(+/-)-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 → (+/-)-1-(6-Isobutylpyridin-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 2099771

Reaction equation

HRID 2099771 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.[Br-].[CH2:42]([Zn+])[CH:43]([CH3:45])[CH3:44]>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>[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]([CH2:42][CH:43]([CH3:45])[CH3:44])[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

4

Reactant 2

HCID 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-carboxylateHCID 178448254HCID 178448254, compound

Product 1

HCID 11490161(+/-)-1-(6-Isobutylpyridin-2-yl)-2-(7-methyl-1H-indazol-5-yl)ethyl 4-(8-fluoro-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxylateYield 73.3%

Reagents, catalysts & solvents 1

HCID 178418397HCID 178418397, compoundCatalyst

Conditions

Temperature
110 °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 (13.9 mg, 0.0229 mmol, 1.0 equiv) and Pd(PPh3)4 (ca. 2 mg). Isobutylzinc bromide (0.5 M in tetrahydrofuran, 0.46 mL, 0.23 mmol, 10 equiv) was then added via syringe under nitrogen. The vial was sealed and heated by microwave at 110° C. for 4 h. Tetrahydrofuran was removed in vacuo and the residue was partitioned between ethyl acetate and 0.5 N sodium hydroxide solution. The organic layer was separated and washed with brine, dried and concentrated. Flash column chromatography 10% methanol/methylene chloride) afforded the desired product (9.8 mg, 73.3%) as a glassy solid. MS (ESI) [M+H]+=585. 1H-NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.60-7.28 (m, 2H), 7.15-6.68 (m, 7H), 6.01 (br., 1H), 4.60-4.40 (m, 1H), 4.40-4.15 (m, 2H), 4.15-3.90 (m, 1H), 3.85-3.15 (m, 2H), 3.03-2.60 (m, 4H), 2.70 (s, 3H), 2.20-2.02 (m, 1H), 1.82-1.40 (m, 4H), 1.40-1.12 (m, 2H), 1.00-0.90 (m, 6H). HPLC tR=1.44 min.

Workup

  1. customThe vial was sealed
  2. customTetrahydrofuran was removed in vacuo
  3. customthe residue was partitioned between ethyl acetate and 0.5 N sodium hydroxide solution
  4. customThe organic layer was separated
  5. washwashed with brine
  6. customdried
  7. concentrationconcentrated

Sources & evidence

ORD record
ord-3b332c49cbe943b096e008c24226e588
Source dataset
uspto-grants-2009_08
Patent number
US07569578B2

Linked notes

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