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

HRID 1716922Notes

Reaction equation

HRID 1716922 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 669388242-Chloro-4-fluoro-N-((2R,4R)-3-(2-methyl-piperidin-4-ylamino)-phenyl)-benzamide hydrochloride

Product 1

HCID 669391412-Chloro-N-((2R,4R)-3-(1,2-dimethyl-piperidin-4-ylamino)-phenyl)-4-fluoro-benzamide hydrochlorideYield 135.8%

Reagents, catalysts & solvents 2

HCID 887MethanolSolvent2×HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

Dissolve 2-chloro-4-fluoro-N-((2R,4R)-3-(2-methyl-piperidin-4-ylamino)-phenyl)-benzamide hydrochloride (Example 41, 30 mg, 0.075 mmol) in methanol (5 mL). Add acetic acid (13 μL, 0.225 mmol) followed by sodium cyanoborohydride (7.1 mg, 0.113 mmol). Cool to 0° C. and add 37% formaldehyde (6.7 μL, 0.083 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 21 mg (68%) of the title compound. Mass spectrum (ion spray): m/z=376.4 (M+1); mp 159-62° 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-dbaa743df28540b5ae181b58e2a60d8a
Source dataset
uspto-grants-2010_09
Patent number
US07803813B2

Reaction notes

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