Methanol → (2R,4S)-5-biphenyl-4-yl-4-((2S,3S)-2,3-diacetoxy-3-carboxy-propionylamino)-2-methyl-pentanoic acid

HRID 1469602Notes

Reaction equation

HRID 1469602 reaction equation
Cl.C([O:9][C:10](=[O:29])[C@H:11]([CH3:28])[CH2:12][C@H:13]([NH2:27])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)C1C=CC=CC=1.[C:30]([O:33][C@@H:34]1[C:38](=[O:39])[O:37][C:36](=[O:40])[C@H:35]1[O:41][C:42](=[O:44])[CH3:43])(=[O:32])[CH3:31].C(Cl)Cl.N1C=CC=CC=1.CO>C(OCC)(=O)C.[Pd]>[C:18]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:17]=[CH:16][C:15]([CH2:14][C@@H:13]([NH:27][C:38](=[O:39])[C@@H:34]([O:33][C:30](=[O:32])[CH3:31])[C@H:35]([O:41][C:42](=[O:44])[CH3:43])[C:36]([OH:37])=[O:40])[CH2:12][C@@H:11]([CH3:28])[C:10]([OH:29])=[O:9])=[CH:20][CH:19]=1

Participants

7

Reactant 4

HCID 887MethanolHCID 12731855Diacetyltartaric anhydride, D-HCID 21875418Pyridine methylene chlorideHCID 67505899HCID 67505899, compound

Product 1

HCID 49821388(2R,4S)-5-biphenyl-4-yl-4-((2S,3S)-2,3-diacetoxy-3-carboxy-propionylamino)-2-methyl-pentanoic acid

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 8857Ethyl AcetateSolvent

Procedure

A solution of (2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid benzyl ester hydrochloride (100 mg, 0.287 mmol) and acetic acid (3S,4S)-4-acetoxy-2,5-dioxo-tetrahydro-furan-3-yl ester (0.431 mmol) in 1:1 methylene chloride/pyridine (1.4 mL) is stirred at room temperature for 24 hours. The solvents are removed under reduced pressure and obtained residue is used directly in the subsequent hydrolysis reaction. Next, a solution of the benzyl ester in ethyl acetate is hydrogenated at 1 atm over 10% Pd/C for 18 hours. Methanol is added and the catalyst is filtered through Celite. The Solvent is removed under reduced pressure and the residue is purified by preparative HPLC using a gradient of 10-100% MeCN/water (0.1% TFA). The proper fractions are lyophilized to furnish (2R,4S)-5-biphenyl-4-yl-4-((2S,3S)-2,3-diacetoxy-3-carboxy-propionylamino)-2-methyl-pentanoic acid. HPLC Retention time 0.95 minutes (condition A); MS 500.3 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (d, J=7.20Hz, 3H), 1.45 (m, 1H), 1.82 (m, 1H), 2.39 (m, 1H), 2.70 (d, J=6.82Hz, 2H), 4.01 (m, 1H), 5.38 (m, 2H), 7.19 (d, J=8.21Hz, 2H), 7.34 (t, 1H), 7.45 (t, 2H), 7.53 (d, J=8.21Hz, 2H), 7.64 (d, J=7.20Hz, 2H), 8.00 (d, J=8.72Hz, 1H).

Workup

  1. customThe solvents are removed under reduced pressure
  2. customobtained residue
  3. customis used directly in the subsequent hydrolysis reaction
  4. filtrationthe catalyst is filtered through Celite
  5. customThe Solvent is removed under reduced pressure
  6. customthe residue is purified by preparative HPLC

Sources & evidence

ORD record
ord-560d5e9d6d9a49c6abcd79be3156b768
Source dataset
uspto-grants-2015_04
Patent number
US09006249B2

Reaction notes

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