Sodium hydride → (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

HRID 921113Notes

Reaction equation

HRID 921113 reaction equation
[CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20]I)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26]CC)=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[F:35][C:36]1[CH:37]=[CH:38][C:39]([O:44][C@H:45]([CH2:47][CH:48]=[CH2:49])[CH3:46])=[C:40]([CH2:42][OH:43])[CH:41]=1.[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:4][C:5]1([CH3:34])[CH2:6][CH2:7][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][O:43][CH2:42][C:40]4[CH:41]=[C:36]([F:35])[CH:37]=[CH:38][C:39]=4[O:44][C@H:45]([CH2:47][CH:48]=[CH2:49])[CH3:46])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[C:24]([OH:26])=[O:25])[CH2:9][CH2:10]1)[CH:2]=[CH2:3]

Participants

6

Reactant 3

HCID 24758Sodium hydrideHCID 118307030(S)-(5-fluoro-2-(pent-4-en-2-yloxy)phenyl)methanolHCID 118318796(S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate

Product 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 acidYield 36.6%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.05 g, 0.086 mmol) and (S)-(5-fluoro-2-(pent-4-en-2-yloxy)phenyl)methanol (0.022 g, 0.103 mmol) in DMF (1 ml) was added sodium hydride (5.13 mg, 0.128 mmol) and the resulting yellow mixture was stirred at rt. After 5 h, the mixture was diluted with EtOAc and washed with 1N HCl followed by water and brine. The organic phase was dried (Na2SO4), filtered and concentrated. The oil was purified by flash chromatography (Biotage; 0%-10% MeOH/DCM; 10 CV) to give (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, 36.6% yield) was obtained as an amber oil. 1H NMR (400 MHz, CDCl3) δ 7.22 (dd, J=9.0, 2.9 Hz, 1H), 6.89 (dd, J=8.1, 3.2 Hz, 1H), 6.84-6.75 (m, 1H), 6.60 (s, 1H), 6.10-5.95 (m, 1H), 5.89-5.75 (m, 1H), 5.52-5.38 (m, 1H), 5.23-4.99 (m, 4H), 4.80 (s, 2H), 4.66 (s, 2H), 4.45-4.28 (m, 1H), 4.06-3.93 (m, 2H), 2.71-2.54 (m, 3H), 2.47 (d, J=5.9 Hz, 1H), 2.40-2.30 (m, 1H), 2.08-1.56 (m, 4H), 1.49-1.01 (m, 15H). LCMS (M+H) calcd for C35H48FN4O6: 639.35. found: 639.2.

Workup

  1. washwashed with 1N HCl
  2. dry with materialThe organic phase was dried (Na2SO4)
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customThe oil was purified by flash chromatography (Biotage; 0%-10% MeOH/DCM; 10 CV)

Sources & evidence

ORD record
ord-0b72ff2212ea4588b3d998a8ab6fdbdb
Source dataset
uspto-grants-2016_03
Patent number
US09273067B2

Reaction notes

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