3-hydroxy-3-phenylpropyl 4-methylbenzenesulfonate -Drug Synthesis Database

【结构式】

【分子编号】57228

【品名】3-hydroxy-3-phenylpropyl 4-methylbenzenesulfonate

【CA登记号】

【分子式】C₁₆H₁₈O₄S

【分子量】306.38252

【元素组成】C 62.72% H 5.92% O 20.89% S 10.47%

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：(III)

The reduction of 3-hydroxy-3-phenylpropionic acid ethyl ester (I) with LiAlH4 in THF gives 1-phenylpropane-1,3-diol (II), which is treated with Ts-Cl and TEA in dichloromethane to yield the monotosylate (III). The optical resolution of (III) by means of (Pd(OAc)2, (-)-sparteine and O2 in hot toluene yields a mixture of the desired (S)-1-phenyl-3-(tosyloxy)-1-propanol (IV) and the propiophenone (V) that is separated by column chromatography. The reaction of (IV) with methylamine in hot THF affords the chiral secondary amine (VI), which is finally condensed with 2-methylphenol (VII) by means of PPh3 and DEAD in ethyl ether to provide the target (R)-tomoxetine.

参考文献中间体

合成目标

【1】 Ali, I.S.; Sudalai, A.; Pd-catalyzed kinetic resolution of benzylic alcohols: A practical synthesis of (R)-tomoxetine and (S)-fluoxetine hydrochlorides. Tetrahedron Lett 2002, 43, 31, 5435.

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)	57231	Ethyl beta-hydroxyhydrocinnamate		C₁₁H₁₄O₃	详情	详情
(II)	57227	1-Phenyl-1,3-propanediol		C₉H₁₂O₂	详情	详情
(III)	57228	3-hydroxy-3-phenylpropyl 4-methylbenzenesulfonate		C₁₆H₁₈O₄S	详情	详情
(IV)	57229	(3S)-3-hydroxy-3-phenylpropyl 4-methylbenzenesulfonate		C₁₆H₁₈O₄S	详情	详情
(V)	57230	3-oxo-3-phenylpropyl 4-methylbenzenesulfonate		C₁₆H₁₆O₄S	详情	详情
(VI)	10008	(1S)-3-(Methylamino)-1-phenyl-1-propanol	114133-37-8	C₁₀H₁₅NO	详情	详情
(VII)	10010	o-Cresol	95-48-7	C₇H₈O	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

The asymmetric epoxidation of (E)-3-phenyl-2-propen-1-ol (I) by means of titanium tetraisopropoxide, (+)-diethyl tartrate (+)-(DET) and tBu-OOH in dichloromethane gives the chiral epoxide (II) (1), which is opened by means of bis(2-methoxyethoxy)aluminum hydride (Red-Al) in DME to yield the chiral diol (III). The regioselective reaction of (III) with Ms-Cl and TEA in ethyl ether affords the primary mesylate (IV), which is treated with methylamine in hot THF to afford the secondary amine (V). Finally this compound is condensed with 4-(trifluoromethyl)chlorobenzene (VI) by means of NaH in dimethylacetamide to give rise to the target (S)-fluoxetine.

参考文献中间体

合成目标

【1】 Gao, Y.; et al.; Catalytic asymmetric epoxidation and kinetic resolution: Modified procedures including in situ derivatization. J Am Chem Soc 1987, 109, 19, 5765.
【2】 Gao, Y.; Sharpless, K.B.; Asymmetric synthesis of both enantiomers of tomoxetine and fluoxetine. Selective reduction of 2,3-epoxycinnamyl alcohol with Red-Al. J Org Chem 1988, 53, 17, 4081.

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)	57231	Ethyl beta-hydroxyhydrocinnamate		C₁₁H₁₄O₃	详情	详情
(II)	57227	1-Phenyl-1,3-propanediol		C₉H₁₂O₂	详情	详情
(III)	57228	3-hydroxy-3-phenylpropyl 4-methylbenzenesulfonate		C₁₆H₁₈O₄S	详情	详情
(IV)	57229	(3S)-3-hydroxy-3-phenylpropyl 4-methylbenzenesulfonate		C₁₆H₁₈O₄S	详情	详情
(V)	57230	3-oxo-3-phenylpropyl 4-methylbenzenesulfonate		C₁₆H₁₆O₄S	详情	详情
(VI)	10008	(1S)-3-(Methylamino)-1-phenyl-1-propanol	114133-37-8	C₁₀H₁₅NO	详情	详情
(VII)	11973	1-Chloro-4-(trifluoromethyl)benzene; 4-Chlorobenzotrifluoride	98-56-6	C₇H₄ClF₃	详情	详情

Extended Information