2,6-Lutidine → 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(R)-(4-methanesulfonyl-phenyl)-propionamide

HRID 546182노트

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HRID 546182 반응식
C(OC(=O)NC1C=CC=C([CH2:14][N:15]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:40])[C@@H:22]([C:29]3[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[C:31](Cl)[CH:30]=3)[CH2:23][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[N:16]2)C=1)(C)(C)C.C(Cl)(=O)C(Cl)=O.NC1C=CN([CH2:54][C:55](C)([OH:57])[CH3:56])N=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[CH:24]1([CH2:23][C@H:22]([C:29]2[CH:30]=[CH:31][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:33][CH:34]=2)[C:21]([NH:20][C:17]2[CH:18]=[CH:19][N:15]([CH2:14][C:55]([OH:57])([CH3:56])[CH3:54])[N:16]=2)=[O:40])[CH2:28][CH2:27][CH2:26][CH2:25]1

참가 물질

7

반응물 4

HCID 79372,6-LutidineHCID 65578Oxalyl chlorideHCID 593449381-(3-amino-1H-pyrazol-1-yl)-2-methylpropan-2-olHCID 67190452HCID 67190452, 화합물

생성물 1

HCID 248895043-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(R)-(4-methanesulfonyl-phenyl)-propionamide수율 75%

시약·촉매·용매 2

HCID 6228Dimethylformamide촉매HCID 6344Dichloromethane용매5회

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온도
25 °C

실험 절차

A solution of 3-cyclopentyl-2-(R)-(4-methanesulfonyl-phenyl)-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 3, 60 mg, 0.20 mmol) was dissolved in methylene chloride (10 mL) and N,N-dimethylformamide (one drop) and cooled to 0° C. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 117 μL, 0.23 mmol) which produced gas evolution and it was then stirred at 0° C. for 15 minutes and 1 h at 25° C. After this time, the reaction was concentrated in vacuo to ⅙ of the original volume. In a separate flask a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in Example 80, 34 mg, 0.22 mmol), 2,6-lutidine (35 μL, 0.30 mmol) and methylene chloride (5 mL) was cooled to 0° C. in an ice bath. To this solution was added the solution of the prepared acid chloride diluted with another portion of methylene chloride (2 mL) dropwise. After addition was complete, the reaction was then allowed to warm to 25° C. and stirred for 16 hours. After this time the reaction was diluted with methylene chloride (10 mL) and washed with a saturated aqueous sodium bicarbonate solution (1×10 mL) and a 1 N aqueous hydrochloric acid solution (1×10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification an AnaLogix Intelliflash system (4 g column, 20% ethyl acetate/hexanes to 80% ethyl acetate/hexanes) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(R)-(4-methanesulfonyl-phenyl)-propionamide (65 mg, 75%) as a white foam: [α]30589=−20.0° (c=0.13, methylene chloride); ES-HRMS m/e calcd for C22H31N3O4S (M+H)+ 434.2108, observed 434.2108; H1-NMR (300 MHz, DMSO-d6) δ ppm 1.03 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.10 (m, 2 H, CH2), 1.35-1.80 (m, 8H, 4×CH2), 2.08 (m, 1H, CH), 3.18 (s, 3H, SO2CH3), 3.86 (s, 2H, NCH2), 3.93 (m, 1H, ArCHCO), 4.65 (s, 1H, OH), 6.45 (d, J=2.1 Hz, 1H, Ar), 7.50 (d, J=2.1 Hz, 1H, Ar), 7.64 (d, J=8.2 Hz, 2H, Ar), 7.88 (d, J=8.2 Hz, 2H, Ar), 10.78 (s, 1H, NH).

후처리

  1. customproduced gas evolution and it
  2. concentrationAfter this time, the reaction was concentrated in vacuo
  3. additionAfter addition
  4. temperatureto warm to 25° C.
  5. stirringstirred for 16 hours
  6. washwashed with a saturated aqueous sodium bicarbonate solution (1×10 mL)
  7. dry with materiala 1 N aqueous hydrochloric acid solution (1×10 mL) and then dried over magnesium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customPurification an AnaLogix Intelliflash system (4 g column, 20% ethyl acetate/hexanes to 80% ethyl acetate/hexanes)

출처 및 근거

ORD 기록
ord-1495e1246f214113bbeab0519149b8bd
출처 데이터셋
uspto-grants-2011_05
특허 번호
US07935699B2

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