化合物配方智能优化设计方法及系统

NOVELTY - Preparation of thiazole or triazole derivatives involves reacting heterocyclic acid with 3-thiosemicarbazide derivative in basic conditions, followed by a treatment with an inorganic base and n-propane phosphonic cyclic anhydride and finally pH adjustment with inorganic acids.

USE - For preparation of thiazole or triazole derivatives (claimed) useful as intermediate for the preparation of compound, which are potent and specific antagonists of D3 receptors.

ADVANTAGE - The process avoids 1-hydroxybenzotriazole (HOBt) and its byproducts with are explosive in nature and 1,3- dicyclohexylcarbodiimide (DCC) and its byproducts that are always difficult to be fully remove, instead it uses n-propane phosphonic cyclic anhydride (T3P), as condensation agent, which is less toxic and safer compared with the other common condensation agents. The reagent does not afford any water insoluble by-product. T3P is used as 50% solution in ethyl acetate and does not need the isolation of the intermediate hydrazine-carbothiamide.

DETAILED DESCRIPTION - Preparation of thiazole or triazole derivatives of formula (I) involves reacting HO-C(O)-Het (IIA) with 3-thiosemicarbazide derivative HS-C(=N-CH2NH2)-NH-R in basic conditions, followed by a treatment with an inorganic base and n- propane phosphonic cyclic anhydride and finally pH adjustment with inorganic acids to give (I) (where X is N).

X'=N or S;

het=(hetero)aryl (mono-tetra-substituted with j);

j=halo, 1-6C alkyl 1-6C alkoxy, halo 1-6C alkyl 2-6C alkenyl, 2- 6C alkynyl, halo 1-6C alkoxy, -C(O)R1, nitro, hydroxy, -NR2R3, cyano or Z';

R1=1-4C alkyl, -OR3 or -NR3R4;

R2 and R3=H or 1- 6C alkyl;and

R=H, 1-6C alkyl, aryl or benzyl (all mono-tetra- substituted with j).