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Diisopropylethylamine → 5-amino-2-(2,6-difluorophenyl)-N-(5-((2R,7R)-5-hydroxy-7-methyloxepan-2-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide

HRID 521948
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HRID 521948 반응식
[CH3:1][CH:2]1[CH2:8][CH:7]([OH:9])[CH2:6][CH2:5][CH:4]([C:10]2[N:11]([CH3:18])[N:12]=[CH:13][C:14]=2[N+:15]([O-])=O)[O:3]1.[NH2:19][C:20]1[S:24][C:23]([C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[N:22][C:21]=1[C:33](O)=[O:34].CCN(C(C)C)C(C)C.CCCP(=O)=O>CO.[OH-].[OH-].[Pd+2]>[NH2:19][C:20]1[S:24][C:23]([C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[N:22][C:21]=1[C:33]([NH:15][C:14]1[CH:13]=[N:12][N:11]([CH3:18])[C:10]=1[C@H:4]1[CH2:5][CH2:6][CH:7]([OH:9])[CH2:8][C@@H:2]([CH3:1])[O:3]1)=[O:34]
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참가 물질

7

반응물 4

HCID 81531DiisopropylethylamineHCID 16167369Propylphosphoric anhydrideHCID 594556885-Amino-2-(2,6-difluorophenyl)thiazole-4-carboxylic acidHCID 867137752-Methyl-7-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-4-ol

생성물 1

HCID 867138805-amino-2-(2,6-difluorophenyl)-N-(5-((2R,7R)-5-hydroxy-7-methyloxepan-2-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide
수율 3%

시약·촉매·용매 2

HCID 9942167Palladium hydroxide촉매HCID 887Methanol용매

실험 절차

A solution of 2-methyl-7-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-4-ol (79 mg, 0.30 mmol) in MeOH (20 mL) was passed through the H-Cube® (full H2, 70° C., flow rate: 1 mL/min, 30 mm 20% Pd(OH)2/C cartridge). The solvent was removed under reduced pressure and the crude residue was re-dissolved in MeOH (1 mL). 5-Amino-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (94 mg, 0.37 mmol) and DIPEA (0.24 mL, 1.40 mmol) were added. Propylphosphonic anhydride solution (0.19 mL, 50% wt in EtOAc, 0.39 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc (10 mL). The organic layer was washed with 1 M aqueous NaOH (3×10 mL), 1 M aqueous HCl (2×10 mL) and brine (10 mL), separated, dried over Na2SO4 and concentrated under reduced pressure. Purification via silica gel chromatography (0-5% 7 M NH3 in MeOH/DCM) gave 108 as a white solid (4 mg, 3% over two steps). 1H NMR (400 MHz, CDCl3) δ 9.69 (d, J=11.8 Hz, 1H), 8.16 (d, J=5.6 Hz, 1H), 7.37-7.30 (m, 1H), 7.04-6.97 (m, 2H), 6.15 (s, 2H), 5.00-4.93 (m, 1H), 4.17 (s, 1H), 4.03 (dd, J=8.0, 6.9 Hz, 1H), 3.77 (s, 3H), 2.11-1.74 (m, 5H), 1.28 (d, J=3.3 Hz, 1H), 1.21 (dd, J=9.2, 6.3 Hz, 3H). Alkyl OH not observed. LCMS (ES+) m/z 464 (M+1).

후처리

  1. customThe solvent was removed under reduced pressure
  2. dissolutionthe crude residue was re-dissolved in MeOH (1 mL)
  3. concentrationThe reaction mixture was concentrated under reduced pressure
  4. dissolutionthe residue was dissolved in EtOAc (10 mL)
  5. washThe organic layer was washed with 1 M aqueous NaOH (3×10 mL), 1 M aqueous HCl (2×10 mL) and brine (10 mL)
  6. customseparated
  7. dry with materialdried over Na2SO4
  8. concentrationconcentrated under reduced pressure
  9. customPurification via silica gel chromatography (0-5% 7 M NH3 in MeOH/DCM)

출처 및 근거

ORD 기록
ord-23c2341186184f4ca28443bc7cfc2139
출처 데이터셋
uspto-grants-2016_05
DOI
10.6084/m9.figshare.5104873.v1
특허 번호
US09328106B2

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