CN106866566A - A kind of preparation method of N (hydroxy phenyl of 2 chlorine 4) N ' (isoxazolyl of 5 methyl 3) urea - Google Patents
A kind of preparation method of N (hydroxy phenyl of 2 chlorine 4) N ' (isoxazolyl of 5 methyl 3) urea Download PDFInfo
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- CN106866566A CN106866566A CN201710096208.1A CN201710096208A CN106866566A CN 106866566 A CN106866566 A CN 106866566A CN 201710096208 A CN201710096208 A CN 201710096208A CN 106866566 A CN106866566 A CN 106866566A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members 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
- C07D261/14—Nitrogen atoms
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention belongs to biomedicine technical field, and in particular to a kind of preparation method of N (hydroxy phenyl of 2 chlorine 4) N ' (isoxazolyl of 5 methyl 3) urea.The preparation method, the mixed liquor A of phenyl chloroformate and organic solvent is slowly added dropwise into the mixed liquid B of the methylisoxazole of 3 amino 5 and organic solvent first, it is stirred at room temperature after completion of dropping, then proceed to add the chlorophenate hydrochlorate of 4 amino 3 to obtain reaction solution, after intensification, reaction a period of time simultaneously monitors reaction process, reaction is finished, appropriate organic solvent is added, stirred, filter, dried, obtained final product.Beneficial effects of the present invention are：It is successfully prepared pharmaceutical intermediate N (hydroxy phenyl of 2 chlorine 4) N ' (isoxazolyl of 5 methyl 3) urea, the preparation method reaction condition is gentle, process is simple, be obtained target product yield and quality it is higher, to synthesis Tivozanib and to reduce its cost significant.
Description
Technical field
The invention belongs to biomedicine technical field, and in particular to a kind of N- (2- chloro-4-hydroxyls phenyl)-N '-(5- first
Base -3- isoxazolyls) urea preparation method.
Background technology
Tivozanib is Mutiple Targets anti-angiogenesis inhibitor PTS, is mainly used in treating kidney, late kidney
First-line treatment in show preferable curative effect, it is 11.8 months and without hair that patient takes mean survival time after Tivozanib
Raw to deteriorate, for the advanced renal cell cancer patient of surgical removal part kidney, curative effect can reach nearly 14.8 months.N- (2- chloro-4-hydroxyls
Phenyl)-N '-(5- methyl -3- isoxazolyls) urea be antineoplastic target medicine Tivozanib key intermediate.Therefore,
Explore N- (2- chloro-4-hydroxyls phenyl)-N '-process is simple of (5- methyl -3- isoxazolyls) urea, mild condition, yield high
Preparation method, to synthesis Tivozanib and to reduce its cost significant.
The content of the invention
The present invention provides a kind of preparation method of N- (2- chloro-4-hydroxyls phenyl)-N '-(5- methyl -3- isoxazolyls) urea,
The features such as it has process is simple, mild condition and yield high.
The technical scheme that the present invention solves above-mentioned technical problem is as follows：A kind of N- (2- chloro-4-hydroxyls phenyl)-N '-(5- first
Base -3- isoxazolyls) urea preparation method, it comprises the following steps：Phenyl chloroformate is slow with the mixed liquor A of organic solvent
Drop in the mixed liquid B of 3- amino -5- methylisoxazoles and organic solvent, be stirred at room temperature after completion of dropping, then proceed to add
Enter 4- amino -3- chlorophenate hydrochlorates and obtain reaction solution, be warming up to 30-85 DEG C, react 3-10h and reaction process is monitored by TLC,
After completion of the reaction, the 1-5 times of organic solvent of reaction solution volume is added, is stirred, filters, is dried, obtained final product.TLC monitors reaction process,
I.e. by point plate judge reaction whether carry out completely, will reaction solution carry out a plate and observation climb whether raw material point in plate back plate disappears
Lose to judge whether to completely.
The specific reaction scheme of above-mentioned preparation method is as follows：
On the basis of above-mentioned technical proposal, the present invention can also have following further specifically chosen.
Specifically, phenyl chloroformate and the amount ratio of organic solvent are 10mmol in mixed liquor A：(10-30)mL.
Specifically, 3- amino -5- methylisoxazoles and the amount ratio of organic solvent are 10mmol in mixed liquid B:(5-30)
mL。
Specifically, 4- amino -3- chlorophenates hydrochlorate, 3- amino -5- methylisoxazoles and phenyl chloroformate in reaction solution
Mol ratio be=1:1：(1-3).
Specifically, organic solvent in organic solvent, mixed liquid B in mixed liquor A and add after completion of the reaction it is organic
Solvent is same solvent and the solvent is dichloromethane, chloroform, 1-METHYLPYRROLIDONE, ethyl acetate and Methylethyl
Any one in ketone.
Compared with prior art, the beneficial effects of the invention are as follows：The present invention is different with phenyl chloroformate, 3- amino -5- methyl
Oxazole, 4- amino -3- chlorophenates hydrochlorate are successfully prepared key intermediate N- (the 2- chloro-4-hydroxyls of Tivozanib for raw material
Phenyl)-N '-(5- methyl -3- isoxazolyls) urea, the preparation method reaction condition is gentle, process is simple, target product is obtained
Yield and quality are higher, to synthesis Tivozanib and to reduce its cost significant.
Specific embodiment
Principle of the invention and feature are described below in conjunction with specific embodiment, example is served only for explaining this hair
It is bright, it is not intended to limit the scope of the present invention.
Embodiment 1
A kind of preparation method of N- (2- chloro-4-hydroxyls phenyl)-N '-(5- methyl -3- isoxazolyls) urea, it includes as follows
Step：
Phenyl chloroformate (1.57g, 10mmol) is dissolved in dichloromethane (20ml) and obtains mixed liquor A, mixed liquor A is slow
It is added drop-wise in the mixed liquid B that 3- amino -5- methylisoxazoles (0.98g, 10mmol) is mixed to form with dichloromethane (5ml), room
, then be added to 4- amino -3- chlorophenates hydrochlorate (1.8g, 10mmol) in above-mentioned mixed liquor and obtain reaction solution by temperature stirring, rises
High-temperature monitors reaction process to 50 DEG C by TLC, and dichloromethane 100ml is added after completion of the reaction, is filtered after being sufficiently stirred for
To white or off-white powder N- (2- chloro-4-hydroxyls phenyl)-N '-(5- methyl -3- isoxazolyls) urea (1.93g, 72%).
Embodiment 2
A kind of preparation method of N- (2- chloro-4-hydroxyls phenyl)-N '-(5- methyl -3- isoxazolyls) urea, it includes as follows
Step：
Phenyl chloroformate (3.14g, 20mmol) is dissolved in dichloromethane (25ml) and obtains mixed liquor A, mixed liquor A is slow
It is added drop-wise in the mixed liquid B that 3- amino -5- methylisoxazoles (0.98g, 10mmol) is mixed to form with dichloromethane (10ml), room
, then be added to 4- amino -3- chlorophenates hydrochlorate (1.8g, 10mmol) in above-mentioned mixed liquor and obtain reaction solution by temperature stirring, rises
High-temperature monitors reaction process to 85 DEG C by TLC, and dichloromethane 80ml is added after completion of the reaction, is filtered after being sufficiently stirred for
To white or off-white powder N- (2- chloro-4-hydroxyls phenyl)-N '-(5- methyl -3- isoxazolyls) urea (2.14g, 79.8%).
Embodiment 3
A kind of preparation method of N- (2- chloro-4-hydroxyls phenyl)-N '-(5- methyl -3- isoxazolyls) urea, it includes as follows
Step：
Phenyl chloroformate (1.57g, 10mmol) is dissolved in 1-METHYLPYRROLIDONE (30ml) and obtains mixed liquor A, will mixed
Liquid A is slowly dropped to 3- amino -5- methylisoxazoles (0.98g, 10mmol) and is mixed to form with 1-METHYLPYRROLIDONE (30ml)
Mixed liquid B in, be stirred at room temperature, 4- amino -3- chlorophenates hydrochlorate (1.8g, 10mmol) is then added to above-mentioned mixed liquor
In reaction solution, rise high-temperature to 30 DEG C, by TLC monitor reaction process, 1-METHYLPYRROLIDONE is added after completion of the reaction
200ml, is filtrated to get white or off-white powder N- (2- chloro-4-hydroxyls phenyl)-N '-(different evils of 5- methyl -3- after being sufficiently stirred for
Oxazolyl) urea (1.98g, 73.9%).
With white powder obtained in embodiment 2 as sample, carry out1H-NMR and ESI-MS is tested, and specific test result is such as
Under：
1H-NMR (400MHz, CDCl3)δ(ppm)：8.94 (1H, s, NH), 8.27 (1H, s, NH), 7.80 (1H, d,
Phenyl-H), 6.89 (1H, d, phenyl-H), 6.71 (1H, dd, phenyl-H), 6.06 (1H, s, isoxazolyl-H),
2.40 (3H, s, CH3)。
ESI-MS m/z：268.1[M+H]+。
Analysis above test data understands that the preparation method that the present invention is provided successfully has synthesized the key of Tivozanib
Intermediate N (2- chloro-4-hydroxyls phenyl)-N '-(5- methyl -3- isoxazolyls) urea.Knowable to the yield data in embodiment,
The yield that the preparation method that the present invention is provided produces target product is higher.
The foregoing is only presently preferred embodiments of the present invention, be not intended to limit the invention, it is all it is of the invention spirit and
Within principle, any modification, equivalent substitution and improvements made etc. should be included within the scope of the present invention.
Claims (5)
1. the preparation method of a kind of N- (2- chloro-4-hydroxyls phenyl)-N '-(5- methyl -3- isoxazolyls) urea, it is characterised in that
Comprise the following steps：By phenyl chloroformate and the mixed liquor A of organic solvent be slowly added dropwise to 3- amino -5- methylisoxazoles with have
In the mixed liquid B of machine solvent, it is stirred at room temperature after completion of dropping, then proceeding to addition 4- amino -3- chlorophenates hydrochlorates must react
Liquid, is warming up to 30-85 DEG C, reacts 3-10h and monitors reaction process by TLC, after completion of the reaction, adds 1-5 times of reaction liquid
Long-pending organic solvent, stirs, filters, dries, and obtains final product.
2. the system of a kind of N- (2- chloro-4-hydroxyls phenyl)-N ' according to claim 1-(5- methyl-3- isoxazolyls) urea
Preparation Method, it is characterised in that phenyl chloroformate and the amount ratio of organic solvent are 10mmol in mixed liquor A：(10-30)mL.
3. the system of a kind of N- (2- chloro-4-hydroxyls phenyl)-N ' according to claim 1-(5- methyl-3- isoxazolyls) urea
Preparation Method, it is characterised in that 3- amino -5- methylisoxazoles and the amount ratio of organic solvent are 10mmol in mixed liquid B:(5-
30)mL。
4. a kind of N- (2- chloro-4-hydroxyls phenyl)-N '-(5- methyl -3- isoxazoles according to any one of claims 1 to 3
Base) urea preparation method, it is characterised in that 4- amino -3- chlorophenates hydrochlorate, 3- amino -5- methylisoxazoles in reaction solution
It is=1 with the mol ratio of phenyl chloroformate:1：(1-3).
5. a kind of N- (2- chloro-4-hydroxyls phenyl)-N ' according to claims 1 to 3-(5- methyl-3- isoxazolyls) urea
Preparation method, it is characterised in that organic solvent in organic solvent, mixed liquid B in mixed liquor A and add after completion of the reaction
Organic solvent for same solvent and the solvent be dichloromethane, chloroform, 1-METHYLPYRROLIDONE, ethyl acetate and first
Any one in base ethyl ketone.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710096208.1A CN106866566A (en) | 2017-02-22 | 2017-02-22 | A kind of preparation method of N (hydroxy phenyl of 2 chlorine 4) N ' (isoxazolyl of 5 methyl 3) urea |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710096208.1A CN106866566A (en) | 2017-02-22 | 2017-02-22 | A kind of preparation method of N (hydroxy phenyl of 2 chlorine 4) N ' (isoxazolyl of 5 methyl 3) urea |
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| CN106866566A true CN106866566A (en) | 2017-06-20 |
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| CN201710096208.1A Pending CN106866566A (en) | 2017-02-22 | 2017-02-22 | A kind of preparation method of N (hydroxy phenyl of 2 chlorine 4) N ' (isoxazolyl of 5 methyl 3) urea |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104876941A (en) * | 2014-02-28 | 2015-09-02 | 南京圣和药业股份有限公司 | Fused tricyclic compound and applications thereof |
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2017
- 2017-02-22 CN CN201710096208.1A patent/CN106866566A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104876941A (en) * | 2014-02-28 | 2015-09-02 | 南京圣和药业股份有限公司 | Fused tricyclic compound and applications thereof |
Non-Patent Citations (1)
| Title |
|---|
| 胡利修: "抗肿瘤靶向药物tivozanib的合成研究", 《中国优秀硕士学位论文全文数据库 工程科技Ⅰ辑》 * |
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Application publication date: 20170620 |