Methanol → 7-(morpholine-4-carbonyl)-3-(thiazol-4-yl)-9H-carbazole-1-carboxamide

HRID 2410870Notes

Reaction equation

HRID 2410870 reaction equation
Br[C:2]1[CH:3]=[C:4]([C:23]([NH2:25])=[O:24])[C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[C:9]([C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16])[CH:8]=3.CC1(C)C(C)(C)OB([C:34]2[N:35]=[CH:36][S:37][CH:38]=2)O1.C([O-])([O-])=O.[Na+].[Na+].CO>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[N:17]1([C:15]([C:9]2[CH:8]=[C:7]3[C:12]([C:13]4[CH:14]=[C:2]([C:34]5[N:35]=[CH:36][S:37][CH:38]=5)[CH:3]=[C:4]([C:23]([NH2:25])=[O:24])[C:5]=4[NH:6]3)=[CH:11][CH:10]=2)=[O:16])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1

Participants

7

Reactant 4

HCID 887MethanolHCID 10340Sodium Carbonate2×HCID 454803194-(Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole2×HCID 666047593-bromo-7-(morpholine-4-carbonyl)-9H-carbazole-1-carboxamide

Product 1

HCID 666046297-(morpholine-4-carbonyl)-3-(thiazol-4-yl)-9H-carbazole-1-carboxamideYield 42.6%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalyst2×HCID 1140TolueneSolvent

Conditions

Temperature
105 °C

Procedure

3-Bromo-7-(morpholine-4-carbonyl)-9H-carbazole-1-carboxamide (50 mg, 0.112 mmol, Example 144A), Pd(Ph3P)4 (7 mg, 6.06 nmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (37 mg, 0.175 mmol), aqueous Na2CO3 (0.15 mL, 0.300 mmol), MeOH (1 mL) and Toluene (2 mL) were combined in a 5 ml microwave vial. The vial was sealed, flushed with nitrogen and heated to 105° C. for 4 hours in an oil bath. Additional Pd(Ph3P)4 (20 mg, 15 nmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (65 mg, 0.308 mmol) and aqueous Na2CO3 (0.30 mL, 0.60 mmol) were added, the vial flushed with nitrogen again and heat to 105° C. for 5 additional hours. The reaction mixture was evaporated to dryness, suspended in water and the crude product was collected by filtration through a medium porosity glass frit. The crude was washed with water, then dissolved off the frit with DMSO and purified by prep HPLC. Product containing fractions were combined and concentrated in vacuum to give 19.4 mg 7-(morpholine-4-carbonyl)-3-(thiazol-4-yl)-9H-carbazole-1-carboxamide. MS (ESI) m/e+=407, m/e−=405, consistent with [M−H]− and [M+H]+. 1H NMR (CD3OD+CDCl3) δ ppm 9.11 (d, 1H, J=2.1), 8.91 (d, 1H, J=1.5), 8.57 (d, 1H, J=1.5), 8.26 (d, 1H, J=8.0), 7.96 (d, 1H, J=1.8), 7.72 (s, 1H), 7.32 (dd, 1H, J=7.9, 1.2), 3.90-3.50 (b, 8H). HPLC retention time 8.02 min. (Sunfire C18 3.5 μm, 4.6×150 mm column, 15 min gradient, 10-100% B, 1 mL/min. Solvent A: 5% CH3CN—95% H2O—0.1% TFA; Solvent B: 95% CH3CN—5% H2O—0.1% TFA).

Workup

  1. customThe vial was sealed
  2. customflushed with nitrogen
  3. customthe vial flushed with nitrogen again
  4. temperatureheat to 105° C. for 5 additional hours
  5. customThe reaction mixture was evaporated to dryness
  6. filtrationthe crude product was collected by filtration through a medium porosity glass frit
  7. washThe crude was washed with water
  8. dissolutiondissolved off the frit with DMSO
  9. custompurified by prep HPLC
  10. additionProduct containing fractions
  11. concentrationconcentrated in vacuum

Sources & evidence

ORD record
ord-b6350f75c18b4b60be9be2f9eaa6c99e
Source dataset
uspto-grants-2014_08
Patent number
US08815840B2

Reaction notes

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