(2R)-2-propyloctanoic acid

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

Procedure: Additionally, it is also possible in the above reaction steps that, for example, in the step (A), a two-carbon adding reaction is carried out using an unsaturated organic metal reagent (e.g., vinyl magnesium chloride, vinyl magnesium bromide, ethynyl magnesium chloride, ethynyl magnesium bromide, etc.) as an organic metal reagent, the resulting (4R)-1-decen-4-ol or (4R)-1-decyn-4-ol is subjected to the reactions of the step (B) or the step (C), and the resulting (2R)-(2-propenyl)octanoic acid or (2R)-(2-propynyl)octanoic acid is reduced by the method mentioned in WO 99/58513 and WO 00/48982 to give (2R)-2-propyloctanoic acid of high purity. Additionally, it is also possible in the above reaction steps that, for example in the step (A), a two-carbon adding reaction

Conditions: temp:108.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under an argon atmosphere, the compound (100 g) produced in Reference Example 3 was dissolved in acetic acid (230 mL) at about 40° C. (inner temperature). A solution of methanesulfonic acid (130 g) in water (182 mL) was added to the above solution, then stirred at about 105-112° C. (inner temperature) for about 13 hours, and cooled to about 28° C. (inner temperature). Then, water (400 mL) and a mixture of n-heptane: isopropyl acetate (5:1) (500 mL) were added and the mixture was extracted. The organic layer was washed twice with water (400 mL) and concentrated to give (2R)-2-propyloctanoic acid having the following physicochemical properties (103 g, 99.3% e.e.). cooled to about 28° C. (inner temperature) were added the mixture was extracted The organic layer was washed twice with water (400 mL) concentrated

Conditions: temp:108.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under an argon atmosphere, the compound (100 g) produced in Reference Example 3 was dissolved in acetic acid (230 mL) at about 40° C. (inner temperature). A solution of methanesulfonic acid (130 g) in water (182 mL) was added to the above solution, then stirred at about 105-112° C. (inner temperature) for about 13 hours, and cooled to about 28° C. (inner temperature). Then, water (400 mL) and a mixture of n-heptane: isopropyl acetate (5:1) (500 mL) were added and the mixture was extracted. The organic layer was washed twice with water (400 mL) and concentrated to give (2R)-2-propyloctanoic acid having the following physicochemical properties (103 g, 99.3% e.e.). cooled to about 28° C. (inner temperature) were added the mixture was extracted The organic layer was washed twice with water (400 mL) concentrated

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

Procedure: (R)-2-propyloctanoic acid (100 mg, 0.48 mmol) was dissolved in 1 mL DMF. HATU (201 mg, 0.53 mmol) and NMM (192 μL, 1.73 mmol) were added and the solution was stirred for 5 min. 1400-W (94 mg, 0.528 mmol) was added and the solution was stirred for 2 h at rt. The reaction was quenched with TFA (142 μL, 1.87 mmol) TFA and MeOH (1 mL) and purified by preparative HPLC (5% to 100%, ACN/water) to give the product (Example 6) as a white solid. 1H-NMR (500 MHz, DMSO-d6) δ 9.80 (s, 1H), 9.22 (s, 1H), 8.76 (s, 1H), 8.37 (t, 1H), 7.34-7.37 (m, 1H), 7.22-7.29 (m, 3H), 4.47 (d, 2H), 4.42 (d, 2H), 2.18-2.24 (m, 4H), 1.46-1.50 (m, 2H), 1.20-1.31 (m, 12H), 0.84-0.87 (m, 6H). MS (ESI) 346 (M+H). the solution was stirred for 2 h at rt purified by preparative HPLC (5% to 100%, ACN/water) to give the product (Example 6) as a white solid

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

Procedure: (R)-2-propyloctanoic acid (100 mg, 0.48 mmol) was dissolved in 1 mL DMF. HATU (201 mg, 0.53 mmol) and NMM (64 μL, 0.58 mmol) were added and the solution was stirred for 5 min. Fasudil (154 mg, 0.53 mmol) was added and the solution was stirred for 2 h at rt. The reaction was quenched with TFA (48 μL, 0.63 mmol) and MeOH (1 mL) and purified by preparative HPLC (50% to 100% ACN/water) to give the product (Example 5) as a white solid. 1H-NMR (500 MHz, CDCl3) δ 9.81 (s, 1H), 8.94 (d, 1H), 8.70 (d, 1H), 8.54-8.60 (m, 2H), 7.98 (t, 1H), 7.28 (s, 1H), 3.71-3.76 (m, 4H), 3.45-3.48 (m, 4H), 2.56-2.58 (m, 1H), 2.04-2.07 (m, 2H), 1.59-1.65 (m, 2H), 1.43-1.44 (m, 2H), 1.26-1.29 (m, 10H), 0.86-0.91 (m, 6H). MS (ESI) 460 (M+H). the solution was stirred for 2 h at rt purified by preparative HPLC (50% to 100% ACN/water) to give the product (Example 5) as a white solid

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

Procedure: (R)-2-propyloctanoic acid (0.05 g, 0.268 mmol) was dissolved in 5 mL, CH2Cl2. Triethylamine (50 μL, 0.359 mmol) and 2-bromoacetophenone (0.06 g, 0.300) were added, and the reaction was stirred at room temperature for 5 hours. Once no SM was seen by TLC, the reaction mixture was concentrated under reduced pressure to remove all triethylamine. The residue was purified by silica-gel chromatography (0-10% EtOAc:hexanes) to give the product (Example 2). Ee of >98.5% was determined by HPLC [Chiralcel OJ-RH 4.6×150 mm; CH3CN/H2O=60/40; flow rate 1 mL min−1; detection, 244 nm; retention time, 10.7 min (S) and 11.9 min (R).] 1H-NMR (CDCl3, 500 MHz) δ 7.91 (d, 2H), 7.61-7.57 (m, 1H), 7.48 (t, 2H), 5.32 (s, 2H), 2.55-2.50 (m, 1H), 1.72-1.68 (m, 2H), 1.52-1.48 (m, 2H), 1.47-1.27 (m, 10H), 0.93 (t, 3H), 0.88 (t, 3H). the reaction mixture was concentrated under reduced pressure to remove all triethylamine The residue was purified by silica-gel chromatography (0-10% EtOAc:hexanes) to give the product (Example 2)

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

Procedure: Using the crystal comprising (2R)-2-propyloctanoic acid and R)-(+)-1-phenylethylamine (6.8 g) produced in the second recrystallization and acetonitrile (102 mL), the same operation as in the second recrystallization was made to give the crystal comprising (2R)-2-propyloctanoic acid and (R)-(+)-1-phenylethylamine (6.0 g, 98.9% e.e.; yield 88%). the same operation as in the second recrystallization to give the crystal

Conditions: temp:108.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under an argon atmosphere, the compound (100 g) produced in Reference Example 3 was dissolved in acetic acid (230 mL) at about 40° C. (inner temperature). A solution of methanesulfonic acid (130 g) in water (182 mL) was added to the above solution, then stirred at about 105-112° C. (inner temperature) for about 13 hours, and cooled to about 28° C. (inner temperature). Then, water (400 mL) and a mixture of n-heptane: isopropyl acetate (5:1) (500 mL) were added and the mixture was extracted. The organic layer was washed twice with water (400 mL) and concentrated to give (2R)-2-propyloctanoic acid having the following physicochemical properties (103 g, 99.3% e.e.). cooled to about 28° C. (inner temperature) were added the mixture was extracted The organic layer was washed twice with water (400 mL) concentrated

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

Procedure: Additionally, it is also possible in the above reaction steps that, for example, in the step (A), a two-carbon adding reaction is carried out using an unsaturated organic metal reagent (e.g., vinyl magnesium chloride, vinyl magnesium bromide, ethynyl magnesium chloride, ethynyl magnesium bromide, etc.) as an organic metal reagent, the resulting (4R)-1-decen-4-ol or (4R)-1-decyn-4-ol is subjected to the reactions of the step (B) or the step (C), and the resulting (2R)-(2-propenyl)octanoic acid or (2R)-(2-propynyl)octanoic acid is reduced by the method mentioned in WO 99/58513 and WO 00/48982 to give (2R)-2-propyloctanoic acid of high purity. Additionally, it is also possible in the above reaction steps that, for example in the step (A), a two-carbon adding reaction