Acetic Acid → HCID 57686969, compound

HRID 547500Notes

Reaction equation

HRID 547500 reaction equation
[F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[N:5][C:6]2[CH2:7][CH2:8][N:9]([C:13]([C:15]34[CH2:22][CH2:21][CH2:20][CH:19]3[CH2:18][C:17](=O)[CH2:16]4)=[O:14])[CH2:10][C:11]=2[CH:12]=1.[C:26]1([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[Na].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl>[C:26]1([CH:32]2[CH2:33][CH2:34][N:35]([CH:17]3[CH2:16][C:15]4([C:13]([N:9]5[CH2:8][CH2:7][C:6]6[N:5]=[CH:4][C:3]([C:2]([F:25])([F:24])[F:1])=[CH:12][C:11]=6[CH2:10]5)=[O:14])[CH:19]([CH2:20][CH2:21][CH2:22]4)[CH2:18]3)[CH2:36][CH2:37]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1

Participants

7

Reactant 5

HCID 176Acetic AcidHCID 698734-PhenylpiperidineHCID 516892Sodium BicarbonateHCID 5360545SodiumHCID 57686980HCID 57686980, compound

Product 1

HCID 57686969HCID 57686969, compound

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Procedure

To a solution of 3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)hexahydropentalen-2(1H)-one (0.175 g, 0.497 mmol) in DCE (4.3 mL) was added 4-phenylpiperidine (0.080 g, 0.50 mmol). The reaction mixture was stirred at ambient temperature for about 2 h then sodium triacetoxyborohydide (0.158 g, 0.745 mmol) and acetic acid (0.043 mL, 0.74 mmol) were added. The reaction mixture was then stirred at ambient temperature for about 18 h. Saturated aqueous sodium bicarbonate was added to the reaction mixture and the product was extracted into DCM (3×10 mL). The solvent was removed under reduced pressure and the crude material was purified by RP-HPLC to provide [2-(4-phenyl-piperidin-1-yl)-hexahydro-pentalen-3a-yl]-(3-trifluoromethyl-7,8-dihydro-5H-[1,6]naphthyridin-6-yl)-methanone as a mixture of four diastereomers (0.075 g). RP-HPLC (Table A, Method c) Rt 2.05 min; m/z: (M+H)+ 498. In addition, the diastereomers were separated using a two-step chiral HPLC method (Step 1: Diastereomer separation: Isocratic using 85% heptane, 7.5% methanol, 7.5% ethanol with 0.2% diethylamine on a Daicel OD-H column (20×250 mm) at 35 deg C. and 12 mL/min flow rate (UV wavelength monitored=265 nm). Step 2: Enantiomer separation: 10-70% gradient over 19 min of isopropanol in heptane with 0.2% diethylamine on a Daicel AD-H column (20×250 mm) at 35 deg C. and 16 ml/min flow rate (UV wavelength monitored=265 nm)) to provide the four enantiomers—the absolute configuration of each compound was not determined. Isomer 1: RP-HPLC (Table A, Method d) Rt 12.66 min. Isomer 2: RP-HPLC (Table A, Method d) Rt 13.57 min. Isomer 3: RP-HPLC (Table A, Method d) Rt 8.46 min. Isomer 4: RP-HPLC (Table A, Method d) Rt 11.76 min.

Workup

  1. stirringThe reaction mixture was then stirred at ambient temperature for about 18 h
  2. extractionthe product was extracted into DCM (3×10 mL)
  3. customThe solvent was removed under reduced pressure
  4. customthe crude material was purified by RP-HPLC

Sources & evidence

ORD record
ord-be42f7e563824260867dad5c89a40a4f
Source dataset
uspto-grants-2011_05
Patent number
US07939544B2

Reaction notes

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