4-Methylmorpholine → (2S,4S)-4-acetylthio-1-(4-nitrobenzyloxycarbonyl)-2-(3-(1H-tetrazol-5-yl)phenylcarbamoyl)pyrrolidine

HRID 1899003Notes

Reaction equation

HRID 1899003 reaction equation
[C:1]([Cl:6])(=O)C([Cl:4])=O.[C:7]([S:10][C@@H:11]1[CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[O:17])[C@H:13]([C:29]([OH:31])=O)[CH2:12]1)(=[O:9])[CH3:8].CN1CCOCC1.[NH:39]1[C:43]([C:44]2[CH:45]=[C:46]([CH:48]=[CH:49][CH:50]=2)[NH2:47])=[N:42][N:41]=[N:40]1>ClCCl.CN(C=O)C>[CH3:13][N+:14]([CH3:15])=[CH:1][Cl:6].[Cl-:4].[C:7]([S:10][C@@H:11]1[CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=2)=[O:17])[C@H:13]([C:29](=[O:31])[NH:47][C:46]2[CH:48]=[CH:49][CH:50]=[C:44]([C:43]3[NH:42][N:41]=[N:40][N:39]=3)[CH:45]=2)[CH2:12]1)(=[O:9])[CH3:8]

Participants

8

Reactant 4

HCID 79724-Methylmorpholine2×HCID 65578Oxalyl chloride2×HCID 135043251-[(4-Nitrophenyl)methyl] (2S,4S)-4-(acetylthio)-1,2-pyrrolidinedicarboxylateHCID 178507542HCID 178507542, compound

Product 2

HCID 77311Chloro-N,N-dimethylformiminium chlorideHCID 178477151(2S,4S)-4-acetylthio-1-(4-nitrobenzyloxycarbonyl)-2-(3-(1H-tetrazol-5-yl)phenylcarbamoyl)pyrrolidineYield 144.8%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
-20 °C

Procedure

Vilsmeier reagent was prepared by treatment of DMF (0.72 ml, 9.25 mmol) in dichloromethane (40 ml) under argon with oxalylchloride (0.72 ml, 8.3 mmol) at -20° C. for 30 minutes (2S,4S)-4-Acetylthio-1-(4-nitrobenzyloxycarbonyl)-2-carboxypyrrolidine (3 g, 8.1 mmol) in dichloromethane (10 ml) was added, followed by N-methylmorpholine (1.1 ml, 10.1 mmol) and stirring continued at -20° C. for 45 minutes. Formation of the acid chloride was found to be incomplete so a further (0.4 ml, 4.6 mmol) oxalylchloride was added and the mixture stirred at -20° C. for 30 minutes. The solvent was removed to give a brown solid which was azeotroped with toluene. The solid was dissolved in dichloromethane (50 ml) and cooled to -20° C. under an atmosphere of argon. A mixture of 3-(1H-tetrazol-5-yl)aniline (1.5 g; 9.3 mmol) and N-methylmorpholine (2.5 ml, 22.9 mmol) in DMF (4 ml) was added and the mixture allowed to warm to ambient temperature over 20 hours. After dilution with dichloromethane (30 mls) the mixture was washed with aqueous 1N HCl solution and brine (50 ml), dried (MgSO4) and the solvent removed by evaporation to give a brown gum. This was purified by flash chromatography on silica, eluting with a gradient of dichloromethane; glacial acetic acid (100:3) to dichloromethane: ethylacetate: glacial acetic acid (40:60:3) and azeotroped with toluene to give (2S,4S)-4-acetylthio-1-(4-nitrobenzyloxycarbonyl)-2-(3-(1H-tetrazol-5-yl)phenylcarbamoyl)pyrrolidine as a pale yellow solid (3 g).

Workup

  1. additionwas added
  2. additionwas added
  3. stirringthe mixture stirred at -20° C. for 30 minutes
  4. customThe solvent was removed
  5. customto give a brown solid which
  6. customwas azeotroped with toluene
  7. dissolutionThe solid was dissolved in dichloromethane (50 ml)
  8. additionwas added
  9. temperatureto warm to ambient temperature over 20 hours
  10. washAfter dilution with dichloromethane (30 mls) the mixture was washed with aqueous 1N HCl solution and brine (50 ml)
  11. dry with materialdried (MgSO4)
  12. customthe solvent removed by evaporation
  13. customto give a brown gum
  14. customThis was purified by flash chromatography on silica
  15. washeluting with a gradient of dichloromethane
  16. customglacial acetic acid (100:3) to dichloromethane: ethylacetate: glacial acetic acid (40:60:3) and azeotroped with toluene

Sources & evidence

ORD record
ord-82f3249760bd445fac0da983b1f085b8
Source dataset
uspto-grants-1996_11
Patent number
US05571805

Reaction notes

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