A kind of preparation method of 4-chloro-7h-pyrrolo[2,3-d]pyrimidine

A 3-d, pyrrole technology, applied in the field of preparation of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine, can solve the problems of poor product appearance, cumbersome operation, and difficult handling, and achieve easy operation, The effect of lowering the reaction temperature and simplifying the operation

Active Publication Date: 2020-03-27
CHANGZHOU YABANG QH PHARMACHEM +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] Although the above process uses formamidine acetate instead of thiourea as a cyclizing agent, which reduces the desulfurization step, the excess phosphorus oxychloride still needs to be distilled out under reduced pressure during chlorination, and the temperature is high, resulting in poor product appearance and many impurities. , if water is added to destroy excessive phosphorus oxychloride, a large amount of phosphorus-containing wastewater will be generated, which is difficult to treat
The crude product needs to be refined with ethyl acetate and activated carbon, and then beaten with ethyl acetate / n-heptane, which is cumbersome to operate

Method used

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  • A kind of preparation method of 4-chloro-7h-pyrrolo[2,3-d]pyrimidine
  • A kind of preparation method of 4-chloro-7h-pyrrolo[2,3-d]pyrimidine
  • A kind of preparation method of 4-chloro-7h-pyrrolo[2,3-d]pyrimidine

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Add 135.1g (1mol) 4-hydroxyl-7H-pyrrolo[2,3-d]pyrimidine to a 2000ml four-necked flask, protect with nitrogen, add m-xylene 410g, add bis(trichloromethyl)carbonate ( BTC) 163.2g (0.55mol), heated to 50-60°C, added dropwise 30.3g (0.3mol) N-methylmorpholine, the dropwise addition time was 1 hour, the dropwise addition was completed, and kept stirring at 50-60°C for 6 Hour. Cool down to 5-15°C, add dropwise 10% liquid caustic soda to adjust pH to 8-9, control temperature <30°C, after dropwise addition, keep stirring at 30-40°C for 0.5-1 hour. Suction filtration, washing with water, and vacuum drying at 80°C for 8 hours gave 143.6 g of off-white solid with a yield of 93.5% and a purity of 99.1%.

[0051] HPLC detection method:

[0052] Column type: Symmetry C18 5um×4.6×250mm

[0053] Mobile phase: acetonitrile: water (2.72g / L NaH 2 PO 4 ) = 20:80

[0054] Wavelength: 254nm

[0055] Flow rate: 0.9ml / min.

[0056] The mass spectrogram of 4-chloro-7H-pyrrolo[2,3-d]pyr...

Embodiment 2

[0064] Add 135.1g (1mol) 4-hydroxy-7H-pyrrolo[2,3-d]pyrimidine to a 2000ml four-neck flask, protect with nitrogen, add 650g of heptane, add bis(trichloromethyl)carbonate (BTC ) 133.5g (0.45mol), heated to 50-60°C, added dropwise 142.1g (1.1mol) N,N-diisopropylethylamine, the dropwise addition time was 1 hour, the dropwise addition was completed, at 50-60°C Keep stirring for 4 hours. Cool down to 5-15°C, add dropwise 5% liquid caustic soda to adjust pH to 8-9, control temperature <30°C, after dropwise addition, keep stirring at 30-40°C for 0.5-1 hour. Suction filtration, washing with water, vacuum drying at 70°C for 12 hours, weighing 144.0 g of off-white solid, yield 93.8%, purity: 99.5%.

Embodiment 3

[0066] Add 135.1g (1mol) of 4-hydroxy-7H-pyrrolo[2,3-d]pyrimidine to a 2000ml four-neck flask, protect it with nitrogen, add 435g of toluene, and add bis(trichloromethyl)carbonate (BTC) 281.9g (0.95mol), heated to 50-60°C, added dropwise 60.6g (0.6mol) N-methylmorpholine, the dropwise addition time was 30 minutes, after the dropwise addition was completed, kept stirring at 50-60°C for 5 hours. Cool down to 5-15°C, add dropwise 5% liquid caustic soda to adjust pH to 8-9, control temperature <30°C, after dropwise addition, keep stirring at 30-40°C for 0.5-1 hour. Suction filtration, washing with water, vacuum drying at 75°C for 10 hours, weighing 143.0 g of off-white solid, yield 93.1%, purity: 99.3%.

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Abstract

The invention discloses a preparation method of 4-chloro-7H-pyrrolo[2,3-d] pyrimidine. The preparation method comprises the following steps: enabling 4-hydroxy-7H-pyrrolo[2,3-d] pyrimidine to undergochlorination reaction with bis(trichloromethyl)carbonate (BTC) in a nonpolar organic solvent under the catalysis of organic base; cooling a reaction solution and then adjusting a pH value to 8 to 9; carrying out insulated stirring, suction filtration, water washing and vacuum drying to obtain the 4-chloro-7H-pyrrolo[2,3-d] pyrimidine. According to the preparation method, the BTC is used for replacing phosphorus oxychloride; after the reaction is finished, reduced pressure distillation on the phosphorus oxychloride is avoided, and a large amount of phosphorus-containing wastewater is prevented;by adopting the organic base as a catalyst, the reaction temperature is reduced, and generation of dimolecular impurities is avoided. The method has the advantages of simple operation, greenness, environment friendliness, easiness in industrial production and the like.

Description

technical field [0001] The invention relates to the technical fields of medicine and chemical industry, in particular to a preparation method of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine. Background technique [0002] 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine is an important raw material for the synthesis of many antibacterial drugs, antineoplastic drugs, and antitrypanosomiasis drugs, and is widely used in the field of medicine. 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine is an important intermediate in the synthesis of JAK inhibitors of rheumatoid arthritis—ruxolitinib and tofacitinib. The demand for Ni, Tofacitinib and its key intermediate 4-chloro-7H-pyrrolo[2,3-d]pyrimidine is increasing, and the design and development of efficient, green and environmentally friendly synthetic routes in line with industrial production has Greater economic value and significance. [0003] The synthesis process of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine reported in the literature is as follows: [0004] P...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 王学成苏文杰朱建民朱伟
Owner CHANGZHOU YABANG QH PHARMACHEM
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