Trifluoroacetic acid → Isoquinolin-3-yl-carbamic acid 2-[3-(2-chloro-3-fluoro-benzyl)-1-methyl-ureido]-3-(2,3-dihydroxy-propoxy)-propyl ester

HRID 409800Notes

Reaction equation

HRID 409800 reaction equation
C(O[C:6]([N:8]([CH3:35])[CH:9]([CH2:25][O:26][CH2:27][CH:28]1[CH2:32][O:31]C(C)(C)[O:29]1)[CH2:10][O:11][C:12](=[O:24])[NH:13][C:14]1[N:15]=[CH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C.C1C([N+]([O-])=O)=CC=C([Cl-]C([O-])=O)C=1.[Cl:65][C:66]1[C:73]([F:74])=[CH:72][CH:71]=[CH:70][C:67]=1[CH2:68][NH2:69]>C(Cl)Cl.C1COCC1>[Cl:65][C:66]1[C:73]([F:74])=[CH:72][CH:71]=[CH:70][C:67]=1[CH2:68][NH:69][C:6](=[O:7])[N:8]([CH:9]([CH2:25][O:26][CH2:27][CH:28]([OH:29])[CH2:32][OH:31])[CH2:10][O:11][C:12](=[O:24])[NH:13][C:14]1[N:15]=[CH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:35]

Participants

7

Reactant 4

HCID 6422Trifluoroacetic acidHCID 81531Diisopropylethylamine2×HCID 50998690(2-Chloro-3-fluorophenyl)methanamineHCID 66622435Isoquinolin-3-yl-carbamic acid 2-(tert-butoxycarbonyl-methyl-amino)-3-(2,2-dimethyl-[1,3]-dioxolan-4-ylmethoxy)-propyl ester

Product 1

HCID 66622147Isoquinolin-3-yl-carbamic acid 2-[3-(2-chloro-3-fluoro-benzyl)-1-methyl-ureido]-3-(2,3-dihydroxy-propoxy)-propyl esterYield 45%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
24 °C

Procedure

To a solution of Isoquinolin-3-yl-carbamic acid 2-(tert-butoxycarbonyl-methyl-amino)-3-(2,2-dimethyl-[1,3]-dioxolan-4-ylmethoxy)-propyl ester (2.9 g, 5.93 mmol) in DCM (200 mL) was added TFA (12 mL) at 0° C. The mixture was stirred for 2 h, concentrated under reduced pressure, and re-dissolved in THF (10 mL) and DIEA (6.6 mL, 37.8 mmol). To this THF solution was added pre-stirred solution of 4-nitrophenylchloroformate (1.33 g, 6.62 mmol), 2-chloro-3-fluorobenzylamine (1.0 g, 6.3 mmol), and DIEA (1.2 mL, 6.9 mmol) in THF (85 mL) at 0° C. The reaction mixture was stirred for 2 h allowing the reaction to gradually warm to 24° C. The mixture was concentrated under reduced pressure, re-dissolved in MeOH, filtered, and purified by RP-HPLC using a mixture of acetonitrile and H2O to give isoquinolin-3-yl-carbamic acid 2-[3-(2-chloro-3-fluoro-benzyl)-1-methyl-ureido]-3-(2,3-dihydroxy-propoxy)-propyl ester (1.1 g, 45% over two steps). LRMS (M+H+) m/z 535.1.

Workup

  1. concentrationconcentrated under reduced pressure
  2. dissolutionre-dissolved in THF (10 mL)
  3. stirringThe reaction mixture was stirred for 2 h
  4. customthe reaction
  5. concentrationThe mixture was concentrated under reduced pressure
  6. dissolutionre-dissolved in MeOH
  7. filtrationfiltered
  8. custompurified by RP-HPLC
  9. additiona mixture of acetonitrile and H2O

Sources & evidence

ORD record
ord-592e363ca961444a8bf8e71818488c6f
Source dataset
uspto-grants-2014_06
Patent number
US08759374B2

Reaction notes

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