p-Toluenesulfonic acid monohydrate → HCID 67980582, compound

HRID 2406944Notes

Reaction equation

HRID 2406944 reaction equation
[CH3:1][CH:2]([CH3:16])[CH2:3][C:4]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][N:7]=1)=O.[F:17][C:18]([F:33])([F:32])[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([BH3-])#N.[Na+]>COCCOC.CO.C(O)(=O)C>[CH3:1][CH:2]([CH3:16])[CH2:3][CH:4]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][N:7]=1)[NH:31][C:28]1[CH:29]=[CH:30][C:25]([C:22]2[CH:23]=[CH:24][C:19]([C:18]([F:17])([F:32])[F:33])=[CH:20][CH:21]=2)=[CH:26][CH:27]=1

Participants

8

Reactant 4

HCID 521998p-Toluenesulfonic acid monohydrateHCID 27827094'-(Trifluoromethyl)[1,1'-biphenyl]-4-amineHCID 5003444Sodium cyanoborohydrideHCID 67980853HCID 67980853, compound

Product 1

HCID 67980582HCID 67980582, compoundYield 15.4%

Reagents, catalysts & solvents 3

HCID 176Acetic AcidSolventHCID 887MethanolSolventHCID 80711,2-DimethoxyethaneSolvent

Procedure

A solution of methyl 6-(3-methylbutanoyl)nicotinate (90 mg, 0.41 mmol), 4′-(trifluoromethyl)biphenyl-4-amine (145 mg, 0.610 mmol) and p-toluenesulfonic acid monohydrate (1.5 mg, 0.008 mmol) in anhydrous 1,2-dimethoxyethane (2.5 mL) was heated to 120° C. for 5 hours over activated molecular sieves in a sealed tube. The suspension was cooled to room temperature. Sodium cyanoborohydride (12.8 mg, 0.203 mmol) in methanol (1 mL) was added dropwise, immediately followed by acetic acid (0.1 mL). The resulting mixture was stirred overnight at room temperature. The reaction was concentrated and the crude residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The aqueous layer was extracted again with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification by preparative TLC (5:1 petroleum ether:ethyl acetate) gave methyl 6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-ylamino)butyl)nicotinate (28 mg, 15%) as a yellow solid. 1H NMR (400 MHz, CDCl3, δ): 9.19 (s, 1H), 8.21-8.24 (d, 1H), 7.54-7.60 (m, 4H), 7.43-7.45 (d, 1H), 7.35-7.37 (d, 2H), 6.61-6.63 (d, 2H), 4.65 (s, 1H), 3.93 (s, 3H), 1.74-1.75 (d, 2H), 0.92-1.02 (m, 6H).

Workup

  1. concentrationThe reaction was concentrated
  2. customthe crude residue was partitioned between ethyl acetate and saturated sodium bicarbonate
  3. extractionThe aqueous layer was extracted again with ethyl acetate
  4. dry with materialThe combined organic layers were dried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customPurification by preparative TLC (5:1 petroleum ether:ethyl acetate)

Sources & evidence

ORD record
ord-a5c8453af4ae423f84e7c063bcdf8993
Source dataset
uspto-grants-2014_08
Patent number
US08809342B2

Reaction notes

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