1,2-Dichloroethane → N-[(1R)-1-(3,5-difluoropyridin-2-yl)ethyl]-3-(5-methylpyridin-2-yl)-5(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)benzamide

HRID 1257555Notes

Reaction equation

HRID 1257555 reaction equation
[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([C:17]3[CH2:24][C:20]4([CH2:23][CH2:22][CH2:21]4)[O:19][N:18]=3)[CH:16]=2)[C:11]([OH:13])=O)=[N:6][CH:7]=1.Cl.[F:26][C:27]1[C:28]([C@H:34]([NH2:36])[CH3:35])=[N:29][CH:30]=[C:31]([F:33])[CH:32]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[F:26][C:27]1[C:28]([C@H:34]([NH:36][C:11](=[O:13])[C:10]2[CH:14]=[C:15]([C:17]3[CH2:24][C:20]4([CH2:21][CH2:22][CH2:23]4)[O:19][N:18]=3)[CH:16]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=3)[CH:9]=2)[CH3:35])=[N:29][CH:30]=[C:31]([F:33])[CH:32]=1

Participants

7

Reactant 5

HCID 111,2-DichloroethaneHCID 81531DiisopropylethylamineHCID 181649HOAtHCID 66691406(R)-1-(3,5-Difluoropyridin-2-yl)ethan-1-amine hydrochlorideHCID 668959553-(5-Methylpyridin-2-yl)-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)benzoic acid

Product 1

HCID 42632728N-[(1R)-1-(3,5-difluoropyridin-2-yl)ethyl]-3-(5-methylpyridin-2-yl)-5(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)benzamideYield 57.9%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of 3-(5-methylpyridin-2-yl)-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)benzoic acid (0.20 g, 0.56 mmol) in N,N-dimethylformamide (2.5 mL) were added (1R)-1-(3,5-difluoropyridin-2-yl)ethanamine hydrochloride salt (0.13 g, 0.67 mmol), EDC (0.16 g, 0.70 mmol), HOAT (0.5 M in DMF; 0.56 mL, 0.28 mmol) and diisopropylethylamine (0.09 mL, 0.56 mmol). The reaction mixture was at ambient temperature and solid was filtered off. Purification by reverse phase HPLC(C-18, 95% water/acetonitrile 5% water/acetonitrile with 0.1% trifluoroacetic acid). Clean fractions were combined and saturated aqueous NaHCO3 was added and the mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with water (3×), brine, dried over sodium sulfate, filtered and concentrated gave the title compound (150 mg). HRMS 463.1948 (M+1). 1H NMR (400 MHz, CDCl3): δ 8.51 (s, 1H); 8.44 (t, J=1.7 Hz, 1H); 8.38 (t, J=1.6 Hz, 1H); 8.29 (d, J=2.4 Hz, 1H); 8.14 (t, J=1.6 Hz, 1H); 7.71 (d, J=8.1 Hz, 1H); 7.63 (d, J=7.6 Hz, 1H); 7.58 (dd, J=8.1, 2.2 Hz, 1H); 7.24-7.16 (m, 1H); 5.71-5.61 (m, 1H); 3.51 (s, 2H); 2.62-2.50 (m, 2H); 2.37 (s, 3H); 2.26-2.18 (m, 2H); 1.90-1.79 (m, 1H); 1.68-161 (m, 1H); 1.54 (d, J=6.7 Hz, 3H).

Workup

  1. customwas at ambient temperature
  2. filtrationsolid was filtered off
  3. customPurification by reverse phase HPLC(C-18, 95% water/acetonitrile 5% water/acetonitrile with 0.1% trifluoroacetic acid)
  4. additionsaturated aqueous NaHCO3 was added
  5. extractionthe mixture was extracted with ethyl acetate (3×)
  6. washThe combined organic extracts were washed with water (3×), brine
  7. dry with materialdried over sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated

Sources & evidence

ORD record
ord-f1d144e9fd5d4a8a89358fe149c6ef43
Source dataset
uspto-grants-2013_06
Patent number
US08461185B2

Reaction notes

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