合成路线1

合成路线2

By esterification of guaiacol (II) with 4-isobutylhydratropoyl chloride (I) by means of H2SO4.

合成路线3

The condensation of 2-methoxyphenol (I) with ethylene oxide (II) gives 2-(2-methoxyphenoxy)ethanol (III), which is treated with SOCl2 to yield 2-(2-methoxyphenoxy)ethyl chloride (IV). The reaction of (IV) with benzylamine (A) gives N-[2-(2-methoxyphenoxy)ethyl]benzylamine (V), which is condensed with 2-methyl-5-bromoacetylbenzenesulfonamide (VI) affording N-[2-(2-methoxyphenoxy)ethyl]-N-[(4-methyl-3-aminosulfonylbenzoyl)methyl]benzylamine (VII). The reduction of (VII) with NaBH4 affords the corresponding protected carbinol (VIII), which is finally debenzylated by hydrogenation with H2 over Pd/C.

合成路线4

Acetylsalicylic acid (I) was converted to acid chloride (II) by refluxing in a SOCl2 solution. Condensation of acid chloride (II) with guaiacol (III) either in the absence or in the presence of tertiary amines gave rise to the target orthoester derivative. Alternatively, the title compound has been prepared by treatment of acetylsalicylic acid (I) with several acid anhydrides, followed by guaiacol (III).

合成路线5

The condensation of 2-methoxyphenol (I) with 2-bromoethanal dimethylacetal (II) by means of K2CO3 in hot DMF gives 2-(2-methoxyphenoxy)ethanal dimethylacetal (III), which is hydrolyzed to the corresponding free aldehyde (IV) with 2N H2SO4 in methanol. The cyclization of (IV) with cysteamine (V) by means of potassium acetate in water affords 2-(2-methoxyphenoxymethyl)thiazolidine (VI), which is finally condensed with ethoxymalonyl chloride (VII) by means of KHCO3 in ethyl acetate.

合成路线6

The condensation of 1-methyl-5-(4-methylbenzoyl)pyrrole-2-acetic acid (I) with glycine ethyl ester (II) by means of carbonyldiimidazole (CDI) and triethylamine in THF gives the corresponding acetamidoacetate (III), which is hydrolyzed with NaOH in THF-water yielding 2-[2-[1-methyl-5-(4-methylbenzoyl)pyrrol-2-yl]acetamido]acetic acid (IV). Finally, this compound is esterified with 2-methoxyphenol (guayacol) (V) by means of CDI in hot THF.

合成路线7

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8

The bromination of 1-acetyl-5-propionylindoline (I) with pyrrolidone hydrotribromide (PTBr) and sulfuric acid in THF gives the alpha-bromo derivative (II), which is reduced with triethylsilane in TFA yielding the 2-bromopropyl compound (III). Nitration of (III) with HNO3 in HOAc affords the 7-nitroindoline (IV), which is reduced to the corresponding amine derivative (V) with H2 over PtO2 in ethanol. The reaction of amine (V) with NaNO2/HCl, followed by treatment with CuCN, provides 1-acetyl-5-(2-bromopropyl)indoline-7-carbonitrile (VI), which is treated with NaN3 in hot ethylene glycol monomethyl ether/water to yield the 2-azidopropyl derivative (VII). Reduction of (VII) with H2 over Pd/BaSO4 in ethanol affords the expected 2-aminopropyl compound (VIII), which is condensed with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl bromide (IX) by means of NaHCO3 in ethanol to provide the secondary amine (X). The intermediate 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl bromide (IX) has been obtained as follows: Alkylation of 2-methoxyphenol (XVIII) with 2,2,2-trifluoroethyl iodide (XIX) by means of K2CO3 in hot DMF gives 1-methoxy-2-(2,2,2-trifluoroethoxy)benzene (XX), which is demethylated by means of BBr3 in dichloromethane to yield the corresponding phenol (XXI). Finally, this compound is alkylated with 1,2-dibromoethane (XXII) and NaOH in water at 120 C (1,2).

合成路线9

The reduction of omega-chloropropiophenone (I) with NaBH4 in ethanol gives 3-chloro-1-phenyl-1-propanol (II), which is treated with butyric anhydride and pyridine in dichloromethane yielding the corresponding racemic ester (III). The optical resolution of (III) with immobilized lipase B from Candida antarctica (CALB) affords a mixture of unreacted (S)-ester and (R)-alcohol (IV) that are separated by column chromatography. The condensation of alcohol (IV) with 2-methoxyphenol (V) by means of PPh3 and diethyl azodicarboxylate (DEAD) in THF gives the corresponding ether (VI), which is finally treated with methylamine in refluxing ethanol.

合成路线10

Coupling of 2-methoxyphenol (I) with 3-fluoronitrobenzene (II) produced the diaryl ether (III). The nitro group of (III) was then reduced by catalytic hydrogenation over Raney-Ni, yielding aniline (IV). Reductive alkylation of (IV) with pyridine-3-carboxaldehyde (V) using NaBH4 furnished the secondary amine (VI). This was finally acylated with 2,2,2-trifluoroethylsulfonyl chloride to produce the title sufonamide.

合成路线11

Guaiacol (I) was alkylated by means of boiling dibromoethane (II) to produce the bromoethyl ether (III). From this, the intermediate amine (VI) was prepared by Gabriel synthesis, via condensation with potassium phthalimide (IV) in hot DMF, followed by hydrazinolysis of the resultant N-substituted phthalimide (V).

合成路线12

合成路线13

合成路线14