Pyridine → Aniline

HRID 1969519Notes

Reaction equation

HRID 1969519 reaction equation
O[CH:2]1[CH2:6][CH:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:4]([CH3:12])[CH2:3]1.N1C=CC=CC=1.CS(Cl)(=O)=O.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[CH3:12][C@@H:4]1[CH2:3][C@@H:2]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:6][C@@H:5]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:12][C@H:4]1[CH2:3][C@H:2]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:6][C@H:5]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1

Participants

8

Reactant 4

HCID 1049PyridineHCID 6115AnilineHCID 31297Methanesulfonyl chlorideHCID 67217193HCID 67217193, compound

Product 3

HCID 6115AnilineHCID 58557577HCID 58557577, compoundHCID 58557707HCID 58557707, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A solution of ethyl 4-hydroxy-2-methylcyclopentanecarboxylate (1.81 g, 10.5 mmol, prepared using P from Example #7, step G and NaBH4) and pyridine (1.28 mL, 15.8 mmol) in THF (52.5 mL) was cooled to about 0° C. Methanesulfonyl chloride (0.90 mL, 12 mmol) was added dropwise. The reaction mixture was stirred at ambient temperature for about 16 h then partitioned between water (50 mL) and DCM (30 mL). The layers were separated and the aqueous layer was extracted with DCM (2×30 mL). The combined organic layers were dried over anhydrous Na2SO4 and concd under reduced pressure to give a white solid. The resulting solid was mixed with aniline (78.0 g, 841 mmol) and heated at about 90° C. for about 16 h. The reaction mixture was concd under reduced pressure and purified by silica gel chromatography eluting with a gradient of 20-100% EtOAc in DCM to yield (1S,2R,4R)-ethyl 2-methyl-4-(phenylamino)cyclopentanecarboxylate and (1R,2S,4S)-ethyl 2-methyl-4-(phenylamino)cyclo-pentanecarboxylate with 29 mol % aniline as an excipient (2.73 g, 75%) as a dark oil: LC/MS (Table 1, Method b) Rt=2.67 min; MS m/z: 248 (M+H)+.

Workup

  1. customthen partitioned between water (50 mL) and DCM (30 mL)
  2. customThe layers were separated
  3. extractionthe aqueous layer was extracted with DCM (2×30 mL)
  4. dry with materialThe combined organic layers were dried over anhydrous Na2SO4 and concd under reduced pressure
  5. customto give a white solid
  6. temperatureheated at about 90° C. for about 16 h
  7. custompurified by silica gel chromatography
  8. washeluting with a gradient of 20-100% EtOAc in DCM

Sources & evidence

ORD record
ord-e1b0f57921324f0b89c11bda1f23b0cb
Source dataset
uspto-grants-2013_04
Patent number
US08426411B2

Reaction notes

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