3-Chloro-4-methylaniline → HCID 59376130, compound

HRID 2273868Notes

Reaction equation

HRID 2273868 reaction equation
C[Al](C)C.[Cl:5][C:6]1[CH:7]=[C:8]([NH2:13])[CH:9]=[CH:10][C:11]=1[CH3:12].C([O:16][C:17]([C@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([C:25](=[O:33])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[C@H:20]1[C:34]1[CH:39]=[CH:38][C:37]([NH:40][CH:41]2[CH2:45][CH2:44][CH2:43][CH2:42]2)=[CH:36][CH:35]=1)=O)C>ClC(Cl)C.C(Cl)Cl>[Cl:5][C:6]1[CH:7]=[C:8]([NH:13][C:17]([C@H:19]2[CH2:24][CH2:23][CH2:22][N:21]([C:25](=[O:33])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])[C@H:20]2[C:34]2[CH:39]=[CH:38][C:37]([NH:40][CH:41]3[CH2:45][CH2:44][CH2:43][CH2:42]3)=[CH:36][CH:35]=2)=[O:16])[CH:9]=[CH:10][C:11]=1[CH3:12]

Participants

6

Reactant 3

HCID 72553-Chloro-4-methylanilineHCID 16682925TrimethylaluminumHCID 59376115HCID 59376115, compound

Product 1

HCID 59376130HCID 59376130, compoundYield 50%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 63651,1-DichloroethaneSolvent2×

Conditions

Temperature
85 °C

Procedure

Me3Al (290 μL, 0.57 mmol, 2M in toluene) was added to a solution of the 3-Chloro-4-methylphenylamine (65 mg, 0.46 mmol) in dry dichloroethane (1 mL) at ambient temperature. Stirred for 20 minutes, then (2R,3S)-2-(4-Cyclopentylaminophenyl)-1-(2-methylbenzoyl)piperidine-3-carboxylic acid ethyl ester (100 mg, 0.23 mmol) dissolved in dry dichloroethane (1 mL) was added to it. The reaction mixture was then heated to 85° C. for 3 h, cooled to r.t, diluted with CH2Cl2 (20 mL), washed with saturated aqueous NaHCO3 solution. The aqueous layer was extracted with CH2Cl2 (20 mL) and the combined organic layer was dried (MgSO4) and concentrated. The residue was purified by reverse phase preparative HPLC (20-95% gradient of CH3CN—H2O with 0.1% TFA as additive), the product containing fractions were pooled together and concentrated. The residue was diluted with CH2Cl2 (30 mL), washed with saturated aqueous NaHCO3 solution. The CH2Cl2 layer was dried (MgSO4) and concentrated to get the pure (2R,3S)-2-(4-Cyclopentylaminophenyl)-1-(2-methylbenzoyl)piperidine-3-carboxylic acid (3-chloro-4-methylphenyl)amide in 50% yield.

Workup

  1. additionwas added to it
  2. temperaturecooled
  3. washwashed with saturated aqueous NaHCO3 solution
  4. extractionThe aqueous layer was extracted with CH2Cl2 (20 mL)
  5. dry with materialthe combined organic layer was dried (MgSO4)
  6. concentrationconcentrated
  7. customThe residue was purified by reverse phase preparative HPLC (20-95% gradient of CH3CN—H2O with 0.1% TFA as additive)
  8. additionthe product containing fractions
  9. concentrationconcentrated
  10. additionThe residue was diluted with CH2Cl2 (30 mL)
  11. washwashed with saturated aqueous NaHCO3 solution
  12. dry with materialThe CH2Cl2 layer was dried (MgSO4)
  13. concentrationconcentrated

Sources & evidence

ORD record
ord-c6096e169ac049378cd73772faa87212
Source dataset
uspto-grants-2015_09
Patent number
US09126939B2

Reaction notes

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