(1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-{[6-(4-phenylbutoxy)hexyl]amino}-1-ethanol -Drug Synthesis Database

【结构式】

【分子编号】52679

【品名】(1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-{[6-(4-phenylbutoxy)hexyl]amino}-1-ethanol

【CA登记号】

【分子式】C₂₈H₄₁NO₄

【分子量】455.63788

【元素组成】C 73.81% H 9.07% N 3.07% O 14.05%

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：(VIII)

The condensation of the phenacyl bromide (I) with the chiral auxiliary (II) by means of DIEA in THF gives the chiral secondary amine (III), which is submitted to a diastereoselective reduction of the carbonyl group by means of CaCl2 and NaBH4 in methanol to yield a 10:1 enriched mixture of the desired (R)-enantiomer (IV), easily separated by crystallization. The reductocondensation of the chiral amine (IV) with 6-(4-phenylbutoxy)hexanal (V) (obtained by oxidation of 6-(4-phenylbutoxy)hexyl bromide (VI) by means of NaHCO3 and DMSO at 150 C) by means of NaBH(OAc)3 in dichloromethane affords the tertiary amine (VII). Elimination of the chiral auxiliary of (VII) by means of H2 over Pd/C in ethanol provides the secondary amine (VIII), which is finally passed through an acidic SCX-2 ion exchange resin in ethanol to eliminate the acetonide group and give rise to the target (R)-salmeterol.

参考文献中间体

合成目标

【1】 Bream, R.N.; et al.; A mild, enantioselective synthesis of (R)-salmeterol via sodium borohydride-calcium chloride asymmetric reduction of a phenacyl phenylglycinol derivative. J Chem Soc - Perkins Trans I 2002, 20, 2237.

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)	10973	(2S)-2-Amino-2-phenyl-1-ethanol; (S)-2-Hydroxy-1-phenylethylamine; (S)-(+)-2-Phenylglycinol; (S)-2-Amino-2-phenyl-1-ethanol	20989-17-7	C₈H₁₁NO	详情	详情
(I)	52359	2-bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1-ethanone		C₁₂H₁₃BrO₃	详情	详情
(III)	52360	1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-[(2-hydroxy-1-phenylethyl)amino]-1-ethanone		C₂₀H₂₃NO₄	详情	详情
(IV)	52361	(1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-{[(1S)-2-hydroxy-1-phenylethyl]amino}-1-ethanol		C₂₀H₂₅NO₄	详情	详情
(V)	52362	6-[(4-phenylbutyl)oxy]hexanal		C₁₆H₂₄O₂	详情	详情
(VI)	31479	1-[4-[(6-bromohexyl)oxy]butyl]benzene; 6-bromohexyl-4-phenylbutyl ether; 6-Bromohexyloxybutylbenzene	94749-73-2	C₁₆H₂₅BrO	详情	详情
(VII)	52363	(1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-{[(1S)-2-hydroxy-1-phenylethyl][6-(4-phenylbutoxy)hexyl]amino}-1-ethanol		C₃₆H₄₉NO₅	详情	详情
(VIII)	52679	(1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-{[6-(4-phenylbutoxy)hexyl]amino}-1-ethanol		C₂₈H₄₁NO₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IX)

The condensation of bromoketone (I) with di-tert-butyl iminodicarboxylate (II) by means of Cs2CO3 in acetonitrile gives the adduct (III), which is monodecarboxylated by reaction with TFA in dichloromethane to yield the carbamate (IV). The asymmetric reduction of the ketonic group of (IV) by means of BH3 and a chiral oxazaborole catalyst affords the (R)-alcohol (V), which is cyclized by means of NaH in DMF to provide the chiral oxazolidinone (VI). The alkylation of (VI) with 6-(4-phenylbutoxy)hexyl bromide (VII) by means of NaH in THF gives the alkylated oxazolidinone (VIII), which is treated with Tms-OK in THF to cleave the oxazolidinone ring, yielding the aminoalcohol (IX). Finally, the acetonide ring of (IX) is cleaved by means of AcOH in methanol to provide salmeterol.

参考文献中间体

合成目标

【1】 Coe, D.M.; Perciaccante, R.; Procopiou, P.A.; Potassium trimethylsilanolate induced cleavage of 1,3-oxazolidin-2 and 5-ones, and application to the synthesis of (R)-salmeterol. Org Biomol Chem 2003, 1, 7, 1106.

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)	52359	2-bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1-ethanone		C₁₂H₁₃BrO₃	详情	详情
(II)	48447	Di-tert-butyl iminodicarboxylate; Iminodicarboxylic acid di-tert-butyl ester	51779-32-9	C₁₀H₁₉NO₄	详情	详情
(III)	64766	6-{2-[bis(tert-butoxycarbonyl)amino]acetyl}-2,2-dimethyl-4H-1,3-benzodioxine		C₂₂H₃₁NO₇	详情	详情
(IV)	64767	tert-butyl 2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethylcarbamate		C₁₇H₂₃NO₅	详情	详情
(V)	64768	tert-butyl (2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethylcarbamate		C₁₇H₂₅NO₅	详情	详情
(VI)	64769	(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one		C₁₃H₁₅NO₄	详情	详情
(VII)	31479	1-[4-[(6-bromohexyl)oxy]butyl]benzene; 6-bromohexyl-4-phenylbutyl ether; 6-Bromohexyloxybutylbenzene	94749-73-2	C₁₆H₂₅BrO	详情	详情
(VIII)	64770	(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-3-[6-(4-phenylbutoxy)hexyl]-1,3-oxazolidin-2-one		C₂₉H₃₉NO₅	详情	详情
(IX)	52679	(1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-{[6-(4-phenylbutoxy)hexyl]amino}-1-ethanol		C₂₈H₄₁NO₄	详情	详情

Extended Information