Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1) → N-((1S,3R,4S)-3-ethyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentyl)acetamide

HRID 1969759ノート

反応式

HRID 1969759 の反応式
[C:1]([NH:4][C@@H:5]1[CH2:9][C@H:8]([C:10]([OH:12])=O)[C@H:7]([CH2:13][CH3:14])[CH2:6]1)(=[O:3])[CH3:2].[NH:15]([C:17]1[N:18]=[C:19]2[CH:25]=[CH:24][N:23]([S:26]([C:29]3[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:20]2=[N:21][CH:22]=1)[NH2:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O>[CH2:13]([C@H:7]1[C@@H:8]([C:10]([NH:16][NH:15][C:17]2[N:18]=[C:19]3[CH:25]=[CH:24][N:23]([S:26]([C:29]4[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=4)(=[O:28])=[O:27])[C:20]3=[N:21][CH:22]=2)=[O:12])[CH2:9][C@@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:6]1)[CH3:14]

参加物

6

反応物 3

HCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 580098102-Hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazineHCID 58557127(1S,2R,4S)-4-acetamido-2-ethylcyclopentanecarboxylic acid

生成物 1

HCID 58557596N-((1S,3R,4S)-3-ethyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentyl)acetamide収率 104.7%

試薬・触媒・溶媒 2

HCID 962Water溶媒HCID 6344Dichloromethane溶媒

実験手順

To a mixture of (1S,2R,4S)-4-acetamido-2-ethylcyclopentanecarboxylic acid (3.03 g, 15.2 mmol) in DCM (90 mL) was added 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (4.20 g, 13.8 mmol, Example #4, Step D), HATU (5.53 g, 14.5 mmol) and TEA (7.72 mL, 55.4 mmol). After stirring at ambient temperature for about 2 h, the reaction was diluted with water (60 mL). The layers were separated and the aqueous layer was extracted with DCM (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 0-5% MeOH in DCM to give N-((1S,3R,4S)-3-ethyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentyl)acetamide (7.0 g, 90%, 87% purity) as a tan foam: LC/MS (Table 1, Method a) Rt=1.96 min; MS m/z: 485 (M+H)+. To a solution of impure N-((1S,3R,4S)-3-ethyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)-cyclo-pentyl)acetamide (9.40 g, 19.4 mmol) in 1,4-dioxane (100 mL) was added TEA (8 mL, 58 mmol) and thionyl chloride (1.9 mL, 27.1 mmol). The reaction mixture was heated at about 80° C. for about 2 h, and then cooled to about 0° C. and saturated aqueous NaHCO3 and EtOAc (100 mL each) were added. The layers were separated and the aqueous layer was extracted with additional EtOAc (2×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 50-100% EtOAc/MeOH/Et2NH (90:9:1) in EtOAc to give N-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)acetamide (6.00 g, 66%): LC/MS (Table 1, Method a) Rt=2.03 min; MS m/z: 467 (M+H)+.

後処理

  1. customThe layers were separated
  2. extractionthe aqueous layer was extracted with DCM (3×50 mL)
  3. washThe combined organic layers were washed with brine (50 mL)
  4. dry with materialdried over anhydrous MgSO4
  5. filtrationfiltered
  6. customThe crude material was purified by silica gel chromatography
  7. washeluting with a gradient of 0-5% MeOH in DCM

出典と根拠

ORDレコード
ord-1d2edc895cc3404da2d49b7a73585a14
出典データセット
uspto-grants-2013_04
特許番号
US08426411B2

反応ノート

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