Sodium Carbonate → tert-butyl N-[2-(2-fluoro-4-pyridyl)-4-[[1-methyl-5-[(4S)-4-[(2,2,2-trifluoroacetyl)amino]azepan-1-yl]pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate

HRID 1915937ノート

反応式

HRID 1915937 の反応式
Br[C:2]1[S:3][C:4]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[C:5]([C:7](=[O:29])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:28])[C:13]=2[N:14]2[CH2:20][CH2:19][CH2:18][C@H:17]([NH:21][C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[CH2:16][CH2:15]2)[N:6]=1.[F:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[CH:41][N:40]=1.CC([O-])=O.[K+].C([O-])([O-])=O.[Na+].[Na+]>C(#N)C.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[F:38][C:39]1[CH:44]=[C:43]([C:2]2[S:3][C:4]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[C:5]([C:7](=[O:29])[NH:8][C:9]3[CH:10]=[N:11][N:12]([CH3:28])[C:13]=3[N:14]3[CH2:20][CH2:19][CH2:18][C@H:17]([NH:21][C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[CH2:16][CH2:15]3)[N:6]=2)[CH:42]=[CH:41][N:40]=1

参加物

7

反応物 4

HCID 10340Sodium CarbonateHCID 517044Potassium AcetateHCID 120601642-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineHCID 86680137tert-butyl N-[2-bromo-4-[[1-methyl-5-[(4S)-4-[(2,2,2-trifluoroacetyl)amino]azepan-1-yl]pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate

生成物 1

HCID 86680136tert-butyl N-[2-(2-fluoro-4-pyridyl)-4-[[1-methyl-5-[(4S)-4-[(2,2,2-trifluoroacetyl)amino]azepan-1-yl]pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate収率 59.8%

試薬・触媒・溶媒 2

HCID 178477754HCID 178477754、化合物触媒HCID 6342Acetonitrile溶媒

実験手順

In a microwave reaction vial, tert-butyl N-[2-bromo-4-[[1-methyl-5-[(4S)-4-[(2,2,2-trifluoroacetyl)amino]azepan-1-yl]pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (100 mg, 0.16 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (110 mg, 0.49 mmol) and PD(DPPF)CL2 (12 mg, 0.016 mmol) were dissolved in acetonitrile (3 mL). 1.0M KOAc (0.25 mL, 0.25 mmol) and 1.0M Na2CO3 (0.25 mL, 0.25 mmol) were added and the reaction was irradiated with microwave at 120° C. for 30 min. The mixture was cooled, filtered through Celite, concentrated and purified via flash chromatography, EA/heptane 0% to 100% to afford tert-butyl N-[2-(2-fluoro-4-pyridyl)-4-[[1-methyl-5-[(4S)-4-[(2,2,2-trifluoroacetyl)amino]azepan-1-yl]pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (60 mg, 58%). This compound was stirred with 4N HCl in dioxane (3 mL, 12 mmol) and methanol (2 mL) at room temperature for 3 h. Solvent was removed under reduced pressure. The residue was dissolved in methanol (3 mL) and water (1 mL), potassium carbonate (67 mg, 0.48 mmol) was added and the mixture was heated at 60° C. for 1.5 h. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EA 3×. The combined organic layers were dried over MgSO4 and the solvent removed under reduced pressure and the residue purified by preparative HPLC to afford 417. 1H NMR (400 MHz, DMSO) δ 9.04 (s, 1H), 8.29 (d, J=5.3 Hz, 1H), 7.74 (d, J=5.3 Hz, 3H), 7.59 (s, 1H), 7.42 (s, 1H), 3.66 (s, 3H), 3.24-3.01 (m, 5H), 1.94-1.73 (m, 3H), 1.67-1.48 (m, 3H). LCMS (ES+) m/z 431 (M+1)

後処理

  1. customIn a microwave reaction vial
  2. customthe reaction was irradiated with microwave at 120° C. for 30 min
  3. temperatureThe mixture was cooled
  4. filtrationfiltered through Celite
  5. concentrationconcentrated
  6. custompurified via flash chromatography, EA/heptane 0% to 100%

出典と根拠

ORDレコード
ord-dd4c1bf91ffc43a6a2846841b1bd50d4
出典データセット
uspto-grants-2013_12
特許番号
US08614206B2

反応ノート

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