CN102617593A - Method for preparing prasugrel intermediate - Google Patents
Method for preparing prasugrel intermediate Download PDFInfo
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- CN102617593A CN102617593A CN2012100645799A CN201210064579A CN102617593A CN 102617593 A CN102617593 A CN 102617593A CN 2012100645799 A CN2012100645799 A CN 2012100645799A CN 201210064579 A CN201210064579 A CN 201210064579A CN 102617593 A CN102617593 A CN 102617593A
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- preparation
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- prasugrel
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- prasugrel intermediate
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention belongs to the technical field of medicinal synthesis, and particularly relates to a method for preparing a prasugrel intermediate. The method is characterized in that a compound (I) and a Grignard reagent (II) react to form the prasugrel intermediate (III). The method has the advantages that the problem that prasugrel contains a large number of impurities and is difficult to purify due to the generation of polybrominated compounds in a compound V-1 in the conventional route is solved; and a process is simple, and a rare reagent is not required.
Description
Technical field
The invention belongs to medical synthesis technical field, be specifically related to the preparation method of one type of prasugrel intermediate.
Background technology
The Thienopyridines medicine is ticlopidine for example, and clopidogrel has been used to treat the formation of thrombus and relevant disease.Prasugrel hydrochloride having also goes on the market trade(brand)name Effient as the oral antiplatelet drug of thiophene pyridines of a new generation.Prasugrel structural formula such as IV are a kind of adp (ADP) receptor antagonists, and it belongs to prodrug, and itself does not have activity, effectively changes into its active metabolite R-138727 in vivo; R-138727 has reduced the dependency of pair cell pigment P-450 enzyme, and rapidly, specific, the irreversible purine bases acceptor that is attached to thrombocyte P2Y12, suppress ADP and regulate hematoblastic activity and gathering.
Patent US5288726 has described classical prasugrel preparation technology:
US5874581 has described the intermediate preparation prasugrel through the silica-based protection of alkane:
CN101250192 has reported through the synthetic prasugrel of the midbody of alkyl protection:
WO2009/006859 has described with the novel process of methylsulfonic acid base as the synthetic prasugrel of leavings group:
WO2010/070677 has described following new prasugrel preparation technology:
CN101775025 has described following preparation technology:
All technology has all experienced III or the VII key intermediate prepares prasugrel, yet nearly all method that these prepare key intermediate all is the condensation of V and VI.
L is leavings group: Br (V-1), Cl (V-2), SO
2Me (V-3); R is Wasserstoffatoms (VI-1) or hydroxy-protective group: tertiary butyl dimethyl-silica-based (VI-2), methyl (VI-3) etc.WO2009/068924 has summarized the preparation of V-1 (L=bromine), but always has a certain amount of dibromo thing, and it is to be difficult to remove; Yet compound V needs rare reagent when being other leavings group replacement, and condition is harsh.
Summary of the invention
The preparation method who the purpose of this invention is to provide one type of prasugrel intermediate, i.e. the preparation of prasugrel key intermediate III, this midbody can be avoided the appearance of bromo-derivative in the preparation process, and technology is simple, does not need rare reagent.
The preparation method of one type of prasugrel intermediate of the present invention obtains prasugrel intermediate (III) through compound (I) and Grignard reagent (II) reaction;
In the general formula: the PG in the compound (I) is a hydroxy-protective group, and R is a carboxy protective group; X is a halogen atom in the Grignard reagent (II).
Wherein, the PG in the compound (I) is preferably alkyl or alkane is silica-based, and PG can be silica-based for methyl, trityl or tertiary butyl dimethyl-.
R in the compound (I) is preferably the hydro carbons group, and R can be methyl, ethyl or propyl group.
X is preferably chlorine atom or bromine atoms in the Grignard reagent (II).
Temperature of reaction of the present invention is preferably 0～70 ℃, and the reaction times is preferably 0.5～10 hour, and the mol ratio of compound (I) and Grignard reagent (II) is preferably 1: 1～and 12.
The preparation of compound (I) can be prepared from through following two kinds of operational paths:
Compound (VIII) bromination obtains compound (IX), and this bromination process dibrominated thing be difficult for to produce, and the rectifying purification of stable is easy to industriallization, thereby has avoided the defective of traditional method.
The invention has the advantages that: overcome the appearance of many bromo-derivatives among the compound V-1 in the traditional route, be difficult to separate, brought a large amount of impurity, caused the problem of purification difficult to prasugrel.It is simple that the present invention has technology simultaneously, do not need the advantage of rare reagent.
Embodiment
Below in conjunction with embodiment the present invention is further specified.
Embodiment 1:
Prasugrel intermediate (III): 2-methoxyl group-5-(α-cyclopropyl carbonyl-2-luorobenzyl)-4,5,6, the preparation of 7-six hydrogen thieno-s [3,2-c] pyridines (pG=methyl).
4.4g magnesium, 200mg iodine join in the 150ml anhydrous tetrahydro furan, the 50ml anhydrous tetrahydro furan that is dissolved with the 15g cyclopropane bromide then dropwise joins in the reaction flask, refluxes then 2 hours, obtains Grignard reagent.Be dissolved with 34.6g 2-methoxyl group-5-(α-methoxycarbonyl-2-luorobenzyl)-4,5,6,7-six hydrogen thieno-s [3; 2-c] the 80mlTHF solution of pyridine (R=methyl) joins in the Grignard reagent gradually, and 50 ℃ were stirred 3 hours, were as cold as 10% ammonium chloride that room temperature adds 50ml then and reduced the solubleness of resultant with this; Add 80ml*4DCM and extract, saturated nacl aqueous solution 100ml*2 washing, dry evaporate to dryness; With the mixing solutions recrystallization of toluene and acetonitrile, vacuum-drying gets 18.2g, yield 51.2%.
Embodiment 2:
Prasugrel intermediate (III): 2-three benzyloxies-5-(α-cyclopropyl carbonyl-2-luorobenzyl)-4,5,6, the preparation of 7-six hydrogen thieno-s [3,2-c] pyridines (PG=trityl).
4.4g magnesium, 200mg iodine join in the 150ml anhydrous diethyl ether, the 50ml anhydrous diethyl ether that is dissolved with the 15g cyclopropane bromide then dropwise joins in the reaction flask, refluxes then 3 hours, obtains Grignard reagent.Be dissolved with 65g 2-three benzyloxies-5-(α-ethoxycarbonyl-2-luorobenzyl)-4,5,6,7-six hydrogen thieno-s [3; 2-c] the 160mlTHF solution of pyridine (R=ethyl) joins in the Grignard reagent gradually, and 40 ℃ were stirred 1 hour, were as cold as 10% ammonium chloride that room temperature adds 80ml then and reduced the solubleness of resultant with this; Add 150ml*4DCM and extract, saturated nacl aqueous solution 120ml*2 washing, dry evaporate to dryness; With the mixing solutions recrystallization of toluene and acetonitrile, vacuum-drying gets 27.15g, yield 42%.
Embodiment 3:
Prasugrel intermediate (III): 2-tertiary butyl dimethyl-is silica-based-5-(α-cyclopropyl carbonyl-2-luorobenzyl)-4,5,6, the preparation of 7-six hydrogen thieno-s [3,2-c] pyridines (PG=tertiary butyl dimethyl-is silica-based).
4.4g magnesium, 200mg iodine join in the 150ml anhydrous diethyl ether, the 50ml anhydrous diethyl ether that is dissolved with 9.48g chloro Trimetylene then dropwise joins in the reaction flask, refluxes then 3 hours, obtains Grignard reagent.Be dissolved with 46.5g 2-tertiary butyl dimethyl-silica-based-5-(α-ethoxycarbonyl-2-luorobenzyl)-4,5,6; The 160mlTHF solution of 7-six hydrogen thieno-s [3,2-c] pyridines (R=ethyl) joins in the Grignard reagent gradually, stirring at room 8 hours; Be as cold as 10% ammonium chloride that room temperature adds 80ml then and reduce the solubleness of resultant, add 100ml*4DCM and extract, saturated nacl aqueous solution 150ml*2 washing with this; Dry evaporate to dryness; With the mixing solutions recrystallization of toluene and acetonitrile, vacuum-drying gets 20.01g, yield 43.6%.
Claims (9)
1. the preparation method of one type of prasugrel intermediate is characterized in that obtaining prasugrel intermediate (III) through compound (I) and Grignard reagent (II) reaction;
In the general formula: the PG in the compound (I) is a hydroxy-protective group, and R is a carboxy protective group; X is a halogen atom in the Grignard reagent (II).
2. the preparation method of one type of prasugrel intermediate according to claim 1 is characterized in that the PG in the compound (I) is that alkyl or alkane are silica-based.
3. the preparation method of one type of prasugrel intermediate according to claim 2 is characterized in that the PG in the compound (I) is that methyl, trityl or tertiary butyl dimethyl-are silica-based.
4. the preparation method of one type of prasugrel intermediate according to claim 1 is characterized in that the R in the compound (I) is the hydro carbons group.
5. the preparation method of one type of prasugrel intermediate according to claim 4 is characterized in that the R in the compound (I) is methyl, ethyl or propyl group.
6. the preparation method of one type of prasugrel intermediate according to claim 1 is characterized in that X is chlorine atom or bromine atoms in the Grignard reagent (II).
7. the preparation method of one type of prasugrel intermediate according to claim 1 is characterized in that temperature of reaction is 0～70 ℃.
8. the preparation method of one type of prasugrel intermediate according to claim 1 is characterized in that the reaction times is 0.5～10 hour.
9. the preparation method of one type of prasugrel intermediate according to claim 1 is characterized in that the compound (I) and the mol ratio of Grignard reagent (II) are 1: 1～1.2.
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| CN2012100645799A CN102617593A (en) | 2012-03-13 | 2012-03-13 | Method for preparing prasugrel intermediate |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104280466A (en) * | 2013-07-09 | 2015-01-14 | 山东新时代药业有限公司 | Method for analyzing and detecting Prasugrel intermediate |
Citations (5)
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| CN101343278A (en) * | 2007-12-11 | 2009-01-14 | 鲁南制药集团股份有限公司 | Preparation method for hydrogenated pyridine derivant and its salt |
| CN101402643A (en) * | 2008-11-11 | 2009-04-08 | 上海现代制药股份有限公司 | Industrial production method for prasugrel |
| CN102030761A (en) * | 2009-12-24 | 2011-04-27 | 浙江普洛家园药业有限公司 | Prasugrel midbody and preparation method thereof |
| CN102276436A (en) * | 2010-06-10 | 2011-12-14 | 浙江九洲药业股份有限公司 | Preparation method of aromatic cyclopropyl ketone compound and purpose |
| CN102311325A (en) * | 2010-06-29 | 2012-01-11 | 山东新华制药股份有限公司 | Method for preparing prasugrel intermediate cyclopropyl-2-fluorine benzyl ketone |
-
2012
- 2012-03-13 CN CN2012100645799A patent/CN102617593A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101343278A (en) * | 2007-12-11 | 2009-01-14 | 鲁南制药集团股份有限公司 | Preparation method for hydrogenated pyridine derivant and its salt |
| CN101402643A (en) * | 2008-11-11 | 2009-04-08 | 上海现代制药股份有限公司 | Industrial production method for prasugrel |
| CN102030761A (en) * | 2009-12-24 | 2011-04-27 | 浙江普洛家园药业有限公司 | Prasugrel midbody and preparation method thereof |
| CN102276436A (en) * | 2010-06-10 | 2011-12-14 | 浙江九洲药业股份有限公司 | Preparation method of aromatic cyclopropyl ketone compound and purpose |
| CN102311325A (en) * | 2010-06-29 | 2012-01-11 | 山东新华制药股份有限公司 | Method for preparing prasugrel intermediate cyclopropyl-2-fluorine benzyl ketone |
Non-Patent Citations (1)
| Title |
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| 段妍琴等: "合成盐酸普拉格雷的工艺改进", 《合成化学》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104280466A (en) * | 2013-07-09 | 2015-01-14 | 山东新时代药业有限公司 | Method for analyzing and detecting Prasugrel intermediate |
| CN104280466B (en) * | 2013-07-09 | 2018-05-01 | 山东新时代药业有限公司 | A kind of analyzing detecting method of prasugrel intermediate |
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Application publication date: 20120801 |