Acetic Acid → 2-Chloro-N-((2S,4S)-3-(1,2-dimethyl-piperidin-4-ylamino)-phenyl)4-fluoro-benzamide hydrochloride

HRID 1591896Notes

Reaction equation

HRID 1591896 reaction equation
Cl.[Cl:2][C:3]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:4]=1[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C@H:15]2[CH2:20][CH2:19][NH:18][C@@H:17]([CH3:21])[CH2:16]2)[CH:9]=1)=[O:6].[C:27](O)(=O)C.C([BH3-])#N.[Na+].C=O.C(=O)(O)[O-].[Na+].[Cl-].[NH4+]>CO.ClCCl>[ClH:2].[Cl:2][C:3]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:4]=1[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C@H:15]2[CH2:20][CH2:19][N:18]([CH3:27])[C@@H:17]([CH3:21])[CH2:16]2)[CH:9]=1)=[O:6]

Participants

9

Reactant 6

HCID 176Acetic AcidHCID 712FormaldehydeHCID 25517Ammonium ChlorideHCID 516892Sodium BicarbonateHCID 5003444Sodium cyanoborohydrideHCID 669390312-Chloro-4-fluoro-N-((2S,4S)-3-(2-methyl-piperidin-4-ylamino)-phenyl)-benzamide hydrochloride

Product 1

HCID 669387572-Chloro-N-((2S,4S)-3-(1,2-dimethyl-piperidin-4-ylamino)-phenyl)4-fluoro-benzamide hydrochlorideYield 108.7%

Reagents, catalysts & solvents 2

HCID 887MethanolSolvent2×HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

Dissolve 2-chloro-4-fluoro-N-((2S,4S)-3-(2-methyl-piperidin-4-ylamino)-phenyl)-benzamide hydrochloride (Example 39, 50 mg, 0.125 mmol) in methanol (5 mL). Add acetic acid (22 μL, 0.375 mmol) followed by sodium cyanoborohydride (11.8 mg, 0.188 mmol). Cool to 0° C. and add 37% formaldehyde (11.2 μL, 0.138 mmol). Warm to room temperature and stir for 18 hr. Add aqueous saturated sodium bicarbonate and dichloromethane. Separate organic layer and extract aqueous with dichloromethane (2×25 mL). Combine organic extracts, dry (MgSO4), filter, and concentrate in vacuo. Purify by column chromatography (0%–10% 2M NH3 in methanol/CH2Cl2) to yield an oil. Make the hydrochloride salt by sonication with one equivalent of ammonium chloride dissolved in methanol to yield 28 mg (54%) of the title compound: mass spectrum (ion spray): m/z 376.2 (M+1); 1H NMR δ (D2O/DCl, ppm) 7.71 (s, 1H), 7.90 (m, 3H), 7.16 (m, 2H), 7.02 (m, 1H), 3.82 (m, 1H), 3.48 (m, 1H), 3.12 (m, 1H), 2.98 (m, 1H), 2.68 (s, 3H), 2.15 (m, 2H), 1.83 (s, 1H), 1.72 (m, 1H), 1.20 (d, J=6.3 Hz, 3H); mp 91–4° C.

Workup

  1. temperatureWarm to room temperature
  2. extractionSeparate organic layer and extract aqueous with dichloromethane (2×25 mL)
  3. dry with materialCombine organic extracts, dry (MgSO4)
  4. filtrationfilter
  5. concentrationconcentrate in vacuo
  6. customPurify by column chromatography (0%–10% 2M NH3 in methanol/CH2Cl2)
  7. customto yield an oil

Sources & evidence

ORD record
ord-bc5cda5a59134d93980bee314f292c90
Source dataset
uspto-grants-2007_11
Patent number
US07291632B2

Reaction notes

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