Water → HCID 86344812, compound

HRID 711191Notes

Reaction equation

HRID 711191 reaction equation
[C:1]([C:5]1[CH:6]=[C:7]([NH:20][C:21]([NH:23][C@@H:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C@H:27]([O:34][C:35]3[CH:36]=[CH:37][C:38]4[N:39]([C:41]([N:44]5[CH2:49][CH2:48][CH2:47][CH2:46][C@@H:45]5[CH3:50])=[N:42][N:43]=4)[CH:40]=3)[CH2:26][CH2:25]2)=[O:22])[N:8]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([O:16]CCO)[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:51][CH2:52][N:53]([CH:57](C)C)[CH:54](C)C.CS(Cl)(=O)=[O:62].O>C(Cl)Cl>[CH:35]([OH:34])=[O:62].[C:1]([C:5]1[CH:6]=[C:7]([NH:20][C:21]([NH:23][C@@H:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C@H:27]([O:34][C:35]3[CH:36]=[CH:37][C:38]4[N:39]([C:41]([N:44]5[CH2:49][CH2:48][CH2:47][CH2:46][C@@H:45]5[CH3:50])=[N:42][N:43]=4)[CH:40]=3)[CH2:26][CH2:25]2)=[O:22])[N:8]([C:10]2[CH:15]=[CH:14][N:13]([CH2:51][CH2:52][N:53]([CH3:57])[CH3:54])[C:12](=[O:16])[CH:11]=2)[N:9]=1)([CH3:2])([CH3:3])[CH3:4]

Participants

6

Reactant 4

HCID 962WaterHCID 31297Methanesulfonyl chlorideHCID 81531DiisopropylethylamineHCID 1177293901-{5-tert-Butyl-2-[2-(2-hydroxy-ethoxy)-pyridin-4-yl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea

Product 1

HCID 86344812HCID 86344812, compoundYield 45%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

Intermediate 67e (86 mg, 0.13 mmol) and DIPEA (49 mg, 65 μL) were suspended in DCM (5 mL) and methanesulfonyl chloride (19 mg, 13 μL, 0.16 mmol) was added, and the reaction was stirred at room temp. After 30 min, H2O (5 mL) and DCM (5 mL) was added, stirred, and passed through a phase separator cartridge and the organics concentrated in vacuo. The resulting residue was then suspended in dimethylamine solution (2M in THF, 2.5 mL) in a microwave vial, sealed with a crimped septum and stirred at 60° C. The reaction was then cooled, concentrated in vacuo, subjected to FCC, eluting with 0-7% 2M NH3 in MeOH/DCM, then purified further by HPLC (Gemini C18, 10-98% MeCN in H2O, 0.1% HCO2H, 20 min gradient, 18 mL/min) and the combined fractions freeze dried to afford the title compound (22 mg, 24%). LCMS (Method 5): Rt 3.55 min, m/z 707.4 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.91 (3H, d, J=6.2 Hz), 1.27 (9H, s), 1.46-1.54 (2H, m), 1.61-1.73 (2H, m), 1.75-1.87 (2H, m), 1.89-1.97 (2H, m), 1.99-2.10 (1H, m), 2.17 (6H, s), 2.15-2.22 (2H, m), 2.87-2.95 (1H, m), 3.13-3.20 (1H, dt, J=12.0, 4.5 Hz), 3.32 (2H, m, obscured by water), 3.98 (2H, t, J=6.2 Hz), 4.83 (1H, q, J=7.9 Hz), 5.53 (1H, t, J=4.1 Hz), 6.37 (1H, s), 6.54-6.56 (1H, m), 6.57-6.61 (1H, dd, J=7.4, 2.4 Hz), 7.18-7.23 (1H, dd, J=2.3, 9.9 Hz), 7.24-7.32 (2H, m), 7.35-7.40 (3H, m), 7.64 (1H, dd, J=0.8, 9.8 Hz), 7.70-7.72 (1H, m), 7.73 (1H, d, J=7.5 Hz), 8.22 (0.25H, s), 8.35 (1H, s).

Workup

  1. stirringstirred
  2. concentrationthe organics concentrated in vacuo
  3. customsealed with a crimped septum
  4. stirringstirred at 60° C
  5. temperatureThe reaction was then cooled
  6. concentrationconcentrated in vacuo
  7. washeluting with 0-7% 2M NH3 in MeOH/DCM
  8. custompurified further by HPLC (Gemini C18, 10-98% MeCN in H2O, 0.1% HCO2H, 20 min gradient, 18 mL/min)
  9. customthe combined fractions freeze dried

Sources & evidence

ORD record
ord-f6959f42942e4500a7412561ae324c59
Source dataset
uspto-grants-2015_11
Patent number
US09181242B2

Reaction notes

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