Thiazole derivatives as dhodh inhibitors and their use
A technology for drugs and uses, applied in the field of thiazole derivatives, can solve problems such as thrombocytopenia
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Embodiment 1
[0062] Example 1: Synthesis method of compound 1-18:
[0063]
[0064] Dissolve ethyl chloroacetoacetate (9.52g, 57.84mmol) in 100mL ethanol, add thioacetamide (4.8g, 63.9mmol) under stirring, heat to reflux temperature, stir and reflux for 2h, when the reaction is over, The solvent was removed from the reaction solution under reduced pressure to obtain 9.80 g of an orange-pink solid with a yield of 91.1%, which was directly used in the next reaction.
[0065] Weigh LiOH.H 2 O (1.25g, 29.7mmol) was dissolved in 50mL of water, and the ester (2.5g, 13.5mmol) synthesized by one-step reaction was added under stirring. The temperature was raised to 90°C. As the reaction progressed, the solid gradually dissolved. The reaction was stopped after 1 hour. The pH of the reaction solution was adjusted to neutral and slightly acidic with dilute hydrochloric acid, and a large amount of solid was precipitated. The filter cake was washed with water and dried to obtain 2.05 g of light yellow solid ...
Embodiment 2
[0126] Example 2: General synthesis method of compound 19-46:
[0127] Synthesis of thiourea
[0128]
[0129] Dissolve the aromatic amine (8mmol, 1eq) in 24mL of acetone, add the weighed triethylenediamine (24mmol, 3eq) under stirring conditions, then add 20mL of carbon disulfide dropwise, a large amount of solids appear, continue to stir at room temperature for 24h, and filter the reaction The filter cake was washed with petroleum ether. After drying, the filter cake was dissolved in 50 mL of chloroform, and BTC (2.7 mmol, 0.33 eq) was weighed and dissolved in 30 mL of chloroform. The mixture was added dropwise to the reaction solution within 1 hour, and the mixture was stirred at room temperature. Solution overnight. After the completion of the reaction, the reaction solution was suction filtered, the filter cake was washed with dichloromethane, and the obtained filtrate was directly added with silica gel and spin-dried, followed by dry loading (PE elution).
[0130] Dissolve NC...
Embodiment 3
[0222] Example 3: Synthesis of compounds 47-63, 64, 65, 77, 89-92
[0223] Compounds 47-48, 50-52, 55-59, 61-62, 89-92 can be synthesized according to the following scheme.
[0224]
[0225] Synthesis method: Dissolve 1mmol of substituted phenylthiourea and 1mmol of 2-chloroacetylacetone (ethyl 2-chloroacetoacetate) in 20mL methanol, reflux overnight, spin dry methanol, add a small amount of dilute potassium carbonate aqueous solution to neutralize and saturate Wash with brine, extract with ethyl acetate, concentrate and dry the organic layer by column chromatography to obtain the product.
[0226] Target compound spectrum data
[0227] 2-(3,4-Methylanilino)-4-methyl-5-acetylthiazole (Compound 47)
[0228]
[0229] 1 H NMR (400MHz, DMSO) δ (ppm): 7.32 (d, J = 8.0 Hz, 1H), 7.28 (s, 1H), 7.11 (d, J = 8.4 Hz, 1H), 2.53 (s, 3H), 2.41 (s, 3H), 2.21 (s, 3H), 2.18 (s, 3H). HRMS(ESI)calcd for C 14 H 16 N 2 OS(M+H + )261.1062, found 261.1065.
[0230] 2-(4-Methyl-3-chloroanilino)-4-methyl-5-ac...
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