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CAS No. : | 134523-00-5 | MDL No. : | MFCD00899261 |
Formula : | C33H35FN2O5 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | XUKUURHRXDUEBC-KAYWLYCHSA-N |
M.W : | 558.64 | Pubchem ID : | 60823 |
Synonyms : |
|
Num. heavy atoms : | 41 |
Num. arom. heavy atoms : | 23 |
Fraction Csp3 : | 0.27 |
Num. rotatable bonds : | 13 |
Num. H-bond acceptors : | 6.0 |
Num. H-bond donors : | 4.0 |
Molar Refractivity : | 158.26 |
TPSA : | 111.79 Ų |
GI absorption : | Low |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -6.19 cm/s |
Log Po/w (iLOGP) : | 3.58 |
Log Po/w (XLOGP3) : | 4.96 |
Log Po/w (WLOGP) : | 6.54 |
Log Po/w (MLOGP) : | 3.48 |
Log Po/w (SILICOS-IT) : | 6.15 |
Consensus Log Po/w : | 4.94 |
Lipinski : | 1.0 |
Ghose : | None |
Veber : | 1.0 |
Egan : | 1.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -5.99 |
Solubility : | 0.000578 mg/ml ; 0.00000103 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -7.05 |
Solubility : | 0.0000503 mg/ml ; 0.00000009 mol/l |
Class : | Poorly soluble |
Log S (SILICOS-IT) : | -9.13 |
Solubility : | 0.000000417 mg/ml ; 0.0000000007 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 3.0 |
Synthetic accessibility : | 4.95 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
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46% | at 60℃; for 40 h; | Example 1 Synthesis of Atorvastatin Lactone 5.0 g (8.6 mmole) of atorvastatin calcium was dissolved in 300 mL ethyl acetate and washed with 300 mL 10percent (w/v) aqueous sodium hydrogen sulfate solution (pH 3). The organic phase was dried over anhydrous magnesium sulfate, filtered and the solvent removed under reduced pressure to afford 2.85 g (5.11 mmole) of atorvastatin acid. This material was dissolved in 300 mL anhydrous toluene and heated at 60° C. for 40 hours, at which time analytical thin-layer chromatography using 4:1 methylene chloride:acetone eluent indicated near-complete conversion of the starting acid to a less polar product. The toluene was removed under reduced pressure and the reaction mixture was fractionated on 300 cc of silica gel using 4:1 methylene chloride: acetone eluent to afford, after combining, concentrating and drying of the appropriate fractions, 2.14 g (3.96 mmol, 46percent overall) of atorvastatin lactone as a white foam. The 400 MHz 1H nuclear magnetic resonance (NMR) spectrum and the electrospray mass spectrum (ES-MS) were consistent with the lactone product. 1H NMR (Me2SO-d6) δ 9.80 (s, 1H), 7.49 (d, 2H), 7.25-7.15 (m, 6H), 7.05 (s, 4H), 6.99 (t, 2H), 5.15 (d, 1H), 4.46 (br s, 1H), 4.02 (s, 1H), 3.97 (m, 1H), 3.89 (m, 1H), 3.21 (q, 1H), 2.55 (dd, 1H), 2.32 (dd, 1H), 1.74 (br s, 2H), 1.6 (m, 2H), 1.36 (d, 6H). ES-MS: obsvd. m/z 541 ([MH]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With methanol; potassium hydroxide; water; | The crude (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid, t-butyl ester (VI-A) was converted to the acid using an excess of KOH/MeOH/Water, followed by lactonization in toluene with catalytic HCI. Chiral HPLC analysis (ChiralCel OF; 1 ml/min ; 60C; 254 nm; 20% IPA:Hexanes) tR (3R,5R) = 26.97 min./tR (3S,5S) =] 33.8 min. tR (3R, 5S) =[38.1 min. /tR (3S,5R) = 61.0 min. indicated an enantiomeric excess of the syn isomer of 85%, favoring the (R,R) configuration. | |
To a solution of 1 g of [R-(R*,R*)]-2-(4-fluorophenyl)-ss;,No.- dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)- carbonyl] -1H-pyrrole-1-heptanoic acid tertiary butyl ester (II) (1.62 mmol) in 3.4 mL of methanol and 2.8 mL of tert- butyl methyl ether, 68.4 mg of NaOH (1.7 mmol, 1.05 equiva- lent) and 5.8 mL of water are added. The reaction mixture is purged with a nitrogen flow for about 5 minutes and heated to the reflux for 2-4 h, until the concentration of starting [R- (R*, R* ) ] -2- ( 4-f luorophenyl ) -(at)i, 8-dihydroxy-5- ( 1-methylethyl ) -3- phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l-heptanoic acid tertiary butyl ester (II) is lower than 0.5%, determined with HPLC method. The reaction mixture is allowed to cool to 20-25 C, active charcoal is added, and the reaction mixture is stirred for ad- ditional 30 min. The reaction mixture is filtered and the pH of the filtrate is set to 8.0-8.2 by the addition of HC1. The reaction mixture is washed with 3 x 2.9 mL of tert-butyl methyl ether and aqueous phases are finally filtered. The re- action mixture is purged with nitrogen flow for about 5 min and 0.179 g of CaCl2 (0,82 mmol of CaCl2-6H20) and 6.8 mL of water are 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. Then 6 mL of water is slowly added into the reaction mixture to provoke the solidification of the thick emulsion-like mixture. Hemi-calcium salt of atorvastatin is formed in the form of particles having a size in the range of mm to several mm which show improved filterability. The precipitate is filtered off after 30 min. The wet cake is washed with water. Collected solid material is dried on air to obtain dry solid atorvastatin hemi-calcium. Example 8 To the solution of 9.22 g of [R-(R*,R*)]-2-(4-fluorophenyl)- beta,delta-dihydroxy-5- (l-methylethyl)-3-phenyl-4-[(phenylamino)- carbonyl]-lH-pyrrole-l-heptanoic acid tertiary butyl ester (II) (15 mmol) in 61 mL of methanol and 52 mL tert-butyl methyl ether, 0.63 g of NaOH (15.7 mmol, 1.05 equivalent) and 104 mL of water are added. The reaction mixture is purged with a nitrogen flow for about 5 minutes and heated to the reflux for 2-4 h, until the concentration of the starting compound [R-(R*, R*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)- 3-phenyl-4- [(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid tertiary butyl ester (II) is lower than 0.5 %, determined by HPLC. The reaction mixture is allowed to cool to 20-25 C and the pH is set to 8.0-8.2 by the addition of HC1. The reaction mixture is washed with 3 x 26 mL of tert-butyl methyl ether and aque- ous phases are finally filtered. The reaction mixture is purged with a nitrogen flow for about 5 min, and 1.80 g of CaCl2 (8.2 mmol of CaC12.6H20) and 64 mL of water are 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 270 mL of water is slowly added into the reaction mix- ture to provoke the solidification of the thick emulsion-like mixture. Hemi-calcium salt of atorvastatin is formed in the form of granules, which show improved filterability. The pre- cipitate is filtered off and the wet cake is washed with a mixture of water and methanol and finally with water. The col- lected solid material is dried on air to obtain dry solid atorvastatin hemi-calcium._:The dry hemi-calcium salt of atorvastatin can optionally be additionally milled on a dry pearl mill. Example 9 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 %)... | ||
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... |
With sodium hydroxide; water; at 75 - 80℃; | Dihydroxy ester (II) (5 g) was taken in water (50 ml) and sodium hydroxide (0.35 g) was added. Temperature was raised to 75-800C and reaction mass was stirred and then cooled. Calcium acetate (1.00 g) was added and stirred for 1 hr and pH was adjusted to 8. Ethyl acetate (40 ml) was added to extract the product from aqueous layer. Organic layer was washed with water and then dried over sodium sulfate. Solvent was removed under vacuum to give a foamy solid residue. The foamy solid residue was taken in diisopropyl ether or cyclohexane or t-butyl methyl ether or isopropyl alcohol (50 ml) and stirred. Contents were filtered and dried to yield amorphous Atorvastatin calcium. Dihydroxy ester (II) (5 g) was taken in water (50 ml) and sodium hydroxide (0.35 g). was added. Temperature was raised to 75-800C and reaction mass was stirred and then cooled. Calcium acetate solution (1.00 g) was added and stirred for 1 hr and pH was adjusted to 8. Ethyl acetate (40 ml) was added to extract the product from aqueous layer. Organic layer was washed with water and then dried over sodium sulfate. Solvent was removed under vacuum to give a foamy solid residue. The foamy solid residue was taken in mixture of cyclohexane and t-butyl methyl ether (50 ml) and stirred. Contents were filtered and dried to yield amorphous Atorvastatin calcium. | |
With methanol; sodium hydroxide; water; at 80℃; for 3h; | Dihydroxy ester (II) (5 g) was taken in water (50 ml) and methanol (5 ml). Sodium hydroxide (0.36g, 1.1 mole eq.) was then added. Temperature was raised to 800C and reaction mass was stirred for 3 hrs at this temp. After reaction completion, reaction mixture was cooled. Calcium acetate solution (1.02 g in 5 ml water) was added at this temperature and then stirred for 1 hr. Ethyl acetate (40 ml) was added to extract the product from aqueous layer. Organic layer was washed with water and then dried over sodium sulfate. Solvent was removed under vacuum to give a foamy solid residue. To the residue tetrahydrofuran (15 ml) was added, stirred and stripped of the tetrahydrofuran under vacuum at 40-500C to get the solid foam. Tetarhydrofuran (15 ml) was added and stirred for dissolution, followed by the addition of this solution to a cyclohexane : t-butyl methyl ether mixture (75 ml : 75 ml) at room temperature. After <n="14"/>the addition, the precipitated material was stirred for one hour. Contents were filtered and dried to yield amorphous Atorvastatin. | |
With sodium hydroxide; water; In butanone; at 60℃; for 2h; | Dihydroxy ester (II) (5 g) was taken in water (25 ml) and methyl ethyl ketone (25 ml).Sodium hydroxide (0.35 g) was then added. Temperature was raised to 600C and reaction mass was stirred for 2 hrs. After the completion of reaction, calcium acetate (1.00 g in 5 ml water) was added and stirred, followed by the cooling of the reaction mixture to room temperature. Methyl ethyl ketone (25 ml) was added to extract the product from aqueous layer. Organic layer was washed with water and then dried over sodium sulfate. Solvent was removed under vacuum to give a foamy solid residue. The foamy solid residue was taken in diisopropyl ether (50 ml) and stirred. Contents were filtered and dried to yield amorphous Atorvastatin. Dihydroxy ester (II) (5 g) was taken in water (25 ml) and methyl ethyl ketone (25 ml) followed by the addition of sodium hydroxide (0.35 g). Temperature of the reaction mixture was raised to 600C and stirred for 2 hrs. After the completion of the reaction, calcium acetate (1.00 g in 5 ml water) was added and stirred for 2 hrs. Reaction mixture was cooled to room temperature. The pH was adjusted to 8. Ethyl acetate (40 ml) was added to extract the product from aqueous layer. Organic layer was washed with water and then dried over sodium sulfate. Solvent was removed under vacuum to give a foamy solid residue. The foamy solid residue was taken in diisopropyl ether or cyclohexane or t-butyl methyl ether or isopropyl alcohol or mixture of cyclohexane and t-butyl methyl ether (50 ml) and stirred. Contents were filtered and dried to yield amorphous Atorvastatin. Dihydroxy ester (II) (5 g) was taken in water (25 ml) and methyl ethyl ketone (25 ml) followed by the addition of sodium hydroxide (0.35 g). Temperature of the reaction <n="12"/>mixture was raised to 600C and stirred for 2 hrs. After the completion of the reaction, Calcium 2-ethyl hexanoate (2.20 g in 5 ml water) was added and stirred for 2 hrs. Reaction mixture was cooled to room temperature. The pH was adjusted to 8. Ethyl acetate (40 ml) was added to extract the product from aqueous layer. Organic layer was washed with water and then dried over sodium sulfate. Solvent was removed under vacuum to give a foamy solid residue. The foamy solid residue was taken in diisopropyl ether or cyclohexane or t-butyl methyl ether or isopropyl alcohol or mixture of cyclohexane and t-butyl methyl ether (50 ml) and stirred. Contents were filtered and dried to yield amorphous Atorvastatin. Dihydroxy ester (II) (5 g) was taken in water (25 ml) and methyl ethyl ketone (25 ml) followed by the addition of sodium hydroxide (0.35 g). Temperature of the reaction mixture was raised to 600C and stirred for 2 hrs. After the completion of the reaction, calcium acetate (1.00 g in 5 ml water) was added and stirred for 2 hrs. Reaction mixture was cooled to room temperature. The pH was adjusted to 8. Ethyl acetate (40 ml) was added to extract the product from aqueous layer. Organic layer was washed with water and then dried over sodium sulfate. Solvent was removed under vacuum to give a foamy solid residue. The foamy solid residue was taken in diisopropyl ether or cyclohexane or t-butyl methyl ether or isopropyl alcohol or mixture of cyclohexane and t-butyl methyl ether (50 ml) and stirred. Contents were filtered and dried to yield amorphous Atorvastatin. Dihydroxy ester (II) (5 g) was taken in methyl ethyl ketone (40 ml) followed by the addition of sodium hydroxide (0.35 g). Temperature of the reaction mixture was raised to 600C and stirred for 2 hrs. After the completion of the reaction, Calcium 2-ethyl hexanoate (2.20 g in 5 ml water) was added and stirred for 2 hrs. Reaction mixture was cooled to room temperature. The pH was adjusted to 8. Ethyl acetate (40 ml) was added to extract the product from aqueous layer. Organic layer was washed with water and then dried over sodium sulfate. Solvent was removed under vacuum to give a foamy <n="13"/>solid residue. The foamy solid residue was taken in diisopropyl ether or cyclohexane or t-butyl methyl ether or isopropyl alcohol or mixture of cyclohexane and t-butyl methyl ether (50 ml) and stirred. Contents were filtered and dried to yield amorphous Atorvastatin. Dihydroxy ester (II) (5 g) was taken in water (25 ml) and methyl ethyl ketone (25 ml) followed by the addition of sodium hydroxide (0.35 g). Temperature of the reaction mixture was raised to 600C and stirred for 2 hrs. After the completion of the reaction, Calcium acetate solution (1.00 g in 5 ml water) was added and stirred for 2 hrs. Reaction mixture was cooled to room temperature. The pH was adjusted to 8. Xylene (50 ml) was added to extract the product from aqueous layer. Organic layer was washed with water and then dried over sodium sulfate. Solvent was removed under vacuum to give a foamy solid residue. The foamy solid residue was taken in diisopropyl ether or cyclohexane or t-butyl methyl ether or isopropyl alcohol or mixture of cyclohexane and t-butyl methyl ether (... | |
With sodium hydroxide; water; at 75 - 80℃; for 12h; | Dihydroxy ester (II) (5 g) was taken in water (50 ml) and sodium hydroxide (0.35 g) was added. Temperature was raised to 75-800C and reaction mass was stirred for 12 hrs and then cooled. Calcium 2-ethyl hexanoate solution (2.20 g) was added and stirred for 1 hr. The pH was adjusted to 8. Ethyl acetate (40 ml) was added to extract the product from aqueous layer. Organic layer was washed with water and then dried over sodium sulfate. Solvent was removed under vacuum to give a foamy solid residue. The foamy <n="11"/>solid residue was taken in diisopropyl ether (50 ml) and stirred. Contents were filtered and dried to yield amorphous Atorvastatin calcium. | |
54.8 g | 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). Colorless solid; IR (KBr) nu 3410, 2964, 2929, 1731, 1652, 1529, 1508, 1438, 1315, 1241, 1226 cm-1; 1H NMR (CD3OD) delta 7.30-7.29 (m, 2H), 7.25-7.20 (m, 4H), 7.15-7.13 (m, 2H), 7.11-7.02 (m, 6H), 4.08 (ddd, J=5.3, 7.8, 16.0 Hz 1H), 4.02-3.98 (m, 1H), 3.91 (ddd, J=5.3, 7.6, 16.0 Hz, 1H), 3.69-3.63 (m, 1H), 3.40-3.34 (m, 1H), 2.41 (dd, J=5.2, 15.5 Hz, 1H), 2.35 (dd, J=7.6, 15.5 Hz, 1H), 1.75-1.6 (m, 2H), 1.56-1.51 (m, 1H), 1.49 (d, J=7.1 Hz, 3H), 1.48 (d, J=7.1 Hz, 3H), 1.47-1.43 (m, 1H); 13C NMR (CD3OD) delta 175.9, 169.5, 163.8 (1JCF=245.5 Hz), 139.9, 139.1, 139.1, 136.4, 134.7 (3JCF=7.2 Hz), 131.0, 130.3 (4JCF=2.9 Hz), 129.6, 128.9, 126.9, 125.2, 123.3, 121.5, 118.1, 116.3 (2JCF=21.6 Hz), 68.6, 67.9, 44.2, 43.3, 42.2, 40.1, 27.7, 22.9, 22.8; 19F NMR (CDCl3) delta -113.8; [alpha]D23 +5 (c 0.94, CH3OH); ESI-MS m/z 581.2 [M+Na]+; HRMS (ESI) Anal. Calcd for C33FH35N2NaO5 m/z 581.2422 [M+Na]+, found; 581.2421. | |
With sodium hydroxide; | he preparation method of atorvastatin arginine salt comprises the following steps:0.369 g (0. 564 mmol) of atorvastatin tert-butyl ester and 5 ml of methanol were added to the reaction vessel, and the mixture was dissolved by stirring.Then add 0. 3ml of lmol / L hydrochloric acid solution,The reaction was stirred at room temperature (30-35 C). The reaction solution was initially white suspension,After a period of time becomes colorless and transparent,TLC detection of raw materials disappeared,Reaction completed;With lmol / L sodium hydroxide solution to adjust the solution to neutral or weakly alkaline, and then adding an equal molar sodium hydroxide solution,TLC follow the reaction, after the reaction is over,The solution is atorvastatin sodium salt solution.Adjust the solution with hydrochloric acid solution rho Eta = 3-4, at this time solution for atorvastatin acid solution; and then adjust the solution to the weakAcid, and then added to the solution 1-1.5 molar equivalent of arginine, heated to 75 C under reflux 6-7 hours, remove the solvent by steaming, Dried in vacuo for 2 h and dissolved in 10 mL of anhydrous methanol. The dried solid was removed by filtration and the L-arginine was removed by filtration.The residue was vacuum dried for 2 hours to obtain atorvastatin arginine salt.The reaction principle of Examples 5-6 is as follows: | |
Put 50 mL of methanol into the reaction flask,125mL water,100 mL of methyl tert-butyl ether,30g of the compound of formula 4,The pH was adjusted to 10.5 to 11.5 with 30% sodium hydroxide under stirring, and the temperature was raised to 40-50 C.Insulation reaction for 2 to 3 hours,The dot plate shows that the raw material reaction is complete.The pH was adjusted to 12 to 13 with 30% sodium hydroxide, the temperature was raised to 50-55 C, and reflux was carried out for 8 to 12 hours. Slowly cool down to 15 ~ 20 C,Adjust the pH to 3~4 with concentrated hydrochloric acid.100 ml of each of methyl tert-butyl ether and water was added, and the layer was allowed to stand to give an organic layer.The organic layer was washed once more with 100 mL of water.Cool the organic layer to 0-10 C,100 mL of n-heptane was slowly added thereto, and crystals were precipitated by stirring for 2 hours, and filtered while stirring for 2 hours.Wet product is dried under reduced pressure at 30~35 C for 8 hours to constant weight.Recognized as a white powdery solid compound of formula 2,The HPLC purity was 98.0-98.5%, the impurity Imp X was about 0.5%, and the impurity Imp F was about 0.3%. |
Yield | Reaction Conditions | Operation in experiment |
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84.35% | EXAMPLE 3 Preparation of <strong>[134523-00-5]Atorvastatin</strong> Calcium Crystalline Form VI 360 liters of acetonitrile and 24 kg of <strong>[134523-00-5]atorvastatin</strong> was taken into a reactor and subjected to heating to 44 C. for 1 hour. 73 liters of 10% aqueous calcium acetate solution was added to the reaction mass and maintained for 1 hour, 15 minutes. 4.5 liters of 10% aqueous sodium hydroxide was added to the above reaction mass and subjected to heating to reflux at 70 C. for 1 hour. The reaction mass was filtered and the solid washed with 45 liters of acetonitrile. 9 liters of 10% sodium hydroxide was added to the above solid and subjected to heating to reflux at 70 C. for a period of about 8 hours. The reaction mass was cooled to 30 C. for a period of about 1.5 hours and centrifuged followed by washing with 112.5 liters of water. The obtained solid material was spin dried for a period of about 2 hours and kept for aerial drying for 30 minutes. The obtained solid material was dried at 55 C., cooled and the solid was thoroughly mixed. Finally the obtained solid material was subjected to rotatory cone vacuum drying to afford 35.8 kg (84.35%) of crystalline Form VI of <strong>[134523-00-5]atorvastatin</strong> calcium. |
Yield | Reaction Conditions | Operation in experiment |
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Example 6: Preparation of [R-(R*, R*)]-2- (4-fluorophenyl)- methylethyl)-3-phenyl-4-[(phenylamino)carbonyll- lH-pyrrole- I -heptanoic acid hemi - calcium salt of Formula I; (a) To a solution of (6-{2-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- phenylcarbamoyl-pyrrole-1-yl]-ethyl}-2,2-dimethyl- [ 1,3]dioxan-4-yl)-acetic acid tert- butyl ester of Formula VIII in methanol and tetrahydrofuran (1:1), 1 N hydrochloric acid (3 equiv) was added and the mixture was stirred at an ambient temperature. After the complete hydrolysis of ketal, the reaction mixture was cooled to 0C and sodium hydroxide pellets (6 equiv) were added. The reaction was then allowed to stir at an ambient temperature. At the end of ester hydrolysis, solvents were removed and residue so obtained was dissolved in water; the aqueous layer was washed with ether and neutralized with 1 N hydrochloric acid. Organics were extracted into ethyl acetate, and concentrated to give a residue. The residue was then purified on column (silica gel 100- 200 mesh) to give [R-(R*, R*)]-2- (4-fluorophenyl)- phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid of Formula IX. | ||
Example 1; Modification"A"of atorvastatin L-lysine salt 36 ml of 10 w/w % aqueous hydrochloric acid is added to a solution of 10.0 g (15.3 mmol) of protected atorvastatin/its chemical name: 1, 1-dimethylethyl (4R-cis)-6- [2- [3-phenyl-4- [ (phenylamino) carbonyl]-2- (4-fluorophenyl)-5- (l-methylethyl)-lH-pyrrol-1-yl] ethyl]-2, 2- dimethyl-1, 3-dioxane-4-acetate; see K. L. Baumann et al.: Tetrahedron Letters, 33,2283-2284 (1992)/in 100 ml of tetrahydrofuran in a 250 ml round bottom flask. The so obtained mixture is stirred at 25 C for 8 h, then 8.8 ml of 50 w/w % aqueous sodium hydroxide is added dropwise and stirring is continued for further 8 h. After completion of the reaction the phases are separated, the organic layer is washed with 65 ml of aqueous sodium chloride solution, and the solvent is evaporated in vacuum. 100 ml of water and 65 ml of ethyl acetate are added to the residue. The pH of the stirred emulsion is adjusted to 4.0 by adding 10 w/w % aqueous orthophosphoric acid solution. The phases are separated and the organic layer, which contains the atorvastatin acid, is washed with 40 ml of aqueous sodium chloride solution twice, dried over sodium sulfate and filtered. The filtrate is diluted with ethyl acetate in a 100 ml volumetric flask exactly to 100 ml and the concentration of the solution is determined by titrimetry (14.5 mmol atorvastatin acid in 100 ml solution). Example 5 Amorphous atorvastatin L-lysine salt 7.1 ml of 10 w/w % aqueous hydrochloric acid is added to a solution of 1.96 g (3 mmol) of protected atorvastatin in 40 ml of tetrahydrofuran in a 100 ml round bottom flask. The so obtained mixture is stirred at 25 C for 8 h, then 1.74 ml of 50 w/w % aqueous sodium hydroxide is added dropwise and stirring is continued for further 8 h. After completion of the reaction the phases are separated, the organic layer is washed with 15 ml of aqueous sodium chloride solution, and the solvent is evaporated in vacuum. 60 ml of water and 60 ml of dichloromethane are added to the residue. The pH of the stirred emulsion is adjusted to 4.0 by adding 10 w/w % aqueous orthophosphoric acid solution. The phases are separated and the organic layer, which contains the atorvastatin acid, is washed with 20 ml of aqueous sodium chloride solution twice, dried over sodium sulfate and filtered. The filtrate is diluted with dichloromethane in a 100 ml volumetric flask exactly to 100 ml and the concentration of the solution is determined by titrimetry (2.67 mmol atorvastatin acid in 100 ml solution). | ||
EXAMPLE 5; Preparation of atorvastatin calcium propylene glycol solvate under hydrous conditions from atorvastatin tert-butyl esterTo a mixture of (4R-cis)-1,1-dimethylethyl-6-{2-[[2-(4-fluorophenyl)]-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-yl]ethyl}-2,2-dimethyl-1,3-dioxane-4-acetate (100 g) and 10 parts MeOH was added 1 eq. 1N aq. HCl solution. The mixture was warmed to about 50 C. and maintained for about 10 h before it was cooled to room temperature. At this point, 2 eq. of 1 N NaOH solution was added and the mixture was warmed to about 60 C. for about 10 h. After cooling to room temperature the reaction mixture was acidified with diluted aqueous HCl solution and extracted three times with 2 parts of isopropyl acetate and the combined organic layers were washed with brine. To the organic solution was added 3 parts of racemic propylene glycol and 0.5 eq Ca(OH)2 in 0.3 parts of water. The resulting mixture was warmed to 55-60 C. and stirred for 8-10 hours to afford a white suspension. The suspension was cooled to 20-25 C. and filtered to furnish atorvastatin calcium propylene glycol solvate after drying under vacuum at 50-60 C. Yield: 77% from the atorvastatin tert-butyl ester. Propylene glycol content: 6% by NMR, KF=0.1%. The DSC and IR of this material are shown as FIGS. 9 and 10 respectively. |
Yield | Reaction Conditions | Operation in experiment |
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46% | In toluene; at 60℃; for 40h; | Example 1 Synthesis of Atorvastatin Lactone 5.0 g (8.6 mmole) of atorvastatin calcium was dissolved in 300 mL ethyl acetate and washed with 300 mL 10% (w/v) aqueous sodium hydrogen sulfate solution (pH 3). The organic phase was dried over anhydrous magnesium sulfate, filtered and the solvent removed under reduced pressure to afford 2.85 g (5.11 mmole) of atorvastatin acid. This material was dissolved in 300 mL anhydrous toluene and heated at 60 C. for 40 hours, at which time analytical thin-layer chromatography using 4:1 methylene chloride:acetone eluent indicated near-complete conversion of the starting acid to a less polar product. The toluene was removed under reduced pressure and the reaction mixture was fractionated on 300 cc of silica gel using 4:1 methylene chloride: acetone eluent to afford, after combining, concentrating and drying of the appropriate fractions, 2.14 g (3.96 mmol, 46% overall) of atorvastatin lactone as a white foam. The 400 MHz 1H nuclear magnetic resonance (NMR) spectrum and the electrospray mass spectrum (ES-MS) were consistent with the lactone product. 1H NMR (Me2SO-d6) delta 9.80 (s, 1H), 7.49 (d, 2H), 7.25-7.15 (m, 6H), 7.05 (s, 4H), 6.99 (t, 2H), 5.15 (d, 1H), 4.46 (br s, 1H), 4.02 (s, 1H), 3.97 (m, 1H), 3.89 (m, 1H), 3.21 (q, 1H), 2.55 (dd, 1H), 2.32 (dd, 1H), 1.74 (br s, 2H), 1.6 (m, 2H), 1.36 (d, 6H). ES-MS: obsvd. m/z 541 ([MH]+). |
hydrogenchloride; In toluene; | The crude (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid, t-butyl ester (VI-A) was converted to the acid using an excess of KOH/MeOH/Water, followed by lactonization in toluene with catalytic HCI. Chiral HPLC analysis (ChiralCel OF; 1 ml/min ; 60C; 254 nm; 20% IPA:Hexanes) tR (3R,5R) = 26.97 min./tR (3S,5S) =] 33.8 min. tR (3R, 5S) =[38.1 min. /tR (3S,5R) = 61.0 min. indicated an enantiomeric excess of the syn isomer of 85%, favoring the (R,R) configuration. | |
In toluene; for 4h;Heating / reflux;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... |
Yield | Reaction Conditions | Operation in experiment |
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The free acid of <strong>[134523-00-5]atorvastatin</strong> 55.8 g (0. 1M) and 37.2 g of sodium valerate (0. 3M) were dissolved in 100 ml toluene. 12.6 g (0. 05M) OF P4OIO was added and mixed with high shear mixing for one hour slowly raising the temperature to 80C. 10 ml of water was added and the high sheer mixing continued for a further hour at 60C. 100 ml of AO. IM sodium carbonate solution was added and the mixture gently stirred then centrifuged and the process repeated. The toluene phase was recovered and washed with 100 ml of 0. 1M hydrochloric acid. The toluene phase was recovered and the toluene and valeric acid removed under vacuum to give the phosphoric ester OF ATORVASTATIN ( [R- (R*, R*)]-2-(4-FLUOROPHENYL)-ss-PHOSPHONO-6-HYDROXY- 5-(1-METHYLETHYL)-3-PHENYL-4-[(PHENYLAMINO) CARBONYL]-LH-PYRROLE-1-HEPTANOIC ACID). |
Yield | Reaction Conditions | Operation in experiment |
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92% | With hydrogenchloride; In tert-butyl methyl ether; water; | Crystalline Form I atorvastatin calcium (US Patent 5,969, 156) (10 grams) was placed in an Erlenmeyer flask (4 L). Water (1L) was added to the flask along with a magnetic stir bar. The contents were stirred until all of the solids were wet. With stirring, MTBE (methyl tert-butyl ether-1 L) was added to the reaction mixture to form a white suspension. Hydrochloric Acid (20 ML-1 N solution) was then added to the suspension with stirring. The contents were stirred until a clear mixture (2 phases) was present (ca. 5 min). The mixture was then transferred into a separatory funnel (4L). The contents were mixed well, and the layers separated. The water layer (lower phase) was placed back into the separatory funnel and additional MTBE (1 L) was added. The contents were mixed well, and the layers were separated. The water layer was discarded, and the MTBE layer was combined with the MTBE layer from the first extraction. The combined MTBE layers were placed back into the funnel and water was added (0.5 L). The contents were mixed well, and the layers were separated. The water layer was discarded, and the MTBE layer was placed into a round-bottomed flask (3 L). The MTBE was then removed via rotary evaporation producing a thin film or amorphous solid. The film/solid was dissolved with acetonitrile (0.2 L) to form a solution. Water (0.8 L) was added to the solution with stirring using a magnetic stir bar. A white suspension was formed that appeared as oil droplets by PLM (polarized-light microscopy). Seed crystals of Form A atorvastatin free acid were added. The contents were then rapidly stirred under a nitrogen bleed for approximately one hour. The solids were isolated by vacuum filtration using a Buchner funnel fitted with a paper filter (No.2). The solids were rinsed using water (0.5 L), and placed in a crystallizing dish. The dish was placed in an oven at 25C maintaining nitrogen until dry (ca. 1 day). This procedure afforded crystalline Form A atorvastatin free acid in a yield of approximately 92%. |
With hydrogenchloride; In water; acetonitrile; at 20℃; for 0.25h;pH 2.35 - 7; | In a 600 mL beaker, a slurry was prepared by charging 100 ML of acetonitrile (ACN) and 400 mL deionized water (20: 80 ACN: water) to 0.5 grams of crystalline Form I atorvastatin calcium (US Patent 5,969, 156). The slurry was stirred at ambient conditions for 15 minutes. All undissolved material was removed by vacuum filtration using a 0. cm nylon-66 membrane filter. The pH of the filtrate was determined to be 6.5-7. 0, which was then adjusted to pH 2.35 with 1N HC1. A cloudy precipitate formed and determined by PLM to be fine droplets of oil. Solvent was evaporated by passing nitrogen over the headspace of the solution with stirring until a heavy white precipitate formed (~15 minutes). The slurry was vacuum filtered through a 0. 45FM nylon-66 membrane filter. The solids were then washed with 100 mL of deionized water and air dried at ambient conditions for 24 hours to afford 0.3 grams of crystalline Form A atorvastatin free acid. | |
With sodium hydrogen sulfate; In water; ethyl acetate; | 5.0 g (8.6 mmole) of atorvastatin calcium was dissolved in 300 mL ethyl acetate and washed with 300 mL 10% (w/v) aqueous sodium hydrogen sulfate solution (pH 3). The organic phase was dried over anhydrous magnesium sulfate, filtered and the solvent removed under reduced pressure to afford 2.85 g (5.11 mmole) of atorvastatin acid. This material was dissolved in 300 mL anhydrous toluene and heated at 60 C. for 40 hours, at which time analytical thin-layer chromatography using 4:1 methylene chloride:acetone eluent indicated near-complete conversion of the starting acid to a less polar product. The toluene was removed under reduced pressure and the reaction mixture was fractionated on 300 cc of silica gel using 4:1 methylene chloride: acetone eluent to afford, after combining, concentrating and drying of the appropriate fractions, 2.14 g (3.96 mmol, 46% overall) of atorvastatin lactone as a white foam. The 400 MHz 1H nuclear magnetic resonance (NMR) spectrum and the electrospray mass spectrum (ES-MS) were consistent with the lactone product. 1H NMR (Me2SO-d6) delta 9.80 (s, 1H), 7.49 (d, 2H), 7.25-7.15 (m, 6H), 7.05 (s, 4H), 6.99 (t, 2H), 5.15 (d, 1H), 4.46 (br s, 1H), 4.02 (s, 1H), 3.97 (m, 1H), 3.89 (m, 1H), 3.21 (q, 1H), 2.55 (dd, 1H), 2.32 (dd, 1H), 1.74 (br s, 2H), 1.6 (m, 2H), 1.36 (d, 6H). ES-MS: obsvd. m/z 541 ([MH]+) |
With monosodium salt of ethylenediaminetetraacetic acid; In water; | Atorvastatin calcium (the form commercially available) is added to a 5% solution of Sodium EDTA in water, in a round bottom flask and stirred briskly. The Sodium EDTA chelates the calcium and renders atorvastatin in its open acid form. Atorvastain acid being water insoluble is extracted and dried. lgram mole equivalent of the atorvastatin extracted as above is digested in 100 ml of ethyl acetate in a round bottom flask fitted with a magnetic stirrer. 1 gram mole equivalent of (S)-2,6-diaminohexanoic acid is added to the above ethyl acetate solution and stirred at ambient room temperature. The reactants, which were initially insoluble in ethyl acetate slowly, react and form atorvastatin (S)-2,6-diaminohexanoic acid complex, which is completely soluble in ethyl acetate solution. The solution of clear ethyl acetate containing atorvastatin (S)-2,6-diaminohexanoic acid complex is then poured into a glass tray and the ethyl acetate is allowed to evaporate till the atorvastatin (S)-2,6-diaminohexanoic acid complex is obtained as a dry product.1 gram mole equivalent of the dry atorvastatin (S)-2,6-diaminohexanoic acid complex obtained as above is dissolved in 200 ml of carbon tetra chloride in a round bottom flask fitted with a magnetic stirrer. To this is added lgram mole equivalent of acyl chloride of (Z)-9-Octadecenoic acid and the solution is stirred for 4 hrs. After completion of the reaction the above solution is poured into the glass tray to allow the carbon tetrachloride to evaporate. The atorvastatin (S)-2,6-diaminohexanoic acid (Z)-9-Octadecenoic complex as obtained above is washed with a 5% solution of sodium carbonate in a separating funnel to neutralize the EPO <DP n="23"/>hydrochloride present in the product. After washing the atorvastatin (S)- 2,6-diaminohexanoic acid (Z)-9-Octadecenoic complex is obtained as a separate oily layer and is separated from the saline sodium carbonate water- solution. The final atorvastatinn (S)-2,6-diaminohexanoic acid (Z)-9- Octadecenoic complex obtained is an oily liquid freely soluble in oils including arachis oil, soya bean oil etc.,; Example 2:Preparation of water-soluble form of Atorvastatin namely Atorvastatin (S)-2,6-diaminohexanoic acid betaine .Atorvastatin calcium (the form commercially available) is added to a 5% solution of Sodium EDTA in water, in a round bottom flask and stirred briskly. The Sodium EDTA chelates the calcium and renders atorvastatin in its open acid form. Atorvastain acid being water insoluble is extracted and dried.lgram mole equivalent of the atorvastatin extracted as above is digested in 100 ml of ethyl acetate in a round bottom flask fitted with a magnetic stirrer. 1 gram mole equivalent of (S)-2,6-diaminohexanoic acid is added to the above ethyl acetate solution and stirred at ambient room temperature. The reactants, which were initially insoluble in ethyl acetate slowly, reacts with the atorvastatin acid and forms atorvastatin (S)-2,6- diaminohexanoic acid complex which is completely soluble in ethyl acetate solution. 'To this solution is added 1 gram mole equivalent of betaine and stirring continued till a precipitate of atorvastatin (S)-2,6- EPO <DP n="24"/>diaminohexanoic acid betaine, which is insoluble in ethyl acetate, is obtained. This precipitate Atorvastatin (S)-2,6-diaminohexanoic acid betaine is spread over in a glass tray to allow the ethyl acetate to evaporate. This atorvastain (S)-2,6-diaminohexanoic acid betaine has a solubility of 100 mg in 100ml of water and lgm in 5ml of lactic acid. As is observed the solubility of atorvastatin (S)-2,6-diaminohexanoic acid betaine in water is far superior to that of atorvastatin calcium whose solubility is documented as being "very slightly soluble" as per (US pharmacopia 2002). As per the US Pharmacopia norms " very slightly soluble" refers to aqueous solubility that ranges from 1/1000 to 1/10,000 mg per ml. Thus it is Observed that solubility of atorvastatin (S)-2,6-diaminohexanoic acid betaine has been increased a 1000-10000 folds higher over that of atorvastatin calcium.; Example 3:Preparation of an oil soluble form of atorvastatin (atorvastatin oil), which also remains as a solution without precipitating in the whole range of pH's as found in the digestive tract of an organism.Atorvastatin calcium (the form commercially available) is added to a 5% solution of Sodium EDTA in water, in a round bottom flask and stirred briskly. The Sodium EDTA chelates the calcium and renders atorvastatin in its open acid form. Atorvastain acid being water insoluble is extracted and dried.1 gram mole equivalent of beta hydroxytricarballylic acid is reacted with 3 gram moles equivalent of sulfurous oxy chloride dissolved in 100 ml of tetrahydrofuran in a round bottom flask at ambient room temperature. EPO <DP n="25"/>lgram mole equivalent each of 2-aminoethanol, 2-aminoethanol (z)-9- octadecenoiate and 2-aminoethanol bis (z)-9-octadecenoiate are added to the above solution in the round bottom flask... | |
With hydrogenchloride; In water; | The procedure described in Example 20 was repeated for atorvastatin (sodium salt; received as atorvastatin calcium as a gift from Biocon, Ltd., Bangalore, India and converted into sodium salt by firstly converting the calcium salt into the free acid by addition of aqueous hydrochloric acid and then, after isolation via extraction, adding one equivalent of aqueous NaOH). <n="43"/>Treatment of the MM6 cells with atorvastatin at a final concentration of 10 muM, 30 muM or 100 muM resulted in dose-dependent 19.9%, 27,0% and 54,4%, respectively, inhibition of MM6 proliferation (mean values, n=5 for each concentration). In contrast, treatment of the MM6 cells with pemirolast (potassium salt) at a final concentration of 100 muM resulted in a negligible mean 9.4% inhibition of proliferation (n=5) (10 muM of pemirolast had an effect very similar to that of 100 muM of pemirolast, n=5, data not shown). When the MM6 cells were treated with 100 muM pemirolast in presence of 100 muM atorvastatin, 100 muM pemirolast caused a synergistic 30.2% inhibition (mean value, n=5) of MM6 proliferation compared to the treatment with 100 muM atorvastatin alone. In the presence of 30 muM of atorvastatin, 100 muM pemirolast inhibited the proliferation by 7.6% (mean value, n=5), and in the presence 10 muM atorvastatin, 100 muM pemirolast did not inhibit proliferation (n=5, data not shown). | |
With hydrogenchloride; In water; ethyl acetate; at 20℃; | Stage I: Preparation of Atorvastatin Atorvastatin calcium (100 g) and de-ionized water (1500 ml) were stirred for 10 minutes at room temperature and pH of the slurry was adjusted to 3.5 by drop-wise addition of 1 N hydrochloric acid. The mixture was stirred for 10 minutes at room temperature and ethyl acetate (1000 ml) was added to the mixture. The mixture was further stirred for 10 minutes and the pH of the solution was adjusted to 5.5 by the addition of hydrochloric acid. After stirring of 10 minutes, a clear solution was obtained. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (500 ml). The combined layer was washed with 1N hydrochloric acid (100 ml) followed by aqueous sodium chloride solution (20 %, 300 ml). The organic layer was concentrated completely under reduced pressure at 30C. Methanol (2 X 100 ml) was added to the concentrated mass and recovered completely under reduced pressure to obtain the title compound as a residue. | |
With hydrogenchloride; In water; ethyl acetate; at 20℃;pH 3.5 - 5.5; | Example 1; Preparation of Form Z of Atorvastatin MagnesiumStage I: Preparation of AtorvastatinAtorvastatin calcium (100 g) and de-ionized water (1500 ml) were stirred for 10 minutes at room temperature and pH of the slurry was adjusted to 3.5 by drop-wise addition of 1 N hydrochloric acid. The mixture was stirred for 10 minutes at room temperature and ethyl acetate (1000 ml) was added to the mixture. The mixture was further stirred for 10 minutes and the pH of the solution was adjusted to 5.5 by the addition of hydrochloric acid. After stirring of 10 minutes, a clear solution was obtained. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (500 ml). The combined layer was washed with 1N hydrochloric acid (100 ml) followed by aqueous sodium chloride solution (20%, 300 ml). The organic layer was concentrated completely under reduced pressure at 30 C. Methanol (2×100 ml) was added to the concentrated mass and recovered completely under reduced pressure to obtain the title compound as a residue. | |
With water; edetate disodium;Product distribution / selectivity; | EXAMPLES; Example 1; Preparation of an Oil Soluble Form of Atorvastatin; Atorvastatin calcium (the form commercially available) is added to a 5% solution of Sodium EDTA in water, in a round bottom flask and stirred briskly. The Sodium EDTA chelates the calcium and renders atorvastatin in its open acid form. Atorvastatin acid being water insoluble is extracted and dried.; Example 2; Preparation of Water-Soluble Form of Atorvastatin Namely Atorvastatin (S)-2,6-diaminohexanoic Acid Betaine; Atorvastatin calcium (the form commercially available) is added to a 5% solution of Sodium EDTA in water, in a round bottom flask and stirred briskly. The Sodium EDTA chelates the calcium and renders atorvastatin in its open acid form. Atorvastatin acid being water insoluble is extracted and dried.; Example 3; Preparation of an Oil Soluble Form of Atorvastatin (Atorvastatin Oil), which Also Remains as a Solution without Precipitating in the Whole Range of pH's as Found in the Digestive Tract of an Organism; Atorvastatin calcium (the form commercially available) is added to a 5% solution of Sodium EDTA in water, in a round bottom flask and stirred briskly. The Sodium EDTA chelates the calcium and renders atorvastatin in its open acid form. Atorvastatin acid being water insoluble is extracted and dried. |
Yield | Reaction Conditions | Operation in experiment |
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In ethyl acetate;Product distribution / selectivity; | Example 1; To a solution of <strong>[134523-00-5]atorvastatin</strong> free acid (10 G, 0.018 mol) in ethyl acetate (200 ML), ranitidine free base (5.7 g, 0.018 mol) was added and stirred. The reaction mixture was concentrated to about 50 ml and chilled to 10 C to afford the mutual salt of <strong>[134523-00-5]atorvastatin</strong> and ranitidine | |
In methanol; 2-methylpropyl acetate;Product distribution / selectivity; | Example 2; To a solution of <strong>[134523-00-5]atorvastatin</strong> free acid (10 G, 0. 018 mol) in isobutyl acetate (200 ML), a solution of ranitidine free base (5.7 G, 0.018 mol), in methanol (20 ml.) was added and stirred. The reaction mixture was concentrated to about 50 ml and diisopropyl ether (50 ML) was added to afford the mutual salt of <strong>[134523-00-5]atorvastatin</strong> and ranitidine |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethyl acetate;Product distribution / selectivity; | Example 1; To a solution of <strong>[134523-00-5]atorvastatin</strong> free acid (10 g, 0. 018 mol) in ethyl acetate (200 ML), metformin free base (2.3 g, 0.018 mol) was added and stirred. The reaction mixture was concentrated to about 25 ml and chilled to 10 C to afford the mutual salt of <strong>[134523-00-5]atorvastatin</strong> and metformin. | |
In ethanol; 2-methylpropyl acetate;Product distribution / selectivity; | Example 2; To a solution of <strong>[134523-00-5]atorvastatin</strong> free acid (10 g, 0. 018 mol) in isobutyl acetate (200 ML), a solution of metformin free base (2.3 g, 0.018 mol), in ethanol (10 ml) was added and stirred. The reaction mixture was concentrated to about 25 ml and diisopropyl ether (25 ml) was added to afford the mutual salt of <strong>[134523-00-5]atorvastatin</strong> and metformin |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; | The present invention is illustrated by way the following non-limiting drawings in which: Figure 1 is a schematic showing a process of preparing ascorbyl sitostanyl or campestanyl <strong>[134523-00-5]atorvastatin</strong> phosphate ester and its sodium SALT; Figure 2 is a schematic showing a process of preparing ascorbyl sitostanyl or campestanyl simavastatin phosphate ester and its sodium salt; Figure 3 is a schematic showing a process of preparing sitostanyl or campestanyl simavastatin phosphate ester; and Figure 4 is a schematic showing a process of preparing sitostanyl or campestanyl <strong>[134523-00-5]atorvastatin</strong> carboxylic ester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; | The present invention is illustrated by way the following non-limiting drawings in which: Figure 1 is a schematic showing a process of preparing ascorbyl sitostanyl or campestanyl <strong>[134523-00-5]atorvastatin</strong> phosphate ester and its sodium SALT; Figure 2 is a schematic showing a process of preparing ascorbyl sitostanyl or campestanyl simavastatin phosphate ester and its sodium salt; Figure 3 is a schematic showing a process of preparing sitostanyl or campestanyl simavastatin phosphate ester; and Figure 4 is a schematic showing a process of preparing sitostanyl or campestanyl <strong>[134523-00-5]atorvastatin</strong> carboxylic ester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; | The present invention is illustrated by way the following non-limiting drawings in which: Figure 1 is a schematic showing a process of preparing ascorbyl sitostanyl or campestanyl <strong>[134523-00-5]atorvastatin</strong> phosphate ester and its sodium SALT; Figure 2 is a schematic showing a process of preparing ascorbyl sitostanyl or campestanyl simavastatin phosphate ester and its sodium salt; Figure 3 is a schematic showing a process of preparing sitostanyl or campestanyl simavastatin phosphate ester; and Figure 4 is a schematic showing a process of preparing sitostanyl or campestanyl <strong>[134523-00-5]atorvastatin</strong> carboxylic ester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; | The present invention is illustrated by way the following non-limiting drawings in which: Figure 1 is a schematic showing a process of preparing ascorbyl sitostanyl or campestanyl <strong>[134523-00-5]atorvastatin</strong> phosphate ester and its sodium SALT; Figure 2 is a schematic showing a process of preparing ascorbyl sitostanyl or campestanyl simavastatin phosphate ester and its sodium salt; Figure 3 is a schematic showing a process of preparing sitostanyl or campestanyl simavastatin phosphate ester; and Figure 4 is a schematic showing a process of preparing sitostanyl or campestanyl <strong>[134523-00-5]atorvastatin</strong> carboxylic ester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; at 20℃; for 96h; | EXAMPLE 4; [R-(R*, R*)]-2-(4-Fluorophenyl)-a,s-dihydroxy-5-(1-methylethyl)-3-phenyl-4- [(phenylamino) carbonyl]-1H-pyrrole-1-heptanoic acid,N-(phenylmethyl)benzenemethanamine (<strong>[134523-00-5]atorvastatin</strong> dibenzylamine);. The dibenzylamine salt of <strong>[134523-00-5]atorvastatin</strong> was synthesized by preparing a stock solution of the free acid of <strong>[134523-00-5]atorvastatin</strong> (US 5,273,995) in acetonitrile (1 g in 40 mL of ACN). A solution of dibenzylamine was prepared by dissolving 351.05 mg (1.0 equivalents) in acetonitrile (100 mL). The stock solution of <strong>[134523-00-5]atorvastatin</strong> free acid was added to the counterion solution with stirring. Over time, additional acetonitrile was added to prevent formation of a gel (100 mL), and the solid was allowed to stir. After 4 days of stirring at ambient temperature, the solids were isolated by vacuum filtration using a Buchner funnel fitted with a paper filter (No.2 Whatman). The solids were rinsed with acetonitrile (75 mL), and placed in a 25C oven under nitrogen to dry overnight to afford <strong>[134523-00-5]atorvastatin</strong> dibenzylamine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; at 20℃; for 96 - 144h;Product distribution / selectivity; | EXAMPLE 12; [R-(R*, R*)]-2-(4-Fluorophenyl)-p,6-dihydroxy-5-(1 -methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-1 H-pyrrole-1-heptanoic acid, 2-amino-2-methylpropan-1-ol (<strong>[134523-00-5]atorvastatin</strong> 2-amino- 2-methylpropan-1-ol);. Method A;The 2-amino-2-methylpropan-1-ol salt of <strong>[134523-00-5]atorvastatin</strong> was synthesized by preparing a stock solution of the free acid of <strong>[134523-00-5]atorvastatin</strong> (US 5,273,995) in acetonitrile (0.8 g in 25 mL of ACN). A solution of 2-amino-2-methylpropan-1-ol was prepared by dissolving 6.1 mg of 2-amino-2-methylpropan-1- ol (1 equivalents) in 0.5 mL of acetonitrile. The stock solution of <strong>[134523-00-5]atorvastatin</strong> free acid (1.21 mL) was added to the counterion solution with stirring. If a gel formed, additional acetonitrile was added as necessary. After 6 days of stirring at ambient temperature, the solids were isolated by vacuum filtration using a 0.45 mum nylon 66 membrane filter. The solids were rinsed with acetonitrile and air dried at ambient conditions to afford atoravastatin 2-amino-2-methylpropan-1-ol. Method B - The 2-amino-2-methylpropan-1-ol salt of <strong>[134523-00-5]atorvastatin</strong> was synthesized by preparing a stock solution of the free acid of <strong>[134523-00-5]atorvastatin</strong> (US 5,273,995) in acetonitrile (1 g in 40 mL of ACN). A solution of 2-amino-2-methylpropan-1-ol was prepared by dissolving 173.08 mg (1.1 equivalents) in acetonitrile (100 mL). The stock solution of <strong>[134523-00-5]atorvastatin</strong> free acid was added to the counterion solution with stirring. Seed crystals of the 2-amino-2-methylpropan-1-ol salt were added. Over time, additional acetonitrile was added to aid in stirring (100 mL), and the solid was allowed to stir. After 4 days of stirring at ambient temperature, the solids were isolated by vacuum filtration using a Buchner funnel fitted with a paper filter (No.2 Whatman). The solids were rinsed with acetonitrile (75 mL), and placed in a 25C oven under nitrogen to dry for two days to afford <strong>[134523-00-5]atorvastatin</strong> 2-amino-2-methylpropan-1-ol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; at 20℃; for 72h; | EXAMPLE 8; [R-(R*, R*)]-2-(4-Fluorophenyl)-[3,b-dihydroxy-5-(1-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-1 H-pyrrole-1-heptanoic acid, tetrahydro-2H-1,4-oxazine (<strong>[134523-00-5]atorvastatin</strong> morpholine);. The morpholine salt of <strong>[134523-00-5]atorvastatin</strong> was synthesized by preparing a stock solution of the free acid of <strong>[134523-00-5]atorvastatin</strong> (US 5,273,995) in acetonitrile (1 g in 40 mL of ACN). A solution of morpholine was prepared by dissolving 160.28 mg (1.1 equivalents) in acetonitrile (100 mL). The stock solution of <strong>[134523-00-5]atorvastatin</strong> free acid was added to the counterion solution with stirring. No salt formed, so the solution was evaporated under N2 until a white solid formed. Acetonitrile was then added to the solid (50 mL), and the solid was allowed to stir. After 3 days of stirring at ambient temperature, the solids were isolated by vacuum filtration using a Buchner funnel fitted with a paper filter (No.2 Whatman). The solids were rinsed with acetonitrile (25 mL), and placed in a 25C oven under nitrogen to dry overnight to afford <strong>[134523-00-5]atorvastatin</strong> morpholine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; at 20℃; for 120h; | EXAMPLE 5 [R-(R*,R*)]-2-(4-Fluorophenyl)-(3,5-dihydroxy-5-(1-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-1 H-pyrrole-1-heptanoic acid,N-ethylethanamine (<strong>[134523-00-5]atorvastatin</strong> diethylamine);. Method A; The diethylamine salt of <strong>[134523-00-5]atorvastatin</strong> (Form A) was synthesized by preparing a stock solution of the free acid of <strong>[134523-00-5]atorvastatin</strong> (US 5,273,995) in acetonitrile (1 g in 40 mL of ACN). A solution of diethylamine was prepared by dissolving 132.33 mg (1.0 equivalents) in acetonitrile (20 mL). The stock solution of <strong>[134523-00-5]atorvastatin</strong> free acid was added to the counterion solution with stirring. Over time, an additional 40 mL of acetonitrile was added to prevent the formation of a gel. After 5 days of stirring at ambient temperature, the solids were isolated by vacuum filtration using a Buchner funnel fitted with a paper filter (No.2 Whatman). The solids were rinsed with acetonitrile (75 mL), and placed in a 25C oven under nitrogen to dry overnight to afford <strong>[134523-00-5]atorvastatin</strong> diethylamine Form A. | |
In acetonitrile; at 20℃; for 120h; | Method B:; The diethylamine salt of <strong>[134523-00-5]atorvastatin</strong> (Form B) was synthesized by preparing a stock solution of the free acid of <strong>[134523-00-5]atorvastatin</strong> (US 5,273,995) in acetonitrile (1 g in 40 mL of ACN). A solution of diethylamine was prepared by dissolving 132.33 mg (1.0 equivalents) in acetonitrile (20 mL). The stock solution of <strong>[134523-00-5]atorvastatin</strong> free acid was added to the counterion solution with stirring. Over time, an additional 40 mL of acetonitrile was added to prevent the formation of a gel. After 5 days of stirring at ambient temperature, the solids were isolated by vacuum filtration using a Buchner funnel fitted with a paper filter (No.2 Whatman). The solids were rinsed with acetonitrile (75 mL) to afford <strong>[134523-00-5]atorvastatin</strong> diethylamine Form B. Note that this procedure is the same as above except that the sample was not oven dried. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With calcium hydroxide; In water; acetone; at 25℃; for 5.25h; | Calcium hydroxide (133 mg) is suspended in acetone (15 mL) and water (10 mL) and stirred for 15 minutes. The free acid of <strong>[134523-00-5]atorvastatin</strong> (US 5,273,995) (1.0 g) is added to this suspension followed by 218 mg of benzoic acid. The reaction is stirred for 5 hours at 25C and evaporated to dryness under vacuum to afford <strong>[134523-00-5]atorvastatin</strong> mono-calcium benzoate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With calcium hydroxide; In ethanol; water; at 25℃; for 5.25h;Product distribution / selectivity; | Calcium hydroxide (133 mg) is suspended in ethanol (15 mL) and water (10 mL) and stirred for 15 minutes. The free acid of <strong>[134523-00-5]atorvastatin</strong> (US 5,273,995) (1.0 g) is added to this suspension followed by 107 mg of acetic acid. The reaction is stirred for 5 hours at 25C and evaporated to dryness under vacuum to afford <strong>[134523-00-5]atorvastatin</strong> mono-calcium acetate. | |
With calcium hydroxide; In water; at 25℃; for 5.25h;Product distribution / selectivity; | Calcium hydroxide (133 mg) is suspended in acetic acid (1 mL) and water (20 mL) and stirred for 15 minutes. The free acid of <strong>[134523-00-5]atorvastatin</strong> (US 5,273,995) (1.0 g) is added to this suspension. The reaction is stirred for 5 hours at 25C and evaporated to dryness under vacuum to afford <strong>[134523-00-5]atorvastatin</strong> mono-calcium acetate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; at 20℃; for 120h; | EXAMPLE 6 [R-(R*, R*)]-2-(4-Fluorophenyl)-a,b-dihydroxy-5-(1-methylethyl)-3-phenyl-4- [(phenylamino) carbonyl]-1H-pyrrole-1-heptanoic acid, tertiary-butylamine (<strong>[134523-00-5]atorvastatin</strong> erbumine); The erbumine salt of <strong>[134523-00-5]atorvastatin</strong> was synthesized by preparing a stock solution of the free acid of <strong>[134523-00-5]atorvastatin</strong> (US 5,273,995) in acetonitrile (1 g in 40 mL of ACN). A solution of tert-butylamine (erbumine) was prepared by dissolving 128.00 mg (1.0 equivalents) in acetonitrile (10 mL). The stock solution of <strong>[134523-00-5]atorvastatin</strong> free acid was added to the counterion solution with stirring. Over time, an additional 120 mL of acetonitrile was added to prevent the formation of a gel. After 5 days of stirring at ambient temperature, the solids were isolated by vacuum filtration using a Buchner funnel fitted with a paper filter (No.2 Whatman). The solids were rinsed with acetonitrile (75 mL), and placed in a 25C oven under nitrogen to dry overnight to afford <strong>[134523-00-5]atorvastatin</strong> erbumine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In isopropyl alcohol; at 20℃; for 168h; | EXAMPLE 10; [R-(R*, R*)]-2-(4-Fluorophenyl)-ss;,No.-dihydroxy-5-(1-methylethyl)-3-phenyl-4- [(phenylamino) carbonyl]-1H-pyrrole-1-heptanoic acid, piperazine (<strong>[134523-00-5]atorvastatin</strong> piperazine); The piperazine salt of <strong>[134523-00-5]atorvastatin</strong> was synthesized by preparing a stock solution of the free acid of <strong>[134523-00-5]atorvastatin</strong> (US 5,273,995) in isopropyl alcohol (2.577 g in 50 mL of IPA). A solution of piperazine was prepared by dissolving 14.4 mg (1.0 equivalents) in isopropyl alcohol (1 mL). The stock solution of <strong>[134523-00-5]atorvastatin</strong> free acid (1.85mL) was added to the counterion solution with stirring. After 7 days of stirring at ambient temperature, the solids were isolated by vacuum filtration using a 0.45 mum nylon 66 membrane filter. The solids were rinsed with isopropyl alcohol and air dried at ambient conditions to afford <strong>[134523-00-5]atorvastatin</strong> piperazine |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; at 20℃; for 96 - 144h;Product distribution / selectivity; | EXAMPLE 9; [R-(R*, R*)]-2-(4-Fluorophenyl)-ss;,No.-dihydroxy-5-(1-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-1 H-pyrrole-1-heptanoic acid, 2-aminoethanol (<strong>[134523-00-5]atorvastatin</strong> olamine);Method A; The olamine salt of <strong>[134523-00-5]atorvastatin</strong> was synthesized by preparing a stock solution of the free acid of <strong>[134523-00-5]atorvastatin</strong> (US 5,273,995) in acetonitrile (0.8 g in 25 mL of ACN). A solution of olamine was prepared by dissolving 15.0 mg of olamine (-2.7 equivalents) in 0.5 mL of acetonitrile. The stock solution of <strong>[134523-00-5]atorvastatin</strong> free acid (3.0 mL) was added to the counterion solution with stirring. If a gel formed, additional acetonitrile was added as necessary. After 6 days of stirring at ambient temperature, the solids were isolated by vacuum filtration using a 0.45 mum nylon 66 membrane filter. The solids were rinsed with acetonitrile and air dried at ambient conditions to afford <strong>[134523-00-5]atorvastatin</strong> olamine;Method B; - The olamine salt of <strong>[134523-00-5]atorvastatin</strong> was synthesized by preparing a stock solution of the free acid of <strong>[134523-00-5]atorvastatin</strong> (US 5,273,995) in acetonitrile (1 g in 40 mL of ACN). A solution of 2- aminoethanol (olamine) was prepared by dissolving 139.77 mg (1.1 equivalents) in acetonitrile (100 mL). The stock solution of <strong>[134523-00-5]atorvastatin</strong> free acid was added to the counterion solution with stirring. Seed crystals of the olamine salt were added. Over time, additional acetonitrile was added to aid in stirring (300 mL), and the solid was allowed to stir. After 4 days of stirring at ambient temperature, the solids were isolated by vacuum filtration using a Buchner funnel fitted with a paper filter (No.2 Whatman). The solids were rinsed with acetonitrile (75 mL), and placed in a 25C oven under nitrogen to dry for two days to afford <strong>[134523-00-5]atorvastatin</strong> olamine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In water; acetonitrile; at 20℃; for 144h; | EXAMPLE 11; [R-(R*, R*)]-2-(4-Fluorophenyl)-ss;,No.-dihydroxy-5-(1-methylethyl)-3-phenyl-4- [(phenylamino) carbonyl]-1H-pyrrole-1-heptanoic acid, sodium (<strong>[134523-00-5]atorvastatin</strong> sodium); The sodium salt of <strong>[134523-00-5]atorvastatin</strong> was synthesized by preparing a stock solution of the free acid of <strong>[134523-00-5]atorvastatin</strong> (US 5,273,995) in acetonitrile (0.634 g in 25 mL of ACN). A solution was prepared by dissolving 2.67 mg of sodium hydroxide (1.0 equivalents) in 0.5 mL of acetonitrile and 0.05 mL of water. The stock solution of <strong>[134523-00-5]atorvastatin</strong> free acid (1.55 mL) was added to the counterion solution with stirring. If a gel formed, additional acetonitrile and water was added as necessary. After 6 days of stirring at ambient temperature, the solids were isolated by vacuum filtration using a 0.45 mum nylon 66 membrane filter. The solids were rinsed with acetonitrile and air dried at ambient conditions to afford <strong>[134523-00-5]atorvastatin</strong> sodium. | |
With sodium hydroxide; In water; | (b) To an aqueous solution of sodium salt of acid of Formula IX (prepared by adding 1 equivalent IN sodium hydroxide solution), an aqueous solution (1M) of calcium acetate (0.55 equiv) was added drop wise. A white precipitate was obtained which was filtered off and washed with a copious amount of water, and dried in vacuum. | |
With sodium hydroxide; In water; | The procedure described in Example 20 was repeated for <strong>[134523-00-5]atorvastatin</strong> (sodium salt; received as <strong>[134523-00-5]atorvastatin</strong> calcium as a gift from Biocon, Ltd., Bangalore, India and converted into sodium salt by firstly converting the calcium salt into the free acid by addition of aqueous hydrochloric acid and then, after isolation via extraction, adding one equivalent of aqueous NaOH). <n="43"/>Treatment of the MM6 cells with <strong>[134523-00-5]atorvastatin</strong> at a final concentration of 10 muM, 30 muM or 100 muM resulted in dose-dependent 19.9%, 27,0% and 54,4%, respectively, inhibition of MM6 proliferation (mean values, n=5 for each concentration). In contrast, treatment of the MM6 cells with pemirolast (potassium salt) at a final concentration of 100 muM resulted in a negligible mean 9.4% inhibition of proliferation (n=5) (10 muM of pemirolast had an effect very similar to that of 100 muM of pemirolast, n=5, data not shown). When the MM6 cells were treated with 100 muM pemirolast in presence of 100 muM <strong>[134523-00-5]atorvastatin</strong>, 100 muM pemirolast caused a synergistic 30.2% inhibition (mean value, n=5) of MM6 proliferation compared to the treatment with 100 muM <strong>[134523-00-5]atorvastatin</strong> alone. In the presence of 30 muM of <strong>[134523-00-5]atorvastatin</strong>, 100 muM pemirolast inhibited the proliferation by 7.6% (mean value, n=5), and in the presence 10 muM <strong>[134523-00-5]atorvastatin</strong>, 100 muM pemirolast did not inhibit proliferation (n=5, data not shown). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With calcium chloride; In water; at 20 - 25℃; for 0.583333 - 0.916667h; | To a solution of 1 g of [R-(R*,R*)]-2-(4-fluorophenyl)-ss;,No.- dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)- carbonyl] -1H-pyrrole-1-heptanoic acid tertiary butyl ester (II) (1.62 mmol) in 3.4 mL of methanol and 2.8 mL of tert- butyl methyl ether, 68.4 mg of NaOH (1.7 mmol, 1.05 equiva- lent) and 5.8 mL of water are added. The reaction mixture is purged with a nitrogen flow for about 5 minutes and heated to the reflux for 2-4 h, until the concentration of starting [R- (R*, R* ) ] -2- ( 4-f luorophenyl ) -(at)i, 8-dihydroxy-5- ( 1-methylethyl ) -3- phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l-heptanoic acid tertiary butyl ester (II) is lower than 0.5%, determined with HPLC method. The reaction mixture is allowed to cool to 20-25 C, active charcoal is added, and the reaction mixture is stirred for ad- ditional 30 min. The reaction mixture is filtered and the pH of the filtrate is set to 8.0-8.2 by the addition of HC1. The reaction mixture is washed with 3 x 2.9 mL of tert-butyl methyl ether and aqueous phases are finally filtered. The re- action mixture is purged with nitrogen flow for about 5 min and 0.179 g of CaCl2 (0,82 mmol of CaCl2-6H20) and 6.8 mL of water are 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. Then 6 mL of water is slowly added into the reaction mixture to provoke the solidification of the thick emulsion-like mixture. Hemi-calcium salt of <strong>[134523-00-5]atorvastatin</strong> is formed in the form of particles having a size in the range of mm to several mm which show improved filterability. The precipitate is filtered off after 30 min. The wet cake is washed with water. Collected solid material is dried on air to obtain dry solid <strong>[134523-00-5]atorvastatin</strong> hemi-calcium. Example 8 To the solution of 9.22 g of [R-(R*,R*)]-2-(4-fluorophenyl)- beta,delta-dihydroxy-5- (l-methylethyl)-3-phenyl-4-[(phenylamino)- carbonyl]-lH-pyrrole-l-heptanoic acid tertiary butyl ester (II) (15 mmol) in 61 mL of methanol and 52 mL tert-butyl methyl ether, 0.63 g of NaOH (15.7 mmol, 1.05 equivalent) and 104 mL of water are added. The reaction mixture is purged with a nitrogen flow for about 5 minutes and heated to the reflux for 2-4 h, until the concentration of the starting compound [R-(R*, R*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)- 3-phenyl-4- [(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid tertiary butyl ester (II) is lower than 0.5 %, determined by HPLC. The reaction mixture is allowed to cool to 20-25 C and the pH is set to 8.0-8.2 by the addition of HC1. The reaction mixture is washed with 3 x 26 mL of tert-butyl methyl ether and aque- ous phases are finally filtered. The reaction mixture is purged with a nitrogen flow for about 5 min, and 1.80 g of CaCl2 (8.2 mmol of CaC12.6H20) and 64 mL of water are 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 270 mL of water is slowly added into the reaction mix- ture to provoke the solidification of the thick emulsion-like mixture. Hemi-calcium salt of <strong>[134523-00-5]atorvastatin</strong> is formed in the form of granules, which show improved filterability. The pre- cipitate is filtered off and the wet cake is washed with a mixture of water and methanol and finally with water. The col- lected solid material is dried on air to obtain dry solid <strong>[134523-00-5]atorvastatin</strong> hemi-calcium._:The dry hemi-calcium salt of <strong>[134523-00-5]atorvastatin</strong> can optionally be additionally milled on a dry pearl mill. Example 9 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 %)... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With calcium hydroxide; water; In methanol;Heating / reflux;Product distribution / selectivity; | A 25 mL reaction tube was charged with water (1.3 mL) and calcium hydroxide (13.3 mg, 0.00018 moles, 1.0 equiv). <strong>[134523-00-5]Atorvastatin</strong> free acid (US 5,273,995) (100 mg, 0.00018 moles, 1.0 equiv. ) and methanol (3 mL) were added to give a thick suspension. The resulting slurry was heated to reflux. The suspension was evaporated to dryness under vacuum on a rotary evaporator to afford a white solid. The solid was dried in a vacuum oven at 50 to 55 C to yield <strong>[134523-00-5]atorvastatin</strong> mono-calcium hydroxide as a white solid (84.9 mg, 88% yield). |
68% | With calcium hydroxide; water; In acetone; at 20 - 25℃; for 50.0333h;Product distribution / selectivity; | A 25 mL reaction tube was charged with water (0.5 mL) and calcium hydroxide (13.2 mg, 0.000178 moles, 1.0 equiv). The mixture was stirred at 20 to 25C. A solution of <strong>[134523-00-5]atorvastatin</strong> free acid (US 5,273,995) (100 mg, 0.000178 moles, 1.0 equiv) dissolved in acetone (0.5 mL) was added dropwise by pipette over about 2 minutes into the aqueous suspension. The resulting slurry was stirred at 20 to 25C for about 48 hours under a nitrogen blanket. Water (2.0 mL) was added to the slury and the mixture was allowed to stir for an additional 2 hours. The product solids were isolated by filtration on a paper filter covered Buchner funnel. The solids were washed twice with room temperature water (2 x 2 mL). The solids were dried under vacuum at 50 to 55C in an oven to yield <strong>[134523-00-5]atorvastatin</strong> mono-calcium hydroxide as a white solid (75 mg, 68% yield). |
With sodium hydroxide; calcium acetate; In tert-butyl methyl ether; water; isopropyl alcohol; for 24h;Product distribution / selectivity; | The free acid of <strong>[134523-00-5]atorvastatin</strong> (US 5,273,995) (1.0g) is dissolved in methyl t-butyl ether (25 ml) and added dropwise to a solution of calcium acetate (311 mg) in water (15 mL) and isopropanol (10 mL). Sodium hydroxide (158 mg) in water (1.0 mL) is added and the contents are stirred for 24 hours. The methyl t-butyl ether is removed under vacuum and the resulting solid is filtered and in water (10 mL) for 24 hours. The solid is dried under vacuum to yield <strong>[134523-00-5]atorvastatin</strong> mono-calcium hydroxide. |
With sodium hydroxide; calcium chloride; In water; at 20 - 80℃; for 21.5h;Product distribution / selectivity; | The free acid of <strong>[134523-00-5]atorvastatin</strong> (US 5,273,995) (1.0 g) is added to a solution of water (10 mL) and sodium hydroxide (144 mg) at ambient temperature. After stirring for 30 minutes a solution of calcium chloride (200 mg) in water (20 mL) is added dropwise over three hours. The temperature is then raised to 50 to 80 and the contents vigorously stirred for 18 hours. Upon cooling the solid is filtered and dried to provide <strong>[134523-00-5]atorvastatin</strong> mono-calcium hydroxide. |
Yield | Reaction Conditions | Operation in experiment |
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With ammonia; In water; acetonitrile; at 20℃; for 48h; | EXAMPLE 1; [R-(R*,R*)]-2-(4-Fluorophenyl)-[3,8-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1 H- pyrrole-1-heptanoic acid, ammonium salt (<strong>[134523-00-5]atorvastatin</strong> ammonium);. The ammonium salt of <strong>[134523-00-5]atorvastatin</strong> was synthesized by preparing a stock solution of the free acid of <strong>[134523-00-5]atorvastatin</strong> (US 5,273,995) in acetonitrile (ACN) (0.634 g in 25 mL of ACN). A solution was prepared by dissolving 12.04 mg of ammonium hydroxide (1.0 equivalents) in acetonitrile (0.5 mL). The stock solution of <strong>[134523-00-5]atorvastatin</strong> free acid (2.24 mL) was added to the counterion solution with stirring. If a gel formed, additional acetonitrile and water was added as necessary. After 2 days of stirring at ambient temperature, the solids were isolated by vacuum filtration using a 0.45 mum nylon 66 membrane filter. The solids were rinsed with acetonitrile and air dried at ambient conditions to afford <strong>[134523-00-5]atorvastatin</strong> ammonium. |
Yield | Reaction Conditions | Operation in experiment |
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In acetonitrile; at 20℃; for 120h; | EXAMPLE 2; [R-(R*,R*)]-2-(4-Fluorophenyl)-[i,8-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1 H- pyrrole-1-heptanoic acid, N-benzyl-2-phenylethylamine (<strong>[134523-00-5]atorvastatin</strong> benethamine).; Method A;: The benethamine salt of <strong>[134523-00-5]atorvastatin</strong> (Form A) was synthesized by preparing a stock solution of the free acid of <strong>[134523-00-5]atorvastatin</strong> (US 5,273,995) in acetonitrile (1 g in 40 mL of ACN). A solution of N-benzyl-2-phenylethylamine (benethamine) was prepared by dissolving 378.59 mg (1.0 equivalents) in acetonitrile (10 mL). The stock solution of <strong>[134523-00-5]atorvastatin</strong> free acid was added to the counterion solution with stirring. Over time, an additional 40 mL of acetonitrile was added to prevent the formation of a gel. After 5 days of stirring at ambient temperature, the solids were isolated by vacuum filtration using a Buchner funnel fitted with a paper filter (No.2 Whatman). The solids were rinsed with acetonitrile (75 mL), and placed in a 25C oven under nitrogen to dry overnight to afford <strong>[134523-00-5]atorvastatin</strong> benethamine Form A. | |
In isopropyl alcohol; at 20℃; for 168h; | Method B; The benethamine salt of <strong>[134523-00-5]atorvastatin</strong> (Form B) was synthesized by preparing a stock solution of the free acid of <strong>[134523-00-5]atorvastatin</strong> (US 5,273,995) in 2-propanol (IPA) (1 g in 40 mL of IPA). A solution of N-benzyl-2-phenylethylamine (benethamine) was prepared by dissolving 388.68 mg (1.1 equivalents) in 2-propanol (100 mL). The stock solution of <strong>[134523-00-5]atorvastatin</strong> free acid was added to the counterion solution with stirring. Seed crystals of the benethamine salt were added. The mixture was reduced to a wet solid under a nitrogen bleed, and the resulting solids were slurried in 2-propanol (40 mL). After 7 days of stirring at ambient temperature, the solids were isolated by vacuum filtration using a Buchner funnel fitted with a paper filter (No.2 Whatman). The solids were rinsed with 2-propanol (25 mL), and placed in a 25C oven under nitrogen to dry overnight to afford <strong>[134523-00-5]atorvastatin</strong> benethamine Form B. |
Yield | Reaction Conditions | Operation in experiment |
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In water; acetonitrile; at 20℃; for 48h; | EXAMPLE 3; [R-(R*,R*)]-2-(4-Fluorophenyl)-(3,S-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1 H- pyrrole-1-heptanoic acid,N,N¹-bis (phenylmethyl)-1,2-ethanediamine (<strong>[134523-00-5]atorvastatin</strong> benzathine).; Method A:; The benzathine salt of <strong>[134523-00-5]atorvastatin</strong> (Form A) was synthesized by preparing a stock solution of the free acid of <strong>[134523-00-5]atorvastatin</strong> (US 5,273,995) in acetonitrile (1 g in 40 mL of ACN). A solution of N,N'-bis(phenylmethyl)-1,2-ethanediamine (benzathine) was prepared by dissolving 220.64 mg (0.5 equivalents) in acetonitrile (80 mL) and water (20 mL). The stock solution of <strong>[134523-00-5]atorvastatin</strong> free acid was added to the counterion solution with stirring. After 2 days of stirring at ambient temperature, the solids were isolated by vacuum filtration using a Buchner funnel fitted with a paper filter (No.2 Whatman). The solids were rinsed with acetonitrile (75 mL), and placed in a 25C oven under nitrogen to dry overnight to afford benzathine Form A. | |
In water; acetonitrile; at 20℃; for 48h; | Method B:; The benzathine salt of <strong>[134523-00-5]atorvastatin</strong> (Form B) was synthesized by preparing a stock solution of the free acid of <strong>[134523-00-5]atorvastatin</strong> (US 5,273,995) in acetonitrile (1 g in 40 mL of ACN). A solution of N,N'-bis(phenylmethyl-1,2-ethanediamine (benzathine) was prepared by dissolving 220.64 mg (0.5 equivalents) in acetonitrile (80 mL) and water (20 mL). The stock solution of <strong>[134523-00-5]atorvastatin</strong> free acid was added to the counterion solution with stirring. After 2 days of stirring at ambient temperature, the solids were isolated by vacuum filtration using a Buchner funnel fitted with a paper filter (No.2 Whatman). The solids were rinsed with acetonitrile (75 mL) to afford <strong>[134523-00-5]atorvastatin</strong> benzathine Form B. Note that this procedure is the same as above except that the sample was not oven dried. |
Yield | Reaction Conditions | Operation in experiment |
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95% | In ethyl acetate; at 25℃; for 24h; | 2.38 g (14.5 mmol) of L-lysine monohydrate is added to the solution of <strong>[134523-00-5]atorvastatin</strong> acid in ethyl acetate and the obtained suspension is stirred at 25 C for 24 h. The crystalline product is filtered off and washed with 30 ml of ethyl acetate twice to yield 10.21 g (95 %) of the title compound. The characteristic bands of its infrared spectrum are the following: 3643,3322, 1646,1583, 1423,1084, 775, 699 cm' the characteristic bands of its Raman spectrum are as follows: 2981, 1647,1480, 734,677, 635,513, 200 cni 1. Mp. : 141 C (decomp. ) |
72% | In dichloromethane; at 25℃; for 24h; | 0.39 g (2.67 mmol) of L-lysine monohydrate is added to the solution of <strong>[134523-00-5]atorvastatin</strong> acid in dichloromethane and the obtained suspension is stirred at 25 C for 24 h. The crystalline product is filtered off and washed with 10 ml of dichloromethane twice to yield 1.53 g (72 %) of the title compound. The characteristic bands of its infrared spectrum are the following: 1648,1596, 1559,1530, 1220,916, 886,808, 749,732, 690,616, 507 cm the characteristic bands of its Raman spectrum are as follows: 3062,2922, 1648,1604, 1530,1481, 1244,1159, 999,820 cm-l. |
In isopropyl alcohol; at 20℃; for 168h; | EXAMPLE 7; [R-(R*, R*)]-2-(4-Fluorophenyl)-ss;,No.-dihydroxy-5-(1-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-1 H-pyrrole-1-heptanoic acid, L-lysine (<strong>[134523-00-5]atorvastatin</strong> L-lysine);. The L-lysine salt of <strong>[134523-00-5]atorvastatin</strong> was synthesized by preparing a stock solution of the free acid of <strong>[134523-00-5]atorvastatin</strong> (US 5,273,995) in isopropyl alcohol (IPA) (2.577 g in 50 mL of IPA). A solution of L-lysine was prepared by dissolving 28.0 mg (1.0 equivalents) in isopropyl alcohol (1 mL). The stock solution of <strong>[134523-00-5]atorvastatin</strong> free acid (2.08 mL) was added to the counterion solution with stirring. After 7 days of stirring at ambient temperature, the solids were isolated by vacuum filtration using a 0.45 mum nylon 66 membrane filter. The solids were rinsed with IPA and allowed to air dry at ambient temperature to afford L-lysine |
In ethanol; water; at 75℃; | The preparation methodof <strong>[134523-00-5]atorvastatin</strong> lysine salt comprises the following steps:Weigh 117mg of<strong>[134523-00-5]atorvastatin</strong>, dissolved in lmL of ethanol, heated to 75 C or so, the solutionwas uniform impermeableShaped to formsolution A;30 mg of lysine wasweighed, dissolved in 0 mL of H20 and heated to about 75 C. The solution washomogenizedForm solution B;The solution B drop bydrop into a solution, mixed solution began to clarify, heated to about 75 Cor so, heated toAbout 75 C about reflux,cooling precipitation crystals, the product isolated, 1Hz NMR, MS and so on,which is <strong>[134523-00-5]atorvastatin</strong> lysine salt |
Yield | Reaction Conditions | Operation in experiment |
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EXAMPLE 3; Preparation and isolation of ATV-epoxy furan and ATV-epoxy dion compounds:1 liter of <strong>[134523-00-5]atorvastatin</strong> solution was prepared in 80% acetonitrile / 20% water (vol / vol)-containing 1 mg of <strong>[134523-00-5]atorvastatin</strong> per ml. The solution was put in a shallow crystallizing dish and was exposed to solar radiation for five hours. Immediatelyafter the solution was acidified with 0.5M phosphoric acid to pH 3.0. The mixture was left at a room temperature for two hours and evaporated under reduced pressure to cca-1/3 of the original mixture volume.Preparative chromatography and structure elucidations were carried out in thesame manner as in the example 1.120 mg of ATV-epoxy furan compound was isolated from the concentrated fractionby freeze-drying. The chromatographic purity was 92.6%.21 mg of ATV-epoxy dion compound was isolated from the concentrated fractionby freeze-drying. The chromatographic purity was 95.1%. |
Yield | Reaction Conditions | Operation in experiment |
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EXAMPLE 2; Preparation and isolation of ATV-cyclolP compound;:2 litres of <strong>[134523-00-5]atorvastatin</strong> solution was prepared in 80% acetonitrile and 20% water (vol/vol), containing 1 mg of <strong>[134523-00-5]atorvastatin</strong> per ml. The solution was put in a shallow crystallizer dish and was exposed to solar radiation for five hours. Immediately after that, the solution was alkalized with 1M solution of potassium hydroxide to pH 8 to 9 and evaporated under reduced pressure until the first occurrence of turbidity. The water bath temperature was kept under 30 C, and the condenser was cooled with water at 0 C. The solution was then clarified with addition of a minimal amount of acetonitrile.Preparative chromatography and structure elucidation was carried out in the same manner as in the example 1.210 mg of pure ATV-cyclolP compound was isolated from the concentrated fraction by freeze drying. The chromatographic purity was 96.6%. |
Yield | Reaction Conditions | Operation in experiment |
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With sodium hydroxide; dihydrogen peroxide; In water; acetonitrile; at 55℃; for 5h; | EXAMPLE 4; Preparation and isolation of ATV-cycloFP compound: 800 ml of solution of <strong>[134523-00-5]atorvastatin</strong> was prepared in acetonitrileT containing 10 mg of<strong>[134523-00-5]atorvastatin</strong> per ml. 4 ml of 12M sodium hydroxide and 40 ml of 30% hydrogenperoxide was added. The solution was stirred at 55C for five hours. The reactionmixture was allowed to cool and decanted. The supernatant was evaporatedunder reduced pressure to cca 50 ml. The remaining water was discarded and thesolid residue was washed with fresh water. The solid residue was then dissolvedin acetonitrile.Preparative chromatography and structure elucidation was carried out in the samemanner as in example 1230 mg of pure ATV-cyclolP compound was isolated from the concentratedfraction by freeze-drying. The chromatographic purity was 98.3%. |
Yield | Reaction Conditions | Operation in experiment |
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4.4 g (88%) | The solid was filtered, washed with Ethanol 96% (2*25 ml) and dried at 65 C. for 20 hrs to give 4.4 g (88%) of Atorvastatin hemi calcium salt with a level of 0.06% of Des-fluoro Atorvastatin. Atorvastatin is obtained in Form VIII by this procedure. |
Yield | Reaction Conditions | Operation in experiment |
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0.98 g (98%) | Example 18 Atorvastatin hemi-calcium salt Form V (1 g) in 1-BuOH (10 ml) and EtOH (10 ml) was heated to reflux for 1 h. The mixture was then cooled to room temperature and stirred at this temperature for additional 16 hrs. Filtration and drying at 65 C. for 24 hrs gave 0.98 g (98%) of Atorvastatin. hemi-calcium salt form IX. | |
The statins which are in turn particularly preferred according to the invention are atorvastatin (commercially available under the name Lipitor from Parke-Davis); cerivastatin (commercially available under the name Lipobay or Baycol from Bayer); fluvastatin (commercially available under the name Lescol from Novartis); lovastatin (commercially available under the name Mevacor from Merck); pravastatin (commercially available under the name Lipostat from Bristol-Myers Squibb); simvastatin (commercially available under the name Zocor from Merck); itavastatin (also called "nisvastatin"; NK-104; systematic name: [S-[R*,S*-(E)]]-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-3,5-dihydroxy-6-heptenoic acid); dalvastatin; mevastatin; ... | ||
Method F Amorphous atorvastatin calcium (U.S. Pat. No. 5,273,995) diffused in a vapor of acetonitrile/water (9:1) to afford crystalline Form V atorvastatin. Crystalline Form V atorvastatin, mp 171.4 C., trihydrate Karl Fischer 4.88% (3 mol of water). |
Method B Fast evaporation of a solution of amorphous atorvastatin calcium (U.S. Pat. No. 5,273,995) in dimethylformamide/water (9:1) affords crystalline Form VIII atorvastatin. Crystalline Form VIII atorvastatin, mp 151 C., dihydrate Karl Fischer 2.98% (2 mol of water). | ||
Method C Fast evaporation of a dimethylformamide/water (saturated) solution of amorphous atorvastatin calcium (U.S. Pat. No. 5,273,995) seeded with crystalline Form VI afforded crystalline Form VI atorvastatin. Crystalline Form VI atorvastatin, mp 145.9 C. | ||
Method D Fast evaporation of a saturated solution of amorphous atorvastatin calcium (U.S. Pat. No. 5,273,995) in acetone/water (1:1) was seeded with crystalline Form VII to afford crystalline Form VII atorvastatin. Crystalline Form VII atorvastatin, mp 195.9 C., 1.5 hydrate Karl Fischer 2.34% (1.5 mol of water). | ||
Form XII Atorvastatin Crystalline Form I atorvastatin calcium (U.S. Pat. No. 5,969,156) was slurried in tetrahydrofuran/water (2:8) at 90 C. for 5 days, filtered, and air dried to afford crystalline Form XII atorvastatin. Crystalline Form XII atorvastatin, mp 210.6 C. | ||
10.1 kg (57.4%) | EXAMPLE 8 [R-(R*,R*)]-2-(4-Fluorophenyl)-beta, delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4[phenylaminocarbonyl]-1H-pyrrole-1-heptanoic acid, calcium salt (2:1) A solution of (4R-cis)-1,1-dimethylethyl 6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate, 7.8 kg (Example 6), (+-)4-fluoro-alpha-[2-methyl-1-oxopropyl]-gamma-oxo-N-beta-diphenyl-benzenebutaneamide mixture of [R-(R*,R*)], [R-(R*,S*)], [S-R*,R*)] and [S-(R*,S*)]isomers, 12.8 kg (Example 7), and 2.1 kg of pivalic acid in 120 L heptane/30 L THF were heated at reflux for 40 hours. The solution was cooled, diluted with 90 L tert-butyl methyl ether and 5.0 L methanol then washed with dilute sodium hydroxide (61.6 L), dilute HCl (62.6 L), then the solvent removed by distillation. The product oil was taken up in methanol (75.0 L) and 1.6 kg 37% HCl in 15 L water was charged and the reaction mixture stirred at room temperature for 12 hours. A solution of 4.0 kg of 50% sodium hydroxide in 20 L of water was charged and stirred at room temperature for 2 hours. The reaction mixture was diluted with water (112 L) and washed with tert-butyl methyl ether (400 L). The aqueous layer containing the product was acidified with HCl (3.8 kg 37%) in 10 L water and taken up in tert-butyl methyl ether (200 L). The product acid was diluted with methanol (66.0 L) and saponified with 1.8 kg of 50% sodium hydroxide in 134 L of water for 30 minutes. The aqueous product layer was isolated and heated at reflux for 16 hours. The solution was cooled then washed with tert-butyl methyl ether (167.5 L). The product salt was diluted with water (134 L) and 2.50 kg of calcium acetate in 66 L water was added and the reaction mixture stirred at room temperature for 1.2 hours as the product precipitated. The calcium salt was taken up in ethyl acetate/heptane (128 L/70 L) at 50 C., and the aqueous phase extracted again with ethyl acetate/heptane (60.0 L/42.0 L) at 50 C. The combined organic extracts were washed with an aqueous calcium acetate/methanol solution (0.63 kg calcium acetate in 165 L water/methanol 10:1), and the product precipitated from the hot (50 C.) organic solvents. The product salt cake was washed with heptane/ethyl acetate and then dried under vacuum to yield 10.1 kg (57.4%) of white solid. 1 H NMR (200 MHz, DMSO-d6): delta 9.82 (s, 1H), 7.52 (d, 2H), 7.22 (m, 6H), 7.08 (m, 4H), 7.00 (m, 2H), 5.75 (s, 1H), 4.80 (s, 1H), 3.96 (m, 1H), 3.79 (m, 2H), 3.54 (m, 1H), 3.24 (m, 1H), 2.11 (m, 2H), 1.98 (m, 2H), 1.59 (m, 2H), 1.26-1.37 (m, 8H). 13 C NMR (50 MHz, DMSO-d6): 8 178.4, 166.2, 163.2, 160.0, 139.4, 136.0, 134.9, 133.4, 133.3, 129.1, 128.7, 128.4, 127.6, 127.3, 125.3, 123.0, 120.6, 119.4, 117.5, 115.5, 115.2, 66.3, 43.9, 43.6, 40.9, 39.1, 25.6, 22.3. | |
Step 7: Preparation of [R-(R*,R*)]-2-(4-Fluorophenyl)-beta-delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, sodium salt A nitrogen purged 500 mL three-neck flask is charged with [R-(R*,R*)]-5-(4-fluorophenyl)-beta,delta-dihydro-2-(1-methylethyl-N,N,4-triphenyl-3-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanamide (4.0 g, methanol (30 mL), and 2.0N aqueous sodium hydroxide (60 mL). The mixture is heated to 70 C. for 4 hours and cooled to room temperature. A white solid is filtered and discarded. The filtrate is washed with tert-butyl methyl ether, and the aqueous layer is acidified to a pH of 2 by the addition of 2N aqueous hydrochloric acid and extracted with tert-butyl methyl ether. The organic layer is separated, mixed with water (200 mL), methanol (20 mL), and brought to a pH of 12 by addition of 2.0N aqueous sodium hydroxide. The aqueous layer is washed with tert-butyl methyl ether (50 mL) and water (100 mL). The aqueous layer contains the sodium salt of [R-(R*,R*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid. | ||
Among the statins, in turn, particular preference according to the invention is given to, atorvastatin (commercially available under the name Lipitor from Parke-Davis/Pfizer); cerivastatin (commercially available under the name Lipobay or Baycol from Bayer); fluvastatin (commercially available under the name Lescol from Novartis); lovastatin (commercially available under the name Mevacor from Merck); pravastatin (commercially available under the name Lipostat from Bristol-Myers squibb); ... | ||
In ethanol; at 100 - 160℃; for 0.266667h;Laser radiation;Purification / work up; | Example 4: Preparation of Non-crystalline Atorvastatin Free Acid[0094] A reference sample of crystalline atorvastatin free acid was analyzed withPXRD and FTER. spectroscopy. As illustrated in Figure 15, the PXRD spectrum of <n="30"/>crystalline atorvastatin free acid is characterized by a PXRD having a number of specific peaks. The FTIR spectrum of the crystalline atorvastatin free acid is illustrated in Figure 17.[0095] A lO mg sample of crystalline atorvastatin free acid was dissolved in 400 mg of absolute ethanol with heating to 16O0C and stirring at 9000 rpm for 11 minutes. The resulting solution was transferred into a 60 mm x 15 mm glass Petri dish, covered with a glass lid, and placed on a hotplate at 100C.[0096] First, the amplitude modulated emission of a 674 nm diode laser was applied to the solution of atorvastatin free acid for 2.5 minutes. Then, the amplitude modulated emission of a 408 nm diode laser was applied for 2.5 minutes, rotating the sample slowly through the approximately 3 cm expanded beam at a distance of 25 cm from the Strachan Device. The 674 nm laser diode beam was passed through a Thorlabs 5x beam expander and a Strachan Device. Using the Strachan Device, the 674 nm beam was adjusted to the 80 percent phase cancellation level to achieve a power of approximately 0.48 mW over the 3 cm diameter beam. The 408 nm beam had a peak power of 2.18 mW after passing through a Thorlabs 5x beam expander and the Strachan Device. The output of the 408 nm beam was also optically phase cancelled using the Strachan Device to achieve a measured 80 percent reduction of transmitted power to 0.44 mW over the 3 cm diameter beam. Both beams were electronically amplitude modulated at 6.25 MHz[0097] The lid of the glass Petri dish was removed, and the solution was allowed to dry through slow evaporation at a room temperature of about 19 to about 200C and about 36 percent humidity. The resultant material dried to a pure transparent glass state. The laser treated atorvastatin free acid was then studied using PXRD. The PXRD pattern was free of the peaks characteristic of crystalline atorvastatin free acid, as illustrated in Figure 16, and was thus, non-crystalline.[0098] The non-crystalline atorvastatin free acid prepared with the process of the invention was then analyzed with FTIR spectroscopy. The resulting FTIR spectrum is illustrated in Figure 18. A comparison of the FTIR spectrum illustrated in Figure 18 with that of the crystalline atorvastatin free acid illustrated in Figure 17, confirms that the treated atorvastatin free acid is the same chemical entity as the crystalline atorvastatin free acid. The FTIR spectrum of atorvastatin free acid reference exhibits somewhat sharper peaks than the spectrum of the non-crystalline laser treated atorvastatin free acid. However, as discussed above, broadening of the FTIR spectroscopic absorption bands is <n="31"/>typical of the non-crystalline compared to the crystalline form of a material because of increased freedom of movement of molecules not confined to a crystal lattice. | |
[Atorvastatin Salt of Thaliporphine] IR(KBr)vmax: 3402, 2959, 1663, 1596, 1510, 1465, 1253, 1107 cm-1 Molecular Weight: 899 ESI-MS (30V): m/z (%) 900 [M+H]+, 342 (100) 1H NMR (CD3OD, 500 MHz):delta 8.14 (s, 1H), 7.29-7.28 (m, 2H), 7.23-7.19 (m, 4H), 7.13-7.00 (m, 8H), 6.89 (s, 1H), 6.67 (s, 1H), 4.06-3.90 (m, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 3.83 (s, 3H), 3.66-3.58 (m, 2H), 3.39-3.35 (m, 2H), 3.19-3.16 (m, 2H), 2.99-2.93 (m, 1H), 2.82-2.78 (m, 5H), 2.65 (t, J=14.0 Hz, 1H), 2.35-2.24 (m, 2H), 1.71-1.65 (m, 2H), 1.53-1.48 (m, 2H), 1.46 (d, J=7.0 Hz, 6H). | ||
[Atorvastatin Salt of Compound 1] IR(KBr)vmax: 3402, 2936, 1655, 1595, 1508, 1438, 1254, 1106 cm-1 Molecular Weight: 1065 ESI-MS (30V): m/z (%) 1066 [M+H]+, 279 (100) 1H NMR (CD3OD, 400 MHz):delta 8.04 and 8.03 (s, 1H), 7.21-7.10 (m, 4H), 7.05-6.88 (m, 14H), 6.75 and 6.73 (s, 1H), 6.59 and 6.57 (s, 1H), 4.24-4.22 (m, 1H), 4.00-3.72 (m, 7H), 3.80 (s, 3H), 3.74 (s, 9H), 3.29-2.50 (m, 8H), 2.24-2.20 (m, 2H), 1.62-1.42 (m, 4H), 1.38 (d, J=7.1 Hz, 6H). | ||
Examples of statins include but are not limited to the following: Simvastatin Atorvastatin Pravastatin Rosuvastatin Pitavastatin Lovastatin | ||
Has anyone told you that you are allergic to any of the following statins? a. lovastatin or Mevacor b. simvastatin or Zocor c. pravastatin or Pravachol d. fluvastatin or Lescol e. atorvastatin or Lipitor |
Yield | Reaction Conditions | Operation in experiment |
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EXAMPLE 2 [R-(R*,R*)-2-(4-fluorophenyl)beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl)-1H-pyrrole-1-heptanoic acid hemicalcium salt (Amorphous Atorvasatin Calcium) The process of Example 1 was repeated with crystalline atorvastatin calcium (10 kg) dissolved in tetrahydrofuran (30 lt) and using n-hexane instead of cyclohexane to give amorphous atorvastatin (9.5 kg.). X-ray crystallography confirmed the amorphous nature of the product. |
Yield | Reaction Conditions | Operation in experiment |
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With sodium iodide; potassium hydrogencarbonate; In chloroform; water; ethyl acetate; N,N-dimethyl-formamide; | 4-(2-Chloro-phenyl)-2-(2-[(5-{7-[2-(4-fluoro-phenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dihydroxy-heptanoyloxymethyl}-2-oxo-[1,3]dioxol-4-ylmethyl)-amino]-ethoxymethyl}-6-methyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-ethylester 5-methyl ester A solution of 4,5-bis(bromomethyl)-1,3-dioxol-2-one (10 g, 36.8 mmol) in ethyl acetate (10 ml) is added dropwise to a mixture of atorvastatin (7.45 g, 12.9 mmol), potassium bicarbonate (3 g) and sodium iodide (0.05 g) in ethyl acetate (60 ml) and N,N-dimethylformamide (20 ml) at 5 C. and the mixture is stirred at room temperature for 8 h. Cold water (30 ml) is added with stirring and the organic phase is separated, washed with 5% aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure and the residue is purified by column chromatography on silica gel to yield the 5-bromomethyl-2-oxo-1,3-dioxol-4-yl)methyl ester of atorvastatin. A mixture of the 5-bromomethyl-2-oxo-1,3-dioxol-4-yl)methyl ester of atorvastatin (7.7 g, 10 mmol), amlodipine (5.25 g, 10 mmol) and potassium bicarbonate (1 g, 10 mmol) in N,N-dimethylformamide (50 ml) is stirred at 0 C. for 8 h. The solvent is removed in vacuo and the residue is dissolved in chloroform. The chloroform solution is washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield the title compound of Example One. |
Yield | Reaction Conditions | Operation in experiment |
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A solution of (4R-cis)-6-(cyanomethyl)-2,2-dimethyl-N,N-bis(phenylmethyl)-1,3-dioxane-4-acetamide (10 0 g, 0.025 mol) in methanol (150 mL) containing anhydrous ammonia (2.25 g) is reacted with hydrogen gas in a Parr shaker at 30 C. in a presence of a slurry of Raney nickel A-7000 (3.7 g). After 3 hours, uptake of hydrogen has ceased, the mixture is cooled to 20 C., the atmosphere is vented and exchanged for nitrogen, the slurry is filtered through celite, and concentrated at reduced pressure to give 9.4 g of (4R-cis)-6-(2-aminoethyl)-2,2-dimethyl-N,N-bis(phenylmethyl)-1,3-dioxane-4-acetamide as an oil; 1 H-NMR (DMSO) delta1.26 (s, 3H), 1.41 (s, 3H), 2.12 (m, 1H), 2.5 (m, 1H), 3.11 (m, 2H), 3.23 (m, 2H), 3.35 (m, 2H), 4.44(m, 2H), 4.48 (m, 2H), 4.52 (m, 4H), 7.3-7.5 (s, 10H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of (4R-cis)-6-(cyanomethyl)-N,N-diethyl-2,2-dimethyl-1,3-dioxane-4-acetamide (10.0 g, 0.037 mol) in methanol (220 mL) containing anhydrous ammonia (3.25 g) is reacted with hydrogen gas in a Parr shaker at 30 C. in a presence of a slurry of Raney nickel A-7000 (4.2 g). After 3 hours, uptake of hydrogen has ceased, the mixture is cooled to 20 C., the atmosphere is vented and exchanged for nitrogen, the slurry is filtered through celite, and concentrated at reduced pressure to give 9.2 g of (4R-cis)-6-(2-aminoethyl)-N,N-diethyl-2,2-dimethyl-1,3-dioxane-4-acetamide as an oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of this nitrile (5.0 g, 0.012 mol) in methanol (70 mL) containing anhydrous ammonia (1.05 g) is reacted with hydrogen gas in a Parr shaker at 30 C. in a presence of a slurry of Raney nickel A-7000 (2.5 g). After 3 hours, uptake of hydrogen has ceased, the mixture is cooled to 20 C., the atmosphere is vented and exchanged for nitrogen, the slurry is filtered through celite, and concentrated in vacuo to give 4.2 g of (4R-cis)-6-(2-aminoethyl)-N-(1,1-dimethylethyl)-2,2-dimethyl-N-(phenylmethyl)-1,3-dioxane-4-acetamide as an oil; Molecular weight 358. GC/MS m/e 358, 343, 301, 287, 260, 243, 227, 204, 176, 148, 132, 91, 84, 57, 43. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of the nitrile (5.0 g, 0.017 mol) in methanol (100 mL) containing anhydrous ammonia (1.5 g) is reacted with hydrogen gas in a Parr shaker at 30 C. in the presence of a slurry of Raney nickel A-7000 (3.8 g). After 3 hours, uptake of hydrogen has ceased, the mixture is cooled to 20 C., the atmosphere is vented and exchanged for nitrogen, the slurry is filtered through celite, and concentrated in vacuo to give 4.85 g of (4R-cis)-1-[[6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetyl]piperidine as an oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide; In ethanol; for 0.0833333h; | <strong>[134523-00-5]Atorvastatin</strong> as the free acid (186.8 g; 0.33 mmol) was dissolved in ethanol (1.5 L) in a three necked round-bottomed flask (volume 3 L) provided with mechanical stirring and a CaC12 tube. Powdered potassium hydroxide (24.3 g; 0.37 mol; 1.1 eq) was added under vigorous stirring over a period of 5 minutes, whereafter the reaction mixture was stirred overnight.The colourless precipitate was isolated by filtration and washed on the filter using cold ethanol (200 mL) followed by drying under vacuum at 45 C for 18 hours. The material was analysed by microanalysis:Calculated: C 66.42 H 5.74 N 4.69Found: C 64.05 H 5.71 N 4.4225Karl Fischer titration showed a water content of 2.64 % in the sample, corresponding to a monohydrate. When correcting for the water content the values were:Calculated: C 64.67 H 5.89 N 4.5730HPLC analysis data: Column: Flow: Wavelength:Nucleosil 10 C18, 5 btm, 4.6 x 250 mm.0.6 mL/min.230 nmMobile phase:Sample conc.' RT:Methanol/buffer pH 7 90:10 (buffer pH 7 was deionised water (950mL) mixed with triethylamine (5.5 mL); conc. phosphoric acid 85 % was added to pH 7)0.02 % (w/w) in mobile phaseca. 4.1 min.The HPLC analysis showed a purity of 100 %.The potassium <strong>[134523-00-5]Atorvastatin</strong> Form I was analysed by DSC analysis and X-ray powder diffractographyThe DSC analysis was performed by analysing a sample of approximately 2 mg by linear heating from 30 C to 300 C in a Mettler DSC 822 apparatus.The melting point by DSC analysis was 155-165 C (See Fig. 1).The X-ray powder diffractogram was performed on a Philips PW 3710 diffractometer using CuK~radiation, wavelengths: (A): 1.54060/1.54443 and an exposure time of 2h 3 min. The Xray powder diffractogram for potassium )ktorvastatin, Form I, presented as Fig. 4, showed a crystalline solid. Said pattern shows characteristic peaks at 20 values of 19.92, 20.98 and 22.08. More particularly, polymorphs Form I showed the following characteristic 20 angle values:2&Ttheta; angle8.49.010.0 10.5 11.24 16.38 17.46 18.12 19.92 20.98 22.08 23.2423.8425.2 27.8 29.6 31.3 32.16 36.34 42.8 | |
With potassium hydroxide; In propan-1-ol; for 0.0833333h; | <strong>[134523-00-5]Atorvastatin</strong> as the free acid (1.0 g; 0.18 mmol) was dissolved in 1-propanol (10 mL) in a round-bottomed flask (volume 50 mL) provided with mechanical stirring and a CaC12 tube. Powdered potassium hydroxide (0. l g; 1.8 mmol; 1.1 eq) was added under vigorous stirring over a period of 5 minutes, and the reaction mixture was stirred overnight.The colourless precipitate was isolated by filtration and washed on the filter using cold' 1propanol (3 mL) followed by drying under vacuum at 45 C for 18 hours. The material was analysed by HPLC analysis, which gave a purity of 100 % using the same HPLC analysis data as in example 1. The melting point by DSC analysis was 173-183 C (See Fig. 2).The X-ray powder diffractogram, obtained as in Example 1 above and presented as Fig. 5, showed an amorphous substance. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethyl acetate; at 20℃; | <strong>[134523-00-5]Atorvastatin</strong> calcium (the form commercially available) is added to a 5% solution of Sodium EDTA in water, in a round bottom flask and stirred briskly. The Sodium EDTA chelates the calcium and renders <strong>[134523-00-5]atorvastatin</strong> in its open acid form. Atorvastain acid being water insoluble is extracted and dried. lgram mole equivalent of the <strong>[134523-00-5]atorvastatin</strong> extracted as above is digested in 100 ml of ethyl acetate in a round bottom flask fitted with a magnetic stirrer. 1 gram mole equivalent of (S)-2,6-diaminohexanoic acid is added to the above ethyl acetate solution and stirred at ambient room temperature. The reactants, which were initially insoluble in ethyl acetate slowly, react and form <strong>[134523-00-5]atorvastatin</strong> (S)-2,6-diaminohexanoic acid complex, which is completely soluble in ethyl acetate solution. The solution of clear ethyl acetate containing <strong>[134523-00-5]atorvastatin</strong> (S)-2,6-diaminohexanoic acid complex is then poured into a glass tray and the ethyl acetate is allowed to evaporate till the <strong>[134523-00-5]atorvastatin</strong> (S)-2,6-diaminohexanoic acid complex is obtained as a dry product.1 gram mole equivalent of the dry <strong>[134523-00-5]atorvastatin</strong> (S)-2,6-diaminohexanoic acid complex obtained as above is dissolved in 200 ml of carbon tetra chloride in a round bottom flask fitted with a magnetic stirrer. To this is added lgram mole equivalent of acyl chloride of (Z)-9-Octadecenoic acid and the solution is stirred for 4 hrs. After completion of the reaction the above solution is poured into the glass tray to allow the carbon tetrachloride to evaporate. The <strong>[134523-00-5]atorvastatin</strong> (S)-2,6-diaminohexanoic acid (Z)-9-Octadecenoic complex as obtained above is washed with a 5% solution of sodium carbonate in a separating funnel to neutralize the EPO <DP n="23"/>hydrochloride present in the product. After washing the <strong>[134523-00-5]atorvastatin</strong> (S)- 2,6-diaminohexanoic acid (Z)-9-Octadecenoic complex is obtained as a separate oily layer and is separated from the saline sodium carbonate water- solution. The final <strong>[134523-00-5]atorvastatin</strong>n (S)-2,6-diaminohexanoic acid (Z)-9- Octadecenoic complex obtained is an oily liquid freely soluble in oils including arachis oil, soya bean oil etc.,; Example 2:Preparation of water-soluble form of <strong>[134523-00-5]Atorvastatin</strong> namely <strong>[134523-00-5]Atorvastatin</strong> (S)-2,6-diaminohexanoic acid betaine .<strong>[134523-00-5]Atorvastatin</strong> calcium (the form commercially available) is added to a 5% solution of Sodium EDTA in water, in a round bottom flask and stirred briskly. The Sodium EDTA chelates the calcium and renders <strong>[134523-00-5]atorvastatin</strong> in its open acid form. Atorvastain acid being water insoluble is extracted and dried.lgram mole equivalent of the <strong>[134523-00-5]atorvastatin</strong> extracted as above is digested in 100 ml of ethyl acetate in a round bottom flask fitted with a magnetic stirrer. 1 gram mole equivalent of (S)-2,6-diaminohexanoic acid is added to the above ethyl acetate solution and stirred at ambient room temperature. The reactants, which were initially insoluble in ethyl acetate slowly, reacts with the <strong>[134523-00-5]atorvastatin</strong> acid and forms <strong>[134523-00-5]atorvastatin</strong> (S)-2,6- diaminohexanoic acid complex which is completely soluble in ethyl acetate solution. 'To this solution is added 1 gram mole equivalent of betaine and stirring continued till a precipitate of <strong>[134523-00-5]atorvastatin</strong> (S)-2,6- EPO <DP n="24"/>diaminohexanoic acid betaine, which is insoluble in ethyl acetate, is obtained. This precipitate <strong>[134523-00-5]Atorvastatin</strong> (S)-2,6-diaminohexanoic acid betaine is spread over in a glass tray to allow the ethyl acetate to evaporate. This atorvastain (S)-2,6-diaminohexanoic acid betaine has a solubility of 100 mg in 100ml of water and lgm in 5ml of lactic acid. As is observed the solubility of <strong>[134523-00-5]atorvastatin</strong> (S)-2,6-diaminohexanoic acid betaine in water is far superior to that of <strong>[134523-00-5]atorvastatin</strong> calcium whose solubility is documented as being "very slightly soluble" as per (US pharmacopia 2002). As per the US Pharmacopia norms " very slightly soluble" refers to aqueous solubility that ranges from 1/1000 to 1/10,000 mg per ml. Thus it is Observed that solubility of <strong>[134523-00-5]atorvastatin</strong> (S)-2,6-diaminohexanoic acid betaine has been increased a 1000-10000 folds higher over that of <strong>[134523-00-5]atorvastatin</strong> calcium. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With calcium acetate; In water; for 1h;pH 8; | Dihydroxy ester (II) (5 g) was taken in water (50 ml) and sodium hydroxide (0.35 g) was added. Temperature was raised to 75-800C and reaction mass was stirred and then cooled. Calcium acetate (1.00 g) was added and stirred for 1 hr and pH was adjusted to 8. Ethyl acetate (40 ml) was added to extract the product from aqueous layer. Organic layer was washed with water and then dried over sodium sulfate. Solvent was removed under vacuum to give a foamy solid residue. The foamy solid residue was taken in diisopropyl ether or cyclohexane or t-butyl methyl ether or isopropyl alcohol (50 ml) and stirred. Contents were filtered and dried to yield amorphous <strong>[134523-00-5]Atorvastatin</strong> calcium. Dihydroxy ester (II) (5 g) was taken in water (50 ml) and sodium hydroxide (0.35 g). was added. Temperature was raised to 75-800C and reaction mass was stirred and then cooled. Calcium acetate solution (1.00 g) was added and stirred for 1 hr and pH was adjusted to 8. Ethyl acetate (40 ml) was added to extract the product from aqueous layer. Organic layer was washed with water and then dried over sodium sulfate. Solvent was removed under vacuum to give a foamy solid residue. The foamy solid residue was taken in mixture of cyclohexane and t-butyl methyl ether (50 ml) and stirred. Contents were filtered and dried to yield amorphous <strong>[134523-00-5]Atorvastatin</strong> calcium. | |
With calcium acetate; In water; butanone; | Dihydroxy ester (II) (5 g) was taken in water (25 ml) and methyl ethyl ketone (25 ml).Sodium hydroxide (0.35 g) was then added. Temperature was raised to 600C and reaction mass was stirred for 2 hrs. After the completion of reaction, calcium acetate (1.00 g in 5 ml water) was added and stirred, followed by the cooling of the reaction mixture to room temperature. Methyl ethyl ketone (25 ml) was added to extract the product from aqueous layer. Organic layer was washed with water and then dried over sodium sulfate. Solvent was removed under vacuum to give a foamy solid residue. The foamy solid residue was taken in diisopropyl ether (50 ml) and stirred. Contents were filtered and dried to yield amorphous <strong>[134523-00-5]Atorvastatin</strong>. | |
With calcium acetate; In methanol; water; for 1h; | Dihydroxy ester (II) (5 g) was taken in water (50 ml) and methanol (5 ml). Sodium hydroxide (0.36g, 1.1 mole eq.) was then added. Temperature was raised to 800C and reaction mass was stirred for 3 hrs at this temp. After reaction completion, reaction mixture was cooled. Calcium acetate solution (1.02 g in 5 ml water) was added at this temperature and then stirred for 1 hr. Ethyl acetate (40 ml) was added to extract the product from aqueous layer. Organic layer was washed with water and then dried over sodium sulfate. Solvent was removed under vacuum to give a foamy solid residue. To the residue tetrahydrofuran (15 ml) was added, stirred and stripped of the tetrahydrofuran under vacuum at 40-500C to get the solid foam. Tetarhydrofuran (15 ml) was added and stirred for dissolution, followed by the addition of this solution to a cyclohexane : t-butyl methyl ether mixture (75 ml : 75 ml) at room temperature. After <n="14"/>the addition, the precipitated material was stirred for one hour. Contents were filtered and dried to yield amorphous <strong>[134523-00-5]Atorvastatin</strong>. |
With calcium 2-ethyl hexanoate; In water; for 1h;pH 8; | Dihydroxy ester (II) (5 g) was taken in water (50 ml) and sodium hydroxide (0.35 g) was added. Temperature was raised to 75-800C and reaction mass was stirred and then cooled. Calcium acetate (1.00 g) was added and stirred for 1 hr and pH was adjusted to 8. Ethyl acetate (40 ml) was added to extract the product from aqueous layer. Organic layer was washed with water and then dried over sodium sulfate. Solvent was removed under vacuum to give a foamy solid residue. The foamy solid residue was taken in diisopropyl ether or cyclohexane or t-butyl methyl ether or isopropyl alcohol (50 ml) and stirred. Contents were filtered and dried to yield amorphous <strong>[134523-00-5]Atorvastatin</strong> calcium. Dihydroxy ester (II) (5 g) was taken in water (50 ml) and sodium hydroxide (0.35 g). was added. Temperature was raised to 75-800C and reaction mass was stirred and then cooled. Calcium acetate solution (1.00 g) was added and stirred for 1 hr and pH was adjusted to 8. Ethyl acetate (40 ml) was added to extract the product from aqueous layer. Organic layer was washed with water and then dried over sodium sulfate. Solvent was removed under vacuum to give a foamy solid residue. The foamy solid residue was taken in mixture of cyclohexane and t-butyl methyl ether (50 ml) and stirred. Contents were filtered and dried to yield amorphous <strong>[134523-00-5]Atorvastatin</strong> calcium. | |
Dihydroxy ester (II) (5 g) was taken in water (25 ml) and methyl ethyl ketone (25 ml) followed by the addition of sodium hydroxide (0.35 g). Temperature of the reaction mixture was raised to 600C and stirred for 2 hrs. After the completion of the reaction, calcium acetate (1.00 g in 5 ml water) was added and stirred for 2 hrs. Reaction mixture was cooled to room temperature. The pH was adjusted to 8. Ethyl acetate (40 ml) was added to extract the product from aqueous layer. Organic layer was washed with water and then dried over sodium sulfate. Solvent was removed under vacuum to give a foamy solid residue. The foamy solid residue was taken in diisopropyl ether or cyclohexane or t-butyl methyl ether or isopropyl alcohol or mixture of cyclohexane and t-butyl methyl ether (50 ml) and stirred. Contents were filtered and dried to yield amorphous <strong>[134523-00-5]Atorvastatin</strong>. Dihydroxy ester (II) (5 g) was taken in water (25 ml) and methyl ethyl ketone (25 ml) followed by the addition of sodium hydroxide (0.35 g). Temperature of the reaction mixture was raised to 600C and stirred for 2 hrs. After the completion of the reaction, calcium acetate (1.00 g in 5 ml water) was added and stirred for 2 hrs. Reaction mixture was cooled to room temperature. The pH was adjusted to 8. Ethyl acetate (40 ml) was added to extract the product from aqueous layer. Organic layer was washed with water and then dried over sodium sulfate. Solvent was removed under vacuum to give a foamy solid residue. The foamy solid residue was taken in diisopropyl ether or cyclohexane or t-butyl methyl ether or isopropyl alcohol or mixture of cyclohexane and t-butyl methyl ether (50 ml) and stirred. Contents were filtered and dried to yield amorphous <strong>[134523-00-5]Atorvastatin</strong>. Dihydroxy ester (II) (5 g) was taken in water (25 ml) and methyl ethyl ketone (25 ml) followed by the addition of sodium hydroxide (0.35 g). Temperature of the reaction mixture was raised to 600C and stirred for 2 hrs. After the completion of the reaction, Calcium acetate solution (1.00 g in 5 ml water) was added and stirred for 2 hrs. Reaction mixture was cooled to room temperature. The pH was adjusted to 8. Xylene (50 ml) was added to extract the product from aqueous layer. Organic layer was washed with water and then dried over sodium sulfate. Solvent was removed under vacuum to give a foamy solid residue. The foamy solid residue was taken in diisopropyl ether or cyclohexane or t-butyl methyl ether or isopropyl alcohol or mixture of cyclohexane and t-butyl methyl ether (50 ml) and stirred. Contents were filtered and dried to yield amorphous <strong>[134523-00-5]Atorvastatin</strong> | ||
Dihydroxy ester (II) (5 g) was taken in water (25 ml) and methyl ethyl ketone (25 ml) followed by the addition of sodium hydroxide (0.35 g). Temperature of the reaction <n="12"/>mixture was raised to 600C and stirred for 2 hrs. After the completion of the reaction, Calcium 2-ethyl hexanoate (2.20 g in 5 ml water) was added and stirred for 2 hrs. Reaction mixture was cooled to room temperature. The pH was adjusted to 8. Ethyl acetate (40 ml) was added to extract the product from aqueous layer. Organic layer was washed with water and then dried over sodium sulfate. Solvent was removed under vacuum to give a foamy solid residue. The foamy solid residue was taken in diisopropyl ether or cyclohexane or t-butyl methyl ether or isopropyl alcohol or mixture of cyclohexane and t-butyl methyl ether (50 ml) and stirred. Contents were filtered and dried to yield amorphous <strong>[134523-00-5]Atorvastatin</strong>. Dihydroxy ester (II) (5 g) was taken in methyl ethyl ketone (40 ml) followed by the addition of sodium hydroxide (0.35 g). Temperature of the reaction mixture was raised to 600C and stirred for 2 hrs. After the completion of the reaction, Calcium 2-ethyl hexanoate (2.20 g in 5 ml water) was added and stirred for 2 hrs. Reaction mixture was cooled to room temperature. The pH was adjusted to 8. Ethyl acetate (40 ml) was added to extract the product from aqueous layer. Organic layer was washed with water and then dried over sodium sulfate. Solvent was removed under vacuum to give a foamy <n="13"/>solid residue. The foamy solid residue was taken in diisopropyl ether or cyclohexane or t-butyl methyl ether or isopropyl alcohol or mixture of cyclohexane and t-butyl methyl ether (50 ml) and stirred. Contents were filtered and dried to yield amorphous <strong>[134523-00-5]Atorvastatin</strong>. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | In ethyl acetate; | Example 9; <strong>[134523-00-5]Atorvastatin</strong> L-ornithine salt To a stirred solution of 1.65 g (2.84 mmol) of <strong>[134523-00-5]atorvastatin</strong> in 66 ml of ethyl acetate, prepared according to the method described in Example 1,0. 37 g (2.84 mmol) of L-ornithine is added. The solvent is evaporated. The residue is suspended in 50 ml of ethanol, boiled and 0.7 ml of water is added. The slightly opalesque warm solution is filtered, then the stirred filtrate is cooled and stirred at 0 C for 5 h. The precipitated product is filtered off, washed with 5 ml of a mixture of ethanol : water = 99: 1 twice and dried in vacuum desiccator to yield 0.92 g (47 %) of the title compound. The characteristic bands of its infrared spectrum are the following: 3376,1654, 1596,1510, 1436,1316, 1214,1158, 842,746, 690 crif 1. Mp. : 150 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | In ethyl acetate; | Example 6; <strong>[134523-00-5]Atorvastatin</strong> DL-lysine salt 25 ml of 0.136 mmol/I <strong>[134523-00-5]atorvastatin</strong> solution in ethyl acetate is prepared according to the method described in Example 1, and 497 mg (3.4 mmol) of DL-lysine is added. The obtained suspension is evaporated to dryness. The residue is dissolved by boiling in 55 ml of a mixture of ethanol: water = 96: 4. After cooling the solution the precipitated crystals are filtered off, washed with 3 ml of a cold mixture of ethanol: water = 96: 4 twice, and dried in vacuum desiccator at room temperatur to yield 1.55 g (65%) of the title compound. The characteristic bands of its infrared spectrum are the following: 3370,1651, 1596,1558, 1509,1436, 1316, 1215,1158, 841,748, 692 cm~l. Mp.: 145 C (decomp. ) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | In methanol; ethyl acetate; at 25℃; for 1h; | Example 8; <strong>[134523-00-5]Atorvastatin</strong> L-arginine salt To a solution of 1.29 g (2.32 mmol) of <strong>[134523-00-5]atorvastatin</strong> in 96.5 ml of ethyl acetate, prepared according to the method described in Example 1, a solution of 0.39 g (2.24 mmol) of L- arginine in 50 ml of methanol is added. The mixture is stirred at 25 C for 1 h, then the solvents are evaporated in vacuum. 20 ml of diisopropyl ether is added to the residue and the so obtained suspension is stirred at 25 C for 5 h. The precipitated product is filtered off and washed with 5 ml of diisopropyl ether twice to yield 1.57 g (96 %) of the title compound. The characteristic bands of its infrared spectrum are the following: 2963,1596, 1528,1509, 1437, 1401,1313, 1223,1157, 843,753, 692 crin 1. Mp.: 138 C (decomp.) |
In ethanol; water; at 75℃; | Weigh 117mg of <strong>[134523-00-5]atorvastatin</strong>, dissolvedin lmL of ethanol, heated to 75 C or so, the solution was uniform impermeableShaped to form solution A; 36 mg of arginine was weighed,dissolved in 0 mL of H20 and heated to about 75 C. The solution washomogenizedForm solution B; The solution was addeddropwise to the solution, and the mixed solution began to clarify. The solutionwas heated to about 75 Cand refluxed. The precipitated crystal was cooled and the product wasisolated. The product was isolated by 1Hz NMR, MS and the like, and it was <strong>[134523-00-5]atorvastatin</strong> Arginine salt. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | In ethyl acetate; at 20℃; for 20h; | Example 7; <strong>[134523-00-5]Atorvastatin</strong> D-lysine salt 520 mg (3.56 mmol) of D-lysine is added to 31. 2 ml of 114 mmol/dm3 <strong>[134523-00-5]atorvastatin</strong> solution in ethyl acetate. The suspension is stirred at room temperature for 20 h, the precipitated <strong>[134523-00-5]atorvastatin</strong> D-lysine salt is filtered off and recrystallized from 18.5 ml of a mixture of ethanol : water = 94: 6 (the dissolution is achieved by addition of 0.9 ml of water). The product is dried in vacuum desiccator to yield 1. 89 g (76 %) of the title compound. The characteristic bands of its infrared spectrum are the following: 3356,1651, 1596,1559, 1529, 1510, 1437, 1316,1158, 840,693 cin-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; Isopropyl acetate; at 55 - 60℃; for 8 - 10h;Product distribution / selectivity; | EXAMPLE 5; Preparation of <strong>[134523-00-5]atorvastatin</strong> calcium propylene glycol solvate under hydrous conditions from <strong>[134523-00-5]atorvastatin</strong> tert-butyl esterTo a mixture of (4R-cis)-1,1-dimethylethyl-6-{2-[[2-(4-fluorophenyl)]-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-yl]ethyl}-2,2-dimethyl-1,3-dioxane-4-acetate (100 g) and 10 parts MeOH was added 1 eq. 1N aq. HCl solution. The mixture was warmed to about 50 C. and maintained for about 10 h before it was cooled to room temperature. At this point, 2 eq. of 1 N NaOH solution was added and the mixture was warmed to about 60 C. for about 10 h. After cooling to room temperature the reaction mixture was acidified with diluted aqueous HCl solution and extracted three times with 2 parts of isopropyl acetate and the combined organic layers were washed with brine. To the organic solution was added 3 parts of racemic propylene glycol and 0.5 eq Ca(OH)2 in 0.3 parts of water. The resulting mixture was warmed to 55-60 C. and stirred for 8-10 hours to afford a white suspension. The suspension was cooled to 20-25 C. and filtered to furnish <strong>[134523-00-5]atorvastatin</strong> calcium propylene glycol solvate after drying under vacuum at 50-60 C. Yield: 77% from the <strong>[134523-00-5]atorvastatin</strong> tert-butyl ester. Propylene glycol content: 6% by NMR, KF=0.1%. The DSC and IR of this material are shown as FIGS. 9 and 10 respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 10. Preparat ion of atorvastat in cal cium<83> In a reactor , 15 g of (6-{2- [2-(4-f luoro-phynyl )-5-i sopropyl-3-phenyl- <n="12"/>4-phenylcarbamoyl-pyrrole-l-yl]-ethyl }-2-phenethyl-[1,3,2]dioxaborinane-4- yl)-acetic acid t-butyl ester was completely dissolved in 150 ml of ethyl acetate. Then, 50 ml of 1 N NaOH was added drop wise over a period of 30 minutes and the mixture was stirred. After that, pH of the solution was adjusted to 1 ~ 2 using 1 N HCl, followed by stirring for additional 30 minutes to separate the organic layer. The separated organic layer was washed with potassium acetate and stirred over a period of 2 hours. The resulting solid was filtered to afford the title compound(7 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage II: Preparation of Form Z of <strong>[134523-00-5]Atorvastatin</strong> MagnesiumThe residue of Stage-I was dissolved in methanol (1000 ml) at room temperature and stirred for 10 minutes. A solution of sodium hydroxide (16 g sodium hydroxide dissolved in 800 ml de-ionized water) was added drop-wise in 30 minutes duration to the solution obtained above at room temperature and stirred for 4 hours. The solution was washed with toluene (2×100 ml) and filtered through Celite bed. The Celite bed was washed with methanol (250 ml). The pH of the combined solution was slowly adjusted to 7.9 by the addition of 1N hydrochloric acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With magnesium acetate; In methanol; water; at 25 - 50℃;Product distribution / selectivity; | The temperature of the solution was slowly raised to 50 C. An aqueous solution of magnesium acetate tetrahydrate (20 g dissolved in 2.4 L of de-ionized water) was added in 1 hour at 50 C. to the solution obtained above. The mixture was slowly cooled 25 C. and stirred for 1 hour at 25 to 30 C., filtered, washed with de-ionized water (250 ml) to obtain a wet material (200 g). The wet material (10 g) was dried under reduced pressure at 40 to 45 C. till the moisture content attained the range of 3 to 5% to obtain the title compound (3.5 g) having XRPD pattern as depicted in FIG. 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 4Preparation of Sildenafil-<strong>[134523-00-5]Atorvastatin</strong>ic Acid Complex SaltIn a flask equipped with a magnetic stirrer, <strong>[134523-00-5]Atorvastatin</strong>ic acid (11.2 g) dissolved in ethanol (50 ml) is poured, to which an aqueous solution of sodium hydroxide (4 g/60 ml) is added under room temperature. After 10 mins, the above-mentioned Sildenafil citrate in the ethanol solution is added for reacting at 50 C. for 20 mins, and the mixture is rapidly filtrated and stood one hour for crystallization to give the Sildenafil-<strong>[134523-00-5]Atorvastatin</strong>ic acid complex salt 16.8 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 18h; | Example 6 Preparation of 1-((3R,5R)-7-(2-(4Z,7Z,1OZ,13Z,16Z,19Z)-docosa-4,7,1O,13,16,19- hexaenamidoethylamino)-3,5-dihydroxy-7-oxoheptyl)-5-(4-fluorophenyl)-2-isopropyl-N,4- diphenyl-1H-pyrrole-3-carboxamide (1-22):OH H2N Nd?QFN[0236j The HC1 salt of (4Z,7Z, 1 OZ, 1 3Z, 1 6Z, 1 9Z)-N-(2-aminoethyl)docosa-4,7, 10,13,16,19- hexaenamide was prepared according to the procedures outlined in WO 2012115695. This material (2.1 g, 5.17 mmol) was taken up in 100 mL of CH2C12 along with <strong>[134523-00-5]atorvastatin</strong> (2.4 g,4.31 mmol), HATU (2 g, 5.17 mmol) and DIEA (4.5 mL). The resulting reaction mixture was stirred at room temperature for 18 h. It was then diluted with CH2C12 and washed with saturated aqueous NH4C1 (25 mL) and brine (50 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by silica gelchromatography (95% CH2C12, 5% MeOH) to afford 1-((3R,5R)-7-(2-(4Z,7Z, 1 OZ, 1 3Z, 1 6Z, 1 9Z)-docosa-4,7, 10,13,16,1 9-hexaenamidoethylamino)-3 ,5-dihydroxy-7- oxoheptyl)-5 -(4-fluorophenyl)-2-isopropyl-N,4-diphenyl- 1 H-pyrrole-3 -carboxamide. MS calculated for C57H71FN405: 910.54; found: [M+H] 911. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With chimera No.17A1V2 derived from CYP102A1 mutant; In aq. phosphate buffer; dimethyl sulfoxide;Enzymatic reaction;Catalytic behavior; | [Example 3] Oxidation of <strong>[134523-00-5]atorvastatin</strong> by wild-type CYP102A1, wild-type CYP102A1 mutants, and chimeras derived from CYP012A1 mutant [97] It was examined whether the wild-type CYP102A1, the CYP102A1 mutants, and the chimeras derived from the CYP102A1 mutants may oxidize <strong>[134523-00-5]atorvastatin</strong>. Typical steady-state reactions was performed by adding 50 pmol CYP102A1 and 80 muM substrate to 0.25 ml of 100 mM potassium phosphate buffer solution (pH 7.4). In order to initiate reactions, the NADPH-generating system was added thereto (final concentrations: 10 mM glucose 6-phosphate, 0.5 mM NADP+, and 1 IU yeast glucose 6-phosphate per ml). A stock solution of <strong>[134523-00-5]atorvastatin</strong> (20 mM) was prepared in DMSO and diluted into the enzyme reaction solution to have a final organic solvent concentration of <1% (v/v).[98] In order to measure human CYP3A4 activity, 50 pmol P450, 100 pmol NADPH-P450 reductase (CPR), 100 pmol cytochrome b5, and 45 muM L-alpha-dilauroyl-sn-glycero-3-phosphocholine (DLPC) were used instead of 50 pmol CYP102A1. After the reaction solution was reacted for 30 minutes at 37, the reaction was terminated with 2-fold of ice-cold dichloromethane.[99] (1) HPLC analysis [100] After centrifugation of the reaction mixture, a supernatant was removed and a solvent was evaporated under nitrogen gas and analyzed using HPLC. A sample (30 ul) was injected into Gemini C18 column (4.6 mm x 150 mm, 5 um, Phenomenex, Torrance, CA). As a mobile phase A, water containing 0.1% formic acid/acetonitrile (80/20, v/v) was used, and as a mobile phase B, acetonitrile/0.1% formic acid (90/10, v/v) was used. The mobile phase A/B (70/30, v/v) was flowed at a rate of 1 ml·min-1 using a gradient pump (LC-20AD, Shimadzu, Kyoto, Japan). Elution solutions were detected by UV at 260 nm.[101] In order to examine whether or not CYP102A1 (P450 BM3) may oxidize <strong>[134523-00-5]atorvastatin</strong>, the abilities of the wild-type CYP102A1 (P450 BM3), the mutants thereof, and the chimeras derived from the CYP102A1 mutants to oxidize <strong>[134523-00-5]atorvastatin</strong> were measured at a fixed substrate concentration (80 muM).[102] The metabolites of <strong>[134523-00-5]atorvastatin</strong> prepared by the human CYP3A4, the bacterial CYP102A1 mutant (16 in Table 2), and the chimera (16A1V3) derived from the CYP102A1 were examined using HPLC chromatograms (measuring UV absorbance at 260 nm).[103] Peaks were confirmed by comparing with retention times of peaks of the metabolites prepared by human CYP3A4 and CYP2C9. The substrate and two main metabolites, that is, 2-hydroxylated product and 4-hydroxylated product were shown.[104] As a result, it might be appreciated that retention times of the peaks of the metabolites exactly coincide with those of the standard 4-OH <strong>[134523-00-5]atorvastatin</strong> and 2-OH <strong>[134523-00-5]atorvastatin</strong> as shown in FIGS. 9 to 10B.[105] (2) LC-MS analysis [106] In order to identify <strong>[134523-00-5]atorvastatin</strong> metabolites produced the wild-type CYP102A1 mutants and the chimeras derived from by CYP102A1 mutants, LC-MS analysis was conducted by comparing LC profiles and fragmentation patterns of <strong>[134523-00-5]atorvastatin</strong> and metabolites thereof.[107] The wild-type CYP102A1 mutants and human CYP3A4 were incubated with 80 muM of <strong>[134523-00-5]atorvastatin</strong> at 37 for 30 minutes in the presence of an NADPH-generating system. Reactions were terminated by the addition of 2-fold ice-cold CH2Cl2. After centrifugation of the reaction mixture, a supernatant was removed and an organic solvent layer was evaporated under nitrogen. The reactant was reconstituted into 100 of a mobile phase by vortex mixing and sonication for 20 sec. An aliquot (10 ) of the prepared solution was injected into the LC column.[108] LC-MS analysis was carried out on Shimadzu LCMS-2010 EV system (Shimadzu Corporation, Japan) having LCMS solution software by electro spray ionization in a positive mode. In a Shim-pack VP-ODS column (250 mm x 2.0 mm i.d., Shimadzu Corporation, Japan) water containing 0.1% formic acid/acetonitrile (80/20, v/v) was used as a mobile phase A, and acetonitrile/0.1% formic acid (90/10, v/v) was used as a mobile phase B. The mobile phase A/B (70/30, v/v) was separated using a gradient pump (LC-20AD, Shimadzu, Kyoto, Japan) at a flow rate of 0.16 ml/min. In order to identify the metabolites, mass spectra were recorded by electro spray ionization in a negative mode. Interface and detector voltages are 4.4 kV and 1.5 kV, respectively. Nebulization gas flow was set at 1.5 ml/min, and interface, curve desolvation line (CDL), and heat block temperatures were 250, 230, and 200, respectively.[109] As a result, it might be appreciated that in mass spectra of the reaction samples, peaks were observed at 7.183 min (4-OH <strong>[134523-00-5]atorvastatin</strong>), 19.583 min (2-OH <strong>[134523-00-5]atorvastatin</strong>), and 21.450 min (<strong>[134523-00-5]atorvastatin</strong>) as shown in total ion current (TIC) profiles of the metabolites prepared by the human CYP3A4 (A) and the chimera 16A1V2 (B) derived from the CYP102A1 mutant of FIG. 11.[110] Further, as shown in FIGS. 12A to 12C, the peaks in mass spectra of 4-hydroxylated products (A), 2-hydroxylated products (B), and <strong>[134523-00-5]atorvastatin</strong> ... | |
With sodium hypochlorite; octabromotetrakis(2,6-dichlorophenyl)porphyrin Fe(III)Cl; In water; acetonitrile; at 80℃; for 0.5h; | <strong>[134523-00-5]Atorvastatin</strong> API (40.0 ?rig. 0.07160 mmol) extracted using 80 rnL 1: 1 methanol: ethanol, filtered and concentrated in vacuo. The resulting- solid taken up in 2:0.25 rnL acetonitrilc: water and transferred to a microwave tube. Octabromo tetrakis(2,&-dichlorophcnybporphyrin Fe(III)Cl (5.77 mg,0.00358 inmol) then added,followed by sodium hypochlorite (88.4 uL, 0.17901 inmol). Reaction run in the microwave at 80C for 50 minutes. (representative, see table below for additional coridi tions).Workup: Reaction diluted with 40 rnL chloroform, Washed 3x 40 mL water. Washed 3x 40 mL brine. Back-extracted aqueous layer with 40 mL chlorofOrm. Orgamc layers5 combined and dried over MgSO4. filtered and concentrated in vacuo. Samples analyzed according to parameters in Example 1.Identification of <strong>[134523-00-5]atorvastatin</strong> metabolites following optimal microwave reaction in the presence of Octabromo tctrakis( ,&dichlorophcnyl)porphyrin Fe( iflC I are provided in Table 5 and F?iG 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 36h; | Example 55 Preparation of 1-((19R,21R)-1-(3',6'-Dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthene]-5-ylamino)-19,21-dihydroxy-17-oxo-1-thioxo-6,9,12-trioxa-2,16-diazatricosan-23-yl)-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide (S54) To <strong>[134523-00-5]Atorvastatin</strong> (20 mg, 35 mumol) in DMF (200 muL) was added DIPEA (24 muL, 140 mumol), FITC-PEG3-NH29 (90 mg, 148 mumol) and PyBOP (27 mg, 50 mumol). The reaction mixture was stirred for 36 hours and then directly applied to a reverse phase C-18 column (gradient water: acetontrile 9:1 to 1:5 containing 0.1% TFA) to yield fluorescein-labeled <strong>[134523-00-5]atorvastatin</strong> (17 mg, 15 mumol, 41 %). 1H NMR (600 MHz, DMSO-d6) delta 9.89 (s, 1H), 9.77 (s, 1H), 8.19 (s, 1H), 8.05 (s, 1H), 7.75 (t, J = 5.6 Hz, 1H), 7.69 (s, 1H), 7.47 (d, J = 8.0 Hz, 2H), 7.24 - 7.13 (m, 8H), 7.07 - 7.01 (m, 4H), 6.99 - 6.92 (m, 2H), 6.66 - 6.63 (m, 2H), 6.59 - 6.52 (m, 4H), 3.94 - 3.87 (m, 1H), 3.79 (dd, J = 11.9, 7.1 Hz, 1H), 3.75 - 3.68 (m, 2H), 3.24 - 3.15 (m, 2H), 3.10 - 2.98 (m, 3H), 2.09 (d, J = 6.3 Hz, 2H), 1.78 (p, J = 6.5 Hz, 2H), 1.64 - 1.53 (m, 4H), 1.53 - 1.43 (m, 1H), 1.41 - 1.30 (m, 8H), 1.28 - 1.17 (m, 2H). 13C NMR (151 MHz, DMSO-d6) delta 171.26, 169.20, 166.81, 161.35, 160.14, 152.53, 136.57, 135.55, 129.79, 129.68, 129.32, 129.11, 128.30, 127.93, 126.03, 123.65, 121.22, 120.04, 118.06, 116.11, 115.96, 113.25, 110.37, 102.88, 70.42, 70.39, 70.23, 70.19, 68.73, 66.63, 66.46, 44.45, 44.26, 41.48, 39.38, 36.36, 29.94, 29.19, 22.98; LC-MS (ESI): calcd for C64H68FN5O12S: 1150.46420 [M+H]+, found: 1150.21 [M+H]+, Rt = 8.81 min; HR-MS found 1151.46229 [M+H]+. |
Tags: 134523-00-5 synthesis path| 134523-00-5 SDS| 134523-00-5 COA| 134523-00-5 purity| 134523-00-5 application| 134523-00-5 NMR| 134523-00-5 COA| 134523-00-5 structure
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