Acetic Acid → HCID 67497711, compound

HRID 1628300Notes

Reaction equation

HRID 1628300 reaction equation
[NH2:1][C@@H:2]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:3]([NH:5][C:6]1[CH:7]=[C:8]([C:18]([F:27])([F:26])[C:19]([O:21]C(C)(C)C)=[O:20])[CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:11]=1)=[O:4].[S:35]1[CH:39]=[C:38]([CH:40]=O)[N:37]=[CH:36]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:27][C:18]([F:26])([C:8]1[CH:9]=[C:10]([C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)[CH:11]=[C:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][CH2:40][C:38]2[N:37]=[CH:36][S:35][CH:39]=2)[CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:7]=1)[C:19]([OH:21])=[O:20]

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 2763214Thiazole-4-carboxaldehydeHCID 5049666Sodium triacetoxyborohydrideHCID 86664837HCID 86664837, compound

Product 1

HCID 67497711HCID 67497711, compoundYield 43%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of (S)-tert-butyl 2-(3-(2-amino-3-phenylpropanamido)-5-(pyridin-4-yl)phenyl)-2,2-difluoroacetate 52.F (300 mg, 0.64 mmol) in DCM (5 mL) was added thiazole-4-carbaldehyde (73 mg, 0.64 mmol). The mixture was stirred for 1 h at room temperature, then acetic acid (30 μL, 0.64 mmol) and sodium triacetoxyborohydride (408 mg, 1.93 mmol) were added and the mixture stirred at room temperature for an additional 2 hours. The mixture was then concentrated and the residue was stirred in THF (5 mL) and concentrated HCl (5 mL) at 50° C. overnight. The mixture was then concentrated and the crude product purified by reverse phase chromatography (0-100% CH3CN/water+0.5% TFA) to afford (S)-2,2-difluoro-2-(3-(3-phenyl-2-(thiazol-4-ylmethylamino)propanamido)-5-(pyridin-4-yl)phenyl)acetic acid 52 as a white solid (140 mg, 43% yield). LCMS ESI (pos.) m/e: 509.0. (M+1). 1H NMR (500 MHz, MeOH-D4) δ ppm 9.14 (d, J=1.96 Hz, 1H), 8.81-8.87 (m, 2H), 8.16 (t, J=1.83 Hz, 1H), 8.12-8.15 (m, 2H), 7.88 (s, 1H), 7.81 (d, J=1.96 Hz, 1H), 7.72 (s, 1H), 7.24-7.37 (m, 5H), 4.46-4.59 (m, 2H), 4.27 (dd, J=9.29, 5.87 Hz, 1H), 3.40-3.51 (m, 1H), 3.27 (dd, J=13.45, 9.29 Hz, 1H).

Workup

  1. stirringthe mixture stirred at room temperature for an additional 2 hours
  2. concentrationThe mixture was then concentrated
  3. stirringthe residue was stirred in THF (5 mL)
  4. customat 50° C.
  5. customovernight
  6. concentrationThe mixture was then concentrated
  7. customthe crude product purified by reverse phase chromatography (0-100% CH3CN/water+0.5% TFA)

Sources & evidence

ORD record
ord-7c6ccadefea54f42be2aa599361240b4
Source dataset
uspto-grants-2014_07
Patent number
US08785468B2

Reaction notes

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