Diisopropylamine → 3-[(2-chlorophenyl)methyl]-2-propylthio-N-(diphenylmethylene)histidine ethyl ester

HRID 273828Notes

Reaction equation

HRID 273828 reaction equation
C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][C:16](=[O:32])[CH2:17][N:18]=[C:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:14].Cl.[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41][N:42]1[C:46]([CH2:47]Cl)=[CH:45][N:44]=[C:43]1[S:49][CH2:50][CH2:51][CH3:52].[Cl-].[NH4+]>O1CCCC1.CN(C)C=O>[CH2:13]([O:15][C:16](=[O:32])[C@H:17]([CH2:47][C:46]1[N:42]([CH2:41][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[Cl:34])[C:43]([S:49][CH2:50][CH2:51][CH3:52])=[N:44][CH:45]=1)[N:18]=[C:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH3:14]

Participants

8

Reactant 5

HCID 7912DiisopropylamineHCID 25517Ammonium ChlorideHCID 319508Ethyl 2-(diphenylmethyleneamino)acetateHCID 19351525HCID 19351525, compoundHCID 178418339Butyllithium

Product 1

HCID 537539713-[(2-chlorophenyl)methyl]-2-propylthio-N-(diphenylmethylene)histidine ethyl esterYield 47.1%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

A solution of diisopropylamine (8.4 mL) in tetrahydrofuran (100 mL) was cooled to -78° C. under argon and a solution of n-butyl lithium (30 mL of 2.5M in hexane) was added. The mixture was stirred at -78° C. for 30 minutes and at 0° C. for 10 minutes. After being recooled to -78° C., a solution of N-(diphenylmethylene)glycine ethyl ester (Tetra. Lett., (1978), 2541, 4625) (15.4 g) in tetrahydrofuran (50 mL) was added, the mixture was stirred for 1 hour at -78° C. and a solution of 1-(2-chlorophenyl)methyl-5-chloromethyl-2-propylthio-1H-imidazole hydrochloride (9.4 g) in dry dimethylformamide (20 mL) was added. The mixture was then stirred at ambient temperature for 18 hours, poured into saturated ammonium chloride solution and the aqueous layer was extracted with methylene chloride. The organic extracts were washed with water, dried with magnesium sulfate concentrated and chromatographed over silica gel with 1% methanol in methylene chloride to afford 6.88 g of 3-[(2-chlorophenyl)methyl]-2-propylthio-N-(diphenylmethylene)histidine ethyl ester. This product (2.59 g) was dissolved in methylene chloride (52 mL), aqueous 1N hydrochloric acid solution (52 mL) was added and the mixture was stirred at 25° C. for 18 hours. The aqueous layer was separated, neutralized to pH 10.5 with sodium carbonate and the product was extracted into methylene chloride. The organic extract was dried with magnesium sulfate and concentrated to give 1.29 g (71%) of 3-[(2-chlorophenyl)methyl]-2-propylthio-histidine ethyl ester as an oil.

Workup

  1. customAfter being recooled to -78° C.
  2. stirringthe mixture was stirred for 1 hour at -78° C.
  3. stirringThe mixture was then stirred at ambient temperature for 18 hours
  4. extractionthe aqueous layer was extracted with methylene chloride
  5. washThe organic extracts were washed with water
  6. dry with materialdried with magnesium sulfate
  7. concentrationconcentrated
  8. customchromatographed over silica gel with 1% methanol in methylene chloride

Sources & evidence

ORD record
ord-e9270948ec1b43649c7562ade79557c9
Source dataset
uspto-grants-1995_02
Patent number
US05387601

Reaction notes

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