Trifluoroacetic acid → 4-{4-[4-Fluoro-3-(1-methylpiperidin-4-yl)-phenyl-amino]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

HRID 2375914Notes

Reaction equation

HRID 2375914 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21](Cl)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][C:26]=1[CH:32]1[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+].C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C>CCOC(C)=O.CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:31][C:28]4[CH:29]=[CH:30][C:25]([F:24])=[C:26]([CH:32]5[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]5)[CH:27]=4)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

8

Reactant 5

HCID 6422Trifluoroacetic acidHCID 90495Di-tert-butyl dicarbonateHCID 516892Sodium BicarbonateHCID 58709797tert-butyl 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylateHCID 587100494-Fluoro-3-(1-methylpiperidin-4-yl)-phenylamine

Product 1

HCID 587099544-{4-[4-Fluoro-3-(1-methylpiperidin-4-yl)-phenyl-amino]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (167 mg, 0.500 mmol), 4-fluoro-3-(1-methylpiperidin-4-yl)-phenylamine (149 mg, 0.600 mmol), N,N-dimethylformamide (3 mL), and trifluoroacetic acid (385 μL, 5.18 mmol) in a sealed tube was heated at 100° C. for 15 h. The mixture was concentrated in vacuo, charged with sodium bicarbonate (504 mg, 6.00 mmol), di-tert-butyldicarbonate (120 mg, 0.550 mmol), and N,N-dimethylformamide (2 mL), and stirred at rt under N2 for 24 h. After that time, the mixture was filtered, and the filtrate was concentrated in vacuo to obtain a brown oil, which was dissolved in EtOAc (30 mL) and washed with water (3×20 mL). The organic phase was concentrated in vacuo to obtain a light-brown oil that was purified by HPLC to give the title compound. 1H NMR (CD3OD, 400 MHz): δ=1.51 (s, 9H), 1.87 (brs, 4H), 2.13-2.20 (m, 2H), 2.32 (s, 3H), 2.54 (brs, 2H), 2.83-2.91 (m, 1H), 2.99-3.01 (m, 2H), 3.65 (brs, 2H), 4.12 (brs, 2H), 6.27 (brs, 1H), 6.56 (s, 1H), 7.03 (t, 1H, J=8.8 Hz), 7.57-7.60 (m, 2H), 8.19 (s, 1H). MS (ES+): m/z 507.17 (75) [MH+]. HPLC: tR=2.16 min (ZQ2000, polar—5 min).

Workup

  1. concentrationThe mixture was concentrated in vacuo
  2. filtrationAfter that time, the mixture was filtered
  3. concentrationthe filtrate was concentrated in vacuo
  4. customto obtain a brown oil, which
  5. washwashed with water (3×20 mL)
  6. concentrationThe organic phase was concentrated in vacuo
  7. customto obtain a light-brown oil that
  8. customwas purified by HPLC

Sources & evidence

ORD record
ord-fe2565beb70d4e7786cc0f5b29a4d6ad
Source dataset
uspto-grants-2008_12
Patent number
US07465726B2

Reaction notes

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