Sodium hydride → ethyl (2S)-2-(tert-butoxy)-2-[(20S,22Z)-15,16-difluoro-4,20,26-trimethyl-11,19,25-trioxa-1,5,7,8-tetraazapentacyclo[24.2.2.16,9.02,7.013,18]hentriaconta-2,4,6(31),8,13(18),14,16,22-octaen-3-yl]acetate

HRID 921131Notes

Reaction equation

HRID 921131 reaction equation
[CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20]I)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[F:35][C:36]1[C:41]([F:42])=[CH:40][C:39]([CH2:43][OH:44])=[C:38]([O:45][C@H:46]([CH2:48]C=C)[CH3:47])[CH:37]=1.[H-].[Na+]>CN(C=O)C.CCOC(C)=O.ClCCCl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.[Cu]I>[C:30]([O:29][C@@H:23]([C:12]1[C:13]([CH3:22])=[N:14][C:15]2=[CH:19][C:18]3=[N:17][N:16]2[C:11]=1[N:8]1[CH2:9][CH2:10][C:5]([CH3:34])([O:4][CH2:1][CH:2]=[CH:3][CH2:47][C@H:46]([CH3:48])[O:45][C:38]2[CH:37]=[C:36]([F:35])[C:41]([F:42])=[CH:40][C:39]=2[CH2:43][O:44][CH2:20]3)[CH2:6][CH2:7]1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])([CH3:33])([CH3:32])[CH3:31]

Participants

9

Reactant 3

HCID 24758Sodium hydrideHCID 118307066(S)-(4,5-difluoro-2-(pent-4-en-2-yloxy)phenyl)methanolHCID 118318796(S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate

Product 1

HCID 118318807ethyl (2S)-2-(tert-butoxy)-2-[(20S,22Z)-15,16-difluoro-4,20,26-trimethyl-11,19,25-trioxa-1,5,7,8-tetraazapentacyclo[24.2.2.16,9.02,7.013,18]hentriaconta-2,4,6(31),8,13(18),14,16,22-octaen-3-yl]acetateYield 27%

Reagents, catalysts & solvents 5

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 11763533(1,3-Bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene)(dichloro)((2-((propan-2-yl)oxy)phenyl)methylidene)rutheniumCatalystHCID 111,2-DichloroethaneSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.10 g, 0.171 mmol) and (S)-(4,5-difluoro-2-(pent-4-en-2-yloxy)phenyl)methanol (0.047 g, 0.205 mmol) in DMF (2 mL) was added sodium hydride (10.26 mg, 0.257 mmol) and the mixture was stirred at rt. After stirring for 4 h, the mixture was diluted with EtOAc and washed with 1N HCl followed by water and brine. The organic phase was dried (Na2SO4), filtered and concentrated. The amber oil was purified by flash chromatography (Biotage; 10% MeOH/DCM; 10 CV). The resulting impure amber oil (11.4 mg, 0.017 mmol) was taken up in DCE (4 mL). Hoveyda-Grubbs catalyst 2nd generation (2.72 mg, 4.34 μmol) then copper(I) iodide (3.31 mg, 0.017 mmol) were added and the mixture was stirred at 90° C. After 3 h, the mixture was cooled to rt and filtered and concentrated. The residue was purified by prep HPLC to give ethyl (2S)-2-(tert-butoxy)-2-[(20S,22Z)-15,16-difluoro-4,20,26-trimethyl-11,19,25-trioxa-1,5,7,8-tetraazapentacyclo[24.2.2.16,9.02,7.013,18]hentriaconta-2,4,6(31),8,13(18),14,16,22-octaen-3-yl]acetate (3.0 mg, 4.57 μmol, 27% yield). LCMS (M+H) calcd for C35H47F2N4O6: 657.34. found: 657.5.

Workup

  1. stirringAfter stirring for 4 h
  2. washwashed with 1N HCl
  3. dry with materialThe organic phase was dried (Na2SO4)
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe amber oil was purified by flash chromatography (Biotage; 10% MeOH/DCM; 10 CV)
  7. stirringthe mixture was stirred at 90° C
  8. temperaturethe mixture was cooled to rt
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customThe residue was purified by prep HPLC

Sources & evidence

ORD record
ord-c1919ffc342b4c7d9547d9f1133da39f
Source dataset
uspto-grants-2016_03
Patent number
US09273067B2

Reaction notes

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