Diisopropylethylamine → tert-butyl N-(2-(2,6-difluorophenyl)-4-((1-methyl-5-(2-((2,2,2-trifluoroacetyl)amino)-8-oxabicyclo[3.2.1]octan-5-yl)pyrazol-4-yl)carbamoyl)thiazol-5-yl)carbamate

HRID 521853ノート

反応式

HRID 521853 の反応式
[F:1][C:2]([F:25])([F:24])[C:3]([NH:5][CH:6]1[CH2:12][CH2:11][C:10](F)([C:13]2[N:14]([CH3:21])[N:15]=[CH:16][C:17]=2[N+:18]([O-])=O)[CH2:9][CH2:8][CH:7]1[OH:23])=[O:4].[H][H].CCN(C(C)C)C(C)C.[C:37]([O:41][C:42]([NH:44][C:45]1[S:49][C:48]([C:50]2[C:55]([F:56])=[CH:54][CH:53]=[CH:52][C:51]=2[F:57])=[N:47][C:46]=1[C:58](O)=[O:59])=[O:43])([CH3:40])([CH3:39])[CH3:38].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C1COCC1.CO.[Pd].C(Cl)Cl>[F:57][C:51]1[CH:52]=[CH:53][CH:54]=[C:55]([F:56])[C:50]=1[C:48]1[S:49][C:45]([NH:44][C:42](=[O:43])[O:41][C:37]([CH3:39])([CH3:38])[CH3:40])=[C:46]([C:58](=[O:59])[NH:18][C:17]2[CH:16]=[N:15][N:14]([CH3:21])[C:13]=2[C:10]23[O:23][CH:7]([CH2:8][CH2:9]2)[CH:6]([NH:5][C:3](=[O:4])[C:2]([F:25])([F:24])[F:1])[CH2:12][CH2:11]3)[N:47]=1

参加物

10

反応物 5

HCID 81531DiisopropylethylamineHCID 2724699PyBOPHCID 674381985-((Tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acidHCID 867138002,2,2-trifluoro-N-(5-fluoro-2-hydroxy-5-(2-methyl-4-nitro-pyrazol-3-yl)cycloheptyl)acetamideHCID 178418361HCID 178418361、化合物

生成物 1

HCID 86713799tert-butyl N-(2-(2,6-difluorophenyl)-4-((1-methyl-5-(2-((2,2,2-trifluoroacetyl)amino)-8-oxabicyclo[3.2.1]octan-5-yl)pyrazol-4-yl)carbamoyl)thiazol-5-yl)carbamate

試薬・触媒・溶媒 4

HCID 23938Palladium触媒HCID 887Methanol溶媒HCID 6344Dichloromethane溶媒HCID 8028Tetrahydrofuran溶媒

実験手順

To a solution of 2,2,2-trifluoro-N-(5-fluoro-2-hydroxy-5-(2-methyl-4-nitro-pyrazol-3-yl)cycloheptyl)acetamide (120 mg, 0.32 mmol) in THF (10 mL) and MeOH (10 mL) was added 10% palladium on carbon (12 mg). The reaction mixture was heated at 40° C. under a 400 psi atmosphere of hydrogen for 3 hr, cooled to room temperature, filtered through Celite®, washing with methanol (50 mL) and concentrated under reduced pressure. The procedure was repeated using the same conditions except with additional aqueous HCl (2 M, 2 mL). To a solution of the residue in DCM (20 mL) was added DIPEA (1.00 mL, 5.74 mmol), 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (123 mg, 0.46 mmol) and PyBOP (409 mg, 0.78 mmol) and the mixture was stirred at room temperature for 16 hr. The reaction was quenched with water (20 mL) and extracted with DCM (150 mL). The organic layer was washed saturated solution of NaHCO3 (30 mL) and water (30 mL), separated, dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel chromatography (80-100% EtOAc/isohexane) gave tert-butyl N-(2-(2,6-difluorophenyl)-4-((1-methyl-5-(2-((2,2,2-trifluoroacetyl)amino)-8-oxabicyclo[3.2.1]octan-5-yl)pyrazol-4-yl)carbamoyl)thiazol-5-yl)carbamate as an off-white solid (58 mg, 27% over two steps). 1H NMR (400 MHz, CDCl3) δ 10.47 (s, 1H), 10.39 (s, 1H), 8.33 (s, 1H), 7.39-7.33 (m, 1H), 7.18-7.10 (m, 2H), 5.91 (d, J=7.7 Hz, 1H), 4.89-4.83 (m, 1H), 4.47-4.38 (m, 1H), 3.86 (s, 3H), 2.47-2.38 (m, 1H), 2.27-1.90 (m, 7H), 1.55 (s, 9H).

後処理

  1. filtrationfiltered through Celite®
  2. washwashing with methanol (50 mL)
  3. concentrationconcentrated under reduced pressure
  4. customThe reaction was quenched with water (20 mL)
  5. extractionextracted with DCM (150 mL)
  6. washThe organic layer was washed saturated solution of NaHCO3 (30 mL) and water (30 mL)
  7. customseparated
  8. dry with materialdried over MgSO4
  9. concentrationconcentrated under reduced pressure
  10. customPurification via silica gel chromatography (80-100% EtOAc/isohexane)

出典と根拠

ORDレコード
ord-a731bc7eb65c4acab555b920797fbf68
出典データセット
uspto-grants-2016_05
特許番号
US09328106B2

反応ノート

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