111 results about "Brivaracetam" patented technology

The invention provides a preparation method of brivaracetam. The preparation method of brivaracetam comprises the following steps of in an alkaline reagent, reacting malonate ester and (R)-epichlorohydrin to obtain lactone (II), reacting the lactone (II) and an ethyl metal-based reagent to obtain an intermediate (III), removing carboxylase to obtain (R)-4-propyl-dihydrofuran-2-ketone (IV), performing ring-opening reaction under the action of a halogenated ring-opening reagent to obtain (R)-3-halogenarated methyl hexanoate or (R)-3- halogenarated methyl hexyl acetate (V), and reacting with (S)-2-aminobutanamide or an acceptable salt, so as to obtain the brivaracetam. The preparation method has the advantages that the high-purity brivaracetam (HPLC (high performance liquid chromatography: greater than 96%) and stereo rotary brivaracetam (chirality HPLC: greater than 98%) can be directly prepared; the silicagel column separation and purification or the chirality preparation column separation and purification is not used, so that the complicated separation and purification step is not performed, the cost is saved, and the preparation method is more suitable for industrial production.

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.

The invention discloses a preparation method of a brivaracetam intermediate. The preparation method comprises the following steps: performing reaction on 4-n-propyl-2(5H)-furanone as a substrate in anaqueous buffer solution of which temperature is 25 to 30 DEG C and a pH value is 6.0 to 9.0 under effects of recombinant alkene reductase and coenzyme as well as a coenzyme regeneration system to generate an intermediate (R)-4-n-propyl-dihydrofuran-2-one. According to the preparation method disclosed by the invention, by adopting specific alkene reductase, the problems of long synthetic route, low yield and high cost of an existing brivaracetam intermediate (R)-4-n-propyl-dihydrofuran-2-one and large environment protection pressure caused by adopting a toxic and dangerous reagent are solved,and the brivaracetam intermediate in the prior art has important industrial application value.

The invention relates to an antiepileptic drug brivaracetam chiral intermediate and a preparing method thereof. The preparing method of a compound, shown in a formula 1, of the brivaracetam chiral intermediate comprises the steps of with S-epichlorohydrin (a compound shown in a formula 7 being an original raw material, conducting open-loop preparing on ethyl metal reagent under the effect of Lewisacid to obtain a compound shown in a formula 6; conducting preparing on the compound shown in the formula 6 in the presence of a metal catalyst through a substitution reaction to obtain a compound shown in a formula 5; conducting cyan alcoholysis on the compound shown in the formula 5 under the effect of acid to obtain a compound shown in a formula 4; preparing the compound shown in the formula 4through the effect of hydroxyl activity reagent to obtain a compound shown in a formula 3; conducting preparing on the compound shown in the formula 3 and nitromethane through an SN2 nucleophilic substitution effect to obtain a compound shown in a formula 2; conducting cyclization preparing on the compound shown in the formula 2 through the effect of concentrated sulfuric acid and an Nef reactionto obtain a compound shown in a formula 1, namely the brivaracetam chiral intermediate. By means of the preparing method, the compound high in optical purity and shown in the formula 1 can be prepared and solve the problem that currently produced brivaracetam needs complex unit operation high in cost like a column chromatography and a chiral preparation column.

The invention discloses a method for preparing furanone compounds, and provides a method for preparing a furanone compound III. The method includes the following steps that in a solvent, in the presence of inorganic salt, a compound II and a reducing agent are subjected to a reduction reaction, and the furanone compound III is obtained; the solvent is a fatty alcohol solvent or a mixed solvent of a fatty alcohol solvent and water. The brivaracetam can be prepared with the furanone compound III only with the three steps, and the synthetic route is short; the ee value of the compound II is larger than 99.0%, racemization does not occur in the reaction process, and the de value of a brivaracetam I crude product is larger than 99.0%; the brivaracetam I crude product is further purified through a crystal instead of a chirality high-pressure-liquid-phase preparing column, and the chirality purity of brivaracetam I can be further increased to be the de value of 99.80% or above; meanwhile, the content of other individual impurities of the brivaracetam I is smaller than 0.1%, and reaches the API level, and the method is suitable for industrial production. The formula is defined in the description.

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.

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.

The present invention provides a scalable synthesis of enantiomerically pure brivaracetam, and related derivatives.