Methanol → (2S)-2-(tert-Butoxy)-2-[(22S)-18-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18,24-undecaen-3-yl]acetic acid

HRID 1482003Notes

Reaction equation

[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:47][CH2:46][C:16]([CH3:48])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:45])[O:23][C:24]2[CH:25]=[C:26]([F:44])[CH:27]=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].CO.O[Li].O>O>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:48])([O:17][CH2:18][CH:19]=[CH:20][CH2:21][C@H:22]([CH3:45])[O:23][C:24]2[CH:25]=[C:26]([F:44])[CH:27]=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:46][CH2:47]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]

Participants

Conditions

Temperature: 70 °C

Procedure

To a solution of methyl(2S)-2-(tert-butoxy)-2-[(22S)-18-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate (11 mg, 0.017 mmol, 1 equiv) in 9:1 MeOH:water (1.1 mL) was added LiOH.H2O (28 mg, 0.671 mmol, 40 equiv). The reaction was heated to 70° C. for 1 h. Upon cooling to ambient temperature, the reaction was filtered and purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 45-85% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Product isolated (7.2 mg, 77%). 1H NMR (500 MHz, DMSO-d6) δ 7.84 (d, J=7.6 Hz, 1H), 7.76 (d, J=6.1 Hz, 2H), 7.28 (t, J=7.6 Hz, 1H), 7.11 (t, J=7.6 Hz, 1H), 7.06 (s, 1H), 7.03 (d, J=7.3 Hz, 1H), 6.89 (d, J=11.6 Hz, 1H), 6.62 (t, J=8.1 Hz, 1H), 5.90-5.80 (m, 1H), 5.68 (br. s., 1H), 5.54 (d, J=15.6 Hz, 1H), 4.44 (br. s., 1H), 3.80-3.65 (m, 3H), 3.39 (d, J=11.3 Hz, 1H), 2.87 (d, J=8.5 Hz, 1H), 2.37 (d, J=8.2 Hz, 1H), 2.33-2.29 (m, 1H), 2.28 (br. s., 3H), 2.08-1.98 (m, 1H), 1.76-1.58 (m, 2H), 1.52-1.40 (m, 2H), 1.01 (s, 3H), 0.94 (s, 9H), 0.83 (d, J=5.8 Hz, 3H); LCMS (ESI, M+1): 642.5.

Workup

temperatureUpon cooling to ambient temperature
filtrationthe reaction was filtered
custompurified via preparative LC/MS with the following conditions
customa 5-minute hold
customProduct isolated (7.2 mg, 77%)

Sources & evidence

ORD record: ord-f970d5352d084536a36ae5e0ff56e140
Source dataset: uspto-grants-2016_08
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09409922B2

Reaction notes

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