WO2007100351A2 - Procede de preparation de la simvastatine et associes produits intermediaires - Google Patents

Procede de preparation de la simvastatine et associes produits intermediaires Download PDF

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WO2007100351A2
WO2007100351A2 PCT/US2006/035824 US2006035824W WO2007100351A2 WO 2007100351 A2 WO2007100351 A2 WO 2007100351A2 US 2006035824 W US2006035824 W US 2006035824W WO 2007100351 A2 WO2007100351 A2 WO 2007100351A2
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formula
lovastatin
reaction mixture
simvastatin
temperature
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PCT/US2006/035824
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English (en)
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WO2007100351A3 (fr
Inventor
Ferenc Korodi
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Teva Gyogyszergyar Zartkoruen Mukodo Reszvenytarsasag
Teva Pharmaceuticals Usa, Inc.
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Priority to EP06814653A priority Critical patent/EP1883634A2/fr
Priority to CA002619236A priority patent/CA2619236A1/fr
Publication of WO2007100351A2 publication Critical patent/WO2007100351A2/fr
Publication of WO2007100351A3 publication Critical patent/WO2007100351A3/fr

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    • 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
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/30—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being unsaturated and containing rings other than six-membered aromatic rings
    • 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
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • 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

  • the invention relates to processes for preparing simvastatin and intermediates of such processes.
  • Simvastatin marketed under the name ZOCOR ® by Merck & Co., is a lipid-lowering agent. After oral ingestion, it is believed that simvastatin, an inactive lactone, is hydrolyzed to the corresponding 3,5-dihydroxy acid form, which then inhibits the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme is believed to catalyze the conversion of HMG-CoA to mevalonate, an early rate- limiting step in the biosynthesis of cholesterol.
  • HMG-CoA 3-hydroxy-3-methylglutaryl-coenzyme A
  • Simvastatin is also known as butanoic acid, 2,2-dimethyl-,l,2,3,7,8,8a- hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)-ethyl]-l- naphthalenyl ester, [lS-[l(alpha),3(alpha),7(beta),8(beta)(25*,45*),-8(alpha)(beta)].
  • Simvastatin (m.w. 418.57) has the structure represented in formula I below.
  • Simvastatin can be synthetically prepared from the fermentation product lovastatin, shown in formula II, by "methylation” processes.
  • lovastatin shown in formula II
  • U.S. Patent No. 4,582,915 describes a process for preparing simvastatin by first converting lovastatin to an alkali metal salt, preferably the potassium salt, of the dihydroxycarboxylate, then methylating the 2-methylbutyryloxy group at the C2-position.
  • Acidity of the ⁇ -protons of the 3,5-dihydroxyheptanoic acid moiety can be decreased by formation of a lovastatin hydroxy acid amide.
  • This dihydroxy amide derivative can be methylated without further protection, as disclosed in U.S. Patent No. 5,763,646, or after protection of the 1,3-diol moiety by (1) tert-butyldimethylsilylation, as disclosed in U.S. Patent No. 4,820,850; (2) the formation of phenylboronic acid derivatives, as disclosed in U.S. Patent No. 5,393,893; (3) the formation of acetonides as disclosed in U.S. Patent No. 6,100,407; or (4) protection using hexamethyldisilazane (HMDS), as disclosed in U.S. Patent No. 6,472,542.
  • HMDS hexamethyldisilazane
  • the present invention provides a process for the preparation of simvastatin and intermediates useful in making simvastatin.
  • the invention relates to a process for the preparation of lovastatin amide of formula III,
  • the molar ratio of the amine of formula HNR 1 R 2 to the lovastatin compound is no more than about 1.5, and R 1 and R 2 are independently selected from hydrogen, straight or branched C 2-8 alkyl, aryl, aryalkyl, and C 3-8 cycloalkyl groups, or together form a ring optionally containing a heteroatom.
  • the period of time can be, e.g., from about 3 hours to about 5 hours and the temperature can be from about 60°C to about 12O 0 C.
  • the amine of formula HNR 1 R 2 can be, e.g., selected from the group consisting of n-butylamine, diethylamine, cyclohexylamine, morpholine, benzylamine and mixtures thereof, e.g., cyclohexylamine, benzylamine or mixtures thereof.
  • the molar ratio of the amine of formula EDSIR 1 R 2 to the lovastatin compound is no more than about 1.2, or from about 1 to about 1.2.
  • the lovastatin compound can be, e.g., an ammonium salt of formula VIII.
  • the process can further comprise:
  • the process can further comprise:
  • the second reaction mixture comprising the lovastatin amide of formula III of step (b) is directly combined with the silylation catalyst and the HMDS.
  • the period of time in step (b) is, e.g., from about 3 to about 5 hours
  • the period of time in step (d) is from about 0.5 to about 10 hours
  • the temperature of step (b) is from about 60° to about 12O 0 C
  • the temperature of step (d) is from about O 0 C to about 40 0 C.
  • the molar ratio of the silylation catalyst to the lovastatin compound can be, e.g., from about 0.0001 to about 0.05.
  • the silylation catalyst can be, e.g., silylhalide or iodine and the molar ratio of the silylhalide or iodine to the lovastatin compound can be, e.g., about 0.02 (if silylhalide), or about 0.004 (if iodine).
  • the molar ratio of the HMDS to the lovastatin compound can be, e.g., from about 1 to about 1.7. Li a certain embodiment, this process can further comprise:
  • the above process further comprises:
  • M is alkali metal atom
  • the above process further comprises:
  • simvastatin dihydroxy acid of formula X may be, e.g., further converted into simvastatin ammonium salt of formula VI, which is then recovered.
  • the simvastatin ammonium salt of formula VI can be converted to simvastatin of formula I.
  • Certain embodiments relate to a process for the preparation of bis (TMS)- lovastatin amide derivative of formula IV, which may comprise:
  • the period of time can be, e.g., from about 0.5 to about 10 hours and the temperature can be from about 0°C to about 40°C.
  • the silylation catalyst can be, e.g., selected from the group consisting of silylhalide, molecular halogen, inorganic salt, organic salt, transition metal phosphonic acid derivative, saccharin and mixtures thereof, e.g., silylhalide, molecular halogen, saccharin or mixtures thereof, e.g., trimethylsilyl iodide, iodine or mixtures thereof.
  • the silylation catalyst can be, e.g., silymalide and the molar ratio of silylhalide to the lovastatin amide of formula III can be from about 0.02 to about 0.025.
  • the silylation catalyst can be, e.g., iodine and the molar ratio of the iodine to the lovastatin amide of formula III can be from about 0.004 to about 0.005.
  • the molar ratio of the HMDS to the lovastatin amide of formula III can be, e.g., from about 1 to about 2.
  • the bis (TMS)-lovastatin amide derivative of formula IV can be converted to simvastatin of formula I using any suitable method.
  • Certain embodiments relate to a process for the preparation of simvastatin dihydroxy acid amide derivative of formula V, which may comprise:
  • the process also includes:
  • methylating agent Any suitable methylating agent may be used.
  • methylating agents include methyl halide (e.g., methyl iodide, etc.), methyl sulfate and mixtures thereof.
  • the seventh reaction mixture can be quenched, for example, with water. If desired, the simvastatin dihydroxy acid amide derivative of formula V can be converted to simvastatin of formula I.
  • the bis (TMS)-lovastatin amide derivative of formula IV is prepared by a process comprising:
  • the period of time can be, e.g., about 0.5-10 hours and the temperature can be from about 0°C to about 40°C.
  • the second reaction mixture comprising the bis (TMS)- lovastatin amide derivative of formula IV can be directly combined with the aprotic organic solvent and the amide derivative.
  • the process may further comprise:
  • the process can also comprise:
  • the alkali base can be, e.g., sodium hydroxide, potassium hydroxide or mixtures thereof.
  • the invention also relates to certain novel compounds, which are useful as synthetic intermediates in the preparation of simvastatin.
  • novel compounds include a compound of formula IV-a:
  • R 1 and R 2 is H and the other of R 1 and R 2 is selected from the group consisting of benzyl radical and cyclohexyl radical; for example, one of R 1 and R 2 is H and the other of R 1 and R 2 is benzyl radical, or one of R 1 and R 2 is H and the other of R 1 and R 2 is cyclohexyl radical.
  • Certain embodiments of the invention also relate to a process for the preparation of simvastatin of formula I, the process comprising: (a) providing a compound of formula IV-a; and
  • the phrase "at a temperature and for a period of time sufficient to convert substantially all of a particular starting material to another compound means that at least about 80%, preferably at least about 85%, more preferably at least about 90%, even more preferably at least about 95%, of the starting material is converted to the another compound.
  • the invention relates to a synthesis of simvastatin (I) from lovastatin (II) according to the following general scheme. (It will be appreciated that the invention also relates to the individual steps and compounds involved therein).
  • this process affords a simple and economical way for commercial scale production of simvastatin in high yield and purity.
  • the first four steps of the process may be combined in a "one-pot" process in which the simvastatin ammonium salt (VI) is the first isolated intermediate. ⁇ midation of Lovastatin
  • the amidation of lovastatin includes combining a lovastatin compound, an inert organic solvent, and an amine of formula HNR 1 R 2 to obtain a first reaction mixture, which is then converted to a second reaction mixture comprising the lovastatin amide of formula III by maintaining the first reaction mixture at a temperature and for a period of time sufficient to convert substantially all of the lovastatin compound to the lovastatin compound of formula III.
  • the temperature can be from about 6O 0 C to about 120 0 C and the period of time of can be at least about 3 hours (preferably about 3-5 hours). In certain embodiments, the temperature is from about 8O 0 C to about HO 0 C, more preferably from about 80 0 C to about 9O 0 C.
  • a Dean-Stark apparatus is used to remove water, which is a byproduct.
  • the lovastatin compound can be selected from the group consisting of
  • a salt of lovastatin acid of formula VII e.g. the ammonium salt of formula
  • the inert organic solvent is benzene, toluene, xylene, tetrahydrofuran (TBDF), or mixtures thereof. More preferably, the inert organic solvent is toluene.
  • R 1 and R 2 groups OfHNR 1 R 2 are independently selected in each instance from hydrogen, straight or branched C 2-8 alkyl, aryl, arylalkyl, and C 3-8 cycloalkyl groups, or together form a ring optionally containing a heteroatom such as O, S, or N.
  • Aryl refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-l,4-benzoxazin-3(4H)-one-7yl, and the like) provided that the point of attachment is through an aromatic ring atom.
  • the aryl is phenyl, naphthyl or 5,6,7,8-tetrahydronaphth-2-yl.
  • the aryl may be substituted or unsubstituted.
  • the substituents may be, for example, an alkyl group, an alkenyl group, a cyclic alkyl group, an aralkyl group, a cyclic alkenyl group, a cyano group, an aryl group, an alkoxy group, an aryloxy group, an alkylthio group, an arylthio group, an alkylsulfonyl group, or an arylsulfonyl group.
  • Arylalkyl refers to an aryl group with at least one alkyl substituent, such as a linear or branched alkyl group preferably having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms.
  • the substituent is exemplified by groups such as methyl, t-butyl, n-heptyl, octyl and the like.
  • the amine of formula HNR 1 R 2 is n-butylamine, diethylamine, cyclohexylamine, morpholine, benzylamine, or mixtures thereof. More preferably, the amine of formula HNR 1 R 2 is cyclohexylamine, benzylamine or mixtures thereof.
  • the inventor has surprisingly discovered that the amidation reaction works well with amines having relatively large groups - i.e. cyclohexyl and benzyl groups.
  • the molar ratio of the amine of formula HNR 1 R 2 to the lovastatin compound is no more than about 1.5, more preferably, no more than about 1.2, e.g., a molar ratio of from about 1 to about 1.2 or about 1 to about 1.5.
  • the use of no or a slight excess of amine is advantageous, because, e.g., the silylation reaction can be performed without the need to first remove the excess amine by, e.g., distillation, a time- consuming operation that can lead to formation of impurities.
  • the lovastatin of formula II and the amine of formula HNR 1 R 2 are commercially available.
  • the lovastatin compound is the ammonium salt of formula VIII.
  • the lovastatin amide of formula III is converted to simvastatin of formula I by a suitable process, e.g., the silylation, methylation, deprotection, and/or lactonization reactions of the general scheme.
  • the temperature can be from about O 0 C to about 4O 0 C
  • the silylation catalyst is silylhalide, molecular halogen, inorganic salt, organic salt, transition metal phosphonic acid derivative, saccharin or mixtures thereof.
  • the silylhalide is trimethylsilyl iodide, trimethylsilyl bromide, trimethylsilyl chloride, or mixtures thereof, more preferably, trimethylsilyl iodide.
  • the molecular halogen is iodine, bromine, or mixtures thereof, more preferably, iodine.
  • the inorganic salt is zinc chloride, tetrabutylammonium fluoride, lithium perchlorate, copper triflate, or mixtures thereof.
  • Preferred transition metal phosphonic acid derivative include phosphonomolybdenic acid, tungstenophosphonic acid, and mixtures thereof.
  • the more preferred silylation catalysts are iodine, trimethylsilyl iodide, saccharin and mixtures thereof.
  • the most preferred silylation catalyst is iodine. Surprisingly, the inventor has discovered that silylation catalysts not only improve the rate of reaction, but also decrease the amount of starting material necessary, which is both unexpected and advantageous.
  • the bis (TMS)-lovastatin amide derivative of formula IV is subsequently converted to simvastatin of formula I by a suitable process, e.g., the methylation, deprotection, and/or lactonization steps of the general scheme.
  • a suitable process e.g., the methylation, deprotection, and/or lactonization steps of the general scheme.
  • the molar ratio of the silylation catalyst to the lovastatin amide of formula III is from about 0.0001 to about 0.06.
  • the silylation catalyst is sirylhalide and the molar ratio of silylhalide to the lovastatin amide of formula III is from about 0.02 to about 0.025, or the silylation catalyst is iodine and the molar ratio of the iodine to the lovastatin amide of formula III is from about 0.004 to about 0.005.
  • the molar ratio of the HMDS to the lovastatin amide of formula III is from about 1 to about 2.
  • the silylation reaction of the present invention is performed with no or a slight excess of HMDS.
  • the lovastatin amide of formula III is prepared by an amidation reaction, e.g., the amidation reaction discussed above. More preferably, the lovastatin of formula III is prepared by the amidation reaction discussed above, and the reaction mixture comprising the amidation reaction product (i.e., the lovastatin amide of formula III) is directly combined with the silylation catalyst and HMDS.
  • the reaction mixture comprising the lovastatin amide of formula III is combined with the silylation catalyst and the HMDS without recovering or purifying the lovastatin amide of formula III from the reaction mixture comprising the lovastatin amide of formula III.
  • the molar ratio of the silylation catalyst to the lovastatin compound is 0.0001 to about 0.05, depending on the catalyst. More preferably, silylhalide is the silylation catalyst and the molar ratio of the silyl halide to the lovastatin compound is about 0.02.
  • iodine is the silylation catalyst and the molar ratio of the iodine to the lovastatin compound is about 0.004.
  • the molar ratio of the HMDS to the lovastatin compound is from about 1 to about 1.7, more preferably, from about 1 to about 1.2.
  • the present invention relates to 2 novel compounds: N- cyclohexyl-7-[l,2,6,7,8,8a(R)-hexahydro-2(S),6(R)-dimethyl-8(S)-[[2(S)- methylbutanoyl] oxy]-l (S)-naphtyl]-3(R),5(R)-bis(trimethylsilyloxy)heptanamide; and N- benzyl-7-[l,2,6,7,8,8a(R)-hexahydro-2(S),6(R)-dimethyl-8(S)-[[2(S)- methylbutanoyl] oxy] - 1 (S)-naphtyl] -3 (R),5 (R)-bis(trimethylsilyloxy)heptanamide.
  • These compounds are embraced by formula IV-a:
  • the compound of formula IV-a wherein one of R 1 and R 2 is H and the other of R 1 and R 2 is cyclohexyl radical can be characterized by data selected from an 1 H- NMR spectrum having hydrogen chemical shifts at about 0.05, 0.73, 0.76, 0.93, 0.97, 1.01-1.09, 1.13, 1.20-1.31, 1.38-1.59, 1.72-1.81, 1.85, 2.05, 2.10, 2.19, 2.25, 2.31, 3.49, 3.63, 4.09, 5.15, 5.37, 5.65, 5.85 and 6.07 ppm, and MS (ESI) spectrum having peaks at about 648.44 (MH + ).
  • the compound of formula TV-a wherein one of R 1 and R 2 is H and the other of R and R is benzyl radical can be characterized by data selected from an 1 H-NMR spectrum having hydrogen chemical shifts at about 0.06, 0.11, 0.84, 0.86, 1.05, 1.07, 1.12, 1.14, 1.33, 1.39, 1.52, 1.62-1.64, 1.89, 1.96, 2.19-2.45, 3.58, 4.16, 4.41, 5.31, 5.48, 5.76, 5.95, 6.60 and 7.18-7.33 ppm; and MS (ESI) spectrum having peaks at about 656.42 (MH + ).
  • the compounds of formula IV-a can be prepared by any suitable process, e.g., the amidation reaction and silylation reaction described above.
  • the compound of formula IV-a is converted to simvastatin by a suitable process, e.g., the methylation, deprotection and/or lactonization steps of the general scheme.
  • a methylation reaction involving the bis (TMS)- lovastatin amide derivative of formula IV can be carried out as follows:
  • the bis (TMS)-lovastatin amide derivative of formula IV is prepared according to the silylation reaction, and the reaction mixture comprising the bis (TMS)-lovastatin amide derivative of formula IV is directly combined with the aprotic organic solvent. That is, the reaction mixture comprising the bis (TMS)-lovastatin amide derivative of formula IV is combined with the aprotic organic solvent without recovering or purifying the bis (TMS)-lovastatin amide derivative of formula IV.
  • the aprotic solvent is aromatic hydrocarbon, ether, or mixtures thereof.
  • the aromatic hydrocarbon is toluene.
  • the ether is tetrahydrofuran (THF), diethyl ether, diisopropyl ether, dioxane, or mixtures thereof. More preferably, the ether is THF. A preferred mixture is that of toluene and THF.
  • THF tetrahydrofuran
  • the amount of the strong base used in the methylation reaction is such that the molar ratio of the strong base to the lovastatin compound is from about 3 to about 6.
  • the strong base is commercially available. More preferably, the strong base is an alkali amide.
  • the alkali amide is lithium amide, sodium amide, lithium diethylamide, lithium N-isopropyl-N-cyclohexylamide, lithium diisopropylamide (LDA), lithium pyrrolidide, or mixtures thereof. More preferably, the base is LDA, lithium pyrrolidide or mixtures thereof.
  • the strong base is prepared in-situ by adding alkyllithium, alkali hydride, or mixtures thereof to a third reaction mixture that includes, in this embodiment, the bis (TMS)-lovastatin amide derivative and an amine derivative.
  • the alkali hydride is sodium hydride, potassium hydride or mixtures thereof.
  • Preferred alkyllithiums include n-butyllithium, n-hexyllithium and mixtures thereof. More preferably, n-butyllithium is used to prepare the strong base.
  • the amine derivative is pyrrolidine.
  • the alkyllithium, the alkali hydride or mixtures thereof is directly added to the bis (TMS)- lovastatin amide derivative of formula IV, instead of preparing the strong base in a workup reaction and then combining it with the bis (TMS)-lovastatin amide derivative of formula IV.
  • the temperature of step (b) is from about -3O 0 C to about -6O 0 C, more preferably, from about -4O 0 C to about -6O 0 C.
  • the temperature of step (c) is from about -30 0 C to about -4O 0 C.
  • the methylating agent is methyl halide, methyl sulfate or mixtures thereof.
  • the methyl halide is methyl iodide, methyl bromide, methyl chloride or mixtures thereof.
  • a preferred methylsulfate is methyl tosylate, methyl mesylate or mixtures thereof.
  • the more preferred methylating agent is methyl iodide.
  • the methylation reaction is preceded by the amidation reaction described above. In this preferred embodiment, preferably, the amount of the methylating agent used is such that the molar ratio of the methylating agent to the lovastatin compound is from about 1.5 to about 3.
  • the temperature of step of step (d) is from about -3O 0 C to about
  • step (f) the temperature of step (f) is from about -1O 0 C to about -2O 0 C.
  • the step of quenching the seventh reaction mixture includes the use of water as a quenching reagent.
  • the water also removes the silyl groups to produce the desired product, simvastatin dihydroxy acid amide derivative of formula V.
  • simvastatin dihydroxy acid amide derivative of formula V is recovered in step (g) by acidifying the organic phase followed by washing with water and evaporating the solvents.
  • simvastatin dihydroxy acid amide derivative of formula V is subsequently converted to simvastatin by a suitable process, e.g., the deprotection and/or lactonization steps disclosed in the general scheme.
  • the amine protecting group of the simvastatin dihydroxy acid amide derivative of formula V can be removed to provide the simvastatin ammonium salt of formula VI.
  • such a process can include:
  • the process also includes: (e) recovering the simvastatin ammonium salt of formula VI.
  • the simvastatin dihydroxy acid amide derivative of formula V is prepared according to a process set forth previously.
  • the water miscible organic solvent is C 1-4 alcohol, ketone, ether or mixtures thereof.
  • Preferred C 1-4 alcohols are methanol, ethanol and mixtures thereof.
  • the more preferred water miscible organic solvent is methanol.
  • the ketone is acetone.
  • a preferred ethers include THF, dioxane and mixtures thereof.
  • the alkali base is sodium hydroxide, potassium hydroxide or mixtures thereof.
  • the alkali salt of formula IX can be converted to simvastatin dihydroxy acid of formula X
  • Simvastatin dihydroxy acid of formula X can be converted to simvastatin ammonium salt of formula VI
  • Simvastatin ammonium salt of formula VI can be recovered by any suitable method, such as cooling to induce precipitation followed by filtering to obtain a wet solid that is then washed.
  • the lactonization of simvastatin ammonium salt of formula VI to simvastatin of formula I may be performed by, for example, a thermally- induced lactonization process, as disclosed in PCT Publication No. WO 2004/071456 A2, which is incorporated herein by reference.
  • Simvastatin of formula I can be further purified by, e.g., a process involving crystallization from a mixture of an aromatic hydrocarbon and a C 5-8 aliphatic hydrocarbon.
  • the HPLC chromatographic measurements were made on an AGILENT 1100 with a ZORBAX SB C18 4,6*75mm- 3,5 ⁇ m, or Hypersil ODS 100*4 mm column, and eluted with a 0.1 % aqueous phosphoric acid solution (eluant A)/acetonitrile (eluant B) mixture as described below, with detection at 240 nm, a flow rate of 1.2mL/min, and an injection volume of 10 ⁇ l.
  • the column temperature was 25 °C and the sample temperature was 5 °C.
  • Lovastatin (10.1 g, 25 mmol) was suspended in a mixture of cyclohexylamine (2.6 g, 3.0 ml, 26.3 mmol) and toluene (25 ml) and the reaction mixture was heated to a temperature of 80 - 9O 0 C to obtain a solution. The solution was stirred at this temperature for 5 hours under nitrogen atmosphere to complete the reaction and obtain a solution including lovastatin cyclohexamide.
  • HMDS lovastatin cyclohexamide
  • the reaction mixture including bis(TMS)-lovastatin cyclohexamide obtained in Example 2 was diluted with THF (100 ml) and cooled to a temperature of -30 to -40°C. Lithium diisopropylamide (60 ml 2 molar solution, 120 mmol) was added to the reaction mixture while stirring at the above temperature under nitrogen. After the addition, the reaction mixture was aged at a temperature of -30 to -35°C for 1.5 hours. The mixture was then cooled to -50°C and methyl iodide (8.9 g, 3.8 ml, 62.5 mmol) was added (after which the temperature increased to 14°C).
  • reaction mixture was stirred at a temperature of -30 to -35°C for 1 hour. The temperature was allowed to increase to -10°C and the reaction mixture was stirred at this temperature for 30 min followed by the addition of water (50 ml). Toluene (50 ml) was added after the water and the organic phase were separated. IM solution of hydrochloric acid (150 ml) was added to the organic phase to obtain a mixture, which was stirred for 15 min and the phases were separated again. After separation of the aqueous phase, the organic phase was washed twice with water (2x 50 ml). The organic phase was concentrated in vacuum to give an oil (about 14 g) containing a simvastatin dihydroxy acid amide derivative.
  • Lovastatin (10.1 g, 25 mmol) was suspended in a mixture of benzylamine
  • Example 5 The reaction mixture obtained in Example 5 was diluted with THF (50 ml) and toluene (50 ml) followed by addition of pyrrolidine (8.9 g, 10.3 ml; 125 mmol) under nitrogen to give a mixture. The mixture was then cooled to -60°C. A solution of n-butyl lithium (78 ml; 125 mmol) was added over 60 minutes while the temperature was kept at -50 to -60°C. After the addition, the reaction mixture was aged at a temperature of -30 to about -4O 0 C for 2 hours.
  • Example 6 The oil of Example 6 was dissolved in methanol (120 ml). Sodium hydroxide (6.4 g, 160 mmol) in water (80 ml) was added to this solution followed by stirring at reflux temperature (75 - 8O 0 C) for 4 hours. The obtained solution was then concentrated under vacuum to about half of its original volume. The concentrated mixture was cooled to 5 0 C and the pH was adjusted to about 7 by addition of aqueous hydrochloric acid solution. Ethyl acetate (175 ml) was added and the pH was adjusted to 3-5. Then, the water phase was separated and the organic phase was diluted with methanol (50 ml) and the pH was adjusted to 9-11 by adding aqueous ammonia solution (6 ml).
  • Simvastatin ammonium salt (6.0 g) in toluene (300 ml) in the presence of butylhydroxytoluene (BHT) (0.08 g) was refluxed for 2 hours, under nitrogen, using a Dean-Stark condenser for removing water. After reflux, the reaction mixture was stirred at 85-90 0 C for 3 hours. The reaction mixture was then evaporated to dryness to form a solid residue.
  • BHT butylhydroxytoluene
  • the solution was treated with charcoal (0.3 g). The charcoal was removed by filtration, and the solution was washed with toluene (4 ml). The solution was then charged into a four-necked round bottomed flask fitted with nitrogen inlet, thermometer, dropping funnel and reflux condenser. The solution was heated to about 60°C and n-hexane (55 ml) was added in a dropwise manner for 1 hour, while stirring. The reaction mixture was then cooled to 0 - 5°C in 1.5 hours and a new portion of hexane (41 ml) was added to the slurry over an hour.
  • simvastatin (5.0 g, 90 % yield, based on the starting material, simvastatin ammonium salt) in a purity of 98 % (HPLC).
  • Lovastatin ammonium salt (11.0 g, 25 mmol) was suspended in a mixture of benzylamine (3.2 g, 3.3 ml, 30 mmol) and toluene (30 ml) and the mixture was heated to reflux temperature. The mixture was stirred at reflux temperature for 3 hours under nitrogen atmosphere using a Dean-Stark water separator to complete the formation of the lovastatin benzylamide.

Abstract

La présente invention concerne de nouveaux processus de préparation de la simvastatine et les produits intermédiaires intervenant au cours de ces processus. Les modes de réalisation préférés comprennent la préparation des amides lovastatine, des dérivés d'amide protégés de la lovastatine, des dérivés d'amide d'acides dihydroxy de la simvastatine, des sels alcalins, des acides dihydroxy de la simvastatine, des sels d'ammonium de la simvastatine, et enfin de la simvastatine.
PCT/US2006/035824 2005-09-13 2006-09-13 Procede de preparation de la simvastatine et associes produits intermediaires WO2007100351A2 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008044243A3 (fr) * 2006-10-09 2010-02-11 Manne Satyanarayana Reddy Nouveau procédé de préparation de statines et leurs sels pharmaceutiquement acceptables
US8252829B2 (en) 2009-06-05 2012-08-28 Link Medicine Corporation Aminopyrrolidinone derivatives and uses thereof
US8455640B2 (en) 2006-05-03 2013-06-04 Msn Laboratories Limited Process for statins and its pharmaceutically acceptable salts thereof
US8487105B2 (en) 2009-01-19 2013-07-16 Msn Laboratories Limited Process for preparing pitavastatin, intermediates and pharmaceuctically acceptable salts thereof
US8987444B2 (en) 2010-01-18 2015-03-24 Msn Laboratories Private Limited Process for the preparation of amide intermediates and their use thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4820850A (en) * 1987-07-10 1989-04-11 Merck & Co., Inc. Process for α-C-alkylation of the 8-acyl group on mevinolin and analogs thereof
WO2003045935A1 (fr) * 2001-11-29 2003-06-05 Fermic S.A. De C.V. Procede d'alkylation du carbone alpha de la chaine secondaire de 2-methylbutyrate de lovastatine
WO2005066150A1 (fr) * 2004-01-02 2005-07-21 Hetero Drugs Limited Nouveau procede de preparation de simvastatine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4820850A (en) * 1987-07-10 1989-04-11 Merck & Co., Inc. Process for α-C-alkylation of the 8-acyl group on mevinolin and analogs thereof
WO2003045935A1 (fr) * 2001-11-29 2003-06-05 Fermic S.A. De C.V. Procede d'alkylation du carbone alpha de la chaine secondaire de 2-methylbutyrate de lovastatine
WO2005066150A1 (fr) * 2004-01-02 2005-07-21 Hetero Drugs Limited Nouveau procede de preparation de simvastatine

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8455640B2 (en) 2006-05-03 2013-06-04 Msn Laboratories Limited Process for statins and its pharmaceutically acceptable salts thereof
WO2008044243A3 (fr) * 2006-10-09 2010-02-11 Manne Satyanarayana Reddy Nouveau procédé de préparation de statines et leurs sels pharmaceutiquement acceptables
US8404841B2 (en) 2006-10-09 2013-03-26 Msn Laboratories Limited Process for the preparation of statins and their pharmaceutically acceptable salts thereof
US8487105B2 (en) 2009-01-19 2013-07-16 Msn Laboratories Limited Process for preparing pitavastatin, intermediates and pharmaceuctically acceptable salts thereof
US8252829B2 (en) 2009-06-05 2012-08-28 Link Medicine Corporation Aminopyrrolidinone derivatives and uses thereof
US8987444B2 (en) 2010-01-18 2015-03-24 Msn Laboratories Private Limited Process for the preparation of amide intermediates and their use thereof

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EP1883634A2 (fr) 2008-02-06
CA2619236A1 (fr) 2007-09-07
KR20080034190A (ko) 2008-04-18

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