Thienopyrrolizine derivative, its preparing method and pharmaceutical composition containing the same
A technology of pyrrolizine and thiophene, which is applied in the field of preparing drugs for the treatment and/or prevention of various tumor diseases, and can solve the problems of unsatisfactory life and health, easy drug resistance, strong toxic and side effects, etc.
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Embodiment 1
[0084] Example 1: 8-[2-(1-pyrrolidinyl)ethoxyimino]-2-methylthio-3-phenyl-8H-thieno[2,3-b]pyrrolizine oxalate
[0085] Step A: Preparation of methyl 3-amino-4-phenyl-5-methylthio-2-thiophenecarboxylate
[0086] In 350mL of N,N-dimethylformamide (DMF), add 58.5g (0.5mol) of phenylacetonitrile, 57.0g (0.75mol) of carbon disulfide, 40.0g (1.0mol) of sodium hydroxide, and stir at about 20-25°C After 30 minutes of reaction, 50 mL of DMF solution of 54.3 g (0.5 mol) of methyl chloroacetate was added dropwise at room temperature. After 3 hours of reaction, 50 mL of DMF solution of 71.0 g (0.5 mol) of methyl iodide was added dropwise, and the reaction was continued for 3 hours. After the reaction was completed, the reaction solution was poured into water, extracted with dichloromethane, the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, evaporated to remove the solvent, and dried to obtain 49.3 g of the product (yield: 35.3%).
[0087] Step B: P...
Embodiment 2-19
[0097] According to the method of Example 1, using carbon disulfide and suitable aryl acetonitrile as starting materials, first prepare 8-hydroxyimino-2-methylthio-3-aryl-8H-thieno[2,3-b ] pyrrolizine, then with the corresponding halogen substituted amine generation substitution reaction, respectively obtain embodiment 2-19 compound:
Embodiment 2
[0098] Example 2: 8-[2-(1-piperidinyl)ethoxyimino]-2-methylthio-3-phenyl-8H-thieno[2,3-b]pyrrolizine oxalate
[0099] E:Z=50:50; 1 H-NMR (CDCl 3): Type E: 1.85(m, 4H), 2.30(brs, 2H), 2.40(s, 3H), 2.78(brs, 2H), 3.46(brs, 2H), 3.67(brs, 2H), 4.87(brs , 2H), 6.06(brt, 1H), 6.55(d, 1H), 6.64(d, 1H), 7.49(m, 5H); Z type: 1.85(m, 4H), 2.30(brs, 2H), 2.47 (s, 3H), 2.78 (brs, 2H), 3.46 (brs, 2H), 3.67 (brs, 2H), 4.87 (brs, 2H), 6.03 (dd, 1H), 6.50-6.53 (m, 2H), 7.49(m, 5H); MS: 424.4(M+H).
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