- 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.
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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
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Read Online
- A novel process for synthesis of Rosuvastatin
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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
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Read Online
- Preparation method of rosuvastatin calcium intermediate
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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 0050-0060
(2021/07/08)
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- Preparation method of rosuvastatin calcium intermediate
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Preparation method of rosuvastatin calcium intermediateTo the preparation method of the compound CL - 9, the compound CL - 8 is subjected to organic alkali treatment to obtain the compound CL - 9. The compound CL - 9 prepared through the route has the advantages of high yield, high purity, controllable impurities, suitability for industrial production and the like.
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Paragraph 0040-0047
(2021/11/21)
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- Efficient and Practical Deacylation Reaction System in a Continuous Packed-Bed Reactor
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The ester deacylation reaction is widely applied in organic synthesis for preparing desired hydroxy compounds, as the acyl group is often used for protecting the hydroxyl group. This reaction is usually performed by acid, base, or enzyme catalysts, which have to be removed by complicated workups such as extraction or filtration in batch mode. Therefore, a simple deacylation process is desirable to improve productivity, especially at the industrial scale. In this work, we established an efficient and practical packed-bed reactor system for undertaking the deacylation reaction using an anion-exchange resin that provides a simple process compared with batch processing. We also demonstrated that this technique is applicable to the preparation of a wide variety of desired pharmaceutical intermediates containing hydroxy groups in good to excellent yields.
- Yasukouchi, Hiroaki,Machida, Koji,Nishiyama, Akira,Mitsuda, Masaru
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supporting information
p. 654 - 659
(2019/04/01)
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- Synthesis method of rosuvastatin calcium side chain key intermediate
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The invention discloses a synthesis method of a rosuvastatin calcium side chain key intermediate and provides a preparation method of the rosuvastatin calcium side chain key intermediate. (S)-2-(epoxypropane-2-yl)methyl acetate is taken as a starting material and subjected to a condensation reaction, a ring opening reaction, a reduction reaction, a hydroxyl group protecting reaction and a debenzylation reaction. The method is simple and convenient to operate, easy in separation and purification, higher in yield and capable of obtaining the intermediate with higher chemical purity and optical purity.
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Paragraph 0045; 0046
(2018/04/28)
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- Preparation method of rosuvastatin calcium medicine intermediate
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The invention belongs to the technical field of medicine chemicals, and particularly relates to a preparation method of a rosuvastatin calcium medicine intermediate. The preparation method comprises the following steps of using monochloroacetaldehyde as the raw material; substituting, condensing, and chirally catalyzing, so as to prepare a compound V; protecting by 2,2-dimethoxypropane, and debenzylating, so as to obtain a target compound I. The preparation method has the advantages that the raw materials are easy to obtain; (S)-5-benzyl-2,2,3-trimethyl-4-thioketone is used as a catalyst for stereo selective reduction, the reaction conditions are mild, the yield rate is higher, and the industrialization production of the component I is easy.
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Paragraph 0029; 0042; 0045; 0050; 0051; 0056
(2018/11/03)
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- Method for preparing heptenoic acid cyclopentyl ester derivative
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The invention discloses a method for preparing a heptenoic acid cyclopentyl ester product by taking (4R-cis)-6-[(acetoxy)methyl]-2,2-dimethyl-1,3-dioxane-4-tert butyl acetate as an initial raw material, and the product is prepared through steps of hydrolysis, replacement and oxidation. The synthesis step is simple, an intermediate can be subjected to a next reaction without refining and purifying steps, for a butt-coupling reaction, the conventional mild technology condition can replace ultralow temperature reaction condition, superbase with high danger is simultaneously replaced, reaction security is increased, the route total yield is high, and the method is suitable for large-scale industrial production.
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Paragraph 0018; 0023; 0028
(2017/04/25)
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- PROCESSES FOR THE PREPARATION OF ROSUVASTATIN OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
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The present invention relates to processes for the preparation of rosuvastatin calcium of formula I and pharmaceutically acceptable salts thereof using novel intermediates, and to a pharmaceutical composition containing the same.
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Page/Page column 25-26
(2016/09/22)
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- Method for preparing solid (4R-cis)-6-formyl-2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate
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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 0061; 0062; 0063; 0064; 0065
(2016/12/07)
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- Stereoselective reduction of δ-hydroxy β-ketoesters to syndiol in achiral micellar system
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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
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p. 1247 - 1251
(2015/11/24)
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- A NOVEL, GREEN AND COST EFFECTIVE PROCESS FOR SYNTHESIS OF TERT-BUTYL (3R,5S)-6-OXO-3,5-DIHYDROXY-3,5-O-ISOPROPYLIDENE-HEXANOATE
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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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- Ru-catalyzed asymmetric hydrogenation of γ-heteroatom substituted β-keto esters
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A series of enantiomerically pure γ-heteroatom substituted β-hydroxy esters were synthesized with high enantioselectivities (up to 99.1% ee) by hydrogenation of γ-heteroatom substituted β-keto esters in the presence of Ru-(S)-SunPhos catalyst. These asymmetric hydrogenations provide key building blocks for a variety of naturally occurring and biologically active compounds.
- Fan, Weizheng,Li, Wanfang,Ma, Xin,Tao, Xiaoming,Li, Xiaoming,Yao, Ying,Xie, Xiaomin,Zhang, Zhaoguo
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experimental part
p. 9444 - 9451
(2012/01/13)
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- Efficient synthesis of (3R,5S)-3,5,6-trihydroxyhexanoic acid derivative as a chiral side chain of statins
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Efficient synthesis of tert-butyl [(3R,5S)-6-hydroxy-methyl-2,2-dimethyl-1, 3-dioxan-4-yl]acetate (1) has been accomplished. Unprecedented hydration of 3 in the presence of lithium chloride provided 4a,b, the primary hydroxyl group of which reacted with pivaloyl- and 1-naphthoyl chloride, respectively, in pyri-dine to give 7a or 7d in improved selectivity. Diastereoselective reduction of 7a and protection-deprotection sequence provided 1.
- Choi, Hyeong-Wook,Shin, Hyunik
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experimental part
p. 1523 - 1525
(2009/04/07)
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- A new and facile preparation of tert-butyl (3R,5S)-6-hydroxy-3,5-O-isopropylidene-3,5-dihydroxyhexanoate
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A facile method for the preparation of tert-butyl (3R,5S)-6-hydroxy-3,5-O-isopropylidene-3,5-dihydroxyhexanoate is described by a chemoenzymatic approach. In this method, one hydroxyl stereocenter at C5 is obtained with a high ee value (up to 98.0%) via an enzymatic transesterification resolution of l-chloro-3-(4-methylbenzyloxy)-2-propanol. The other hydroxyl stereocenter at C3 was built with 98.0% de, by acid-hydrolysis of a 1,3-diol-acetonide syn/anti-10. It is noteworthy that the reduction of β-hydroxy ketone 8 with sodium borohydride can be carried out smoothly in aqueous isopropyl alcohol with a high diastereomeric ratio syn/anti (drs:a) of 4.0:1.
- Sun, Fenglai,Xu, Gang,Wu, Jianping,Yang, Lirong
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p. 2454 - 2461
(2008/03/13)
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- PROCESS FOR PREPARING OPTICALLY ACTIVE 2- 6-(HYDROXY-METHYL)-1,3-DIOXAN-4-YL]ACETIC ACID DERIVATIVES
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The present invention is to provide a production technology by which an optically active 2-[6-(hydroxymethyl)-1,3-dioxan-4-yl]acetic acid derivative, which are of value as pharmaceutical intermediates, can be produced from inexpensive and readily available starting materials without using any extraordinary equipment such as an ultra-low-temperature reactor. The present invention is a production process of an optically active 2-[6-(hydroxymethyl)-1,3-dioxan-4-yl]acetic acid derivative ???which comprises reacting an enolate, prepared by permitting a base or a 0-valent metal to act on an acetic acid ester derivative with (S)-β-hydroxy-γ-butyrolactone at a temperature not lower than -30°C to give a dihydroxyoxohexanoic acid derivative, ???treating the same with an acylating agent in the presence of a base to produce a dihydroxyoxohexanoic acid monoacyl derivative, ???reducing this compound with a microorganism to produce a trihydroxyhexanoic acid monoacyl derivative, ???treating this compound with an acetal-forming reagent in the presence of an acid catalyst to produce an acyloxymethyldioxanylacetic acid derivative, and ???finally, subjecting this compound to solvolysis in the presence of a base.
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- Synthesis of artificial HMG-CoA reductase inhibitors based on the olefination strategy
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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
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p. 364 - 372
(2007/10/02)
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- Practical large scale synthesis of tert-butyl (3R,5S)-6-hydroxy-3,5-O-isopropylidene-3,5-dihydroxyhexanoate: Essential building block for HMG-CoA reductase inhibitors
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Title compound 7 (96% ee, > 98% de) is synthesized enantioselectively in six steps (36% overall yield) from the commercial β-keto ester 8 on a multi-kg scale.
- Beck,Jendralla,Kesseler
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p. 1014 - 1018
(2007/10/02)
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- Process for preparing tert-butyl (3R,5S)-6-hydroxy-3,5--O--isopropylidene-3,5-dihydroxyhexanoate
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A novel process is described for preparing tert-butyl (3R, 5S ) 6-hydroxy-3,5-O-isopropylidene-3,5-dihydroxyhexanoate of the formula I STR1 which is a valuable structural element for preparing inhibitors of HMG-CoA reductase.
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- Process for the preparation of 1,3-dioxane derivatives useful in the preparation of HMG-COA reductase inhibitors
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A novel, overall process for the preparation of a compound of the formula I: STR1 where R1 and R2 are each independently hydrogen, an alkyl group, a cycloalkyl group, an aryl group or, taken together with the carbon atom to which they are attached, form a cycloalkyl group; and R3 is hydrogen, an alkyl group, or an aryl group, or salts thereof, useful as intermediates in the preparation of HMG-CoA reductase inhibitors; novel methods within the overall process; and novel intermediates produced by those methods.
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- 2,4-DIHYDROXYADIPIC ACID DERIVATIVE
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A novel 2,4-dihydroxyadipic acid derivative of the formula: STR1 wherein R1 and R4 are the same or different and each a hydrogen atom, an alkyl group, an aralkyl group, an aryl group or a silyl group, and R2 and R3 are the same or different and each a hydrogen atom or a protective group of a hydroxy group or together form a ring, which is useful as a common intermediate in the synthesis of HMG-CoA reductase inhibitor
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- 2,4,6-substituted phenol derivatives
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A 2,4,6-substituted phenol having the formula (I): STR1 wherein X is S or CH2 ; R1 and R2 are the same or different from each other and each is a lower alkyl group; R3 is a group of the formula: STR2 in which R4 is hydrogen atom or a lower alkyl group; R5 and R6 are the same or different from each other and each is hydrogen atom, a lower alkyl group, or a phenyl group which may be substituted, or a pharmaceutically acceptable salt thereof is useful as an active agent in a pharmaceutical composition. The pharmaceutical composition comprises a therapeutically effective amount of a compound having the formula (I), as an effective ingredient, in association with a pharmaceutically acceptable substantially nontoxic carrier or excipient. The pharmaceutical composition can be useful in the treatment of lipemia of mammals. Additionally the compounds can be used as antiatherosclerotic agents and antilipenic agents.
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- New chiral blocks for introducing the side chain of HMG-CoA reductase inhibitors
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A couple of versatile building blocks (8 and 9) of the side chain portion found in many HMG-CoA reductase inhibitors have been prepared. The successful introduction of the side chain to an aromatic ring by 8 or 9 has been demonstrated.
- Urabe,Matsuka,Sato
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p. 4183 - 4186
(2007/10/02)
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- Process for the production of 3,5,6-trihydroxyhexanoic acid derivative
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A compound of a 3,5,6-trihydroxyhexanoic acid derivative of the formula: STR1 wherein P1 and P2 are independently hydrogen atoms or hydroxy-protecting groups, or together form a ring, and R is an alkyl group is effectively prepared by a process comprising steps of: reacting a butyronitrile derivative of the formula: STR2 wherein P1 and P2 are the same as defined above with an α-haloacetate of the formula: wherein X is a halogen atom, and R is the same as defined above in the presence of a metallic catalyst selected from the group consisting zinc and zinc-copper to form a keto acid derivative of the formula: STR3 wherein P1, P2 and R are the same as defined above, and then reducing the obtained keto-acid derivative of the formula (IV).
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- Stereoselective synthesis of HR 780 a new highly potent HMG-CoA reductase inhibitor
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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
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p. 2545 - 2548
(2007/10/02)
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- Optically active 3-demethylmevalonic acid derivatives, and intermediates
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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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