Cesium carbonate → 4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-naphthalene-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

HRID 1185458Notes

Reaction equation

HRID 1185458 reaction equation
[CH:1]1([NH:4][C:5]([C@@H:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12](=[O:15])[CH2:13]Br)=[O:6])[CH2:3][CH2:2]1.[CH2:16]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:52])[C@@H:28]([NH:38][C:39]([C:41]2[CH:50]=[C:49]([OH:51])[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH:42]=2)=[O:40])[CH2:29][CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])[CH2:23][CH2:22]1)=[O:20])[CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:16]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:52])[C@@H:28]([NH:38][C:39]([C:41]2[CH:50]=[C:49]([O:51][CH2:13][C:12]([N:8]3[CH2:9][CH2:10][CH2:11][C@H:7]3[C:5](=[O:6])[NH:4][CH:1]3[CH2:3][CH2:2]3)=[O:15])[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH:42]=2)=[O:40])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH2:23][CH2:22]1)=[O:20])[CH3:17]

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 685998254-{(S)-4-tert-Butoxycarbonyl-2-[(4-hydroxy-naphthalene-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl esterHCID 68600753(S)-1-(2-Bromo-acetyl)-pyrrolidine-2-carboxylic acid cyclopropylamide

Product 1

HCID 686010024-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-naphthalene-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

To a solution of 100 mg of (S)-1-(2-Bromo-acetyl)-pyrrolidine-2-carboxylic acid cyclopropylamide and 93 mg of 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-hydroxy-naphthalene-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester in 2 ml of DMF, 118 mg of cesium carbonate was added and the reaction mixture was heated to 80° C. for 5 h. Then, the reaction mixture was diluted with water and filtered through a chem Elut® cartridge by eluting with ethyl acetate. The solvents were removed under reduced pressure and the residue was dissolved in 1 ml of DCM and 0.2 ml of TFA. After 16 h at RT 10 ml of toluene was added and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. Yield: 40 mg MS (ES+): m/e=652.

Workup

  1. filtrationfiltered through a chem Elut® cartridge
  2. washby eluting with ethyl acetate
  3. customThe solvents were removed under reduced pressure
  4. dissolutionthe residue was dissolved in 1 ml of DCM
  5. additionAfter 16 h at RT 10 ml of toluene was added
  6. customthe solvents were removed under reduced pressure
  7. customThe residue was purified by preparative HPLC (
  8. washC18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA)
  9. additionThe fractions containing the product
  10. customwere evaporated
  11. customto yield a white solid

Sources & evidence

ORD record
ord-02b1de8b46f241aca04ef13147df5ed2
Source dataset
uspto-grants-2014_03
Patent number
US08669266B2

Reaction notes

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