Sodium Hydroxide → (S,E)-2-(tert-butoxy)-2-(2-((4-fluoro-3-methylbenzyl)carbamoyl)-5-methyl-7-(4-methylpent-1-en-1-yl)pyrazolo[1,5-a]pyrimidin-6-yl)acetic acid

HRID 1630326Notes

Reaction equation

HRID 1630326 reaction equation
[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:30])=[N:14][C:15]2[N:16]([N:24]=[C:25]([C:27]([OH:29])=O)[CH:26]=2)[C:17]=1/[CH:18]=[CH:19]/[CH2:20][CH:21]([CH3:23])[CH3:22])[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][NH2:39])=[CH:34][C:33]=1[CH3:40].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH-].[Na+]>CN(C=O)C.CN(C1C=CN=CC=1)C.CO.O>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:30])=[N:14][C:15]2[N:16]([N:24]=[C:25]([C:27](=[O:29])[NH:39][CH2:38][C:35]3[CH:36]=[CH:37][C:32]([F:31])=[C:33]([CH3:40])[CH:34]=3)[CH:26]=2)[C:17]=1/[CH:18]=[CH:19]/[CH2:20][CH:21]([CH3:22])[CH3:23])[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]

Participants

10

Reactant 5

HCID 14798Sodium HydroxideHCID 81531DiisopropylethylamineHCID 2774599(4-Fluoro-3-methylphenyl)methanamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 71259118(S,E)-6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-5-methyl-7-(4-methylpent-1-en-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid

Product 1

HCID 71258168(S,E)-2-(tert-butoxy)-2-(2-((4-fluoro-3-methylbenzyl)carbamoyl)-5-methyl-7-(4-methylpent-1-en-1-yl)pyrazolo[1,5-a]pyrimidin-6-yl)acetic acidYield 31.9%

Reagents, catalysts & solvents 4

HCID 142844-(Dimethylamino)pyridineCatalystHCID 887MethanolSolventHCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

To a mixture of (S,E)-6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-5-methyl-7-(4-methylpent-1-en-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (30 mg, 0.072 mmol) and (4-fluoro-3-methylphenyl)methanamine (20.00 mg, 0.144 mmol) in DMF (1.5 mL) was added DIEA (0.063 mL, 0.359 mmol), HATU (54.6 mg, 0.144 mmol) and DMAP (1.756 mg, 0.014 mmol) and the resulting mixture was stirred at room temp for 16 h. At this point LCMS indicated completion of reaction. Water was then added and the mixture was extracted with ether (25 mL), washed with brine (15 mL), dried (Na2SO4), filtered and concentrated. Crude was then treated with 1N NaOH (0.216 mL, 0.216 mmol) in MeOH (1.500 mL) at 60° C. for 5 h. Mixture was then cooled and purified by prep-HPLC to afford (S,E)-2-(tert-butoxy)-2-(2-((4-fluoro-3-methylbenzyl)carbamoyl)-5-methyl-7-(4-methylpent-1-en-1-yl)pyrazolo[1,5-a]pyrimidin-6-yl)acetic acid (12.2 mg, 0.023 mmol, 31.6% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.91 (t, J=6.4 Hz, 1H), 7.25 (d, J=7.3 Hz, 1.5H), 7.22-7.17 (m, 1.5H), 7.12-7.00 (m, 2H), 6.93 (s, 1H), 5.34 (br. s., 1H), 4.46 (t, J=5.6 Hz, 2H), 2.63 (s, 3H), 2.34 (t, J=6.3 Hz, 2H), 2.22 (s, 3H), 1.88-1.77 (m, 1H), 1.08 (s, 9H), 1.00 (dd, J=6.7, 2.4 Hz, 6H). LCMS (M+H)=511.33.

Workup

  1. customcompletion of reaction
  2. extractionthe mixture was extracted with ether (25 mL)
  3. washwashed with brine (15 mL)
  4. dry with materialdried (Na2SO4)
  5. filtrationfiltered
  6. concentrationconcentrated
  7. temperatureMixture was then cooled
  8. custompurified by prep-HPLC

Sources & evidence

ORD record
ord-50616c4214234eda879f61ff472e53e1
Source dataset
uspto-grants-2014_07
Patent number
US08791108B2

Reaction notes

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