A method for preparing 2-aminopyrimidine-5-boronic acid pinacol ester

An aminopyrimidine and methoxyboronic acid technology, which is applied in the field of pharmaceutical intermediate synthesis, can solve the problems of large amount of coupling catalyst, heavy metal residues in the product, and the need for ultra-low temperature reaction, and achieves the effect of mild synthesis process conditions and avoiding ultra-low temperature reaction.

Active Publication Date: 2016-09-14
天津维智精细化工有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] The above method: 1) the amount of coupling catalyst is large, the cost is high, and the product has heavy metal residues; 2) when the amino group is protected by benzophenone, the condensation product cannot be obtained according to the first step of the patent method, and Boc protection needs to be used. Protect all the nitrogen; the method of direct reaction without protecting the amino group has unstable yield and poor reproducibility, and all these methods have the disadvantage of requiring ultra-low temperature reaction

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  • A method for preparing 2-aminopyrimidine-5-boronic acid pinacol ester

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Embodiment 1

[0016] A method for preparing 2-aminopyrimidine-5-boronic acid pinacol ester, comprising the following steps:

[0017] Add 11.5g (0.1mol) of 2-chloropyrimidine, 21.3g (0.12mol) of brominating reagent NBS and 80mL of acetonitrile into the reaction flask, and add a catalytic amount of BF at room temperature 3 -Et 2 O 2.8g (0.02mol), after adding, be warming up to reflux reaction 5-8 hour, after TLC detects that reaction is finished, cool down, after filtering out insoluble solid, after depressurizing distillation solvent, add ethyl acetate to dissolve, dropwise add 45mL saturated Na 2 CO 3 The solution was washed, the organic layer was separated, and 60 mL of ethyl acetate was added to the aqueous layer. After layering again, the organic layers were combined, washed with saturated saline, and spin-dried to obtain 14.1 g of light yellow 2-chloro-5-bromopyrimidine solid, which was directly used in the next reaction. 1 H-NMR (400MHz, CDCl3): 8.70 (s, 2H).

[0018] Under the pr...

Embodiment 2

[0021] A method for preparing 2-aminopyrimidine-5-boronic acid pinacol ester, comprising the following steps:

[0022] Add 11.5g (0.1mol) of 2-chloropyrimidine, 21.3g (0.12mol) of brominating reagent NBS and 80mL of ethylene glycol dimethyl ether into the reaction flask, and add a catalytic amount of BF at room temperature 3 -Et 2 O 4.2g (0.03mol), after adding, be warming up to reflux reaction 5-8 hour, after TLC detects that reaction is finished, cool down, after filtering out insoluble solid, after depressurizing distillation solvent, add ethyl acetate to dissolve, dropwise add 45mL saturated Na 2 CO 3 The solution was washed, the organic layer was separated, and 60 mL of ethyl acetate was added to the aqueous layer. After layering again, the organic layers were combined, washed with saturated saline, and spin-dried to obtain 13.2 g of light yellow 2-chloro-5-bromopyrimidine solid, which was directly used in the next reaction. 1 H-NMR (400MHz, CDCl3): 8.70 (s, 2H).

[...

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Abstract

A method of preparing 2-aminopyrimidine-5-boronic acid pinacol ester is disclosed. The method includes subjecting 2-chloropyrimidine that is a raw material and NBS to bromization under catalysis of BF3-Et2O to obtain 2-chloro-5-bromopyrimidine; reacting the 2-chloro-5-bromopyrimidine with n-Bu3MgLi at a temperature ranging from -20 DEG C to -10 DEG C; adding methoxyboronic acid pinacol ester or isopropoxyboronic acid pinacol ester; performing boronization to obtain 2-chloropyrimidine-5-boronic acid pinacol ester; adding into ammonia water or a methanol-ammonia solution; and reacting at 80-100 DEG C in a sealed manner to obtain the 2-chloropyrimidine-5-boronic acid pinacol ester. Synthetic process conditions of the method are mild. An ultralow-temperature reaction is avoided. Reactions can be performed continuously. A pure product can be obtained only by simple recrystallization of the final product.

Description

technical field [0001] The invention relates to a method for preparing 2-aminopyrimidine-5-boronic acid pinacol ester, which belongs to the field of synthesis of pharmaceutical intermediates. technical background [0002] The type I PI3K inhibitor Apitolisib and the kinase inhibitor Votrient, known to be on the market or under research, both contain a 2-aminopyrimidine group, and more studies still regard this fragment as an important structural unit. As one of the key intermediates, 2-aminopyrimidine-5-boronic acid pinacol ester has a synthetic method with public information: mainly including 1) using 2-amino-5-iodopyrimidine and pinacol borane in Pd( PPh) 4 Under catalysis (reference: Org.Biomol.Chem., 2011,9,3139) or 2-amino-5-bromopyrimidine and biboronic acid pinacol ester in PdCl 2 Coupling in the presence of dppf (reference: WO 2012 / 109423 A1); 2) using the same raw material to protect the amino group with Boc (reference: CN102399235A and CN102367260A) or dibenzylid...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F5/02
CPCC07F5/02
Inventor 冷延国桂迁张进余锦华
Owner 天津维智精细化工有限公司
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