Toluene → 4-[3-(2-Chloro-3-fluoro-benzyl)-1-methyl-ureido]-5-(isoquinolin-3-ylcarbamoyloxy)-pentanoic acid methyl ester

HRID 416374Notes

Reaction equation

HRID 416374 reaction equation
[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][CH:6]([N:16]([CH3:29])[C:17]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[Cl:28])=[O:18])[CH2:7][O:8][Si](C(C)(C)C)(C)C.CCCC[N+:35]([CH2:44][CH2:45][CH2:46][CH3:47])([CH2:40][CH2:41][CH2:42][CH3:43])CCCC.[F-].[C:49]1(C)C=CC=CC=1.C1C2C(=CC=CC=2)C=C([C:66]([N:68]=[N+]=[N-])=[O:67])N=1>C1COCC1>[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][CH:6]([N:16]([CH3:29])[C:17]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[Cl:28])=[O:18])[CH2:7][O:8][C:66](=[O:67])[NH:68][C:44]1[N:35]=[CH:40][C:41]2[C:46]([CH:45]=1)=[CH:47][CH:49]=[CH:43][CH:42]=2

Participants

6

Reactant 4

HCID 1140TolueneHCID 2724141Tetrabutylammonium FluorideHCID 579473563-Isoquinolinecarbonyl azideHCID 666220565-(Tert-butyl-dimethyl-silanyloxy)-4-[3-(2-chloro-3-fluoro-benzyl)-1-methyl-ureido]-pentanoic acid methyl ester

Product 1

HCID 666223034-[3-(2-Chloro-3-fluoro-benzyl)-1-methyl-ureido]-5-(isoquinolin-3-ylcarbamoyloxy)-pentanoic acid methyl esterYield 71%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
24 °C

Procedure

To a solution of 5-(tert-Butyl-dimethyl-silanyloxy)-4-[3-(2-chloro-3-fluoro-benzyl)-1-methyl-ureido]-pentanoic acid methyl ester (21.0 g, 45.6 mmol) in THF (450 mL) was slowly added TBAF (1 M in THF, 68.4 mL, 68.4 mmol). The reaction was stirred at 24° C. for 1 h. THF was removed. The residue was diluted with EtOAc (600 mL) and washed with saturated aq. NH4Cl and brine. The organic layers were dried over Na2SO4 and concentrated. The resulting residue was dissolved in toluene and added into a toluene solution of isoquinoline-3-carbonyl azide (9.07 g, 45.6 mmol) at 100° C. The reaction mixture was heated to 100° C. for 1 h and then concentrated. Resulting residue was purified on silica gel column using hexanes and EtOAc to give 4-[3-(2-chloro-3-fluoro-benzyl)-1-methyl-ureido]-5-(isoquinolin-3-ylcarbamoyloxy)-pentanoic acid methyl ester (16.8 g, 71%) as a colorless oil. LRMS (M+H+) m/z 517.1.

Workup

  1. customTHF was removed
  2. additionThe residue was diluted with EtOAc (600 mL)
  3. washwashed with saturated aq. NH4Cl and brine
  4. dry with materialThe organic layers were dried over Na2SO4
  5. concentrationconcentrated
  6. dissolutionThe resulting residue was dissolved in toluene
  7. temperatureThe reaction mixture was heated to 100° C. for 1 h
  8. concentrationconcentrated
  9. customResulting residue was purified on silica gel column

Sources & evidence

ORD record
ord-0854973a7ea64b578c0af41f6a21eefc
Source dataset
uspto-grants-2012_01
Patent number
US08088793B2

Reaction notes

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