1-Methylhomopiperazine → Methyl 2-(3-fluoro-4-methoxyphenyl)-5-(4-methoxybenzyl)-7-(4-methyl-1,4-diazepan-1-yl)-5h-pyrido[3,2-b]indole-4-carboxylate

HRID 2410792Notes

Reaction equation

HRID 2410792 reaction equation
Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([F:32])[CH:25]=4)[CH:21]=[C:20]([C:33]([O:35][CH3:36])=[O:34])[C:7]=3[N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:9]=2[CH:10]=1.[CH3:37][N:38]1[CH2:44][CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C>CC([O-])=O.CC([O-])=O.[Pd+2]>[F:32][C:26]1[CH:25]=[C:24]([C:22]2[CH:21]=[C:20]([C:33]([O:35][CH3:36])=[O:34])[C:7]3[N:8]([CH2:11][C:12]4[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=4)[C:9]4[CH:10]=[C:2]([N:41]5[CH2:42][CH2:43][CH2:44][N:38]([CH3:37])[CH2:39][CH2:40]5)[CH:3]=[CH:4][C:5]=4[C:6]=3[N:23]=2)[CH:29]=[CH:28][C:27]=1[O:30][CH3:31]

Participants

5

Reactant 3

HCID 2283491-MethylhomopiperazineHCID 27342152-(Di-tert-butylphosphino)biphenylHCID 66604715HCID 66604715, compound

Product 1

HCID 66605316Methyl 2-(3-fluoro-4-methoxyphenyl)-5-(4-methoxybenzyl)-7-(4-methyl-1,4-diazepan-1-yl)-5h-pyrido[3,2-b]indole-4-carboxylateYield 67.2%

Reagents, catalysts & solvents 1

HCID 167845palladium(II) acetateCatalyst

Conditions

Temperature
110 °C

Procedure

A microwave vial containing a mixture of methyl 7-chloro-2-(3-fluoro-4-methoxyphenyl)-5-(4-methoxybenzyl)-5H-pyrido[3,2-b]indole-4-carboxylate (60 mg, 0.12 mmol), 1-methyl-1,4-diazepane (41 mg, 0.36 mmol), biphenyl-2-yldi-tert-butylphosphine (14 mg, 0.048 mmol), and Pd(OAc)2 (5.3 mg, 0.024 mmol) was flushed with nitrogen. Toluene (0.5 mL) was added and the vial was sealed and heated at 110° C. for 20 hr. The reaction was partitioned between EtOAc and water, the organic phase was washed with brine and the product was captured on an SCX column, washed with MeOH and then removed with 2 N NH3 in MeOH. The solvent was removed to leave crude methyl 2-(3-fluoro-4-methoxyphenyl)-5-(4-methoxybenzyl)-7-(4-methyl-1,4-diazepan-1-yl)-5H-pyrido[3,2-b]indole-4-carboxylate (47 mg). This was placed in a microwave vial, TFA (3 mL) and anisole (0.088 mL, 0.81 mmol) were added. The vial sealed and heated at 70° C. for 3 hr. The solvents were removed and the residue was dissolved in MeOH and applied onto an SCX column. This was washed with MeOH and product was released with 2 N NH3 in MeOH to leave crude methyl 2-(3-fluoro-4-methoxyphenyl)-7-(4-methyl-1,4-diazepan-1-yl)-5H-pyrido[3,2-b]indole-4-carboxylate (37 mg). This was suspended in 7 N NH3 in MeOH (5 mL) and heated at 80° C. for 15 hr. Preparative HPLC (100×30 mm Luna C18 column, gradient elution with A:B=100:0 to A:B=40:60 [A=95% H2O:5% MeOH:0.1% TFA; B=5% H2O:95% MeOH:0.1% TFA] over 20 min) followed by SCX capture and release with 2 N NH3 in MeOH afforded 2-(3-fluoro-4-methoxyphenyl)-7-(4-methyl-1,4-diazepan-1-yl)-5H-pyrido[3,2-b]indole-4-carboxamide (3.2 mg, 6.8 μmol, 7% yield overall) as an orange solid. MS (ESI) m/z 448.29 (M+H). 1H NMR (500 MHz, MeOD) δ ppm 8.24 (1H, d, J=8.85 Hz), 8.06 (1H, s), 7.82- 7.94 (2H, m), 7.24 (1H, t, J=8.55 Hz), 6.97 (1H, d, J=2.14 Hz), 6.91 (1H, dd, J=8.85, 2.44 Hz), 3.97 (5H, br. s.), 3.73 (2H, t, J=5.95 Hz), 3.38-3.66 (4H, m), 3.00 (3H, s), 2.28-2.43 (2H, m).

Workup

  1. additionA microwave vial containing
  2. customwas flushed with nitrogen
  3. additionToluene (0.5 mL) was added
  4. customthe vial was sealed
  5. customThe reaction was partitioned between EtOAc and water
  6. washthe organic phase was washed with brine
  7. washwashed with MeOH
  8. customremoved with 2 N NH3 in MeOH
  9. customThe solvent was removed

Sources & evidence

ORD record
ord-f187840cc3e44c8b8cddac4e97f19fac
Source dataset
uspto-grants-2014_08
Patent number
US08815840B2

Reaction notes

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