850649-62-6

Basic information

• Product Name: Alogliptin benzoate
• Synonyms: (R)-2-((6-(3-aMinopiperidin-1-yl)-3-Methyl-2,4-dioxo-3,4-dihydropyriMidin-1(2H)-yl)Methyl)benzonitrile benzoate;2-[6-[3(R)-AMinopiperidin-1-yl]-3-Methyl-2,4-dioxo-1,2,3,4-tetrahydropyriMidin-1-ylMethyl]benzonitrile benzoate Monobenzoate;Alogliptin benzoate 2-[[6-[(3R)-3-Amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]benzonitrile benzoate;Alogliptin(Alogliptin benzoate;Alogliptin API;(R)-2-((6-(3-Aminopiperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benz;ALOGLIPTIN BENZOATE;2-[[6-[(3R)-3-Amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]benzonitrile benzoate
• CAS NO: 850649-62-6
• Molecular Formula: C18H21N5O2.C7H6O2
• Molecular Weight: 461.519
• EINECS: 1592732-453-0
• Product Categories: Inhibitors;antidiabetic;Final material;pharmaceutical intermediate
• Mol File: 850649-62-6.mol

Chemical Properties

• Boiling Point: 671.2 °C at 760 mmHg
• Flash Point: 359.7 °C
• Appearance: white powder
• Vapor Pressure: 6.22E-19mmHg at 25°C
• Storage Temp.: Refrigerator, under inert atmosphere
• Solubility: Chloroform (Slightly, Heated), DMSO (Slightly, Heated), Methanol (Slightly, Heat
• CAS DataBase Reference: Alogliptin benzoate(CAS DataBase Reference)
• NIST Chemistry Reference: Alogliptin benzoate(850649-62-6)
• EPA Substance Registry System: Alogliptin benzoate(850649-62-6)

Safety Data

• Hazardous Substances Data: 850649-62-6(Hazardous Substances Data)

Usage

Indications and Usage

Alogliptin (benzoic acid) is a type-2 diabetes medication, and it is a type of serine protease dipeptidyl peptidase IV (DPP-4) inhibitor developed by the Japanese company Takeda. Alogliptin, used alone or in combination with other blood sugar-lowering medication, is usually well-tolerated in type-2 diabetes patients. This medication has a low risk of hypoglycemia, with Alogliptin treatment groups ≤8.3% and placebo groups ≤10.5%, and shows no difference between young and elderly patients. In addition to effectively lowering blood sugar, this medicine also lowers the risks of hypoglycemia and weight increase, overcoming great obstacles in patient treatment and providing new hope for diabetes treatment.

Mechanisms of Action

Alogliptin selectively inhibits DPP-4 to reduce the inactivation of glucagon-like peptide 1 (GLP-1) and increase the GLP-1 levels in the body, thus lowering blood sugar. Once blood sugar reaches normal levels, it will cease its sugar-lowering effects, thus effectively reducing the risks of hypoglycemia. Additionally, DPP-4 inhibitor also slows gastric emptying, increases the feeling of fullness, and controls appetite, thus helping patients control their weight.

Adverse reactions

Common side effects of Alogliptin include nasopharyngitis, headaches, and upper respiratory tract infection. Most side effects are light to moderate and are unrelated to dosage.

Biological Activity

alogliptin is a novel, highly selective and potent inhibitor of serine protease dipeptidylpeptidase-4 (dpp-4) with ic50 value of less than 10 nm [1].alogliptin has been reported to significantly reduce plasma dpp-4 activity and increase active glp-1 levels in a dose-dependent manner in ob/ob mice. besides, alogliptin after 4 weeks administration remarkably reduced non-fasting glycosylated hemoglobin, non-fasting plasma glucose and triglyceride levels, as well as siginificantly increased non-fasting plasma insulin and fasting pancreatic insulin content in ob/ob mice. moreover, alogliptin treated ob/ob mice have shown the increase of early-phase insulin secretion and the decrease of plasma glucose auc [2]

Clinical Use

Alogliptin benzoate is a dipeptidyl peptidase IV (DPPIV) inhibitor discovered by Takeda Pharmaceuticals and approved in Japan in 2010 for the treatment of type II diabetes mellitus. Alogliptin is an oral drug for once a day dosing to complement diet and exercise. Alogliptin is the most selective marketed DPPIV inhibition and has similar PK and PD properties compared to previous entries. The discovery, structure-activity relationship of related analogs, and synthesis of this compound have been recently published.

Synthesis

The most convenient synthesis for scale-up will be highlighted from several published routes. Commercially available 2-cycanobenzyl amine 1 was reacted with methylisocyanate in DCM at ambient temperature to provide N-methyl urea 2 in 85% yield. Reaction of the urea 2 with dimethyl malonate in refluxing ethanol with sodium ethoxide as base gave the cyclized trione 3 in 78-85% yield. The trione 3 was then refluxed in neat POCl3 to provide the penultimate chloride crude 4 in 95% yield which was reacted with Boc-protected diamine 5 in the presense of potassium carbonate in DMF to furnish alogliptin I in 93-96% yield. Treatment of alogliptin with benzoic acid in ethanol at 60-70 °C followed by crystallization delivered the desired alogliptin benzoate (I).

references

[1] feng j, zhang z, wallace mb, stafford ja, kaldor sw, kassel db, navre m, shi l, skene rj, asakawa t, takeuchi k, xu r, webb dr, gwaltney sl 2nd. discovery of alogliptin: a potent, selective, bioavailable, and efficacious inhibitor of dipeptidyl peptidase iv. j med chem. 2007 may 17;50(10):2297-300.[2] moritoh y1, takeuchi k, asakawa t, kataoka o, odaka h. chronic administration of alogliptin, a novel, potent, and highly selective dipeptidyl peptidase-4 inhibitor, improves glycemic control and beta-cell function in obese diabetic ob/ob mice. eur j pharmacol. 2008 jul 7;588(2-3):325-32.

InChI:InChI=1/C18H21N5O2.C7H6O2/c1-21-17(24)9-16(22-8-4-7-15(20)12-22)23(18(21)25)11-14-6-3-2-5-13(14)10-19;8-7(9)6-4-2-1-3-5-6/h2-3,5-6,9,15H,4,7-8,11-12,20H2,1H3;1-5H,(H,8,9)/t15-;/m1./s1

Upstream product

• 850649-61-5 alogliptin 
• 65-85-0 benzoic acid 
• 127294-73-9 (R)-piperidin-3-ylamine 
• 1108732-05-3 S-Alogliptin 
• 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 
• 4318-56-3 3-methyl-6-chlorouracil 
• 865758-95-8 2-[(6-chloro-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)methyl]benzonitrile 
• 334618-23-4 3-(R)-aminopiperidine dihydrochloride 
• 344957-25-1 2-(aminomethyl)benzonitrile 
• 309956-78-3 (R)-piperidin-3-ylcarbamic acid tert-butyl ester 
• 98-92-0 nicotinamide 
• 7032-11-3 1,4,5,6-tetrahydropyridine-3-carboxamide 
• 612-13-5 2-cyanobenzyl chloride 

Relevant articles and documents

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.

Novel preparation process of alogliptin benzoate

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.

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.

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.

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.