VRC-3807, -Drug Synthesis Database

【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 合成路线2

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.

参考文献中间体

【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.

参考文献中间体

【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	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

Drug NewChemical Entity Original Patent(1)