isobutyl 4-bromo-3-fluorophenylcarbamate -Drug Synthesis Database

【结构式】

【分子编号】49691

【品名】isobutyl 4-bromo-3-fluorophenylcarbamate

【CA登记号】

【分子式】C₁₁H₁₃BrFNO₂

【分子量】290.1321632

【元素组成】C 45.54% H 4.52% Br 27.54% F 6.55% N 4.83% O 11.03%

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：(IV)

The reaction of 3-fluoroaniline (I) with isobutyl chloroformate (II) by means of K2CO3 in dichloromethane/water gives the carbamate (III), which is brominated with 1,3-dibromo-5,5-dimethylhydantoin (DBDH) to yield the 4-bromo-3-fluorophenyl carbamate (IV). The condensation of (IV) with tetrahydrothiopyran-4-one (V) by means of EtMgBr and BuLi in THF affords the tertiary alcohol (VI), which is dehydrated by means of TFA in dichloromethane and oxidized with NaIO4 in methanol/water to provide the unsaturated sulfoxide (VII). The stereoselective reduction of (VII) by means of H2 over Pt/C in DMF gives the cis sulfoxide (VIII). The cyclization of the carbamate (VIII) with (S)-3-chloropropane-1,2-diol (IX) by means of Li t-amylate in DMF gives the oxazolidinone (X), whose free OH group is activated with 2,5-dichlorobenzenesulfonyl chloride (XI) and TEA in dichloromethane to yield the sulfonate (XII). The reaction of (XII) with NH4OH in methanol/acetonitrile affords the aminomethyl derivative (XIII), which is finally acylated with acetic anhydride (XIV) to provide the target sulfoxide.

参考文献中间体

合成目标

【1】 Gage, J.R.; et al.; Stereodivergent synthesis of sulfoxide-containing oxazolidinone antibiotics. Tetrahedron Lett 2000, 41, 22, 4301.

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)	20697	3-fluoroaniline; 3-fluorophenylamine	372-19-0	C₆H₆FN	详情	详情
(II)	13423	1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate	543-27-1	C₅H₉ClO₂	详情	详情
(III)	49690	isobutyl 3-fluorophenylcarbamate		C₁₁H₁₄FNO₂	详情	详情
(IV)	49691	isobutyl 4-bromo-3-fluorophenylcarbamate		C₁₁H₁₃BrFNO₂	详情	详情
(V)	49692	Tetrahydrothiopyran-4-one; Tetrahydro-4H-thiopyran-4-one; 4-Oxothiane	1072-72-6	C₅H₈OS	详情	详情
(VI)	49693	isobutyl 3-fluoro-4-(4-hydroxytetrahydro-2H-thiopyran-4-yl)phenylcarbamate		C₁₆H₂₂FNO₃S	详情	详情
(VII)	49694	4-[2-fluoro-4-[(isobutoxycarbonyl)amino]phenyl]-3,6-dihydro-2H-thiopyranium-1-olate		C₁₆H₂₀FNO₃S	详情	详情
(VIII)	49695	4-[2-fluoro-4-[(isobutoxycarbonyl)amino]phenyl]tetrahydro-2H-thiopyranium-1-olate		C₁₆H₂₂FNO₃S	详情	详情
(IX)	49696	(S)-(+)-Alpha-Chlorohydrin; (S)-(+)-3-Chloro-1,2-propanediol; (S)-3-Chloro-1,2-propanediol	60827-45-4	C₃H₇ClO₂	详情	详情
(X)	49697	4-[2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]tetrahydro-2H-thiopyranium-1-olate		C₁₅H₁₈FNO₄S	详情	详情
(XI)	49698	2,5-Dichlorobenzenesulfonic acid	88-42-6	C₆H₄Cl₂O₃S	详情	详情
(XII)	49699	4-[4-[(5R)-5-([[(2,5-dichlorophenyl)sulfonyl]oxy]methyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl]tetrahydro-2H-thiopyranium-1-olate		C₂₁H₂₀Cl₂FNO₆S₂	详情	详情
(XIII)	49700	4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl]tetrahydro-2H-thiopyranium-1-olate		C₁₅H₁₉FN₂O₃S	详情	详情
(XIV)	49701	Acetic anhydride; Acetyl oxide	108-24-7	C₄H₆O₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

The reaction of 3-fluoroaniline (I) with isobutyl chloroformate (II) by means of K2CO3 in dichloromethane/water gives the carbamate (III), which is brominated with 1,3-dibromo-5,5-dimethylhydantoin (DBDH) to yield the 4-bromo-3-fluorophenyl carbamate (IV). The condensation of (IV) with tetrahydrothiopyran-4-one (V) by means of EtMgBr and BuLi in THF affords the tertiary alcohol (VI), which is dehydroxylated by means of poly(methylhydrosiloxane) (PMHS), (Me3Si)2O and Ts-OH in toluene to provide the intermediate (VII). The stereoselective oxidation of (VII) to the trans sulfoxide (VIII) is performed by means of Ti(OiPr)4 and tert-butyl hydroperoxide in the presence of diisopropyl D-tartrate. The cyclization of the carbamate (VIII) with (S)-3-chloropropane-1,2-diol (IX) by means of Li t-amylate in DMF gives the oxazolidinone (X), whose free OH group is activated with 3-nitrobenzenesulfonyl chloride and TEA in dichloromethane to yield the sulfonate (XII). The reaction of (XII) with NH4OH in methanol/acetonitrile affords the aminomethyl derivative (XIII), which is finally acylated with propionic anhydride (XIV) to provide the target sulfoxide.

参考文献中间体

合成目标

【1】 Gage, J.R.; et al.; Stereodivergent synthesis of sulfoxide-containing oxazolidinone antibiotics. Tetrahedron Lett 2000, 41, 22, 4301.

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)	20697	3-fluoroaniline; 3-fluorophenylamine	372-19-0	C₆H₆FN	详情	详情
(II)	13423	1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate	543-27-1	C₅H₉ClO₂	详情	详情
(III)	49690	isobutyl 3-fluorophenylcarbamate		C₁₁H₁₄FNO₂	详情	详情
(IV)	49691	isobutyl 4-bromo-3-fluorophenylcarbamate		C₁₁H₁₃BrFNO₂	详情	详情
(V)	49692	Tetrahydrothiopyran-4-one; Tetrahydro-4H-thiopyran-4-one; 4-Oxothiane	1072-72-6	C₅H₈OS	详情	详情
(VI)	49693	isobutyl 3-fluoro-4-(4-hydroxytetrahydro-2H-thiopyran-4-yl)phenylcarbamate		C₁₆H₂₂FNO₃S	详情	详情
(VII)	49702	isobutyl 3-fluoro-4-tetrahydro-2H-thiopyran-4-ylphenylcarbamate		C₁₆H₂₂FNO₂S	详情	详情
(VIII)	49706	4-[2-fluoro-4-[(isobutoxycarbonyl)amino]phenyl]tetrahydro-2H-thiopyranium-1-olate		C₁₆H₂₂FNO₃S	详情	详情
(IX)	49696	(S)-(+)-Alpha-Chlorohydrin; (S)-(+)-3-Chloro-1,2-propanediol; (S)-3-Chloro-1,2-propanediol	60827-45-4	C₃H₇ClO₂	详情	详情
(X)	49707	4-[2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]tetrahydro-2H-thiopyranium-1-olate		C₁₅H₁₈FNO₄S	详情	详情
(XI)	49703	m-nitrobenzenesulfonic acid; 3-nitrobenzenesulfonic acid	98-47-5	C₆H₅NO₅S	详情	详情
(XII)	49704	4-[2-fluoro-4-[(5R)-5-([[(3-nitrophenyl)sulfonyl]oxy]methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]tetrahydro-2H-thiopyranium-1-olate		C₂₁H₂₁FN₂O₈S₂	详情	详情
(XIII)	49705	4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl]tetrahydro-2H-thiopyranium-1-olate		C₁₅H₁₉FN₂O₃S	详情	详情
(XIV)	49701	Acetic anhydride; Acetyl oxide	108-24-7	C₄H₆O₃	详情	详情

Extended Information