CN104788482B - A kind of method preparing 2-aminopyrimidine-5-boric acid pinacol ester - Google Patents
A kind of method preparing 2-aminopyrimidine-5-boric acid pinacol ester Download PDFInfo
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- CN104788482B CN104788482B CN201510032746.5A CN201510032746A CN104788482B CN 104788482 B CN104788482 B CN 104788482B CN 201510032746 A CN201510032746 A CN 201510032746A CN 104788482 B CN104788482 B CN 104788482B
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- boric acid
- acid pinacol
- pinacol ester
- aminopyrimidine
- chloropyrimide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
- C07F5/02—Boron compounds
Abstract
The invention discloses a kind of method preparing 2 aminopyrimidine 5 boric acid pinacol esters, from raw material 2 chloropyrimide, at BF3‑Et2Under O catalysis, bromo is occurred to obtain 2 chlorine 5 Bromopyrimidines with NBS；This intermediate and n Bu subsequently3MgLi 20～10 DEG C of reactions, be subsequently added methoxyl group boric acid pinacol ester or isopropoxy boric acid pinacol ester carry out boronation after obtain 2 chloropyrimide 5 boric acid pinacol esters；It is subsequently added in ammonia or methanolic ammonia solution, after 80～100 DEG C of sealing reactions, obtains 2 aminopyrimidine 5 boric acid pinacol esters.Synthetic technological condition of the present invention is gentle, it is to avoid ultralow temperature reaction, and reacts and can be carried out continuously, and only need to carry out simple recrystallization when end product can get sterling.
Description
Technical field
The present invention relates to a kind of method preparing 2-aminopyrimidine-5-boric acid pinacol ester, belong to pharmaceutical intermediate synthesis field.
Technical background
Known listing or in grinding new drug I type PI3K inhibitor Apitolisib and inhibitors of kinases Votrient, all contain 2-aminopyrimidine group, and have more research will this segment as important construction unit.2-aminopyrimidine-5-boric acid pinacol ester, as one of them key intermediate, is disclosed the synthetic method of data: mainly include 1 at present) use 2-amino-5-iodine pyrimidine and pinacol borine at Pd (PPh)4Under catalysis, (reference: Org.Biomol.Chem., 2011,9,3139) or 2-amino-5-Bromopyrimidine and connection boric acid pinacol ester are at PdCl2Coupling in the presence of dppf (reference: WO 2012/109423 A1)；2) after using same raw material amino Boc (reference: CN102399235A and CN102367260A) or diphenyl methylene (reference: US 2008/0269523 A1) to be protected; (or do not protect directly; reference: Eur.J.Org.Chem.2007; 5712) ultralow temperature reaction at butyl lithium/triisopropyl borate ester/-78 DEG C is used to be initially formed boric acid; subsequently after deprotection, react into ester followed by with pinacol.
Said method: 1) coupling catalyst large usage quantity, cost is high, and product has heavy-metal residual；2) when amino uses benzophenone protection, can not get condensation product according to the patented method first step, need all to protect with by nitrogen when using Boc protection；Amino does not protect the method yield instability of direct reaction, poor reproducibility, and such method all to there is the shortcoming needing ultralow temperature to react.
Summary of the invention
The technical problem to be solved is to provide a kind of new method preparing 2-aminopyrimidine-5-boric acid pinacol ester, comprises the following steps:
The first step, at BF3-Et2Under O catalytic action, 2-chloropyrimide and NBS back flow reaction in acetonitrile or glycol dinitrate ether solvents, obtain 2-chloro-5-Bromopyrimidine；
Second step, maintain the temperature at-20～-10 DEG C 2.5M n-BuLi is joined in n-BuMgBr, be prepared as n-Bu3MgLi, the 2-chloro-5-Bromopyrimidine maintaining this temperature the first step to be obtained subsequently is dissolved in oxolane and instills in above-mentioned solution, it is incubated 1 hour, dropping methoxyl group boric acid pinacol ester or isopropoxy boric acid pinacol ester, be incubated 1 hour, and solution is raised to room temperature, it is stirred overnight, add saturated ammonium chloride cancellation, be extracted with ethyl acetate, be evaporated and obtain 2-chloropyrimide-5-boric acid pinacol ester；
3rd step, in autoclave pressure, 2-chloropyrimide-5-boric acid pinacol the ester obtained by second step adds in ammonia or ammonia methanol, 80～100 DEG C are reacted 6 hours, solution filters after adding oxolane or acetic acid ethyl dissolution after being spin-dried for, and again adds recrystallizing methanol after solvent evaporated and obtains 2-aminopyrimidine-5-boric acid pinacol ester.
Further, in the described first step, 2-chloropyrimide and NBS, BF3-Et2The mol ratio of O is 1: 1-1.5: 0.05-0.3.
Further, in described second step, the mol ratio of n-BuLi Yu n-BuMgBr is 2: 1；2-chloro-5-Bromopyrimidine and n-Bu3The mol ratio of MgLi, methoxyl group boric acid pinacol ester or isopropoxy boric acid pinacol ester is 1: 0.4-0.5: 1.1-1.5.
Further, in described 3rd step, 2-chloropyrimide-5-boric acid pinacol ester and ammonia or ammonia Methanol Molar amount ratio 1: 2-5.
Reaction equation is as follows:
Invention beneficial effect
Synthetic technological condition of the present invention is gentle, it is to avoid ultralow temperature reaction, and reacts and can be carried out continuously, and only need to carry out simple recrystallization when end product can get sterling.
Detailed description of the invention
Embodiment 1
A kind of method preparing 2-aminopyrimidine-5-boric acid pinacol ester, comprises the following steps:
In reaction bulb, add 2-chloropyrimide 11.5g (0.1mol), bromide reagent NBS 21.3g (0.12mol) and acetonitrile 80mL, under room temperature, add catalytic amount BF3-Et2O 2.8g (0.02mol), after addition, is warming up to back flow reaction 5-8 hour, and TLC detects after completion of the reaction, cooling, after filtering out insoluble solids, after decompression solvent distillation, adds acetic acid ethyl dissolution, then is added dropwise to the saturated Na of 45mL2CO3Solution washs, and separates organic layer, and water layer adds 60mL ethyl acetate, then after secondary clearing, after merging organic layer, saturated aqueous common salt washs, and is spin-dried for obtaining light yellow 2-chloro-5-Bromopyrimidine solid 14.1g, is directly used in the next step.1H-NMR (400MHz, CDCl3): 8.70 (s, 2H).
nullUnder nitrogen protection，The n-BuMgBr solution (1M tetrahydrofuran solution) that addition 29.2mL prepares in advance in reaction bulb is cooled to-20 DEG C，In maintaining subsequently, temperature drips 23.4mL n-BuLi (2.5M hexane solution)-20～-10 DEG C，Drip complete insulated and stirred after 30 minutes，The 2-chloro-5-Bromopyrimidine 14.1g (73mmol) that the first step is obtained and anhydrous tetrahydro furan 40mL，Drip Bi Baowen 1 hour，TLC detection exchange is completely，Maintain the anhydrous tetrahydrofuran solution of this temperature dropping methoxyl group boric acid pinacol ester 13.3g (84mmol) subsequently，It is incubated 1 hour，Solution is warmed to room temperature naturally，It is stirred overnight，Adding saturated ammonium chloride cancellation adjusts PH to be 4-5，Ethyl acetate 70mL extracts，Merging organic layer is evaporated and obtains 2-chloropyrimide-5-boric acid pinacol ester solid crude product 12.1g，G/C content is more than 95%，Yield 69%，Can be directly entered in next step reaction；1H-NMR (400MHz, CDCl3): 8.60 (s, 2H), 1.29 (s, 12H).
In 100mL autoclave pressure, 2-chloropyrimide-5-boric acid pinacol ester 12.1g (50mmol) obtained by second step adds in 22.5g 28% ammonia (180mmol), 100 DEG C seal reaction 6 hours, solution filters after adding 150mL acetic acid ethyl dissolution after being spin-dried for, again add recrystallizing methanol after solvent evaporated and obtain white crystalline solid 2-aminopyrimidine-5-boric acid pinacol ester 8.6g, yield 78%.1H-NMR (400MHz, CDCl3): 8.58 (s, 2H), 5.80 (s, 2H), 1.32 (s, 12H)；
Embodiment 2
A kind of method preparing 2-aminopyrimidine-5-boric acid pinacol ester, comprises the following steps:
In reaction bulb, add 2-chloropyrimide 11.5g (0.1mol), bromide reagent NBS 21.3g (0.12mol) and glycol dimethyl ether 80mL, under room temperature, add catalytic amount BF3-Et2O 4.2g (0.03mol), after addition, is warming up to back flow reaction 5-8 hour, and TLC detects after completion of the reaction, cooling, after filtering out insoluble solids, after decompression solvent distillation, adds acetic acid ethyl dissolution, then is added dropwise to the saturated Na of 45mL2CO3Solution washs, and separates organic layer, and water layer adds 60mL ethyl acetate, then after secondary clearing, after merging organic layer, saturated aqueous common salt washs, and is spin-dried for obtaining light yellow 2-chloro-5-Bromopyrimidine solid 13.2g, is directly used in the next step.1H-NMR (400MHz, CDCl3): 8.70 (s, 2H).
nullUnder nitrogen protection，Under nitrogen protection，The n-BuMgBr solution (1M tetrahydrofuran solution) that addition 29.2mL prepares in advance in reaction bulb is cooled to-20 DEG C，In maintaining subsequently, temperature drips 23.4mL n-BuLi (2.5M hexane solution)-20～-10 DEG C，Drip complete insulated and stirred after 30 minutes，The 2-chloro-5-Bromopyrimidine 14.1g (73mmol) that the first step is obtained and anhydrous tetrahydro furan 40mL，Drip Bi Baowen 1 hour，TLC detection exchange is completely，Maintain the anhydrous tetrahydrofuran solution of this temperature dropping isopropoxy boric acid pinacol ester 15.6g (84mmol) subsequently，It is incubated 1 hour，Solution is warmed to room temperature naturally，It is stirred overnight，Adding saturated ammonium chloride cancellation adjusts PH to be 4-5，Ethyl acetate 80mL extracts，Merging organic layer is evaporated and obtains 2-chloropyrimide-5-boric acid pinacol ester solid crude product 10.5g，G/C content is more than 96%，Yield 64%，Can be directly entered in next step reaction；1H-NMR (400MHz, CDCl3): 8.60 (s, 2H), 1.29 (s, 12H).
In 100mL autoclave pressure, 2-chloropyrimide-5-boric acid pinacol ester 7.2g (30mmol) obtained by second step adds in 9.42mL 7M methanolic ammonia solution (66mmol), 80 DEG C seal reaction 8 hours, solution adds filtration after 100mL oxolane dissolves after being spin-dried for, again add recrystallizing methanol after solvent evaporated and obtain white crystalline solid 2-aminopyrimidine-5-boric acid pinacol ester 4.4g, yield 66%.1H-NMR (400MHz, CDCl3): 8.58 (s, 2H), 5.80 (s, 2H), 1.32 (s, 12H).
Claims (2)
1. the method preparing 2-aminopyrimidine-5-boric acid pinacol ester, it is characterised in that comprise the following steps:
The first step, at 0.05-0.3 equivalent BF3-Et2Under O catalytic action, 2-chloropyrimide and 1-1.5 equivalent NBS back flow reaction in acetonitrile or glycol dinitrate ether solvents, obtain 2-chloro-5-Bromopyrimidine；
Second step, maintains the temperature at-20 ~-10 DEG C and joins in n-BuMgBr by 2.5M n-BuLi, be prepared as n-Bu3MgLi, the 2-chloro-5-Bromopyrimidine maintaining this temperature the first step to be obtained subsequently is dissolved in oxolane and instills in above-mentioned solution, it is incubated 1 hour, dropping methoxyl group boric acid pinacol ester or isopropoxy boric acid pinacol ester, be incubated 1 hour, and solution is raised to room temperature, it is stirred overnight, add saturated ammonium chloride cancellation, be extracted with ethyl acetate, be evaporated and obtain 2-chloropyrimide-5-boric acid pinacol ester；
3rd step, in autoclave pressure, 2-chloropyrimide-5-boric acid pinacol the ester obtained by second step adds in 2-5 equivalent ammonia or in methanolic ammonia solution, 80 ~ 100 DEG C are reacted 6 hours, solution filters after adding oxolane or acetic acid ethyl dissolution after being spin-dried for, and again adds recrystallizing methanol after solvent evaporated and obtains 2-aminopyrimidine-5-boric acid pinacol ester.
A kind of method preparing 2-aminopyrimidine-5-boric acid pinacol ester, it is characterised in that: in described second step, the mol ratio of described n-BuLi Yu n-BuMgBr is 2:1；Described 2-chloro-5-Bromopyrimidine and n-Bu3The mol ratio of MgLi, methoxyl group boric acid pinacol ester or isopropoxy boric acid pinacol ester is 1:0.4-0.5:1.1-1.5.
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| CN101910150A (en) * | 2007-11-05 | 2010-12-08 | 诺瓦提斯公司 | 4-benzylamino-1-carboxyacyl-piperidine derivatives as CETP inhibitors useful for the treatment of diseases such as hyperlipidemia or arteriosclerosis |
| CN101993419A (en) * | 2009-08-20 | 2011-03-30 | 浙江九洲药业股份有限公司 | Preparation method of 4-[(5-bromo-4,6-dichloro-2-pyrimidinyl)amino] cyanobenzene |
| CN102381944A (en) * | 2011-08-29 | 2012-03-21 | 南京大学 | Method for synthesizing C-13 and C-14 labelled bisphenol A and C-13 and C-14 labelled tetrabromobisphenol A |
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Effective date of registration: 20180517 Address after: 301914 No. 4, Cuiping Road, economic development zone, Ji Zhou District, Tianjin Patentee after: Weizhi Precision Chemical Co., Ltd., Tianjin Address before: 061108 Western District of Lingang Economic and Technological Development Zone, Huanghua, Cangzhou, Hebei Patentee before: CANGZHOU PURUI ORIENT TECHNOLOGY CO., LTD. |