- Synthesis process of alogliptin benzoate
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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.
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- Development and Scale-Up of an Asymmetric Synthesis Process for Alogliptin
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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.
- Yamada, Masatoshi,Hirano, Sayuri,Tsuruoka, Ryoji,Takasuga, Masahiro,Uno, Kenichi,Yamaguchi, Kotaro,Yamano, Mitsuhisa
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p. 327 - 336
(2021/03/01)
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- Preparation method of alogliptin benzoate
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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.
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Paragraph 0028; 0031; 0033; 0036
(2021/01/29)
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- Dynamic resolution method of R-configuration alogliptin, and R-configuration alogliptin preparation method
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The invention provides a dynamic resolution method of R-configuration alogliptin, and an R-configuration alogliptin preparation method. According to the preparation method, benzaldehyde is used as a resolving agent, racemic alogliptin is subjected to chiral resolution through a dynamic resolution technology, and the obtained R-configuration alogliptin is high in purity, high in overall yield and low in isomer content. According to the preparation method of the invention, the process complexity can be greatly reduced, the process path adopting expensive raw materials is avoided, and the preparation cost of chiral alogliptin is remarkably reduced.
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Paragraph 0047-0050; 0051-0056; 0058-0089
(2020/01/12)
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- Simple preparation method of alogliptin benzoate
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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.
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- Industrial production method of Alogliptin benzoate
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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.
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- Preparation method of alogliptin
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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.
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Paragraph 0019; 0020; 0023-0028
(2019/06/08)
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- Pd/PTABS: Catalyst for Room Temperature Amination of Heteroarenes
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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.
- Murthy Bandaru, Siva Sankar,Bhilare, Shatrughn,Chrysochos, Nicolas,Gayakhe, Vijay,Trentin, Ivan,Schulzke, Carola,Kapdi, Anant R.
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p. 473 - 476
(2018/01/28)
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- Preparation method of alogliptin benzoate
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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.
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- Preparation process of alogliptin benzoate
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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.
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- One-pot preparation method of Alogliptin
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The invention relates to an improved preparation method of Alogliptin. The preparation method comprises mixing and heating 6-chloro-3-methyluracil shown in the formula A, 2-cyanobenzyl bromide shown in the formula B and an alkali in an organic solvent for a reaction for some time, adding (R)-3-aminopiperdine dihydrochloride shown in the formula C into the reaction product, and carrying out a heating reaction process to obtain Alogliptin through a one-pot method. The improved preparation method solves the problem that the traditional method has harsh reaction conditions, pollutes the environment, produces more impurities and has a low yield, and is conducive to industrial production.
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Paragraph 0016; 0017; 0018
(2017/08/27)
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- Alogliptin benzoate preparation method
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The present invention provides an alogliptin benzoate preparation method, which comprises treating an intermediate IV reaction solution, and specifically comprises: heating the intermediate IV reaction solution to a temperature of 50-80 DEG C, adding a diluted alcohol while hot, cooling to a temperature of 0-40 DEG C to make the crystal be crystallized, adding water after a lot of the crystals are crystallized, carrying out stirring washing, filtering, and drying to obtain the intermediate IV. According to the present invention, the intermediate IV is prepared by using the one-pot method, a certain amount of the diluted alcohol is added at the high temperature, the saturated solution is formed after the cooling, and the cooling is continuously performed to crystallize, such that the crystal caking problem caused by the direct water precipitation is avoided, the intermediate IV crystal is uniformly dispersed, sticking on the wall and the agglomeration do not exist, the sticking onto the stirring slurry does not exist, the operation is convenient, and the method is suitable for industrial production.
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- PROCESS FOR PRODUCING HETEROCYCLIC COMPOUND
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The present invention provides a method of efficiently producing an optically active 6-(3-aminopiperidin-1-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine derivative. The optically active piperidine-3-carboxamide or a derivative thereof, which is obtained by subjecting 1,4,5,6-tetrahydropyridine-3-carboxamide or a derivative thereof to an asymmetric reduction in the presence of a catalyst, is used as an intermediate.
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- argues a row sandbank new crystal and its preparation method
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The invention relates to an alogliptin novel crystal form and a preparation method thereof. The crystal form presents in a substantially pure crystal morphology, has good performance in aspects such as stability, is helpful for storing, is beneficial to operate in a production process, can be used for preparing drugs for treating diabetes, and can also be used for preparing a pharmaceutically acceptable salt thereof.
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Paragraph 0064-0065
(2017/08/25)
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- Preparation method of dipeptidyl peptidase IV inhibitor
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The invention provides a preparation method of a dipeptidyl peptidase IV inhibitor. The preparation method utilizes isopropanol and water as solvents and a volume ratio of isopropanol to water is 1-8: 1 so that a product yield and product purity are greatly improved and reaction time is shortened. An intermediate is subjected to beating and purification under action a poor solvent. The purification method is simple in operation, a product yield and product purity are high, and the production process is easy to control and is suitable for industrial production.
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- PROCESS FOR PREPARATION OF ALOGLIPTIN
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Provided is a novel process for the preparation of alogliptin.
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- argues a row sandbank a method for synthesis of benzoic acid
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The invention discloses a synthetic method of alogliptin benzoate. The synthetic method of the alogliptin benzoate comprises the steps of carrying out amidation reaction on (R)-3-Boc-amino piperidine and ethyl hydrogen malonate which are taken as raw materials to synthesize (R)-3-(3-Boc-amino piperidine-1-yl)-3-oxo ethyl propionate; then carrying out a ring closing reaction on the (R)-3-(3-Boc-amino piperidine-1-yl)-3-oxo ethyl propionate and 1-(2-cyano-benzyl)-3-methylurea; then carrying out deprotection under an acid condition, so that alogliptin is obtained; and finally carrying out salifying on the alogliptin and benzoic acid, so that the alogliptin benzoate is obtained. The synthetic method of the alogliptin benzoate has the advantages that a synthetic route and technology are simplified and optimized, a reagent is easily available, cost is reduced, total yield is relatively high, using requirement can be met by producing the alogliptin benzoate in a large scale, and the synthetic method of the alogliptin benzoate is efficient, environment-friendly and applicable to industrial production.
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- argues a row sandbank a process for the preparation of benzoic acid
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The invention discloses a preparation method of alogliptin benzoate shown in a formula 1 in the specification for treating type 2 diabetes mellitus. The preparation method has the advantages that raw materials are easy to obtain, reaction conditions are mild and the operation is simple and convenient, and is suitable for large-scale industrial production.
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Paragraph 0018-0020
(2017/02/09)
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- Preparation method of alogliptin
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The invention discloses a preparation method of alogliptin. The preparation method comprises following steps: 1), 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidinyl-1-yl methyl)-benzonitrile (IV) and (R)-3-Boc-aminopiperidine are subjected to substitution reaction in the presence of an alkali in an alcoholic solvent so as to obtain a compound IX; and 2) the protecting groups of t-butyloxycarboryl of the compound IX are removed with an acid so as to obtain alogliptin (V). The synthetic route is disclosed in the invention, the alkali used in the step 1) is an organic alkali, the alcoholic solvent is selected from steric hindrance alcohols, and the acid used in the step 2) is selected from carboxylic acids. Advantages of the preparation method are that: the steric hindrance alcohol is taken as the solvent in the synthesis process from the compound IV to the compound V, so that reaction of allyl site alpha-C1 with the solvent and generation of impurities are avoided effectively; the organic carboxylic acid with low acidity is used for removing Boc protecting groups, so that chemical structure destroy is not caused; and using of para-toluenesulfonic acid is avoided, so that introduction of impurities with genotoxicity caused by application of para-toluenesulfonic acid when a lower alcohol is taken as the solvent is avoided.
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Paragraph 0069; 0070
(2016/10/10)
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- A method for refining argues a row sandbank benzoic acid
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The invention discloses a method for refining alogliptin benzoate. The method for refining the alogliptin benzoate comprises that 6-chloro-3-methyl uracil and 2-cyano benzyl bromide are taken as initial raw materials, a two-step amination reaction and a one-step salt forming reaction are sequentially carried out, so that an alogliptin benzoate crude product is obtained, and then the obtained alogliptin benzoate crude product is crystallized in methyl alcohol in presence of benzoic acid, so that the alogliptin benzoate refined product is obtained. The method for refining the alogliptin benzoate has the advantages that yield and purity of alogliptin benzoate can be effectively improved, operation is simple and cost is low.
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- argues a row sandbank a method for synthesis of benzoic acid
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The invention discloses a synthesis method of alogliptin benzoate. The synthesis method comprises the following steps: putting 2-cyano benzyl bromide, 3-3metyl-6-chlorouracil and tri-n-butylamine in methylbenzene and stirring for reaction; cooling, adding water and stirring for crystallization; filtering and washing with water to obtain 2-(6-chlorine-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimdine-1-metyl)-benzonitrile; adding 2-(6-chlorine-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimdine-1-metyl)-benzonitrile, (R)-3-piperidinamine dihydrochloride and alkali into ethyl alcohol and stirring for reaction; purifying and salifying with benzoic acid to obtain alogliptin benzoate. The synthesis method disclosed by the invention is mild in condition, easy to control, non-toxic, environment-friendly, high in purity and high in yield.
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- A NOVEL PROCESS FOR PREPARATION OF ALOGLIPTIN BENZOATE
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The present invention provides a novel process for preparing Alogliptin free base and its benzoate salt which comprises insitu condensation process to produce protected Alogliptin by reacting 6-chloro-3-methylpyrimidine-2, 4(1H, 3H)-dione with 2-(halo methyl) benzonitirle in presence of a base, aprotic solvent followed by insitu reaction with protected (3R)-piperidin-3-amine at elevated temperature. The protected Alogliptinis deprotected to obtain Alogliptin free base and further converted to Alogliptin benzoate.
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- Discovery of highly potent DPP-4 inhibitors by hybrid compound design based on linagliptin and alogliptin
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Highly potent DPP-4 inhibitors have been identified by hybrid compound design based on linagliptin and alogliptin. The most promising compound 2h (IC50 = 0.31 nM) exhibited 8.5-fold and 2.5-fold more potent activity than that of alogliptin (IC50 = 2.63 nM) and linagliptin (IC 50 = 0.77 nM), respectively. Compound 2h had a good inhibition selectivity for DPP-4 over DPP-8/9 and thus was selected for further biological evaluation, including oral glucose tolerance, plasma DPP-4 inhibitory activity, pharmacokinetic profile, acute toxicity and hERG inhibition. The assay results showed that 2h displayed significant in vivo glucose-lowering effect and low risk of toxicity. Further studies are expected to confirm 2h as a potential drug candidate for the treatment of type 2 diabetes.
- Lai, Zeng-Wei,Li, Chunhong,Liu, Jun,Kong, Lingyi,Wen, Xiaoan,Sun, Hongbin
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p. 547 - 560
(2014/07/21)
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- NOVEL SALTS OF ALOGLIPTIN
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The present invention provides a novel process for the preparation of amorphous alogliptin benzoate. The present invention also provides amorphous alogliptin benzoate co-precipitated on copovidone, process for its preparation and pharmaceutical compositions comprising it. The present invention further provides novel salts of alogliptin, processes for their preparation and pharmaceutical compositions comprising them. The present invention further provides crystalline hydrochloride salt of alogliptin, process for its preparation and pharmaceutical compositions comprising it. The present invention further provides crystalline tartrate salt of alogliptin, process for its preparation and pharmaceutical compositions comprising it.
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- CRYSTALLINE FORM OF AN ORGANIC COMPOUND
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The present invention is directed to a crystalline form of 2-[6-[3(R)-aminopiperidin-1 -yl]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1 -ylmethyl]-benzonitrile, a process for the preparation of said crystalline form and the use thereof in the manufacture of a pharmaceutical composition.
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Page/Page column 15-16
(2010/07/09)
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- Discovery of alogliptin: A potent, selective, bioavailable, and efficacious inhibitor of dipeptidyl peptidase IV
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Alogliptin is a potent, selective inhibitor of the serine protease dipeptidyl peptidase IV (DPP-4). Herein, we describe the structure-based design and optimization of alogliptin and related quinazolinone-based DPP-4 inhibitors. Following an oral dose, these noncovalent inhibitors provide sustained reduction of plasma DPP-4 activity and a lowering of blood glucose in animal models of diabetes. Alogliptin is currently undergoing phase 111 trials in patients with type 2 diabetes.
- Feng, Jun,Zhang, Zhiyuan,Wallace, Michael B.,Stafford, Jeffrey A.,Kaldor, Stephen W.,Kassel, Daniel B.,Navre, Marc,Shi, Lihong,Skene, Robert J.,Asakawa, Tomoko,Takeuchi, Koji,Xu, Rongda,Webb, David R.,Gwaltney II, Stephen L.
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p. 2297 - 2300
(2008/02/05)
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- POLYMORPHS OF BENZOATE SALT OF 2-[[6-[(3R)-3-AMINO-1-PIPERIDINYL]-3,4-DIHYDRO-3-METHYL-2,4-DIOXO-1(2H)-PYRIMIDINYL]METHYL]-BENZONITRILE AND METHODS OF USE THEREFOR
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Compositions comprising Compound I, wherein the Compound I is present in one or more polymorphic forms. Also provided are kits and articles of manufacture with compositions comprising one or more polymorphs of Compound I, and methods of using the compositions to treat various diseases.
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Page/Page column 14; 14-15
(2008/06/13)
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- Dipeptidyl peptidase inhibitors
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Compounds, pharmaceuticals, kits and methods are provided for use with DPP-IV and other S9 proteases that comprise a compound comprising Formula I: wherein M is N or CR4; Q1 and Q2 are each independently selected from the group consisting of CO, SO, SO2, and C=NR9; and each R1, R2, R3, R4 and R9 are as defined herein.
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Page/Page column 43-44
(2008/06/13)
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