CN102702224A - Preparation method of type I clopidogrel hydrogen sulfate - Google Patents
Preparation method of type I clopidogrel hydrogen sulfate Download PDFInfo
- Publication number
- CN102702224A CN102702224A CN2012102122432A CN201210212243A CN102702224A CN 102702224 A CN102702224 A CN 102702224A CN 2012102122432 A CN2012102122432 A CN 2012102122432A CN 201210212243 A CN201210212243 A CN 201210212243A CN 102702224 A CN102702224 A CN 102702224A
- Authority
- CN
- China
- Prior art keywords
- clopidogrel
- preparation
- type
- reaction
- drying
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a preparation method of type I clopidogrel hydrogen sulfate, belonging to the technical field of preparation of medical substances. The preparation method of the type I clopidogrel hydrogen sulfate comprises the following steps of: reacting clopidogrel hydrogen sulfate with an alkali in an organic solvent and water to obtain clopidogrel alkali; adding clopidogrel alkali into a mixed solvent of isopropyl ether and isopropanol, and acidifying to obtain a suspension; and filtering and drying to obtain the type I clopidogrel hydrogen sulfate. The method has the advantages of mild reaction conditions, small damages of used solvent to human bodies, safety, reaction yield of 85-93 percent and suitability for large-scale industrial production.
Description
Technical field
The present invention relates to a kind of preparation method of I type bisulfate clopidogrel, belong to the pharmaceutical substance preparing technical field.
Background technology
The hydrosulfate of its chemistry of clopidogrel S (+) by name-2-(2-chloro-phenyl-)-2 (4,5,6,7-THTP [3,2-c] and pyridine-5) methyl acetate, structural formula is as follows:
Bisulfate clopidogrel is the vitriol of clopidogrel; It is a kind of anticoagulant; Because it can optionally suppress ADP (ADP) and its combining and the activation of the gp GP II b/ III a mixture of the ADP of secondary mediation of acceptor, but therefore anticoagulant.Except that ADP, clopidogrel can also suppress the platelet aggregation of other agonist induction through blocking the amplification of the platelet activation that is caused by the ADP that discharges.It is the earliest by French drugmaker celo luxuriant and rich with fragrance (Sanofi) invention; Since 2005; Clopidogrel is used for treatment clinically as anticoagulation medicine and the prevention myocardial infarction begins to use in a large number clinical cardiac; Take the sickness rate that clopidogrel can obviously reduce myocardial infarction, and few side effects.Clopidogrel has become the medicine of former on global marketing type, and annual sales amount is above 6,000,000,000 dollars.Because clopidogrel product consumption clinically constantly increases; Sell good; Sanofi company has applied for a USP again in order to protect its existing market in 1998, require the clopidogrel new crystal of its discovery of protection; Promptly, claim that new crystal is the II type with original clopidogrel crystal formation-the I type is corresponding.Caused the research interest of people to the clopidogrel crystal formation for this reason; Up to the present, find that clopidogrel is a kind of multi-crystalline compounds, according to literature survey; What bibliographical information was wherein arranged just has seven kinds, and I type, II type, III type, IV type, V-type, VI type and armorphous etc. are arranged.Wherein, business-like mainly is I type and two kinds of crystal formations of II type.
Different crystal formations can be according to the X-powdery diffractometry, and method such as infrared is confirmed.Wherein main 2-Theta angle diffraction peak is about in the X-powder diagram of I type bisulfate clopidogrel: 9.2,25.5 ± 0.2,23.2,23.4,20.6,10.9,18.5,15.2,17.9 etc.; The infrared absorpting light spectra spectra collection of I type bisulfate clopidogrel records (the light clef is 1220), and is as shown in Figure 7.
Can judge according to bisulfate clopidogrel crystalline X-diffractogram and infrared absorpting light spectra and to belong to which kind of crystal formation.Consider that from the kinetics of crystallization aspect I type bisulfate clopidogrel crystalline forms and belongs to kinetic control, and II type bisulfate clopidogrel crystal belongs to thermodynamic control, so the formation of different crystal forms requires special temperature and special conditions such as solvent.Document about the preparation of I type bisulfate clopidogrel is many, and related technical problem is choice of Solvent mostly, Chinese patent CN200610023434; CN200410009028, CN200610029489, CN200710069957 have introduced the preparation of I type bisulfate clopidogrel; The solvent of design mainly comprises the ester class; Ketone, ethers, single solvents such as alkanes.But through experiment, according to the document of being reported, the not getable product of most method, but obtain other crystal formations or amorphous products or mix crystal formation.
The method for preparing I type product of U.S. Pat 20030114479 reports is simple relatively; Directly be dissolved in methyl alcohol to bisulfate clopidogrel, solvent evaporated adds solvent ether or t-butyl methyl ether and stirs the regular hour then; Thereby obtained I type product; But we are difficult to obtain pure title product through experiment showed, with t-butyl methyl ether, and fine with the ether effect.But ether is a kind of very strong narcotic, and high volatility has many toxic actions to human body; And ether is inflammable, brings very big unsafe factor to industrialized production.
Summary of the invention
The preparation method who the purpose of this invention is to provide a kind of I type bisulfate clopidogrel, this method adopt the mixed solvent of isopropyl ether and Virahol to prepare the higher I type bisulfate clopidogrel crystal of purity, and mixed solvent is safe, easy to operate.
The preparation method of I type bisulfate clopidogrel of the present invention; Be in organic solvent and water; Earlier make clopidogrel base by bisulfate clopidogrel and alkali reaction; Then clopidogrel base is added in the mixed solvent of isopropyl ether and Virahol and obtains suspension liquid through acidifying, again through filter, drying makes I type bisulfate clopidogrel.
The preparation method of described I type bisulfate clopidogrel specifically may further comprise the steps:
(1) bisulfate clopidogrel is dissolved in the mixed solvent of organic solvent and water, it is 7～9 continued reaction 2 ~ 4 hours that 7～13 ℃ of stirrings of temperature control add sodium hydrogencarbonate or yellow soda ash adjusting pH value down, and reaction is left standstill separatory after finishing, and extraction is got organic phase, drying.Decompression was removed organic solvent and is obtained clopidogrel base after drying finished, and wherein said bisulfate clopidogrel refers to non-I type bisulfate clopidogrel, and when organic solvent was methylene dichloride, effect was best;
(2) clopidogrel base that step (1) is obtained adds in the mixed solvent of isopropyl ether and Virahol; After being cooled to 5～15 ℃, slowly drip the vitriol oil, the mol ratio of the vitriol oil and clopidogrel base is 0.9～1.1:1; After dropwising; Continue to stir 14～18h, the volume ratio of the two is 1:9～9:1 in the mixed solvent of wherein said isopropyl ether and Virahol, preferred 3:7～7:3; Both are all in ml.
(3) suspension liquid that step (2) is obtained filters and promptly obtains I type bisulfate clopidogrel; Fully remove the mixed solvent of isopropyl ether and Virahol, then with resulting white solid 35～45 ℃ and-0.08～-the 0.1Mpa condition under dry 20～24h make.
Methods such as the crystal formation of prepared bisulfate clopidogrel can pass through the X-diffraction, and is infrared are confirmed.
The diffraction peak of X-ray diffraction is 9.15 ± 0.05,25.50 ± 0.20,23.15 ± 0.05,23.80,20.54,10.85 ± 0.05,18.40,17.90,15.26 etc.; And present method need not add crystal seed can obtain the very high I type bisulfate clopidogrel of purity.The purity determination methods is following: if 2 θ angles are 12～13 ° of basic not absorptions in the X diffraction spectrogram, then this compound is high-purity I type product; If other absorption peak is the same with the absorption of I type in the X diffraction spectrogram, but in 12～13 ° of zones, 2 θ angles absorption is arranged, then this compound is the mixture of I type and other crystal formations.
The principal character peak is about 2986,1753,1175,1067,841,584,480,462 in the infrared spectrum, 430cm
-1Deng.
Beneficial effect of the present invention is following:
Reaction conditions of the present invention is gentle, and employed solvent is less to human harm, safety, and reaction yield is 85～93%, is suitable for large batch of suitability for industrialized production.
Description of drawings
Fig. 1 is the X-powder diffraction spectrum of the I type bisulfate clopidogrel prepared among the embodiment 1;
Fig. 2 is the infrared absorpting light spectra of the I type bisulfate clopidogrel prepared among the embodiment 1;
Fig. 3 is the X-powder diffraction spectrum of the I type bisulfate clopidogrel prepared among the embodiment 2;
Fig. 4 is the infrared absorpting light spectra of the I type bisulfate clopidogrel prepared among the embodiment 2;
Fig. 5 is the X-powder diffraction spectrum of the I type bisulfate clopidogrel prepared among the embodiment 3;
Fig. 6 is the infrared absorpting light spectra of the I type bisulfate clopidogrel prepared among the embodiment 3;
Fig. 7 is the X-powder diffraction spectrum of the I type bisulfate clopidogrel prepared among the embodiment 4;
Fig. 8 is the infrared absorpting light spectra of the I type bisulfate clopidogrel prepared among the embodiment 4;
Fig. 9 is the X-powder diffraction spectrum of the I type bisulfate clopidogrel prepared among the embodiment 5;
Figure 10 is the infrared absorpting light spectra of the I type bisulfate clopidogrel prepared among the embodiment 5;
Figure 11 is the infrared absorpting light spectra (the light clef is 1220) of the I type bisulfate clopidogrel prepared in the prior art.
Embodiment
Below in conjunction with embodiment the present invention is done and to further describe.
Embodiment 1
Get bisulfate clopidogrel 11.00g and place the 250mL round-bottomed flask, add methylene dichloride 40.0mL and purified water 40.0mL then, temperature is controlled at 8 ℃, and using sodium hydrogencarbonate to regulate the pH value is 7.Continued stirring reaction 2 hours down at 8 ℃.After reaction finished, separatory, water were used the 10mL dichloromethane extraction, merged organic phase, and organic phase is washed with the 10mL purified water.In organic phase, add the 1.50g anhydrous magnesium sulfate, stir dry 5h.The drying after-filtration that finishes, 40 ± 3 ℃ ,-0.08～-steam under the 0.1MPa and desolventize, obtain oily matter 7.90g clopidogrel base.Distillation finishes, and adds 135mL isopropyl ether and 15mL Virahol, is cooled to 6 ℃; After treating that clopidogrel base dissolves fully, under this temperature, slowly add the 2.65g vitriol oil, after dropwising; Stirring reaction 16h reaction finishes, suction filtration, 40 ± 3 ℃ ,-0.08～-0.1MPa under vacuum-drying 24h; Obtain white solid I type bisulfate clopidogrel 9.89g, the reaction yield scope is 89.9%.
Its X-powder diffraction spectrum is as shown in Figure 1, and 2 θ angles are 12～13 ° of basic not absorptions in the X diffraction spectrogram, and this compound is high-purity I type product.
Main 2 θ diffraction peaks and corresponding d value are:
| ?2θ | 9.16 | 15.26 | 23.14 | 23.80 | 20.54 | 10.88 | 18.40 | 17.90 | 25.48 |
| ?d | 9.6467 | 5.8015 | 3.8406 | 3.7356 | 4.3205 | 8.1252 | 4.8179 | 4.9513 | 3.4929 |
Infrared absorption spectra is as shown in Figure 2, and the principal character peak is about 2985.81,1753.29,1174.65,1066.64,840.96,584.43cm
-1Deng.
Get bisulfate clopidogrel 27.50g and place the 500mL round-bottomed flask, add methylene dichloride 100.0mL and purified water 100.0mL then, be cooled to 8 ℃, using yellow soda ash to regulate the pH value is 9.Continued stirring reaction 2 hours down at 8 ℃.After reaction finished, separatory, water were used the 30mL dichloromethane extraction, merged organic phase, and organic phase is washed with the 30mL purified water.In organic phase, add the 3.80g anhydrous magnesium sulfate, stir dry 5h.The drying after-filtration that finishes, 40 ± 3 ℃ ,-0.08～-steam under the 0.1MPa and desolventize, obtain oily matter 20.40g clopidogrel base.Distillation finishes, and adds 165mL isopropyl ether and 165mL Virahol, is cooled to 6 ℃; After treating that clopidogrel dissolves fully, under this temperature, slowly add the 6.69g vitriol oil, after dropwising; Stirring reaction 16h reaction finishes, suction filtration, 40 ± 3 ℃ ,-0.08～-0.1MPa under vacuum-drying 24h; Obtain white solid 25.25g, the reaction yield scope is 91.8%.
Its X-powder diffraction spectrum is as shown in Figure 3, and 2 θ angles are 12～13 ° of basic not absorptions in the X diffraction spectrogram, and this compound is high-purity I type product.
Main 2 θ diffraction peaks and corresponding d value are:
| ?2θ | 9.12 | 15.26 | 23.12 | 23.80 | 20.54 | 10.88 | 18.40 | 17.90 | 25.48 |
| ?d | 9.6889 | 5.8015 | 3.8439 | 3.7356 | 4.3205 | 8.1252 | 4.8179 | 4.9513 | 3.4929 |
Infrared absorption spectra is as shown in Figure 4, and the principal character peak is about 2985.81,1753.29,1174.65,1066.64,840.96,582.50cm
-1Deng.
Get bisulfate clopidogrel 46.2g and place the 1000mL round-bottomed flask, add methylene dichloride 168.0mL and purified water 168.0mL then, be cooled to 8 ℃, using sodium hydrogencarbonate to regulate the pH value is 8.Continued stirring reaction 2.5 hours down at 8 ℃.After reaction finished, separatory, water were used the 50mL dichloromethane extraction, merged organic phase, and organic phase is washed with the 50mL purified water.In organic phase, add the 6.00g anhydrous magnesium sulfate, stir dry 5h.The drying after-filtration that finishes, 40 ± 3 ℃ ,-0.08～-steam under the 0.1MPa and desolventize, obtain 32.50g oily matter clopidogrel base.Distillation finishes, and adds 63.0mL isopropyl ether and 567.0mL Virahol, is cooled to 6 ℃; After treating that clopidogrel dissolves fully, under this temperature, slowly add the 9.90g vitriol oil, after dropwising; Stirring reaction 16h reaction finishes, suction filtration, 40 ± 3 ℃ ,-0.08～-0.1MPa under vacuum-drying 24h; Obtain white solid 39.48g, the reaction yield scope is 85.4%.
Its X-powder diffraction spectrum is as shown in Figure 5, and 2 θ angles are 12～13 ° of basic not absorptions in the X diffraction spectrogram, and this compound is high-purity I type product.
Main 2 θ diffraction peaks and corresponding d value are:
| ?2θ | 9.18 | 15.24 | 23.16 | 23.84 | 20.56 | 10.90 | 18.46 | 17.92 | 25.50 |
| ?d | 9.6257 | 5.8090 | 3.8373 | 3.7294 | 4.3164 | 8.1103 | 4.8024 | 4.9459 | 3.4902 |
Infrared absorption spectra is as shown in Figure 6, and the principal character peak is about 2985.81,1751.36,1174.65,1066.64,840.96,582.50cm
-1Deng.
Get bisulfate clopidogrel 33.0g and place the 1000mL round-bottomed flask, add methylene dichloride 120.0mL and purified water 120.0mL then, be cooled to 12 ℃, regulate pH value about 9 with yellow soda ash.Continued stirring reaction 3 hours down at 12 ℃.After reaction finished, separatory, water were used the 40mL dichloromethane extraction, merged organic phase, and organic phase is washed with the 40mL purified water.In organic phase, add the 4.60g anhydrous magnesium sulfate, stir dry 5h.The drying after-filtration that finishes, 40 ± 3 ℃ ,-0.08～-steam under the 0.1MPa and desolventize, obtain oily matter 24.48g clopidogrel base.Distillation finishes, and adds 210.0mL isopropyl ether and 90.0mL Virahol, is cooled to 10 ℃; After treating that clopidogrel dissolves fully, under this temperature, slowly add the 8.03g vitriol oil, after dropwising; Stirring reaction 14h reaction finishes, suction filtration, 40 ± 3 ℃ ,-0.08～-0.1MPa under vacuum-drying 24h; Obtain white solid 29.6g, the reaction yield scope is 89.8%.
Its X-powder diffraction spectrum is as shown in Figure 7, and 2 θ angles are 12～13 ° of basic not absorptions in the X diffraction spectrogram, and this compound is high-purity I type product.
Main 2 θ diffraction peaks and corresponding d value are:
| ?2θ | 9.18 | 15.26 | 23.16 | 23.80 | 20.54 | 10.90 | 18.40 | 17.90 | 25.48 |
| d | 9.6257 | 5.8015 | 3.8373 | 3.7356 | 4.3205 | 8.1103 | 4.8179 | 4.9513 | 3.4929 |
Infrared absorption spectra is as shown in Figure 8, and the principal character peak is about 2985.81,1753.29,1174.65,1066.64,839.03,584.43cm
-1Deng.
Embodiment 5
Get bisulfate clopidogrel 69.3g and place the 1000mL round-bottomed flask, add methylene dichloride 252mL and purified water 252.0mL then, be cooled to 10 ℃, using sodium hydrogencarbonate to regulate the pH value is 8.Continued stirring reaction 2.5 hours down at 10 ℃.After reaction finished, separatory, water were used the 80.0mL dichloromethane extraction, merged organic phase, and organic phase is washed with the 80.0mL purified water.In organic phase, add the 9.00g anhydrous magnesium sulfate, stir dry 5h.The drying after-filtration that finishes, 40 ± 3 ℃ ,-0.08～-steam under the 0.1MPa and desolventize, obtain 48.75g oily matter clopidogrel base.Distillation finishes, and adds 150.0mL isopropyl ether and 350.0mL Virahol, is cooled to 14 ℃; After treating that clopidogrel dissolves fully, under this temperature, slowly add the 14.9g vitriol oil, after dropwising; Stirring reaction 18h reaction finishes, suction filtration, 40 ± 3 ℃ ,-0.08～-0.1MPa under vacuum-drying 24h; Obtain white solid 60.57g, the reaction yield scope is 87.4%.
Its X-powder diffraction spectrum is as shown in Figure 9, and 2 θ angles are 12～13 ° of basic not absorptions in the X diffraction spectrogram, and this compound is high-purity I type product.
Main 2 θ diffraction peaks and corresponding d value are:
| 2θ | ?9.18 | ?15.24 | ?23.16 | ?23.82 | ?20.56 | ?10.88 | ?18.44 | ?17.92 | ?25.50 |
| ?d | ?9.6257 | ?5.8090 | ?3.8373 | ?3.7325 | ?4.3164 | ?8.1252 | ?4.8075 | ?4.9459 | ?3.4902 |
Infrared absorption spectra is shown in figure 10, and the principal character peak is about 2983.88,1753.29,1174.65,1066.64,839.03,584.43cm
-1Deng.
Claims (9)
1. the preparation method of an I type bisulfate clopidogrel; It is characterized in that making clopidogrel base by bisulfate clopidogrel and alkali reaction earlier; Then clopidogrel base is added in the mixed solvent of isopropyl ether and Virahol and obtains suspension liquid through acidifying, again through filter, drying makes I type bisulfate clopidogrel.
2. preparation method according to claim 1, the volume ratio that it is characterized in that said isopropyl ether and Virahol is 1:9～9:1, both are all in ml.
3. preparation method according to claim 2, the volume ratio that it is characterized in that said isopropyl ether and Virahol is 3:7～7:3, both are all in ml.
4. preparation method according to claim 1 is characterized in that 5～15 ℃ of said souring temperatures.
5. according to claim 1 or 4 described preparing methods, it is characterized in that the mode that said acidifying adopts the vitriol oil to drip, the mol ratio of the vitriol oil and clopidogrel base is 0.9～1.1:1.
6. preparation method according to claim 5, it is characterized in that the said vitriol oil dropwises after, react 14～18h again.
7. preparation method according to claim 1 is characterized in that said alkali is sodium hydrogencarbonate or yellow soda ash.
8. preparation method according to claim 1 is characterized in that 7～13 ℃ of the temperature of reaction of said bisulfate clopidogrel and alkali, 2～4 hours reaction times, pH value in reaction 7～9.
9. preparation method according to claim 1 is characterized in that 35～45 ℃ of said drying temperatures, drying pressure-0.08～-0.1Mpa, time of drying 20～24h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012102122432A CN102702224A (en) | 2012-06-25 | 2012-06-25 | Preparation method of type I clopidogrel hydrogen sulfate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012102122432A CN102702224A (en) | 2012-06-25 | 2012-06-25 | Preparation method of type I clopidogrel hydrogen sulfate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102702224A true CN102702224A (en) | 2012-10-03 |
Family
ID=46895322
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2012102122432A Pending CN102702224A (en) | 2012-06-25 | 2012-06-25 | Preparation method of type I clopidogrel hydrogen sulfate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102702224A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104610274A (en) * | 2013-11-05 | 2015-05-13 | 亚宝药业集团股份有限公司 | Type I clopidogrel hydrogen sulfate salt preparation method |
| CN107501289A (en) * | 2017-09-07 | 2017-12-22 | 山东齐都药业有限公司 | Preparation method of the bisulfate clopidogrel about material D |
| CN110606854A (en) * | 2018-06-14 | 2019-12-24 | 华东理工大学 | Controllable preparation method of I crystal form clopidogrel hydrogen sulfate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1690060A (en) * | 2004-04-19 | 2005-11-02 | 上海开特国际贸易有限公司 | Process for preparing I-clopidogrel hydrogen sulfate |
| CN1812993A (en) * | 2003-07-02 | 2006-08-02 | 埃吉斯药物工厂 | Process for preparing crystalline polymorph of blood platelet coagulation inhibitor |
-
2012
- 2012-06-25 CN CN2012102122432A patent/CN102702224A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1812993A (en) * | 2003-07-02 | 2006-08-02 | 埃吉斯药物工厂 | Process for preparing crystalline polymorph of blood platelet coagulation inhibitor |
| CN1690060A (en) * | 2004-04-19 | 2005-11-02 | 上海开特国际贸易有限公司 | Process for preparing I-clopidogrel hydrogen sulfate |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104610274A (en) * | 2013-11-05 | 2015-05-13 | 亚宝药业集团股份有限公司 | Type I clopidogrel hydrogen sulfate salt preparation method |
| CN104610274B (en) * | 2013-11-05 | 2017-04-19 | 亚宝药业集团股份有限公司 | Type I clopidogrel hydrogen sulfate salt preparation method |
| CN107501289A (en) * | 2017-09-07 | 2017-12-22 | 山东齐都药业有限公司 | Preparation method of the bisulfate clopidogrel about material D |
| CN107501289B (en) * | 2017-09-07 | 2019-06-14 | 山东齐都药业有限公司 | Preparation method of the bisulfate clopidogrel in relation to substance D |
| CN110606854A (en) * | 2018-06-14 | 2019-12-24 | 华东理工大学 | Controllable preparation method of I crystal form clopidogrel hydrogen sulfate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105273095A (en) | Preparation method for sugammadex and intermediates thereof | |
| CN102875531B (en) | A kind of (R)-lansoprazole anhydrous crystal forms and preparation method thereof | |
| CN102702224A (en) | Preparation method of type I clopidogrel hydrogen sulfate | |
| CN106365986A (en) | Compounds and preparation methods thereof, and uses of compounds in synthesis of brivaracetam | |
| CN102993032B (en) | Synthetic method of methoxamine hydrochloride | |
| CN108484536B (en) | Synthetic method of orlistat intermediate of weight-reducing drug | |
| CN102850347B (en) | The method for splitting of a kind of pyrazole derivatives or its salt | |
| CN102249976B (en) | Preparation method of optically pure (-)-clausenamide compound | |
| CN100478327C (en) | L-dopa methyl ester hydrochloride preparation method | |
| CN105348063A (en) | New method for synthesizing and refining medicinal paeonol | |
| CN103254197A (en) | Preparation method of anagrelide hydrochloride | |
| CN102040616A (en) | Preparation method of cefozopran hydrochloride | |
| CN104961787B (en) | Synthetic method of cordycepin | |
| CN103288693B (en) | Method for preparing 1-mercaptopyrene and intermediate compound thereof | |
| CN110128385A (en) | A kind of quercetin derivative and its synthetic method by lauroyl chloride chemical modification | |
| CN102838579A (en) | Method for preparing 1,3,6,7-tetrahydroxy xanthone | |
| CN102351812A (en) | Methanesulfonic acid cinepazide crystal form III and preparation method thereof | |
| CN103374049B (en) | One prepares 5,6, the method for 4 '-trihydroxyflavone-7-0-D-glucuronic acid | |
| CN103044361B (en) | Preparation method of (2R,3S)-epoxidation amino-benzene butane | |
| CN103145666B (en) | 4-substituted alpha-pyrone derivative as well as preparation method and application thereof | |
| CN103408423A (en) | Nature active product L-cichoric acid synthesis process | |
| CN103524353A (en) | Preparation method for high-purity memantine hydrochloride | |
| CN103254112A (en) | Bisindole alkaloid derivative, and synthesis method and application thereof | |
| CN102827060B (en) | Synthetic method of 5-trifluoromethyl pyrrole-2-formic acid | |
| JP4087589B2 (en) | Method for producing camptothecin |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20121003 |