Diisopropylethylamine → 4-[8-Chloro-2-(4-isopropylthiazol-2-yl)-7-methoxyquinolin-4-yloxy]-2-(1-ethoxycarbonyl-2-vinylcyclopropylcarbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester

HRID 1669568Notes

Reaction equation

HRID 1669568 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[C:23]3[C:18](=[C:19]([Cl:26])[C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[N:17]=[C:16]([C:27]3[S:28][CH:29]=[C:30]([CH:32]([CH3:34])[CH3:33])[N:31]=3)[CH:15]=2)[CH2:10][CH:9]1[C:35](O)=[O:36])=[O:7])([CH3:4])([CH3:3])[CH3:2].S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH2:49]([O:51][C:52]([C@@:54]1([NH2:59])[CH2:56][C@H:55]1[CH:57]=[CH2:58])=[O:53])[CH3:50].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[C:23]3[C:18](=[C:19]([Cl:26])[C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[N:17]=[C:16]([C:27]3[S:28][CH:29]=[C:30]([CH:32]([CH3:34])[CH3:33])[N:31]=3)[CH:15]=2)[CH2:10][CH:9]1[C:35](=[O:36])[NH:59][C:54]1([C:52]([O:51][CH2:49][CH3:50])=[O:53])[CH2:56][CH:55]1[CH:57]=[CH2:58])=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 46737761(1R,2S)-ethyl 1-amino-2-vinylcyclopropanecarboxylate 4-methylbenzenesulfonateHCID 673193434-[8-Chloro-2-(4-isopropylthiazol-2-yl)-7-methoxyquinolin-4-yloxy]-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester

Product 1

HCID 673198764-[8-Chloro-2-(4-isopropylthiazol-2-yl)-7-methoxyquinolin-4-yloxy]-2-(1-ethoxycarbonyl-2-vinylcyclopropylcarbamoyl)pyrrolidine-1-carboxylic acid tert-butyl esterYield 70.6%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

To a stirred solution of 4-[8-chloro-2-(4-isopropylthiazol-2-yl)-7-methoxyquinolin-4-yloxy]-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (48, 3.4 g, 6.20 mmol) in dry DMF (50 mL) was added (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid ethyl ester tosylate (2.23 g, 6.82 mmol) and diisopropylethylamine (2.70 mL, 17.1 mmol). Then, HATU (2.59 g, 6.82 mmol) was added at 0° C. under nitrogen. After 30 min at 0° C., the reaction mixture was successively allowed to warm up to room temperature for 4 h, then diluted with water (150 mL) and extracted with EtOAc (3×150 mL). The organic layers were combined and washed with a saturated solution of NaHCO3, water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. Purification by column chromatography (gradient EtOAc/CH2Cl2, 0:1 to 2:8) afforded 3.0 g (70%) of the title product 49: m/z=685 (M+H)+.

Workup

  1. extractionextracted with EtOAc (3×150 mL)
  2. washwashed with a saturated solution of NaHCO3, water and brine
  3. dry with materialdried (MgSO4)
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customPurification by column chromatography (gradient EtOAc/CH2Cl2, 0:1 to 2:8)

Sources & evidence

ORD record
ord-f6521400b6b540d18aa29244c8958b21
Source dataset
uspto-grants-2011_08
Patent number
US07989471B2

Reaction notes

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