CN113307777B - Alogliptin benzoate intermediate and preparation method of Alogliptin benzoate - Google Patents
Alogliptin benzoate intermediate and preparation method of Alogliptin benzoate Download PDFInfo
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Abstract
The invention provides an alogliptin benzoate intermediate and an industrialized preparation method of alogliptin benzoate, wherein the alogliptin benzoate intermediate prepared by the method has the yield of not less than 88% and the purity of not less than 99.5%; the alogliptin benzoate bulk drug prepared by the method has the D90 not more than 220 microns, and preferably not more than 200 microns. The prepared medicinal composition has various indexes meeting the medicinal requirements, has stable quality in the placing process, and can ensure the clinical curative effect and the medication safety.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to an alogliptin benzoate intermediate and a preparation method of alogliptin benzoate.
Background
Alogliptin benzoate (alogliptininzoate), trade name
The chemical name is 2- [ [6- [ (3R) -3-aminopiperidine-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl]Methyl radical]Benzonitrile benzoate, a serine protease dipeptidyl peptidase IV (DPP-IV) inhibitor developed by wutian pharmaceutical company, was approved by the ministry of labour of pachyson japan in 4 months in 2010, was approved by the U.S. Food and Drug Administration (FDA) for the treatment of type 2 diabetes in 1 month in 2013, and is currently approved for marketing in china.
Alogliptin benzoate structural formula
Alogliptin benzoate as a DPP-4 inhibitor can promote the degradation and inactivation of glucagon-like peptide-1 (GLP-1) so as to maintain the stability of blood glucose concentration. Glucagon-like peptide-1 is the key to promote glycogen synthesis in liver tissue, muscle and fat. GLP-1 is secreted in intestinal tract after meal, and can suppress appetite and gastric emptying, inhibit glucagon production, and increase insulin content, thereby reducing blood sugar content. The alogliptin benzoate has high selectivity, can play a role in reducing blood sugar when the blood sugar is high, and can stop playing the role in reducing the blood sugar when the blood sugar concentration in a body is reduced to a certain degree, so that the risk of too low blood sugar is avoided to a great extent.
Regarding the synthetic route of alogliptin benzoate, the prior art discloses the following:
scheme 1: chinese patent CN104086527 discloses another synthesis method of alogliptin benzoate, which comprises the steps of taking (R) -3-Boc-aminopiperidine and monoethyl malonate as raw materials, performing amidation reaction to synthesize (R) -3- (3-Boc-aminopiperidin-1-yl) -3-oxopropanoic acid ethyl ester, performing ring-closing reaction with 1- (2-cyanobenzyl) -3-methylurea, performing deprotection under an acidic condition to obtain alogliptin, and finally forming a salt with benzoic acid to obtain alogliptin benzoate, wherein the specific steps are as follows: (1) Carrying out amidation reaction on (R) -3-Boc-aminopiperidine and malonic acid monoethyl ester serving as raw materials to synthesize (R) -3- (3-Boc-aminopiperidine-1-yl) -3-oxo ethyl propionate; (2) Performing a ring closing reaction on the (R) -3- (3-Boc-aminopiperidin-1-yl) -3-oxopropanoic acid ethyl ester obtained in the step (1) and 1- (2-cyanobenzyl) -3-methylurea under the catalysis of a base reagent; (3) Deprotecting the product (III) obtained in the step (2) under acidic conditions to obtain alogliptin (IV); (4) Salifying the alogliptin (IV) obtained in the step (3) and benzoic acid to prepare alogliptin benzoate (I),
the specific route is as follows:
the reaction route uses (R) -3-Boc-aminopiperidine and the like to protect amino and remove protection of toluenesulfonic acid, increases workload and reduces the yield of final products to a certain extent, thus being not suitable for industrial production.
Scheme 2: chinese patents CN104193726, CN109232532, CN108727280 and the like disclose a synthetic method using 3-methyl-6-chlorouracil as a starting material, and the specific steps are as follows: (1) Reacting 2-cyanobenzyl bromide and 3-methyl-6-chlorouracil in a solvent such as toluene, DMSO/DMF mixed solvent and the like to obtain 2- (6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl) -benzonitrile; (2) 2- (6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl) -benzonitrile with (R) -3-aminopiperidine dihydrochloride and base are added to ethanol, stirred to react, and purified and salified with benzoic acid to give 2- ({ 6- [ (3R) -3-aminopiperidin-1-yl ] -3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl } methyl) -benzonitrile monobenzoate.
The reaction route is shown as the following formula:
the synthetic route has the advantages of simple and easily obtained raw materials, short reaction route, mild reaction conditions, simple and convenient operation and suitability for industrial production; the yield and the purity of the intermediate are not ideal, the process conditions need to be further optimized, and the purity of the product is improved.
Scheme 3: chinese patent CN102942556 discloses a preparation method of alogliptin benzoate, which is further improved on the basis of a synthetic route 2, 6-chloro-3-methyluracil is used as a raw material to react with 2-cyanobenzyl bromide to prepare 2- (6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-ylmethyl) -benzonitrile, then the benzonitrile and (R) -3-Boc-aminopiperidine are subjected to substitution reaction, after the reaction is finished, boc is removed to obtain alogliptin, and finally the alogliptin benzoate is prepared by salifying with benzoic acid.
The synthetic route is as follows:
the synthetic route has the advantages of short reaction route, simple and easily obtained raw materials and relatively mild conditions, but the Boc protection and p-toluenesulfonic acid deprotection performed in the synthetic route increase process steps, and simultaneously reduce the yield of the final product to a certain extent, so the synthetic route is not suitable for industrial production.
Therefore, the prior art needs to be improved, and a synthesis process which is mild in reaction conditions, easy in raw material obtaining, high in yield and purity and suitable for industrial production is found.
Disclosure of Invention
The invention aims to research the alogliptin preparation process, and unexpectedly discovers a preparation process of alogliptin benzoate, which can obviously improve the yield and the purity and is suitable for industrial production.
Firstly, the invention provides a preparation method of alogliptin benzoate intermediate 2- (6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl) -benzonitrile, the alogliptin benzoate intermediate obtained by the preparation method has the yield not lower than 88% and the purity not lower than 99.5%; preferably, the yield is not lower than 90 percent, and the purity is not lower than 99.7 percent; more preferably, the yield is not less than 91% and the purity is not less than 99.9%.
A preparation method of alogliptin benzoate intermediate 2- (6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl) -benzonitrile comprises the following steps: adding an organic solvent, 6-chloro-3-methyluracil and diisopropylethylamine into a reaction tank, heating, stirring until the materials are clear, adding 2-cyanobenzyl bromide, continuously heating to 60 +/-5 ℃, and carrying out heat preservation reaction for 2-2.5 h. After the reaction is finished, the temperature is reduced to 10 +/-2 ℃, purified water is slowly added within 2 +/-0.5H, after the addition is finished, the mixture is stirred and crystallized for 1.5 +/-0.5H, the mixture is centrifuged, the wet powder is washed by the purified water and dried in vacuum, and the intermediate 2- (6-chlorine-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl) -benzonitrile is obtained.
In the above preparation method, the 2-cyanobenzyl bromide is added in an amount of 1.03 to 1.07 times equivalent, preferably 1.03 to 1.05 times equivalent, and more preferably 1.04 times equivalent of 6-chloro-3-methyluracil.
In the above preparation method, the amount of diisopropylethylamine added is 1.15 to 1.25 times equivalent, preferably 1.2 times equivalent to 6-chloro-3-methyluracil.
In the preparation method, the organic solvent is a mixed solvent of N-methyl pyrrolidone and toluene, and the volume ratio of the organic solvent to the mixed solvent is 1; preferably 1; more preferably 1.
In the above preparation method, the organic solvent is added in a volume amount of 6 to 10 times, preferably 6 to 8 times, the weight of 6-chloro-3-methyluracil. In some embodiments of the invention, the amount of 6-chloro-3-methyluracil charged is 4Kg and the amount of organic solvent added is 24-40L, preferably 24-32L.
In the above production method, the purified water is added in a volume amount of 7 to 9 times, preferably 8 times, the weight of 6-chloro-3-methyluracil. In some embodiments of the invention, the feed amount of 6-chloro-3-methyluracil is 4Kg and the amount of purified water added is 28-36L, preferably 32L.
In the above preparation method, the 6-chloro-3-methyluracil is preferably added in an amount of not less than 500g, more preferably not less than 1Kg, and still more preferably not less than 4Kg.
In the preparation method, the yield of the intermediate 2- (6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl) -benzonitrile is not less than 88%, and the purity is not less than 99.5%; preferably, the yield is not lower than 90 percent, and the purity is not lower than 99.7 percent; more preferably, the yield is not less than 91% and the purity is not less than 99.9%.
In the above preparation method, the intermediate 2- (6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl) -benzonitrile is white or off-white powder.
The yield is the molar yield, and the purity is the HPLC purity by adopting an area normalization method; the equivalent weight in the invention is a molar equivalent and is expressed by eq.
Further, the invention provides a preparation method of alogliptin benzoate.
A preparation method of alogliptin benzoate comprises the following steps:
step A: adding a solvent, sodium carbonate, (R) -3-aminopiperidine dihydrochloride and an intermediate 2- (6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-ylmethyl) -benzonitrile into a reaction tank, heating to 80 +/-5 ℃, carrying out heat preservation reaction for 5.5-6H, and after the reaction is finished, concentrating the feed liquid under reduced pressure until no continuous liquid is distilled off.
And B: adding purified water 1 to the concentrate, adding dichloromethane 1 in two portions, extracting the aqueous phase for 2 times, combining the dichloromethane phases, washing the dichloromethane phase with purified water 2, extracting twice with dilute hydrochloric acid, combining the dilute hydrochloric acid phases, and washing the dilute hydrochloric acid phase with dichloromethane 2.
And C: slowly adding a sodium carbonate solution into the dilute hydrochloric acid phase, stirring for 1.5 +/-0.5 h, adding dichloromethane 3, extracting and separating for 2 times, washing the dichloromethane phase with purified water 3, drying dichloromethane with anhydrous sodium sulfate, filtering, and washing a filter cake with dichloromethane 4; concentrating under reduced pressure to solid.
Step D: and D, adding the solid obtained in the step C and absolute ethyl alcohol 2 into a reaction kettle, starting stirring, heating to 65 +/-5 ℃, adding benzoic acid after the materials are dissolved, stirring until the solid is separated out, carrying out heat preservation reaction for 60 +/-5 min, cooling to 20 +/-5 ℃, stirring for crystallization for 1-1.5 h, centrifuging, washing with absolute ethyl alcohol 3, centrifuging, spin-drying, and carrying out vacuum drying to obtain alogliptin benzoate.
In the step A, the solvent is a mixed solvent of ethanol and water, and the volume ratio of the ethanol to the water is 5:1.
In the step A, the solvent is added in a volume amount of 5 to 7 times, preferably 5.5 to 6.5 times of the weight of the intermediate. In some embodiments of the invention, the intermediate is charged in an amount of 6Kg and the solvent is added in an amount of 30 to 42L, preferably 33 to 39L.
In the step A, the addition amount of the sodium carbonate is 1.6 to 1.8 times of the equivalent of the intermediate, and preferably 1.7 times of the equivalent.
The above stepsIn A, the sodium carbonate is powdery sodium carbonate, preferably D 90 Sodium carbonate in powder form with a particle size of not more than 200 μm, more preferably D 90 Powdery sodium carbonate with the particle size not exceeding 180 mu m.
In the step A, the amount of the (R) -3-aminopiperidine dihydrochloride added is 1.03 to 1.08 times equivalent, preferably 1.04 to 1.06 times equivalent, and more preferably 1.05 times equivalent of the intermediate.
In the step B, the purified water 1 is added in a volume amount of 2.5 to 3.5 times, preferably 3 times, the weight of the intermediate (in the step A). In some embodiments of the invention, the amount of intermediate fed in step A is 6Kg and the volume of purified water 1 added in step B is 15-21L, preferably 18L.
In the step B, the dichloromethane 1 is added in a volume amount of 4 to 6 times, preferably 5 times of the weight of the intermediate. In some embodiments of the invention, the amount of intermediate charged in step A is 6Kg and the volume of dichloromethane charged in step B is 24-36L, preferably 30L.
In the step B, the adding volume amounts of the purified water 2 and the dichloromethane 2 are respectively 1-2 times of the weight of the intermediate. In some embodiments of the invention, the amount of intermediate fed in step A is 6Kg, the volume of purified water 2 added in step B is 6 to 12L, and the volume of dichloromethane 2 added in step B is 6 to 12L.
In the step B, the dilute hydrochloric acid is dilute hydrochloric acid with the molar concentration of 0.5-0.7N (mol/L).
In the step B, the diluted hydrochloric acid is added in a volume amount which is 9 to 14 times, preferably 11 to 12 times of the weight of the intermediate. In some embodiments of the invention, the amount of intermediate charged in step A is 6Kg and the volume of diluted hydrochloric acid charged in step B is 54 to 84L, preferably 66 to 72L.
In the step C, the concentration of the sodium carbonate solution is 18-22%, preferably 20%.
In the step C, the weight of the sodium carbonate solution is 2.3 to 2.8 times, preferably 2.5 times of that of the intermediate in the step A.
In the step C, the dichloromethane 3 is added in a volume amount of 7-9, preferably 8, of the weight of the intermediate. In some embodiments of the invention, the amount of intermediate charged in step A is 6Kg and the volume of dichloromethane 3 charged in step C is 42 to 54L, preferably 48L.
In the step C, the weight of the anhydrous sodium sulfate is 1 time of that of the intermediate.
In the step C, the adding volume amounts of the purified water 3 and the dichloromethane 4 are respectively 2-3 times of the weight of the intermediate. In some embodiments of the invention, the amount of intermediate fed in step A is 6Kg, the volume of purified water 3 added in step C is 12-18L, and the volume of dichloromethane 4 added in step C is 12-18L.
In the step D, the adding volume of the absolute ethyl alcohol 2 is 7-9 times of the weight of the intermediate in the step A. In some embodiments of the invention, the amount of intermediate charged in step A is 6Kg and the volume of absolute ethanol added in step D is 42-54L.
In the step D, the addition amount of the benzoic acid is 1 time equivalent of the intermediate.
In the step D, the addition volume of the absolute ethyl alcohol 3 is 2-3 times of the weight of the intermediate. In some embodiments of the invention, the amount of the intermediate charged in step A is 6Kg and the volume of the absolute ethyl alcohol 3 charged in step D is 12 to 18L.
Further, the invention provides a recrystallization refining method of alogliptin benzoate.
A refining method of alogliptin benzoate comprises the following steps: adding absolute ethyl alcohol 4 and alogliptin benzoate into a reaction tank, heating to 80-85 ℃, stirring until the absolute ethyl alcohol 4 and alogliptin benzoate are completely dissolved, cooling to 50-55 ℃, controlling the system temperature to be 50-55 ℃, stirring for 3.5-4.5 hours, continuously cooling to 5-10 ℃, controlling the system temperature to be 5-10 ℃, stirring for 0.8-1.2 hours, filtering, washing with absolute ethyl alcohol, and drying in vacuum to obtain alogliptin benzoate.
In the refining method, the temperature is reduced to 50-55 ℃ from 80-85 ℃ to 50-55 ℃ within 0.9-1.1 hours.
In the refining method, the temperature is continuously reduced to 5-10 ℃ for 1.7-2.2 hours, and the temperature is reduced from 50-55 ℃ to 5-10 ℃.
In the refining method, the addition volume of the absolute ethyl alcohol 4 is 17-20 times of the addition weight of the alogliptin benzoate. In some embodiments of the invention, alogliptin benzoate is 5Kg, and the volume of absolute ethyl alcohol 4 added is 85 to 100L.
The alogliptin benzoate prepared by the refining method has uniform particle size distribution, the uniform particle size distribution refers to the particle size distribution of a sample detected by the method provided by the invention, and the spectrum of the alogliptin benzoate is displayed in a single peak.
The alogliptin benzoate prepared by the refining method is white or off-white crystal powder, and D90 is not more than 220 μm, preferably not more than 200 μm; d50 is not less than 10 μm, preferably not less than 20 μm; the specific surface area is 300 to 1200 square meters per kilogram, preferably 400 to 900 square meters per kilogram.
Further, the alogliptin benzoate prepared by the refining method is white or off-white crystalline powder, and the D90 is not less than 100 μm, preferably not less than 120 μm; d50 is not higher than 70 μm, preferably not higher than 60 μm; the specific surface area is 300 to 1200 square meters per kilogram, preferably 400 to 900 square meters per kilogram.
The "D90 of not more than 220 μm" is 90% by number of particles having a diameter of not more than 220 μm.
Further, the invention provides a preparation method of the bulk drug of the fogliptin benzoate, which comprises the following steps:
(1) Preparation of alogliptin benzoate intermediate 2- (6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl) -benzonitrile:
adding an organic solvent, 6-chloro-3-methyluracil and diisopropylethylamine into a reaction tank, heating, stirring until the materials are clear, adding 2-cyanobenzyl bromide, continuously heating to 60 +/-5 ℃, and carrying out heat preservation reaction for 2-2.5 h. After the reaction is finished, the temperature is reduced to 10 +/-2 ℃, purified water is slowly added within 2 +/-0.5H, after the addition is finished, the mixture is stirred and crystallized for 1.5 +/-0.5H, the mixture is centrifuged, the wet powder is washed by the purified water and dried in vacuum, and an intermediate 2- (6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl) -benzonitrile is obtained.
(2) Preparation of alogliptin benzoate:
step A: adding a solvent, sodium carbonate, (R) -3-aminopiperidine dihydrochloride and an intermediate 2- (6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl) -benzonitrile into a reaction tank, heating to 80 +/-5 ℃, carrying out heat preservation reaction for 5.5-6H, and after the reaction is finished, concentrating the feed liquid under reduced pressure until no continuous liquid is distilled off.
And B: adding purified water 1 to the concentrate, adding dichloromethane 1 in two portions, extracting the aqueous phase for 2 times, combining the dichloromethane phases, washing the dichloromethane phase with purified water 2, extracting twice with dilute hydrochloric acid, combining the dilute hydrochloric acid phases, and washing the dilute hydrochloric acid phase with dichloromethane 2.
And C: slowly adding a sodium carbonate solution into the dilute hydrochloric acid phase, stirring for 1.5 +/-0.5 h, adding dichloromethane 3, extracting and separating for 2 times, washing the dichloromethane phase with purified water 3, drying dichloromethane with anhydrous sodium sulfate, filtering, and washing a filter cake with dichloromethane 4; concentrating under reduced pressure to obtain solid.
Step D: and D, adding the solid obtained in the step C and absolute ethyl alcohol 2 into a reaction kettle, starting stirring, heating to 65 +/-5 ℃, adding benzoic acid after the materials are dissolved, stirring until the solid is separated out, carrying out heat preservation reaction for 60 +/-5 min, cooling to 20 +/-5 ℃, stirring for crystallization for 1-1.5 h, centrifuging, washing with absolute ethyl alcohol 3, centrifuging, spin-drying, and carrying out vacuum drying to obtain alogliptin benzoate.
(3) Refining of alogliptin benzoate:
adding absolute ethyl alcohol 4 and alogliptin benzoate into a reaction tank, heating to 80-85 ℃, stirring until the absolute ethyl alcohol 4 and alogliptin benzoate are completely dissolved, cooling to 50-55 ℃, controlling the system temperature to be 50-55 ℃, stirring for 3.5-4.5 hours, continuously cooling to 5-10 ℃, controlling the system temperature to be 5-10 ℃, stirring for 0.8-1.2 hours, filtering, washing with absolute ethyl alcohol, and drying in vacuum to obtain the alogliptin benzoate bulk drug.
The alogliptin benzoate provided by the invention is white or off-white crystalline powder, and D90 is 100-220 μm, preferably 120-200 μm; d90 is 10-70 μm, preferably 20-60 μm; the specific surface area is 300 to 1200 square meters per kilogram, preferably 400 to 900 square meters per kilogram.
The invention further provides a method for detecting the purity of the alogliptin benzoate intermediate 2- (6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl) -benzonitrile: adopting high performance liquid chromatography, wherein the chromatographic conditions are as follows: octadecylsilane chemically bonded silica was used as a filler (C18 column, 250X 4.6mm,5 μm); mobile phase: 0.1% trifluoroacetic acid-acetonitrile (55; column temperature: 35 ℃; flow rate: 1.0ml/min; detection wavelength: 278nm; solvent: and (3) acetonitrile.
Further, the detection method further comprises the following steps: taking the intermediate 2- (6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl) -benzonitrile, and adding a solvent to dilute to 0.8-1.2mg/ml to obtain a test solution; the purity of the intermediate 2- (6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl) -benzonitrile was calculated by area normalization.
The invention further provides a method for detecting the granularity of alogliptin benzoate, which comprises the following steps:
a detection instrument: the Malvern laser particle analyzer (model: MS 3000) has the following system parameters:
a detection instrument: the Malvern laser particle analyzer (model: MS 3000) has the following system parameters:
| parameter name | Set value |
| Sample injector | AeroS |
| Refractive index of sample | 1.52 |
| Rate of absorption of particles | 0.1 |
| Density of | 1g/cm 3 |
| Time of measurement | 12s |
| Background scan time | 12s |
| Number of | 1 time of |
| Degree of shade | 0.5％-6％ |
| Time of settling | 0s |
| Air pressure | 4bar |
| | 50％ |
| Of the venturi type | Standard venturi tube |
| Hopper clearance | 2mm |
| Cleaning type | Standard of merit |
| Analysis mode | General purpose |
The determination method comprises the following steps: taking a proper amount of alogliptin benzoate raw material, adding the alogliptin benzoate raw material into a hopper, and measuring until the light shading degree reaches 0.5-6%.
In another aspect, the invention also provides an alogliptin benzoate pharmaceutical formulation, a pharmaceutical composition comprising alogliptin benzoate prepared according to the method of the present invention and a pharmaceutically acceptable carrier, and optionally, other therapeutic components may be further present in the pharmaceutical composition.
When the pharmaceutical composition comprises alogliptin benzoate prepared according to the method of the present invention and a pharmaceutically acceptable carrier, the alogliptin benzoate can be prepared into solid preparations, preferably oral tablets or sustained release tablets, and the preparations can be prepared by using corresponding auxiliary materials known by those skilled in the art and adopting corresponding known preparation technologies of pharmaceutical preparations.
The alogliptin benzoate intermediate, the alogliptin benzoate and the pharmaceutical composition containing the alogliptin benzoate prepared by the method meet the medicinal requirements in all indexes, are stable in quality in the process of placement, and can ensure the clinical curative effect and the medication safety.
Drawings
FIG. 1: example 3 liquid chromatogram;
FIG. 2: example 7 liquid chromatogram;
FIG. 3: example 13 particle size distribution pattern;
FIG. 4 is a schematic view of: example 14 particle size distribution profile;
FIG. 5: comparative example 6 particle size distribution map;
FIG. 6: comparative example 7 particle size distribution map;
FIG. 7: comparative example 10 particle size distribution map.
The method for detecting the purity of alogliptin benzoate intermediate 2- (6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl) -benzonitrile comprises the following steps: high performance liquid chromatography
Chromatographic conditions are as follows: octadecylsilane bonded silica gel was used as a filler (C18 column, 250X 4.6mm,5 μm), and the mobile phase: 0.1% trifluoroacetic acid-acetonitrile (55: 35 ℃, flow rate: 1.0ml/min, detection wavelength: 278nm.
Solvent: and (3) acetonitrile.
Test solution: taking about 25mg of the product, precisely weighing, placing in a 25ml measuring flask, adding a solvent, performing ultrasonic treatment to dissolve, diluting to scale, and shaking up to obtain a test solution.
The determination method comprises the following steps: precisely measuring 10 μ l of the test solution, injecting into a liquid chromatograph, and recording the chromatogram until the retention time of the main peak is 5 times. If an impurity peak exists in the chromatogram of the test solution, the purity is calculated according to an area normalization method.
Detailed Description
The invention discloses an alogliptin benzoate intermediate and a preparation method of alogliptin, and a person skilled in the art can realize the intermediate by combining the related principle of pharmaceutical chemistry and properly improving the process parameters by taking the contents of the invention as reference. It is expressly intended that all such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the scope of the invention. While the invention has been described in terms of preferred embodiments, it will be apparent to those skilled in the art that variations may be applied, or changes and combinations may be made, in the methods and applications described herein to achieve and use the inventive techniques without departing from the spirit, scope, and content of the invention.
The present invention is further illustrated by the following examples, which are not intended to limit the invention in any way.
Example 1: preparation of alogliptin benzoate intermediate 2- (6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl) -benzonitrile
Adding 16L of N-methyl pyrrolidone, 12L of toluene, 4Kg (24.91 mol) of 6-chloro-3-methyl uracil and 3.9Kg (30.17mol, 1.21eq) of diisopropylethylamine into a reaction tank, heating, stirring until the materials are dissolved, adding 5.1Kg (26.02mol, 1.04eq) of 2-cyanobenzyl bromide, continuously heating to 60 +/-5 ℃, and keeping the temperature for reaction for 2.2 hours. After the reaction is finished, the temperature is reduced to 10 +/-2 ℃, 32L of purified water is slowly added within 2H, after the addition is finished, the mixture is stirred and crystallized for 1.5H, the centrifugation is carried out, the purified water is used for washing wet powder, the ethanol is used for pulping, and the vacuum drying is carried out, thus obtaining 6.29Kg (22.82 mol) of intermediate 2- (6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl) -benzonitrile. White powder, yield 91.61% and purity 99.90%.
Example 2: preparation of alogliptin benzoate intermediate 2- (6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl) -benzonitrile
Adding 8L of N-methylpyrrolidone, 6L of toluene, 2Kg (12.46 mol) of 6-chloro-3-methyl uracil and 1.95Kg (15.09mol, 1.21eq) of diisopropylethylamine into a reaction tank, heating, stirring until the materials are dissolved, adding 2.57Kg (13.11mol, 1.05eq) of 2-cyanobenzyl bromide, continuously heating to 60 +/-5 ℃, and carrying out heat preservation reaction for 2.2 hours. After the reaction is finished, the temperature is reduced to 10 +/-2 ℃, 16L of purified water is slowly added within 2H, after the addition is finished, the mixture is stirred and crystallized for 1.5H, the centrifugation is carried out, the purified water is used for washing wet powder, the ethanol is used for pulping, and the vacuum drying is carried out, thus obtaining 3.14Kg (11.39 mol) of intermediate 2- (6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl) -benzonitrile. White powder, yield 91.41%, purity 99.91%.
Example 3: preparation of alogliptin benzoate intermediate 2- (6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl) -benzonitrile
Adding 4L of N-methyl pyrrolidone, 3L of toluene, 1Kg (6.23 mol) of 6-chloro-3-methyl uracil and 0.98Kg (7.58mol, 1.22eq) of diisopropylethylamine into a reaction tank, heating, stirring until the materials are dissolved, adding 1.28Kg (6.53mol, 1.05eq) of 2-cyanobenzyl bromide, continuously heating to 60 +/-5 ℃, and keeping the temperature for reaction for 2.2 hours. After the reaction is finished, the temperature is reduced to 10 +/-2 ℃, 8L of purified water is slowly added within 2H, after the addition is finished, the mixture is stirred and crystallized for 1.5H, the centrifugation is carried out, the purified water is used for washing wet powder, the ethanol is used for pulping, and the vacuum drying is carried out, thus obtaining 1.57Kg (5.69 mol) of intermediate 2- (6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl) -benzonitrile. White powder, yield 91.33% and purity 99.92%. See figure 1 for details.
Example 4: preparation of alogliptin benzoate intermediate 2- (6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl) -benzonitrile
Adding 14.3L of N-methyl pyrrolidone, 10L of toluene, 4Kg (24.91 mol) of 6-chloro-3-methyl uracil and 4Kg (30.95mol, 1.24eq) of diisopropylethylamine into a reaction tank, heating, stirring until the materials are dissolved, adding 5.05Kg (25.76mol, 1.03eq) of 2-cyanobenzyl bromide, continuously heating to 60 +/-5 ℃, and keeping the temperature for reaction for 2 hours. After the reaction is finished, the temperature is reduced to 10 +/-2 ℃, 28L of purified water is slowly added within 1.5H, after the addition is finished, the mixture is stirred and crystallized for 1.5H, the centrifugation is carried out, the purified water is used for washing wet powder, the ethanol is used for pulping, and the vacuum drying is carried out, so as to obtain 6.23Kg of intermediate 2- (6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl) -benzonitrile (22.60 mol). White powder, yield 90.73%, purity 99.75%.
Example 5: preparation of alogliptin benzoate intermediate 2- (6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl) -benzonitrile
Adding 17.8L of N-methylpyrrolidone, 14.2L of toluene, 4Kg (24.91 mol) of 6-chloro-3-methyl uracil and 3.8Kg (29.40mol, 1.18eq) of diisopropylethylamine into a reaction tank, heating, stirring until the materials are dissolved, adding 5.2Kg (26.53mol, 1.07eq) of 2-cyanobenzyl bromide, continuously heating to 60 +/-5 ℃, and keeping the temperature for reaction for 2.5 hours. After the reaction is finished, the temperature is reduced to 10 +/-2 ℃, 36L of purified water is slowly added within 2.5H, after the addition is finished, the mixture is stirred and crystallized for 2.5H, the centrifugation is carried out, the purified water is used for washing wet powder, the ethanol is used for pulping, and the vacuum drying is carried out, thus obtaining 6.21Kg (22.53 mol) of intermediate 2- (6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl) -benzonitrile. White powder, yield 90.45%, purity 99.81%.
Example 6: preparation of alogliptin benzoate intermediate 2- (6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl) -benzonitrile
Adding 16L of N-methyl pyrrolidone, 10.4L of toluene, 4Kg (24.91 mol) of 6-chloro-3-methyl uracil and 3.7Kg (28.63mol, 1.15eq) of diisopropylethylamine into a reaction tank, heating, stirring until the materials are dissolved, adding 5.2Kg (26.53mol, 1.07eq) of 2-cyanobenzyl bromide, continuously heating to 60 +/-5 ℃, and keeping the temperature for reaction for 2 hours. After the reaction is finished, the temperature is reduced to 10 +/-2 ℃, 28L of purified water is slowly added within 1.5H, after the addition is finished, the mixture is stirred and crystallized for 1.5H, the centrifugation is carried out, the purified water is used for washing wet powder, the ethanol is used for pulping, and the vacuum drying is carried out, thus obtaining 6.17Kg (22.38 mol) of intermediate 2- (6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl) -benzonitrile. White powder, yield 89.84% and purity 99.69%.
Example 7: preparation of alogliptin benzoate
Step A: adding 30L of absolute ethyl alcohol, 6L of purified water, 3.92Kg (36.98mol, 1.70eq) of sodium carbonate (the particle size D90 of the sodium carbonate is not more than 180 mu m), (3.97 Kg (22.94mol, 1.05eq) of R) -3-aminopiperidine dihydrochloride and 6Kg (21.76 mol) of intermediate into a reaction tank, heating to 80 +/-5 ℃, carrying out heat preservation reaction for 5.8h, and after the reaction is finished, concentrating the feed liquid under reduced pressure until no continuous liquid is distilled off;
and B: adding 18L of purified water to the concentrate of step A, adding 30L of dichloromethane twice, extracting the aqueous phase for 2 times, combining the dichloromethane phases, washing the dichloromethane phase with 9L of purified water, extracting twice with 70L (35L for the first time, 35L for the second time) of 0.5N dilute hydrochloric acid, combining the dilute hydrochloric acid phases, and washing the dilute hydrochloric acid phase with 9L of dichloromethane;
step C: slowly adding 15L of 20% sodium carbonate solution into the dilute hydrochloric acid phase in the step B, stirring for 1.5h, adding 48L of dichloromethane, extracting and separating for 2 times, washing the dichloromethane phase with 15L of purified water, drying the dichloromethane phase with 6Kg of anhydrous sodium sulfate, filtering, and washing a filter cake with 15L of dichloromethane; concentrating under reduced pressure to obtain solid;
step D: and C, adding 48L of the solid obtained in the step C and 48L of absolute ethyl alcohol into the reaction kettle, starting stirring, heating to 65 +/-5 ℃, adding 2.65Kg of benzoic acid (21.70mol, 1.00eq) after the materials are dissolved, stirring until the solid is separated out, carrying out heat preservation reaction for 60min, cooling to 20 +/-5 ℃, stirring and crystallizing for 1.2h, centrifuging, washing by 15L of absolute ethyl alcohol, centrifuging, drying by spin drying, and carrying out vacuum drying to obtain 7.89Kg (17.10 mol) of alogliptin benzoate. The yield of the white-like crystal powder is 78.58%, single impurity is 0.01%, and total impurity is 0.05%.
Example 8: preparation of alogliptin benzoate
Step A: adding 15L of absolute ethyl alcohol, 3L of purified water, 2Kg (18.87mol, 1.73eq) of sodium carbonate (the particle size D90 of the sodium carbonate is not more than 180 mu m), 1.99Kg (11.50mol, 1.06eq) of R) -3-aminopiperidine dihydrochloride and 3Kg (10.88 mol) of intermediate into a reaction tank, heating to 80 +/-5 ℃, carrying out heat preservation reaction for 5.7 hours, and after the reaction is finished, concentrating the feed liquid under reduced pressure until no continuous liquid is distilled off;
and B: adding 9L of purified water into the concentrate obtained in the step A, adding 15L of purified water twice, extracting the water phase for 2 times, combining dichloromethane phases, washing the dichloromethane phase with 5L of purified water, extracting twice with 30L (15L for the first time and 15L for the second time) of 0.6N diluted hydrochloric acid, combining diluted hydrochloric acid phases, and washing the diluted hydrochloric acid phases with 5L of dichloromethane;
step C: slowly adding 7L of 22% sodium carbonate solution into the dilute hydrochloric acid phase in the step B, stirring for 1.5h, adding 24L of dichloromethane, extracting and separating for 2 times, washing the dichloromethane phase with 7.5L of purified water, drying the dichloromethane phase with 3Kg of anhydrous sodium sulfate, filtering, and washing a filter cake with 7.5L of dichloromethane; concentrating under reduced pressure to obtain solid.
Step D: and D, adding 24L of the solid obtained in the step C and 24L of absolute ethyl alcohol into the reaction kettle, starting stirring, heating to 65 +/-5 ℃, adding 1.33Kg of benzoic acid (10.89mol, 1.00eq) after the materials are dissolved out, stirring until the solid is separated out, keeping the temperature for reaction for 60min, cooling to 20 +/-5 ℃, stirring for crystallization for 1.4h, centrifuging, washing with 7.5L of absolute ethyl alcohol, centrifuging for spin-drying, and drying in vacuum to obtain 3.92Kg of alogliptin benzoate (8.49 mol). White-like crystalline powder, yield 78.03%, mono-impurity 0.01%, total impurity 0.05%.
Example 9: preparation of alogliptin benzoate
Step A: adding 7.5L of absolute ethyl alcohol, 1.5L of purified water, 1Kg (9.43mol, 1.73eq) of sodium carbonate (the particle diameter D90 of the sodium carbonate is not more than 180 mu m), (1 Kg (5.78mol, 1.06eq) of R) -3-aminopiperidine dihydrochloride and 1.5Kg (5.44 mol) of intermediate into a reaction tank, heating to 80 +/-5 ℃, keeping the temperature for reaction for 5.6 hours, and after the reaction is finished, concentrating the feed liquid under reduced pressure until no continuous liquid is distilled off.
And B: to the concentrate of step A, purified water 4.5L was added in two portions of 7.5L, the aqueous phase was extracted 2 times, the methylene chloride phases were combined, the methylene chloride phase was washed with 5L of purified water, extracted twice with 15L (first 7L, second 8L) of 0.67N dilute hydrochloric acid, the dilute hydrochloric acid phases were combined, and the dilute hydrochloric acid phase was washed with 5L of methylene chloride.
And C: slowly adding 4L of 18% sodium carbonate solution into the dilute hydrochloric acid phase in the step B, stirring for 1.5h, adding 12L of dichloromethane, extracting and separating for 2 times, washing the dichloromethane phase with 4L of purified water, drying the dichloromethane phase with 1.5Kg of anhydrous sodium sulfate, filtering, and washing a filter cake with 4L of dichloromethane; concentrating under reduced pressure to obtain solid;
step D: and C, adding the solid obtained in the step C and 12L of absolute ethyl alcohol into a reaction kettle, starting stirring, heating to 65 +/-5 ℃, adding 0.665Kg (5.45mol, 1.00eq) of benzoic acid after the materials are dissolved, stirring until the solid is separated out, carrying out heat preservation reaction for 60min, cooling to 20 +/-5 ℃, stirring and crystallizing for 1.3h, centrifuging, washing with 4L of absolute ethyl alcohol, centrifuging, drying by spin-drying, and carrying out vacuum drying to obtain 1.96Kg (4.25 mol) of alogliptin benzoate. White-like crystalline powder, yield 78.13%, single impurity 0.02%, total impurity 0.06%. See figure 2 for details.
Example 10: preparation of alogliptin benzoate
Step A: adding 27.5L of absolute ethyl alcohol, 5.5L of purified water, 3.8Kg (35.85mol, 1.65eq) of sodium carbonate (the particle size D90 of the sodium carbonate is not more than 185 mu m), (3.9 Kg (22.53mol, 1.04eq) of R) -3-aminopiperidine dihydrochloride and 6Kg (21.76 mol) of intermediate into a reaction tank, heating to 80 +/-5 ℃, preserving heat for reaction for 5.9h, and after the reaction is finished, concentrating the feed liquid under reduced pressure until no continuous liquid is distilled off;
and B: adding purified water 15L into the concentrate of the step A, adding 7.5L24L in two times, extracting the water phase for 2 times, combining the dichloromethane phases, washing the dichloromethane phase with purified water 10L, extracting twice with 0.5N dilute hydrochloric acid 66L (first 36L, second 30L), combining the dilute hydrochloric acid phases, and washing the dilute hydrochloric acid phase with dichloromethane 10L;
and C: slowly adding 15L of 21% sodium carbonate solution into the dilute hydrochloric acid phase in the step B, stirring for 1h, adding 45L of dichloromethane, extracting and separating for 2 times, the dichloromethane phase is washed with 14L of purified water, and the dichloromethane phase is dried over 6Kg of anhydrous sodium sulfate, filtered, and the filter cake is washed with 14L of dichloromethane; concentrating under reduced pressure to obtain solid;
step D: and D, adding 45L of the solid obtained in the step C and anhydrous ethanol into the reaction kettle, starting stirring, heating to 65 +/-5 ℃, adding 2.65Kg of benzoic acid (21.70mol, 1.00eq) after the materials are dissolved, stirring until the solid is separated out, carrying out heat preservation reaction for 58min, cooling to 20 +/-5 ℃, stirring and crystallizing for 1.3h, centrifuging, washing by 14L of anhydrous ethanol, centrifuging, drying by spin drying, and carrying out vacuum drying to obtain 7.74Kg of alogliptin benzoate (16.77 mol). The yield of the white-like crystal powder is 77.07%, the single impurity content is 0.02%, and the total impurity content is 0.06%.
Example 11: preparation of alogliptin benzoate
Step A: adding 32.5L of absolute ethyl alcohol, 6.5L of purified water, 4.1Kg (38.68mol, 1.78eq) of sodium carbonate (the particle size D90 of the sodium carbonate is not more than 190 mu m), (4 Kg (23.111mol, 1.06eq) of R) -3-aminopiperidine dihydrochloride and 6Kg (21.76 mol) of intermediate into a reaction tank, heating to 80 +/-5 ℃, carrying out heat preservation reaction for 6 hours, and after the reaction is finished, concentrating the feed liquid under reduced pressure until no continuous liquid is distilled out;
and B, step B: adding 21L of purified water into the concentrate obtained in the step A, adding 36L of purified water twice, extracting the water phase for 2 times, combining dichloromethane phases, washing the dichloromethane phase with 11L of purified water, extracting twice with 72L (first 36L and second 36L) of 0.5N dilute hydrochloric acid, combining dilute hydrochloric acid phases, and washing the dilute hydrochloric acid phase with 11L of dichloromethane;
and C: slowly adding 15L of 20% sodium carbonate solution into the dilute hydrochloric acid phase in the step B, stirring for 2h, adding 50L of dichloromethane, extracting and separating for 2 times, washing the dichloromethane phase with 16L of purified water, drying the dichloromethane phase with 6Kg of anhydrous sodium sulfate, filtering, and washing a filter cake with 16L of dichloromethane; concentrating under reduced pressure to obtain solid;
step D: and C, adding 50L of the solid obtained in the step C and 50L of absolute ethyl alcohol into the reaction kettle, starting stirring, heating to 65 +/-5 ℃, adding 2.65Kg of benzoic acid (21.70mol, 1.00eq) after the materials are dissolved, stirring until the solid is separated out, carrying out heat preservation reaction for 55min, cooling to 20 +/-5 ℃, stirring and crystallizing for 1.1h, centrifuging, washing by 16L of absolute ethyl alcohol, centrifuging, drying by spin-drying, and carrying out vacuum drying to obtain 7.71Kg (16.71 mol) of alogliptin benzoate. The yield of the white-like crystal powder is 76.79%, the single impurity content is 0.02%, and the total impurity content is 0.07%.
Example 12: preparation of alogliptin benzoate
Step A: adding 25L of absolute ethyl alcohol, 5L of purified water, 3.7Kg (34.91mol, 1.60eq) of sodium carbonate (the particle size D90 of the sodium carbonate is not more than 200 mu m), (3.9 Kg (22.53mol, 1.04eq) of R) -3-aminopiperidine dihydrochloride and 6Kg (21.76 mol) of intermediate into a reaction tank, heating to 80 +/-5 ℃, carrying out heat preservation reaction for 5.5h, and after the reaction is finished, concentrating the feed liquid under reduced pressure until no continuous liquid is distilled off;
and B: adding 18L of purified water to the concentrate of step A, adding 24L of purified water twice, extracting the aqueous phase for 2 times, combining the dichloromethane phases, washing the dichloromethane phase with 7L of purified water, extracting twice with 65L (35L for the first time, 33L for the second time) of 0.5N dilute hydrochloric acid, combining the dilute hydrochloric acid phases, and washing the dilute hydrochloric acid phases with 7L of dichloromethane;
and C: slowly adding 15L of 20% sodium carbonate solution into the dilute hydrochloric acid phase in the step B, stirring for 1.5h, adding 42L of dichloromethane, extracting and separating for 2 times, washing the dichloromethane phase with 12L of purified water, drying the dichloromethane phase with 6Kg of anhydrous sodium sulfate, filtering, and washing a filter cake with 12L of dichloromethane; concentrating under reduced pressure to obtain solid;
step D: and C, adding 42L of the solid obtained in the step C and absolute ethyl alcohol into the reaction kettle, starting stirring, heating to 65 +/-5 ℃, adding 2.65Kg of benzoic acid (21.70mol, 1.00eq) after the materials are dissolved, stirring until the solid is separated out, carrying out heat preservation reaction for 65min, cooling to 20 +/-5 ℃, stirring and crystallizing for 1.5h, centrifuging, washing by 12L of absolute ethyl alcohol, centrifuging, drying by spin drying, and carrying out vacuum drying to obtain 7.62Kg of alogliptin benzoate (16.51 mol). The yield of the white-like crystal powder is 75.87%, single impurity is 0.02%, and total impurity is 0.08%.
Example 13: purification of alogliptin benzoate
Adding 90L of absolute ethyl alcohol and 5Kg of alogliptin benzoate into a reaction tank, heating to 80-85 ℃, stirring until the absolute ethyl alcohol and the alogliptin benzoate are completely dissolved, cooling to 50.8 ℃ within 1 hour, precipitating a small amount of crystals, controlling the system temperature to be 50-55 ℃, stirring for 4 hours, cooling to 8.2 ℃ within 2hours, controlling the system temperature to be 5-10 ℃, stirring for 1 hour, filtering, washing with 12L of absolute ethyl alcohol, and drying in vacuum to obtain the alogliptin benzoate4.33Kg of gliptin, white crystalline powder; the yield was 86.67%, single hetero 0.01%, total hetero 0.02%. The sample is subjected to particle size detection, the particle size distribution is uniform, the spectrum is a single peak, and D5048.8 mu m; d90139 mu m. Specific surface area: 455.1m 2 (iv) Kg. See figure 3 for details.
Example 14: purification of alogliptin benzoate
Adding 40L of absolute ethyl alcohol and 2Kg of alogliptin benzoate into a reaction tank, heating to 80-85 ℃, stirring until the absolute ethyl alcohol and the alogliptin benzoate are completely dissolved, cooling to 50.1 ℃ within 1 hour, separating out a small amount of crystals, controlling the system temperature to be 50-55 ℃, stirring for 4 hours, cooling to 8.3 ℃ within 2hours, controlling the system temperature to be 5-10 ℃, stirring for 1 hour, filtering, washing with 5L of absolute ethyl alcohol, and drying in vacuum to obtain 1.71Kg of alogliptin benzoate and white crystalline powder; the yield is 85.73 percent, the single impurity content is 0.01 percent, and the total impurity content is 0.03 percent. The sample is subjected to particle size detection, the particle size distribution is uniform, the spectrum is a single peak, and D5044.3 mu m; d90197 μm. Specific surface area: 597.0m 2 Perkg. See figure 4 for details.
Example 15: purification of alogliptin benzoate
Adding 85L of absolute ethyl alcohol and 5Kg of alogliptin benzoate into a reaction tank, heating to 80-85 ℃, stirring until the absolute ethyl alcohol and the alogliptin benzoate are completely dissolved, cooling to 53.6 ℃ in 0.9h, separating out a small amount of crystals, stirring for 3.5h at 50-55 ℃ of the system temperature, cooling to 5.4 ℃ at 1.8h, stirring for 0.9h at 5-10 ℃ of the system temperature, filtering, washing with 12L of absolute ethyl alcohol, and drying in vacuum to obtain 4.24Kg of alogliptin benzoate and white crystalline powder; the yield was 84.78%, single hetero 0.01%, and total hetero 0.03%. And (3) carrying out particle size detection on the sample, wherein the particle size distribution is uniform, the spectrum is' unimodal, and D50:45.6 mu m; d90168 μm. Specific surface area: 473.8m 2 /Kg。
Example 16: purification of alogliptin benzoate
Adding 88L of absolute ethyl alcohol and 5Kg of alogliptin benzoate into a reaction tank, heating to 80-85 ℃, stirring until the absolute ethyl alcohol and alogliptin benzoate are completely dissolved, cooling to 53.1 ℃ for 1.1h, separating out a small amount of crystals, stirring for 4.5h at 50-55 ℃ for the system temperature, cooling to 6.4 ℃ for 2.2h, stirring for 1.1h at 5-10 ℃ for the system temperature, filtering, washing with 13L of absolute ethyl alcohol, and drying in vacuum to obtain 4.16Kg of alogliptin benzoate and white crystalline powder; harvesting machineThe ratio is 83.25%, the single impurity is 0.01%, and the total impurity is 0.03%. The sample is subjected to particle size detection, the particle size distribution is uniform, the spectrum is a single peak, and D5040.7 mu m; d90137 μm. Specific surface area: 477.8m 2 /Kg
Comparative example 1: preparation of alogliptin benzoate intermediate 2- (6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl) -benzonitrile
Comparative examples 1-1 to comparative examples 1-5: the organic solvent, other process parameters and procedures were the same as in example 3. The results are as follows:
comparative examples 1 to 6: adding 4L of DMF, 3L of dimethyl sulfoxide, 1Kg (6.23 mol) of 6-chloro-3-methyl uracil and 0.98Kg (7.58mol, 1.22eq) of diisopropylethylamine into a reaction tank, heating, stirring until the materials are dissolved, adding 1.28Kg (6.53mol, 1.05eq) of 2-cyanobenzyl bromide, continuously heating to 60 +/-5 ℃, and keeping the temperature for reaction for 2.2 hours. After the reaction is finished, the temperature is reduced to 10 +/-2 ℃, the reaction system is viscous, the solidification phenomenon occurs, and the reaction can not be continued.
The reaction is influenced by factors such as the type and polarity of a solvent, and the solvent with larger acute degree such as N-methyl pyrrolidone, DMF, dimethyl sulfoxide and the like can accelerate the reaction and the side reaction, so that the product purity of an intermediate is influenced; the reaction rate of solvents with lower polarity, such as toluene, is slower, so that the raw material reaction is incomplete, and the yield is influenced, therefore, the invention unexpectedly discovers that the specific solvents mixed according to a specific proportion, namely the organic solvent is a mixed solvent of N-methylpyrrolidone and toluene, and the volume ratio of the organic solvent to the mixed solvent is 1; preferably 1; more preferably 1.75, the reaction rate can be ensured, the progress of side reactions can be significantly suppressed, and the purity of the product can be ensured.
Comparative example 2: preparation of alogliptin benzoate intermediate 2- (6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl) -benzonitrile
The addition of 2-cyanobenzyl bromide was varied, and the other process parameters and steps were the same as in example 3. The results are as follows:
the reaction is influenced by the ratio of the reactant 2-cyanobenzyl bromide to 6-chloro-3-methyl uracil, and when the equivalent weight of the 2-cyanobenzyl bromide is larger, namely not lower than 1.08, the unreflected 2-cyanobenzyl bromide can react with an intermediate further to generate another new impurity to influence the product purity of the intermediate; when the equivalent of the-cyanobenzyl bromide is small, namely less than 1.03, the raw material reaction is incomplete, and the yield is influenced, so that the invention has an unexpected discovery that when the addition amount of the 2-cyanobenzyl bromide is 1.03-1.07 times of the equivalent of the 6-chloro-3-methyl uracil, preferably 1.03-1.05 times of the equivalent, and more preferably 1.04 times of the equivalent, the reactants can be reacted completely, the yield is ensured, and the generation of remarkable impurities and the purity of the product are ensured.
Comparative example 3: preparation of alogliptin benzoate intermediate 2- (6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl) -benzonitrile
The time of addition of purified water was varied, and other process parameters and procedures were the same as in example 3. The results were as follows:
the adding time of the purified water also influences the reaction, and the adding speed of the purified water is too fast, so that the reaction is accelerated, and the yield and the purity are influenced; the adding time is too long, so that the production period is prolonged; thus purified water was added slowly over 2. + -. 0.5 h.
Comparative example 4: preparation of alogliptin benzoate
The particle size of the sodium carbonate in step A was changed, and other process parameters and steps were the same as in example 9. The results are as follows
The particle size of sodium carbonate affects the progress of the reaction, and when the particle size of sodium carbonate is large, the yield is lowered.
Comparative example 5: preparation of alogliptin benzoate
The concentration and the amount of the diluted hydrochloric acid in the step B are changed, and other process parameters and steps are the same as those of the example 9. The results are as follows:
the concentration of the dilute hydrochloric acid influences the reaction, when the concentration of the dilute hydrochloric acid is more than 0.7N, the dilute hydrochloric acid may react with alogliptin to generate alogliptin hydrochloride, and the generated alogliptin hydrochloride is separated out from the reaction system, so that the yield is reduced.
Comparative example 6: purification of alogliptin benzoate
Adding 40L of absolute ethyl alcohol and 2Kg of alogliptin benzoate into a reaction tank, heating to 80-85 ℃, stirring until the absolute ethyl alcohol and the alogliptin benzoate are completely dissolved, heating to 1 h-50.1 ℃, separating out a small amount of crystals, controlling the system temperature to 50-55 ℃, stirring for 3h, cooling to 8.3 ℃ for 2h, controlling the system temperature to 5-10 ℃, stirring for 1h, filtering, washing with 5L of absolute ethyl alcohol, and drying in vacuum to obtain 1.69Kg of alogliptin benzoate and white crystalline powder; the yield is 84.70%, the single impurity content is 0.02%, and the total impurity content is 0.05%. The sample is subjected to particle size detection, the particle size distribution is uneven, the map is double-peak, and D5023.6 mu m; d90137 μm; specific surface area: 948.5m 2 Perkg. See figure 5 for details.
Comparative example 7: purification of alogliptin benzoate
Adding 40L of absolute ethyl alcohol and 2Kg of alogliptin benzoate into a reaction tank, heating to 80-85 ℃, stirring until the absolute ethyl alcohol and the alogliptin benzoate are completely dissolved, cooling to 50.1 ℃ in 40 minutes, separating out a small amount of crystals, stirring for 2.5h at 50-55 ℃ of the system temperature, cooling to 8.3 ℃ at 2h, stirring for 1h at 5-10 ℃ of the system temperature, filtering, washing with 5L of absolute ethyl alcohol, and drying in vacuum to obtain 1.70Kg of alogliptin benzoate and white crystalline powder; the yield is 84.86%, the single impurity content is 0.01%, and the total impurity content is 0.04%. The sample is subjected to particle size detection, the particle size distribution is uneven, the spectrum is bimodal, and D5042.9 mu m; d90237 mu m; specific surface area: 553.1m 2 Perkg. Detailed description of the drawings6。
Comparative example 8: purification of alogliptin benzoate
Adding 40L of absolute ethyl alcohol and 2Kg of alogliptin benzoate into a reaction tank, heating to 80-85 ℃, stirring until the absolute ethyl alcohol and the alogliptin benzoate are completely dissolved, cooling to 50.1 ℃ within 0.5h, separating out a small amount of crystals, controlling the system temperature to 50-55 ℃, stirring for 1h, cooling to 8.3 ℃ within 2h, controlling the system temperature to 5-10 ℃, stirring for 1h, filtering, washing with 5L of absolute ethyl alcohol, and drying in vacuum to obtain 1.67Kg of alogliptin benzoate and white crystalline powder; the yield is 83.49%, the single impurity content is 0.02%, and the total impurity content is 0.05%. The sample is subjected to particle size detection, the particle size distribution is uniform, the map is a single peak, and D505.59 mu m; d907.77 μm; specific surface area: 1117m 2 /Kg。
Comparative example 9: purification of alogliptin benzoate
Adding 40L of absolute ethyl alcohol and 2Kg of alogliptin benzoate into a reaction tank, heating to 80-85 ℃, stirring until the absolute ethyl alcohol and the alogliptin benzoate are completely dissolved, cooling to 50.1 ℃ in 1 hour, separating out a small amount of crystals, reducing the temperature to 35 in 1 hour by adopting a gradient cooling method, reducing the temperature to 25 ℃ in 1 hour, reducing the temperature to 15 ℃ in 1 hour, stirring for 1 hour at 5 ℃ in 1 hour at 5 ℃ to 7 ℃ for 1 hour, filtering, washing with 5L of absolute ethyl alcohol, and drying in vacuum to obtain 1.70Kg of alogliptin benzoate and white crystalline powder; the yield is 84.78%, single impurity content is 0.02%, and total impurity content is 0.06%. The sample is subjected to particle size detection, the particle size distribution is uniform, the map is a single peak, and D501.2 mu m; d901.7 μm; specific surface area: 4863m 2 /Kg
Comparative example 10: purification of alogliptin benzoate
Adding 32L of absolute ethyl alcohol and 2Kg of alogliptin benzoate into a reaction tank, heating to 80-85 ℃, stirring until the absolute ethyl alcohol and the alogliptin benzoate are completely dissolved, cooling to 50.1 ℃ within 1 hour, separating out a large amount of crystals, controlling the system temperature to be 50-55 ℃, stirring for 4 hours, cooling to 8.3 ℃ within 2hours, controlling the system temperature to be 5-10 ℃, stirring for 1 hour, filtering, washing with 5L of absolute ethyl alcohol, and drying in vacuum to obtain 1.67Kg of alogliptin benzoate and white crystalline powder; the yield is 83.65%, single impurity is 0.02%, and total impurity is 0.05%. The sample is subjected to particle size detection, the particle size distribution is uniform, the map is a single peak, and D501.1 mu m; d901.5 μm; specific surface area: 5637m 2 (iv) Kg. See figure 7 for details.
As can be seen from comparative examples 6-10, the refining process influences the particle size of the invention, and the alogliptin benzoate prepared by the refining process provided by the invention has uniform particle size distribution and can meet the requirements of preparations.
EXAMPLE 17 preparation of alogliptin benzoate tablets
Tablets were prepared according to the following formulation using alogliptin benzoate prepared in examples 13 to 16, comparative example 6, comparative example 7 and comparative example 10, respectively.
(1) Each prescription consists of:
(3) The preparation method comprises the following steps:
mixing alogliptin with lactose, adding microcrystalline cellulose, adding an appropriate amount (about 10ml/100 tablets) of a 3 (w/v)% hydroxypropylmethylcellulose aqueous solution to obtain a soft material, granulating with a 18-mesh sieve, drying at 60 ℃ for 1 hour, grading with the 18-mesh sieve, adding cross-linked polyvinylpyrrolidone, colloidal silicon dioxide and magnesium stearate, tabletting to obtain tablets, and coating the obtained tablets with opadry;
(4) The content uniformity and dissolution curve of the sample wafer were measured.
Note: the reference formulation for the dissolution profile was NESINA (nisinan), specification: 12.5mg.
According to test results, the content uniformity of tablets prepared by adopting the alogliptin benzoate prepared by the invention meets the specification, and the f2 values of dissolution curves in 4 mediums with different pH values ((a) 0.01mol/L hydrochloric acid, (b) a pH 4.5 acetic acid buffer solution, (c) a pH 6.8 phosphoric acid buffer solution and (d) water are all more than 80.
Tablets prepared by the alogliptin benzoate prepared in comparative examples 6 and 7 have unqualified content uniformity, and the f2 values of dissolution curves in 4 mediums with different pH values ((a) 0.01mol/L hydrochloric acid, (b) pH 4.5 acetic acid buffer solution, (c) pH 6.8 phosphoric acid buffer solution, and (d) water are all less than 60, so that the quality is not qualified.
Tablets prepared by using alogliptin benzoate prepared in comparative example 10 have the content uniformity specified, but the dissolution curves in 4 media with different pH values ((a) 0.01mol/L hydrochloric acid, (b) pH 4.5 acetic acid buffer solution, (c) pH 6.8 phosphoric acid buffer solution, and (d) water have f2 values less than 50, and do not have the in vitro dissolution behavior similar to that of the original tablet.
EXAMPLE 18 stability test
Taking a proper amount of samples of examples 13-16, and carrying out temperature control at 40 +/-2 ℃; the sample was left at 75% + -5% relative humidity for 6 months, and sampled at the end of 0, 1, 2, 3 and 6 months, respectively, to determine the properties, related substances, contents and the like.
The alogliptin benzoate prepared by the method is accelerated to stand for 6 months, and has stable quality.
Stability test results for alogliptin benzoate samples prepared in examples 13 to 16
Claims (3)
1. A refining method of alogliptin benzoate comprises the following steps: adding absolute ethyl alcohol and alogliptin benzoate into a reaction tank, heating to 80-85 ℃, stirring until the absolute ethyl alcohol and alogliptin benzoate are completely dissolved, cooling to 50-55 ℃, controlling the system temperature to be 50-55 ℃, stirring for 3.5-4.5 hours, continuously cooling to 5-10 ℃, controlling the system temperature to be 5-10 ℃, stirring for 0.8-1.2 hours, filtering, washing with absolute ethyl alcohol, and vacuum drying to obtain alogliptin benzoate;
the temperature is reduced to 50-55 ℃ for 0.9-1.1 hours from 80-85 ℃ to 50-55 ℃; the temperature is continuously reduced to 5-10 ℃ for 1.7-2.2 hours, and is reduced from 50-55 ℃ to 5-10 ℃;
the volume of the absolute ethyl alcohol is 17-20 times of the weight of the alogliptin benzoate;
the refined alogliptin benzoate is white or off-white crystalline powder with uniform particle size distribution; d90 is not more than 200 μm; d90 is not less than 120 mu m; d50 is not higher than 60 μm; d50 is not less than 20 μm; the specific surface area is 400-900 square meters per kilogram.
2. A pharmaceutical composition comprising alogliptin benzoate prepared according to claim 1 and a pharmaceutically acceptable carrier, optionally, other therapeutic ingredients may also be present in the pharmaceutical composition.
3. The pharmaceutical composition of claim 2, which is an oral tablet.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2007035629A2 (en) * | 2005-09-16 | 2007-03-29 | Takeda Pharmaceutical Company Limited | Process for the preparation of pyrimidinedione derivatives |
| CN104592195A (en) * | 2013-10-31 | 2015-05-06 | 江苏万邦生化医药股份有限公司 | A preparing process of alogliptin benzoate |
| CN104803976A (en) * | 2015-05-18 | 2015-07-29 | 苏州亚宝药物研发有限公司 | Industrial production method of Alogliptin benzoate raw material medicine |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2007035629A2 (en) * | 2005-09-16 | 2007-03-29 | Takeda Pharmaceutical Company Limited | Process for the preparation of pyrimidinedione derivatives |
| CN104592195A (en) * | 2013-10-31 | 2015-05-06 | 江苏万邦生化医药股份有限公司 | A preparing process of alogliptin benzoate |
| CN104803976A (en) * | 2015-05-18 | 2015-07-29 | 苏州亚宝药物研发有限公司 | Industrial production method of Alogliptin benzoate raw material medicine |
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