2-methylbutanoic acid

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound, off-white solid (84 mg, 82%), MS (ISP) m/z=413.5 [(M+H)+], mp 210° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and (RS)-2-methyl-butyric acid.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Methylbutyric acid (50 mg, 0.487 mmol) was reacted with PTU (70 mg, 0.244 mmol) as the same manner as the synthesis of 1-(1-isobutyrylpiperidin-4-yl)-3-(4-(trifluoromethyl)phenyl)urea yielding the final product (80 mg, 0.215 mmol, 88% yield). 1H NMR (d6-DMSO, 300 Mhz): δ 8.77 (d, J=8.4 Hz, 1H), 7.57 (s, 4H), 6.37 (s, 1H), 4.22 (m, 1H), 3.88 (d, J=13.2 Hz, 1H), 3.71 (m, 1H), 3.17 (t, J=12.8 Hz, 1H), 2.84 (m, 2H), 1.85 (m, 2H), 1.54 (m, 1H), 1.29 (m, 3H), 0.97 (s, 3H), 0.81 (d, J=6 Hz, 3H).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5.49 g of (+)-2-methylbutanoic acid,8.50 g of 4-hydroxy biphenyl and 20 ml of toluene were charged into a flask and then 4.0 ml (55 mmol) of thionyl chloride was added thereto with stirring. The resulting mixture was maintained at a temperature of 70°~80° C. and reacted for 8 hours. After the completion of the reaction, the resulting product was cooled to room temperature, added with water to decompose the excess amount of thionyl chloride, washed with water and dried on anhydrous magnesium sulfate. After the removal of solvent, it was purified by a column chromatography of silica gel to obtain 12.69 g of (+)-2-methylbutanoic acid biphenyl having an oily specific rotation [α]25 (16.46 wt% in chloroform) of +15.1°. The resulting mixture was maintained at a temperature of 70°~80° C. reacted for 8 hours After the completion of the reaction washed with water dried on anhydrous magnesium sulfate After the removal of solvent, it was purified by a column chromatography of silica gel

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5.49 g of (+)-2-methylbutanoic acid,8.50 g of 4-hydroxy biphenyl and 20 ml of toluene were charged into a flask and then 4.0 ml (55 mmol) of thionyl chloride was added thereto with stirring. The resulting mixture was maintained at a temperature of 70°~80° C. and reacted for 8 hours. After the completion of the reaction, the resulting product was cooled to room temperature, added with water to decompose the excess amount of thionyl chloride, washed with water and dried on anhydrous magnesium sulfate. After the removal of solvent, it was purified by a column chromatography of silica gel to obtain 12.69 g of (+)-2-methylbutanoic acid biphenyl having an oily specific rotation [α]25 (16.46 wt% in chloroform) of +15.1°. The resulting mixture was maintained at a temperature of 70°~80° C. reacted for 8 hours After the completion of the reaction washed with water dried on anhydrous magnesium sulfate After the removal of solvent, it was purified by a column chromatography of silica gel

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: tert-butyl piperidin-4-ylcarbamate (1 g, 5 mmol), 4-(N,N-dimethylamino)piperidine (0.73 g, 6 mmol) and EDCI (1.15 g, 6 mmol) were added into a solution of 2-methylbutanoic acid (0.612 g, 6 mmol) in CH2Cl2 (200 mL). The reaction was stirred overnight at rt. The reaction was quenched with the addition of 0.1 M HCl. The organic layer was further washed with sat. NaHCO3 solution followed by sat. NaCl solution. The organic layers was concentrated under vacuo. The product was purified by flash chromatography (Hex:EtOAc/1:1) yielding final product 15 (1.3 g, 4.6 mmol, 91.5% yield). H-NMR (DMSO-d6) ∂ 0.79 (q, J=5 Hz, 3H), 0.95 (m, 3H), 1.2-1.3 (m, 2H), 1.38 (s, 9H), 1.50 (m, 2H), 1.73 (t, J=15 Hz, 1H), 2.6-2.7 (m, 2H), 3.06 (t, J=12 Hz, 1H), 3.46 (m, 1H), 3.88 (d, J=12 Hz, 1H), 4.26 (m, 1H), 6.85 (d, J=8 Hz, 1H). The reaction was quenched with the addition of 0.1 M HCl The organic layer was further washed with sat. NaHCO3 solution The organic layers was concentrated under vacuo The product was purified by flash chromatography (Hex:EtOAc/1:1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound, off-white solid (84 mg, 82%), MS (ISP) m/z=413.5 [(M+H)+], mp 210° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and (RS)-2-methyl-butyric acid.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound, off-white solid (84 mg, 82%), MS (ISP) m/z=413.5 [(M+H)+], mp 210° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and (RS)-2-methyl-butyric acid.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A process for the preparation of 3-methyl-butyric acid comprising (a) oxidizing 3-methyl-butanol with the strain Gluconobacter roseus DSM 9364 to produce 3-methyl-butyric acid and (b) recovering the 3-methyl-butyric add produced in (a).