合成路线1

The formylation of 6-bromo-1,3-benzodioxole-5-carbaldehyde dimethyl acetal (I) with BuLi and DMF gives the 6-formyl derivative (II), which is reduced with NaBH4 in ethanol to yield the corresponding carbinol (III). The cyclization of (III) with dimethyl acetylenedicarboxylate (V) in hot acetic acid (through the nonisolated intermediate (IV)) affords dimethyl 1,4-epoxy-6,7-(methylenedioxy)naphthalene-2,3-dicarboxylate (VI), which is hydrogenated with H2 over Pd/C in ethyl acetate to give the (1R*,2S*,3R*,4S*)-tetrahydro derivative (VII). The reduction of (VII) with LiAlH4 in refluxing ethyl ether affords the corresponding bis carbinol (VIII), which is treated with acetic anhydride to afford the diacetate (IX). The enzymatic monodeacetylation of (VIII) with PPL enzyme in DMSO/buffer gives (1R,2R,3S,4S)-2-(acetoxymethyl)-1,4-epoxy-3-(hydroxymethyl)-6,7-(methylenedioxy)-1,2,3,4-tetrahydronaphthalene (X), which is silylated with TBDMS-Cl and imidazole in DMF yielding the silyl ether (XI). The hydrolysis of the acetoxy group of (XI) with K2CO3 in methanol affords the carbinol (XII), which is oxidized with oxalyl chloride in dichloromethane affording the carbaldehyde (XIII). The exchange of the silyl protecting group of (XIII) (for stability problems) provided the triisopropylsilyl ether (XIV), which is treated with sodium methoxide in methanol to open the epoxide ring yielding the hydroxy aldehyde (XV). The protection of the hydroxy group of (XV) with 2-(trimethylsilyl)ethoxymethyl chloride and DIEA in dichloromethane provides the corresponding ether (XVI). The carbinol (III) can also be obtained directly from 6-bromo-1,3-benzodioxole-5-carbaldehyde dimethyl acetal (I) by reaction with formaldehyde and BuLi in THF.

合成路线2

The reaction of 7-fluoro-4-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2,5-dione (I) with POCl3 and N,N-dimethyl-p-toluidine in hot toluene gives 2-chloro-7-fluoro-4-methyl-4,5-dihydro-3H-1,4-benzodiazepin-5 one (II), which is condensed with N-(dimethylaminomethylene)glycine ethyl ester (III) (obtained by condensation of glycine ethyl ester (IV) with dimethylformamide (V) and TEA in dichloromethane) to yield a mixture of intermediates (VI) and (VII). Finally, these compounds are cyclized in refluxing AcOH to provide the target flumazenil.

合成路线3

By condensation of 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methylpenta-2,4-diene-1-triphenylphosphonium bromide (I) with 3-formylcrotonic acid butyl ester (II) by means of NaH in DMF to yield 9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethylnona-2,4,6,8-tetraen-1-oic acid butyl ester (III), which is then hydrolyzed with KOH in refluxing ethanol - water. The starting products (I) and (II) are obtained as follows: 1) The methylation of 2,3,5-trimethylphenol (IV) with KOH and methyl iodide in refluxing aqueous ethanol gives 2,3,5-trimethylanisole (V), which is then carbonylated with POCl3 and DMF (A) to afford 4-methoxy-2,3,6-trimethylbenzaldehyde (VI). The condensation of (VI) with acetone (B) by means of NaOH gives 4-(4-methoxy-2,3,6-trimethylphenyl)-3-buten-2-one (VII), which by a Grignard reaction with ethynylmagnesium bromide (C) in THF is converted into 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-3-hydroxy-4-penten-1-yne (VIII). The controlled hydrogenation of (VIII) with H2 over a Pd catalyst in hexane yields 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-3-hydroxy-1,4-pentadiene (IX), which is finally treated with triphenylphosphonium bromide in benzene at 60 C to give the phosphonium salt (I). 2) The oxidation of dibutyl L-(+)-tartrate (X) with lead tetraacetate in benzene gives butyl glyoxalate (XI), which is then condensed with propionic aldehyde (D) by means of dibutylamine (E) to afford ester (II).

合成路线4

The methylation of 2,3,5-trimethylphenol (I) with MeI and KOH in 10% aqueous ethanol gives 2,3,5-trimethylanisole (II), which is formylated with DMF and POCl3 yielding 2,3,6-trimethyl-p-anisylaldehyde (III). The condensation of (III) with acetone (B) by means of NaOH affords 4-(4-methoxy-2,3,6-trimethylphenyl)but-3-en-2-one (IV), which by a Grignard reaction with ethynylmagnesium bromide (C) in THF is converted into the acetylenic alcohol (V). Partial hydrogenation of (V) with H2 over Pd/C in hexane gives dienic alcohol (VI), which is condensed with triphenylphosphine hydrobromide in benzene affording 5-(4-methoxy-2,3,6 trimethylphenyl)-3-methylpenta-2,4-diene-1-triphenylphosphonium bromide (VII). A Wittig condensation of (VII) with butyl 3-formylcrotonate (VIII) by means of NaH in DMF gives butyl 9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethylnona-2,4,6,8-tetraenoate (IX), which is hydrolyzed with KOH in refluxing ethanol-water yielding the corresponding free acid (X). This acid is converted into the acyl chloride (XI) by treatment with PCl3 in refluxing benzene. Finally, this compound is treated with ethylamine (E) in ether. The butyl 3-formylcrotonate (VIII) is obtained as follows: The oxidation of dibutyl tartrate (XII) with lead tetraacetate in benzene gives butyl glyoxalate (XIII), which is then condensed with propionaldehyde (XIV) by heating at 110 C with dibutyl-amine (D).

合成路线5

The protection of 4-bromo-2-methoxyphenol (I) with ethyl vinyl ether (II) and TsOH in dichloromethane gives the ethoxyethyl ether (III), which is treated with n-BuLi in THF to yield the phenyl lithium compound (IV). The reaction of (IV) with 2H-labeled DMF (V), followed by hydrolysis with HCl, affords the labeled 4-hydroxy-3-methoxybenzaldehyde (VI), which is finally condensed with pentane-2,4-dione (VII) by means of B2O3 and tetrahydroquinoline in DMF.

合成路线6

The protection of 4-bromo-2-methoxyphenol (I) with ethyl vinyl ether (II) and TsOH in dichloromethane gives the ethoxyethyl ether (III), which is treated with n-BuLi in THF to yield the phenyl lithium compound (IV). The reaction of (IV) with 14C-labeled DMF (V), followed by hydrolysis with HCl, affords the labeled 4-hydroxy-3-methoxybenzaldehyde (VI), which is finally condensed with pentane-2,4-dione (VII) by means of B2O3 and tetrahydroquinoline in DMF.

合成路线7

Vilsmeier reaction between 2,4-dimethylpyrrole (I) and dimethylformamide (II) by means of phosphorous oxychloride in dichloroethane provides carbaldehyde (III), which is then condensed with 2-indolinone (IV) in ethanol in the presence of piperidine.

合成路线8

Finally, etoricoxib is obtained by several related ways: Cyclization of ketosulfone (XXIV) with 2-chloromalondialdehyde (XXIX) or the aniline derivative (XXX) and ammonium acetate in hot propionic acid. Cyclization of ketosulfone (XXIV) with aminoacrolein (XXXI) in the absence of ammonium acetate. Aminoacrolein (XXXI) is prepared by treatment of chloromalondialdehyde (XXIX) with isopropanol, yielding the ether (XXXII) and followed by reaction with ammoniun hydroxide. Cyclization of the lithium enolate of ketosulfone (XXIV) with 2,3-dichloroacrolein (XXXIII) -- obtained by treatment of chloromalondialdehyde (XXIX) with oxalyl chloride and DMF in toluene -- followed by reaction with ammonium acetate or anhydrous ammonia. Reaction of ketosulfone (XXIV) with 2-chloro-1,3-bis(dimethylamino)trimethinium hexaflourophosphate salt (XXXIV) in the presence of an equimolar amount of t-BuOK followed by treatment with HOAc/TFA and then heating at reflux with an excess of ammonium hydroxide. 2-Chloro-1,3-bis(dimethylamino)trimethinium hexaflourophosphate salt (XXXIV) is obtained by reaction of chloroacetic acid (XXXV) with hot dimethylformamide (XXXVI) and POCl3, and then the reaction mixture is treated with 5N NaOH and hexafluorophosphoric acid in water.

合成路线9

Ethylenediaminetetraacetic acid (EDTA) (I) on heating with formamide (A), afforded IGRF-154 (II). The latter compound was suspended in dimethylformamide (C), heated with morpholine (B) in ethanol and then refluxed with formalin. The final product crystallized on cooling.

合成路线10

合成路线11

Vilsmeier-Haack formylation of 6-chloro-5-fluoroindole (I) with dimethylformamide (XIII) by means of POCl3 gives 6-chloro-5-fluoroindole-3-carbaldehyde (XIV), which by Henry reaction with nitroethane (XV) in the presence of NH4OAc yields 6-chloro-5-fluoro-3-(2-nitroprop-1-enyl)indole (XVI). Reduction of the unsaturated nitro compound (XVI) by means of LiAlH4 in refluxing THF provides the trypt amine derivative (XVII), which is then subjected to Pictet-Spengler cyclization with 5-chloroisatin (XII) by means of p-TsOH in EtOH at 110 °C to afford spiro racemate (XVIII). Finally, chiral chromatography of racemate (XVIII) affords the desired (1R,3S)-enantiomer .