[go: up one dir, main page]

US20080188552A1 - New salts of HMG-CoA reductase inhibitors - Google Patents

New salts of HMG-CoA reductase inhibitors Download PDF

Info

Publication number
US20080188552A1
US20080188552A1 US11/901,634 US90163407A US2008188552A1 US 20080188552 A1 US20080188552 A1 US 20080188552A1 US 90163407 A US90163407 A US 90163407A US 2008188552 A1 US2008188552 A1 US 2008188552A1
Authority
US
United States
Prior art keywords
pravastatin
salt
hmg
alkyl
coa reductase
Prior art date
Legal status (The legal status 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 status listed.)
Abandoned
Application number
US11/901,634
Inventor
Zlatko Pflaum
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Lek Pharmaceuticals dd
Original Assignee
Lek Pharmaceuticals dd
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 Lek Pharmaceuticals dd filed Critical Lek Pharmaceuticals dd
Priority to US11/901,634 priority Critical patent/US20080188552A1/en
Publication of US20080188552A1 publication Critical patent/US20080188552A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/02—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C211/09—Diamines
    • C07C211/10—Diaminoethanes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/02—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C211/03—Monoamines
    • C07C211/07—Monoamines containing one, two or three alkyl groups, each having the same number of carbon atoms in excess of three
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/02—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C211/09—Diamines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/02—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C211/14—Amines containing amino groups bound to at least two aminoalkyl groups, e.g. diethylenetriamines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C211/34—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton
    • C07C211/35—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton containing only non-condensed rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/30—Oxygen atoms, e.g. delta-lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • Lovastatin, pravastatin, simvastatin, mevastatin, atorvastatin and derivatives and analogs thereof are examples of known as HMG-CoA reductase inhibitors which are used as antihypercholesterolemic agents.
  • the majority of them are produced biotechnologically by fermentation using microorganisms of different species identified as species belonging to Aspergillus, Monascus, Nocardia, Amycolatopsis, Mucor or Penicillium genus, some are obtained by treating the fermentation products using the methods of chemical synthesis, thus leading to semi-synthetic substances, or they are the products of total chemical synthesis.
  • the present invention relates to a new industrial process for isolation and/or purification of HMG-CoA reductase inhibitors via salts thereof with specific amines.
  • the invention enables a user to obtain the pure amine salts of HMG-CoA reductase inhibitors from the fermentation broth in case the substances are produced by biotechnological (microbiological) processes, or from the reaction mixture in case the substances are produced by semisynthetic or total chemical synthesis.
  • the step of forming salts with amine may be one of the steps in the process for isolation and/or purification of HMG-CoA reductase inhibitors or precursor substances thereof.
  • the amines described in the present specification are very useful for the formation of salts in the composition of media in processes for biotechnological modification of HMG-CoA reductase inhibitors or precursors thereof.
  • the salts thus formed may be used as the starting substances or intermediates for the preparation of semisynthetic derivatives and analogs thereof, or by employing simple techniques known from the literature, if required, to be converted into the pharmaceutically acceptable salts and lactones, respectively.
  • GB 2055100A also describes the formation of the sodium and calcium salts of lovastatin, which comprises the extraction in methanol, two steps of preparative liquid reverse-phase chromatography, crystallization from methanol and recrystallization from ethanol, and the conversion into the salt using an aqueous solution of sodium or calcium hydroxide.
  • lovastatin comprises the extraction in methanol, two steps of preparative liquid reverse-phase chromatography, crystallization from methanol and recrystallization from ethanol, and the conversion into the salt using an aqueous solution of sodium or calcium hydroxide.
  • the methods described do not yield a product of the purity comparable to the product obtained by using the present invention.
  • EP 65,835 discloses the preparation of the L-ornithine and t-octylamine salts of tetrahydro-M4 or tetrahydro-IsoM4(wherein M4 denotes a specific HMG-CoA reductase inhibitor, M4 and IsoM-4 representing the isomers hydroxylated at 6- and 3-biphenyl ring position, respectively, and “tetrahydro” means that the condensed biphenyl ring system is fully hydrogenated) as final products, that is from the respectively purified sodium salts thereof, but not as intermediates via which the isolation would be carried out.
  • salts of tetrahydro-M-4 or IsoM:4 with ammonia, an amino acid or an organic amine are also contemplated as final products, including octylamine, 2-ethylhexylamine, benzylamine, ⁇ -methyl-benzylamine, phenethylamine, dibenzylamine, N-methylbenzylamine, N,N-dimethylbenzylamine, N,N-diethylbenzylamine, N-ethyl-N-methylbenzylamine, tribenzylamine, cyclopentylamine, cyclohexylamine cycloheptylamine, N-methylcyclopentylamine, N-ethylcyclohexylamine, N-ethylcycloheptylamine, dicyclohexylamine, N,N-dimethylcyclopentylamine, N,N-dimethylcyclohexylamine, N,N-diethyl
  • GB 2073199A also discloses the preparation of different salts of HMG-CoA reductase inhibitors from the already isolated substance in the lactone form.
  • U.S. Pat. Nos. 5,763,653 and 5,763,646 disclose the preparation of the cyclopropylamine and n-butylamine amides of lovastatin and their use in a process of chemical semisynthesis of simvastatin.
  • U.S. Pat. No. 5,403,860 discloses, as final products, amine salts of octahydronaphthalene oxime derivatives of HMG-CoA inhibitors, the derivatives deriving from ML-236A, ML-236B, MB-530A and MB-530B.
  • t-octylamine, dibenzylamine, dicyclohexylamine, morpholine, D-phenylglycine alkylester and D-glucosamine salts are mentioned.
  • the preparation of lactone is one of the least economical steps in the production of HMG-CoA reductase inhibitors since losses in the course of the conversion from the acid into the lactone form and optionally further into the salts are greater than 20%. Therefore, there is a constant need for the starting substances and/or the intermediate substances which would be sufficiently pure, with small losses during their conversion, low costs, and the preparation per se should be technologically simple.
  • HMG-CoA reductase inhibitors form the salts with certain amines which crystallize from mother liquor once they are formed. It has surprisingly been found that crystals of the amine salt of the desired HMG-CoA reductase inhibitor of high purity may be obtained from the liquors containing a large number of impurities and undesired HMG-CoA reductase inhibitor analogs. Contrary to the statements from U.S. Pat. No.
  • HMG-CoA reductase inhibitors of the present invention can be excellently used as starting materials or intermediates of semisynthetic preparation or biotechnological modification of HMG-CoA reductase inhibitors and, furthermore, for the conversion into pharmaceutically acceptable salts or into the lactone form of the respective HMG-CoA reductase inhibitors. Accordingly, the novel amine salts of HMG-CoA reductase inhibitors of the present invention are also highly valuable as such.
  • the present invention provides:
  • the amine which is used according to the present invention for the formation of the salts with a HMG-CoA reductase inhibitor is selected from the group consisting of organic amines of the following-formulae I and II:
  • R 1 , R 2 , R 3 , and R 4 independently denote
  • X denotes a hydrogen atom, a hydroxyl group, a halogen or a methyl group
  • n and n independently denote an integer from 0 to 5;
  • NR 1 R 2 or NR 3 R 4 denote a heterocyclic ring having 3 to 7 methylene groups, one of these groups being optionally substituted by an oxygen or a sulfur atom or an amine group;
  • X, m and n are as defined above;
  • R′ 1 , R′ 2 , and R′ 3 are the same or different and denote hydrogen, alkyl, alkenyl, amino- or hydroxy-or alkoxy-substituted alkyl or alkenyl, or substituted amino- alkyl or alkenyl, provided that R′ 1 , R′ 2 , and R′ 3 are not hydrogen at the same time; or
  • R′ 1 , and R′ 2 , and optionally R′ 3 together with the nitrogen atom form an optionally substituted heterocyclic ring system including the nitrogen atom as a ring member, and optionally including an additional hetero atom, and if, R′ 3 is not part of the ring system it is independently selected from hydrogen, alkyl, alkenyl, amino- or hydroxy- or alkoxy-substituted alkyl, or substituted amino- alkyl; or
  • R′ 1 is a group of general formula III,
  • R′ is optionally substituted aliphatic hydrocarbon cyclic system having 3 to 8 carbon atoms in the ring.
  • R′ 4 is hydrogen, or alkyl, amino- or hydroxy- or alkoxy- substituted alkyl, or substituted amino- alkyl, or a group of the same general formula as R′ 1 as defined herein above;
  • R′ 2 and R′ 3 are the same as R′ 1 or hydrogen, alkyl, alkenyl, amino- or hydroxy- or alkoxy- substituted alkyl, or substituted amino- alkyl or alkenyl, or
  • R′ 1 is an optionally substituted aryl group of general formula IV;
  • R′ 5 is hydrogen and one or more substituents, and m is zero or in integer from 1 to 5; and R′ 2 and R′ 3 may be independently hydrogen, alkyl, amino- or hydroxy- or alkoxy- substituted alkyl, or substituted amino- alkyl, or groups of the same general formula R′ 1
  • substitutions which are not explicitly specified are usual “inert” substituents, such as halogens, a hydroxyl group, alkyl having 1 to 4 carbon atoms, alkoxyl having 1 to 4 carbon atoms, acyloxyl having 1 to 4 carbon atoms and esterified carboxyl having 1 to 4 carbon atoms
  • amines which form the salt with HMG-CoA reductase inhibitors are: 1,2-dimethylpropylamine, 3-(2-aminoethylamino)-propylamine, n-butylamine, secondary butylamine, tertiary butylamine (TBA), dibutylamine, tertiary amylamine, cyclopentylamine, cyclohexylamine, cycloheptylamine, dicyclohexylamine (DCHA), N-methylcyclohexylamine, N,N′-diisopropylethylenediamine (DIPEDA), N,N′-diethylenediamine, N-methyl-1,3-propanediamine, N-methylethylenediamine, N,N,N′,N′-tetramethyl-1,2-diaminoethane, N,N,N′,N′-tetramethyl-1,4-diaminobutane, N
  • the amine is selected from the group consisting of n-butylamine, secondary butylamine, TBA, dibutylamine, tertiary amylamine, cyclohexylamine, DCHA, N-methylcyclohexylamine and DIPEDA.
  • the amine may particularly be selected from the group consisting of TBA, DIPEDA, DCHA and N-methylcyclohexylamine.
  • amines specified above are advantageous over the direct isolation via the salts with ammonia in terms of purification efficiency. Furthermore, amines having a larger organic group, and especially those having bulky groups, generally show a more readily crystallization and to a lower extent form salts with unwanted side products when compared with amines having small organic groups. Accordingly, amines having at least one hydrocarbon residue with secondary or tertiary carbon atoms, or with cyclic hydrocarbon structure (either aromatic or aliphatic), and organic diamines are particularly suitable for the present invention.
  • HMG-CoA reductase inhibitors Any type of HMG-CoA reductase inhibitors can be used according to the present invention. Those HMG-CoA reductase inhibitors selected from the group consisting of mevastatin, pravastatin, lovastatin, simvastatin, fluvastatin and atorvastatin have shown good results and are particularly preferred.
  • the amine salt is most effectively formed directly from the crude medium of the respective HMG-CoA reductase inhibitor, which crude medium is usually derived from a fermentation broth as the result of a biotechnological process or from a reaction mixture as the result of a semisynthesis or the total synthesis and usually contains the desired HMG-CoA reductase inhibitor together with unwanted side products and impurities.
  • the crude medium may preferably contain the HMG-CoA reductase inhibitor in its acid from, and the formation of the amine salt may be effected by simply adding the amine to the crude medium.
  • the crude medium may be an organic phase or a mixture of an organic or an aqueous phase where the impure HMG-CoA reductase inhibitor is present in an organic solvent, such as ethyl acetate, ether or acetonitrile. Ethyl acetate is preferred as the organic solvent.
  • the crude medium in the organic phase is preferably obtained from the fermentation broth by a process including the step of extracting the HMG-CoA reductase inhibitor into the aforementioned organic solvent.
  • the process for the preparation of the amine salts of HMG-CoA reductase inhibitors may include the following steps:
  • the term “contacting” includes the known techniques for the preparation of the sails from substances with acid properties and substances with alkaline properties.
  • the crystallization is preferably carried out at a temperature between 0 and 30° C., more preferably between 4 and 22° C.
  • organic solvent means organic solvents which are used in industry such as ethyl acetate, butyl acetate, ether and acetonitrile, including their aqueous mixtures.
  • the amines specified above effectively form salts with the HMG-CoA reductase inhibitors, they are also particularly suitable as auxiliary materials or processing aids in a process for preparing the HMG-CoA reductase inhibitor in a purified form.
  • Previously isolated HMG-CoA reductase inhibitors can be thus obtained in a higher purity.
  • the purified form is usually prepared by crystallization. Accordingly, the present invention provides a process for the isolation and/or purification of a HMG-CoA reductase inhibitor.
  • the salt as specified above is suitably used as the starting substance or the intermediate substance in a process for preparing the HMG-CoA reductase inhibitor which is in a modified form, in a pharmaceutically active salt form or in the lactone form.
  • the modified form is obtained by chemical modification or biotechnological modification, which modifications are known to those skilled in the art.
  • the pharmaceutically active salt is preferably a metal salt, such as the sodium salt or the calcium salt.
  • a process for the semi-synthetic preparation of HMG-CoA reductase inhibitors means the preparation of HMG-CoA reductase inhibitors using any of the known chemical modifications of the HMG-CoA reductase inhibitors.
  • An example of such process is the semisynthesis of simvastatin from lovastatin as the starting substance.
  • the TBA salt of lovastatin is used as the starting substance.
  • a process for the biotechnological modification of HMG-CoA reductase inhibitors means the preparation of HMG-CoA reductase inhibitors using microorganisms or enzymatic systems thereof for modifying HMG-CoA reductase inhibitors.
  • An example of such process is the biotechnological conversion of mevastatin into pravastatin.
  • the amine salt is preferably the TBA salt.
  • a process for the conversion of the amine salts of HMG-CoA reductase inhibitors into the pharmaceutically acceptable salts of HMG-CoA reductase inhibitors includes processes for the preparation of HMG-CoA reductase inhibitors by one of the known methods wherein the amine salts of HMG-CoA reductase inhibitors are used as the starting substance.
  • Specific examples or converted salts are the sodium salts of pravastatin and fluvastatin and the calcium salt of atorvastatin.
  • conversion of the amine salts of HMG-CoA reductase inhibitors into HMG-CoA reductase inhibitors in the lactone form includes processes for the preparation of HMG-CoA reductase inhibitors in the lactone form by one of the known methods wherein the amine salts of HMG-CoA reductase inhibitors are used as the starting substance.
  • Examples of HMG-CoA reductase inhibitors converted into the lactone form are lovastatin, mevastatin or simvastatin.
  • Mevastatin 200 g was suspended in 30% volume/volume (v/v) aqueous acetonitrile solution (2500 ml). 3 equivalents of trimethylamine were added and the mixture was heated to 80° C. and stirred for 30 minutes After the completed reaction, acetonitrile was evaporated, the remaining solution was acidified to pH 4 with phosphoric acid and extracted into ethyl acetate (2 ⁇ 1000 ml). The pooled extracts were dried by the addition of 30 g of sodium soleplate, the desiccant was filtered off and the solution was concentrated (950 ml). TBA (1.5 equivalents) was added to the solution and crystallization was carried out for 30 minutes at 8° C.
  • the crystals formed were filtered and washed with ethyl acetate (2 ⁇ 100 ml) and subsequently dried at 40° C. for 15 hours.
  • the crystals obtained (the TBA salts of mevastatin 215 g) were while in color with a HULK purity of 96.8%.
  • the yield of the hydrolysis and crystallization was 91%.
  • a fermentation broth (160 L) obtained by the fermentation with a microorganism Aspergillus terreus ATCC 20544 and having a lovastatin content of 1 g/L was transferred from the fermenter into the tank (400 L) and pH was adjusted to 10 with the addition of 1 M aqueous sodium hydroxide 10 minutes of vigorous stirring the pH of the broth was decreased to 9 by adding 1 M sulphuric acid solution and the biomass was filtered off.
  • the filtrate obtained was acidified to a pH value of 6.5 with 1 M sulphuric acid solution and 160 L of ethyl acetate was added. The slurry was subsequently stirred for 20 minutes.
  • lovastatin in the form of free acid in concentrated ethyl acetate extract was 10.1 g/L.
  • lovastatin solution HPLC purity 72.7%) in the form of free acid in ethyl acetate (800 ml) 1.05 equivalents of TBA were added. After crystals were crystallized out, they were filtered off, washed with ethyl acetate (2 ⁇ 50 ml) and dried in a vacuum oven at 35° C. for 24 hours. The yield: 8.06 g of crystals of the TBA salt of lovastatin with a HPLC purity of 99.2%.
  • Lovastatin (5 g) was treated according to the process for hydrolysis disclosed in example 1 and sodium salt thereof (4.8 g) was prepared and dissolved in 100 ml of water. pH was adjusted to 4 with phosphoric acid (10% aqueous solution) and the formed free acid of lovastatin was extracted from the water phase into ethyl acetate (2 ⁇ 100 ml). Hie pooled ethyl acetate extracts were dried with sodium sulphate, the solution was filtered off and concentrated to ca. 100 ml. To the solution, prepared in the above manner (ca. 100 ml). 1.05 equivalents of tertiary amylamine were added.
  • Pravastatin 11 g, HPLC purity 97.25% in the form of Na salt was dissolved in water (100 ml) and pH was adjusted to 4 with phosphoric acid (10% aqueous solution). The resulting free acid was extracted from the water phase into ethyl acetate (2 ⁇ 100 ml). The pooled ethyl acetate extracts were dried with sodium sulphate, the solution was filtered off and concentrated to a volume of ca. 100 ml.
  • pravastatin in the free acid form was prepared from the sodium salt of pravastatin (HPLC purity 83.6%). Further the salt or pravastatin with secondary butylamine was prepared by the process described in example 5. White crystals with a HPLC purity or 97.3% were obtained.
  • the colonies of microorganism Amycolatopsis orientalis ATCC 19795 were transferred to a sterile potter and homogenized.
  • the resulting colonies were transferred to agar slopes and incubated in the thermostat at 26° to 30° C. for 7 to 14 days.
  • surfaces of agar slopes were overgrown by cultures of homogeneous, folded, smooth, white to pale greyish-blue mycelium
  • 10 ml of sterile water was poured onto the agar slopes, the culture was scraped off with the pipette and the contents transferred into the potter. A portion (0.5 to 1 ml) of the resulting culture was then inoculated into the vegetative medium.
  • Agar medium for the preparation of agar slopes and petri plates.
  • Raw material Amount Dextrin 10 g Consumer's glucose 5 g Casaminic acid 3 g Yeast extract 4 g Agar 15 g Sterile water up to 1000 ml No pH adjustment needed.
  • the inoculum grown on the slope at 26° to 30° C. for 10 days and prepared according to the above-described method was inoculated in a 500-ml Erlenmeyer flask containing 50 ml of the vegetative medium. After 24 hours of shaking at 220 rpm at 28° C. the culture was transferred onto the fermentation medium.
  • Vegetative medium Raw material Amount Corn starch for fermentation 20 g Soybean flour for fermentation 14 g Glucose 10 g Yeast extract 5 g NaH 2 PO 4 ⁇ 2H 2 O 3.3 g Tap water to 1000 ml
  • the solution of the TBA salt of mevastatin and glucose (1200 g of glucose and 70 g of TBA salt of mevastatin (assay of mevastatin: 80%) dissolved in 5 L of water) was continually added to the medium at the flow rate 2 ml/min.
  • 70% oxygen saturation of the medium was maintained by stirring with the frequency between 300 and 600 rpm.
  • Fermentation medium Raw material Amount Corn starch for fermentation 20 g Soybean flour for fermentation 5 g Glucose 10 g Yeast extract 5 g Antifoam agent 10 g All raw materials were dissolved in tap water, the pH was then adjusted to 7.4.
  • Simvastatin (1.95 g) was suspended in 50 ml of 30% (v/v) acetonitrile, triethylamine (1 ml) was added and the solution was heated for 20 minutes at 70° C. After completion of reaction acetonitrile was evaporated from the solution, the remaining solution was acidified to pH 4 with phosphoric acid. Simvastatin in the acid form was extracted into ethyl acetate (2 ⁇ 50 ml) and the pooled extracts were dried with 2 g of sodium sulphate. The desiccant was filtered off and the ethyl acetate solution was concentrated to 20 ml. To the solution 1.05 equivalents of TBA were added and crystallization was carried out for 1 hour at 8° C. The product was filtered off and dried at 40° C. for 1 hour. Hie yield: 2 g of the TBA salt of simvastatin.
  • Simvastatin (20 g) was dissolved in the mixture of water (80 ml) and 8M KOH (18 ml). The solution was stirred in nitrogen atmosphere for two hours at room temperature.
  • Pravastatin (30 g, HPLC purity 90.2%) in the form of Na salt was dissolved in water (100 ml) and pH was adjusted to 3 with HCl (10% aqueous solution). The resulting free acid was extracted from the water phase into ethyl acetate (3 ⁇ 200 ml). The pooled ethyl acetate extracts were dried with sodium sulphate, the solution was filtered off and 7.604 g of N-methylcyclohexylamine was added (drop by drop at intensive stirring). After crystals were crystallized out, they were filtered off and recrystallized from the mixture of ethyl acetate/methanol. The yield: 21 g of crystals of pravastatin N-methylcyclohexylamine salt with a HPLC purity of 99.28%.
  • atorvastatin in the free acid form 1 g was dissolved in methanol (20 ml) and 1.1 molar equivalents of dicyclohexylamine (DCHA) in 50 ml of n-hexane was added. After four hours at 8° C. the DCHA salt of atorvastatin crystallized. White precipitate was filtered off and dried in a rotary evaporator Yield: 1.1 g of DCHA salt of atorvastatin.
  • DCHA dicyclohexylamine

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrane Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Lovastatin, pravastatin, simvastatin, mevastatin, atorvastatin, and derivatives and analogs thereof are known as HMG-CoA reductase inhibitors and are used as antihypercholesterolemic agents. The majority of them are produced by fermentation using microorganisms of different species identified as species belonging to Aspergillus, Monascus, Nocardia, Amycolatopsis, Mucor or Penicillium genus, some are obtained by treating the fermentation products using the methods of chemical synthesis or they are the products of total chemical synthesis. The present invention relates to the new amine salts of HMG-CoA reductase inhibitors, the preparation thereof, the preparation of pure HMG-CoA reductase inhibitors via amine salts thereof, use of the amine salts of HMG-CoA reductase inhibitors in the process for semisynthetic preparation of HMG-CoA reductase inhibitors, use of the amine salts of HMG-CoA reductase inhibitors in the process for biotechnological modification of HMG-CoA reductase inhibitors as well as the conversion of the amine salts of HMG-CoA reductase inhibitors into the pharmaceutically acceptable salts of the HMG-CoA reductase inhibitors and the conversion of the amine sails of HMG-CoA reductase inhibitors into the HMG-CoA reductase inhibitors in the lactone form.

Description

  • This is a continuation of application U.S. Ser. No. 10/966,000 filed Oct. 15, 2004 which is a continuation of U.S. Ser. No. 10/320,285 filed Dec. 16, 2002, now U.S. Pat. No. 6,838,566 which is a continuation of U.S. patent application Ser. No. 09/787,387, now U.S. Pat. No. 6,583,295 which is based on International Application No. PCT/IB99/01554, filed Sep. 17, 1999 which claims priority of Slovenian patent application No. P-9800240 filed Sep. 18, 1998. These applications are incorporated herein by reference.
    • TECHNICAL FIELD AND BACKGROUND ART
  • Lovastatin, pravastatin, simvastatin, mevastatin, atorvastatin and derivatives and analogs thereof are examples of known as HMG-CoA reductase inhibitors which are used as antihypercholesterolemic agents. The majority of them are produced biotechnologically by fermentation using microorganisms of different species identified as species belonging to Aspergillus, Monascus, Nocardia, Amycolatopsis, Mucor or Penicillium genus, some are obtained by treating the fermentation products using the methods of chemical synthesis, thus leading to semi-synthetic substances, or they are the products of total chemical synthesis.
  • The present invention relates to a new industrial process for isolation and/or purification of HMG-CoA reductase inhibitors via salts thereof with specific amines. The invention enables a user to obtain the pure amine salts of HMG-CoA reductase inhibitors from the fermentation broth in case the substances are produced by biotechnological (microbiological) processes, or from the reaction mixture in case the substances are produced by semisynthetic or total chemical synthesis. The step of forming salts with amine may be one of the steps in the process for isolation and/or purification of HMG-CoA reductase inhibitors or precursor substances thereof. The amines described in the present specification are very useful for the formation of salts in the composition of media in processes for biotechnological modification of HMG-CoA reductase inhibitors or precursors thereof. The salts thus formed may be used as the starting substances or intermediates for the preparation of semisynthetic derivatives and analogs thereof, or by employing simple techniques known from the literature, if required, to be converted into the pharmaceutically acceptable salts and lactones, respectively.
  • The processes for the isolation and purification of antihypercholesterolemic agents known from patent and technical literature include different combinations of extraction, chromatography, lactonization and crystallization methods. Some of them additionally include the isolation and purification via different salts. In U.S. Pat. Nos. 9,342,767 and 4,319,039, the ammonium salt of lovastatin (in the carboxylate form) is isolated directly from the organic phase which has been extracted from the fermentation medium. In the same patent the preparation of ethylenediamine, tetramethylammonium, potassium and N-methylglucamine salts as well as the salts of different amino acids such as L-lysine, L-arginine and L-ornithine is also described. The aforementioned salts are prepared from the already purified substance and the option for their use in the process of isolation or purification is not mentioned. GB 2055100A also describes the formation of the sodium and calcium salts of lovastatin, which comprises the extraction in methanol, two steps of preparative liquid reverse-phase chromatography, crystallization from methanol and recrystallization from ethanol, and the conversion into the salt using an aqueous solution of sodium or calcium hydroxide. However, without including various chromatography methods, the methods described do not yield a product of the purity comparable to the product obtained by using the present invention. U.S. Pat. No. 4,346,227 discloses a process for the preparation of the sodium salt of pravastatin, wherein chromatographic techniques are also used but the final product is obtained only after lyophilization which is not an economical process in a large scale production operations. EP 65,835 discloses the preparation of the L-ornithine and t-octylamine salts of tetrahydro-M4 or tetrahydro-IsoM4(wherein M4 denotes a specific HMG-CoA reductase inhibitor, M4 and IsoM-4 representing the isomers hydroxylated at 6- and 3-biphenyl ring position, respectively, and “tetrahydro” means that the condensed biphenyl ring system is fully hydrogenated) as final products, that is from the respectively purified sodium salts thereof, but not as intermediates via which the isolation would be carried out. Other salts of tetrahydro-M-4 or IsoM:4 with ammonia, an amino acid or an organic amine are also contemplated as final products, including octylamine, 2-ethylhexylamine, benzylamine, α-methyl-benzylamine, phenethylamine, dibenzylamine, N-methylbenzylamine, N,N-dimethylbenzylamine, N,N-diethylbenzylamine, N-ethyl-N-methylbenzylamine, tribenzylamine, cyclopentylamine, cyclohexylamine cycloheptylamine, N-methylcyclopentylamine, N-ethylcyclohexylamine, N-ethylcycloheptylamine, dicyclohexylamine, N,N-dimethylcyclopentylamine, N,N-dimethylcyclohexylamine, N,N-diethylcycloheptylamine, pyrrolidine, N-methylpyrrolidine, piperidine, N-methylpiperidine and morpholine. GB 2073199A also discloses the preparation of different salts of HMG-CoA reductase inhibitors from the already isolated substance in the lactone form. U.S. Pat. Nos. 5,763,653 and 5,763,646 disclose the preparation of the cyclopropylamine and n-butylamine amides of lovastatin and their use in a process of chemical semisynthesis of simvastatin. U.S. Pat. No. 5,403,860 discloses, as final products, amine salts of octahydronaphthalene oxime derivatives of HMG-CoA inhibitors, the derivatives deriving from ML-236A, ML-236B, MB-530A and MB-530B. As final amine salts, t-octylamine, dibenzylamine, dicyclohexylamine, morpholine, D-phenylglycine alkylester and D-glucosamine salts are mentioned.
    • Technical Problem
  • In industry there exists a constant need for rationalization of the production and shortening of the production processes as well as for the use of least expensive starting raw materials or intermediate substances. To date the isolation of the final products in the case of HMG-CoA reductase inhibitors has been a multi-stage process wherein each step adds its share to the losses resulting in the final yield rarely greater than 60%. In addition, a product in the lactone form or lactone converted into the sodium salt is used as the starting substance in the process of semisynthesis (e.g. in a process for preparing simvastatin) or biochemical conversion (e.g. in a process for preparing pravastatin). The preparation of lactone is one of the least economical steps in the production of HMG-CoA reductase inhibitors since losses in the course of the conversion from the acid into the lactone form and optionally further into the salts are greater than 20%. Therefore, there is a constant need for the starting substances and/or the intermediate substances which would be sufficiently pure, with small losses during their conversion, low costs, and the preparation per se should be technologically simple.
    • SUMMARY OF THE INVENTION
  • In our developmental and research work we have surprisingly found that HMG-CoA reductase inhibitors form the salts with certain amines which crystallize from mother liquor once they are formed. It has surprisingly been found that crystals of the amine salt of the desired HMG-CoA reductase inhibitor of high purity may be obtained from the liquors containing a large number of impurities and undesired HMG-CoA reductase inhibitor analogs. Contrary to the statements from U.S. Pat. No. 5,403,860 that lower yields are obtained when using the salts of HMG-CoA reductase inhibitor as starting or intermediate substances in a process for preparing the substances (Ia) mentioned below, we have surprisingly found that, when using the amine salts HMG-CoA reductase inhibitors according to the present invention, the yields and the purity of the prepared HMG-CoA reductase inhibitors are equal to or greater than when using the HMG-CoA reductase inhibitors in the lactone form.
  • Figure US20080188552A1-20080807-C00001
  • Furthermore, we surprisingly discovered that in processes for the biotechnological modification of HMG-CoA reductase inhibitors the formation of amine salts of HMG-CoA reductase inhibitors in the medium which derives from the fermentation liquor provides, in comparison with the mere metal salts as described in publicly accessible literature, an efficient means for the isolation and/or purification of HMG-CoA reductase inhibitors by means of simple crystallization. The amines which are described in the present specification and which readily form salts with HMG-CoA reductase inhibitors are thus particularly suitable as auxiliary materials or processing aids for the isolation and/or purification of HMG-CoA reductase inhibitors. Furthermore, they can be excellently used as starting materials or intermediates of semisynthetic preparation or biotechnological modification of HMG-CoA reductase inhibitors and, furthermore, for the conversion into pharmaceutically acceptable salts or into the lactone form of the respective HMG-CoA reductase inhibitors. Accordingly, the novel amine salts of HMG-CoA reductase inhibitors of the present invention are also highly valuable as such.
  • The present invention provides:
  • a) the novel salts of HMG-CoA reductase inhibitors with organic amines, wherein those specific salts are excluded which are disclosed in the prior art, but in different contexts as mentioned above,
  • b) a process for the preparation of salts of HMG-CoA reductase inhibitors with amines,
  • c) a use of salts of HMG-CoA reductase inhibitors with amines as processing aids or starting substances or intermediate substances in various processes,
  • d) a process for the preparation of the pure HMG-CoA reductase inhibitors from/via amine salts thereof,
  • e) a process for the semisynthetic preparation of HMG-CoA reductase inhibitors, wherein the amine salts of HMG-CoA reductase inhibitors are used as the starting substances,
  • f) a process for the biotechnological modification of HMG-CoA reductase inhibitors, wherein one of the components of the medium is the amine salt of HMG-CoA reductase inhibitors,
  • g) a process for the conversion of the amine salts of HMG-CoA reductase inhibitors into the pharmaceutically acceptable salts of HMG-CoA reductase inhibitors, and
  • h) a process for the conversion of the amine salts of HMG-CoA reductase inhibitors into HMG-CoA reductase inhibitors in the lactone form.
  • The amine which is used according to the present invention for the formation of the salts with a HMG-CoA reductase inhibitor is selected from the group consisting of organic amines of the following-formulae I and II:
  • Figure US20080188552A1-20080807-C00002
  • wherein:
  • a1) R1, R2, R3, and R4 independently denote
      • a hydrogen atom
      • a straight or branched alkyl group having 1 to 8 carbon atoms, or
      • a cycloalkyl group having 3 to 8 carbon atoms, or
      • an arylalkyl group wherein the alkyl group is methyl or ethyl and the aryl group is phenyl, which is optionally substituted by an N-alkyl or N,N-dialkyl group wherein the alkyl group is alkyl having 1 to 4 carbon atoms, or
      • an arylalkyl group which is optionally substituted by one or more substituents,
      • a hydroxyalkyl group having 2 to 4 carbon atoms, or
      • an aminoalkyl group having 2 to 4 carbon atoms, which are optionally substituted by an N-alkyl or N,N-dialkyl group wherein the alkyl group is alkyl having 1 to 4 carbon atoms;
  • X denotes a hydrogen atom, a hydroxyl group, a halogen or a methyl group;
  • m and n independently denote an integer from 0 to 5; or
  • a2) NR1R2 or NR3R4 denote a heterocyclic ring having 3 to 7 methylene groups, one of these groups being optionally substituted by an oxygen or a sulfur atom or an amine group; X, m and n are as defined above;
  • Figure US20080188552A1-20080807-C00003
  • wherein:
  • b1) R′1, R′2, and R′3 are the same or different and denote hydrogen, alkyl, alkenyl, amino- or hydroxy-or alkoxy-substituted alkyl or alkenyl, or substituted amino- alkyl or alkenyl, provided that R′1, R′2, and R′3 are not hydrogen at the same time; or
  • b2) R′1, and R′2, and optionally R′3, together with the nitrogen atom form an optionally substituted heterocyclic ring system including the nitrogen atom as a ring member, and optionally including an additional hetero atom, and if, R′3 is not part of the ring system it is independently selected from hydrogen, alkyl, alkenyl, amino- or hydroxy- or alkoxy-substituted alkyl, or substituted amino- alkyl; or
  • b3) R′1, is a group of general formula III,

  • R′—(CHR′4)m—  III
  • wherein m is zero or an integer from 1 to 5, R′ is optionally substituted aliphatic hydrocarbon cyclic system having 3 to 8 carbon atoms in the ring. R′4 is hydrogen, or alkyl, amino- or hydroxy- or alkoxy- substituted alkyl, or substituted amino- alkyl, or a group of the same general formula as R′1 as defined herein above; R′2 and R′3 are the same as R′1 or hydrogen, alkyl, alkenyl, amino- or hydroxy- or alkoxy- substituted alkyl, or substituted amino- alkyl or alkenyl, or
  • b4) R′1 is an optionally substituted aryl group of general formula IV;
  • Figure US20080188552A1-20080807-C00004
  • wherein R′5 is hydrogen and one or more substituents, and m is zero or in integer from 1 to 5; and R′2 and R′3 may be independently hydrogen, alkyl, amino- or hydroxy- or alkoxy- substituted alkyl, or substituted amino- alkyl, or groups of the same general formula R′1
  • Substitutions which are not explicitly specified are usual “inert” substituents, such as halogens, a hydroxyl group, alkyl having 1 to 4 carbon atoms, alkoxyl having 1 to 4 carbon atoms, acyloxyl having 1 to 4 carbon atoms and esterified carboxyl having 1 to 4 carbon atoms
  • Advantageous examples of amines which form the salt with HMG-CoA reductase inhibitors are: 1,2-dimethylpropylamine, 3-(2-aminoethylamino)-propylamine, n-butylamine, secondary butylamine, tertiary butylamine (TBA), dibutylamine, tertiary amylamine, cyclopentylamine, cyclohexylamine, cycloheptylamine, dicyclohexylamine (DCHA), N-methylcyclohexylamine, N,N′-diisopropylethylenediamine (DIPEDA), N,N′-diethylenediamine, N-methyl-1,3-propanediamine, N-methylethylenediamine, N,N,N′,N′-tetramethyl-1,2-diaminoethane, N,N,N′,N′-tetramethyl-1,4-diaminobutane, N,N,N′,N′-tetramethyl-1,6-diaminohexane, 1,2-dipiperidinethane, dipiperidinemethane, 2-amino-3,3-dimethylbutane, N,N-dimethylcyclohexylamine, neopentylamine, adamantylamine, N,N-diethylcyclohexylamine, N-isopropylcyclohexylamine, N-methyl-cyclohexylamine, cyclobutylamine and norborylamine. Preferably in terms of crystallization efficiency, combined with low toxicity and low costs, the amine is selected from the group consisting of n-butylamine, secondary butylamine, TBA, dibutylamine, tertiary amylamine, cyclohexylamine, DCHA, N-methylcyclohexylamine and DIPEDA. The amine may particularly be selected from the group consisting of TBA, DIPEDA, DCHA and N-methylcyclohexylamine.
  • The amines specified above are advantageous over the direct isolation via the salts with ammonia in terms of purification efficiency. Furthermore, amines having a larger organic group, and especially those having bulky groups, generally show a more readily crystallization and to a lower extent form salts with unwanted side products when compared with amines having small organic groups. Accordingly, amines having at least one hydrocarbon residue with secondary or tertiary carbon atoms, or with cyclic hydrocarbon structure (either aromatic or aliphatic), and organic diamines are particularly suitable for the present invention.
  • Any type of HMG-CoA reductase inhibitors can be used according to the present invention. Those HMG-CoA reductase inhibitors selected from the group consisting of mevastatin, pravastatin, lovastatin, simvastatin, fluvastatin and atorvastatin have shown good results and are particularly preferred.
  • For isolating and purifying the desired HMG-CoA reductase inhibitor, the amine salt is most effectively formed directly from the crude medium of the respective HMG-CoA reductase inhibitor, which crude medium is usually derived from a fermentation broth as the result of a biotechnological process or from a reaction mixture as the result of a semisynthesis or the total synthesis and usually contains the desired HMG-CoA reductase inhibitor together with unwanted side products and impurities. The crude medium may preferably contain the HMG-CoA reductase inhibitor in its acid from, and the formation of the amine salt may be effected by simply adding the amine to the crude medium. The crude medium may be an organic phase or a mixture of an organic or an aqueous phase where the impure HMG-CoA reductase inhibitor is present in an organic solvent, such as ethyl acetate, ether or acetonitrile. Ethyl acetate is preferred as the organic solvent. After the biotechnological treatment, the crude medium in the organic phase is preferably obtained from the fermentation broth by a process including the step of extracting the HMG-CoA reductase inhibitor into the aforementioned organic solvent.
  • The process for the preparation of the amine salts of HMG-CoA reductase inhibitors may include the following steps:
  • a) contacting the medium containing the HMG-CoA reductase inhibitor, which is preferably in the acid form in an organic solvent, with at least one of the amines specified above,
  • b) optionally forming crystallization nuclei by known techniques,
  • c) filtering the crystals crystallized out,
  • d) washing the crystals with an organic solvent, and
  • e) drying the crystals.
  • The term “contacting” includes the known techniques for the preparation of the sails from substances with acid properties and substances with alkaline properties. The crystallization is preferably carried out at a temperature between 0 and 30° C., more preferably between 4 and 22° C.
  • The term “organic solvent” means organic solvents which are used in industry such as ethyl acetate, butyl acetate, ether and acetonitrile, including their aqueous mixtures.
  • Since the amines specified above effectively form salts with the HMG-CoA reductase inhibitors, they are also particularly suitable as auxiliary materials or processing aids in a process for preparing the HMG-CoA reductase inhibitor in a purified form. Previously isolated HMG-CoA reductase inhibitors can be thus obtained in a higher purity. The purified form is usually prepared by crystallization. Accordingly, the present invention provides a process for the isolation and/or purification of a HMG-CoA reductase inhibitor.
  • In further aspects of the present invention, the salt as specified above is suitably used as the starting substance or the intermediate substance in a process for preparing the HMG-CoA reductase inhibitor which is in a modified form, in a pharmaceutically active salt form or in the lactone form. Specifically, the modified form is obtained by chemical modification or biotechnological modification, which modifications are known to those skilled in the art. The pharmaceutically active salt is preferably a metal salt, such as the sodium salt or the calcium salt.
  • In this connection, the term “a process for the semi-synthetic preparation of HMG-CoA reductase inhibitors” means the preparation of HMG-CoA reductase inhibitors using any of the known chemical modifications of the HMG-CoA reductase inhibitors. An example of such process is the semisynthesis of simvastatin from lovastatin as the starting substance. Most preferably, the TBA salt of lovastatin is used as the starting substance.
  • Furthermore, the term “a process for the biotechnological modification of HMG-CoA reductase inhibitors” means the preparation of HMG-CoA reductase inhibitors using microorganisms or enzymatic systems thereof for modifying HMG-CoA reductase inhibitors. An example of such process is the biotechnological conversion of mevastatin into pravastatin. The amine salt is preferably the TBA salt.
  • Furthermore, the term “a process for the conversion of the amine salts of HMG-CoA reductase inhibitors into the pharmaceutically acceptable salts of HMG-CoA reductase inhibitors” includes processes for the preparation of HMG-CoA reductase inhibitors by one of the known methods wherein the amine salts of HMG-CoA reductase inhibitors are used as the starting substance. Specific examples or converted salts are the sodium salts of pravastatin and fluvastatin and the calcium salt of atorvastatin.
  • Furthermore, the term “conversion of the amine salts of HMG-CoA reductase inhibitors into HMG-CoA reductase inhibitors in the lactone form” includes processes for the preparation of HMG-CoA reductase inhibitors in the lactone form by one of the known methods wherein the amine salts of HMG-CoA reductase inhibitors are used as the starting substance. Examples of HMG-CoA reductase inhibitors converted into the lactone form are lovastatin, mevastatin or simvastatin.
  • The present invention is illustrated but in no way limited by the following examples.
    • EXAMPLES Example 1 Preparation of Free Acid of Mevastatin and Conversion Thereof into Salt Thereof with Tertiary Butylamine (TBA)
  • Mevastatin (200 g) was suspended in 30% volume/volume (v/v) aqueous acetonitrile solution (2500 ml). 3 equivalents of trimethylamine were added and the mixture was heated to 80° C. and stirred for 30 minutes After the completed reaction, acetonitrile was evaporated, the remaining solution was acidified to pH 4 with phosphoric acid and extracted into ethyl acetate (2×1000 ml). The pooled extracts were dried by the addition of 30 g of sodium soleplate, the desiccant was filtered off and the solution was concentrated (950 ml). TBA (1.5 equivalents) was added to the solution and crystallization was carried out for 30 minutes at 8° C. The crystals formed were filtered and washed with ethyl acetate (2×100 ml) and subsequently dried at 40° C. for 15 hours. The crystals obtained (the TBA salts of mevastatin 215 g) were while in color with a HULK purity of 96.8%. The yield of the hydrolysis and crystallization was 91%.
    • Example 2 Preparation of the Sodium Salt of Mevastatin From the TBA Salt of Mevastatin
  • The TBA salt of mevastatin (1 g), obtained by the process disclosed in example 1, was dissolved in 3 ml of ethanol (96% v/v) and sodium hydroxide (40 g/L of ethanol) was added. The resulting mixture was precipitated in the ethyl acetate (60 ml). After the crystallization (30 min) at 8° C. the crystals were filtered off, washed with ethyl acetate and dried. The product: crystals of the sodium salt of mevastatin (0.65 g) pale brown in color with a HPLC purity of 98%.
    • Example 3 Isolation of the TBA Salts of Lovastatin from the Fermentation Broth
  • A fermentation broth (160 L) obtained by the fermentation with a microorganism Aspergillus terreus ATCC 20544 and having a lovastatin content of 1 g/L was transferred from the fermenter into the tank (400 L) and pH was adjusted to 10 with the addition of 1 M aqueous sodium hydroxide 10 minutes of vigorous stirring the pH of the broth was decreased to 9 by adding 1 M sulphuric acid solution and the biomass was filtered off. The filtrate obtained was acidified to a pH value of 6.5 with 1 M sulphuric acid solution and 160 L of ethyl acetate was added. The slurry was subsequently stirred for 20 minutes. The aqueous and ethyl acetate phases were separated by extraction centrifuge and the ethyl acetate extract was concentrated in a rotavapor to the volume of 14 L. The concentration of lovastatin in the form of free acid in concentrated ethyl acetate extract was 10.1 g/L. To the obtained lovastatin solution (HPLC purity 72.7%) in the form of free acid in ethyl acetate (800 ml) 1.05 equivalents of TBA were added. After crystals were crystallized out, they were filtered off, washed with ethyl acetate (2×50 ml) and dried in a vacuum oven at 35° C. for 24 hours. The yield: 8.06 g of crystals of the TBA salt of lovastatin with a HPLC purity of 99.2%.
    • Example 4 Preparation of the Salt of Lovastatin with Tertiary Amylamine
  • Lovastatin (5 g) was treated according to the process for hydrolysis disclosed in example 1 and sodium salt thereof (4.8 g) was prepared and dissolved in 100 ml of water. pH was adjusted to 4 with phosphoric acid (10% aqueous solution) and the formed free acid of lovastatin was extracted from the water phase into ethyl acetate (2×100 ml). Hie pooled ethyl acetate extracts were dried with sodium sulphate, the solution was filtered off and concentrated to ca. 100 ml. To the solution, prepared in the above manner (ca. 100 ml). 1.05 equivalents of tertiary amylamine were added. After crystals were crystallized out, they were filtered off, washed with ethyl acetate (2×10 ml) and dried in a vacuum oven (35° C., 24 hours) The yield: 4.8 g of crystals of the tertiary amylamine salt with a HPLC purity of 98.6%.
    • Example 5 Preparation of Pravastatin in the Free Acid Form and Conversion Into the (±) 1,2-Dimethylpropylamine Salt Thereof
  • Pravastatin (11 g, HPLC purity 97.2%) in the form of Na salt was dissolved in water (100 ml) and pH was adjusted to 4 with phosphoric acid (10% aqueous solution). The resulting free acid was extracted from the water phase into ethyl acetate (2×100 ml). The pooled ethyl acetate extracts were dried with sodium sulphate, the solution was filtered off and concentrated to a volume of ca. 100 ml.
  • To the concentrate (9 ml) thus obtained, 1.5 equivalents of (±)-1,2-dimethyl-propylamine were added. After crystals were crystallized out, they were filtered off, washed with ethyl acetate (2×10 ml) and dried in a vacuum oven at 35° C. The yield: crystals yellow in color with a HPLC purity of 98.28%.
    • Examples 6-13 The Conversion of the Free Acid Form of Pravastatin into the Amine Salt Form as Described in Example 5 was Repeated with other Amines
  • The amines used and results are shown in the table below.
  • Ex. AMINE EFFECT HPLC purity
    6 3-(2 aminoethylamino)- An oil is formed* —
    propylamine
    7 N,N1-diisopropyl- Pale yellow crystals 99.3%
    ethylenediamine
    8 N,N1-diisopropyl- Yellow crystals 99.3%
    ethylenediamine
    9 N-methyl-1,3- An oil is formed* —
    propanediamine
    10 N-methylethylenediamine An oil is formed —
    11 Secondary-butylamine White crystals 98.9%
    12 Tertiary-butylamine (TBA) Yellowish crystals 97.4%
    13 Tertiary - amylamine Off-white crystals 97.9%
    *from an oil formed, crystals are crystallized out overnight at 4° C.
    • Example 14 Preparation of the Salt of Pravastatin with Secondary Butylamine from the Crude Sodium Salt of Pravastatin
  • According to the process described in example 5, pravastatin in the free acid form was prepared from the sodium salt of pravastatin (HPLC purity 83.6%). Further the salt or pravastatin with secondary butylamine was prepared by the process described in example 5. White crystals with a HPLC purity or 97.3% were obtained.
    • Example 15 Preparation of the Sodium Salt of Pravastatin from the TBA Salt of Pravastatin (1)
  • 8.9 g of the TBA salt of pravastatin as obtained in example 12 were dissolved in 22 ml of ethanol (96%) and subsequently precipitated in 450 ml of ethyl acetate. Crystallization was carried out at 8° C. for 60 minutes, the crystals formed were filtered off, washed with two 50 ml portions of ethyl acetate and dried at 40° C. for 5 hours. 1 g of the recrystallized TBA salt of pravastatin, obtained in the above-described manner, was dissolved in 5 ml of ethanolic solution of 0.43N NaOH and precipitated in 60 ml of ethanol. After 30 minutes at 8° C., crystals formed were filtered off and dried. The formed crystals of the sodium salt of pravastatin (0.75 g) were dark yellow in color.
    • Example 16 Preparation of the Sodium Salt of Pravastatin from the TBA Salt of Pravastatin (2)
  • The process described in example 15 was repeated wherein 1 g of the recrystallized TBA salt of pravastatin was dissolved in 3 ml of water, instead of ethanolic solution of 0.43N NaOH, and subsequently an aqueous sodium carbonate solution (equivalent) was added. The obtained solution was diluted with 5 ml of ethanol and the resulting sodium salt was precipitated with ethyl acetate. After 30 minutes at 8° C., crystals formed were filtered off and dried. The formed crystals of the sodium salt of pravastatin (0.65 g) were yellow in color.
    • Example 17 Preparation of Pravastatin from the TBA Salt of Mevastatin Preparation of Inoculum for Production
  • The colonies of microorganism Amycolatopsis orientalis ATCC 19795 were transferred to a sterile potter and homogenized. The resulting colonies were transferred to agar slopes and incubated in the thermostat at 26° to 30° C. for 7 to 14 days. During that time surfaces of agar slopes were overgrown by cultures of homogeneous, folded, smooth, white to pale greyish-blue mycelium Further, 10 ml of sterile water was poured onto the agar slopes, the culture was scraped off with the pipette and the contents transferred into the potter. A portion (0.5 to 1 ml) of the resulting culture was then inoculated into the vegetative medium.
  • Agar medium for the preparation of agar slopes and petri plates.
    Raw material Amount
    Dextrin 10 g
    Consumer's glucose 5 g
    Casaminic acid 3 g
    Yeast extract 4 g
    Agar 15 g
    Sterile water up to 1000 ml
    No pH adjustment needed.
    • Vegetative Phase of Fermentation
  • The inoculum grown on the slope at 26° to 30° C. for 10 days and prepared according to the above-described method was inoculated in a 500-ml Erlenmeyer flask containing 50 ml of the vegetative medium. After 24 hours of shaking at 220 rpm at 28° C. the culture was transferred onto the fermentation medium.
  • Vegetative medium:
    Raw material Amount
    Corn starch for fermentation 20 g
    Soybean flour for fermentation 14 g
    Glucose 10 g
    Yeast extract 5 g
    NaH2PO4 × 2H2O 3.3 g
    Tap water to 1000 ml
    • Conversion of the TBA Salts of Mevastatin Into Pravastatin
  • The contents of fifteen Erlenmeyer flasks with the culture, prepared according to the above-described method, were used to inoculate the fermenter (50 L) with 30 L of fermentation medium. After 20-hour fermentation, the solution of the TBA salt of mevastatin and glucose (1200 g of glucose and 70 g of TBA salt of mevastatin (assay of mevastatin: 80%) dissolved in 5 L of water) was continually added to the medium at the flow rate 2 ml/min. During the fermentation 70% oxygen saturation of the medium was maintained by stirring with the frequency between 300 and 600 rpm. Analyses of the concentration of pravastatin in the fermentation broth showed the total final concentration of pravastatin in the fermentation broth to be 690 g/kg of broth after 76 hours of fermentation at temperature between 24° and 30° C., indicating a 40% conversion of mevastatin into pravastatin.
  • Fermentation medium:
    Raw material Amount
    Corn starch for fermentation 20 g
    Soybean flour for fermentation 5 g
    Glucose 10 g
    Yeast extract 5 g
    Antifoam agent 10 g
    All raw materials were dissolved in tap water, the pH was then adjusted to 7.4.
    • Example 18 Preparation of TBA Salt of Simvastatin
  • Simvastatin (1.95 g) was suspended in 50 ml of 30% (v/v) acetonitrile, triethylamine (1 ml) was added and the solution was heated for 20 minutes at 70° C. After completion of reaction acetonitrile was evaporated from the solution, the remaining solution was acidified to pH 4 with phosphoric acid. Simvastatin in the acid form was extracted into ethyl acetate (2×50 ml) and the pooled extracts were dried with 2 g of sodium sulphate. The desiccant was filtered off and the ethyl acetate solution was concentrated to 20 ml. To the solution 1.05 equivalents of TBA were added and crystallization was carried out for 1 hour at 8° C. The product was filtered off and dried at 40° C. for 1 hour. Hie yield: 2 g of the TBA salt of simvastatin.
    • Example 19 Conversion of the TBA Salt of Simvastatin into Simvastatin Lactone
  • The TBA salt of simvastatin (1.6 g), obtained by the process disclosed in example 18, was dissolved in water (36 ml), the solution was then acidified to pH 3.7 with an aqueous phosphoric acid solution and simvastatin in the acid form was extracted into ethyl acetate (2×50 ml). The pooled extracts were dried with sodium sulphate (2 g) and the desiccant was then filtered off. The ethyl acetate solution was concentrated to 20 ml.
  • To the solution trifluoroacetic acid (0.5 ml) was added and the reaction mixture was heated for 25 minutes at 50° C. After completion of the reaction, the ethyl acetate solution was extracted with 5%(w/w) aqueous solution of ammonium hydrogen carbonate. The organic phase was dried with sodium sulphate (2 g), the desiccant was filtered off and the ethyl acetate solution was concentrated to 4 ml. Crystallization was carried out for 1 hour at 8° C. The product was then filtered off and dried at 40° C. for 1 hour. The yield: 0.9 g of simvastatin in the acid form.
    • Example 20 Preparation of Free Acid of Simvastatin
  • Simvastatin (20 g) was dissolved in the mixture of water (80 ml) and 8M KOH (18 ml). The solution was stirred in nitrogen atmosphere for two hours at room temperature.
  • After that 120 ml of ethyl acetate was added and pH was adjusted to 2-3 with 5% aqueous solution of HCl. Ethyl acetate phase was washed with mixture of water (100 ml). 5% aqueous solution of HCl and 5% aqueous solution of NaCl (50 ml). The obtained ethyl acetate phase was then dried for three hours with addition of 20 g MgSO4 anhydrite and filtrated
    • Preparation of Amine Salt
  • After that 18 ml of N-methylcyclobexylamine was added into the ethyl acetate phase. After two days at temperature between 0 and 5 degrees C. crystals of simvastatin N-methylcyclohexylamine salt were formed obtained crystals were filtered off and washed with 20 ml of ethyl acetate, 40 ml ethyl acetate/n-heptane (1:1) and 40 ml of pentane. The yield: 20.5 g of N-methylcyclohexylamine salt of simvastatin. The yield calculated to the starting simvastatin was 79%. The same results were obtained also with cyclohexylamine (by the use of the same method).
    • Example 21 Preparation of Pravastatin in Purified Form
  • Pravastatin (30 g, HPLC purity 90.2%) in the form of Na salt was dissolved in water (100 ml) and pH was adjusted to 3 with HCl (10% aqueous solution). The resulting free acid was extracted from the water phase into ethyl acetate (3×200 ml). The pooled ethyl acetate extracts were dried with sodium sulphate, the solution was filtered off and 7.604 g of N-methylcyclohexylamine was added (drop by drop at intensive stirring). After crystals were crystallized out, they were filtered off and recrystallized from the mixture of ethyl acetate/methanol. The yield: 21 g of crystals of pravastatin N-methylcyclohexylamine salt with a HPLC purity of 99.28%.
    • Example 22 Preparation of Free Acid of Atorvastatin
  • Calcium salt of atorvastatin (3 g) was suspended in 100 ml water. The pH was adjusted with the phosphoric acid to 4 and after that free acid of atorvastatin was extracted with ethyl acetate (3×100 ml ). Combined ethyl acetate extract was dried and 2.7 g of oil containing atorvastatin in the free acid form was obtained.
    • Preparation of Amine Salt
  • 1 g of atorvastatin in the free acid form was dissolved in acetonitrile (100 ml) and 1.1 molar equivalents of TBA was added. The obtained mixture was concentrated to 30 ml and after four hours at 8° C. the TBA salt of atorvastatin crystallized. White precipitate was filtered off and dried in a rotary evaporator. Yield: 1 g of TBA salt of atorvastatin.
    • Example 23 Preparation of Amine Salt
  • 1 g of atorvastatin in the free acid form was dissolved in methanol (20 ml) and 1.1 molar equivalents of dicyclohexylamine (DCHA) in 50 ml of n-hexane was added. After four hours at 8° C. the DCHA salt of atorvastatin crystallized. White precipitate was filtered off and dried in a rotary evaporator Yield: 1.1 g of DCHA salt of atorvastatin.

Claims (21)

1-48. (canceled)
49. The sodium salt of pravastatin in a crystalline form.
50. The sodium salt of pravastatin in solid form made by a process comprising the steps of:
(a) dissolving an amine salt of pravastatin in an alkaline solution containing sodium cations;
(b) adding ethyl acetate to said alkaline solution;
(c) cooling of said alkaline solution; and
(d) forming and isolating the solid salt of pravastatin sodium;
wherein the amine salt of pravastatin comprises
an amine selected from the group consisting of amines of formulae I and II:
Figure US20080188552A1-20080807-C00005
wherein
a1) R1, R2, R3 and R4 independently denote:
a hydrogen atom;
a straight or a branched alkyl group having 1 to 8 carbon atoms;
a cycloalkyl group having 3 to 8 carbon atoms;
an arylalkyl group wherein the alkyl group is methyl or ethyl and the aryl group is phenyl, which is optionally substituted by an N-alkyl or N,N-dialkyl group wherein the alkyl group is alkyl having 1 to 4 carbon atoms;
an arylalkyl group which is optionally substituted by one or more substituents;
a hydroxyalkyl group having 2 to 4 carbon atoms; or
an aminoalkyl group having 2 to 4 carbon atoms, which are optionally substituted by an N-alkyl or N,N-dialkyl group wherein the alkyl group is alkyl having 1 to 4 carbon atoms;
X denotes a hydrogen atom, a hydroxyl group, a halogen or a methyl group;
m and n independently denote an integer from 0 to 5; or
a2) NR1R2 or NR3R4 denote a heterocyclic ring having 3 to 7 methylene groups attached to a hydrogen atom, one of these groups being optionally substituted by an oxygen or a sulphur atom or an imine group; and X, m and n are the same as defined above;
Figure US20080188552A1-20080807-C00006
wherein:
b1) R′1, R′2, and R′3 are the same or different and denote hydrogen, alkyl, alkenyl, amino- or hydroxy- or alkoxy-substituted alkyl or alkenyl, or substituted ammo-substituted alkyl or alkenyl, provided that R′1, R′2 and R′3 are not hydrogen at the same time; or
b2) R′1, and R′2, and optionally R′3, together with the nitrogen atom form an optionally substituted heterocyclic ring system including the nitrogen atom as a ring member, and optionally including an additional hetero atom, and if R′3 is not part of the ring system it is independently selected from hydrogen, alkyl, alkenyl, amino- or hydroxyl- or alkoxy-substituted alkyl, or substituted amino-substituted alkyl; or
b3) R′1 is an optionally substituted cyclic group of formula III,

R′(CHR′4)m—  III
wherein m is zero or an integer from 1 to 5, R′ is optionally substituted aliphatic hydrocarbon cyclic system having 3 to 8 carbon atoms in the ring, R′4 is hydrogen, alkyl, amino- or hydroxy- or alkoxy-substituted alkyl, substituted amino-substituted alkyl, or a group of the same formula as R′1 as defined herein above; R′2 and R′3 are the same as R′1 or hydrogen, alkyl, alkenyl, amino- or hydroxy- or alkoxy-substituted alkyl, or substituted amino-substituted alkyl or alkenyl; or
b4) R′1 is an optionally substituted aryl group of formula IV:
Figure US20080188552A1-20080807-C00007
wherein R′5 is hydrogen or one or more substituents, and m is zero or an integer from 1 to 5; and R′2 and R′3 may be independently hydrogen, alkyl, amino- or hydroxyl or alkoxy-substituted alkyl, or substituted amino-substituted alkyl, or groups of the same general formula R′1.
51. The sodium salt of pravastatin according to claim 49, wherein the amine salt of pravastatin is the tertiarybutyl amine salt of pravastatin.
52. The sodium salt of pravastatin according to claim 50, wherein the amine salt of pravastatin is dissolved in an alkaline ethanol/water mixture in step (a).
53. The sodium salt of pravastatin according to claim 50, wherein the amine salt of pravastatin is dissolved in an ethanolic solution and/or aqueous solution of NaOH or Na2CO3.
54. The sodium salt of pravastatin according to claim 50, wherein the amine salt of pravastatin sodium dissolved in step a) is prepared by
dissolving pravastatin in the free acid form in ethyl acetate and
adding the respective amine into said solution, thereby crystallizing said amine salt of pravastatin.
55. A pharmaceutical composition containing the sodium salt of pravastatin according to claim 49.
56. A method of treating hypercholesteremia in humans, comprising administering to a patient in need of such treatment an antihypercholesterolemic effective amount of the sodium salt of pravastatin according to claim 49.
57. The sodium salt of pravastatin according to claim 50, wherein the amine salt of pravastatin is the tertiarybutyl amine salt of pravastatin.
58. The sodium salt of pravastatin according to claim 51, wherein the amine salt of pravastatin is dissolved in an alkaline ethanol/water mixture in step (a).
59. The sodium salt of pravastatin according to claim 51, wherein the amine salt of pravastatin is dissolved in an ethanolic solution and/or aqueous solution of NaOH or Na2CO3.
60. The sodium salt of pravastatin according to claim 52, wherein the amine salt of pravastatin is dissolved in an ethanolic solution and/or aqueous solution of NaOH or Na2CO3.
61. The sodium salt of pravastatin according to claim 51, wherein the amine salt of pravastatin sodium dissolved in step a) is prepared by
dissolving pravastatin in the free acid form in ethyl acetate and
adding the respective amine into said solution, thereby crystallizing said amine salt of pravastatin.
62. The sodium salt of pravastatin according to claim 52, wherein the amine salt of pravastatin sodium dissolved in step a) is prepared by
dissolving pravastatin in the free acid form in ethyl acetate and
adding the respective amine into said solution, thereby crystallizing said amine salt of pravastatin.
63. The sodium salt of pravastatin according to claim 53, wherein the amine salt of pravastatin sodium dissolved in step a) is prepared by
dissolving pravastatin in the free acid form in ethyl acetate and
adding the respective amine into said solution, thereby crystallizing said amine salt of pravastatin.
64. A method of treating hypercholesteremia in humans, comprising administering to a patient in need of such treatment an antihypercholesterolemic effective amount of the sodium salt of pravastatin according to claim 50.
65. A method of treating hypercholesteremia in humans, comprising administering to a patient in need of such treatment an antihypercholesterolemic effective amount of the sodium salt of pravastatin according to claim 51.
66. A method of treating hypercholesteremia in humans, comprising administering to a patient in need of such treatment an antihypercholesterolemic effective amount of the sodium salt of pravastatin according to claim 52.
67. A method of treating hypercholesteremia in humans, comprising administering to a patient in need of such treatment an antihypercholesterolemic effective amount of the sodium salt of pravastatin according to claim 53.
68. A method of treating hypercholesteremia in humans, comprising administering to a patient in need of such treatment an antihypercholesterolemic effective amount of the sodium salt of pravastatin according to claim 54.
US11/901,634 1998-09-18 2007-09-18 New salts of HMG-CoA reductase inhibitors Abandoned US20080188552A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US11/901,634 US20080188552A1 (en) 1998-09-18 2007-09-18 New salts of HMG-CoA reductase inhibitors

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
SIP-9800240 1998-09-18
SI9800240A SI20070A (en) 1998-09-18 1998-09-18 NOVEL SALTS OF INHIBITORS OF HMG-CoA REDUCTASE
US09/787,387 US6583295B1 (en) 1998-09-18 1999-09-17 Salts of HMG-CoA reductase inhibitors
PCT/IB1999/001554 WO2000017150A1 (en) 1998-09-18 1999-09-17 NEW SALTS OF HMG-CoA REDUCTASE INHIBITORS
US10/320,285 US6838566B2 (en) 1998-09-18 2002-12-16 Salts of HMG-CoA reductase inhibitors
US10/966,000 US20050049422A1 (en) 1998-09-18 2004-10-15 New salts of HMG-CoA reductase inhibitors
US11/901,634 US20080188552A1 (en) 1998-09-18 2007-09-18 New salts of HMG-CoA reductase inhibitors

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US10/966,000 Continuation US20050049422A1 (en) 1998-09-18 2004-10-15 New salts of HMG-CoA reductase inhibitors

Publications (1)

Publication Number Publication Date
US20080188552A1 true US20080188552A1 (en) 2008-08-07

Family

ID=20432331

Family Applications (4)

Application Number Title Priority Date Filing Date
US09/787,387 Expired - Lifetime US6583295B1 (en) 1998-09-18 1999-09-17 Salts of HMG-CoA reductase inhibitors
US10/320,285 Expired - Lifetime US6838566B2 (en) 1998-09-18 2002-12-16 Salts of HMG-CoA reductase inhibitors
US10/966,000 Abandoned US20050049422A1 (en) 1998-09-18 2004-10-15 New salts of HMG-CoA reductase inhibitors
US11/901,634 Abandoned US20080188552A1 (en) 1998-09-18 2007-09-18 New salts of HMG-CoA reductase inhibitors

Family Applications Before (3)

Application Number Title Priority Date Filing Date
US09/787,387 Expired - Lifetime US6583295B1 (en) 1998-09-18 1999-09-17 Salts of HMG-CoA reductase inhibitors
US10/320,285 Expired - Lifetime US6838566B2 (en) 1998-09-18 2002-12-16 Salts of HMG-CoA reductase inhibitors
US10/966,000 Abandoned US20050049422A1 (en) 1998-09-18 2004-10-15 New salts of HMG-CoA reductase inhibitors

Country Status (15)

Country Link
US (4) US6583295B1 (en)
EP (2) EP1114021B1 (en)
JP (1) JP3834203B2 (en)
KR (1) KR100699368B1 (en)
CN (1) CN1228304C (en)
AT (1) ATE271026T1 (en)
AU (1) AU765373C (en)
CA (1) CA2343646A1 (en)
DE (1) DE69918697T2 (en)
HU (1) HUP0103007A3 (en)
IL (1) IL142055A (en)
IS (1) IS2113B (en)
NZ (1) NZ509583A (en)
SI (1) SI20070A (en)
WO (1) WO2000017150A1 (en)

Families Citing this family (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0251582A (en) * 1988-08-12 1990-02-21 Kyokado Eng Co Ltd Grout
SI20305A (en) * 1999-08-06 2001-02-28 LEK, tovarna farmacevtskih in kemi�nih izdelkov, d.d. Pravastatin sodium salt crystals
AU782143B2 (en) * 1998-09-18 2005-07-07 Lek Pharmaceuticals D.D. Crystals of the sodium salt of pravastatin
EP1491522A1 (en) * 1999-02-03 2004-12-29 Institute for Drug Research Ltd. Microbial process for preparing pravastatin
GB0003305D0 (en) 2000-02-15 2000-04-05 Zeneca Ltd Pyrimidine derivatives
US6806290B2 (en) 2000-06-09 2004-10-19 Lek Pharmaceuticals D.D. Stabilized pharmaceutically effective composition and pharmaceutical formulation comprising the same
JP2004501121A (en) * 2000-06-09 2004-01-15 エルイーケー　ファーマシューティカルズ　ディー．ディー． Compound having stable pharmaceutical effect and pharmaceutical preparation containing the same
JP3737801B2 (en) * 2000-10-05 2006-01-25 テバ ジョジセルジャール レースベニュタールシャシャーグ Pravastatin sodium substantially free of pravastatin lactone and epipravastatin, and a composition comprising the same
JP2002121172A (en) * 2000-10-16 2002-04-23 Sankyo Co Ltd Method for purifying pravastatin or pharmacologically acceptable salt thereof
NL1017548C2 (en) 2001-03-09 2002-09-10 Synthon Bv A lactonization process.
EP1404303A4 (en) * 2001-06-21 2006-03-15 Andrx Pharmaceuticals Inc Stable pharmaceutical compositions containing pravastatin
JP2003026634A (en) * 2001-07-17 2003-01-29 Mercian Corp Method for producing pravastatin sodium salt
JP2003093045A (en) * 2001-09-26 2003-04-02 Godo Shusei Co Ltd Useful microorganism for transformation
ATE409476T1 (en) * 2002-06-13 2008-10-15 Novartis Pharma Gmbh CALCIUM SALTS OF STATINS FROM INDOLE
US20080293750A1 (en) * 2002-10-17 2008-11-27 Anna Helgadottir Susceptibility Gene for Myocardial Infarction, Stroke, Paod and Methods of Treatment
US20060019269A1 (en) * 2002-10-17 2006-01-26 Decode Genetics, Inc. Susceptibility gene for myocardial infarction, stroke, and PAOD, methods of treatment
WO2005014541A1 (en) * 2003-08-12 2005-02-17 Biocon Limited Novel antihypercholesterolemic compound
EP1562912A2 (en) 2003-08-28 2005-08-17 Teva Pharmaceutical Industries Limited Process for preparation of rosuvastatin calcium
CN101318923A (en) * 2003-09-17 2008-12-10 沃尼尔·朗伯有限责任公司 Crystalline forms of 'r-(r*,r*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-'(phenylamino)carbonyl!-1h-pyrrole-1-heptanoic acid
GB0324791D0 (en) 2003-10-24 2003-11-26 Astrazeneca Ab Chemical process
US7777034B2 (en) 2003-11-24 2010-08-17 Teva Pharmaceutical Industries Ltd. Crystalline ammonium salts of rosuvastatin
WO2005056534A1 (en) 2003-12-02 2005-06-23 Teva Pharmaceutical Industries Ltd. Reference standard for characterization of rosuvastatin
EP1709008A1 (en) * 2004-01-19 2006-10-11 Ranbaxy Laboratories Limited Salts of hmg-coa reductase inhibitors and use thereof
US8158362B2 (en) * 2005-03-30 2012-04-17 Decode Genetics Ehf. Methods of diagnosing susceptibility to myocardial infarction and screening for an LTA4H haplotype
US20100216863A1 (en) * 2004-01-30 2010-08-26 Decode Genetics Ehf. Susceptibility Gene for Myocardial Infarction, Stroke, and PAOD; Methods of Treatment
US7875731B2 (en) * 2004-05-05 2011-01-25 Pfizer Inc. Salt forms of [R-(R*,R*)]-2-(4-fluorophenyl)-β, δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)Carbonyl]-1H-pyrrole-1-heptanoic acid
WO2006017357A1 (en) 2004-07-13 2006-02-16 Teva Pharmaceutical Industries Ltd. A process for the preparation of rosuvastatin involving a tempo-mediated oxidation step
NZ552390A (en) * 2004-08-06 2010-01-29 Transform Pharmaceuticals Inc Novel fenofibrate formulations and related methods of treatment
US20090042979A1 (en) * 2004-08-06 2009-02-12 Transform Pharmaceuticals Inc. Novel Statin Pharmaceutical Compositions and Related Methods of Treatment
BRPI0514189A (en) * 2004-08-06 2008-06-03 Transform Pharmaceuticals Inc statin pharmaceutical compositions and related treatment methods
WO2006072963A1 (en) * 2005-01-10 2006-07-13 Concord Biotech Limited Process for preparing simvastatin from lovastatin amine salts in three steps
KR100945763B1 (en) 2005-02-22 2010-03-08 테바 파마슈티컬 인더스트리즈 리미티드 How to prepare rosuvastatin
CA2499047A1 (en) * 2005-03-01 2006-09-01 Apotex Pharmachem Inc. Process for producing atorvastatin hemicalcium
JP4813841B2 (en) * 2005-07-25 2011-11-09 キユーピー株式会社 Method for producing pravastatin sodium
EP1805148A2 (en) 2005-08-16 2007-07-11 Teva Pharmaceutical Industries Ltd. Crystalline rosuvastatin intermediate
PL211815B1 (en) * 2007-11-19 2012-06-29 Inst Chemii Organicznej Polska Akademia Nauk Enzyme, levostatin esterase, mounted in a carrier, which is not soluble in water, the manner of mounting of enzyme, application of enzyme, flow biocatalythic reactor and production method and/or simvastatin treatment
WO2009078033A2 (en) * 2007-12-18 2009-06-25 Themis Medicare Limited Isolation and recovery of simvastatin in lactone form or in the form of an acid salt from the harvested fermentation broth
WO2011089559A1 (en) * 2010-01-22 2011-07-28 Orchid Chemicals And Pharmaceuticals Limited A novel polymorphic form of atorvastatin salts
WO2012063115A2 (en) 2010-11-11 2012-05-18 Jubilant Life Sciences Ltd. Process for the preparation of rosuvastatin calcium via novel amine intermediate
CN114031496B (en) * 2021-11-30 2024-09-27 广东蓝宝制药有限公司 A method for preparing high-purity pravastatin 1,1,3,3-tetramethylbutylamine

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4319039A (en) * 1979-06-15 1982-03-09 Merck & Co., Inc. Preparation of ammonium salt of hypocholesteremic fermentation product
US4342767A (en) * 1980-01-23 1982-08-03 Merck & Co., Inc. Hypocholesteremic fermentation products
US4346227A (en) * 1980-06-06 1982-08-24 Sankyo Company, Limited ML-236B Derivatives and their preparation
US5223415A (en) * 1990-10-15 1993-06-29 Merck & Co., Inc. Biosynthetic production of 7-[1',2',6',7',8',8a'(R)-hexahydro-2'(S),6'(R)-dimethyl-8'(S)-hydroxy-1'(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid (triol acid)
US5356896A (en) * 1991-12-12 1994-10-18 Sandoz Ltd. Stabilized pharmaceutical compositions comprising an HMG-CoA reductase inhibitor compound
US5403860A (en) * 1987-10-27 1995-04-04 Sankyo Company, Limited Octahydronaphthalene oxime compounds for cholesterol synthesis inhibition
US5763646A (en) * 1997-03-13 1998-06-09 Ranbaxy Laboratories, Ltd. Process for manufacturing simvastatin from lovastatin or mevinolinic acid
US5763653A (en) * 1997-03-13 1998-06-09 Ranbaxy Laboratories, Ltd. Key intermediates in the manufacture of simvastatin
US6740775B1 (en) * 1999-08-06 2004-05-25 Lek Pharmaceuticals D.D. Crystalline sodium salt of pravastatin

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES493726A0 (en) 1979-07-27 1981-06-16 Sankyo Co A PROCEDURE FOR THE PREPARATION OF SALTS AND ESTERS OF MONACOLINE K USEFUL AS ANTITLIPERCOLESTEREMIC AGENTS.
JPS57123140A (en) 1981-01-23 1982-07-31 Sankyo Co Ltd Ml-236b carboxylic acid amine salt and remedy for hyperlipemia containing said salt as active component
JPS57185275A (en) * 1981-05-07 1982-11-15 Sankyo Co Ltd Tetrahydro-dum-4 and tetrahydro-isodum-4 and their derivatives
US5089523A (en) * 1990-05-11 1992-02-18 E. R. Squibb & Sons, Inc. Fluorinated derivatives of mevinic acids
HU221849B1 (en) 1991-12-12 2003-02-28 Novartis Ag. Stabilized medicaments containing hmg-coa reductase inhibitor fluvastatin

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4319039A (en) * 1979-06-15 1982-03-09 Merck & Co., Inc. Preparation of ammonium salt of hypocholesteremic fermentation product
US4342767A (en) * 1980-01-23 1982-08-03 Merck & Co., Inc. Hypocholesteremic fermentation products
US4346227A (en) * 1980-06-06 1982-08-24 Sankyo Company, Limited ML-236B Derivatives and their preparation
US5403860A (en) * 1987-10-27 1995-04-04 Sankyo Company, Limited Octahydronaphthalene oxime compounds for cholesterol synthesis inhibition
US5223415A (en) * 1990-10-15 1993-06-29 Merck & Co., Inc. Biosynthetic production of 7-[1',2',6',7',8',8a'(R)-hexahydro-2'(S),6'(R)-dimethyl-8'(S)-hydroxy-1'(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid (triol acid)
US5356896A (en) * 1991-12-12 1994-10-18 Sandoz Ltd. Stabilized pharmaceutical compositions comprising an HMG-CoA reductase inhibitor compound
US5763646A (en) * 1997-03-13 1998-06-09 Ranbaxy Laboratories, Ltd. Process for manufacturing simvastatin from lovastatin or mevinolinic acid
US5763653A (en) * 1997-03-13 1998-06-09 Ranbaxy Laboratories, Ltd. Key intermediates in the manufacture of simvastatin
US6740775B1 (en) * 1999-08-06 2004-05-25 Lek Pharmaceuticals D.D. Crystalline sodium salt of pravastatin
US7078558B1 (en) * 1999-08-06 2006-07-18 Lek Pharmaceutical And Chemical Company D.D. Crystals of the sodium salt of pravastatin
US20060183929A1 (en) * 1999-08-06 2006-08-17 Lek Pharmaceutical And Chemical Company D.D. Crystals of the sodium salt of pravastatin

Also Published As

Publication number Publication date
HUP0103007A2 (en) 2002-05-29
CN1318046A (en) 2001-10-17
US6838566B2 (en) 2005-01-04
US20050049422A1 (en) 2005-03-03
IL142055A (en) 2004-06-20
EP1114021A1 (en) 2001-07-11
ATE271026T1 (en) 2004-07-15
EP1114021B1 (en) 2004-07-14
DE69918697D1 (en) 2004-08-19
AU765373B2 (en) 2003-09-18
CN1228304C (en) 2005-11-23
JP3834203B2 (en) 2006-10-18
AU5528599A (en) 2000-04-10
DE69918697T2 (en) 2005-07-28
HUP0103007A3 (en) 2003-10-28
EP1466886A2 (en) 2004-10-13
SI20070A (en) 2000-04-30
IS5891A (en) 2001-03-15
IS2113B (en) 2006-06-15
AU765373C (en) 2005-05-26
CA2343646A1 (en) 2000-03-30
IL142055A0 (en) 2002-03-10
KR20010071959A (en) 2001-07-31
US6583295B1 (en) 2003-06-24
NZ509583A (en) 2003-10-31
EP1466886A3 (en) 2009-02-25
JP2002526467A (en) 2002-08-20
KR100699368B1 (en) 2007-03-27
US20030120086A1 (en) 2003-06-26
WO2000017150A1 (en) 2000-03-30

Similar Documents

Publication Publication Date Title
US6838566B2 (en) Salts of HMG-CoA reductase inhibitors
EP0074222B1 (en) Mb-530b derivatives, their preparation and pharmaceutical compositions containing them
EP0702679B1 (en) Process for the isolation of lovastatin
US6521762B2 (en) Process for purifying lovastatin and simvastatin with reduced levels of dimeric impurities
IE51477B1 (en) Hydrogenation products of mevinolin and dihydromevinolin a process for preparing the same and an antihypercholesterolemic pharmaceutical composition containing the same
US4343814A (en) Hypocholesterolemic fermentation products
EP0070649B1 (en) Ml-236b derivatives, a process for their preparation and pharmaceutical compositions containing them
EP0570245B1 (en) Octahydronaphthalene oxime derivatives for cholesterol biosynthesis inhibition, their preparation and use
US7189558B2 (en) Process for producing pravastatin sodium salt using streptomyces flavidovirens dsm 14455
WO1997021699A1 (en) Process for making 1,2-dioxolanes
AU2001241833A2 (en) A process for purifying lovastatin and simvastatin with reduced levels of dimeric impurities
KR20040107647A (en) Process for preparing intermediate of simvastatin
NZ552342A (en) An improved process for lactonization in the preparation of statins

Legal Events

Date Code Title Description
STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION