(2-Amino-1,3-thiazol-4-yl)acetic acid → Tert-butyl (2S,5R)-2-(4-{[(2-amino-1,3-thiazol-4-yl)acetyl]amino}-3-bromobenzyl)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidine-1-carboxylate

HRID 887170Notes

Reaction equation

HRID 887170 reaction equation
[NH2:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][C@@H:7]2[CH2:11][CH2:10][C@H:9]([C@H:12]([OH:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:8]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:4][C:3]=1[Br:29].[NH2:30][C:31]1[S:32][CH:33]=[C:34]([CH2:36][C:37](O)=[O:38])[N:35]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[NH2:30][C:31]1[S:32][CH:33]=[C:34]([CH2:36][C:37]([NH:1][C:2]2[CH:28]=[CH:27][C:5]([CH2:6][C@@H:7]3[CH2:11][CH2:10][C@H:9]([C@H:12]([OH:19])[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:8]3[C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])=[CH:4][C:3]=2[Br:29])=[O:38])[N:35]=1

Participants

7

Reactant 4

HCID 34665(2-Amino-1,3-thiazol-4-yl)acetic acidHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 57907390Tert-butyl(2S,5R)-2-(4-amino-3-bromobenzyl)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidine-1-carboxylate

Product 1

HCID 57907380Tert-butyl (2S,5R)-2-(4-{[(2-amino-1,3-thiazol-4-yl)acetyl]amino}-3-bromobenzyl)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidine-1-carboxylateYield 81%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 6228DimethylformamideSolvent

Procedure

To a solution of 115 mg (0.25 mmol) of tert-butyl (2S,5R)-2-(4-amino-3-bromobenzyl)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidine-1-carboxylate (i-80a) and (2-amino-1,3-thiazol-4-yl)acetic acid (77 mg, 0.30 mmol) in 3.0 mL anhydrous DMF was added HOBt (44 mg, 0.32 mmol) followed by EDC (66 mg) and DIEA (0.22 mL, 1.25 mmol). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 16 h. The mixture was washed with water and extracted with dichloromethane (2×2 mL). The organics were combined, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified by Gilson reverse phase HPLC eluting with a gradient of 10-90% acetonitrile in water with 0.05% TFA buffer to afforded the product (105 mg, 81%). m/z (ES) 601(M)+ and 603 (M+2)+, also 623 (MNa)+ and 625 (MNa+2)+.

Workup

  1. washThe mixture was washed with water
  2. extractionextracted with dichloromethane (2×2 mL)
  3. dry with materialdried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated in vacuum
  6. customThe residue was purified by Gilson reverse phase HPLC
  7. washeluting with a gradient of 10-90% acetonitrile in water with 0.05% TFA buffer

Sources & evidence

ORD record
ord-9dd7368fcf5b4febad4304e8e9cd5172
Source dataset
uspto-grants-2012_08
Patent number
US08247415B2

Reaction notes

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