Diisopropylethylamine → Ethyl 4-(4-fluoro-3-((3-(3-methylisoxazol-5-yl)ureido)methyl)benzyl)piperazine-1-carboxylate

HRID 1169601Notes

Reaction equation

HRID 1169601 reaction equation
[NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[CH:3]=1.CCN(C(C)C)C(C)C.Cl[C:18](OC1C=CC([N+]([O-])=O)=CC=1)=[O:19].[NH2:30][CH2:31][C:32]1[CH:33]=[C:34]([CH:47]=[CH:48][C:49]=1[F:50])[CH2:35][N:36]1[CH2:41][CH2:40][N:39]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:38][CH2:37]1>C1COCC1.C(OCC)(=O)C.C1COCC1.C(Cl)Cl>[F:50][C:49]1[CH:48]=[CH:47][C:34]([CH2:35][N:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:38][CH2:37]2)=[CH:33][C:32]=1[CH2:31][NH:30][C:18]([NH:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[CH:3]=1)=[O:19]

Participants

8

Reactant 4

HCID 81531DiisopropylethylamineHCID 821294-Nitrophenyl chloroformateHCID 845905-Amino-3-methylisoxazoleHCID 24859219Ethyl 4-(3-(aminomethyl)-4-fluorobenzyl)piperazine-1-carboxylate

Product 1

HCID 23661358Ethyl 4-(4-fluoro-3-((3-(3-methylisoxazol-5-yl)ureido)methyl)benzyl)piperazine-1-carboxylateYield 5.6%

Reagents, catalysts & solvents 3

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolventHCID 21919333Tetrahydrofurane dichloromethaneSolvent

Procedure

5-Amino-3-methyl-isoxazole (100 mg, 1.02 mmol, 1.0 equiv.) was added to a vial and dissolved in anhydrous THF (EMD, 5 mL) and redistilled DIPEA (196 ul, 1.12 mmol, 1.1 equiv.) under atmosphere of N2. To this solution 4-nitrophenyl chloroformate (205 mg, 1.02 mmol, 1.0 equiv.) was added directly and the vial was purged again with nitrogen. After 10 minutes, the reaction turned off-white and opaque; after 12 hours of stirring at room temperature the mixture became yellow in color. The presence of the intermediate carbamate was confirmed by TLC (10% MeOH/DCM) and reverse phase LC/MS: a strong UV peak was observed but the mass was not observed in positive ionization mode. Ethyl 4-(3-(aminomethyl)-4-fluorobenzyl)piperazine-1-carboxylate (139 mg, 1.02 mmol, 1.0 equiv.) in a minimal amount of THF/DCM and added drop-wise to the reaction vessel under atmosphere of N2. The mixture was stirred for 1 hour then heated to 65° C. for 2 hours. The reaction was allowed to cool to room temperature and then diluted with ethyl acetate (30 mL), washed with 1N NaOH (2×10 mL) and brine (1×10 mL), and dried over Na2SO4. The organic layer was then concentrated under reduced pressure to yield a yellow oil. The yellow oil was loaded onto a Biotage samplet and purified via automated silica gel chromatography in MeCN/DCM (Linear gradient from 15% to 74% [300 mL], held at 74%[140 mL], linear gradient from 74% to 100% [300 mL], and held at 100% [400 mL]) to provide 24 mg of ethyl 4-(4-fluoro-3-((3-(3-methylisoxazol-5-yl)ureido)methyl)benzyl)piperazine-1-carboxylate.

Workup

  1. customthe vial was purged again with nitrogen
  2. stirringThe mixture was stirred for 1 hour
  3. temperaturethen heated to 65° C. for 2 hours
  4. temperatureto cool to room temperature
  5. washwashed with 1N NaOH (2×10 mL) and brine (1×10 mL)
  6. dry with materialdried over Na2SO4
  7. concentrationThe organic layer was then concentrated under reduced pressure
  8. customto yield a yellow oil
  9. custompurified

Sources & evidence

ORD record
ord-c7da3cc4a1e743da8227b47fee744864
Source dataset
uspto-grants-2010_11
Patent number
US07825120B2

Reaction notes

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