2,6-Lutidine → 4-(1-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-butyl)-benzoic acid methyl ester

HRID 546103ノート

反応式

HRID 546103 の反応式
[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13](NC2C=CN(C)N=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[CH3:42][O:43][C:44](=[O:61])[C:45]1[CH:50]=[CH:49][C:48]([CH:51]([N:55]2[CH:59]=[CH:58][C:57]([NH2:60])=[N:56]2)[CH2:52][CH2:53][CH3:54])=[CH:47][CH:46]=1>C(Cl)Cl>[CH3:42][O:43][C:44](=[O:61])[C:45]1[CH:46]=[CH:47][C:48]([CH:51]([N:55]2[CH:59]=[CH:58][C:57]([NH:60][C:13](=[O:14])[C@@H:12]([C:4]3[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=3)[CH2:22][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)=[N:56]2)[CH2:52][CH2:53][CH3:54])=[CH:49][CH:50]=1

参加物

6

反応物 4

HCID 79372,6-LutidineHCID 65578Oxalyl chlorideHCID 671891404-[1-(3-Amino-pyrazol-1-yl)-butyl]-benzoic acid methyl esterHCID 671896933-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-1-methyl-pyrazole

生成物 1

HCID 671891004-(1-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-butyl)-benzoic acid methyl ester収率 47%

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, 131 mg, 0.40 mmol) was dissolved in methylene chloride (2 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (200 μL, 0.40 mmol) was added and the reaction stirred at 25° C. for 10 min. The solution was chilled to 0° C. and 2,6-lutidine (92 μL, 0.79 mmol) was added. The reaction continued to stir at 0° C. for 15 min. 4-[1-(3-Amino-pyrazol-1-yl)-butyl]-benzoic acid methyl ester (108 mg, 0.40 mmol) was dissolved in methylene chloride (2 mL) and added dropwise to the reaction. The ice bath was removed and the reaction continued to stir at 25° C. for 30 min. The reaction was diluted with ethyl acetate (50 mL), washed with water (2×15 mL), 1.0 M aqueous hydrochloric acid solution (10 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate and concentrated in vacuo to an orange foam. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% ethyl acetate/methylene chloride to 20% ethyl acetate/methylene chloride) afforded 4-(1-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-butyl)-benzoic acid methyl ester (110 mg, 47%) as a white foam: ESI-LRMS m/e calcd for C30H36ClN3O5S [M+] 585.2, found 586.5 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 0.93-1.02 (m, 3H, CH3), 1.05-1.22 (m, 2H, CH2), 1.22-1.40 (m, 2H, CH2), 1.42-2.00 (m, 8H, 4×CH2), 2.02-2.45 (m, 3H, CH2 and CH), 3.26 (s, 3H, SO2CH3), 3.52 (t, J=7.5 Hz, 1H, CH), 3.91 (s, 3H, OCH3), 5.11 (m, 1H, NCH), 6.74 (d, J=2.2 Hz, 1H, Ar), 7.27 (d, Jo=8.2 Hz, 2H, Ar), 7.40 (d, J=2.2 Hz, 1H, Ar), 7.45 (dd, Jo=8.2, Jm=1.6 Hz, 1H, Ar), 7.58 (d, Jm=1.6 Hz, 1H, Ar), 7.98 (d, Jo=8.2 Hz, 2H, Ar), 8.04 (brs, 1H, NH), 8.09 (d, Jo=8.2 Hz, 1H, Ar).

後処理

  1. temperatureThe solution was chilled to 0° C.
  2. stirringto stir at 0° C. for 15 min
  3. additionadded dropwise to the reaction
  4. customThe ice bath was removed
  5. stirringto stir at 25° C. for 30 min
  6. additionThe reaction was diluted with ethyl acetate (50 mL)
  7. washwashed with water (2×15 mL), 1.0 M aqueous hydrochloric acid solution (10 mL), saturated aqueous brine solution (10 mL)
  8. dry with materialdried over magnesium sulfate
  9. concentrationconcentrated in vacuo to an orange foam
  10. customPurification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% ethyl acetate/methylene chloride to 20% ethyl acetate/methylene chloride)

出典と根拠

ORDレコード
ord-1838e0e675e84d93be044c7ad6b547d5
出典データセット
uspto-grants-2011_05
特許番号
US07935699B2

反応ノート

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