Acetyl bromide → (R)-1-[3-(4-Chloro-3-methyl-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone

HRID 967364Notes

Reaction equation

HRID 967364 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][C@@H:21]([OH:24])[CH2:22]O)[N:9]=2)=[CH:4][C:3]=1[CH3:25].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(Br)(C)=O.C([O-])([O-])=O.[K+].[K+]>CC(OC)(OC)OC.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][C@@H:21]3[CH2:22][O:24]3)[N:9]=2)=[CH:4][C:3]=1[CH3:25]

Participants

7

Reactant 4

HCID 10482Acetyl bromideHCID 11430Potassium CarbonateHCID 466102Benzenesulfonic acid, 4-methyl-, compd. with pyridine (1:1)HCID 69158619(r)-1-[3-(4-Chloro-3-methyl-phenyl)-1-(2,3-dihydroxy-propyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone

Product 1

HCID 86585175(R)-1-[3-(4-Chloro-3-methyl-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneYield 37.1%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 15050Trimethyl orthoacetateSolvent

Conditions

Temperature
0 °C

Procedure

(R)-1-[3-(4-Chloro-3-methyl-phenyl)-1-(2,3-dihydroxy-propyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (452 mg, 1.24 mmol) and pyridinium p-toluenesulfonate (85 mg) were combined in MeC(OMe)3 (50 mL) and briefly sonicated. The mixture was stirred for 17 h, concentrated, and the residue dissolved in CH2Cl2 (8 mL). The solution was cooled to 0° C. and treated with AcBr (0.15 mL, 2.0 mmol). After 5 h the mixture was partitioned between EtOAc (300 mL) and saturated aqueous NaHCO3 (75 mL). The EtOAc layer was washed with H2O (75 mL) and brine (75 mL), dried over Na2SO4 and concentrated. The residue was combined with K2CO3 (243 mg, 1.84 mmol) in MeOH (50 mL) and stirred for 3 h then worked up as described above. Purification by column chromatography (silica, 10-40% acetone/CH2Cl2) gave 159 mg (37%) of the title compound. Chiral HPLC (Daicel OD, 0.5% Et2NH/MeOH) analysis indicated >95% optical purity. HPLC (reverse phase conditions), tR=4.97 min. MS (electrospray): exact mass calculated for C18H20ClN3O2 [M++Na], 368.11. m/z found 368.05. 1H NMR (CDCl3, 400 MHz, a mixture of amide rotamers): 7.54 (br d, J=6.3 Hz, 2H), 7.41-7.35 (m, 3H), 7.29 (dd, J=8.2, 1.9 Hz, 1H), 4.81 and 4.74 (A and B of AB quartet, Jab=15.7 Hz, 2H), 4.60 (s, 2H), 4.48 (dd, J=15.2, 2.4 Hz, 1H), 4.42 (dd, J=15.4, 2.8 Hz, 1H), 4.13 (t, J=4.7 Hz, 1H), 4.09 (dd, J=4.6 Hz, 1H), 3.93 (m, 2H), 3.74 (t, J=5.8 Hz, 1H), 3.73 (t, J=5.8 Hz, 1H), 3.34 (m, 2H), 2.85-2.75 (m, 6H), 2.53 (dd, J=4.6, 2.5 Hz, 1H), 2.48 (dd, J=4.6, 2.6 Hz, 1H), 2.43 (s, 3H), 2.41 (s, 3H), 2.20 (s, 3H), 2.15 (s, 3H).

Workup

  1. custombriefly sonicated
  2. concentrationconcentrated
  3. dissolutionthe residue dissolved in CH2Cl2 (8 mL)
  4. customAfter 5 h the mixture was partitioned between EtOAc (300 mL) and saturated aqueous NaHCO3 (75 mL)
  5. washThe EtOAc layer was washed with H2O (75 mL) and brine (75 mL)
  6. dry with materialdried over Na2SO4
  7. concentrationconcentrated
  8. stirringstirred for 3 h
  9. customPurification by column chromatography (silica, 10-40% acetone/CH2Cl2)

Sources & evidence

ORD record
ord-cbad099625a54a6d910a948ca5ec410d
Source dataset
uspto-grants-2005_10
Patent number
US06953793B2

Reaction notes

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