Triethylamine → HCID 131732384, compound

HRID 921650Notes

Reaction equation

HRID 921650 reaction equation
[C:1](Cl)(=[O:7])[O:2][CH2:3][CH2:4][O:5][CH3:6].[NH2:9][C@@H:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:17]([Cl:40])=[C:18]([NH:24][C:25]3[N:30]=[C:29]([NH:31][CH:32]4[CH2:34][CH2:33]4)[C:28]4=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:27]4[N:26]=3)[CH:19]=[C:20]([C:22]#[N:23])[CH:21]=2)[CH2:12][C@H:11]1[O:41][Si:42]([CH:49]([CH3:51])[CH3:50])([CH:46]([CH3:48])[CH3:47])[CH:43]([CH3:45])[CH3:44].C(N(CC)CC)C>ClCCl>[Cl:40][C:17]1[C:18]([NH:24][C:25]2[N:30]=[C:29]([NH:31][CH:32]3[CH2:33][CH2:34]3)[C:28]3=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:27]3[N:26]=2)=[CH:19][C:20]([C:22]#[N:23])=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][C@@H:10]([NH:9][C:1](=[O:7])[O:2][CH2:3][CH2:4][O:5][CH3:6])[C@H:11]([O:41][Si:42]([CH:46]([CH3:48])[CH3:47])([CH:49]([CH3:51])[CH3:50])[CH:43]([CH3:44])[CH3:45])[CH2:12]1

Participants

5

Reactant 3

HCID 8471Triethylamine2×HCID 694002-Methoxyethyl chloroformate3×HCID 86708497HCID 86708497, compound

Product 1

HCID 131732384HCID 131732384, compoundYield 53.5%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

2-methoxyethyl carbonochloridate (5.08 mg, 0.037 mmol) was added to a solution of 2-((3-((3R,4R)-4-amino-3-((triisopropylsilyl)oxy)piperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 174D, 19 mg, 0.031 mmol) and triethylamine (8.53 μl, 0.061 mmol) in dichloromethane (1 mL) and the reaction solution was stirred at room temperature overnight. More 2-methoxyethyl carbonochloridate (5.08 mg, 0.037 mmol) was added and stirring continued over the weekend, still about 30% SM left. More triethylamine (100 μL) and 2-methoxyethyl carbonochloridate (20 μL) was added and stirred for another day. The reaction mixture was diluted with dichloromethane and washed with cold saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo, and the crude product was purified by flash chromatography on silica gel using an automated ISCO system (24 g column, eluting with 0-40% ethyl acetate/dichloromethane) to give 2-methoxyethyl ((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino) imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-((triisopropylsilyl)oxy)piperidin-4-yl)carbamate (12 mg).

Workup

  1. stirringstirring
  2. waitleft
  3. stirringstirred for another day
  4. washwashed with cold saturated sodium bicarbonate
  5. dry with materialThe organic layer was dried over magnesium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customthe crude product was purified by flash chromatography on silica gel using
  9. washan automated ISCO system (24 g column, eluting with 0-40% ethyl acetate/dichloromethane)

Sources & evidence

ORD record
ord-95930f99faae43198ada96943c3efe5f
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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