(S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(((5-fluoro-2-((S)-pent-4-en-2-yloxy)benzyl)oxy)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate → ethyl (2S)-2-(tert-butoxy)-2-[(20S,22Z)-15-fluoro-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 921116Notes

Reaction equation

HRID 921116 reaction equation
[CH2:1]([O:4][C:5]1([CH3:48])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][O:21][CH2:22][C:23]4[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=4[O:30][C@H:31]([CH2:33][CH:34]=[CH2:35])[CH3:32])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:36])[C:12]=2[C@H:37]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:7][CH2:6]1)C=C>ClCCCl.C1(C)C=C(C)C=C(C)C=1N1CCN(C2C(C)=CC(C)=CC=2C)C1=[Ru](Cl)(Cl)=CC1C=CC=CC=1OC(C)C.[Cu]I>[C:44]([O:43][C@@H:37]([C:12]1[C:13]([CH3:36])=[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]([CH3:48])([O:4][CH2:1][CH:35]=[CH:34][CH2:33][C@H:31]([CH3:32])[O:30][C:24]2[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:23]=2[CH2:22][O:21][CH2:20]3)[CH2:6][CH2:7]1)[C:38]([O:40][CH2:41][CH3:42])=[O:39])([CH3:46])([CH3:47])[CH3:45]

Participants

5

Reactant 1

HCID 118318797(S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(((5-fluoro-2-((S)-pent-4-en-2-yloxy)benzyl)oxy)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate

Product 1

HCID 118318798ethyl (2S)-2-(tert-butoxy)-2-[(20S,22Z)-15-fluoro-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 32.5%

Reagents, catalysts & solvents 3

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-DichloroethaneSolvent

Conditions

Temperature
90 °C

Procedure

To a solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(((5-fluoro-2-((S)-pent-4-en-2-yloxy)benzyl)oxy)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.1481 g, 0.222 mmol) in DCE (500 mL) were added (1,3-dimesitylimidazolidin-2-ylidene)(2-isopropoxybenzylidene)ruthenium(VI) chloride (0.035 g, 0.056 mmol) and copper(I) iodide (0.042 g, 0.222 mmol) and the resulting solution was stirred at 90° C. for 3 h. The mixture was cooled to rt and concentrated. The residue was purified by flash chromatography (Biotage; 0%-100% EtOAc/hexane; 20 CV) to give ethyl (2S)-2-(tert-butoxy)-2-[(20S,22Z)-15-fluoro-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: (0.0461 g, 0.072 mmol, 32.5% yield) as a pale brown foam. LCMS (M+H) calcd for C35H48FN4O6: 639.35. found: 639.5.

Workup

  1. temperatureThe mixture was cooled to rt
  2. concentrationconcentrated
  3. customThe residue was purified by flash chromatography (Biotage; 0%-100% EtOAc/hexane; 20 CV)

Sources & evidence

ORD record
ord-6d4e4fdd787e4a6785d86d774a72e6b5
Source dataset
uspto-grants-2016_03
Patent number
US09273067B2

Reaction notes

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