(S)-2-((tert-butoxycarbonyl)amino)-3,3-bis(4-fluorophenyl)propanoic acid → tert-butyl (2S,5S)-2-[(2-{[N-(tert-butoxycarbonyl)-4-fluoro-beta-(4-fluorophenyl)-L-phenylalanyl]amino}-6-fluorophenoxy)methyl]-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)morpholine-4-carboxylate

HRID 629745Notes

Reaction equation

O(Cl)Cl.[P+5].[NH2:5][C:6]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:7]=1[O:8][CH2:9][C@H:10]1[O:15][CH2:14][C@@H:13]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[N:12]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:11]1.[C:37]([O:41][C:42]([NH:44][C@H:45]([C:61](O)=[O:62])[CH:46]([C:54]1[CH:59]=[CH:58][C:57]([F:60])=[CH:56][CH:55]=1)[C:47]1[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=1)=[O:43])([CH3:40])([CH3:39])[CH3:38]>N1C=CC=CC=1>[C:37]([O:41][C:42]([NH:44][C@H:45]([C:61]([NH:5][C:6]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:7]=1[O:8][CH2:9][C@H:10]1[O:15][CH2:14][C@@H:13]([CH2:16][O:17][Si:18]([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:20])[CH3:19])[N:12]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:11]1)=[O:62])[CH:46]([C:54]1[CH:59]=[CH:58][C:57]([F:60])=[CH:56][CH:55]=1)[C:47]1[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=1)=[O:43])([CH3:39])([CH3:40])[CH3:38]

Participants

Conditions

Temperature: 0 °C

Procedure

Phosphorus (V) oxychloride (118 μl, 1.262 mmol) was added to a solution of tert-butyl (2S,5S)-2-[(2-amino-6-fluorophenoxy)methyl]-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)morpholine-4-carboxylate (540 mg, 1.147 mmol) and N-(tert-butoxycarbonyl)-4-fluoro-β-(4-fluorophenyl)-L-phenylalanine (433 mg, 1.147 mmol) in pyridine (5.74 mL) at −15° C. The reaction was stirred for 30 minutes then warmed to 0° C. and stirred for another 1.5 hours. LC/MS at this time only shows pyridine and desired product. The reaction was quenched with a saturated aqueous solution of KH2PO4 and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic fractions were dried over MgSO4, filtered and the solvent was evaporated under reduced pressure to afford the title compound (977 mg, 1.106 mmol, 96% yield) as an off-white foam, MS (ESI): m/z=730.51 (M+H-boc). 94% pure by LC/MS. The material was taken on crude to the next step.

Workup

stirringstirred for another 1.5 hours

Sources & evidence

ORD record: ord-a24fa33fce5b446ea61dd838153155f4
Source dataset: uspto-grants-2016_04
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09315475B2

Reaction notes

Loading…