CN106749181A - A kind of method for preparing Ni Lapani - Google Patents
A kind of method for preparing Ni Lapani Download PDFInfo
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- CN106749181A CN106749181A CN201611191453.2A CN201611191453A CN106749181A CN 106749181 A CN106749181 A CN 106749181A CN 201611191453 A CN201611191453 A CN 201611191453A CN 106749181 A CN106749181 A CN 106749181A
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- SWUANUQBXJNXGP-UHFFFAOYSA-N CC(C)(C)OC(N(CCC1)CC1c(cc1)ccc1N)=O Chemical compound CC(C)(C)OC(N(CCC1)CC1c(cc1)ccc1N)=O SWUANUQBXJNXGP-UHFFFAOYSA-N 0.000 description 1
- NSLOBVGASZUPDO-UHFFFAOYSA-N COC(c1cccc(C=O)c1[N+]([O-])=O)=O Chemical compound COC(c1cccc(C=O)c1[N+]([O-])=O)=O NSLOBVGASZUPDO-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/07—Optical isomers
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Abstract
The invention discloses the preparation method of a kind of compound 2 [4 ((3S) 3 piperidyl) phenyl] formamide of 2H indazoles 7, benzyl quaternary ammonium salt is generated by the reaction of 4 nitrobenzophenone pyridines and benzyl halogen, by sodium borohydride selective reduction pyridine quaternary ammonium salt, 3 (4 aminophenyl) piperidines are obtained in the presence of palladium reagent, (S) 3 (4 halogenophenyl) piperidines is obtained in the presence of chiral selectors, it is condensed with the nitrobenzene methyl of 3 formoxyl 2 again and pyrazole ring is formed in the presence of sodium azide, (molecular entity is to prepare Niraparib by amine solution afterwards:2 [4 ((3S) 3 piperidyl) phenyl] formamides of 2H indazoles 7).
Description
Technical field：The present invention is chemical medicine field, and specially one kind prepares 2- [4- ((3S) -3- piperidyls) benzene
Base] -2H- indazole -7- formamides method
Background technology：
Niraparib (molecular entity is 2- [4- ((3S) -3- piperidyls) phenyl] -2H- indazole -7- formamides), belongs to
PARP inhibitor, this is targeted drug of the class for PARP genes, and it is not all effective to any cancer, and is primarily used for
The patient of BRCA1/2 gene mutations, this embodies the cancer " precisely medical treatment " often said now.
PARP full name poly (ADP-ribose) polymerase, it is capable of identify that the single-stranded breakpoints of DNA, starts DNA and repairs.
Due to many induced by chemotherapeutic agents DNA damages, and cancer cell is repaired further through DNA and produces drug resistance, therefore 1990s starts research and development
PARP inhibitor, it is intended to strengthen the curative effect of chemotherapeutics, the bumpy course of PARP inhibitor is exactly from here on.Start
Research is not very smooth, and the toxicity of chemotherapy drugs in combination PARP inhibitor is very big, and PARP inhibitor is used as chemotherapy ancillary drug
Original intention is gone bankrupt.But two Nature of 2005 achieve breakthrough, PARP inhibitor is used alone can kill DNA
Repair deficiency cancer cell, particularly BRCA1/2 saltant types cancer cell (BRCA participates in DNA and repairs).
It is BRCA gene mutations related oophoroma, breast cancer that Niraparib submits indication in advance, it should can be second
The PARP inhibitor of listing, last year AstraZeneca has had listed that PARP inhibitor Olaparib olaparibs (are also named
Lynparza), it sells peak value and is expected to reach annual 2000000000 because effect is significant is approved for the oophoroma of BRCA mutation
Dollar！YNPARZA (olaparib) olaparibs hard capsule is ovarian cancer patients oral medication new drug, and the U.S. initially ratifies：
Company in 2014：AstraZeneca
The morbidity of oophoroma may be relevant with the following aspects：Pathogenesis of cancer external factor (including chemistry, physics, life
The carcinogens such as thing)；Pathogenesis of cancer internal factor (including immunologic function, endocrine, heredity, mental element etc.), and diet
Trophic disturbance and bad life habits etc..The multiple women for being born in climacteric.More than the 35 years old multiple epithelial ovarian cancers of person, and
Young and childhood women is generally reproduction cell class malignant tumour.
Especially epithelioma is difficult to early detection to malignant tumor of ovary, and etiology unknown in addition to inherited ovarian, does not have one
Level precautionary measures, advocate that early diagnosis is early controlled, and strives for early detection lesion at present, and the research about early diagnosing is in progress.
Oophoroma is the primary cause of death of U.S.'s gynecological tumor, is the dead the fifth-largest reason of female cancer, only not
The oophoroma women of foot 40% can cure.The incidence of oophoroma with age, 60-70 age bracket incidence of disease highests,
Middle position diagnosis of age 63 years old, is progressive stage disease during 70% diagnosis.
Epidemiological study has identified the hazards of oophoroma.Pregnancy and for the first time production≤25 years old, using oral
Contraceptive and breast-feeding can reduce 30%-60% risks；Never gave birth to, ＞ pregnancies in 35 years old and production for the first time then increase
Ovarian cancer risk.Data show that hormone therapy and inflammatory pelvic disease may increase ovarian cancer risk.Ovarian stimulation body
Outer increase ovary LMP tumor risks of becoming pregnant.Obesity seems unrelated with most aggressive oophoroma type.Have BRCA1 and
BRCA2 genotype, the family history influenceed by Jessica Lynch's syndrome (first degree relative that patient has 2 or more suffers from oophoroma) and morning
Phase morbidity is relevant, and such patient accounts for 5% human ovarian cancer patients.
High Risk Females (or have BRCA1 or there is BRCA2 to be mutated) preventative ovary salpingotomy can reduce oophoroma and
Carcinoma of fallopian tube, but Primary peritoneal carcinoma may be suffered from.Sometimes invisible oophoroma can be found after preventative oophorosalpingectomy,
Illustrate to want careful pathological examination.Operation risk includes enteron aisle, bladder, uterus, injury of blood vessel.Recent studies have shown that fallopian tubal
It is the origin of some oophoromas and primary peritoneal cancer.Environmental factor there is no conclusive result with oophoroma.
Yuan Yan companies are preparing 2- [4- ((3S) -3- piperidyls) phenyl] -2H- indazole -7- formamide tosilate
During monohydrate, following several middle methods have been used：
It is Journal of Medicinal Chemistry, 2009, Vol.52, No.22 report synthesis road in route 1
Line：During Niraparib is synthesized, when pyridine ring is reduced is platinum oxide, and the reagent cost is higher, wherein pyrazole ring
Synthesis be sodium azide, the step amplify prepare in it is relatively hazardous, to avoid using the reagent, the route to be finally synthesizing
After going out the Niraparib of racemization, chiral resolution is carried out using supercritical chiral splitter, the process costs are high, be unfavorable for amplifying
Prepare.
The Org.Process Res.Dev.2011,15,831-840 of route 2 are reported：The synthetic route is first by chirality
The mode of fractionation obtains (S) -3- (4- aminophenyls) piperidines, is condensed with 3- formoxyl -2- nitrobenzene methyls afterwards, and folded
Pyrazole ring is constructed in the presence of sodium nitride, after ammonia and acid under conditions of synthesize Niraparib molecules, in the route
Use is also platinum oxide during reduction pyridine ring, relatively costly, is that to use is also sodium azide method pyrazole ring is built, unfavorable
Generated in amplifying.
The Org.Process Res.Dev.2014,18,215-227 of route 3 are reported：(S) -3- (4- aminophenyls) piperidines
It is to be obtained by the reduction of (S) -3- (4- aminophenyls) -2 piperidones, and (S) -3- (4- aminophenyls) -2 piperidones are from specific
Enzyme be obtained using the mode of biofermentation, the method has certain limitation, and the enzyme of selection needs specifically to turn out, and
It is relatively costly and the synthetic route is more long.
The present invention uses route 4, with 3- (4- aminophenyls) pyridine as raw material, by sodium borohydride reduction quaternary ammonium salt, then
(S) -3- (4- aminophenyls) piperidines is prepared with the method for chiral resolution after palladium reagent reduction, it is to avoid the use of Yuan Yan companies
The direct 3- of platinum oxide (4- nitrobenzophenones) pyridines reduce cost come the method for preparing 3- (4- aminophenyls) piperidines, (S) -3-
After (4- aminophenyls) piperidines is condensed with 2- formoxyl -6- methyl formates nitrobenzene, into three nitrogen Zo in the presence of sodium azide
Ring, and effect in ammonium hydrogen carbonate carries out amine solution and prepares 2- [4- ((3S) -3- piperidyls) phenyl] -2H- indazole -7- formamides
(Nirapari) cost of preparation, is this method reduce, condition is gentleer, yield is higher and simple operation and other advantages, is adapted to work
Skill amplifies generation.
The content of the invention：
The present invention prepares 2- [4- ((3S) -3- piperidyls) phenyl] -2H- indazole -7- formamides to toluene to announce one kind
The method of sulfonate, wherein：
Formula 1X=Cl, Br
The reducing agent of formula 2 is:NaBH4, borine, red aluminum, LiAlH4
The palladium reagent of formula 3 is:Pd/C, Pd (OH)2, Raney-Ni
The resolution reagent of formula 4 is：L-TARTARIC ACID, L- (-)-dibenzoyl tartaric acid
The reagent of ammonolysis is in formula 5：Ammonia, ammonium hydrogen carbonate
Reagent in formula of the invention 1 for benzyl is cylite, benzyl chloride, with toluene, tetrahydrofuran, benzyl chloride or bromine
Change benzyl and make solvent, heat 70-110 DEG C.
In formula 2 for selective reduction pyridine ring reagent be NaBH4, borine, red aluminum, LiAlH4, solvent is methyl alcohol, second
Alcohol, tetrahydrofuran.
It is used for reducing nitro in formula 3, alkene and de- benzyl go back reagent for palladium carbon (5%, 10%), palladium dydroxide, rhodium carbon,
Raney-Ni, preferably palladium carbon (10%), wherein palladium dydroxide, Hydrogen Vapor Pressure are 8-15 atmospheric pressure, and preferably 12 atmospheric pressure are molten
Agent is that solvent is methyl alcohol, ethanol, toluene.
In formula 4 in chiral resolution 3- (4- halogenophenyls) piperidines, when halogen atom can be chlorine, bromine, iodine atom, tear open
Point reagent is L-TARTARIC ACID, L- (-)-dibenzoyl tartaric acid, and solvent is methyl alcohol, acetonitrile, ethanol, tetrahydrofuran, acetone, preferably
Methyl alcohol.
Ammonolysis reagent in formula 5 in aminolysis step is ammonia, ammonium hydrogen carbonate, reaction temperature can at room temperature, or
Airtight condition reaction under heating condition.
The synthetic operation of formula 1 is：After substrate is mixed with halogenation benzyl, reacted after being heated to uniform temperature, after completion of the reaction
Room temperature is cooled to, there is solid to separate out, solid is filtered, filter cake is washed with complete, obtains Light brown solid.
The synthetic operation of formula 2 is：After solvent dissolving is added in substrate, system is cooled to 0 DEG C, reducing agent is added in batches
Enter in reaction system, addition finish after, and at such a temperature react 30 minutes, after be warmed to room temperature reaction 8 hours, reaction is finished
Afterwards, after most of solvent is evaporated, water is added, and is extracted with ethyl acetate, dried, evaporate the solid after solvent.
The synthetic operation of formula 3 is：In autoclave, substrate is dissolved in solvent in (methyl alcohol, ethanol), adds acetic acid, urge
Agent, is being passed through hydrogen, reacts under pressure, filters afterwards, and filtrate decompression is steamed, and adds ethyl acetate dissolving, is used in combination
Sodium hydroxide solution is washed, and decompression steams solvent and obtains product.
The synthetic operation of formula 4 is：Substrate is dissolved in solvent, after adding resolution reagent, after being heated to reflux 1 hour, slowly
Room temperature is cooled to, crystal is slowly separated out, crystal, solid is filtered out
The synthetic operation of formula 5 is：Solvent (solvent can be methyl alcohol, ethanol, acetonitrile) is added in substrate, after being dissolved,
After adding ammonium hydrogen carbonate, capping heats 100 DEG C and reacts 12 hours, is cooled to room temperature, filters out insoluble matter, and dilute salt is added dropwise
Acid is simultaneously stirred continuously up to reaction solution pH is 3 or so, decompression in 3 hours is stirred at room temperature and steams partial solvent, adds water, is used in combination
Dichloromethane is washed, and decompression steams solvent and obtains off-white powder.
Specific embodiment
Example 1 will add cylite 120mL in the 30.0g of compound 2 (0.15mol), and reaction solution is heated into 110 DEG C instead
Answer 10 hours, after be cooled to room temperature, there is solid to separate out, filter out solid, and washed 2 times with hexane, gained solid is put into air blast
45 DEG C of dryings of baking oven, obtain brown color 45.2g.
The compound 4 of example 2 must be prepared with reference to example 1
Example 3 will be added in 130mL methyl alcohol in compound 3 (43.0g, 0.12mol), and reaction solution is cooled into 3-5 DEG C, point
After adding sodium borohydride (18.2g, 0.48mol), addition to finish, after stirring 30 minutes at such a temperature, reaction 8 is warmed to room temperature
Hour, after decompression steams most of methyl alcohol, water 110mL is added, and be extracted with ethyl acetate 2 (2*
150mL), organic phase anhydrous sodium sulfate drying, faint yellow solid 22.8g is steamed to obtain by organic phase pressurization.
The preparation of the compound 5,6 of example 4 can also be prepared by compound 4, referring in particular to example 3
Example 5 will add methyl alcohol 110mL in autoclave in the mixture (19.0g, 0.065mol) of compound 5,6, add
Acetic acid 30mL, add palladium dydroxide 1.5g, after be passed through hydrogen, after under 12 atmospheric pressure react 24 hours, after completion of the reaction, mistake
Solid is leached, and the most of decompression of methyl alcohol in filtrate is steamed, add 1mL sodium hydroxide solution 130mL, after stirring 20 minutes,
It is extracted with ethyl acetate 2 times (2*100mL), organic phase saturated lemon washes 1 time (100mL), organic phase anhydrous sodium sulfate
Dry, organic phase pressurization is steamed into obtain faint yellow solid 9.3g.
Example 6 will add acetonitrile 110mL in compound 7 (25g, 0.13mol), after being heated to backflow, be dividedly in some parts L- wine
Stone acid (15.2g, 0.104mol), addition is flowing back 2 hours after finishing, and is slowly dropped to 10 DEG C (in 1.5 hours), and in the temperature
Under be stirred overnight, after filtering out solid, will in solid add ethanol 85mL, be heated to backflow after and stirring 1 hour, after be down to room
Warm crystallization 8 hours, filters out solid, and (45 DEG C) of drying under reduced pressure obtains off-white powder 16.4g, will add acetic acid in gained solid
Ethyl ester 50mL, and 0.1M sodium hydroxide solution 30mL are added, after stirring 20 minutes, 2 times (2*50mL) is extracted with ethyl acetate, have
Machine saturated lemon is washed 1 time (100mL), organic phase anhydrous sodium sulfate drying, steams faint yellow by organic phase pressurization
Grease 8.7g, middle addition dichloromethane 60mL, di-tert-butyl dicarbonate (10.8g, 0.05mol), add triethylamine (5.70g,
0.057mol), DMAP (0.460g, 3.80mmol), reacts 8 hours at room temperature, reaction solution is washed with saturated sodium bicarbonate, nothing
Aqueous sodium persulfate is dried, and organic phase pressurization is steamed to obtain into faint yellow solid 12.1g.
Example 7 will add DMF 210mL in compound 9 (83.0g, 0.43mol), add DMF-DMA 220mL, heat afterwards
Reacted 18 hours to 130 DEG C, be cooled to room temperature, add water 450mL stirrings, there is solid to separate out, filtered out solid and wash with water, and
(45 DEG C) of drying under reduced pressure obtains brown solid 96.3g
Example 8 will add DMF 350mL in compound 10 (90.0g, 0.36mol), by sodium metaperiodate (192.6g,
1.44mol) it is dissolved into 490mL, is added drop-wise in reaction solution, added in half an hour, be added dropwise to after finishing, 3 is reacted at room temperature
Hour, water 650mL stirrings are added, there is solid to separate out, filter out solid and wash with water, and (45 DEG C) of drying under reduced pressure obtains brown solid
77.2g。
Example 9 will add n-hexane in compound 11 (23.0g, 0.11mol) and compound 8 (30.4.0g, 0.11mol)
160mL, and reflux temperature is heated to, react 18 hours at such a temperature, solid is filtered out, and washed with n-hexane, and depressurize dry
Dry (45 DEG C) obtain brown solid 41.2g.
Example 10 will in compound 12 (25.0g, 0.054mol) plus DMF 80mL, add sodium azide (3.5g,
0.054mol), and 2,6- lutidines (7.1g) is added, reaction solution is heated to 120 DEG C, reacts 24 hours at such a temperature,
Room temperature is cooled to, water 100mL is added, 2 times (2*50mL) is extracted with tetrahydrofuran, organic phase is washed with water 1 time, rear anhydrous sodium sulfate
Dry, organic phase pressurization is steamed into obtain faint yellow solid 18.6g.Use recrystallizing methanol.
Methyl alcohol 80mL is added in the compound 13 (12.0g, 0.028mol) of example 11, after being dissolved, ammonium hydrogen carbonate is added
Afterwards, capping, heats 100 DEG C and reacts 12 hours, is cooled to room temperature, filters out insoluble matter, watery hydrochloric acid is added dropwise and is stirred continuously
Until reaction solution pH is 3 or so, decompression in 3 hours is stirred at room temperature and steams partial solvent, add water, and washed with dichloromethane,
Decompression steams solvent and obtains off-white powder, solid ethyl alcohol recrystallization, and (45 DEG C) of drying under reduced pressure obtains off-white powder 8.2g.
Claims (5)
1. the reagent in formula one for benzyl is cylite, and benzyl chloride does molten with toluene, tetrahydrofuran, benzyl chloride or cylite
Agent, heats 70-110 DEG C.
2. the reagent in formula one for selective reduction pyridine ring is NaBH4, borine, red aluminum, LiAlH4, solvent is methyl alcohol, second
Alcohol, preferably tetrahydrofuran, NaBH4,LiAlH4。
3. it is used for reducing nitro in formula one, alkene and de- benzyl go back reagent for palladium carbon (5%, 10%), palladium dydroxide, rhodium carbon,
Raney-Ni, preferably palladium carbon (10%), wherein palladium dydroxide, Hydrogen Vapor Pressure are 8-15 atmospheric pressure, and preferably 12 atmospheric pressure are molten
Agent is that solvent is methyl alcohol, ethanol, toluene.
4. in formula one in chiral resolution 3- (4- aminophenyls) piperidines, resolution reagent is L-TARTARIC ACID, L- (-)-dibenzoyl
Tartaric acid, solvent is methyl alcohol, acetonitrile, ethanol, tetrahydrofuran, preferably acetone, methyl alcohol.
5. the ammonolysis reagent in formula one in aminolysis step is ammonia, and ammonium hydrogen carbonate, reaction temperature at room temperature, or can add
Airtight condition reaction under heat condition, reaction temperature is 80-110 DEG C.
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108084157A (en) * | 2018-02-12 | 2018-05-29 | 安庆奇创药业有限公司 | A kind of synthetic method of Ni Lapani |
| CN108283628A (en) * | 2018-04-20 | 2018-07-17 | 湖南博隽生物医药有限公司 | A kind of anticancer drug microcapsule formulation and preparation method thereof |
| CN109134351A (en) * | 2018-09-21 | 2019-01-04 | 武汉理工大学 | S-3-(4- aminophenyl) piperidines synthetic method |
| WO2019072237A1 (en) | 2017-10-13 | 2019-04-18 | Zai Lab (Shanghai) Co., Ltd. | Process for preparing intermediate of anti-tumor drug niraparib and intermediate thereof |
| CN109796457A (en) * | 2019-03-28 | 2019-05-24 | 苏州国匡医药科技有限公司 | A kind of preparation method and applications of 2- (3- (azetidine -3- base) piperidin-1-yl) ethyl -1- alcohol |
| CN109810047A (en) * | 2018-03-02 | 2019-05-28 | 上海博邦医药科技有限公司 | (R) synthetic method of the chiral intermediate of -3- Phenylpiperidine or/and (S) -3- Phenylpiperidine and Ni Lapani |
| CN110156751A (en) * | 2019-05-28 | 2019-08-23 | 江苏食品药品职业技术学院 | A kind of new method preparing Ni Lapani and its intermediate |
| CN110343088A (en) * | 2019-07-17 | 2019-10-18 | 东南大学 | A kind of derivative and its preparation method and application based on PARP inhibitor Niraparib |
| CN110407704A (en) * | 2019-08-19 | 2019-11-05 | 常州沃腾化工科技有限公司 | A kind of synthetic method of 3- formoxyl -2- nitrobenzene methyl |
| CN115611860A (en) * | 2021-07-13 | 2023-01-17 | 上海博璞诺科技发展有限公司 | Method for synthesizing nilapanib |
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| US10927077B2 (en) | 2017-10-13 | 2021-02-23 | Zai Lab (Shanghai) Co., Ltd. | Process for preparing intermediate of anti-tumor drug niraparib and intermediate thereof |
| WO2019072237A1 (en) | 2017-10-13 | 2019-04-18 | Zai Lab (Shanghai) Co., Ltd. | Process for preparing intermediate of anti-tumor drug niraparib and intermediate thereof |
| EP3694836A4 (en) * | 2017-10-13 | 2020-09-02 | Zai Lab (Shanghai) Co., Ltd. | Process for preparing intermediate of anti-tumor drug niraparib and intermediate thereof |
| JP2020536948A (en) * | 2017-10-13 | 2020-12-17 | ザイ ラボ （シャンハイ） カンパニー、リミテッド． | Manufacturing methods and intermediates for synthesizing intermediates for the antitumor drug Nilaparib |
| CN108084157A (en) * | 2018-02-12 | 2018-05-29 | 安庆奇创药业有限公司 | A kind of synthetic method of Ni Lapani |
| CN109810047A (en) * | 2018-03-02 | 2019-05-28 | 上海博邦医药科技有限公司 | (R) synthetic method of the chiral intermediate of -3- Phenylpiperidine or/and (S) -3- Phenylpiperidine and Ni Lapani |
| CN108283628A (en) * | 2018-04-20 | 2018-07-17 | 湖南博隽生物医药有限公司 | A kind of anticancer drug microcapsule formulation and preparation method thereof |
| CN109134351A (en) * | 2018-09-21 | 2019-01-04 | 武汉理工大学 | S-3-(4- aminophenyl) piperidines synthetic method |
| CN109134351B (en) * | 2018-09-21 | 2022-03-11 | 武汉理工大学 | Synthesis method of S-3- (4-aminophenyl) piperidine |
| CN109796457A (en) * | 2019-03-28 | 2019-05-24 | 苏州国匡医药科技有限公司 | A kind of preparation method and applications of 2- (3- (azetidine -3- base) piperidin-1-yl) ethyl -1- alcohol |
| CN110156751A (en) * | 2019-05-28 | 2019-08-23 | 江苏食品药品职业技术学院 | A kind of new method preparing Ni Lapani and its intermediate |
| CN110343088B (en) * | 2019-07-17 | 2021-05-11 | 东南大学 | Derivative based on PARP inhibitor Niraparib and preparation method and application thereof |
| CN110343088A (en) * | 2019-07-17 | 2019-10-18 | 东南大学 | A kind of derivative and its preparation method and application based on PARP inhibitor Niraparib |
| CN110407704A (en) * | 2019-08-19 | 2019-11-05 | 常州沃腾化工科技有限公司 | A kind of synthetic method of 3- formoxyl -2- nitrobenzene methyl |
| CN110407704B (en) * | 2019-08-19 | 2022-05-17 | 常州沃腾化工科技有限公司 | Synthetic method of 3-formyl-2-nitrobenzoic acid methyl ester |
| CN115611860A (en) * | 2021-07-13 | 2023-01-17 | 上海博璞诺科技发展有限公司 | Method for synthesizing nilapanib |
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Application publication date: 20170531 |