Methanol → (2S)-2-(tert-Butoxy)-2-{15-fluoro-4,26-dimethyl-10-oxo-19,25-dioxa-1,7,11,31-tetraazapentacyclo[24.2.2.16,9.02,7.013,18]hentriaconta-2,4,6(31),8,13(18),14,16-heptaen-3-yl}acetic acid

HRID 1481984Notes

Reaction equation

HRID 1481984 reaction equation
[C:1]([O:5][C@@H:6]([C:11]1[C:38]([CH3:39])=[CH:37][C:36]2=[N:40][C:33]3=[CH:34][N:35]2[C:12]=1[N:13]1[CH2:44][CH2:43][C:16]([CH3:45])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:25]=[CH:26][C:27]([F:42])=[CH:28][C:29]=2[CH2:30][NH:31][C:32]3=[O:41])[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:38]([CH3:39])=[CH:37][C:36]2=[N:40][C:33]3=[CH:34][N:35]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:45])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:25]=[CH:26][C:27]([F:42])=[CH:28][C:29]=2[CH2:30][NH:31][C:32]3=[O:41])[CH2:43][CH2:44]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]

Participants

5

Reactant 3

HCID 887MethanolHCID 168937Lithium hydroxide, monohydrateHCID 118316265Methyl(2S)-2-(tert-butoxy)-2-{15-fluoro-4,26-dimethyl-10-oxo-19,25-dioxa-1,7,11,31-tetraazapentacyclo[24.2.2.16,9.02,7.013,18]hentriaconta-2,4,6(31),8,13(18),14,16-heptaen-3-yl}acetate

Product 1

HCID 118316266(2S)-2-(tert-Butoxy)-2-{15-fluoro-4,26-dimethyl-10-oxo-19,25-dioxa-1,7,11,31-tetraazapentacyclo[24.2.2.16,9.02,7.013,18]hentriaconta-2,4,6(31),8,13(18),14,16-heptaen-3-yl}acetic acidYield 47.7%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of methyl(2S)-2-(tert-butoxy)-2-{15-fluoro-4,26-dimethyl-10-oxo-19,25-dioxa-1,7,11,31-tetraazapentacyclo[24.2.2.16,9.02,7.013,18]hentriaconta-2,4,6(31),8,13(18),14,16-heptaen-3-yl}acetate (22 mg, 0.035 mmol, 1 equiv) in 9:1 MeOH:water (1 mL) was added LiOH.H2O (44 mg, 1.06 mmol, 30 equiv). The reaction was heated to 60° 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×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: 20-60% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to provide the product (10.2 mg, 46%). 1H NMR (500 MHz, DMSO-d6) δ 8.72-8.62 (m, 1H), 8.01 (s, 1H), 7.29-7.18 (m, 2H), 7.05 (dd, J=8.4, 2.9 Hz, 1H), 6.97 (dd, J=8.7, 4.4 Hz, 1H), 5.91 (br. s., 1H), 4.31 (br. s., 2H), 4.08-3.95 (m, 2H), 3.86-3.79 (m, 2H), 3.50-3.40 (m, J=5.2 Hz, 2H), 2.95 (d, J=7.9 Hz, 1H), 2.60 (d, J=7.6 Hz, 1H), 2.38 (s, 3H), 1.89-1.60 (m, 10H), 1.21 (s, 3H), 1.17 (s, 9H); LCMS (ESI, M+1): 611.5. —OH

Workup

  1. temperatureUpon cooling to ambient temperature
  2. filtrationthe reaction was filtered
  3. custompurified via preparative LC/MS with the following conditions
  4. customa 5-minute hold

Sources & evidence

ORD record
ord-40947716d46f4335b914a7ca21ea6256
Source dataset
uspto-grants-2016_08
Patent number
US09409922B2

Reaction notes

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