1638544-64-5

Usage

Uses

Used in Pharmaceutical Industry:
(S)-Alogliptin Benzoate Salt is used as an impurity in the development and production of Alogliptin (A575425), an oral antihyperglycemic agent. It contributes to the overall effectiveness of the drug by targeting the DPP-4 enzyme, which plays a crucial role in blood sugar regulation. By inhibiting this enzyme, Alogliptin helps to increase the levels of insulin and decrease the levels of glucose in the blood, thus managing diabetes more effectively.
Additionally, as an impurity, (S)-Alogliptin Benzoate Salt may be subject to further research and development to understand its potential impact on the efficacy and safety of Alogliptin. This could lead to improvements in the drug's formulation and administration, ultimately benefiting patients with type 2 diabetes.

Upstream product

• 1246610-74-1 2-[[6-[(3R)-3-tert-butoxycarbonylamino-1-piperidinyl]-3,4-dihydro-2,4-dioxo-3-methyl-1(2H)-pyrimidinyl]methyl]benzonitrile 
• 65-85-0 benzoic acid 
• 7032-11-3 1,4,5,6-tetrahydropyridine-3-carboxamide 
• 98-92-0 nicotinamide 
• 309956-78-3 (R)-piperidin-3-ylcarbamic acid tert-butyl ester 
• 865758-96-9 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzonitrile 
• 22115-41-9 2-(bromomethyl)benzonitrile 
• 865758-95-8 2-[(6-chloro-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)methyl]benzonitrile 
• 850649-61-5 alogliptin 
• 334618-23-4 3-(R)-aminopiperidine dihydrochloride 
• 344957-25-1 2-(aminomethyl)benzonitrile 
• 127294-73-9 (R)-piperidin-3-ylamine 
• 612-13-5 2-cyanobenzyl chloride 
• 4318-56-3 3-methyl-6-chlorouracil 

Relevant academic research and scientific papers

Development and Scale-Up of an Asymmetric Synthesis Process for Alogliptin

Alogliptin (1) benzoate is a potent, highly selective inhibitor of serine protease dipeptidyl-peptidase IV, approved by US FDA for the treatment of type 2 diabetes. Herein, we report a more cost-effective process that includes ruthenium-catalyzed asymmetric hydrogenation followed by Hofmann rearrangement of 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzonitrile (10) to introduce a chiral amino moiety at a late stage. Use of an inexpensive and readily available nicotinamide (6) for a chiral aminopiperidine core and iodobenzene diacetate (PIDA) under mild and specific conditions allowed us to access 1 with excellent total yield and comparable quality to that manufactured by the original process.

Preparation method of alogliptin benzoate

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.

Synthesis process of alogliptin benzoate

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

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.

Industrial production method of Alogliptin benzoate

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.

Preparation method of alogliptin

The invention provides a preparation method of alogliptin. 2-(6-chlorine-3-methyl-2,4-prohexadione-3,4-dihydro-2H-pyrimidine-1-yl-methyl)benzonitrile, (R)-3-aminopiperidine dihydrochloride and sodiumbicarbonate or potassium bicarbonate react in an organic solvent to prepare a compound, the yield of the alogliptin and alogliptin benzoate is increased, the purity of the alogliptin and the alogliptin benzoate is improved, operation is easy, environmental protection is achieved, and the preparation method is suitable for industrial production of the alogliptin and the alogliptin benzoate.

Simple preparation method of alogliptin benzoate

The invention relates to an alogliptin benzoate preparation method, which comprises that 3,3-dihalogenated-N-methyl acrylamide sequentially reacts with (R)-3-Boc-aminopiperidine and 2-cyano benzylamine to prepare (R)-3-(3-Bocamino)piperidine-1-yl-3-(2-cyano)benzylamino-N-methacrylamide, the obtained material reacts with a carbonylation reagent to prepare alogliptin, and the alogliptin and benzoicacid are subjected to salt forming to prepare alogliptin benzoate. According to the present invention, the method has advantages of inexpensive and easily available raw materials, simple operation andless wastewater, and is suitable for the industrial production of alogliptin benzoate.

Preparation method of alogliptin benzoate

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 process of alogliptin benzoate

The invention discloses a preparation process of alogliptin benzoate, wherein the preparation process comprises the steps: carrying out nucleophilic substitution of 3-methyl-6-chlorouracil and 2-cyanobromobenzyl under alkaline conditions to obtain 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl methyl)-benzonitrile (a compound 1); then substituting with (R)-3-aminoperidol dihydrochloride to obtain (R)-2-[(6-(3-aminoperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl]benzonitrile (a compound 2); and finally, salifying with benzoic acid to obtain alogliptin benzoate (a compound 3), determining the structure of the target compound at each step by MS and 1H-NMR, and determining the purity by HPLC. The method has the advantages of easy availability of raw materials, mild reaction conditions and simple operation, can be used for production in large quantities to meet the needs of use, is a high-efficiency green environmental-protection process and is suitable for industrialized production.

A preparing method for alogliptin benzoate

The invention provides a preparing method for alogliptin benzoate, and particularly provides a method for preparing 2-[[6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl]methyl]benzonitrile monobenzoate shown as a formula (I). The compound is a novel medicine treating diabetes mellitus type 2. The alogliptin benzoate (HPLC purity of which is greater than 99.95%) can be prepared in a high yield and high purity by the method, a process is simple and convenient to operate and the method is suitable for industrial production.