PROCESS FOR THE PRODUCTION OF ATORVASTATIN CALCIUM IN AMORPHOUS FORM
Field of the Invention
Processes tor the production of atorvastatin calcium of high purity in an amorphous form are provided.
Background of the Invention
Atorvaslatin is known by the chemical name [R-(R*, #*)]-2-(4-fluorophenyl)-13,6-dihydroxy-5-(l-methyletliyl)-3-phenyl-4-f(phenylamino)carbonyl]-l//-pyiTole-l-heptanoic acid. The hemi-calcium salt of atorvastatin is useful as an inhibitor of the enzyme 3-hydroxy-3- methylglutaryl-coen/yme A reductase (HMG-CoA reductase) and is thus useful as a hypolipidemic and hypocholesterolemic agent.
U.S. Patent Nos. 5,273,995; 5,003,080; 5,097,045; 5,103,024; 5,124,482; 5,149,837; 5,155,251; 5,216,174; 5,245,047; 5,248,793; 5,280,126; 5,397,792; and 5,342,952, disclose various processes and intermediates for preparing atorvastatin. Several processes have been reported for the preparation of amorphous form of atorvastatin calcium in U.S. Patent Nos, 6,528,660 and 6,613,916; U.S. Patent Application Publication Nos. 2002/183378 and 2003/109569, and International (PCT) Patent Applications WO 01/2899, WO 02/57228, WO 02/83637, WO 02/83638, WO 03/18547 and WO 03/68739.
Summary of the Invention
In one embodiment, a process for the production of atorvastatin calcium in amorphous form is provided comprising:
a) reacting a solution of (4/?-cis)-l ,1 -dimethylethyl-6-{2-[2-(4-fluorophenyl)-5-(l-methyl(;ihyl)-3-phenyl-4-[(phenylan-iino)-carbonyl]-l//-pyrrol-lyl]ethyl}-2)2-dimethyl-1,3 -dioxane-4-acetate (Compound H, as shown in Scheme I) in a water miscible solvx-ni with an acid to obtain \R-(R*,R*)}-1,1 -dimethylethyl-2-(4-i]iiorophenyD-ft6-dihydroxy-5-(l-iuethylethyl)-3-phenyl-4-
SUBSTITUTB SHEET (RULE 26)

[(phenylamino)carbonyl]-l//-pyiTole-l-heptanoate (Compound I, as shown in Scheme I);
b) treating Compound I with :in alkali metal hydroxide to obtain an alkali
metal sail ofaiorvustalin;
c) washing the solution of alkali metal salt of atorvastatin with a solvent
immiscible or slightly miscible in water;
d) treating the washed solution of alkali metal salt of atorvastatin with a
calcium salt or calcium hydroxide io obtain atorvastatin calcium;
e) isolating crude atorvastatin calcium;
f) purifying crude atorvastatin calcium by dissolving in a mixture of
tetrahydrofuran and rnelhariol, and precipitating with water to obtain pure
atorvastatin calcium in crystalline form; and
g) converting crystalline pure atorvastatin calcium so obtained into amorphous
form .SCHEME!

(Figure Remove)
iii another embodiment, a process for purifying atorvastatin calcium is provided comprising dissolving crude atorvastatin calcium in a mixture of letrahydrofuran and
methanol, and precipitating with water to obtain pure atorvastatin calcium in crystalline form.
In an additional embodiment, a process for the production of stabilized atorvastatin calcium in amorphous form is provided comprising:
a) dissolving crystalline alorvaslatin calcium and an antioxidant in a solvent;
b) adding the solution of atorvastatin calcium and antioxidant to an anti-
solvent; and
c) separaung precipitated, amorphous atorvastatin calcium from the resulting
suspension.
In yet another embodiment, a process for the production of atorvastatin calcium in amorphous form is provided comprising:
a) dissolving crystalline atorvastatin calcium in a hydroxylic solvent;
b) adding the obtained solution of atorvastatin calcium to a non-hydroxylic
anti-solvent, wherein the non-hydroxylic anti-solvent has a higher boiling point
than the hydroxylic solvent;
c) concentrating the solution so obtained to remove the hydroxylic solvent;
and
d) separating precipitated amorphous atorvastatin calcium from the resulting
suspension,
The acid used lor deketalization of Compound H to afford Compound 1 may be an inorganic acid. Examples of inorganic acids include hydrochloric, hydrobromic, sulphuric, phosphoric and nitric acids. Suitable water-miscible solvents for the deketalization process include acetonitnle. alcohols such as methanol, ethanol, propanol, and isoprupanol; cyclic ethers such as dioxane and tetrahydroftlran; ketones such as acetone and mixtures thereof
Compound 1 can he hydrolysed Widi an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide and lithium hydroxide. The reaction mixture may be maintained at apH of at least 9, for example, about 12, to result in efficient hydrolysis and to minimize side product formation. The reaction mixture is then washed with a water-
immiscible or slightly vvalcr-miscible solvent to remove unreacted compounds and other impurities. Suitable solvents for the washing include ethers such as methyl tertiary butyl ether, diethyl ether, methyl ethyl ether and dibutyl ether; esters such as ethyl acetate and isopropyl acetate; and hydrocarbons such as toluene and petroleum ether.
The solution of alkali metal salt of atorvastatin obtained is reacted with calcium hydroxide or a calcium salt such as calcium acetate, calcium chloride, calcium sulfate, calcium nitrate and calcium phosphate. The reaction may be performed at a temperature of about 45 to 55 1>C. The pH of the solution of alkali metal salt of atorvastatin may be lowered to about 7.8 to 8.2 with an acid before addition of the calcium salt to facilitate isolation of crude atorvastatin calcium.
Any residual water-immiscible or slightly water-miscible solvent remaining in the reaction mixture may be removed under reduced pressure to aid precipitation. Water may be used as an antisolvent to effect precipitation of crude atorvastatin calcium in good yields. Water may be added at a temperature of about 55 to 65 °C to avoid rapid precipitation and seeds of crystalline atorvastatin calcium may also be added to the mixture. Crude atorvastatin calcium may be isolated in high yields by cooling the reaction mixture to a temperature of about 20 to 35 "C and stirring at the same temperature for several hours before filtration or centrifugation.
Crude atorvastatin calcium is purified by crystallization using tetrahydrofuran and methanol as solvents and water as anti-solvent. Purification involves removal of unreacted compounds, side product and other impurities. Tetrahydrofuran, methanol and water may be used in the volume ratio 1:1:4 to obtain atorvastatin calcium of high purity. Water may be added at a temperature of about 60 to 65 UC. Seeds of crystalline atorvastatin calcium may be added to facilitate precipitation, in a particular embodiment, seeds of crystalline atorvasuuin calcium are added at a temperature of about 50 UC. Crystalline atorvastatin calcium may be isolated by cooling the mixture to a temperature of about 30 to 35 "C and stirring at the same temperature for several hours before filtration or centrifugation.
Crystalline pure atorvastatin calcium may be converted into the amorphous form by methods known in the art such as U.S. Patent Nos. 6,528,660 and 6,613,916; International (PCT) Patent Applications WO 01/28999, WO 03/99785, WO 03/78379,
WO 03/18547 and WO 02/57228; and U.S. Patent Application Publication No. 2002/183378, which are incorporated herein by reference.
Amorphous alorvastatiu calcium may also be obtained by having an additional step wherein the pure crystalline atorvastatiri calcium (where "pure" is meant in the sense of chemical purity) obtained after step 1) is suspended in a mixture of methanol and water in the volume ratio I to 5 and stirred with seed crystals of crystalline Form I, to obtain atorvastatin calcium in crystalline Form 1. The stirring may be performed at a temperature of about 10 to 65 °C, for example, about 30 to 45 °C.
Alternatively, pure crystalline atorxaslatin calcium (where "pure" is meant in the sense of chemical purity) obtained after step f) is suspended in a mixture of methanol and water in the volume ratio 3 to 2 and stirred with seed crystals of crystalline Form II, to obtain atorvastatin calcium in crystalline .1 onn II. The volume of methanol and water mixture may be about 15 to 25 times, for example, about 20 times, the weight of the atorvastatin calcium to be suspended. The stirring may be performed at a temperature of about 10 to 65 °C, for example, about 25 to 45 °('.
In yet another variant, a further additional step may be performed wherein crystalline Form I of atorvastatin calcium obtained above is suspended in a mixture of methanol and water in the volume ratio 3 to 2 and stirred with seed crystals of crystalline Form II, to obtain atorvastatin calcium in crystalline Form II. The volume of methanol and water mixture may be about 1 5 to 25 limes, for example, about 20 times, the weight of the atorvastatin calcium to be suspended. The stirring may be performed at a temperature of about 10 to 65 °C. for example, about 2:; to 45 °C.
Amorphous atorvastatin calcium may be obtained by dissolving crystalline atorvastatin calcium in a solvent, and adding the resulting solution to an anti-solvent. An anti-solvent is a liquid that does not dissolve atorvastatin calcium. Examples of solvents include ketones such as acetone and methyl isobutyl ketone; esters such as ethyl acetate and isopropyl acetate; chlorinated hydrocarbons such as methylene chloride and ethylene dichloricle: cyclic ethers such as dioxan and tetrahydrofuran; alcohols such as methanol, ethanol and isopropauol; nitriies such as acetonilrile; dipolar aprotic solvents such as dimethylsulfoxide and dimethylformamide; and mixtures thereof with water. Examples of anti-solvents include hydrocarbons, such as cyclohexane, hexanes, heptanes, petroleum
ethers, toluene, xylene and the like; dialkyl ethers such as diethyl ether, diisopropyl ether, and the like; and can readily be determined by one ordinarily skilled in the art.
An anlioxidani rna\ be added to the atorvastatin calcium solution to obtain stabilized, amorphous atorvastatin calcium. Examples of suitable antoxidants include butylated hydroxyanisole, butylaled hydroxytoluene and tertiary-butylated hydroquinone.
Detailed Description ofjhe Invention
The term 'stabilized atorvastatin calcium1 means the hemi-calcium salt of atorvastatin having a level of purity, which is provided and maintained through the use of antioxidants.
Stabilized, amorphous atorvastatin calcium can be obtained with purity of at least 97%, for example when determined by high performance liquid chromatography (HPLC) analysis. In general, stabilized, amorphous atorvastatin calcium having a purity of at least 99% may be obtained, in some particular embodiments, stabilized, amorphous alorvastatin calcium having a purity of at least 99.5% may be obtained.
The atorvastatin calcium, solution may be dried (moisture removal) before its addition to the non-solubili/.ing liquid. This may be accomplished by, for example, filtration through dry molecular sieves. Alternatively or additionally, drying of the solution may be achieved by a process, wherein the solution is made using excess solvent, which is then concentrated to remove moisture from the- solution.
Examples ofhydroxylic solvents which may be used for dissolving atorvastatin calcium include alcohols such as rnethanol, ethanol, propanol, isopropanol, and mixtures thereof with water. Examples of non-hydroxylic anti-solvents which may have a higher boiling point than the hydroxylic solvent include hydrocarbons, such as cyclohexane, hexanes, heptanes, petroleum ethers, toluene, xylene and the like; dialkyl ethers such as diisopropyl ether, and the like; and can readily be determined by one ordinarily skilled in the art.
The solution of atoivastatin calcium having the desired hydroxylic solvent and non-hydroxylic anti-solvent is concentrated to remove the hydroxylic solvent either partially or completely to precipitate amorphous atorvastatin calcium. In a manner similar
to that detailed above, an antioxidant may be added to the hydroxylic solution of atorvaslatin calcium to obtain stabilized, amorphous atorvastatin calcium. Similarly, the atorvastatin calcium hydroxylic solution may also be treated as detailed above for moisture removal.
(4^-c/.v)-l?l-dinietl]ylethyl-6-{2-[2-(4-fluorophenyl)-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)"Carbonyl|-l //-pyrrol- lyl Jethyl j- -2,2-dimethyl-1,3~dioxane-4-acetale (Compound H, as shown in Scheme 1) may be obtained by methods known in the art, such as those described in U.S. Patent Nos. 5.003,080; 5,103,024; 5,155,251 and Tetrahedron Let!., 33 (17), 2279-82 (1992), which are incorporated herein by reference.
In a particular embodiment, Compound H may be obtained as described in reaction Scheme I by
a) treating (//if,3-dihydroxy-5-(l-methylethyl)-3-pheiiyl-4-[(pbenylamino)-cai boiiyl]-l//-pyiTole-l-heptanoic acid, sodium salt (Atorvastatin Sodium)
The pli of the reaction mixture obtained above was adjusted to about 12 by adding 10% w/v aqueous sodium hydroxide solution at 25-30 °C and the resulting mixture was stirred for about 6 hours at 25-30 "C. The progress of the reaction was monitored by HPLC. The pli of the reaction mixture was monitored and maintained at about 12 throughout the course of the reaction by adding 10% w/v aqueous sodium hydroxide solution. After the reaction was complete, ihe mass was filtered and concentrated to about 84 L.
Crude l^-(/?*,/?*)J-2-(4-nuoropbenyl)-/3,6-dihyclroxy-5-(l-methylethyl)-3-phenyl-4-[(pbenyIamino)-carbouvll-l//-pyiTol-l-lieptanoic acid, calcium salt (2:1) (Atorvastatiu Calcium Crude)
De-ionised water (89 L), methanol (19 L), and methyl tertiary butyl ether (60 L), were added to the concentrated reaction mass obtained above with continuous stirring. The layers were separated. The aqueous layer was washed with methyl tertiary butyl ether
and filtered through a sparkler filter. The filtrate was collected in a reactor and its pH adjusted to 7.9-8.1 with 6 N hydrochloric acid. This mixture was heated to 48 °C.
To this mixture, an aqueous solution of calcium acetate (1.33 Kg, 8.41 moles) in water (48 L) was added slowly and heated to 51 °C. The contents were stirred at 51-54 °C until a clear solution was obtained. Crystalline atorvastatin calcium Form 1 seeds (77g) were added arid stirred. Methyl tertiary buiyl ether was recovered under reduced pressure. The temperature was raised to 58 °C and de-ionised water (11 L) was added. The contents were cooled to 50 °C and a second lot ofatorvastatin calcium Form I seeds (33g) were added. The contents were further cooled slowly to 30 °C over a period of 3-4 hours and filtered. The wet cake was washed with a mixture of methanol and de-ionised water. The material was dried al 45-50 CC to yield 8 Kg ofatorvastatin calcium having a purity of 97.5% determined by HPLC.
Pure Crystalline Atorvastatin Calcium
The crude product obtained above was charged to a reactor containing methanol (16 L) and tetrahydrofuran (40 L). The contents are stirred to get a clear solution and filtered tlirough a sparkler filter followed by washing over hyflo bed with methanol (32 L).
The filtrate was heated 10 65 °C and re fluxed for 30-60 minutes. To this, de-ionised water (about 120 L) was added slowly over a period of 1 -2 hours until turbidity appeared. At the onset of turbidity, crystalline atorvaslatin calcium Form I seeds (8g) were added. The contents were stirred for 30 minutes at 68-72 "C and de-ionised water (about 40L) was added. The contents were cooled to 50 °C and atorvastatin calcium Form 1 seeds (24g) were added with continuous stirring. The contents were further cooled to 35 °C and stirred for 5 hours at 33-35 °C and then filtered. The wet cake was washed with a mixture of letrahydrofuran, methanol and de-ionixetl water (volume ratio 1:1:4) and then dried at 50-55 °C under reduced pressure to yield 7.36 Kg of cyrstalline atorvastatin calcium.
Preparation of Crystalline Atorvastatin Calcium (Form-I)
The above dried product was added to a reactor containing de-ionized water (108,8 L) and methanol (19.2 L). The contents were stirred lor 10 minutes and heated to 45 °C. To this, crystalline atorvastatin calcium form I seeds (730g) were added and the mixture was stirred at 40 °C to 45 °C until the IR spectrum of the sample was comparable with the seed crystals. The contents were filtered and washed with a mixture of de-ioni/ed water and methanol (volume ratio 6:1). The wet cake was dried at 50-55 °C to yield 7.2 Kg of crystalline atorvastatin calcium having a purity of 99.7% determined by ITPLC.
Atorvastatiu Calcium Amorphous
Tetrahydrofuran (16.38 L) was added to crystalline atorvastatin calcium Form I (6.3 Kg, 5.2moles) obtained above followed by butylated hydroxyanisole (63 g, 0.5 moles). The contents were stirred for 30 minutes at 20 to 25 °C to get a solution. This solution was filtered over a hyflo bed followed by washing of the hyflo bed with tetrahydrofuran (2.52 L), and the filtrate was collected. The filtrate was added slowly over a period of 4 to 5 hours to cyclohexarie (189 L) ai 25 °C. The contents were stirred for 60 minutes, centrifuged and washed with cyciohexane. The material was dried under vacuum at 60 °C to 70 °C for 12 hours to yield 5.67 Kg of amorphous atorvastatin calcium having a purity of 99.54% determined by HPLC.
.Example 2: Preparation of Atorvastatin Calcium Amorphous
Tetrahydrofurau (10 L) was added to atorvastatin calcium Form I (1 K.g) obtained as per Example 1 above, followed by butylated hydroxyanisole (3 g). The contents were stirred for 15 minutes at 20 to 25 UC to get a solution. This solution was filtered over hyflo bed followed by washing of the hyflo bed with tetrahydrofuran (0.4 L), and the filtrate was collected and concentrated to a volume of about 3 L at 62 to 70 °C. The solution was cooled to 20 °C and added slowly over a period of 4 to 5 hours to cyciohexane (30 L) at 20 to 23 °C. The contents were stirred for 60 minutes and filtered. The wet cake was washed with cyciohexane. The material was dried under vacuum at 60 °C to 70 °C for 12 hours to yield 0.9 Kg of amorphous atorvastatin calcium having a purity of 99.45% determined by HPLC.
Preparation or' Crystalline Atorvastatin jCalcmm (Form-ll)
A mixture of methanol (1 80 ml) and de-ionized water (120 ml) was added to crystalline atorvastatin calcium form 1(15 g) at room temperature. The temperature was raised to 25 °C, seeds of crystalline atorvastatin calcium form 11 (1 .5 g) were added, and the suspension was stirred at 25 °C. The suspension became very thick after about 24 hours and a mixture ofmelhanol (90 ml) and de-ionized water (60 ml) was added to resume stirring. The suspension was further stirred at 25 °C for another 24 hours and then filtered. The filtered solids were dried under reduced pressure at 70 °C for 48 hours to get 14.7 g of crystalline atorvastatin calcium. The XRD spectrum of the product matched with that of Form- 1 1 of atorvastatin calcium.
Example 4
A mixture of methanol (1 .2 L) and de-ionixed water (800 nil) was added to crystalline atorvastatin calcium Form I (100 g) at room temperature. The temperature was raised to 45 °C slowly, seeds of crystalline atorvastatin calcium form II (10 g) were added, and the suspension stirred at 45 °C. The suspension became very thick after about 24 hours and a mixture of methanol (600 ml) and de-ioni/ed water (400 ml) was added to resume stirring. The suspension was again warmed to 45 °(..' and further stirred at the same temperature for another 24 hours and then liltered. The filtered solids were dried under reduced pressure at 70 °C for 48 hours to get 98 g of crystalline atorvastatin calcium. The XRD spectrum of the product matched with that ol'Fonn-U oi atorvastatin calcium.
Bx ample 5: Purification of Ator vasta tin CaJ cium (without seeding)
The crude atorvastatin calcium obtained as per Example 1 was charged to a reactor containing methanol (1 6 1 > and tetrahydrofuran (40 L). The contents are stirred to get a clear solution and tillered through a sparkler filter, followed by washing over hyflo bed with methanol (32 L). The filtrate was heated to 65 °C and refluxed for 30-60 minutes. To this, de-ionised water (about 120 L) was added slowly over a period of 1-2 hours until turbidity appeared. The contents were stirred for 30 minutes at 68-72 °C and de-ionised water (about 40L) was added. The contents were cooled to 35 °C and stirred for 5 hours at
33-35 °C and then filtered. The wet cake was washed with a mixture of tetrahydroluran, methanol and de-ionized water (volume ratio 1:1:4) and then dried at 50-55 °C under reduced pressure to yield 7 33 K.g of cyrstalline atorvastatin calcium.
Example 6: Preparation of Atorvastatin Calcium Amorphous
Tetrahydrofuran (480 ml) was added to crystalline atorvastatin calcium obtained above in Example 5 (60 g), followed by butylated hydroxyanisole (0.6 g). The contents were stirred, de-ionised water (24 ml) was added and the mixture was stirred for 15 minutes at 20 to 25 °C to get a clear solution. Molecular sieves (240 g, Siliporite NK30 AP(i£l powdered) were added to the solution and the mixture was stirred for 2 hours at 20 to 25 °C. This solution was filtered through a molecular sieves bed, followed by washing of the bed with tetrahydroftiran (120 ml). The filtrate was collected and concentrated to a volume of about 210 ml at 60 to 70 °C. The concentrated solution was cooled to 25 °C and added slowly over a period of 2 hours to cyclohexane (1800 ml) at 22 to 25 °C tinder moderate stirring. The contents were stirred vigourously for 30 minutes at the same temperature and filtered. The wet cake was washed with cyclohexane (60 ml). The material was dried under reduced pressure at 60 °C to 70 °C for 6 hours to yield 54 g of amorphous atorvastatin calcium. Siliporite NK30 AP is registered Uademurk oi'CEC'A, France
Example 7: Preparation of Crystalline Atorvastatin Calcium (Form II)
A mixture of methunol (1.2 L) and de-ionized water (800 ml) was added to crystalline atorvasuuin calcium obtained above in example 5 (100 g) at room temperature. The temperature was raised to 45 °C slowly, seeds of crystalline atorvaslatin calcium form 0(10 g) were added, and the suspension stirred at 45 °C. The suspension became very thick after about 24 hours and a mixture of methanol (600 ml) and de-ionized water (400 ml) was added to resume stirring. The suspension was again warmed to 45 °C and further stirred at the same temperature for another 24 hours and then filtered. The filtered solids were dried under reduced pressure at 70 °C tor 48 hours to get 98 g of crystalline atorvastatin calcium. The XRD spectrum of the product matched with that of Form-II of atorvastatin calcium.
Example 8: Preparation of Atorvastatin Calcium Amorphous
Tetrahydrofuran (10 L) was added to atorvastatin calcium crystalline Form II (1 Kg) followed by butylated hydroxyanisole (3 g). The contents were stirred for 15 minutes at 20 to 25 °C to get a solution. This solution was filtered over a hyflo bed followed by washing of the hyflo bed with tetrahydrofuran (0.4 L), and the filtrate was collected and concentrated to a volume of about 3 L at 62 to 70 °C. The solution was cooled to 20 °C and added slowly over a period of 4 to 5 hours to cyclohexane (30 L) at 20 to 23 °C. The contents were stirred for 60 minutes and filtered. The wet cake was washed with cyclohexane. The material was dried under vacuum at 60 °C to 70 °C for 12 hours to yield 0.9 Kg of amorphous atorvastatin calcium having a purity of 99.5% determined by HPLC.
Example 9: . AtoryasmtiiLCalckim Amorphous
Methanol (100 mL) was added to atorvastatin calcium form II (10 g). The contents were stirred for 40 minutes at 20 to 25° C to get a clear solution. Butylated hydroxyanisole (O.lg) was then added and the mixture stirred for 30 minutes. Methanol (50 ml) was then recovered at 40° C under reduced pressure in 30 minutes. The solution was cooled to 20 to 25° C and added slowly over a period of one hour to cyclohexane (300m L) at 20 to 30° C. The solution was stirred for 1 hour ai 25° ('. The obtained clear solution was concentrated to a volume of about 300 L at 60 lo 70° C (approximately 50 ml methanol was distilled out). The obtained suspension was then cooled to 20 to 25° C with stirring in 30 minutes and filtered. The xvet cake was washed with cyclohexane. The material was dried under vacuum at 60 °C to 70 QC for 1 hour to yield 9.0 g of amorphous atorvastatin calcium.
Example 1 0: Preparation of (4R-cis)-\, 1 -dimethylethyl-[6-(2-aminoethyl)-2,2-dimethyl: J Jicet at e iCotiipj?und_F)
-l, l-diinethylethyl-6-cyauo-5-hydroxy-3-oxohexauoate (Compound C)
n-Butyl lithium and diisopropylamme are mixed at -40 °C for the formation of lithium diisopropylaniiiie. l,l-l)imethylethyl acetate (Compound B) in tetrahydrofuran is
then added at -50 °C and the mixture stirred at -20 to 25 °C for 1 hour. The reaction mixture is further cooled to -50 °C and (^j-ethyl-4-cyano-3-hydroxybutanoate is added maintaining temperature at -20 to -25 °C arid kept at the same temperature for 2 hours. The reaction is monitored for completion by thin layer chromatography. The reaction is quenched with a 2 A' solution of hydrochloric acid and the product was extracted with ethyl acetate, washed with water and brine followed by complete evaporation of solvent to get the title compound which is taken to the next step without further purification.
[R-(R*, R*)]-l,l-dimethylethyl 6-cyaiio-3, 5-dihydroxyhexanoate Compound D)
To a mixture of tetrahydrofuran and methanol containing (^)-l,l-dimethylethyl-6-cyano-5-hydroxy-3-oxohexanoate (Compound C) is added diethyl methoxyborane slowly at -80 to -90 °C and stirred for 30 minutes at the same temperature. Sodium borohydride is added in lots maintaining temperature at -80 to -90 °C and stirred for 5 hours at -80 to -90 °C. After completion of reaction, the temperature is slowly raised to 0 °C then to room temperature in 2 hours, ami the reaction quenched with glacial acetic acid slowly in 30 minute while maintaining temperature between 0 to 40 °C. The mixture is concentrated to approximately 20% of total volume. Methanol is added and recovered to remove borane derivatives. The product is extracted with ethyl acetate, washed with water and then brine. The organic layer is concentrated to approximately 20% of original volume. Tetrahydrofuran is then added and recovered completely under reduced pressure to get the title compound as a concentrated mass, which is taken to the next step.
(4/i-m)-l,l-Dimethylethyl-[6-cyanomethyl-2,2-dimethyl-l,3-dioxau]-4-acetate (Compound E)
A mixture of 2,2-dimethoxy propane containing [/^-(^*,7?*)]-l,l-dimethylethyl-6-cyano-3,5-dihydroxyhexanoate (Compound D), acetone and methanesulfonic acid is stirred for 3 to 4 hours at 29 to 30 °C and the reaction monitored for completion by thin layer chromatography. The reaction is then quenched with 5% w/v aqueous sodium bicarbonate solution .slowly to adjust pH to about 7 and extracted with ethyl acetate. The organic layer is concentrated and the solvent recovered completely under reduced
pressure. The residue is crystallized with hexane to get the title compound as a crude product, which is recrystallizecl with niethanol and water to get the pure compound.
(4/?-c7s)-l,l-Dimethylethyl-[()-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate (Compound F)
Pure (4R-cis)- 1 , l-dimethylethyi-[6-cyanoniethyl-2,2-diniethyl- 1 ,3-dioxan]-4- acetate (Compound E) dissolved in ammonia saturated niethanol is hydrogenated in the presence of activated Raney nickel by applying hydrogen pressure of 4.5 to 5 kg/cm" at room temperature under stirring for 4 to 1 2 hours, The reaction is monitored for completion by gas chromatography, The catalyst is filtered through liyflo bed and concentrated to recover niethanol completely under reduced pressure to get the title compound.
Example 1 1 : Preparation of crystalline, atorvastatin calcium form- 1 seed Part A - Prepai atiou of Crude Atorvastatiu Calcium
[J?-(U*^*)]-l,l-l>imethylethyl-2-(4-nuoroplienyl)-|8,<5-dihydroxy-5-(l-methylethyl)-3-pheuyl-4-l(pheiiylamino)carboiiyl]-l/jr-pyrrole-l-beptaiioate (Compound I)
To a solution of Compound H (57g) in niethanol (1.71L), 1 N hydrochlonc acid solution (1 16 niL) was added drop wise at 20-25 °C in 15 minutes. The reaction mixture was stirred at the same temperature for about 5 hours, and monitored by TLC (hexane:ethanol :: 6:4). 1 N hydrochloric acid solution (10 niL) was then added and the reaction mixture was further stirred for about 2.5 hours.
)-j8, 5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-|(pueuylainiuo)-carbouyl]-l//~pyiTole-l-lieptauoic acid, sodium salt (Atorvastatin Sodium)
The p.H of the reaction mixture obtained above was adjusted to about 12 by adding 10% w/V aqueous sodium hydroxide solution at 25-30 UC and the resulting mixture was stirred for about 6 hours at 25-30 UC. The progress of the reaction was monitored by HPLC. The pli of the reaction mixture was monitored and maintained at abotit 12 throughout the
course of the reaction by adding 10% w/v aqueous sodium hydroxide solution. After the reaction was complete, the mass was filtered and concentrated to get the title compound as a white precipitate.
l/?-(/?=i^*)j-2-(4-nuoiophenyl)-^-dihydroxy-5-(l-methytethyl)-3-plieny]-4-Kphenylamiuoj-carbouyl|-.lW-pyrrol-I-heptaiioic acid, calcium salt (2:1) (Atorvastatiu Calcium)
De-ioni/ed water (500 mL), methanol (200 mL), and methyl tertiary butyl ether (200 mL), were added to atorvastatin sodium obtained above and stirred to obtain a solution. The layers were separated. The aqueous layer was washed with methyl tertiary butyl ether(200 mL), and filtered through hyflo bed. The hyilo bed was washed with a mixture of methanol (25 mL') and methyl tertiary butyl ether (25 mL), The filtrate was warmed to 50 °0 and its pH adjusted to about 10 with concentrated hydrochloric acid. To this mixture, an aqueous solution of calcium acetate (7.52 g) in water (275 mL) was added slowly in 1.5 hours at 50 °C. Some turbidity was observed at this stage. Methyl tertiary butyl ether (20 mL) was added. Some methyl tertiary butyl ether spontaneously evaporated at this stage. The mixture was heated to 80 °C to obtain a clear solution. The contents were stirred for 20 minutes at the same temperature and then allowed to cool for 1,5 hours. The contents were further cooled to 25 °C and .stirred for 30 minutes at the same temperature and then filtered. The wet product was slurry washed with a mixture of methanol and de-ionized water (2:1, 100 mL) and filtered. The material was dried at 45 °C for 8 hours to yield 43.38 g of atorvastatin calcium. The XRD spectrum of the product mainly showed two very broad peaks.
Part B- Preparation of crystalline atorvastatin calcium form-I seed Step I
Atorvastatin calcium (2 g) obtained above was suspended in de-ionized water (20 ml) and stirred for 20 hours at about 30C C. The suspension was then filtered and dried under reduced pressure at 40 lo 43" C' for 3 Lours to get 1.9g of the product. The XRD spectrum of the product showed a change in pattern irom that of the starting atorvasiatin calcium. An increase in sharp peaks indicating increased crystailmity was observed.
Step II
Atorvastatin calcium (1.8 g, same as that used as starting compound in step 1) and atorvastatin calcium (0,2 g. obtained from step 1 above) were suspended in a mixture of de-ionized water (34 ml) and methanol (6 ml). The temperature was raised slowly to 38 to 40 °C and the suspension was stirred for 16 hours at the same temperature. The suspension was then cooled to 35 °C, filtered and dried under reduced pressure at 40 to 45 °C for 4 hours to get 1.9 g of the product. The XRD spectrum of the product showed a change in pattern from that of the starting atorvastatin calcium. The XRD spectrum of the product matched with that of Form-1 of atorvastatin calcium.
Example 12: Preparation of crystalline atorvastarin calcium form-TI seed
A mixture of melhanol (360 ml) and de-ionized water (240 ml) was added to a mixture of amorphous atorvastatin calcium (15 g) and crystalline atorvastatin calcium lorni 1 (15 g), the suspension \\;.s warmed lu 45 °C slowly and stirred at the same temperature. The suspension became very thick after 24 hours and a mixture of methanol (180 ml) and de-ionized water (120 ml) was added to resume stirring. The suspension was warmed to 45 °C and further stirred at the same temperature for 24 hours and then filtered. The filtered solids were dried under reduced pressure at 70 °C for 48 hours to get 27 g of crystalline atorvastatin calcium. The XRD spectrum of the product matched with that of Form-IJ of atorvastatin calcium.

We claim!
1. A process for the production of atorvastatin calcium in amorphous form comprising:
a) reacting a solution of (4jR-cis)-l,l-dimethylethyl-6-{2-[2-(4-flLiorophenyl)-
5-(l-methylethyl)-3-phenyl-4-[(phenylamino)-carbonyl]-lJ::/-pyi-rol-lyl]ethyl}-2,2-
dimethyl-l,3-dioxane-4-acetate (Compound H) in a water-miscible solvent with an
acid to obtain [^-{^^^"}]-l,l-dimethylethyl-2-(4-fluorophenyl)-^,5-dihydroxy-5-
(l-inethylethyl)-3-phenyl-4-[(phenylammo)carbonyl]-lJft'-pyrrole-l-heptanoate
(Compound I);
b) treating Compound 1 with an alkali metal hydroxide to obtain an alkali
metal salt of atorvastatin;
c) washing ifae solution of alkali metal salt of atorvastatin with a solvent
immiscible or slightly miscible in water;
d) treating the washed solution of alkali metal salt of atorvastatin with a
calcium sail or calcium hydroxide 10 obtain atorvastatin calcium;
e) isolating crude atorvastatin calcium;
f) purifying crude atorvastatin calcium by dissolving in a mixture of
tetrahydrofuran and raethanol, and precipitating with water to obtain pure
atorvastatin calcium in crystalline form; and
g) converting crystalline pure atorvastatin calcium so obtained into amorphous
form.
2. A process for purifying atorvastatin calcium comprising dissolving crude
atorvastatin calcium in a mixture of tetrahydrofuran and methanol. and
precipitating with water to obtain pure atorvastatin calcium in crystalline form.
3. The process of claim 2, wherein the acid used is an inorganic acid.
4. The process of claim 3, wherein the acid is selected from the group consisting of
hydrochloric, hydrobromic. sulphuric, phosphoric and nitric acids.
5. The process of claim 1, wherein the water-miscible solvent is selected from the
group consisting of acetonitrile, alcohols, cyclic ethers, ketones and mixtures
thereof.
6. The process of claim 5. wherein alcohols are selected from the group consisting of
methanol, ethanol, propanol, and isopropanol.
7. The process of claim 1, wherein the reaction of step b) is carried out at a pH of
about 12.
8. The process of claim 1. wherein the alkali metal hydroxide is selected from the
group consisting of sodium hydroxide, potassium hydroxide and lithium
hydroxide.
9. The process uf claim 1, wherein the solvent immiscible or slightly miscible in
water is selected from the group consisting of ethers, esters, and hydrocarbons.
10. The process of claim 9. wherein ethers are selected from the group consisting of
methyl tertiary butyl ether, diethyl ether, methyl ethyl ether and dibutyl ether.
11. The process of claim 1, wherein the pH of the solution of step c) is lowered to
about 7.8 to 8.2 with an acid before proceeding with step d).
12. The process of claim 1, wherein step d) is performed at a temperature of about 45
to 55 °C.
13. The process of claim 1, wherein the calcium salt is selected from the group
consisting of calcium acetate, calcium chloride, calcium sulfate, calcium nitrate
and calcium phosphate.
14. The process of claim 1, wherein any residual solvent immiscible or slightly
miscible in water remaining in the reaction mixture is removed after step d) is
removed under reduced pressure.
15. The process of claim 1. wherein crude atorvastatin calcium is precipitated by-
addition of water.
16. The process of claim 15, wherein water is added at a temperature of about 55 to
65°C.
17. The process of claim 1, 15 or 16, wherein seeds of crystalline atorvastatin calcium
are added to the reaction mixture.
18. The process of claim 1, or 15 to 17, wherein crude atorvastatin calcium is isolated
by cooling the reaction mixture to a temperature of about 20 to 35 °C.
19. The process of claim 1 or 2, wherein tetrahydrofuran, methariol and water are in
the volume- ratio 1: 1 :4.
20. The process of claim 1, 2 or 19, wherein water is added at a temperature of about
60 to 65 °C
21. The process of claims 1,2, 19 or 20, wherein seeds of crystalline atorvastatin
calcium are added to facilitate the precipitation.
22. The process of claim 21, wherein seeds of crystalline atorvastatin calcium are
added at a temperature of about 50 °C.
23. The process of claims 1, or 19 lo 22, wherein pure atorvastatin calcium is isolated
by cooling the mixture to a temperature of about 30 to 35 °C.
24. The process of claim 1, which comprises an additional step wherein the pure
crystalline atorvastatin calcium obtained after step f) is suspended in a mixture of
methanot and water in the volume ratio 1 to 5 and stirred with seed crystals of
crystalline form 1, to obtain alorvastatin calcium in crystalline form 1,
25. The process of claim 24, wherein the stirring is performed at a temperature of
about 30 to 4V'C.
26. The process of claim 1, which comprises an additional step wherein the pure
crystalline atorvastutin calcium obtained after step 1) is suspended in 15 to 25
volumes (w.n weight of atorvastatin calcium) of a mixture of methanol and water
in the volume ratio 3 to 2 and stirred with seed crystals of crystalline form II, to
obtain atorvastatiu calcium in crystalline form 11.
27. The process of claim 24, which comprises a further additional step wherein the
obtained crystalline form I of atorvastatin calcium is suspended in 15 to 25
volumes (w.r.t weight of atorvastatin calcium) of a mixture of meth.an.ol and water
in the volume ratio 3 to 2 and stirred with seed crystals of crystalline form II, to
obtain atorvaslatin calcium in crystalline form II.
28. The process of claim 26 or 27, wherein the stirring is performed at a temperature of
about 10 to t>5 °C.
29. The process of claim 1 , wherein amorphous atorvastatin calcium is obtained by
dissolving pure crystalline atorvastatin calcium in tetrahydrofuran and adding the
resulting solution to cyclohexane.
30. The process oi'claira 29, wherein water is added to tetrahydrofuran to dissolve
u:e c'stailine atorvastatin calcium,
31. A process foi ihe production of stabili/ed, amorphous atorvastatin calcium
comprising:
aj dissolving crystalline atorvastatin calcium and an antioxidant in a solvent;
bi adding ihe atorvasuuin calcium and antioxidant solution to an antisolvent;
and
c) separating precipitated, amorphous atorvastatin calcium from the resulting suspension 10 obtain stabilized, amorphous atorvastatin calcium.
32. A process lor the production or'aiorvastatin calcium in amorphous form
comprising:
a) dissolving crystalline atorvastarin calcium in a hydroxylic: solvent;
b) adding the obtained solution of atorvastatin calcium to a non-hydroxylic
anti-solvent, wherein the non-hydroxylic anti-solvent has a higher boiling
point Hum the hydroxylic solvent;
c) eoncenirating the .solution io obtained to remove the hydroxylic solvent;
and
d5 iepa;auug precipitated amorphous atorvasiiithi cdici.un iron; the resulting suspension to obtain amorphous atorvastatin calcium.
33. The process of claim 32, wherein an antioxidant is added to the solution of
atorvastatin calcium in hydroxylic solvent,
34. The process of claim 31 or 33. wherein the antioxidant is selected from the group
consisting of butyl ated hydroxyamsole, butylated hydroxytoluene and tertiary-
butylated hydroquinone.
35. The process of claim i, wherein the conversion to amorphous form is achieved
according to the process of claim 31, 32 or 33.
36. The process o f claim 30 to 33, wherein the solution of atorvastatin calcium is dried
before precipitation of amorphous atorvastatin calcium,
37. The process of claim 36, wherein the solution is filtered through dry molecular
sieves.
38. The process of claim 36, wherein the solution is made using excess of solvent,
which is then concentrated to achieve drying.
39. The process of claim 31, wherein the solvent is selected from the group consisting
of ketones, esters, chlorinated hydrocarbons, cyclic ethers, alcohols, nitriles,
dipolar aprtic solvents, and mixtures thereof with water.
40. The process of claim 39, wherein the cyclic ethers are selected from the group
consisting of dioxan, tetrahydrofuran, and mixtures thereof.
41. The process ui' claim 31, wherein the anti-solvent is selected from the group
consisting of hydrocarbons and dialkyl ethers.
42. The process of claim 32, wherein die hydroxylic solvent is selected from the group
consisting of alcohols, and mixtures thereof with water.
43. The process of claim 39 or 42, wherein alcohols are selected from the group
consisting of methanoi, ethauol, propanol, and isopropanol.
44. The process of claim 32, wherein the non-hydroxylic anti-solvent is selected from
the group consisting of hydrocarbons and dialkyl ethers.
45. The process of claim 41 or 44, wherein the hydrocarbons are selected from the
group consisting of cyclohexane, hexane, heptane, petroleum ethers, toluene, and
xvlene.
46. The process of claim 1 , wherein (4R-cis)- 1 , 1 -climethylethyl-6- {2-[2-(4-
fluorophenyl)-5-(l-methyiethyl)-3-phenyl-4-[(phenylamino)-carbonyl]-l/f-pyrrol-
lyl]ethyl}-2,2-dimethyl- 1 ,3-dioxane-4-acetate (Compound H) is obtained by
a) treating (R)- ethyl 4-cyano-3-hydroxybutanoate (Compound A) with 1,1-
dimethylethv'lacetate (Compound B), in the presence of n-butyl lithium and
diisopropyl amine to obtain (A1)-! J