Ammonium Chloride → 2-Pyridinecarboxylic acid, 5-[4-[[1-[2-fluoro-3-(hydroxymethyl)phenyl]-3-azetidinyl]oxy]-1-piperidinyl]-, methyl ester

HRID 1021309Notes

Reaction equation

HRID 1021309 reaction equation
[Si]([O:8][CH2:9][C:10]1[C:11]([F:27])=[C:12]([N:16]2[CH2:19][CH:18]([O:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH2:17]2)[CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.Br[C:29]1[CH:30]=[CH:31][C:32]([C:35]([O:37][CH3:38])=[O:36])=[N:33][CH:34]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1.[Cl-].[NH4+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)(Cl)Cl.C1COCC1.O1CCOCC1>[F:27][C:11]1[C:10]([CH2:9][OH:8])=[CH:15][CH:14]=[CH:13][C:12]=1[N:16]1[CH2:17][CH:18]([O:20][CH:21]2[CH2:22][CH2:23][N:24]([C:29]3[CH:30]=[CH:31][C:32]([C:35]([O:37][CH3:38])=[O:36])=[N:33][CH:34]=3)[CH2:25][CH2:26]2)[CH2:19]1

Participants

11

Reactant 6

HCID 25517Ammonium ChlorideHCID 62657Potassium Phosphate, TribasicHCID 7016458Methyl 5-bromopyridine-2-carboxylateHCID 11078149TBAF tetrahydrofuranHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 86686249HCID 86686249, compound

Product 1

HCID 683090672-Pyridinecarboxylic acid, 5-[4-[[1-[2-fluoro-3-(hydroxymethyl)phenyl]-3-azetidinyl]oxy]-1-piperidinyl]-, methyl esterYield 35%

Reagents, catalysts & solvents 4

HCID 178418476HCID 178418476, compoundCatalystHCID 6212ChloroformSolventHCID 8028TetrahydrofuranSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

4-({1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]azetidin-3-yl}oxy)piperidine (250 mg) and dioxane (7 ml) were mixed, and methyl 5-bromopyridine-2-carboxylate (170 mg), palladium acetate (II)(15 mg), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (60 mg), and tripotassium phosphate (400 mg) were added thereto, followed by stirring 100° C. for 48 hours. The reaction mixture was cooled to room temperature, and filtered by the addition of CHCl3 and Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc). The purified product thus obtained was mixed with THF (5 ml), and a 1.0 M TBAF/THF solution (0.63 ml) was added thereto, followed by stirring at room temperature for 1 hour. A saturated aqueous ammonium chloride solution and CHCl3 were added to the reaction mixture, and the organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain methyl 5-[4-({1-[2-fluoro-3-(hydroxymethyl)phenyl]azetidin-3-yl}oxy)piperidin-1-yl]pyridine-2-carboxylate (92 mg).

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. filtrationfiltered by the addition of CHCl3 and Celite
  3. concentrationthe filtrate was concentrated under reduced pressure
  4. customThe residue was purified by silica gel column chromatography (hexane/EtOAc)
  5. customThe purified product thus obtained
  6. stirringby stirring at room temperature for 1 hour
  7. dry with materialthe organic layer was dried over Na2SO4
  8. concentrationconcentrated under reduced pressure
  9. customThe obtained residue was purified by silica gel column chromatography (CHCl3/MeOH)

Sources & evidence

ORD record
ord-2e0270fdcbdc40b0a39f0a941ae0896d
Source dataset
uspto-grants-2014_05
Patent number
US08716470B2

Reaction notes

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