合成路线:Reaction of 2-acetylthiophene (I) with paraformaldehyde and dimethylamine in ethanol gives 3-(dimethylamino)-1-(2-thienyl)-1-propanone (II),which is enantioselectively reduced with a 2:1 complex of (2R,3S)-4-(dimethylamino)-3-methyl-1,2-diphenyl-2-butanol (III) and LiAlH4 in toluene to yield (S)-3-(dimethylamino)-1-(2-thienyl)-1-propanol (IV).The condensation of (IV) with 1-fluoronaphthalene (V) by means of NaH in DMSO affords the corresponding naphthyl ether (VI),which is finally monodemethylated with 2,2,2-trichloroethyl chloroformate and Zn in toluene and treated with oxalic acid.
参考文献标题:Chiral synthesis of 1-aryl-3-aminopropan-1-ols
文献作者:Staszak,M.A.; Staten,G.S.; Weigel,L.O.(Eli Lilly and Company)
参考来源:CA 2042346; EP 0457559; JP 1992226948
合成路线:Reaction of 2-acetylthiophene (I) with paraformaldehyde and dimethylamine in ethanol gives 3-(dimethylamino)-1-(2-thienyl)-1-propanone (II),which is enantioselectively reduced with a 2:1 complex of (2R,3S)-4-(dimethylamino)-3-methyl-1,2-diphenyl-2-butanol (III) and LiAlH4 in toluene to yield (S)-3-(dimethylamino)-1-(2-thienyl)-1-propanol (IV).The condensation of (IV) with 1-fluoronaphthalene (V) by means of NaH in DMSO affords the corresponding naphthyl ether (VI),which is finally monodemethylated with 2,2,2-trichloroethyl chloroformate and Zn in toluene and treated with oxalic acid.
参考文献标题:Asymmetric synthesis and absolute stereochemistry of LY248686
文献作者:Frazier,J.; Staszak,M.; Weigel,L.; Staten,G.; Deeter,J.
参考来源:Tetrahedron Lett 1990,31(49),7101
合成路线:Reaction of thiophene-2-carboxylic acid (VIII) with oxalyl chloride and PPh3 gives the corresponding acyl chloride (IX),which is condensed with vinyltributylstannane,yielding 1-(2-thienyl)-2-propen-1-one (X).The addition of HCl to the double bond of (X) affords 3-chloro-1-(2-thienyl)-1-propanone (XI),which is reduced with BH3 and the chiral (R)-oxazaborolidine catalyst (XII) in THF to give (S)-3-chloro-1-(2-thienyl)-1-propanol (XIII) (4).Treatment of (XIII) with NaI in acetone affords the (S)-3-iodopropanol derivative (XIV),which is condensed with methylamine in THF to provide (S)-3-(methylamino)-1-(2-thienyl)-1-propanol (XV).Finally,this compound is condensed with 1-fluoronaphthalene (V) by means of NaH in DMA.The Friedel-Crafts condensation of thiophene (XVI) with 3-chloropropionyl chloride (XVII) by means of SnCl4 in benzene gives the previously reported 3-chloro-1-(2-thienyl)-1-propanone (XI),which is reduced with NaBH4 in ethanol to yield the racemic alcohol (XVIII).Optical resolution of (XVIII) performed by means of immobilized CALB (Novozyme 435,Novo-Nordisk A/S) affords the previously reported (S)-alcohol (XIII).
参考文献标题:Chemo-enzymatic synthesis of the antidepressant duloxetine and its enantiomer
文献作者:Liu,H.; Hoff,B.H.; Anthonsen,T.
参考来源:Chirality 2000,12(1),26
合成路线:Reaction of thiophene-2-carboxylic acid (VIII) with oxalyl chloride and PPh3 gives the corresponding acyl chloride (IX),which is condensed with vinyltributylstannane,yielding 1-(2-thienyl)-2-propen-1-one (X).The addition of HCl to the double bond of (X) affords 3-chloro-1-(2-thienyl)-1-propanone (XI),which is reduced with BH3 and the chiral (R)-oxazaborolidine catalyst (XII) in THF to give (S)-3-chloro-1-(2-thienyl)-1-propanol (XIII) (4).Treatment of (XIII) with NaI in acetone affords the (S)-3-iodopropanol derivative (XIV),which is condensed with methylamine in THF to provide (S)-3-(methylamino)-1-(2-thienyl)-1-propanol (XV).Finally,this compound is condensed with 1-fluoronaphthalene (V) by means of NaH in DMA.The Friedel-Crafts condensation of thiophene (XVI) with 3-chloropropionyl chloride (XVII) by means of SnCl4 in benzene gives the previously reported 3-chloro-1-(2-thienyl)-1-propanone (XI),which is reduced with NaBH4 in ethanol to yield the racemic alcohol (XVIII).Optical resolution of (XVIII) performed by means of immobilized CALB (Novozyme 435,Novo-Nordisk A/S) affords the previously reported (S)-alcohol (XIII).
合成路线:The reaction of thiophene-2-[14C]carboxylic acid (VII) with oxalyl chloride and PPh3 gives the corresponding labeled acyl chloride (VIII),which is condensed with vinyltributylstannane,yielding 1-(2-thienyl)-[1-14C]prop-2-en-1-one (IX).The addition of HCl to the double bond of (IX) affords 3-chloro-1-(2-thienyl)-[1-14C]propan-1-one (X),which is reduced with BH3 and the chiral (R)-oxazaborolidine catalyst (XI) in THF to give (S)-3-chloro-1-(2-thienyl)-[1-14C]propan-1-ol (XII).Treatment of (XII) with NaI in acetone affords the labeled (S)-3-iodopropanol derivative (XIII),which is condensed with methylamine in THF to provide (S)-3-(methylamino)-1-(2-thienyl)-[1-14C]propan-1-ol (XIV).Finally,this compound is condensed with 1-fluoronaphthalene (V) by means of NaH in DMA.
合成路线:The reaction of thiophene-2-carboxylic acid (I) with oxalyl chloride and PPh3 gives the corresponding acyl chloride (II),which is condensed with vinyltributylstannane to yield 1-(2-thienyl)-2-propen-1-one (III).The addition of HCl to the double bond of (III) affords 3-chloro-1-(2-thienyl)-1-propanone (IV),which is reduced with BH3 and the chiral (S)-oxazaborolidine catalyst (V) in THF to give the (R)-3-chloro-1-(2-thienyl)-1-propanol (VI).The condensation of (VI) with [1-14C]-1-naphthol (VII) by means of DEAD and PPh3 in THF affords the labeled naphthyl ether derivative (VIII),which is treated with NaI in acetone to give the labeled iodo derivative (IX).Finally,this compound is treated with methylamine in hot THF.
参考文献标题:An asymmetric synthesis of duloxetine hydrochloride,a mixed uptake inhibitor of serotonin and norepinephrine,and its C-14 labeled isotopomers
文献作者:Wheeler,W.J.; Kuo,F.
参考来源:J Label Compd Radiopharm 1995,36(3),213
合成路线:Reaction of 2-acetylthiophene (I) with paraformaldehyde and dimethylamine in ethanol gives 3-(dimethylamino)-1-(2-thienyl)-1-propanone (II),which is enantioselectively reduced with a 2:1 complex of (2R,3S)-4-(dimethylamino)-3-methyl-1,2-diphenyl-2-butanol (III) and LiAlH4 in toluene to yield (S)-3-(dimethylamino)-1-(2-thienyl)-1-propanol (IV).The condensation of (IV) with 1-fluoronaphthalene (V) by means of NaH in DMSO affords the corresponding naphthyl ether (VI),which is finally monodemethylated with 2,2,2-trichloroethyl chloroformate and Zn in toluene and treated with oxalic acid.
合成路线:The ketone intermediate (II) can also be reduced with NaBH4 in ethanol to the racemic alcohol (VII),which is submitted to optical resolution with (S)-(+)-mandelic acid to provide the (S)-enantiomer (IV) already described.
合成路线:Reaction of thiophene-2-carboxylic acid (VIII) with oxalyl chloride and PPh3 gives the corresponding acyl chloride (IX),which is condensed with vinyltributylstannane,yielding 1-(2-thienyl)-2-propen-1-one (X).The addition of HCl to the double bond of (X) affords 3-chloro-1-(2-thienyl)-1-propanone (XI),which is reduced with BH3 and the chiral (R)-oxazaborolidine catalyst (XII) in THF to give (S)-3-chloro-1-(2-thienyl)-1-propanol (XIII) (4).Treatment of (XIII) with NaI in acetone affords the (S)-3-iodopropanol derivative (XIV),which is condensed with methylamine in THF to provide (S)-3-(methylamino)-1-(2-thienyl)-1-propanol (XV).Finally,this compound is condensed with 1-fluoronaphthalene (V) by means of NaH in DMA.The Friedel-Crafts condensation of thiophene (XVI) with 3-chloropropionyl chloride (XVII) by means of SnCl4 in benzene gives the previously reported 3-chloro-1-(2-thienyl)-1-propanone (XI),which is reduced with NaBH4 in ethanol to yield the racemic alcohol (XVIII).Optical resolution of (XVIII) performed by means of immobilized CALB (Novozyme 435,Novo-Nordisk A/S) affords the previously reported (S)-alcohol (XIII).
合成路线:The reaction of 2-acetylthiophene (I) with [14C]-paraformaldehyde and dimethylamine in ethanol gives 3-(dimethylamino)-1-(2-thienyl)-[3-14C]propan-1-one (II),which is enantioselectively reduced in toluene with a 2:1 complex of (2R,3S)-4-(dimethylamino)-3-methyl-1,2-diphenyl-2-butanol (III) and LiAlH4 in toluene to yield (S)-3-(dimethylamino)-1-(2-thienyl)-[3-14C]propan-1-ol (IV).The condensation of (IV) with 1-fluoronaphthalene (V) by means of NaH in DMSO affords the corresponding naphthyl ether (VI),which is finally monodemethylated with 2,2,2-trichloroethyl chloroformate and Zn in toluene.
合成路线:The reaction of [carbonyl-14C]-2-acetylthiophene (I) with paraformaldehyde and dimethylamine in ethanol gives 3-(dimethylamino)-1-(2-thienyl)-[1-14C]propan-1-one (II),which is enantioselectively reduced with a 2:1 complex of (2R,3S)-4-(dimethylamino)-3-methyl-1,2-diphenyl-2-butanol (III) and LiAlH4 in toluene,yielding (S)-3-(dimethylamino)-1-(2-thienyl)[1-14C] propan-1-ol (IV).The condensation of (IV) with 1-fluoronaphthalene (V) by means of NaH in DMSO affords the corresponding naphthyl ether (VI),which is finally monodemethylated with 2,2,2-trichloroethyl chloroformate and Zn in toluene.
合成路线:The reaction of thiophene-2-[14C]carboxylic acid (VII) with oxalyl chloride and PPh3 gives the corresponding labeled acyl chloride (VIII),which is condensed with vinyltributylstannane,yielding 1-(2-thienyl)-[1-14C]prop-2-en-1-one (IX).The addition of HCl to the double bond of (IX) affords 3-chloro-1-(2-thienyl)-[1-14C]propan-1-one (X),which is reduced with BH3 and the chiral (R)-oxazaborolidine catalyst (XI) in THF to give (S)-3-chloro-1-(2-thienyl)-[1-14C]propan-1-ol (XII).Treatment of (XII) with NaI in acetone affords the labeled (S)-3-iodopropanol derivative (XIII),which is condensed with methylamine in THF to provide (S)-3-(methylamino)-1-(2-thienyl)-[1-14C]propan-1-ol (XIV).Finally,this compound is condensed with 1-fluoronaphthalene (V) by means of NaH in DMA.
合成路线:The reaction of thiophene-2-carboxylic acid (I) with oxalyl chloride and PPh3 gives the corresponding acyl chloride (II),which is condensed with vinyltributylstannane to yield 1-(2-thienyl)-2-propen-1-one (III).The addition of HCl to the double bond of (III) affords 3-chloro-1-(2-thienyl)-1-propanone (IV),which is reduced with BH3 and the chiral (S)-oxazaborolidine catalyst (V) in THF to give the (R)-3-chloro-1-(2-thienyl)-1-propanol (VI).The condensation of (VI) with [1-14C]-1-naphthol (VII) by means of DEAD and PPh3 in THF affords the labeled naphthyl ether derivative (VIII),which is treated with NaI in acetone to give the labeled iodo derivative (IX).Finally,this compound is treated with methylamine in hot THF.
参考文献标题:Duloxetine oxalate
文献作者:Sorbera,L.A.; Castar,R.M.; Castar,J.
参考来源:Drugs Fut 2000,25(9),907
合成路线:The enantioselective reduction of 3-chloro-1-(2-thienyl)-1-propanone (I) by means of BH3 catalyzed by (R)-1-methyl-3,3-diphenyltetrahydropyrrolo[1,2-c][1,3,2]oxazaborole (II) in THF gives 3-chloro-1-(2-thienyl)propan-1(S)-ol (III),which is treated with methylamine and NaI in acetone/THF to yield (S)-N-methyl-N-[3-(2-thienyl)propyl]amine (IV).Finally,this compound is condensed with 1-fluoronaphthalene (V) by means of NaH in DMA to provide duloxetine.Alternatively,the enantioselective reduction of 3-chloro-1-(2-thienyl)-1-propanone (I) by means of BH3 catalyzed by (S)-1-methyl-3,3-diphenyltetrahydropyrrolo[1,2-c][1,3,2]oxazaborole (VI) in THF gives 3-chloro-1-(2-thienyl)propan-1(R)-ol (VII),which is condensed with 1-naphthol (VIII) by means of DEAD and PPh3 to yield the expected aryl ether (IX),with inversion of the configuration.Finally,this compound is treated with methylamine and NaI in acetone/THF to provide duloxetine.
参考文献标题:Duloxetine (Cymbalta(TM)),a dual inhibitor of serotonin and norepinephrine reuptake
文献作者:Bymaster,F.P.; Beedle,E.E.; Findlay,J.; Gallagher,P.T.; Krushinski,J.H.; Mitchell,S.; Robertson,D.W.; Thompson,D.C.; Wallace,L.; Wong,D.T.
参考来源:Bioorg Med Chem Lett 2003,13(24),4477
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