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triethylamine; Trimethylacetic acid; In tetrahydrofuran; hexane; at 50℃;Heating / reflux;Product distribution / selectivity; |
Example 1 : Triethylammonium pivalate as catalyst; hexane: THF as solvent; Schematic:Diketone of atorvastatin (1.09 eq, 84.4g) is added to a solution of l,l-dimethyl-(4R- cw)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxane-4-acetate [TBIN] (50.69g, 185.4 mmol) in THF (112.6 g) and hexane (42.7 g) and the mixture warmed to 5O0C under an N2 atmosphere. At 50°C pivalic acid (0.7 eq, 13.3g) is added, followed by triethylamine (0.7 eq., 13.2 g) and the resulting suspension heated at reflux under a nitrogen atmosphere until reaction completion, with concomitant removal of water.On completion the reaction mixture is cooled to 25°C before addition of MTBE (157 g). The solution is washed with a 5.5 percent (w/w) solution of KOH, then a 3.5 percent (w/w) of HCl, separated and then the organic layer is vacuum distilled with stirring to a thick oil. At the distillation end-point acetone (100 ml) and IPA (100ml) were added and the mixture was heated to 5O0C until a solution is achieved. Water (50ml) was added to the solution and the mixture was allowed to cool to room temperature over two hours, then cooled to 0°C and stirred for 1 hr. The crystals were isolated by filtration and washed with IPA (50ml at 00C). The product was dried in a vacuum oven maintaining the temperature at <40°C. |
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hydrogenchloride; triethylamine; In tetrahydrofuran; tert-butyl methyl ether; at 50℃;Heating / reflux;Product distribution / selectivity; |
Example 9: Triethylammonium hydrochloride as catalyst; MTBE :THF as solvent; Diketone of atorvastatin (1.09 eq, 8.32 g) is added to a solution of l,l-dimethyl-(4R- cfs)-6-(2-ammoethyl)-2,2-dimethyl-l,3-dioxane-4-acetate (5 g, 18.3 mmol) in MTBE (6.7g) and THF (5.4 g) and the mixture warmed to 500C under an N2 atmosphere. At 500C triethylamine (0.7 eq, 1.29g) is added, followed by 36percent hydrogen chloride (0.7 eq, 1.30 g) and the resulting suspension heated at reflux under a nitrogen atmosphere until reaction completion, with concomitant removal of water. |
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triethylamine; Trimethylacetic acid; In tetrahydrofuran; tert-butyl methyl ether; at 50℃;Heating / reflux;Product distribution / selectivity; |
Example 2: Triethylammonium pivalate as catalyst; MTBE: THF as solvent; Diketone of atorvastatin (1.09 eq, 84.4g) is added to a solution of l,l-dimethyl-(4R- m)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxane-4-acetate (50.69g, 185.4 mmol) inTHF (57.7 g) and MTBE (99.4 g) and the mixture warmed to 500C under an N2 atmosphere. At 50°C pivalic acid (0.7 eq, 13.3g) is added, followed by triethylamine (0.7 eq., 13.2 g) and the resulting suspension heated at reflux under a nitrogen atmosphere until reaction completion, with concomitant removal of water.On completion the reaction mixture is cooled to 25°C before addition of MTBE (157 g). The solution is washed with a 5.5 percent (w/w) solution of KOH (230 ml), then a 3.5 percent (w/w) of HCl (250 ml), separated and then the organic layer is vacuum distilled with stirring to a thick oil. At the distillation end-point acetone (100 ml) and IPA (100ml) were added and the mixture was heated to 50°C until a solution is achieved. Water(50ml) was added to the solution and the mixture was allowed to cool to room temperature over two hours, then cooled to 0°C and stirred for 1 hr. The crystals were isolated by filtration and washed with IPA (50ml at 0°C). The product was dried in a vacuum oven maintaining the temperature at <40°C. |
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N-ethyl-N,N-diisopropylamine; Trimethylacetic acid; In toluene; at 50℃;Heating / reflux;Product distribution / selectivity; |
Example 4: Diisopropylethylammonium pivalate as catalyst; toluene as solvent; Diketone of atorvastatin (1.09 eq, 8.32 g) is added to a solution of l,l-dimethyl-(4R- cw)-6-(2-aminoethyl)-2,2-dirnethyl-l,3-dioxane-4-acetate (5.Og, 18.3 mmol) in Toluene (13 g) and the mixture warmed to 5O0C under an N2 atmosphere. At 50°C pivalic acid (0.7 eq, 1.15 g) is added, followed by diisopropylethylamine (0.7 eq., 1.65 g) and the resulting suspension heated at reflux under a nitrogen atmosphere until reaction completion, with concomitant removal of water |
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sodium hydroxide; Trimethylacetic acid; In toluene; at 50℃;Heating / reflux;Product distribution / selectivity; |
Example 8: Sodium pivalate as catalyst; Toluene as solvent; Diketone of atorvastatin (1.09 eq, 5.03 g) is added to a solution of l,l-dimethyl-(4R- c/s)-6-(2-aminoethyl)-2,2 -dimethyl- l,3-dioxane-4-acetate (3 g, 10.9 mmol) in toluene (8.65g) and the mixture warmed to 50°C under an N2 atmosphere. At 500C pivalic acid (0.7 eq, 0.69g) is added, followed by 50percent sodium hydroxide (0.61 g, 7.6 mmol) and the resulting suspension heated at reflux under a nitrogen atmosphere until reaction completion, with concomitant removal of water. |
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sodium hydroxide; Trimethylacetic acid; In tetrahydrofuran; tert-butyl methyl ether; at 50℃;Heating / reflux;Product distribution / selectivity; |
Example 6: Sodium pivalate as catalyst; MTBE:THF as solvent; Diketone of atorvastatin (1.09 eq, 8.32 g) is added to a solution of l,l-dimethyl-(4R- m)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxane-4-acetate (5 g, 18.3 mmol) in THF (5.3 g) and MTBE (6.7g). and the mixture warmed to 50°C under an N2 atmosphere. At 50°C pivalic acid (0.7 eq, 0.34g) is added, followed by 50percent sodium hydroxide (1 g, 12.5 mmol) and the resulting suspension heated at reflux under a nitrogen atmosphere until reaction completion, with concomitant removal of water. |
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zinc diacetate; In tetrahydrofuran; tert-butyl methyl ether; at 50℃;Heating / reflux;Product distribution / selectivity; |
Example 5: Zinc acetate as catalyst; MTBE :THF as solvent; Diketone of atorvastatin (1.09 eq, 8.3g) is added to a solution of l,l-dimethyl-(4R- c/5')-6-(2-aminoethyl)-252-dimethyl-l,3-dioxane-4-acetate (5.0g, 18.5 mmol) in THF (5.7 g) and MTBE (6.7g). Zinc acetate (1.59g, 12.9 mmol) is added and the resulting suspension then heated at reflux under a nitrogen atmosphere until reaction completion, with concomitant removal of water. |
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N-ethylmorpholine;; Trimethylacetic acid; In toluene; at 50℃;Heating / reflux;Product distribution / selectivity; |
Example 3: N-ethylmorpholine pivalate as catalyst; Toluene as solvent; Diketone of atorvastatin (1.09 eq, 8.32 g) is added to a solution of l,l-dimethyl-(4R- cw)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxane-4-acetate (5.Og, 18.3 mmol) in Toluene (13 g) and the mixture warmed to 50°C under an N2 atmosphere. At 50°C pivalic acid (0.7 eq, 1.15 g) is added, followed by n-ethylmorpholine (0.7 eq., 1.47 g) and the resulting suspension heated at reflux under a nitrogen atmosphere until reaction completion, with concomitant removal of water. |
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calcium hydroxide; Trimethylacetic acid; In tetrahydrofuran; tert-butyl methyl ether; at 50℃;Heating / reflux;Product distribution / selectivity; |
Example 7: Calcium pivalate as catalyst; MTBE:THF as solvent; Diketone of atorvastatin (1.09 eq, 8.32 g) is added to a solution of l,l-dimethyl-(4R- c/5)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxane-4-acetate (5 g, 18.3 mmol) in THF(5.3 g) and MTBE (6.7g). and the mixture warmed to 500C under an N2 atmosphere. EPO <DP n="13"/>At 500C pivalic acid (0.7 eq, 1.15g) is added, followed by calcium hydroxide (0.47 g, 6.35mmol) and the resulting suspension heated at reflux under a nitrogen atmosphere until reaction completion, with concomitant removal of water. |
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80.0 grams of (4R-cis)-1 ,1-dimethylethyl-6-(2-aminoethyl)-2,2-dimethyl-1 ,3- dioxane-4-acetate, 1200 ml of cyclohexane and 104 grams of (+/-)-4-fluoro-alpha-2- methyl-1-oxopropyl-gamma-oxo-N-beta-diphenyl benzene were stirred at 25-3O0C for 15-20 EPO <DP n="10"/>minutes. 16 grams of pivalic acid were added, and then the reaction mass was heated to reflux under azeotropic conditions until completion of the reaction. The solvent was evaporated below 7O0C under reduced pressure, lsopropyl alcohol (160 ml) was added and evaporated under reduced pressure. 400 ml of isopropyl alcohol was added to the residue below 500C, then the mixture was cooled to 25- 3O0C for about 6-8 hours. The mixture was further cooled to 0-10°C and stirred for 2-3 hours. The separated solid was filtered and washed with 160 ml of isopropyl alcohol. The obtained solid was dried at 60-70°C to yield 120 grams of the title compound |
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With Trimethylacetic acid; In tetrahydrofuran; hexane; at 75℃; for 96h;Product distribution / selectivity; |
Example 1: (Comparative)50 g tert-butyl isopropylidene (TBIN), prepared as described in Tetrahedron Letters, 1992, 2279, 13.25 g wet sponge nickel catalyst, 28percent ammonia solution (137.5 ml) and 375 ml isopropyl alcohol (IPA) are added to a pressure vessel. The mixture is reduced with 50 psi of hydrogen, then filtered and concentrated in vacuo. The resulting oil is dissolved in 250 ml warm toluene, water washed and again concentrated in vacuo to give an amino ester. The amino ester, 85 g 4-fluoro-alpha-(2- methyl-l-oxopropyl)-gamma-oxo-N,beta-diphenyl-benzenebutanamide (diketone of atorvastatin), 12.5 g pivalic acid, 137.5 ml tetrahydrofuran (THF) and 137.5 ml hexanes are charged to an argon inerted pressure vessel which is sealed and heated to 750C for 96 hours. After cooling the solution is diluted with 400 ml methyl tert- butyl ether (MTBE) and washed firstly with dilute aqueous sodium hydroxide followed by dilute aqueous hydrochloric acid. The mixture is then concentrated in vacuo to give an acetonide ester.The acetonide ester is dissolved in 275 ml warm methanol and aqueous hydrochloric acid (5 g of 37percent hydrochloric acid in 75 ml of water) is added. The mixture is stirred at 300C to produce a diol ester. 100 ml methyl tert-butyl ether and aqueous sodium hydroxide (150 ml of H2O and 25 g of 50percent aqueous sodium hydroxide) are then added and the mixture stirred at 3O0C to produce a sodium salt. 600 ml water is added and the mixture washed twice with 437.5 ml methyl tert-butyl ether. Residual methyl tert-butyl ether and some methanol is removed from the aqueous layer by atmospheric distillation to a temperature of 87-9O0C. The mixture is stirred at 75-850C for 18 hours, then cooled, acidified and extracted into 875 ml toluene. The mixture is heated at reflux for 4 hours and water is removed azeotropically. After cooling, the mixture is filtered and washed with toluene. The crude lactone is then recrystallised from toluene and lactone is isolated as an white solid.Yield: 36 g ; 59.8percent from tert-butyl isopropylidene. Impurity level: crude Methyl ester 1.3 percent. pure Methyl ester 0.6 percent.; Example 2 50 g tert-butyl isopropylidene (TBIN), prepared as described in Tetrahedron Letters,1992, 2279, 13.25 g wet sponge nickel catalyst, 28percent ammonia solution (137.5 ml) and 375 ml isopropyl alcohol (IPA) are added to a pressure vessel. The mixture is reduced with 50 psi of hydrogen, then filtered and concentrated in vacuo. The resulting oil is dissolved in 250 ml warm toluene, water washed and again concentrated in vacuo to give an amino ester. The amino ester, 85 g 4-fluoro-alpha-(2- methyl-l-oxopropyl)-gamma-oxo-N,beta-diphenyl-benzenebutanamide (diketone of atorvastatin prepared by a method disclosed in United States Patent Number 5,155,251 which is herein incorporated by reference and Bauman K.L, Butler D.E., Deering C.F., et al Tetrahedron Letters 1992;33:2283-2284), 12.5 g pivalic acid, 137.5 ml tetrahydrofuran (THF) and 137.5 ml hexanes are charged to an argon inerted pressure vessel which is sealed and heated to 750C for 96 hours. After cooling the solution is diluted with 400 ml methyl tert-butyl ether (MTBE) and washed firstly with dilute aqueous sodium hydroxide followed by dilute aqueous EPO <DP n="9"/>hydrochloric acid. The mixture is then concentrated in vacuo to give an acetonide ester.The acetonide ester is dissolved in 275 ml warm methanol and aqueous hydrochloric acid (5 g of 37percent hydrochloric acid in 75 ml of water) is added. The mixture is stirred at 3O0C to produce a diol ester. 100 ml methyl tert-butyl ether and aqueous sodium hydroxide (150 ml of H2O and 25 g of 50percent aqueous sodium hydroxide) are then added and the mixture stirred at 3O0C to produce a sodium salt. 600 ml water is added and the mixture washed twice with 437.5 ml methyl tert-butyl ether.In this case, the mixture is distilled under atmospheric pressure to a batch temperature of 70-750C. A vacuum of approximately -0.25 bar is then applied and distillation is continued until the methanol content of the mixture is reduced to less than 2.6percentw/v. The batch is stirred at 75-85°C for 18 hours, then cooled, acidified and extracted into 875 ml toluene. The mixture is heated at reflux for 4 hours and water removed azeotropically. After cooling the mixture is filtered, washed with toluene and dried directly. Lactone is isolated as awhite solid.Yield: 37.9 g ; 63percent from tert-butyl isopropylidene. Impurity level : Methyl ester 0.16percent.; Example 3 50 g tert-butyl isopropylidene (TBIN), prepared as described in Tetrahedron Letters, 1992, 2279, 13.25 g wet sponge nickel catalyst, 28percent ammonia solution (137.5 ml) and 375 ml isopropyl alcohol (IPA) are added to a pressure vessel. The mixture is reduced with 50 psi of hydrogen, then filtered and concentrated in vacuo. The resulting oil is dissolved in 250 ml warm toluene, water washed and again concentrated in vacuo to give an amino ester. ... |
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With Trimethylacetic acid; In cyclohexane; at 20℃;Heating / reflux; |
Diketo compound (V) (1.50 g) was taken in cyclohexane (10 ml) at room temperature. Amino ketal compound (FV) (1.00 g) in cyclohexane was added followed by the addition of pivalic acid (0.11 g). The reaction mixture was refluxed and after the completion of the reaction, reaction mixture was cooled and the precipitate filtered. Dried the material in vacuum oven at 50-550C for 2 hr (moisture content is approx. 0.5 percent) to get crude compound III, which was recrystallized in isopropyl alcohol to give pure compound III as a solid. Compound III (1.40 gm) was then taken into methanol (20 ml) and stirred followed by the addition of dilute hydrochloric acid. Reaction mixture was warmed and stirred. After the completion of the reaction, reaction mixture was cooled and water was added. The precipitated material was filtered and dried under vacuum at 50-550C for 12 hrs to afford the desired product II. |
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In a 2 L round bottom flask equipped with a mechanical stirrer and temperature monitoring facility, Stetter compound i.e. 4-(4-Fluorophenyl)-2-isobutryl-4-oxo-N- phenyl butryl amide (100 g, 0.24 mole) and Amino side chain i.e. [6-(2-aminoethyl)-2,2-dimethyl-[l,3]dioxan-4-yl]-acetic acid tert-butyl ester (261.9 g, 0.96 mole) was added at 25-35 0C. To this reaction vessel 2 L cyclohexane, 100 ml THF and Pivalic acid (11.0 g, 0.11 mole) were added under same temperature condition. The reaction mixture was heated up to reflux temperature 70-85 °C and the reflux was maintained for 18 hrs. After cooling the reaction mixture to room temperature (25-35 0C), 500 ml water was added and stirred for 20 min. To this reaction mixture Liq. Ammonia was added to adjust the pH between 8.5-9.5 and stirred for 30 min. at room temperature.Now for separating the layers, aq. layer is extracted with 2 x 500 ml MDC. From the combined MDC and cyclohexane layer, MDC and cyclohexane were distilled out. At <n="8"/>this stage weight of the residue was 389.0 g. Now 720 ml IPA was added in to reaction mixture and the temperature raised up to 50-60 0C within 1 hr. Stirred for 30 min. at 50-60 0C. Slowly 327 ml water was added at 50-60 0C within 1 hour and then cooled down to room temperature 25-35 0C. Further stirred for 5 hrs at the same temperature and then filtered and washed with 50 ml x 2 mixture of IPA and water (11:5). Finally dried for 12 hrs at 50-550C to obtain 117.3 g dry cake of (4R-cis)-6-[-2-[3-phenyl-4- (phenyl-carbamoyl)-2-(4-flourophenyl)-5-(l-methyl-ethyl)-pyrrol-l-yl]-ethyl]-2,2-di methyl-[l,3]dioxane-4-yl-acetic acid-tertriay butyl ester (Atorvastatin protected diol). |
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Trimethylacetic acid; In 2-methyl THF; for 30 - 35h;Heating / reflux; |
(4R-6R)-6-aminoethyl-2,2-dimethyl-l,3-dioxane-4-acetic acid tert-hvXyl ester (compound of formula IV) (50gms); 2-[2-(4-Fluoro-rhohenyl)-2-oxo-l-phenyl-ethyl]-4-methyl- 3-oxo-pentanoic acid phenylamide (compound of formula V) (68.9 gm); pivalic acid (11.96 gm) and 2-Methyl THF (750 ml) were stirred with reflux, water is removed through dean stark apparatus during the course of reaction. The mixture was refluxed for about 30-35 hours. After cooling, the reaction mixture was concentrated. Thus obtained oily residue is dissolved in 2-propanol (350 ml) with heating. The mixture cooled slowly to room temperature and stirred for 2 hours, further cooled to 15-200C and stirred for one hour. The solid precipitate out which is filtered, washed with IPA and dried at 600C overnight to give the title compound as off white solid (63 gm; Purity: >99 percent).(4R-6R)-6-aminoethyl-2,2-dimethyl-l,3-dioxane-4-acetic acid tert-butyl ester (compound of formula IV) (50 gms); 2-[2-(4-Fluoro-phenyl)-2-oxo-l-phenyl-ethyl]-4- methyl-3-oxo-pentanoic acid phenylamide (compound of formula V) (68.9 gm); pivalic acid (11.96 gm) and 2-Methyl THF (750 ml) were stirred with reflux, water is removed through dean stark apparatus during the course of reaction. Thus obtained oily residue is dissolved in 2-propanol (350 ml) with heating. Water (138 ml) was added drop wise. The reaction mixture was cooled slowly till reaches room temperature and stirred for 2 hours. The solid precipitate out which is filtered, washed with 2- propanol and dried overnight at 600C to give [R-(R*, EPO <DP n="13"/>R*)]-2-(4-fluorophenyl)-beta,delta-dioxane-5-(l-metlalphaylethyl)-3-phenyl-4-[(phenylaralphaino) carbonyl]-lH-pyrrole-l-heptanoic acid tert-butyl ester as off white solid, (63 gm; Purity:- >99 percent).(4R-6R)-6-amialphaoethyl-2,2-dimethyl-l,3-dioxane-4-acetic acid tert-butyl ester (compound of formula IV) (50 gms); 2-[2-(4-Fluoro-phenyl)-2-oxo-l-phenyl-ethyl]-4- methyl-3-oxo-pentanoic acid phenylamide (compound of formula V) (68.9 gm); pivalic acid (11.96 gm) and 2-Methyl THF (750 ml) were stirred and refulx. The water is removed during the course of reaction. After reaction completion, about (400 ml )of solvent was distilled out and then cooled to 25-300C, stirred for 2 hours further cooled to 10-150C, Stirred for 30 minutes and filtered, washed with 2- methyl THF (100 ml), and dried at 55-600C overnight to give the title compound as an off white solid. (60 gm; Purity: >99 percent). |
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With Trimethylacetic acid; In cyclohexane; at 20 - 78℃; |
EXAMPLE 5: 58g (4R-cis)- 1 , 1 -dimethylethyl-6-(2-aminomethyl)-2,2-dimethyl- 1 ,3 -dioxane-4-acetate is charged with 480 ml of cyclohexane at RT followed by the addition of 84 g of DKT III and 12 g of pivalic acid at RT. The reaction mass is heated to reach at 78°C and water is removed azeotropically. Reaction is maintained for 62 hrs and is monitored. After the completion, reaction mass is quenched with sodium bicarbonate solution. Organic layer separated is washed thoroughly till it is free from acidity. Cyclohexane from the organic layer is recovered under vacuum. Residue so obtained is dissolved in isopropanol and product is isolated by the addition of water at 30-35°C.Product is further purified from isopropanol. |
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(4R-cis)-1,1-dimethylethyl-6-{2-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)-carbonyl]-1H-pyrrol-1 yl]ethyl}-2,2-dimethyl-1,3-dioxane-4-acetate (Compound H) A mixture of (4R-cis)-1,1-dimethylethyl-6-(2-aminoethyl)-2,2-dimethyl-1, 3-dioxane]-4-acetate (9 Kg, 32.96 moles), (+-)- 4-fluoro-alpha-(2-methyl-1-oxopropyl)-y-oxo-N,beta-diphenylbenzenebutaneamide (13.33 Kg, 31.93 moles), n-heptane (90 L), tetrahydrofuran (22.5 L), toluene (22.5 L) and pivalic acid (2.18 Kg, 21.30 moles) was heated to reflux temperature for about 40 hrs. The reaction was monitored for completion by HPLC. The reaction mass was cooled and diluted with toluene. The reaction mixture was then washed initially with aqueous sodium hydroxide solution (0.5 N), then with aqueous hydrochloric acid solution (0.5 N) and followed by brine (10percent). The organic layer was treated with activated carbon, and filtered through a hyflo filter. The organic layer was concentrated to 10percent of the total volume under vacuum. Isopropyl alcohol (34 L) was then added, and the solvent recovered under vacuum, followed by repeated addition of isopropyl alcohol and solvent recovery under vacuum. The residue was dissolved in isopropyl alcohol and de-ionized water (45 L) was added till turbidity appeared. Further de-ionized water (60 L) was added gradually. The precipitated product was filtered, washed with a mixture of isopropyl alcohol and de-ionized water (2:1) and dried to get the title compound (16.2 Kg, 24.77 moles, 94percent by HPLC). The crude product was purified by dissolving in isopropyl alcohol (128 L) at 50 to 55 °C, concentrating the solution and cooling the residual mass slowly under stirring. The solid thus obtained was filtered, washed with chilled isopropyl alcohol and dried at 40 to 45 °C to give pure Compound H (13.2 Kg, 20.20 moles, purity: 99percent by HPLC). |
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Example 1; Preparation of amorphous [R- (R*, R* ]- (4-fluorophenvl)-a, 6-dihvdroxv-5- (1-methylethel .-3-phenyl-4- [(phenylamino) carbonyl]-lH-pyrrole-1-heptanoic acid. calcium salt (2: 1) (Atorvastatin Calcium Amorphous); (4R-cis)-1, 1-dimethylethyl-6-{2-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4- [(phenylamino)-carbonyl]-lH-pyrrol-lyllethyl}-2, 2-dimethyl-1, 3-dioxane-4-acetate (Compound H); A mixture of (4R-cis)-1, 1-dimethylethyl-6- (2-aminoethyl)-2, 2-dimethyl-1, 3- dioxane] -4-acetate (9 Kg, 32.96 moles), ()-4-fluoro-a- (2-methyl-l-oxopropyl)-y-oxo- N,-diphenylbenzenebutaneamide (13.33 Kg, 31.93 moles), n-heptane (90 L), tetrahydrofuran (22.5 L), toluene (22.5 L) and pivalic acid (2.18 Kg, 21.30 moles) was heated to reflux temperature for about 40 hrs. The reaction was monitored for completion by HPLC. The reaction mass was cooled and diluted with toluene. The reaction mixture was then washed initially with aqueous sodium hydroxide solution (0.5 N), then with aqueous hydrochloric acid solution (0.5 1V) and followed by brine (10percent). The organic layer was treated with activated carbon, and filtered through a hyflo filter. The organic layer was concentrated to 10percent of the total volume under vacuum. Isopropyl alcohol (34 L) was then added, and the solvent recovered under vacuum, followed by repeated addition of isopropyl alcohol and solvent recovery under vacuum. The residue was dissolved in isopropyl alcohol and de-ionized water (45 L) was added till turbidity appeared. Further de-ionized water (60 L) was added gradually. The precipitated product was filtered, washed with a mixture of isopropyl alcohol and de-ionized water (2: 1) and dried to get the title compound (16.2 Kg, 24.77 moles, 94percent by HPLC). The crude product was purified by dissolving in isopropyl alcohol (128 L) at 50 to 55 °C, concentrating the solution and cooling the residual mass slowly under stirring. The solid thus obtained was filtered, washed with chilled isopropyl alcohol and dried at 40 to 45 °C to give pure Compound H (13.2 Kg, 20.20 moles, purity: 99percent by HPLC). |
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With Trimethylacetic acid; In tetrahydrofuran; n-heptane; toluene; for 40h;Heating / reflux; |
A mixture of (4R-cis)-1,1-dimethylethyl-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane]-4-acetate (9 Kg, 32.96 moles), (+-)-4-fluoro-alpha-(2-methyl-1-oxopropyl)-gamma-oxo-N,beta-diphenylbenzenebutaneamide (13.33 Kg, 31.93 moles), n-heptane (90 L), tetrahydrofuran (22.5 L), toluene (22.5 L) and pivalic acid (2.18 Kg, 21.30 moles) was heated to reflux temperature for about 40 hrs. The reaction was monitored for completion by HPLC. The reaction mass was cooled and diluted with toluene. The reaction mixture was then washed initially with aqueous sodium hydroxide solution (0.5 N), then with aqueous hydrochloric acid solution (0.5 N) and followed by brine (10percent). The organic layer was treated with activated carbon, and filtered through a hyflo filter. The organic layer was concentrated to 10percent of the total volume under vacuum. Isopropyl alcohol (34 L) was then added, and the solvent recovered under vacuum, followed by repeated addition of isopropyl alcohol and solvent recovery under vacuum. The residue was dissolved in isopropyl alcohol and de-ionized water (45 L) was added till turbidity appeared. Further de-ionized water (60 L) was added gradually. The precipitated product was filtered, washed with a mixture of isopropyl alcohol and de-ionized water (2:1) and dried to get the title compound (16.2 Kg, 24.77 moles, 94percent by HPLC). The crude product was purified by dissolving in isopropyl alcohol (128 L) at 50 to 55° C., concentrating the solution and cooling the residual mass slowly under stirring. The solid thus obtained was filtered, washed with chilled isopropyl alcohol and dried at 40 to 45° C. to give pure Compound H (13.2 Kg, 20.20 moles, purity: 99percent by HPLC). |
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With Trimethylacetic acid; In tetrahydrofuran; n-heptane; toluene; for 40h;Heating / reflux; |
A mixture of (4R-cis)-1,1-dimethylethyl-6-(2-aminoethyl)-2,2-dimethyl-1, 3-dioxane]-4-acetate (9 Kg, 32.96 moles), (+/-)- 4-fluoro-alpha-(2-methyl-1-oxopropyl)-gamma-oxoN,beta-diphenylbenzenebutaneamide (13.33 Kg, 31.93 moles), n-heptane (90 L), tetrahydrofuran (22.5 L), toluene (22.5 L) and pivalic acid (2.18 Kg, 21.30 moles) was heated to reflux temperature for about 40 hrs. The reaction was monitored for completion by HPLC. The reaction mass was cooled and diluted with toluene. The reaction mixture was then washed initially with aqueous sodium hydroxide solution (0.5 N), then with aqueous hydrochloric acid solution (0.5 N) and followed by brine (10percent). The organic layer was treated with activated carbon, and filtered through a hyflo filter. The organic layer was concentrated to 10percent of the total volume under vacuum. Isopropyl alcohol (34 L) was then added, and the solvent recovered under vacuum, followed by repeated addition of isopropyl alcohol and solvent recovery under vacuum. The residue was dissolved in isopropyl alcohol and de-ionized water (45 L) was added till turbidity appeared. Further de-ionized water (60 L) was added gradually. The precipitated product was filtered, washed with a mixture of isopropyl alcohol and de-ionized water (2: 1) and dried to get the title compound (16.2 Kg, 24.77 moles, 94percent by HPLC). The crude product was purified by dissolving in isopropyl alcohol (128 L) at 50 to 55 °C, concentrating the solution and cooling the residual mass slowly under stirring. The solid thus obtained was filtered, washed with chilled isopropyl alcohol and dried at 40 to 45 °C to give pure Compound H (13.2 Kg, 20.20 moles, purity: 99percent by HPLC). |
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With Trimethylacetic acid; In n-heptane; at 100℃; |
To a mixture of 4-fluoro-a-[2-methyl-l-oxopropyl]-y-oxo-N-P-diphenyl- benzenebutanamide and Cis- 1 , 1 -dimethylethyl-6-(2-aminoethyl)-2,2dimethyl- 1,3- dioxane-4-acetate in heptane, pivalic acid was added over it at 25-35 °C. Reaction mass was heated to reflux (100°C) till completion of reaction. After completion of reaction, heptane was distilled out partially and cooled to 65-75°C. The obtained solution was slowly added to isopropanol contain seeded crystal of compound of formula (II) (form- II) at 0-10°C OR to reaction mass in heptane, isopropanol was added followed by optionally seeded with crystal of compound of formula (II) (form-II) at 40-50°C and gradually cooled to 0-10°C. Product was filtered off, washed with chilled isopropanol and dried under vacuum at 50°C. |
| 65 g |
With 2,2-dimethylpropanoic anhydride; In 2-methyltetrahydrofuran; at 150℃; for 4h;Autoclave; Inert atmosphere; Green chemistry; |
500 mL 2-methyltetrahydrofuran was added to a 1000 mL autoclave. [(4R,6R)-2,2-dimethyl-6-(2-aminoethyl)-[1,3]-dioxan-4-yl-acetic acid tert-butyl ester 27.3 g was added, [5-methyl-4-isopropyl-2-phenyl-1-(4-fluorophenyl)-3-(phenylcarbamoyl)-1,4-hexanedione] 41.7 g, stirring Slowly add 46.5 g of pivalic anhydride, Close the reactor cover and replace the air in the reactor with nitrogen twice. Raise the temperature to 150 °C and react for 4 hours. After the reaction is over, The solvent 2-methyltetrahydrofuran 480 mL was concentrated and concentrated under reduced pressure. And 50.1 g of pivalic acid, A viscous oil was obtained. Add 100ml of water to the oil, 100 mL of isopropanol, warmed to 40 °C, Slowly cool to 20 °C to precipitate a yellow solid, Filtering, Drying to get 65.0 g of atorvastatin intermediate (4R,6R)-6-{2-[5-isopropyl-3-phenyl-2-(4-fluorophenyl)-4-(phenylcarbamoyl)-pyrrol-1-yl-ethyl}-2,2-dimethyl-[1,3]-dioxan-4-yl-acetic acid tert-butyl ester. |
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With Trimethylacetic acid; In tetrahydrofuran; toluene;Reflux; |
9 g of crude ATS-9 (purity 99percent, containing impurities Beta) and atorvastatin mother core M4 were put into a reaction vessel, and 0.5 g of trimethylacetic acid, 100 mL of n-heptane, 30 mL of tetrahydrofuran, and 2 mL of toluene were added. The mixture was heated to reflux with stirring, and the reaction was monitored by HPLC to obtain an atorvastatin calcium condensate, and the content of the impurity A was found to be 0.6percent. |
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With Trimethylacetic acid; In tetrahydrofuran; n-heptane; for 60h;Reflux; |
100 mL of tetrahydrofuran and 100 mL of n-heptane were sequentially added to a 500 mL three-necked flask.10.0 g of ATS-9 and 15 g of B-4, 1.5 g of pivalic acid, and the mixture was heated to reflux for 60 hours. After completion of the reaction by TLC, the mixture was concentrated under reduced pressure, and 30 mL of ethanol was added to the obtained slurry, and the mixture was heated to 50 to 60 ° C to dissolve. The solution is cooled to 8-12 ° C and stirred for 3 hours.Filtration gave a white solid. |
Chemistry
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Material Science
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