CN104387383A - Synthetic method of novel apixaban precursor compound - Google Patents
Synthetic method of novel apixaban precursor compound Download PDFInfo
- Publication number
- CN104387383A CN104387383A CN201410579870.9A CN201410579870A CN104387383A CN 104387383 A CN104387383 A CN 104387383A CN 201410579870 A CN201410579870 A CN 201410579870A CN 104387383 A CN104387383 A CN 104387383A
- Authority
- CN
- China
- Prior art keywords
- compound
- synthetic method
- eliquis
- precursor compound
- structural formula
- 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.)
- Granted
Links
- RQNAOIQEGPVYTC-UHFFFAOYSA-N CCOC(c(c(CCN1c(cc2)ccc2[N+]([O-])=O)c2C1=O)n[n]2-c(cc1)ccc1OC)=O Chemical compound CCOC(c(c(CCN1c(cc2)ccc2[N+]([O-])=O)c2C1=O)n[n]2-c(cc1)ccc1OC)=O RQNAOIQEGPVYTC-UHFFFAOYSA-N 0.000 description 1
- 0 CCOC(c(c(CCOS(C)(=O)=O)c1C(Nc(cc2)ccc2[N+](*)[O-])=O)n[n]1-c(cc1)ccc1OC)=O Chemical compound CCOC(c(c(CCOS(C)(=O)=O)c1C(Nc(cc2)ccc2[N+](*)[O-])=O)n[n]1-c(cc1)ccc1OC)=O 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a synthetic method of a novel apixaban precursor compound. The synthetic method comprises the following steps: the apixaban precursor compound (5) (shown in the specification) is subjected to cyclization to obtain the lactam target product apixaban precursor compound I (shown in the specification). According to the invention, the apixaban precursor compound (5) is adopted to prepare ethyl 1-(4-methoxyphenyl)-6-(4-nitrophenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate, the yield can reach 87%, and in the entire synthetic route, the lowest yield of each step can reach over 80%, the total yield can reach about 49%, and valuable catalysts or reagents polluting the environment seriously are not used in the entire process.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, be specifically related to a kind of synthetic method of Eliquis precursor compound.
Background technology
Eliquis (apixaban), is a kind of oral Selective activation Ⅹ factor inhibitors, is developed jointly by Pfizer and Bristol Myers Squibb.The pre-preventing thrombosis of energy, but hemorrhage untoward reaction is lower than old medicine warfarin, for accepting the thrombus prevention of hip or knee replacement patient with operation.Chemical name is 1-(4-p-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidine-1-base) phenyl]-4,5,6,7-tetrahydrochysene-1H-pyrazoles [3,4-c] pyridine-3-carboxamide, now complete the relevant clinical test of prevention full hip-joint and TKA posterior vein thromboembolism (VTE), and obtain European Union in May, 2011 its listing for this indication permitted, at the beginning of 2013 China have approved Eliquis 2.5mg every day the scheme of twice for be grown up hip or knee replacements patient postoperative venous thromboembolism pre-.
Eliquis precursor compound 4,5,6,7-tetrahydrochysene-1-(4-p-methoxy-phenyl)-6-(4-nitrophenyl)-7-oxo-1H-pyrazolo [3,4-C] pyridine-3-carboxylic acid ethyl ester is the key intermediate of synthesis Eliquis bulk drug, there is demand widely in bulk drug market at home and abroad, and U.S. chemical abstract registration number CAS:536759-91-8 has the structure of I:
CN102675314 discloses the route of following synthesis Eliquis precursor compound I:
In above-mentioned synthetic method, need through the important reaction of a few step in the process of synthesis Eliquis precursor compound I: i.e. [3+2] ring-closure reaction of intermediate III and II, this ring-closure reaction must add a large amount of organic basess, and the yield of ring-closure reaction product only has 72%; Produce a large amount of acid gas when intermediate V and phosphorus pentachloride react simultaneously and can form a large amount of spent acid with aftertreatment, easily pollute; Last raw material single stage method accomplishes intermediate V, and aftertreatment purification ratio is more difficult, and the recycling of use to solvent of mixed solvent simultaneously creates new problem.
Summary of the invention
The object of the invention is to overcome prior art Eliquis precursor compound 4,5,6,7-tetrahydrochysene-1-(4-p-methoxy-phenyl)-6-(4-nitrophenyl)-7-oxo-1H-pyrazolo [3,4-C] pyridine-3-carboxylic acid ethyl ester synthesis in exist above-mentioned defect, the synthetic method of the Eliquis precursor compound I providing a kind of productive rate higher.
It is as follows that the present invention realizes the technical scheme that above-mentioned purpose adopts:
A kind of synthetic method of Eliquis precursor compound 4,5,6,7-tetrahydrochysene-1-(4-p-methoxy-phenyl)-6-(4-nitrophenyl)-7-oxo-1H-pyrazolo [3,4-C] pyridine-3-carboxylic acid ethyl ester, comprising:
Eliquis precursor compound 5:
lactan target product Eliquis precursor compound I is obtained through closing ring:
synthesis step comprises:
Compound 5 in organic solvent, is 35 DEG C of reactions 2 ~ 3 hours in temperature, obtains described Eliquis precursor compound I under the effect of sodium ethylate.
In above-mentioned steps, sodium ethylate highly basic works the hydrogen evolution nitrogen anion pulled out on acid amides, attack methane sulfonyl.
Preferably, in above-mentioned steps, the mole dosage of sodium ethylate is 2.5 ~ 3.5 times of described compound 5 mole dosage.
The structural formula of described Eliquis precursor compound 5 is as follows:
synthesis step comprises:
Compound 4 and methane sulfonyl chloride in organic solvent, are 0 ~ 5 DEG C of reaction 2 ~ 3 hours in temperature, obtain described Eliquis precursor compound 5 under the effect of diisopropylethylamine,
The structural formula of described compound 4 is:
Further, described compound 4 is 1:(1 ~ 1.3 with the mol ratio of methane sulfonyl chloride), be preferably 1:(1.1 ~ 1.2).
In above-mentioned steps, diisopropylethylamine plays acid binding agent.
Preferably, in above-mentioned steps, the mole dosage of diisopropylethylamine is 1.1 ~ 1.4 times of described compound 4 mole dosage.
The synthetic method of described compound 4, comprising:
(1) compound 2 and [(4-p-methoxy-phenyl) diazanyl] ethyl chloroacetate are obtained by reacting compound 3 in a solvent under triethylamine effect;
(2) described compound 3 is obtained by reacting compound 4 in 40 ~ 60 DEG C in a solvent under hydrochloric acid effect;
Wherein, the structural formula of described compound 2 is:
The structural formula of described compound 3 is:
The structural formula of described compound 4 is:
Further, in step (1), described compound 2 is 1:(1.5 ~ 2.5 with the mol ratio of [(4-p-methoxy-phenyl) diazanyl] ethyl chloroacetate), be preferably 1:(2.0 ~ 2.1).
The synthetic method of described compound 2, comprising:
under triethylamine effect, be obtained by reacting compound 1 with triphosgene, the structural formula of described compound 1 is:
B () described compound 1 is with 2,3 dihydro furan under tert-butyl lithium effect, be obtained by reacting compound 2 in-78 DEG C, the structural formula of described compound 2 is:
Further, the temperature of reaction of step (a) is 20-30 DEG C.
Further, in step (a), described in
be 1:(1 ~ 1.2 with the mol ratio of triphosgene), preferred 1:1.
Tert-butyl lithium in step (b) plays pulls out hydrogen effect, forms carbanion.
Complete synthesis route is as follows:
Compared with prior art, adopt the present invention by Eliquis precursor compound (5) Eliquis precursor compound (I) 4 processed, 5,6,7-tetrahydrochysene-1-(4-p-methoxy-phenyl)-6-(4-nitrophenyl)-7-oxo-1H-pyrazolo [3,4-C] method of pyridine-3-carboxylic acid ethyl ester, the yield of Eliquis precursor compound (I) can reach 87%.And in the reaction preparing Eliquis precursor compound (5), without the need to adding catalysis (helping) agent, simplify the separation and purification operation of product, and the reaction times is short, yield reaches 92%.And avoid in total process in the complete synthesis route taking p-Nitroaniline as initiator and use valuable catalyzer and the large reagent of environmental pollution, whole building-up process is not only polluted little, easy process, and yield minimum in each step also reaches 80%, total recovery also reaches about 49%.
Accompanying drawing explanation
Fig. 1 is the proton nmr spectra spectrogram of Compound I 4,5,6,7-tetrahydrochysene-1-(4-p-methoxy-phenyl)-6-(4-nitrophenyl)-7-oxo-1H-pyrazolo [3,4-C] the pyridine-3-carboxylic acid ethyl ester that the embodiment of the present invention 1 provides.
Embodiment
Embodiment is a kind of preferred version of the present invention, not does any pro forma restriction to the present invention, also has other variant and remodeling under the prerequisite not exceeding the technical scheme described in requirement.
Embodiment 1
Compound 1:
synthesis
138g (1mol) p-Nitroaniline is added in reaction flask, 101g (1mol) triethylamine, 2000ml methylene dichloride, room temperature 25 DEG C drips the 2000ml dichloromethane solution of 296g (1mol) triphosgene, keeps this thermotonus 3 ~ 5 hours, HPLC follows the tracks of reaction until p-Nitroaniline reacts completely, add 3000ml water, layering, organic phase concentrates, underpressure distillation obtains obtaining the compound 1 of 164g, molar yield: 100%.
Compound 2:
synthesis
5.25g (75mmol) 2 is added in reaction flask, 3-dihydrofuran, 40ml tetrahydrofuran (THF), be cooled to-78 DEG C, drip the tert-butyl lithium Skellysolve A solution of 23ml (39mmol) 1.7M, drip off and stir 5 minutes at such a temperature, drip the 20ml tetrahydrofuran solution of 4.92g (30mmol) compound 1, drip off and stir 30 minutes at such a temperature, HPLC follows the tracks of reaction until compound 1 reacts completely, drip 30ml saturated ammonium chloride solution, 100ml extraction into ethyl acetate, anhydrous sodium sulfate drying, concentrated solvent, add the making beating of 30ml methyl tertiary butyl ether, suction filtration, 40 DEG C of vacuum-drying 4h obtain the compound 2 of 5.7g, molar yield: 81%.
Compound 3:
synthesis
1.4g (6mmol) compound 2 is added in reaction flask, 3.1g (12mmol) [(4-p-methoxy-phenyl) diazanyl] ethyl chloroacetate, 1.8g (18mmol) triethylamine, 25ml ethyl acetate, be warming up to 70 DEG C of stirring reaction 1-2 hour, HPLC follows the tracks of reaction until compound 2 reacts completely, add 25ml shrend to go out reaction, layering, organic layer uses saturated sodium bicarbonate successively, water, saturated sodium-chloride washs, anhydrous sodium sulfate drying 4h, filter, by concentrated for filter vacuum dry, crude product 15ml methyl tertiary butyl ether recrystallization obtains the compound 3 of 2.59g, molar yield: 95%.
Compound 4:
synthesis
2.7g (6mmol) compound 3,20ml ethyl acetate is added, 20ml ethanol in reaction flask, 0.5ml concentrated hydrochloric acid, is warming up to 50 DEG C of stirring reaction 1-2 hour, and HPLC follows the tracks of reaction until compound 3 reacts completely, add 25ml shrend to go out reaction, layering, organic layer washs with saturated sodium bicarbonate, water, saturated sodium-chloride successively, anhydrous sodium sulfate drying 4h, filter, by concentrated for filter vacuum dry, crude product 13ml ethyl alcohol recrystallization obtains the compound 4 of 2.16g, molar yield: 80%.
Compound 5:
synthesis
1.36g (3mmol) compound 4 is added in reaction flask, 0.5g (3.9mmol) diisopropylethylamine, 25ml methylene dichloride, 0 DEG C drips 0.41g (3.6mmol) methane sulfonyl chloride, finish, react 2-3 hour, HPLC at this temperature and follow the tracks of reaction until compound 4 reacts completely.The cancellation of 25ml saturated sodium bicarbonate solution, layering, organic layer is successively with 1NHCl, water, saturated sodium-chloride washing, anhydrous sodium sulfate drying 4h, filters, by concentrated for filter vacuum dry, crude product 10ml ethyl alcohol recrystallization obtains the compound 5 of 1.47g, molar yield: 92%.
Compound I:
synthesis
In reaction flask, add 0.53g (1mmol) compound 5,10ml ethanol, 3mlDMF, is cooled to 0 DEG C, adds 0.2g (3mmol) sodium ethylate.Be warming up to about 35 DEG C reaction 2-3 hour, LCMS follows the tracks of reaction until compound 5 reacts completely, 20ml saturated ammonium chloride solution is added to reaction solution, 20ml ethyl acetate, layering extracts, organic over anhydrous dried over sodium sulfate 4h, filter, by concentrated for filter vacuum dry, 5ml ethyl alcohol recrystallization obtains the compound 6 of 0.38g, molar yield: 87%.Purity 99%, i.e. Eliquis precursor compound, chemical name: 4,5,6,7-tetrahydrochysene-1-(4-p-methoxy-phenyl)-6-(4-nitrophenyl)-7-oxo-1H-pyrazolo [3,4-C] pyridine-3-carboxylic acid ethyl ester.Product
1h-NMR (400MHz, CDCl3) δ: 8.23 (d, J=9.2Hz, 2H), 7.53 (d, J=9.2Hz, 2H), 7.47 (d, J=9.2Hz, 2H), 6.95 (d, J=9.2Hz, 2H), 4.49 (q, J=7.2Hz, 2H), 4.23 (t, J=6.8Hz, 2H), 3.82 (s, 3H), 3.39 (t, J=6.8Hz, 2H), 1.45 (t, J=7.2Hz, 3H) ppm.
Last it is noted that the foregoing is only the preferred embodiments of the present invention, be not limited to the present invention, although with reference to previous embodiment to invention has been detailed description, for a person skilled in the art, it still can be modified to the technical scheme described in foregoing embodiments, or carries out equivalent replacement to wherein portion of techniques feature.Within the spirit and principles in the present invention all, any amendment done, equivalent replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (9)
1. a synthetic method of Eliquis precursor compound I, comprising:
Eliquis precursor compound 5:
lactan target product Eliquis precursor compound I is obtained through closing ring:
Compound 5 in organic solvent, is 35 DEG C of reactions 2 ~ 3 hours in temperature, obtains described Eliquis precursor compound I under the effect of sodium ethylate.
2. the synthetic method of Eliquis precursor compound I according to claim 1, it is characterized in that, the mole dosage of sodium ethylate is 2.5 ~ 3.5 times of described compound 5 mole dosage.
3. a synthetic method for Eliquis precursor compound 5, the structural formula of described Eliquis precursor compound 5 is as follows:
synthesis step comprises,
Compound 4 and methane sulfonyl chloride in organic solvent, are 0 ~ 5 DEG C of reaction 2 ~ 3 hours in temperature, obtain described Eliquis precursor compound 5 under the effect of diisopropylethylamine,
The structural formula of described compound 4 is:
4. the synthetic method of compound 5 according to claim 3, is characterized in that, described compound 4 is 1:(1 ~ 1.3 with the mol ratio of methane sulfonyl chloride), be preferably 1:(1.1 ~ 1.2).
5. the synthetic method of compound 5 according to claim 3, it is characterized in that, the mole dosage of diisopropylethylamine is 1.1 ~ 1.4 times of described compound 4 mole dosage.
6. the synthetic method of compound 4, comprising:
(1) compound 2 and [(4-p-methoxy-phenyl) diazanyl] ethyl chloroacetate are obtained by reacting compound 3 in a solvent under triethylamine effect;
(2) described compound 3 is obtained by reacting compound 4 in 40 ~ 60 DEG C in a solvent under hydrochloric acid effect;
Wherein, the structural formula of described compound 2 is:
The structural formula of described compound 3 is:
The structural formula of described compound 4 is:
7. the synthetic method of compound 2 according to claim 6, it is characterized in that, in step (1), described compound 2 is 1:(1.5 ~ 2.5 with the mol ratio of [(4-p-methoxy-phenyl) diazanyl] ethyl chloroacetate), be preferably 1:(2.0 ~ 2.1).
8. the synthetic method of compound 2, comprising:
(a)
under triethylamine effect, be obtained by reacting compound 1 with triphosgene, the structural formula of described compound 1 is:
B () described compound 1 is with 2,3 dihydro furan under tert-butyl lithium effect, be obtained by reacting compound 2 in-78 DEG C, the structural formula of described compound 2 is:
.
9. the synthetic method of compound 2 according to claim 8, is characterized in that in step (a), described in
be 1:(1 ~ 1.2 with the mol ratio of triphosgene), preferred 1:1.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201410579870.9A CN104387383B (en) | 2014-10-24 | 2014-10-24 | A kind of synthetic method of Eliquis precursor compound |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201410579870.9A CN104387383B (en) | 2014-10-24 | 2014-10-24 | A kind of synthetic method of Eliquis precursor compound |
Publications (2)
Publication Number | Publication Date |
---|---|
CN104387383A true CN104387383A (en) | 2015-03-04 |
CN104387383B CN104387383B (en) | 2016-03-23 |
Family
ID=52605357
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201410579870.9A Expired - Fee Related CN104387383B (en) | 2014-10-24 | 2014-10-24 | A kind of synthetic method of Eliquis precursor compound |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN104387383B (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104950066A (en) * | 2015-06-30 | 2015-09-30 | 成都百裕科技制药有限公司 | Method for detecting Apixaban intermediate II through reversed-phase high-performance liquid chromatogram |
CN105732622A (en) * | 2016-04-18 | 2016-07-06 | 山东罗欣药业集团股份有限公司 | Preparation method of apixaban |
CN113504317A (en) * | 2021-06-22 | 2021-10-15 | 哈尔滨珍宝制药有限公司 | Detection method and application of genotoxic impurities in apixaban |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102675314A (en) * | 2012-06-14 | 2012-09-19 | 南京正科制药有限公司 | Method for synthesizing apixaban |
WO2013119328A1 (en) * | 2012-02-07 | 2013-08-15 | Assia Chemical Industries Ltd. | Solid state forms of apixaban |
-
2014
- 2014-10-24 CN CN201410579870.9A patent/CN104387383B/en not_active Expired - Fee Related
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013119328A1 (en) * | 2012-02-07 | 2013-08-15 | Assia Chemical Industries Ltd. | Solid state forms of apixaban |
CN102675314A (en) * | 2012-06-14 | 2012-09-19 | 南京正科制药有限公司 | Method for synthesizing apixaban |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104950066A (en) * | 2015-06-30 | 2015-09-30 | 成都百裕科技制药有限公司 | Method for detecting Apixaban intermediate II through reversed-phase high-performance liquid chromatogram |
CN104950066B (en) * | 2015-06-30 | 2016-06-08 | 成都百裕科技制药有限公司 | The method of reversed-phase high-performance liquid chromatography detection Eliquis intermediate II |
CN105732622A (en) * | 2016-04-18 | 2016-07-06 | 山东罗欣药业集团股份有限公司 | Preparation method of apixaban |
CN113504317A (en) * | 2021-06-22 | 2021-10-15 | 哈尔滨珍宝制药有限公司 | Detection method and application of genotoxic impurities in apixaban |
Also Published As
Publication number | Publication date |
---|---|
CN104387383B (en) | 2016-03-23 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Mou et al. | Carbene-catalyzed LUMO activation of alkyne esters for access to functional pyridines | |
CN101535220B (en) | Process for producing fullerene derivative | |
CN104387383B (en) | A kind of synthetic method of Eliquis precursor compound | |
CN108484477A (en) | A kind of synthetic method of 5- acyl groups benzo [a] carbazole compound | |
US7767825B2 (en) | 2,2′,6,6′-tetraoxazolinyl biphenyl ligand and method for preparing the same | |
CN106632484B (en) | Preparation method of tenofovir alafenamide | |
CN108059610B (en) | Preparation method of 3-acyl spiro-trienone compound | |
Casaschi et al. | Palladium catalysed tandem cyclisation–anion capture. Part 7: Synthesis of derivatives of α-amino esters, nitrogen heterocycles and β-aryl/heteroaryl ethylamines via in situ generated vinylstannanes | |
CN103896940B (en) | A kind of synthetic method of Eliquis | |
CN111763222B (en) | Intermediate for preparing edoxaban free base and preparation method and application thereof | |
JP2007230963A (en) | Method for producing 2,4-disubstituted pyridine | |
CN104844593A (en) | Synthetic method for Apixaban drug intermediate | |
Liu et al. | Enantiopure 2, 6-disubstituted piperidines bearing one alkene-or alkyne-containing substituent: preparation and application to total syntheses of indolizidine-alkaloids | |
CN111440109A (en) | Preparation method of N-methyl-3-methylmercapto-4-amino maleimide compound | |
CN103059046B (en) | Preparation method of faropenem | |
CN114539304A (en) | Synthesis method and application of 1, 3-azasilane compounds | |
CN109776546B (en) | Method for preparing indolopyrrolidone compound | |
CN109384702B (en) | Preparation method of N-dithiocarbamate indole compound | |
CN109053631B (en) | Synthetic method for synthesizing benzo [1,3] oxazine-2-thioketone through isothiocyanate and 2-sulfonyl alkyl phenol | |
Chetcuti et al. | Incorporating metal-metal multiple bonds into heterometallic chains: bis [tris (trimethylstanyl) tin] tetrakis (dimethylamido) dimolybdenum and-ditungsten and related compounds | |
CN104926747B (en) | The preparation method and use of Huan Ji oxazolin ligands with optical activation | |
KR102451135B1 (en) | Ortho-carborane-fused pyrazole compounds and their preparation method | |
JP2008106004A (en) | Method for producing benzene derivative and method for producing cyclohexene derivative useful therefor | |
CN115304557B (en) | Enamine derivative and preparation method thereof | |
CN115057816B (en) | 4-aminoquinoline compound, preparation method thereof and application thereof in anti-tumor drugs |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20160323 Termination date: 20181024 |