4-Methylmorpholine → n-((r/s)-Methylphenyl-phosphinyl)-n-(3-picolyl) d-leucine methyl ester

HRID 355448Notes

Reaction equation

HRID 355448 reaction equation
[CH3:1][P:2](Cl)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[CH3:11][O:12][C:13](=[O:27])[C@@H:14]([CH2:23][CH:24]([CH3:26])[CH3:25])[NH:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.CN1CCOCC1>ClCCl.CN(C)C1C=CN=CC=1>[CH3:11][O:12][C:13](=[O:27])[C@@H:14]([CH2:23][CH:24]([CH3:25])[CH3:26])[N:15]([P:2]([CH3:1])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3])[CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1

Participants

6

Reactant 3

HCID 79724-MethylmorpholineHCID 21983Methyl(phenyl)phosphinoyl chloride2×HCID 54454922N-(3-picolyl) D-leucine methyl ester

Product 1

HCID 131720914n-((r/s)-Methylphenyl-phosphinyl)-n-(3-picolyl) d-leucine methyl ester

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

Methylphenylphosphinic chloride (12.23 g, 70 mmol) is taken up in dichloromethane (100 mL) and cooled to 0° C. To this is added a solution of N-(3-picolyl) D-leucine methyl ester (15.5 g, 65.6 mmol) and N-methyl morpholine (19.24 mL, 175 mmol) in dichloromethane (100 mL). A catalytic amount of 4-dimethylaminopyridine is added and the reaction stirs for 16 hours at room temperature. More methylphenylphosphinic chloride is added (2 g, 11.46 mmol). The reaction continues to stir for 24 hours until complete. By TLC, the diastereomers do not separate. The product is purified by silica gel flash chromatography (5:95 ethanol:ethyl acetate) to give N-((R/S)-methylphenyl-phosphinyl)-N-(3-picolyl) D-leucine methyl ester as an oil. To this ester is added a solution of NH2OK (250 mL, 1.76M in methanol) prepared as described in Fieser and Fieser, Vol. 1, p. 478. The reaction is stirred for 16 hours at which time TLC indicates completion. The reaction mixture is neutralized with 1M aqueous HCl and the volatiles are removed. The product is purified by silica gel flash chromatography (10:90 ethanol:ethyl acetate) to give 8.6 g of N-hydroxy-2(R)-[[(R/S)-methylphenylphosphinyl]3-picolylamino]-4-methylpentanamide as a 60 (R)/40 (S) mixture of diastereomers: MS-IS m/z 376 [M+H]+, 398[M+Na]+. (R1 =3-pyridyl methyl, R2 =isobutyl, R3 =methyl, R4 =phenyl).

Workup

  1. customBy TLC, the diastereomers do not separate
  2. customThe product is purified by silica gel flash chromatography (5:95 ethanol:ethyl acetate)

Sources & evidence

ORD record
ord-adc5a2d6e8c64e4394827a77f97f9b0b
Source dataset
uspto-grants-1998_11
Patent number
US05830915

Reaction notes

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