| 95.3% |
With hydrogenchloride; In methanol; water; at 35℃; for 2h; |
First, 90 mL of methanol and 10 g of Compound L1 were placed in a 250 mL three-necked flask.12 mL of a hydrochloric acid solution having a mass concentration of 5% was slowly added dropwise, and reacted at 35 C for 2 h.TLC monitoring reaction is completed, adding saturated NaHCO3 solution to adjust the pH value of the reaction system is 7;Filtering, washing the filter cake with 25 mL × 2 distilled water, and drying at 60 C;The obtained crude atorvastatin tert-butyl ester and 30 mL of isopropanol were added to a 50 mL single-mouth bottle for 30 min, frozen and decrystallized, suction filtered, washed with 5 mL of frozen isopropanol, and blast dried at 60 C.The weigh was 9.53 g, the yield was 95.3%, and the purity was 99.97%. |
| 89.9% |
With hydrogenchloride; water; In acetonitrile; at 45℃; for 4h;Product distribution / selectivity; |
10 g, 15.3 mmol of (4R-cis)-6-{2-[2-(4-fluorophenyl)-5-(1- methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]pyrrole-1-yl]- ethyl}-2,2-dimethyl-1,3-dioxane-4-acetic acid tertiary butyl ester (I) is added to a 500 mL reaction flask and suspended in 45 mL of acetonitrile, 18.8 mL of water and 2.4 mL of 1M HC1. The reaction mixture is heated to 45 C until all starting ma- terial is dissolved and the reaction is followed by HPLC method. After 4 h the reaction mixture is cooled to room tem- perature, and 100 mL of water is added. The solid precipitate is filtered off and the cake is washed with 50 mL of a solvent mixture comprising acetonitrile and water (1:1, v/v). The wet cake is dried at 20-25 C on air till constant weight. 8.45 g, 89.9 %, of [R-(R*,R*)]-2-(4-fluorophenyl)-ss;,No.- dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)- carbonyl]-lH-pyrrole-l-heptanoic acid tertiary butyl ester (II) is isolated having a melting range of 142-145 C. The pu- rity of the obtained product is higher than 99 %. |
| 85% |
With hydrogenchloride; In water; acetonitrile; at 25 - 35℃; for 0.5 - 0.75h; |
110.0 grams of (4R-cis)-1 ,1-dimethylethyl-6[2[-(4-fluorophenyl]-5-(1- methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1yl]ethyl]-2,2- dimethyl-1,3-dioxane-4-acetate was dissolved in 1100 ml of acetonitrile at 30- 350C. A solution of concentrated hydrochloric acid (44 ml) in water (396 ml) was added to the reaction mass at 25-30C over about 30-45 minutes. After stirring the contents at 25-3O0C until the completion of the reaction, the reaction mass was diluted with 1100 ml of water. The pH of the reaction mass was adjusted to 7-8 by adding a solution of sodium carbonate (31.6 grams) in water (158 ml) at 10-15C. The formed solid was filtered and washed with 550 ml of water. Wet solid was dissolved in a mixture of 924 ml of acetonitrile and 365 ml of water at 70-750C. The solution was cooled to 25-300C for about 1-2 hours, and the precipitated solid was filtered and washed with a mixture of 146 ml of acetonitrile and 73 ml of water. The washed solid was dried at 50-600C for about 8-12 hours to yield 85 grams of the title compound |
|
With hydrogenchloride; water; In acetonitrile; at 45 - 49℃; for 5.5h;Product distribution / selectivity; |
To a solution of 1.32 g of (4R-cis)-6-(2-aminoethyl)-2,2- dimethyl-1,3-dioxane-4-acetic acid tertiary butyl ester (4.8 mmol, 1.2 equiv. ) in a 9: 1 mixture of heptane and toluene (30 mL), 0.49 g of 2-methylbutyric acid (0.52 mL, 4.8 mmol, 1.2 equiv. ) and 1.66 g of 4-fluoro-alpha-[2-methyl-1-oxopropyl]-g-oxo- N,P-diphenylbenzenebutaneamide (4.0 mmol) are consecutively added. The heterogeneous mixture is stirred at reflux under an argon atmosphere for 22 h. The resulting yellow solution is allowed to cool to room temperature, diluted with 30 mL of tert.-butyl methyl ether and washed consecutively with 50 mL of 1M NaOH, 30 mL of 1M HC1 and finally with brine. Evaporati- on of solvents results in a viscous light brown colored resi- due, which is dissolved in 12 mL of acetonitrile, 2.2 mL of water and 0.6 mL of 1M HC1. The resulting clear solution is stirred overnight, during that period some precipitation oc- curs. 10 mL of water is added followed by 20 mL acetonitrile, the latter being preferably used to bring a semisolid precipi- tate into a filterable one. The stirring is continued for at least lh. The solid is filtered off, the air-dried material is crystallized twice from acetonitrile and the product is vacuum dried at 20-25 C till constant weight. 0.70 g, 28.5 % of crystallized tertiary butyl ester of [R- (R*,R*)]-2-(4-fluorophenyl)-(at),8-dihydroxy-5-(1-methylethyl)-3- phenyl-4- [(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid (II) is isolated having a melting range of 90-96 C. The pu- rity of the obtained product is about 96 %. Example 2 To a solution of 1.32 g (4R-cis)-6-(2-aminoethyl)-2,2- dimethyl-1,3-dioxane-4-acetic acid tertiary butyl ester (4.8 mmol) in a 9: 1 mixture of heptane and toluene (30 mL), 0.245 g of 2-methylbutyric acid (0.26 mL, 2.4 mmol) and 1.66 g of 4- fluoro-a- [2-methyl-I-oxopropyl] -y-oxo-N, p-diphenylbenzene- butaneamide (4.0 mmol) are consecutively added. The heteroge- neous mixture is stirred at reflux under an argon atmosphere for 48 h. The resulting yellow solution is allowed to cool to room temperature, diluted with 30 mL of tert-butyl methyl ether and washed consecutively with 50 mL of 1M NaOH, 30 mL of 1M HC1 and finally with brine. Evaporation of solvents results in a viscous orange colored residue, which is dissolved in 12 mL of acetonitrile, 2.2 mL of water and 0.6 mL of 1M HC1. The resulting mixture is heated at 45-49 C with stirring for 5.5 h, until the consumption of the intermediate of formula (I) is found to be almost complete according to HPLC analysis. The mixture is allowed to cool and the stirring is continued at 20-25 C for 2 h, during that period some precipitation took place. 10 mL of water is added followed by 10 mL of acetoni- trile, the latter being preferably used to bring a semisolid precipitate into a filterable slurry and the stirring is con- tinued for about lh. The solid is filtered off, the filter ca- ke is washed with 4 mL of 50% (v/v) aqueous acetonitrile and the product is vacuum dried at 20-25 C till constant weight (0.754 g). The remaining filtrate is stirred at room tempera- ture overnight. A second crop of solid is filtered off, washed with 4 mL of 50% (v/v) aqueous acetonitrile and the product is vacuum dried at 20-25 C till constant weight (0.373 g), which is of identical quality to the first crop according to HPLC analysis. 1.127 g, 45.8% of crystallized tertiary butyl ester of [R- (R*, R* ) ] -2- (4-fluorophenyl) -(3, 8-dihydroxy-5- (1-methylethyl) -3- phenyl-4- [(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid (II) is isolated having a melting range of 84-91 C. The pu- rity of the obtained product is higher than 98 %. |
|
With hydrogenchloride; water; In acetonitrile; at 20 - 50℃; for 9.5h; |
To a solution of 5.47 g of (4R-cis)-6-(2-aminoethyl)-2,2- dimethyl-1,3-dioxane-4-acetic acid tertiary butyl ester (20 mmol, 1.0 equiv. ) in a 9: 1 mixture of heptane and toluene (150 mL) are added consecutively 2.04 g of pivalic acid (2.30 mL, 20 mmol, 1.0 equiv. ) and 8.30 g of 4-fluoro-a-[2-methyl-l- oxopropyl]-gamma-oxo-N,ss;-diphenylbenzenebutaneamide (20 mmol). The heterogeneous mixture is stirred at reflux under an argon at- mosphere for 25 h. The resulting yellow solution is allowed to cool to room temperature, diluted with 150 mL of tert-butyl methyl ether and washed consecutively with 150 mL of 1M NaOH, 2 x 150 mL of 1M HC1 and finally with brine. Evaporation of solvents resulted in a bright yellow colored foam, which is dissolved in 60 mL of acetonitrile, 11 mL of water and 3.0 mL of 1M HC1. The resulting mixture is heated at 45-50 C with stirring for 6.5 h, until the consumption of the intermediate having formula (I) is found to be almost complete according to HPLC analysis. The mixture is allowed to cool, 50 mL of water is added and the stirring is continued at 20-25 C for 2 h, during that period some material deposited. Then 50 mL of ace- tonitrile is added in order to bring a semisolid precipitate into a filterable slurry and the stirring is continued for about lh. The solid is filtered off, the filter cake is washed with 20 mL of 50% (v/v) aqueous acetonitrile and vacuum dried at 20-25 C till constant weight. 4.77 g (39 %) of the com- pound of formula (II) is isolated with melting range 90-95 C and higher than 98 % purity. To the solution of 4.75 g of ester (II) (7.73 mmol) in 16.5 mL of methanol and 14 mL of tert-butyl methyl ether, 0.325 g of NaOH (8.1 mmol, 1,05 equiv. ) and 29 mL of water are added. The reaction mixture is purged with a nitrogen flow for about 5 minutes, heated to the reflux for 4 h and cooled to room tem- perature. The pH of solution was adjusted to 11 with 2M NaOH and the reflux continued for 3 h. The reaction mixture is al- lowed to cool to 20-25 C, the pH is set to 8.0-8.2 by the ad- dition of HCl. The mixture is washed with 3 x 15 mL of tert- butyl methyl ether and the aqueous phases are finally fil- tered. The reaction mixture is purged with a nitrogen flow for about 5 minutes, and 0.836 g of CaCl2No.6H2O (3.82 mmol, 0.99 equiv. ) in 19 mL of water is added in a 15-20 min interval at 20-25 C. After the complete addition of CaCl2, the reaction mixture is stirred for additional 15-30 min and 80 mL of water is slowly added into the reaction mixture to provoke the so- lidification of the thick emulsion-like mixture. Hemi-calcium salt of atorvastatin is formed in the form of granules, which show improved filterability. The solid is filtered off after 2 h. The wet cake is washed with a mixture of water and methanol and finally with water. The collected solid material is dried on air to obtain 3.817 g (33% from 4-fluoro-a-[2-methyl-l- oxopropyl]-gamma-oxo-N,ss;-diphenylbenzenebutaneamide) of dry solid atorvastatin hemi-calcium. |
|
With hydrogenchloride; water; In acetonitrile; at 45 - 49℃; for 5.5h;Product distribution / selectivity; |
To a solution of 1.32 g (4R-cis)-6-(2-aminoethyl)-2,2- dimethyl-1,3-dioxane-4-acetic acid tertiary butyl ester (4.8 mmol) in a 9: 1 mixture of heptane and toluene (30 mL), 0.245 g of 2-methylbutyric acid (0.26 mL, 2.4 mmol) and 1.66 g of 4- fluoro-a- [2-methyl-I-oxopropyl] -y-oxo-N, p-diphenylbenzene- butaneamide (4.0 mmol) are consecutively added. The heteroge- neous mixture is stirred at reflux under an argon atmosphere for 48 h. The resulting yellow solution is allowed to cool to room temperature, diluted with 30 mL of tert-butyl methyl ether and washed consecutively with 50 mL of 1M NaOH, 30 mL of 1M HC1 and finally with brine. Evaporation of solvents results in a viscous orange colored residue, which is dissolved in 12 mL of acetonitrile, 2.2 mL of water and 0.6 mL of 1M HC1. The resulting mixture is heated at 45-49 C with stirring for 5.5 h, until the consumption of the intermediate of formula (I) is found to be almost complete according to HPLC analysis. The mixture is allowed to cool and the stirring is continued at 20-25 C for 2 h, during that period some precipitation took place. 10 mL of water is added followed by 10 mL of acetoni- trile, the latter being preferably used to bring a semisolid precipitate into a filterable slurry and the stirring is con- tinued for about lh. The solid is filtered off, the filter ca- ke is washed with 4 mL of 50% (v/v) aqueous acetonitrile and the product is vacuum dried at 20-25 C till constant weight (0.754 g). The remaining filtrate is stirred at room tempera- ture overnight. A second crop of solid is filtered off, washed with 4 mL of 50% (v/v) aqueous acetonitrile and the product is vacuum dried at 20-25 C till constant weight (0.373 g), which is of identical quality to the first crop according to HPLC analysis. 1.127 g, 45.8% of crystallized tertiary butyl ester of [R- (R*, R* ) ] -2- (4-fluorophenyl) -(3, 8-dihydroxy-5- (1-methylethyl) -3- phenyl-4- [(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid (II) is isolated having a melting range of 84-91 C. The pu- rity of the obtained product is higher than 98 %. |
|
With hydrogenchloride; water; In methanol; at 35℃; for 3h; |
To the suspension of 20 g (4R-cis)-1,1-Dimethylethyl-6-{2-[[2-(4-flurophenyl)]-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-Pyrrole-1-yl]ethyl}-2,2-dimethyl-1,3-dioxane-4-actate 13 in 200 mL methanol was added 30 mL 1N HCl dropwise. The resulting mixture is heated at about 35 C. for 3 h and then cooled down to room temperature. The solid was filtered and washed with water. After filtering and drying 14 g white powder was obtained. 1H-NMR(300 MHz, CDCl3): delta(ppm)=7.21-7.13 (m, 9H); 7.06 (d, 2H); 7.02-6.95 (m, 3H); 6.87 (s, 1H); 4.17-4.07 (m, 2H); 3.97-3.88 (m, 1H); 3.79-3.69 (m, 3H); 3.63-3.53 (m, 1H); 2.32 (d, 2H); 1.74-1.57 (m, 2H); 1.54 (d, 6H); 1.49-1.42 (m, 10H); 1.25 (d, 1H). |
|
With Indion 525 (H+ form); In acetonitrile; at 20℃; |
EXAMPLE 2; [00034] Preparation of Atorvastatin Calcium Salt; [00035] (4R-cis)-6-[2-[3-phenyl-4-(phenylcarbamoyl)-2-(4-fluorophenyl)-5-(l- methylethyl)-pyrrol- 1 -yl]-ethyl]-2,2-dimethyl-[l ,3]dioxane-4-yl-acetic acid-t-butyl ester (3.4 g) was dissolved in an acetonitrile (70 ml). Indion 525 (H+ form) (3.4 g) was added and the reaction mixture was stirred at room temperature. The reaction was monitored by TLC. The reaction mixture was decanted to remove the Indion 525 resin. Solid sodium hydroxide (0.34 g) was dissolved in water (5 ml) and added to the reaction mixture and stirred for about 2 hours. The reaction was monitored by TLC. The solvents were then removed under reduced pressure. The sodium salt obtained was dissolved in methanol (55 ml) at a temperature of about 500C and then water (42 ml) was added. The solution was filtered and the clear solution was stirred at a temperature of about 55C. A solution of calcium acetate (0.6 g) in water (7 ml) was added at 55C. The reaction mixture was maintained for about 30 minutes. The reaction mixture was cooled to room temperature and then to a temperature of about 150C. The off-white solid obtained was filtered. The solid was dried at a temperature of about 500C under vacuum to obtain the calcium salt of atorvastatin (2.4 g). [00036] IR (cm"1): OH str. 3412, CH Str aliph. 2960. EPO <DP n="14"/>[00037] PMR (in delta): (in CDCl3), 1.26 (m, 2H), 1.37 (m, 6H), 1.59 (m, 2H), 2.04(m, 2H), 3.24-3.96 (m, 5H), 4.80 (brs., IH), 5.75(brs., IH), 7.0-7.22 (m, 12H), 7.52 (d, 2H), 9.82 (s, IH).[00038] The CI mass shows m/z 558 [M-Ca+]. |
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With hydrogenchloride; methanol; water; at 30℃;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, 28% 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 37% 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 50% 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 ; 59.8% from tert-butyl isopropylidene. Impurity level: crude Methyl ester 1.3 %. pure Methyl ester 0.6 %.; Example 2 50 g tert-butyl isopropylidene (TBIN), prepared as described in Tetrahedron Letters,1992, 2279, 13.25 g wet sponge nickel catalyst, 28% 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 37% 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 50% 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 2.6%w/v. The batch is stirred at 75-85C 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 ; 63% from tert-butyl isopropylidene. Impurity level : Methyl ester 0.16%.; Example 3 50 g tert-butyl isopropylidene (TBIN), prepared as described in Tetrahedron Letters, 1992, 2279, 13.25 g wet sponge nickel catalyst, 28% 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- EPO <DP n="10"/>methyl-l-oxopropyl)-ga... |
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With hydrogenchloride; In methanol; water; |
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 %) 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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With hydrogenchloride; ethanol; water; at 40℃; for 9h; |
Example 3: Preparation of Atorvastatin Hemi-calcium Wet Form V[00066] Process water (155 kg), 32% HCl (9 kg), absolute ethanol (650 kg), and pyrrole acetonide ester (PAE) (65 kg) were fed into a 2500 L reactor. The reaction mixture was warmed up to about 400C and stirred at 79 rpm for 9 hours to obtain a clear solution. Absolute ethanol (260 kg) was added to the reaction mixture, and the additional portion of absolute ethanol (260 kg) was distilled out during 3 hrs at 45C/61mmHg. Calcium hydroxide (11.25 kg) was added at 4O0C, and the reaction mixture was stirred at 7O0C for 5.5 hrs. The salts was filtrated out and washed with absolute ethanol (37.5 kg). Process water (650 kg) was added at about 64C during 34 minutes. The mixture was heated to 82C, and stirred at this temperature for 15 minutes. The mixture was cooled to 700C during 22 minutes, and then to 210C during 5 hrs. The obtained slurry was stirred at 210C for 3 hrs. The product was filtered by 4 cycles using a centrifuge, and after each cycle was washed with process water (2x18.1 kg). 139.6kg of wet atorvastatin hemi-calcium salt was obtained, characterized by a PXRD pattern having two peaks at about 5.5 and 7.8 degrees two theta +/- 0.2 degrees two-theta and one broad peak in at 18-23 degrees two theta +/- 0.2 degrees two- theta. |
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With hydrogenchloride; water; In isopropyl alcohol; at 25 - 45℃; |
To a stirred mixture of t-butyl ester intermediate (III) (100 gm, 0.153 moles) and isopropanol (1500 ml) kept at about 25-30 0C, dilute HCl (15 ml, 0.15 w/v) was added and warmed to 40- 45 0C till the ester intermediate (III) disappeared as indicated by HPLC. After the ester was completely hydrolyzed sodium hydroxide (14.67 gm, 0.367 moles) in water (110 ml) was added and refluxed to 78-82 0C till the diol ester (II) was completely converted to sodium salt. The reaction mixture was cooled to 25-30 0C and stirred for about 3 hours. The crude sodium salt was washed with isopropanol (2 x 100 ml). The wet sodium salt was then charged into 1000 ml of isopropanol containing 5% water and heated to 78-82 0C for about an hour, cooled to 25-30 0C, and then stirred for 1-2 hours, filtered under N2 atmosphere and dried under vacuum to obtain crystalline atorvastatin sodium of purity 99.6%. Melting point: 136.7-139.2 0C.The, purification of the crude atorvastatin sodium may be repeated one or more time to get crystalline form with purity above 99.6%. |
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With hydrogenchloride; In methanol; water; at 20 - 26℃; for 6.25 - 7.75h;Product distribution / selectivity; |
[R-(R*,R*)]-1,1-Dimethylethyl-2-(4-fluorophenyl)-[3,8-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1Hpyrrole-1-heptanoate (Compound I) To a solution of Compound H (10 Kg, 15.29 moles) in methanol (217 L), 1 N hydrochloric acid solution (21 L, 16.04 moles) was added at 20-26 C in 15 minutes. The reaction mixture was stirred at the same temperature until the reaction was complete (about 6 hours, monitoring by HPLC). ; Part A - Preparation of Crude Atorvastatin Calcium[R-(R*,R*)]-1,1-Dimethylethyl-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoate (Compound I) To a solution of Compound H (57g) in methanol (1.71L), 1 N hydrochloric acid solution (116 mL) was added drop wise at 20-25 C in 15 minutes. The reaction mixture was stirred at the same temperature for about 5 hours, and monitored by TLC (hexane:ethanol :: 6:4). 1 N hydrochloric acid solution (10 mL) was then added and the reaction mixture was further stirred for about 2.5 hours. |
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With hydrogenchloride; methanol; water; at 20 - 26℃; for 6.25 - 7.75h;Product distribution / selectivity; |
[R-(R*, R*)]-1, 1-Dimethylethyl-2-(4-fluorophenyl)-ss, 6-dihydroxy-5-(1-methylethyl)-3- phenyl-4-[(phenylamino) carbonyl]-lH-pyrrole-1-heptanoate (Compound I); To a solution of Compound H (10 Kg, 15.29 moles) in methanol (217 L), 1 Nhydrochloric acid solution (21 L, 16.04 moles) was added at 20-26 C in 15 minutes. The reaction mixture was stirred at the same temperature until the reaction was complete (about 6 hours, monitoring by HPLC).; Example 11; Preparation of crystalline atorvastatin calcium form-I seed; Part A; Preparation of Crude Atorvastatin Calcium; [R-(R*R*)]-1, 1-Dimethylethyl-2-(4-fluorophenyl)-ss, 6-dihydroxy-5-(1-methylethyl)-3- phenyl-4-[(phenylamino) carbonyl]-lH-pyrrole-1-heptanoate (Compound I) To a solution of Compound H (57g) in methanol (1.71L), 1 N hydrochloric acid solution (116 mL) was added drop wise at 20-25 C in 15 minutes. The reaction mixture was stirred at the same temperature for about 5 hours, and monitored by TLC (hexane: ethanol: : 6: 4). 1 N hydrochloric acid solution (10 mL) was then added and the reaction mixture was further stirred for about 2.5 hours. |
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With hydrogenchloride; water; In methanol; at 20 - 26℃; for 6.25 - 7.75h;Product distribution / selectivity; |
[R-(R*,R*)]-1,1-Dimethylethyl-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoate (Compound I)To a solution of Compound H (10 Kg, 15.29 moles) in methanol (217 L), 1 N hydrochloric acid solution (21 L, 16.04 moles) was added at 20-26 C. in 15 minutes. The reaction mixture was stirred at the same temperature until the reaction was complete (about 6 hours, monitoring by HPLC).; EXAMPLE 11Preparation of Crystalline Atorvastatin Calcium Form-I SeedPart A-Preparation of Crude Atorvastatin Calcium[R-(R*,R*)]-1,1-Dimethylethyl-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoate (Compound I)To a solution of Compound H (57 g) in methanol (1.71 L), 1 N hydrochloric acid solution (116 mL) was added drop wise at 20-25 C. in 15 minutes. The reaction mixture was stirred at the same temperature for about 5 hours, and monitored by TLC (hexane:ethanol::6:4). 1 N hydrochloric acid solution (10 mL) was then added and the reaction mixture was further stirred for about 2.5 hours. |
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With hydrogenchloride; water; In methanol; at 20 - 25℃; for 7.75h; |
To a solution of Compound H (57 g) in methanol (1.71 L), 1 N hydrochloric acid solution (116 mL) was added drop wise at 20-25 C. in 15 minutes. The reaction mixture was stirred at the same temperature for about 5 hours, and monitored by TLC (hexane:ethanol::6:4). 1 N hydrochloric acid solution (10 mL) was then added and the reaction mixture was further stirred for about 2.5 hours. |
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With hydrogenchloride; In water; acetonitrile; at 30 - 35℃; |
Example-1Preparation of [R-(R*,R*)-1,1-dimethylethyl-2-(4-fluorophenyl)-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoate 100 gm of (3R,5R) tert-butyl (6-{2-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-1-yl]-ethyl}-2,2-dimethyl-[1,3]dioxane-4-yl)acetate and 1 Lit acetonitrile were taken in round bottom flask. 100 mL 1N HCl solution in 300 mL of water was added dropwise at 30 C. to 35 C. and stirred for 2 hours. The reaction mixture was cooled to 20 C. to 25 C. and pH was adjusted to 7.5 to 8.0 with 5% NaOH. The solution was filtered and washed with mixture of acetonitrile and water and dried at 50 C. to 55 C. to obtain [R-(R*,R*)]-1,1-dimethylethyl-2-(4-fluorophenyl)-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-1H-pyrrole-1-heptanoate. |
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With hydrogenchloride; water; In acetonitrile; at 20 - 25℃; |
Example 6Preparation of [R-(R* Jt*)1-2-(4-fluorophenyD-B,delta-dihydroxy-5-fl-methgammalethyl) phenyl-4-ffphengammalammo)carponvIl-l/f-pyrrole-l-heptanoic acid tertiary butyl ester; 26,67 g of (4R-cis)-6-{2-[3-phenyl-4-(phenylcarbamoyl)-2-(4-fluorophenyl)-5-(l- methylethyl)pyrrol-l-yl]ethyl}-2,2-dimethyl-[l,3]dioxane-4-yl acetic acid tertiary butyl ester (Ia) is suspended in 120 niL of acetonitrile, 23 mL of water and 6.3 mL of IM HCl. The reaction mixture is stirred at 20-25 CC until all (4R-cis)-6-{2-[3-phenyl-4-(phenylcarbamoyl)- 2-(4-fluorophenyl)-5-(l-methylethyl)pyrrol-l-yl]ethyl}-2,2-dimethyl-[l,3]dioxane-4-yl acetic acid tertiary butyl ester (Ia) is dissolved and the reaction is followed with HPLC method. After 24 h 267 mL of water was added. The solid precipitate is filtered off and the cake is washed with 100 mL of water unitll the pH value of the filtrate is 5-7. The wet cake is dried at 20-30 0C on air for approximately 1 hour till constant weight, optionally granulated and dried for 4 hours at 40-50C.22,54 g of tertiary butyl ester [R-(R* ,R*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(l- methylethyl)phenyl-4-[(phenylamino)carbonyl]-l//-pyrrole-l-heptanoic acid is isolated The purity of the obtained product is higher than 99.9%. |
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With water;hydrogenchloride; In methanol; at 20 - 26℃; for 6 - 7.75h;Product distribution / selectivity; |
To a solution of Compound H (10 Kg, 15.29 moles) in methanol (217 L), 1 N hydrochloric acid solution (21 L, 16.04 moles) was added at 20-26 C in 15 minutes. The reaction mixture was stirred at the same temperature until the reaction was complete (about 6 hours, monitoring by HPLC); To a solution of Compound H (57g) in methanol (1.71L), 1 N hydrochloric acid solution (116 mL) was added drop wise at 20-25 C in 15 minutes. The reaction mixture was stirred at the same temperature for about 5 hours, and monitored by TLC (hexane:ethanol :: 6:4). 1 N hydrochloric acid solution (10 mL) was then added and the reaction mixture was further stirred for about 2.5 hours. |
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With hydrogenchloride; In tetrahydrofuran; methanol; at 0 - 20℃; for 0.5h; |
A mixture of amine 15 (40.2 mg, 0.147 mmol), diketone 16 (55.8 mg, 0.133 mmol), pivalic acid (12.0 mg, 0.118 mmol) in n-hexane/toluene/THF=1:4:1 (0.48 mL) was heated at 110 C for 30 h under Ar. After cooling to room temperature, the mixture was diluted with AcOEt and washed with satd NaHCO3 aq, then dried over Na2SO4. The resulting residue after evaporation was dissolved in THF (0.5 mL). To the solution was added 2 N HCl in MeOH (1 mL) at 0 C and the resulting solution was stirred at room temperature for 30 min. The mixture was diluted with CH2Cl2, and resulting biphasic mixture was separated. Organic layer was washed with satd NaHCO3 aq and brine, then dried over Na2SO4. The filtrate was concentrated under reduced pressure and the resulting residue was dissolved in wet THF (0.2 mL). 1 N NaOH aq (2 mL) was added at 0 C and the resulting solution was stirred at room temperature for 6 h. The mixture was diluted with CH2Cl2 and 1N HCl aq. The resulting biphasic mixture was extracted with CH2Cl2. The combined organic layers were washed with brine, then dried over Na2SO4. Volatiles were removed under reduced pressure and the resulting solid residue was purified by flash chromatography (CH2Cl2/MeOH 18/1) on silica gel to give atorvastatin as a colorless solid. (54.8 mg, 67% over three steps). |
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With hydrogenchloride; In methanol; at 20℃;pH 1; |
The preparation method of atorvastatin arginine salt comprises the following steps:Atorvastatin tert-butyl ester 10g, 70mL anhydrous methanol in the250mL of three bottles, stirring at room temperature;5 mL was added dropwiseConcentrated hydrochloric acidPH 1, stirring at room temperature, a few minutes after the solution clear and transparent, the process of TLC detection (chloroform: methanol = 50: 1), an hour later, the reaction is completed.The reaction bottle placed in ice bath, with 5mol / L NaOH solution alkali rho Eta = 13-14, 3h after the reaction is completed,The methanol in the reaction mixture was removed by rotary evaporation, and the remaining residue was poured into 100 mL of water,The suspension was washed with 100 mL of X2 methyl tert-butyl ether.Methyl tert-butyl ether was removed and removed,The remaining water was acidified with 1 mol / L HC1 solution to pH = 3-4 and the solution was extracted with 80 mL of ethyl acetateThe separated organic phase was adjusted to rho H = 6-7 with a saturated solution of 110) 3, and a small amount of water was separated off and the organic phase was separatedSaturated sodium chloride solution 40mL washed once, anhydrous sodium sulfate drying 2h, steamed to remove ethyl acetate,To give atorvastatin acid 7. 5 g.The resulting 7. 5 g of atorvastatin acid was mixed with 30 mL of anhydrous methanol, 4. 7 g of L-arginine, and 5 mL of waterDissolved in three bottles, heated to reflux 8h5)The solvent was removed by rotary evaporation, dried in vacuo for 2 h, and dried in 50 mL of anhydrous methanol. The solid was removed by filtration,Acid, repeated five times, steam to remove methanol, the residue dried with vacuum oil chestnut 2h, atorvastatin arginine salt 7. 2gThe atorvastatin arginine salt yield in this example was 72.9%. |
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With hydrogenchloride; In methanol; water; at 22℃;Inert atmosphere; |
A mixture of compound of formula IV (20 g; diamino-ester IVa content --0.28%) in a mixture of hydrochloric acid (3.6 mL), water (36 mL) and MeOH (420 mL) was stined under inertatmosphere at 22±3C. After completion of the reaction, the pH of the mixture was made alkaline by addition of 6N aqueous lithium hydroxide (40 mL). The mixture was maintained at temperature 40±3C for 14h when HPLC analysis revealed completion of ester hydrolysis; HPLC analysis revealed the content of impurity-VIa to be 0.02%. After carbon treatment, the mass was concentrated under reduced pressure and the residue obtained was dissolved in amixture of water (180 mL) and methanol (80 mL);The reaction mass was washed with MtBE and gradually added to a mixture of aqueous calcium acetate and seed material, while maintaining temperature of 52±3C. After maintaining for 17h at the same temperature, the mixture was cooled to ambient temperature and filtered to afford crystalline Atorvastatin (17 g, 92% yield). HPLC purity: 98.06%, Impurity VIa: 0.02%, Impurity IVb: 1.13%. |
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With hydrogenchloride; water; In methanol; at 25 - 30℃; |
100 g (O. l52mole) of crude (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5- (l-methyl-ethyl)-pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester obtained from (example 1) is dissolved in methanol 13 vol (w/v) at 40-50 C till complete dissolution, hydrochloric acid (26 g of 36.5% in 87 ml water solution was added to the reaction mass at 25-30C. After stirring the contents at 25-30C until the completion of the reaction as monitored on HPLC. Methanol is distilled off under the reduced pressure. Concentrated reaction mass is poured into sodium hydroxide solution (19.55 g in 650 ml water) and stirred till the completion of the reaction as monitored by HPLC resulting into [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid sodium salt. Reaction mass is concentrated under reduced pressure followed by the addition of mixture containing 1000 ml water and 500ml Methyl tert-butyl ether. The aqueous layer is collected to adjust pH of the mass was 8.6 to 8.7 at about 40C using dilute acetic acid followed by addition of solution containing calcium acetate (18 gm, 0.112 mol) in 225 ml water at about 40C.Slurry was agitated for 30 min at about 50C and cooled to 45C, maintained for 120 min and filtered, washed the cake with 50 ml water. Dry the product under vacuum at 50-55 C for 12-14 hr to obtain [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid calcium trihydrate having purity 99.7%+, and dimer impurity 0.03%. |
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With hydrogenchloride; In methanol; water; at 30℃; for 5h; |
Into a 2000ml reactor, put 120g of intermediate L1 and 600ml of methanol, then add the prepared hydrochloric acid solution (142g of purified water, 16.4g of hydrochloric acid), slowly warm up to 30 , react for 5 hours, TLC spot monitoring, raw material spot The disappearance is the end of the reaction. |
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