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Efficient preparation method of pyrrolo[2,3-d] pyrimidine compound

A technology for compounds and pyrimidines, which is applied in the field of efficient preparation of pyrrolo[2,3-d]pyrimidine compounds, can solve the problems that the synthetic route is not suitable for large-scale industrial production, the production energy consumption is large, and the total yield is low. , to avoid the use of highly toxic and explosive reagents, reduce production energy consumption, and achieve the effect of simple operation

Active Publication Date: 2017-05-31
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] In the above method for synthesizing RDEA427, there are the following problems: 1) the total yield is too low (less than 1.9%); 2) high temperature and low temperature conditions are frequently used, and the production energy consumption is large; 3) the highly toxic reagent hydrogen fluoride-pyridine solution and easily Detonation reagent butyl nitrite;
[0007] 4) The last six steps all need to be processed by column chromatography, which is not environmentally friendly and economical
Therefore, the synthetic route is not suitable for large-scale industrial production

Method used

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  • Efficient preparation method of pyrrolo[2,3-d] pyrimidine compound
  • Efficient preparation method of pyrrolo[2,3-d] pyrimidine compound
  • Efficient preparation method of pyrrolo[2,3-d] pyrimidine compound

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Embodiment 1

[0047] (1) Synthesis of compound 2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (IV)

[0048]

[0049]Dissolve 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (1.00g, 5.32mmol) in 5mL N,N-dimethylformamide, add dropwise to 3mL hydrogenation at 0°C Sodium 60% (dissolved in mineral oil, 0.23g, 5.85mmol) in N,N-dimethylformamide suspension, react at 0°C for 15min, then slowly drop (2-(chloroform Oxy)ethyl)trimethylsilane (1mL, 5.85mmol), react at room temperature for 4h. After the reaction, 150 mL of water was added to the reaction liquid, extracted three times with ethyl acetate (3×40 mL), the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, concentration under reduced pressure, and column chromatography, 1.35 g of intermediate compound IV was obtained as a transparent oil with a yield of 80%. 1 H NMR (400MHz, DMSO-d 6 )δ: 7.99 (d, J = 3.68Hz, 1H, pyrrole-H), 6.82 (d, J = 3.68Hz, 1...

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Abstract

The invention discloses an efficient preparation method of a pyrrolo[2,3-d] pyrimidine compound. The method comprises the following steps: an intermediate compound IV is formed from a compound II and a compound III as starting raw materials through a nucleophilic reaction under the action of alkali; an intermediate compound V is formed from the intermediate compound IV and a compound 4-hydroxy-3,5-dimethylbenzonitrile through an aromatic nucleophilic substitution reaction under the action of alkali; a key intermediate compound VI is formed from the intermediate compound V and 4-aminobenzonitrile through a Buchwald-Hartwig coupling reaction under the action of alkali and a catalyst / ligand; an intermediate compound VII is formed from the key intermediate compound VI under the action of trifluoroacetic acid and subjected to alkaline hydrolysis, and a target product is formed. The method is high in reaction selectivity, simple to operate and good in atom economy, does not use highly toxic reagents and explosive reagents, reduces production energy consumption and increases the total yield to 39%.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a high-efficiency preparation method of pyrrolo[2,3-d]pyrimidine compounds for treating AIDS. Background technique [0002] RDEA427, the chemical name is 4-((2-((4-cyanophenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-3,5-dimethyl Benzonitrile is a new generation of HIV-1 non-nucleoside reverse transcriptase inhibitors being developed by Ardea Biosciences, a subsidiary of AstraZeneca. RDEA427 has subnanomolar or nanomolar inhibitory activity against HIV-1 wild strains and a variety of common clinical drug-resistant strains, and is not easy to induce CYP metabolic enzymes. It has weak binding ability (not easy to produce "off-target effect" and cause toxicity), good pharmacokinetic properties (half-life of 41 hours, clearance rate of 0.24L / h / kg), excellent druggability, and is expected to be marketed eventually. [0003] However, there is only one synthetic metho...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 刘新泳黄伯世展鹏康东伟
Owner SHANDONG UNIV