1,2-Dichloroethane → (S)--N--[(1S,2R,3RS)-1-(cyclohexylmethyl)-4-ethyl-2,3-dihydroxyhexyl]-alpha-[(R)-alpha-(3,3-dimethyl-2-oxobutyl)hydrocinnamamido]imidazole-4-propionamide

HRID 1657248Notes

Reaction equation

HRID 1657248 reaction equation
[NH2:1][C@@H:2]([CH2:23][C:24]1[N:25]=[CH:26][NH:27][CH:28]=1)[C:3]([NH:5][C@@H:6]([CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C@@H:7]([OH:15])[CH:8]([OH:14])[CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[O:4].[C:29]([CH2:35][C@@H:36]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:37](O)=[O:38])(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31].C(N1CCOCC1)C.C(Cl)CCl>CN(C)C=O>[CH:17]1([CH2:16][C@H:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][C:37](=[O:38])[C@@H:36]([CH2:35][C:29](=[O:34])[C:30]([CH3:31])([CH3:33])[CH3:32])[CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:23][C:24]2[N:25]=[CH:26][NH:27][CH:28]=2)[C@@H:7]([OH:15])[CH:8]([OH:14])[CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1

Participants

6

Reactant 4

HCID 111,2-DichloroethaneHCID 7525EthylmorpholineHCID 18611819(R)-alpha-(pivaloylmethyl)hydrocinnamic acidHCID 178445066(S)-alpha-amino-N-[(1S,2R,3RS)-1-(cyclohexylmethyl)-4-ethyl-2,3-dihydroxyhexyl]imidazole-4-propionamide

Product 1

HCID 178445065(S)--N--[(1S,2R,3RS)-1-(cyclohexylmethyl)-4-ethyl-2,3-dihydroxyhexyl]-alpha-[(R)-alpha-(3,3-dimethyl-2-oxobutyl)hydrocinnamamido]imidazole-4-propionamideYield 64.6%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A mixture of 880 mg (2.23 mmol) of (S)-α-amino-N-[(1S,2R,3RS)-1-(cyclohexylmethyl)-4-ethyl-2,3-dihydroxyhexyl]imidazole-4-propionamide, 608 mg (2.45 mmol) of (R)-α-(pivaloylmethyl)hydrocinnamic acid (see EPA 0 184 550), 0.35 ml (2.76 mmol) of 4-ethylmorpholine, 662 mg (4.9 mmol) of HBT and 529 mg (2.76 mmol) of EDC in 20 ml of dimethylformamide is stirred at room temperature overnight. Thereafter, the reaction mixture is evaporated to dryness in a high vacuum, the residue is poured into a mixture of ice and 2N sodium bicarbonate solution and extracted three times with ethyl acetate. The extracts are washed in succession with saturated ammonium chloride solution, 2N sodium bicarbonate solution and saturated sodium chloride solution and combined. After drying the organic solution over magnesium sulphate the solvent is evaporated under reduced pressure and the residue (1.01 g), for purification, is chromatographed on 70 g of silica gel using a 20:1:0.1 mixture of methylene chloride, methanol and ammonia as the eluting agent. Crystallization of the thus-obtained crude product from methylene chloride/methanol/ether yields 900 mg of (S)-N-[(1S,2R,3RS)-1-(cyclohexylmethyl)-4-ethyl-2,3-dihydroxyhexyl]-α-[(R)-α-(3,3-dimethyl-2-oxobutyl)hydrocinnamamido]imidazole-4-propionamide, melting point 160°, MS: 624 (M)+.

Workup

  1. customThereafter, the reaction mixture is evaporated to dryness in a high vacuum
  2. additionthe residue is poured into a mixture of ice and 2N sodium bicarbonate solution
  3. extractionextracted three times with ethyl acetate
  4. washThe extracts are washed in succession with saturated ammonium chloride solution, 2N sodium bicarbonate solution and saturated sodium chloride solution
  5. dry with materialAfter drying the organic solution over magnesium sulphate the solvent
  6. customis evaporated under reduced pressure
  7. customthe residue (1.01 g), for purification
  8. customis chromatographed on 70 g of silica gel using
  9. additiona 20:1:0.1 mixture of methylene chloride, methanol and ammonia as the eluting agent
  10. customCrystallization of the
  11. customthus-obtained crude product from methylene chloride/methanol/ether

Sources & evidence

ORD record
ord-6b462040398a4ce1a1ed48951fc9c9c4
Source dataset
uspto-grants-1993_10
Patent number
US05256645

Reaction notes

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