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

반응식

HRID 2099772 반응식
[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

참가 물질

5

반응물 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

생성물 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-carboxylate수율 97%

시약·촉매·용매 2

HCID 11186Zinc cyanide (Zn(CN)2)촉매HCID 178418397HCID 178418397, 화합물촉매

반응 조건

온도
200 °C

실험 절차

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.

후처리

  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

출처 및 근거

ORD 기록
ord-d7b8a1bf44174c229a9cac683f4241de
출처 데이터셋
uspto-grants-2009_08
특허 번호
US07569578B2

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