- α-Unsubstituted Pyrroles by NHC-Catalyzed Three-Component Coupling: Direct Synthesis of a Versatile Atorvastatin Derivative
-
A practical one-pot cascade reaction protocol provides direct access to valuable 1,2,4-trisubstituted pyrroles. The process involves an N-heterocyclic carbene (NHC)-catalyzed Stetter-type hydroformylation using glycolaldehyde dimer as a novel C1 building-block, followed by a Paal-Knorr condensation with primary amines. The reaction makes use of simple and commercially available starting-materials and catalyst, an important feature regarding applicability and utility. Low catalyst loading under mild reaction conditions afforded a variety of 1,2,4-substituted pyrroles in a transition-metal-free reaction with high step economy and good yields. This methodology is applied in the synthesis of a versatile Atorvastatin precursor, in which a variety of modifications at the pyrrole core structure are possible.
- Fleige, Mirco,Glorius, Frank
-
-
Read Online
- An efficient synthesis of highly substituted pyrrole and bis pyrrole derivatives
-
(Chemical Equation Presented) An efficient synthesis of highly substituted pyrrole and bis pyrrole derivatives is reported.
- Sagyam, Rajeshwar Reddy,Vurimidi, Himabindu,Padi, Pratap Reddy,Ghanta, Mahesh Reddy
-
-
Read Online
- Ru-NHC-Catalyzed Asymmetric Hydrogenation of 2-Quinolones to Chiral 3,4-Dihydro-2-Quinolones
-
Direct enantioselective hydrogenation of unsaturated compounds to generate chiral three-dimensional motifs is one of the most straightforward and important approaches in synthetic chemistry. We realized the Ru(II)-NHC-catalyzed asymmetric hydrogenation of 2-quinolones under mild reaction conditions. Alkyl-, aryl- and halogen-substituted optically active dihydro-2-quinolones were obtained in high yields with moderate to excellent enantioselectivities. The reaction provides an efficient and atom-economic pathway to construct simple chiral 3,4-dihydro-2-quinolones. The desired products could be further reduced to tetrahydroquinolines and octahydroquinolones.
- Daniliuc, Constantin,Glorius, Frank,Hu, Tianjiao,Lückemeier, Lukas
-
supporting information
p. 23193 - 23196
(2021/09/25)
-
- Atorvastatin Derived HMG-CoA Reductase Degradation Inducing Compound
-
The present invention relates to a HMG-CoA reductase degradation-inducing compound and, more specifically, to a bifunctional compound in which atorvastatin and E3 ubiquitin ligase binding moiety are chemically linked as HMG-CoA reductase binding moiety, to a production method thereof, to a HMG-CoA reductase degradation method using the same, and to a pharmaceutical composition for preventing or treating HMG-CoA reductase-related diseases, comprising the same.
- -
-
Paragraph 0137; 0364; 0380-0382
(2020/12/01)
-
- Preparation method of atorvastatin calcium isomers
-
The invention relates to a preparation method of atorvastatin calcium isomers [R-(R*,R*)]-2-(3-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-2-phenyl-4-[(aniline)carbonyl]-1H-pyrrole-1-calciumenanthate salt (IMP-1 for short) and [R-(R*,R*)]-3-(2-fluorophenyl)-beta, delta-dihydroxyl -5-(1-Methylethyl)-3-phenyl-4-[(anilino)carbonyl]-1H-pyrrole-1- calcium enanthate salt (IMP-2 for short). According to the preparation method, a preparation method of a reference substance is provided for the quality research of drugs, and an important guiding significance is provided for the safe medicationof atorvastatin calcium.
- -
-
Paragraph 0022-0034; 30051-0052
(2018/09/11)
-
- Preparation method of atorvastatin calcium
-
The invention belongs to the technical field of medicine preparation and particularly relates to a patent application about a novel preparation method of atorvastatin calcium. The method includes steps of preparing intermediates including: 2-methyl-3-carbonyl-methyl pentanoate, 2-methyl-3,5-dicarbonyl-5-anilino-butane, 4-methyl-3-oxo-N-phenyl-2-benzylidene pentanamide, 4-(4-fluorophenyl)-2-(2-methylpropionyl)-4-oxo-N-beta-diphenyl butyrylamide. The preparation method employs cheap and easy-to-obtained raw materials, has simple reactions and operations, and has great industrial application prospect. In conclusion, the preparation method has high reaction efficiency and product yield, is good in repeatability, is suitable for industrial production and has great application value and promotion and application significance.
- -
-
-
- Synthesis of Indoles and Pyrroles Utilizing Iridium Carbenes Generated from Sulfoxonium Ylides
-
Metal carbenes can undergo a myriad of synthetic transformations. Sulfur ylides are potential safe precursors of metal carbenes. Herein, we report cascade reactions that involve carbenoids derived from sulfoxonium ylides for the efficient and regioselective synthesis of indoles and pyrroles. The tandem action of iridium and Br?nsted acid catalysts enables rapid assembly of the heterocycles from unmodified anilines or readily accessible enamines under microwave irradiation. The key mechanistic steps are the catalytic transformation of the sulfoxonium ylide into an iridium–carbene complex, followed by N?H or C?H functionalization of an aniline or enamine, respectively, and a final acid-catalyzed cyclization. The present method was successfully applied to the synthesis of the densely functionalized pyrrole subunit of atorvastatin.
- Vaitla, Janakiram,Bayer, Annette,Hopmann, Kathrin H.
-
supporting information
p. 4277 - 4281
(2017/04/03)
-
- Eco-friendly aftertreatment method of 4-methyl-3-oxo-N-phenylvaleramide
-
The invention discloses an eco-friendly aftertreatment method of 4-methyl-3-oxo-N-phenylvaleramide. The method comprises that methyl isobutyrylacetate and aniline undergo a condensation reaction, then the reaction liquid is subjected to pressure reduction condensation, aniline is recovered, the reaction products crystallize in water, the crystals are filtered and dried so that 4-methyl-3-oxo-N-phenylvaleramide is obtained, residual aniline in the water is recovered and recycled and the crystallization mother liquor is recycled. The method can be operated simply, realizes easy recovery of aniline, has an aniline recovery rate greater than or equal to 90%, only utilizes water, is free of other organic solvents, prevents low-boiling point and toxic organic solvent use and exhaust gas discharge, produces the product with less impurity content of 99.5% and reduces three-waste discharge in the whole process.
- -
-
Paragraph 0014; 0015; 0016; 0017; 0018; 0019; 0020; 0021
(2017/07/01)
-
- COMPOUNDS ACTIVE TOWARDS BROMODOMAINS
-
Disclosed are compounds towards bromodomains, pharmaceutical compositions containing the compounds and use of the compounds in therapy.
- -
-
Page/Page column 292
(2016/05/02)
-
- The total synthesis of calcium atorvastatin
-
A practical and convergent asymmetric route to calcium atorvastatin (1) is reported. The synthesis of calcium atorvastatin (1) was performed using the remote 1,5-anti asymmetric induction in the boron-mediated aldol reaction of β-alkoxy methylketone (4) with pyrrolic aldehyde (3) as a key step. Calcium atorvastatin was obtained from aldehyde (3) after 6 steps, with a 41% overall yield.
- Dias, Luiz C.,Vieira, Adriano S.,Barreiro, Eliezer J.
-
supporting information
p. 2291 - 2296
(2016/03/01)
-
- Efficient Synthesis of the Nucleus of Atorvastatin Calcium
-
An efficient synthetic route for the parent nucleus of atorvastatin calcium was successfully established through the modification of the related reactions. Under the optimized conditions, compound 1 was obtained in 61.2% yield (lit. 51.4%) from methyl isopropyl ketone via five steps. Two impurities generated by the aldol condensation of methyl isopropyl ketone were identified by gas chromatography-mass spectrometry and their generation can be inhibited by reducing the mixing time of methyl isopropyl ketone and NaH. One oxybromination protocol with hydrogen peroxide was employed to make the best of bromine. A debromination by-product was isolated and confirmed by 1H NMR, 13C NMR, and high-resolution mass spectrometry and its generation mechanism was discussed. The impurity can be inhibited by protecting the reaction from light and easily removed by recrystallization.
- Xing, Yuzhi,Chen, Shipeng,Zhou, Yingtao,Liu, Na,Chen, Ligong,Li, Yang
-
p. 2832 - 2840
(2015/12/23)
-
- Highly enantioselective epoxidation catalyzed by cinchona thioureas: Synthesis of functionalized terminal epoxides bearing a quaternary stereogenic center
-
A brilliant debut! Cinchona thioureas have been reported for the first time as catalysts in the area of asymmetric oxidations. They efficiently promote an unprecedented highly enantioselective epoxidation of deactivated 1,1-disubstituted alkenes to terminal epoxides containing a quaternary stereogenic center (see scheme). Copyright
- Russo, Alessio,Galdi, Gerardina,Croce, Gianluca,Lattanzi, Alessandra
-
supporting information; experimental part
p. 6152 - 6157
(2012/06/30)
-
- A PROCESS FOR PREPARATION OF 4-FLUORO-α-[2-METHYL-L-OXOPROPYL]-γ-OXO-N-β-DIPHENYLBENZENE BUTANE AMIDE
-
A process for preparation of 4-fluoro-alpha-[2-methyl-l -oxopropyl]-gama-oxo-N- beta-diphenylbenzene butane amide also known as a diketone intermediate of atorvastatin, completely devoid of impurities 3,4-difluoro-alpha-[2-methyl-l-oxopropyl]-gama-oxo-n-beta-diphenylbenzene butane amide; methyl, 2 {-2[-(4-fluorophenyl)-2-oxo- 1 -phenyl ethyl)] } -4-methyl-3-oxo pentanoate; 1,4-bis(4-fluorophenyl)-2,3-diphenylbutane- 1,4-dione, 1 -(4-fluorophenyl)-2-phenyl ethanone; l-(4-fluorophenyl)-2-phenyl ethanone and containing about 0.05% or less of 2-methyl- l-oxopropyl]-gama-oxo-N-beta- diphenylbenzene butane amide. In that process the said diketone intermediate of formula 1 is obtained by maintaining temperature -25° C to 50° C during Friedel-Crafts acylation, in situ halogenation of formula II in presence of a solvent and nucleophilic substitution from a compound of formula III with formula IV in presence of a base.
- -
-
Page/Page column 21-22
(2012/11/07)
-
- CONDENSED RING PYRIDINE COMPOUNDS AS SUBTYPE-SELECTIVE MODULATORS OF SPHINGOSINE-1-PHOSPHATE-2 (S1P2) RECEPTORS
-
The invention provides compounds represented by the formula I, each of which compounds may have sphingosine-1-phosphate receptor agonist and or antagonist biological activity, wherein these compounds selected from the group consisting of wherein A, B, C, D, X, Y, Z and R3 are defined in the specification. Said compounds are useful for treating a disease or condition of a mammal selected from the group consisting of ocular diseases; systemic vascular barrier related diseases; allergies and other inflammatory diseases; cardiac diseases or conditions; fibrosis; pain and wounds.
- -
-
Page/Page column 37
(2011/04/25)
-
- Enamine-based domino strategy for C-acylation/deacetylation of acetoacetamides: A practical synthesis of -keto amides
-
A practical three-step route for C-acylation/deacetylation of acetoacetamides is described. Initial enamination of the acetoacetamides with Boc-monoprotected ethylenediamine provides β-enamino amides, which are acylated at the -carbon with excellent selectivity. The C-acylated derivatives undergo domino fragmentation in acidic media to give the corresponding β-keto amides accompanied by 2-methyl-4,5-dihydro-1H-imidazole. Georg Thieme Verlag Stuttgart.
- Angelov, Plamen
-
experimental part
p. 1273 - 1275
(2010/07/03)
-
- SYNTHETIC INTERMEDIATES, PROCESS FOR PREPARING PYRROLYLHEPTANOIC ACID DERIVATIVES THEREFROM
-
There are provided intermediates used to prepare a derivative, (3R,5R)-7-[2-(4-fluorphenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-lH-pyrrol-l-yl]-3,5-di hydroxyheptanoic acid, which has an effect to suppress cholesterol in blood, and a process for preparing pyrrolylheptanoic acid derivatives therefrom. In accordance with the present invention, the 5-(4-fluorphenyl)-2-isopropyl-4-phenyl-lH-pyrrole-3-carbonyl derivative is provided as one of the novel synthetic intermediates that are used to prepare pyrrolylheptanoic acid derivatives including a derivative, (3R,5R)-7-[2-(4-fluorphenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-lH-pyrrol-l-yl]-3,5-di hydroxyheptanoic acid. Therefore, the (3R,5R)-7-[2-(4-fluorphenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-lH-pyrrol-l-yl]-3,5-di hydroxyheptanoic acid derivative may be prepared from the carbonyl derivative in a high yield for a short time period under a moderate condition.
- -
-
Page/Page column 9
(2009/08/14)
-
- METHOD FOR THE PREPARATION OF 4-FLUORO-ALPHA-[2-METHYL-1-OXOPROPYL]-y-OXO-N-BETA-DIPHENYLBENZENEBUTANAMIDE AND PRODUCTS THEREFROM
-
A method for the preparation of 4-fluoro-α-[2-methyl-1-oxopropyl]-y-oxo-N-β-diphenylbenzenebutanamide also known as 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-pentanoic acid phenylamide of the formula I containing about 0.1% or less of α-[2-methyl-1-oxopropyl]-γ-oxo-N-p-diphenylbenzene butanamide, about 0.05% or less of difluoro-α-[2-methyl-1-oxopropyl]-y-oxo-N-β-diphenylbenzene butanamide and about 0.1% or less of 3-[2-(4-Fluorophenyl)-2-oxo-1-phenyl-ethoxy]-4-methyl-pent-2-enoic acid phenylamide.
- -
-
Page/Page column 7
(2009/12/23)
-
- NOVEL PROCESS FOR THE PREPARATION OF 4-FLUORO-ALPHA-[2-METHYL -1-OXOPROPYL]-GAMMA-OXO-N-?-DIPHENYLBENZENEBUTANAMIDE AND PRODUCTS THEREFROM
-
A novel process for the preparation of 4-fluoro-α-[2-methyl-1-oxopropyl]-γ-oxo-N-β-diphenylbenzenebutanamide also known as 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-pentanoic acid phenylamide of the formula (I) containing about 0.1% or less of α-[2-methyl-1-oxopropyl]-γ-oxo-N-β-diphenylbenzene butanamide, about 0.05 % or less of difluoro -α-[2-methyl-1-oxopropyl]-γ-oxo-N-β-diphenylbenzene butanamide and about 0.1% or less of 3-[2-(4-Fluorophenyl)-2-oxo-1-phenyl-ethoxy]-4-methyl-pent-2-enoic acid phenylamide.
- -
-
Page/Page column 19
(2009/12/27)
-
- SUBSTITUTED PYRROLE DERIVATIVES AS HMG-COA REDUCTASE INHIBITORS
-
The present invention relates to substituted pyrrole derivatives of Formula (I), wherein (Y), with the proviso that one of R2, R4 and R5 is a heterocycle and with the further provision that if R2 is not a heterocycle then either R4 or R5 alone is not unsubstituted pyridyl, which can be used as 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors. Compounds disclosed herein can function as cholesterol lowering agents and can be used for the treatment of cholesterol-related diseases and related symptoms. Processes for the preparation of disclosed compounds are provided, as well as pharmaceutical compositions containing the disclosed compounds, and methods of treating cholesterol-related diseases and related symptoms.
- -
-
-
- SUBSTITUTED PYRROLE DERIVATIVES
-
The present invention relates to substituted pyrrole derivatives, which can be used as 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors. Compounds disclosed herein can function as cholesterol lowering agents and can be used for the treatment of cholesterol-related diseases and related symptoms. Processes for the preparation of disclosed compounds are provided, as well as pharmaceutical compositions containing the disclosed compounds, and methods of treating cholesterol-related diseases and related symptoms.
- -
-
-
- Synthesis of deuterium-labeled atorvastatin and its metabolites for use as internal standards in a LC/MS/MS method developed for quantitation of the drug and its metabolites in human serum
-
D5-labeled isotopomers of atorvastatin, atorvastatin lactone and its hydroxy metabolites were synthesized as internal standards for use in a LC/MS/MS method developed for the simultaneous quantitative determination of atorvastatin and its hydroxy metabolites in human serum. d5-Atorvastatin and d5-atorvastatin lactone were prepared from d5-aniline whereas their corresponding hydroxy metabolites were synthesized using d5-benzaldehyde.
- Chen, Bang-Chi,Sundeen, Joseph E.,Guo, Peng,Bednarz, Mark S.,Hangeland, Jon J.,Ahmed, Syed Z.,Jemal, Mohammed
-
p. 261 - 270
(2007/10/03)
-
- Process for the synthesis of protected esters of (S)-3,4-dihydroxybutyric acid
-
The invention is an improved process for the preparation of a compound of formula I wherein R and R1 are each independently alkyl of from 1 to 3 carbon atoms; and R2 is alkyl of from 1 to 8 carbon atoms. STR1
- -
-
-
- Process for the synthesis of (4R-cis)-1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate
-
An improved process for the preparation of (4R-cis)-1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate is described where a hydroxy ester derivative is converted in two steps to the desired product, as well as valuable intermediates used in the process.
- -
-
-
- Process for the synthesis of (5R)-1,1-dimethylethyl-6-cyano-5-hydroxy-3-oxo-hexanoate
-
An improved process for the preparation of (5R)-1,1-dimethylethyl-6-cyano-5-hydroxy-3-oxo-hexanoate is described where a halo hydroxyester or other activated dihydroxyester is converted in two steps to the desired product.
- -
-
-
- Process for trans-6-(2-(substituted-pyrrol-1-yl)alkyl)pryan-2-one inhibitors of cholesterol synthesis
-
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.
- -
-
-
- 7(1H-pyrrol-3-YL)-substituted 3,5-dihydroxyhept-6-enoic acids, 7-(1H-pyrrol-3-YL)-substituted 3,5-dihyroxyhept-anoic acids, their corresponding delta-lactones and salts, their use as medicaments and pharmaceutical products and intermediates
-
7-[1H-pyrrol-3-yl]-substituted 3,5-dihydroxyhept-6-enoic acids, 7-[1H-pyrrol-3-yl]-substituted 3,5-dihydroxyheptanoic acids of the formula I STR1 in which A, B, R1, R2, R3, R4 and R5 have the indicated meanings, and the corresponding δ-lactones of the formula II STR2 processes for the preparation of these compounds, their use as medicaments and pharmaceutical products are described. In addition, new intermediates for the preparation of the compounds of the formulae I and II are described.
- -
-
-
- Synthesis and Biological Activity of New HMG-CoA Reductase Inhibitors. 2. Derivatives of 7-(1H-Pyrrol-3-yl)-substituted-3,5-dihydroxyhept-6(E)-enoic (-heptanoic) Acids
-
A series of 7-(1H-pyrrol-3-yl)-substituted-3,5-dihydroxyhept-6(E)-enoates (-heptanoates) 1 and 2 have been prepared and tested for inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase.The most potent compounds exceeded mevinolin's activity in vitro and in vivo.
- Jendralla, H.,Baader, E.,Bartmann, W.,Beck, G.,Bergmann, A.,et al.
-
-