Hydrochloric Acid → (S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-hydroxy-4,4-dimethylpentyl 6-fluoroisoquinolin-3-ylcarbamate

HRID 340981Notes

Reaction equation

HRID 340981 reaction equation
C([O:4][CH2:5][C:6]([CH3:35])([CH3:34])[CH2:7][C@H:8]([N:25]([C:27](OC(C)(C)C)=[O:28])[CH3:26])[CH2:9][O:10][C:11](=[O:24])[NH:12][C:13]1[N:14]=[CH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([F:23])=[CH:18][CH:17]=2)(=O)C.Cl.CCN(C(C)C)C(C)C.[Cl:46][C:47]1[C:66]([F:67])=[CH:65][CH:64]=[CH:63][C:48]=1[CH2:49][NH:50]C(=O)OC1C=CC([N+]([O-])=O)=CC=1>C1COCC1>[F:23][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[N:14][C:13]([NH:12][C:11](=[O:24])[O:10][CH2:9][C@@H:8]([N:25]([CH3:26])[C:27]([NH:50][CH2:49][C:48]1[CH:63]=[CH:64][CH:65]=[C:66]([F:67])[C:47]=1[Cl:46])=[O:28])[CH2:7][C:6]([CH3:35])([CH3:34])[CH2:5][OH:4])=[CH:22]2

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 81531DiisopropylethylamineHCID 579475384-Nitrophenyl 2-chloro-3-fluorobenzylcarbamateHCID 57947839(S)-4-(tert-butoxycarbonyl(methyl)amino)-5-(6-fluoroisoquinolin-3-ylcarbamoyloxy)-2,2-dimethylpentyl acetate

Product 1

HCID 57947737(S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-hydroxy-4,4-dimethylpentyl 6-fluoroisoquinolin-3-ylcarbamateYield 54.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of (S)-4-(tert-butoxycarbonyl(methyl)amino)-5-(6-fluoroisoquinolin-3-ylcarbamoyloxy)-2,2-dimethylpentyl acetate (1.9 g, 3.8 mmol) in THF (50 mL) was added HCl (4 N in 1,4-dioxane, 19 mL, 76 mmol). The reaction mixture was stirred at RT for 1 h and concentrated to dryness. The residue was suspended in THF (100 mL). To the suspension were added DIEA (2.0 mL, 11.4 mmol) and 4-nitrophenyl 2-chloro-3-fluorobenzylcarbamate (1.2 g, 3.8 mmol). The reaction mixture was stirred at RT for 2 h and concentrated. The residue was purified on RP-HPLC using a mixture of acetonitrile and water to give (S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-hydroxy-4,4-dimethylpentyl 6-fluoroisoquinolin-3-ylcarbamate (1.1 g, 53%). LRMS (M+H+) m/z 535.5

Workup

  1. concentrationconcentrated to dryness
  2. stirringThe reaction mixture was stirred at RT for 2 h
  3. concentrationconcentrated
  4. customThe residue was purified on RP-HPLC
  5. additiona mixture of acetonitrile and water

Sources & evidence

ORD record
ord-b5c316e05fa949809196cc0c50e75e04
Source dataset
uspto-grants-2014_11
Patent number
US08895582B2

Reaction notes

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