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

HRID 2375819Notes

Reaction equation

HRID 2375819 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][CH:29]=[CH:28]2.CCN(C(C)C)C(C)C.Cl>CCCCO.C(Cl)Cl.CO>[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][CH:29]=[CH:28]5)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 788675-AminoindoleHCID 81531DiisopropylethylamineHCID 58709797tert-butyl 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate

Product 1

HCID 116333694-[4-(1H-Indol-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

Reagents, catalysts & solvents 3

HCID 2631-ButanolSolventHCID 887MethanolSolventHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
120 °C

Procedure

A suspension of 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (606.0 mg, 1.810 mmol, 1 eq) and 5-aminoindole (548.9 mg, 4.153 mmol, 2.3 eq) in n-BuOH (30 mL) was stirred at 120° C. for 23 h, after which it was concentrated in vacuo, to a dark brown foam. The crude material (1.2974 g) was dissolved in mixtures of DCM and MeOH (DCM alone was insufficient), to which DiPEA (0.4 mL, 2 mmol, 1 eq) was added to ensure that material was free base and not HCl salt. The crude material was adsorbed onto Hydromatrix, dry loaded, and purified by chromatography on silica gel [Jones Flashmaster, 50 g/150 mL cartridge, eluting with MeOH:DCM 1%→5% →10%]. Trituration of combined and concentrated product fractions in DCM/sonication gave the title compound as white solid. 1H NMR (400 MHz, DMSOd6): δ=1.43 (s, 9H), 2.44 (s, br, 2H), 3.55 (t, J=5.6 Hz, 2H), 4.03 (s, br, 2H), 6.35 (s, br, 1H), 6.40 (t, J=2.0 Hz, 1H), 6.67 (s, br, 1H), 7.29-7.41 (m, 3H), 8.03 (s, br, 1H), 8.19 (s, 1H), 9.14 (s, —NH), 10.99 (s, —NH), 11.81 (d, J=1.6 Hz, —NH). MS (ES+): m/z 431.04 (100) [MH+]. HPLC: tR=2.42 min (ZQ2000, polar—5 min).

Workup

  1. concentrationafter which it was concentrated in vacuo, to a dark brown foam
  2. additionwas added
  3. customdry loaded
  4. custompurified by chromatography on silica gel [Jones Flashmaster, 50 g/150 mL cartridge, eluting with MeOH:DCM 1%→5% →10%]
  5. customTrituration of combined and concentrated product fractions in DCM/sonication

Sources & evidence

ORD record
ord-42f1b4157e2b4c198b7a5a492ebcdd77
Source dataset
uspto-grants-2008_12
Patent number
US07465726B2

Reaction notes

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