合成路线1

合成路线2

The condensation of diethyl (2-methoxyphenoxy)malonate (I) with pyrimidine-2-carboxamidine (II) by means of NaOMe (Na in MeOH), followed by treatment with NaOH, provides the dihydroxy pyrimidine derivative (III), which is converted into the dichloro derivative (IV) by treatment with refluxing PCl5 and DIEA. Compound (IV) can also be obtained from the pyrimidinedione (V) by reaction with phosphorus oxychloride at 90 C. Reaction of compound (IV) with 4-tert-butylbenzenesulfonamide (VI), performed either directly in DMSO or by means of benzyltriethylammonium chloride (BTEAC) or tetrabutylammonium bromide (TBAB) and K2CO3 in refluxing toluene, gives compound (VII). Finally, this compound is converted into bosentan by reaction with sodium and ethylene glycol (VIII).

合成路线3

The conversion of 2-chloropyrimidine (I) to pyrimidine-2-carboxamidine (III) is performed by known methods through the intermediate pyrimidine-2-carbonitrile (II). The cyclization of (III) with 2-(2-methoxyphenoxy)malonic acid diethyl ester (IV) -prepared by condensation of 2-chloromalonic acid diethyl ester (V) with guaiacol (VI)- yields the bipyrimidinedione (VII). This compound is treated with refluxing POCl3 to afford the dichlorobipyrimidine (VIII). The chlorine monosubstitution in (VIII) with 4-tert-butylphenylsulfonamide (IX), K2CO3 and tetrabutylammonium bromide (TBAB) in toluene provides the substituted sulfonamide (X), which is submitted to a second chlorine substitution with ethyleneglycol mono-tert-butyl ether (XI) by means of NaOH in hot toluene to give the tert-butyl-intermediate (XII). Finally, this compound is deprotected by reaction with formic acid yielding the formate ester (XIII), which is hydrolyzed with NaOH in ethanol/water, and submitted to crystallization in refluxing ethanol/water to afford the target bosentan.

合成路线4

The known dichloropyrimidine derivative (I) was condensed with 2-phenylethenesulfonamide (II) in the presence of NaH in DMF to furnish the N-pyrimidinylsulfonamide (III). Displacement of the remaining chlorine of (III) by means of methanolic NaOMe provided the corresponding methyl ether (IV). The title potassium salt was then prepared by treatment of sulfonamide (IV) with ethanolic KOH.

合成路线5

Nucleophilic substitution of the dichloropyrimidine derivative (I) with 2-phenylvinylsulfonamide (II) in the presence of NaH in DMF affords the sulfonamido pyrimidine (III). The remaining chloro group of (III) is subsequently displaced with the sodium alkoxide derived from 2-fluoroethanol (IV) to provide the target fluoroethyl ether.

合成路线6

The sulfonation of 1-phenyl-1-butene (I) with sulfuryl chloride in hot DMF provided sulfonyl chloride (II), which was then treated with ammonium hydroxyde to give sulfonamide (III). Coupling of the known dichloro bipyrimidinyl derivative (IV) with the sodium salt of sulfonamide (III) yielded the N-pyrimidinyl sulfonamide (V). The remaining chloride was then displaced with sodium methoxide in DMF, and the resultant sulfonamide was finally converted to the potassium salt with ethanolic KOH.