【结 构 式】 |
【分子编号】56305 【品名】(5R)-3-[3-fluoro-4-(4-thiomorpholinyl)phenyl]-5-(hydroxymethyl)-1,3-oxazolidin-2-one 【CA登记号】 |
【 分 子 式 】C14H17FN2O3S 【 分 子 量 】312.3650632 【元素组成】C 53.83% H 5.49% F 6.08% N 8.97% O 15.37% S 10.27% |
合成路线1
该中间体在本合成路线中的序号:(I)The known thiomorpholine derivative (I) was oxidized to the corresponding sulfoxide (II) employing either sodium metaperiodate or osmium tetroxide in the presence of N-methylmorpholine-N-oxide. Sulfonylation of the primary hydroxyl group of (II) with 3-nitrobenzenesulfonyl chloride and Et3N gave rise to the nosylate (IV), which was then displaced with ammonium hydroxide to furnish amine (IV). This was finally condensed with ethyl dithioacetate to produce the target thioacetamide.
【1】 Hester, J.B. Jr.; Perricone, S.C.; Nidy, E.G.; Poel, T.-J. (Pharmacia Corp.); Oxazolidinone antibacterial agents having a thiocarbonyl functionality. EP 0984947; JP 2002501530; US 6218413; WO 9854161 . |
【2】 Hester, J.B. Jr.; Perricone, S.C.; Nidy, E.G.; Poel, T.-J. (Pharmacia Corp.); Oxazolidinone antibacterial agents having a thiocarbonyl functionality. EP 1133493; JP 2002531455; WO 0032599 . |
【3】 Mesfin, G.-M.; Jensen, R.K. (Pharmacia Corp.); Use of thioamide oxazolidinones for the treatment of bone resorption and osteoporosis. WO 0180841 . |
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) | 56305 | (5R)-3-[3-fluoro-4-(4-thiomorpholinyl)phenyl]-5-(hydroxymethyl)-1,3-oxazolidin-2-one | C14H17FN2O3S | 详情 | 详情 | |
(II) | 56306 | 4-{2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-1lambda~4~,4-thiazinan-1-one | C14H17FN2O4S | 详情 | 详情 | |
(III) | 56307 | {(5R)-3-[3-fluoro-4-(1-oxo-1lambda~4~,4-thiazinan-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl 3-nitrobenzenesulfonate | C20H20FN3O8S2 | 详情 | 详情 | |
(IV) | 56308 | 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl}-1lambda~4~,4-thiazinan-1-one | C14H18FN3O3S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(VIII)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 |