CN110818688A - Argatroban degradation impurity and preparation method thereof - Google Patents
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Abstract
The invention relates to argatroban degradation impurities and a preparation method thereof, wherein the impurities are (2R,4R) -4-methyl-1- [ N' - ((R, S) -3-methyl-1, 2,3, 4-tetrahydro-8-quinolinesulfonyl-L-citrullinyl ] -2-piperidinecarboxylic acid, the preparation method comprises the steps of taking L-citrulline as a raw material, carrying out condensation reaction with 2R, 4R-ethyl piperidinecarboxylate, carrying out condensation reaction with 3-methyl-8-quinolinesulfonyl chloride under the action of organic base to obtain an intermediate 2, carrying out hydrogenation reduction on the intermediate 2 under the catalysis of palladium carbon, further carrying out hydrolysis reaction in an alkaline water alcohol solution, and purifying by a column.
Description
Technical Field
The invention relates to a compound with medical application and a preparation method thereof, in particular to preparation, application and detection of an impurity-degrading compound I of an anticoagulant argatroban.
Background
The molecular structural formula of Argatroban (Argatroban) is shown as the following formula:
the chemical name is (2R,4R) -4-methyl-1- [ N- [ ((R, S) -3-methyl-1, 2,3, 4-tetrahydro-8-quinoline) sulfonyl]-L-arginine]-2-piperazinesPicolinic acid of formula C23H36N6O5S, relative molecular mass of 508.63, CAS registry number of 74863-84-6, argatroban is a new thrombin inhibitor developed by Mitsubishi pharmaceutical corporation, Japan, reversibly binds to the thrombin active site, and can be used for anticoagulant therapy of patients with ischemic cerebral infarction in acute stage. The U.S. Food and Drug Administration (FDA) approved in 2000 the use of the smuhkrine Beecham and Texas biotechnology injectable antithrombotic small molecule drug argatroban for the treatment and prevention of thrombosis and heparin-induced immune disease thrombocytopenia and for the treatment of patients in need of percutaneous coronary intervention. The multicenter second phase clinical trial results published on the 28 th international stroke congress at the american stroke society on 3, 5 days 2003 show that argatroban has significant safety in its therapeutic efficacy in the treatment of acute ischemic stroke. In 2011, 5 and 10 days, argatroban injection, namely a ready-to-use product, is approved by the U.S. Food and Drug Administration (FDA) to be used for preventing or treating thrombus, and the applicable population is patients with thrombocytopenia caused by heparin. The argatroban injection is also used as an anticoagulant for patients with thrombocytopenia or high-risk percutaneous coronary intervention caused by combined heparin.
In the reported literature, the main synthetic routes to argatroban are divided into two categories:
1. taking N-nitro-L-BOC-arginine as a starting material, carrying out a condensation reaction with (2R,4R) -ethyl piperidinecarboxylate, and then removing a BOC protecting group; reacting with 3-methyl-8-quinoline sulfonyl chloride for condensation reaction, hydrolyzing and hydrogenating under high pressure to obtain the argatroban finished product. The route diagram is shown as the following formula:
2. N-nitro-L-arginine and 3-methyl-8-quinoline sulfonyl chloride are subjected to condensation reaction, then are condensed with (2R,4R) -ethyl piperidine formate under the action of phosphorus oxychloride, and are subjected to ethyl ester hydrolysis and high-pressure hydrogenation reaction to finally obtain the finished argatroban product, wherein the synthetic route diagram of the argatroban product is shown as the following formula:
impurities are a key quality attribute of medicines and belong to key research objects in the whole chemical research and development process. The degradation impurities refer to impurities generated by chemical changes of raw material medicaments and preparations in the production and storage processes, and some process impurities also can be degradation impurities.
An alkali-degradable impurity of argatroban is disclosed in the overview Form document (abbreviated as IF document) in argatroban japanese pharmaceutical specifications and has the following chemical formula:
the inventor obtains an argatroban bulk drug sample according to the prior synthesis technology, and forced degradation tests on argatroban show that argatroban is unstable under acid and alkali conditions, and the solution of argatroban is easy to degrade under ultraviolet irradiation. The inventor finds that a new degraded impurity with lower content exists in an argatroban bulk drug sample, detects the molecular weight of the argatroban bulk drug by LC-MS detection on an alkali destruction solution, then concentrates a reaction solution, performs high-pressure preparation, separation and purification to obtain a small amount of samples of a target product, analyzes an H-NMR spectrum, synthesizes mass spectrum signals, analyzes and judges that the product is a compound with a new structure, and has a structural formula as follows:
the process impurities are one of the key factors for the quality research of the bulk drugs and the preparations. For better argatroban quality research, it is necessary to obtain a standard substance of corresponding impurities so as to perform corresponding detection on the argatroban, and control the standard substance within a safe and reasonable limit range, thereby improving and controlling the argatroban quality and safety.
The argatroban degradation impurity obtained by the invention can be used for qualitative and quantitative analysis of impurities in argatroban production, so that the quality standard of argatroban is improved, and important guiding significance is provided for safe medication.
Disclosure of Invention
The invention discloses argatroban degradation impurities with a structure shown as a formula I,
the invention further discloses a preparation method of argatroban degradation impurities with the structure of formula I, which comprises the following reaction steps:
(1) taking L-citrulline as an initial raw material, carrying out condensation reaction with 2R, 4R-ethyl piperidine formate under the catalysis of a condensing agent, directly carrying out condensation reaction on the obtained product and 3-methyl-8-quinolinesulfonyl chloride under the action of organic base after the reaction is finished, and carrying out column purification to obtain an intermediate 2 with the chemical name of (2R,4R) -4-methyl-1- ((S) -2- (3-methylquinoline-8-sulfonylamino) -5-citrullinyl) ethyl piperidine-2-formate;
(2) and (3) carrying out hydrogenation reduction on the intermediate 2 under the catalysis of palladium carbon, filtering the reaction solution to remove the palladium carbon, then carrying out spin drying, carrying out hydrolysis reaction on the concentrate in an alkaline water alcohol solution, and carrying out column purification to obtain the product, namely the compound I.
Wherein the chemical structure of the intermediate 2 is as follows:
wherein, the catalyst used in the condensation reaction in the step (1) is selected from: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 1-Hydroxybenzotriazole (HOBT), Dicyclohexylcarbodiimide (DCC) and the like, preferably EDCI, wherein the molar equivalent of the catalyst is 1.0-2.0, preferably 1.1-1.2 compared with L-citrulline; the reaction solvent is one or a mixture of several dissolved solvents selected from dichloromethane, tetrahydrofuran, 1, 4-dioxane and N, N-dimethylformamide, and is preferably tetrahydrofuran, wherein the weight volume ratio of L-citrulline to tetrahydrofuran is 1: 20-40. Preferably, the molar equivalent ratio of citrulline to EDCI:2R, 4R-ethyl piperidinecarboxylate in step (1): 1: 1.1-1.2: 1;
wherein, in the alkaline water alcohol solution in the step (2), the inorganic base is lithium hydroxide, the molar concentration of the alkaline water is 0.5-1.5 mol/L, and the weight ratio of the solvent is as follows: 1: 10-30.
Preferably, the step (1) comprises the following operation steps:
(a) adding L-citrulline, ethyl 2R, 4R-piperidinecarboxylate and a proper amount of tetrahydrofuran into a reaction bottle, stirring to 0-10 ℃ under ice bath, adding EDCI, stirring for 1-1.5 hours under heat preservation, heating to room temperature for reaction for 2-3 hours, and carrying out HPLC tracking reaction until no L-citrulline is left as a reaction end point.
(b) Stopping the reaction, adding a proper amount of purified water to quench the reaction, distilling under reduced pressure at 45 ℃ to remove the reaction solvent, and pumping by an oil pump. Dissolving the obtained product with a proper amount of N, N-dimethylformamide, adding triethylamine with a certain molar equivalent at room temperature, reacting for 3-4 hours, and carrying out HPLC (high performance liquid chromatography) tracking reaction until no raw materials are left, so as to stop the reaction.
(c) Concentrating the reaction solution to dryness, and separating and purifying by a silica gel column to obtain an intermediate 2.
Preferably, the step (2) comprises the following operation steps:
(a) adding the intermediate 2, 10% palladium carbon and a certain amount of anhydrous methanol into a hydrogenation reaction kettle; the mass volume ratio of the intermediate 2 to the anhydrous methanol is 1: 10-20.
(b) Replacing for 2 times with nitrogen, replacing for 5 times with hydrogen, heating to 50-55 ℃, and stirring for reacting for 24 hours.
(c) Cooling to room temperature, filtering to remove palladium carbon, and distilling the filtrate at 40-45 ℃ under reduced pressure to remove the solvent;
(d) adding the obtained product into a certain amount of 1mol/L lithium hydroxide ethanol aqueous solution, stirring at room temperature, and stopping the reaction when TLC points on the plate until no raw material point remains. And (3) regulating the pH value of the system to 3-4 by using hydrochloric acid, concentrating the reaction solution under reduced pressure until the reaction solution is dry, and purifying the reaction solution by using a silica gel column to finally obtain a compound 1, namely argatroban degradation impurities.
The method for researching the degradation products mainly comprises structural characteristic analysis, influencing factor experiments and forced degradation experiments, the degradation products of the drugs generated by reaction products such as hydrolysis, oxidation, ring-opening polymerization and the like are researched, impurity analysis is carried out, and the method is very important for ensuring the quality of the drugs. Based on the structural characteristics, possible degradation products can be analyzed, and the degradation impurities can be subjected to determination of an impurity spectrum through influencing factors and forced degradation experiments. Influence factors and special environment of forced degradation often have great deviation with normal storage condition, influence factor experiment generally can consider temperature, humidity, illumination, air exposure etc. to the influence of product quality, and the damage of forced degradation experiment generally investigation acid, alkali, oxidation, temperature, humidity to product quality.
The invention discovers and synthesizes the argatroban degradation impurity compound I, and carries out synthesis preparation research, thereby providing an impurity reference substance for analysis and detection of argatroban finished products and ensuring that the quality of the argatroban finished products is qualified.
In the synthesis method of the present invention, the purity of the compound I is required to be 95% or more.
The argatroban degradation impurity compound I prepared by the method can be used for qualitative and quantitative analysis of impurities in the argatroban production process, and the whole process of the related detection method is as follows:
mobile phase A: 10mM ammonium acetate and 5mM sodium n-heptane sulfonate
Mobile phase B: acetonitrile/methanol (500:300)
| Time(min) | Solution A(％) | Solution B(％) |
| 0 | 60 | 40 |
| 20 | 60 | 40 |
| 35 | 50 | 50 |
| 50 | 20 | 80 |
| 60 | 20 | 80 |
| 60.1 | 60 | 40 |
| 72.1 | 60 | 40 |
A chromatographic column: 4.6mm × 25 cm; 3mm packing L1
Flow rate: 0.6ml/min
Column temperature: 40 deg.C
The invention takes low-cost L-citrulline as a starting raw material, obtains high-purity argatroban degradation impurities through condensation, hydrogenation reduction and hydrolysis reaction, can be used for detecting argatroban bulk drugs, can be used as an impurity reference substance for preparing samples, and has the following purity: more than 95 percent.
The invention further provides a preparation method of the argatroban degradation impurity compound I, reaction materials in the preparation process are cheap and easy to obtain, the route is simple, the reaction conditions are mild and easy to control, and compared with a preparation method of performing alkali destruction on an argatroban sample and then performing preparation, separation and purification, the method for directionally synthesizing the degradation impurity has the advantages of higher yield, lower material cost and more convenient operation. The method for preparing argatroban degradation impurities can be further used for preparing other argatroban impurities and derivatives thereof.
Drawings
FIG. 1 shows the hydrogen nuclear magnetic resonance spectrum of argatroban degradation impurity compound I
Detailed Description
It will be understood by those skilled in the art, based upon the disclosure herein, that various modifications and improvements may be made to the invention without departing from the spirit and scope of the invention. They are intended to fall within the scope of protection of the patent as defined by the claims of the present application. Furthermore, it should be understood that the examples provided herein are for the purpose of illustrating the invention and should not be construed as limiting the invention.
The present invention will be described in further detail with reference to specific examples.
The synthetic route can be represented by the following formula:
example 1: preparation of intermediate 2
10.00g (57.08mmol) of L-citrulline, 9.78g (57.08mmol) of ethyl 2R, 4R-piperidinecarboxylate and 100ml of tetrahydrofuran were placed in a 250ml three-necked round-bottomed flask, and 13.13g (68.49mmol) of EDCI was added thereto under ice-water bath, followed by stirring for 1 to 2 hours. The temperature is raised to room temperature, and stirring is continued for 3-4 hours until no raw material point exists (tracking the reaction by Thin Layer Chromatography (TLC) or High Performance Liquid Chromatography (HPLC)). After the reaction was completed, 5ml of purified water was added to the system, and the reaction was quenched and stirred for 20 minutes. The reaction solution was distilled under reduced pressure at 45 ℃ to remove the solvent, and then was dried by an oil pump until no solvent was present.
The concentrate was dissolved in 30ml of N, N-dimethylformamide, and 17.29g (171.24mmol) of triethylamine was added to the reaction flask, followed by stirring at room temperature for 3 to 4 hours until no starting material was present (following the reaction by Thin Layer Chromatography (TLC) or High Performance Liquid Chromatography (HPLC)). The reaction was concentrated to dryness, and the mixture was subjected to silica gel powder mixing by dry method, and subjected to silica gel column separation and purification to obtain 3.11g of intermediate 2, yield 10.21%, and HPLC purity 98.23%.
Mass spectrometry data: 534.8(M + H), 556.7(M + Na)
Example 2: preparation of argatroban degradation impurity
3.00g (5.62mmol) of intermediate 2, 0.30g of 10% palladium on carbon and 40ml of anhydrous methanol were mixed at room temperature. Stirred for 30 minutes until homogeneous. And replacing the nitrogen for 2 times and replacing the hydrogen for 5 times, wherein the pressure of the hydrogen is 15-20 atmospheric pressures, heating to 50-55 ℃, and stirring for reacting for 24 hours. Stopping heating, cooling to room temperature, performing suction filtration to recover the palladium-carbon, and leaching the palladium-carbon with 10ml of anhydrous methanol. The filtrate was distilled under reduced pressure at 45 ℃ to remove the solvent.
Dissolving the obtained product with 15ml of 1mol/L sodium hydroxide aqueous solution and 10ml of absolute ethyl alcohol, stirring and reacting for 5-6 hours at room temperature, and stopping the reaction when no raw material is left on a TLC point plate. Adjusting the pH value of the system to 3-4 by using concentrated hydrochloric acid, concentrating the reaction solution under reduced pressure to dryness, and purifying by using a silica gel column to finally obtain 1.25g of a compound 1, namely argatroban degradation impurity, wherein the yield is 43.64%, and the HPLC purity is 99.52%.
Mass spectrometry data: 510.7(M + H)
It will be apparent to those skilled in the art that various changes and modifications can be made in the above embodiments without departing from the scope and spirit of the invention as defined in the appended claims, and all changes and modifications that come within the meaning and range of equivalency of the claims are to be embraced within their scope and are intended to be embraced therein.
Claims (4)
1. An argatroban degradation impurity with a structure of formula I,
2. a process for the preparation of argatroban degradation impurities as claimed in claim 1, characterized by comprising the following reaction steps:
(1) taking L-citrulline as an initial raw material, carrying out condensation reaction with 2R, 4R-ethyl piperidine formate under the catalysis of a condensing agent, directly carrying out condensation reaction on the obtained product and 3-methyl-8-quinolinesulfonyl chloride under the action of organic base after the reaction is finished, and carrying out column purification to obtain an intermediate 2 with the chemical name of (2R,4R) -4-methyl-1- ((S) -2- (3-methylquinoline-8-sulfonylamino) -5-citrullinyl) ethyl piperidine-2-formate;
(2) and (3) carrying out hydrogenation reduction on the intermediate 2 under the catalysis of palladium carbon, filtering the reaction solution to remove the palladium carbon, then carrying out spin drying, carrying out hydrolysis reaction on the concentrate in an alkaline water alcohol solution, and carrying out column purification to obtain the product, namely the compound 1.
3. The preparation method according to claim 2, wherein the molar equivalent ratio of citrulline to ethyl EDCI:2R, 4R-piperidinecarboxylate in step (1): 1: 1.1-1.2: 1, wherein the organic solvent is selected from organic solvents such as dichloromethane, trichloromethane, tetrahydrofuran, acetone and the like, or any mixture of the organic solvents.
4. The preparation method according to claim 2, wherein the alkaline solution in step (2) and the inorganic base are lithium hydroxide, wherein the molar concentration of alkaline is 0.5-1.5 mol/L, and the weight ratio of the solvents is: 1: 10-30.
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Cited By (3)
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| CN111471085A (en) * | 2020-04-16 | 2020-07-31 | 江巨东 | Method for continuously preparing argatroban |
| CN112625086A (en) * | 2020-12-25 | 2021-04-09 | 北京悦康科创医药科技股份有限公司 | Preparation method of argatroban impurity G |
| CN117269357A (en) * | 2023-09-22 | 2023-12-22 | 北京沃邦医药科技有限公司 | Detection method for determining impurity C in Argatroban |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111471085A (en) * | 2020-04-16 | 2020-07-31 | 江巨东 | Method for continuously preparing argatroban |
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| CN112625086B (en) * | 2020-12-25 | 2022-04-05 | 北京悦康科创医药科技股份有限公司 | Preparation method of argatroban impurity G |
| CN117269357A (en) * | 2023-09-22 | 2023-12-22 | 北京沃邦医药科技有限公司 | Detection method for determining impurity C in Argatroban |
| CN117269357B (en) * | 2023-09-22 | 2024-04-26 | 北京沃邦医药科技有限公司 | Detection method for determining impurity C in Argatroban |
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Application publication date: 20200221 |