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【结 构 式】

【药物名称】VRC-3807

【化学名称】N-[3-[3-Fluoro-4-[N-methyl-N-(thioformyl)amino]phenyl]-2-oxooxazolidin-5(S)-ylmethyl]thioacetamide

【CA登记号】324788-67-2

【 分 子 式 】C14H16FN3O2S2

【 分 子 量 】341.42892

【开发单位】Pfizer (Originator), Vicuron Pharmaceuticals (Originator)

【药理作用】Antibacterial Drugs, ANTIINFECTIVE THERAPY, Oxazolidinones

合成路线1

Jones oxidation of 2-fluoro-4-nitrotoluene (I) afforded carboxylic acid (II). After activation of (II) as the corresponding acid chloride with SOCl2, reaction with lithium tert-butoxide furnished the tert-butyl ester (III). Reduction of the nitro group of (III) by means of iron powder in the presence of ammonium chloride gave amine (IV), which was converted to carbamate (V) upon treatment with benzyl chloroformate. The chiral oxazolidinone (VII) was prepared by condensation of the lithium salt of carbamate (V) with (R)-glycidyl butyrate (VI). After activation of the primary hydroxyl of (VII) as the corresponding mesylate, displacement with NaN3 in hot DMF provided the alkyl azide (VIII). Tert-Butyl ester cleavage in (VIII) by means of trifluoroacetic acid afforded the carboxylic acid (IX). Curtius rearrangement of acid (IX) with diphenylphosphoryl azide in the presence of tert-butanol generated the tert-butyl carbamate (X). Further N-alkylation of carbamate (X) using iodomethane and LiH gave the N-methyl analogue (XI). Then, reduction of the azido group of (XI) to the primary amine (XII) was accomplished by treatment with triphenylphosphine followed by aqueous hydrolysis.

1 Singh, U.; Gordeev, M.F.; Luehr, G.W.; Gadwood, R.C.; Jain, R.; Hackbarth, C.J.; Trias, J.; Patel, D.V.; Lopez, S.; Acyclic C-group oxazolidinones: Antimicrobial 4'-acylamino, 4'-urea and 4'-thiourea phenyloxazolidinones. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1045.
2 Patel, D.V.; Gadwood, R.C.; Gordeev, M.F.; Luehr, G.W. (Pharmacia Corp.); Oxazolidinones and their use as antiinfectives. EP 1200416; US 6441005; WO 0109107 .
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) 55902 2-Fluoro-4-nitrotoluene; 4-Nitro-2-fluorotoluene 1427-07-2 C7H6FNO2 详情 详情
(II) 55903 2-Fluoro-4-nitrobenzoic acid 403-24-7 C7H4FNO4 详情 详情
(III) 55904 tert-butyl 2-fluoro-4-nitrobenzoate C11H12FNO4 详情 详情
(IV) 55905 tert-butyl 4-amino-2-fluorobenzoate C11H14FNO2 详情 详情
(V) 55906 tert-butyl 4-{[(benzyloxy)carbonyl]amino}-2-fluorobenzoate C19H20FNO4 详情 详情
(VI) 18385 (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate 60456-26-0 C7H12O3 详情 详情
(VII) 55907 tert-butyl 2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]benzoate C15H18FNO5 详情 详情
(VIII) 55908 tert-butyl 4-[(5R)-5-(azidomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorobenzoate C15H17FN4O4 详情 详情
(IX) 55909 4-[(5R)-5-(azidomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorobenzoic acid C11H9FN4O4 详情 详情
(X) 58661 tert-butyl 4-[(5R)-5-(azidomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenylcarbamate C15H18FN5O4 详情 详情
(XI) 58662 tert-butyl 4-[(5R)-5-(azidomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl(methyl)carbamate C16H20FN5O4 详情 详情
(XII) 58663 tert-butyl 4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl(methyl)carbamate C16H22FN3O4 详情 详情

合成路线2

Amine (XII) was acylated by acetic anhydride in pyridine to afford acetamide (XIII). The N-Boc protecting group of (XIII) was then removed under acidic conditions to give amine (XIV), which was converted into formamide (XV) by treatment with p-nitrophenyl formate. Finally, thionation of both amide groups of (XV) by means of Lawesson's reagent in hot dioxane provided the target bis-thioamide.

1 Singh, U.; Gordeev, M.F.; Luehr, G.W.; Gadwood, R.C.; Jain, R.; Hackbarth, C.J.; Trias, J.; Patel, D.V.; Lopez, S.; Acyclic C-group oxazolidinones: Antimicrobial 4'-acylamino, 4'-urea and 4'-thiourea phenyloxazolidinones. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1045.
2 Patel, D.V.; Gadwood, R.C.; Gordeev, M.F.; Luehr, G.W. (Pharmacia Corp.); Oxazolidinones and their use as antiinfectives. EP 1200416; US 6441005; WO 0109107 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XII) 58663 tert-butyl 4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl(methyl)carbamate C16H22FN3O4 详情 详情
(XIII) 58664 tert-butyl 4-{(5S)-5-[(acetylamino)methyl]-2-oxo-1,3-oxazolidin-3-yl}-2-fluorophenyl(methyl)carbamate C18H24FN3O5 详情 详情
(XIV) 58665 N-({(5S)-3-[3-fluoro-4-(methylamino)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide C13H16FN3O3 详情 详情
(XV) 58666 N-[((5S)-3-{3-fluoro-4-[formyl(methyl)amino]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide C14H16FN3O4 详情 详情
Extended Information