Citric Acid → 2-(4-{6-[3-(4-tert-Butylbenzamido)-2-methylphenyl]-4-methyl-3-oxo-3,4-dihydropyrazin-2-ylamino}phenyl)-2-[isopropyl(methyl)amino]acetic Acid

HRID 888444Notes

Reaction equation

HRID 888444 reaction equation
[C:1]([C:5]1[CH:46]=[CH:45][C:8]([C:9]([NH:11][C:12]2[C:13]([CH3:44])=[C:14]([C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([CH:31]([N:37]([CH:39]([CH3:41])[CH3:40])[CH3:38])[C:32]([O:34]CC)=[O:33])=[CH:27][CH:26]=4)[C:21](=[O:42])[N:20]([CH3:43])[CH:19]=3)[CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1COCC1.[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.C(O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][C:12]2[C:13]([CH3:44])=[C:14]([C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([CH:31]([N:37]([CH:39]([CH3:40])[CH3:41])[CH3:38])[C:32]([OH:34])=[O:33])=[CH:27][CH:26]=4)[C:21](=[O:42])[N:20]([CH3:43])[CH:19]=3)[CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:45][CH:46]=1)([CH3:2])([CH3:3])[CH3:4]

Participants

7

Reactant 4

HCID 311Citric AcidHCID 3939Lithium HydroxideHCID 8028TetrahydrofuranHCID 57625127Ethyl 2-(4-{6-[3-(4-tert-Butylbenzamido)-2-methylphenyl]-4-methyl-3-oxo-3,4-dihydropyrazin-2-ylamino}phenyl)-2-[isopropyl(methyl)amino]acetate

Product 1

HCID 576251502-(4-{6-[3-(4-tert-Butylbenzamido)-2-methylphenyl]-4-methyl-3-oxo-3,4-dihydropyrazin-2-ylamino}phenyl)-2-[isopropyl(methyl)amino]acetic AcidYield 55%

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 962WaterSolvent

Conditions

Temperature
60 °C

Procedure

A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 28 (400 mg, 0.642 mmol), THF (5 mL) and ethanol (5 mL). A solution of lithium hydroxide (124 mg, 10.2 mmol) in water (5 mL) was added, and the mixture was heated at 60° C. for 48 h. After this time, the reaction was cooled to room temperature, and the mixture was slowly acidified to pH 4.0 with 10% aqueous citric acid. The resulting precipitate was filtered, and the filter cake was washed with water (20 mL), then triturated with a 1:10 mixture of methylene chloride/ethyl acetate (20 mL). The resulting residue was dried to a constant weight under vacuum at 45° C. to afford 29 in 55% yield (210 mg) as an off-white solid: mp 197-198° C.; 1H NMR (500 MHz, DMSO-d5) δ 9.91 (s, 1H), 9.29 (s, 1H), 7.99 (d, 2H, J=8.5 Hz), 7.95 (d, 2H, J=8.5 Hz), 7.55 (d, 2H, J=8.5 Hz), 7.39 (d, 2H, J=8.5 Hz), 7.35 (dd, 1H, J=7.0, 1.5 Hz), 7.32-7.28 (m, 2H), 7.24 (s, 1H), 4.23 (s, 1H), 3.56 (s, 3H), 3.30 (m, 1H), 2.30 (s, 3H), 2.23 (s, 3H), 1.33 (s, 9H), 1.13 (d, 3H, J=6.5 Hz), 1.10 (d, 3H, J=6.5 Hz); MS (ESI+) m/z 596 (M+H).

Workup

  1. customA 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer
  2. temperaturereflux condenser
  3. temperatureAfter this time, the reaction was cooled to room temperature
  4. filtrationThe resulting precipitate was filtered
  5. washthe filter cake was washed with water (20 mL)
  6. customtriturated with a 1:10 mixture of methylene chloride/ethyl acetate (20 mL)
  7. customThe resulting residue was dried to a constant weight under vacuum at 45° C.

Sources & evidence

ORD record
ord-291b95e6ac0b4ba9b38f9a15076f61fd
Source dataset
uspto-grants-2012_08
Patent number
US08247550B2

Reaction notes

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