Dicyclohexylcarbodiimide → (3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidin-3-yl 4-((di-tert-butoxyphosphoryl)oxy)butanoate

HRID 921713노트

반응식

HRID 921713 반응식
[Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([N:15]([CH2:25][CH3:26])[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:12]3=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:11]3[N:10]=2)=[CH:6][C:5]([C:32]#[N:33])=[CH:4][C:3]=1[N:34]1[CH2:39][CH2:38][C@@H:37]([NH:40][C:41](=[O:44])[O:42][CH3:43])[C@H:36]([OH:45])[CH2:35]1.[C:46]([O:50][P:51]([O:58][CH2:59][CH2:60][CH2:61][C:62](O)=[O:63])([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])([CH3:49])([CH3:48])[CH3:47].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:46]([O:50][P:51]([O:58][CH2:59][CH2:60][CH2:61][C:62]([O:45][C@H:36]1[C@H:37]([NH:40][C:41]([O:42][CH3:43])=[O:44])[CH2:38][CH2:39][N:34]([C:3]2[CH:4]=[C:5]([C:32]#[N:33])[CH:6]=[C:7]([NH:8][C:9]3[N:14]=[C:13]([N:15]([CH2:25][CH3:26])[CH2:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[C:12]4=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:11]4[N:10]=3)[C:2]=2[Cl:1])[CH2:35]1)=[O:63])([O:53][C:54]([CH3:55])([CH3:56])[CH3:57])=[O:52])([CH3:49])([CH3:48])[CH3:47]

참가 물질

6

반응물 3

HCID 10868DicyclohexylcarbodiimideHCID 148030474-((Di-tert-butoxyphosphoryl)oxy)butanoic acidHCID 131732393methyl((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate

생성물 1

HCID 86708584(3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidin-3-yl 4-((di-tert-butoxyphosphoryl)oxy)butanoate수율 50.1%

시약·촉매·용매 2

HCID 142844-(Dimethylamino)pyridine촉매HCID 6344Dichloromethane용매2회

실험 절차

To a suspension of methyl ((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate (100 mg, 0.158 mmol) and 4-((di-tert-butoxyphosphoryl)oxy)butanoic acid (141 mg, 0.475 mmol) in DCM (5 mL) at 0° C., was added DCC (98 mg, 0.475 mmol) followed by DMAP (1.936 mg, 0.016 mmol) and stirred at room temperature for overnight. After completion of the starting material (by LC-MS), reaction mixture was diluted with DCM (2 mL) and filtered through celite and filtrate was washed with water and brine. Combined organic extracts were dried over anhydrous Na2SO4, concentrated. The resultant residue was purified by flash chromatography on silica gel using an ISCO system (eluted with 7:3 Hexanes and EtOAc) to afford (3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4 (ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-((meth oxycarbonyl)amino)piperidin-3-yl 4-((di-tert-butoxyphosphoryl)oxy)butanoate (72 mg) as pale yellow solid.

후처리

  1. customAfter completion of the starting material (by LC-MS), reaction mixture
  2. filtrationfiltered through celite and filtrate
  3. washwas washed with water and brine
  4. dry with materialCombined organic extracts were dried over anhydrous Na2SO4
  5. concentrationconcentrated
  6. customThe resultant residue was purified by flash chromatography on silica gel using
  7. washan ISCO system (eluted with 7:3 Hexanes and EtOAc)

출처 및 근거

ORD 기록
ord-333dc3e7c42245668960ff4a2a0facf8
출처 데이터셋
uspto-grants-2016_03
특허 번호
US09273057B2

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