Acetic Acid → HCID 67955564, compound

HRID 872278Notes

Reaction equation

HRID 872278 reaction equation
[Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][C:16]1[C:21]([CH:22]=O)=[CH:20][CH:19]=[CH:18][N:17]=1.Cl.[F:25][C:26]1([F:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(CC)CC)C.C(O)(=O)C.C([BH3-])#N>ClC(Cl)C>[Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][C:16]1[C:21]([CH2:22][N:29]2[CH2:30][CH2:31][C:26]([F:32])([F:25])[CH2:27][CH2:28]2)=[CH:20][CH:19]=[CH:18][N:17]=1

Participants

7

Reactant 5

HCID 176Acetic AcidHCID 8471TriethylamineHCID 498716Cyano-borohydrideHCID 27583514,4-Difluoropiperidine hydrochlorideHCID 86666457HCID 86666457, compound

Product 1

HCID 67955564HCID 67955564, compound

Reagents, catalysts & solvents 1

HCID 63651,1-DichloroethaneSolvent

Procedure

A mixture of 2-{[4-bromo-1-(cyclopropylmethyl)-1H-benzotriazol-5-yl]oxy}pyridine-3-carbaldehyde (13, 20 mg, 0.05 mmol, 1 equiv.) and 4,4-difluoropiperidine hydrochloride (13 mg, 0.08 mmol, 1.5 equiv) in dichloroethane (1 mL) was treated with triethylamine (14 uL, 0.10 mmol, 2 equiv) and stirred for 5 min. The mixture was treated with acetic acid (14 uL, 0.25 mmol, 5 equiv) and resin-bound MP-cyanoborohydride (50 mg, 2.08 mmol/g, 2 equiv.) and was irradiated at 110° C. in a microwave reactor for 20 min. The mixture was cooled to ambient temperature and partitioned between sodium bicarbonate (saturated aqueous, 50 mL) and ethyl acetate (3×30 mL). The combined organic layers were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified via silica gel chromatography (100:0 to 30:70; hexanes:ethyl acetate) to afford 4-bromo-1-(cyclopropylmethyl)-5-({3-[(4,4-difluoropiperidin-1-yl)methyl]pyridin-2-yl}oxy)-1H-benzotriazole (194) as a white powder, 1H NMR (400 MHz, CDCl3) δ 7.98 (dd, 1H, J=4.9, 2.0 Hz), 7.85 (br d, 1H, J=7.4 Hz), 7.56 (d, 1H, J=8.8 Hz), 7.36 (d, 1H, J=8.8 Hz), 7.04 (dd, 1H, J=7.5, 4.9 Hz), 4.52 (d, 2H, J=7.1 Hz), 3.85 (s, 2H), 2.73 (ap t, 4H, J=5.3 Hz), 2.11-2.01 (m, 4H), 1.47-1.37 (m, 1H), 0.71-0.67 (m, 2H), 0.54-0.50 (m, 2H) ppm. High resolution mass spectrometry (ES+) m/z=478.1062, [(M+H)+ calculated for C21H23BrF2N5O: 478.1049].

Workup

  1. customwas irradiated at 110° C. in a microwave reactor for 20 min
  2. custompartitioned between sodium bicarbonate (saturated aqueous, 50 mL) and ethyl acetate (3×30 mL)
  3. dry with materialThe combined organic layers were dried with sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customThe residue was purified via silica gel chromatography (100:0 to 30:70; hexanes:ethyl acetate)

Sources & evidence

ORD record
ord-302e7b2fa0d94c138a0dd60417ced024
Source dataset
uspto-grants-2015_03
Patent number
US08975286B2

Reaction notes

Loading…