Hydrochloric Acid → HCID 70805182, compound

HRID 1519062Notes

Reaction equation

HRID 1519062 reaction equation
Cl.Cl[CH:3]([C:8]1[C:9](=[O:17])[C:10]([OH:16])=[C:11]([CH3:15])[N:12]([CH3:14])[CH:13]=1)[C:4]([F:7])([F:6])[F:5].[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.Cl.CN>O.C(#N)C>[OH:16][C:10]1[C:9](=[O:17])[C:8]([CH:3]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)[C:4]([F:7])([F:6])[F:5])=[CH:13][N:12]([CH3:14])[C:11]=1[CH3:15].[OH:16][C:10]1[C:9](=[O:17])[C:8]([CH:3]([NH:18][CH3:19])[C:4]([F:7])([F:6])[F:5])=[CH:13][N:12]([CH3:14])[C:11]=1[CH3:15]

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 795ImidazoleHCID 6329MethylamineHCID 86672815HCID 86672815, compound2×

Product 2

HCID 70805182HCID 70805182, compoundYield 64%HCID 70805183HCID 70805183, compound

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 6342AcetonitrileSolvent

Procedure

3-Hydroxy-1,2-dimethyl-5-[2,2,2-trifluoro-1-(piperidin-1-yl)ethyl]pyridin-4(1H)-one (Apo7054) was prepared from the reaction of 5-(1-chloro-2,2,2-trifluoroethyl)-3-hydroxy-1,2-dimethylpyridin-4(1H)-one hydrochloride (304 mg, 1.0 mmol) and piperidine (2.0 mL, 20.3 mmol). The reaction was completed within 20 min, and Apo7054 was obtained as a solid product (232 mg). Yield=73%; HPLC Method 1, purity (AUC)=99.4% at 280 nm; 1H NMR (DMSO-D6) δ (ppm): 7.66 (s, 1H), 4.83-4.94 (m, 1H), 3.71 (s, 3H), 2.56 (m, 2H), 2.41 (m, 2H), 2.27 (s, 3H), 1.46 (br, 4H), 1.28 (br, 2H); MS-ESI m/z 305 [M+1]+ (100%), 220. (ii) 3-Hydroxy-1,2-dimethyl-5-[2,2,2-trifluoro-1-(1H-imidazol-1-yl)ethyl]pyridin-4(1H)-one (Apo7055) was prepared from 5-(1-chloro-2,2,2-trifluoroethyl)-3-hydroxy-1,2-dimethylpyridin-4(1H)-one hydrochloride (505 mg, 1.7 mmol) and imidazole (3.5 g, 51.4 mmol). The reaction was stopped when analysis of the HPLC chromatogram (Method 1) of the reaction mixture indicated higher than 98% conversion. The reaction mixture was concentrated to give a solid. The solid was dissolved in de-ionized water (4 mL), and the pH of the solution was adjusted to 6.5 with a 6.00 N hydrochloric acid solution. The resulting solution was repeatedly extracted with dichloromethane (15 mL×4, 30 mL×2). The organic fractions were combined, dried over sodium sulfate, filtered, and concentrated. The desired compound Apo7055 was obtained as a solid from dichloromethane (320 mg). Yield=64%; HPLC purity (AUC): 99.7% at 280 nm); 1H NMR (DMSO-D6) δ (ppm): 8.15 (s, 1H), 7.98 (s, 1H), 7.52 (s, 1H), 6.96 (s, 1H), 6.66 (q, J=9.1 Hz, 1H), 3.76 (s, 3H), 2.29 (s, 3H). MS-ESI m/z 288 [M+1]+, 220 (100%). (iii) 3-Hydroxy-1,2-dimethyl-5-[2,2,2-trifluoro-1-(methylamino)ethyl]pyridin-4(1H)-one (Apo7056) was prepared from 5-(1-chloro-2,2,2-trifluoroethyl)-3-hydroxy-1,2-dimethylpyridin-4(1H)-one hydrochloride (400 mg, 1.4 mmol) and methylamine (3.0 mL, 34.4 mmol). The reaction was essentially completed within 15 min. The reaction mixture was concentrated to give a solid. A sample of salt free Apo7056 product was obtained by purification using the Biotage instrument (C18 reversed phase; eluant: water and acetonitrile; gradient, 100:0 to 100:4). (48 mg).

Workup

  1. concentrationThe reaction mixture was concentrated
  2. customto give a solid
  3. extractionThe resulting solution was repeatedly extracted with dichloromethane (15 mL×4, 30 mL×2)
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customwas obtained as a solid from dichloromethane (320 mg)
  8. concentrationThe reaction mixture was concentrated
  9. customto give a solid
  10. customA sample of salt free Apo7056 product was obtained by purification

Sources & evidence

ORD record
ord-c8d450e6ee6c4fa8a99dec4263837ba2
Source dataset
uspto-grants-2015_07
Patent number
US09073865B2

Reaction notes

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