Isopropanol → 4-[4-(3-Chloro-1H-indazol-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

HRID 2375854Notes

Reaction equation

HRID 2375854 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].[NH2:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][N:29]=[C:28]2[Cl:34].C(O)(C)C.ClC1C2C(=CC=C(NC3C4C=C(C5CCNCC=5)NC=4N=CN=3)C=2)NN=1.C(N(CC)C(C)C)(C)C.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C>>[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:24][C:25]4[CH:26]=[C:27]5[C:31](=[CH:32][CH:33]=4)[NH:30][N:29]=[C:28]5[Cl:34])[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

7

Reactant 6

HCID 3776IsopropanolHCID 81531DiisopropylethylamineHCID 90495Di-tert-butyl dicarbonateHCID 58709797tert-butyl 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylateHCID 178478422(3-chloro-1H-indazol-5-yl)-[6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amineHCID 178507360HCID 178507360, compound

Product 1

HCID 1784517324-[4-(3-Chloro-1H-indazol-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

Conditions

Temperature
90 °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 (49.6 mg, 0.148 mmol) and 5-amino-3-chloroindazole (26.5 mg, 0.155 mmol) in isopropyl alcohol (2.5 mL, 0.033 mol) in a sealed tube was heated to 90° C. (bath temp.) for 3.5 h. The bath temperature was increased to 105° C., and heating was continued overnight. The bath temperature was increased to 120° C., and heating was continued for 5 d. LC/MS at that time indicated loss of Boc group, i.e., (3-chloro-1H-indazol-5-yl)-[6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine, C18H16ClN7, MW=365.83. Solvents were evaporated. The reddish residue was suspended in N,N-dimethylformamide (3 mL). N,N-diisopropylethylamine (52 μL, 0.30 mmol) and di-tert-butyldicarbonate (33 mg, 0.15 mmol) were added, and the mixture was stirred at rt for 2 h. DMF was evaporated, water and CH2Cl2 were added, and the insoluble brown material was filtered off and washed with CH2Cl2 and water. The layers of the filtrate were separated; the organic layer was washed with water (2×) and brine and dried over MgSO4. The drying agent was filtered off, and the filtrate was concentrated, redissolved in MeOH, passed a through 0.45 μm filter, and purified by MDP. One obtained the title compound as light tan solid. MS (ES+): m/z 465.9/467.9 (100/38) [MH+]. HPLC: tR=2.7 min (ZQ2000, polar—5 min). 1H NMR (DMSO-d6, 400 MHz): δ=1.43 (s, 9H), 2.37-2.44 (brs, 2H), 3.51-3.58 (mc, 2H), 3.99-4.07 (m, 2H), 6.36 (s, 1H), 6.54 (s, 1H), 7.49 (d, J=8.8 Hz, 1H), 7.55 (d, J=8.8 Hz, 1H), 8.05 (s, 1H), 8.12 (s, 1H), 9.21 (s, 1H), 11.88 (brs, 1H), 13.43 (brs, 1H).

Workup

  1. temperatureThe bath temperature was increased to 105° C.
  2. temperatureheating
  3. temperatureThe bath temperature was increased to 120° C.
  4. temperatureheating
  5. waitwas continued for 5 d
  6. customSolvents were evaporated
  7. customDMF was evaporated
  8. additionwater and CH2Cl2 were added
  9. filtrationthe insoluble brown material was filtered off
  10. washwashed with CH2Cl2 and water
  11. customThe layers of the filtrate were separated
  12. washthe organic layer was washed with water (2×) and brine
  13. dry with materialdried over MgSO4
  14. filtrationThe drying agent was filtered off
  15. concentrationthe filtrate was concentrated
  16. dissolutionredissolved in MeOH
  17. filtrationfilter
  18. custompurified by MDP

Sources & evidence

ORD record
ord-147332adfbbc465ea64aed6a051fc797
Source dataset
uspto-grants-2008_12
Patent number
US07465726B2

Reaction notes

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