37 results about "Dieckmann condensation" patented technology

The invention relates to the field of organic synthesis and medicine, and discloses a preparation method for N-substituted methyl-3,5-disubstituted benzylidene base-4-piperidone and biological activity for efficiently inhibiting cell line proliferation such as leukemia, ovarian cancer, breast cancer, liver cancer and esophagus cancer. The method includes: starting from various substituted methylamine and methyl acrylate, sequentially going through Michael addition, Dieckmann condensation, acidolysis and decarboxylation to obtain N-substituted methyl-4-piperidone, and subjecting the N-substituted methyl-4-piperidone to aldol reaction with substituted benzaldehyde to obtain a target compound N-substituted methyl-3,5-disubstituted benzylidene base-4-piperidone. The target compound can selectively and efficiently inhibit cell line proliferation such as leukemia, ovarian cancer, breast cancer, liver cancer and esophagus cancer, and activity of inhibiting carcinoma cell line proliferation is obviously higher than conventional chemotherapeutic 5-fluorouracil.

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.

The invention discloses an industrial production method of high purity loxoprofen sodium dehydrate; according to the method, adipic acid diester is taken as a starting material for Dieckmann condensation reaction with 2-(4-bromomethyl phenyl) propionate under strong alkaline conditions, the yield and quality of compound II are effectively improved, because the adipic acid diester on the market is lower in cost than 2-ethoxy carbonyl cyclopentanone, the production cost can be greatly reduced; the compound obtained by reaction is processed sequentially by hydrolysis and decarboxylation under acidic conditions, in the hydrolysis and decarboxylation process, generated low boiling point alcohol solvents and carbon dioxide gas can be removed by atmospheric distillation, the reaction can be effectively promoted, the reaction time is shortened, the conversion rate is improved; and finally the final product loxoprofen sodium dehydrate is generated under the condition of aqueous sodium hydroxide solution. The preparation method can greatly reduce the manufacturing cost of loxoprofen sodium, and is more suitable for the industrialized production than the existing technology.

The invention provides a tetrahydropyridopyridone derivative as shown in a general formula (I), and a preparation method thereof. The method comprises the following steps of: preparing N,N-bi(methoxycarbonyl group) substituted benzylamine (b) by carrying out Michael addition on substituted benzylamine (a) and methyl acrylate, carrying out Dieckmann condensation on (b) under the action of sodium alcoholate, subsequently carrying out hydrolysis and decarboxylation under the action of acid so as to obtain N-substituted benzyl-4-piperidone (d), carrying out an aldol condensation reaction on (d) and bimolecular aromatic aldehyde so as to obtain N-substituted-3,5-bi(substituted benzylidene piperidine-4-ketone (e), and refluxing and heating (e) malononitrile and ammonium acetate in ethanol so as to obtain a final product as shown in the general formula (I). The tetrahydropyridopyridone derivative is simple in process and convenient to produce in scale, and the compound (I) has a good inhibition effect on multiplication of leukemia K562 cells, ovarian cancer HO-8910 cells and liver cancer SMMC-7721 cells. Therefore, the invention further provides an application of the compound as shown in the general formula (I) in preparing medicaments for preventing multiplication of the leukemia K562 cells, the ovarian cancer HO-8910 cells and the liver cancer SMMC-7721 cells.

The invention provides 2, 3, 5, 7-tetrasubstituted dihydro-pyrazolo piperidine derivative and a preparation method and application thereof. The derivative is 2, 3-bis(substituted phenyl)-5-subsituted arylmethyl-7-substituted benzylidene dihydro-pyrazolo piperidine derivative, having the following formula (I). The preparation method includes using substituted arylmethyl amine and methyl acrylate as raw materials; subjecting the materials to Michael addition, Dieckmann condensation and hydrolysis-decarboxylation sequentially; allowing for Aldol reaction with substituted benzaldehyde to obtain intermediate N-substituted arylmethyl-3, 5-bis(substituted benzylidene)-4-piperidone; allowing for condensation with substituted phenylhydrazine to obtain a compound according to the formula (I). The derivative is efficient in inhibiting multiplication of various carcinoma cell lines such as leukemia, esophagus cancer, ovarian cancer and breast cancer in human, is well stably metabolic in liver microsomes of human and rat, is free of direct and competitive inhibition on five enzymes of liver microsomes, such as CYP3A4, CYP2D6, CYP2C9, CYP1A2 and CYP2C19, is highly bioavailable, is low in toxicity to normal cells, and is available for the preparation of drugs for the cancers.

The invention provides a method for continuous production of dimethyl succinylo succinate. The technical scheme employs continuous drip adding to carry out Claisen condensation reaction on dimethyl succinate and sodium methoxide and Dieckmann condensation reaction, and can realize continuous discharge, after a certain product is collected, and then dilute sulfuric acid acidification is carried out to obtain dimethyl succinylo succinate. The method provided by the invention is designed based on classical experimental principles, and the operation mode is improved to form a brand-new technological process. The technical scheme shortens the reaction time, also reduces energy consumption, significantly improves the production efficiency, and at the same time overcomes the problem of large quality difference between different batches in batch production. The method provided by the invention takes innovative technological improvement and achieves good technical effect, simultaneously has the characteristics of low cost and easy realization, thus having good popularization prospect.

The invention relates to a preparation method of 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine, which is an important intermediate for preparing arginine vasopressin V2 receptor antagonist Tolvaptan. The preparation method comprises the following steps: with methyl 2-amido-5-chlorobenzoate and ethyl 4-bromobutyrate as starting raw materials, reacting at a low temperature under the effect of an acid binding agent to generate secondary amine first, then carrying out Dieckman condensation reaction at a raised temperature to generate an intermediate mixture III, and finally carrying out hydrolysis to obtain the target compound 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine. Compared with the existing method, the method provided by the invention has the advantages that the reaction steps are reduced, the two-step reaction is simplified to one-step reaction through temperature control, so the operation is simple, the processing is convenient, the product purity is high, and the yield is also greatly improved, thus the production cost can be reduced, and the benefits are increased.

The invention relates to a Dolasetron isomer or salt thereof, a preparation method for the Dolasetron isomer or salt thereof and application of the Dolasetron isomer or salt thereof. In the preparation method, the Dolasetron isomer or salt thereof is prepared from outside-hexahydro-8-hydroxy-2,6-methylene-2H-quinolizidine-3(4H)-ketone or salt thereof serving as a raw material by esterifying and salifying. The invention also provides two methods for synthesizing outside-hexahydro-8-hydroxy-2,6-methylene-2H-quinolizidine-3(4H)-ketone. The outside-hexahydro-8-hydroxy-2,6-methylene-2H-quinolizidine-3(4H)-ketone is prepared from the compound (6) shown in the specification and serving as a raw material by the steps of reducing, protecting hydroxyl, performing Dieckmann condensation and performing hydrolysis and decarboxylation, or by the steps of reducing, performing Mitsunbu esterification, performing hydrolysis, protecting hydroxyl, performing Dieckmann condensation and performing hydrolysis and decarboxylation. The invention also relates to application of the Dolasetron isomer or the salt thereof to preparation of Dolasetron, or application of the salt of the Dolasetron isomer to preparation of control products for detection.

The invention relates to a tert-butyl-7,9-dioxo-2,6-diazaspiro[4.5]decane-2-formate preparation method. A purpose of the present invention is to mainly solve the technical problem that no method is suitable for industrial synthesis in the prior art. The method comprises four steps, and comprises: dissolving a compound 1 in ethanol to generate a compound 2 under the action of ammonium acetate and monoethyl malonate; in the presence of potassium carbonate, making the compound 2 act with ethyl malonyl chloride in a mixed solution of tetrahydrofuran and water to obtain a compound 3; and carrying out a Dieckmann condensation reaction on the compound 3, toluene and sodium methoxide, treating to obtain a compound 4, and carrying out heating decarboxylating on the compound 4 in water and acetonitrile to obtain a compound 5, wherein the reaction formula is defined in the specification. According to the present invention, the obtained compound can be used as the useful intermediates or productsfor synthesis of a plurality of medicaments.

The invention discloses equisetin-derived 2, 4-pyrrolidine-diketone compounds. The diketone compounds have the structure shown in the specification, wherein R1 is hydrogen, alkyl, aryl or a heteroatom group containing O and N; R2 is hydrogen or alkyl; R3 is hydrogen or alkyl. A synthesis method of the diketone compounds comprises eight steps, wherein aldehyde II is prepared in the four steps; a polyene compound III is prepared through a Wittig reaction or Horner-Wadswort-Emmons reaction; a compound IV' is prepared through a Diels-Alder reaction; finally a compound V is prepared by ammonolysis and Dieckmann condensation. The compounds have relatively high biological activity and bring the foundation to the research and development of anti-cancer medicaments; the raw materials used in synthesis are simple and easy to obtain; the synthesis process is simple to carry out; the yield is relatively high.

The invention discloses a N-substituted benzyl tetrahydropyridine with -5-substituted indole and preparation method and application thereof, and the structure is shown in the general formula (I): substituted benzene methylamine (ethylamine) and methyl acrylate are raw materials, and an intermediate N-substituted benzylpiperidine (phenylethylpiperidine)-4-ketone is obtained by three steps of reaction such as Michael addition, Dieckmann condensation and hydrolysis decarboxylation or the like in sequence, and the object (I) is obtained by condensation reaction of the intermediate and 5-substituted indole. The compound (I) can effectively inhibit proliferation of human leukemia K562, Jurkat, U937, THP-1 cell line, the human esophagus cancer ECA-109 cell line, human liver cancer SMMC-7721 cell line, human ovary cancer HO-8910 cell line, human breast cancer MCF-7 cell line, breast cancer MDA-MB-231 cell line; the compound has a good metabolism stability in the human and rat liver microsomes; The compound does not have mechanical inhibition effects for five enzymes of human liver microsomes such as CYP3A4, CYP 2D6, CYP2C9, CYP1A2 and CYP2C19 or the like; the compound can induce the cell cycle G2/M retardance and promote cancer cell apoptosis and inhibit cancer cell propagation.

The invention provides a tetrahydropyridine oxapicene derivative and a preparation method thereof. The method comprises the following steps: subjecting substituted amine (a) and methyl acrylate to Michael additive reaction to prepare N,N-bis(beta-methyl propionate) substituted amine (b), subjecting the N,N-bis(beta-methyl propionate) substituted amine (b) to Dieckmann condensation under the action of sodium alkoxide and hydrolysis and decarboxylation under the action of acid to obtain N-substituted piperidine-4-ketone (d), and subjecting two active methylenesand and bimolecular aromatic aldehydes of the N-substituted piperidine-4-ketone (d) to reaction to remove bimolecular water to obtain N-substituted-3,5-2-benzylpiperidine-4-ketone (e); and carrying out reflowing and heating on the N-substituted-3,5-2-benzylpiperidine-4-ketone (e) and malononitrile in normal butanol to obtain a final product shown as a general formula (I). The preparation method is simple in process and convenient for mass production; and the obtained product has a favorable inhibiting effect for the cell proliferation of leukemia K562, oophoroma HO-8910 and liver cancer SMMC-7721.

The invention provides a dihydro-pyrazolo hexahydropyridine derivative and a preparation method thereof. The method comprises the following steps of: performing Michael addition reaction of substituted amine (a) and methyl acrylate to prepare N,N-bis(beta-methyl propionate) substituted amine (b); performing Dieckmann condensation of (b) under the action of sodium alcoholate and hydrolyzing and decarboxylating under the action of acid to obtain yellow oily matter N-substituted piperidine-4-ketone (d); reacting (d) and aromatic aldehyde to remove bimolecular water to obtain N-substitution-3,5-dibenzal piperidine-4-ketone (e); and performing reaction of (e) to form the dihydro-pyrazolo hexahydropyridine derivative. The preparation method is simple, and the dihydro-pyrazolo hexahydropyridine derivative is convenient to produce in large scale; and a lead compound of the prepared dihydro-pyrazolo hexahydropyridine new medicine has the obvious inhibitory activity on leukemia K562 cancer cellproliferation, and has the obvious practicality in the production of modern medicines.

The invention discloses a N-heterocyclic methyl tetrahydropyridine-5-substituted indole and preparation method and application thereof, and the structure is shown in the general formula (I): heterocyclic methylamine and methyl acrylate are raw materials, and an intermediate N-heterocyclic methyl-4-piperidone is obtained by three steps of reaction such as Michael addition, Dieckmann condensation and hydrolysis decarboxylation or the like in sequence, and the object (I) is obtained by condensation reaction of the intermediate and 5-substituted indole. The compound (I) can effectively inhibit propagation of cell lines such as human leukemia K562, Jurkat, U937, THP-1; human esophagus cancer ECA-109; human liver cancer SMMC-7721; human ovary cancer HO-8910; human breast cancer MCF-7 and breast cancer MDA-MB-231; the compound inhibits the propagation of cancer cells by promoting cancer cell apoptosis. The compound can be applied to preparation of anticancer medicament.

The invention provides a preparation method of a substituted thiophene-3-one compound, comprising: subjecting material A and material B to Michael addition reaction to obtain an addition product; subjecting the addition product to Dieckmann condensation reaction to obtain a substituted thiophene-3-one compound having a structure shown as formula (IV) that is shown in the description. The preparation method provided by the application has the advantages that using solvents and strong bases is not required, reaction materials are low in price and easy to obtain, no wastewater is produce, and therefore, the preparation method has good environmental friendliness; compared with existing preparation methods, the preparation method has a short synthetic route, can be performed under mild conditions and features good yield stability and good repeatability, which is helpful for greatly increasing total yield of the substituted thiophene-3-one compound and helpful for industrial popularization.

The invention relates to the field of chemical and medicinal chemistry, and discloses a N-substituted tetrahydropyridine bound indole compound with a structure shown as a formula (I), and the compound can be used for effectively inhibiting cell proliferation of leukemia K562, ovarian cancer HO-8910 and liver cancer SMMC-7721. The preparation method comprises the following steps: preparing N,N-bis(beta-methyl propionate) substituted amine from substituted amine and methyl acrylate by means of a Michael addition reaction; performing Dieckmann condensation in the action of sodium alcoholate, andperforming hydrolysis and decarboxylation in the action of acid to prepare N-substituted piperidine-4-ketone; and performing a condensation reaction to the product and indole or substituted indole. The preparation method has the advantages of simple process and easiness for production; and the compound can be used for preparing medicaments for treating leukemia, ovarian cancer or liver cancer.

The present invention provides a process for preparing a compound of the following general formula (2): wherein R¹ represents a monovalent hydrocarbon group having 1 to 10 carbon atoms, and R³ represents a hydrogen atom or a methyl group, the process comprising: subjecting a compound of the following general formula (1): wherein R¹ and R² represent, independently of each other, a monovalent hydrocarbon group having 1 to 10 carbon atoms, R³ represents a hydrogen atom or a methyl group, and the wavy bond represents an E-configuration, a Z-configuration, or a mixture thereof, to a Dieckmann condensation in the presence of base to form the compound (2).

The invention provides a preparation method of a quininone derivative, and belongs to the field of pharmaceutical chemical industry. According to the method disclosed by the invention, the 3-quininonederivative is obtained by taking a diethanolamine derivative as a starting material through chlorination or methanesulfonic acid and diethyl malonate cyclization and Dieckmann Condensation. The product produced by the method has the characteristics of high purity, high yield, low cost, simple operation and stable process.