7-acetyl-3-methyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide → 7-(2-hydroxypropan-2-yl)-3-methyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide

HRID 2361409Notes

Reaction equation

HRID 2361409 reaction equation
[C:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([N:23]5[C:32](=[O:33])[C:31]6[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=6)[N:25]=[CH:24]5)[C:18]=4[CH3:34])=[C:15]([CH3:35])[N:14]=[C:13]([C:36]([NH2:38])=[O:37])[C:9]=3[NH:10]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:39][Mg]Br>O1CCCC1>[OH:3][C:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([N:23]5[C:32](=[O:33])[C:31]6[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=6)[N:25]=[CH:24]5)[C:18]=4[CH3:34])=[C:15]([CH3:35])[N:14]=[C:13]([C:36]([NH2:38])=[O:37])[C:9]=3[NH:10]2)=[CH:6][CH:5]=1)([CH3:39])[CH3:2]

Participants

4

Reactant 2

HCID 679951397-acetyl-3-methyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamideHCID 178418573HCID 178418573, compound2×

Product 1

HCID 679945537-(2-hydroxypropan-2-yl)-3-methyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamideYield 24%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 7-acetyl-3-methyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide (51 mg, 0.102 mmol) in tetrahydrofuran (10.0 mL) at 0° C. was added methylmagnesium bromide (3 M in diethyl ether, 0.169 mL, 0.508 mmol). The mixture was stirred for 30 min. HPLC analysis indicated that there was still a significant amount of starting material remaining. Additional methylmagnesium bromide (0.10 mL) was added, and the reaction mixture was stirred for an additional 30 min. at 0° C. The reaction was slowly quenched with water and extracted with ethyl acetate (3×). The organic layers were combined, washed with brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by purification by flash silica gel chromatography using a mixture ethyl acetate and hexane (50%-62%-75%-88%-100%) and reverse phase preparative HPLC afforded 7-(2-hydroxypropan-2-yl)-3-methyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide (24% yield) as an off-white solid and as a mixture of atropisomers. LC/MS M+1=518.2. 1H NMR (500 MHz, MeOD) δ 8.42-8.38 (m, 1H), 8.33 (dt, J=8.0, 1.7 Hz, 1H), 7.93-7.87 (m, 1H), 7.83-7.77 (m, 2H), 7.70-7.59 (m, 3H), 7.53-7.44 (m, 1H), 7.25-7.15 (m, 1H), 7.06 (d, J=8.6 Hz, 0.6H), 6.81 (d, J=8.3 Hz, 0.4H), 2.51-2.46 (m, 3H), 1.81-1.78 (m, 3H), and 1.62-1.56 (m, 6H).

Workup

  1. stirringthe reaction mixture was stirred for an additional 30 min. at 0° C
  2. customThe reaction was slowly quenched with water
  3. extractionextracted with ethyl acetate (3×)
  4. washwashed with brine
  5. dry with materialdried over anhydrous sodium sulfate
  6. concentrationConcentration under reduced pressure
  7. customfollowed by purification by flash silica gel chromatography

Sources & evidence

ORD record
ord-da6c44577caf460086ecb672208b5ce3
Source dataset
uspto-grants-2014_04
Patent number
US08685969B2

Reaction notes

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