Pyridine → HCID 58717686, compound

HRID 1245102Notes

Reaction equation

HRID 1245102 reaction equation
[CH3:1][O:2][C:3](=[O:36])[C@@H:4]([NH:25][C:26](=[O:35])[C:27]1[CH:32]=[C:31]([Br:33])[CH:30]=[CH:29][C:28]=1[NH2:34])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:8][CH:7]=1.[CH3:37][CH:38]([CH2:43][C:44]([CH3:47])([CH3:46])C)[CH2:39][C:40](Cl)=[O:41].N1C=CC=C[CH:49]=1>C(Cl)Cl>[Br:33][C:31]1[CH:30]=[CH:29][C:28]([NH:34][C:40](=[O:41])[CH2:39][C:38]([CH3:37])([CH3:49])[CH2:43][CH:44]([CH3:46])[CH3:47])=[C:27]([CH:32]=1)[C:26]([NH:25][C@@H:4]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:10][CH:11]=1)[C:3]([OH:36])=[O:2])=[O:35].[CH3:1][O:2][C:3](=[O:36])[C@@H:4]([NH:25][C:26](=[O:35])[C:27]1[CH:32]=[C:31]([Br:33])[CH:30]=[CH:29][C:28]=1[NH:34][C:40](=[O:41])[CH2:39][C:38]([CH3:37])([CH3:49])[CH2:43][CH:44]([CH3:46])[CH3:47])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][CH:11]=1

Participants

6

Reactant 3

HCID 1049PyridineHCID 1619293,5,5-Trimethylhexanoyl chlorideHCID 68870114HCID 68870114, compound

Product 2

HCID 58717686HCID 58717686, compoundHCID 68870800HCID 68870800, compound

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A solution of (2S)-(2-amino-5-bromo-benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester (54.5 mg, 0.10 mmol) from example 294 in 1 mL dry CH2Cl2 was treated with 3,5,5-trimethylhexanoyl chloride(1.2 eq., 23 microL, 0.12 mmol) and pyridine (1.5 eq., 12 microL, 0.15 mmol) in succession and stirred under an atmosphere of dry N2 for one hour, then concentrated in vacuo. The crude residue was purified by flash column chromatography (hexanes, EtOAc) to afford the desired amide, (2S)-[5-Bromo-2-(3,3,5-trimethyl-hexanoylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester, in quantitative yield (68 mg, 100%). The methyl ester (20 mg, 29 micromol) was dissolved in 2.0 mL THF and 0.5 mL MeOH and saponified with 2N aqueous LiOH solution (0.25 mL), as described in general procedure C, to afford the title compound, (2S)-[5-Bromo-2-(3,3,5-trimethyl-hexanoylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid (20 mg, 100%), as a white solid. LCMS 673 (M+1)+. 1H NMR (400 MHz, CDCl3) 10.74 [s, 1H], 8.51 [d, 1H], 7.51 [m, 3H], 7.43 [m, 2H], 7.27–7.30 [m, 2H], 7.16–7.26 [m, 5H], 6.98 [d, 2H], 6.88 [d, 2H], 6.59 [d, 1H], 5.03 [dd, 1H], 3.28 [dq, 2H], 2.36 [m, 1H], 2.14 [m, 1H], 1.11–1.25 [m, 3H], 1.00 [s, 3H], 0.92 [s, 3H], 0.91 [d, 6H].

Workup

  1. concentrationconcentrated in vacuo
  2. customThe crude residue was purified by flash column chromatography (hexanes, EtOAc)

Sources & evidence

ORD record
ord-f51ce04a66364a729284f06ec7c6e126
Source dataset
uspto-grants-2006_10
Patent number
US07122580B2

Reaction notes

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