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1-biphenylylacetoxy-3-(2-methoxyphenoxy)-propan-2-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydroxide;
EXAMPLE 1 1-Biphenylylacetoxy-3-(2-methoxyphenoxy)-propan-2-ol (Compound Ia) A suspension of 20 g of 2-(2,3-epoxypropoxy)-1-methoxybenzene, 70 g of biphenylylacetic acid, 100 cc of 1N sodium hydroxide, is kept under reflux for one hour. After cooling to room temperature, the suspension is extracted three times with 75 cc each of ether. The combined ether extracts are then washed with 8% sodium carbonate and then water up to neutrality. After drying and evaporation of the solvent under vacuum, a dense oil is obtained which solidifies after stirring a few hours with diisopropyl ether. The product is recrystallized from diethyl ether/diisopropyl ether in a ratio of 1:1. Yield: 37 g (85%); m.p.: 70 C.; Empirical formula: C24 H24 O5
With Sulfated tungstate; at 70℃; for 2.0h;Green chemistry;
General procedure: Sulfated tungstate (10 wt%) was added to a solution of cyclohexene oxide (1 g, 10.18 mmol) and aniline (0.95 g, 10.18 mmol) in solvent-free condition and the mixture was stirred at room temperature. The progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction mixture was diluted with ethyl acetate (15 ml) and filtered to recover the catalyst. Organic layer washed with water (10 ml), dried over Na2SO4 and concentrated under reduced pressure to give the crude product which was purified by chromatography on silica gel (60-120) with hexane-ethyl acetate (8:2) as eluent to get pure 2-(phenylamino) cyclohexanol as a white solid.
85%
In methanol; at 60℃; for 5.0h;
S3 Synthesis of Ranolazine: N- (2,6-Dimethylphenyl)-2-(1-piperazinyl)acetamide 800 g, 2-(2-methylphenoxymethyl) Ethylene Oxide 583 g , 4000 mL of methanol were sequentially added, and refluxed at 60 C for 5 h. TLC monitored the progress of the reaction. After the conversion of the starting material was completed, the solvent was removed by concentration under reduced pressure to give crude crude ranolazine, which was then recrystallized from ethanol-n-hexane (volume ratio 1:2) to obtain Ranolazine
In toluene; at 120℃; for 5.0h;Product distribution / selectivity;
Step 4: Preparation of Ranolazine; N-(2,6-dimethyl phenyl)- 1-piperazine acetamide (50 g), l-methoxy-2-(oxiranyl methoxy) benzene (40 g) and toluene (400 ml) was refluxed for 5 hours at 1200C. The reaction was monitored by high performance liquid chromatography. The reaction mixture was cooled to 25- 300C and dilute hydrochloric acid (70 ml cone, hydrochloric acid in 500 ml demineralized water) was added to the reaction mass. Aqueous layer obtained was washed with toluene and sodium bicarbonate was added to it in lots till a pH of 7-8 was obtained, followed by the addition of methylene chloride. The reaction mass was extracted with methylene dichloride, the solvent was distilled out under reduced pressure. Crude ranolazine was taken in ethanol (300 ml) and heated to reflux at 800C till clear solution. The solvent (50 ml) was distilled out at atmospheric pressure. The reaction mass was cooled to 20-300C and stirred for 2 hours. Further reaction mass was cooled to 5-1O0C and stirred for 2 hours at 5-100C. The solid thus obtained was filtered, washed with ethanol (50 ml) and dried at 50-60 0C to afford 70 g of the title compound having purity 99.58% by high performance liquid chromatography.; Step 4: Preparation of Ranolazine; N-(2,6-dimethyl phenyl)- 1-piperazine acetamide (125 g), l-methoxy-2-(oxiranyl methoxy) benzene (100 g) and toluene (I t) was refluxed for 5 hours at 1200C. The reaction was monitored was done by high performance liquid chromatography. The reaction mixture was cooled to 25-3O0C and dilute hydrochloric acid (175 ml cone, hydrochloric acid in 1.25 / demineralized water) was added to the reaction mass. Aqueous layer obtained was washed with toluene (250 ml) and sodium bicarbonate was added to it in lots till a pH of 7-8 was obtained, followed by the addition of methylene chloride. The reaction mass was extracted with methylene dichloride, the solvent was distilled out under reduced pressure.Purification of RanolazineCrude ranolazine obtained above was taken in ethanol (750 ml) was and heated to reflux at 8O0C. Clarity of the solution was checked. The solvent (125 ml) was distilled out at atmospheric pressure. The reaction mass was cooled to 20-300C and stirred for 2 hours. Further reaction mass was cooled to 5-100C and stirred for 2 hours at 5-100C. The solid was filtered and washed with ethanol (125 ml) to afford 175 g of the title compound having purity 99.49% by high performance liquid chromatography.
In isopropyl alcohol; at 82 - 83℃; for 3.0h;Inert atmosphere;Product distribution / selectivity;
This is another example demonstrating a process for preparing ranolazine in accordance with an embodiment of the invention.1-[(2,6-dimethylphenyl)aminocarbonyl]piperazine (20 g, 80.86 mmol, HPLC purity 99.55%) and 13.84 g (76.80 mmol, HPLC purity 91.95%) of 1-phenoxy-2,3-epoxypropane was suspended in isopropanol (120 mL) under a nitrogen atmosphere. Then the mixture was heated slowly to reflux temperature (82-83 C.) and the solution was maintained at reflux temperature for 3 hours.The solution was then cooled to 20-25 C. Precipitation was observed upon cooling to a temperature of about 30 C. The reaction mass was stirred at room temperature. Finally, the suspension was filtered and the solid was with isopropanol (2×10 mL). Yield: 45.16 g of wet crude ranolazine (91.4%, 31.61 g of estimated dry mass). HPLC purity: 98.84%.43.76 g of crude ranolazine (estimated dry mass: 30.63 g) was suspended in 137.2 mL of methyl ethyl ketone and the suspension was heated to 80 C. Immediately thereafter the solution was cooled to 20-25 C. and maintained at that temperature for 1 hour. The suspension was filtered and washed with methyl ethyl ketone (10 mL). 31.57 g of wet ranolazine (24.86 g of estimated dry mass) was obtained (purification yield: 81.16%). HPLC purity: 99.76%.30.56 g of ranolazine (24.07 g of estimated dry mass) was suspended in 103 mL of methyl ethyl ketone and the suspension was heated to 80 C. The suspension was cooled to 20-25 C. and maintained at that temperature for 1 hour. The suspension was filtered, washed with methyl ethyl ketone (10 mL) and dried in vacuum oven at 50-60 C. until a constant weight. 22.73 g of ranolazine base was obtained (purification yield: 94.4%, global yield 70%). HPLC purity: 99.91%.
In methanol; ethyl acetate;Reflux;Product distribution / selectivity;
Preparation D. N-(2,6-dimethylphenyl)-1 -piperazine acetamide (20 g), 1 -(2- methoxyphenoxy)-2,3-epoxypropane (19 g), ethyl acetate (100 mL), and water (100 mL) are charged into a round-bottom flask and stirred for 5-10 minutes. The mixture is heated to reflux temperature and maintained for 10-11 hours. The mixture is cooled to 0-50C and maintained for 45-60 minutes. The formed solid is filtered and washed with ethyl acetate (20 mL). The solid is dried at 60-650C, to afford 27.6 g of the title compound. Purity by HPLC: 97.86%.
In methanol; at 65℃;
A mixture of l-[(2,6-Dimethylphenyl)aminocarbonylmethyl]piperazine (125 gm), l-(2- methoxy phenoxy)-2,3-epoxypropane (96 gm) and methanol (750 ml) was refluxed for 6-8 hours at 650C. The reaction mixture was initially cooled to 25-30C, followed by cooling to 0-5C and stirring for 4 hours. The resulting solid was filtered, the product was washed with pre cooled methanol (60 ml), and the material was suction dried followed by drying under vacuum at 50-55C to give 175 gm of crude ranolazine. Content of Impurities: '0.58 RRt' impurity: 0.06%; '1.16 RRt' impurity: 0.06%; dimer impurity- 1: 0.16%; dimer impurity-2: 0.05%; dimer impurity-3: 0.22%; impurity-4: 0.08%; impurity-5: 0.01%; and impurity-6: 0.07%.
Step 3: Preparation of ranolazine (I); 100 gm Piperazine acetamide (II) was dissolved in 'solvent mixture comprising 500 ml of toluene and 100 ml of methanol. To this solution 109.12 gm of epoxide (III) was added. The reaction mixture was stirred at 50-550C till completion. The reaction mass was concentrated under reduced pressure. To the residue water (500 ml) and dichloromethane (500 ml) was added. The pH of the reaction mass was adjusted between 1-1.5 using dilute hydrochloric acid. The organic layer was separated and the aqueous layer was washed with dichloromethane (2 x 200 ml). The aqueous layer was separated and basified with 200 ml of 5N NaOH solution. Product was extracted with dichloromethane (3 x 500 ml). The combined organic layer was washed with water and 20% brine solution. The organic layer was concentrated to afford an oily product. Yield: 155 gm, HPLC purity: 98%. To the oily mass acetone (400 ml) was charged and stirred for 1 hour at 45-5O0C. The slurry was cooled to 25- 3O0C and stirred for an hour. Further cooled to 5-100C. The solid was filtered, washed with chilled acetone (100 ml) and dried to give crude ranolazine base as solid. Yield: 145 gm, purity 99.5%.
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