WO2009082362A1

WO2009082362A1 - A method for producing statins in pure form

Info

Publication number: WO2009082362A1
Application number: PCT/TR2008/000124
Authority: WO
Inventors: Serdar Unlu; Tuncer Aslan; Tuba Bicer; Yildiz Gulkok; Selda Turhan; Melek Koroglu; Berna Okcelik
Original assignee: Ulkar Kimya San. Ve Tic. A.S.
Priority date: 2007-11-05
Filing date: 2008-11-05
Publication date: 2009-07-02

Abstract

This invention provides a new method for the preparation of statins comprising hydrolyzing a mixture of compounds of the following formulas (Formula III and IV).

Description

A METHOD FOR PRODUCING STATINS IN PURE FORM

Technical Field

This invention relates to a process for producing statins in pure form.

Background of Inventions

Statins are a group of drugs that currently most therapeutically effective agent for reducing low density lipoprotein(LDL) particle concentration in the blood stream of patients at risk for cardiovascular diseases.

Statins work by inhibiting HMG-CoA reductase, an enzyme in the metabolic pathway for the synthesis of the cholesterol. This enzyme catalyses the conversion of HMG-CoA to mevalonate which is the rate determining step in the biosynthesis of cholesterol.

A decreased production of cholesterol stimulates low density lipoprotein (LDL) receptor and consequently reduces the concentration of LDL particles in the blood stream. This reduces the risk of coronary artery disease.

Atorvastatin, lovastatin, fluvastatin, pravastatin, rosuvastatin, cerivastatin and simvastatin are examples of known statins. Atorvastatin (disclosed in US4681893) and rosuvastatin (discloed in USRE37314) are used as calcium salt. Lovastatin (disclosed in

US4231938) and simvastatin (disclosed in US444784) are used in the form of lactone.

Fluvastatin (disclosed in 5354772), cerivastatin (disclosed in US5006530) and pravastatin (disclosed in US4346227) are used as sodium salt.

Starting from diol protected tertiary-butyl ester is known in the synthesis of the statins having Formula I.

Formϋl (I) Wherein

M is a metal and n is an integer, Ri is -CH₂-CH₂- or -CH=CH-; R₂ is selected from

-aromatic or aliphatic C₃-Ci_g-hydrocarbon rings, which can optionally be substituted with one or more selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, amine, nitro, thiol, sulfoxy, sulfone groups, which can optionally be substituted and/or form further rings, and halogen atoms; -aromatic or aliphatic C₃-Cis-heterocycles, which can optionally be substituted with one or more selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, alkyloxy, amide, amine, nitro, thiol, sulfoxy, sulfone groups, which can optionally be substituted and/or form further rings, and halogen atoms; whereby R₂ and R₃ together can form an aromatic or aliphatic C₃-Cis-heterocycle, which can optionally be substituted with one or more selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, alkyloxy, amide, amine, nitro, thiol, sulfoxy, sulfone groups, which can optionally be substituted and/or form further rings, and halogen atoms;

As shown above, the free acid of atorvastatin is openedto the lavtonization. Atorvastatin and its lactone form is disclosed in US4681893.

For example compound II is known from the patents US 5,103,024, EP 330172 and patent application WO 03/024959 Al as an intermediate in the synthesis of Atorvastatin.

Formula (II) Wherein

Ri and R₂ are the same as above

R₃ is hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl or tertiary butyl.

There is another patent application WO 02/083637 Alwhich tell us preparation of amorphous Atorvastatin starting from diol protected tertiary-butylester. According to this document compound with the formula (II) reacted with a methanolic solution in the presence of aqueous acid such as hydrochloric acid to cleave the diol protecting group and giving a mixture of corresponding lacton, methyl ester, tertiary-butyl ester and Atorvastatin acid. To purify unreacted diol protected tertiary-butylester, aqueous sodium hydroxide solution is added and diol protected tertiary-butyl ester is removed by extraction. CaCl₂ was added into solution and crude Atorvastatin Calcium which has to be further purified was obtained. Although in the patent application WO 02/083637 Al the progress of the deprotection reaction for diol protected tertiary-butylester is well analyzed, the process has some disadvantages. Firstly, diol protected tertiary-butylester is not well soluble in methanolic HCl, therefore the reaction take place for 15 hours. Secondly, the reaction is not completed, i.e some of the starting material like diol protected tertiary-butylester, diol protected Atorvastatin remained as impurities which influence the purity of the final products has to be removed by extraction. Thirdly, pH adjustment is necessary to add exact amount of NaOH solution. Finally, to get amorpous atorvastatin calcium, CaCl₂ was added at 50-55 ⁰C which can cause side product formation.

WO2007/028412 discloses that certain hydroxylammonium salts can be successfully used to directly convert the compounds of formula (II) to the lactones. This reaction proceeds in a single step and in the absence of strong mineral acids or bases and this reaction results in lactones of high purity. Without using strong acids such as hydrochloric acid, risk of degrading some of the starting and/or target compounds leading to a reduced yield is eliminated. Converting the diol protected tertiary-butyl ester to the lactone in a single step decreases the process time. But this process is not suitable for the large scale production and this cause a decrease in the the purity of lactone and yield. Aim of the Invention

It is therefore an object of this invention to describe a new method for producing statin compounds of Formula (I) from compounds of Formula (II) which can be easily repeatable, suitable for large scale production and eliminate the disadvantages disclosed in the prior art.

Detailed Description of the Invention

This invention provides a new method for the preparation of statins comprising hydrolyzing a mixture of compounds of the following formulas

R³

(HI) (IV)

Wherein

Ri, R₂ and R3 are the same as above

In general, during the statin synthesis diol protected ester is hydrolyzed in alcohol. After this reaction lactone and diol ester is formed but also some of the diol protected ester remain as an impurity. This invention disclose a method which converts the intermediates comprising such impurities to pure statins.

Surprisingly, when we tried to remove protecting group of diol protected tertiary butyl ester of the Atorvastatin (IV) iri a solvent system such as a mixture of acetone/methanol/water under acidic conditions. The use of acetone increase the solubility of the starting material as a results shortened the reaction time. But still trace amount of diol protected Atorvastatin and diol protected tertiarybutyl ester of Atorvastatin remain as an impurity which affect the quality of the final product. To solve this problem acetone and methanol are distilled of under reduced pressure and fresh methanol and acid were added to the residue. The solution is heated up to 50-70 ⁰C and the progress of the reaction was followed by TLC (dichloromethane/methanol w/w 15:1) and HPLC. The reaction was completed for 30-45 minutes. The solution is concentrated under reduced pressure to remove methanol. An organic solvent such as ethyl acetate, dichloromethane, ether, toluen is added and the phases were separated. The organic phase was washed three times with water, concentrated under reduced pressure to give a solid. TLC analysis shows that the mixture contains three main spots. A sample was taken and the spots were isolated by flash chromatography in pure form. ¹H-NMR and ¹³C-NMR spectra showed that the three compounds are tertiary butyl ester, methyl ester and lacton of atorvastatin. To the residue containing tertiary butyl ester, methyl ester and lacton of atorvastatin an alcohol was added together with 1-3 equivalent of metal hydroxide solution such as NaOH, KOH and LiOH at room temperature. The solution was stirred at 25-45 ⁰C for 30-60 minutes. The TLC analysis showed that all the esters were hydrolyzed. A CaCl₂, Ca(OAc)₂ or their hydrate solution in an alcohol or water is added in to the mixture containing Atorvastatin alkali metal hydroxide solution such as Atorvastatin sodium at a temperature from 20 to 80 ⁰C. The solution is stirred for 15-30 minutes and filtered to remove any solid material. To get amorpous product either this solution is added in to water within 5-15 minutes or water was added in to this solution while stirring. After drying Atorvastatin Calcium was obtained in 78-85% overall yield with a purity of 99.75% by HPLC.

It is another object of the invention to obtain final product of formula (I) with purity of higher than 99.3%, especially higher than 99.5% by adding the acid in two portions and doing extraction under acidic conditions. If acid is added at once and the extraction is done near neutral or under basic conditions due to formation of too many known and unknown side products the purity of the final compound of formula (I) drops up to 60- 90%.

The compounds of Formula (II) are formed as intermediates in the synthesis of the statins of Formula (I). In a further step, they need to be deprotected in order to form the desired active compounds.

When deprotecting larger and potentially unstable organic compounds having many functional groups such as those of formula (II), a balance must be found between the fact that at higher temperatures with longer reaction time these compounds have the tendency to degrade, resulting in a lower yield, and the necessity that the temperature is high enough so that the deprotection reaction proceeds within a reasonable period of time.

Any compound act as a source of H⁺-ions to remove the diol protected group and ester can be used for the deprotection reaction such as mineral acid like hydrochloric acid, sulfuric acid or hydroxylammonium, salts like hydroxylamine hydrochloride or sulfate.

One or 4 equivalent of mineral acid or ammonium salts is used during the deprotection reaction. Because of the low water content of the reaction mixture the reaction proceeds at a more moderate pH value than the agents used in previous examples and results in high yields with less degradation product.

In an embodiment of the invention the reaction is carried in a mixture of solvents in the presence of small amount of water, the solvents are protic solvents, preferably an alcohol-ketone mixture, more preferably a Ci-C₆ alcohol, especially an alcohol selected from the group consisting of methanol, ethanol and isopropanol.

In another embodiment of the invention after removing methanol and aceton the extraction with an organic solvent should be done under acidic conditions. If the exraction is done after pH adjustment to a range of from 6 to 10 too many side products form aspecially when hydroxyamonium salts are used as acids.

In a further embodiment of the invention an acid is reacted with the compound of formula (II) at a temperature from 20 to 80 ⁰C, preferably from 50 to 80 ⁰C.

It has been found that in the above-named temperature ranges, the reactions can be performed in 10 minutes to 2 hours while obtaining a good yield.

In a further embodiment of the invention, the compound of formula (II) is reacted with the acids for 20 minutes to 60 minutes hours, preferably for 35 to 45 minutes.

Since the deprotection reaction involves heating a larger organic compound in the presence of a reactive agent, a longer reaction time is always connected with the risk of degrading large amounts of the starting or the target compound. Too short a reaction time on the other hand will result in an incomplete deprotection. It has been found that in the above-named time ranges a virtually complete deprotection can be achieved while only small quantities of the desired compound are degraded, leading to good yields.

Preferably the compound of the formula (I) is a compound that shows HMG-CoA reductase inhibitory activity especially one selected from the consisting of the metal salts of Cerivastatin, Fluvastatin, Pravastatin, Atorvastatin and Rosuvastatin.

In an embodiment of the invention the metal hydroxide is an alkali metal hydroxide selected from the group consisting of lithium hydroxide, potassium hydroxide and sodium hydroxide, especially sodium hydroxide.

Sodium hydroxide is a preferred agent for the hydrolysis of the lacton and esters of the formulas (III) and (IV) respectively. Further sodium salt of some statins, for example sodium salt of Atorvastatin easily be converted into Atorvastatin calcium or hydrates thereof which can be handled more easily for formulation purposes and a more stable salt.

In an embodiment of the invention the solvent use in the hydrolysis step is a protic solvent, preferably an alcohol, more preferably a Ci-C₆ alcohol and especially an alcohol selected from the group consisting of methanol, ethanol and 2-propanol.

In a further embodiment of the invention sodium hydroxide is reacted with the mixture of the compound of formulas (III) and (IV) at a temperature from 20 to 80 ⁰C, preferably from 35 to 45 ⁰C.

In an embodiment of the invention the compound of formulas (III) and (IV) is reacted with the sodium hydroxide for 10 minutes to 80 minutes hours, preferably for 30 to 60 minutes.

In another embodiment of the invention the method further comprises the step of the converting sodium salt of Atorvastatin to Atorvastatin Calcium or hydrates thereof with a calcium salt, especially salt selected from the group consisting of CaCl₂ and Ca(OAc)₂.

In a further embodiment of the invention the method further comprises isolating formed Ca(OH)₂ from the solution containing final product before precipitation.

Statins salts such as Atorvastatin Calcium is not well soluble in water and organic solvents. This property allows to control purification of the product from insoluble inorganic salt. Thus first solid material like Ca(OH)₂ can be removed from the solution by filtration and then statins such as Atorvastatin Calcium and their hydrates can be precipitates by adding water into solution.

In a further embodiment of the invention a fast precipitation is a particularly preferred method for getting amorphous final product. It can be affected simply adding the water in a short time into a stirring solution containing final product at room temperature.

It is worth to notice that rate of precipitation together with the temperature is more important than addition of alcohol containing atorvastatin into water or vice versa.

It is understood that the above features and the features described below can be used not only in their described combination but also in other combinations or in isolation without departing from the scope of the invention.

The invention is now further illustrated by means of examples. These examples are not intended to limit the scope of the invention any way.

General procedure for the production and reaction of Statins

/

R3

Mn÷(0H-)_n

A compound of the formula (II) is dissolved in a solvent mixture in the presence of one equivalent acid at 20-80 ⁰C for 10-60 minutes. The progress of the reaction is monitored by TLC and HPLC. After most of the starting material (II) converted to the mixture of the compound of the formulas (III) and (IV), the stirring of the solution is stopped. TLC analysis shows that almost more than 90% is the tertiarybutylester and the rest is the trace amount of other ester, lacton and starting material. The solution is concentrated under reduced pressure to remove acetone and methanol. Additional amount of an alcohol and acid are added, the mixture is stirred at 20-80 ⁰C for 10-60 minutes. TLC and HPLC analysis show no starting material is present in the solution.

The reaction mixture is concentrated under reduced pressure, an organic solvent is added into reaction medium and extracted. The organic phase containing the compounds of the formulas (III) and (IV) are washed 2-4 times with water until pH of the aqueous phase is in a range of 4.0-5.5. The organic is concentrated. To the residue containing compound of the formulas (III) and (IV) a C₁-C₆ alcohol and metal hydroxide in water are added. The solution is stirred at 20-80 ⁰C for 10-60 minutes.

TLC analysis shows all the starting materials are hydrolyzed. To the this mixture Ca salt is added after stirring for 10-30 minutes the mixture the solid material are removed by filtration. To the solution water was added while stirring in 5-30 minutes at 20-80 ⁰C, preferably water is added in 5-10 minutes around room temperature. This is important to get amorphous product. The precipitated product let in the solution for 0.5-2 hours without stirring filtered and dried at elevated temperature under vacuum.

Example 1

Preparation of [R-(R*,R*)]-2-(4-fluorophenyl),D D-dihydroxy-5-(l-methylethyl)-3- phenyl -4-[(phenylamino)carbonyl)-lHpyrrole-l-heptanoic acid hemicalcium salt starting from diol protected tertiarybutyl ester

A 2000 L GLR was charged with 137 kg methanol, 63 kg of aceton, 27.5 kg of water and 26.6 Kg of (4R-cis)-l,l-Dimethylethyl-6-[2-[-(4-fluorophenyl)-5-(l-isopropyl)-3- phenyl-4- [(phenylaminocarbonyl)- lH[pyrrol-l -yl]2,2-dimethylethyl- 1 ,3 -dixoane-4- acetate, namely diol protected tertiarybutyl of atorvastatin at room temperature. To this suspension was added 2.84 kg(l eqv.) of hydroxylaminehydrochloride. The suspension was heated to 55-°65 C and became a clear solution. The mixture was stirred at this temperature for 35-45 minutes. TLC analysis showed that most of the starting material was converted to the corresponding acid and esters. Acetone and methanol was removed under reduced pressure. To the residue 137 kg of methanol and 6.5 kg of hydroxylamine hydrochloride was added. The solution was heated to 55-°65 ⁰C and stirred at this temperature for 15-30 minutes. TLC analysis showed that all the starting material was consumed. The solution was concentrated under reduced pressure. To the residue 246 kg of ethyl acetate and 267 kg of water was added and the phases were separated. The organic phase was washed with two times 267 kg of water. The organic phase containing mixture of the compound of the formula (III) and(IV) was concentrated under reduced pressure. To the residue 95 kg of methanol and NaOH solution ( 2 eqv. 3.28 kg NaOH was dissolved in 26.7 kg of water) were added. The mixture was stirred at 35-45 ⁰C for 30-40 minutes. TLC analysis showed that all the starting materials were converted into the sodium salt of Atorvastatin. A CaCl₂ solution (0.5 eqv., 3 kg of CaCl₂ ' 2H₂O dissolved in 26 kg of water) was added to the atorvastatin sodium solution at 35-45 ⁰C. The solution was stirred for 10-30 minutes and filtered over 0.5 micron filter to remove any solid particles. To the filtered solution containing Atorvastatin Calcium 750 kg of water was added in 5-10 minutes while stirring. The product was immediately precipitated to get amorphous form by fast addition of water. After waiting 30-60 minutes, the product was centrifuged and washed with a 18 kg mixture of methanol water (1:1). The product was dried for 12-15h at 50-60 ⁰C under vacuum and was obtained 20.2 kg in 82% yield with a purity of 99.75 % by HPLC. XRD difragtogram shows that the product is amorphous.

Example 2

Preparation of Atorvastatin Calcium 3 H₂O starting from diol protected tertiarybutyl ester by using ethanol instead of methanol and hydrochloric acid instead of hydroxylamine hydrochloride

A 2 L flask was charged with 515 g ethanol, 240 g of aceton, and 100 g of (4R-cis)-l,l- Dimethylethyl-6-[2-[-(4-fluorophenyl)-5-(l-isopropyl)-3-phenyl-4- [(phenylaminocarbonyl)- lH[pyrrol- 1 -yl]2,2-dimethylethyl- 1 ,3 -dixoane-4-acetate, namely diol protected tertiarybutyl of atorvastatin at room temperature. To this suspension was added 20 g 10 N, 31%, 1 eqv.) of hydrochloric acid. The suspension was heated to 55-°65 C and became a clear solution. The mixture was stirred at this temperature for 35-45 minutes. TLC analysis showed that most of the starting material was converted to the corresponding acid and esters. Acetone and ethanol was removed under reduced pressure. To the residue 515 g of ethanol and 46 g of hydrochloric acid was added. The solution was heated to 55-°65 ⁰C and stirred at this temperature for 15- 30 minutes. TLC analysis showed that all the starting material was consumed. The solution was concentrated under reduced pressure. To the residue 925 g of ethyl acetate and 1000 g of water was added and the phases were separated. The organic phase was washed with two times 1000 g of water. The organic phase containing mixture of the compound of the formula (III) and (IV) was concentrated under reduced pressure. To the residue 357 g of ethanol and NaOH solution ( 2 eqv. 12.52 g NaOH was dissolved in 100 g of water) were added. The mixture was stirred at 35-45 ⁰C for 30-40 minutes. TLC analysis showed that all the starting materials were converted into the sodium salt of Atorvastatin. A CaCl₂ solution (0.5 eqv., 11.27 g of CaCl₂ ^• 2H₂O dissolved in 98 g of water) was added to the atorvastatin sodium solution at 35-45 ⁰C. The solution was stirred for 10-30 minutes and filtered over 0.5 micron filter to remove any solid particles. To the filtered solution containing Atorvastatin Calcium 2820 g of water was added in 5-10 minutes while stirring. The product was immediately precipitated to get amorphous form by fast addition of water. After waiting 30-60 minutes, the product was centrifuged and washed with a 68 g mixture of ethanol water (1:1). The product was dried for 12-15h at 50-60 ⁰C under vacuum and was obtained 68 g in 73% yield with a purity of 99.43 % by HPLC. XRD diffractogram shows that the product is amorphous.

Claims

1. Process for producing some of the statins compounds with the general formula

(I) Wherein

-aromatic or aliphatic C₃-Ci₈-hydrocarbon rings, which can optionally be substituted with one or more selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, amine, nitro, thiol, sulfoxy, sulfone groups, which can optionally be substituted and/or form further rings, and halogen atoms;

-aromatic or aliphatic C₃-Ci₈-heterocycles, which can optionally be substituted with one or more selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, alkyloxy, amide, amine, nitro, thiol, sulfoxy, sulfone groups, which can optionally be substituted and/or form further rings, and halogen atoms; whereby R₂ and R₃ together can form an aromatic or aliphatic C₃-Ci₈-heterocycle, which can optionally be substituted with one or more selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, alkyloxy, amide, amine, nitro, thiol, sulfoxy, sulfone groups, which can optionally be substituted and/or form further rings, and halogen atoms; comprising the steps i) removing reaction of formula (II) from protection group

(II) ii) hydrolyzing the formula (III) and formula (IV) which are formed as a result of this reaction with alkaline metal hydroxide to form alkaline metal salt of statins.

(III) (IV) wherein R₁ and R₂ are the same as defined above, R₃ is hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl or tertiary butyl

2. Method according to any one of claim 1, characterized in that the lactone of formula (I) is a compound that shows HMG-CoA reductase inhibitory activity.

3. Method according to claim 1 to 2, characterized in that the lactone of formula (I) is selected from the group consisting of Lovastatin and Simvastatin.

4. Method according to anyone of claims , characterized in that it further comprises the step of treating mixture of the compound of the formula (III) and lactone of formula IV

(I) with a metal hydroxide in order to obtain a compound of the following formula wherein R₁ and R₂ are the same as defined above; wherein M is any metal; and wherein n is an integer.

5. Method according to the claim 4, characterized in that the compound of formula (I) is a compound that shows HMG-CoA reductase inhibitory activity.

6. Method according to the claim 4 to 5, characterized in that the compound of formula (I) is selected from the group consisiting of the metal salts of Atorvastatin, Cerivastatin,

Fluvastatin, Pravastatin and Rosuvastatin.

7. Method according to anyone of claims 4 to 6, characterized in that the metal hydroxide is an alkali metal hydroxide.

8. Method according to claim 7, characterized in that the alkali metal hydroxide is sodium hydroxide.

9. Method according to anyone of claims 4 to 8, characterized in that the compound of formula (I) is a metal salt of Atorvastatin.

10. Method according to claim 9, characterized in that it furher comprises the step of converting the metal salt of Atorvastatin into a calcium salt of Atorvastatin.

11. Method according to claim 10, characterized in that the step of converting the metal salt of Atorvastatin into a calcium salt of Atorvastatin comprises treating the metal salt of Atorvastatin with a calcium salt.

12. Method according to claim 11, characterized in that the calcium salt is selected from the group consisiting of CaCi₂ and Ca(OAc)₂.

13. Method according to any one of claims, characterized in that R₃ is a hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl or tertiary butyl group.

14. Method according to any one of claims, characterized in that a deprotecting agent which acts as a source of H⁺-ions is an acid.

15. Method according to any one of claims, characterized in that acids are mineral acid such as HCl, H₂SO₄ or hydroxylammonium sulfates and hydroxylammonium chlorides.

16. Method according to any one of claims, characterized in that the solvent comprises a mixture of solvents.

17. Method according to the claim 16, characterized in that the mixture of solvents comprises at least one Ci-C₆ alcohol, at least one lower liquid ketone and water.

18. Method according to claim 17, characterized in that the at least one Ci-C₆ alcohol is selected from the group consisting of methanol, ethanol and isopropanol.

19. Method according to any one of claims 4 to 18, characterized in that compound of formula (I) is Atorvastatin Calcium trihydrate.

20. Method according to any one of claims 4 to 198, characterized in that Atorvastatin Calcium trihydrate is in amorphous form.