Potassium Phosphate, Tribasic → Methyl 7-(2-morpholinoethoxy)-2-(3-(trifluoromethyl)phenyl)-5h-pyrido[3,2-b]indole-4-carboxylate

HRID 2410768Notes

Reaction equation

HRID 2410768 reaction equation
[F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.Br[C:15]1[CH:16]=[C:17]([C:37]([O:39][CH3:40])=[O:38])[C:18]2[NH:19][C:20]3[CH:21]=[C:22]([O:28][CH2:29][CH2:30][N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[CH:23]=[CH:24][C:25]=3[C:26]=2[N:27]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>CC([O-])=O.CC([O-])=O.[Pd+2]>[O:34]1[CH2:35][CH2:36][N:31]([CH2:30][CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]3[C:26]4[N:27]=[C:15]([C:5]5[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=5)[CH:16]=[C:17]([C:37]([O:39][CH3:40])=[O:38])[C:18]=4[NH:19][C:20]=3[CH:21]=2)[CH2:32][CH2:33]1

Participants

6

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 27343883-(Trifluoromethyl)phenylboronic acidHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl2×HCID 86663030methyl 2-bromo-7-(2-morpholinoethoxy)-5H-pyrido[3,2-b]indole-4-carboxylate

Product 1

HCID 66604728Methyl 7-(2-morpholinoethoxy)-2-(3-(trifluoromethyl)phenyl)-5h-pyrido[3,2-b]indole-4-carboxylateYield 102%

Reagents, catalysts & solvents 1

HCID 167845palladium(II) acetateCatalyst2×

Conditions

Temperature
70 °C

Procedure

A mixture of 3-(trifluoromethyl)phenylboronic acid (51 mg, 0.27 mmol), methyl 2-bromo-7-(2-morpholinoethoxy)-5H-pyrido[3,2-b]indole-4-carboxylate (90 mg, 0.21 mmol), powdered potassium phosphate tribasic (114 mg, 0.539 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (17 mg, 0.041 mmol), and Pd(OAc)2 (4.7 mg, 0.021 mmol) in a microwave vial was flushed with nitrogen. THF (1 mL) was added, the vial was capped, and the reaction was heated in a 70° C. oil bath for 18 hr. Additional Pd(OAc)2 (4.7 mg, 0.021 mmol) and dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (17 mg, 0.041 mmol) were added, the vial was resealed, and heating was continued for 16 hr. The reaction was filtered and the collected solid was washed with THF. The filtrate was applied onto an SCX column and washed with DCM and then MeOH. Release with 2 N NH3 in MeOH afforded crude methyl 7-(2-morpholinoethoxy)-2-(3-(trifluoromethyl)phenyl)-5H-pyrido[3,2-b]indole-4-carboxylate (107 mg). This was suspended in 7 N NH3 in MeOH (5 mL) in a sealed microwave vial and heated at 80° C. overnight. Preparative HPLC (100×30 mm Luna C18 column, gradient elution with A:B=30:70 to A:B=0:100 [A=10 mM NH4OAc in 5% aqueous CH3CN; B=10 mM NH4OAc in 95% aqueous CH3CN] over 20 min) followed by removal of the solvents on a SPEEDVAC® gave 7-(2-morpholinoethoxy)-2-(3-(trifluoromethyl)phenyl)-5H-pyrido[3,2-b]indole-4-carboxamide (48 mg, 0.094 mmol, 44% yield) as a yellow solid. MS (ESI) m/z 483.1 (M−H). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.51 (1H, s), 8.62 (3H, s), 8.47 (1H, s), 8.16 (1H, d, J=8.55 Hz), 7.92 (1H, s), 7.69-7.83 (2H, m), 7.31 (1H, d, J=1.53 Hz), 6.92 (1H, dd, J=8.70, 1.68 Hz), 4.19 (2H, t, J=5.49 Hz), 3.61 (4H, t, J=4.43 Hz), 2.77 (2H, t, J=5.49 Hz), 2.51 (4H, br. s.).

Workup

  1. customwas flushed with nitrogen
  2. additionTHF (1 mL) was added
  3. customthe vial was capped
  4. temperatureheating
  5. filtrationThe reaction was filtered
  6. washthe collected solid was washed with THF
  7. washwashed with DCM

Sources & evidence

ORD record
ord-cb4e090e6a944038b56b6b1834cf9b3e
Source dataset
uspto-grants-2014_08
Patent number
US08815840B2

Reaction notes

Loading…