Sodium Hydroxide → (S)-2-(tert-butoxy)-2-(7-(4,4-dimethylpiperidin-1-yl)-2-((4-fluoro-3-methylbenzyl)carbamoyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetic acid

HRID 1630330노트

반응식

HRID 1630330 반응식
[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:32])=[N:14][C:15]2[N:16]([N:26]=[C:27]([C:29](O)=[O:30])[CH:28]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][NH2:41])=[CH:36][C:35]=1[CH3:42].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]([CH3:32])=[N:14][C:15]2[N:16]([N:26]=[C:27]([C:29](=[O:30])[NH:41][CH2:40][C:37]3[CH:38]=[CH:39][C:34]([F:33])=[C:35]([CH3:42])[CH:36]=3)[CH:28]=2)[C:17]=1[N:18]1[CH2:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][CH2:23]1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:2])[CH3:4]

참가 물질

10

반응물 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 71259137(S)-6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(4,4-dimethylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylic acid

생성물 1

HCID 71259091(S)-2-(tert-butoxy)-2-(7-(4,4-dimethylpiperidin-1-yl)-2-((4-fluoro-3-methylbenzyl)carbamoyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetic acid수율 41.2%

시약·촉매·용매 4

HCID 142844-(Dimethylamino)pyridine촉매HCID 887Methanol용매HCID 962Water용매HCID 6228Dimethylformamide용매

실험 절차

To a mixture of (S)-6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(4,4-dimethylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylic acid (50 mg, 0.112 mmol) and (4-fluoro-3-methylphenyl)methanamine (31.2 mg, 0.224 mmol) in DMF (2 mL) was added DIEA (0.098 mL, 0.560 mmol), HATU (85 mg, 0.224 mmol) and DMAP (2.74 mg, 0.022 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 ethyl acetate (25 mL), washed with brine (15 mL), dried (Na2SO4), filtered and concentrated. Crude was then treated with 1N NaOH (0.336 mL, 0.336 mmol) in MeOH (2.000 mL) at 60° C. for 5 h. The mixture was then cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(7-(4,4-dimethylpiperidin-1-yl)-2-((4-fluoro-3-methylbenzyl)carbamoyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetic acid (26.2 mg, 0.046 mmol, 41.2% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.76 (t, J=6.3 Hz, 1H), 7.27 (d, J=7.6 Hz, 1H), 7.23-7.17 (m, 1H), 7.10 (t, J=9.0 Hz, 1H), 6.82 (s, 1H), 5.43 (s, 1H), 4.48 (d, J=6.1 Hz, 2H), 3.32-3.39 (m, 4H), 2.23 (s, 3H), 1.92 (s, 3H), 1.60 (br. s., 2H), 1.46 (br. s., 2H), 1.14 (s, 9H), 1.07 (br. s., 6H). LCMS (M+H)=540.5.

후처리

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

출처 및 근거

ORD 기록
ord-76ed01e1319d4214b2659a856ff6e402
출처 데이터셋
uspto-grants-2014_07
특허 번호
US08791108B2

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