Hydrochloric Acid → [5-(5-{3-Cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1,2,3,4-tetrahydro-1-isoquinolinyl]acetic acid hydrochloride

HRID 2383325Notes

Reaction equation

HRID 2383325 reaction equation
[CH:1]1[C:10]2[C:5](=[C:6]([C:11]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=4)[C:21]#[N:22])[O:13][N:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]=1.C(OCC)(=O)[CH2:29][C:30]([O-:32])=[O:31].[Li+].[OH-].O.[ClH:40]>C1COCC1.CS(C)=O.CO>[ClH:40].[C:21]([C:20]1[CH:23]=[C:16]([C:14]2[O:13][N:12]=[C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH2:4][CH2:3][NH:2][CH:1]4[CH2:29][C:30]([OH:32])=[O:31])[N:15]=2)[CH:17]=[CH:18][C:19]=1[O:24][CH:25]([CH3:27])[CH3:26])#[N:22]

Participants

8

Reactant 5

HCID 313Hydrochloric Acid2×HCID 962WaterHCID 3939Lithium Hydroxide2×HCID 3595298Propanedioic acid, monoethyl esterHCID 595910795-[3-(3,4-Dihydro-5-isoquinolinyl)-1,2,4-oxadiazol-5-yl]-2-[(1-methylethyl)oxy]benzonitrile

Product 1

HCID 68730521[5-(5-{3-Cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1,2,3,4-tetrahydro-1-isoquinolinyl]acetic acid hydrochloride

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 22036561Dimethyl sulfoxide methanolSolvent

Procedure

A solution of 5-[3-(3,4-dihydro-5-isoquinolinyl)-1,2,4-oxadiazol-5-yl]-2-[(1-methylethyl)oxy]benzonitrile (Preparation 8, 96.2 mg, 0.268 mmol) and mono ethyl malonate (95 μl, 0.805 mmol) in THF (2 mL) was irradiated in the microwave to 120° C. for 10 min. Concentration gave a yellow oil that was purified by MDAP to two fractions containing both the desired carboxylic acid plus the corresponding ethyl ester. The fractions were combined and redissolved in MeOH-THF-water (1:1:1, 1.5 mL). LiOH (9.7 mg, 0.403 mmol) was added and the solution irradiated to 100° C. for 18 min. More LiOH (4.2 mg, 0.175 mmol) and water (300 μl) were added and the solution irradiated to 100° C. for 3 min. The reaction mixture was acidified to pH2 with 2M aqueous HCl and the resulting precipitate filtered to give a white solid. This was dissolved in DMSO-MeOH, added to an SCX cartridge, eluting with methanolic ammonia. Concentration gave a white solid, that was suspended in 1M aqueous HCl and irradiated at 100° C. for 5.5 h. The white precipitate was filtered and dried in vacuo overnight to give the title compound as a white solid (25.5 mg). 1H NMR (400 MHz, CDCl3) δ 9.56 (2H, br. S), 8.52 (1H, d), 8.41 (1H, dd), 8.00 (1H, d), 7.61 (1H, d), 7.57 (1H, d), 7.52 (1H, t), 5.01-4.94 (2H, m), 1.39 (6H, d), remaining aliphatic signals obscured by solvent peaks; m/z (ES) 419 [M+H]+.

Workup

  1. concentrationConcentration
  2. customgave a yellow oil that
  3. customwas purified by MDAP to two fractions
  4. additioncontaining both the desired carboxylic acid plus the corresponding ethyl ester
  5. dissolutionredissolved in MeOH-THF-water (1:1:1, 1.5 mL)
  6. customthe solution irradiated to 100° C. for 18 min
  7. customthe solution irradiated to 100° C. for 3 min
  8. filtrationthe resulting precipitate filtered
  9. customto give a white solid
  10. additionadded to an SCX cartridge
  11. washeluting with methanolic ammonia
  12. concentrationConcentration
  13. customgave a white solid, that
  14. customirradiated at 100° C. for 5.5 h
  15. filtrationThe white precipitate was filtered
  16. customdried in vacuo overnight

Sources & evidence

ORD record
ord-81b8f12d8d4e48e0b28fe8ca299773d7
Source dataset
uspto-grants-2012_09
Patent number
US08263620B2

Reaction notes

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