- FUSED TRICYCLIC KRAS INHIBITORS
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Disclosed are compounds of Formula (I), methods of using the compounds for inhibiting KRAS activity and pharmaceutical compositions comprising such compounds. The compounds are useful in treating, preventing or ameliorating diseases or disorders associated with KRAS activity such as cancer.
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Page/Page column 147-149
(2021/10/22)
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- Preparation method of (R)-6-cyan-5-hydroxy-3-tert-butyl carbonyl hexanoate
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The invention discloses a preparation method of (R)-6-cyan-5-hydroxy-3-tert-butyl carbonyl hexanoate. The preparation method comprises the following steps: under the protection of nitrogen, adding tert-butyl acetate and 1,8-diazabicyclo-undecenoic-7-alkene into 2-methyltetrahydrofuran to prepare a solution A; dissolving (R)-4-cyan-3-ethyl hydroxybutyrate into 2-methyltetrahydrofuran to obtain a solution B; adding the solution A and the solution B into a small amount of 2-methyltetrahydrofuran dropwise, controlling the reaction temperature to be 20 to 30 DEG C, and performing stirring reactionfor 1 to 5 hours after adding the solution A and the solution B dropwise and simultaneously; adding water into the reaction system dropwise, standing and layering; performing reduced-pressure concentration on organic phase to obtain the (R)-6-cyan-5-hydroxy-3-tert-butyl carbonyl hexanoate, recovering a solvent simultaneously, and concentrating aqueous phase to recover the 1,8-diazabicyclo-undecenoic-7-alkene. According to the preparation method, low-temperature liquid nitrogen is not needed, energy consumption is low, dangerous reagents such as metal lithium and sodium are not used, the process is safe, the solvent and the reagents can be recovered after reaction, and environmental friendliness is achieved.
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Paragraph 0022-0023; 0025; 0027
(2018/06/15)
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- PROCESS FOR CROSSED CLAISEN CONDENSATION REACTIONS PROMOTED BY LITHIUM AMIDE IN LIQUID AMMONIA
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The present invention provides a use of lithium amide in liquid ammonia as a base to produce an enolate from at least one ester starting material in a crossed Claisen condensation reaction, wherein at least one ester starting material is a β-hydroxy ester. Also provided is a method of producing lithium amide in situ for use in a crossed Claisen condensation reaction, wherein lithium is added to liquid ammonia, followed by an electron transfer agent, as well as a method of carrying out a crossed Claisen condensation reaction using an ester starting material and a β-hydroxy ester, using lithium amide in liquid ammonia produced in situ.
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Paragraph 0066-0074
(2015/07/22)
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- PROCESS FOR CROSSED CLAISEN CONDENSATION REACTIONS PROMOTED BY LITHIUM AMIDE IN LIQUID AMMONIA
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The present invention provides a use of Iithium amide in liquid ammonia as a base to produce an enolate from at least one ester starting material in a crossed Claisen condensation reaction, wherein at least one ester starting material is a β-hydroxy ester. Also provided is a method of producing lithium amide in situ for use in a crossed Claisen condensation reaction, wherein lithium is added to liquid ammonia, followed by an electron transfer agent, as well as a method of carrying out a crossed Claisen condensation reaction using an ester starting material and a β-hydroxy ester, using lithium amide in liquid ammonia produced in situ.
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Page/Page column 12
(2014/02/15)
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- CONTINUOUS PROCESS FOR THE PRODUCTION OF BETA-KETO ESTERS BY CLAISEN CONDENSATION
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The invention concerns a continuous process for the production of compounds having the general formula (6) comprising providing to a reaction zone a continuous stream of an alkyl acetate and a continuous stream of an alkali metal or alkaline earth metal amide base and contacting the continuous streams together in the reaction zone to yield an enolate compound, providing to the or a separate reaction zone a continuous stream of a compound of formula (5) and contacting the continuous stream of compound (5) with a continuous stream of the enolate in the or the separate reaction zone at a temperature above 20°C to yield an intermediate compound and treating the intermediate compound of formula (1) with an acid to yield the compound of formula (6).
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Page/Page column 14
(2011/05/06)
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- PROCESS FOR THE PRODUCTION OF ATORVASTATIN CALCIUM IN AMORPHOUS FORM
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A process for the production of amorphous atorvastatin calcium and stabilized, amorphous atorvastatin calcium is provided.
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Page/Page column 10-11
(2009/09/07)
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- Synthesis of some impurities and/or degradation products of atorvastatin
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Synthesis of some impurities and/or degradation products of atorvastatin, calcium (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl) pyrrol-1-yl]-3,5-dihydroxyheptanoate, is described. These include its desfluoro analog, the corresponding (3S,5S)-and (3S,5R)-epimers, atorvastatin lactone, and some other potential impurities. The synthesized compounds as well as the corresponding intermediates were characterized by 1H NMR, 13C NMR and MS.
- Stach, Jan,Havlicek, Jaroslav,Placek, Lukas,Radl, Stanislav
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p. 229 - 246
(2008/12/22)
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- COMPOSITIONS AND METHODS FOR PRODUCING STEREOISOMERICALLY PURE STATINS AND SYNTHETIC INTERMEDIATES THEREFOR
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The present disclosure provides ketoreductase enzymes having improved properties as compared to a naturally occurring wild-type ketoreductase enzyme. Also provided are polynucleotides encoding the engineered ketoreductase enzymes, host cells capable of expressing the engineered ketoreductase enzymes, method of using the engineered ketoreductase enzymes to synthesize a variety of chirally pure compounds, and the chirally pure compounds prepared therewith.
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- Process for the production of atorvastatin calcium un amorphous form
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A process for the production of amorphous atorvastatin calcium and stabilized, amorphous atorvastatin calcium is provided.
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Page/Page column 3; 17
(2010/11/30)
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- ENZYMATIC PROCESSES FOR THE PRODUCTION OF 4-SUBSTITUTED 3-HYDROXYBUTYRIC ACID DERIVATIVES AND VICINAL CYANO, HYDROXY SUBSTITUTED CARBOXYLIC ACID ESTERS
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The present invention provides methods and composition for preparing 4-substituted 3-hydroxybutyric acid derivatives by halohydrin dehalogenase-catalyzed conversion of 4-halo-3-hydroxybutyric acid derivatives. The present invention further provides methods and compositions for preparing 4-halo-3-hydroxybutyric acid derivatives by ketoreductase-catalyzed conversion of 4-halo-3ketobutyric acid derivatives. The present invention also provides methods and compositions for preparing vicinal cyano, hydroxyl substituted carboxylic acid esters.
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Page/Page column 63
(2008/06/13)
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- Process for the production of atorvastatin calcium in amorphous form
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A process for the production of amorphous atorvastatin calcium and stabilized, amorphous atorvastatin calcium is provided.
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Page/Page column 5; 9
(2010/02/14)
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- CRYSTALLINE FORM OF ATORVASTATIN HEMI CALCIUM
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The present invention relates to novel crystalline form R of atorvastatin hemi calcium salt and hydrates thereof useful as pharmaceutical agents, to methods for their production and isolation, to pharmaceutical compositions which include novel crystalline form R of atorvastatin hemi calcium salt and hydrates thereof and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment.
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Page/Page column 12
(2010/02/14)
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- The synthesis of (4R-cis)-1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate, a key intermediate for the preparation of CI-981, a highly potent, tissue selective inhibitor of HMG-CoA reductase
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Three alternative methods for the synthesis of the optically active heptanoate (6), a key intermediate in the preparation of a highly potent and tissue selective HMG Co-A reductase inhibitor are described.
- Brower,Butler,Deering,Le,Millar,Nanninga,Roth
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p. 2279 - 2282
(2007/10/02)
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- Process for trans-6-(2-(substituted-pyrrol-1-yl)alkyl)pryan-2-one inhibitors of cholesterol synthesis
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An improved process for the preparation of trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-ones by a novel synthesis is described where 1,6-heptadien-4-ol is converted in eight operations to the desired products, as well as an improved process for the preparation of (2R-trans) and trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N-4-diphenyl-1-[2-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide by a novel synthesis where 4-methyl-3-oxo-N-phenylpentanamide is converted in eight operations to the desired product or alternatively 4-fluoro-α-[2-methyl-1-oxopropyl]-γ-oxo-N,β-diphenylbenzenebutaneamide is converted in one step to the desired product, and additionally, a process for preparing (2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide from (R)-4-cyano-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]butanoic acid, as well as other valuable intermediates used in the processes.
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