Tetrahydrofuran → 1-{1-[1-(1-Methyl-cyclopropanecarbonyl)-piperidin-4-yloxy] isoquinolin-4-yl}-3-[5-(1-methyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-yl]-urea

HRID 729629Notes

Reaction equation

HRID 729629 reaction equation
[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([C:21]3([CH3:24])[CH2:23][CH2:22]3)=[O:20])[CH2:15][CH2:14]2)=[N:4][CH:3]=1.C1COCC1.ClC(Cl)(Cl)C[O:33][C:34](=O)[NH:35][C:36]1[N:37]([C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=2)[N:38]=[C:39]([C:41]2([CH3:44])[CH2:43][CH2:42]2)[CH:40]=1>>[CH3:24][C:21]1([C:19]([N:16]2[CH2:17][CH2:18][CH:13]([O:12][C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:2]([NH:1][C:34]([NH:35][C:36]4[N:37]([C:45]5[CH:46]=[CH:47][C:48]([CH3:51])=[CH:49][CH:50]=5)[N:38]=[C:39]([C:41]5([CH3:44])[CH2:42][CH2:43]5)[CH:40]=4)=[O:33])=[CH:3][N:4]=3)[CH2:14][CH2:15]2)=[O:20])[CH2:23][CH2:22]1

Participants

4

Reactant 3

HCID 8028Tetrahydrofuran2×HCID 57832814[4-(4-Amino-isoquinolin-1-yloxy)-piperidin-1-yl]-(1-methyl-cyclopropyl)-methanoneHCID 57832815[5-(1-methyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-yl]-carbamic acid 2,2,2-trichloroethyl ester

Product 1

HCID 160614691-{1-[1-(1-Methyl-cyclopropanecarbonyl)-piperidin-4-yloxy] isoquinolin-4-yl}-3-[5-(1-methyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-yl]-ureaYield 68%

Conditions

Temperature
46.5 °C

Procedure

Add [4-(4-Amino-isoquinolin-1-yloxy)-piperidin-1-yl]-(1-methyl-cyclopropyl)-methanone (Preparation 23, 331.00 g, 1.02 moles), THF (3.97 L, 48.79 moles), [5-(1-Methyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-yl]-carbamic acid 2,2,2-trichloro-ethyl ester (Preparation 18, 410.00 g, 1.02 moles), and DIPE (159.00 g, 1.22 moles) to a 12 L Morton flask equipped with overhead stirrer, thermocouple, and reflux condenser. Reflux the mixture for 22 hours. Cool reaction to <50° C. and treat with carbon (Darco G-60; 33.00 g, 2.75 moles). Stir the slurry for 30 minutes at 43-50° C., then filter over micro fiber paper and Hyflo Super Cel® (27.00 g). Seed the filtrate and allow to cool at ambient temperature during precipitation. Pack the resulting slurry in ice and stir overnight. Filter the solids, wash with THF (300.00 mL, 3.69 moles), and dry under reduced pressure at 40° C. Subject residue to silica gel chromatography eluting with 1:3 acetone/DCM, then 30% acetone in DCM to obtain 401 g (68%) 1-{1-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yloxy]-isoquinolin-4-yl}-3-[5-(1-methyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-yl]-urea as a white solid 1H NMR (300 MHz, DMSO-d6): δ 0.56 (t, J=6.0 Hz, 2H), 0.73 (t, J=6.0 Hz, 2H), 0.84 (t, J=6.0 Hz, 2H), 0.92 (t, J=6.0 Hz, 2H), 1.27 (s, 3H), 1.41 (s, 3H), 1.73-1.81 (m, 2H), 1.99-2.08 (m, 2H), 2.41 (s, 3H), 3.52-3.65 (m, 2H), 3.83-3.96 (m, 2H), 5.47-5.58 (m, 1H), 6.22 (s, 1H), 7.37 (d, J=8.1 Hz, 2H), 7.44 (d, J=8.1 Hz, 2H), 7.65-7.71 (m, 1H), 7.78-7.83 (m, 2H), 8.12 (s, 1H), 8.27 (d, J=8.4 Hz, 1H), 8.58 (s, 1H), 8.69 (s, 1H).

Workup

  1. customequipped with overhead stirrer
  2. temperaturethermocouple, and reflux condenser
  3. temperatureReflux the mixture for 22 hours
  4. temperatureCool
  5. customreaction to <50° C.
  6. additiontreat with carbon (Darco G-60; 33.00 g, 2.75 moles)
  7. filtrationfilter over micro fiber paper and Hyflo Super Cel® (27.00 g)
  8. temperatureto cool at ambient temperature during precipitation
  9. stirringstir overnight
  10. filtrationFilter the solids
  11. customdry under reduced pressure at 40° C
  12. washSubject residue to silica gel chromatography eluting with 1:3 acetone/DCM

Sources & evidence

ORD record
ord-9bcd13d9e2cf479c915527aaf6df0203
Source dataset
uspto-grants-2009_09
Patent number
US07582638B2

Reaction notes

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