CN108329322B - Preparation method of vildagliptin cyclic amidine impurity - Google Patents
Preparation method of vildagliptin cyclic amidine impurity Download PDFInfo
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- CN108329322B CN108329322B CN201810441527.6A CN201810441527A CN108329322B CN 108329322 B CN108329322 B CN 108329322B CN 201810441527 A CN201810441527 A CN 201810441527A CN 108329322 B CN108329322 B CN 108329322B
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- C07—ORGANIC CHEMISTRY
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
The invention discloses a preparation method of vildagliptin cycloamidine impurities, which comprises the steps of adding vildagliptin (I) into a reaction solvent, adding alkali, heating to 30-180 ℃, reacting for 2-8 hours, and purifying a reaction solution to obtain vildagliptin cycloamidine impurities (II). The invention provides a method for synthesizing vildagliptin cyclic amidine impurities for the first time, which takes vildagliptin as a raw material, prepares the vildagliptin cyclic amidine impurities by adopting one-step cyclization reaction, and has the advantages of mild reaction conditions, easy operation and high yield. The product meeting the quality standard can be obtained through simple purification, and the research and development cost is effectively reduced.
Description
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to a preparation method of vildagliptin cycloamidine impurities.
Background
Vildagliptin is developed by Nowa company, is approved to be marketed by the European Union in 2007, is officially approved to be marketed in China by CFDA (carbon fiber demand data) at 8.15.2011, vildagliptin can be used in combination with biguanides, thiazolidinediones and sulfonylurea drugs to treat type II diabetes, and vildagliptin has the effects of reducing fasting and postprandial blood sugar levels, secreting postprandial glucagon and improving β cell function, so that a new choice is provided for treatment of type II diabetes patients, sales of vildagliptin after marketing is strong, 6.77 billion dollars are achieved in 2011, and total sales of vildagliptin 3 quarters before 2012 are close to 6.55 billion dollars.
The structure of vildagliptin cyclic amidine degradation impurities is as follows:
in recent years, with the approach of vildagliptin patent period, the research and development of vildagliptin are accelerated by domestic pharmaceutical imitation manufacturers, the research on impurities is an important link in the process of drug development, and the establishment of quality standards needs a certain amount of standard products, so that the development of a synthetic method of impurities is an important task of drug development.
The vildagliptin cycloamidine impurity is a specific degradation impurity in vildagliptin preparations, the synthesis method of the impurity has no literature report so far, the impurity can only be extracted from the preparations in the current research and development process, and the process for extracting the impurity from the preparations is complex and has extremely high cost.
Disclosure of Invention
The invention aims to research a synthetic method for degrading vildagliptin cyclic amidine impurities, obtain the impurities by means of directional synthesis, provide reliable standard products for drug research and development and effectively reduce research and development cost.
The technical scheme adopted by the invention is as follows:
a preparation method of vildagliptin cycloamidine impurities comprises the steps of adding vildagliptin (I) into a reaction solvent, adding alkali, heating to 30-180 ℃, reacting for 2-8 hours, and purifying a reaction solution to obtain vildagliptin cycloamidine impurities (II), wherein the reaction formula is as follows:
a preparation method of vildagliptin cycloamidine impurities comprises the steps of adding vildagliptin (I) into liquid alkali, heating to 30-180 ℃, reacting for 2-8 hours, and purifying reaction liquid to obtain vildagliptin cycloamidine impurities (II), wherein the reaction formula is as follows:
the purification steps are as follows: and cooling the reaction solution to room temperature, filtering, spin-drying the filtrate, adding a reaction solvent for dissolving, washing with water, drying, and evaporating to dryness to obtain vildagliptin cycloamidine impurities.
Preferably, the temperature is increased to 40-120 ℃.
Preferably, the reaction solvent is one or more of methanol, ethanol, water, isopropanol, DMF, DMA, acetonitrile, tetrahydrofuran, dichloromethane, chloroform, dioxane.
Preferably, the base is one or more of triethylamine, tri-n-butylamine, pyridine, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide and potassium hydroxide.
Preferably, the liquid base is one or more of triethylamine, tri-n-butylamine and pyridine.
Preferably, the molar ratio of the compound I to the base is 1: 1-1: 10.
Preferably, the purification steps are: then cooled to room temperature and filtered, the filtrate was evaporated to dryness, and a mixed solution of methanol and dichloromethane, methanol: the volume ratio of the dichloromethane is 1: and 10, washing with water, drying and evaporating to obtain vildagliptin cycloamidine impurity (II).
The preparation method has the yield more than or equal to 75 percent.
The invention has the beneficial effects that:
the invention provides a method for synthesizing vildagliptin cyclic amidine impurities for the first time, which takes vildagliptin as a raw material, prepares the vildagliptin cyclic amidine impurities by adopting one-step cyclization reaction, and has the advantages of mild reaction conditions, easy operation and high yield. The product meeting the quality standard can be obtained through simple purification, and the research and development cost is effectively reduced.
Detailed Description
The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto:
example 1: preparation of vildagliptin cycloamidine impurity
30.3g of vildagliptin (I) (0.1mol) and 200ml of ethanol are added into a 1000ml four-mouth bottle provided with a mechanical stirring device, a condenser tube, a thermometer and a heating device, then 200ml of aqueous solution of 20g of sodium hydroxide (0.5mol) is added, the temperature is raised to 40 ℃, and the reaction is finished after 5 hours. Cooling to room temperature, filtering, evaporating the filtrate to dryness, adding 500ml of a mixed solution of methanol and dichloromethane (methanol: dichloromethane is 1:10 (v: v)), stirring to dissolve, filtering, evaporating the filtrate to dryness to obtain a white solid, namely the vildagliptin amide degradation impurity (II), wherein the yield is 85%.
Example 2: preparation of vildagliptin cycloamidine impurity
30.3g of vildagliptin (I) (0.1mol) and 200ml of methanol are added into a 1000ml four-mouth bottle provided with a mechanical stirring device, a condenser tube, a thermometer and a heating device, then 200ml of aqueous solution of 28g of potassium hydroxide (0.5mol) is added, the temperature is raised to 60 ℃, and the reaction is finished after 5 hours. Cooling to room temperature, filtering, evaporating the filtrate to dryness, adding 500ml of a mixed solution of methanol and dichloromethane (methanol: dichloromethane is 1:10 (v: v)), stirring to dissolve, filtering, evaporating the filtrate to dryness to obtain a white solid, namely the vildagliptin amide degradation impurity (II), wherein the yield is 80%.
Example 3: preparation of vildagliptin cycloamidine impurity
30.3g of vildagliptin (I) (0.1mol) and 200ml of DMF are added into a 1000ml four-mouth bottle provided with a mechanical stirring device, a condenser tube, a thermometer and a heating device, then 200ml of aqueous solution of 28g of potassium hydroxide (0.5mol) is added, the temperature is raised to 70 ℃, and the reaction is finished after 5 hours. Cooling to room temperature, filtering, evaporating the filtrate to dryness, adding 500ml of a mixed solution of methanol and dichloromethane (methanol: dichloromethane is 1:10 (v: v)), stirring to dissolve, filtering, evaporating the filtrate to dryness to obtain a white solid, namely the vildagliptin amide degradation impurity (II), wherein the yield is 90%.
Example 4: preparation of vildagliptin cycloamidine impurity
30.3g of vildagliptin (I) (0.1mol) and 200ml of acetonitrile are added into a 1000ml four-neck flask equipped with a mechanical stirring, condensing tube, thermometer and heating device, and then 200ml of aqueous solution of 28g of potassium hydroxide (0.5mol) is added, the temperature is raised to 60 ℃, and the reaction is finished after 5 hours. Cooling to room temperature, filtering, evaporating the filtrate to dryness, adding 500ml of a mixed solution of methanol and dichloromethane (methanol: dichloromethane is 1:10 (v: v)), stirring to dissolve, filtering, evaporating the filtrate to dryness to obtain a white solid, namely the vildagliptin amide degradation impurity (II), wherein the yield is 90%.
Example 5: preparation of vildagliptin cycloamidine impurity
30.3g of vildagliptin (I) (0.1mol) is added into a 100ml four-mouth bottle provided with a mechanical stirring device, a condenser tube, a thermometer and a heating device, 39.5g of pyridine (0.5mol) is added, the temperature is raised to 60 ℃, the reaction is carried out for 5 hours, and the reaction is finished. Cooling to room temperature, filtering, evaporating to dryness, adding 500ml of a mixed solution of methanol and dichloromethane (methanol: dichloromethane is 1:10 (v: v)), stirring to dissolve, filtering, evaporating the filtrate to dryness to obtain a white solid, namely the vildagliptin amide degradation impurity (II), wherein the yield is 90%.
HPLC(99.0％)
ESI(m/z):304.2M+1]
1HNMR(CDCl3，600M)1.51(d,1H,J＝12Hz),1.59(d,1H,J＝12Hz),1.70(q,4H,J＝12Hz),1.89-2.31(m,13H),3.46-3.51(m,1H)，3.63-3.67(m,1H)，3.71-3.74(m,1H)，4.06-4.09(m,1H)，6.43(br,1H)。
13CNMR(CDCl3，150M)23.1，29.8，30.9，31.1，34.9，37.90，37.94，44.0，44.1，44.7，46.9，48.2，60.8，60.9，69.7，163.3，165.6。
Claims (6)
1. A preparation method of vildagliptin cyclic amidine impurities is characterized by comprising the following steps: adding vildagliptin (I) into a reaction solvent, adding alkali, heating to 30-180 ℃, reacting for 2-8 hours, and purifying the reaction solution to obtain vildagliptin cycloamidine impurities (II), wherein the reaction solvent is one or more of methanol, ethanol, propanol, DMF, DMA, tetrahydrofuran, dichloromethane, chloroform and dioxane; the alkali is one or more of sodium hydroxide and potassium hydroxide; the molar ratio of the compound I to the alkali is 1: 5-1: 10, and the reaction formula is as follows:
2. a preparation method of vildagliptin cyclic amidine impurities is characterized by comprising the following steps: adding liquid alkali into vildagliptin (I), heating to 30-180 ℃, reacting for 2-8 hours, and purifying the reaction liquid to obtain vildagliptin cycloamidine impurities (II), wherein the liquid alkali is one or more of triethylamine, tri-n-butylamine and pyridine; the molar ratio of the compound I to the alkali is 1: 5-1: 10, and the reaction formula is as follows:
3. the method of claim 1 or 2, wherein: the purification steps are as follows: and cooling the reaction solution to room temperature, filtering, spin-drying the filtrate, adding a reaction solvent for dissolving, washing with water, drying, and evaporating to dryness to obtain vildagliptin cycloamidine impurities.
4. The method of claim 1 or 2, wherein: heating to 40-120 ℃.
5. The method of claim 3, wherein: the purification steps are as follows: then cooled to room temperature and filtered, the filtrate was evaporated to dryness, and a mixed solution of methanol and dichloromethane, methanol: the volume ratio of the dichloromethane is 1: and 10, washing with water, drying and evaporating to obtain vildagliptin cycloamidine impurity (II).
6. The method of claim 1 or 2, wherein: the yield is more than or equal to 75 percent.
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| CN104557943A (en) * | 2014-12-23 | 2015-04-29 | 扬子江药业集团四川海蓉药业有限公司 | Preparation method of vildagliptin impurities |
| CN104672243A (en) * | 2015-02-10 | 2015-06-03 | 华润赛科药业有限责任公司 | Method for preparing vildagliptin degraded impurities |
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| CN106146510A (en) * | 2015-03-31 | 2016-11-23 | 深圳翰宇药业股份有限公司 | A kind of preparation method of vildagliptin degradation impurity |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US8404727B2 (en) * | 2009-01-07 | 2013-03-26 | Glenmark Pharmaceuticals S.A. | Pharmaceutical composition that includes a dipeptidyl peptidase-IV inhibitor |
| WO2011101861A1 (en) * | 2010-01-29 | 2011-08-25 | Msn Laboratories Limited | Process for preparation of dpp-iv inhibitors |
| WO2014020462A1 (en) * | 2012-08-01 | 2014-02-06 | Alembic Pharmaceuticals Limited | Improved process for preparation of vildagliptin intermediate |
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| CN104672243A (en) * | 2015-02-10 | 2015-06-03 | 华润赛科药业有限责任公司 | Method for preparing vildagliptin degraded impurities |
| CN106146510A (en) * | 2015-03-31 | 2016-11-23 | 深圳翰宇药业股份有限公司 | A kind of preparation method of vildagliptin degradation impurity |
| CN105153165A (en) * | 2015-07-30 | 2015-12-16 | 上海医药集团青岛国风药业股份有限公司 | Preparation method for vildagliptin impurity |
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