Hydrochloric Acid → 1-(3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)ethanone

HRID 1848073Notes

Reaction equation

HRID 1848073 reaction equation
Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:28]=[CH:27][C:15]4[N:16]=[C:17]([NH:19][C@@H:20]5[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]5[OH:26])[S:18][C:14]=4[CH:13]=3)[CH:9]=[N:10][C:5]2=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:34]([O:36]CC)=[CH2:35])CCC.Cl>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[OH:26][C@@H:21]1[CH2:22][CH2:23][CH2:24][CH2:25][C@H:20]1[NH:19][C:17]1[S:18][C:14]2[CH:13]=[C:12]([CH2:11][N:8]3[C:6]4=[N:7][C:2]([C:34](=[O:36])[CH3:35])=[CH:3][CH:4]=[C:5]4[N:10]=[CH:9]3)[CH:28]=[CH:27][C:15]=2[N:16]=1

Participants

6

Reactant 3

HCID 313Hydrochloric AcidHCID 619414Stannane, tributyl(1-ethoxyethenyl)-HCID 71550847(1R,2R)-2-((6-((5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Product 1

HCID 715487401-(3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)ethanoneYield 21%

Reagents, catalysts & solvents 2

HCID 11979704Tetrakis(triphenylphosphine)palladiumCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
110 °C

Procedure

A stirred mixture of (1R,2R)-2-((6-((5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (100 mg, 0.218 mmol) from Example 78, tributyl(1-ethoxyvinyl)tin (157 mg, 0.436 mmol) in anhydrous DMF (2 mL) at rt was purged for 15 min with a stream of argon. To the resulting mixture was added tetrakis(triphenylphosphine) palladium (0) (38 mg, 0.0327 mmol). The reaction vessel was sealed and the mixture was stirred at 110° C. for 2 h. After cooling to rt, 2 M aq HCl (0.5 mL) was added, and the mixture was stirred at rt for 1.5 h. 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 crude 1-(3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)ethanone. The crude product was triturated with Et2O and the solid was collected by filtration and dried to afford 1-(3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)ethanone (19 mg, 21%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.22 (d, J=8.5 Hz, 1H), 8.00 (d, J=7.5 Hz, 1H), 7.92 (d, J=8.3 Hz, 1H), 7.80 (s, 1H), 7.26-7.39 (m, 2H), 5.55 (s, 2H), 4.77 (d, J=4.9 Hz, 1H), 3.50 (m, 1H), 3.30 (m, 1H), 2.74 (s, 3H), 2.02 (m, 1H), 1.87 (m, 1H), 1.55-1.67 (m, 2H), 1.12-1.32 (m, 4H). LCMS (ESI) m/z 422 (M+H)+.

Workup

  1. customwas purged for 15 min with a stream of argon
  2. customThe reaction vessel was sealed
  3. temperatureAfter cooling to rt
  4. stirringthe mixture was stirred at rt for 1.5 h
  5. customThe mixture was purified directly by reverse-phase
  6. 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
  7. customto afford crude 1-(3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)ethanone
  8. customThe crude product was triturated with Et2O
  9. filtrationthe solid was collected by filtration
  10. customdried

Sources & evidence

ORD record
ord-4a4a87bdc88643cdbe3c72d2d54bc48f
Source dataset
uspto-grants-2015_02
Patent number
US08952058B2

Reaction notes

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