, reaction, and then concentrating under reduced pressure becomes enriched material;
(3) add organic solvating agent in enriched material, preferred acetone, stirring and dissolving, place, and separates out solid, and drying, obtain the finished product prasugrel hydrobromide acetic acid compound.
4. according to the synthetic method of claim 2 or the described prasugrel hydrobromide acetic acid of 3 any one compound, it is characterized in that in step (1), mixed solvent is the solvent that water and organic solvent weight ratio 0.1-1:1-0.1 are mixed.
5. according to the synthetic method of claim 2 or the described prasugrel hydrobromide acetic acid of 3 any one compound, it is characterized in that organic solvent is selected from one or more in acetonitrile, ethanol, methyl alcohol, tetrahydrofuran (THF), ethyl acetate, acetone, ether.
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