Diisopropylethylamine → (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-((4-(2-(hydroxymethyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate

HRID 921079Notes

Reaction equation

HRID 921079 reaction equation
[CH2:1]([O:4][C:5]1([CH3:36])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:21]=[N+:22]=[N-:23])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:24])[C:12]=2[C@H:25]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[CH2:45][OH:46])#[CH:38].CCN(C(C)C)C(C)C>C1COCC1.CCOCC.[Cu]I>[CH2:1]([O:4][C:5]1([CH3:36])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:21]4[CH:38]=[C:37]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=5[CH2:45][OH:46])[N:23]=[N:22]4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:24])[C:12]=2[C@H:25]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]

Participants

7

Reactant 3

HCID 81531DiisopropylethylamineHCID 11007947(2-Ethynylphenyl)methanolHCID 118318736HCID 118318736, compound

Product 1

HCID 118318749(S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-((4-(2-(hydroxymethyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetateYield 43.6%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a stirred clear solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(azidomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.0946 g, 0.189 mmol), (2-ethynylphenyl)methanol (0.125 g, 0.947 mmol) and DIEA (0.165 ml, 0.947 mmol) in THF (5 mL) was added CuI (0.072 g, 0.379 mmol) at rt. After 48 h, the reaction mixture was diluted with Et2O (50 mL), washed with 1% NH4OH (2×10 mL), brine (10 mL), dried (MgSO4), filtered and concentrated to give yellow solid which was purified by prep-HPLC to afford (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-((4-(2-(hydroxymethyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.0521 g, 0.082 mmol, 43.6% yield) as off-white solid. 1H NMR (500 MHz, CDCl3) δ 8.02 (s, 1H), 7.51-7.55 (m, 1H), 7.45-7.49 (m, 1H), 7.33-7.38 (m, 2H), 6.54 (s, 1H), 5.96-6.05 (m, 1H), 5.89 (br. s., 1H), 5.82 (s, 2H), 5.45 (d, J=16.87 Hz, 1H), 5.26-5.38 (m, 1H), 5.18 (qd, J=1.58, 10.40 Hz, 1H), 4.64 (s, 2H), 4.13-4.28 (m, 2H), 4.00 (d, J=5.2 Hz, 2H), 2.62 (s, 3H), 1.83-2.04 (m, 3H), 1.65-1.73 (m, 1H), 1.31 (s, 3H), 1.22-1.26 (m, 12H). LCMS (M+H)=632.7.

Workup

  1. washwashed with 1% NH4OH (2×10 mL), brine (10 mL)
  2. dry with materialdried (MgSO4)
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customto give yellow solid which
  6. customwas purified by prep-HPLC

Sources & evidence

ORD record
ord-6ee4d37258404dca8f84cc1695b44a19
Source dataset
uspto-grants-2016_03
Patent number
US09273067B2

Reaction notes

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