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A synthesis method, inhibitor technology, applied in the direction of organic chemistry, etc.
Active Publication Date: 2019-02-22
ZHEJIANG NORMAL UNIVERSITY
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[0067] Example 1: Synthesis of Intermediate A-2
[0068] Add 10mmol A-1 and 20mL THF to the reactor, cool the reactor to 0°C, add 5.5mL of 2mol / L ethylmagnesium bromide THF solution, stir for 30min, slowly add saturated ammonium chloride solution to stop After the reaction, the reaction mixture was extracted twice with ethyl acetate, the combined ethyl acetate was dried, and the ethyl acetate was recovered to obtain a crude product, which could be directly used in the next reaction.
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[0069] Example 2: Synthesis of Intermediate A-3
[0070] 10 mmol of A-2 obtained in Example 1 was dissolved in 20 mL of THF, 10 mL of 50% sulfuric acid solution was added, and the temperature was raised to 60° C. with stirring. After 2 h of reaction, the reaction solution was extracted twice with ethyl acetate, and the combined ethyl acetate was dried. After the ethyl acetate was recovered, 1.2 g of the product was obtained after column chromatography with petroleum ether ethyl acetate (10:1), the yield was 39%, and the HPLC purity was ≥96%. 1 H-NMR (400MHz, CDCl 3 ): δ1.11-1.18(t,3H),1.31-1.33(t,3H),2.66-2.69(m,2H),4.21-4.25(m,2H),4.34-4.41(t,4H),5.19 (s, 2H) 7.36-7.40 (m, 5H). MS(ESI): 304.66.
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[0071] Example 3: Synthesis of Intermediate A-4
[0072] 10 mmol of intermediate A-3 was dissolved in 15 mL of methanol, 10 mL of 20% NaOH solution was added, and after stirring at room temperature for 2 h, the reaction solution was acidified to strong acidity with 20% hydrochloric acid, extracted twice with ethyl acetate, and the combined ethyl acetate was passed through After drying and recovering ethyl acetate, 2.7 g of intermediate A-4 was obtained, the yield was 98%, and the HPLC purity was ≥99%. 1 H-NMR (400MHz, CDCl 3 ): δ1.11-1.15(t, 3H), 2.68-2.72(m, 2H), 4.39-4.45(m, 4H), 5.19(s, 2H), 7.39-7.41(m, 5H). MS(ESI): 276.70.
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Abstract
The invention discloses a synthesis method of a JAK (Janus Kinase) inhibitor. The synthesis method comprises the following steps: carrying out condensation on an intermediate A-8 and an intermediate B-3 to obtain an intermediate AB-1; carrying out deprotection on the intermediate AB-1 to obtain an intermediate AB-2; carrying out cyclization on the AB-2 to obtain an intermediate AB-3; carrying outthe deprotection on the intermediate AB-3 to obtain an intermediate AB-4; carrying out the deprotection on the AB-4 again to obtain an intermediate AB-5; carrying out condensation reaction on the AB-5to obtain the JAK inhibitor 1. The synthesis method disclosed by the invention has the main advantages that the intermediate A-8 is prepared through a chiral catalysis method in a high-yield and high-chiral-purity manner, and the intermediate B-3 and the JAK inhibitor 1 are prepared in a high-yield manner. Useless enantiomers are nearly not generated so that the pressure on the environment is reduced; meanwhile, the reaction yield is high, the operation is simple and the post-treatment is simple and convenient. According to the synthesis method, reaction conditions also can be applied to large-batch preparation and are suitable for industrial production, so that the synthesis method has relatively high practical value and social and economic benefits.
Description
technical field [0001] The invention relates to the technical field of drug synthesis, and relates to a method for synthesizing a JAK inhibitor by adopting a chiral catalytic method. Background technique [0002] JAK (just another kinase or janus kinase) kinase is a kind of non-receptor tyrosine kinase family, and four members have been found, namely JAK1, JAK2, JAK3 and TYK1. The substrate of JAK is STAT, that is, signal transducer and activator of transcription (STAT). STAT is dimerized after being phosphorylated by JAK, and then passes through the nuclear membrane and enters the nucleus to regulate the expression of related genes. This signaling pathway is called the JAK-STAT pathway. Therefore, JAK plays an important role in the pathophysiological process of immune-mediated diseases. It can be used to treat some autoimmune diseases, such as atopic dermatitis, rheumatoid arthritis, psoriasis, ulcerative colitis, etc. In 2017, the first oral targeted drug for rheumatoid a...
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