D-Alanine → (R)-2-[(1-Cyano-4-hydroxy-8-phenoxy-isoquinoline-3-carbonyl)-amino]-propionic acid

HRID 706222Notes

Reaction equation

HRID 706222 reaction equation
CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:4].[NH2:25][C@@H:26]([C:28]([OH:30])=[O:29])[CH3:27].C[O-].[Na+].CO>>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][C@H:26]([CH3:27])[C:28]([OH:30])=[O:29])=[O:4])[N:6]=1)#[N:24]

Participants

4

Reactant 3

HCID 71080D-AlanineHCID 23694274Sodium methanolate methanolHCID 671101071-Cyano-4-hydroxy-8-phenoxy-isoquinoline-3-carboxylic acid methyl ester

Product 1

HCID 67110268(R)-2-[(1-Cyano-4-hydroxy-8-phenoxy-isoquinoline-3-carbonyl)-amino]-propionic acidYield 79.5%

Procedure

A mixture of 1-cyano-4-hydroxy-8-phenoxy-isoquinoline-3-carboxylic acid methyl ester (95 mg, 0.30 mmole), D-Alanine (529 mg, 5.94 mmole) and 0.5 M sodium methoxide/methanol (11.3 mL) was refluxed for three days before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (25 mL) and extracted with dichloromethane (3×30 mL). The remaining aqueous layer was acidified to pH=3 with 1N HCl (8 mL). The white suspension was extracted with ethyl acetate (30 mL) and dichloromethane (30 mL). The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo to give the title compound as a white solid (90 mg): 1H NMR (DMSO-d6, 200 MHz): δ=13.52 (bs, 1H), 9.15 (br s, 1H), 8.30 (d, 1H), 8.10 (m, 1H), 7.67 (t, J=8 Hz, 1H), 7.42 (m, 2H), 7.17 (m, 3H), 4.83 (q, 1H), 1.68 (d, J=7.0 Hz, 3H)); MS: (+) m/z 378.29 (M+1).

Workup

  1. temperaturewas refluxed for three days before it
  2. concentrationconcentrated in vacuo
  3. dissolutionThe residue was dissolved in water (25 mL)
  4. extractionextracted with dichloromethane (3×30 mL)
  5. extractionThe white suspension was extracted with ethyl acetate (30 mL) and dichloromethane (30 mL)
  6. washThe combined organic layers were washed with brine
  7. dry with materialdried over MgSO4
  8. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-e6afdbc0d4984ad38c6745a77811045f
Source dataset
uspto-grants-2015_11
Patent number
US09174976B2

Reaction notes

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