CN105085541A - Method for preparing prasugrel analogue - Google Patents
Method for preparing prasugrel analogue Download PDFInfo
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- CN105085541A CN105085541A CN201410191364.2A CN201410191364A CN105085541A CN 105085541 A CN105085541 A CN 105085541A CN 201410191364 A CN201410191364 A CN 201410191364A CN 105085541 A CN105085541 A CN 105085541A
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- organic alkali
- alkali agents
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- DTGLZDAWLRGWQN-UHFFFAOYSA-N prasugrel Chemical class C1CC=2SC(OC(=O)C)=CC=2CN1C(C=1C(=CC=CC=1)F)C(=O)C1CC1 DTGLZDAWLRGWQN-UHFFFAOYSA-N 0.000 title claims abstract description 14
- 238000000034 method Methods 0.000 title abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 35
- 238000006243 chemical reaction Methods 0.000 claims abstract description 21
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims abstract description 21
- 238000002360 preparation method Methods 0.000 claims abstract description 18
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims abstract description 17
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 11
- 239000005051 trimethylchlorosilane Substances 0.000 claims abstract description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- 239000003513 alkali Substances 0.000 claims description 19
- 239000003795 chemical substances by application Substances 0.000 claims description 17
- 239000007810 chemical reaction solvent Substances 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 7
- 239000011259 mixed solution Substances 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 3
- 238000010511 deprotection reaction Methods 0.000 claims description 3
- JALHGCPDPSNJNY-UHFFFAOYSA-N [5-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-6,7-dihydro-4h-thieno[3,2-c]pyridin-2-yl] acetate;hydron;chloride Chemical compound Cl.C1CC=2SC(OC(=O)C)=CC=2CN1C(C=1C(=CC=CC=1)F)C(=O)C1CC1 JALHGCPDPSNJNY-UHFFFAOYSA-N 0.000 abstract description 8
- 229960004947 prasugrel hydrochloride Drugs 0.000 abstract description 8
- 239000000126 substance Substances 0.000 abstract description 3
- 239000013558 reference substance Substances 0.000 abstract description 2
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 abstract 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 abstract 1
- 239000007795 chemical reaction product Substances 0.000 abstract 1
- 239000000047 product Substances 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 3
- AEMXNRIHRLEYAK-UHFFFAOYSA-N pyridin-2-yl acetate Chemical compound CC(=O)OC1=CC=CC=N1 AEMXNRIHRLEYAK-UHFFFAOYSA-N 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 208000007536 Thrombosis Diseases 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 150000002576 ketones Chemical group 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 208000004476 Acute Coronary Syndrome Diseases 0.000 description 1
- -1 IV compound Chemical class 0.000 description 1
- 229940127218 antiplatelet drug Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- KAVSMINTEBGDTI-UHFFFAOYSA-N pyridine;thiophene Chemical class C=1C=CSC=1.C1=CC=NC=C1 KAVSMINTEBGDTI-UHFFFAOYSA-N 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229950004288 tosilate Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
Abstract
The invention relates to a method for preparing a prasugrel analogue. The method comprises the following steps: reacting a compound I with trimethylchlorosilane, reacting the reaction product with a compound II, and deprotecting the product of the second reaction to obtain a compound III; and reacting the compound III with acetic anhydride to obtain a compound IV. The compound IV can be used as a reference substance for detecting related substances of prasugrel hydrochloride, and is used for controlling the purity of raw materials or preparations of prasugrel hydrochloride.
Description
Technical field
The present invention relates to the preparation method of a kind of prasugrel analogue 5-(the chloro-1-of 5-(2-fluorophenyl)-2-oxopentyl)-4,5,6,7-tetramethylene sulfide [3,2-c] pyridine-2-yl acetate.
Background technology
Prasugrel hydrochloride (PrasugrelHydrochloride) is by Lilly Co., Eli. and Japan the one or the three altogether thiophene pyridines Novel anti-platelet agent jointly researched and developed of drugmaker, is used for the treatment of the artery thrombosis event that reduces in the Protein in Patients With Acute Coronary Syndrome accepting PCI treatment and reduces stent thrombosis.
The chemical structural formula of prasugrel hydrochloride is as follows:
Prasugrel analogue 5-(the chloro-1-of 5-(2-fluorophenyl)-2-oxopentyl)-4 has been recorded in prasugrel hydrochloride drug registration standard, 5,6,7-tetramethylene sulfide [3,2-c] pyridine-2-yl acetate (shown in structural formula IV), limit is 0.3%, according to ICH governing principle, needs to carry out Structural Identification to this analogue.Prasugrel analogue is shown below:
Patent WO2012052788 reports a kind of synthetic method of this prasugrel analogue, with compound V (tosilate) and the chloro-1-of the bromo-5-of 1-(2-fluorophenyl) pentane-2-ketone (compound ii) direct reaction, prasugrel analogue (IV) is prepared again with acetic anhydride one kettle way, yield is lower, and there is keto-enol change in compound V in solution system, ketone form structure generating portion open loop in acid or alkali environment is decomposed, and reaction impurities is more.
Compound ii and compound V are shown below:
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of highly purified preparation method of high yield of prasugrel analogue (IV).Said method comprising the steps of:
Step (1): react with compound ii again after chemical compounds I is first reacted with trimethylchlorosilane (TMSCl) under reaction solvent exists, then carry out deprotection reaction and obtain compound III; Step (2): compound III and acetic anhydride are obtained formula compounds Ⅳ.
Concrete reaction scheme is as follows:
The reaction solvent A of the use in described step (1) be selected from methylene dichloride, acetonitrile one or more; Temperature of reaction is-15 ~ 40 DEG C, preferably-5 ~ 15 DEG C, most preferably 0 ~ 15 DEG C; Reaction times is 0.5 ~ 24 hour, preferred 3-10 hour.In addition, keep close to neutral for making reaction system, one or more organic alkali agents can be added in reaction solution, described organic alkali agents is selected from triethylamine, N, one or more in N-diisopropylethylamine, described organic alkali agents can add in the following order: chemical compounds I and reaction solvent mixing, stir, add appropriate first part of organic alkali agents (with in and chemical compounds I salt acid group) after, add trimethylchlorosilane, add appropriate second part of organic alkali agents (hydrochloric acid generated with neutralization reaction) again, finally add the mixed solution of chemical compounds I and the 3rd part of organic alkali agents.The charging capacity mol ratio of described first part of organic alkali agents and chemical compounds I is preferably 1:1; The charging capacity mol ratio of second part of organic alkali agents and trimethylchlorosilane is preferably 1:1; The charging capacity mol ratio of the 3rd part of organic alkali agents and chemical compounds I is preferably 2:1 ~ 1:1, is more preferably 1.1:1.
The reaction solvent B that described step (2) uses is DMF, one or more in acetonitrile; Temperature of reaction is-10 ~ 20 DEG C, preferably-5 ~ 5 DEG C; Reaction times is 0.5 ~ 24 hour.
Preparation method of the present invention, improves the yield of prasugrel analogue, reduces the Costco Wholesale of prasugrel analogue.Wherein, the yield in documents WO2012052788 is lower, and detects purity through the present inventor and be about 91%, need be further purified.And in technical scheme of the present invention, be 54% with the yield that starting material compound I calculates, purity can reach more than 98%.
In addition, there is keto-enol change in chemical compounds I in solution system, and ketone form structure generating portion open loop in acid or alkali environment is decomposed, and reaction impurities is more.In the present invention, chemical compounds I first reacts with trimethylchlorosilane and protects hydroxyl; not easily there is open loop and decompose in the structure formed; avoid reacting with compound ii generating ether by product simultaneously; obtained compound III is separated after deprotection base; compounds Ⅳ is obtained again with acetic anhydride; therefore, the compounds Ⅳ purity for preparing of the present invention is higher.
Formula IV compound 5-(the chloro-1-of 5-(2-fluorophenyl)-2-oxopentyl)-4 prepared by the present invention, 5,6,7-tetramethylene sulfide [3,2-c] pyridine-2-yl acetate, can be used as the related substance detection reference substance of prasugrel hydrochloride, for the quality control of prasugrel hydrochloride and related preparations thereof.
Embodiment
The present invention will in hereafter by the more detailed description of embodiment, and these embodiments exemplarily for further illustrating, and should not be considered as limitation of the present invention.
Embodiment 1: the preparation of formula III compound
Method one:
By chemical compounds I (9g, 0.047mol), methylene dichloride 54ml, triethylamine (4.7g, 0.047mol) mix and blend, control temperature of reaction at 0 ~ 5 DEG C, add trimethylchlorosilane (6.1g, 0.056mol), add triethylamine (5.6g again, 0.056mol), stir 0.5h, add compound ii (13.8g, 0.047mol) with triethylamine (5.3g, mixed solution 0.052mol), at 0 ~ 5 DEG C of stirring reaction 5h, add water 30ml, separatory, methylene dichloride is mutually with water 30ml washing, concentrating under reduced pressure, residue is separated to obtain compound III (12.9g through silica gel column chromatography [moving phase: ethyl acetate-light petrol (1:5)], yield 74.6%).
1H-NMR(CDCl
3)δ:7.16～7.38(m,4H)，4.73(d,1H),6.04(d,1H)，4.09(m,1H)，3.53(m,2H)，2.82～3.06(d,2H)，2.64(m,2H)，2.51～3.89(t,2H)，2.03(m,2H)，1.90～2.33(m,2H)。
Method two:
By chemical compounds I (10g, 0.052mol), acetonitrile 50ml, triethylamine (5.2g, 0.052mol) mix and blend, control temperature of reaction at 1 ~ 15 DEG C, add trimethylchlorosilane (6.8g, 0.062mol), add triethylamine (6.2g again, 0.062mol), stir 0.5h, add compound ii (15.3g, 0.052mol) with triethylamine (5.8g, mixed solution 0.058mol), at 10 ~ 15 DEG C of stirring reaction 3h, add 20% sodium chloride aqueous solution 30ml, separatory, acetonitrile phase concentrating under reduced pressure, residue is separated to obtain compound III (14.1g through silica gel column chromatography [moving phase: ethyl acetate-light petrol (1:5)], yield 73.7%).
Embodiment 2: the preparation of formula II compound
Method one:
By compound III (8g, 0.022mol) and N, dinethylformamide 50ml mix and blend, be cooled to-5 ~ 0 DEG C, drip triethylamine (3.9g successively, 0.039mol) with diacetyl oxide (4g, 0.039mol), reaction 4h, adds water 250ml and ethyl acetate 150ml, separatory, ethyl acetate uses 10% brine It mutually, concentrating under reduced pressure, and residue is separated to obtain compounds Ⅳ (6.5g through silica gel column chromatography [moving phase: ethyl acetate-light petrol (1:5)], yield 72.1%), purity 98.6%.ESI-MS(m/z):410.1[M+H]
+；
1H-NMR(500MHz,CDCl
3)δ:7.46(m,1H)，7.36(m,1H)，7.21(m,1H)，7.18(m,1H)，6.27(s,1H)，4.77(s,1H)，3.56～3.47(m,4H)，2.90(m,1H)，2.81(t,2H)，2.73(m,1H)，2.72～2.68(m,2H)，2.28(s,3H)，2.02(m,2H)；
13C-NMR(500MHz,CDCl
3)δ:206.5，167.7，161.3，149.7，130.6，130.3，129.1，125.7，124.6，121.4，116.0，112.0，70.8，50.5，48.4，44.2，36.7，26.4，24.9，20.7。
Method two:
By compound III (10g, 0.027mol) with acetonitrile 50ml mix and blend, be cooled to 0 ~ 5 DEG C, drip triethylamine (4.9g successively, 0.049mol) with diacetyl oxide (5g, 0.049mol), reaction 2h, concentrating under reduced pressure is except desolventizing, residue adds water 100ml and ethyl acetate 200ml, stir, separatory, ethyl acetate uses 10% aqueous NaCl wash mutually, concentrating under reduced pressure, residue is separated to obtain compounds Ⅳ (8.1g, yield 73.2%) through silica gel column chromatography [moving phase: ethyl acetate-light petrol (1:5)], purity 98.5%.
Claims (10)
1. a preparation method for prasugrel analogue IV, is characterized in that comprising step as follows:
Step (1): react with compound ii again after chemical compounds I is first reacted with trimethylchlorosilane, then carry out deprotection reaction and obtain compound III;
Compound III and acetic anhydride are obtained formula compounds Ⅳ by step (2), and reaction scheme is as follows:
2. preparation method according to claim 1, it is characterized in that the reaction of step (1) is carried out under reaction solvent A exists, described reaction solvent A is one or more in methylene dichloride, acetonitrile.
3. preparation method according to claim 2, is characterized in that adding organic alkali agents in reaction process, described organic alkali agents be selected from triethylamine, DIPEA one or more.
4. preparation method according to claim 3, it is characterized in that feeding sequence is: chemical compounds I and reaction solvent A mix, stir, after adding first part of organic alkali agents, add trimethylchlorosilane, add second part of organic alkali agents again, finally add the mixed solution of compound ii and the 3rd part of organic alkali agents.
5. preparation method according to claim 4, is characterized in that the charging capacity mol ratio of described first part of organic alkali agents and chemical compounds I is preferably 1:1; The charging capacity mol ratio of second part of organic alkali agents and trimethylchlorosilane is preferably 1:1; The charging capacity mol ratio of the 3rd part of organic alkali agents and chemical compounds I is preferably 2:1 ~ 1:1, is more preferably 1.1:1.
6. the preparation method according to claim 1-5, is characterized in that the temperature of reaction of step (1) is-15 ~ 40 DEG C, preferably-5 ~ 15 DEG C, most preferably 0 ~ 15 DEG C.
7. the preparation method according to claim 1-5, is characterized in that the reaction times of step (1) is 0.5 ~ 24 hour, preferred 3-10 hour.
8. preparation method according to claim 1, it is characterized in that step (2) reaction under reaction solvent B exists, described reaction solvent B is one or more in DMF, acetonitrile.
9. preparation method according to claim 1, is characterized in that the temperature of reaction of step (2) is-10 ~ 20 DEG C, preferably-5 ~ 5 DEG C.
10. preparation method according to claim 1, is characterized in that the reaction times of step (2) is 0.5 ~ 24 hour.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410191364.2A CN105085541A (en) | 2014-05-07 | 2014-05-07 | Method for preparing prasugrel analogue |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410191364.2A CN105085541A (en) | 2014-05-07 | 2014-05-07 | Method for preparing prasugrel analogue |
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| Publication Number | Publication Date |
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| CN105085541A true CN105085541A (en) | 2015-11-25 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201410191364.2A Pending CN105085541A (en) | 2014-05-07 | 2014-05-07 | Method for preparing prasugrel analogue |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112047959A (en) * | 2020-10-21 | 2020-12-08 | 深圳市祥根生物科技有限公司 | Preparation method of prasugrel ring-opening chlorinated impurity |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101675058A (en) * | 2007-03-02 | 2010-03-17 | 第一三共株式会社 | Process for the preparation of high-purity prasugrel hydrochloride |
| CN102002056A (en) * | 2010-11-02 | 2011-04-06 | 北京赛科药业有限责任公司 | Method for preparing intermediate of prasugrel |
| WO2013014295A1 (en) * | 2011-07-28 | 2013-01-31 | Laboratorios Lesvi, S. L. | Process for preparing prasugrel |
| CN102977115A (en) * | 2012-11-16 | 2013-03-20 | 江苏先声药业有限公司 | Novel synthetic method of prasugrel free base |
-
2014
- 2014-05-07 CN CN201410191364.2A patent/CN105085541A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101675058A (en) * | 2007-03-02 | 2010-03-17 | 第一三共株式会社 | Process for the preparation of high-purity prasugrel hydrochloride |
| CN102002056A (en) * | 2010-11-02 | 2011-04-06 | 北京赛科药业有限责任公司 | Method for preparing intermediate of prasugrel |
| WO2013014295A1 (en) * | 2011-07-28 | 2013-01-31 | Laboratorios Lesvi, S. L. | Process for preparing prasugrel |
| CN102977115A (en) * | 2012-11-16 | 2013-03-20 | 江苏先声药业有限公司 | Novel synthetic method of prasugrel free base |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112047959A (en) * | 2020-10-21 | 2020-12-08 | 深圳市祥根生物科技有限公司 | Preparation method of prasugrel ring-opening chlorinated impurity |
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Application publication date: 20151125 |