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【结 构 式】

【分子编号】68066

【品名】(R)-5-(aminomethyl)-3-(3-fluoro-4-thiomorpholinophenyl)oxazolidin-2-one

【CA登记号】 

【 分 子 式 】C14H18FN3O2S

【 分 子 量 】311.38

【元素组成】C 54.00% H 5.83% F 6.10% N 13.49% O 10.28% S 10.30%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(XIa)

Condensation of 1,2-difluoro-4-nitrobenzene (I) with thiomorpholine (II) using DIEA in refluxing acetonitrile at 85 °C yields 4-(2-fluoro-4-nitrophenyl)thiomorpholine (III) , which is then reduced by means of either Na2S2O4 in THF , Fe in the presence of NH4Cl in refluxing H2O/EtOH/dioxane , or by catalytic hydrogenation over Raney-Ni in THF/H2O (1) or sulfided Pd/C in MeOH , providing 3-fluoro-4-thiomorpholin-4-ylaniline (IV) . Acylation of amine (IV) with benzyl chloroformate (V), optionally in the presence of DMA , in THF affords carbamate (VI) , which then cyclizes with (R)-(–)-glycidyl butyrate (VII) using BuLi in THF at –78 °C to produce the 5-(hydroxymethyl)-2-oxazolidinone derivative (VIII). Reaction of the primary alcohol (VIII) with MsCl using Et3N in CH2Cl2 or with TsCl in pyridine yields the corresponding mesylate (IXa) or tosylate (IXb) , respectively, which by substitution with NaN3 in DMF at 65-85 °C provides azide (X). Staudinger reduction of azide (X) with PPh3 in THF/H2O then yields the corresponding amine (XIa). Finally, amine (XIa) or its hydrochloride (XIb) are acylated with acetic anhydride (XII) in the presence of pyridine in CH2Cl2 or NaOH in H2O/MeOH/CH2Cl2 .

1 Barbachyn, M.R., Hutchinson, D.K., Brickner, S.J. et al. Identification of a novel oxazolidinone (U-100480) with potent antimycobacterial activity. J Med Chem 1996, 39(3): 680-5.
2 Brickner, S.J., Barbachyn, M.R., Hutchinson, D.K. (Pfizer, Inc.). Substituted oxazine and thiazine oxazolidinone antimicrobials. US 5880118.
3 Barbachyn, M.R., Brickner, S.J., Hutchinson, D.K. (Pfizer, Inc.). Substituted oxazine and thiazine oxazolidinone antimicrobials. EP 0717738, JP 1997502436, US 5688792, WO 1995007271.
4 Brickner, S.J., Nuermberger, E., Stover, C.K. (Pfizer, Inc.). Combination therapy for tuberculosis. CN 102143748, EP 2340022, JP 20122502017, KR 2011063518, US 2011190199, WO 2010026526.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IXa) 68063 (R)-(3-(3-fluoro-4-thiomorpholinophenyl)-2-oxooxazolidin-5-yl)methyl methanesulfonate   C15H19FN2O5S2 详情 详情
(IXb) 68064 (R)-(3-(3-fluoro-4-thiomorpholinophenyl)-2-oxooxazolidin-5-yl)methyl 4-methylbenzenesulfonate   C21H23FN2O5S2 详情 详情
(XIa) 68066 (R)-5-(aminomethyl)-3-(3-fluoro-4-thiomorpholinophenyl)oxazolidin-2-one   C14H18FN3O2S 详情 详情
(XIb) 68067 (R)-5-(aminomethyl)-3-(3-fluoro-4-thiomorpholinophenyl)oxazolidin-2-one hydrochloride   C14H18FN3O2S.HCl 详情 详情
(I) 17013 1,2-difluoro-4-nitrobenzene; 3,4-Difluoronitrobenzene 369-34-6 C6H3F2NO2 详情 详情
(II) 36317 thiomorpholine 123-90-0 C4H9NS 详情 详情
(III) 68060 4-(2-fluoro-4-nitrophenyl)thiomorpholine   C10H11FN2O2S 详情 详情
(IV) 68061 3-fluoro-4-thiomorpholinoaniline   C10H13FN2S 详情 详情
(V) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(VI) 68062 benzyl (3-fluoro-4-thiomorpholinophenyl)carbamate   C18H19FN2O2S 详情 详情
(VII) 18385 (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate 60456-26-0 C7H12O3 详情 详情
(VIII) 56305 (5R)-3-[3-fluoro-4-(4-thiomorpholinyl)phenyl]-5-(hydroxymethyl)-1,3-oxazolidin-2-one C14H17FN2O3S 详情 详情
(X) 68065 (R)-5-(azidomethyl)-3-(3-fluoro-4-thiomorpholinophenyl)oxazolidin-2-one   C14H16FN5O2S 详情 详情
(XII) 49701 Acetic anhydride; Acetyl oxide 108-24-7 C4H6O3 详情 详情
Extended Information