CN102532157A - Medicinal acid addition salt compounds of prasugrel, and preparation method thereof - Google Patents
Medicinal acid addition salt compounds of prasugrel, and preparation method thereof Download PDFInfo
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- CN102532157A CN102532157A CN2010105912316A CN201010591231A CN102532157A CN 102532157 A CN102532157 A CN 102532157A CN 2010105912316 A CN2010105912316 A CN 2010105912316A CN 201010591231 A CN201010591231 A CN 201010591231A CN 102532157 A CN102532157 A CN 102532157A
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Abstract
The invention belongs to the technical field of drug preparation, and relates to medicinal acid addition salt compounds of prasugrel, and a preparation method thereof. According to the method, the prasugrel is dissolved or suspended in an organic solvent according to a mass ratio of the prasugrel to the organic solvent of 1:3-7; an acid solution is added to the organic solvent to carry out a reaction to prepare the medicinal acid addition salt compound of the prasugrel, wherein a molar ratio of the acid in the acid solution to the prasugrel is 1:1-2, the reaction temperature is -20-70 DEG C, and the reaction time is 0.5-10 hours. According to the present invention, with the salt forming research of the prasugrel and the partial organic acids or the partial inorganic acids, a part of prasugrel salt compounds with characteristics of easy synthesis, good water solubility and good stability are developed, wherein the compounds can be used for preparation of clinical anticoagulant drugs, antithrombotic drugs, and drugs for treatment the related diseases, and provide good effects.
Description
Technical field
The invention belongs to the pharmaceutical technology field, be specifically related to pharmaceutically acceptable acid additive salt compound of 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 be [3,2-c] pyridines-5 (4H)-yl also]-1-cyclopropyl-2-(2-fluorophenyl) ethyl ketone; Its structural formula such as figure below; Be the strong effect of a new generation thrombocyte P2Y12 receptor blocking agent of new generation, be applied to stable stenocardia and acute coronary syndrome intervene operation, can significantly reduce the incidence of ischemic event.Can improve its water-soluble and bioavailability through the prasugrel free alkali being processed salt, therefore particularly important in study of pharmacy.
Patent 200810014873.2 discloses the preparation method of the organic acid or the inorganic acid salt of prasugrel; Organic acid is methylsulfonic acid, fumaric acid, acetic acid, oxalic acid, Succinic Acid, tartrate, Whitfield's ointment or Xaxa, and mineral acid is Hydrogen bromide, hydroiodic acid HI, sulfuric acid or phosphoric acid.
USP 6693115B2 discloses the preparation method of the hydrochloride and the PHENRAMINE MALEATE of prasugrel.
Summary of the invention
The purpose of this invention is to provide pharmaceutically acceptable acid additive salt compound of a kind of prasugrel and preparation method thereof, remedy the deficiency of prior art.
The pharmaceutically acceptable acid additive salt compound of a kind of prasugrel of the present invention is characterized in that having following structure:
N=1 wherein, 2 or 3, A is acid, is preferably nitric acid.
This compound comprises its semihydrate among the present invention, monohydrate, sesqui hydrate, duohydrate, two sesquialter hydrates; Trihydrate, three sesquialter hydrates, four times of hydrates, four sesquialter hydrates, pentahydrate; Five sesquialter hydrates, hexahydrate, six sesquialter hydrates, heptahydrate, seven sesquialter hydrates; Eight hydrates, octuple semihydrate, nonahydrate, nine sesquialter hydrate or decahydrates.
The preparation method of the pharmaceutically acceptable acid additive salt compound of prasugrel of the present invention comprises the steps:
Mass ratio according to prasugrel and solvent is 1: 3～7; With prasugrel dissolving or be suspended in the organic solvent; Add acidic solution and in organic solvent, react, temperature of reaction-20～70 ℃, 0.5～10 hour reaction times; Generate title product, title product is collected promptly got the prasugrel salt compound again.
In above-mentioned preparation feedback:
(1) temperature of reaction changes with the variation of reagent or solvent etc., but temperature of reaction is usually at-20～70 ℃, preferred-15～50 ℃; More preferably-10～30 ℃; Reaction times also changes along with reagent or variation of temperature, 0.5～10 hour reaction times usually, preferred 1～4 hour.
(2) acid is excessive with respect to prasugrel in reaction, and prasugrel: the sour mol ratio in the acidic solution is 1: 1～2, preferred 1: 1～1.5.If acidic solution is the mixed solution of acid and organic solvent, then acid is 1: 1～4 with the volume of organic solvent ratio.
(3) selected organic solvent comprises ethers in reaction, alcohols, nitrile, ketone, halogenated alkane, the mixture of one or both in alkane or the aromatic hydrocarbons organic solvent or multiple arbitrary proportion.1: 1 ethanol/dichloromethane of organic solvent preferred volume ratio is 1: 2 acetone perhaps.
The invention has the advantages that through salify research prasugrel and part organic acid or mineral acid; Found a part of prasugrel salt compounds that is prone to synthesize, have good aqueous solubility and good stability; Can be used for preparing clinical anticoagulation, antithrombotic and treatment relative disease, have good effect.
Embodiment
Below in conjunction with embodiment the present invention is described further.
Embodiment 1:
The 2.5g prasugrel is dissolved in 1: 1 the ethanol/dichloromethane organic solvent of 8g volume ratio; In this organic solvent, drip concentrated nitric acid 0.5ml, reaction is 2 hours under the room temperature, till the TLC detection reaction fully; Concentrate the after-filtration deposition, get prasugrel nitrate salt bullion.Use ethyl alcohol recrystallization, get prasugrel nitrate salt elaboration 2.65g, yield 90.8%.Purity 99.8% (HPLC), 93 ℃ of fusing points.
Embodiment 2:
The 2.5g prasugrel is dissolved in 1: 1 the ethanol/dichloromethane organic solvent of 10g volume ratio; In this organic solvent, drip 1: 1 the ethanol/dichloromethane mixed solution of volume ratio of concentrated nitric acid 0.6ml and 1ml; Reaction is 4 hours under the room temperature; Till the TLC detection reaction is fully, concentrate the after-filtration deposition, get prasugrel nitrate salt bullion.Use ethyl alcohol recrystallization, get prasugrel nitrate salt elaboration 2.85g, yield 97.6%.Purity 99.8% (HPLC), 93 ℃ of fusing points.
Embodiment 3:
The 2.5g prasugrel is dissolved in 1: 2 the acetone organic solvent of 14g volume ratio; In this organic solvent, drip concentrated nitric acid 0.6ml, ice bath reacted 3 hours down, till the TLC detection reaction fully; Concentrate the after-filtration deposition, get prasugrel nitrate salt bullion.Use acetone recrystallization, get prasugrel nitrate salt elaboration 2.78g, yield 95.2%.Purity 99.8% (HPLC), 92 ℃ of fusing points.
Embodiment 4:
The 2.5g prasugrel is dissolved in 1: 2 the acetone organic solvent of 17g volume ratio; In this organic solvent, drip 1: 2 the acetone mixed solution of volume ratio of concentrated nitric acid 0.6ml and 2ml; Reaction is 8 hours under the room temperature; Till the TLC detection reaction is fully, concentrate the after-filtration deposition, get prasugrel nitrate salt bullion.Use ethyl alcohol recrystallization, get prasugrel nitrate salt elaboration 2.82g, yield 96.5%.Purity 99.8% (HPLC), 93 ℃ of fusing points.
Claims (9)
1. the pharmaceutically acceptable acid additive salt compound of a prasugrel is characterized in that having following structure:
N=1 wherein, 2 or 3, A is acid.
2. the pharmaceutically acceptable acid additive salt compound of prasugrel according to claim 1 is characterized in that A is a nitric acid.
3. the pharmaceutically acceptable acid additive salt compound of prasugrel according to claim 1 is characterized in that this compound comprises its semihydrate, monohydrate, sesqui hydrate, duohydrate; Two sesquialter hydrates, trihydrate, three sesquialter hydrates, four times of hydrates, four sesquialter hydrates; Pentahydrate, five sesquialter hydrates, hexahydrate, six sesquialter hydrates, heptahydrate; Seven sesquialter hydrates, eight hydrates, octuple semihydrate, nonahydrate, nine sesquialter hydrate or decahydrates.
4. the preparation method of the pharmaceutically acceptable acid additive salt compound of the described prasugrel of claim 1; It is characterized in that the mass ratio according to prasugrel and organic solvent is 1: 3～7, with prasugrel dissolving or be suspended in the organic solvent, acidic solution is joined in the organic solvent react again; The acid in the acidic solution and the mol ratio of prasugrel are 1: 1～2; Temperature of reaction-20～70 ℃ in 0.5～10 hour reaction times, can make the pharmaceutically acceptable acid additive salt compound of prasugrel.
5. the preparation method of the pharmaceutically acceptable acid additive salt compound of prasugrel according to claim 4 is characterized in that described organic solvent is an ethers, alcohols; Nitrile; Ketone, halogenated alkane, the mixture of one or both in alkane or the aromatic hydrocarbons organic solvent or multiple arbitrary proportion.
6. the preparation method that the pharmaceutically acceptable acid additive salt compound of asking 5 described prasugrels is arranged according to right is characterized in that described organic solvent is 1: 1 a ethanol/dichloromethane of volume ratio.
7. the preparation method that the pharmaceutically acceptable acid additive salt compound of asking 5 described prasugrels is arranged according to right is characterized in that described organic solvent is 1: 2 a acetone of volume ratio.
8. the preparation method of the pharmaceutically acceptable acid additive salt compound of prasugrel according to claim 4 is characterized in that the sour mol ratio in prasugrel and the acidic solution is 1: 1～1.5.
9. the preparation method of the pharmaceutically acceptable acid additive salt compound of prasugrel according to claim 4 is characterized in that temperature of reaction is-10～30 ℃, and the reaction times is 1～4 hour.
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| CN2010105912316A CN102532157A (en) | 2010-12-16 | 2010-12-16 | Medicinal acid addition salt compounds of prasugrel, and preparation method thereof |
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| CN2010105912316A CN102532157A (en) | 2010-12-16 | 2010-12-16 | Medicinal acid addition salt compounds of prasugrel, and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103848845A (en) * | 2012-12-07 | 2014-06-11 | 天津市汉康医药生物技术有限公司 | Prasugrel sesquihydrate and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1452624A (en) * | 2000-07-06 | 2003-10-29 | 三共株式会社 | Hydropyridine deriv. acid addition salts |
| CN101255169A (en) * | 2008-03-26 | 2008-09-03 | 山东大学 | Prasugrel salt and preparation method thereof |
| US20090069369A1 (en) * | 2007-09-12 | 2009-03-12 | Protia, Llc | Deuterium-enriched prasugrel |
-
2010
- 2010-12-16 CN CN2010105912316A patent/CN102532157A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1452624A (en) * | 2000-07-06 | 2003-10-29 | 三共株式会社 | Hydropyridine deriv. acid addition salts |
| US20090069369A1 (en) * | 2007-09-12 | 2009-03-12 | Protia, Llc | Deuterium-enriched prasugrel |
| CN101255169A (en) * | 2008-03-26 | 2008-09-03 | 山东大学 | Prasugrel salt and preparation method thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103848845A (en) * | 2012-12-07 | 2014-06-11 | 天津市汉康医药生物技术有限公司 | Prasugrel sesquihydrate and preparation method thereof |
| CN103848845B (en) * | 2012-12-07 | 2015-12-23 | 天津市汉康医药生物技术有限公司 | Prasugrel times semihydrate and preparation method thereof |
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Application publication date: 20120704 |