CN105949128A - Preparation method of nilotinib intermediate-3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline - Google Patents
Preparation method of nilotinib intermediate-3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline Download PDFInfo
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- CN105949128A CN105949128A CN201610363885.0A CN201610363885A CN105949128A CN 105949128 A CN105949128 A CN 105949128A CN 201610363885 A CN201610363885 A CN 201610363885A CN 105949128 A CN105949128 A CN 105949128A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D233/61—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms not forming part of a nitro radical, attached to ring nitrogen atoms
Abstract
The invention provides a preparation method of a nilotinib intermediate-3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline. The preparation method comprises the following steps of adding 3-bromo-5-(trifluoromethyl)aniline, 4-methylimidazole, D-glucosamine hydrochloride, CuI, Cs2CO3, DMSO and water into a reaction vessel in sequence, and reacting for 8 to 12 hours at 90 to 110 DEG C; adding ethyl acetate into reaction liquid, taking a supernatant after centrifugal separation, and obtaining the 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline after concentration and drying. The purity of a product prepared by the invention can reach 98 percent or above, the yield can reach 95 percent or above, and the preparation method provided by the invention has the advantages of being low in production cost, high in reaction yield, low in environmental pollution and the like, and is more suitable for industrial production.
Description
Technical field
The invention belongs to technical field of organic synthesis, be specifically related to a kind of AMN107 intermediate 3-(4-methyl isophthalic acid H-
Imidazoles-1-base) preparation method of-5-(trifluoromethyl) aniline.
Background technology
AMN107 is a kind of novel ATP competitive inhibitor, and it is based on aminopyrimidine and has relatively
High affinity.AMN107 can combine with ABL tyrosine kinase, promotes P-ring to fold, thus covers
The binding site of ATP, hinders the combination of substrate, it is impossible to smoothly completes the phosphorylation of ATP, thus suppresses
The activity of enzyme, generates the inactive conformation of BCR/ABL albumen.The hydrochloride hydrate of nilotinib can be used
In the chronic myelocytic leukemia that treatment imatinib mesylate is the most invalid, Selective depression is by tyrosinase mutant
The Philadelphia Chromosome Positive chronic myelocytic leukemia caused.
3-(4-methyl-1 H-imidazole-1-group)-5-(trifluoromethyl) aniline is the key intermediate of synthesis AMN107,
Relevant report both domestic and external has a lot, is most commonly that and exists with 3-bromo-5-5-trifluoromethylaniline and 4-methylimidazole
Nucleophilic substitution is there is in the presence of 8-hydroxyquinoline, CuI, NaOH, CaO, DMSO.But this synthesis
It is high to there is production cost in method, and the problems such as reaction yield is low, and environmental pollution is big are not suitable for industrialized production.
Summary of the invention
In order to solve the deficiencies in the prior art, the invention provides a kind of AMN107 intermediate 3-(4-methyl isophthalic acid H-
Imidazoles-1-base) preparation method of-5-(trifluoromethyl) aniline, use D-Glucosamine Hydrochloride fictitious hosts high
High, the 8-hydroxyquinoline part that environmental pollution is big, there is production cost low, reaction yield is high, and environmental pollution is little
Etc. advantage, it is more suitable for industrialized production.
The present invention solves the technical scheme that technical problem used:
The preparation method of AMN107 intermediate 3-(4-methyl-1 H-imidazole-1-group)-5-(trifluoromethyl) aniline, bag
Include following steps:
(1) in reaction vessel, it is sequentially added into 3-bromo-5-5-trifluoromethylaniline, 4-methylimidazole, D-amino Portugal
Grape sugar hydrochlorate, CuI, Cs2CO3, DMSO and water, react 8～12 hours in 90～110 DEG C.
(2) in step (1) gained reactant liquor, add ethyl acetate, after centrifugation, take upper strata
Liquid, obtains 3-(4-methyl-1 H-imidazole-1-group)-5-(trifluoromethyl) aniline after concentrate drying.
As preferably, 3-bromo-5-5-trifluoromethylaniline described in step (1), 4-methylimidazole, Cs2CO3、
The molar ratio of D-Glucosamine Hydrochloride and CuI is 1:1:1.8～2.2:0.05～0.2:0.05～0.2.
As preferably, the consumption of DMSO described in step (1) is 0.5～0.8L/mol 3-bromo-5-trifluoromethyl
Aniline.
As preferably, the consumption of water described in step (1) is 0.5～0.8L/mol 3-bromo-5-5-trifluoromethylaniline.
As preferably, 2 times that feed intake that volume is DMSO of ethyl acetate described in step (2).
The synthetic route of 3-of the present invention (4-methyl-1 H-imidazole-1-group)-5-(trifluoromethyl) aniline is:
The invention have the benefit that
Preparation method product purity the most of the present invention is up to more than 98%, and yield is up to more than 95%.
2. using D-Glucosamine Hydrochloride fictitious hosts high, the 8-hydroxyquinoline etc. that environmental pollution is big is joined
Body, also mitigates the pollution to environment while reducing production cost.
Detailed description of the invention
The present invention is explained further below in conjunction with embodiment, but the present invention is not done any type of by embodiment
Limit.
Embodiment 1
24g (0.1mol) 3-bromo-5-5-trifluoromethylaniline, 8.2g (0.1mol) 4-first it is sequentially added in there-necked flask
Base imidazoles, 65.2g (0.2mol) Cs2CO3, 1.9g (0.01mol) CuI, 2.2g (0.01mol) D-glucosamine
Hydrochlorate, then adds 50mL DMSO and 50mL water, and stirring is allowed to dissolve, and controls reaction temperature and is
100 DEG C, successive reaction 10 hours.Reaction adds 100mL ethyl acetate after terminating, and takes after centrifugation
Layer liquid, obtains 3-(4-methyl-1 H-imidazole-1-group)-5-(trifluoromethyl) aniline after concentrate drying, HPLC purity is
98.53%, yield is 95.25%.
Embodiment 2
24g (0.1mol) 3-bromo-5-5-trifluoromethylaniline, 8.2g (0.1mol) 4-it is sequentially added in reaction vessel
Methylimidazole., 58.7g (0.18mol) Cs2CO3, 0.95g (0.005mol) CuI, 1.1g (0.005mol) D-amino
Glucosamine salt hydrochlorate, then adds 60mL DMSO and 80mL water, and stirring is allowed to dissolve, and controls reaction
Temperature is 90 DEG C, successive reaction 12 hours, and reaction adds 120mL ethyl acetate, centrifugation after terminating
After take upper liquid, after concentrate drying 3-(4-methyl-1 H-imidazole-1-group)-5-(trifluoromethyl) aniline.HPLC
Purity is 98.66%, and yield is 96.18%.
Embodiment 3
24g (0.1mol) 3-bromo-5-5-trifluoromethylaniline, 8.2g (0.1mol) 4-it is sequentially added in reaction vessel
Methylimidazole., 71.7g (0.22mol) Cs2CO3, 3.8g (0.02mol) CuI, 4.4g (0.02mol) D-amino Portugal
Grape sugar hydrochlorate, then adds 80mL DMSO and 60mL water, and stirring is allowed to dissolve, and controls reaction temperature
Degree is 110 DEG C, successive reaction 8 hours, and reaction adds 160mL ethyl acetate, after centrifugation after terminating
Take upper liquid, after concentrate drying, obtain 3-(4-methyl-1 H-imidazole-1-group)-5-(trifluoromethyl) aniline.HPLC is pure
Degree is 98.09%, and yield is 95.77%.
The foregoing is only presently preferred embodiments of the present invention, not in order to limit the present invention, all in the present invention
Spirit and principle within any amendment, equivalent and the improvement etc. made, should be included in the guarantor of the present invention
Within the scope of protecting.
Claims (6)
1. the preparation method of AMN107 intermediate 3-(4-methyl-1 H-imidazole-1-group)-5-(trifluoromethyl) aniline, it is characterised in that described preparation method comprises the following steps:
(1) in reaction vessel, it is sequentially added into 3-bromo-5-5-trifluoromethylaniline, 4-methylimidazole, D-Glucosamine Hydrochloride, CuI, Cs2CO3, DMSO and water, react 8 ~ 12 hours in 90 ~ 110 DEG C.
2.(2) add in step (1) gained reactant liquor, ethyl acetate, after centrifugation, take upper liquid, after concentrate drying, obtain 3-(4-methyl-1 H-imidazole-1-group)-5-(trifluoromethyl) aniline.
Preparation method the most according to claim 1, it is characterised in that 3-bromo-5-5-trifluoromethylaniline described in step (1), 4-methylimidazole, Cs2CO3, the molar ratio of D-Glucosamine Hydrochloride and CuI be 1:1:1.8 ~ 2.2:0.05 ~ 0.2:0.05 ~ 0.2.
Preparation method the most according to claim 1, it is characterised in that the consumption of DMSO described in step (1) is 0.5 ~ 0.8L/mol 3-bromo-5-5-trifluoromethylaniline.
Preparation method the most according to claim 1, it is characterised in that the consumption of water described in step (1) is 0.5 ~ 0.8L/mol 3-bromo-5-5-trifluoromethylaniline.
Buddhist nun's preparation method the most according to claim 1, it is characterised in that 2 times that feed intake that volume is DMSO of ethyl acetate described in step (2).
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610363885.0A CN105949128A (en) | 2016-05-27 | 2016-05-27 | Preparation method of nilotinib intermediate-3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline |
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| CN201610363885.0A CN105949128A (en) | 2016-05-27 | 2016-05-27 | Preparation method of nilotinib intermediate-3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106932522A (en) * | 2015-12-31 | 2017-07-07 | 上海奥博生物医药技术有限公司 | The assay method of impurity compound I contents in a kind of nilotinib |
| CN109553544A (en) * | 2017-09-27 | 2019-04-02 | 浙江普利药业有限公司 | A kind of synthetic method of C14H10Cl2NNaO2 |
-
2016
- 2016-05-27 CN CN201610363885.0A patent/CN105949128A/en active Pending
Non-Patent Citations (4)
| Title |
|---|
| DONGPING CHENG ET AL.: "D-Glucosamine—a natural ligand for the N-arylation of imidazoles with aryl and heteroaryl bromides catalyzed by CuI", 《GREEN CHEM.》 * |
| FABIO BELLINA AND RENZO ROSSI: "Regioselective Functionalization of the Imidazole Ring via Transition Metal-Catalyzed C-N and C-C Bond Forming Reactions", 《ADV. SYNTH. CATAL.》 * |
| MING WEN ET AL.: "An efficient D-glucosamine-based copper catalyst for C–X couplings and its application in the synthesis of nilotinib intermediate", 《RSC ADVANCES》 * |
| 宋沙沙等: "氨基葡萄糖衍生物配体在不对称合成中的应用进展", 《有机化学》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106932522A (en) * | 2015-12-31 | 2017-07-07 | 上海奥博生物医药技术有限公司 | The assay method of impurity compound I contents in a kind of nilotinib |
| CN109553544A (en) * | 2017-09-27 | 2019-04-02 | 浙江普利药业有限公司 | A kind of synthetic method of C14H10Cl2NNaO2 |
| CN109553544B (en) * | 2017-09-27 | 2022-02-08 | 浙江普利药业有限公司 | Method for synthesizing diclofenac sodium |
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