合成路线1

Esterification of 5-chlorothiophene-2-carboxylic acid (I) with MeOH in the presence of H2SO4 at 53 °C gives the corresponding methyl ester (II), which is either brominated using Br2 and AlCl3 in CHCl3 or iodinated by means of BTMA-ICl2 and ZnCl2 in AcOH at 70 °C, yielding the corresponding 4-bromo- or 4-iodo-thiophenecarboxylates (IIIa or IIIb). Metalation of 1-methylpyrazole (IV) with BuLi in THF, followed by condensation with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (V) affords the pyrazolylboronate (VI), which is then condensed with either thienyl bromide (IIIa) or iodide (IIIb) by means of Pd(t-Bu3P)2 and K2CO3 in 1,4-dioxane/water at 70 °C to produce methyl 5-chloro-4-(1-methylpyrazol-5-yl)-2-thiophenecarboxylate (VII). Treatment of compound (VII) with NCS in THF at 70 °C gives the chloropyrazole derivative (VIII), which by ester hydrolysis with NaOH in H2O/MeOH/THF provides the corresponding carboxylic acid (IX). Condensation of acid (IX) with amine (X) by means of PyBroP and DIEA in CH2Cl2 gives amide (XI), which is finally deprotected with NH2NH2 in THF/MeOH (1). Scheme 1.Amine intermediate (X) is prepared by reduction of N-Boc-(3-fluorophenyl) alanine (XII) with BH3·THF in THF to afford the primary alcohol (XIII), which is then subjected to Mitsunobu coupling with phthalimide (XIV) using PPh3 and DIAD in THF to provide compound (XV). Finally, compound (XV) is deprotected by cleavage of the N-Boc group with HCl in MeOH .