1-(Aminomethyl)cyclohexan-1-ol → 1-(((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)methyl)cyclohexanol

HRID 1848056Notes

Reaction equation

[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16](S(C)=O)[S:17][C:13]=3[CH:12]=2)[CH:2]=1.N1C2C(=NC=CC=2)N(CC2C=CC3N=C(S(C)(=O)=O)SC=3C=2)C=1.[NH2:46][CH2:47][C:48]1([OH:54])[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16]([NH:46][CH2:47][C:48]4([OH:54])[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]4)[S:17][C:13]=3[CH:12]=2)[CH:2]=1

Participants

Conditions

Temperature: 125 °C

Procedure

A 4:1 mixture of 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole and 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfonyl)benzo[d]thiazole (50 mg) from Step 2 of Example 63 was dissolved in anhydrous DMA (1.5 mL), and then 1-(aminomethyl)cyclohexanol (79 mg, 0.608 mmol) from Step 1 of this Example and DIEA (98 mg, 0.760 mmol) were added. The reaction vessel was sealed and the mixture was heated with stirring at 125° C. for 15 h. LCMS analysis indicated that the reaction was not complete. Further amounts of 1-(aminomethyl)cyclohexanol (79 mg, 0.608 mmol) from Step 1 of this Example and DIEA (98 mg, 0.760 mmol) were added and the mixture stirred at 125° C. for further 5 h. After cooling to rt, the mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs Diphenyl column as the stationary phase to afford 1-(((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)methyl)cyclohexanol (10 mg) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.38 (dd, J=1.1, 4.7 Hz, 1H), 8.09 (dd, J=1.2, 8.0 Hz, 1H), 7.96 (t, J=5.6 Hz, 1H), 7.67 (s, 1H), 7.19-7.33 (m, 3H), 5.48 (s, 2H), 4.42 (br s, 1H), 1.12-1.62 (m, 12H). LCMS (ESI) m/z 394 (M+H)+.

Workup

customThe reaction vessel was sealed
temperaturethe mixture was heated
stirringthe mixture stirred at 125° C. for further 5 h
temperatureAfter cooling to rt
customthe mixture was purified directly by reverse-phase
additiona mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs Diphenyl column as the stationary phase

Sources & evidence

ORD record: ord-58c9083100df4260b765d87e43ab74c9
Source dataset: uspto-grants-2015_02
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08952058B2

Reaction notes

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