2-Methylhexanoic 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:

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

Procedure: Following General Procedure C-P above using 2-methylhexanoic acid and 5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, as described in Example 7-B, the title compound was prepared. The molecular weight as determined by mass spectrometry (FD) was: 422 (M+H).

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1.25 g (8.1 mM) of (-)-2-methylhexanoic acid ([α]D26 -6.15 degrees (c 1.073, methanol)), 20 ml of dry tetrahydrofuran and 0.90 g (8.9 mM) of dry triethylamine was cooled on an ice bath, and 0.84 g (8.1 mM) of ethyl chloroformic acid was added dropwise thereto in 5 minutes, followed by 1 hour of stirring at 0° C. A white salt precipitated at this time was removed by filtration. To a mixture of 0.46 g (12.1 mM) of sodium borohydride and 8 ml of distilled water under stirring at 0° C., the above filtrate was added dropwise in 20 min., followed by stirring at room temperature for 3 hours. After the reaction, 2N-hydrochloric acid was added to give pH 1, and the organic layer was separated. The remaining aqueous layer was subjected to extraction with ether, and the ether extract was mixed with the organic layer. The mixture was washed with 1N-sodium bicarbonate aqueous solution and dried on sodium sulfate. After the removal of solvent by distillation, the product was subjected to distillation by a Kugelrohr distiller. At 95° C./4 mmHg, (+)-2-cyano-2-methyl-1-hexanol was obtained in an amount of 0.55 g (Yield:48.5%), [α]D26 +0.66 degree (c 1.823, ether). was cooled on an ice bath followed by 1 hour A white salt precipitated at this time was removed by filtration To a mixture of 0.46 g (12.1 mM) of sodium borohydride and 8 ml of distilled water under stirring at 0° C. the above filtrate was added dropwise in 20 min. by stirring at room temperature for 3 hours After the reaction, 2N-hydrochloric acid was added to give pH 1 the organic layer was separated The remaining aqueous layer was subjected to extraction with ether the ether extract was mixed with the organic layer The mixture was washed with 1N-sodium bicarbonate aqueous solution dried on sodium sulfate After the removal of solvent by distillation the product was subjected to distillation by a Kugelrohr distiller

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

Procedure: Following General Procedure C-P above using 2-methylhexanoic acid and 5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, as described in Example 7-B, the title compound was prepared. The molecular weight as determined by mass spectrometry (FD) was: 422 (M+H).

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

Procedure: Following General Procedure C-P above using 2-methylhexanoic acid and 5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, as described in Example 7-B, the title compound was prepared. The molecular weight as determined by mass spectrometry (FD) was: 422 (M+H).

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

Procedure: Escherichia coli MR-2103 (FERM BP-3835) was seeded on 50 ml of LB medium (1% polypeptone, 0.5% yeast extract, 0.5% NaCl) containing 50 μg/ml ampicillin and cultured at 37° C. for 20 hours under shaking. After the completion of the cultivation, the culture solution was centrifuged. The total volume of the cells harvested were washed with ion-exchanged water and then suspended in 50 ml of 50 mM phosphate buffer (pH 7.0). To this cell suspension, 5 g of racemic methyl α-methylhexanoate was added and reacted at 30° C. for 20 hours. During the reaction, the pH of the reaction solution was adjusted at 7.0 using in NaOH aqueous solution. After the completion of the reaction, cells were removed by centrifugation and unreacted methyl α-methylhexanoate was extracted with ethyl acetate. The organic layer was dehydrated by adding thereto anhydrous sodium sulfate and the solvent was removed by evaporation. The organic layer was further distilled and purified to thereby obtain 1.9 g of optically active methyl α-methylhexanoate. The specific rotation of this optically active methyl α-methylhexanoate was measured and found to be [α]25 D =+16.3. Then, after the pH of the aqueous layer was lowered to 2.0 with dilute sulfuric acid, the acid in the aqueous layer was extracted with ethyl acetate. The organic layer was dehydrated by adding thereto anhydrous sodium sulfate and the solvent was removed by evaporation. The organic layer was further distilled and purified to thereby obtain 1.3 g of optically active α-methylhexanoic acid. The specific rotation of this sample was measured and found to be [α]25 D =-16.3. the acid in the aqueous layer was extracted with ethyl acetate by adding anhydrous sodium sulfate and the solvent was removed by evaporation The organic layer was further distilled purified

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

Procedure: Escherichia coli MR-2103 (FERM BP-3835) was seeded on 50 ml of LB medium (1% polypeptone, 0.5% yeast extract, 0.5% NaCl) containing 50 μg/ml ampicillin and cultured at 37° C. for 20 hours under shaking. After the completion of the cultivation, the culture solution was centrifuged. The total volume of the cells harvested were washed with ion-exchanged water and then suspended in 50 ml of 50 mM phosphate buffer (pH 7.0). To this cell suspension, 5 g of racemic methyl α-methylhexanoate was added and reacted at 30° C. for 20 hours. During the reaction, the pH of the reaction solution was adjusted at 7.0 using in NaOH aqueous solution. After the completion of the reaction, cells were removed by centrifugation and unreacted methyl α-methylhexanoate was extracted with ethyl acetate. The organic layer was dehydrated by adding thereto anhydrous sodium sulfate and the solvent was removed by evaporation. The organic layer was further distilled and purified to thereby obtain 1.9 g of optically active methyl α-methylhexanoate. The specific rotation of this optically active methyl α-methylhexanoate was measured and found to be [α]25 D =+16.3. Then, after the pH of the aqueous layer was lowered to 2.0 with dilute sulfuric acid, the acid in the aqueous layer was extracted with ethyl acetate. The organic layer was dehydrated by adding thereto anhydrous sodium sulfate and the solvent was removed by evaporation. The organic layer was further distilled and purified to thereby obtain 1.3 g of optically active α-methylhexanoic acid. The specific rotation of this sample was measured and found to be [α]25 D =-16.3. the acid in the aqueous layer was extracted with ethyl acetate by adding anhydrous sodium sulfate and the solvent was removed by evaporation The organic layer was further distilled purified

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 2-methylhexanoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 2-methylhexanoyl isothiocyanate was prepared using the resultant 2-methylhexanoyl chloride as a starting compound according to the description of the literature. 2-Methylhexanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (44 mg, yield 58%). The solvent was removed by distillation, and 2-methylhexanoyl isothiocyanate was prepared to prepare a solution The reaction solution was concentrated the residue was purified by chromatography on silica gel