4-Methylmorpholine → HCID 58748205, compound

HRID 1162650Notes

Reaction equation

HRID 1162650 reaction equation
[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:10]([NH:11][C:12]([O:14]CC[Si](C)(C)C)=O)[CH2:9][N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:7]1)=[O:5])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Cl:46][C:47]1[S:51][C:50](C(O)=O)=[CH:49][CH:48]=1.CN1CCOCC1.ClC(OCC(C)C)=O>C(#N)C.C1COCC1>[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:10]([NH:11][C:12]([C:50]2[S:51][C:47]([Cl:46])=[CH:48][CH:49]=2)=[O:14])[CH2:9][N:8]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:7]1)=[O:5])[CH3:2]

Participants

8

Reactant 5

HCID 79724-MethylmorpholineHCID 62365Isobutyl chloroformateHCID 950485-Chloro-2-thiophenecarboxylic acid2×HCID 2724141Tetrabutylammonium FluorideHCID 42643275HCID 42643275, compound

Product 1

HCID 58748205HCID 58748205, compoundYield 43.2%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
50 °C

Procedure

40.2 (3S,4R)-4-(2-Trimethylsilanylethoxycarbonylamino)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (1.4 g; 3 mmol) is dissolved in acetonitrile (15 ml) and TBAF (1.372 g; 4 mmol) is added under an argon atmosphere. The mixture is stirred for 18 h at 50° C. 5-Chlorothiophene-2-carboxylic acid (1.272 g; 8 mmol) is dissolved in THF (10 ml), N-methyl morpholine (0.86 ml; 8 mmol) followed by isobutyl chloroformate (1.03 ml; 8 mmol) is added at 0° C. to this solution. After 30 min stirring at 25° C. this solution is added to the reaction mixture above. After 18 h at 25° C. additional 0.5 equivalents of activated 5-chloro-thiophene-2-carboxylic acid is added. The whole mixture is stirred for 3 d at 25° C., evaporated to dryness, dissolved in DCM/THF and washed with 1N aq. HCl solution, 10% aq. Na2CO3 solution. The organic phase is dried over Na2SO4. Flash chromatography over silica gel using DCM/MeOH/NH3 as eluent yielded 0.522 g (37.2%) (3S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester. Light brown oil. MS 403.5 [M+H+].

Workup

  1. additionis added at 0° C. to this solution
  2. stirringAfter 30 min stirring at 25° C. this solution
  3. additionis added to the reaction mixture above
  4. stirringThe whole mixture is stirred for 3 d at 25° C.
  5. customevaporated to dryness
  6. dissolutiondissolved in DCM/THF
  7. washwashed with 1N aq. HCl solution, 10% aq. Na2CO3 solution
  8. dry with materialThe organic phase is dried over Na2SO4

Sources & evidence

ORD record
ord-e552afe2afe044bf83eaa68c702a0b63
Source dataset
uspto-grants-2010_10
Patent number
US07820699B2

Reaction notes

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