合成路线1

The reaction of 2-bromothiophene (I) with the monosodium salt of ethylene glycol (II) in the same solvent gives 2-(2-hydroxyethoxy)thiophene (III), which is condensed with 3,4-dihydro-2H-pyran (IV) by means of p-toluenesulfonic acid in THF yielding the corresponding tetrahydropyranyl ether (V). The reaction of (V) with N-(benzenesulfonyl)aziridine (VI) by means of BuLi in THF - hexane affords N-[2-[5-(2-hydroxyethoxy)thien-2-yl]ethyl]benzenesulfonamide (VII), which is finally oxidized with silver oxide in aqueous NaOH.

合成路线2

Suzuki coupling of 4-tolylboronic acid (I) with 2-bromothiophene (II) under palladium catalysis provided tolylthiophene (III). Subsequent chlorosulfonation of (III) with chlorosulfonic acid in the presence of PCl5 and POCl3 afforded sulfonyl chloride (IV), which was finally condensed with the aminoisoxazole (V) using NaH in THF to furnish the target sulfonamide.

合成路线3

The iodination of 2-hydroxybenzaldehyde (I) with iodine chloride in dichloromethane gives 2-hydroxy-5-iodobenzaldehyde (II), which is protected with Mem-Cl by means of NaH and 1,3-dimethylperhydropyrimidin-2-one (DMPU) in THF yielding the ether derivative (III). The reduction of (III) with NaBH4 in THF affords the benzyl alcohol (IV), which is brominated with NBS and triphenylphosphine in THF to give the benzyl bromide (V). The condensation of (V) with the protected aminopyrrolidinone (VI) by means of NaH and DMPU in THF yields the benzylpyrrolidinone (VII), which is treated with Zn(CN)2 and palladium tetrakis(triphenylphosphine) in DMF to provide the benzonitrile (VIII). The deprotection of (VIII) with HCl gas in ethyl acetate gives the primary amine (IX), which is sulfonated with 5-(3-pyridyl)thiophene-2-sulfonyl chloride (X) in pyridine yielding the sulfonamide (XI). Finally, this compound is treated first with HCl gas in ethanol, and then with NH3 in methanol to convert the cyano group of (XI) into the amidino group of the target compound. The intermediate sulfonyl chloride (X) has been obtained as follows: The condensation of 3-bromopyridine (XII) with 2-bromothiophene (XIII) by means of Mg and NiCl2 in refluxing ethyl ether gives 2-(3-pyridyl)thiophene (XIV), which is chlorosulfonated by means of BuLi, SO2 and SO2Cl2 in THF to yield intermediate (X).

合成路线4

Cyclization of ethoxymethylenemalonodinitrile (XVII) with hydrazine gives 5-aminopyrazole-4-carbonitrile (XVIII), which is further cyclized with acetamide (X) in refluxing AcOH to yield the 3-cyanopyrazolo[1,5-a]pyrimidine derivative (XIX). Finally, this compound is condensed with 2-bromothiophene (XX) by means of Mg.

合成路线5

Cyclization of 5-aminopyrazole-4-carboxylic acid ethyl ester (XXI) with either, 3,3-diethoxypropionic acid ethyl ester (XXII) or 3-oxopropionic acid ethyl ester (XXIII) in refluxing AcOH gives 7-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (XXIV), which is treated with POCl3 to yield the corresponding chloro derivative (XXV). Condensation of compound (XXV) with 3-(N-methylacetamido)phenylboronic acid (XXVI) by means of Pd(PPh3)4 and Na2CO3 in ethanol affords the pyrazolo-[1,5-a]pyrimidine-carboxylic acid ethyl ester (XXVII), which is finally condensed with 2-bromothiophene (XX) and Mg.

合成路线6

合成路线7

In one method, metalation of 1-bromo-4-fluorobenzene (XI) with Mg in 2-MeTHF at 90 °C gives 4-fluorophenyl magnesium bromide (XII), which then couples with 2-bromothiophene (XIII) in the presence of NiCl2·dppe and AcOH in 2-MeTHF at 22 °C or in the presence of Pd(OAc)2 and DPPP in THF to yield 2-(4-fluorophenyl)thiophene (XIV). Finally, this compound undergoes Friedel–Crafts acylation with 5-iodo-2-methylbenzoic acid (XV) (initially chlorinated with SOCl2 in CH2Cl2) using AlCl3 in CH2Cl2, and subsequent reduction with (Me2SiH)2O in refluxing acetonitrile .
In another method, hydrolysis of methyl 5-bromo-2-methylbenzoate (XVI) with NaOH in MeOH at 50 °C gives rise to the benzoic acid (XVII) , which is then chlorinated with (COCl)2 in the presence of DMF in CH2Cl2 to yield 5-bromo-2-methylbenzoyl chloride (XVIII). Friedel–Crafts reaction of acyl chloride (XVIII) with 2-(4-fluorophenyl) thiophene (XIV) in the presence of AlCl3 in CH2Cl2 affords ketone (XIX), which is then reduced by means of Et3SiH and BF3·Et2O in CH2Cl2/acetonitrile to afford 2-(5-bromo-2-methylbenzoyl)-5-(4-fluorophenyl)thiophene (III) . Finally, compound (III) is iodinated with NaI and CuI in the presence of (MeNHCH2)2 in refluxing toluene/diglyme (IV) .
Alternatively, coupling of 4-fluorophenylboronic acid (XX) with either 2-bromothiophene (XIII) in the presence of PdCl2(PPh3)2 and Na2CO3 in dimethoxyethane at 75-80 °C or with 2-iodothiophene (XXI) in the presence of PdCl2(PPh3)2 at 50 °C affords 2-(4-fluorophenyl) thiophene (XIV) .