Triethylamine → 3-(2-Chlorophenyl)-5-methylisoxazole-4-carboxylic acid [4-dimethylamino-4-(3-fluorophenyl)cyclohexyl]amide

HRID 418310Notes

Reaction equation

HRID 418310 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C:8]2([N:15]([CH3:17])[CH3:16])[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[C:36]([C:37](Cl)=[O:38])=[C:35]([CH3:40])[O:34][N:33]=1.[OH-].[Na+]>CN(C1C=CN=CC=1)C.ClCCl>[CH3:16][N:15]([CH3:17])[C:8]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:13][CH2:12][CH:11]([NH:14][C:37]([C:36]2[C:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[Cl:25])=[N:33][O:34][C:35]=2[CH3:40])=[O:38])[CH2:10][CH2:9]1

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 14798Sodium HydroxideHCID 965904-Isoxazolecarbonyl chloride, 3-(2-chlorophenyl)-5-methyl-HCID 579041991-(3-fluorophenyl)-N,N-dimethylcyclohexane-1,4-diamine

Product 1

HCID 116982073-(2-Chlorophenyl)-5-methylisoxazole-4-carboxylic acid [4-dimethylamino-4-(3-fluorophenyl)cyclohexyl]amide

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent2×

Procedure

The non-polar diastereoisomer of 1-(3-fluorophenyl)-N,N-dimethylcyclohexane-1,4-diamine (350 mg) was placed with 220 μI triethylamine (1.05 molar equivalents) and catalytic amounts of DMAP (about 5 mg) in 3.5 ml dichloromethane, 400 mg 3-(2-chlorophenyl)-5-methylisoxazole-4-carbonylchloride (1.05 molar equivalents), dissolved in 2 ml dichloromethane, were added dropwise at −10° C. to and the mixture was stirred overnight while being heated to room temperature. For working up, the mixture was made alkaline (pH>10) with 2-molar sodium hydroxide solution, with ice cooling, the organic phase was separated, the aqueous phase extracted with dichloromethane (20 ml) and the combined organic phases dried over sodium sulphate, filtered and evaporated to dryness. The resultant crude product (690 mg) was chromatographed on silica gel (4.0×15 cm) with methanol/ethyl acetate (V:V=1:1). 530 mg of the non-polar diastereoisomer of 3-(2-chlorophenyl)-5-methylisoxazole-4-carboxylic acid [4-dimethylamino-4-(3-fluorophenyl)cyclohexyl]amide were obtained, which, dissolved in 50 ml 2-butanone were converted overnight into the corresponding hydrochloride by adding 21 μl water and 150 μl chlorotrimethylsilane, then evaporating to dryness, and stirring with 10 ml ethyl acetate (380 mg, Mp. 231-232° C.).

Workup

  1. additionwere added dropwise at −10° C. to and the mixture
  2. customwith ice cooling, the organic phase was separated
  3. extractionthe aqueous phase extracted with dichloromethane (20 ml)
  4. dry with materialthe combined organic phases dried over sodium sulphate
  5. filtrationfiltered
  6. customevaporated to dryness
  7. customThe resultant crude product (690 mg) was chromatographed on silica gel (4.0×15 cm) with methanol/ethyl acetate (V:V=1:1)

Sources & evidence

ORD record
ord-fc14becf4089445ebc5e44925e712498
Source dataset
uspto-grants-2012_01
Patent number
US08093272B2

Reaction notes

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