Oxalyl chloride → N-[(2-chloro-6-methylphenyl)carbonyl]-4-[1,3-dimethy-2,4-dioxo-6-(trifluoromethyl)-5-pyrimidinyl]-L-phenylalanine methyl ester

HRID 844870Notes

Reaction equation

HRID 844870 reaction equation
[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.Cl.[CH3:19][O:20][C:21](=[O:45])[C@H:22]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[C:32](=[O:44])[N:33]([CH3:43])[C:34](=[O:42])[N:35]([CH3:41])[C:36]=2[C:37]([F:40])([F:39])[F:38])=[CH:27][CH:26]=1)[NH2:23].CCN(C(C)C)C(C)C>ClCCl.CN(C=O)C>[CH3:19][O:20][C:21](=[O:45])[C@H:22]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]2[C:32](=[O:44])[N:33]([CH3:43])[C:34](=[O:42])[N:35]([CH3:41])[C:36]=2[C:37]([F:40])([F:38])[F:39])=[CH:29][CH:30]=1)[NH:23][C:4]([C:3]1[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:2]=1[Cl:1])=[O:6]

Participants

7

Reactant 4

HCID 65578Oxalyl chlorideHCID 81531DiisopropylethylamineHCID 888702-Chloro-6-methylbenzoic acidHCID 69337552HCID 69337552, compound

Product 1

HCID 69342795N-[(2-chloro-6-methylphenyl)carbonyl]-4-[1,3-dimethy-2,4-dioxo-6-(trifluoromethyl)-5-pyrimidinyl]-L-phenylalanine methyl esterYield 33.2%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolvent2×

Procedure

A solution of 2-chloro-6-methylbenzoic acid (190 mg, 1.14 mmol) in dichloromethane (7 mL) containing DMF (4 drops) was treated with oxalyl chloride (0.42 mL, 4.8 mmol) and the mixture was stirred for 2 h. The mixture was concentrated, azeotroping with toluene to remove traces of oxalyl chloride and the residue was used directly in the next step. A mixture of the above prepared acid chloride, 4-(1,3-dimethyl-2,4-dioxo-6-(trifluoromethyl)-5-pyrimidinyl)-L-phenylalanine methyl ester hydrochloride salt (423 mg, 1.003 mmol) in dichloromethane (5 mL) was treated with DIPEA (0.625 mL, 4.46 mmol) and the resulting light brown solution was stirred for 3 days. The mixture was concentrated, diluted with ethyl acetate, washed with 1 N HCl and brine solution and was dried over magnesium sulfate. Filtration and evaporation afforded a residue, which was purified by silica gel chromatography using a Biotage column (40s) to give N-[(2-chloro-6-methylphenyl)carbonyl]-4-[1,3-dimethy-2,4-dioxo-6-(trifluoromethyl)-5-pyrimidinyl]-L-phenylalanine methyl ester as a white foam (179 mg, 33%). ES-HRMS m/e calcd for C25H23ClN3O5 (M+Na) 560.1171, found 560.1172.

Workup

  1. concentrationThe mixture was concentrated
  2. customazeotroping with toluene
  3. customto remove traces of oxalyl chloride
  4. additionA mixture of the
  5. stirringthe resulting light brown solution was stirred for 3 days
  6. concentrationThe mixture was concentrated
  7. additiondiluted with ethyl acetate
  8. washwashed with 1 N HCl and brine solution
  9. dry with materialwas dried over magnesium sulfate
  10. filtrationFiltration and evaporation
  11. customafforded a residue, which
  12. customwas purified by silica gel chromatography

Sources & evidence

ORD record
ord-817072244f8344cda6fcf3ade58a634e
Source dataset
uspto-grants-2002_04
Patent number
US06380387B1

Reaction notes

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