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Preparation method of pharmaceutical intermediate 2,4-dichloro-5-pyrimidine formaldehyde

A technology of pyrimidine carboxaldehyde and intermediate, which is applied in the field of preparation of pharmaceutical intermediate 2,4-dichloro-5-pyrimidine carboxaldehyde, can solve the problems of long steps, low yield, harsh reaction conditions and the like, and achieves mild reaction conditions, The effect of high yield and simple post-processing

Inactive Publication Date: 2018-08-31
ZHENGZHOU GECKO SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] It can be seen from the above synthetic methods that the current methods either have harsh reaction conditions, or have the problems of long steps and low yields.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0011] In the reaction bottle, add the solvent DMF (336mL), cool down to -5°C, slowly add phosphorus oxychloride (153g) dropwise, control the reaction temperature of the mixed system at no more than 5°C, and complete the dropwise addition of phosphorus oxychloride , add aluminum trichloride (66.7g), stir for 30min, then add 112g (1mol) of uracil in batches to the above mixed system in solid form, control the reaction temperature not to exceed 5°C, stir for 2h, then slowly warm up to room temperature Continue to stir the reaction until the starting material disappears. Add 1120mL of phosphorus oxychloride to the reaction system and raise the temperature to reflux for 5h, then evaporate and recover phosphorus oxychloride, pour the residue into the rapidly stirring ice-water mixture, and precipitate 2,4-dichloro-5-pyrimidine Formaldehyde solid 150g, yield 85.2%, purity 99.0%.

Embodiment 2

[0013] In the reaction bottle, add the solvent DMF (560mL), cool down to 5°C, slowly add phosphorus oxychloride (230g) dropwise, control the reaction temperature of the mixed system at no more than 5°C, and drop the phosphorus oxychloride completely. Add aluminum trichloride (133g), stir for 30min, then add 112g (1mol) of uracil in batches to the above mixing system in solid form, control the reaction temperature not to exceed 5°C, stir for 2h, then slowly raise the temperature to room temperature and continue stirring React until the starting material disappears. Then add 560 mL of phosphorus oxychloride to the reaction system and raise the temperature to reflux for 5 hours, then evaporate to recover phosphorus oxychloride, pour the residue into the rapidly stirring ice-water mixture, and precipitate 2,4-dichloro-5-pyrimidine Formaldehyde solid 160g, yield 91%, purity 99.3%.

Embodiment 3

[0015] In the reaction flask, add the solvent DMF (336mL), cool down to -5°C, slowly add phosphorus oxychloride (230g) dropwise, control the reaction temperature of the mixed system at no more than 5°C, and complete the dropwise addition of phosphorus oxychloride , add boric acid (61.8g), stir for 30min, then add 112g (1mol) of uracil in batches to the mixed system in the form of solid, control the reaction temperature not to exceed 5°C, after stirring for 2h, slowly raise the temperature to room temperature and continue to stir the reaction until Raw material disappears. Add 1120mL of phosphorus oxychloride to the reaction system and raise the temperature to reflux for 5h, then evaporate and recover phosphorus oxychloride, pour the residue into the rapidly stirring ice-water mixture, and precipitate 2,4-dichloro-5-pyrimidine Formaldehyde solid 158g, yield 89.8%, purity 99.1%.

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Abstract

The invention discloses a preparation method of a pharmaceutical intermediate 2,4-dichloro-5-pyrimidine formaldehyde, and belongs to the technical field of pharmaceutical synthesis. According to the key point of the technical scheme, the preparation method comprises the steps: uracil is used as a starting material, Vilsmeier-Haack reaction is carried out at low temperature and aldehyde groups arenot subjected to chlorination reaction under protection of a protective agent aluminum trichloride or boric acid, then heating is carried out, and chlorination reaction is carried out with phosphorusoxychloride to generate the target product pharmaceutical intermediate 2,4-dichloro-5-pyrimidine formaldehyde. The preparation method has the advantages of mild reaction conditions, high yield and good product purity, and is a synthetic method with industrial production value.

Description

technical field [0001] The invention belongs to the technical field of synthesis of pharmaceutical intermediates, in particular to a preparation method of the pharmaceutical intermediate 2,4-dichloro-5-pyrimidine formaldehyde. Background technique [0002] 2,4-dichloro-5-pyrimidine formaldehyde is an important drug intermediate, which can continue to react to generate 2,3-dichloro-5-cyanopyrimidine, and the aldehyde group can be oxidized to generate carboxylic acid. Chlorine can undergo nucleophilic substitution reactions to generate pyrimidine derivatives. At present, the synthetic methods of 2,4-dichloro-5-pyrimidine formaldehyde are mainly divided into the following categories: 1. Using 2,4-dichloro-5-bromo(iodo)pyrimidine as starting raw material, by reacting with Grignard reagent or butyllithium, and then react with DMF, methyl formate or N-formylmorpholine to obtain the target molecule (WO2011156698A2; Organic Letters, 2014, 16(19), 4972-4975; WO2016026445A1), the syn...

Claims

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Application Information

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IPC IPC(8): C07D239/30
CPCC07D239/30
Inventor 郭利兵范丽明
Owner ZHENGZHOU GECKO SCI
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