Hydrochloric Acid → 1-{[1-(2-tert-Butoxycarbonylamino-3,3-dimethyl-butyryl)-4-(3-ethoxy-isoquinolin-1-yloxy)-pyrrolidine-2-carbonyl]-amino}-2-ethyl-cyclopropanecarboxylic acid

HRID 2405782Notes

Reaction equation

HRID 2405782 reaction equation
[C:1]([O:5][C:6]([NH:8][CH:9]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:10]([N:12]1[CH2:16][CH:15]([OH:17])[CH2:14][CH:13]1[C:18]([NH:20][C:21]1([C:26]([OH:28])=[O:27])[CH2:23][CH:22]1[CH2:24][CH3:25])=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].Cl[C:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[C:42]([O:50][CH2:51][CH3:52])[N:41]=1.Cl>CS(C)=O>[C:1]([O:5][C:6]([NH:8][CH:9]([C:29]([CH3:31])([CH3:30])[CH3:32])[C:10]([N:12]1[CH2:16][CH:15]([O:17][C:40]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH:43]=[C:42]([O:50][CH2:51][CH3:52])[N:41]=2)[CH2:14][CH:13]1[C:18]([NH:20][C:21]1([C:26]([OH:28])=[O:27])[CH2:23][CH:22]1[CH2:24][CH3:25])=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 23665647Potassium tert-butoxideHCID 574451481-Chloro-3-ethoxyisoquinolineHCID 686163761-{[1-(2-tert-Butoxycarbonylamino-3,3-dimethylbutyryl)-4-hydroxypyrrolidine-2-carbonyl]-amino}-2-ethyl-cyclopropanecarboxylic acid

Product 1

HCID 686307641-{[1-(2-tert-Butoxycarbonylamino-3,3-dimethyl-butyryl)-4-(3-ethoxy-isoquinolin-1-yloxy)-pyrrolidine-2-carbonyl]-amino}-2-ethyl-cyclopropanecarboxylic acidYield 42%

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Procedure

1-{[1-(2-tert-Butoxycarbonylamino-3,3-dimethylbutyryl)-4-hydroxypyrrolidine-2-carbonyl]-amino}-2-ethyl-cyclopropanecarboxylic acid (See Example 33), 0.21 g, 0.46 mmol) was diluted in DMSO (4 mL) and treated with potassium tert-butoxide (0.26 g, 2.3 mmol) at rt for 30 min. 1-Chloro-3-ethoxyisoquinoline (0.100 g, 0.48 mmol) was added and the solution allowed to age overnight. Icewater was added, followed by 1M HCl until the solution reaches pH 3. Extraction with EtOAc was followed by washing of the combined organics with brine and drying over anhydrous Na2SO4 prior to concentration in vacuo. The resulting residue was purified by preparatory HPLC to produce 0.127 g (42%) of 1-{[1-(2-tert-Butoxycarbonylamino-3,3-dimethyl-butyryl)-4-(3-ethoxy-isoquinolin-1-yloxy)-pyrrolidine-2-carbonyl]-amino-}2-ethyl-cyclopropanecarboxylic acid as a white solid. LCMS found 626.90 [M+].

Workup

  1. customallowed to age overnight
  2. additionIcewater was added
  3. extractionExtraction with EtOAc
  4. washby washing of the combined organics with brine
  5. dry with materialdrying over anhydrous Na2SO4
  6. concentrationto concentration in vacuo
  7. customThe resulting residue was purified by preparatory HPLC

Sources & evidence

ORD record
ord-059bd77a0a6c4b128cb2d54b9da44b3c
Source dataset
uspto-grants-2014_08
Patent number
US08809267B2

Reaction notes

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