2,6-Lutidine → {3-[(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionylamino]-pyrazol-1-yl}-acetic acid tert-butyl ester

HRID 1261480

반응식

HRID 1261480 반응식
[CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:23])([F:22])[F:21])[C:12]2=[O:24])[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[C:31]([O:35][C:36](=[O:44])[CH2:37][N:38]1[CH:42]=[CH:41][C:40]([NH2:43])=[N:39]1)([CH3:34])([CH3:33])[CH3:32].N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[C:31]([O:35][C:36](=[O:44])[CH2:37][N:38]1[CH:42]=[CH:41][C:40]([NH:43][C:8](=[O:9])[C@@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:21])([F:22])[F:23])[C:12]2=[O:24])[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:39]1)([CH3:34])([CH3:32])[CH3:33]

참가 물질

7

반응물 4

HCID 79372,6-LutidineHCID 65578Oxalyl chlorideHCID 62111572tert-butyl 2-(3-amino-1H-pyrazol-1-yl)acetateHCID 70945341(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionic acid

생성물 1

HCID 70674336{3-[(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionylamino]-pyrazol-1-yl}-acetic acid tert-butyl ester수율 100%

시약·촉매·용매 2

HCID 6228Dimethylformamide촉매HCID 6344Dichloromethane용매3회

실험 절차

A solution of (S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionic acid (100 mg, 0.29 mmol, prepared as in Example 1) in methylene chloride (4 mL) and N,N-dimethylformamide (4 drops) was treated with a solution of oxalyl chloride in methylene chloride (2.0 M, 150 μL, 0.30 mmol) and stirred for 15 min at room temperature. After this time, the reaction mixture was then concentrated in vacuo and the resulting residue was dissolved in methylene chloride (4 mL) and then added dropwise to a separate reaction flask containing a mixture of (3-amino-pyrazol-1-yl)-acetic acid tert-butyl ester (prepared as in US 20080021032, Example 3, 86 mg, 0.44 mmol) and 2,6-lutidine (100 μL, 0.87 mmol) in methylene chloride (3 mL) at room temperature. The resulting reaction mixture was then stirred at room temperature for 2 h. The reaction mixture was then quenched by the addition of methanol and then diluted with methylene chloride. The organic layer was then concentrated in vacuo with silica gel (2.0 g). The silica gel with absorbed material was placed in a SIM and purified via Biotage flash column chromatography (40 S silica gel column, 25% ethyl acetate/hexanes) to afford {3-[(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionylamino]-pyrazol-1-yl}-acetic acid tert-butyl ester (151 mg, 100%) as a white foam: HR-ES(+) m/e calcd for C26H31N4O4F3 [M+H]+ 521.2370, observed 521.2368; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.49 (s, 1H), 8.08 (d, J=7.46 Hz, 1H), 7.81 (d, J=7.67 Hz, 1H), 7.63 (t, J=7.67 Hz, 1H), 7.33 (d, J=2.34 Hz, 1H), 6.73 (d, J=2.34 Hz, 1H), 5.02 (dd, J=7.03, 8.52 Hz, 1H), 4.70-4.81 (m, 1H), 4.53-4.69 (m, 3H), 1.10-2.25 (m, 20H).

후처리

  1. concentrationAfter this time, the reaction mixture was then concentrated in vacuo
  2. dissolutionthe resulting residue was dissolved in methylene chloride (4 mL)
  3. additionadded dropwise to a separate reaction flask
  4. additioncontaining
  5. customThe resulting reaction mixture
  6. stirringwas then stirred at room temperature for 2 h
  7. customThe reaction mixture was then quenched by the addition of methanol
  8. additiondiluted with methylene chloride
  9. concentrationThe organic layer was then concentrated in vacuo with silica gel (2.0 g)
  10. custompurified via Biotage flash column chromatography (40 S silica gel column, 25% ethyl acetate/hexanes)

출처 및 근거

ORD 기록
ord-106015c5c99e4a0bb848991891b0fe2d
출처 데이터셋
uspto-grants-2013_06
특허 번호
US08470866B2

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