Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
  • C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
  • C07C69/675—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids of saturated hydroxy-carboxylic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/28—Phosphorus compounds with one or more P—C bonds
  • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
  • C07F9/40—Esters thereof
  • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
  • C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/28—Phosphorus compounds with one or more P—C bonds
  • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
  • C07F9/40—Esters thereof
  • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
  • C07F9/4025—Esters of poly(thio)phosphonic acids
  • C07F9/4053—Esters of poly(thio)phosphonic acids containing substituents selected from B, Si, P (other than -PO3H2 groups in free or esterified form), or a metal
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/07—Optical isomers

Definitions

• the invention relates to new synthesis of Rosuvastatin intermediates.
• LDL low density lipoprotein
• Statin drugs are currently the most therapeutically effective drugs available for reducing the level of LDL in the blood stream of a patient at risk for cardiovascular disease.
• statin drugs disrupt the synthesis of cholesterol and other sterols in the liver by competitively inhibiting the 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase enzyme (“HMG-CoA reductase”).
• HMG-CoA reductase catalyzes the conversion of HMG-CoA to mevalonate, which is the rate determining step in the biosynthesis of cholesterol. Consequently, HMG-CoA reductase inhibition leads to a reduction in the rate of formation of cholesterol in the liver.
• Decreased production of cholesterol causes an increase in the number of LDL receptors and corresponding reduction in the concentration of LDL particles in the bloodstream. Reduction in the LDL level in the bloodstream reduces the risk of coronary artery disease. (J.A.M.A. 1984; 251: 351-74).
• statins include: inter alia, compactin, lovastatin, simvastatin, pravastatin, fluvastatin, cerivastatin and atorvastatin, which are administered in their lactone form, as sodium salts, or as calcium salts.
• Rosuvastatin (7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino) pyrimidin-5-yl]-(3R,5S)-dihydroxy-(E)-6-heptenoic acid) calcium, an HMG-CoA reductase inhibitor, can lower LDL-cholesterol and triglycerides levels more effectively than first generation statin drugs.
• Rosuvastatin calcium has the following chemical formula:
• rosuvastatin calcium, intermediates of rosuvastatin, and their preparation are disclosed in U.S. Pat. No. 5,260,440, herein the '440 patent.
• PCT publication No. WO 03/097614 discloses the synthesis of rosuvastatin from the late intermediate methyl (3R)-3-(tert-butyldimethylsilyloxy)-5-oxo-6-triphenyl-phosphoranylidene hexanate, an intermediate disclosed in the '440 patent.
• PCT publication No. WO 00/49014 discloses the synthesis of rosuvastatin using intermediates with other side chains via a Wittig reaction.
• EP 850,902 discloses the removal of triphenylphosphine derivatives in mixtures.
• PCT publication No. WO 03/087112 discloses the synthesis of rosuvastatin from an intermediate t-butyl (3R)-3-(t-butyldimethylsilyloxy)-6-dimethoxyphosphinyl-5-oxohexanate (“19TBPO”).
• 19TBPO t-butyl-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidine-5-yl]-(3R)-3-hydroxy-5-oxo-6-heptenate (“TB21”), a key intermediate in the preparation of rosuvastatin, by going through 19TBPO intermediate.
• the process is illustrated in the following scheme:
• rosuvastatin calcium can contain extraneous compounds or impurities that can come from many sources. These can include unreacted starting materials, by-products of the reaction, products of side reactions, or degradation products. Impurities in rosuvastatin or any active pharmaceutical ingredient (API) are undesirable, and, in extreme cases, might even be harmful to a patient being treated with a dosage form of the API in which a sufficient amount of impurities are present.
• API active pharmaceutical ingredient
• the present invention encompasses a non protected hydroxyl group intermediate, 19 OH-XYPO, having the following formula:
• X is O, N, or S
• Y is selected from the group consisting of: a C 1 -C 4 alkyl, aryl, and alkyl aryl group, preferably 19 OH-TBPO, having the following formula:
• the present invention encompasses a process for preparing 19 OH-XYPO (particularly 19 OH-TBPO), comprising combining a compound, 19-OH-MBSG-XY, having the following formula:
• OH-MBSG preferably OH-MBSG, having the following formula:
• the present invention provides a process for preparing 19 OH-XYPO (particularly 19 OH-TBPO) and further converting it to TB21 and/or rosuvastatin and pharmaceutically accepted salts thereof.
• the present invention provides a compound, OH-MBSG-XY, having the following formula:
• X is O, N, or S
• Y is selected from the group consisting of: a C 1 -C 4 alkyl, aryl, and alkyl aryl group, preferably OH-MBSG, wherein the compound has a purity of at least about 95.5% as measured by GC method.
• the present invention provides a process for preparing OH-MBSG-XY (particularly OH-MBSG) and further converting it to TB21 and/or rosuvastatin and pharmaceutically accepted salts thereof.
• the present invention also provides a process for purifying OH-MBSG and/or 19 OH-TBPO by using a thin film evaporator, more preferably a thin wiped-film evaporator
• the present invention encompasses a process for preparing compound TB21 by a Wittig-Horner reaction comprising combining 19 OH-XYPO (particularly 19 OH-TBPO), FPP-aldehyde and a base.
• the present invention encompasses a process for preparing TB21 having the following formula:
• DMMP dimethylmethylphosphonate
• a base which is capable of making a carbanion on DMMP to obtain a non protected hydroxyl group intermediate 19 OH-TBPO; and combining the obtained 19 OH-TBPO with FPP-aldehyde and a base.
• the present invention a process for preparing TB21 and further converting it to rosuvastatin and pharmaceutically accepted salts thereof.
• the present invention a process for purifying a one or more of rosuvastatin intermediates 19 OH-XYPO of formula:
• X is O, N, or S
• Y is selected from the group consisting of: a C 1 -C 4 alkyl, aryl, and alkyl aryl group comprising applying a force under pressure of less than one atmosphere to increase surface area of a feed containing the intermediate, thereby providing the intermediate in purified form.
• the process comprises feeding the intermediate to a thin film evaporator is used.
• the process comprises feeding the intermediate to a thin film evaporator with wiper blades.
• X is O and Y is t-butyl.
• the present invention a process for preparing TB21 and further converting it to rosuvastatin and pharmaceutically accepted salts thereof.
• the term “Wittig-Horner” refers to a condensation reaction of an aldehyde with a phosphonate derivative to create a double bond (also known as a Horner-Wadsworth-Emmons reaction).
• a Horner-Wadsworth-Emmons reaction See—Maryanoff et al. “The Wittig olefination reaction”, Chem. Rev. (1989) 89, 863-927; Boutagy et al. “Olefin synthesis with organic phosphonate carbanions”, Chem. Rev. (1974), 74 (1), 87-99; Wadsworth et al.
• room temperature refers to a temperature of about 20° C. to about 27° C.
• OH-MBSG refers to (R)-1-tert-butyl 5-methyl 3-hydroxypentanedioate having the following formula:
• 19 OH-TBPO refers to the intermediate (R)-butyl 5-(methoxycarbino)-2-hydroxy-4-oxopentanoate having the following formula:
• FPP-aldehyde refers to 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino) pyrimidine, having the following formula:
• TB21 refers to t-butyl-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidine-5-yl]-(3R)-3-hydroxy-5-oxo-6-heptenate, having the following formula:
• TBRE refers to t-butyl-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidine-5-yl]-(3R,5S)-3,5-dihydroxy-6-heptenate, having the following formula:
• X is O, N, or S
• Y is selected from the group consisting of: a C 1 -C 4 alkyl, aryl, and alkyl aryl group.
• OH-MBSG-XY refers to the compound of formula:
• X is O, N, or S, and selected from the group consisting of: a C 1 -C 4 alkyl, aryl, and alkyl aryl group,
• the present invention encompasses a non protected hydroxyl group intermediate, 19 OH-XYPO having the following structure:
• X is O, N, or S
• Y is selected from the group consisting of: a C 1 -C 4 alkyl, C 6 -C 12 aryl, and C 6 -C 12 alkyl aryl group.
• X is O and Y is a C 1 -C 4 alkyl group, more preferably, Y is a t-butyl ester, providing 19 OH-TBPO, with the following formula:
• 19 OH-XYPO is a key intermediate in the preparation of rosuvastatin calcium.
• the intermediate 19 OH-TBPO is a transparent to yellowish oil that cannot be purified by conventional scalable methods, such as crystallization.
• 19 OH-TBPO decomposes at high temperatures of about 100° C., and therefore cannot be purified by conventional distillation. Removing the impurities by conventional distillation without causing decomposition would require maintaining 19 OH-TBPO under low pressure of less than about 0.3 mm Hg and high temperature of about 120° C. These requirements render conventional distillation methods inappropriate for the purification of large scale quantities of 19 OH-TBPO, and therefore conventional distillation of 19 OH-TBPO is not industrially applicable.
• the invention provides a process for the purification of rosuvastatin intermediates, OH-MBSG-XY (particularly OH-MBSG) and/or 19 OH-XYPO (particularly 19 OH-TBPO), wherein the process is suitable for industrial use, as it does not entail chromatography steps.
• This process includes distilling the impurities of 19 OH-TBPO and OH-TBPO with a thin film evaporator (TFE) device.
• TFE thin film evaporator
• a thin film evaporator allows a temperature increase during the distillation process without decomposition of OH-MBSG-XY (particularly OH-MBSG) and/or 19 OH-XYPO (particularly 19 OH-TBPO), allowing the preparation of pure materials.
• a typical thin-film evaporator comprises of two major assemblies: a heated body and a close-clearance rotor.
• a feed travels to a rotating distributor plate. The feed can be from the top, which would then fall naturally by gravity onto the plate.
• Optional Wiper blades along with centrifugal force, resulting from the rotation of the plate, then create a thin film by distributing the feed, optimally evenly, over the wall. Due to reduced pressure in the plate chamber and the resulting increase in surface area, the volatile components readily evaporate. The remaining “pure” solid is pushed to the sides by the blades and collected.
• the feed is typically in the form of an oil which is obtained by removing the solvent in which OH-MBSG-XY (particularly OH-MBSG) and/or 19 OH-XYPO (particularly 19 OH-TBPO) is in.
• the feed can also be in the form of a solution.
• the solvent is typically removed in an evaporator, which leaves the oil (without solvent).
• these two operations evaporation of solvent and then purification of the oil
• TFE There can be a first rotating distributor plate, above a second plate, and the first and second plates can be heated at different temperatures.
• the OH-MBSG-XY (particularly OH-MBSG) is purified by the TFE method.
• OH-MBSG-XY (particularly OH-MBSG) is fed into the thin film evaporator, and the evaporation is performed at a temperature of about 130° C. to about 200° C., more preferably of about 150° C. to about 160° C.
• the evaporation is performed under a pressure of about 0 mbar to about 15 mbar, more preferably of about 0.5 mbar to about 5 mbar, yet more preferably of about 0.97 mbar to about 1.2 mbar.
• the OH-MBSG-XY (particularly OH-MBSG) obtained by the thin film evaporation method of the invention has a purity of at least about 95.5%, more preferably of at least about 98.4%, and even more preferably of at least about 99.5% area by GC.
• the obtained OH-MBSG has an assay purity of at least about 98.4%, more preferably of at least about 99%, and most preferably of at least about 100% w/w.
• the present invention provides OH-MBSG-XY (particularly OH-MBSG) having a purity of at least about 90%, more preferably of at least about 95%, and even more preferably of at least about 98% area by GC.
• OH-MBSG-XY (particularly OH-MBSG) has a purity of at least about 95.5%, more preferably of at least about 98.4%, and even more preferably of at least about 99.5% area as measured by GC.
• the OH-MBSG-XY (particularly OH-MBSG) has an assay purity of at least about 98.4%, more preferably of at least about 99%, and most preferably of at least about 100% w/w.
• the 19 OH-XYPO (particularly 19 OH-TBPO) is purified by the TFE method.
• 19 OH-XYPO (particularly 19 OH-TBPO) is fed into the thin film evaporator, and the evaporation is performed at a temperature of about 130° C. to about 200° C., more preferably of about 150° C. to about 160° C.
• the evaporation is performed under a pressure of about 0 mbar to about 15 mbar, more preferably of about 0.97 mbar to about 1.2 mbar.
• the OH-MBSG-XY (particularly OH-MBSG) and/or 19 OH-XYPO (particularly 19 OH-TBPO) obtained by the thin film evaporation method of the invention has a purity of at least about 95.5%, more preferably of at least about 98.4%, and even more preferably of at least about 99.5% area as measured by GC.
• the obtained 19 OH-TBPO has an assay purity of at least about 98.4%, more preferably of at least about 99%, and most preferably of at least about 100% w/w.
• the present invention provides a process of purifying OH-MBSG-XY (particularly OH-MBSG) and/or 19 OH-XYPO (particularly 19 OH-TBPO) and further converting them to Rosuvastatin.
• the 19 OH-XYPO (particularly 19 OH-TBPO) can be prepared by a process comprising combining a compound OH-MBSG-XY (particularly OH-MBSG, having the following formula:
• DMMP dimethylmethylphosphonate
• OH-XYPO can be prepared from OH-MBSG-XY.
• the process can be carried out by dissolving DMMP in an organic solvent that is inert to a strong base, and adding dropwise or slowly a base that is sufficiently strong to produce a carbanion.
• bases include LDA, sodium or lithium salts of Hexamethyldisilazane, sec-BuLi, tert-BuLi, NaH, KH, KtBuO, NaBuO, and C 4 to C 10 alkyl lithium.
• the organic solvent is selected from the group consisting of: dimethoxyethane (“DME”), hexane, methylene chloride tetrahydrofuran (“THF”) and dioxane.
• the organic solvent is THF, most preferably, dry THF (contains less than 2% water by volume).
• the solution can be cooled, such as to a temperature of about ⁇ 50° C. to about ⁇ 100° C., more preferably, to a temperature of about ⁇ 75° C.
• the base capable of making a carbanion on DMMP is preferably BuLi.
• n-BuLi is added to the solution to obtain a reaction mixture.
• the reaction mixture can be maintained at a temperature of about ⁇ 50° C. to about ⁇ 100° C. More preferably, the reaction mixture is maintained at a temperature of about ⁇ 70° C. to about ⁇ 100° C.
• n-BuLi is dissolved in hexane.
• a base is used to allow formation of the carbanion reaction to occur.
• the base after reaction provide a metal cation (M+) that is selected from the group consisting of lithium, sodium, potassium and cesium. More preferably, M+ is lithium to the base used for the preparation of the phosphonate.
• OH-MBSG-XY can be combined with the reaction mixture in 4 portions.
• OH-MBSG-XY is added in intervals of about 5 minutes to about 60 minutes, more preferably, in intervals of about 30 minutes on gram scale.
• the reaction mixture Prior to the addition of OH-MBSG-XY (particularly OH-MBSG), the reaction mixture can be stirred.
• the stirring can be done at a temperature of about ⁇ 50° C. to about ⁇ 100° C., more preferably, at a temperature of about ⁇ 70° C. to about ⁇ 75° C.
• the stirring can be for about 1 hour to about 6 hours, more preferably, for about 3 hours.
• the reaction mixture can be washed to remove impurities.
• the washing can be with the same solvent used during the process.
• the reaction mixture can be stirred.
• the stirring is at a temperature of about ⁇ 50° C. to about ⁇ 100° C.
• the stirring is for about 2 hours.
• the reaction mixture can be quenched by adding an agent that has an available proton.
• the quenching may be done using water, organic acid or inorganic acid.
• the quenching is with AcOH and EtOAc.
• the reaction mixture can be heated to bring the temperature to about ⁇ 10 to about 30° C., such as about room temperature or a temperature of about 20° C., before separation. Water can be added to the heated reaction mixture to obtain a two phase system in order to perform the extraction of 19 OH-XYPO (particularly 19 OH-TBPO).
• the two phases are separated.
• the aqueous phase is extracted.
• the extraction can be done with polar solvents such as CH 2 Cl 2 , Diethylcarbonate, Methyl ethyl ketone, Methyl iso-butyl ketone, cyclopenthylmethylether, t-buteyl methyl ether, diethyl ether, diisopropylether, more preferably with EtOAc (ethyl acetate).
• polar solvents such as CH 2 Cl 2 , Diethylcarbonate, Methyl ethyl ketone, Methyl iso-butyl ketone, cyclopenthylmethylether, t-buteyl methyl ether, diethyl ether, diisopropylether, more preferably with EtOAc (ethyl acetate).
• the organic layer is dried and filtered.
• the drying is done with dehydrating reagent or molecular sieves, more preferably, with a dehydrating reagent.
• the dehydrating reagent is sodium sulfate (Na 2 SO 4 ) or magnesium sulfate (MgSO 4 ), more preferably Na 2 SO 4 .
• the obtained dried and filtered layer is further concentrated to obtain a residue of 19 OH-XYPO (particularly 19 OH-TBPO).
• the concentration is under a pressure of less than one atmosphere, or a pressure of less than 100 mmHg, such as in a vacuum.
• the concentration is done by vacuum distillation.
• the vacuum distillation is done whilst heating, such as to a temperature of about 20° C. to about 90° C.
• the obtained non protected hydroxyl group intermediate, 19 OH-XYPO is further purified by a thin film evaporator.
• a thin film evaporator In a large scale apparatus, both concentrations of 19 OH-XYPO (particularly 19 OH-TBPO) after extraction and purification could be performed in a TFE.
• 19 OH-XYPO obtained by the processes of the invention may be further used to prepare rosuvastatin and pharmaceutically accepted salts thereof, for example, according to the procedures described in PCT publication No. WO 06/091771.
• the 19 OH-XYPO (particularly 19 OH-TBPO), obtained, optionally by the thin film evaporation purification, can be converted to TB21 (or another ester) by a Wittig-Horner reaction.
• the process for preparing compound TB21 by a Wittig-Horner reaction comprises combining 19 OH-TBPO, FPP-aldehyde and a base,
• 19 OH-XYPO can be dissolved in a dry solvent (contain less than 2% water by volume).
• dry solvents include, but are not limited to, ethereal solvents such as tetrahydrofuran (“THF”), dioxane, dimethoxyethane (“DME”), aromatic solvents such as toluene, chlorinated solvents and acetonitrile. More preferably, the solvent is dry THF.
• the solution can be cooled, such as to a temperature of about ⁇ 20° C. to about 10° C., more preferably to about 0° C.
• Suitable bases for the Wittig-Horner reaction include but are not limited to, metal hydrides, MOMe, MOH, MOtBu, M 2 CO 3 , wherein M can be sodium, potassium, lithium or cesium, BuLi or other lithiated bases, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), and DABCO (diazabicyclo[2.2.2]octane).
• the base is KOtBu.
• the base is preferably added to the cooled solution to obtain a reaction mixture.
• the base can be added under stirring.
• the reaction mixture can be stirred at a temperature of about ⁇ 20° C. to about 40° C., more preferably at about 0° C.
• the reaction mixture can be further stirred.
• the stirring can be for about 1 minute to about 1 hour, more preferably for about 15 minutes.
• FPP-aldehyde is added to the reaction mixture.
• the reaction mixture can be stirred, such as at a temperature of about 0° C. to about 60° C., more preferably at about 40° C.
• the mixture can be stirred for about 1 hour to about 12 hours, such as about 7 hours.
• reaction can be quenched, such as by using an acid, including AcOH (acetic acid).
• an acid including AcOH (acetic acid).
• the reaction mixture can be optimized for recovery of the product, by adding water (and optionally brine) and a water immiscible organic solvent such as ethyl acetate to obtain two phases.
• the phases can be then separated.
• the organic phase can be washed such as with water or saturated bicarbonate and brine. In one embodiment, the washing is done with saturated bicarbonate and brine.
• the remaining solvent is removed to obtain TB21.
• the removal of the solvent is under pressure of less than one atmosphere, such as vacuum (less than 100 mmHg).
• the compound TB21 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
• TB21 obtained by the processes of the invention may be further converted to rosuvastatin and pharmaceutically accepted salts thereof.
• the conversion may be done according to PCT publication No. WO 06/091771 and according to US RE37,314.
• the procedure described in PCT publication No. WO 06/091771 includes converting TB21 to rosuvastatin through the intermediate TBRE.
• TBRE is obtained by a reduction of the intermediate TB21 according to the scheme provided below:
• Rosuvastatin may be obtained upon saponification of TBRE according to the scheme provided below:
• Rosuvastatin obtained by the processes of the invention may be further converted to a pharmaceutically acceptable salt of rosuvastatin, preferably the calcium salt.
• a pharmaceutically acceptable salt of rosuvastatin preferably the calcium salt.
• the process of converting rosuvastatin into its pharmaceutically acceptable salt includes contacting rosuvastatin with calcium hydroxide, or with a stronger base such as sodium hydroxide.
• the base is preferably combined dropwise with a reaction mixture of rosuvastatin at a suitable temperature, such as a temperature of about 25° C. ⁇ 5° C.
• the reaction mixture may be washed with a suitable water immiscible organic solvent.
• Suitable water immiscible organic solvents include, but are not limited to, hydrocarbons; preferably the water immiscible organic solvent is toluene.
• the water immiscible organic solvent may be removed by phase separation. Remaining water immiscible organic solvent may be removed by distillation of the reaction mixture, preferably at a temperature of about 40° C. to about 45° C. under reduced pressure (below about 50 mmHg).
• the reaction mixture may then be combined with an alkali metal, including a source of calcium such as calcium chloride or calcium acetate, to form the salt of rosuvastatin.
• a source of calcium such as calcium chloride or calcium acetate
• calcium chloride may be added dropwise to a reaction mixture of rosuvastatin at a suitable temperature, such as a temperature of about 35° C. to about 45° C., and preferably at about 40° C., over a period of about thirty to about ninety minutes.
• Active carbon may be combined with a reaction mixture of rosuvastatin to remove impurities from the reaction mixture. If active carbon is used during the conversion of rosuvastatin into its pharmaceutically acceptable salt, the active carbon may be used before or after contacting rosuvastatin with an alkali metal.
• the conversion of rosuvastatin into its pharmaceutically acceptable salt may also include filtering the reaction mixture.
• the reaction mixture may be filtered, such as with Synter and Hyflo®, before or after washing with a water immiscible organic solvent.
• Wiped Film Evaporator made by Pope. 0.02 m2 heat transfer area, 50 mm diameter, made in glass with three Teflon wipers
• DMMP (25.57 g) was dissolved in dry THF (140 mL) and the solution was cooled to ⁇ 75° C.
• n-BuLi 2.5M in hexane, 73.3 mL was added dropwise, keeping the temperature below ⁇ 70° C.
• the mixture was stirred at ⁇ 70-75° C. for 3 h.
• Hydroxy-MBSG (10 g) was added in 4 portions every half an hour.
• THF (10 mL) was used to wash traces of hydroxy MBSG from the syringe. After stirring for 2 h at ⁇ 70-75° C., the mixture was quenched with AcOH (12 mL) and EtOAc (100 mL). The mixture was heated to 20° C.
• Hydroxy-MBSG (OH-MBSG) can be obtained by enzymatic reaction of dimethylhydroxyglutarate and esterification according to WO 03/087112, incorporated by inference.
• the mixture was then extracted with toluene (3000 mL) and stirred at RT for half an hour. An aqueous phase formed and was isolated. The aqueous phase was concentrated under reduced pressure at 40° C. to half of the volume. Half of the remaining aqueous phase was transferred to a 500 mL reactor and water (110 mL) was added, creating a solution. The solution was stirred at RT for 5 minutes. Ca(OAc) (8.8 g) was added dropwise to the solution over 117 min. at RT. The solution was stirred at RT for 1 hour, filtered, and washed with 60 mL of water, yielding a powdery compound (26 g, 94%).

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• 2008
  • 2008-07-14 WO PCT/US2008/008635 patent/WO2009009152A1/fr not_active Ceased
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