cas 79902-63-9, Simvastatin | Articles data

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For the preparation of simvastatin method
The present invention discloses a simvastatin preparation method, which comprises using lovastatin and alkyl amine to prepare lovastatin amide, protecting the hydroxyl in the lovastatin amide molecules, carrying out methylation on the protected lovastatin amide to obtain protected simvastatin amide, carrying out deprotection, alkaline hydrolysis and ammonium salt forming on the protected simvastatin amide to obtain a simvastatin ammonium salt, and carrying out cyclization on the simvastatin ammonium salt to generate simvastatin. According to the present invention, the methyl cyclohexane is adopted as the methylation reaction solvent, such that the tetrahydrofuran consumption is reduced, the cost is reduced, the production safety is improved, and the solvent recovery and reuse process is simplified.
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(2017/08/25)

Functional Micelles for Hard Tissue Targeted Delivery of Chemicals
Compositions and methods for targeting agents to hard tissue are provided.
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(2016/12/16)

Preparation method for simvastatin
The invention discloses a preparation method for simvastatin. The preparation method for simvastatin comprises the following steps: subjecting a simvastatin ammonium salt to cyclization, decoloring and concentration so as to obtain a crude simvastatin product; and then subjecting the crude simvastatin product to refining so as to obtain medical simvastatin. Compared with conventional preparation methods, the preparation method provided by the invention has the advantages of substantial improvement of product yield, effective reduction in impurities in the medical simvastatin and enhancement of product quality; and the preparation method can simplify technological operation and is suitable for industrialization.
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Paragraph 0041; 0042

(2017/01/02)

METHODS FOR PREPARING STATIN COMPOUNDS BY LACTONIZATION
A method for preparing a statin compound by lactonization is disclosed, which comprises the following step: lactonizing a compound of formula II into the compound of formula I in the presence of a strong acid catalyst and a dehydrant in a first solvent, wherein Z represents H, ammonium, or a metal cation, R1 is H or C1-C6 alkyl, preferably H or CH3, R2 is CH3, OH, CH2OH, CH2OC(O)R3, CH2OR3, or COOR4, preferably CH3 or OH, R3 and R4 are independently selected from the group consisting of H and C1-C6 alkyl.
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Page/Page column 8

(2012/10/18)

METHODS FOR PREPARING STATIN COMPOUNDS BY LACTONIZATION
A method for preparing a statin compound by lactonization is disclosed, which comprises the following step: lactonizing a compound of formula II into the compound of formula I in the presence of a strong acid catalyst and a dehydrant in a first solvent, wherein Z represents H, ammonium, or a metal cations; R1 is H or C1-C6 alkyl, preferably H or CH3, R2 is CH3, OH, CH2OH, CH2OC(O)R3, CH2OR3, or COOR4, preferably CH3 or OH, R3 and R4 are independently selected from the group consisting of H and C1-C6 alkyl.
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Page/Page column 5-6

(2012/12/13)

Process for Preparing Substantially Pure Simvastatin
This invention relates to an improved process for preparing substantially pure simvastatin (I), chemically known as (1S,3R,7S,8S,8aR)-8-[2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2-H-pyran-2-yl]ethyl]-3 ,7-dimeth-yl-1,2,3,7,8,8a-Hexahydronaphthalen-1-yl2,2-dimethyl butanoate, which comprises of: a) treating lovastatin (II) with an alkali metal hydroxide in a chosen suitable alcoholic solvent followed by relactonization to obtain the diol lactone intermediate (III) in a single vessel. b) selective silylation of 4-hydroxy group of diol lactone intermediate (III) with a chosen suitable silylating reagent to obtain mono silylated intermediate diol lactone (IV). c) acylation of the mono silylated intermediate (IV) to form silylated simvastatin (V) Or optionally, preparing silylated simvastatin (V) starting from Lovastatin (II) without isolating diol lactone (III) and monosilylated diol lactone (IV) and d) finally, removal of the silyl protecting group on silylated simvastatin (V) followed by purification to provide substantially pure simvastatin (I).
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Page/Page column 6

(2011/11/30)

Drug or Supplement Combination with Conjugated Linoleic Acid for Fat Loss in Mammals
Food, feed or drug combinations with conjugated linoleic acid are described that cause enhanced fat loss in mammals more efficiently than any of the individual components of the combination. Food, feed, or drugs that activate AMP activated protein kinase, agonists of nuclear receptors that bind RXR in adipocytes, or statin inhibitors were found to be more effective for fat loss when combined with conjugated linoleic acid.
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(2010/06/22)

ISOLATION AND RECOVERY OF SIMVASTATIN IN LACTONE FORM OR IN THE FORM OF AN ACID SALT FROM THE HARVESTED FERMENTATION BROTH
The present invention relates to a novel process for isolation and recovery of compounds such as biosynthetically produced simvastatin in either lactone form or in the form of its acid salt in high yield and purity, from microbial fermentation broth and isolating the said statin from harvested microbial broth.
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Page/Page column 4

(2009/07/03)

Process for Producing Simvastatin
The present invention discloses a process for producing Simvastatin and intermediate thereof. The present invention uses inexpensive and easily available reagents, its condition is mild, and it leaves out the protective and deprotective steps, which are necessary in prior methods. Compared with prior art, the esterifying condition in 8-position is greatly simplified.
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Page/Page column 7; 10

(2009/03/07)

PROCESS FOR THE MODIFICATION OF THE SOLID STATE OF A COMPOUND AND CO-AMORPHOUS COMPOSITIONS PRODUCED WITH SAME
The invention provides a process for preparing non-crystalline organic compositions and non-crystalline, co-amorphous blends of organic compounds.
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Page/Page column 24-25

(2009/05/28)

PROCESS FOR PREPARING SIMVASTATIN
Preparation of simvastatin.
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Page/Page column 3

(2009/03/07)

New synthesis of simvastatin
A noninfringing synthesis of simvastatin 1, starting from lovastatin 2, is presented. This synthesis features the protection of the free hydroxyl group of the lovastatin with 3,4-dihydro-2H-pyran (DHP) and opening of the lactone ring with n-BuNH2 to afford amide 4 as a key intermediate. Copyright Taylor & Francis Group, LLC.
Singamsetty, Radha Krishna,Vujjini, Satish Kumar,Manne, Nagaraju,Venkata Naga, Brahmeshwara Rao Mandava,Himabindu, Vurimidi,Battacharya, Apurba,Ghanta, Mahesh Reddy,Bandichhor, Rakeshwar
experimental part
p. 4452 - 4459
(2009/04/11)

Process for preparing simvastatin and intermediates thereof
Novel processes for the preparation of simvastatin and intermediates of such processes. Preferred embodiments include the preparation of lovastatin amides, protected lovastatin amide derivatives, simvastatin dihydroxy acid amide derivatives, alkali salts, simvastatin dihydroxy acids, simvastatin ammonium salts, and simvastatin.
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Page/Page column 12

(2010/11/27)

PROCESS FOR PREPARING SIMVASTATIN
A process for preparing simvastatin, intermediate compounds, and a solid premix comprising simvastatin and butylated hydroxyanisole.
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Page/Page column 9/2

(2010/11/27)

IMPROVED PROCESS FOR MANUFACTURING STATINS
The present invention provides an improved process for manufacturing statins comprising the following steps (i) reacting lovastatin with butyl amine to produce lovastatin amide (ii) isolating lovastatin butylamide in solid form by crystallization, from organic solvent (iii) optionally subjecting to hydroxyl protection to get diprotected lovastatin butylamide, (iv) subjecting proteceted or unprotected amide so obtained to C-Methylation employing lithium pyrrolidide prepared in situ by reacting butyl lithium and pyrrolidine, isolating the title product by conventional methods, and converting to its pharmacologically acceptable salt by known methods.
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Page/Page column 8

(2010/11/27)

Amorphous simvastatin
Amorphous simvastatin is prepared by rapidly removing solvent from a solution comprising simvastatin. The solution can also comprise a pharmaceutically acceptable carrier, to form a dispersion of amorphous simvastatin in the carrier.
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Page/Page column 3

(2008/06/13)

PROCESS FOR MANUFACTURE OF SIMVASTATIN
An improved method for manufacture of simvastatin of formula (I) in high purity. The process for preparation of compound (I) comprises Formula I the steps of agitating a compound of formula (II), Formula II wherein R is hydrogen, NH4+ or an alkali metal in an organic solvent and in an inert atmosphere at a temperature of between 27° C to 40° C in the presence of a weak acid followed by neutralization with an organic base and obtaining compound of formula (I) in high purity and substantially free of impurities through a step of isolation and crystallization.
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Page/Page column 14; 15; 16

(2008/06/13)

PROCESS FOR PREPARING SIMVASTATIN FROM LOVASTATIN AMINE SALTS IN THREE STEPS
The application describes a new process for preparing Simvastatin from Lovastatin amine salts in three steps. Lovastatin was hydrolysed to acid form and then isolated in the form of amine salt like cyclopropyl or t-octyl amine etc. The salts isolated were methylated directly without any protection and deprotection of hydroxy groups. The Simvastatin ammonium salt was produced directly, converted to Simvastatin by conventional methods and then purified to Simvastatin.
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Page/Page column 7-8

(2008/06/13)

AN IMPROVED PROCESS FOR LACTONIZATION IN THE PREPARATION OF STATINS
The present invention relates to an improved and industrial friendly process for lactonization to produce compound of the Formula [I], from compound of the Formula [II] in presence of an inorganic compound as a suitable lactonizing agent, preferably alkali metal hydrogen sulfate, and crystallizing the obtained lactone product in a solvent; or treating compound of the Formula [II] in the presence of an inorganic compound preferably alkali metal hydrogen sulfate using phase transfer catalyst in heterogeneous phase followed by crystallizing the obtained lactone product in a solvent.
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Page/Page column 6

(2008/06/13)

Processes for the preparation of simvastatin
Improved processes for the preparation of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) inhibitors, e.g., simvastatin, and their intermediates are provided. In one embodiment, a process for the preparation of a carboxylic acid amine salt of formula I is provided wherein R1 and R2 are as defined herein, the process comprising reacting lovastatin with an amine of formula III: in an aqueous medium to provide the carboxylic acid amine salt of formula I. The process further includes the steps of lithiating the carboxylic acid amine salt of formula I to form the corresponding 2,2-dimethylbutyrate intermediate of formula IIa lactonizing the 2,2-dimethylbutyrate intermediate (IIa) to provide simvastatin and pharmaceutically acceptable salts thereof. Also provided is an improved process for lactonization of the intermediates herein using peptide coupling reagents.
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Page/Page column 13

(2010/02/14)

METHODS FOR MAKING SIMVASTATIN AND INTERMEDIATES
The invention provides synthetic chemical and chemoenzymatic methods of producing simvastatin and various intermediates. In one aspect, enzymes such as hydrolases, e.g., esterases, are used in the methods of the invention.
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Page/Page column 74-75

(2008/06/13)

AN IMPROVED METHOD FOR MANUFACTURE OF 4-HYDROXY PYRAN-2-ONE DERIVATIVES
A process for preparation of 4-hydroxy-pyran-2-one derivative of formula (I), wherein R is (a), and wherein R1 and R2 are methyl and R3 is hydrogen or methyl, comprising the steps of, heating a compound of formula (II), wherein R is as defined before, and R4 is hydrogen, NH4+ or an alkali metal, in a solvent mixture consisting of an aromatic hydrocarbon and a ketone in an inert atmosphere at a temperature of between 60°C to 92°C in the absence or presence of orthophosphoric acid or its alkali dihydrogen salts or alkali hydrogen salts of a dibasic acid, followed by optional neutralization of the reaction mixture with an organic base and obtaining compound of formula (I) in high purity and substantially free of impurities through a step of isolation and crystallization. The process leads to formation of derivatives of formula (I) in high purity with dimmer impurity (III) less than 0.1% and anhydro impurity (IV) below 0.15%.
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Page/Page column 26; 27

(2008/06/13)

LACTONIZATION PROCESS
The instant invention discloses a process for preparation of compound of formula (II) comprising treatment of compound of formula (I) with sulphuric acid, wherein the sulphuric acid is added in one portion, at less than 0.8 equivalents of compound of formula (I); at a temperature less than -150 C; for a time less than 1 hour; in a water miscible solvent, preferably acetonitrile, where G = unsubstituted or substituted alkyl, aryl or hetero aryl and X = H or metal or amine.
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Page/Page column 8-9

(2008/06/13)

Process for lactonization to produce simvastatin
There is disclosed a process for the manufacture of simvastatin of Formula I which comprises heating a compound, namely acid or ammonium salt of compound of Formula II, where Z is H or NH4 in an organic solvent at a temperature of 130-140° C. NameResidenceCitizenshipRamesh403, Janapriya Pramila EnclaveIndiaDandalaUma Nagar, Kundanbagh, BegumpetHyderabad - 500 016 (India)Sonny505, Vishal Towers, A BlockIndiaSebastianA.S. Raju Nagar, Kukatpally,Hyderabad - 500 072 (India)Sanapureddy4/134, Pakeerpalli,IndiaJagan MohanSankarapuram (post)ReddyCuddapah - 516 002 (India)MeenakshisunderamD-1, Hidden Treasure ApartmentsIndiaSivakumaranNear Ayyappa Swami Temple LaneSomajiguda, Hyderabad - 500 082(India)
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Page 3

(2010/02/05)

Treatment of type 1 diabetes with PDE5 inhibitors
The use of a PDE5 inhibitor without substantial PDE2 inhibiting activity, or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of Type 1 Diabetes. A method of treating Type 1 Diabetes in an individual suffering from Type 1 Diabetes, which method comprises administering to said individual an effective amount of a PDE5 inhibitor without substantial PDE2 inhibiting activity, or a pharmaceutically acceptable salt thereof.
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(2008/06/13)

Process for preparing simvastatin
The present invention relates to an improved process for preparing simvastatin and more particularly, the improved process for preparing simvastatin expressed by formula 1 with high yield and high purity by performing the following sequential processes comprising: (i) hydrolysis of lovastatin as starting material with potassium t-butoxide in an organic solvent and small amount of water under a mild reaction condition, followed by lactonization of the obtained solid intermediate with preventing from formation of by-products; (ii) protection of an alcohol group with t-butyldimethylsilyl group which can be easily removed with concentrated hydrochloric acid without the formation of by-products; (iii) acylation of the obtained protected intermediate with acyloxytriphenyl phosphonium salt as an acylating agent under a mild reaction condition; and (iv) removal of the silyl protective group with a concentrated hydrochloric acid. The present invention is to provide the improved process of preparing simvastatin expressed by formula 1 environmentally sound, economically efficient, and industrially useful.
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Page 6 - 7

(2010/02/06)

A convenient procedure for the methylation of lovastatin: Synthesis of simvastatin
A new synthetic method for the preparation of the cholesterol lowering drug simvastatin 1 from the naturally occurring lovastatin 2 is reported. The synthesis relies upon deactivation of the α-carbon of the δ-lactone via conversion of the lactone group of lovastatin 2 to its carboxylic acid-amine salt derivative and then methylation of the 2-methylbutyrate-side chain of 3.
Dabak, Kadir,Keskin, Hulya
p. 29 - 34
(2007/10/03)

Process for the removal of a silyloxy protecting group from 4-silyloxy-tetrahydro-pyran-2-ones
This invention relates to a novel method for the removal of a silyl protecting group from the 4-hydroxy group of tetrahydropyran-2-ones, which method is particularly suitable in the process for the preparation of simvastatin and derivatives and analogs thereof.
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(2008/06/13)

Process for manufacturing simvastatin and novel intermediates thereof
The present invention provides intermediates of formula IIb and IIc useful for the preparation of Simvastatin: wherein R1and R2are each independently an alkyl, heteroalkyl, aryl or heteroaryl moiety, or R1and R2, taken together, form a heterocyclic moiety containing 5-8 atoms; wherein each of the foregoing alkyl and heteroalkyl moieties may be linear or branched, substituted or unsubstituted, cyclic or acyclic or saturated or unsaturated, and each of the foregoing heterocyclic, aryl and heteroaryl moieties may be substituted or unsubstituted.
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(2008/06/13)

Process to manufacture simvastatin and intermediates
A process is disclosed for the preparation of simvastatin which enables highly regio selective C-methylation of the 2′-position group of lovastatin without requiring protection/deprotection of 13-OH of lovastatin and lactone ring opening/closure.
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(2008/06/13)

Method for producing pharmaceutical dosage forms
The invention relates to a method for producing a granulate while using spray-dried D-mannitol and to the production of pharmaceutical dosage forms comprised of granulates of this type. The invention additionally relates to granulates obtained by using this method and to pharmaceutical dosage forms, which contain statins, especially cerivastatin, and which can be produced from said granulates.
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(2008/06/13)

Salts of HMG-CoA reductase inhibitors
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, the use of the amine salts of HMG-CoA reductase inhibitors in the process for semisynthetic preparation of HMG-CoA reductase inhibitors, the 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 salts of HMG-CoA reductase inhibitors into the HMG-CoA reductase inhibitors in the lactone form.
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(2008/06/13)

Process for producing simvastatin
The present invention relates to a process for producing Simvastatin comprising acylating 6(R)-[2-(8′(S)-hydroxy-2′(S), 6′(R)-dimethyl-1′, 2′, 6′, 7′, 8′, 8′a(R)-hexahydronaphthyl-1′(S)ethyl-4(R)-t-butyldimethylsilyloxy-3,4,5,6-tetrahydro-2H-pyran-2-on with the carboxylic acid compound of formula (VI): wherein R is methyl, ethyl, propyl, n-butyl, t-butyl or phenyl, and hydroxylating the resulting compound.
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(2008/06/13)

A new method for the synthesis of antihypercholesterolemic agent simvastatin
A new synthetic method for the preparation of the cholesterol-lowering drug simvastatin from the naturally occurring lovastatin is reported. The synthesis employs first the protection of the OH group of lovastatin (1) and then the protection of the lactone C=O group to prevent enolization via conversion to the orthoesters 4a and 4b. Alkylation of the 2-methylbutyrate side chain is then successfully achieved. Removal of the protecting groups affords antihypercholesterolemic agent simvastatin (2).
Dabak, Kadir,Adiyaman, Mustafa
p. 673 - 677
(2007/10/03)

Highly purified simvastatin compositions
The present invention relates to a process to prepare semi synthetic statins, to intermediates formed during said process and to highly purified simvastatin produced by the process.
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(2008/06/13)

Lactonization process
Lactonization of statins can be achieved using a lactonization agent that forms a hydrated complex with the produced water that is insoluble in the reaction solvent. By binding the produced water in an insoluble complex, the reaction is pulled to the lactone side, using mild conditions in short reactions times and with reduced risk of impurities.
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(2008/06/13)

Process for the preparation of simvastatin and analogs thereof
Lovastatin, pravastatin, simvastatin, mevastatin, 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, and some are obtained by treating the fermentation products using the methods of chemical synthesis for example simvastatin. This invention relates to the novel method for the acylation of sterically hindered alcohols which is applicable in the process for the preparation of simvastatin and derivatives thereof.
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(2008/06/13)

Process for producing simvastatin
A process for manufacturing Simvastatin is provided comprising reacting lovastatin with an organic boronic acid to produce a derivative of lovastatin (lovastatin phenylboronate) methylating the 2-methylbutyryloxy group on the lovastatin derivative to form a 2,2-dimethylbutyryloxy group on the lovastatin derivative and thereafter removing the boronate group to produce simvastatin.
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(2008/06/13)

Process for the production of semi synthetic statins via novel intermediates
A process has been provided to produce semi synthetic statins, as for instance simvastatin with a high yield, for another statin, preferably a naturally occurring statin, as for instance lovastatin. Also a number of novel intermediate compounds, prepared during said process, has been provided.
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(2008/06/13)

Process for producing simvastatin
This invention provides an easy and efficient process for producing a simvastatin of great use as an HMG-CoA reductase inhibitor, which comprises deacylation of lovastatin with an inorganic base and a secondary or tertiary alcohol and subjecting the resulting diol lactone to selective protection with a ketal or acetal protective group, acylation and deprotection-lactonization to give simvastatin.
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(2008/06/13)

Process for producing simvastatin and/or its derivatives
A process for the production of simvastatin and its analogues that is efficient, economical and convenient involves the use of hydroxyl protected intermediates of formula (III) or (VII). These intermediates allow for direct alkylation of the butyrate side chain followed by deprotection and reformation of the lactone ring. R1 is hydrogen or methyl; R2 represents a straight or branched chain alkyl group having 1 to 8 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, or an aralkyl group having 1 to 6 carbon atoms in the alkyl chain; R3 and R4 each independently represent an alkyl group, an ether group, a thioether group, an aryl group, an aralkyl group, an alkenyl group, a cyclic ether group, or a cyclic thioether group; and R5 and R6 each independently represent hydrogen, an alkyl group, an aryl group, an aralkyl group, an alkoxy group, or an ether group.
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(2008/06/13)

A cost-efficient synthesis of simvastatin via high-conversion methylation of an alkoxide ester enolate
A cost-efficient synthesis of simvastatin (2), starting from mevinolin (lovastatin) (la) or its precursor mevinolinic acid (Ib), is reported. This synthesis involves the use of a new intermediate, lovastatin cyclopropylamide (3), eliminating two chemical steps of protection and deprotection of the open dihydroxy form of (la). Synthesis is based on the high-conversion methylation of an alkoxide ester enolate and involves only four chemical steps. Methylation reaction conditions have been optimized to get +~ 99.5% conversion. Process is economical on large-scale and product (2) is obtained in 85% overall yield.
Thaper, Rajesh K.,Kumar, Yatendra,Kumar, S.M. Dileep,Misra, Satyananda,Khanna, Jag Mohan
p. 476 - 479
(2013/09/08)

Process of lactonization in the preparation of statins
A novel process of lactonizaton in the preparation of statins (e.g., the HMG--CoA reductase inhibitors lovastatin and simvastatin) employs very mild reaction conditions. The improved process comprises dissolving the open ring hydroxy acid form of the statins in an organic solvent by heating at a temperature, which ranges from ambient to reflux of the solvent, under anhydrous conditions to produce a solution, treating the solution with a mild catalyst at a temperature from about ambient to 50° C., and adding water to the solution to cause the statins in lactone form to crystalize from the reaction mixture. The mild catalyst used in the reaction is a salt of an organic base with an organic or inorganic acid, such as pyridine hydrobromide, pyridine hydrochloride, or pyridinium, p-toluene sulfonate. The organic solvent comprises a lower alkanol, a non-alcoholic polar solvent, or a mixture of the two.
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(2008/06/13)

Process for preparing 6(R)-{2-8'(S)-2",2"-dimethylbutyryloxy-2'(S)-6'(R)-dimethyl-1',2',6'7',8' 8'A(R)-hexahydronapthyl-1'(S)-ethyl}-4(R)-hydroxy-3,4,5,6-tetrahydro-2H- pyran-2-one
An acylation process using a sulfonic acid, a salt of the sulfonic acid, or a mixture thereof, as a catalyst. Compound 6 is prepared by protecting the 4-hydroxyl group on the pyranone ring of the 8'-hydroxy compound 2 to form a β-protected compound 3, acylating the 8-hydroxy group on the polyhydronaphthyl ring of compound 3 to give protected ester, compound 4, then removing the protecting group, where the compounds 6, 2, 3 and 4 are as described in the specification.
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(2008/06/13)

Process of lactonization in the preparation of statins
An improved process of lactonization in the preparation of statins (e.g., the HMG--CoA reductase inhibitors lovastatin and simvastatin) employs very mild reaction conditions. The improved process comprises treating the open ring hydroxy acid form of the statins with an excess of acetic acid and in the absence of a strong acid catalyst under mild heating conditions (e.g., ambient to 55° C.), and adding an anti-solvent to the reaction mixture, thereby causing the statins in lactone form to crystalize from the reaction mixture. The acetic acid serves as both a solvent and a catalyst for the lactonization reaction.
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(2008/06/13)

Process for manufacturing simvastatin from lovastatin or mevinolinic acid
A process for preparing simvastatin from lovastatin or mevinolinic acid in salt form comprises treating either starting material with cyclopropyl or butyl amine, the pyranone ring thereby being opened when lovastatin is the starting material, adding a methyl group to the 2-methylbutyrate side chain, and thereafter closing the open pyranone ring to produce simvastatin. The process is performed without protecting and deprotecting the two hydroxy groups of the open pyranone ring. In a preferred embodiment, the starting material is treated with cyclopropyl amine which produces simvastatin via the novel intermediate lovastatin cyclopropyl amide.
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(2008/06/13)

Key intermediates in the manufacture of simvastatin
A process for preparing simvastatin from lovastatin or mevinolinic acid in salt form comprises treating either starting material with cyclopropyl or butyl amine, the pyranone ring thereby being opened when lovastatin is the starting material, adding a methyl group to the 2-methylbutyrate side chain, and thereafter closing the open pyranone ring to produce simvastatin. The process is performed without protecting and deprotecting the two hydroxy groups of the open pyranone ring. In a preferred embodiment, the starting material is treated with cyclopropyl amine which produces simvastatin via the novel intermediate lovastatin cyclopropyl amide.
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(2008/06/13)

Process for producing simvastatin and analogs thereof
A process is disclosed for the preparation of simvastatin and its analogs through a novel intermediate (III), which enables a selective α carbon alkylation of the C-8 acyl side chain.
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(2008/06/13)

Synthesis of Synvinolin: Extremely High Conversion Alkylation of an Ester Enolate
An efficient process for the commercial preparation of the therapeutically important cholesterol lowering drug synvinolin (2: simvastatin, ZOCOR) from mevinolin (1: lovastatin, MEVACOR) is reported.The synthesis relies upon deactivation of the δ-lactone carbonyl toward enolization via conversion to the bisbutylamide 7.An extremely high conversion (99.7percent) ester enolate alkylation of 7 affords 8 and 9.Subsequent desilylation and intramolecularly assisted basic amide hydrolysis in the presence of the dimethylbutyrate ester moiety yields 12, which is lactonized to 2.The overall yield from 1 to 2 is 86percent.
Askin, D.,Verhoeven, T. R.,Liu, T. M.-H.,Shinkai, I.
p. 4929 - 4932
(2007/10/02)

Process for the lactonization of mevinic acids and analogs thereof
A process for the lactonization of mevinic acid HMG-CoA reductase inhibitors and analogs thereof is disclosed.
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(2008/06/13)