phenyl N-(1,3-thiazol-2-yl)carbamate → (R)-7-(4-methylpiperazine-1-carbonyl)-4-(3-(3-thiazol-2-ylureido)piperidin-1-yl)-9H-carbazole-1-carboxamide

HRID 661920Notes

Reaction equation

HRID 661920 reaction equation
[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[C:20]3[C:19]4[C:14](=[CH:15][C:16]([C:21]([N:23]5[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]5)=[O:22])=[CH:17][CH:18]=4)[NH:13][C:12]=3[C:11]([C:30]([NH2:32])=[O:31])=[CH:10][CH:9]=2)[CH2:3]1.[S:33]1[CH:37]=[CH:36][N:35]=[C:34]1[NH:38][C:39](=O)[O:40]C1C=CC=CC=1>C1COCC1>[CH3:29][N:26]1[CH2:27][CH2:28][N:23]([C:21]([C:16]2[CH:15]=[C:14]3[C:19]([C:20]4[C:8]([N:4]5[CH2:5][CH2:6][CH2:7][C@@H:2]([NH:1][C:39]([NH:38][C:34]6[S:33][CH:37]=[CH:36][N:35]=6)=[O:40])[CH2:3]5)=[CH:9][CH:10]=[C:11]([C:30]([NH2:32])=[O:31])[C:12]=4[NH:13]3)=[CH:18][CH:17]=2)=[O:22])[CH2:24][CH2:25]1

Participants

4

Reactant 2

HCID 651148phenyl N-(1,3-thiazol-2-yl)carbamateHCID 59375032(R)-4-(3-aminopiperidin-1-yl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide

Product 1

HCID 59375003(R)-7-(4-methylpiperazine-1-carbonyl)-4-(3-(3-thiazol-2-ylureido)piperidin-1-yl)-9H-carbazole-1-carboxamideYield 47.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
60 °C

Procedure

A solution of (R)-4-(3-aminopiperidin-1-yl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide (Example 17-1, 23 mg, 0.053 mmol) and TEA (0.015 mL, 0.106 mmol) in THF (3 mL) was treated with phenyl thiazol-2-ylcarbamate (17.49 mg, 0.079 mmol). The mixture was stirred at 60° C. for 1.5 h, then at 70° C. for 2 h, then was concentrated and purified by preparative HPLC. The isolated TFA salt was partitioned between DCM and NaHCO3 (aq), and the organic phase was dried and concentrated to provide (R)-7-(4-methylpiperazine-1-carbonyl)-4-(3-(3-thiazol-2-ylureido)piperidin-1-yl)-9H-carbazole-1-carboxamide as a white solid (14 mg, 43%). 1H NMR (400 MHz, methanol-d4) δ 8.27 (1H, d, J=7.9 Hz), 7.87 (1H, d, J=8.3 Hz), 7.68 (1H, d, J=1.1 Hz), 7.28 (1H, d, J=7.9 Hz), 7.18 (1H, br. s.), 6.93 (1H, d, J=3.7 Hz), 6.87 (1H, d, J=8.3 Hz), 4.25 (1H, br.), 3.82 (2H, br.), 3.41-3.68 (3H, m), 3.19 (3H, br.), 2.36-2.63 (4H, m), 2.33 (3H, s), 1.84-2.20 (3H, m), 1.71 (1H, br. s.). Mass spectrum m/z 561.3 (M+H)+.

Workup

  1. waitat 70° C. for 2 h
  2. concentrationwas concentrated
  3. custompurified by preparative HPLC
  4. customThe isolated TFA salt was partitioned between DCM and NaHCO3 (aq)
  5. customthe organic phase was dried
  6. concentrationconcentrated

Sources & evidence

ORD record
ord-ee98bcd18f794016b7f0021f6bcada2b
Source dataset
uspto-grants-2011_12
Patent number
US08084620B2

Reaction notes

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