(S)-2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(((4-chloro-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)-16-chloro-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 921134Notes

Reaction equation

HRID 921134 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]=[CH:27][C:26]([Cl:29])=[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.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[CH2:7][CH2:6][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][CH:27]=[C:26]([Cl:29])[CH:25]=2)[CH2:10][CH2:9]1)[C:38]([OH:40])=[O:39])([CH3:45])([CH3:44])[CH3:43]

Participants

5

Reactant 1

HCID 118307039(S)-2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(((4-chloro-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 123765054(2S)-2-(tert-butoxy)-2-[(20S)-16-chloro-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 7.32%

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)-2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(((4-chloro-2-((S)-pent-4-en-2-yloxy)benzyl)oxy)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetic acid (41.4 mg, 0.063 mmol) in DCE (2 mL) were added Hoveyda-Grubbs catalyst 2nd generation (9.90 mg, 0.016 mmol) and copper(I) iodide (12.03 mg, 0.063 mmol) and the mixture was stirred at 90° C. After 1.5 h, the mixture was cooled to rt and filtered and concentrated. The crude material was purified via preparative HPLC to afford (2S)-2-(tert-butoxy)-2-[(20S)-16-chloro-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 (2.9 mg, 4.62 μmol, 7.32% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.31 (d, J=8.1 Hz, 1H), 7.10 (s, 1H), 6.94 (d, J=7.0 Hz, 1H), 6.48 (s, 1H), 6.34 (d, J=5.9 Hz, 1H), 5.65 (br. s., 1H), 4.75 (d, J=11.7 Hz, 1H), 4.67-4.47 (m, 5H), 4.34-4.22 (m, 1H), 3.64 (d, J=12.8 Hz, 1H), 3.39-3.27 (m, 6H), 2.49 (s, 3H), 2.41 (d, J=3.3 Hz, 1H), 2.27-2.15 (m, 1H), 1.82 (d, J=5.5 Hz, 3H), 1.68-1.55 (m, 1H), 1.32 (s, 3H), 1.20 (s, 12H). LCMS (M+H) calcd for C33H44ClN4O6: 627.29. found: 627.5.

Workup

  1. temperaturethe mixture was cooled to rt
  2. filtrationfiltered
  3. concentrationconcentrated
  4. customThe crude material was purified via preparative HPLC

Sources & evidence

ORD record
ord-436fc9ac250c468aada36b3bd250fed6
Source dataset
uspto-grants-2016_03
Patent number
US09273067B2

Reaction notes

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