(S)-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)acetic acid → (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),8,13,15,17,22-octaen-3-yl]acetic acid

HRID 921114Notes

Reaction equation

HRID 921114 reaction equation
[CH2:1]([O:4][C:5]1([CH3:46])[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]C=C)[CH3:32])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:36])[C:12]=2[C@H:37]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C:38]([OH:40])=[O:39])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]>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.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:42]([O:41][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]([CH3:46])([O:4][CH2:1][CH:2]=[CH:3][CH2:32][C@H:31]([CH3:33])[O:30][C:24]2[C:23]([CH2:22][O:21][CH2:20]3)=[CH:28][C:27]([F:29])=[CH:26][CH:25]=2)[CH2:6][CH2:7]1)[C:38]([OH:40])=[O:39])([CH3:43])([CH3:44])[CH3:45]

Participants

5

Reactant 1

HCID 118307075(S)-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)acetic acid

Product 1

HCID 118318799(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),8,13,15,17,22-octaen-3-yl]acetic acidYield 51.6%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 131734905(1,3-dimesitylimidazolidin-2-ylidene)(2-isopropoxybenzylidene)ruthenium(VI) chloride Hoveyda-Grubbs IICatalystHCID 111,2-DichloroethaneSolvent

Conditions

Temperature
90 °C

Procedure

To a solution of (S)-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)acetic acid (20 mg, 0.031 mmol) in DCE (75 mL) were added (1,3-dimesitylimidazolidin-2-ylidene)(2-isopropoxybenzylidene)ruthenium(VI) chloride/Hoveyda-Grubbs II (4.90 mg, 7.83 μmol) and copper(I) iodide (5.96 mg, 0.031 mmol) and the mixture was stirred at 90° C. After 3 h, the reaction was concentrated. The crude material was purified via preparative HPLC to afford (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),8,13,15,17,22-octaen-3-yl]acetic acid (9.8 mg, 0.016 mmol, 50.2% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.19-6.92 (m, 3H), 6.57-6.38 (m, 1H), 6.11-5.87 (m, 1H), 5.81-5.64 (m, 1H), 5.59-5.46 (m, 1H), 4.94-4.47 (m, 4H), 4.45-4.31 (m, 1H), 4.01-3.78 (m, 1H), 3.74-3.47 (m, 1H), 2.51 (br. s., 13H), 1.71-1.49 (m, 1H), 1.33-1.06 (m, 14H). LCMS (M+H) calcd for C33H44FN4O6: 611.32. found: 611.5.

Workup

  1. concentrationthe reaction was concentrated
  2. customThe crude material was purified via preparative HPLC

Sources & evidence

ORD record
ord-f85b2dfe2c2a4d7b8003a87035743e47
Source dataset
uspto-grants-2016_03
Patent number
US09273067B2

Reaction notes

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