CN106905234A - A kind of method for synthesizing the ethoxyquinoline of 6 amino of HKI-272 intermediate 3 cyano group, 4 chlorine 7 - Google Patents
A kind of method for synthesizing the ethoxyquinoline of 6 amino of HKI-272 intermediate 3 cyano group, 4 chlorine 7 Download PDFInfo
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- CN106905234A CN106905234A CN201710238261.0A CN201710238261A CN106905234A CN 106905234 A CN106905234 A CN 106905234A CN 201710238261 A CN201710238261 A CN 201710238261A CN 106905234 A CN106905234 A CN 106905234A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
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Abstract
The invention discloses a kind of method for synthesizing the ethoxyquinoline of 6 amino of HKI-272 intermediate 3 cyano group, 4 chlorine 7, comprise the following steps：Step 1,2 (nitro benzoyl of 4 ethyoxyl, 2 chlorine 5) 3 aminoacrylonitriles are obtained by the nitrobenzene methyl of 4 ethyoxyl, 2 chlorine 5 in the case where catalyst 1 is acted on the condensation of 3 aminoacrylonitriles；There is ring-closure reaction in step 2,2 (nitro benzoyl of 4 ethyoxyl, 2 chlorine 5) 3 aminoacrylonitriles, the ethyoxyl Isosorbide-5-Nitrae EEDQ of 3 cyano group, 4 oxo, 6 nitro 7 is obtained under alkali effect；There is chlorination in step 3, the ethyoxyl Isosorbide-5-Nitrae EEDQ of 3 cyano group, 4 oxo, 6 nitro 7, the ethoxyquinoline of 3 cyano group, 4 chlorine, 6 nitro 7 is obtained with POCl3；There is reduction reaction in step 4, the ethoxyquinoline of 3 cyano group, 4 chlorine, 6 nitro 7, target product is obtained under the effect of catalyst 2 with hydrazine hydrate.The synthetic method step of the ethoxyquinoline of 6 amino of HKI-272 intermediate 3 cyano group, 4 chlorine 7 that the present invention is provided is few, reaction condition is gentle, and reagent is inexpensive, be easy to get, simple to operate, total recovery is higher, and a new approach is provided to prepare HKI-272 and intermediate.
Description
Technical field
The invention belongs to organic preparing technical field, and in particular to -4- is chloro- for one kind synthesis HKI-272 intermediate 3- cyano group
The method of 6- amino -7- ethoxyquinolines.
Background technology
HKI-272 (formula A), chemistry entitled (E)-N- 4- [the chloro- 4- of 3- (2- pyridomethoxies) anilino-] -3- cyano group -
7- ethyoxyl -6- quinoline } -4- dimethylamino -2- crotonamides are Wyeth companies of the U.S. and Puma biotechnologies company joint
Develop, be a kind of irreversible general ErbB1 and ErbB2 receptor tyrosine kinase inhibitors, can Selective depression ErbB1 and
ErbB2 tyrosine kinase activities, have to the HER-2 positive breast cancer patients with terminal in advance through or without Herceptin treatment
There is the inhibitor of good efficacy and tolerance.In July, 2016, PUMA biotechnologies company discloses the experiment of clinical 5th year of III phase
As a result, its non-metastatic recurrence rate to early stage HER-2 positive breast cancer is 90.4%, is reduced than comfort group relative risk
26%, therefore, warp-wise FDA have submitted application for quotation for PUMA biotechnologies company.
The chloro- 6- amino -7- ethoxyquinolines of formula (I) chemical compound 3-cyano -4- are the key intermediates for synthesizing HKI-272,
Synthesis for HKI-272 has very important significance.Patent US7399865 discloses formula (I) the compound 3- of acetylation
The synthesis technique of the chloro- 6- acetamidos -7- ethoxyquinolines of cyano group -4-, the technique is with 2- Amino-5-nitrophenols as former
Material, reduced through acetylation, etherificate, palladium charcoal after 3- ethyoxyl -4- acetamido aniline again with 2- cyano group -3- ethoxy-c olefin(e) acids
Ethyl ester is condensed, and formula (I) the compound 3- of acetylation is obtained again through chloro after 250 DEG C of high temperature cyclizations in Dowtherm A
The chloro- 6- acetamidos -7- ethoxyquinolines of cyano group -4-.
Synthetic route is：
Exist in the technique except initiation material such as palladium charcoal, 2- cyano group -3- ethoxy-c olefin(e) acid second costly need to be used
Outside the reagents such as ester, need to also be in 250 DEG C of more than pyroreaction 20h in the presence of the 5th step ring-closure reaction, it is secondary anti-easily to there is charing etc. in raw material
Should, post processing is difficult；Yield is low, operation inconvenience, process safety difference the problems such as, in addition, Dowtherm A be high boiling solvent,
Not only consumption is big, and is difficult to reclaim, and high cost is polluted to environment.
Document Chinese Journal of Pharmaceuticals, 2014,45 (8), 701-705 also reports formula (I) the compound 3- of acetylation
The synthetic method of the chloro- 6- acetamidos -7- ethoxyquinolines of cyano group -4-, the technique be with 4-HBA methyl esters as raw material,
Through nitrification, reduction, acetylation, etherificate, nitrify again, restore after with trans- 3- (dimethylamino) acrylonitrile be condensed, then occur again
The chloro- 6- acetamidos -7- ethoxyquins of formula (I) chemical compound 3-cyano -4- of acetylation are obtained through the reaction of 9 steps for cyclization, chloro etc.
Quinoline.
Synthetic route is：
Although the technique optimize the steps such as reduction, cyclization, but process route is oversize, and total recovery is low；In addition, raw material is trans-
3- (dimethylamino) acrylonitrile price is also costly.
The content of the invention
The technical problems to be solved by the invention be overcome the chloro- 6- amino of existing preparation formula (I) chemical compound 3-cyano -4- -
Raw material is not easy to obtain in the technology of 7- ethoxyquinolines report, expensive, production cost is high, yield is low, complex operation, process safety
Difference etc. is unfavorable for the defect of industrialized production, there is provided a kind of effective preparation 3- cyano group chloro- 6- amino -7- ethoxyquinolines of -4-
Method, the method step is few, reaction condition is gentle, production cost is relatively low, be adapted to industrialized production.
Technical scheme is summarized as follows：
Step (1), by formula (II) compound 4- ethyoxyl -2- chloro-5-nitrobenzoic acids methyl esters under catalyst action with
3- aminoacrylonitriles are condensed to yield formula (III) compound 2- (the chloro- 5- nitro benzoyls of 4- ethyoxyls -2-) -3- amino propylene
Nitrile；There is ring-closure reaction under alkali effect in step (2), formula (III) compound, and prepared formula (IV) chemical compound 3-cyano -4- oxos -
6- nitro -7- ethyoxyl -1,4- EEDQs；There is chlorination in step (3), formula (IV) compound, be obtained with POCl3
The chloro- 6- nitros -7- ethoxyquinolines of formula (V) chemical compound 3-cyano -4-；Step (4), formula (V) compound is in copper-aluminium composite catalyzing
Agent effect is lower and hydrazine hydrate occurs reduction reaction, and formula (I) the chemical compound 3-cyano chloro- 6- amino -7- ethoxyquinolines of -4- are obtained.
Synthetic route is：
With cheap 4- ethyoxyl -2- chloro-5-nitrobenzoic acid methyl esters as raw material, catalyst 1 is for reaction in step (1)
Solid base ZrO2-Cr2O3, its ratio 0.9~1.2 with the amount of formula (II) combinations of materials：1.
The catalyst structure is simple, and a large amount of preparations are easy to conventional experimental technique.Urged after being dried through filtering after reaction
Agent can direct reuse more than 5 times, often reuse 1 time, yield about declines 2%.
Most suitable reaction temperature is first to be stirred at room temperature in described step (1), then back flow reaction.
Alkali in described step (2) is any one or a few the group in the carbonate of alkali metal or alkaline-earth metal
Close, wherein it is preferred that potassium carbonate, and the ratio of itself and the amount of the material of formula (III) compound is 1~1.5：1.
Catalyst 2 in described step (4) is ZnCl2- CuCl composite catalysts, and ZnCl2Consumption be formula (V) change
The consumption of the 8-12% of the amount of compound material, CuCl is the 0.8-1.2% of the amount of formula (V) combinations of materials.
The advantage of this technique：Reagent used is inexpensive, be easy to get, and simple to operate, step is few, and total recovery is higher.
Specific embodiment
With reference to specific embodiment is implemented, the present invention is further illustrated.It should be understood that these embodiments are merely to illustrate this
Invention rather than limitation the scope of the present invention.
Raw material used or reagent are commercially available in addition to special instruction in embodiment.
The system of formula (III) compound of embodiment 1 2- (the chloro- 5- nitro benzoyls of 4- ethyoxyls -2-) -3- aminoacrylonitriles
It is standby
By 50mmol 3- aminoacrylonitriles, 50mmol solid base catalysts ZrO2-Cr2O3Added with 50mL tetrahydrofurans anti-
In answering bottle, be stirred at room temperature it is uniform, then by 55mmol 4- ethyoxyls -2- chloro-5-nitrobenzoic acids methyl esters and 15mL tetrahydrofurans
Mixture is instilled in above-mentioned reaction bulb, is dripped off after stirring reaction 2h at room temperature, then the 2h that flows back, cooled and filtered catalyst, is urged
Agent is dried rear reusable.Decompression boils off solvent, to 400mL dichloromethane is added in residue, moisture is distilled with 50mL
Three washings, merge organic layer, and solvent is boiled off with decompression after anhydrous sodium sulfate drying, obtain formula (III) compound, yield 87%.
The preparation of embodiment 2 formula (IV) chemical compound 3-cyano -4- oxo -6- nitro -7- ethyoxyl -1,4- EEDQs
By 40mmol formulas (III) compound, 40mmol Anhydrous potassium carbonates and 40mL DMF add reaction bulb in, in 50~60
Stirring reaction 4h at DEG C, is cooled to room temperature, adds 60mL water, stirs 0.5h, the solid for separating out is filtered, by thick solid ethanol weight
Crystallization, drying under reduced pressure obtains formula (IV) compound, yield 90%.
The preparation of the chloro- 6- nitros-7- ethoxyquinolines of formula (V) chemical compound 3-cyano of embodiment 3-4-
During 40mmol formulas (IV) compound and 180mL POCl3s added into reaction bulb, heating stirring backflow 3h.Will reaction
Bottle is cooled to 0 DEG C or so, and at this temperature slowly pours into reaction bulb 1500mL 2mol/L sodium carbonate liquors, stirs
0.5h, suction filtration, filter cake is washed with warm water, and drying under reduced pressure obtains formula (V) compound, yield 88%.
The preparation of the chloro- 6- amino-7- ethoxyquinolines of formula (I) chemical compound 3-cyano of embodiment 4-4-
By in 50mmol formulas (V) compound, 100mL ethanol and 100mL distilled water addition reaction bulb, system temperature is risen to
50 DEG C, sequentially add 2.5g activated carbons, the ZnCl of 0.5mmol CuCl and 50mL 0.01M2Solution, 60 are risen to by system temperature
DEG C, the hydrazine hydrate of 100mL 80% is slowly added dropwise, flow back 1.5h after dripping off.Cooling, leaches solid, and is washed with ethanol, depressurizes
Ethanol is steamed, then with 150mL ethyl acetate extractive reaction mixed liquor in three times, combined ethyl acetate layer, anhydrous sodium sulfate is done
It is dry.Dry, the solid that drying under reduced pressure is obtained is concentrated under reduced pressure into, formula (I) compound, yield 92% is obtained.
Claims (4)
1. it is a kind of synthesize the HKI-272 intermediate 3- cyano group chloro- 6- amino -7- ethoxyquinolines of -4- method, the synthetic method
Reaction equation be：
Comprise the following steps：
Step 1, by formula (II) compound 4- ethyoxyls -2- chloro-5-nitrobenzoic acids methyl esters catalyst 1 effect under with 3- amino
Acrylonitrile condensation is obtained formula (III) compound 2- (the chloro- 5- nitro benzoyls of 4- ethyoxyls -2-) -3- aminoacrylonitriles；
There is ring-closure reaction under alkali effect in step 2, formula (III) compound, and prepared formula (IV) chemical compound 3-cyano -4- oxos -
6- nitro -7- ethyoxyl -1,4- EEDQs；
There is chlorination in step 3, formula (IV) compound, formula (V) the chemical compound 3-cyano chloro- 6- nitre of -4- is obtained with POCl3
Base -7- ethoxyquinolines；
There is reduction reaction in step 4, formula (V) compound, formula (I) compound 3- cyanogen is obtained under the effect of catalyst 2 with hydrazine hydrate
The chloro- 6- amino -7- ethoxyquinolines of base -4-.
2. one kind according to claim 1 synthesizes the HKI-272 intermediate 3- cyano group chloro- 6- amino -7- ethoxyquins of -4-
The method of quinoline, it is characterised in that：Catalyst 1 in described step 1 is solid base ZrO2-Cr2O3；Itself and formula (II) compound
The ratio of the amount of material is 0.9~1.2：1.
3. one kind according to claim 1 synthesizes the HKI-272 intermediate 3- cyano group chloro- 6- amino -7- ethoxyquins of -4-
The method of quinoline, it is characterised in that：Alkali in described step 2 for any one in the carbonate of alkali metal or alkaline-earth metal or
Several combinations, it is 1~1.5 with the ratio of the amount of the material of formula (III) compound：1.
4. one kind according to claim 1 synthesizes the HKI-272 intermediate 3- cyano group chloro- 6- amino -7- ethoxyquins of -4-
The method of quinoline, it is characterised in that：Catalyst 2 in described step 4 is ZnCl2- CuCl composite catalysts, and ZnCl2Consumption
It is the 8-12% of the amount of formula (V) combinations of materials, the consumption of CuCl is the 0.8-1.2% of the amount of formula (V) combinations of materials.
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| CN201710238261.0A CN106905234B (en) | 2017-04-12 | 2017-04-12 | A method of the synthesis chloro- 6- amino -7- ethoxyquinoline of linatinib intermediate 3- cyano -4- |
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| CN201710238261.0A CN106905234B (en) | 2017-04-12 | 2017-04-12 | A method of the synthesis chloro- 6- amino -7- ethoxyquinoline of linatinib intermediate 3- cyano -4- |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110240563A (en) * | 2019-05-09 | 2019-09-17 | 南京法恩化学有限公司 | A kind of rich preparation method for Buddhist nun of card |
| CN110845409A (en) * | 2019-12-06 | 2020-02-28 | 海门慧聚药业有限公司 | Method for synthesizing neratinib intermediate |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005028443A2 (en) * | 2003-09-15 | 2005-03-31 | Wyeth A Corporation Of The State Of Delaware, Usa | Protein tyrosine kinase enzyme inhibitors |
| WO2005113509A1 (en) * | 2004-05-20 | 2005-12-01 | Japan Tobacco Inc. | Novel 4-oxoquinoline compound and use thereof as hiv integrase inhibitor |
| CN101180269A (en) * | 2005-05-25 | 2008-05-14 | 惠氏公司 | Method of preparing 3-cyano-quinolines and intermediates made thereby |
| CN101437785A (en) * | 2006-03-06 | 2009-05-20 | 日本烟草产业株式会社 | Method for producing 4-oxoquinoline compound |
| CN102070524A (en) * | 2011-01-12 | 2011-05-25 | 无锡好芳德药业有限公司 | Method for preparing 3-cyano-4-halogenated quinoline derivatives |
| CN102731395A (en) * | 2011-04-15 | 2012-10-17 | 中国科学院上海药物研究所 | Intermediate compound of antitumor drug neratinib and its preparation method and use |
| WO2016210345A1 (en) * | 2015-06-25 | 2016-12-29 | The California Institute For Biomedical Research | Composition and methods for inhibiting mammalian sterile 20-like kinase 1 |
-
2017
- 2017-04-12 CN CN201710238261.0A patent/CN106905234B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005028443A2 (en) * | 2003-09-15 | 2005-03-31 | Wyeth A Corporation Of The State Of Delaware, Usa | Protein tyrosine kinase enzyme inhibitors |
| WO2005113509A1 (en) * | 2004-05-20 | 2005-12-01 | Japan Tobacco Inc. | Novel 4-oxoquinoline compound and use thereof as hiv integrase inhibitor |
| CN101180269A (en) * | 2005-05-25 | 2008-05-14 | 惠氏公司 | Method of preparing 3-cyano-quinolines and intermediates made thereby |
| CN101437785A (en) * | 2006-03-06 | 2009-05-20 | 日本烟草产业株式会社 | Method for producing 4-oxoquinoline compound |
| CN102070524A (en) * | 2011-01-12 | 2011-05-25 | 无锡好芳德药业有限公司 | Method for preparing 3-cyano-4-halogenated quinoline derivatives |
| CN102731395A (en) * | 2011-04-15 | 2012-10-17 | 中国科学院上海药物研究所 | Intermediate compound of antitumor drug neratinib and its preparation method and use |
| WO2016210345A1 (en) * | 2015-06-25 | 2016-12-29 | The California Institute For Biomedical Research | Composition and methods for inhibiting mammalian sterile 20-like kinase 1 |
Non-Patent Citations (2)
| Title |
|---|
| 李亚楠，等: "马来酸来那替尼的合成工艺研究", 《化工管理》 * |
| 陈峰，等: "来那替尼的合成", 《中国医药工业杂志》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110240563A (en) * | 2019-05-09 | 2019-09-17 | 南京法恩化学有限公司 | A kind of rich preparation method for Buddhist nun of card |
| CN110845409A (en) * | 2019-12-06 | 2020-02-28 | 海门慧聚药业有限公司 | Method for synthesizing neratinib intermediate |
| CN110845409B (en) * | 2019-12-06 | 2022-04-12 | 江苏慧聚药业股份有限公司 | Method for synthesizing neratinib intermediate |
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Denomination of invention: A Method for Synthesizing the Intermediate 3-Cyano-4-chloro-6-amino-7-ethoxyquinoline of Lenatinib Effective date of registration: 20230425 Granted publication date: 20190423 Pledgee: Industrial and Commercial Bank of China Limited Yutai sub branch Pledgor: Shandong jinjili New Material Co.,Ltd. Registration number: Y2023980039217 |
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