With potassium carbonate; sodium iodide In N,N-dimethyl-formamide at 30 - 35℃; for 18 h;
N-(2,6-Dimethyl-phenyl)-2-{4-[2-hydroxy-3-(2-methoxy-phenoxy)-propyl]-piperazin-1-yl}-acetamide: A mixture of 1-(2-methoxy-phenoxy)-3-piperazin-1-yl-propan-2-ol (2 g, 7.52 mmol), 2-chloro-N-(2,6-dimethyl-phenyl)-acetamide (1.84 g, 9.34 mmol), anhydrous potassium carbonate (2 g, 14.5 mmol) and sodium iodide (74 mg, 0.5 mmol) in dimethylformamide (5 mL) was maintained at 30-35° C. for about 18 hours. The mixture was quenched with water and standard extractive work up afforded a crude residue which was purified by flash column chromatography on silica gel (2*16 cm, dichloromethane/methanol/triethylamine=100/2/1 elution) to afford the title compound (1.1 g, 34percent). 1H NMR (300 MHz, CDCl3) δ 7.11 (s, 3H), 6.98-6.90 (m, 4H), 4.19 (br. s, 1H), 4.05 (d, 2H, J=5.4 Hz), 3.87 (s, 3H), 3.30-3.24 (m, 2H), 2.76-2.63 (m, 10H), 2.25 (s, 6H); LC-MS: m/z=428 (MH)+; HPLC: 99percent (Purity).
Reference：
[1] Patent: US2008/312247, 2008, A1, . Location in patent: Page/Page column 31-32
[2] Patent: WO2006/8753, 2006, A1, . Location in patent: Page/Page column 7; 8
[3] Organic Process Research and Development, 2012, vol. 16, # 10, p. 1660 - 1664
2
[ 5294-61-1 ]
[ 95635-55-5 ]
Yield
Reaction Conditions
Operation in experiment
87.4%
With potassium carbonate In ethanol; toluene for 3 h; Reflux
3.4: 1-bromo-3-(2-methoxyphenoxy)-2-propylalcohol as a raw material[0047][0048]2.6 g (0.014 mol) of 1-bromo-3-(2-methoxyphenoxy)-2-propylalcohol, 3.1 g (0.012 mol) of N-(2,6-dimethylphenyl)-1-piperazinylacetamide, 5.5 g (0.04 mol) of potassium carbonate, 25 ml of ethanol and 50 ml of toluene were successively added into a reaction flask and heated under reflux for 3 h till completion.[0049]The former fraction whose main ingredient was ethanol was collected by atmospheric distillation and then filtrated. The filtrate was washed with 3N HCl to get liquid having a pH of 1-2 and further treated with 50 ml of saturated sodium carbonate solution to adjust pH to 9-10. The product was extracted three times with 25 ml of dichloromethane each and the lower organic phase was combined. After the dichloromethane was removed by distillation under reduced pressure and rotary evaporation, the yellow viscous liquid was obtained and then further dissolved in about 10 ml of methonal. The tetrahydrofuran was then dropwise added under reflux till turbidity. The product was slowly crystallized with cooling and filtrated to get 3.73 g of white solid having a yield of 87.4percent by vacuum drying at 40° C.[0050]The result of 1HNMR (CDCl3) confirmed that the compound obtained is ranolazine. Purity by HPLC (area normalization method): 99.3percent.
With potassium carbonate In methanol; toluene for 4.5 h; Reflux
3.1: 1-chloro-3-(2-methoxyphenoxy)-2-propylalcohol as a raw material[0035][0036]2.5 g (0.01 mol) of 1-chloro-3-(2-methoxyphenoxy)-2-propylalcohol, 3.1 g (0.012 mol) of N-(2,6-dimethylphenyl)-1-piperazinylacetamide, 4.1 g (0.03 mol) of potassium carbonate, 25 ml of methanol and 50 ml of toluene were successively added into a reaction flask and heated under reflux for 4.5 h till completion.[0037]The fraction whose main ingredient was methanol was collected by atmospheric distillation at boiling point of 62-68° C. and then filtrated. The filtrate was washed with 3N HCl to get 50 ml of liquid having a pH of 1-2 and further treated with 50 ml of saturated sodium carbonate solution to adjust pH to 9-10. The product was extracted three times with 20 ml of dichloromethane each and the lower organic phase was combined. After the dichloromethane was removed by distillation under reduced pressure and rotary evaporation, the yellow viscous liquid was obtained and then further dissolved in about 10 ml of methonal. The tetrahydrofuran was then dropwise added under reflux till turbidity. The product was slowly crystallized with cooling and filtrated to get 3.42 g of white solid having a yield of 80.1percent by vacuum drying at 40° C.[0038]1HNMR (CDCl3): 2.22,s, 6H, 2.60˜2.62,t, 4H, 2.75,s, 6H, 3.21,s, 2H, 3.45,s, 3H; 3.85,s, 3H, 4.02˜4.04,t, 2H, 4.16,s, 1H, 6.88˜6.90,t, 2H, 6.91˜6.96,m, 2H, 7.08˜7.1,m, 3H, 8.65,s, 1H. The result confirmed that the compound obtained is ranolazine. Purity by HPLC (area normalization method): 99.1percent.
General procedure: Sulfated tungstate (10 wtpercent) 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.
Reference：
[1] Tetrahedron Letters, 2013, vol. 54, # 48, p. 6455 - 6459
[2] Chemical and Pharmaceutical Bulletin, 2009, vol. 57, # 11, p. 1218 - 1222
[3] Organic Process Research and Development, 2012, vol. 16, # 5, p. 748 - 754
[4] Patent: WO2008/47388, 2008, A2, . Location in patent: Page/Page column 13; 15
[5] Patent: US2009/318697, 2009, A1, . Location in patent: Page/Page column 4
[6] Patent: WO2010/25370, 2010, A2, . Location in patent: Page/Page column 52
[7] Patent: WO2010/43976, 2010, A2, . Location in patent: Page/Page column 19
[8] Patent: WO2010/97805, 2010, A1, . Location in patent: Page/Page column 9
[9] Organic Process Research and Development, 2012, vol. 16, # 10, p. 1660 - 1664
5
[ 1427177-23-8 ]
[ 90-05-1 ]
[ 95635-55-5 ]
Reference：
[1] Green Chemistry, 2013, vol. 15, # 3, p. 756 - 767
[2] RSC Advances, 2016, vol. 6, # 54, p. 49150 - 49157
Reference：
[1] Organic Process Research and Development, 2012, vol. 16, # 5, p. 748 - 754
[2] Organic Process Research and Development, 2012, vol. 16, # 10, p. 1660 - 1664
[3] Organic Process Research and Development, 2012, vol. 16, # 10, p. 1660 - 1664
[4] Organic Process Research and Development, 2012, vol. 16, # 10, p. 1660 - 1664
[5] Organic Process Research and Development, 2012, vol. 16, # 10, p. 1660 - 1664
[6] Organic Process Research and Development, 2012, vol. 16, # 10, p. 1660 - 1664
[7] Organic Process Research and Development, 2012, vol. 16, # 10, p. 1660 - 1664
[8] Organic Process Research and Development, 2012, vol. 16, # 10, p. 1660 - 1664
[9] Organic Process Research and Development, 2012, vol. 16, # 10, p. 1660 - 1664
[10] Patent: US2013/90475, 2013, A1,
[11] Patent: US2013/90475, 2013, A1,
[12] Patent: WO2016/142819, 2016, A2,
12
[ 5294-61-1 ]
[ 95635-55-5 ]
Reference：
[1] Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 2005, vol. 61, # 4, p. 665 - 671
[2] Green Chemistry, 2013, vol. 15, # 3, p. 756 - 767
[3] RSC Advances, 2016, vol. 6, # 54, p. 49150 - 49157
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[ 95635-55-5 ]
Reference：
[1] Organic Process Research and Development, 2012, vol. 16, # 10, p. 1660 - 1664
Preparation of Ranolazine base from its di hydrochloride salt; 20 gms Ranolazine dihydrohloride at room temperature is added to a mixture containing 150 ml water and 50 ml acetone and 20 ml liquor ammonia. It is stirred for two hrs. The precipitated base, was. filtered and dried under vacuum at 70 C to get crystalline form of Ranolazine base characterized by XRD & DSC as shown in Figure V & VI. Yield = 12 gms.
With sodium hydroxide; In dichloromethane; water; at 25 - 35℃;
Ranolazine dihydrochloride (5 g) and water (25 mL) are charged into a round-bottom flask and stirred for 5-10 minutes. A 40% sodium hydroxide solution (10 mL) is added and the mixture is stirred for 5-10 minutes. Dichloromethane (25 mL) is added at 25-35C and stirred for 10-15 minutes. The layers are separated and the aqueous layer is extracted with dichloromethane (2x5 mL). The combined organic layer is washed with water (10 ml_) and the solvent from the organic layer is evaporated completely under reduced pressure at 35-400C. The residue is cooled to 25-35C. Acetone (5 ml_) is added to the residue and the solvent is evaporated completely at 40-450C. The residue is cooled to 25-35C and acetone (15 mL) is added. The mixture is cooled to 0-50C and maintained for 30- 45 minutes. The solid is filtered, washed with acetone (5 mL), and dried at 60- 650C1 to afford the 3.3 g of the title compound. Purity by HPLC: 99.36%.
With potassium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 30 - 35℃; for 18.0h;
N-(2,6-Dimethyl-phenyl)-2-{4-[2-hydroxy-3-(2-methoxy-phenoxy)-propyl]-piperazin-1-yl}-acetamide: A mixture of 1-(2-methoxy-phenoxy)-3-piperazin-1-yl-propan-2-ol (2 g, 7.52 mmol), 2-chloro-N-(2,6-dimethyl-phenyl)-acetamide (1.84 g, 9.34 mmol), anhydrous potassium carbonate (2 g, 14.5 mmol) and sodium iodide (74 mg, 0.5 mmol) in dimethylformamide (5 mL) was maintained at 30-35 C. for about 18 hours. The mixture was quenched with water and standard extractive work up afforded a crude residue which was purified by flash column chromatography on silica gel (2*16 cm, dichloromethane/methanol/triethylamine=100/2/1 elution) to afford the title compound (1.1 g, 34%). 1H NMR (300 MHz, CDCl3) delta 7.11 (s, 3H), 6.98-6.90 (m, 4H), 4.19 (br. s, 1H), 4.05 (d, 2H, J=5.4 Hz), 3.87 (s, 3H), 3.30-3.24 (m, 2H), 2.76-2.63 (m, 10H), 2.25 (s, 6H); LC-MS: m/z=428 (MH)+; HPLC: 99% (Purity).
With potassium carbonate;sodium iodide; In N,N-dimethyl-formamide; at 30 - 35℃; for 18.0h;
Preparation of crude (+)-1-[3-(2-Methoxyphenoxy)-2-hydroxypropyl]-4-[N-(2,6-dimethylphenyl)carbamoylmethyl] piperazine dihydrochloride; A mixture of 90 gms l-[3-(2-Memoxyphenoxy)-2-hydroxypropyl ] piperazine, 85 gms [(2,6-dtmetliylphenyl) aminocarbonyl methyl)chloride, 120 gms anhydrous potassium carbonate and 3.6 gms sodium iodide in 260 ml dimethyl fonnamide is stirred at room temperature (30-35 C) for 18 Hrs. The reaction mixture is quenched in 1600 ml water and extracted thrice with 300 ml methylene dichloride each time . Combined methylene dichloride layer is treated with a mixture of 1100 ml aqueous hydrochloric acid (35 %) & 900 ml water. Acidic aqueous layer is basified with ammonia, extracted with methylene dichloride and solvent is evaporated to get Ranolazine base. Yield = 140 gms ,The above Ranolazine base is taken in 2160 j ml j acetone and 100 hydrochloric acid gas dissolved in isopropyl alcohol is added at room temperature till pH is acidic. The precipitated dihydrochloride compound is filtered, is washed with acetone to give the Ranolazine dihydrochloride Yield = 144 gm.
With hydrogenchloride; In ethanol; water; at 25 - 35℃; for 0.5h;Heating / reflux;Product distribution / selectivity;
Step 5: Preparation of <strong>[95635-55-5]Ranolazine</strong> Dihvdroehloride; Concentrated hydrochloric acid (23 ml) was added to ranolazine (50 g) in ethanol (500 ml) at 25-3O0C and reaction mass was heated for 30 minutes at reflux temperature and charcolized. The filtrate was cooled to 5-10 0C. The solid thus obtained, was filtered, and washed with chilled ethanol (50 ml) to obtain 54 g of the title compound having purity 99.80 % by high performance liquid chromatography.Yield - 92%; Step 5: Preparation of <strong>[95635-55-5]Ranolazine</strong> Dihvdrochloride; Concentrated hydrochloric acid (55 ml) was added to ranolazine (100 g) in ethanol (1000 ml) at 25-3O0C and reaction mass was heated for 30 minutes at reflux temperature and charcolized. The filtrate was cooled to 5-10 0C. The solid thus obtained, was filtered, and washed with chilled ethanol (100 ml)M:o obtain 108 g of the title compound having purity of 99.64 % by high performance liquid chromatography.Yield - 92%
With hydrogenchloride; In isopropyl alcohol; acetone; at 20℃;Acidic conditions;
Example 2; Preparation of crude (+)-1-[3-(2-Methoxyphenoxy)-2-hydroxypropyl]-4-[N-(2,6-dimethylphenyl)carbamoylmethyl] piperazine dihydrochloride; A mixture of 90 gms l-[3-(2-Memoxyphenoxy)-2-hydroxypropyl ] piperazine, 85 gms [(2,6-dtmetliylphenyl) aminocarbonyl methyl)chloride, 120 gms anhydrous potassium carbonate and 3.6 gms sodium iodide in 260 ml dimethyl fonnamide is stirred at room temperature (30-35 C) for 18 Hrs. The reaction mixture is quenched in 1600 ml water and extracted thrice with 300 ml methylene dichloride each time . Combined methylene dichloride layer is treated with a mixture of 1100 ml aqueous hydrochloric acid (35 %) & 900 ml water. Acidic aqueous layer is basified with ammonia, extracted with methylene dichloride and solvent is evaporated to get <strong>[95635-55-5]Ranolazine</strong> base. Yield = 140 gms ,The above <strong>[95635-55-5]Ranolazine</strong> base is taken in 2160 j ml j acetone and 100 hydrochloric acid gas dissolved in isopropyl alcohol is added at room temperature till pH is acidic. The precipitated dihydrochloride compound is filtered, is washed with acetone to give the <strong>[95635-55-5]Ranolazine</strong> dihydrochloride Yield = 144 gm.
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%.
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%.
With pyrographite; In methanol; at 54℃;Product distribution / selectivity;
20 gm of <strong>[95635-55-5]Ranolazine</strong> obtained in Example 11 was charged in a flask containing methanol (120 ml) and heated to about 54C for complete dissolution. 1 gm carbon was added to the reaction mixture and the reaction mixture was filtered through hyflow bed and washed with methanol (10 ml). The filtrate was concentrated at 700C under vacuum to remove 80 ml of methanol. The concentrated reaction mixture was cooled to 25-300C and stirred for about 1-2 hours. The reaction suspension was cooled to 00C and stirred for 40 minutes. The solid was filtered and washed with methanol (6 ml), The wet solid was dried at 50-60 C to get 17.5 gm of the titled compound. Melting range: 120.5 C - 122 C Purity by HPLC: 99.94 % w/w
In acetone; at 25℃;Reflux;Purification / work up;
<strong>[95635-55-5]Ranolazine</strong> (25 g) and acetone (250 mL) are charged into a round-bottom flask and stirred for 5-10 minutes. The mixture is heated to reflux temperature and maintained for 15-30 minutes. The solution is cooled to 25-35C and maintained for 45-60 minutes. The formed solid is filtered, washed with acetone (25 mL), and suction dried for 15-30 minutes. Acetone (150 mL) is charged to the wet solid and stirred for 5-10 minutes. The mixture is heated to reflux temperature and maintained for 15-30 minutes. The solution is cooled to 25-350C and maintained for 45-60 minutes. The formed solid is filtered, washed with acetone (15 mL), and dried at 60-650C, to afford the 18.2 g of the title compound. Purity by HPLC: 99.89%.
In methanol; acetone; at 0 - 55℃;Purification / work up;
<strong>[95635-55-5]Ranolazine</strong> (100.0 g), methanol (100 mL), and acetone (400 mL) are charged into an automated reactor at 27C. The mixture is heated to 55C at 1.80C per minute. The mixture is cooled to O0C at -1.50C per minute between 55C and 300C, and -0.2C per minute between 30C and 00C. The mixture is maintained at O0C for 2-3 hours. The solid is filtered, washed with chilled acetone (100 mL), and dried at 7O0C, to afford 80.0 g of the title compound. Particle size distribution: Di0: 13.262 mum; D5o: 41.574 mum; D90: 89.060 mum.Specific surface area: 0.291 m2/g; span: 1.823.
In methanol; acetone; at 2.5 - 55℃;Industry scale;Purification / work up;
Acetone (16.5 L), methanol (5.5 L), and ranolazine (5.5 kg) are charged into a reactor. The mass is heated to 55+/-2C and maintained for 40 minutes. The mass is cooled to 40-500C, then is filtered and the solid is washed with acetone (5.5 L). The filtrate is cooled to 2.5+/-2.5C and maintained for 4 hours. The mass is filtered and the solid is washed with chilled acetone (5.5 L) and dried at 60-650C under reduced pressure, to afford 4.5 kg of the title compound.Particle size distribution: D10: 5.026 mum; D50: 18.770 mum; D90: 39.137 mum. Specific surface area by Malvern method: 1.63 m2/g; span: 1.817 by Malvern method; specific surface area by BET method: 0.46 m2/g.
In methanol; acetone; at 2℃;Reflux;Purification / work up;
<strong>[95635-55-5]Ranolazine</strong> (20 g), acetone (80 mL) and methanol (20 mL) are charged into a round bottom flask and stirred for 5 minutes. The mixture is heated to 54C and maintained at reflux for 20 minutes. The mixture is cooled to 25-35C, then further cooled to 2-5C and maintained for 3-4 hours. The precipitated solid is filtered under reduced pressure and washed with acetone (20 mL). The solid is dried at 70-730C, to afford 16.5 g of the title compound.Purity by HPLC: 99.93%; compound of Formula (II): 0.4 ppm; compound of Formula (III): less than 0.16 ppm; chloro impurity of Formula (lib): 0.1 ppm.Purity by GC: 2,6-dimethyl aniline of Formula (VII): not detected; epichlorohydrin of Formula (VIII): not detected.
In methanol; acetone; at 2 - 56℃;Purification / work up;
<strong>[95635-55-5]Ranolazine</strong> (250.0 g), acetone (1 L), and methanol (250 mL) are charged into a round-bottom flask and stirred for 5 minutes. The mixture is heated to 56C and stirred for 30 minutes. The solution is filtered and the filtrate is charged into a round-bottom flask. The solution is cooled to 2-4C and maintained for 45 minutes. The solid is filtered, washed with chilled acetone (250 mL), and dried at 74C, to afford 210 g of the title compound.Purity by HPLC: 99.946%; water content: 0.2%; ROI (residue on ignition): 0.053%; bulk density before tapping: 0.353 g/mL; bulk density after tapping: 0.477 g/mL; methanol content: 200 ppm; acetone content: 476 ppm; toluene content: 14.5 ppm by a gas chromatography method.Particle size distribution: Di0: 4.420 mum; D50: 16.147 mum; D90: 30.439 mum.Specific surface area: 0.705 m2/g; span: 1.611.
In methanol; at 25℃;Reflux;Purification / work up;
<strong>[95635-55-5]Ranolazine</strong> (10 g) and methanol (10 mL) are charged into a round-bottom flask and stirred for 5-10 minutes. The mixture is heated to reflux temperature and maintained for 10-15 minutes. The solution is cooled to 25-35C and maintained for 30-45 minutes. Acetone (50 mL) is added and the mixture is maintained at 25- 35C for 45-60 minutes. The formed solid is filtered, washed with acetone (20 mL), and dried at 60-650C, to afford 7.0 g of the title compound. Purity by HPLC: 99.89%.
In tetrahydrofuran; water; at 0 - 55℃;Purification / work up;
Crude ranolazine (10 gm, Content of Impurities: '0.78 RRt' impurity: 0.28%; ' 1.23 RRt' impurity: 0.05%; dimer impurity-1 : 0.11%; dimer impurity-2: 0.02%; dimer impurity-3: 0.17%; HPLC Purity: 98.72%) was dissolved in tetrahydrofuran (38 ml) at 45-55C. The solution was filtered through a hyflo bed and washed with tetrahydrofuran (5ml) at 45-55C. The resulting solution was followed by slow addition of water (170 ml) at the same temperature. The reaction mixture was cooled to 0-5C and stirred for 4 hours. The resulting product was filtered and washed with chilled water (20 ml). The resulting solid was dried under vacuum at 50-55C to give 9 gm of pure ranolazine (HPLC Purity: 99.96%). Content of Impurities: '0.78 RRt' impurity: Below detection limit (BDL); ' 1.23 RRt' impurity: Below detection limit; Dimer Impurity-1 : Below detection limit; Dimer Impurity-2: Below detection limit; Dimer Impurity-3 : Below detection limit
In cyclohexane; acetone; at 10 - 50℃;Purification / work up;
Example 13:; Crude ranolazine (50 gm) was taken in acetone (200 ml) with stirring at room temperature and heated upto 45-5O0C for an hour. The mixture was cooled to room temperature and stirred for an hour. The mixture was further cooled to 10-150C with stirring. The solid product was filtered and washed with acetone (40 ml) to afford wet ranolazine. The wet cake was charged in cyclohexane (200 ml) and stirred for an hour at 45-5O0C. The mixture was further stirred for an hour at room temperature and then stirred for an hour at 15-200C. The product was filtered, washed and dried with cyclohexane (50 ml) to give pure ranolazine. Yield: 45.3 gm (90.6%), HPLC purity: 99.90%.
7
[ 2210-74-4 ]
[ 1131-01-7 ]
[ 95635-55-5 ]
Yield
Reaction Conditions
Operation in experiment
In methanol; for 5.0h;Reflux;
N-(2,6-dimethylphenyl)-l-piperazine acetamide (20 gm), l-(2-methoxy phenoxy)-2,3-epoxy propane (16 gm) and methanol (150 ml) were charged in a flask and heated to reflux. The reaction mixture was stirred at reflux for about 5 hours and carbon treatment given to methanol layer. Taken methanol layer and distilled off completely under vacuum. 48 ml of methanol was added to the residue and stirred at 25-30C for about 1-2 hours. The reaction mixture was cooled to about 0-5C and stirred for about 1 hour. The solid was filtered and washed with methanol (6 ml) . The wet solid was dried at 50-600C to get 28 gm of the title compound. Purity by HPLC: 99.89 % w/w
Example 5; Preparation of crystalline <strong>[95635-55-5]Ranolazine</strong> Tosylate; <strong>[95635-55-5]Ranolazine</strong> base (1 g) was dissolved in isopropyl alcohol (7 ml) at 22-25C, followed by the slow addition of p-toluenesulfonic acid (1 g) at 22-25C. The reaction mixture was cooled to 0-5C and stirred for 2 hours. The separated solid was filtered and washed with isopropyl alcohol (2 ml) and then dried under vacuum at 50-60C to yield 1.3 g of crystalline ranolazine tosylate (Melting Range: 162-168C).
Example 2; Preparation of crystalline <strong>[95635-55-5]Ranolazine</strong> Maleate; <strong>[95635-55-5]Ranolazine</strong> base (2 g) was dissolved in isopropyl alcohol (14 ml) at 22-25C, followed by slow addition of a solution of maleic acid (1.2 g) in isopropyl alcohol (10 ml) at 22-25C. The resulting mass was stirred for 3 hours at 22-25C. The separated solid was filtered and washed with isopropyl alcohol/hexane (5 ml/10 ml) and then dried under vacuum at 50-600C to yield 2.5 g of crystalline ranolazine maleate (Melting Range: 142-148C).
Example 3; Preparation of crystalline <strong>[95635-55-5]Ranolazine</strong> Fumarate; <strong>[95635-55-5]Ranolazine</strong> base (2 g) was dissolved in isopropyl alcohol (14 ml) at 22-25C, followed by slow addition of a solution of tumeric acid (1.2 g) in isopropyl alcohol (30 ml) at 22-25C. The resulting mass was stirred for 4 hour at 22-250C. The separated solid was filtered and washed with isopropyl alcohol (5 ml) and then dried under vacuum at 50-60C to yield 2.2 g of crystalline ranolazine fumarate (Melting Range: 109-150C).
Example 1; Preparation of crystalline <strong>[95635-55-5]Ranolazine</strong> Oxalate; <strong>[95635-55-5]Ranolazine</strong> base (2 g) was dissolved in isopropyl alcohol (14 ml) at 22-25C, followed by slow addition of a solution of oxalic acid (1.3 g) in isopropyl alcohol (10 ml) at 22-25C. The resulting mass was stirred for 4 hours at 22-250C. The resulting solid was filtered, washed with isopropyl alcohol /hexane (5 ml/10 ml) and then dried under vacuum at 50-60C to yield 2.2 g of crystalline ranolazine oxalate (Melting Range: 142-148C).
Example 4; Preparation of crystalline <strong>[95635-55-5]Ranolazine</strong> Besylate; <strong>[95635-55-5]Ranolazine</strong> base (2 g) was dissolved in isopropyl alcohol (100 ml) at 42-450C, followed by the slow addition of benzenesulfonic acid (1.6 g) at 42-45C. The reaction mixture was cooled to 0-50C and stirred for 2 hours. The separated solid was filtered and washed with isopropyl alcohol (5 ml) and then dried under vacuum at 50-600C to yield 2.3 g of crystalline ranolazine besylate.
1-[3-(2-methoxyphenoxy)-2-hydroxypropyl]-4-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine dihydrobromide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogen bromide; In methanol; water; at 30 - 35℃;Product distribution / selectivity;
Example 7; Preparation of crystalline <strong>[95635-55-5]Ranolazine</strong> dihydrobromide; <strong>[95635-55-5]Ranolazine</strong> base (5 g) was dissolved in methanol (25 ml) at 30-35C, followed by the addition of 49% aqueous hydrobromic acid (3 ml) at 30-35C over a period of 10 minutes and stirring for 60 minutes. The resulting solid was isolated by adding diethyl ether (175 ml) at 20-250C and then dried under vacuum at 50-600C to yield 6.8 g of crystalline ranolazine dihydrobromide.
Added 1000 ml of water to R.B Flask 109 gms piperazine was added and stirred to dissolve. pH was adjusted to 5.0-5.5 with 0-phosphoric acid. After stirring for 1- 2- h at room temperature. Filtered the reaction mass and solid was isolated as piperazine monophosphate monohydrate and charged further to R.B Flask containing 1000 ml water. 100 gms of [(2,6-Dimethylphenyl)-amino carbonyl methyl)chloride (6) was added and heated the reaction mixture at reflux temperature for 7-8 h. Cooled the reaction mixture at 25-30C and adjusted the pH to 5.5-6.0 with dilute sodium hydroxide solution filtered. Filtrate was washed with 100 ml x 2 methylene chloride and further basified with dilute sodium hydroxide solution and extracted with 500 ml x 3 methylene chloride. Combined organic layer was washed with saturated brine solution and 80 gm of 1-(2- Methoxy phenoxy)-2,3-epoxy propane (3) was added. Distilled out Methylene chloride under reduced pressure, added 500 ml methanol and refluxed for 5-6 h. Cooled the reaction mass to room temperature, added 500 ml water, cooled to 0C and filtered the product to get cmde Ranolazine. Yield: 80%; purity >99%.
Added 1000 ml of water to R.B Flask 109 gms piperazine was added and stirred to dissolve. pH was adjusted to 5.0-5.5 with 0-phosphoric acid, 100 gms of [(2,6- Dimethylphenyl)-amino carbonyl methyl)chloride (6) was added and heated the reaction mixture at reflux temperature for 7-8 h. Cooled the reaction mixture at 25-30C and adjusted pH to 5.5-6.0 with dilute sodium hydroxide solution and filtered. Filtrate was washed with 100 ml x 2 methylene chloride and further basified with dilute sodium hydroxide solution and extracted with 500 ml x 3 methylene chloride. Combined organic layer was washed with saturated brine solution and 80 gm of 1-(2-Methoxy phenoxy)-2, 3-epoxy propane (3) was added. Distilled out Methylene chloride under reduced pressure, added 500 ml methanol and refluxed for 5-6 h. Cooled the reaction mass to room temperature and added 500 ml water and cooled to 0C. Filtered the product to get cmde Ranolazine. Yield: 80%; purity >99%.
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