- Simple route to synthesize (E)-3-propyl-4-oxo-2-butenoic acid esters through the Z isomer
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Esters of 3-alkyl-4-oxo-2-butenoic acid, which are very important synthons, are not equally accessible in both E and Z configurations. The (Z)-isomers can be easily obtained from 3-alkyl-4-hydroxybutenolides, in turn prepared by aminoalkylation of aliphatic aldehydes with glyoxylic acid. The (E)-isomers, on the contrary, result from laborious procedures: the condensation of aldehydes with glyoxylic acid, followed by separation from γ-hydroxybutenolide by-product and esterification, or of aldehyde enamines with glyoxylic esters, followed by Z ester by-product conversion into γ-aminobutenolide and purification. Here, we describe a straightforward route to the title compounds, applied to methyl (E)-3-propyl-4-oxo-2-butenoate, avoiding any problematic by-product or isomer chromatographic separation: pentanal and glyoxylic acid are condensed to 3-propyl-4-hydroxybutenolide, which is converted to methyl (Z)-3-propyl-4-oxo-2-butenoate and then isomerized to E ester under acidic conditions.
- Bolchi, Cristiano,Roda, Gabriella,Pallavicini, Marco
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- Intermediate for synthesizing brivaracetam and preparation method thereof
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The invention provides an intermediate compound for synthesizing brivaracetam, namely (2S)-2-(5-oxy-3-propyl-2, 5-dihydrofuran-2-yl) amino) butylamide (I), and a preparation method of the intermediatecompound. The compound (I) comprises (S)-2(((R)-5-oxy-3-propyl-2, 5-dihydrofuran-2-yl) amino) butyramide (I)-R, or (S)-2-(((S)-5-oxy-3-propyl-2, 5-dihydrofuran-2-yl) amino) butyramide (I)-S, or a mixture of (I)-R and (I)-S in any proportion. The compound shown in the formula (I) can be used for synthesizing brivaracetam, and a novel method is provided for designing a concise and efficient brivaracetam synthesis route.
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Paragraph 0017-0018
(2021/02/10)
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- PROCESS FOR THE PREPARATION OF BRIVARACETAM
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The present invention relates to a process for the preparation of brivaracetam, a compound of formula I and salts thereof. The present invention also relates to a compound of formula II and a compound of formula IIA, process for its preparation and conversion thereof to brivaracetam, the compound of formula I.
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Paragraph 0099
(2021/06/26)
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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; 31; 32
(2020/07/31)
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- Asymmetric catalytic preparation method of brivaracetam
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The invention discloses a preparation method of brivaracetam, which adopts cheap and accessible hydrogen as a hydrogen source, can implement asymmetric preparation of brivaracetam in a catalytic system with rhodium (I) as a metal center, and has the advantages of mild reaction conditions, simplicity, controllability, high yield, high enantioselectivity, environment friendliness, favorable atom economy, low cost and the like. In addition, the invention also provides the brivaracetam compound prepared by the method.
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Paragraph 0070-0072
(2020/11/12)
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- Brivaracetam intermediate and preparation method thereof
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The invention provides a compound, 3-(((S)-1-amino-1-oxobutyl-2-yl)amino)methyl)hexanoic acid (I) and a preparation method thereof. The compound (I) comprises (R)-3-(((S)-1-amino-1-oxobutyl-2-yl)amino)methyl)hexanoic acid (I)-R, or (S)-3-(((S)-1-amino-1-oxobutyl-2-yl)amino)methyl)hexanoic acid (I)-S, or a mixture of (I)-R and (I)-S in any proportion. The compound shown in the formula (I) can be used for synthesizing brivaracetam, and a new thought and a new method are provided for designing a concise and efficient route for synthesizing brivaracetam.
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Paragraph 0015; 0016
(2020/01/08)
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- Preparation method of brivaracetam isomer (2S,4S)
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The invention discloses a preparation method of a brivaracetam isomer (2S,4S). The preparation method comprises the following step: in an alcohol solvent, carrying out a salt forming reaction as shownin a formula (shown in the specification) on a compound I and a resolving agent to obtain a compound as of a formula S, wherein the resolving agent is (+)-camphorsulfonic acid, D-(+)-camphanic acid,L-(-)-dibenzoyltartaric acid, D-(+)-dibenzoyltartaric acid, L-(-)-tartaric acid, L-(-)-phenylalaninol or S-(-)-phenylethylamine. The preparation method provided by the invention is low in price and easily available in raw material and mild in reaction condition. By adopting a chemical resolution method, a chromatographic column is not used, so that the preparation method is simple to operate, lowin cost and suitable for production on a large scale. The formula is as shown in the description.
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Paragraph 0073-0076; 0105-0108; 0124-0127; 0143-0146
(2019/04/27)
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- PROCESS FOR PREPARING BRIVARACETAM
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The present invention relates to a new process for preparing brivaracetam. (Ib)
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Page/Page column 6-7
(2017/06/23)
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- Brivaracetam and preparation method of intermediate thereof
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The invention discloses a preparation method of a brivaracetam intermediate shown in B-VI. The preparation method comprises the following steps of dissolving B-IV and R-phenylethylamine into a solvent, crystallizing, filtering, and recrystallizing, so as to obtain B-V; then, converting into B-VI. The preparation method has the advantages that a chiral chromatographic column separation isomer is not needed in the preparation process, and only the simple steps of extraction, washing, drying, concentration and the like are performed, so as to separate effective ingredients; the separation process is simple, and the production cost of brivaracetam is greatly reduced. A formula is shown in the description.
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Paragraph 0064; 0065; 0081; 0082; 0098; 0099; 0115; 0116
(2017/07/19)
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- CONTINUOUS PROCESS FOR PREPARING BRIVARACETAM
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The present invention relates to a continuous flow process for preparing brivaracetam.
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Page/Page column 9
(2017/09/02)
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- THREE COMPONENT CO-CRYSTAL FORMATION BETWEEN DIASTEREOMERIC MIXTURES OF 3-ALKYL-4-((S)-1'PHENYLETHYLAMINO) BUTANOIC ACID AND OPTICALLY PURE 1, 1'-BI-2-NAPHTHOL
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A ternary co-crystal consisting of 1 :0.5:0.5 molar proportion of (S)-1,1'-bi-2-naphthol, 3(S)-propyl-4-[(S)1 '-phenyl-ethylamino]-butanoic acid and 3(R)-propyl-4-[(S)1'- phenyl-ethylamino]-butanoic acid having characteristic powder X-ray diffraction pattern with 2Θ values of 8.41, 9.38, 10.32, 12.16, 15.52, 15.51, 17.84, 17.95, 19.16, 20.37, 21.74, 22.55, 24.44, 25.65, 28.40, 29.15, 29.69, 31.31, 33.54, 34.40, 35.43 (±0.2) and having differential scanning calorimetric peak at about 189.23 ° C when analyzed at the rate of heating of 10°C per minute and process for preparing the same. A process for resolution of (S)-1,1'-bi-2-naphthol from RS-1,1'-bi-2-naphthol.
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Page/Page column 20-21
(2012/02/02)
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- METHOD OF RESOLUTION OF (RS)- 1,1'-BI-2-NAPHTHOL FOR OBTAINING ENANTIOMERIC PURE I.E. (S)-(-)-1,1'-BI-2-NAPHTHOL AND/OR (R)-(+)-1,1'-BI-2-NAPHTHOL VIA CO-CRYSTAL FORMATION WITH OPTICALLY ACTIVE DERIVATIVES OF y -AMINO ACIDS
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Novel method for synthesis of optically pure (S)-(?)-1,1′-bi-2-naphthol and/or (R)-(+)-1,1′-bi-2-naphthol via resolution of racemic (RS)-1,1′-bi-2-naphthol through formation of co-crystal with optically active derivatives of γ-amino acids.
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Page/Page column 10
(2013/02/27)
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- METHOD FOR PREPARATION OF ENANTIOMERICALLY ENRICHED AND/OR RACEMIC GAMMA-AMINO ACIDS
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A process for preparation of enantiomerically enriched and/or racemic γ-amino acids, particularly those useful for preparing γ-amino acids that exhibit binding affinity to the human α2δ calcium channel subunit, including pregabalin and related compounds such as 3-n-propyl-4-aminobutyric acid.
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Page/Page column 23-24
(2011/08/04)
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- METHOD OF RESOLUTION OF (RS) - 1, 1 ' - BI - 2 - NAPHTHOL FOR OBTAINING ENANTIOMERIC PURE I.E. (S) - (-) " 1, 1 ' "BI - 2 -NAPHTHOL AND/OR (R) - ( ) - 1, 1 ' - BI - 2 - NAPHTHOL VIA CO - CRYSTAL FORMATION WITH OPTICALLY ACTIVE DERIVATIVES OF GAMMA -AMINO ACIDS
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Novel method for synthesis of optically pure (S)-(-)-1,1'-bi-2-naphthol and/or (R)-(+)-1,1'-bi-2-naphthol via resolution of racemic (RS)-1,1'-bi-2-naphthol through formation of co-crystal with optically active derivatives of γ -amino acids.
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Page/Page column 24
(2011/08/04)
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- PROCESS FOR PREPARING 2-OXO-1-PYRROLIDINE DERIVATIVES
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The present invention relates to a new process for preparing 2-oxo- I -pyrrolidine derivatives of general formula (I) wherein the substituents are as defined in the specification.
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Page/Page column 8
(2008/06/13)
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- Lactone Chemistry. Synthesis of β-Substituted, γ-Functionalized Butanolides and Butenolides and Succinaldehydic Acids from Glyoxylic Acid
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The Mannich-type aminoalkylation reaction of enolizable aldehydes with morpholine and glyoxylic acid instead of formaldehyde was investigated: in basic and neutral media were obtained α,γ-dimorpholinobutanolides 2 and α-morpholino-γ-hydroxybutanolides 1, respectively.In acidic medium the spontaneous elimination of the α-morpholino group afforded the γ-hydroxybutenolide 8.The reaction pathways were suggested from the isolation and characterization of some intermediates of the Mannich reaction.These lactone structures constitute versatile synthetic intermediates for the preparation of β-substituted succinaldehydic acids 15 and 5-substituted 3-(2H)-pyridazinones 13 and 14.
- Bourguignon, J. J.,Wermuth, C. G.
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p. 4889 - 4894
(2007/10/02)
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