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Method for synthesizing 2-chloro/hydroxypyrimidine-5-carboxylic acid

A synthesis method and chloropyrimidine technology, applied in the directions of organic chemistry, reagents, educts, etc., can solve problems such as low yield and achieve the effect of good operation reproducibility

Active Publication Date: 2019-03-15
常州琦诺生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method avoids the problem of low yield when the traditional CO2 method is used to enlarge the scale, and the operation reproducibility between batches is good

Method used

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  • Method for synthesizing 2-chloro/hydroxypyrimidine-5-carboxylic acid
  • Method for synthesizing 2-chloro/hydroxypyrimidine-5-carboxylic acid

Examples

Experimental program
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Effect test

Embodiment 1

[0026] Under nitrogen protection, add 2-chloro-5-bromopyrimidine (19.3 g, 0.1 mol) and THF 35mL into a three-necked reaction flask, then cool down to -10°C, and start to dropwise add 1.3M isopropylmagnesium chloride-lithium chloride tetrahydrofuran solution (100 mL, 0.13 mol). After the dropwise addition was completed, the reaction was continued for 1.5 hours, and then a solution of Boc2O (24.0 g, 0.11 mol) dissolved in THF (25 mL) was started to be added dropwise.

[0027] After the reaction is completed by sampling and detection, add 10% hydrochloric acid to quench to neutrality, then add 36% hydrochloric acid to adjust to pH1 HNMR(400MHz, DMSO-d6): 13.66(s, 1H), 9.14(s, 2H).

Embodiment 2

[0029] Under the protection of nitrogen, add 2-chloro-5-bromopyrimidine (19.3 g, 0.1 mol) and 35 mL of 2-MeTHF into the three-necked reaction flask, then lower the temperature to -70°C to -75°C, and start adding 2.5M n-butyllithium dropwise / hexane solution (48mL, 0.12mol). After the dropwise addition was completed, the reaction was continued for 1 hour, and then a solution of Boc2O (24.0 g, 0.11 mol) dissolved in 2-MeTHF (25 mL) was added dropwise. .

[0030] After the reaction is finished, add 10% hydrochloric acid to quench to neutrality, then add 36% hydrochloric acid to adjust to pH<1, stir at room temperature for 3-4 hours, then add 1M sodium hydroxide to adjust pH=1-2, separate organic layer, washed twice with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated to dryness by filtration, mixed solvent of dichloromethane / toluene was added for beating, and then vacuum-dried to obtain 13.0 g of light yellow solid 2-chloropyrimidine-5-ca...

Embodiment 3

[0032] Under nitrogen protection, 2-chloro-5-bromopyrimidine (19.3 g, 0.1 mol) and THF 35 mL were added to a three-necked reaction flask, then the temperature was lowered to 0°C, and 1M n-Bu3MgLi tetrahydrofuran solution (0.35 mol) was added dropwise. After the dropwise addition was completed, the reaction was continued for 2.5 hours, and then a solution of Boc2O (24.0 g, 0.11 mol) dissolved in THF (25 mL) was added dropwise.

[0033] After the reaction was completed, 10% hydrochloric acid was added to quench to neutrality, then 36% hydrochloric acid was added to adjust to pH<1, stirred at room temperature for 4 hours, then 1M potassium hydroxide was added to adjust pH=2-3, the layers were separated, and two Extract twice with 80 mL of methyl chloride, combine the organic layers, wash with saturated brine, and dry over anhydrous magnesium sulfate. The solvent was evaporated to dryness by filtration, mixed solvent of dichloromethane / toluene was added for beating, and then vacuu...

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Abstract

The invention discloses a method for synthesizing 2-chloro / hydroxypyrimidine-5-carboxylic acid, and belongs to the field of synthesis of pharmaceutical intermediates. The invention comprises the following steps: reacting 2-chloro-5-bromopyrimidine with Boc2O under action of an active metallic reagent; then, adding an aqueous acid solution or an aqueous alkali solution to reflux at room temperature; and treating to obtain 2-chloropyrimidine-5-carboxylic acid and 2-hydroxypyrimidine-5-carboxylic acid, respectively. The method avoids a problem of low yield during scale-up by a method of feeding CO2, has good batch-to-batch operation reproducibility, and provides a new way for production scale-up.

Description

technical field [0001] The invention relates to the synthesis of pyrimidine compounds, in particular to a synthesis method of 2-chloro / hydroxypyrimidine-5-carboxylic acid, belonging to the technical field of pharmaceutical intermediate synthesis. Background technique [0002] 2-Hydroxypyrimidine-5-carboxylic acid and 2-chloropyrimidine-5-carboxylic acid are both pharmaceutical and chemical intermediates, which are used as raw materials for amides in pyrimidine drugs. Among the existing synthetic methods, there is only one document reporting the direct synthesis of 2-hydroxypyrimidine-5-carboxylic acid. [0003] J. Med. Chem., 2000, 43 (21), 3995–4004 reported that 2 -Methylthiopyrimidine-5-carboxylic acid ethyl ester, 2-methylthiopyrimidine-5-carboxylic acid ethyl ester followed by basic KOH conditions to give 2-hydroxypyrimidine-5-carboxylic acid. Subsequent reaction of 2-hydroxypyrimidine-5-carboxylic acid under PCl3 conditions affords 2-chloropyrimidine-5-carboxylic aci...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/30C07D239/36
CPCC07D239/30C07D239/36Y02P20/141
Inventor 张进刘宗伦刘增仁冷延国
Owner 常州琦诺生物科技有限公司
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