4-Methylmorpholine → ethyl 3-bromo-4-({(1S)-4-(4-methoxyphenyl)-1-[(tert-butoxycarbonylmethylamino)carbonyl]butyl}thio)benzoate

HRID 1817198Notes

Reaction equation

HRID 1817198 reaction equation
Cl.[C:2]([O:6][C:7](=[O:10])[CH2:8][NH2:9])([CH3:5])([CH3:4])[CH3:3].C1(N=C=NC2CCCCC2)CCCCC1.[Br:26][C:27]1[CH:32]=[C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:30]=[CH:29][C:28]=1[S:38][C@@H:39]([CH2:43][CH2:44][CH2:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=1)[C:40](O)=[O:41].CN1CCOCC1>ClCCl.O>[Br:26][C:27]1[CH:32]=[C:31]([CH:30]=[CH:29][C:28]=1[S:38][C@H:39]([C:40]([NH:9][CH2:8][C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:10])=[O:41])[CH2:43][CH2:44][CH2:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=1)[C:33]([O:35][CH2:36][CH3:37])=[O:34]

Participants

7

Reactant 4

HCID 79724-MethylmorpholineHCID 10868DicyclohexylcarbodiimideHCID 2725036Glycine tert-butyl ester hydrochlorideHCID 57880345(2S)-2-{[2-bromo-4-(ethoxycarbonyl)phenyl]thio}-5-(4-methoxyphenyl)pentanoic acid

Product 1

HCID 57880333ethyl 3-bromo-4-({(1S)-4-(4-methoxyphenyl)-1-[(tert-butoxycarbonylmethylamino)carbonyl]butyl}thio)benzoate

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

Glycine tert-butyl ester hydrochloride (2.03 g) and dicyclohexylcarbodiimide (DCC) (2.5 g) were added to a solution of (2S)-2-{[2-bromo-4-(ethoxycarbonyl)phenyl]thio}-5-(4-methoxyphenyl)pentanoic acid (the compound of Reference Example 8) (96% e.e.) in dichloromethane (56.4 ml) at −5° C., and N-methylmorpholine (1.26 ml) was added dropwise thereto. After stirring at the same temperature for 1.5 hours, water was added thereto and the resulting mixture was filtered through Celite. The filtrate was extracted with chloroform and the extract solution was washed with a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the solvent was distilled off under reduced pressure. The residue was purified by a silica gel column chromatography (hexane/ethyl acetate=3/1) to obtain ethyl 3-bromo-4-({(1S)-4-(4-methoxyphenyl)-1-[(tert-butoxycarbonylmethylamino)carbonyl]butyl}thio)benzoate (4.83 g, 98% e.e.). The optical purity analysis conditions are as follows. [Optical purity analysis conditions: column=AD-H (Chiralcel, DAICEL Chemical Industries Ltd.); detecting wavelength (UV)=254 nm; flow rate: 1.0 ml/min; mobile phase=n-hexane/isopropyl alcohol/TFA (90/10/0.1)]

Workup

  1. filtrationthe resulting mixture was filtered through Celite
  2. extractionThe filtrate was extracted with chloroform
  3. washthe extract solution was washed with a saturated aqueous ammonium chloride solution
  4. dry with materiala saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate
  5. customThe drying agent was removed by filtration
  6. distillationthe solvent was distilled off under reduced pressure
  7. customThe residue was purified by a silica gel column chromatography (hexane/ethyl acetate=3/1)

Sources & evidence

ORD record
ord-5adb679f42a84bd494a68b8018e39476
Source dataset
uspto-grants-2009_10
Patent number
US07598240B2

Reaction notes

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