| 89.9% |
With lithium aluminium tetrahydride In tetrahydrofuran at 25℃; for 3.5 h; |
1618 mL (1618 mmol) of a 1 mol / L lithium aluminum hydride / tetrahydrofuran solution was added to a 2 L four-necked flask equipped with a stirring blade and a thermometer,Pyridine carboxylic acid compound 120 g (404 mmol)In 1,800 mL of tetrahydrofuran was added dropwise over 30 minutes while maintaining the internal temperature at around 25 ° C., and the mixture was stirred at 25 ° C. for 3 hours.70 mL of water was added while cooling the reaction solution with water, and the mixture was stirred. Then, the organic layer and the aqueous layer were separated, and the obtained organic layer was sequentially washed with 70 mL of a 15 wtpercent sodium hydroxide aqueous solution and then with 200 mL of water, and separated, .The obtained organic layer was concentrated under reduced pressure to obtain a crude product of a pyridine methanol compound. 840 mL of isopropyl acetate was added to the crude product of the pyridine methanol compound and heated to 60 ° C. to dissolve the crude product, and then 840 mL of heptane was added dropwise at an internal temperature of 50 ° C. or higher.The solution was cooled to 5 ° C., the slurry of the pyridine methanol compound was aged at around 5 ° C. for 2 hours, and the slurry solution was filtered by vacuum filtration.The filtered crystals were washed with a mixed solution of 60 mL of isopropyl acetate and 60 mL of heptane, and then the obtained white crystals were dried under reduced pressure at 40 ° C. for 5 hours,102 g (363 mol, production yield: 89.9percent) of a pyridine methanol compound was obtained as white crystals (purity: 99.53percent). |
| 89% |
With sodium tetrahydroborate; zinc(II) chloride In tetrahydrofuran at 60 - 85℃; for 16 h; |
To a 1000 ml three-necked flask, 600 ml of tetrahydrofuran, 2- (4-methyl-2-phenyl-1-piperazinyl)(134 g, 0.45 mol),Zinc chloride (306 g, 2.25 mol) was added sodium borohydride (85 g, 2.25 mol) in portions carefully. The temperature was raised to 60-85 ° C after addition and reflux with stirring for 16 hours, cooled to 0 ° C and carefully quenched with methanol The reaction mixture was removed under reduced pressure. 600 ml of 6N hydrochloric acid was added and the mixture was heated to 80 ° C with heating and stirred for 1 hour. The mixture was cooled to room temperature and extracted with methylene chloride (2 L × 3). The organic phase was dried over 1 kg of anhydrous sodium sulfate, A white solid was obtained. The white solid was further dried by blowing with air at 50 ° C to give 113 g of 1-(3-hydroxymethylpyridin-2-yl) -4-methyl-2-phenylpiperazine as a white solid in 89percent yield. |
| 89.9% |
With lithium aluminium tetrahydride In tetrahydrofuran at 25℃; for 3.5 h; |
A stirrer,In a 2 L four-necked flask equipped with a thermometer,1618 mL (1618 mmol) of a 1 mol / L lithium aluminum hydride / tetrahydrofuran solution was added,Pyridine carboxylic acid compound 120 g (404 mmol)Was dissolved in 1800 mL of tetrahydrofuran was added dropwise over 30 minutes while maintaining the internal temperature at around 25 ° C.,And the mixture was stirred at 25 ° C. for 3 hours.While cooling the reaction solution with water, 70 mL of water was added and stirred,The organic layer and the aqueous layer were separated,The obtained organic layer was washed with 70 mL of a 15 wtpercent sodium hydroxide aqueous solution,Then,Wash sequentially with 200 mL of water,And separated.The obtained organic layer was concentrated under reduced pressure,A crude product of pyridine methanol compound was obtained.To a crude product of pyridine methanol compound,840 mL of isopropyl acetate was added,Heated to 60 ° C.,After dissolving the crude product,840 mL of heptane was added dropwise at an internal temperature of 50 ° C. or higher.The solution was cooled to 5 ° C.,The slurry of the pyridine methanol compound was aged at around 5 ° C. for 2 hours,By vacuum filtration,The slurry solution was filtered.The filtered crystals were washed with a mixed solution of 60 mL of isopropyl acetate and 60 mL of heptane,The obtained white crystals were dried under reduced pressure at 40 ° C. for 5 hours,102 g (363 mol, production yield: 89.9percent) of a pyridine methanol compound as white crystals(Purity: 99.53percent, moisture content: 320 ppm). |
| 88% |
With sodium bis(2-methoxyethoxy)aluminium dihydride In tetrahydrofuran; toluene at 25℃; for 12.5 h; |
5.0 g (16.8 mmol) of the pyridinecarboxylic acid obtained in Preparation Example 1 and 60 ml of tetrahydrofuran were added to a 200 ml four-necked flask equipped with a two-piece stirring blade having a diameter of 3.6 cm, and stirred at 25 ° C. To the obtained suspension, 15.7 g (50.4 mmol) of 65percent sodium bis(2-methoxyethoxy)aluminumhydride / toluene solution was added dropwise over 30 minutes while maintaining the internal temperature at around 25 ° C, and the mixture was stirred at 25 ° C for 12 hours (reaction conversion rate: 99.9percent). While cooling the reaction solution with water, a solution obtained by mixing 11.8 g of (+)-sodium potassium tartrate tetrahydrate and 17 ml of water was added and stirred, then the aqueous layer was separated and the obtained organic layer was washed with 2.6 ml of 15percent brine, and the solvent was distilled off under reduced pressure to obtain a crude product of pyridine methanol body as a pale yellow oil. 25 ml of toluene was added to the obtained oily matter and dissolved, and insoluble matter was removed by filtration and 25 ml of heptane was added to the solution, and the mixture was stirred for 5 hours. The precipitated solid was collected by filtration under reduced pressure, and the obtained wet body was dried under reduced pressure at 80 ° C for 20 hours to obtain 4.2 g of pyridine methanol body as white crystals (yield: 88percent). As a result of analyzing this crystal by HPLC, the purity of the pyridine methanol product was 99.89percent and the content of the methyl form was 0.029percent. |
| 81% |
With sodium bis(2-methoxyethoxy)aluminium dihydride In tetrahydrofuran; toluene at 40℃; for 5 h; Inert atmosphere |
a 1 L three-necked flask equipped with a stirring blade and a thermometer, 60 g (201.8 mmol) of a pyridine carboxylic acid compound was suspended in 270 mL of tetrahydrofuran and cooled to 10 ° C. 240 g (706.2 mmol) of a toluene solution of 70percent sodium dihydrobis (2-methoxyethoxy) aluminate was added dropwise under a nitrogen stream, and the mixture was reacted at 40 ° C. for 5 hours. After completion of the reaction, 275 mL of a 35 mass percent Rochelle salt aqueous solution was added, and the organic layer and the aqueous layer were separated. After washing by adding 120 mL of 25 mass percent saline to the organic layer, separation was performed, and the obtained organic layer was concentrated under reduced pressure. 240 mL of toluene was added to the obtained residue, and the mixture was heated to 60 to 65 ° C., and insoluble matter was filtered off. After concentrating the toluene layer under reduced pressure, 57 g of a crude product of pyridine methanol compound was obtained. (Crude yield 99percent).The rough object 57g of the aforementioned pyridinemethanol compound was added to the 1-L three necked flask furnished with an impeller and a thermometer. After having added 420 g of isopropyl acetate to this, heating at 60 degrees C and dissolving this rough object, the solution was cooled to 5 degrees C, and the slurry liquid of the pyridinemethanol compound was riped near 5 degree C for about 2 hours. The white crystals obtained by filtering the slurry solution after aging are moved to a 1L glass flask, It dried in vacuum at 40 degrees C for 2 hours, dried in vacuum by the rotating evaporator by 0.5kpa, and obtained the pyridinemethanol compound 43.5g (153.7 mol) as white crystals (76percent of yield, the HPLC purity of 99.9percent, the amount of residual solvents of 250 ppm of isopropyl acetate). The crystal coating weight to the reaction container wall surface at the time of crystallization was less than 1mass percent, and the crystal coating weight to the revolving dry inside-of-a-plane wall was also less than 1mass percent. |
| 80% |
With sodium bis(2-methoxyethoxy)aluminium dihydride In tetrahydrofuran; toluene at 10 - 40℃; for 5 h; Inert atmosphere |
10.0 g (33.6 mmol) of the pyridine carboxylic acid compound obtained in Preparation Example 1 and 45 mL of tetrahydrofuran were added to a 300 mL four-necked flask equipped with a stirring blade and a thermometer to suspend them and cooled to 10 ° C. Under nitrogen atmosphere, 70percent SDMA in toluene solution 34. After 0 g (117.7 mmol) was added dropwise, the reaction was carried out at around 40 ° C. for 5 hours.After completion of the reaction, 54.0 g (67.0 mmol) of a 35 mass percent Rochelle salt aqueous solution was added, and then organic solutionThe medium layer and the aqueous layer were separated. 25 mL of a 25 mass percent sodium chloride aqueous solution was added to the organic solvent layer, and the solution was stirred by stirring at around 25 ° C. for 30 minutes, and liquid separation was carried out. The amount of the pyridine methanol compound contained in the aqueous layer obtained by liquid separation was 1.1percent based on the theoretical yield. On the other hand, the organic solvent layer obtained by liquid separation was concentrated under reduced pressure to obtain a residue. To this residue, 75 mL of tetrahydrofuran was added and after stirring for 30 minutes at around 25 ° C., insoluble matter was filtered off.The resulting tetrahydrofuran solution was concentrated under reduced pressure, 70 mL of isopropyl acetate was added to the residue, and the mixture was heated to around 60 ° C.After the residue had dissolved, 70 mL of heptane was added dropwise at 50 ° C. or more.The obtained solution was cooled to around 5 ° C. and stirred at about the same temperature for about 2 hours.The precipitated solids were separated by filtration, and the obtained wet bodies were dried under reduced pressure at 40 ° C. for 12 hours to obtain 7.6 g (26.9 mmol) of a pyridine methanol compound.(Purity: 99.90percent, production yield: 80.0percent) |
| 76% |
With lithium aluminium tetrahydride In tetrahydrofuran at 5℃; for 3 h; Reflux; Inert atmosphere |
In a 1 L three-necked flask equipped with a stirring blade and a thermometer, 20.3 g (68.3 mmol) of the type II crystal pyridine carboxylic acid obtained in Example 1 was dissolved in 100 mL of anhydrous tetrahydrofuran, and the solution was heated to 5 ° C. After cooling, a suspension of 7.8 g (205.5 mmol) of lithium aluminum hydride diluted with 80 ml of THF was gradually added under a nitrogen stream, and the mixture was reacted under heating reflux for 3 hours. After completion of the reaction, it was cooled to 0 ° C., 82 mL of distilled water was gradually added dropwise, and the mixture was stirred at room temperature for 1 hour, and the precipitated inorganic salt was separated by filtration. The filtrate was concentrated under reduced pressure to obtain 18.2 g of a crude product of a pyridine methanol compound (crude yield 99percent, excess reduced form 0.2percent). Diethyl ether (400 mL) was added to the crude product, and after heating to 40 ° C., the mixture was cooled to 5 ° C. and recrystallized to obtain 14.5 g (51.1 mmol) of a pyridine methanol compound (yield: 76percent HPLC purity 98.7percent, excess reduced form 0.2 °percent). |
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