cas 124752-23-4, tert-Butyl (4R-cis)-6-formaldehydel-2,2-dimethyl-1,3-dioxane-4-acetate

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A new way to tert-Butyl [(4R,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate, a key intermediate of atorvastatin synthesis
A new synthesis of tert-butyl [(4R,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate, a key intermediate of the synthesis of an effective HMG-CoA reductase inhibitor atorvastatin, is described. The synthesis is based on the Henry reaction of nitromethane and tert-butyl [(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl] acetate. The formed nitroaldol was then O-acetylated and the sodium borohydride reduction of the intermediate provided tert-butyl [(4R,6R)-2,2-dimethyl-6-nitroethyl-1,3-dioxan-4-yl] acetate. Catalytic hydrogenation of the nitro group led to the title compound.
Radl, Stanislav
p. 2275 - 2283
(2003)
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Preparation method of rosuvastatin calcium intermediate
The invention belongs to the technical field of medicinal chemistry and relates to the technical field of drug synthesis, particularly to a preparation method of a high-purity rosuvastatin calcium intermediate. The preparation method of the high-purity rosuvastatin calcium intermediate comprises controlling reaction PH and temperature and applied amount of sodium hypochlorite to control the content of impurities in the high-purity rosuvastatin calcium intermediate shown as the formula I', thereby improving the yield and purity of finished products. The content of impurity compound I' in the high-purity rosuvastatin calcium intermediate prepared through the method is lower than 0.05%. The preparation method of the high-purity rosuvastatin calcium intermediate is highly significant to quality improvement of industrialized production products of the high-purity rosuvastatin calcium intermediate, and further achieves certain assisting and supporting effects on quality improvement as well as registration and declaration of rosuvastatin calcium drugs.
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Paragraph 0033-0049

(2021/07/08)

Method for preparing rosuvastatin side chain through oxidation in continuous flow micro-channel reactor
The invention relates to a method for preparing a rosuvastatin side chain through oxidation in a continuous flow micro-channel reactor. In the micro-channel reactor, a compound D6 is oxidized by sodium hypochlorite to synthesize a compound D7; the reaction flow is shown in the specification. The method solves the problems that existing preparation methods are long in reaction time, high in requirements on reaction condition, incapable of continuous product, high in cost and the like. The method has the advantages of simplicity and safety in operation, short reaction time, high product conversion rate, high product purity and the like, materials after reaction can be directly subjected to aftertreatment operation, aftertreatment is simple, the product yield is 92% or above, the product purity is 99.8%, and the method is particularly suitable for industrial large-scale production.
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Paragraph 0042-0089

(2020/08/12)

Preparation method of rosuvastatin side chain intermediate
The invention belongs to the technical field of medicines, and particularly provides a preparation method of a rosuvastatin side chain intermediate. The method comprises the following steps: (1) dissolving a compound I, an oxidation catalyst and a phase transfer catalyst in an organic solvent A, respectively adding a buffer solution of alkali and an oxidant, and reacting to obtain a compound II; and (2) dissolving the compound II crude product in an organic solvent B, heating for dissolving, adding purified water, separating out a solid, filtering and drying to obtain a compound II refined product. The yield of the rosuvastatin side chain intermediate prepared by the technology is higher than 95%, the HPLC purity is higher than 99.70%, and the generated carboxylic acid impurity is lower than 0.2%. The method has the advantages of mild reaction conditions, no need of ultralow temperature, no water and other harsh reaction conditions, no foul gas generation in the reaction process, environmental protection, easy amplification generation, easy realization of the reaction temperature, and facilitation of industrial production.
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Paragraph 0047-0063; 0079-0082; 0086-0087

(2020/08/30)

Rosuvastatin calcium intermediate, preparation method thereof and application of intermediate
The invention discloses a rosuvastatin calcium intermediate, a preparation method thereof and an application of the intermediate. The synthesis process of the intermediate is environmentally friendly,simple and convenient to operate and low in EHS (environment health safety) risk, raw materials are easily available, and used chemical reagents are low in toxicity and low in price, so that the synthesis process of the intermediate is a green synthesis process suitable for industrial production. In addition, the intermediate is applied to synthesis of rosuvastatin calcium and key intermediates thereof, has short route and high yield, effectively reduces the industrial production cost of rosuvastatin calcium, and has a higher industrial application prospect.
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(2019/04/17)

A method for preparing a rosuvastatin calcium intermediate
The invention relates to the technical field of pharmaceutical chemistry, particularly the field of process optimization and cost control for pharmaceutical intermediate preparation, and more particularly relates to an impurity in preparation of a rosuvastatin calcium intermediate and a method for synthesizing the intermediate from the impurity. A compound I' is reacted with ozone and a reductantto obtain a compound IV and an important intermediate III, the compound IV is further subjected to reduction and substitution to prepare another intermediate II important in preparation of the rosuvastatin calcium intermediate, and the compound II and the compound III are adopted to prepare an intermediate compound I. Through recovery and utilization of the impurity compound I', the preparation cost of the compound I is significantly reduced. The method is simple in process and suitable for industrial large-scale production.
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Paragraph 0023; 0027

(2019/01/08)

A novel process for synthesis of Rosuvastatin
A novel process for the preparation of antihypercholesterolemic drug rosuvastatin calcium using novel intermediates has been described. Novel intermediates have been characterized by using IR, NMR and Mass spectroscopy.
Nagender Rao,Reddy, Reguri Buchi,Mukkanti,Konda, Venu
p. 1018 - 1022
(2017/03/22)

Method for preparing solid (4R-cis)-6-formyl-2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate
The invention discloses a method for preparing solid (4R-cis)-6-formyl-2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate and belongs to the pharmaceutical and chemical field. The method includes the following steps that a compound III is dissolved in a mixed solvent of methanol and water, potassium carbonate is added for hydrolysis, potassium carbonate is filtered out and removed, methanol is removed through distillation, an organic solvent is added, and an organic solvent solution of a compound II is obtained after washing; secondly, TEMPO, potassium bromide and sodium bicarbonate are added, stirred, mixed and cooled, then a sodium hypochlorite solution is added dropwise, stirring reaction is carried out, after reaction, a sodium thiosulfate solution is quenched, washed, dried and condensed, and a crude product of a compound I is obtained; thirdly, an organic solvent is added, cooled and stirred after being heated and dissolved and is crystallized and filtered to obtain solid crystal of the compound I. The preparation method is safe, environmentally friendly, easy and convenient to operate, high in yield, high in purify and capable of facilitating large-scale production.
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Paragraph 0066; 0067; 0068

(2016/12/07)

A 2 - ((4R, 6S) - 6-formyl -2,2-di-substituted -1,3-dioxane-4-yl) ethyl ester preparation method
The invention relates to a simple and convenient preparation method of 2-((4R,6S)-6-formyl-2,2-disubstituted-1,3-dioxane-4-yl)acetate. The 2-((4R,6S)-6-formyl-2,2-disubstituted-1,3-dioxane-4-yl)acetate has a structure shown in a formula I. The preparation method comprises the following steps: by taking butadiene and 3,3-dialkyloxypropionate or 3-alkyloxyacrylate as raw materials, cyclizing under the catalysis of lewis acid to substitute benzaldehyde to form cyclic protection, then hydrolyzing and performing cyclization reaction with corresponding aldehyde (ketone) or dimethylacetal and diethylacetal thereof to prepare the 2-((4R,6S)-6-vinyl-2,2-disubstituted-1,3-dioxane-4-yl)acetate, and then preparing I through three-step reaction of vinyl ozonization. The preparation method is easily available in raw materials, and short in reaction process, a chiral center is constructed by utilizing the stabilization form of an equatorial bond of a hexatomic ring chair type structure, a flammable and combustible asymmetric reducer is not used, and the preparation method is simple and convenient and environment-friendly, and suitable for industrial production of chiral side chains of statins.
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Paragraph 0068; 0081; 0086; 0087

(2017/02/24)

Stereoselective reduction of δ-hydroxy β-ketoesters to syndiol in achiral micellar system
A novel, efficient and stereo-selective process for synthesis of statin side chain, a key intermediate for statin type cholesterol lowering drugs such as Lipitor (atorvastatin) and Crestor (rosuvastatin) in achiral micellar media is reported. The key feature of this process is sodium borohydride reduction of δ-hydroxy β-ketoester in achiral micellar system in 92% de, thereby avoiding metal chelation methods which employ triakylborane, titanium (IV) isopropoxide or cerium (III) chloride prior to reduction.
Roy, Bhairab Nath,Singh, Girij Pal,Lathi, Piyush Suresh,Agrawal, Manoj K,Mitra, Rangan
p. 1247 - 1251
(2015/11/24)

T-butyl type 2-[ (4R, 6S)-6-formylbenzoate -2, 2-dimethyl -1, 3-Dioxian-4-yl] acetate and its manufacturing method
The present invention provides a crystalline t-butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4-yl]acetate and a preparation method therefor.
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Paragraph 0041

(2016/12/16)

Process for the preparation of (E)-tert-butyl-2-(6-(2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl,methylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate as a rosuvastatine intermediate
The present invention relates to a method for manufacturing (E)-tert-butyl-2-(6-(2-(4-(4-fluorophenyl)-6-isopropy l-2-(N-methyl,methylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl) acetate as rosubastatine intermediate that is frequently used for treating hyperlipidemia. According to the method for manufacturing in the present invention, (E)-tert-butyl-2-(6-(2-(4-(4-fluorophenyl)-6-isopropy-2-(N-methyl,methylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl) acetate as a rosubastatine intermediate made of solid with high and consistent purity can be mass-produced by using t-butyl 2-((4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4yl) acetate having optical activation in the form of solid with high purity.
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Paragraph 0114-0115

(2016/12/26)

Ni/Cu-Catalyzed Defluoroborylation of Fluoroarenes for Diverse C-F Bond Functionalizations
Ni/Cu-catalyzed transformation of fluoroarenes to arylboronic acid pinacol esters via C-F bond cleavage has been achieved. Further versatile derivatization of an arylboronic ester has allowed for the facile two-step conversion of a fluoroarene to diverse functionalized arenes, demonstrating the synthetic utility of the method.
Niwa, Takashi,Ochiai, Hidenori,Watanabe, Yasuyoshi,Hosoya, Takamitsu
supporting information
p. 14313 - 14318
(2015/11/27)

A NOVEL, GREEN AND COST EFFECTIVE PROCESS FOR SYNTHESIS OF TERT-BUTYL (3R,5S)-6-OXO-3,5-DIHYDROXY-3,5-O-ISOPROPYLIDENE-HEXANOATE
The present invention provides a process of preparation of an intermediate useful for the preparation of statins more particularly the present invention relates to an eco-friendly and cost effective process for the preparation of tert -butyl (3R,5S)-6-oxo-3,5-dihydroxy- 3,5-O-isopropylidene-hexanoate [I].
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Page/Page column 45; 46

(2015/01/07)

NOVEL INTERMEDIATES FOR THE PREPARATION OF HMG-CoA REDUCTASE INHIBITORS
The present invention provides a process for preparing novel intermediates of Formula wherein, R1 can be hydrogen, C1-C4 alkyl, halogen, nitro, hydroxy, or C1-C4 alkoxy; Rx can be selected from hydrophobic residue of HMG-CoA reductase inhibitors; which can be effectively used for the preparation of HMG-CoA reductase inhibitors such as rosuvastatin and pharmaceutically acceptable salts thereof.
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Paragraph 0063

(2013/06/27)

Process For The Preparation Of Amide Intermediates And Their Use Thereof
The present invention relates to an improved process for the preparation of amide intermediates useful in the preparation of cholesterol reducing agents.
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Page/Page column 15

(2013/02/27)

NOVEL PYRIMIDINE DERIVATIVE AND METHOD FOR PRODUCING HMG-CoA REDUCTASE INHIBITOR INTERMEDIATE
The problem to be solved of the present application is to provide a method for producing a novel pyrimidine derivative from an inexpensive compound which is industry-available with ease, and a method for producing an important intermediate of an HMG-CoA reductase inhibitor. The problem can be solved by, for example, reacting the compound (1) with the compound represented by (OR1) 3P to obtain the phosphonate ester (3) and reacting the phosphonate ester (3) with the compound (4) in the presence of a base to obtain an HMG-CoA reductase inhibitor intermediate (5).
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Page/Page column 9-10

(2011/08/08)

IMPROVED PROCESS FOR THE PREPARATION OF AMIDE INTERMEDIATES AND THEIR USE THEREOF
The present invention relates to an improved process for the preparation of amide intermediates useful in the preparation of cholesterol reducing agents.
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Page/Page column 35

(2011/08/04)

A PROCESS FOR THE PREPARATION OF INTERMEDIATES OF ROSUVASTATIN
The present invention provides a process for the preparation of the rosuvastatin intermediates and their conversion to rosuvastatin or its pharmaceutically acceptable salts thereof.
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Page/Page column 12; 18; 23

(2008/12/05)

Development of a practical synthesis of novel, pyrrole-based HMG-CoA reductase inhibitors
This paper describes the development of an efficient and scalable second generation synthesis of novel, pyrrole-based HMG-CoA reductase inhibitors. Compound 1 was identified as part of a discovery program aimed at finding improved treatments for hypercholesterolemia. Herein, we describe an efficient synthesis of its highly functionalized pyrrole core followed by attachment of the 3,5-dihydroxyhexanoic acid side chain via ylide olefination chemistry.
Pfefferkorn, Jeffrey A.,Bowles, Daniel M.,Kissel, William,Boyles, David C.,Choi, Chulho,Larsen, Scott D.,Song, Yuntao,Sun, Kuai-Lin,Miller, Steven R.,Trivedi, Bharat K.
p. 8124 - 8134
(2008/02/08)

Processes to produce intermediates for rosuvastatin
Intermediate compounds for preparing rosuvastatin are prepared by a process comprising oxidizing hydroxy groups to aldehyde groups, using sodium hypochlorite and 2,2,6,6-tetramethyl piperidinyl oxy free radical (TEMPO) as a catalyst.
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Page/Page column 2-3

(2008/06/13)

N-ALKYL PYRROLES AS HMG-COA REDUCTASE INHIBITORS
HMGCo-A reductase inhibitor compounds useful as hypocholesterolemic and hypolipidemic compounds are provided. Also provided are pharmaceutical compositions of the compounds. Methods of making and methods of using the compounds are also provided. Formula (I).
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Page/Page column 52; 145-146

(2010/02/12)

Synthesis of artificial HMG-CoA reductase inhibitors based on the olefination strategy
Synthetic methods were studied for optically active 6-oxo-3,5-isopropylidenedioxyhexanoate esters (4), which could be used as a key precursor of various kinds of artificial analogs of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. An enantiomer (+)-4 was prepared by asymmetric reduction of β,δ-diketo esters derived from the Taber's alcohol or L-tartrate followed by a series of chemical transformations, and the desired enantiomer (-)-4 was prepared by the same asymmetric reduction starting from D-tartrate. The key intermediate (-)-4 was finally converted into a highly potent HMG-CoA reductase inhibitor, NK-104.
Hiyama,Minami,Takahashi
p. 364 - 372
(2007/10/02)

STEREOSELECTIVE REDUCTION OF β,δ-DIKETO ESTERS DERIVED FROM TARTARIC ACID. A FACILE ROUTE TO OPTICALLY ACTIVE 6-OXO-3,5-syn-ISOPROPYLIDENEDIOXYHEXANOATE, A VERSATILE SYNTHETIC INTERMEDIATE OF ARTIFICIAL HMG Co-A REDUCTASE INHIBITORS.
Reduction of β,δ-diketo esters derived from tartaric acid with HAl(i-Bu)2 gave stereoselectively β-hydroxy-δ-keto esters which were reduced with NaBH4 and Et2BOMe to β,δ-syn-dihydroxy esters.This strategy was successfully applied to the synthesis of t-butyl (3R,5S)-6-oxo-3,5-isopropylidenedioxyhexanoate starting from D-tartrate.
Minami, Tatsuya,Takahashi, Kyoko,Hiyama, Tamejiro
p. 513 - 516
(2007/10/02)

Synthesis, biological profile, and quantitative structure - Activity relationship of a series of novel 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors
A series of 9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(alkyltetrazol-5-yl)-6,8-nonad ienoic acid derivatives 1 were synthesized and found to inhibit competitively the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. The analogues having 1N-methyltetrazol-5-yl attached to the C8-position (3a, 4a, R1 = R2 = F) are the most active in suppressing cholesterol biosynthesis in both in vitro and in vivo models: the IC50 for the chiral form of 3a is 19 nM, K(i) = 4.3 x 10-9 M when K(m) for HMG-CoA is 28 x 10-6 M; the ED50 (oral) value corresponding to the lactone derivative (4a, BMY 22089) is approximately 0.1 mg/kg. Further, BMY 21950 is nearly 2 orders of magnitude more active in parenchymal hepatocytes, from which most of the serum cholesterol originates, than in other cell preparations (such as spleen, testes, ileum, adrenal, and ocular lens epithelial cells; Table III). This apparent tissue specificity may be highly beneficial since the blocking of cholesterol biosynthesis in other vital organs could eventually lead to undesirable side effects. In addition to the chemical synthesis and biological evaluation, a theoretical study aimed at relating the HMG-CoA reductase inhibitory potency to the three-dimensional structure of the inhibitors was undertaken. With a combination of molecular mapping and 3D-QSAR techniques, it was possible to determine a logical candidate for the conformation of the bound inhibitor and to quantitatively relate inhibitory potency to the shape and size of both the binding site and the C8-substituent.
Sit,Parker,Motoc,Han,Balasubramanian,Catt,Brown,Harte,Thompson,Wright
p. 2982 - 2999
(2007/10/02)

Stereoselective synthesis of HR 780 a new highly potent HMG-CoA reductase inhibitor
HR 780 (1) a new HMG-CoA reductase inhibitor has been synthesized stereoselectively starting from L-malic acid. Wittig olefination employing phosphonium halides, phosphonates and phosphane oxides have been investigated.
Wess,Kesseler,Baader,Bartmann,Beck,Bergmann,Jendralla,Bock,Holzstein,Kleine,Schnierer
p. 2545 - 2548
(2007/10/02)

Optically active 3-demethylmevalonic acid derivatives, and intermediates
A process for the preparation of optically active 3-de-methylmevalonic acid derivatives, and intermediates A process for the preparation of optically active 3-de-methylmevalonic acid derivatives of the formula I STR1 (3,5-dihydroxy carboxylic acid derivatives) or of the formula II STR2 (β-hydroxy lactones) in which R, R1 and Y have the indicated meanings, is described. The invention furthermore relates to aldehydes of the formula XII STR3 in which M represents the indicated protective groups. The 3-demethylmevalonic acid derivatives of this invention are useful for lowering cholesterol levels of a host.
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(2008/06/13)