36results about How to "Reasonable choice of reaction process" patented technology

Production of 2-chlorine-5-fluorine-nicotinate and acid is carried out by 2-chlorine-5-fluorine-nicotinate and related carboxylic acid selective dechlorinating, and 2-chlorine-5-fluorine-nicotinate hydrolyzing 2-chlorine-5-fluorine-niacin under the exist of alkaline substances. It can be used for 2-chlorine-5-fluorine-nicotinate and 2-chlorine-5-fluorine-niacin medicine intermediate.

The invention discloses a synthesizing method of Alikelun of hypertension proteinogenase inhibitor, which comprises the following steps: adopting (1S, 4S, 2'S)-(4-benzyloxy methyl-2-hydroxy-1-{2-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-3-methyl-butyl}-5-methyl-hexyl)-carbonic tert-butyl as raw material; catalyzing; hydrogenating; removing benzyl; separating two R and S-typed diastereomers through column chromatography; obtaining (1S, 2S, 4S, 2'S)-(2-hydroxy-4-methylol-1-{2-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-3-methyl-butyl}-5-methyl-hexyl)-carbonic tert-butyl ester; oxidizing into (1S, 3S, 1'S, 4'S)-{1-(4-isopropyl-5-oxo-tetrahydrofuran-2-radical)-3-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-4-methyl-amyl}-carbonic tert-butyl ester; proceeding amide ester exchange to obtain (1 S, 3S, 1'S, 4'S)-(4-(2-amino formyl-2-methyl-propyl amino formyl)-2-hydroxy-1-{2-[4-methoxy-3-(3-methoxy-propoxy-benzyl]-3-methyl-butyl}-5-methyl-hexyl) carbonic tert-butyl ester; removing terbu-carbonyl to produce Aliskiren.

The invention relates to an industrial method for preparing 3- amino- 2, 2- bimethyl propionamide, which is a segment in high pressure protein proenzyme inhibitor. The invention takes normal and cheap cyanoacetamide as raw material, alkalyating two nethyls, catalytic hydrogenating or adding reducant agent and getting 3- amnio- 2, 2- bimethyl propionamide. The chenmical reaction is shown in the graph. The invention solves problems of difficulty of getting raw material, low productivity and long process line, needs no column chromatography and purification, avoids toxic potassium cyanide and realizes large scale production.

The invention relates to a method for preparing 1-(1-naphtaline) ethylamine possessing optical activity, which mainly solves problems of current process of expensive original raw material, long synthesizing process, low yield coefficient, and over-high cost and the like; the invention has chiral aspartic acid as chiral resolving agent, water or solution of water and dioxane as solvent; under a heating condition, racemate 1-(1-naphtaline) ethylamine is reacted with chiral aspartic acid to form enantiomeric salt. Then, according to different solubility of 1-(1-naphtaline) ethylamine to enantiomeric salt, splitting is carried out, and two configurations (S configuration and R configuration) of 1-(1-naphtaline) ethylamine are separated and prepared; chiral e.e. value for one time of splittingcan reach over 98 percent, with yield coefficient over 30 percent. The method is mainly used for preparing S configuration 1-(1-naphtaline) ethylamine and R configuration 1-(1-naphtaline) ethylamine drug intermediate possessing optical activity and template compound researched and developed by innovative small molecule drugs.

The invention relates to a synthetic method for trandolapril key intermediate (2S, 3aR and 7as)-octahydro-1H-indole-2-carboxylic acid. The method comprises the following steps: obtaining a pair of cis 1, 2-cyclohexane dimethyl acid mono-methyl ester after refluxing hexahydrophthalic anhydride by methanol, splitting the cis 1, 2-cyclohexane dimethyl acid mono-methyl ester by (-) N, N-dimethyl amino diol to obtain 1, 2-cyclohexane dimethyl acid mono-methyl ester of (1R, cis) and (1S, cis) respectively; refluxing (1R, cis)-1, 2-cyclohexane dimethyl acid mono-methyl ester obtained by reclaiming mother liquor in hydrochloric acid to obtain cyclohexane o-dioctyl phthalate, and cyclizing the cyclohexane o-dioctyl phthalate to obtain an initial raw material of the hexahydrophthalic anhydride; and circulating the processes unceasingly to improve the impurity of the (1R, cis)-1, 2-cyclohexane dimethyl acid mono-methyl ester, and then directly entering a follow-up synthesizing process. The process effectively solves the problems of treatment of (1S, cis) 1, 2-cyclohexane dimethyl acid mono-methyl ester after racemization of (d1)1, 2-cyclohexane dimethyl acid mono-methyl ester and yield of (1R, cis)-1, 2-cyclohexane dimethyl acid mono-methyl ester, improves utilization efficiency of raw materials, reduces cost of products, is more suitable for industrialized production, can effectively improve follow-up reaction efficiency, and saves energy of a system.

The invention relates to a novel synthesis method for cis-octahydropyrrolo[3,2-b]pyrrole, and mainly solves the technical problems that raw materials are expensive, reaction conditions are harsh, a reaction route is long, the reaction operation is inconvenient, and a large number of isomers are generated through ring closure in the conventional cis-octahydropyrrolo[3,2-b]pyrrole preparation process. The method comprises the following steps of: performing alkylation reaction of industrially available 3-pyrrolidone serving as an initiative raw material and an allyl compound directly under the action of acid to obtain a 3-tetrahydro-pyrrolidone substitute; performing reductive amination reaction to obtain a 3-aminopyrrolidine derivative; performing protective group adding reaction; and performing ozonization reduction ring-closing reaction and dehydroxylation reaction on the 3-aminopyrrolidine derivative added with the protective group to obtain a corresponding cis-octahydropyrrolo[3,2-b]pyrrole derivative. The target product and important intermediates can be widely applied to synthesizing various pyrrole derivatives.

The present invention relates to continuous industrial preparation process of N-tert-butoxy carbonyl-5-aza-2-oxa-3-one-dicyclo-[2, 2, 1] heptane. The present invention prepares N-tert-butoxy carbonyl-5-aza-2-oxa-3-one-dicyclo-[2, 2, 1] heptane with facile L-hydroxy praline as material, and through methyl esterification, tert-butoxy carbonyl radical protection, paratoluene sulfonation, hydrolysis and lactonization. The present invention has lowered cost, raised yield, less environmental pollution and no need of column chromatographic purification, and may be used in industrial production.

The invention relates to an industrialized preparation method of an N-alkyl substituted-imidazole-5-carboxylic-acid / ester compound, which uses conventional and easily-obtained cranuric chloride as a raw material to react with DMF to generate a gold reagent, and react with alkyl-substituted glycinate to obtain N-alkyl substituted-imidazole-5-carboxylic ester under an alkali condition a loop closure way. N-alkyl substituted-imidazole-5-carboxylic acid can be obtained by hydrolysis. The invention solves the problems of long line, low yield, difficult purification and no scale production of the prior art and can realize the scale industrialized production.

The invention discloses a method for preparing S-1-aminoindane through separation. D-mandelic acid is taken as a chirality resolving agent, a mixed solution of alcohol and water is taken as a solvent, under the condition of heating reflux, 1-aminoindane is dropwise added and racemized, the 1-aminoindane is reacted with the D-mandelic acid to form diastereomeric salt, and the D-mandelate of the S-1-aminoindane is obtained through crystallization and separation according to different solubility of the diastereomeric salt; the S-1-aminoindane is obtained by conducting purification and alkalization on the D-mandelate; all the solutions containing the D-mandelate are mixed, the alcohol is removed through steaming, acidification is conducted on the solution, and the D-mandelate can be recycled. The method for preparing the S-1-aminoindane through the separation has the advantages of being mild in condition, easy to operate, high in product yield, high in optical purity, capable of recycling and reusing the resolving agent and the like, and the method is extremely suitable for industrial production of the S-1-aminoindane.

This invention relates to a process for synthesizing optically active omega-aryl-(2S)-N-tert-butyloxycarbonyl-alpha-amino acid derivative, more specifically, omega-aryl-(2S)-N-tert-butyloxycarbonyl-alpha-amino acid ester. The process comprises: preparing omega-arylalkyl bromide into Grignard reagent, reacting with ethyl N-tert-butyloxycarbonyl-L-pyroglutamate to obtain omega-aryl-5-one-(S)-N-tert-butyloxycarbonyl-alpha-amino acid ethyl ester, and reducing to obtain omega-aryl-(2S)-N-tert-butyloxycarbonyl-alpha-amino acid ethyl ester. The process has such advantages as reasonable reaction process, abundant raw materials, short synthesis time, and no need for expensive enzyme reagents, and is suitable for mass production.

This invention relates to a method for synthesizing optically active 5-aryl-(S)-N-tert-butyloxycarbonyl-alpha-aminopentanoic acid derivative. The method comprises: preparing conventional and abundant phenyl bromide into Grignard reagent, reacting with ethyl N-tert-butyloxycarbonyl-L-pyroglutamate to obtain ethyl 5-aryl-5-one-(S)-N-tert-butyloxycarbonyl-alpha-pentanoate, and reducing to obtain ethyl 5-aryl-(S)-N-tert-butyloxycarbonyl-alpha-pentanoate. The method has such advantages as short reaction time and low cost, and is suitable for mass production. The method solves the problems of long synthesis time, unable industrial production, expensive Pd reagent or enzyme reagent, and high synthesis cost faced by the present technique.

The invention relates to an industrial preparation method of 5-methylpyrazin-2-amine. In the invention, the 5-methylpyrazin-2-amine is prepared from general and easily obtained 5-methyl-2-pyrazinecarboxylic acid by the steps of azidation, Curtius rearrangement and Boc desorption. The chemical reaction formula is shown in the specification. The invention solves the problems of high cost, low yield, environment pollution and the like in the prior art, does not need column chromatography for purification, and can realize large-scale industrial production.

The invention relates to a 3,3-gem-difluoro cyclobutanecarboxylic acid industrial preparation method. The method mainly solves the technical problem of existing preparing methods that the price of the raw material 3-oxo-cyclobutylcarboxylic acid or 3-methylenecyclobutane-carbonitrile and the price of the fluoro reagent DAST are high, and therefore large-scale production can not be conducted. According to the 3,3-gem-difluoro cyclobutanecarboxylic acid industrial preparation method, conventional methyl acrylate and 1,1-dichloro-2,2-difluoroethylene which are easy to obtain are taken as raw materials, and 3,3-gem-difluoro cyclobutanecarboxylic acid is obtained through addition, hydrolysis and hydrogenation. Please see the description for the chemical equation. The 3,3-gem-difluoro cyclobutanecarboxylic acid industrial preparation method is simple, practical and quite low in preparing cost.

The invention relates to an industrial preparation method of spiral (benzo (e) (1,3) oxazine-2, 4'-piperidine)-4(3H)-ketonic, which uses economical, easily-obtained and scale-produced salicylic acid (and various para-orientation salicylic acids) and N-protecting piperidone (including Boc, Cbz, acyl groups and alkyl group protection) as raw materials, and spiral (benzo (e) (1,3) oxazine-2, 4'-piperidine)-4(3H)-ketonic is obtained after methyl esterification, aminolysis and the close under the catalysis of piperidine or morpholino. The invention solves the problems of complex reaction, low purity and yield, and the like in the prior art, does not need column chromatography purification and can realize scale industrial production.

The present invention relates to industrial preparation process of N-tert-butoxy carbonyl-5-aza-2-oxa-3-one-dicyclo-[2, 2, 1] heptane in one kettle. The present invention prepares N-tert-butoxy carbonyl-5-aza-2-oxa-3-one-dicyclo-[2, 2, 1] heptane with facile L-hydroxy praline as material, and through methyl esterification, tert-butoxy carbonyl radical protection, paratoluene sulfonation, hydrolysis and lactonization. The present invention has lowered cost, raised yield, less environmental pollution and no need of column chromatographic purification, and may be used in industrial production.

The invention relates to an industrialized preparation method of using 2-bromothiazole for compounding thiazole-2-methanamide in a one-boiler mode, which uses cheap and easily-obtained 2-bromothiazole as a raw material to obtain thiazole-2-methanamide after carbonyl-inserting reaction, chlorination and ammonolysis. The reaction formula is as above. The invention solves the problems of environmental pollution, safety danger in production, high cost, low yield, and the like in the prior art, the intermediate product is not required to be purified, the target product can be obtained in one step, the operation is simple, and the large-scale industrialized production can be realized.

The invention relates to a synthetic method for trandolapril key intermediate (2S, 3aR and 7as)-octahydro-1H-indole-2-carboxylic acid. The method comprises the following steps: obtaining a pair of cis 1, 2-cyclohexane dimethyl acid mono-methyl ester after refluxing hexahydrophthalic anhydride by methanol, splitting the cis 1, 2-cyclohexane dimethyl acid mono-methyl ester by (-) N, N-dimethyl amino diol to obtain 1, 2-cyclohexane dimethyl acid mono-methyl ester of (1R, cis) and (1S, cis) respectively; refluxing (1R, cis)-1, 2-cyclohexane dimethyl acid mono-methyl ester obtained by reclaiming mother liquor in hydrochloric acid to obtain cyclohexane o-dioctyl phthalate, and cyclizing the cyclohexane o-dioctyl phthalate to obtain an initial raw material of the hexahydrophthalic anhydride; and circulating the processes unceasingly to improve the impurity of the (1R, cis)-1, 2-cyclohexane dimethyl acid mono-methyl ester, and then directly entering a follow-up synthesizing process. The process effectively solves the problems of treatment of (1S, cis) 1, 2-cyclohexane dimethyl acid mono-methyl ester after racemization of (d1)1, 2-cyclohexane dimethyl acid mono-methyl ester and yield of (1R, cis)-1, 2-cyclohexane dimethyl acid mono-methyl ester, improves utilization efficiency of raw materials, reduces cost of products, is more suitable for industrialized production, can effectively improve follow-up reaction efficiency, and saves energy of a system.

Production of 2-chlorine-5-fluorine-nicotinate and acid is carried out by 2-chlorine-5-fluorine-nicotinate and related carboxylic acid selective dechlorinating, and 2-chlorine-5-fluorine-nicotinate hydrolyzing 2-chlorine-5-fluorine-niacin under the exist of alkaline substances. It can be used for 2-chlorine-5-fluorine-nicotinate and 2-chlorine-5-fluorine-niacin medicine intermediate.

The present invention relates to industrial preparation process of N-tert-butoxy carbonyl-5-aza-2-oxa-3-one-dicyclo-[2, 2, 1] heptane in one kettle. The present invention prepares N-tert-butoxy carbonyl-5-aza-2-oxa-3-one-dicyclo-[2, 2, 1] heptane with facile L-hydroxy praline as material, and through methyl esterification, tert-butoxy carbonyl radical protection, paratoluene sulfonation, hydrolysis and lactonization. The present invention has lowered cost, raised yield, less environmental pollution and no need of column chromatographic purification, and may be used in industrial production.

The invention relates to a method of de-tert-alkyl amine, which mainly solves the technical problems of over strong reacting conditions and low yield of the prior method. The method of de-tert-alkyl amine is characterized in that tertiary tert-alkyl acid amide is reacted in the mixed solution of trifluoroacetic acid and water and is hydrolyzed into corresponding carboxylic acids, the volume ratio of the trifluoroacetic acid and water is 1-100: 0-5, and the reacting formula is as above. In the formula, R and R' are the alkyl group or the aromatic group of C1 to C20, and the reaction temperature is from the room temperature to the solvent reflux temperature. The invention hydrolyzes the tertiary tert-alkyl amine into corresponding carboxylic acids under a mild condition.

The invention relates to a method for preparing 3-aza-bicyclo[4.1.0]heptane-6-formic acid with a protective group, and mainly solves the technical problem that multi-step chromatographic purification is needed in the conventional process for preparing the 3-aza-bicyclo[4.1.0]heptane-6-formic acid. The method comprises the following steps of: performing reflux alkylation reaction on conventional and readily available ethyl isonicotinate serving as a raw material and halohydrocarbon in alcohol solution to obtain quaternary ammonium; performing cyanoborohydride reaction to obtain amino-protected 1,2,3,6-tetrahydropyridine-4-ethyl formate; not performing purification, and directly performing ring-closing reaction to obtain a three-membered ring; and performing alkaline hydrolysis reaction to obtain amino-protected 3-aza-bicyclo[4.1.0]heptane-6-formic acid. The 3-aza-bicyclo[4.1.0]heptane-6-formic acid with the protective group is an important medicinal intermediate.

The present invention relates to continuous industrial preparation process of N-tert-butoxy carbonyl-5-aza-2-oxa-3-one-dicyclo-[2, 2, 1] heptane. The present invention prepares N-tert-butoxy carbonyl-5-aza-2-oxa-3-one-dicyclo-[2, 2, 1] heptane with facile L-hydroxy praline as material, and through methyl esterification, tert-butoxy carbonyl radical protection, paratoluene sulfonation, hydrolysis and lactonization. The present invention has lowered cost, raised yield, less environmental pollution and no need of column chromatographic purification, and may be used in industrial production.

The invention relates to an industrialized preparation method of using 2-bromothiazole for compounding thiazole-2-methanamide in a one-boiler mode, which uses cheap and easily-obtained 2-bromothiazoleas a raw material to obtain thiazole-2-methanamide after carbonyl-inserting reaction, chlorination and ammonolysis. The reaction formula is as below. The invention solves the problems of environmental pollution, safety danger in production, high cost, low yield, and the like in the prior art, the intermediate product is not required to be purified, the target product can be obtained in one step, the operation is simple, and the large-scale industrialized production can be realized.

The invention relates to the organic synthesis field, and especially discloses a 5-bromo-2-furfural synthesis method. The 5-bromo-2-furfural synthesis method which treats furfural and bromine as raw materials is characterized in that the method comprises the following steps: placing the raw materials in an aprotic solvent, reacting at 25-70DEG C for 2-24h under the initiation of resorcinol and sulfur, concentrating, washing, drying to obtain an oily product, processing the oily product by using a mixed solution comprising water and alcohol to obtain a crude product, and recrystallizing to obtain pure 5-bromo-2-furfural. The method has the advantages of reasonable selection of the reaction technology, mild product condition, simple operation, stable product quality, high product purity, and avoiding of the aldehyde group protection and deprotection, and the separation and purification of an intermediate in a multistep reaction.

The invention relates to a method for synthesizing substituted amino carboxylic acid, in particular to a method for synthesizing the substituted amino carboxylic acid by utilization of Ugi reaction. The method mainly solves the technical problems of rigorous reaction conditions and low industrialization degree in the prior synthesis method. The method adopts the technical proposal that the method adopts tert-butyl isonitrile which can be obtained by commercialization as a raw material, obtains corresponding t-butyl carboxamide through the Ugi reaction, and obtains the substituted amino carboxylic acid by mildly hydrolyzing the t-butyl carboxamide under the action of trifluoroacetic acid and water. The synthesis technology is as shown in the formula. In the technology, R, R1 and R2 refer to alkyl groups or aryl groups between C1 and C20; the volume ratio of the trifluoroacetic acid to the water in the second step, namely TFA:H2O, is between 1:5 and 100:0; and the reaction temperature is between the room temperature and the solvent reflux temperature.

The process of preparing 4, 7-diazaindole includes the following steps: 1. reaction of amino-3-methyl pyrazine and pivaloyl chloride or Boc anhydride to obtain 2-pivaloyl amino-3-methyl pyrazine or 2-tert-butyloxyformamido-3-methyl pyrazine; 2. reaction of the obtained 2-pivaloyl amino-3-methyl pyrazine or 2-tert-butyloxyformamido-3-methyl pyrazine with R2Li and HCOR3 to produce aldehyde intermediate; and 3. eliminating the protecting ring of the intermediate to obtain 4, 7-diazaindole. The present invention is one effective process of synthesizing 4, 7-diazaindole as one medicine intermediate.