- A novel and efficient synthesis of Entecavir
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A practical synthesis of Entecavir (1) has been accomplished in 10 steps with 21% overall yield. The key steps to construct the five-membered carbocyclic framework 2 are a ring-closing metathesis and a diethyl-aluminum 2,2,6,6-tetramethyl piperidide (DA-TMS) mediated epoxide isomerization. Furthermore, the guanine was introduced by modified Mitsunobu reaction.
- Liu, Xiaoyu,Jiao, Xiaozhen,Wu, Qian,Tian, Chengsen,Li, Renze,Xie, Ping
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Read Online
- Total Synthesis of Entecavir: A Robust Route for Pilot Production
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A practical synthetic route for pilot production of entecavir is described. It is safe, robust, and scalable to kilogram scale. Starting from (S)-(+)-carvone, this synthetic route consists of a series of highly efficient reactions including a Favorskii rearrangement-elimination-epimerization sequence to establish the cyclopentene skeleton, the Baeyer-Villiger oxidation/rearrangement to afford the correct configuration of the secondary alcohol, and a directed homoallylic epoxidation followed by epoxide ring-opening to introduce the hydroxyl group suitable for the Mitsunobu reaction. In addition, the synthesis contains only four brief chromatographic purifications.
- Xu, Hua,Wang, Fang,Xue, Weicai,Zheng, Yunjie,Wang, Qi,Qiu, Fayang G.,Jin, Yehua
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Read Online
- Novel preparation method and intermediates of entecavir
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The invention provides novel intermediates used for entecavir synthesis, compounds shown as a formula II and a formula III in the description, and a novel method for synthesizing entecavir by using the novel intermediates. When the novel intermediates are used for synthesizing entecavir, not only can the synthesis yield be remarkably improved, but also the production cost can be reduced.
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- Improved entecavir intermediate synthesis process and improved entecavir synthesis process
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The invention discloses an improved entecavir intermediate synthesis process and an improved entecavir synthesis process, and relates to the technical field of drug synthesis. The invention disclosesan improved entecavir intermediate synthesis process. In the synthesis process of an amino protection reaction product, amino protecting groups are added in batches; and the ratio of the reaction rawmaterials is optimized, so that the problems of long reaction time and relatively low amino protection reaction yield due to adoption of a one-time complete feeding mode in an existing synthesis modeare solved, the synthesis time of an amino protection reaction product is shortened to 50-70 minutes, and the obtained product is high in yield and purity. According to the improved entecavir synthesis process, in the amino protection reaction product synthesis process, reaction conditions are effectively optimized, and the purity of obtained entecavir reaches 99% or above.
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Paragraph 0017; 0053; 0055; 0066; 0067; 0070
(2020/10/14)
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- Entecavir intermediate, synthetic method thereof and synthetic method of entecavir
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The invention belongs to the technical field of organic synthesis, and provides an entecavir intermediate, a synthesis method thereof and a method for synthesizing entecavir by using the entecavir intermediate. The intermediate and the methods have the advantages of easily available raw materials, low price, shortest synthesis steps, mild reaction conditions, easiness in control, simple equipmentrequirements, high total yield of products and easiness in industrial production.
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- Entecavir intermediate and synthesis method thereof as well as method for synthesis of entecavir
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The invention relates to an entecavir intermediate and a preparation method thereof and a method for synthesis of entecavir by using the intermediate. The methods for synthesis of the entecavir and the entecavir intermediate have the advantages of controllable chirality, high yield and high product purity, raw materials are wide in source, reagents are cheap and easily available, the reaction is simple, the operation is simple and convenient, green and environment-friendly effects are achieved, and the method is suitable for industrial large-scale production.
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Paragraph 0199; 0210-0211; 0216-0220
(2019/05/15)
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- Method for synthesizing entecavir
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The invention provides a method for synthesizing entecavir. The method comprises the steps of carrying out condensation ring-closure reaction, bromination addition reaction, reduction reaction, Witting reaction and the like. The method has the beneficial effects that the reaction raw material is easy to obtain, the reaction process is simple in operation, the requirement on reaction equipment is low, the reaction condition is relatively mild and the yield and the content are high.
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- A new scalable synthesis of entecavir
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A new synthesis of entecavir from D-glucose in an average total yield of 3.5% was achieved via an intramolecular nitrile oxide cycloaddition (INOC) reaction and a Peterson olefination as key-steps. The present process was designed for industrial application, using widely available raw materials, simple and cheap reagents and avoiding low reaction temperatures, which are very common in the synthetic approaches towards similarly complex structures.
- Gioti, Efthymia G.,Koftis, Theocharis V.,Neokosmidis, Efstratios,Vastardi, Elli,Kotoulas, Stefanos S.,Trakossas, Sakellarios,Tsatsas, Theodoros,Anagnostaki, Elizabeth E.,Panagiotidis, Theodoros D.,Zacharis, Constantinos,Tolika, Evanthia P.,Varvogli, Anastasia-Aikaterini,Andreou, Thanos,Gallos, John K.
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p. 519 - 527
(2017/12/29)
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- Entecavir industrial preparation method (by machine translation)
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The invention discloses entecavir industrial preparation method, which belongs to the technical field of organic synthesis. Including: Nysted reagent and intermediate VIII reaction, after the reaction is finished adding quenching fluid and holding the reaction system pH value of 7.0 - 8.5, obtained after the completion of reaction intermediates IX; intermediate IX react with hydrochloric acid, after the reaction is finished by adding the extractant and adjust pH value to 6.5 - 7.0, taking organic phase concentrated to 1/15 - 1/10 volume, crystallization, solid-liquid separation to obtain the intermediate X; intermediate with boron trichloride in dichloromethane in the X reaction, intermediate X with boron trichloride in a molar ratio of 1:5 - 10, the reaction temperature is - 30 — - 20 °C, after the reaction is finished cooling to - 30 °C following, dripping methanol, after the completion of the dropping the evaporation and once again by adding methanol, concentrated under reduced pressure, dryness and add into the water with the organic solvent of the extractant B, [...], adjust pH value to 6.5 - 7.0, concentrated, refine to get entecavir. (by machine translation)
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- Entecavir intermediate and its preparation method
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The invention discloses an entecavir intermediate and a preparation method thereof. A provided preparation method for an entecavir intermediate compound 3 comprises the following steps: performing reducing reaction on a compound 4 in a solvent, so as to obtain the compound 3. A provided preparation method for an entecavir intermediate compound 4 comprises the following steps: performing transacetalation reaction on a compound 5 and a compound 18 in an organic solvent under an acid condition, so as to obtain the compound 4. The preparation methods are cheap and easily available in raw materials, mild in reaction conditions, relatively high in product yield, good in atom economy, friendly to environment, and suitable for industrialized production.
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Paragraph 0154-0156; 0161-0162
(2017/10/28)
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- Entecavir intermediate and its preparation method
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The invention discloses an entecavir intermediate and a preparation method thereof. A provided preparation method for an entecavir intermediate compound 10 comprises the following steps: performing reducing reaction on an ester compound 11 in an organic solvent under the effect of a reducing agent, so as to obtain the compound 10. A provided preparation method for an entecavir intermediate compound 11 comprises the following steps: reacting a compound 12 with a hydroxyl protection reagent in an organic solvent in the presence of an acid to add a hydroxyl protection group, so as to obtain the compound 11. The preparation methods are cheap and easily available in raw materials, mild in reaction conditions, relatively high in product yield, good in atom economy, friendly to environment, and suitable for industrialized production.
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Paragraph 0151-0153; 0158; 0159
(2017/12/28)
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- Entecavir intermediate and its preparation method
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The invention discloses an entecavir intermediate and a preparation method thereof. A provided preparation method for an entecavir intermediate compound 8 comprises the following steps: performing hydroxyl protection group removal reaction on a compound 9 in a solvent under an acidic condition, so as to obtain the compound 8. A provided preparation method for an entecavir intermediate compound 9 comprises the following steps: performing hydroxyl protection group adding reaction on a compound 10 in an aprotic organic solvent under an alkali condition, so as to obtain the compound 9. The preparation methods are cheap and easily available in raw materials, mild in reaction conditions, relatively high in product yield, good in atom economy, friendly to environment, and suitable for industrialized production.
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Paragraph 0148; 0149; 0153; 0154; 0155
(2017/12/28)
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- A method for preparing entecavir
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The invention belongs to the technical field of pharmaceutical preparation, and specifically relates to a preparation method of a hepatitis B therapeutic entecavir. The method comprises the following steps: (1) under a nitrogen condition, carrying out reaction on Zn, tetrahydrofuran and CH2Br2 to obtain a NYSted reagent; (2) adding Ente-8, CH2Cl2 and NYSted into a reaction pot to prepare Ente-9; (3) adding THF (Tetrahydrofuran), CeRh2Ga, methanol and Ente-9 into a reaction bottle, stirring and adding HCl(3N) to obtain Ente-10; and (4) adding Ente-10 and dichloromethane into the reaction pot, dropwise adding CH2Cl2 liquor of BCl3, carrying out reaction to obtain an Entecavir coarse product, and refining to obtain a pure product. Compared with the prior art, the preparation method of entecavir provided by the invention has the characteristics of high yield, good product purity, simple operation of posttreatment, environment-friendliness, adaptability to industrialized product and the like.
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Paragraph 0037; 0038
(2017/10/31)
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- A kind of preparation method of the midbody of entecavir, and intermediate
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The invention discloses Entecavir intermediates and a preparation method thereof. The preparation method of an Entecavir intermediate represented by a formula IV or IV' shown in descriptions comprises the following step of enabling a compound V to be subjected to amino protecting group and hydroxyl protecting group removal reaction in the presence of protonic acid in a solvent. The preparation method disclosed by the invention has the advantages that raw materials are cheap and are easily obtained, reaction conditions are mild, side reactions are few, the yield is high, the pollution to the environment is little, and the intermediates are easily purified and separated, so that the preparation method is applicable to industrial production.
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- Preparation method of antiviral drug Entecavir
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The invention discloses a preparation method of an antiviral drug Entecavir. The preparation method comprises the following steps of 1, performing cyclization reaction on a compound shown in a formula D under the existence of tert-butyl peroxybenzoate, sodium carbonate and R-1,1'-bi-2-naphthol, so as to obtain a compound shown in a formula D; 2, performing mitsunobu reaction on the compound shown in the formula D and 2-amino-6-chloro-purine, so as to obtain a compound shown in a formula F; 3, hydrolyzing the compound shown in the formula F in an acid water solution, so as to obtain the Entecavir. The invention also discloses a preparation method of the compound shown in the formula D. The preparation method has the advantages that the number of reaction steps is reduced, the whole yield rate is greatly improved, the yield rates of an intermediate of the compound in the formula A and an intermediate of the compound in the formula E are particularly improved, the removal protection of hydroxyl is easy by ketal protection, and the yield rate of the Entecavir is further guaranteed; the conditions are mild, and the preparation method is suitable for industrialized production.
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- A kind of preparation method of the midbody of entecavir, and intermediate
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The invention discloses Entecavir intermediates and a preparation method thereof. The preparation method of an Entecavir intermediate represented by a formula VIII shown in descriptions comprises the following step of enabling compounds IX and VIII' to be subjected to ring cleavage reaction in the presence of alkali in a non-aprotic organic solvent. The invention further discloses an Entecavir intermediate compound represented by a formula X or IX shown in descriptions. The preparation method disclosed by the invention has the advantages that raw materials are cheap and are easily obtained, the reaction conditions are mild, side reactions are few, the yield is high, the pollution to the environment is little, and the intermediates are easily purified and separated, so that the preparation method is applicable to industrial production.
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- SYNTHETIC METHOD OF ENTECAVIR AND INTERMEDIATE COMPOUNDS THEREOF
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The present invention relates to preparation method of drugs and intermediate compounds thereof, in particular, to preparation method of entecavir, intermediate compounds thereof and synthetic method of said intermediate compounds.
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- A method for preparation of a purine derivative and intermediates
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The invention discloses a preparation method and intermediates of purine derivatives. According to the preparation method, a compound II and a compound III have a coupling reaction in an organic solvent under the actions of alkali and palladium catalysts to prepare the purine derivatives. Compared with the prior art, the raw materials used in the preparation method are cheap and common, and the preparation method is simple and efficient, is suitable for industrial production and provides a new way for the synthesis of entecavir drugs.
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Paragraph 0169-0171
(2016/12/01)
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- A novel method for the synthesis of inventive compounds
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The invention belongs to the field of drug synthesis and relates to an entecavir compound and a synthetic method of an intermediate of the entecavir compound. The novel synthetic method comprises: by taking (S)-3-hydroxyl dimethyl adipate as an initial raw material, preparing an intermediate 9 through hydroxyl TBS protection, Dieckmann condensation reaction, ketone protection to ketal, ester group reduction to hydroxyl, hydroxyl protection, deprotection, ketone to silyl enol ether and Rubottom oxidizing reaction; and preparing entecavir from the intermediate 9 through wittig reaction, Mitsunobu reaction, silicon preventing radical group removal and basic hydrolysis. The novel synthetic method provided by the invention is mild and easily controllable in reaction condition, simple to operate, high in product yield, high in purity and suitable for industrialized mass production.
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- Method for synthesizing Entecavir
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The invention discloses a method for synthesizing Entecavir and belongs to the technical field of medicine synthesis methods. According to the method, Entecavir is synthesized through taking 1,3-propanediol as a starting raw material, carrying out oxidation so as to form an aldehyde, then, producing an unsaturated ester, and then, carrying out reactions such as reduction, asymmetric epoxidation, ring opening, silane protecting group removing, hydroxyl protection, deprotection, oxidation, ring closing, oxidation, reduction, condensation and deprotection. According to the method, the used raw material is cheap and readily available, and the reaction conditions are mild and are easy in control, so that the industrial production is facilitated.
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- PROCESS FOR THE PREPARATION OF ENTECAVIR THROUGH NOVEL INTERMEDIATES
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The present invention relates to a novel process for the preparation of the antiviral drug compound Entecavir, through novel intermediates.
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Page/Page column 22; 23
(2015/04/28)
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- PROCESS FOR PREPARATION OF ENTECAVIR
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Provided is a process for preparing a compound of Formula (I), comprising de-protecting a compound of Formula (III) in a solvent in the presence of a Lewis acid, with the properties of reduced steps and less solvent.
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Page/Page column 8
(2014/01/17)
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- ENTECAVIR SYNTHESIS METHOD AND INTERMEDIATE COMPOUND THEREOF
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The present invention relates to a preparation method for a medicine and an intermediate compound thereof, specifically, relates to a preparation method for entecavir, an intermediate compound thereof, and a synthesis method for the intermediate compound.
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- Total synthesis of entecavir
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Entecavir (BMS-200475) was synthesized from 4-trimethylsilyl-3-butyn-2-one and acrolein. The key features of its preparation are: (i) a stereoselective boron-aldol reaction to afford the acyclic carbon skeleton of the methylenecylopentane moiety; (ii) its cyclization by a Cp2TiCl- catalyzed intramolecular radical addition of an epoxide to an alkyne; and (iii) the coupling with a purine derivative by a Mitsunobu reaction.
- Velasco, Javier,Ariza, Xavier,Badía, Laura,Bartra, Martí,Berenguer, Ramon,Farràs, Jaume,Gallardo, Joan,Garcia, Jordi,Gasanz, Yolanda
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p. 5482 - 5491
(2013/07/25)
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- PROCESS FOR PREPARING AN ANTIVIRAL DRUG AND INTERMEDIATES THEREOF
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Process for preparing an antiviral drug and intermediates thereof It comprises the preparation of entecavir of formula (I), or a pharmaceutically acceptable salt thereof, or a hydrate thereof by submitting a compound of formula (III) where X is an halogen selected from Cl, Br, and I, first to a hydrolysis reactionusing formic acid and then to a deprotection reaction, and isolating the entecavir either as free base or as a pharmaceutically acceptable salt. It also comprises intermediates which intervene in this preparation process.
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- ENTECAVIR SYNTHESIS METHOD AND INTERMEDIATE COMPOUND THEREOF
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The present invention relates to a method for preparation of a medicine and to intermediate compounds thereof, specifically, relates to a method for preparation of entecavir, to intermediate compounds thereof, and to a method for synthesis of the intermediate compounds.
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- Process for preparing entecavir and intermediates thereof
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It comprises the preparation of entecavir of formula (I), or a pharmaceutically acceptable salt thereof, or a hydrate thereof by submitting a compound of formula (III) where X is an halogen selected from Cl, Br, and I, first to a hydrolysis reaction using formic acid and then to a deprotection reaction, and isolating the entecavir either as free base or as a pharmaceutically acceptable salt. It also comprises intermediates which intervene in this preparation process.
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- Synthesis of Entecavir (BMS-200475)
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A synthesis of Entecavir (BMS-200475) was achieved starting from 1,3-propanediol in 15 steps and 23.4% overall yield. A unique feature of the synthetic route is that the five-membered carbocyclic core is installed by an intramolecular nitrile oxide cycloaddition (INOC) reaction and the guanine moiety is introduced by a Mitsunobu reaction. The route is characteristic of low cost, high yield and easy operation.
- Zhou, Bing,Li, Yuanchao
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p. 502 - 504
(2012/02/02)
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- Preparation process of an antiviral drug and intermediates thereof
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Preparation process of an antiviral drug and intermediates thereof It comprises a preparation process of entecavir comprising: submitting a (1S,3R)-3-(tert-butyldimethylsilyloxy)-1-(oxiran-2-yl)pent-4-yn-1-ol (VIII) to a double esterification and to a radicalary cyclization, yielding a compound of formula (V), where either a compound of formula (VIII) is submitted to a first esterification reaction, then to a catalytic radicalary cyclization using titanocene dichloride as catalyst in the presence of Mn/2,4,6-collidine HCl or Zn/2,4,6-collidine/trimethylsilyl chloride, and finally to a second esterification reaction or, alternatively, the compound of formula (VIII) is submitted first to a catalytic radicalary cyclization, and then to an esterification reaction. Entecavir can be obtained by submitting compound (V) to a desilylation reaction to remove the TBS group and then to a Mitsunobu coupling with 2-amino-6-chloroguanine, followed by hydrolysis. It also relates to some new intermediates of the process.
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- PROCESS FOR THE SYNTHESIS OF CARBONUCLEOSIDE AND INTERMEDIATES FOR USE THEREIN
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Disclosed is a process for preparing a carbonucleoside of formula (1) and intermediates for use therein. The process involves the step of reacting a compound of formula (2) with a compound of formula (3) under Mitsunobu-type reaction conditions to obtain a compound of formula (4), wherein PG1, PG2, PG3 and PG4 are protecting groups. The compound of formula (4) is deprotected to form the compound of formula (1), as shown below.
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- NOVEL INTERMEDIATE AND PROCESS FOR PREPARING ENTECAVIR USING SAME
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The present invention relates to a novel, high-yield and low-cost method for preparing entecavir, [1-S-(1α,3α,4β)]-2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one, an antiviral agent, and novel intermediates used therein.
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Page/Page column 4
(2011/10/19)
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- Process for Preparing Entecavir and its Intermediates
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A process of making entecavir comprising converting a compound of formula (M5) to entecavir, wherein the two PGs on the formula (M5) are taken together to form an optionally substituted six- or seven-member cyclic ring.
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Page/Page column 18
(2011/09/14)
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- NOVEL INTERMEDIATE AND PROCESS FOR PREPARING ENTECAVIR USING SAME
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The present invention relates to a novel, high-yield and low-cost method for preparing entecavir, [1-S-(1α,3α,4,β]-2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one, an antiviral agent, and novel intermediates used therein.
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Page/Page column 19-20
(2010/07/09)
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- Process for the preparation of entecavir and novel intermediates thereof via carbon-silicon oxidation
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Processes for preparing entecavir and novel intermediates thereof using carbon-silicon oxidation.
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Page/Page column 23-24
(2008/06/13)
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- BMS-200475, a novel carbocyclic 2'-deoxyguanosine analog with potent and selective anti-hepatitis B virus activity in vitro
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BMS-200475, a never carbocyclic analog of 2'-deoxyguanosine, is a potent inhibitor of hepatitis B virus in vitro (ED50 = 3 nM) with relatively low cytotoxicity (CC50 = 21-120 μM). A practical 10-step asymmetric synthesis was developed affording BMS-200475 in 18% overall chemical yield and > 99% optical purity. The enantiomer of BMS-200475 as well as the adenine, thymine, and iodouracil analogs are much less active.
- Bisacchi,Chao,Bachard,Daris,Innaimo,Jacobs,Kocy,Lapointe,Martel,Merchant,Slusarchyk,Sundeen,Young,Colonno,Zahler
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p. 127 - 132
(2007/10/03)
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- Hydroxymethyl (methylenecyclopentyl) purines and pyrimidines
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Antiviral activity is exhibited by compounds having the formula STR1 and its pharmaceutically acceptable salts.
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