CN101985450B - Prasugrel salt and preparation method thereof - Google Patents
Prasugrel salt and preparation method thereof Download PDFInfo
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- CN101985450B CN101985450B CN2010105340849A CN201010534084A CN101985450B CN 101985450 B CN101985450 B CN 101985450B CN 2010105340849 A CN2010105340849 A CN 2010105340849A CN 201010534084 A CN201010534084 A CN 201010534084A CN 101985450 B CN101985450 B CN 101985450B
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Abstract
The invention relates to Prasugrel salt and a preparation method thereof. The Prasugrel salt compound has a structure as formula II, wherein HA is acid, including cystine, asparagine, phenylalanine, threonine, tyrosine, glutamine, serine, methionine, tryptophane, valine, leucine, isoleucine, glycine, alanine and proline.
Description
Technical field
The present invention relates to platelet suppressant drug prasugrel (Prasugrel) salt and preparation method thereof.
Background technology
The compound of structure shown in the formula I is the precursor structure (being called the prasugrel base in this patent) of oral antiplatelet drug Prasugrel (prasugrel), is come to develop with Japanese first pharmacy, three deciliters by United States pharmaceutical company's gift.U.S. Pat 5288726 discloses several kinds of new THTPs and the pyridine compounds and their that comprises formula I compound, and they have anticoagulation, antithrombotic effect preferably, can be used for the treatment of relative diseases such as heart trouble.
Usually, use the pharmacy acceptable salt of medicinal compound.As far as antiplatelet drug for example formula I compound also be so, this makes that the pharmacy acceptable salt of this compounds of preparation is particularly important.To this, forefathers have also done certain work in this respect.U.S. Pat 6693115B2 discloses vitriol, nitrate salt, phosphoric acid salt, trifluoroacetate, mesylate, tosilate, hydrochloride and the PHENRAMINE MALEATE of formula I compound; The particularly preparation of hydrochloride and PHENRAMINE MALEATE, the form of these two kinds of salt they stability and drug effect aspect raising is in various degree all arranged.
Patent WO2009066326A2 discloses Hydrogen bromide, Phenylsulfonic acid, oxalic acid, fumaric acid, oxysuccinic acid, SUMATRIPTAN SUCCINATE of formula I compound etc.
Patent WO2009062044A2 discloses tartrate, Hydrocerol A, phenylformic acid, hydroiodic acid HI, acetate, propionic acid, caproic acid, enanthic acid, formic acid, malonate of formula I compound etc.
Vitriol, hydrobromate, hydriodate, nitrate salt, oxalate, trifluoroacetate, mesylate, tosilate of formula I compound etc. are disclosed among the Chinese patent CN101177430A.
The pharmaceutical salts form of fumaric acid, Succinic Acid, tartrate, Whitfield's ointment, Xaxa, phosphoric acid etc. is disclosed among the Chinese patent CN101255169.
A large amount of prasugrel organic acid salts is disclosed among the Chinese patent CN101633662A.
Though disclose a large amount of prasugrel salts in numerous patents; But the performance of various salt such as solvability, thermostability, moisture absorption etc. are not all provided detailed evaluation and test; Through the disclosed salt of our researchs, except that three common disclosed hydrochlorides and PHENRAMINE MALEATE, other various salt do not have remarkable advantages on pharmaceutical characteristic; Above-mentioned character is said then quite important to pharmacy acceptable salt, the pharmacy acceptable salt that therefore continues the searching novel type is still quite important.
Summary of the invention
In order to remedy the prior art deficiency, obtain the well behaved pharmaceutically acceptable prasugrel salt that can be sure of, we have screened various acid, and unexpected the discovery has several to be suitable for preparing prasugrel salt in the amino acid.Therefore the present invention provides several kinds of new prasugrel salts and preparation method thereof.
Prasugrel salt compound of the present invention has the structure shown in the formula II:
Wherein, HA is acid, is selected from Gelucystine, l-asparagine acid, phenylalanine(Phe), Threonine, tyrosine, glutamine, Serine, methionine(Met), tryptophane, Xie Ansuan, leucine, Isoleucine, glycocoll, L-Ala, proline(Pro).
Preferably, the HA among the formula II is Gelucystine, phenylalanine(Phe), Threonine.
The preparation method of prasugrel salt compound of the present invention comprises the steps:
With prasugrel base and acid in molar ratio 1: 1-2 reacts in organic solvent, and 0～100 ℃ of temperature of reaction was reacted 1～24 hour, generates title product, from reaction solution, collects prasugrel salt.
Said organic solvent comprises one of ethers, alcohols, nitrile, ketone, halogenated alkane, alkane or aromatic hydrocarbons organic solvent or combination.The consumption of organic solvent is advisable can dissolve prasugrel.
Preferably, among the above-mentioned preparation method, earlier the prasugrel base is dissolved in the organic solvent, is dissolved in acid in the same organic solvent again and is added drop-wise in the organic solution of prasugrel base and react.
Prasugrel salt compound of the present invention; Particularly prasugrel cystine salt, prasugrel phenylalanine(Phe) salt, prasugrel Threonine salt have good water-solubility, thermostability and lower moisture absorption and salt of the prior art and relatively have the following advantages:
Comparative data is following:
Solubleness is relatively in the water:
| Hydrochloride | PHENRAMINE MALEATE | Cystine salt | Phenylalanine(Phe) salt | Threonine salt | |
| 25℃ | 3 | 2.5 | 2.7 | 2.4 | 2.6 |
| 35℃ | 3.6 | 3.2 | 3.3 | 3.0 | 3.3 |
| 45℃ | 4.3 | 3.8 | 4.0 | 3.5 | 4.1 |
Thermostability compares:
Supply test agent in 50 ℃ of vacuum held, detect its different period purity and change.
| 1h | 3h | 6h | 10h | |
| Hydrochloride | 99.8％ | 99.8％ | 99.7％ | 99.6％ |
| PHENRAMINE MALEATE | 99.8％ | 99.7％ | 99.5％ | 99.4％ |
| Cystine salt | 99.8％ | 99.8％ | 99.8％ | 99.7％ |
| Phenylalanine(Phe) salt | 99.8％ | 99.8％ | 99.7％ | 99.7％ |
| Threonine salt | 99.8％ | 99.8％ | 99.8％ | 99.8％ |
Moisture absorption compares:
Supply test agent in 25 ℃, relative humidity 50% held, detecting its quality increases per-cent.
| 1h | 5h | 10h | 24h | |
| Hydrochloride | 0.5％ | 1.2％ | 3％ | 5％ |
| PHENRAMINE MALEATE | 0.1％ | 0.2％ | 0.9％ | 1.2％ |
| Cystine salt | 0.1％ | 0.1％ | 0.3％ | 0.8％ |
| Phenylalanine(Phe) salt | 0 | 0.1％ | 0.3％ | 0.5％ |
| Threonine salt | 0 | 0.2％ | 0.6％ | 1％ |
Excellent results:
The present invention is through to the sour salify research of prasugrel alkali and part, found that a part has good aqueous solubility, Heat stability is good, prasugrel salt compounds that water absorbability is low, the medicine that is used to prepare clinical anticoagulation, antithrombotic and treats relative disease.
Embodiment
For more detailed explanation the present invention, provide following preparation instance.But scope of the present invention is not limited to this.
Embodiment 1: the prasugrel cystine salt
Prasugrel base 3.73g is dissolved in proper amount of acetone/methyl alcohol (volume ratio 1/1), drips the aforementioned organic solution of Gelucystine 2.52g, reflux 2h, cooled and filtered gets prasugrel cystine salt bullion.Use re-crystallizing in ethyl acetate, get prasugrel cystine salt elaboration 4.9g.Fusing point: 250 ℃ (charing).
Embodiment 2: prasugrel phenylalanine(Phe) salt
Prasugrel base 3.73g is dissolved in proper amount of acetone/methyl alcohol (volume ratio 1/1), drips the aforementioned organic solution of phenylalanine(Phe) 1.73g, reflux 2h, cooled and filtered gets prasugrel phenylalanine(Phe) salt bullion.Use re-crystallizing in ethyl acetate, get prasugrel phenylalanine(Phe) salt elaboration 4.19g.Fusing point: 250 ℃ (charing).
Embodiment 3: prasugrel Threonine salt
Prasugrel base 3.73g is dissolved in proper amount of acetone/methyl alcohol (volume ratio 1/1), drips the aforementioned organic solution of Threonine 1.25g, reflux 2h, cooled and filtered gets prasugrel Threonine salt bullion.Use re-crystallizing in ethyl acetate, get prasugrel Threonine salt elaboration 3.44g.Fusing point: 250 ℃ (charing).
Claims (2)
1. prasugrel salt compound, said compound has the structure shown in the formula II:
Wherein, HA is acid, is selected from Gelucystine, phenylalanine(Phe) or Threonine.
2. the preparation method of the described prasugrel salt compound of claim 1; It is characterized in that; Comprise the steps: prasugrel base and corresponding acid in molar ratio 1: 1-2 reacts in organic solvent; 0～100 ℃ of temperature of reaction was reacted 1～24 hour, from reaction solution, collected prasugrel salt.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN2010105340849A CN101985450B (en) | 2010-11-02 | 2010-11-02 | Prasugrel salt and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN2010105340849A CN101985450B (en) | 2010-11-02 | 2010-11-02 | Prasugrel salt and preparation method thereof |
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| CN101985450A CN101985450A (en) | 2011-03-16 |
| CN101985450B true CN101985450B (en) | 2012-07-11 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102260276A (en) * | 2011-06-10 | 2011-11-30 | 云南白药集团股份有限公司 | Prasugrel citrate and its preparation method |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6693115B2 (en) * | 2000-07-06 | 2004-02-17 | Sankyo Company, Limited | Acid addition salts of hydropyridine derivatives |
| CN101177430A (en) * | 2007-12-11 | 2008-05-14 | 鲁南制药集团股份有限公司 | Hydrogenated pyridine derivative and method for preparing salt thereof |
| CN101633662A (en) * | 2009-07-30 | 2010-01-27 | 巢杰 | Prasugrel pharmaceutical acid addition salt as well as preparation method and pharmaceutical application thereof |
| CN101255169B (en) * | 2008-03-26 | 2010-11-10 | 山东大学 | Prasugrel salt and preparation method thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100261908A1 (en) * | 2007-11-09 | 2010-10-14 | Dr. Reddy's Laboratories Ltd. | Processes for the preparation of prasugrel , and its salts and polymorphs |
| WO2009066326A2 (en) * | 2007-11-19 | 2009-05-28 | Msn Laboratories Limited | Improved process for the preparation of prasugrel and its pharmaceutically acceptable salts |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6693115B2 (en) * | 2000-07-06 | 2004-02-17 | Sankyo Company, Limited | Acid addition salts of hydropyridine derivatives |
| CN101177430A (en) * | 2007-12-11 | 2008-05-14 | 鲁南制药集团股份有限公司 | Hydrogenated pyridine derivative and method for preparing salt thereof |
| CN101255169B (en) * | 2008-03-26 | 2010-11-10 | 山东大学 | Prasugrel salt and preparation method thereof |
| CN101633662A (en) * | 2009-07-30 | 2010-01-27 | 巢杰 | Prasugrel pharmaceutical acid addition salt as well as preparation method and pharmaceutical application thereof |
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| CN101985450A (en) | 2011-03-16 |
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Owner name: CHINA RESOURCES SAIKE PHARMACEUTICAL CO., LTD. Free format text: FORMER NAME: BEIJING SAIKE PHARMACEUTICAL CO., LTD. |
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Address after: 100021 Beijing city Chaoyang District West business center boziwan Jinhai rich 402 (A) 21 storey building Patentee after: China Resources Saike Pharmaceutical Co., Ltd. Address before: 100021 Beijing city Chaoyang District West business center boziwan Jinhai rich 402 (A) 21 storey building Patentee before: Saike Pharmaceutical Co., Ltd., Beijing |