(S)-2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-5-methyl-2-(((5-methyl-2-((S)-pent-4-en-2-yloxy)benzyl)oxy)methyl)pyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetic acid → (2S)-2-(tert-butoxy)-2-[(20S)-4,15,20,26-tetramethyl-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 921122Notes

Reaction equation

HRID 921122 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]([CH3:29])[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:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C:38]([OH:40])=[O:39])[CH2:7][CH2:6]1)C=C>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:35]=[CH:34][CH2:33][C@H:31]([CH3:32])[O:30][C:24]2[C:23]([CH2:22][O:21][CH2:20]3)=[CH:28][C:27]([CH3:29])=[CH:26][CH:25]=2)[CH2:10][CH2:9]1)[C:38]([OH:40])=[O:39])([CH3:43])([CH3:45])[CH3:44]

Participants

5

Reactant 1

HCID 118307085(S)-2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-5-methyl-2-(((5-methyl-2-((S)-pent-4-en-2-yloxy)benzyl)oxy)methyl)pyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetic acid

Product 1

HCID 123933559(2S)-2-(tert-butoxy)-2-[(20S)-4,15,20,26-tetramethyl-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 6.7%

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)-5-methyl-2-(((5-methyl-2-((S)-pent-4-en-2-yloxy)benzyl)oxy)methyl)pyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetic acid (32.7 mg, 0.052 mmol) in DCE (4 mL) were added Hoveyda-Grubbs catalyst 2nd generation (8.07 mg, 0.013 mmol) and copper(I) iodide (9.81 mg, 0.052 mmol) and the mixture was stirred at 90° C. After 3 h, the mixture was cooled to rt and concentrated. The crude material was purified via preparative HPLC to give (2S)-2-(tert-butoxy)-2-[(20S)-4,15,20,26-tetramethyl-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 (2.1 mg, 5.64% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.10 (s, 1H), 7.03 (d, J=6.6 Hz, 1H), 6.88 (d, J=8.4 Hz, 1H), 6.52 (s, 1H), 6.08-5.93 (m, 1H), 5.78 (s, 1H), 5.75-5.67 (m, 1H), 4.82 (d, J=12.1 Hz, 1H), 4.71-4.56 (m, 4H), 4.56-4.39 (m, 2H), 4.01-3.79 (m, 2H), 3.73 (t, J=11.2 Hz, 1H), 3.35 (br. s., 1H), 3.17 (br. s., 1H), 2.74-2.59 (m, 1H), 2.45-2.31 (m, 2H), 2.29-2.14 (m, 5H), 1.89 (t, J=12.5 Hz, 2H), 1.68 (td, J=12.8, 4.0 Hz, 1H), 1.56 (td, J=13.0, 4.4 Hz, 1H), 1.26-1.19 (m, 6H), 1.19-1.01 (m, 9H). LCMS (M+H) calcd for C14H20FN3O4S: 607.35. found: 607.4.

Workup

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

Sources & evidence

ORD record
ord-51bb4b6cc074493f9f43b8bd07252d96
Source dataset
uspto-grants-2016_03
Patent number
US09273067B2

Reaction notes

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