Ammonium Chloride → 4-[2-(5-Bromo-2-fluoro-phenyl)-[1,3]dithian-2-yl]-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester

HRID 518154Notes

Reaction equation

HRID 518154 reaction equation
[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([CH:8]2[S:13][CH2:12][CH2:11][CH2:10][S:9]2)[CH:7]=1.[Li+].CC([N-]C(C)C)C.[O:23]=[C:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1.[NH4+].[Cl-]>C1COCC1>[C:33]([O:32][C:30]([N:27]1[CH2:28][CH2:29][C:24]([C:8]2([C:6]3[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[F:14])[S:9][CH2:10][CH2:11][CH2:12][S:13]2)([OH:23])[CH2:25][CH2:26]1)=[O:31])([CH3:36])([CH3:34])[CH3:35]

Participants

6

Reactant 4

HCID 25517Ammonium ChlorideHCID 735900tert-Butyl 4-oxopiperidine-1-carboxylate2×HCID 2724682Lithium diisopropylamideHCID 114036102-(5-Bromo-2-fluorophenyl)-1,3-dithiane

Product 1

HCID 113064294-[2-(5-Bromo-2-fluoro-phenyl)-[1,3]dithian-2-yl]-4-hydroxy-piperidine-1-carboxylic acid tert-butyl esterYield 40.7%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
-78 °C

Procedure

A solution of 2-(5-bromo-2-fluoro-phenyl)[1,3]dithiane (19 g, 64.84 mmol) in THF (100 ml) was added to a degassed and stirred 2 M solution of LDA (32.42 ml, 64.84 mmol) in THF dry (150 ml) at −78° C. and the reaction was carried out at −20° C. for 30 min. The reaction was cooled down again to −78° C. and tert-butyl 4-oxo-1-piperidinecarboxylate (13.03 g, 65.5 mmol) in THF (100 ml) was added dropwise. After 30 min, a further portion of tert-butyl 4-oxo-1-piperidinecarboxylate was added (0.5 g, 0.25 mmol). After 1 h, the reaction mixture was poured into a saturated NH4Cl solution (200 ml) and extracted with AcOEt. The combined organic fractions were washed with water (100 ml), brine (100 ml), dried over Na2SO4, then filtered and evaporated to give a yellow oil. The crude product was purified by column chromatography (AcOEt/hexane 30/70) to give 4-[2-(5-bromo-2-fluoro-phenyl)-[1,3]dithian-2-yl]-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester as a white solid (13 g).

Workup

  1. customa degassed
  2. customdry (150 ml) at −78° C.
  3. waitAfter 30 min
  4. waitAfter 1 h
  5. extractionextracted with AcOEt
  6. washThe combined organic fractions were washed with water (100 ml), brine (100 ml)
  7. dry with materialdried over Na2SO4
  8. filtrationfiltered
  9. customevaporated
  10. customto give a yellow oil
  11. customThe crude product was purified by column chromatography (AcOEt/hexane 30/70)

Sources & evidence

ORD record
ord-f4d508fbd56849559f54a4fd1ae3f365
Source dataset
uspto-grants-2015_08
Patent number
US09115148B2

Reaction notes

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