Triethylamine → 1-[[4-[8-Chloro-2-(4-isopropylthiazol-2-yl)-7-methoxyquinolin-4-yloxy]-1-(2,2-dimethylnon-8-enoyl)pyrrolidine-2-carbonyl]amino]-2-vinylcyclopropanecarboxylic acid ethyl ester

HRID 1669572Notes

Reaction equation

HRID 1669572 reaction equation
[CH3:1][C:2]([CH3:13])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])[C:3]([OH:5])=O.C(Cl)(=O)C(Cl)=O.[CH2:20]([O:22][C:23]([C:25]1([NH:30][C:31]([CH:33]2[CH2:37][CH:36]([O:38][C:39]3[C:48]4[C:43](=[C:44]([Cl:51])[C:45]([O:49][CH3:50])=[CH:46][CH:47]=4)[N:42]=[C:41]([C:52]4[S:53][CH:54]=[C:55]([CH:57]([CH3:59])[CH3:58])[N:56]=4)[CH:40]=3)[CH2:35][NH:34]2)=[O:32])[CH2:27][CH:26]1[CH:28]=[CH2:29])=[O:24])[CH3:21].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH2:20]([O:22][C:23]([C:25]1([NH:30][C:31]([CH:33]2[CH2:37][CH:36]([O:38][C:39]3[C:48]4[C:43](=[C:44]([Cl:51])[C:45]([O:49][CH3:50])=[CH:46][CH:47]=4)[N:42]=[C:41]([C:52]4[S:53][CH:54]=[C:55]([CH:57]([CH3:58])[CH3:59])[N:56]=4)[CH:40]=3)[CH2:35][N:34]2[C:3](=[O:5])[C:2]([CH3:1])([CH3:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])=[O:32])[CH2:27][CH:26]1[CH:28]=[CH2:29])=[O:24])[CH3:21]

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 65578Oxalyl chlorideHCID 594971782,2-Dimethylnon-8-enoic acidHCID 673186401-[[4-[8-Chloro-2-(4-isopropylthiazol-2-yl)-7-methoxyquinolin-4-yloxy]pyrrolidine-2-carbonyl]amino]-2-vinylcyclopropanecarboxylic acid ethyl ester

Product 1

HCID 673197771-[[4-[8-Chloro-2-(4-isopropylthiazol-2-yl)-7-methoxyquinolin-4-yloxy]-1-(2,2-dimethylnon-8-enoyl)pyrrolidine-2-carbonyl]amino]-2-vinylcyclopropanecarboxylic acid ethyl esterYield 100.3%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolvent2×

Procedure

To a solution of 2,2-dimethylnon-8-enoic acid (52, 239 mg, 1.3 mmol) in dry CH2Cl2 (10 mL) was added oxalyl chloride (165 mg, 2.6 mmol) and 2 drops of DMF. After 3 h at room temperature, the reaction mixture was concentrated and co-evaporated with toluene. This crude acid chloride was successively re-dissolved in CH2Cl2 and added to a stirred solution of 1-[[4-[8-chloro-2-(4-isopropylthiazol-2-yl)-7-methoxyquinolin-4-yloxy]pyrrolidine-2-carbonyl]amino]-2-vinylcyclopropanecarboxylic acid ethyl ester (50, 380 mg, 0.65 mmol) and triethylamine (264 μL, 1.95 mmol) in CH2Cl2 (30 mL). After 1.5 h, the resulting solution was successively washed with a saturated solution of NaHCO3 and brine, dried (MgSO4), filtered and concentrated under reduced pressure. Purification by flash chromatography (gradient EtOAc/CH2Cl2 0:1 to 2:8) afforded the title product (53) as a colorless oil (490 mg, 100%): m/z=751 (M+H)+.

Workup

  1. concentrationthe reaction mixture was concentrated and co-evaporated with toluene
  2. dissolutionThis crude acid chloride was successively re-dissolved in CH2Cl2
  3. waitAfter 1.5 h
  4. washthe resulting solution was successively washed with a saturated solution of NaHCO3 and brine
  5. dry with materialdried (MgSO4)
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customPurification by flash chromatography (gradient EtOAc/CH2Cl2 0:1 to 2:8)

Sources & evidence

ORD record
ord-020a133ffe3745b298d550d2effa2d68
Source dataset
uspto-grants-2011_08
Patent number
US07989471B2

Reaction notes

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