Hydrochloric Acid → {2,6-difluoro-4-[2-((1S,2R)-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl)ethoxy]phenyl}acetic acid

HRID 1474726Notes

Reaction equation

HRID 1474726 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[CH:24][C:23]([CH2:26][O:27][CH3:28])=[CH:22][N:21]=3)[CH2:16][CH2:15]2)[CH:5]=[C:4]([F:29])[C:3]=1[CH2:30][C:31]([O:33]C)=[O:32].CO.[OH-].[Na+].Cl>O1CCCC1.O>[F:29][C:4]1[CH:5]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:21]=[CH:22][C:23]([CH2:26][O:27][CH3:28])=[CH:24][N:25]=3)[CH2:16][CH2:15]2)[CH:7]=[C:2]([F:1])[C:3]=1[CH2:30][C:31]([OH:33])=[O:32]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 887MethanolHCID 14798Sodium HydroxideHCID 117684495Methyl{2,6-difluoro-4-[2-((1S,2R)-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl)ethoxy]phenyl}acetate

Product 1

HCID 89583798{2,6-difluoro-4-[2-((1S,2R)-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl)ethoxy]phenyl}acetic acid

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of methyl {2,6-difluoro-4-[2-((1S,2R)-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl)ethoxy]phenyl}acetate (3.15 g, 6.62 mmol) in 21 ml of tetrahydrofuran was added 14 ml of methanol and 14 ml of water. 5 M sodium hydroxide (4.50 ml, 22.5 mmol) was added and the mixture stirred at RT overnight. 2 M hydrochloric acid (11.3 ml, 22.5 mmol) was added to adjust the pH of the solution to 4. The volatiles were removed under vacuum, and the aqueous phase extracted with dichloromethane (3×30 ml). The organic layers were combined, dried over magnesium sulphate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (Biotage column, 50 g) using a gradient eluent of 0-60% EtOAc:hexanes (700 ml) to afford the title compound. 1H NMR (CDCl3): δ 8.29 (s, 2H), 6.48 (d, J=9.1 Hz, 2H), 4.67-4.74 (m, 2H), 4.26 (s, 2H), 4.00-4.04 (m, 2H), 3.67 (s, 2H), 3.34 (s, 3H), 2.84-2.91 (m, 2H), 2.12-2.18 (m, 1H), 1.83 (d, J=12.4 Hz, 2H), 1.48-1.55 (m, 1H), 1.33-1.41 (m, 2H), 1.05-1.12 (m, 1H), 0.87-0.94 (m, 1H), 0.64-0.71 (m, 1H), 0.58-0.64 (m, 1H), −0.10 (m, 1H). LC/MS (m/z) 463.4 (M+H)+.

Workup

  1. customThe volatiles were removed under vacuum
  2. extractionthe aqueous phase extracted with dichloromethane (3×30 ml)
  3. dry with materialdried over magnesium sulphate
  4. filtrationfiltered
  5. concentrationthe filtrate was concentrated under reduced pressure
  6. customThe residue was purified by column chromatography on silica gel (Biotage column, 50 g)

Sources & evidence

ORD record
ord-b6c194081310444ab177cc90a9385860
Source dataset
uspto-grants-2015_04
Patent number
US09018224B2

Reaction notes

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