Dimethylamine → (2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamide

HRID 383972

반응식

HRID 383972 반응식
[C:1](N1C=CN=C1)(N1C=CN=C1)=O.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[CH:21]([N:32]1[C@H:37]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:36](=[O:42])[NH:35][C@H:34]([CH:43]2[CH2:51][C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH2:44]2)[C:33]1=[O:52])[C:22]([NH:24][C:25]1C=CC=CC=1O)=[O:23].CNC.O1CCCC1>ClCCl>[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[C@@H:21]([N:32]1[C@H:37]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:36](=[O:42])[NH:35][C@H:34]([CH:43]2[CH2:44][C:45]3[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:51]2)[C:33]1=[O:52])[C:22]([N:24]([CH3:1])[CH3:25])=[O:23]

참가 물질

6

반응물 4

HCID 674DimethylamineHCID 8028TetrahydrofuranHCID 682631,1'-CarbonyldiimidazoleHCID 11649656(2RS)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(2-hydroxyphenyl)ethanamide

생성물 1

HCID 11465834(2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamide수율 62%

시약·촉매·용매 1

HCID 6344Dichloromethane용매

실험 절차

Carbonyldiimidazole (4.80 g, 1.54 equiv.) was suspended in anhydrous dichloromethane (40 mL) and the suspension was left at room temperature for 15 minutes. (2RS)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(2-hydroxyphenyl)ethanamide (10.50 g, pre-dried in vacuo over P4O10 for 24 hours) was then added with stirring and the resultant solution was stirred at room temperature for 6 hours. The resulting yellow solution was then treated with a 2.0M solution of dimethylamine in tetrahydrofuran (54 mL, 5.6 equiv.) and the resulting mixture was stirred at room temperature for 16 hours. The solvents plus residual dimethylamine were removed under reduced pressure and the reaction mixture was taken up in dichloromethane (200 mL) and washed with 1M hydrochloric acid (200 mL). The organic phase was separated using a hydrophobic frit and was evaporated under reduced pressure to ca. 50 mL. The crude product was applied to 4×90 g silica Biotage™ columns on a Quad 3 system; each column being eluted with (i) 2:1 v/v ethyl acetate:cyclohexane (12×50 mL fractions), (ii) ethyl acetate (12×50 mL fractions), (iii) 9:1 v/v ethyl acetate:methanol to give (2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamide (5.753 g, 62%) as a colourless solid.

후처리

  1. stirringthe resulting mixture was stirred at room temperature for 16 hours
  2. customThe solvents plus residual dimethylamine were removed under reduced pressure
  3. washwashed with 1M hydrochloric acid (200 mL)
  4. customThe organic phase was separated
  5. customwas evaporated under reduced pressure to ca. 50 mL
  6. washeach column being eluted with (i) 2:1 v/v ethyl acetate

출처 및 근거

ORD 기록
ord-627bd4cc012f4d4aa17169c4e7b7d8c5
출처 데이터셋
uspto-grants-2013_02
특허 번호
US08367673B2

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