Isobutyl chloroformate → (3,4-Difluoro-phenyl)-[(4-hydroxymethyl-2-methyl-phenylcarbamoyl)-methyl]-carbamic acid tert-butyl ester

HRID 1267915Notes

Reaction equation

HRID 1267915 reaction equation
[C:1]([O:5][C:6]([N:8]([CH2:17][C:18]([OH:20])=O)[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(Cl)=O)C(C)C.C([SiH2][O:34][C:35](C)(C)[C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[C:38]([CH3:43])[CH:37]=1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C.O.C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:7])[N:8]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=1)[CH2:17][C:18](=[O:20])[NH:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][OH:34])=[CH:37][C:38]=1[CH3:43])([CH3:2])([CH3:3])[CH3:4]

Participants

8

Reactant 4

HCID 62365Isobutyl chloroformateHCID 2724141Tetrabutylammonium FluorideHCID 18542398[tert-Butoxycarbonyl-(3,4-difluorophenyl)-amino]-acetic acidHCID 1317238684-(Tert-butyl-dimethyl-silanyloxymethyl)-2-methyl-phenylamine

Product 1

HCID 54409487(3,4-Difluoro-phenyl)-[(4-hydroxymethyl-2-methyl-phenylcarbamoyl)-methyl]-carbamic acid tert-butyl esterYield 34.6%

Reagents, catalysts & solvents 3

HCID 8028TetrahydrofuranSolvent3×HCID 8471TriethylamineSolvent2×HCID 22728543Water ethylacetateSolvent

Procedure

To a solution of [tert-butoxycarbonyl-(3,4-difluorophenyl)-amino]-acetic acid (5.74 g) in tetrahydrofuran (40 ml) at 0° C. was added triethylamine (3.2 ml) followed by isobutylchloroformate (2.9 ml) dropwise. After stirring for lhr, triethylamine (3.2 ml) was added followed by 4-(tert-butyl-dimethyl-silanyloxymethyl)-2-methyl-phenylamine (5.0 g) in tetrahydrofuran (3 ml), and the reaction warmed to room temperature and then heated at 58° C. overnight. After cooling to 0° C., tetrabutylammonium fluoride (7.6 ml of a 1M solution in tetrahydrofuran) was added dropwise and the reaction warmed to room temperature. After 3 hrs, the solution was poured into ethyl acetate/water and the organic layer separated, washed with KHSO4 (10% solution in water), water and brine, dried (Na2SO4) and concentrated. Purification of the residue by silica gel chromatography (eluting with 3% methanol in dichloromethane) gave an orange solid. Recrystallisation from 2-propanol/isohexane gave the sub-title compound as white crystals (2.8 g).

Workup

  1. additionwas added
  2. temperatureheated at 58° C. overnight
  3. temperatureAfter cooling to 0° C.
  4. temperaturethe reaction warmed to room temperature
  5. customthe organic layer separated
  6. washwashed with KHSO4 (10% solution in water), water and brine
  7. dry with materialdried (Na2SO4)
  8. concentrationconcentrated
  9. customPurification of the residue
  10. washby silica gel chromatography (eluting with 3% methanol in dichloromethane)
  11. customgave an orange solid
  12. customRecrystallisation from 2-propanol/isohexane

Sources & evidence

ORD record
ord-dcfa202c93de4d2da71fc5a9be09d6c8
Source dataset
uspto-grants-2003_04
Patent number
US06555541B1

Reaction notes

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