Isopropanol → tert-Butyl (4-{(1S,2R)-2-({[5,5-dimethyl-2-(4-methylphenyl)-1,3-dioxan-2-yl]methyl}thio)-1-[(4-fluorophenyl)amino]-3-oxo-3-[(4S)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]propyl}phenoxy)acetate

HRID 254095Notes

Reaction equation

[CH3:1][C:2]1([CH3:32])[CH2:7][O:6][C:5]([CH2:15][S:16][CH2:17][C:18]([N:20]2[C@@H:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:23][O:22][C:21]2=[O:31])=[O:19])([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[O:4][CH2:3]1.[F:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]=[CH:41][C:42]2[CH:56]=[CH:55][C:45]([O:46][CH2:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[CH:44][CH:43]=2)=[CH:36][CH:35]=1.C(N(C(C)C)C(C)C)C.C(O)(C)C>C(Cl)Cl.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4].Cl[Ti](Cl)(Cl)Cl.O>[CH3:1][C:2]1([CH3:32])[CH2:3][O:4][C:5]([CH2:15][S:16][C@@H:17]([C:18](=[O:19])[N:20]2[C@@H:24]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:23][O:22][C:21]2=[O:31])[C@H:41]([C:42]2[CH:56]=[CH:55][C:45]([O:46][CH2:47][C:48]([O:50][C:51]([CH3:52])([CH3:53])[CH3:54])=[O:49])=[CH:44][CH:43]=2)[NH:40][C:37]2[CH:36]=[CH:35][C:34]([F:33])=[CH:39][CH:38]=2)([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[O:6][CH2:7]1

Participants

Conditions

Temperature: -30 °C

Procedure

Tetraisopropyl orthotitanate (0.37 ml, 1.23 mmol) was added to a solution of TiCl4 (1M in CH2Cl2, 3.3 ml, 3.3 mmol) in CH2Cl2 (50 ml) at 0° C. under inert atmosphere. The mixture was stirred for ten minutes. (4S)-3-[({[5,5-Dimethyl-2-(4-methylphenyl)-1,3-dioxan-2-yl]methyl}thio)acetyl]-4-phenyl-1,3-oxazolidin-2-one (2.0 g, 4.4 mmol) in dry CH2Cl2 (50 ml) was added dropwise over 20 minutes and the mixture was stirred for ten minutes. tert-Butyl (4-{[(4-fluorophenyl)imino]methyl}phenoxy)acetate (2.9 g, 8.8 mmol) in dry CH2Cl2 (50 ml) was added dropwise over 30 minutes. The mixture was cooled to −30° C. and stirred for 20 minutes. Ethyl diisopropyl amine (1.5 ml, 8.8 mmol) in 10 ml dry CH2Cl2 was added dropwise over ten minutes. The mixture was stirred at −30° C. for four hours. The mixture was cooled to −78° C. and isopropanol (60 ml) was added. The temperature was allowed to reach room temperature over two hours. H2O (100 ml) was added and the mixture was stirred for 20 minutes and extracted twice with diethyl ether. The combined organic layers were washed with water, dried (MgSO4) and concentrated under reduced pressure. Purification by flash-chromatography (hexane:EtOAc 5:1 then 4:1) afforded 2.55 g (74%) of the title compound as a white solid. 1H-NMR (CDCl3, 200 MHz): δ 0.6 (s, 3H), 1.3 (s, 3H), 1.5 (s, 9H), 2.4 (s, 3H), 2.6-2.9 (m, 2H), 3.3-3.5 (m, 4H), 4.1-4.3 (m, 1H), 4.5 (s, 2H), 4.6-4.8 (m, 2H), 5.0-5.3 (s, broad, 1H), 5.2 (m, 1H), 5.7 (d, 1H), 6.4 (m, 2H), 6.6-6.8 (m, 4H), 6.9 (m, 2H), 7.1-7.4 (m, 9H).

Workup

stirringthe mixture was stirred for ten minutes
stirringstirred for 20 minutes
stirringThe mixture was stirred at −30° C. for four hours
temperatureThe mixture was cooled to −78° C.
stirringthe mixture was stirred for 20 minutes
extractionextracted twice with diethyl ether
washThe combined organic layers were washed with water
dry with materialdried (MgSO4)
concentrationconcentrated under reduced pressure
customPurification by flash-chromatography (hexane:EtOAc 5:1

Sources & evidence

ORD record: ord-207d0fe0814648fca9284ceb1f02c7cd
Source dataset: uspto-grants-2011_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07871998B2

Reaction notes

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