1-Hydroxybenzotriazole → HCID 58709759, compound

HRID 2375932Notes

Reaction equation

HRID 2375932 reaction equation
Cl.Cl.Cl.[CH3:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]3[C:16]4[CH:23]=[C:22]([C:24]5[CH2:25][CH2:26][NH:27][CH2:28][CH:29]=5)[NH:21][C:17]=4[N:18]=[CH:19][N:20]=3)=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[N:30]1([CH2:36][CH2:37][C:38](O)=[O:39])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.ON1C2C=CC=CC=2N=N1.N=C=N.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]3[C:16]4[CH:23]=[C:22]([C:24]5[CH2:25][CH2:26][N:27]([C:38](=[O:39])[CH2:37][CH2:36][N:30]6[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]6)[CH2:28][CH:29]=5)[NH:21][C:17]=4[N:18]=[CH:19][N:20]=3)=[CH:11][CH:12]=2)[CH:7]=[N:6]1

Participants

7

Reactant 5

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 1177821-Piperidinepropanoic acidHCID 160435CarbodiimideHCID 69275387HCID 69275387, compound

Product 1

HCID 58709759HCID 58709759, compound

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a suspension of (1-methyl-1H-indazol-5-yl)-[6-(1,2,3,6-tetrahydro-pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine tris-hydrochloride (155.3 mg, 0.3381 mmol, 1 eq), 1-piperidinepropanoic acid (150.1 mg, 0.9548 mmol, 2.8 eq), 1-hydroxybenzotriazole (HOBt) (46.7 mg, 0.346 mmol, 1 eq), and PS-carbodiimide (1.37 mmol/g loading; 1008.7 mg, 1.38 mmol, 4 eq) in anhydrous DMF (10 mL), DiPEA (290 μL, 1.7 mmol, 5 eq) was added and was shaken at rt for 13 h. The resin was filtered off and rinsed several times with DMF. The filtrate was concentrated in vacuo at medium temp (bath temp: max 42° C.), redissolved in MeOH and DCM, and concentrated again under reduced pressure. The crude material was adsorbed onto Hydromatrix, dry loaded, and purified by chromatography on silica gel [Jones Flashmaster, 10 g/70 mL cartridge, eluting with MeOH:DCM 5%→10% →7N NH3(MeOH):DCM 3%→5%]. Fractions containing product were combined and concentrated in vacuo, affording the title compound as an off-white solid. 1H NMR (400 MHz, DMSOd6): δ=1.30-1.40 (mc, 2H), 1.45-1.53 (mc, 4H), 2.30-2.41 (s, br, 4H), 2.41-2.63 (m, 6H), 3.69 (t, J=5.6 Hz, 2H), 4.03 (s, 3H), 4.23 & 4.13 (s, br, rotamers, 2H), 6.41 (s, br, 1H), 6.75 & 6.77 (s, br, rotamers, 1H), 7.60 (d, J=9.2 Hz, 1H), 7.69 (dd, J=8.8, 2.0 Hz, 1H), 8.01 (s, 1H), 8.26 (d, J=2.0 Hz, 1H), 8.38 & 8.39 (s, br, rotamers, 1H), 9.34 (s, —NH), 11.90 & 11.93 (s, rotamers, 1H). MS (ES+): m/z 485.11 (45) [MH+]. HPLC: tR=1.72 min (ZQ2000, polar—5 min).

Workup

  1. filtrationThe resin was filtered off
  2. washrinsed several times with DMF
  3. concentrationThe filtrate was concentrated in vacuo at medium temp (bath temp: max 42° C.)
  4. dissolutionredissolved in MeOH
  5. concentrationDCM, and concentrated again under reduced pressure
  6. customdry loaded
  7. custompurified by chromatography on silica gel [Jones Flashmaster, 10 g/70 mL cartridge, eluting with MeOH:DCM 5%→10% →7N NH3(MeOH):DCM 3%→5%]
  8. additionFractions containing product
  9. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-83ea3d74196942d5bbd63be6fa4c0d3b
Source dataset
uspto-grants-2008_12
Patent number
US07465726B2

Reaction notes

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