CN105753882A - Medicinal acid addition compound of prasugrel, and preparation method thereof - Google Patents
Medicinal acid addition compound of prasugrel, and preparation method thereof Download PDFInfo
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- CN105753882A CN105753882A CN201410777365.5A CN201410777365A CN105753882A CN 105753882 A CN105753882 A CN 105753882A CN 201410777365 A CN201410777365 A CN 201410777365A CN 105753882 A CN105753882 A CN 105753882A
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- prasugrel
- acid addition
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Abstract
The invention belongs to the technical field of pharmacy, and relates to a medicinal acid addition compound of prasugrel, and a preparation method thereof. The method comprises the following steps: dissolving or suspending prasugrel in an organic solvent according to a mass ratio of prasugrel to the organic solvent of 1:3-7, adding an acidic solution to the organic solvent according to a molar ratio of an acid in the acidic solution to prasugrel of 1:1-2, and reacting at -20-70DEG C for 0.5-10h to prepare the medicinal acid addition compound of prasugrel. Parts of like prasugrel salt compounds with the advantages of easy synthesis, good water solubility and good stability are found through researches of salt formation of prasugrel and parts of organic acids or inorganic acids, and the medicinal acid addition compound of prasugrel can be used to prepare clinic anticoagulation and antithrombotic medicines for treating relevant diseases, and has a very good effect.
Description
Technical field
The invention belongs to pharmaceutical technology field, pharmaceutically acceptable acid addition salt being specifically related to a kind of prasugrel and preparation method thereof.
Background technology
Prasugrel (Prasugrel) is a kind of replacement hydrogenated pyridine compounds, chemical name is 2-[2-(acetoxyl group)-6,7-dihydro-thiophene also [3,2-c] pyridine-5 (4H)-Ji]-1-cyclopropyl-2-(2-fluorophenyl) ethyl ketone, its structural formula such as following formula, it it is potent a new generation of a new generation platelet P2Y12 receptor blocking agent, it is applied to stable angina pectoris and acute coronary syndrome gets involved operation, the incidence rate of ischemic event can be substantially reduced.Its water solublity and bioavailability can be improved by prasugrel free alkali is made salt, therefore particularly important in study of pharmacy.
Patent 200810014873.2 discloses the organic acid of prasugrel or the preparation method of inorganic acid salt, organic acid is methanesulfonic acid, fumaric acid, acetic acid, oxalic acid, succinic acid, tartaric acid, salicylic acid or aspirin, and mineral acid is hydrobromic acid, hydroiodic acid, sulphuric acid or phosphoric acid.
United States Patent (USP) 6693115B2 discloses the hydrochlorate of prasugrel and the preparation method of maleate.
Summary of the invention
Pharmaceutically acceptable acid addition salt that it is an object of the invention to provide a kind of prasugrel and preparation method thereof, makes up the deficiencies in the prior art.
The pharmaceutically acceptable acid addition salt of a kind of prasugrel of the present invention, it is characterised in that there is following structure:
Wherein n=1,2 or 3, A is acid, it is preferred to nitric acid.
In the present invention, this compound includes its semihydrate, monohydrate, half as much again hydrate, dihydrate, two times of semihydrates, trihydrate, three times of semihydrates, four times of hydrates, four times of semihydrates, pentahydrate, five times of semihydrates, hexahydrate, six times of semihydrates, heptahydrate, seven times of semihydrates, eight hydrates, octuple semihydrate, nonahydrate, nine times of semihydrates or decahydrate.
The preparation method of the pharmaceutically acceptable acid addition salt of the prasugrel of the present invention, comprises the steps:
It is 1:3～7 according to the mass ratio of prasugrel and solvent, prasugrel is dissolved or is suspended in organic solvent, add acid solution to react in organic solvent, reaction temperature-20～70 DEG C, 0.5～10 hour response time, generate target product, then target product is collected and obtains prasugrel salt compound.
In above-mentioned preparation is reacted:
(1) reaction temperature changes with the change of reagent or solvent etc., but reaction temperature is generally at-20～70 DEG C, it is preferable that-15～50 DEG C, more preferably-10～30 DEG C, response time changes, 0.5～10 hour usual response time also with the change of reagent or temperature, it is preferable that 1～4 hour.
(2) acid is excessive relative to prasugrel in the reaction, prasugrel: the sour mol ratio in acid solution is 1:1～2, it is preferable that 1:1～1.5.If the mixed liquor that acid solution is acid and organic solvent, then acid is 1:1～4 with the volume ratio of organic solvent.
(3) organic solvent selected in the reaction includes ethers, alcohols, nitrile, ketone, halogenated alkane, the mixture of alkane or the one or two or more arbitrary proportion in aromatic hydrocarbons organic solvent.The ethanol/dichloromethane of organic solvent preferred volume ratio 1:1 or the acetone/diethyl ether of 1:2.
It is an advantage of the current invention that by the salt that becomes of prasugrel with part organic acid or mineral acid is studied, it is found that a part is easily-synthesized, has the prasugrel salt compounds of good aqueous solubility and good stability, can be used for preparing clinical anticoagulation, antithrombotic and treatment relevant disease, there is good effect.
Detailed description of the invention
Below in conjunction with embodiment, the invention will be further described.
Embodiment 1:
2.5g prasugrel is dissolved in the ethanol/dichloromethane organic solvent of 8g volume ratio 1:1, in this organic solvent, drip concentrated nitric acid 0.5ml, react 2 hours under room temperature, till TLC detection reacts completely, filter precipitation after concentration, obtain prasugrel nitrate crude product.With ethyl alcohol recrystallization, obtain prasugrel nitrate fine work 2.65g, yield 90.8%.Purity 99.8% (HPLC), fusing point 93 DEG C.
Embodiment 2:
2.5g prasugrel is dissolved in the ethanol/dichloromethane organic solvent of 10g volume ratio 1:1, the ethanol/dichloromethane mixed liquor of the volume ratio 1:1 of concentrated nitric acid 0.6ml and 1ml is dripped in this organic solvent, react 4 hours under room temperature, till TLC detection reacts completely, filter precipitation after concentration, obtain prasugrel nitrate crude product.With ethyl alcohol recrystallization, obtain prasugrel nitrate fine work 2.85g, yield 97.6%.Purity 99.8% (HPLC), fusing point 93 DEG C.
Embodiment 3:
2.5g prasugrel is dissolved in the acetone/diethyl ether organic solvent of 14g volume ratio 1:2, in this organic solvent, drips concentrated nitric acid 0.6ml, react 3 hours under ice bath, till TLC detection reacts completely, filter precipitation after concentration, obtain prasugrel nitrate crude product.With acetone recrystallization, obtain prasugrel nitrate fine work 2.78g, yield 95.2%.Purity 99.8% (HPLC), fusing point 92 DEG C.
Embodiment 4:
2.5g prasugrel is dissolved in the acetone/diethyl ether organic solvent of 17g volume ratio 1:2, the acetone/diethyl ether mixed liquor of the volume ratio 1:2 of concentrated nitric acid 0.6ml and 2ml is dripped in this organic solvent, react 8 hours under room temperature, till TLC detection reacts completely, filter precipitation after concentration, obtain prasugrel nitrate crude product.With ethyl alcohol recrystallization, obtain prasugrel nitrate fine work 2.82g, yield 96.5%.Purity 99.8% (HPLC), fusing point 93 DEG C.
Claims (9)
1. the pharmaceutically acceptable acid addition salt of a prasugrel, it is characterised in that there is following structure:
Wherein n=1,2 or 3, A is acid.
2. the pharmaceutically acceptable acid addition salt of prasugrel according to claim 1, it is characterised in that A is nitric acid.
3. the pharmaceutically acceptable acid addition salt of prasugrel according to claim 1, it is characterised in that this compound includes its semihydrate, monohydrate, half as much again hydrate, dihydrate, two times of semihydrates, trihydrate, three times of semihydrates, four times of hydrates, four times of semihydrates, pentahydrate, five times of semihydrates, hexahydrate, six times of semihydrates, heptahydrate, seven times of semihydrates, eight hydrates, octuple semihydrate, nonahydrate, nine times of semihydrates or decahydrate.
4. the preparation method of the pharmaceutically acceptable acid addition salt of the prasugrel described in a claim 1, it is characterized in that according to the mass ratio of prasugrel and organic solvent be 1:3～7, prasugrel is dissolved or is suspended in organic solvent, again acid solution is joined in organic solvent and react, the mol ratio of the acid in acid solution and prasugrel is 1:1～2, reaction temperature-20～70 DEG C, in 0.5～10 hour response time, can be prepared by the pharmaceutically acceptable acid addition salt of prasugrel.
5. the preparation method of the pharmaceutically acceptable acid addition salt of prasugrel according to claim 4, it is characterised in that described organic solvent is ethers, alcohols, nitrile, ketone, halogenated alkane, the mixture of alkane or the one or two or more arbitrary proportion in aromatic hydrocarbons organic solvent.
6. the preparation method having the pharmaceutically acceptable acid addition salt seeking the prasugrel described in 5 according to right, it is characterised in that described organic solvent is the ethanol/dichloromethane of volume ratio 1:1.
7. the preparation method having the pharmaceutically acceptable acid addition salt seeking the prasugrel described in 5 according to right, it is characterised in that described organic solvent is the acetone/diethyl ether of volume ratio 1:2.
8. the preparation method of the pharmaceutically acceptable acid addition salt of prasugrel according to claim 4, it is characterised in that prasugrel is 1:1～1.5 with the sour mol ratio in acid solution.
9. the preparation method of the pharmaceutically acceptable acid addition salt of prasugrel according to claim 4, it is characterised in that reaction temperature is-10～30 DEG C, the response time is 1～4 hour.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410777365.5A CN105753882A (en) | 2014-12-15 | 2014-12-15 | Medicinal acid addition compound of prasugrel, and preparation method thereof |
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| CN201410777365.5A CN105753882A (en) | 2014-12-15 | 2014-12-15 | Medicinal acid addition compound of prasugrel, and preparation method thereof |
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| CN201410777365.5A Pending CN105753882A (en) | 2014-12-15 | 2014-12-15 | Medicinal acid addition compound of prasugrel, and preparation method thereof |
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Application publication date: 20160713 |
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