- For the preparation of simvastatin method
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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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- Lov-D acyltransferase mediated acylation
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Methods for the improved acylation of chemical substrates using LovD acyltransferases, thioesters having acyl groups, and (i) thiol scavengers and/or (ii) precipitating agents are presented. An improved method for the production of simvastatin using (i) activated charcoal as a thiol scavenger and/or (ii) ammonium hydroxide as a precipitating agent is also presented.
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Page/Page column 26; 27
(2016/08/17)
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- A simvastatin ammonium salt can be used for synthesizing process for the preparation of the acyl donor
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The invention relates to a preparation method of acyl donor capable of synthesizing simvastatin ammonium salt, which comprises the following steps: in a nitrogen protective atmosphere, reacting 2-mercaptoethanol and 2,2-dimethyl butyryl chloride at -5 to +5 DEG C for 2-6 hours, reacting at 20-30 DEG C for 8-12 hours to generate 2,2-dimethylbutyric acid-2-sulfhydrylglycolate, reacting the 2,2-dimethylbutyric acid-2-sulfhydrylglycolate with acetyl chloride at 0-10 DEG C for 2-3 hours, and reacting at 20-30 DEG C for 6-12 hours to generate the simvastatin ammonium salt side chain acyl donor 2,2-dimethylbutyric acid-2-sulfhydrylethoxyglycolate. The method has the advantages of cheap and accessible synthesis raw materials and simple synthesis technique, and is easy to amplify; and the 2-mercaptoethanol is low in boiling point and easy to recycle and reuse, thereby reducing the pollution and further lowering the cost, and thus, the product has high competitive power.
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Paragraph 0044-0047
(2017/05/04)
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- ISOLATION AND RECOVERY OF SIMVASTATIN IN LACTONE FORM OR IN THE FORM OF AN ACID SALT FROM THE HARVESTED FERMENTATION BROTH
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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 10-12
(2009/07/18)
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- ISOLATION AND RECOVERY OF SIMVASTATIN IN LACTONE FORM OR IN THE FORM OF AN ACID SALT FROM THE HARVESTED FERMENTATION BROTH
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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 3; 4
(2009/07/03)
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- New synthesis of simvastatin
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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
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experimental part
p. 4452 - 4459
(2009/04/11)
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- Process for preparing simvastatin and intermediates thereof
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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 12/1
(2010/11/27)
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- PROCESS FOR PREPARING SIMVASTATIN
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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)
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- IMPROVED PROCESS FOR MANUFACTURING STATINS
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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 7
(2010/11/27)
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- PROCESS FOR PREPARING SIMVASTATIN FROM LOVASTATIN AMINE SALTS IN THREE STEPS
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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 6-7
(2008/06/13)
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- METHODS FOR MAKING SIMVASTATIN AND INTERMEDIATES
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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 66-68; 69
(2008/06/13)
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- Processes for the preparation of simvastatin
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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 12-13
(2010/02/14)
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- Process for lactonization to produce simvastatin
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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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- A cost-efficient synthesis of simvastatin via high-conversion methylation of an alkoxide ester enolate
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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
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p. 476 - 479
(2013/09/08)
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- Synthesis of Synvinolin: Extremely High Conversion Alkylation of an Ester Enolate
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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.
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p. 4929 - 4932
(2007/10/02)
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