WO2009047576A1 - Process for preparation of pharmaceutical intermediates - Google Patents

Process for preparation of pharmaceutical intermediates Download PDF

Info

Publication number
WO2009047576A1
WO2009047576A1 PCT/HU2008/000121 HU2008000121W WO2009047576A1 WO 2009047576 A1 WO2009047576 A1 WO 2009047576A1 HU 2008000121 W HU2008000121 W HU 2008000121W WO 2009047576 A1 WO2009047576 A1 WO 2009047576A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
rosuvastatin
general formula
acid
compound
Prior art date
Application number
PCT/HU2008/000121
Other languages
French (fr)
Inventor
Balázs VOLK
Pál VÁGÓ
Gyula Simig
Péter TÖMPE
József Barkóczy
Tibor Mezei
Ferenc Bartha
György RUZSICS
Adrienn Karasz
Imre KIRÁLY
Kálmán NAGY
Original Assignee
EGIS GYÓGYSZERGYÁR Nyilvánosan Müködö Részvénytársaság
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by EGIS GYÓGYSZERGYÁR Nyilvánosan Müködö Részvénytársaság filed Critical EGIS GYÓGYSZERGYÁR Nyilvánosan Müködö Részvénytársaság
Publication of WO2009047576A1 publication Critical patent/WO2009047576A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom

Definitions

  • the present invention is related to a process for the preparation of (+)- 7-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)- pyrimidin-5-yl]-(3i?,55)-dihydroxy-hept-6-enoic acid of the Formula
  • (+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl- amino)-pyrimidin-5-yl]-(3i -; ,5jS)-dihydroxy-hept-6-enoic acid of the Formula (I) is known under the International Non-proprietary Name rosuvastatin.
  • Rosuvastatin is a pharmaceutically active ingredient suitable for influencing lipid metabolism, which exerts its activity by inhibiting cholesterol biosynthesis in the liver, thus decreasing the cholesterol concentration of blood plasma.
  • Rosuvastatin of the Formula (I) and salt thereof, especially the calcium salt are used in the therapy for the treatment of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis.
  • (+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl- amino)-pyrirnidin-5-yl]-(3i -5 55)-dihydroxy-hept-6-enoic acid of the Formula (I) has been disclosed for the first time in European Patent No. 521471.
  • rosuvastatin is produced by saponification of a rosuvastatin alkylester, optionally the acid is set free from the rosuvastatin salt obtained by the saponification and the rosuvastatin acid or a salt thereof obtained directly by saponification are transformed into a pharmaceutically acceptable salt, preferably into calcium salt.
  • the quality of pharmaceutically active ingredients used in medicaments are determined by strict regulatory requirements. Some of these requirements are related to the chemical purity and stability of the pharmaceutically active ingredients. Further regulatory criteria for medicinal products is that such product must comply with the quality and stability criteria of the authorities. Such criteria are determined by and published in the pharmacopoeial monographs. Compliance with the regulatory criteria is a basic requirement for the issuance of marketing authorization of the medicament concerned. During the use of rosuvastatin for the manufacture of medicaments, the high purity, appropriate stability and the ease of formulation are important requirements.
  • Rosuvastatin of the Formula (I) and rosuvastatin sodium salt of the Formula (TL) are important pharmaceutical intermediates during the preparation of rosuvastatin salts used in medicaments, such as calcium salt and zinc salt.
  • rosuvastatin salts used in medicaments such as calcium salt and zinc salt.
  • the objective of our research was to provide a process which allows the manufacture of rosuvastatin of the Formula (I) and rosuvastatin sodium salt of the Formula (H) in reproducible high quality suitable for the production of medicaments on an industrial scale.
  • T represents hydroxy, or T and Q together form a single bond or T and R together form an oxymethylene group substituted by one or two alkyl groups;
  • R represents hydrogen or R and T together form an oxymethylene group substituted by one or two alkyl groups
  • Q represents hydrogen, an alkyl group comprising 1 to 6 carbon atoms, an alkenyl group comprising 2 to 6 carbon atoms or a cation, or Q and T can form a single bond.
  • rosuvastatin of the Formula (I) and rosuvastatin sodium salt of the Formula (II) suitable as starting material for the manufacture of pharmaceutically active ingredients suitable for the manufacture of medicaments can be produced on an industrial scale in a simple and reproducible way and in good quality.
  • ,alkyl means a straight or branched-chain saturated hydrocarbon group comprising 1 to 6 carbon atoms, e.g. methyl, ethyl, 1 -propyl, 2-propyl, 1-methylpropyl etc.
  • ,alkenyl represents a straight or branched chain hydrocarbon group containing one double bond, e.g. etenyl, 1- propenyl etc.
  • a metal ion preferably an alkali metal ion, an alkali earth metal ion or an ammonium ion substituted by one or more alkyl groups is to be meant.
  • Hydrolysis of the compounds of the general Formula (III), wherein Q represents an alkyl group comprising 1 to 6 carbon atoms or an alkenyl group comprising 2 to 6 carbon atoms, preferably ethyl group or t-buryl group, T represents hydroxy group, R represents hydrogen, can be performed alternatively by hydrolysing the starting compound of the general Formula (III) in water, in an organic solvent or in the mixture thereof in the presence of an organic or mineral acid and isolating rosuvastatin acid of the Formula (I), wherein Q and R represent hydrogen, T is hydroxy and if desired, converting rosuvastatin acid into rosuvastatin sodium salt of the Formula (II).
  • a compound of the general Formula (IH), wherein Q is an alkyl-group, preferably ethyl-group or t-butyl group, T and R together form an oxymethylene group substituted by one of two alkyl groups, preferably by two methyl groups, is hydrolysed in the presence of a base, in an organic solvent or in aqueous-organic solution and thus producing a compound of the general Formula (III), wherein Q is cation, T and R together form an oxymethylene group substituted by one or two alkyl groups, preferably by two methyl groups, optionally converting the salt thus obtained into a carboxylic acid of the general Formula (HI), wherein Q is hydrogen, T and R together form an oxymethylene group substituted by one or two alkyl groups, preferably by two methyl groups, transforming the product thus obtained under acidic conditions into rosuvastatin of the Formula (I) and if desired, converting rosuvastat
  • rosuvastatin of the Formula (I) and sodium salt thereof are produced by transforming a compound of the general Formula (HI), wherein T and R form an oxymethylene group substituted by one or two alkyl groups, preferably by two methyl groups, Q represents alkyl group, preferably ethyl group or t-butyl group by treating with an organic or inorganic acid in water or in an aqueous-organic solvent into a compound of the general Formula (III), wherein T is hydroxy, R is hydrogen, Q is alkyl, subsequently hydrolysing the ester thus obtained in organic solvent or hi water or in the mixture thereof using a base, converting the thus obtained salt of the general Formula (III), wherein Q represents a cation, into rosuvastatin of the Formula (I) and optionally converting rosuvastatin into sodium salt thereof.
  • HI compound of the general Formula (HI)
  • T and R form an oxymethylene group substituted by one or two alkyl groups, preferably by two
  • reaction can be carried out by directly transforming a compound of the general Formula (JR), wherein Q represents an alkyl group, preferably ethyl group or t-butyl group, T and R forms together an oxymethylene group substituted by one or two alkyl groups, preferably by two methyl groups in presence of a mineral acid in an organic solvent or in a mixture of water and an organic solvent into rosuvastatin of the Formula (I) and optionally transforming the acid thus obtained into sodium salt thereof.
  • Q represents an alkyl group, preferably ethyl group or t-butyl group
  • T and R forms together an oxymethylene group substituted by one or two alkyl groups, preferably by two methyl groups in presence of a mineral acid in an organic solvent or in a mixture of water and an organic solvent into rosuvastatin of the Formula (I) and optionally transforming the acid thus obtained into sodium salt thereof.
  • a compound of the general Formula (HI), wherein R is hydrogen, T and Q together form a single bond is transformed by a ring opening reaction in an organic solvent, in water or in the mixture thereof in the presence of an acid or base into a compound of the general Formula (HI), wherein T represents hydroxy, R is hydrogen, Q is hydrogen or cation, and isolating rosuvastatin of the Formula (I) or if desired, converting into sodium salt of the Formula (II); or liberating rosuvastatin of the Formula (I) from a salt wherein Q represents a cation and optionally converting into sodium salt.
  • High purity rosuvastatin sodium of the Formula (II) can be advantageously used as an intermediate in the production of pharmaceutically acceptable rosuvastatin salts, e.g. rosuvastatin calcium or rosuvastatin zinc salts.
  • a process for the preparation of high purity rosuvastatin sodium salt of the Formula (II), which comprises reacting a compound of the general Formula (DI), wherein T represents hydroxy, R is hydrogen, Q is an alkyl group comprising 1 to 6 carbon atoms, preferably ethyl-group with an approximately equimolar amount of aqueous sodium hydroxide solution at room temperature using an aqeuous-ethanolic solvent, filtering the reaction mixture, evaporating the solvent, washing the residue with ethylacetate after diluting with water, evaporating the aqueous layer, removing residual ethanol and water, solidifying rosuvastatin sodium by adding diisopropylether to the residue and optionally after thorough powdering, stirring rosuvastatin sodium of the Formula (II) in ethanolic suspension and filtering the product.
  • DI general Formula
  • Alkaline hydrolysis of the compounds of the general Formula (III), wherein the meaning of Q is an alkyl group or an alkenyl group, preferably ethyl group or t-butyl group, T represents hydroxy group, R represents hydrogen, can be carried out in water or in an inert solvent, preferably in an aliphatic alcohol comprising 1 to 4 carbon atom, acetonitrile, an aliphatic ketone comprising 3 to 8 carbon atoms, an aliphatic ester comprising 2 to 8 carbon atoms or in an aliphatic ether comprising 4 to 8 carbon atoms or in a mixture thereof.
  • a 1.0-1.25 molar equivalent amount of a base preferably an alkali hydroxide, e.g. sodium hydroxide can be used.
  • the base may be used in solid form, but it is more preferable to use in a 0.05-10 mol/dm3 or saturated aqueous solution.
  • the reaction can be carried out between room temperature and the boiling temperature of the reaction mixture, preferably between 40 and 65 0 C. The reaction proceeds easily, the reaction time depending on the temperature is approx. 0.25-12 hours.
  • Suitable solvents are aliphatic alcohols comprising 1 to 4 carbon atom, acetonitrile, an aliphatic ketone comprising 3 to 8 carbon atoms, an aliphatic ester comprising 2 to 8 carbon atoms or an aliphatic ether comprising 4 to 8 carbon atoms or a mixture thereof.
  • the reaction can be carried out between room temperature and the boiling temperature of the reaction mixture.
  • the reaction time depending on the temperature is several hours.
  • a strong mineral or organic acid e.g. an aqueous solution of a hydrogen halogenide, sulfuric acid, an aromatic or aliphatic sulfonic acid, e.g. benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, preferably aqueous hydrochloric acid solution
  • a strong mineral or organic acid e.g. an aqueous solution of a hydrogen halogenide, sulfuric acid, an aromatic or aliphatic sulfonic acid, e.g. benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, preferably aqueous hydrochloric acid solution
  • a strong mineral or organic acid e.g. an aqueous solution of a hydrogen halogenide, sulfuric acid, an aromatic or aliphatic sulfonic acid,
  • the concentration of the acid used in the reaction can be between 0.2- lO mol/dm 3 '.
  • a hydrogen halogenide or sulfuric acid can be used as mineral acid.
  • an organic acid an aliphatic sulfonic acid comprising 1 to 4 carbon atoms or an aromatic sulfonic acid can be used.
  • hydrogen chloride is applied in the form of an aqueous solution.
  • the reaction can be carried out at a temperature between room temperature and the boiling temperature of the reaction mixture, preferably at a temperature between 50 and 80 0 C.
  • the reaction time depending on the reaction temperature, is several hours.
  • the acid can be used in an equimolar amount, but preferably, the amount of the acid is in 2.0-40-fold molar excess relative to the molar amount of the starting material.
  • (+)-7-[4-(4-fluorophenyl)-6- isopropyl-2-(me ⁇ anesulfonyl-methyl-amino)-pyrimidin-5-yl]-(3i?,55)- dihydroxy-hept-6-enoic acid sodium salt (1:1) can contain solvent bound as solvates, especially water.
  • the amount of solvent bound in rosuvastatin sodium salt of the Formula (II) depends on the process of the preparation and the conditions of drying and may range in the product between 0.01 and 30 weight%.
  • Rosuvastatin sodium salt thus obtained is isolated according to the process described in Example 3 and transformed into high-purity rosuvastatin sodium salt or the solution of rosuvastatin sodium of the Formula (II) is directly used for the preparation of a pharmaceutically acceptable salt of rosuvastatin.
  • the residue is diluted with 200 ml of water and extracted three times with 75 ml of ethylacetate each and the aqueous layer is evaporated at the pressure of 20 Hgmm. From the residue, 50 ml of ethanol is evaporated twice and the thus obtained solids are stirred in 200 ml of diisopropylether and filtered.
  • the isolation of the sodium salt of rosuvastatin is performed as follows. 200 ml of water are added to the residue and the solution is extracted three times with 75 ml of ethylacetate each and the aqueous layer is evaporated at the pressure of 20 Hgmm. From the residue, 50 ml of ethanol are evaporated twice and the solids are stirred in 200 ml of diisopropyl ether and filtered. Thus 43.8 g (97 %) of rosuvastatin sodium salt identical in all respects to that obtained in Example 2 are produced. The salt is crushed and homogenized thoroughly and stirred in 300 ml of ethanol at room temperature for two hours. The white suspension is filtered, the solids are washed with 20 ml of ethanol and dried in vacuo protected from light at the temperature of 50 0 C.
  • [l,3]dioxan-4-yl)-acetic acid tert-butylester are dissolved at room temperature in 100 ml of tetrahydrofurane and 50 ml of 10 weight% hydrochloric acid solution are added in 30 minutes. The solution is stirred for further 30 minutes and cooled on ice. With continuous ice cooling, 2 M sodium hydroxide solution are added to the reaction mixture until pH 6 is reached (approx. 36 ml) in such a manner that the temperature of the reaction mixture does not exceed 15 0 C. Subsequently 150 ml of water are added and the solution is extracted twice with dichloromethane (75 ml each).
  • reaction mixture is stirred for two hours at room temperature. Subsequently, while cooling on ice, 2 M sodium hydroxide solution is added to the reaction mixture until pH 6 is reached, in a speed that the temperature of the reaction mixture does not exceed 15 0 C. Subsequently 150 ml of water are added and the reaction mixture is extracted twice with 75 ml of dichloromethane each. The organic layer is dried over sodium sulfate and evaporated at the pressure of 20 Hgmm. The pale yellow oily residue crystallized upon addition of diisopropylether (20 ml). The white solids are stirred in diisopropylether, filtered and recrystallized from the mixture of water (40 ml) and ethanol (35 ml). Yield, 7.81 g (84 %)
  • the residue is diluted with 40 ml of water and extracted three times with 15 ml of ethylacetate each, the aqueous layer is evaporated at the pressure of 20 Hgmm. From the residue, 2x10 ml of ethanol is evaporated and the solids thus obtained are stirred in 40 ml of diisopropyl-ether and filtered.
  • the mixture is filtered through a G4 sintered glass filter and the ethanol is evaporated at the pressure of 20 Hgmm.
  • the residue is mixed with 200 ml of water and extracted three times with 75 ml of ethylacetate each and the aqueous layer is evaporated at the pressure of 20 Hgmm. From the residue 2x50 ml of ethanol are evaporated and the solids are stirred in 200 ml of diisopropylether and filtered.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention provides an improved process for the preparation of (+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-(3R,5S)- dihydroxy-hept-6-enoic acid and sodium salt thereof. A further subject of the present invention is high purity (+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-(3R,5S)-dihydroxy-hept-6-enoic acid sodium salt and process for the preparation thereof. The compound of the general Formula (I) and sodium salt thereof are valuable pharmaceutical intermediates during the production of high purity pharmaceutically active ingredients suitable for the regulation of lipid metabolism.

Description

Process for preparation of pharmaceutical intermediates
FIELD OF THE INVENTION
The present invention is related to a process for the preparation of (+)- 7-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)- pyrimidin-5-yl]-(3i?,55)-dihydroxy-hept-6-enoic acid of the Formula
(I)
Figure imgf000002_0001
0)
and (+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl- amino)-pyrimidin-5-yl]-(3i?,5iS)-dihydroxy-hept-6-enoic acid sodium salt (1:1) of the Formula (H).
Figure imgf000003_0001
(H)
TECHNICAL BACKGROUND OF THE INVENTION
(+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl- amino)-pyrimidin-5-yl]-(3i-;,5jS)-dihydroxy-hept-6-enoic acid of the Formula (I) is known under the International Non-proprietary Name rosuvastatin. Rosuvastatin is a pharmaceutically active ingredient suitable for influencing lipid metabolism, which exerts its activity by inhibiting cholesterol biosynthesis in the liver, thus decreasing the cholesterol concentration of blood plasma. Rosuvastatin of the Formula (I) and salt thereof, especially the calcium salt are used in the therapy for the treatment of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis.
(+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl- amino)-pyrirnidin-5-yl]-(3i-555)-dihydroxy-hept-6-enoic acid of the Formula (I) has been disclosed for the first time in European Patent No. 521471.
According to the disclosure of said patent, rosuvastatin is produced by saponification of a rosuvastatin alkylester, optionally the acid is set free from the rosuvastatin salt obtained by the saponification and the rosuvastatin acid or a salt thereof obtained directly by saponification are transformed into a pharmaceutically acceptable salt, preferably into calcium salt.
There are several processes known in the art for the preparation of rosuvastatin, esters thereof and rosuvastatin calcium salt. These processes utilize different intermediate products.
In Published International Patent Applications WO2006/126035 and WO2005/042522, processes for the preparation of rosuvastatin and salts thereof are disclosed, wherein the key intermediates are the ketal ester of rosuvastatin. Preparation and transformation of rosuvastatin ketal acid and salts thereof have been disclosed in International Patent Application No. WO2006/126035. The subject of Published International Patent Application No. WO2003/097614 and WO2005/023778 is a process for the preparation of rosuvastatin starting from alkyl esters thereof. The use of rosuvastatin lactone for the manufacture of the free acid has been disclosed in Published International Patent Application No. WO2005/040134, WO2005/077916 and WO2006/136407. Rosuvastatin zinc salt, properties and preparation thereof have been disclosed for the first time in Published International Patent Application WO 2007/119085. The compound is stable against heat and light, which are advantageous properties during pharmaceutical processing and the use of the medicament.
SUMMARY OF THE INVENTION
The quality of pharmaceutically active ingredients used in medicaments are determined by strict regulatory requirements. Some of these requirements are related to the chemical purity and stability of the pharmaceutically active ingredients. Further regulatory criteria for medicinal products is that such product must comply with the quality and stability criteria of the authorities. Such criteria are determined by and published in the pharmacopoeial monographs. Compliance with the regulatory criteria is a basic requirement for the issuance of marketing authorization of the medicament concerned. During the use of rosuvastatin for the manufacture of medicaments, the high purity, appropriate stability and the ease of formulation are important requirements.
Rosuvastatin of the Formula (I) and rosuvastatin sodium salt of the Formula (TL) are important pharmaceutical intermediates during the preparation of rosuvastatin salts used in medicaments, such as calcium salt and zinc salt. During our research-development work, we have found that it is not possible to reproducibly produce rosuvastatin and rosuvastatin sodium salt in high purity on an industrial scale by the use of processes known from the prior art, e.g. using the process disclosed in European Patent No. 521471.
The objective of our research was to provide a process which allows the manufacture of rosuvastatin of the Formula (I) and rosuvastatin sodium salt of the Formula (H) in reproducible high quality suitable for the production of medicaments on an industrial scale.
The above objective is solved according to the present invention.
DETAILED DESCRIPTION OF THE INVENTION
According to the first aspect of the present invention, there is provided an improved process for the reproducible preparation of (+)-7-[4-(4- fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)- pyrimidin-5-yl]-(3i?,55)-dihydroxy-hept-6-enoic acid of the Formula (I) and (+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl- methyl-arnino)-pyrirnidin-5-yl]-(3i-,55)-dihydroxy-hept-6-enoic acid sodium salt of the Formula (H) on an industrial scale in high quality.
In the process, a compound of the general Formula (III)
Figure imgf000007_0001
(HI) can be used as starting material, wherein
T represents hydroxy, or T and Q together form a single bond or T and R together form an oxymethylene group substituted by one or two alkyl groups;
R represents hydrogen or R and T together form an oxymethylene group substituted by one or two alkyl groups;
Q represents hydrogen, an alkyl group comprising 1 to 6 carbon atoms, an alkenyl group comprising 2 to 6 carbon atoms or a cation, or Q and T can form a single bond.
Surprisingly, we have found that using the process according to the present invention, rosuvastatin of the Formula (I) and rosuvastatin sodium salt of the Formula (II) suitable as starting material for the manufacture of pharmaceutically active ingredients suitable for the manufacture of medicaments can be produced on an industrial scale in a simple and reproducible way and in good quality.
In the present description, the expression ,,alkyl" means a straight or branched-chain saturated hydrocarbon group comprising 1 to 6 carbon atoms, e.g. methyl, ethyl, 1 -propyl, 2-propyl, 1-methylpropyl etc.
The expression ,,alkenyl" represents a straight or branched chain hydrocarbon group containing one double bond, e.g. etenyl, 1- propenyl etc.
Under the expression ,,cation", a metal ion, preferably an alkali metal ion, an alkali earth metal ion or an ammonium ion substituted by one or more alkyl groups is to be meant.
According to the process of the present invention, (+)-7-[4-(4- fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)- pyrimidin-5-yl]-(3i-,55)-dihydroxy-hept-6-enoic acid of the Formula (I) and (+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl- methyl-ammo)-pyrirnidήi-5-yl]-(3i!!,55)-dihydroxy-hept-6-enoic acid sodium salt of the Formula (II) are produced by
a) transforming a compound of the general Formula (III), wherein T represents hydroxy group, R represents hydrogen, Q represents an alkyl group comprising 1 to 6 carbon atoms or an alkenyl group comprising 2 to 6 carbon atoms, preferably ethyl group by hydrolysis into a compound of the general Formula (IH), wherein the meaning of T and R is as defined above, Q is hydrogen or cation, preferably sodium ion, optionally converting the thus obtained compound of the general Formula (IH) into rosuvastatin of the Formula (I) or transforming a compound of the general Formula (IH), wherein the meaning of T and R is defined above into rosuvastatin sodium salt of the Formula (H) and isolating the product, or
b) transforming a compound of the general Formula (HI), wherein R and R together form an oxymethylene group substituted by one or two alkyl groups, Q is an alkyl group comprising 1 to 6 carbon atoms or an alkenyl group comprising of 2 to 6 carbon atoms by hydrolysis into a compound of the general Formula (III), wherein the meaning of T and R is as defined above, Q is hydrogen or cation, reacting the thus obtained product with strong acid resulting in the formation of a compound of the general Formula (IH), wherein T represents hydroxy, R represents hydrogen, Q represents hydrogen and optionally transforming the product thus obtained into rosuvastatin sodium salt of the Formula (II), or
c) transforming a compound of the general Formula (HT), wherein T and R together form an oxymethylene group substituted by one or two alkyl groups in the presence of a strong acid into a compound of the general Formula (III), wherein the meaning of T is hydroxy, R is hydrogen, Q is hydrogen, an alkyl group comprising 1 to 6 carbon atoms or an alkenyl group comprising 2 to 6 carbon atoms, isolating rosuvastatin of the Formula (I) thus obtained and if desired, transformed into rosuvastatin sodium salt of the Formula (II), or optionally transforming the compound obtained into a compound of the general Formula (HI), wherein Q is hydrogen or cation, T is hydroxy, R is hydrogen and setting free the rosuvastatin acid, or converting a compound of the general Formula (HI), wherein T is hydroxy, R is hydrogen, Q is hydrogen into rosuvastatin sodium salt of the Formula (II) and isolating the product, or
d) transforming a compound of the general Formula (III), wherein T and Q together form a single bond, R is hydroxy, into a compound of the general Formula (III), wherein T is hydroxy, R is hydrogen, Q represents hydrogen or cation, and optionally converting the product thus obtained into rosuvastatin of the Formula (I) or converting the compound of the general Formula (III), wherein the meaning of T and R is as defined above, Q is hydrogen into rosuvastatin sodium salt of the Formula (II) and isolating the product. Among the compound of the general Formula (III), preferable starting compounds are those wherein Q represents ethyl or t-butyl group. Further preferable starting compounds of the general Formula (HI) are those, wherein T and T together form an oxymethylene group of the Formula (TV),
Figure imgf000011_0001
(IV) wherein the substituents R and R are hydrogen or an alkyl group comprising 1 to 4 carbon atoms (together with the adjoining and included carbon atoms forming a 2,2-dimethyl-l,3-dioxane ring).
According to variant a) of the process according to the present invention, a compound of the general Formula (III), wherein Q is an alkyl group comprising 1 to 6 carbon atoms or an alkenyl group comprising 2 to 6 carbon atoms, preferably ethyl-group or t-butyl- group, T is hydroxy, R is hydrogen is hydrolysed in water, in an organic solvent or using an aqueous-organic solvent system in the presence of a base, rosuvastatin salt of the general Formula (III), wherein Q represents cation, preferably sodium ion, T represents hydroxy group, R represents hydrogen is optionally isolated or transformed by reacting with an inorganic or organic acid into rosuvastatin of the Formula (I) (wherein Q and R represent hydrogen, T represents hydroxy) and if desired, transforming the acid into rosuvastatin sodium salt of the Formula (II).
Hydrolysis of the compounds of the general Formula (III), wherein Q represents an alkyl group comprising 1 to 6 carbon atoms or an alkenyl group comprising 2 to 6 carbon atoms, preferably ethyl group or t-buryl group, T represents hydroxy group, R represents hydrogen, can be performed alternatively by hydrolysing the starting compound of the general Formula (III) in water, in an organic solvent or in the mixture thereof in the presence of an organic or mineral acid and isolating rosuvastatin acid of the Formula (I), wherein Q and R represent hydrogen, T is hydroxy and if desired, converting rosuvastatin acid into rosuvastatin sodium salt of the Formula (II).
According to variant b) of the process according to the present invention, a compound of the general Formula (IH), wherein Q is an alkyl-group, preferably ethyl-group or t-butyl group, T and R together form an oxymethylene group substituted by one of two alkyl groups, preferably by two methyl groups, is hydrolysed in the presence of a base, in an organic solvent or in aqueous-organic solution and thus producing a compound of the general Formula (III), wherein Q is cation, T and R together form an oxymethylene group substituted by one or two alkyl groups, preferably by two methyl groups, optionally converting the salt thus obtained into a carboxylic acid of the general Formula (HI), wherein Q is hydrogen, T and R together form an oxymethylene group substituted by one or two alkyl groups, preferably by two methyl groups, transforming the product thus obtained under acidic conditions into rosuvastatin of the Formula (I) and if desired, converting rosuvastatin into sodium salt thereof and isolating the product.
According to variant c) of the process according to the present invention, rosuvastatin of the Formula (I) and sodium salt thereof are produced by transforming a compound of the general Formula (HI), wherein T and R form an oxymethylene group substituted by one or two alkyl groups, preferably by two methyl groups, Q represents alkyl group, preferably ethyl group or t-butyl group by treating with an organic or inorganic acid in water or in an aqueous-organic solvent into a compound of the general Formula (III), wherein T is hydroxy, R is hydrogen, Q is alkyl, subsequently hydrolysing the ester thus obtained in organic solvent or hi water or in the mixture thereof using a base, converting the thus obtained salt of the general Formula (III), wherein Q represents a cation, into rosuvastatin of the Formula (I) and optionally converting rosuvastatin into sodium salt thereof.
Alternatively, the reaction can be carried out by directly transforming a compound of the general Formula (JR), wherein Q represents an alkyl group, preferably ethyl group or t-butyl group, T and R forms together an oxymethylene group substituted by one or two alkyl groups, preferably by two methyl groups in presence of a mineral acid in an organic solvent or in a mixture of water and an organic solvent into rosuvastatin of the Formula (I) and optionally transforming the acid thus obtained into sodium salt thereof. According to variant d) of the process according to the present invention, a compound of the general Formula (HI), wherein R is hydrogen, T and Q together form a single bond, is transformed by a ring opening reaction in an organic solvent, in water or in the mixture thereof in the presence of an acid or base into a compound of the general Formula (HI), wherein T represents hydroxy, R is hydrogen, Q is hydrogen or cation, and isolating rosuvastatin of the Formula (I) or if desired, converting into sodium salt of the Formula (II); or liberating rosuvastatin of the Formula (I) from a salt wherein Q represents a cation and optionally converting into sodium salt.
According to a second aspect of the present invention, there is provided high purity (+)-7-[4-(4-fluorophenyl)-6-isopropyl-2- (memanesulfonyl-memyl-amino)-pyrimidin-5-yl]-(3i-,55)-dihydroxy- hept-6-enoic acid sodium salt (1:1) having purity at least 99.5%, preferably 99.9%. High purity rosuvastatin sodium of the Formula (II) can be advantageously used as an intermediate in the production of pharmaceutically acceptable rosuvastatin salts, e.g. rosuvastatin calcium or rosuvastatin zinc salts.
According to a third aspect of the present invention, there is provided a process for the preparation of high purity rosuvastatin sodium salt of the Formula (II), which comprises reacting a compound of the general Formula (DI), wherein T represents hydroxy, R is hydrogen, Q is an alkyl group comprising 1 to 6 carbon atoms, preferably ethyl-group with an approximately equimolar amount of aqueous sodium hydroxide solution at room temperature using an aqeuous-ethanolic solvent, filtering the reaction mixture, evaporating the solvent, washing the residue with ethylacetate after diluting with water, evaporating the aqueous layer, removing residual ethanol and water, solidifying rosuvastatin sodium by adding diisopropylether to the residue and optionally after thorough powdering, stirring rosuvastatin sodium of the Formula (II) in ethanolic suspension and filtering the product.
Alkaline hydrolysis of the compounds of the general Formula (III), wherein the meaning of Q is an alkyl group or an alkenyl group, preferably ethyl group or t-butyl group, T represents hydroxy group, R represents hydrogen, can be carried out in water or in an inert solvent, preferably in an aliphatic alcohol comprising 1 to 4 carbon atom, acetonitrile, an aliphatic ketone comprising 3 to 8 carbon atoms, an aliphatic ester comprising 2 to 8 carbon atoms or in an aliphatic ether comprising 4 to 8 carbon atoms or in a mixture thereof.
In the reaction, a 1.0-1.25 molar equivalent amount of a base, preferably an alkali hydroxide, e.g. sodium hydroxide can be used. The base may be used in solid form, but it is more preferable to use in a 0.05-10 mol/dm3 or saturated aqueous solution.
The reaction can be carried out between room temperature and the boiling temperature of the reaction mixture, preferably between 40 and 65 0C. The reaction proceeds easily, the reaction time depending on the temperature is approx. 0.25-12 hours. The acidic hydrolysis of the compounds of the general Formula (III), wherein Q represents an alkyl group comprising 1 to 6 carbon atoms or an alkenyl group comprising 2 to 6 carbon atoms, preferably ethyl group or t-butyl group, T represents hydroxy, R represents hydrogen, is carried out in an inert solvent or in the mixture thereof, which may contain water. Suitable solvents are aliphatic alcohols comprising 1 to 4 carbon atom, acetonitrile, an aliphatic ketone comprising 3 to 8 carbon atoms, an aliphatic ester comprising 2 to 8 carbon atoms or an aliphatic ether comprising 4 to 8 carbon atoms or a mixture thereof.
The reaction can be carried out between room temperature and the boiling temperature of the reaction mixture. The reaction time depending on the temperature is several hours.
In the acidic hydrolysis reaction, a strong mineral or organic acid, e.g. an aqueous solution of a hydrogen halogenide, sulfuric acid, an aromatic or aliphatic sulfonic acid, e.g. benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, preferably aqueous hydrochloric acid solution can be used.
The concentration of the acid used in the reaction can be between 0.2- lO mol/dm3'.
In the case when a compound of the general Formula (III), wherein Q represents an alkyl group, preferably ethyl group or t-butyl group, T and R together form an oxymethylene group substituted by one or two alkyl groups, preferably by two methyl groups, is to be transformed into the corresponding compound containing the unprotected hydroxy groups (a compound of the general Formula (III), wherein Q is hydrogen, an alkyl group comprising 1 to 6 carbon atoms or an alkenyl group comprising 2 to 6 carbon atoms, T is hydroxy, R is hydrogen), the starting compound of the Formula (HI) is reacted with a strong mineral or organic acid in an inert solvent, preferably in an aliphatic alcohol comprising 1 to 4 carbon atom, acetonitrile, an aliphatic ketone comprising 3 to 8 carbon atoms, an aliphatic ester comprising 2 to 8 carbon atoms or in an aliphatic ether comprising 4 to 8 carbon atoms or in a mixture thereof.
In the reaction, a hydrogen halogenide or sulfuric acid can be used as mineral acid. As an organic acid, an aliphatic sulfonic acid comprising 1 to 4 carbon atoms or an aromatic sulfonic acid can be used. Preferably, hydrogen chloride is applied in the form of an aqueous solution.
The reaction can be carried out at a temperature between room temperature and the boiling temperature of the reaction mixture, preferably at a temperature between 50 and 80 0C. The reaction time, depending on the reaction temperature, is several hours.
The acid can be used in an equimolar amount, but preferably, the amount of the acid is in 2.0-40-fold molar excess relative to the molar amount of the starting material. In our experiments, we have found that (+)-7-[4-(4-fluorophenyl)-6- isopropyl-2-(meώanesulfonyl-methyl-amino)-pyrimidin-5-yl]-(3i?,55)- dihydroxy-hept-6-enoic acid sodium salt (1:1) can contain solvent bound as solvates, especially water. The amount of solvent bound in rosuvastatin sodium salt of the Formula (II) depends on the process of the preparation and the conditions of drying and may range in the product between 0.01 and 30 weight%.
Further details of our invention are demonstrated in the following examples without limiting the invention to the examples in any way.
Example 1
7-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)- pyrimidin-5-yl]-(3i?,55)-dihydroxy-hept-6-enoic acid sodium salt (1:1)
1.27 g (2.5 mmol) of ethyl-7-[4-(4-fluorophenyl)-6-isopropyl-2- (methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-(3i?,55)-dihydroxy- hept-6-enoate are stirred in the mixture of 10 ml acetonitrile and 5.0 ml of 1:1 (v/v) diluted hydrochloric acid for two hours at room temperature and subsequently 2 g of solid sodium chloride are added to the reaction mixture. The organic layer is separated and washed twice with 10 ml of 10 weight% sodium chloride solution. Thereafter the stirring is resumed and 1.0 ml of 2.5 M sodium hydroxide solution is added to the reaction mixture dropwise. Rosuvastatin sodium salt thus obtained is isolated according to the process described in Example 3 and transformed into high-purity rosuvastatin sodium salt or the solution of rosuvastatin sodium of the Formula (II) is directly used for the preparation of a pharmaceutically acceptable salt of rosuvastatin.
Example 2
7-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)- pyrimidin-5-yl]-(3i-,55)-dihydroxy-hept-6-enoic acid sodium salt (1:1)
45 g (90.0 mmol) of ethyl-7-[4-(4-fluorophenyl)-6-isopropyl-2- (methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-(3i-555)-dihydroxy- hept-6-enoate are stirred in 1000 ml of ethanol until complete dissolution at room temperature and at the same temperature in 20 minutes, 360 ml of 0.25 M sodium hydroxide solution (90.0 mmol) are added dropwise. After a further 4 hour reaction time, the solution is filtered through a G4 sintered glass filter and the ethanol is evaporated at the pressure of 20 Hgmm. The residue is diluted with 200 ml of water and extracted three times with 75 ml of ethylacetate each and the aqueous layer is evaporated at the pressure of 20 Hgmm. From the residue, 50 ml of ethanol is evaporated twice and the thus obtained solids are stirred in 200 ml of diisopropylether and filtered.
Yield, 43.8 g5 white solids.
Purity approx. 97 %.
Melting point, starts melting from 130 °C.
IR (KBr): 3419, 2970, 1548, 1383, 1150 cm"1
1H-NMR (DMSCW6, 500 MHz): δ 7.72 (dd, J=8.8, 5.9 Hz, 2H), 7.27 (t, J=8.9 Hz, 2H)5 6.52 (dd, J=I 5.9, 1.2 Hz, IH), 5.54 (dd, J=I 6.1 Hz, 5.9 Hz, IH), 5.11 (br s, IH), 4.41 (br s, IH), 4.21 (m, IH), 3.65 (m, IH), 3.55 (s, 3H), 3.45 (s, 3H), 3.43 (m, IH), 3.35 (br s, 2H), 2.04 (dd, J=15.0, 3.8 Hz, IH), 1.85 (dd, J=15.0, 8.4 Hz, IH), 1.48 (m, IH), 1.28 (m, IH), 1.23 (d, 3H), 1.21 (d, 3H) ppm. Example 3
High purity 7-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl- methyl-arnino)-pyrimidin-5-yl]-(3i?55<S)-dihydroxy-hept-6-enoic acid sodium salt (1:1)
45.9 g (90.0 mmol) of ethyl-7-[4-(4-fluorophenyl)-6-isopropyl-2- (methanesulfonyl-methyl-amino)-pyrirnidui-5-yl]-(3i-,5)S)-dihydroxy- hept-6-enoate are stirred in 1000 ml of ethanol until complete dissolution and in 20 minutes, 360 ml of 0.25 M sodium hydroxide solution (90.0 mmol) are added dropwise. After further 4 hour reaction time, the solution is filtered through a G4 sintered glass filter and the ethanol is evaporated at the pressure of 20 Hgmm.
The isolation of the sodium salt of rosuvastatin is performed as follows. 200 ml of water are added to the residue and the solution is extracted three times with 75 ml of ethylacetate each and the aqueous layer is evaporated at the pressure of 20 Hgmm. From the residue, 50 ml of ethanol are evaporated twice and the solids are stirred in 200 ml of diisopropyl ether and filtered. Thus 43.8 g (97 %) of rosuvastatin sodium salt identical in all respects to that obtained in Example 2 are produced. The salt is crushed and homogenized thoroughly and stirred in 300 ml of ethanol at room temperature for two hours. The white suspension is filtered, the solids are washed with 20 ml of ethanol and dried in vacuo protected from light at the temperature of 50 0C.
Yield, 38.63 g (88 %).
The purity of the product according to HPLC assay is higher than
99.95 %. Example 4
7-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)- pyrimidin-5-yl]-(3i-,5S)-dihydroxy-hept-6-enoic acid tert-butylester
10.0 g (17.3 mmol) of (6-{2-[4-(4-fluoroρhenyl)-6-isoρroρyl-2- (memanesulfonyl-methyl-ammo)-pyrimidm^
[l,3]dioxan-4-yl)-acetic acid tert-butylester are dissolved at room temperature in 100 ml of tetrahydrofurane and 50 ml of 10 weight% hydrochloric acid solution are added in 30 minutes. The solution is stirred for further 30 minutes and cooled on ice. With continuous ice cooling, 2 M sodium hydroxide solution are added to the reaction mixture until pH 6 is reached (approx. 36 ml) in such a manner that the temperature of the reaction mixture does not exceed 15 0C. Subsequently 150 ml of water are added and the solution is extracted twice with dichloromethane (75 ml each). The organic layer is dried over sodium sulfate and evaporated at the pressure of 20 Hgmm. After evaporating the solvent, the pale yellow oily residue solidifies upon triturating with diisopropylether (20 ml). The white solids are stirred in diisopropylether, filtered and crystallized from the mixture of water (40 ml) and ethanol (35 ml). Yield, 7.54 g (81 %)
Melting point, 139-140 0C. IR(KBr): 3375,2976, 1735, 1606, 1542, 1510, 1381, 1340, 1226, 1149,964 cm-1.
1H-NMR(CDCl3, 500MHz): 7.65 (dd, 2H, J= 8.8, 5.5 Hz), 7.09 (t, 2H, J= 8.7Hz), 6.64 (dd, IH, J= 16.0, 1.4Hz), 5.46 (dd, IH, J= 16.1, 5.3 Hz), 4.45 (m, IH), 4.17 (m, IH), 3.84 (m, IH), 3.71 (m, IH), 3.57 (s, 3H), 3.52 (s, 3H), 3.38 (m, IH), 2.38 (d, 2H), 1.52 (m, IH), 1.47 (s, 9H), 1.45 (m, IH), 1.27 (d, 6H)ppm.
13C-NMR (CDCl3, 500 MHz): 174.89, 172.08, 163.42, 163.17 (d, J = 249.5 Hz), 157.23, 139.47, 134.53 (d, J = 3.4 Hz), 132.11 (d, J = 8.3 Hz), 122.50, 121.45, 114.95 (d, J = 21.5 Hz), 81.79, 71.91, 68.58, 42.39, 42.20, 41.87, 33.06, 32.07, 28.06, 21.58, 21.55 ppm.
Elemental analysis
Calculated: C 58,08 H 6,75 N 7,82 S 5 ,96 %.
Measured: C 58,16 H 6,87 N 7,97 S 5 ,80 %.
Example 5
7-[4-(4-Fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl- amino)-pyrimidin-5-yl]- (3i-,55)-dihydroxy-hept-6-enoic acid sodium salt (1:1)
A. 7- [4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl- amino)-pyrirnidin-5-yl]-(3i2,5<S)-dmydroxy-hept-6-enoic acid tert- butylester 10.0 g (17.3 mmol) of (6-{2-[4-(4-fluorophenyl)-6-isopropyl-2- (methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-vinyl}-2,2-dimethyl- [l,3]dioxan-4-yl)-acetic acid tert-butylester are dissolved in 100 ml of tetrahydrofurane at room temperature and 50 ml of 10 weight% hydrochloric acid solution are added in 30 minutes. The reaction mixture is stirred for two hours at room temperature. Subsequently, while cooling on ice, 2 M sodium hydroxide solution is added to the reaction mixture until pH 6 is reached, in a speed that the temperature of the reaction mixture does not exceed 15 0C. Subsequently 150 ml of water are added and the reaction mixture is extracted twice with 75 ml of dichloromethane each. The organic layer is dried over sodium sulfate and evaporated at the pressure of 20 Hgmm. The pale yellow oily residue crystallized upon addition of diisopropylether (20 ml).The white solids are stirred in diisopropylether, filtered and recrystallized from the mixture of water (40 ml) and ethanol (35 ml). Yield, 7.81 g (84 %)
B. 7-[4-(4-Fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl- amino)-pyrimidin-5-yl]- (3i?,5<S)-dihydroxy-hept-6-enoic acid sodium salt (1:1)
7 g (14.5 mmol) of 7-[4-(4-fluorophenyl)-6-isopropyl-2- (methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-(3i-,5iS)-dihydroxy- hept-6-enoic acid tert-butylester are stirred until complete dissolution in 200 ml of ethanol and at room temperature in 20 minutes 58 ml of 0.25 M sodium hydroxide solution (14.5 mmol) are added dropwise. The mixture is reacted for 4 hours at the temperature of 60 0C, the solution is filtered through a G4 sintered glass filter and the ethanol is evaporated at the pressure of 20 Hgmm. The residue is diluted with 40 ml of water and extracted three times with 15 ml of ethylacetate each, the aqueous layer is evaporated at the pressure of 20 Hgmm. From the residue, 2x10 ml of ethanol is evaporated and the solids thus obtained are stirred in 40 ml of diisopropyl-ether and filtered.
Yield, 6.65 g (91 %).
The product is identical in all respects with that obtained in
Example 2.
Example 6
7-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)- pyrimidin-5-yl]- (3i.,55)-dihydroxy-hept-6-enoic acid
10 g (17.3 mmol) of (6-{2-[4-(4-fluoroρhenyl)-6-isopropyl-2- (methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-vinyl}-2,2-dimethyl- [l,3]dioxan-4-yl)-acetic acid tert-butylester are dissolved in 100 ml of tetrahydrofurane at room temperature and with intense stirring, 60 ml (60 mmol) of 1 M sodium hydroxide solution are added and the reaction mixture is kept at its boiling temperature for 8 hours. After cooling down, 100 ml of ethylacetate are added, the organic layer is extracted with 40 ml of water and the organic layer is evaporated. The residue is dissolved in 200 ml of water and while cooling on ice, the solution is made acidic using 1 M hydrochloric acid solution. The precipitated product is filtered and washed twice with 50 ml of water each.
(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl- amino)-pyrimidin-5-yl]-vinyl}-2,2-dimethyl-[l,3]dioxan-4-yl)-acetic acid is dissolved in 250 ml of tetrahydrofurane and 40 ml (40 mmol) of 1 M hydrochloric acid are added and allowed to react for 30 minutes at 80 °C. The reaction mixture is evaporated and the residue is extracted with 100 ml of water and 100 ml of ethylacetate. The organic layer is dried over magnesium sulfate, filtered and the solvent is evaporated.
Yield, 6.50 g (78 %).
Example 7
7-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)- pyrimidin-5-yl]- (3i?,5S)-dihydroxy-hept-6-enoic acid
10 g (17.3 mmol) of (6-{2-[4-(4-fluorophenyl)-6-isopropyl-2- (methanesulfonyl-memyl-amino)-pyriπiidin-5-yl]-vinyl}-2,2-dimethyl- [l,3]dioxan-4-yl)-acetic acid t-butylester are mixed with 250 ml of tetrahydrofurane and 40 ml (40 mmol) of 1 M hydrochloric acid solution and reacted at the temperature of 80 °C for 2 hours. The reaction mixture is evaporated and the residue is extracted with 100 ml of water and 100 ml of ethylacetate. The organic layer is dried over magnesium sulfate, filtered and the solvent is evaporated. Yield, 6.75 g (81 %) Example δ
7-[4-(4-Fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl- amino)-pyrimidin-5-yl]- (3J?,5.S)-dihydroxy-hept-6-enoic acid zinc salt
(2:1)
31.06 g (61.7 mmol) of rosuvastatin sodium salt prepared according to the process of Example 3 are dissolved in 400 ml of water and the solution is filtered through a G4 sintered glass filter. 26.0 ml 1.0 M zinc sulfate solution (26.0 mmol) are added dropwise to the filtrate in 15 minutes. The precipitated white solids are filtered, washed with water and dried at room temperature protected from light at the pressure of 0.1 Hgmm. Yield 24.48 g (92 %).
Example 9
7-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)- pyrimidin-5-yl]-(3i?,5S)-dihydroxy-hept-6-enoic acid zinc salt (2:1)
306.0 g (0.60 mol) of ethyl-7-[4-(4-fluorophenyl)-6-isoρropyl-2- (methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-(3i-,55)-dihydroxy- hept-6-enoate are dissolved in 2400 ml of ethanol and with external water cooling, 300 ml of 2,5 M (0.75 mol) of sodium hydroxide solution are added dropwise in 20 minutes and the mixture is allowed to react for 30 minutes while heating with a 60 °C-temperature water bath. Thereafter the mixture is cooled with ice-water mixture below the temperature of 10 0C and 50.0 ml (0.15 mol) of 3.0 M hydrochloric acid solution are added dropwise, stirred for 10 minutes and while maintaining cooling, 300 ml of 1.0 M (0.30 mol) zinc sulfate solution is added dropwise and stirring the mixture at room temperature. Subsequently 500 ml of 10 weight% sodium chloride solution are added to the reaction mixture and the greatest part of ethanol is evaporated in vacuo at a 60 °C water bath. The residue is extracted with 300 ml of ethylacetate, the organic layer is separated and the aqueous layer is extracted repeatedly twice with 100 ml of ethylacetate. The ethylacetate solutions are combined and washed with 300 ml of 10 weight% sodium chloride solution and stirred for one hours after addition of 1.0 g of activated carbon and 5.0 g of magnesium sulfate. Thereafter half of the solvent is evaporated and the concentrated solution is added dropwise into 2000 ml of diethyl ether while stirring continuously. The stirring is continued until a filterable white solid is obtained, which is filtered and washed with diethylether. Yield, 216.O g (70 %)
Example 10
7-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)- pyrimidin-5-yl]-(3i-,55)-dihydroxy-hept-6-enoic acid zinc salt (2:1)
A. 7-[4-(4-Fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl- amino)-pyrimidin-5-yl]-(3i-:ι5-?)-dihydroxy-hept-6-enoic acid sodium salt (1:1) 45 g (90.0 mmol) of ethyl-7-[4-(4-fluorophenyl)-6-isopropyl-2- (methanesulfonyl-melhyl-atnino)-pyrimidin-5-yl]-(3i?,55)-dihydroxy- hept-6-enoate are stirred in 1000 ml of ethanol until complete dissolution and in 20 minutes, 360 ml of 0.25 M sodium hydroxide solution (90.0 mmol) are added dropwise at room temperature. After 4 hours reaction time, the mixture is filtered through a G4 sintered glass filter and the ethanol is evaporated at the pressure of 20 Hgmm. The residue is mixed with 200 ml of water and extracted three times with 75 ml of ethylacetate each and the aqueous layer is evaporated at the pressure of 20 Hgmm. From the residue 2x50 ml of ethanol are evaporated and the solids are stirred in 200 ml of diisopropylether and filtered.
Yield, 43.8 g (97 %).
The product is identical in all respects with the product of
Example 2.
B. 7-[4-(4-Fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl- amino)-pyrimidin-5-yl]-(3i-,5iS)-dihydroxy-hept-6-enoic acid zinc salt (2:1)
1.04 g (2.07 mmol) of the rosuvastatin sodium salt obtained in the previous stage are dissolved in 20 ml of methanol at room temperature and the solution is filtered through a G4 sintered glass filter. 1.0 ml of 1.0 M methanolic zinc chloride solution (1.0 mmol) is added dropwise to the well-stirred filtrate in 30 minutes. After further 30-minutes stirring, the solution is evaporated. The white solid residue is stirred in 10 ml of water, filtered, washed with water and dried at room temperature protected from light at the pressure of 0.1 Hgmm.
Yield, 0.96 g (94 %), The product is identical in all respects with that of Example 1.

Claims

What we claim is,
1. Process for the preparation of (+)-7-[4-(4-fluorophenyl)-6- isopropyl-2-(methanesulfonyl-methyl-amino)-pyrirnidin-5-yl]-(3i?,5)S)- dihydroxy-hept-6-enoic acid of the Formula (I)
Figure imgf000031_0001
(I) and (+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl- amino)-pyrimidin-5-yl]-(3i?,55)-dihydroxy-hept-6-enoic acid sodium salt of the Formula (I), which comprises
a) transforming a compound of the general Formula (III),
Figure imgf000032_0001
(HI) wherein T represents hydroxy, R is hydrogen, Q is an alkyl group comprising 1 to 6 carbon atoms or an alkenyl group comprising 2 to 6 carbon atoms, preferably ethyl-group, by hydrolysis into a compound of the general Formula (III) wherein the meaning of T and R is as defined above, Q is hydrogen or cation and optionally converting the product thus obtained into rosuvastatin of the Formula (I) or transforming a product of the general Formula (III), wherein the meaning of T and R is defined above, Q is hydrogen, into rosuvastatin sodium salt of the Formula (II)
Figure imgf000033_0001
(IT) and isolating the product, or
b) transforming a compound of the general Formula (III), wherein T and R together form an oxymethylene group substituted by one or two alkyl groups, Q represents an alkyl group comprising 1 to 6 carbon atoms or an alkenyl group comprising 2 to 6 carbon atoms by hydrolysis into a compound of the general Formula (III), wherein the definition of T and R is as defined above, Q is hydrogen or cation; converting the product thus obtained by reacting with a strong acid into a compound of the general Formula (IH), wherein R is hydroxy, R is hydrogen, Q is hydrogen and if desired, transforming the product thus obtained into sodium salt of the Formula (II), or c) reacting a compound of the general Formula (HI), wherein T and R together form an oxymethylene group substituted by one or two alkyl groups, Q represents an alkyl group comprising 1 to 6 carbon atoms or an alkenyl group comprising 2 to 6 carbon atoms with a strong acid, and the thus obtained compound of the Formula (I), wherein T represents hydroxy, Q and R represents hydrogen, is isolated and optionally transformed into sodium salt of the Formula (TL), or in the case when a compound of the general Formula (IH) is obtained, wherein T is hydroxy, R is an alkyl group comprising 1 to 6 carbon atoms or an alkenyl group comprising 2 to 6 carbon atoms, the product thus obtained is converted into a compound of the general Formula (HI), wherein T is hydroxy, R is hydrogen, Q is hydrogen or cation and setting rosuvastatin of the Formula (I) free or transforming rosuvastatin thus obtained into rosuvastatin sodium salt of the Formula (II), or
d) transforming a compound of the general Formula (III), wherein T and Q together form a single bond, R is hydroxy, into a compound of the general Formula (III), wherein T is hydroxy, R is hydrogen, Q is hydrogen or cation, and if desired, setting rosuvastatin of the Formula (I) free from a product thus obtained, wherein Q is cation, or transforming rosuvastatin thus obtained into sodium salt thereof and the product is isolated.
2. Process for the preparation of rosuvastatin of the Formula (I) or rosuvastatin sodium salt of the Formula (II), which comprises hydrolysing a compound of the general Formula (ID), wherein Q represents an alkyl group comprising 1 to 6 carbon atoms or an alkenyl group comprising 2 to 6 carbon atoms, preferably ethyl group or t- butyl group, T is hydroxy, R is hydrogen in an organic solvent, in water or in the mixture thereof in presence of a base and the thus obtained compound of the general Formula (HI), wherein Q is cation, T is hydroxy, R is hydrogen, is optionally isolated or converted into rosuvastatin of the Formula (I) by reacting with an inorganic or organic salt and if desired, transforming rosuvastatin thus obtained into rosuvastatin sodium salt.
3. Process for the preparation of rosuvastatin of the Formula (I) or rosuvastatin sodium salt of the Formula (II), which comprises hydrolysing a compound of the general Formula (III), wherein Q represents an alkyl group comprising 1 to 6 carbon atoms or an alkenyl group comprising 2 to 6 carbon atoms, preferably ethyl group or t- butyl group, T represents hydroxy, R is hydrogen in an organic solvent, in water or in the mixture thereof in the presence of an organic or mineral acid, isolating rosuvastatin of the Formula (I) and if desired, converting rosuvastatin thus obtained into rosuvastatin sodium salt.
4. Process for the preparation of rosuvastatin of the Formula (I) or rosuvastatin sodium salt of the Formula (I), which comprises transforming a compound of the general Formula (II), wherein Q represents an alkyl group or an alkenyl group, preferably ethyl group or t-butyl group, T and R together form an oxymethylene group substituted by one or two alkyl groups, preferably by two methyl groups in presence of a base in an organic solvent, in water or in a mixture thereof into a compound of the general Formula (III), wherein Q is cation, T and R together form an oxymethylene group substituted by one or two alkyl groups, preferably by two methyl groups, optionally setting free the carboxylic acid of the general Formula (III), wherein Q is hydrogen, T and R together form an oxymethylene group substituted by one or two alkyl groups and converting the compound of the general Formula (IE) thus obtained in presence of an acid into rosuvastatin of the Formula (I) and if desired, transforming the free acid into sodium salt thereof.
5. Process for the preparation of rosuvastatin of the Formula (I) or rosuvastatin sodium salt of the Formula (II), which comprises transforming a compound of the general Formula (III), wherein T and R together form an oxymethylene group substituted by one or two alkyl groups, preferably by two methyl groups, Q represents an alkyl group, preferably ethyl group or t-butyl group in presence of an organic or inorganic acid in an organic solvent optionally containing water into a compound of the general Formula (III), wherein T represents hydroxy, R represents hydrogen, Q is alkyl group, optionally isolating the product, hydrolysing the thus obtained ester of the general Formula (III) in presence of a base using an organic solvent or in a mixture of water and an organic solvent, and converting the salt of the general Formula (III), wherein T is hydroxy, R is hydrogen, Q is cation, into rosuvastatin of the Formula (I) and optionally transforming into sodium salt thereof.
6. Process for the preparation of rosuvastatin of the Formula (I) or sodium salt thereof, which comprises converting a compound of the general Formula (HI), wherein Q represents alkyl group, preferably ethyl group or t-butyl group, T and R together form an oxymethylene group substituted by one or two alkyl groups, preferably by two methyl groups, in the presence of a mineral acid in an organic solvent or in the mixture of water and an organic solvent directly into rosuvastatin of the Formula (I) and optionally converting the product thus obtained into sodium salt.
7. Process for the preparation of rosuvastatin of the Formula (I) or rosuvastatin sodium of the Formula (II), which comprises transforming a compound of the general Formula (III), wherein R is hydrogen, T and Q together form a single bond, in presence of an acid or a base in organic solvent into a compound of the general Formula (in), wherein T is hydroxy, R is hydrogen, Q is hydrogen or cation, optionally isolating rosuvastatin of the Formula (I) thus obtained and if desired, converting into the sodium salt of the Formula (II) or converting the salts of the general Formula (HI), wherein Q is cation into rosuvastatin and transforming the acid into sodium salt thereof.
8. Process according to any of claims 1 to 7, characterized in that as solvent, water, an aliphatic alcohol comprising 1 to 4 carbon atoms, acetontrile, an aliphatic ketone comprising 3 to 8 carbon atoms, an aliphatic ester comprising 2 to 8 carbon atoms or an aliphatic ether comprising 4 to 8 carbon atoms are used.
9. Process according to any of claims 1 to 7, characterized in that the reaction is performed between 0 0C and the boiling temperature of the reaction mixture, preferably between 25 and 80 "C, the most advantageously between 25 and 50 °C.
10. Process according to any of claims 1, 2, 4, 5 or 7, characterized in that the hydrolysis is performed in the presence of 1.0-1.25 molar equivalent base.
11. Process according to claim 10 characterized in that as base, an organic or inorganic basic compound, preferably an alkali metal hydroxide, the most advantageously sodium hydroxide is used.
12. Process according to any of claims 10 or 11, characterized in that the base is applied as solid, saturated aqueous solution or as a 0.05-10 mol/dm3 solution.
13. Process according to claim 3 characterized in that the acidic hydrolysis is carried out in the presence of a strong mineral or organic acid, e.g. hydrochloric acid, hydrogen bromide, sulfuric acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, preferably in the presence of hydrochloric acid.
14. Process according to claim 13 characterized in that the concentration of the acid is between 0.2-10,0 mol/dm3.
15. Process according to any of claims 4 to 6, characterized by that for preparing the compounds of the general Formula (HI), wherein T is hydroxy, R is hydrogen, Q is alkyl or alkenyl, the corresponding compound of the general Formula (HI), wherein T and R together form an oxymethylene group substituted by one or two alkyl groups, preferably by two methyl groups, Q is alkyl or alkenyl, is reacted with a strong mineral or organic acid, e.g. with hydrochloric acid, hydrogen bromide, sulfuric acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid or ethanesulfonic acid.
16. Process according to claim 15, characterized in that the strong mineral or organic acid is used in 1.0-40.0 molar equivalent amount.
17. High purity (+)-7-[4-(4-fluorophenyl)-6-isopropyl-2- (metiianesulfonyl-methyl-arnino)-pyrimidin-5-yl]-(3i-,5jS)-dihydroxy- hept-6-enoic acid sodium salt (1:1) and solvates thereof.
18. Process for the preparation of rosuvastatin sodium salt of the Formula (II), which comprises reacting a compound of the general Formula (III), wherein the meaning of T is hydroxy, R is hydrogen, Q represents an alkyl group comprising 1 to 6 carbon atoms, preferably ethyl group with approximately equimolar amount of sodium hydroxide at room temperature in an aliphatic alcohol comprising 1 to 4 carbon atoms which may optionally contain water, the reaction mixture is filtered, the solvent is evaporated, the residue is extracted with an aliphatic ester comprising 2 to 8 carbon atoms after dilution with water, the aqueous layer is evaporated, the solvent is removed and rosuvastatin sodium salt is solidified in a mixture of an aliphatic alcohol comprising 1 to 4 carbon atoms and an aliphatic ether comprising 2 to 8 carbon atoms and optionally suspended and stirred in an aliphatic alcohol.
19. High purity (+)-7-[4-(4-fiuorophenyl)-6-isopropyl-2- (methanesulfonyl-methyl-ammo)^yrimidin-5-yl]-(3jR,55)-dihydroxy- hept-6-enoic acid sodium salt (1:1) obtainable by reacting a compound of the general Formula (III), wherein T is hydroxy, R is hydrogen, Q is an alkyl group comprising 1 to 6 carbon atoms, preferably ethyl group, with approximately equimolar amount of sodium hydroxide at room temperature in an aliphatic alcohol comprising 1 to 4 carbon atoms, the solvent is evaporated, the aqueous residue is extracted with an aliphatic ester type solvent comprising 2 to 8 carbon atoms, preferably with ethylacetate, the aqueous layer is evaporated, removing the solvents from the residue and solidifying the product of the Formula (II) in a mixture of an aliphatic alcohol comprising 1 to 4 carbon atoms and an aliphatic ether comprising 2 to 8 carbon atoms and optionally suspended and stirred in an aliphatic alcohol.
PCT/HU2008/000121 2007-10-12 2008-10-13 Process for preparation of pharmaceutical intermediates WO2009047576A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HU0700668A HU230637B1 (en) 2007-10-12 2007-10-12 Process for producing intermediates of rosuvastatin
HUP0700668 2007-10-12

Publications (1)

Publication Number Publication Date
WO2009047576A1 true WO2009047576A1 (en) 2009-04-16

Family

ID=89987810

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/HU2008/000121 WO2009047576A1 (en) 2007-10-12 2008-10-13 Process for preparation of pharmaceutical intermediates

Country Status (2)

Country Link
HU (1) HU230637B1 (en)
WO (1) WO2009047576A1 (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011010174A1 (en) * 2009-07-24 2011-01-27 Egis Gyógyszergyár Nyilvánosan Működő Crystalline form i rosuvastatin zinc salt
US8212035B2 (en) 2007-02-08 2012-07-03 Aurobindo Pharma Ltd. Process for preparation of rosuvastatin calcium field of the invention
US8318933B2 (en) 2006-10-31 2012-11-27 Aurobindo Pharma Ltd Process for preparing rosuvastatin calcium
JP2013542977A (en) * 2010-11-16 2013-11-28 エギシュ ヂョヂセルヂャール ニルヴァーノサン ミケデ レースヴェーニタールササーグ Crystalline pharmaceutically active ingredient
JP2014524933A (en) * 2011-07-26 2014-09-25 ダウ アグロサイエンシィズ エルエルシー Method for isolating 4-chloro-2-fluoro-3-substituted-phenylboronic acid

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0521471A1 (en) * 1991-07-01 1993-01-07 Shionogi Seiyaku Kabushiki Kaisha Pyrimidine derivatives as HMG-CoA reductase inhibitors
WO2004014872A1 (en) * 2002-08-13 2004-02-19 Astrazeneca Uk Limited Process for preparing the calcium salt of rosuvastatin
WO2006038111A1 (en) * 2004-10-07 2006-04-13 Pfizer Products Inc. Benzoimidazole derivatives useful as antiproliferative agents

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0521471A1 (en) * 1991-07-01 1993-01-07 Shionogi Seiyaku Kabushiki Kaisha Pyrimidine derivatives as HMG-CoA reductase inhibitors
WO2004014872A1 (en) * 2002-08-13 2004-02-19 Astrazeneca Uk Limited Process for preparing the calcium salt of rosuvastatin
WO2006038111A1 (en) * 2004-10-07 2006-04-13 Pfizer Products Inc. Benzoimidazole derivatives useful as antiproliferative agents

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8318933B2 (en) 2006-10-31 2012-11-27 Aurobindo Pharma Ltd Process for preparing rosuvastatin calcium
US8212035B2 (en) 2007-02-08 2012-07-03 Aurobindo Pharma Ltd. Process for preparation of rosuvastatin calcium field of the invention
WO2011010174A1 (en) * 2009-07-24 2011-01-27 Egis Gyógyszergyár Nyilvánosan Működő Crystalline form i rosuvastatin zinc salt
JP2013500250A (en) * 2009-07-24 2013-01-07 エギシュ ヂョヂセルヂャール ニルヴァーノサン ミケデ レースヴェーニタールササーグ Crystalline Form I Rosuvastatin Zinc Salt
EA020944B1 (en) * 2009-07-24 2015-02-27 Эгиш Дьёдьсердьяр Ньильваношан Мюкеде Ресвеньтаршашаг Crystalline form i rosuvastatin zinc salt
US9023838B2 (en) 2009-07-24 2015-05-05 Egis Gyogyszergyar Nyilvanosan Muekoedoe Crystalline form I rosuvastatin zinc salt
CN102548971B (en) * 2009-07-24 2015-09-16 埃吉斯药物股份公开有限公司 The crystal formation I of superstatin zinc salt
JP2013542977A (en) * 2010-11-16 2013-11-28 エギシュ ヂョヂセルヂャール ニルヴァーノサン ミケデ レースヴェーニタールササーグ Crystalline pharmaceutically active ingredient
JP2014524933A (en) * 2011-07-26 2014-09-25 ダウ アグロサイエンシィズ エルエルシー Method for isolating 4-chloro-2-fluoro-3-substituted-phenylboronic acid

Also Published As

Publication number Publication date
HU230637B1 (en) 2017-05-29
HUP0700668A2 (en) 2009-05-28

Similar Documents

Publication Publication Date Title
EP1912952B1 (en) Process for preparing amorphous rosuvastatin calcium free of impurities
SU1535379A3 (en) Method of producing 5-substituted 2,4-diaminopyrimidines or their acid-additive salts
EP2013188B1 (en) Rosuvastatin zinc salt
NO310819B1 (en) Chloropyrimide intermediates and process for their preparation
NZ512560A (en) HMG CoA Reductase Inhibitor Crystalline bis[(E)-7- [ 4-(4- fluorophenyl)- 6-isopropyl-2-[methyl (methylsulfonyl) amino] pyrimidin -5-YL] (3R,5S)-3, 5-dihydroxyhept -6-enoic acid]calcium salt
JP2008044948A (en) Process for manufacturing calcium salt of rosuvastatin(e)-7-[4-(4-fluorophenyl)-6-iosopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3r, 5s)-3,5-dihydroxyhept-6-enoic acid and crystalline intermediate thereof
WO2009047576A1 (en) Process for preparation of pharmaceutical intermediates
JP2013543884A (en) Manufacturing method for high-purity pharmaceutical intermediates
JP5558492B2 (en) Major intermediates for the synthesis of rosuvastatin or pharmaceutically acceptable salts thereof
US9040696B2 (en) Method for preparing rosuvastatin salts
KR20140017207A (en) Rosuvastatin isopropyl amine salt, the preparation method thereof and the preparation method of rosuvastatin hemicalcium salt using the same
WO2009047577A1 (en) Process for preparation of rosuvastatin zinc salt
EA021942B1 (en) Process for the preparation of rosuvastatin salts
US20060199855A1 (en) Process for producing atorvastatin hemicalcium
CN106674281B (en) A kind of Rosuvastatin midbody compound, preparation method and its usage
KR20120092788A (en) New statin intermediate, the preparation of the same and the preparation of rosuvastatin using the same
CN107311939B (en) Preparation method of substituted pyrimidone derivative
DE2714392A1 (en) URACIL DERIVATIVES, THE PROCESS FOR THEIR MANUFACTURING AND MEDICINAL PRODUCTS CONTAINING THEM
JPH06239841A (en) 6.7-dihydro-5h-cyclopenta(d)pyrimidine derivative
KR20020002772A (en) Novel catechol pyrimidine derivatives, preparation methods thereof and pharmaceutical compositions containing catechol pyrimidine derivatives
TW201731847A (en) Synthetic method of entecavir and intermediate compounds thereof
JPS60149523A (en) Anti-inflammatory analgesic agent

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08837522

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08837522

Country of ref document: EP

Kind code of ref document: A1