- COMPOUND AND USE THEREOF IN SYNTHESIS OF BRIVARACETAM INTERMEDIATE AND CRUDE DRUG
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The present application provides a compound in formula III, and further provides a use of the compound in the synthesis of a Brivaracetam intermediate and a crude drug, and a synthesis method. A raw material involved in the method of the present application is low in costs and easily available; (R)-4-propyl-dihydrofuran-2-ketone having high optical purity can be prepared; complicated separation and purification steps are avoided; costs are reduced, and the method is more applicable to industrial production.
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Page/Page column 0096-0100
(2021/08/27)
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- Preparation method of brivaracetam intermediate
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The invention relates to a preparation method of a brivaracetam intermediate, and belongs to the field of medicinal chemistry. The preparation method comprises the following steps: reacting a compound II with urea to generate dilactam, and hydrolyzing under an alkaline condition to obtain a compound III; performing chiral resolution on the compound III to obtain a compound IV; reacting the compound IV with sodium hypochlorite to obtain a compound V; and reacting the compound V with nitrite to obtain a compound I. The raw materials used in the method are low in cost and easy to obtain, the intermediate compound is easy to purify, the process reaction steps are few, the operation is simple, the stereoselectivity is good, and the yield is high; and the method is suitable for industrial production.
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- Preparation method of brivaracetam intermediate
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The invention provides a preparation method of a brivaracetam intermediate (R)-3-propyl-gamma-butyrolactone, which comprises the following steps: by taking 4-chloro-4-oxobutyric acid methyl ester as a starting raw material, connecting a chiral auxiliary group, introducing R configuration propyl, removing a ligand, reducing carboxyl, and finally esterifying to form a ring, thereby obtaining the (R)-3-propyl-gamma-butyrolactone. The synthesis route ingeniously utilizes the chiral adjuvant (R)-4-benzyl-2-oxazolidinone, optimizes the reaction conditions, has the advantages of few reaction steps, high yield, good reaction stereoselectivity and the like, meanwhile, the raw materials are cheap and easy to obtain, the operation is simple, convenient and safe, and the method has a better industrial application prospect;.
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Paragraph 0025; 0070-0071
(2021/09/04)
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- Preparation method of (R)-4-propyl-dihydrofuran-2-one and preparation intermediate of (R)-4-propyl-dihydrofuran-2-one
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The invention discloses a preparation method of (R)-4-propyl-dihydrofuran-2-one and a preparation intermediate of (R)-4-propyl-dihydrofuran-2-one. The preparation method of the intermediate comprisesthe following steps: (1) in the presence of an acid or an alkali, carrying out hydrolysis reaction on a compound I to obtain a compound II or a salt thereof; and (2) carrying out reduction reaction onthe compound II or the salt thereof and a reducing agent to obtain a compound III. According to the preparation route disclosed by the invention, the use of flammable and explosive reaction reagentsin the existing route is avoided; reagents which are low in cost and easy to obtain in industry are used; compared with the prior art, the method has the advantages of low cost, safety in production,realization of the purification and the separation of the intermediate by using the acid-base property of the compound and adopting the mode of adjusting the pH value of the system in the reaction process and the post-treatment operation, avoiding of recrystallization, filtration and other tedious operation modes, simplification of the operation, and suitableness for industrial large-scale production.
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Paragraph 0071-0076
(2020/07/14)
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- Synthesis method of (R)-4-propyldihydrofuran-2-ketone
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The invention discloses a synthesis method of (R)-4-propyldihydrofuran-2-ketone, and belongs to the field of organic chemical synthesis. A new process route is developed to overcome the defects that (R)-4-propyldihydrofuran-2-ketone is relatively high in material price, low in product purity, difficult to produce and amplify and the like. Meldrum's acid and R-epichlorohydrin are used as initial raw materials, and the compound is obtained by taking (1S, 5R)-3-oxabicyclo [3.1. 0]-2-hexanone as an intermediate through a two-step reaction of closing a three-membered ring and opening a ring by using a Grignard reagent. The (R)-4-propyldihydrofuran-2-ketone is synthesized by adopting the synthesis method, a novel process route is adopted in the process, the total molar yield is greater than 50%,and the method has the characteristics of novel and short route, high optical purity, low cost and the like.
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Paragraph 0016; 0022; 0025-0026; 0027; 0030-0031
(2020/12/30)
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- ENANTIOSELECTIVE SYNTHESIS OF BRIVARACETAM AND INTERMEDIATES THEREOF
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The present invention relates to an improved and economical process for enantioselective synthesis and purification of a novel key intermediate of Brivaracetam. Further, the present invention also relates to a process for the preparation of a chirally pure Brivaracetam of formula I utilizing the said intermediate.
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Page/Page column 25; 33; 34
(2020/07/31)
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- Synthesis method of R-3-propyl-gamma-butyrolactone
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The invention discloses a synthetic method of R-3-propyl-gamma-butyrolactone, and belongs to the technical field of organic synthesis. The method comprises the following steps: by taking D-malic acidas a raw material, performing monomethyl esterification, reduction, halogenation or sulfonic acid esterification, and finally coupling with a Grignard reagent under the catalysis of zinc chloride to obtain a brivaracetam intermediate that is the R-3-propyl-gamma-butyrolactone. The method has the advantages of cheap and easily available starting raw materials, good stereoselectivity, no need of chiral resolution, mild condition, short route and the like, and provides a feasible scheme for brivaracetam process research.
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Paragraph 0042; 0053; 0056
(2020/07/12)
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- (R)-4-propyl-dihydrofuran-2-one preparation method
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The invention discloses a synthesis method of a brivaracetam intermediate, and relates to a compound represented by a formula I.
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Paragraph 0005
(2020/03/06)
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- Synthesis and olfactory evaluation of optically active β-alkyl substituted γ-lactones and whiskey lactone analogues
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Optically active β-alkyl substituted γ-lactones and whiskey lactone analogues were synthesized, and the odor properties were evaluated. During the preparation of the chiral intermediates, we found good reaction conditions for the highly enantioselective esterification of 3-arylmethyl-2-methyl-1-propanols to kinetically resolve them. The results of the olfactory evaluations of the synthesized lactones revealed that the alkyl groups on the γ-lactone rings played an important role for the odor profiles.
- Kato, Daiki,Kawasaki, Masashi,Morita, Yuko,Okada, Takuya,Tanaka, Yasuo,Toyooka, Naoki
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- Preparation method of 4 substituted-gamma butyrolactone
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The invention belongs to the field of medicinal chemistry, and relates to preparation of (R)-4-propyl-dihydrofuran-2-one represented by a formula I.
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- Preparation method of brivaracetam
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The invention discloses a preparation method of brivaracetam, and belongs to the field of pharmaceutical synthesis chemistry. Aiming at the problems of complex synthesis route, low yield, high cost, and the like of a target compound in the prior art, the invention provides a novel preparation method, which comprises the following steps: 1) carrying out asymmetric reduction on a compound II under the action of a chiral catalyst to obtain a compound III; 2) reacting the compound III with a halogenating reagent to obtain an intermediate namely a compound IV, and 3) reacting the compound IV with L-amino butanamide to obtain a compound I. The method has the advantages of simple process, low production cost, and easy industrial production.
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Paragraph 0022; 0040-0063
(2020/08/27)
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- Identification, characterization, synthesis and strategy for minimization of potential impurities observed in the synthesis of brivaracetam
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A first systematic impurity profile research concerning nine observed and potential process related impurities of antiepileptic drug brivaracetam is reported. Among which three (impurity G/H/I) have not been discovered or reported before, these nine impurities were monitored by HPLC, and their structures were identified on the basis of MS and NMR spectroscopy. In addition to the formation, synthesis, and characterization, strategies for minimizing these impurities to the levels accepted by ICH are also described in this report.
- Liao, Shouzhu,Chen, Hongjun,Wang, Guifei,Wu, Shuming,Yang, Zaiyou,Luo, Weihe,Liu, Zhuanfeng,Gao, Xun,Qin, Junhai,Li, Chuan-hua,Wang, Zhongqing
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supporting information
(2020/05/25)
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- PROCESS FOR PREPARING OPTICALLY PURE (R)-4-N-PROPYL-DIHYDROFURAN-2(3H)-ONE
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The present invention discloses a process for preparing optically pure (R)-4-n-propyl-dihydrofuran-2(3H)-one, belonging to the field of chemical synthesis. According to the process, optically pure (S)-3-n-pentanoyl-4-substituted oxazol-2-one is used as a starting material, and after alkylation, reduction, cyano hydrolysis, lactonization, the product optically pure (R)-4-n-propyl-dihydrofuran-2(3H)-one is given. The preparation process has the advantages of easy availability of raw materials, low price, high yield, high optical purity of product, simple reaction conditions and simple operations.
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Paragraph 0107-0109
(2019/12/10)
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- Method for preparing 4-chiral substituted gamma-butyrolactone
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The invention discloses a method for preparing 4-chiral substituted gamma-butyrolactone. The method comprises the following steps: (a) performing chiral reduction on substituted succinic anhydride serving as a raw material to obtain a compound 2; (b) preparing a corresponding compound 3 from the compound 2 by a reaction of transforming hydroxyl into amino; (c) performing chiral resolution on the compound 3 through chiral solution acids to obtain a compound 4; and (d) performing a deamination reaction on the compound 4 to obtain a final product compound 5. The substituent group R is selected from C1-C8 straight-chain or branched alkyl, 3-8 component alicyclic group, aryl, heteroaryl, Ar(CH2)n-radical, wherein Ar represents aryl and heteroaryl, and n equals to 1-6. The invention provides a novel synthesizing route, raw materials are easily available, and conventional substituted succinic anhydride has bulk production; the operation steps are conventional chemical reactions, are simple and easy and have strong operability; and a final product has good chiral selectivity, has an ee value of between 85-99.5 percent, and has high purity.
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- PROCESS FOR ASYMMETRIC SYNTHESIS OF (R)-4-PROPYLDIHYDROFURAN-2 (3H)-ONE
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The invention relates to a process for the asymmetric synthesis of (R)-4-propyldihydrofuran-2(3H)-one starting with trans-2-hexen-l-al and nitromethane, wherein the stereocentre is generated for the first time by an organocatalytic method, which is therefore highly economical and industrially scalable, and has a very low environmental impact (Formula I).
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- Preparation method of butyrolactone compound and intermediate thereof
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The invention discloses a preparation method of a butyrolactone compound and an intermediate thereof, and particularly discloses a preparation method of a compound 7. The preparation method is high inyield, simple and convenient to operate and suitable for industrial production.
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- Preparation method of (R)-4 - propyl -dihydrofuran -2 - ketone with optical purity (by machine translation)
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The invention relates to a preparation method, namely (R)-4 - propyl -dihydrofuran -2 - ketone with optical purity. The synthesis route is as follows: the compound 4 - propyl -2 - furanone is reduced to obtain compound 1 (R)-4 - propyl -dihydrofuran -2 4 - ketone by asymmetric -2 - reduction, and chemical purity ≥ 9998%. A simple and feasible asymmetric catalytic method is adopted to synthesize the target product. Compared with a biological enzyme method, a resolution racemization method, a natural chiral source synthesis method and other methods, the method has the advantages that the performance. (by machine translation)
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Paragraph 0020-0024
(2019/10/01)
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- In the preparation of intermediate compound RA west cloth tile tanzania [...] lactone in the use of the
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The invention relates to compounds in the preparation of intermediate west cloth tile tanzania RA [...] lactone in the use of the, compound RA will compound BW - CX chiral resolution to obtain the BW - C, represented by the formula, The application of the use preparation west cloth tile tanzania intermediate when the west cloth tile tanzania, without chiral column split, simple process flow, solves the problems of large-scale production process is difficult to preheating of the west cloth tile tanzania.
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Paragraph 0025; 0037-0040
(2019/07/10)
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- Preparation method of chiral gamma-butYRolactone and intermediate thereof
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The invention discloses a (R)-4-propyl-4, 5-dihydrofuran-2 (3H) and a preparation method of the intermediate and a preparation method of the intermediate. The raw materials used in the preparation method of the intermediate are cheap, the reaction conditions are mild, the butt-joint reaction can be realized only by use of a weak base, and the operation is simple. The intermediate disclosed by theinvention is used for preparing (R)-4-propyl-4, 5-dihydrofuran-2 (3H) -one, so that the subsequent reaction and operation can be simplified.
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Paragraph 0108-0110
(2019/04/26)
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- A west cloth tile tanzania intermediate and west cloth tile tanzania synthetic method (by machine translation)
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The invention discloses a west cloth tile tanzania intermediate and west cloth tile tanzania synthesis method, the method comprises removing Carboxyl, then obtained after the hydrogenation reaction of the chiral separation Can be further used for the synthesis of west cloth tile tanzania. The west cloth tile tanzania intermediate synthetic method of this invention, the use of raw materials, the reaction operation is comparatively simple, easy control of reaction conditions. West cloth tile tanzania synthesis method of the present invention, the yield is high, and the synthesized west cloth tile tanzania purity can be up to 99% or more, the overall cost of synthesizing more advantages. (by machine translation)
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- A (R)-4 - propyl - dihydrofuran -2 - ketone
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The invention discloses a process for preparing (R)- 4 - propyl - dihydrofuran - 2 - one method, the key intermediate type B compound, type C compound and its preparation method; (R)- 4 - propyl - dihydrofuran - 2 - one of the preparation method of the operability of the strong, is suitable for industrial production.
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Paragraph 0098-0115
(2019/04/10)
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- Preparation method of Brivaracetam intermediate
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The invention discloses a preparation method of a Brivaracetam intermediate, wherein the reaction equation is shown as follows: diethyl malonate, bromopropane and an aprotic polar solvent are used forpreparing a compound of formula (1) under the action of an alkali; the compound of formula (1), tert-butyl bromoacetate and an aprotic polar solvent are used to prepare a compound of formula (2) under the action of an alkali; the compound of formula (2) and a polar solvent are used to prepare a compound of formula (3) under the action of an alkali; the compound of formula (3) is used to prepare acompound of formula (4) at high temperature; the compound of formula (4) and a polar solvent are used to prepare a compound of formula (5) under the action of an alkali; the compound of formula (5) and the resolving agent prepare the compound of formula (6) under the resolving solvent; the compound of formula (6) and a reducing agent are subjected to reduction reaction and hydrolysis reaction toprepare a compound of the formula (7). According to the invention, conventional raw materials are selected and can be prepared through conventional reactions, the optical purity materials are easier to purify, and the method is suitable for large-scale industrial production.
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- Synthesizing method of butyrolactone derivative
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The invention discloses a synthesizing method of a butyrolactone derivative. The synthesizing method comprises the following steps of (1) activating (R)-2-propyl-ethylene oxide shown in a formula (II)by a titanium reagent, and performing addition reaction by an organic zinc compound, so as to obtain a compound shown in a formula (III); (2) performing molecular lactone exchange reaction on the compound shown in the formula (III) under the acid condition, so as to obtain the butyrolactone derivative shown in a formula (I). The synthesizing method has the advantages that the synthesizing steps are simple, the production cost is low, the selectivity of areas is strong, and the yield rate is high; the synthesizing route is shown in the description.
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- Novel preparation method for butyrolactone derivative
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The invention discloses a novel preparation method for a butyrolactone derivative. The method includes the steps of: (1) reacting pentanoic acid shown as formula (II) with ethyl bromoacetate under theaction of lithium diisopropylamide to obtain a compound shown as formula (III); (2) splitting the compound shown as formula (III) with chiral phenylethylamine to obtain a compound shown as formula (IV); (3) subjecting the compound shown as formula (IV) to reduction of carboxyl by borane so as to obtain a compound shown as formula (V); and (4) carrying out cyclization reaction on the compound shown as formula (V) to obtain a butyrolactone derivative shown as formula (I). The brand new butyrolactone derivative synthesis method provided by the invention has the advantages of low cost of synthetic raw material pentanoic acid, need of just 4-step reaction, and good stereoselectivity, and can obviously reduce the production cost. And the synthesis route is shown as the specification.
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Paragraph 0037; 0038; 0039; 0043; 0044; 0048; 0049; 0053
(2018/03/24)
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- Preparation method of butyrolactone derivative
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The invention discloses a preparation method of a butyrolactone derivative. The method includes the steps of: (1) subjecting pentanoic acid shown as formula (II) to chiral lithiation reaction, then carrying out reaction with ethyl bromoacetate to obtain a compound shown as formula (III); (2) conduction reduction of carboxyl by borane on the compound shown as formula (III) to obtain a compound shown as formula (IV); and (3) subjecting the compound shown as formula (IV) to dehydration cyclization reaction, thus obtaining the butyrolactone derivative shown as formula (I). The brand new butyrolactone derivative synthesis method provided by the invention has the advantages of low cost of the synthetic raw material pentanoic acid, need of just 3-step reaction, and good stereoselectivity, therebysignificantly lowering the production cost. And the synthesis route is shown as the specification.
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Paragraph 0037; 0039; 0042
(2018/03/24)
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- A new chemoenzymatic synthesis of the chiral Key intermediate of the antiepileptic Brivaracetam
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Brivaracetam is a new anticonvulsant compound, recently approved as an antiepileptic drug. This drug substance presents a 4-substituted pyrrolidone structure: the (4R)-configuration of the stereocenter present on the heterocyclic ring is the main target of the synthesis. The described method allows to prepare the suitable optically pure 2-substituted primary alcohol by means of a Pseudomonas fluorescens lipase-catalyzed transesterification. The obtained (2R)-alcohol was easily transformed into the (3R)-3-propylbutyrolactone, an advanced intermediate of brivaracetam. The described synthetic pathway is completed with the chromatographic methods and the NMR analyses necessary to establish the chemical and the optical purity of the intermediates and of the final lactone.
- Ciceri, Samuele,Grisenti, Paride,Elahi, Shahrzad Reza,Ferraboschi, Patrizia
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- Preparation method of butyrolactone derivative
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The invention discloses a preparation method of a butyrolactone derivative. The preparation method includes the following steps that 1, a compound shown in the formula (II) is resolved with chiral phenylethylamine to obtain a compound shown in the formula (III); 2, the compound shown in the formula (III) is subjected to carboxyl reduction with borane to obtain a compound shown in the formula (IV);3, the compound shown in the formula (IV) is subjected to cyan-hydrolysis under the alkaline condition to obtain a carboxylic acid derivative shown in the formula (V), and a dehydration cyclization reaction is conducted to obtain the butyrolactone derivative shown in the formula (I). The new synthesis method of the butyrolactone derivative has the advantages that the cost of synthesis materials is low, only five reaction steps are needed, and thus the production cost can be obviously reduced. The synthesis route is shown in the description.
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Paragraph 0039; 0042
(2018/03/26)
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- Method for synthesizing butyrolactone derivative
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The invention discloses a method for synthesizing a butyrolactone derivative. The method comprises steps as follows: (1), after being activated by a titanium reagent, an epoxy compound represented asa formula (II) is subjected to an addition reaction by a Grignard reagent, and a compound represented as a formula (III) is obtained; (2), the compound represented as the formula (III) is subjected tocyano hydrolysis under the alkaline condition, and a carboxylic acid derivative represented as a formula (IV) is obtained; (3), the carboxylic acid derivative represented as the formula (IV) is subjected to a dehydration cyclization reaction, and the butyrolactone derivative represented as a formula (I) is obtained. The method has the advantages of being simple in synthesis step, low in production cost and high in functional group selectivity, regioselectivity and yield; the synthetic route is shown in the description.
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Paragraph 0030; 0031; 0032; 0035; 0036; 0039; 0040; 0043
(2018/05/16)
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- Preparation method of butyrolactone derivative
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The invention discloses a preparation method of a butyrolactone derivative. The preparation method comprises the following steps: firstly, substituting a compound in a formula (II) with a propyl Grignard reagent to obtain a compound in a formula (III); secondly, removing benzyl protection of the compound in the formula (III) to obtain a compound in a formula (IV); thirdly, substituting hydroxyl inthe compound in the formula (IV) with cyanogroup to obtain a compound in a formula (V); fourthly, removing tertiary butyl protection of the compound in the formula (V) to obtain a compound in a formula (VI); fifthly, carrying out carboxyl reduction on the compound in the formula (VI) to obtain a compound in a formula (VII); sixthly, carrying out cyano hydrolysis on the compound in the formula (VII) under the alkaling condition to obtain a carboxylic acid derivative in a formula (VIII), and then carrying out dehydration cyclization reaction to obtain the butyrolactone derivative in the formula(I). The preparation method disclosed by the invention has the advantages of good stereoselectivity, simplicity and convenience in operation, higher total yield and suitability for enlarged production. The synthetic route is as follows (The route is shown in the description.).
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Paragraph 0049; 0051; 0057; 0058; 0064; 0065; 0071
(2018/04/02)
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- Novel butyrolactone derivative synthesizing method
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The invention discloses a novel butyrolactone derivative synthesizing method. The method comprises the following steps: (1) pentanoic acid shown in a formula (II) reacts with bromoacetonitrile after achiral lithiation reaction, and a compound shown in a formula (III) is obtained; (2) a carboxyl group of the compound shown in the formula (III) is reduced by borane, and a compound shown in the formula (IV) is obtained; (3) a cyano group of the compound represented in the formula (IV) is hydrolyzed under the basic condition, a carboxylic acid derivative represented in the formula (V) is obtainedand subjected to a dehydration cyclization reaction, and the butyrolactone derivative represented in the formula (I) is obtained. The method has the advantages that the synthesis cost of raw materialpentanoic acid is low, only four steps are needed, the stereoselectivity is good, and accordingly, the production cost can be obviously reduced. The synthesis route is shown in the description.
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Paragraph 0038; 0040; 0044
(2018/05/16)
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- NOVEL PROCESS FOR THE PREPARATION OF BRIVARACETAM
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The present invention relates to a cost effective, novel and efficient process for the preparation of Brivaracetam which offers industrially viable, highly pure Brivaracetam in high yields and avoiding chiral resolutions by chromatography and enzymatic resolutions.
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- Optically pure (R)-4-n-propyl-dihydrofuran-2(3H)-one preparation method
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The present invention relates to an optically pure (R)-4-n-propyl-dihydrofuran-2(3H)-one preparation method, wherein optically pure (S)-3-n-pentanoyl-4-substituted oxazole-2-one is used as a raw material, alkylation reaction with an olefin or alkyne reagent, reducing removal of a chiral auxiliary group, oxidation of double bond or triple bond and other steps are performed to prepare the opticallypure (R)-4-n-propyl-dihydrofuran-2(3H)-one. According to the present invention, the preparation method has characteristics of easily available raw material, low cost, high total yield, high optical purity of the obtained product, simple reaction conditions and simple operation process.
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- Intermediate compounds for preparing brivaracetam, and preparation method and application thereof
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The invention provides intermediate compounds for preparing brivaracetam, and a preparation method and an application thereof. The invention also provides an intermediate compound A and an intermediate compound B and preparation methods thereof, and a synthetic route for preparing the brivaracetam by adopting the intermediate compound B. According to a technical scheme of the invention, the brivaracetam with high quality and high optical purity and intermediates thereof can be obtained; the ratio of the brivaracetam in four optical isomers is more than 99.5%; a silica gel column is not neededto be used for separation and purification; expensive chiral high-performance liquid chromatography is not needed to be used for resolution; complicated separation and purification steps are avoided;the waste of raw materials is avoided; the cost of production is reduced; and the preparation methods provided by the invention are more applicable to industrial production.
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Paragraph 0056; 0078-0079
(2019/01/04)
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- Preparation method of (R)-3-propyl-gamma-butyrolactone
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The invention discloses a preparation method of (R)-3-propyl-gamma-butyrolactone. The method comprises the following steps: with (S)-3-hydroxyl-gamma-butyrolactone as an initial raw material, activating hydroxyl by using sulfonate, reacting the hydroxyl-activated compound with a Grignard reagent in the presence of a copper catalyst, a cocatalyst and a nitrogen-containing compound to generate (R)-3-propyl-gamma-butyrolactone. The preparation method has the advantages that the process route is simple, the raw materials are cheap and easy to obtain, the synthesis route is short, the reaction conditions are mild, the operation is simple and convenient, the yield is high, and the stereoselectivity is good, the problems of the prior art that chiral separation and chiral column separation are needed in reaction, the yield is low and the chemical selectivity is poor are solved, and an important value is provided for the process research of brivaracetam.
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Paragraph 0043; 0048; 0049; 0050; 0053; 0057; 0058; 0059
(2018/10/11)
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- Preparation method for brivaracetam intermediate
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The invention discloses a preparation method for (R)-4-propyl-4,5-dihydrofuran-2-one. The preparation method comprises the following steps: subjecting a carboxylic acid compound to chiral resolution so as to obtain an R-configuration carboxylic acid compound and an S-configuration carboxylic acid compound; and separately subjecting the R-configuration carboxylic acid compound and/or the S-configuration carboxylic acid compound to a reaction so as to obtain (R)-4-propyl-4,5-dihydrofuran-2-one. According to the preparation method, a synthetic route is ingeniously designed, and the two opticallypure isomers obtained through chiral resolution of the carboxylic acid compound are separately utilized by different reaction routes, so the target compound is eventually prepared; and the method improves the utilization rate of the isomers while ensuring optical purity and eliminates the cumbersome steps of racemization and re-splitting of the other half of the isomers.
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- New synthesis method of brivaracetam
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The invention provides a synthesis method of brivaracetam. The method adopts cheap and easily available pentanoic acid or valeryl halide as an initial raw material, and provides a brand new synthesis route of a brivaracetam medicine, and the whole reaction route has a high total yield. The method has the advantages of high productivity, low cost, and suitableness for large-scale industrial production.
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- Method for preparing brivaracetam
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The invention discloses a method for preparing brivaracetam. The method for preparing brivaracetam comprises the following step that in an organic solvent, under the condition of anhydrous and inert gas shielding, a compound V and L-2-aminobutanamide are subjected to a condensation reaction to obtain brivaracetam I. According to the method for preparing brivaracetam, brivaracetam is prepared through only four steps of reacting, the reaction steps are short, the total yield is high, aftertreatment steps and purifying methods are simple, a product with the de value larger than 99.80% can be prepared only through recrystallization, the grade API is reached, the production cost is low, and the method is suitable for industrial production. The formula is shown in the description.
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Paragraph 0065; 0066; 0067
(2017/05/27)
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- Preparing method for caproic acid derivative
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The invention discloses a preparing method for a caproic acid derivative and provides a preparing method for a caproic acid derivative IV. The method comprises the following steps that in a polar nonprotic organic solvent, a compound III and an iodization reagent are subjected to a nucleophilic substitution reaction under inert gas shielding, and the caproic acid derivative IV is obtained. Brivaracetam can be prepared from the caproic acid derivative IV only through two steps, the synthetic route is short, the reaction condition is mild, posttreatment is simple, the reaction yield is high, and the production cost is low. Racemization does not happen in the reaction process, further purification is conducted through crystallization instead of a chiral high-pressure liquid phase preparing column, the chiral purity of the brivaracetam I can be improved till the de value is larger than 99.80%, meanwhile, the content of other single impurities of the brivaracetam I is smaller than 0.1%, the API level is reached, and the method is suitable for industrial production. The expression is shown in the description.
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Paragraph 0067; 0068; 0069; 0070
(2017/05/27)
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- A furyl ketone compound preparation method (by machine translation)
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The invention discloses a furyl ketone compound. The invention provides a furyl ketone compound III of the preparation method, comprises the following steps: in the solvent, the presence of an inorganic salt, the compound II with a reducing agent to the reduction reaction, to obtain the furyl ketone compound III, the solvent is an aliphatic alcohol solvent or aliphatic alcohol solvent mixed solvent with water. The furyl ketone compound III can be prepared by only three step west cloth tile Tanzania, short synthetic route; compound II ee value is greater than 99.0%, the reaction process is not racemization, obtained crude I west cloth tile Tanzania de value is greater than 99.0%; by crystallization is not chiral high-pressure liquid phase preparation column for further purification, can be I west cloth tile Tanzania chiral purity to further improve to de value 99.80% above, at the same time other shan Zawest cloth tile Tanzania I of less than 0.1%, reach the level of the API, is suitable for industrial production. (by machine translation)
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Paragraph 0065; 0066; 0067; 0068
(2017/08/28)
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- Synthesis method of substituted chiral gamma-butanolide
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The invention relates to a synthesis method of chiral gamma-butanolide represented by formula I. The method has the advantages of low cost, high enantioselectivity, and wide application prospect in synthesis of important bioactive compounds or key drug intermediates. In the formula I, R is selected from a C1-C6 linear or branched alkyl group, a C2-C8 linear or branched alkenyl group, a C2-C8 linear or branched alkynyl group, a 3-8-membered alicyclic group, an aryl group, a heteroaryl group and an Ar(CH2)n group, wherein Ar represents an aryl group or a heteroaryl group, and n is 1-6.
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- PROCESSES TO PRODUCE BRIVARACETAM
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The present invention provides a scalable synthesis of enantiomerically pure brivaracetam, and related derivatives.
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Page/Page column 42
(2016/12/22)
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- Synthetic method of 4-substituted chiral gamma-butyrolactone
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The invention relates to a synthetic method of 4-substituted chiral gamma-butyrolactone shown as a formula I. The cost is lower, the enantioselectivity is high, and the synthetic method has broad application prospect in synthesis of important biologically active compounds or key drug intermediates. The formula I is shown in the specification, wherein R is selected from C1-C6 linear or branched alkyl groups, C2-C8 linear or branched alkenyl-alkyl groups, C2-C8 linear or branched alkynyl-alkyl groups, 3-8-membered cycloaliphatic groups, aryl groups, heteroaryl groups and Ar(CH2)n-groups, Ar represents the aryl groups and the heteroaryl groups, and n ranges from 1 to 6.
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Paragraph 0024
(2016/10/31)
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- Method for preparing chiral 4-substituted dihydrofuran-2(3H)-ketone
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The invention provides a method for preparing chiral 4-substituted dihydrofuran-2(3H)-ketone. The method comprises the following steps: (a) dropwise adding acyl chloride (3) into an organic solvent solution of a compound (1), enabling reaction to obtain an acyl chloride intermediate solution, then dropwise adding an organic solvent solution of a compound (2) and enabling reaction to obtain a compound (4); (b) dropwise adding a bis(trimethylsilyl)amide alkali metal salt solution into an organic solvent solution of the compound (4), enabling reaction, dropwise adding a compound (5) into the obtained reaction liquid and enabling reaction to obtain a compound (6); (c) enabling reaction between the compound (6) and alkali to obtain a compound (7); (d) enabling reaction between the compound (7) and a reducing agent to obtain a compound (8), wherein R is selected from aryl, arylmethyl or alkyl, R1, R2 and R3 are independently selected from alkyl, and X is selected from Cl, Br or I. The method is simple in process, strong in operability and easy for industrial production. The reaction route is shown in the description.
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- A Biocatalytic Route to the Novel Antiepileptic Drug Brivaracetam
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An asymmetric synthesis of the novel antiepileptic drug Brivaracetam 1 is described. The stereochemistry of the 4-n-propyl substituent is introduced by a biocatalytic resolution of (rac)-methyl 2-propylsuccinate 4-tert-butyl ester 4. The selection of the resolution substrate and the screening of enzymes were carried out from our in-house screening platform. The development and scale-up of the best conditions, including solvent media, pH control, workup, and enzyme supply, led up to a successful demonstration conducted at 1 kg scale in a 10 L vessel. The chiral intermediate (R)-2-propylsuccinic acid 4-tert-butyl ester 6 was reproducibly obtained in 42% yield and 97% ee all along the development. The control of the stereochemistry via the biocatalytic resolution allowed the production of Brivaracetam 1 within the required commercial quality specifications.
- Schülé, Arnaud,Merschaert, Alain,Szczepaniak, Christophe,Maréchal, Christophe,Carly, Nicolas,O'Rourke, John,Ates, Célal
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p. 1566 - 1575
(2016/09/23)
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- Highly Enantiospecific Synthesis of 4-Alkyl and 4,5-Dialkyl Substituted 4,5-Dihydrofuran-2(3H)-ones from Optically Active (E)- and (Z)-Alk-1-enyl p-Tolyl Sulphoxides: Application to the Synthesis of Lignan Lactones
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Stereochemically and optically pure 2-substituted ethylenic p-tolyl sulphoxides (R)-E-(4) and (R)-Z-(4) undergo readily and stereospecifically an additive Pummerer rearrangement reaction with dichloroketene to give trans- and cis-β-alkyl-α,α-dichloro-γ-p-tolylthio-γ-butyrolactone derivatives (5), respectively.Sequential reductive dechlorination and desulphurization lead to (-)-(S)-, from trans-(5), and (+)-(R)-β-alkyl-γ-butirolactones (7), from cis-(5), with a high optical purity, respectively.Reaction of the intermediate tolylthio derivatives (6) with allyltributylstannane gives β-alkyl-γ-allyl-γ-butyrolactones (15) and (16).These sequential reactions can be successfully applied to the synthesis of (+)-(R)-β-piperonylbutyrolactone (20), the key intermediate for the synthesis of antileukemic lignan lactones, in high chemical and optical yields.Acylation of compound (20) with 3,4,5-trimethoxybenzoyl chloride furnishes (+)-podorhizon (21).
- Kosugi, Hiroshi,Tagami, Katsuya,Takahashi, Akira,Kanna, Hiroshi,Uda, Hisashi
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p. 935 - 943
(2007/10/02)
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- ASYMMETRIC SYNTHESIS OF β-SUBSTITUTED γ-BUTYROLACTONES
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Highly optically pure β-substituted γ-butyrolactones (V) were obtained in good yields by the reaction of (E)-(2R,3S)-6-alkylidene-3,4-dimethyl-2-phenylperhydro-1,4-oxazepine-5,7-dione (I) with phenylthiomethyllithium, followed by i) treatment with trimethyloxonium tetrafluoroborate and ii) acid hydrolysis.
- Mukaiyama, Teruaki,Fujimoto, Katsumi,Hirose, Takuji,Takeda, Takeshi
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p. 635 - 638
(2007/10/02)
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