Acetic Acid → 2,4,6-Trifluoro-n-[6-(1-cyclopropylmethyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide dihydrochloride salt

HRID 404242Notes

Reaction equation

HRID 404242 reaction equation
[F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[O:14])[N:8]=1)=[O:5].[CH:27]1([CH:30]=O)[CH2:29][CH2:28]1.C(O)(=O)C.[Na].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Cl:50]CCl>CO>[ClH:50].[ClH:50].[F:26][C:21]1[CH:22]=[C:23]([F:25])[CH:24]=[C:2]([F:1])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH:15]2[CH2:16][CH2:17][N:18]([CH2:30][CH:27]3[CH2:29][CH2:28]3)[CH2:19][CH2:20]2)=[O:14])[N:8]=1)=[O:5]

Participants

7

Reactant 5

HCID 176Acetic AcidHCID 6344DichloromethaneHCID 123114CyclopropanecarboxaldehydeHCID 179803372,4,6-trifluoro-N-(6-(piperidine-4-carbonyl)pyridin-2-yl)benzamideHCID 131725371CID 131725371

Product 1

HCID 179803042,4,6-Trifluoro-n-[6-(1-cyclopropylmethyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide dihydrochloride saltYield 77%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

Combine 2,4,6-trifluoro-N-[6-(piperidin-4-ylcarbonyl)pyridin-2-yl]benzamide (0.05 g, 0.138 mmol), cyclopropylmethanal (0.10 g, 1.38 mmol) and dichloromethane (5 mL), and stir at ambient temperature. After 15 minutes, add glacial acetic acid (0.02 mL, 0.35 mmol) followed by sodium-triacetoxyborohydride (0.038 g, 0.18 mmol) with stirring. After 3 hrs., dilute the reaction mixture with methanol (5 mL) and load on an SCX column (10 g). Wash the column with methanol, elute with 2M ammonia/methanol, and concentrate the eluent. Purify the residue by flash chromatography, eluting with 10% ammonia/methanol in dichloromethane, to obtain the free base of the title compound (0.045 g, 77%). Dissolve the free base in dichloromethane (5 mL), treat with 1M hydrogen chloride in diethylether (0.25 mL), and concentrate the mixture to obtain the dihydrochloride salt. M.p.=140° C.; HRMS: Obs. m/z 418.1743; Calc. m/z 418.1742; 1H NMR (CDCl3): 11.51 (bs, 1H), 10.34 (bs, 1H), 8.38 (m, 1H), 8.11 (m, 1H), 7.78 (d, 1H), 7.42 (m, 2H), 3.79 (m, 1H), 3.64 (m, 2H), 2.98 (m, 4H), 2.17 (m, 2H), 1.99 (m, 2H), 1.13 (m, 1H), 0.65 (m, 2H), 0.39 (m, 2H).

Workup

  1. waitAfter 3 hrs
  2. washWash the column with methanol
  3. washelute with 2M ammonia/methanol
  4. concentrationconcentrate the eluent
  5. customPurify the residue by flash chromatography
  6. washeluting with 10% ammonia/methanol in dichloromethane

Sources & evidence

ORD record
ord-74e9dfc881644b909b45cf25006e0104
Source dataset
uspto-grants-2014_06
Patent number
US08748459B2

Reaction notes

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