1-Chloro-4-methoxyisoquinoline → (2S,4R)-1-((2S,3R)-2-(tert-butoxycarbonylamino)-3,7-dimethylnon-8-enoyl)-4-(4-methoxyisoquinolin-1-yloxy)pyrrolidine-2-carboxylic acid

HRID 2361593Notes

Reaction equation

HRID 2361593 reaction equation
[C:1]([O:5][C:6]([NH:8][CH:9]([C@H:21]([CH3:29])[CH2:22][CH2:23][CH2:24][CH:25]([CH3:28])[CH:26]=[CH2:27])[C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18]([OH:20])=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([O:41][CH3:42])=[CH:33][N:32]=1.CC([O-])(C)C.[K+]>CS(C)=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:21]([CH3:29])[CH2:22][CH2:23][CH2:24][CH:25]([CH3:28])[CH:26]=[CH2:27])[C:10]([N:12]1[CH2:16][C@H:15]([O:17][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]([O:41][CH3:42])=[CH:33][N:32]=2)[CH2:14][C@H:13]1[C:18]([OH:20])=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

5

Reactant 3

HCID 222501441-Chloro-4-methoxyisoquinolineHCID 23665647Potassium tert-butoxideHCID 86685808(2S,4R)-1-((3R)-2-((tert-butoxycarbonyl)amino)-3,7-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid

Product 1

HCID 86685807(2S,4R)-1-((2S,3R)-2-(tert-butoxycarbonylamino)-3,7-dimethylnon-8-enoyl)-4-(4-methoxyisoquinolin-1-yloxy)pyrrolidine-2-carboxylic acidYield 40%

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Procedure

To a solution of (2S,4R)-1-((3R)-2-((tert-butoxycarbonyl)amino)-3,7-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid (1.5 g, 3.6 mmol) in DMSO was added 1-chloro-4-methoxyisoquinoline (840 mg, 4.4 mmol) followed by t-BuOK (1M sol. in THF, 18 mL) at room temperature under nitrogen atmosphere. The reaction mass was stirred at room temperature for 4 h. The reaction mass was quenched with aqueous citric acid solution and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to get crude compound. The crude compound was purified by combiflash to get desired product (800 mg, 40%) as off-white solid. 1H NMR (400 MHz, CDCl3): δ ppm 8.11-8.09 (m, 2H), 7.70-7.66 (t, J=7.4 Hz, 1H), 7.56-7.51 (t, J=8.0 Hz, 1H), 7.47 (s, 1H), 5.78 (bs, 1H), 5.69-5.65 (m, 1H), 5.14-5.11 (m, 1H), 4.96-4.88 (m, 3H), 4.43-4.41 (m, 1H), 4.27-4.24 (m, 1H), 3.99 (s, 4H), 2.75-2.73 (m, 1H), 2.67-2.65 (m, 1H), 2.10 (bs, 1H), 1.88-1.85 (m, 2H), 1.31 (s, 9H), 1.24 (s, 2H), 0.98-0.96 (m, 4H), 0.91-0.86 (m, 4H) MS: MS m/z 568.2 (M++1).

Workup

  1. customThe reaction mass was quenched with aqueous citric acid solution
  2. extractionextracted with ethyl acetate
  3. dry with materialThe combined organic layer was dried over anhydrous Na2SO4
  4. concentrationconcentrated under reduced pressure
  5. customto get crude compound
  6. customThe crude compound was purified by combiflash

Sources & evidence

ORD record
ord-1ae8ccbd03e24dd1a9114dfe13150b86
Source dataset
uspto-grants-2014_04
Patent number
US08691757B2

Reaction notes

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