Dimethylformamide → (+/-)-1-(6-Cyanopyridin-2-yl)-2-(7-methyl-1H-indazol-5-yl)ethyl 4-(8-fluoro-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxylate

HRID 2099772

Reaction equation

HRID 2099772 reaction equation
[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[N:8]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH:22]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36](Br)[N:35]=3)[CH2:23][C:24]3[CH:25]=[C:26]4[C:30](=[C:31]([CH3:33])[CH:32]=3)[NH:29][N:28]=[CH:27]4)=[O:20])[CH2:15][CH2:14]1)[CH2:7]2.[CH3:41][N:42](C=O)C>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.[C-]#N.[C-]#N.[Zn+2]>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[N:8]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH:22]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([C:41]#[N:42])[N:35]=3)[CH2:23][C:24]3[CH:25]=[C:26]4[C:30](=[C:31]([CH3:33])[CH:32]=3)[NH:29][N:28]=[CH:27]4)=[O:20])[CH2:15][CH2:14]1)[CH2:7]2

Participants

5

Reactant 2

HCID 6228DimethylformamideHCID 11261982(+/-)-1-(6-bromopyridin-2-yl)-2-(7-methyl-1H-indazol-5-yl)ethyl 4-(8-fluoro-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxylate

Product 1

HCID 11215021(+/-)-1-(6-Cyanopyridin-2-yl)-2-(7-methyl-1H-indazol-5-yl)ethyl 4-(8-fluoro-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxylateYield 97%

Reagents, catalysts & solvents 2

HCID 11186Zinc cyanide (Zn(CN)2)CatalystHCID 178418397HCID 178418397, compoundCatalyst

Conditions

Temperature
200 °C

Procedure

A microwave tube was charged with (±)-1-(6-bromopyridin-2-yl)-2-(7-methyl-1H-indazol-5-yl)ethyl 4-(8-fluoro-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxylate (18 mg, 0.0296 mmol, 1.0 equiv) and Pd(PPh3)4 (ca. 4 mg) and Zn(CN)2 (14 mg, 0.12 mmol, 4 equiv). DMF (0.5 mL) was added via syringe. The vial was sealed and heated by microwave at 200° C. for 20 min. Tetrahydrofuran was removed in vacuo and the residue was partitioned between ethyl acetate and ammonium hydroxide solution. The organic layer was separated and washed with water, brine, dried and concentrated. Flash column chromatography (10% methanol/methylene chloride) afforded the desired product (15.9 mg, 97%) as a white solid. MS (ESI) [M+H]+=554. 1H-NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.72 (br., 1H), 7.62-7.54 (m, 1H), 7.37 (br., 1H), 7.18-6.70 (m, 6H), 6.08-5.83 (m, 1H), 4.65-3.80 (m, 6H), 3.55-3.10 (m, 2H), 3.10-2.64 (m, 2H), 2.53 (s, 3H), 1.90-1.40 (m, 4H). HPLC tR=1.90 min.

Workup

  1. customThe vial was sealed
  2. customTetrahydrofuran was removed in vacuo
  3. customthe residue was partitioned between ethyl acetate and ammonium hydroxide solution
  4. customThe organic layer was separated
  5. washwashed with water, brine
  6. customdried
  7. concentrationconcentrated

Sources & evidence

ORD record
ord-d7b8a1bf44174c229a9cac683f4241de
Source dataset
uspto-grants-2009_08
Patent number
US07569578B2

Linked notes

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