CN106905234B - A method of the synthesis chloro- 6- amino -7- ethoxyquinoline of linatinib intermediate 3- cyano -4- - Google Patents
A method of the synthesis chloro- 6- amino -7- ethoxyquinoline of linatinib intermediate 3- cyano -4- Download PDFInfo
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- CN106905234B CN106905234B CN201710238261.0A CN201710238261A CN106905234B CN 106905234 B CN106905234 B CN 106905234B CN 201710238261 A CN201710238261 A CN 201710238261A CN 106905234 B CN106905234 B CN 106905234B
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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 methods for synthesizing the chloro- 6- amino -7- ethoxyquinoline of linatinib intermediate 3- cyano -4-; include the following steps: step 1,4- ethyoxyl -2- chloro-5-nitrobenzoic acid methyl esters is condensed under the effect of catalyst 1 with 3- aminoacrylonitrile, 2- (the chloro- 5- nitro benzoyl of 4- ethyoxyl -2-) -3- aminoacrylonitrile is made；Step 2, under alkali effect cyclization reaction occurs for 2- (the chloro- 5- nitro benzoyl of 4- ethyoxyl -2-) -3- aminoacrylonitrile, and 3- cyano -4- oxo -6- nitro -7- ethyoxyl-Isosorbide-5-Nitrae-dihydroquinoline is made；Step 3, chlorination occurs for 3- cyano -4- oxo -6- nitro -7- ethyoxyl-Isosorbide-5-Nitrae-dihydroquinoline and phosphorus oxychloride, and the chloro- 6- nitro -7- ethoxyquinoline of 3- cyano -4- is made；Step 4, with hydrazine hydrate reduction reaction occurs for the chloro- 6- nitro -7- ethoxyquinoline of 3- cyano -4- under the effect of catalyst 2, and target product is made.The synthetic method step of the chloro- 6- amino -7- ethoxyquinoline of linatinib intermediate 3- cyano -4- provided by the invention is few, reaction condition is mild, and reagent is inexpensive, is easy to get, easy to operate, total recovery is higher, provides a new approach for preparation linatinib and intermediate.
Description
Technical field
The invention belongs to organic preparation technical fields, and in particular to a kind of synthesis linatinib intermediate 3- cyano -4- is chloro-
The method of 6- amino -7- ethoxyquinoline.
Background technique
Linatinib (formula A), entitled (E)-N- { 4- [the chloro- 4- of 3- (2- pyridomethoxy) the anilino-] -3- cyano-of chemistry
7- ethyoxyl -6- quinoline } -4- dimethylamino -2- crotonamide is Wyeth company, the U.S. and Puma biotechnology company joint
Develop, be a kind of irreversible general ErbB1 and ErbB2 receptor tyrosine kinase inhibitors, can selective depression ErbB1 and
ErbB2 tyrosine kinase activity has the prior HER-2 positive breast cancer patients with terminal through or without Herceptin treatment
There is the inhibitor of good efficacy and tolerance.In July, 2016, PUMA biotechnology company disclose III phase clinical 5th year and test
As a result, it is 90.4% to the non-metastatic recurrence rate of early stage HER-2 positive breast cancer, reduced than comfort group relative risk
26%, therefore, PUMA biotechnology company has submitted application for quotation to FDA.
The chloro- 6- amino -7- ethoxyquinoline of formula (I) chemical compound 3-cyano -4- is the key intermediate for synthesizing linatinib,
It has very important significance for the synthesis of linatinib.Patent US7399865 discloses formula (I) the compound 3- of acetylation
The synthesis technology of the chloro- 6- acetamido -7- ethoxyquinoline of cyano -4-, the technique are with 2- Amino-5-nitrophenol for original
Material, through acetylation, etherificate, palladium charcoal restore after 3- ethyoxyl -4- acetamido aniline again with 2- cyano -3- ethoxy-c olefin(e) acid
Ethyl ester condensation, obtains formula (I) the compound 3- of acetylation again through chloro after 250 DEG C of high temperature cyclizations in Dowtherm A
The chloro- 6- acetamido -7- ethoxyquinoline of cyano -4-.
Synthetic route are as follows:
Exist in the technique in addition to starting material such as palladium charcoal, 2- cyano -3- ethoxy-c olefin(e) acid second costly need to be used
Outside the reagents such as ester, there is also the 5th step cyclization reactions the pair such as charing easily occurs instead in 250 DEG C of pyroreaction 20h or more, raw material
It answers, post-processing is difficult；The problems such as yield is low, inconvenient, and process safety is poor, in addition, Dowtherm A is high boiling solvent,
Not only dosage is big, and is difficult to recycle, at high cost, pollutes the environment.
Document Chinese Journal of Pharmaceuticals, 2014,45 (8), 701-705 also report formula (I) the compound 3- of acetylation
The synthetic method of the chloro- 6- acetamido -7- ethoxyquinoline of cyano -4-, the technique be using 4-HBA methyl esters as raw material,
Through nitrification, reduction, acetylation, etherificate, nitrify, restore again after with trans- 3- (dimethylamino) acrylonitrile be condensed, then occur again
Cyclization, chloro etc. react the chloro- 6- acetamido -7- ethoxyquin of formula (I) chemical compound 3-cyano -4- that acetylation is made through 9 steps
Quinoline.
Synthetic route are as follows:
Although the technique optimizes reduction, cyclization, but process route is too long, and total recovery is low；In addition, raw material is trans-
3- (dimethylamino) acrylonitrile price is also more expensive.
Summary of the invention
The technical problem to be solved by the present invention is to 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- ethoxyquinoline report, valuableness, high production cost, yield are low, complicated for operation, process safety
Difference etc. is unfavorable for the defect of industrialized production, provides a kind of effective preparation chloro- 6- amino -7- ethoxyquinoline of 3- cyano -4-
Method, this method step is few, reaction condition is mild, lower production costs, is suitble to industrialized production.
Technical solution of the present invention is summarized as follows:
Step (1), by formula (II) compound 4- ethyoxyl -2- chloro-5-nitrobenzoic acid methyl esters under the action of catalyst with
3- aminoacrylonitrile is condensed to yield formula (III) compound 2- (the chloro- 5- nitro benzoyl of 4- ethyoxyl -2-) -3- amino propylene
Nitrile；Step (2), formula (III) compound occur cyclization reaction under alkali effect, formula (IV) chemical compound 3-cyano -4- oxo-are made
6- nitro -7- ethyoxyl -1,4- dihydroquinoline；Chlorination occurs for step (3), formula (IV) compound and phosphorus oxychloride, is made
The chloro- 6- nitro -7- ethoxyquinoline of formula (V) chemical compound 3-cyano -4-；Step (4), formula (V) compound is in copper-aluminium composite catalyzing
Agent effect is lower and reduction reaction occurs for hydrazine hydrate, and the chloro- 6- amino -7- ethoxyquinoline of formula (I) chemical compound 3-cyano -4- is made.
Synthetic route are as follows:
Using 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, 0.9~1.2:1 of ratio with the amount of formula (II) combinations of materials.
The catalyst structure is simple, is easy to largely prepare with conventional experimental method.It is urged after filtering is dried after reaction
Agent can be direct reuse 5 times or more, and every to reuse 1 time, yield about declines 2%.
Most suitable reaction temperature is first to be stirred at room temperature in the step (1), then back flow reaction.
Alkali in the step (2) is any one or a few the group in the carbonate of alkali or alkaline earth metal
It closes, wherein it is preferred that potassium carbonate, and the ratio of itself and the amount of the substance of formula (III) compound is 1~1.5:1.
Catalyst 2 in the step (4) is ZnCl2- CuCl composite catalyst, and ZnCl2Dosage be formula (V) change
The 8-12% of the amount of object substance is closed, the dosage of CuCl is the 0.8-1.2% of the amount of formula (V) combinations of materials.
The advantages of this technique: reagent used is inexpensive, is easy to get, and easy to operate, step is few, and total recovery is higher.
Specific embodiment
Below 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
It invents rather than limits the scope of the invention.
Raw material used in embodiment or reagent are commercially available in addition to special instruction.
The system of embodiment 1 formula (III) compound 2- (the chloro- 5- nitro benzoyl of 4- ethyoxyl -2-) -3- aminoacrylonitrile
It is standby
By 50mmol 3- aminoacrylonitrile, 50mmol solid base catalyst ZrO2-Cr2O3It is added with 50mL tetrahydrofuran anti-
It answers in bottle, is stirred at room temperature uniformly, then by 55mmol 4- ethyoxyl -2- chloro-5-nitrobenzoic acid methyl esters and 15mL tetrahydrofuran
Mixture instills in above-mentioned reaction flask, is stirred to react 2h after dripping off at room temperature, then the 2h that flows back, cooled and filtered catalyst is urged
Agent is dried rear reusable.Decompression boils off solvent, and 400mL methylene chloride is added into residue, distills moisture with 50mL
It washs three times, merges organic layer, boil off solvent with decompression after anhydrous sodium sulfate drying, obtain formula (III) compound, yield 87%.
The preparation of 2 formula of embodiment (IV) chemical compound 3-cyano -4- oxo -6- nitro -7- ethyoxyl -1,4- dihydroquinoline
40mmol formula (III) compound, 40mmol Anhydrous potassium carbonate and 40mL DMF are added in reaction flask, in 50~60
It is stirred to react 4h at DEG C, is cooled to room temperature, 60mL water is added, stirs 0.5h, the solid of precipitation is filtered, by thick solid ethyl alcohol weight
Crystallization, is dried under reduced pressure to obtain formula (IV) compound, yield 90%.
The preparation of the chloro- 6- nitro -7- ethoxyquinoline of embodiment 3 formula (V) chemical compound 3-cyano -4-
40mmol formula (IV) compound and 180mL phosphorus oxychloride are added in reaction flask, heating stirring reflux 3h.It will reaction
Bottle is cooled to 0 DEG C or so, and at this temperature slowly pours into 1500mL 2mol/L sodium carbonate liquor in reaction flask, stirs
0.5h is filtered, and filter cake is washed with warm water, is dried under reduced pressure to obtain formula (V) compound, yield 88%.
The preparation of the chloro- 6- amino -7- ethoxyquinoline of embodiment 4 formula (I) chemical compound 3-cyano -4-
50mmol formula (V) compound, 100mL ethyl alcohol and 100mL distilled water are added in reaction flask, system temperature is risen to
50 DEG C, sequentially add the ZnCl of 2.5g active carbon, 0.5mmol CuCl and 50mL 0.01M2System temperature is risen to 60 by solution
DEG C, the hydrazine hydrate of 100mL 80% is slowly added dropwise, flow back 1.5h after dripping off.It is cooling, solid is filtered out, and use ethanol washing, depressurized
Ethyl alcohol is steamed, then extracts reaction mixture, combined ethyl acetate layer in three times with 150mL ethyl acetate, anhydrous sodium sulfate is done
It is dry.It is concentrated to dryness, the solid being dried under reduced pressure, obtains formula (I) compound, yield 92%.
Claims (4)
1. a kind of method for synthesizing the chloro- 6- amino -7- ethoxyquinoline of linatinib intermediate 3- cyano -4-, the synthetic method
Reaction equation are as follows:
Include the following steps:
Step 1, by formula (II) compound 4- ethyoxyl -2- chloro-5-nitrobenzoic acid methyl esters catalyst 1 effect under with 3- amino
Acrylonitrile, which is condensed, is made formula (III) compound 2- (the chloro- 5- nitro benzoyl of 4- ethyoxyl -2-) -3- aminoacrylonitrile；It is described
Catalyst 1 be solid base ZrO2-Cr2O3；
Step 2, under alkali effect cyclization reaction occurs for formula (III) compound, and formula (IV) chemical compound 3-cyano -4- oxo-is made
6- nitro -7- ethyoxyl -1,4- dihydroquinoline；
Step 3, chlorination occurs for formula (IV) compound and phosphorus oxychloride, and the chloro- 6- nitre of formula (V) chemical compound 3-cyano -4- is made
Base -7- ethoxyquinoline；
Step 4, with hydrazine hydrate reduction reaction occurs for formula (V) compound under the effect of catalyst 2, and formula (I) compound 3- cyanogen is made
The chloro- 6- amino -7- ethoxyquinoline of base -4-；The catalyst 2 is ZnCl2- CuCl composite catalyst.
2. a kind of chloro- 6- amino -7- ethoxyquin of synthesis linatinib intermediate 3- cyano -4- according to claim 1
The method of quinoline, it is characterised in that: the solid base catalyst ZrO in the step 12-Cr2O3With formula (II) combinations of materials
The ratio of amount is 0.9~1.2:1.
3. a kind of chloro- 6- amino -7- ethoxyquin of synthesis linatinib intermediate 3- cyano -4- according to claim 1
The method of quinoline, it is characterised in that: alkali in the step 2 be in the carbonate of alkali or alkaline earth metal any one or
Several combinations, the ratio with the amount of the substance of formula (III) compound are 1~1.5:1.
4. a kind of chloro- 6- amino -7- ethoxyquin of synthesis linatinib intermediate 3- cyano -4- according to claim 1
The method of quinoline, it is characterised in that: the composite catalyst ZnCl in the step 42In-CuCl, ZnCl2Dosage be formula (V) change
The 8-12% of the amount of object substance is closed, the dosage of CuCl is the 0.8-1.2% of the amount of formula (V) combinations of materials.
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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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