(1R)-3-chloro-1-(2-thienyl)-1-propanol -Drug Synthesis Database

【结构式】

【分子编号】40512

【品名】(1R)-3-chloro-1-(2-thienyl)-1-propanol

【CA登记号】

【分子式】C₇H₉ClOS

【分子量】176.66656

【元素组成】C 47.59% H 5.13% Cl 20.07% O 9.06% S 18.15%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(VI)

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.

参考文献中间体

合成目标

【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

合成路线2

该中间体在本合成路线中的序号：(VII)

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.

参考文献中间体

合成目标

【1】 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.; Duloxetine (Cymbalta(TM)), a dual inhibitor of serotonin and norepinephrine reuptake. Bioorg Med Chem Lett 2003, 13, 24, 4477.

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)	40507	3-chloro-1-(2-thienyl)-1-propanone		C₇H₇ClOS	详情	详情
(II)	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
(III)	40509	(1S)-3-chloro-1-(2-thienyl)-1-propanol		C₇H₉ClOS	详情	详情
(IV)	40511	(1S)-3-(methylamino)-1-(2-thienyl)-1-propanol	116539-55-0	C₈H₁₃NOS	详情	详情
(V)	40503	1-fluoronaphthalene	321-38-0	C₁₀H₇F	详情	详情
(VI)	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
(VII)	40512	(1R)-3-chloro-1-(2-thienyl)-1-propanol		C₇H₉ClOS	详情	详情
(VIII)	22935	alpha-naphthol; 1-naphthol	90-15-3	C₁₀H₈O	详情	详情
(IX)	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

Extended Information