CN103159670A - Synthetic method of apixaban intermediate 1-(4-nitrobenzophenone)-2-piperidone - Google Patents
Synthetic method of apixaban intermediate 1-(4-nitrobenzophenone)-2-piperidone Download PDFInfo
- Publication number
- CN103159670A CN103159670A CN2011104279566A CN201110427956A CN103159670A CN 103159670 A CN103159670 A CN 103159670A CN 2011104279566 A CN2011104279566 A CN 2011104279566A CN 201110427956 A CN201110427956 A CN 201110427956A CN 103159670 A CN103159670 A CN 103159670A
- Authority
- CN
- China
- Prior art keywords
- piperidone
- transfer catalyst
- valeryl chloride
- phase
- mineral alkali
- 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
- TYMLOMAKGOJONV-UHFFFAOYSA-N Nc(cc1)ccc1[N+]([O-])=O Chemical compound Nc(cc1)ccc1[N+]([O-])=O TYMLOMAKGOJONV-UHFFFAOYSA-N 0.000 description 2
- VPCQXIGQMFWXII-UHFFFAOYSA-N [O-][N+](c(cc1)ccc1N(CCCC1)C1=O)=O Chemical compound [O-][N+](c(cc1)ccc1N(CCCC1)C1=O)=O VPCQXIGQMFWXII-UHFFFAOYSA-N 0.000 description 2
- SVNNWKWHLOJLOK-UHFFFAOYSA-N O=C(CCCCCl)Cl Chemical compound O=C(CCCCCl)Cl SVNNWKWHLOJLOK-UHFFFAOYSA-N 0.000 description 1
- VJNCTPKILOLNSS-UHFFFAOYSA-N [O-][N+](c(cc1)ccc1NC(CCCCBr)=O)=O Chemical compound [O-][N+](c(cc1)ccc1NC(CCCCBr)=O)=O VJNCTPKILOLNSS-UHFFFAOYSA-N 0.000 description 1
- FCEDLTRFGDDBLV-UHFFFAOYSA-N [O-][N+](c(cc1)ccc1NC(CCCCCl)=O)=O Chemical compound [O-][N+](c(cc1)ccc1NC(CCCCCl)=O)=O FCEDLTRFGDDBLV-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
Abstract
The invention discloses a synthetic method of an apixaban intermediate 1-(4-nitrobenzophenone)-2-piperidone. The 1-(4-nitrobenzophenone)-2-piperidone is formed through an integrated reaction of paranitroaniline and halogenate valeryl chloride under the condition that phase transfer catalyst exists and in a mixed system of inorganic base aqueous solution and aprotic solvent. The synthetic method of the apixaban intermediate 1-(4-nitrobenzophenone)-2-piperidone is reasonable in process condition, easy to operate, high in reaction yield, low in production cost and almost free of discharging of the three wastes.
Description
Technical field
The present invention relates to the synthetic method of a kind of Eliquis intermediate 1-(4-nitrophenyl)-2-piperidone.
Background technology
Eliquis (apixaban) belongs to amino benzoxazole compounds, is a kind of highly selective, reversible zymoplasm factor Xa inhibitor, and at first by 100 o'clock Mei-Shi Guibao research and development, Pfizer in 2007 and 100 o'clock Mei-Shi Guibao joint development of reaching an agreement.Be used for accepting the thrombus prevention of buttocks or knee replacement patient with operation in 2011 by the approval of European Drug Administration mechanism.In addition, Eliquis can also be used for the treatment of atrial fibrillation (AF) patient with preventing apoplectic.The structural formula of Eliquis (apixaban) is as follows:
In the synthetic method of Eliquis, most economical route all passes through intermediate 1-(4-nitrophenyl)-2-piperidone, as Chinese patent CN101065379, Chinese patent CN101967145A passes through 1-(4-nitrophenyl)-2-piperidone and synthesizes Eliquis.
Then CN101065379 adds phase-transfer catalyst and mineral alkali KOH reaction to generate the method for cyclic lactam-----1-(4-nitrophenyl)-2-piperidone by using p-Nitroaniline and haloalkyl acyl chlorides in the situation that mineral alkali salt of wormwood generates acid amides.The method has been used two kinds of mixed solvents, two kinds of mixed bases, and complicated operation, controlled low, cause yield on the low side.
CN101967145A is by joining p-Nitroaniline and tertiary amine organic bases in anhydrous solvent, generate acid amides with the 5-Chlorovaleryl Chloride reaction, continuation adds the very strong metal organic bases of alkalescence in reaction solution, as NaH and KOtBu, need strict control anhydrous in the method process, and used the metal organic bases, produced hydrogen, dangerous property in amplification process.
Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art, the synthetic method of a kind of more economical 1-easily (4-nitrophenyl)-2-piperidone is provided.
The synthetic method of a kind of Eliquis intermediate 1-(4-nitrophenyl)-2-piperidone, it is characterized in that with p-Nitroaniline and halo valeryl chloride in the presence of phase-transfer catalyst, in the mixed system of the aqueous solution of mineral alkali and aprotic solvent, generate 1-(4-nitrophenyl)-2-piperidone through integrated reacting; Described phase-transfer catalyst is crown ether, cyclodextrin, polyoxyethylene glycol compounds or quaternary ammonium compound; Aprotic solvent is selected from one or more the mixture in chlorine benzene,toluene,xylene, methylene dichloride, chloroform, tetracol phenixin, 1,2 ethylene dichloride and tetrahydrofuran (THF).
Reaction formula of the present invention is
Wherein X is Cl, Br or I.
Halo valeryl chloride of the present invention is selected from 5-Chlorovaleryl Chloride, 5-bromine valeryl chloride or 5-iodine valeryl chloride.
The preferred phase-transfer catalyst of the present invention is quaternary ammonium compound.
Mineral alkali of the present invention is selected from salt of wormwood, sodium carbonate, sodium hydroxide or potassium hydroxide.
The preferred mineral alkali of the present invention is potassium hydroxide.
Mol ratio between p-Nitroaniline of the present invention, mineral alkali and halo valeryl chloride is 1.0: 2.5: 1.3-1.0: 3.5: 1.6.
The mass ratio of phase-transfer catalyst of the present invention and p-Nitroaniline is 1: 100-1: 10.
The volume ratio of water of the present invention and aprotic solvent is 1.0: 1.0-1.0: 10.0.
Processing condition of the present invention are reasonable, and are simple to operate, and reaction yield is high, and production cost is low, and basic three-waste free discharge has larger economic benefit.
Embodiment
Embodiment 1:
Synthesizing of 1-(4-nitrophenyl)-2-piperidone
15 (0.1mol) p-Nitroaniline is dissolved in the 300ml methylene dichloride, add the alkaline solution (12g sodium hydroxide+water 150ml) for preparing, add Tetrabutyl amonium bromide 0.75g, under vigorous stirring, drip the 60g 5-Chlorovaleryl Chloride, keep 25 ℃ of reactions 16 hours.The TLC reaction is completed, layering, and organic phase is washed with 100ml, anhydrous sodium sulfate drying, concentrated doing obtains yellow solid, then obtains yellow crystals 19.8g with re-crystallizing in ethyl acetate, yield 90%.
1HNMR(400MHz，CDCl
3，ppm)δ：8.27(d，J＝8.7Hz，2H)，7.52(d，J＝8.7Hz，2H)，3.75(t，J＝5.9Hz，2H)，2.64(t，J＝6.4Hz，2H)，1.95-2.02(m，4H).
Embodiment 2:
Synthesizing of 1-(4-nitrophenyl)-2-piperidone
150g (1mol) p-Nitroaniline is dissolved in the 3000ml chloroform, add the alkaline solution (168g sodium hydroxide+water 1500ml) for preparing, add Tetrabutyl amonium bromide 6g, under vigorous stirring, drip the 600g 5-Chlorovaleryl Chloride, keep 25 ℃ of reactions 16 hours.The TLC reaction is completed, layering, and organic phase is washed with 1000ml, anhydrous sodium sulfate drying, concentrated doing obtains yellow solid, then obtains yellow crystals 193.8g, yield 88% with the methyl tertiary butyl ether making beating.
Claims (8)
1. the synthetic method of an Eliquis intermediate 1-(4-nitrophenyl)-2-piperidone, it is characterized in that with p-Nitroaniline and halo valeryl chloride in the presence of phase-transfer catalyst, in the mixed system of the aqueous solution of mineral alkali and aprotic solvent, generate 1-(4-nitrophenyl)-2-piperidone through integrated reacting; Described phase-transfer catalyst is crown ether, cyclodextrin, polyoxyethylene glycol compounds or quaternary ammonium compound; Aprotic solvent is selected from one or more the mixture in chlorine benzene,toluene,xylene, methylene dichloride, chloroform, tetracol phenixin, 1,2 ethylene dichloride and tetrahydrofuran (THF).
2. the method for claim 1, is characterized in that the halo valeryl chloride is selected from 5-Chlorovaleryl Chloride, 5-bromine valeryl chloride or 5-iodine valeryl chloride.
3. the method for claim 1, is characterized in that phase-transfer catalyst is quaternary ammonium compound.
4. the method for claim 1, is characterized in that mineral alkali is selected from salt of wormwood, sodium carbonate, sodium hydroxide or potassium hydroxide.
5. method as claimed in claim 4, is characterized in that mineral alkali is the hydroxide clock.
6. the method for claim 1, is characterized in that the mol ratio between p-Nitroaniline, mineral alkali and halo valeryl chloride is 1.0: 2.5: 1.3-1.0: 3.5: 1.6.
7. the method for claim 1, the mass ratio that it is characterized in that phase-transfer catalyst and p-Nitroaniline is 1: 100-1: 10.
8. the method for claim 1, the volume ratio that it is characterized in that water and aprotic solvent is 1.0: 1.0-1.0: 10.0.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011104279566A CN103159670A (en) | 2011-12-16 | 2011-12-16 | Synthetic method of apixaban intermediate 1-(4-nitrobenzophenone)-2-piperidone |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011104279566A CN103159670A (en) | 2011-12-16 | 2011-12-16 | Synthetic method of apixaban intermediate 1-(4-nitrobenzophenone)-2-piperidone |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103159670A true CN103159670A (en) | 2013-06-19 |
Family
ID=48583238
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011104279566A Pending CN103159670A (en) | 2011-12-16 | 2011-12-16 | Synthetic method of apixaban intermediate 1-(4-nitrobenzophenone)-2-piperidone |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103159670A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104341336A (en) * | 2013-08-02 | 2015-02-11 | 上海科胜药物研发有限公司 | Novel method for synthesizing apixaban important intermediate |
| CN109970626A (en) * | 2018-12-30 | 2019-07-05 | 南京正荣医药化学有限公司 | A kind of preparation method of 2- piperidones alkali metal salt |
| CN110003206A (en) * | 2019-05-15 | 2019-07-12 | 江西国药有限责任公司 | A kind of preparation method of Eliquis |
| CN113264870A (en) * | 2021-05-27 | 2021-08-17 | 神隆医药（常熟）有限公司 | Preparation method of Apixaban intermediate suitable for industrial production |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101065379A (en) * | 2004-09-28 | 2007-10-31 | 布里斯托尔-迈尔斯斯奎布公司 | Process for preparing 4,5-dihydro-pyrazolo [3,4-c] pyrid-2-ones |
| WO2010030983A2 (en) * | 2008-09-15 | 2010-03-18 | Auspex Pharmaceuticals, Inc. | Pyrazole carboxamide inhibitors of factor xa |
| CN101967145A (en) * | 2010-09-09 | 2011-02-09 | 华东理工大学 | Method for preparing antithrombotic medicament apixaban |
-
2011
- 2011-12-16 CN CN2011104279566A patent/CN103159670A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101065379A (en) * | 2004-09-28 | 2007-10-31 | 布里斯托尔-迈尔斯斯奎布公司 | Process for preparing 4,5-dihydro-pyrazolo [3,4-c] pyrid-2-ones |
| WO2010030983A2 (en) * | 2008-09-15 | 2010-03-18 | Auspex Pharmaceuticals, Inc. | Pyrazole carboxamide inhibitors of factor xa |
| CN101967145A (en) * | 2010-09-09 | 2011-02-09 | 华东理工大学 | Method for preparing antithrombotic medicament apixaban |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104341336A (en) * | 2013-08-02 | 2015-02-11 | 上海科胜药物研发有限公司 | Novel method for synthesizing apixaban important intermediate |
| WO2015018289A1 (en) * | 2013-08-02 | 2015-02-12 | 上海科胜药物研发有限公司 | Novel method for synthesizing key intermediate of apixaban |
| CN105358529A (en) * | 2013-08-02 | 2016-02-24 | 上海科胜药物研发有限公司 | Novel method for synthesizing key intermediate of apixaban |
| US9656958B2 (en) | 2013-08-02 | 2017-05-23 | Shanghai Syncores Technologies Inc. Ltd. | Method for synthesizing key intermediate of apixaban |
| CN105358529B (en) * | 2013-08-02 | 2018-09-25 | 上海科胜药物研发有限公司 | A kind of new method of synthesis Eliquis important intermediate |
| CN104341336B (en) * | 2013-08-02 | 2018-10-16 | 上海科胜药物研发有限公司 | A kind of new method of synthesis Eliquis important intermediate |
| CN109970626A (en) * | 2018-12-30 | 2019-07-05 | 南京正荣医药化学有限公司 | A kind of preparation method of 2- piperidones alkali metal salt |
| CN110003206A (en) * | 2019-05-15 | 2019-07-12 | 江西国药有限责任公司 | A kind of preparation method of Eliquis |
| CN113264870A (en) * | 2021-05-27 | 2021-08-17 | 神隆医药（常熟）有限公司 | Preparation method of Apixaban intermediate suitable for industrial production |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JO3023B1 (en) | Process For Preparing N-Alkylnal Trexone Halides | |
| CN103159670A (en) | Synthetic method of apixaban intermediate 1-(4-nitrobenzophenone)-2-piperidone | |
| CN105985225A (en) | Preparation methods for LCZ-696 and intermediate thereof | |
| CN103214455A (en) | Method for preparing bilastine | |
| CN103724258A (en) | Preparation method of sorafenib | |
| CN103833560A (en) | Preparation method of (S)-5-chloro-alpha-cyclopropinyl-2-amino-alpha-trifluoromethyl phenylcarbinol | |
| CN105315256A (en) | Industrialization-suitable preparation method of high-purity trelagliptin succinate | |
| CN105418502A (en) | Intermediate for synthesizing paroxetine and preparation method for intermediate and use of intermediate | |
| JP2008507578A (en) | Process for producing 4- [2- (dimethylamino) ethoxy] benzylamine as itopride hydrochloride intermediate | |
| CN107540575B (en) | Preparation method of sitagliptin intermediate | |
| CN101880249B (en) | Process method for synthetizing tert-butyl sulfinamide | |
| CN104725345A (en) | Clean production process of 2-thiopheneacetic acid | |
| CN105111163B (en) | A kind of synthetic method of 4 (4 aminophenyl) 3 morpholones | |
| CN112939893B (en) | Synthesis method of 4- (4-aminophenyl) -3-morpholinone | |
| CN104693090A (en) | Silodosin and preparation methods for intermediates thereof | |
| CN104557763B (en) | Method for synthesizing 2-isopropyl-4-(methylaminomethyl)thiazole | |
| CN104672180B (en) | Chiral preparation method of [(1S)-3-methyl-1-[[(2R)-2-methylepoxyethyl]carbonyl]butyl]tert-butyl carbamate | |
| CN107129440B (en) | A kind of total synthesis method of natural products (+)-negamycin | |
| CN103524502B (en) | Prepare the method for Tadalafei | |
| CN102002056B (en) | Method for preparing intermediate of prasugrel | |
| CN103936662B (en) | 1-R1-3, 3-difluoro-4-R2-piperidine and its derivatives and its prepn | |
| CN105152903A (en) | Preparation method for aliphatic dicarboxylic acids | |
| CN105085439B (en) | A kind of preparation method of epoxiconazole intermediate | |
| CN104327001B (en) | Aryne synthetic method | |
| JPH0782207A (en) | Production of fluorenone and oxidation catalyst used therein |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20130619 |