Tetrahydrofuran → (2S)-2-(tert-Butoxy)-2-[(22S)-4,17,22,28-tetramethyl-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]acetic acid

HRID 1482004Notes

Reaction equation

HRID 1482004 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][CH:19]=[CH:20][CH2:21][C@H:22]([CH3:45])[O:23][C:24]2[CH:25]=[C:26](F)[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].[CH2:49]1COCC1.O[Li].O>CO.[Pd]>[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]=[CH:26][C:27]([CH3:49])=[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]([OH:9])=[O:8])([CH3:3])([CH3:2])[CH3:4]

Participants

6

Reactant 3

HCID 8028TetrahydrofuranHCID 168937Lithium hydroxide, monohydrateHCID 123468036Methyl(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]acetate

Product 1

HCID 118316274(2S)-2-(tert-Butoxy)-2-[(22S)-4,17,22,28-tetramethyl-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]acetic acidYield 27%

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 887MethanolSolvent

Conditions

Temperature
60 °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),16,18,24-undecaen-3-yl]acetate (20 mg, 0.030 mmol, 1 equiv) in MeOH (2 mL) was added 10% Pd/C (6 mg, 0.006 mmol, 0.2 equiv). The reaction was then stirred under a balloon of H2 for 2 h. The reaction was then filtered through Celite eluting with MeOH. The filtrate was then concentrated in vacuo. The crude hydrogenation product was taken upon in MeOH (1.5 mL), water (1 mL0, and THF (0.5 mL) and LiOH.H2O (37 mg, 0.913 mmol, 30 equiv) was added. The reaction was heated to 60° C. for 2 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: 50-90% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to provide the product (5.2 mg, 27%). 1H NMR (500 MHz, DMSO-d6) δ 8.07 (br. s., 2H), 7.97 (s, 1H), 7.50 (t, J=7.8 Hz, 1H), 7.35 (t, J=7.6 Hz, 1H), 7.29-7.21 (m, 2H), 7.08 (d, J=11.0 Hz, 1H), 6.83 (t, J=8.1 Hz, 1H), 5.79 (br. s., 1H), 4.70 (br. s., 1H), 3.82 (t, J=11.3 Hz, 1H), 2.63 (d, J=8.2 Hz, 1H), 2.39 (s, 3H), 1.94-1.57 (m, 12H), 1.52 (br. s., 1H), 1.19 (s, 3H), 1.15 (s, 9H), 1.12 (d, J=5.8 Hz, 3H); LCMS (ESI, M+1): 644.35.

Workup

  1. filtrationThe reaction was then filtered through Celite
  2. washeluting with MeOH
  3. concentrationThe filtrate was then concentrated in vacuo
  4. additionwas added
  5. temperatureUpon cooling to ambient temperature
  6. filtrationthe reaction was filtered
  7. custompurified via preparative LC/MS with the following conditions
  8. waitGradient: 50-90% B over 15 minutes
  9. customa 5-minute hold

Sources & evidence

ORD record
ord-55cd611a2adc4b9db0dd20754c152232
Source dataset
uspto-grants-2016_08
Patent number
US09409922B2

Reaction notes

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