- 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.
- -
-
Paragraph 0022; 0080-0088; 0098-0101
(2021/08/28)
-
- 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.
- -
-
Paragraph 0035; 0038; 0045-0046
(2021/05/08)
-
- 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.
- Yamada, Masatoshi,Hirano, Sayuri,Tsuruoka, Ryoji,Takasuga, Masahiro,Uno, Kenichi,Yamaguchi, Kotaro,Yamano, Mitsuhisa
-
p. 327 - 336
(2021/03/01)
-
- 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
-
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.
- -
-
-
- 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.
- -
-
-
- 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.
- -
-
Paragraph 0021; 0022
(2019/06/08)
-
- 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.
- -
-
Paragraph 0019; 0021; 0022; 0025; 0029; 0030
(2019/01/06)
-
- 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.
- -
-
-
- Alogliptin benzoate preparation method
-
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.
- -
-
-
- PROCESS FOR PRODUCING HETEROCYCLIC COMPOUND
-
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.
- -
-
-
- Preparation and after-treatment method for high-purity alogliptin benzoate
-
The invention relates to optimization and improvement of a preparation and after-treatment method for alogliptin benzoate. In the Boc deprotection process, alkali extraction and acid precipitation methods are adopted, and impurities which do not contain basic groups are effectively removed on the basis of simplifying the process. Moreover, the solvent and temperature control is optimized in the salifying process, and the product quality and yield are improved.
- -
-
-
- One-pot preparation method of Alogliptin
-
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.
- -
-
Paragraph 0019
(2017/08/27)
-
- argues a row sandbank a method for synthesis of benzoic acid
-
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.
- -
-
-
- argues a row sandbank a process for the preparation of benzoic acid
-
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.
- -
-
-
- PROCESS FOR PREPARATION OF ALOGLIPTIN
-
Provided is a novel process for the preparation of alogliptin.
- -
-
Paragraph 0147
(2016/12/12)
-
- A new method for preparing argues a row sandbank benzoic acid
-
The invention discloses a novel method for preparing alogliptin benzoate ((R)2-[6-[3(R)-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidine-1(2H)-yl)methyl]benzonitrile benzoate). The method comprises the steps of alkylation, phase transfer catalysis reaction, catalytic hydrogenation, salt formation protection and the like. The process is novel in routes, short in the steps, high in reaction yield, and low in production costs; the method has larger implementing value and social economic benefit.
- -
-
Paragraph 0049; 0053; 0054
(2016/12/01)
-
- PROCESS FOR THE PREPARATION OF ALOGLIPTIN
-
The invention concerns a process for the preparation of 2-[[6-[(3R) -3-amino-l-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-l(2H)- pyrimidinyl]methyl]benzonitrile commonly known as alogliptin and its pharmaceutically acceptable benzoate salt. Alogliptin is a dipeptidyl peptidase-4 inhibitor (DPP-4) that is designed to slow the inactivation of incretin hormones glucagon-like peptide-1 (GLP-1) and glucose- dependent insulinotropic peptide (GIP). It is used as antidiabetic drug. Formula (I)
- -
-
Page/Page column 15; 16
(2016/11/21)
-
- A preparing process of alogliptin benzoate
-
The invention relates to a preparing process of alogliptin benzoate that is a medicine for treating diabetes mellitus type 2. The process includes reacting 6-chloro-3-methyluracil which is adopted as a raw material and 2-cyanobenzyl bromide to obtain 2-[(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)methyl]benzonitrile, performing a substitution reaction with (R)-3-Boc-aminopiperdine, removing Boc after the reaction is finished to obtain alogliptin, and salting with benzoic acid to obtain the alogliptin benzoate. The process is characterized in that: in the substitution reaction, an acid-binding agent which is potassium carbonate is added, and water is added after the reaction is finished to allow the protected alogliptin to precipitate so as to obtain the alogliptin with Boc protection; and in the deprotection and salting reaction, the alogliptin with Boc protection is deprotected in an ethanol solution of thionyl chloride, and the benzoic acid is added into an ethyl acetate solution of the alogliptin, refluxed and salted to obtain the alogliptin benzoate.
- -
-
-
- A method for refining argues a row sandbank benzoic acid
-
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.
- -
-
-
- argues a row sandbank a method for synthesis of benzoic acid
-
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.
- -
-
-
- argues a row sandbank crystalline forms of benzoic acid and its preparation method
-
The invention discloses a novel crystal form of alogliptin benzoate ((R)-2-[(6-(3-aminopiperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl]benzonitrile benzoic acid) and a preparation method thereof. The novel crystal form is a polycry
- -
-
Paragraph 0045
(2017/02/17)
-
- A NOVEL PROCESS FOR PREPARATION OF ALOGLIPTIN BENZOATE
-
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.
- -
-
-
- LAMINATED TABLET AND MANUFACTURING METHOD THEREFOR
-
According to the present invention, a multilayer tablet showing suppressed layer separation and a production method thereof are provided. A concave portion having a depth of not less than 0.1 mm Ka is formed on at least one surface Sa of the both front and back surfaces (Sa, Sb) of a multilayer tablet. Particularly, a multilayer structure obtained by, in tableting, forming a convex portion for forming the concave portion on at least the upper punch, and preliminarily compressing all layers in the multilayer tablet with the upper punch to form a concave portion having the same shape with a depth of not less than 0.1 mm on the upper surface of all layers, wherein the powder materials of the next layer are protruding into the concave portion, is a preferable embodiment.
- -
-
Paragraph 0109; 0114
(2014/01/18)
-
- NOVEL SALTS OF ALOGLIPTIN
-
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.
- -
-
-
- PROCESS FOR THE PREPARATION OF ALOGLIPTIN
-
The present invention is based on the discovery of a process for preparing pyrimidin- dione compounds, especially alogliptin and its derivatives, which comprises the reaction of a urea derivative of formula (VIII) with a malonic acid or its derivatives to form intermediates of formulae (VII) or (VII-A), which are subsequently converted to a compound of formula (II) upon introduction of a leaving group X. Compound (II) then reacts with an amine to form compound (I), which is optionally converted to its salts of formula (IV).
- -
-
Page/Page column 28
(2010/11/05)
-
- CRYSTALLINE FORM OF AN ORGANIC COMPOUND
-
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.
- -
-
Page/Page column 17-18
(2010/07/09)
-
- DIPEPTIDYL PEPTIDASE INHIBITORS
-
Methods of making compounds of the formula (I) wherein the variables are as defined herein. Also, methods of making compounds that may be used to inhibit dipeptidyl peptidase.
- -
-
Page/Page column 23-24
(2009/12/02)
-
- 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
-
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.
- -
-
Page/Page column 15
(2008/06/13)
-
