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【结 构 式】

【分子编号】40505

【品名】2-thiophenecarboxylic acid

【CA登记号】527-72-0

【 分 子 式 】C5H4O2S

【 分 子 量 】128.15156

【元素组成】C 46.86% H 3.15% O 24.97% S 25.02%

与该中间体有关的原料药合成路线共 3 条

合成路线1

该中间体在本合成路线中的序号:(VIII)

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).

1 Sorbera, L.A.; Castaner, R.M.; Castaner, J.; Duloxetine oxalate. Drugs Fut 2000, 25, 9, 907.
2 Wheeler, W.J.; Kuo, F.; An asymmetric synthesis of duloxetine hydrochloride, a mixed uptake inhibitor of serotonin and norepinephrine, and its C-14 labeled isotopomers. J Label Compd Radiopharm 1995, 36, 3, 213.
3 Hoff, B.H.; Liu, H.; Anthonsen, T.; Chemo-enzymatic synthesis of the antidepressant duloxetine and its enantiomer. Chirality 2000, 12, 1, 26.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(V) 40503 1-fluoronaphthalene 321-38-0 C10H7F 详情 详情
(VIII) 40505 2-thiophenecarboxylic acid 527-72-0 C5H4O2S 详情 详情
(IX) 14103 2-Thiophenecarbonyl chloride 5271-67-0 C5H3ClOS 详情 详情
(X) 40506 1-(2-thienyl)-2-propen-1-one C7H6OS 详情 详情
(XI) 40507 3-chloro-1-(2-thienyl)-1-propanone C7H7ClOS 详情 详情
(XII) 20631 (R)-Methyl oxazaborolidine; (3aR)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole 112022-83-0 C18H20BNO 详情 详情
(XIII) 40509 (1S)-3-chloro-1-(2-thienyl)-1-propanol C7H9ClOS 详情 详情
(XIV) 40510 (1S)-3-iodo-1-(2-thienyl)-1-propanol C7H9IOS 详情 详情
(XV) 40511 (1S)-3-(methylamino)-1-(2-thienyl)-1-propanol 116539-55-0 C8H13NOS 详情 详情
(XVI) 13297 Thiophene 110-02-1 C4H4S 详情 详情
(XVII) 18936 3-chloropropanoyl chloride 625-36-5 C3H4Cl2O 详情 详情
(XVIII) 40508 3-chloro-1-(2-thienyl)-1-propanol C7H9ClOS 详情 详情

合成路线2

该中间体在本合成路线中的序号:(VII)

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.

1 Sorbera, L.A.; Castaner, R.M.; Castaner, J.; Duloxetine oxalate. Drugs Fut 2000, 25, 9, 907.
2 Wheeler, W.J.; Kuo, F.; An asymmetric synthesis of duloxetine hydrochloride, a mixed uptake inhibitor of serotonin and norepinephrine, and its C-14 labeled isotopomers. J Label Compd Radiopharm 1995, 36, 3, 213.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(V) 40503 1-fluoronaphthalene 321-38-0 C10H7F 详情 详情
(VII) 40505 2-thiophenecarboxylic acid 527-72-0 C5H4O2S 详情 详情
(VII) 45145 2-thiophenecarboxylic acid C5H4O2S 详情 详情
(VIII) 14103 2-Thiophenecarbonyl chloride 5271-67-0 C5H3ClOS 详情 详情
(VIII) 45146 2-thiophenecarbonyl chloride C5H3ClOS 详情 详情
(IX) 40506 1-(2-thienyl)-2-propen-1-one C7H6OS 详情 详情
(IX) 45147 1-(2-thienyl)-2-propen-1-one C7H6OS 详情 详情
(X) 40507 3-chloro-1-(2-thienyl)-1-propanone C7H7ClOS 详情 详情
(X) 45148 3-chloro-1-(2-thienyl)-1-propanone C7H7ClOS 详情 详情
(XI) 20631 (R)-Methyl oxazaborolidine; (3aR)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole 112022-83-0 C18H20BNO 详情 详情
(XII) 40509 (1S)-3-chloro-1-(2-thienyl)-1-propanol C7H9ClOS 详情 详情
(XII) 45149 (1S)-3-chloro-1-(2-thienyl)-1-propanol C7H9ClOS 详情 详情
(XIII) 40510 (1S)-3-iodo-1-(2-thienyl)-1-propanol C7H9IOS 详情 详情
(XIII) 45150 (1S)-3-iodo-1-(2-thienyl)-1-propanol C7H9IOS 详情 详情
(XIV) 40511 (1S)-3-(methylamino)-1-(2-thienyl)-1-propanol 116539-55-0 C8H13NOS 详情 详情
(XIV) 45151 (1S)-3-(methylamino)-1-(2-thienyl)-1-propanol C8H13NOS 详情 详情

合成路线3

该中间体在本合成路线中的序号:(I)

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.

1 Wheeler, W.J.; Kuo, F.; Approaches to an asymmetric synthesis of duloxetine, a mixed uptake inhibitor of serotonin and norepinephrine, and its C-14 labeled analogs. Synthesis and Applications of Isotopically Labelled Compounds 1994, 597-603.
2 Sorbera, L.A.; Castaner, R.M.; Castaner, J.; Duloxetine oxalate. Drugs Fut 2000, 25, 9, 907.
3 Wheeler, W.J.; Kuo, F.; An asymmetric synthesis of duloxetine hydrochloride, a mixed uptake inhibitor of serotonin and norepinephrine, and its C-14 labeled isotopomers. J Label Compd Radiopharm 1995, 36, 3, 213.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 40505 2-thiophenecarboxylic acid 527-72-0 C5H4O2S 详情 详情
(II) 14103 2-Thiophenecarbonyl chloride 5271-67-0 C5H3ClOS 详情 详情
(III) 40506 1-(2-thienyl)-2-propen-1-one C7H6OS 详情 详情
(IV) 40507 3-chloro-1-(2-thienyl)-1-propanone C7H7ClOS 详情 详情
(V) 28292 (S)-Methyl oxazaborolidine; (3aS)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole 112022-81-8 C18H20BNO 详情 详情
(VI) 40512 (1R)-3-chloro-1-(2-thienyl)-1-propanol C7H9ClOS 详情 详情
(VII) 22935 alpha-naphthol; 1-naphthol 90-15-3 C10H8O 详情 详情
(VII) 45152 1-naphthol C10H8O 详情 详情
(VIII) 40513 (1S)-3-chloro-1-(2-thienyl)propyl 1-naphthyl ether; 2-[(1S)-3-chloro-1-(1-naphthyloxy)propyl]thiophene C17H15ClOS 详情 详情
(VIII) 45153 (1S)-3-chloro-1-(2-thienyl)propyl 1-naphthyl ether; 2-[(1S)-3-chloro-1-(1-naphthyloxy)propyl]thiophene C17H15ClOS 详情 详情
(IX) 40514 (1S)-3-iodo-1-(2-thienyl)propyl 1-naphthyl ether; 2-[(1S)-3-iodo-1-(1-naphthyloxy)propyl]thiophene C17H15IOS 详情 详情
(IX) 45154 2-[(1S)-3-iodo-1-(1-naphthyloxy)propyl]thiophene; (1S)-3-iodo-1-(2-thienyl)propyl 1-naphthyl ether C17H15IOS 详情 详情
Extended Information