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

HRID 546123ノート

反応式

HRID 546123 の反応式
[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]([OH:24])=O)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[C:31](Cl)(=O)[C:32](Cl)=O.N1C(C)=CC=CC=1C.NC1C=CN(CC2(O)CC2)N=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3([OH:24])[CH2:32][CH2:31]3)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]

参加物

6

反応物 4

HCID 79372,6-LutidineHCID 65578Oxalyl chlorideHCID 67189335{3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-acetic acidHCID 671908511-(3-Amino-pyrazol-1-ylmethyl)-cyclopropanol

生成物 1

HCID 241785392-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(1-hydroxy-cyclopropylmethyl)-1H-pyrazol-3-yl]-propionamide収率 45%

試薬・触媒・溶媒 1

HCID 6344Dichloromethane溶媒3 回

反応条件

温度
25 °C

実験手順

2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 248 mg, 0.75 mmol) was dissolved in methylene chloride (4 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (0.376 mL, 0.75 mmol) was added and the reaction stirred at 25° C. for 15 min. The solution was chilled to 0° C. and 2,6-lutidine (175 μL, 1.50 mmol) was added dropwise. The reaction continued to stir at 0° C. for 15 min. The 1-(3-amino-pyrazol-1-ylmethyl)-cyclopropanol (115 mg, 0.75 mmol) was added as a pre-dissolved reaction in methylene chloride (4 mL), the ice bath was removed and the reaction continued to stir at 25° C. for 25 min. The reaction was diluted with methylene chloride (50 mL), washed with water (2×25 mL), saturated aqueous brine solution (1×20 mL), dried over magnesium sulfate and concentrated in vacuo to a beige foam. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 0% ethyl acetate/methylene chloride to 80% ethyl acetate/methylene chloride) afforded 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(1-hydroxy-cyclopropylmethyl)-1H-pyrazol-3-yl]-propionamide (158 mg, 45%) as a white brittle foam: ESI-LRMS m/e calcd for C22H28ClN3O4S [M+] 465.15, found 466.20 [M+H+], 488.11 [M+Na+]; 1H NMR (400 MHz, CDCl3) δ ppm 0.65-0.72 (m, 2H, CH2), 0.87-0.92 (m, 2H, CH2), 1.08-1.25 (m, 2H, CH2), 1.44-1.98 (m, 8H, 4×CH2), 2.15-2.38 (m, 1H, CH), 3.24 (brs, 1H, OH), 3.28 (s, 3H, SO2CH3), 3.60 (t, J=7.5 Hz, 1H, CH), 4.06 (s, 2H, NCH2), 6.71 (d, Jo=2.3 Hz, 1H, Ar), 7.32 (d, Jo=2.3 Hz, 1H, Ar), 7.49 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.62 (d, Jm=1.7 Hz, 1H, Ar), 8.09 (d, Jo=8.2 Hz, 1H, Ar), 8.12 (s, 1H, NH).

後処理

  1. temperatureThe solution was chilled to 0° C.
  2. stirringto stir at 0° C. for 15 min
  3. customthe ice bath was removed
  4. stirringto stir at 25° C. for 25 min
  5. additionThe reaction was diluted with methylene chloride (50 mL)
  6. washwashed with water (2×25 mL), saturated aqueous brine solution (1×20 mL)
  7. dry with materialdried over magnesium sulfate
  8. concentrationconcentrated in vacuo to a beige foam
  9. customPurification by flash column chromatography (Merck silica gel 60, 40-63 μm; 0% ethyl acetate/methylene chloride to 80% ethyl acetate/methylene chloride)

出典と根拠

ORDレコード
ord-b38c2413eef441a1a9c115e5f340fe3c
出典データセット
uspto-grants-2011_05
特許番号
US07935699B2

反応ノート

読み込み中…