865758-96-9Relevant articles and documents
Synthesis process of alogliptin benzoate
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Paragraph 0007; 0092; 0121-0144, (2021/02/10)
The invention discloses a synthesis process of alogliptin benzoate. The synthesis process comprises the following steps: 1, preparing an initial raw material 6-chlorouracil; 2, preparing 2-((6-chlorine-2, 4-dioxo-3, 4-dihydro-2H-pyrimidine-1-radical)methyl)cyanophenyl; 3, preparing 2-[(6-chlorine-3, 4-dihydro-3-methyl-2, 4-dioxo-1(2H)-pyrimidinyl)methyl]benzonitrile; 4, preparing alogliptin; 5, preparing alogliptin benzoate. According to the invention, the alogliptin benzoate is synthesized by taking cheap and easily available 6-chlorouracil, alpha bromo-o-methylbenzonitrile and (R)-3-aminopiperidine as raw materials through reactions such as alkylation, methylation, affinity substitution, salification and the like; according to the synthetic route, raw materials are cheap and easy to obtain, the synthetic cost is reduced, all steps are classic reactions, and synthesis improvement is easy; the improved process is low in raw material cost, simple to operate, mild in reaction condition,simple in post-treatment and suitable for industrial production.
Preparation method of alogliptin benzoate intermediate and preparation method of alogliptin benzoate
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Paragraph 0074-0079; 0092-0095, (2021/08/28)
The invention provides a reparation method of an alogliptin benzoate intermediate and a preparation method of alogliptin benzoate. The yield of the alogliptin benzoate intermediate prepared by the method is not lower than 88%, and the purity is not lower than 99.5%; and according to the alogliptin benzoate raw material medicine prepared by the method, D90 does not exceed 220 microns, and preferably does not exceed 200 microns. All indexes of the prepared pharmaceutical composition meet medicinal requirements, the quality is stable in the storage process, and the clinical curative effect and medication safety can be guaranteed.
3, 4-dihydropyrimidine benzonitrile derivative as well as preparation method and application thereof
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Paragraph 0026-0027; 0065, (2021/03/13)
The invention provides a 3, 4-dihydropyrimidine benzonitrile derivative as well as a preparation method and application thereof. The invention discloses a structure of a specific impurity (RRT is an impurity of 1.22) generated in the process of preparing alogliptin benzoate by adopting the route of the original research patent for the first time. The series of impurities have a warning structure,and the content of the impurities in the alogliptin benzoate finished product needs to be detected according to related limits of the genetically toxic impurities. The invention further provides a preparation and purification method of the high-purity compound shown in the formula (A) and a detection method of the content of the impurity compound in the alogliptin benzoate medicine, and thereforequality control over the alogliptin benzoate medicine is achieved.
Preparation method of alogliptin benzoate
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Paragraph 0028-0029; 0033-0034, (2021/01/29)
The invention discloses a preparation method of alogliptin benzoate. Main starting materials of the preparation method are 6-chloro-3-methyluracil, o-cyanobenzyl bromide, (R)-3-Boc-aminopiperidine andbenzoic acid. According to the method, all indexes meet the specification, meanwhile, dangerous reagents such as sodium hydride and highly toxic methyl iodide are prevented from being used in the reaction process, the requirement for the operation process is not strict, and water-free and oxygen-free conditions are not needed; a high-boiling-point mixed solvent is not used in the reaction, and the solvent is easy to recycle; the selected starting materials are available in the market and easy to obtain, and large-scale production is facilitated; in addition, starting materials or intermediates in the synthetic route are good in stability and convenient to store and control, and genotoxic impurities are avoided in the reaction process; and the synthesis process is environment-friendly.
Novel preparation process of alogliptin benzoate
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Paragraph 0027; 0038-0040; 0047-0048; 0049-0050; 0051-0052, (2021/05/08)
The invention discloses a novel preparation process of alogliptin benzoate. The method comprises the steps: reacting 3-methyl-6-chlorouracil serving as an initial raw material with 2-cyanobenzyl bromide under an alkaline condition by taking toluene as a solvent to obtain 2-[(6-chloro-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl)methyl]benzonitrile, then reacting the solvent system with (R)-3-Boc-aminopiperidine under an alkaline condition, dissociating a protecting group by using acid to obtain alogliptin, and carrying out salifying reaction on the alogliptin and benzoic acid to finally prepare the alogliptin benzoate which is an anti-type 2 diabetes medicine. The preparation method adopts a one-pot method, has the advantages of low raw material cost, high yield, reduction of post-treatment operation of each chemical reaction in multi-step reaction, great shortening of the production period, few impurities generated in the reaction, high product quality, relative reduction of the use amount of chemical reagents, relatively environmental protection and the like, and is beneficial to industrial production.
Refining method of alogliptin benzoate
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Paragraph 0116-0118, (2021/06/06)
The invention discloses a refining method of alogliptin benzoate, which is characterized in that an alogliptin benzoate crude product (the purity is 99.73%) is used as a starting raw material, the alogliptin benzoate crude product is dissolved by adding an organic solvent, and is cooled to crystallize to obtain a high-purity target product alogliptin benzoate solid, and the purity of the alogliptin benzoate solid can reach 99.99% through HPLC detection. Compared with the prior art, the toxicity of the used solvent is low, the mother liquor solvent can be recycled, and the environmental pollution is small; and the operation is simple and feasible, and industrial large-scale production is facilitated.
Industrial production method of Alogliptin benzoate
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Paragraph 0049-0066; 0106-0120; 0155-0169, (2019/02/04)
The invention relates to an industrial production method of Alogliptin benzoate, and belongs to the technical field of industrial pharmacy. The method comprises three steps of 1, preparing an Alogliptin intermediate AG I; 2, preparing an Alogliptin intermediate AG II; 3, preparing the Alogliptin benzoate. The industrial production method has the beneficial effects that the reaction conditions areproper; the operation is simple and convenient; the realization is easy; only the Alogliptin intermediate AG II is prepared; then, the AG II and benzoic acid are subjected to tetrahydrofuran synthesis; the Alogliptin benzoate can be obtained; the process is saved; the cost is reduced; used solvents have small environment pollution; the operation is safe; under the large-scale industrial productioncondition, the existing average yield is only about 30 percent; under the condition that the final yield reaches 19.32kg, the finial product yield reaches 94.77 percent; the total yield reaches 60.11percent; high quality and purity can be maintained; the production efficiency is greatly improved.
Pd/PTABS: Catalyst for Room Temperature Amination of Heteroarenes
Murthy Bandaru, Siva Sankar,Bhilare, Shatrughn,Chrysochos, Nicolas,Gayakhe, Vijay,Trentin, Ivan,Schulzke, Carola,Kapdi, Anant R.
supporting information, p. 473 - 476 (2018/01/28)
A mild and highly efficient catalytic amination procedure for chloroheteroarenes at ambient temperature using the Pd/PTABS catalytic system is reported. The protocol is selective for the amination of chloroheteroarenes using secondary amines such as piperidine, pyrrolidine, and several others. The exceptional mildness of the developed protocol is beneficial for the synthesis of a crucial Buparlisib intermediate as well as the formal synthesis of Alogliptin in competitive yields.
Preparation method of alogliptin benzoate
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Paragraph 0042; 0043; 0051, (2018/05/16)
The invention discloses a preparation method of alogliptin benzoate. The preparation method of alogliptin benzoate comprises the following steps of, firstly, reacting 3-methyl-6-chlorouracil with 2-cyanobenzyl bromide to obtain 2-(6-chloro-3-methyl-2, 4-dioxo-3, 4-dihydro-2H-pyrimidine-1-methyl)-benzonitrile; secondly, reacting 2-(6-chloro-3-methyl-2, 4-dioxo-3, 4-dihydro-2H-pyrimidine-1-methyl)-benzonitrile with (R)-3-aminoperidine dihydrochloride to obtain alogliptin; thirdly, salifying alogliptin with benzoic acid to obtain alogliptin benzoate. According to the preparation method of alogliptin benzoate, condensation reaction in the first step is implemented in dichloromethane solvent and under reflux conditions, thereby being mild in conditions and capable of achieving a yield higher than 90%; condensation reaction in the second step is implement in water or water-methylbenzene mixed solution to avoid production of disubstituted impurities and achieving high product purity.
Preparation method of alogliptin benzoate impurity
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Paragraph 027; 0028, (2018/04/01)
The invention relates to a preparation method of alogliptin benzoate impurity and belongs to the technical field of pharmaceutical chemicals. The preparation method of alogliptin benzoate impurity provided by the invention comprises the following steps: (1) preparing TM1 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)cyanophenyl by taking 6-chloro-3-methylpyrimidin-2,4(1H,3H)-diketone as a raw material which reacts with 2-bromomethyl cyanophenyl; (2) preparing alogliptin benzoate impurity BP1 through a reaction between the TM1 and monohydric alcohol in an alkaline condition, wherein the structural formula of the BP1 is shown in the description. The preparation method provided by the invention is convenient to operate, the reaction conditions are mild and controllable,the side reactions are reduced, and therefore, the target product alogliptin benzoate is easy to separate and purify and has high purity.
