1-Butanol → Methyl(2S)-2-[(22S)-5-bromo-17-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]-2-(tert-butoxy)acetate

HRID 1482057Notes

Reaction equation

HRID 1482057 reaction equation
[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([Br:42])[C:38]2=[N:43][C:35]3=[C:36](Br)[N:37]2[C:12]=1[N:13]1[CH2:49][CH2:48][C:16]([CH3:50])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:47])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:46])=[CH:28][C:29]=2[C:30]2[CH:45]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.CCCCO.C([O-])([O-])=O.[Cs+].[Cs+]>CC([O-])=O.CC([O-])=O.[Pd+2].O.CN(C=O)C>[Br:42][C:39]1[C:38]2=[N:43][C:35]3=[CH:36][N:37]2[C:12]([N:13]2[CH2:14][CH2:15][C:16]([CH3:50])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:47])[O:23][C:24]4[CH:25]=[CH:26][C:27]([F:46])=[CH:28][C:29]=4[C:30]4[CH:45]=[C:34]3[CH:33]=[CH:32][CH:31]=4)[CH2:48][CH2:49]2)=[C:11]([C@H:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:7]([O:9][CH3:10])=[O:8])[C:40]=1[CH3:41]

Participants

8

Reactant 4

HCID 2631-ButanolHCID 10796Cesium carbonateHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 118316310Methyl(2S)-2-(tert-butoxy)-2-[(22S)-5,8-dibromo-17-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

Product 1

HCID 118316311Methyl(2S)-2-[(22S)-5-bromo-17-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]-2-(tert-butoxy)acetateYield 47%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalyst2×HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
85 °C

Procedure

A solution of methyl(2S)-2-(tert-butoxy)-2-[(22S)-5,8-dibromo-17-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 (150 mg, 0.184 mmol, 1 equiv), SPhos (15 mg, 0.037 mmol, 0.2 equiv), Pd(OAc)2 (8 mg, 0.037 mmol, 0.2 equiv), n-BuOH (0.055 mL, 0.74 mmol, 4 equiv), and Cs2CO3 (90 mg, 0.276 mmol, 1.5 equiv) in 10:1 DMF:water (3.6 mL) was heated to 80° C. for 2 h. More Pd(OAc)2 (41 mg) was added and the reaction was stirred for 3 h. The reaction was then removed from heat and stirred at ambient temperature for 4 d. More Pd(OAc)2 (10 mg) was heated to 85° C. for 5 h. The reaction was then removed from heat. Upon cooling to ambient temperature, the reaction was diluted with EtOAc and washed with water. The EtOAc was dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash column chromatography (0-100% EtOAc [2% TEA]/hexane) to provide the product (63 mg, 47%). 1H NMR (400 MHz, CDCl3) δ 8.33 (d, J=8.0 Hz, 1H), 8.11 (d, J=6.8 Hz, 2H), 7.54 (t, J=7.7 Hz, 1H), 7.31 (d, J=7.8 Hz, 1H), 7.11 (dd, J=9.0, 3.0 Hz, 1H), 7.03-6.90 (m, 2H), 6.15 (br. s., 1H), 4.47 (d, J=6.3 Hz, 1H), 3.95 (t, J=11.2 Hz, 1H), 3.80-3.66 (m, 5H), 3.57-3.42 (m, 2H), 3.09 (d, J=11.3 Hz, 1H), 2.71 (d, J=11.8 Hz, 1H), 2.57 (s, 3H), 2.01-1.66 (m, 10H), 1.28 (s, 3H), 1.24 (s, 9H), 1.11 (d, J=6.0 Hz, 3H). LCMS (ESI, M+1): 736.20.

Workup

  1. customThe reaction was then removed
  2. temperaturefrom heat
  3. stirringstirred at ambient temperature for 4 d
  4. customThe reaction was then removed
  5. temperaturefrom heat
  6. temperatureUpon cooling to ambient temperature
  7. additionthe reaction was diluted with EtOAc
  8. washwashed with water
  9. dry with materialThe EtOAc was dried (Na2SO4)
  10. concentrationconcentrated in vacuo
  11. customThe crude product was purified by flash column chromatography (0-100% EtOAc [2% TEA]/hexane)

Sources & evidence

ORD record
ord-371a27b1c053473786d68b1c6a573852
Source dataset
uspto-grants-2016_08
Patent number
US09409922B2

Reaction notes

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