CN105153165B - A kind of preparation method of vildagliptin impurity - Google Patents

A kind of preparation method of vildagliptin impurity Download PDF

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CN105153165B
CN105153165B CN201510457176.4A CN201510457176A CN105153165B CN 105153165 B CN105153165 B CN 105153165B CN 201510457176 A CN201510457176 A CN 201510457176A CN 105153165 B CN105153165 B CN 105153165B
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CN105153165A (en
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刘振玉
祖金祥
周振宇
卢伟伸
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Shanghai Pharmaceutical Group Qingdao Guofeng Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D487/04—Ortho-condensed systems

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Abstract

The invention discloses a kind of preparation method of vildagliptin impurity, comprise the following steps：（1）L proline methyl esters react generation compound 1 in the basic conditions with chloracetyl chloride；（2）The adamantanol condensation reaction of 1 and 3 amino of compound 1 generates compound 2；（3）Compound 2 occurs self-condensation reaction and obtains vildagliptin diketopiperazine in the basic conditions.The present invention vildagliptin diketopiperazine synthetic method, using L proline methyl esters be raw material in the basic conditions with chloracetyl chloride prepare compound 1, the adamantanol of 1 and 3 amino of compound 1 be condensed generates compound 2；Compound 2 occurs self-condensation reaction and obtains vildagliptin diketopiperazine in the basic conditions.The synthetic method is simple, reaction condition is gentle, workable, is the product that can obtain meeting quality standard through simple purification, effectively reduces R＆D costs.

Description

A kind of preparation method of vildagliptin impurity
Technical field
The invention belongs to medicinal chemistry art, it is related to the vildagliptin impurity i.e. preparation method of vildagliptin diketopiperazine.
Background technology
Vildagliptin is developed by Novartis Co., Ltd, obtains within 2007 European Union's approval listing.The CFDA on the 15th of August in 2011 is formally criticized Quasi- vildagliptin is in Discussion on Chinese Listed.Vildagliptin can be treated with biguanides, thiazolidinediones, sulfonylurea drugs drug combination Type II diabetes.Vildagliptin has reduction on an empty stomach and level of postprandial blood sugar, after the meal glucagon secretion and raising β cell work( The effect of energy, new selection is provided for the treatment of patients with NIDDM.Sales growth is powerful after vildagliptin listing, 2011 Up to 6.77 hundred million dollars, total sale in the third quarter is just close to 6.55 hundred million dollars before 2012.
It is the structure of vildagliptin diketopiperazine below
Impurity research is an important link in drug discovery process, and the foundation of quality standard needs a certain amount of mark Quasi- product, so the synthetic method of exploitation impurity is a vital task of drug development.
Vildagliptin diketopiperazine is a specific degradation impurity, the synthetic method mesh of the impurity in vildagliptin preparation Before untill without document report, can only extract and obtain from preparation in R＆D process, and the technique that the impurity is extracted from preparation is answered Miscellaneous, cost is high.
The content of the invention
The purpose of the present invention is to study the synthetic method of vildagliptin diketopiperazine, and this is obtained by the means of controlled syntheses Impurity, provides reliable standard items, and effectively reduce R＆D costs for drug research and development.
The technical scheme that the present invention takes is：
A kind of preparation method of vildagliptin impurity, comprises the following steps：
(1) L-PROLINE methyl esters reacts generation compound 1 in the basic conditions with chloracetyl chloride；
(2) compound 1 generates compound 2 with the condensation reaction of 3- amino-1-adamantane alcohols；
(3) compound 2 occur in the basic conditions self-condensation reaction obtain vildagliptin diketopiperazine.
A kind of preparation method of vildagliptin impurity, preferred scheme is：Comprise the following steps：
(1) chloracetyl chloride is added in solvent, by L-PROLINE methyl esters, triethylamine or/and n-butylamine or/and pyridine reagent Add in solvent, in the solvent for being added dropwise to dissolving chloracetyl chloride, stirring reaction adds water extracting and demixing, is then washed with water and washs Organic phase, organic phase is dried, and obtains compound 1；Described solvent be dichloromethane or/and THF or/and ethyl acetate or/and Butyl acetate or/and 1,2- dichloroethanes；
(2) compound 1 is added in acetone or/and 2- butanone or/and methyl tertbutyl ketone, the solution of compound 1 is made, 3- amino-1-adamantane alcohols, potassium carbonate or/and sodium carbonate, KI or/and sodium iodide are added in acetone, are heated to reflux, and The solution of compound 1 is instilled, stirring reaction filters, filtrate is spin-dried for while hot, adds water dissolving, add dichloromethane extraction, Water washing is added to by organic, organic phase is dried and is spin-dried for, compound 2 is obtained；
(3) compound 2 and alkali are added in reaction dissolvent, reaction temperature is 30~100 DEG C, stirring reaction is filtered, and is added Water and dichloromethane, volume ratio are 3：2, organic phase is washed with water extracting and demixing, layering, and organic phase is dried and is spin-dried for, must be tieed up Ge Lieting diketopiperazines.
The reaction dissolvent that the compound 2 of step (3) prepares vildagliptin diketopiperazine is methanol, ethanol, DMF, DMA, second One or more in nitrile, tetrahydrofuran, 2- methyltetrahydrofurans, ether, dichloromethane, chloroform, dioxane.
The alkali that step (3) is used is triethylamine, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, hydrogenation One or more in sodium, hydrofining, Sodamide.
The compound 2 of step (3) is 1 with the mol ratio of alkali:1 to 1:10.
Step (1) is preferably：
Chloracetyl chloride is added in dichloromethane, then L-PROLINE methyl esters and triethylamine are dissolved in dichloromethane, is dripped Add to dissolving chloracetyl chloride dichloromethane in, stirring reaction 1 hour, add water extracting and demixing, be then washed with water wash it is organic Phase, organic phase is dried, and obtains compound 1, wherein chloracetyl chloride：L-PROLINE methyl esters：The mol ratio of triethylamine is 1.5：1：1.
Step (2) is preferably：
Compound 1 is added in acetone, the solution of compound 1 is made, by 3- amino-1-adamantane alcohols, potassium carbonate, iodate Potassium is added in acetone, is heated to reflux, and instills the solution of compound 1, and stirring reaction 1 hour filters, filtrate is spin-dried for while hot, Water dissolving is added, dichloromethane extraction is added, water washing is added to by organic, organic phase drying decompression is spin-dried for, chemical combination is obtained Thing 2, wherein, compound 1：3- amino-1-adamantane alcohols：Potassium carbonate：The mol ratio of KI is：1：1.5：1：0.05.
Step (3) is preferably：
It is 1 by mol ratio：1 compound 2 and potassium carbonate are added in DMF, 50 DEG C of stirring reactions 3 hours, and filtering adds water And dichloromethane, volume ratio is 3：2, organic phase is washed with water extracting and demixing, layering, and organic phase is dried and is spin-dried for, get Wei Ge Arrange spit of fland diketopiperazine.
Step (3) can be：
It is 1 by mol ratio：1 compound 2 and potassium carbonate are added in tetrahydrofuran, 60 DEG C of stirring reactions 3 hours, filtering, Water and dichloromethane are added, volume ratio is 3：2, organic phase is washed with water extracting and demixing, layering, and organic phase is dried and is spin-dried for, Obtain vildagliptin diketopiperazine.
Step (3) can also be：
It is 1 by mol ratio：1 compound 2 and sodium hydride are added in tetrahydrofuran, 50 DEG C of stirring reactions 4 hours, filtering, Water and dichloromethane are added, volume ratio is 3：2, organic phase is washed with water extracting and demixing, layering, and organic phase is dried and is spin-dried for, Obtain vildagliptin diketopiperazine.
The beneficial effects of the invention are as follows：
The present invention vildagliptin diketopiperazine synthetic method, using L-PROLINE methyl esters as raw material in the basic conditions with Chloracetyl chloride prepare compound 1, compound 1 and 3- amino-1-adamantane alcohols condensation generation compound 2；Compound 2 is in alkaline bar Part, which is issued, is born from body condensation reaction and obtains vildagliptin diketopiperazine.The synthetic method is simple, reaction condition gentle, operability By force, through simple purification it is the product that can obtain meeting quality standard, effectively reduces R＆D costs.
Embodiment
With reference to specific embodiment, the present invention is described further, but protection scope of the present invention is not limited in This.
The preparation of the compound 1 of embodiment 1
16.9g is added in equipped with mechanical agitation, condenser pipe, thermometer, the 1000ml four-hole bottles of heater The chloracetyl chloride of (0.15mol), adds 70ml dichloromethane, then by 12.9g (0.1mol) L-PROLINE methyl esters and 10.1g (0.1mol) triethylamine, which is dissolved in 200ml dichloromethane, to be slowly added dropwise in reaction bulb, stirring reaction 1 hour, adds 200ml water Extracting and demixing, then uses 200ml water washing organic phases again, and organic phase is dried and is spin-dried for, compound 1 is obtained.
The preparation of the compound 2 of embodiment 2
To equipped with addition 25g (0.15mol) in mechanical agitation, condenser pipe, thermometer, the 1000ml four-hole bottles of heater 3- amino-1-adamantane alcohols, 13.8g (0.1mol) potassium carbonate, 0.85g KIs and 200ml acetone, are heated to reflux, by 20.5g (0.1mol) compound 1, which is dissolved in 200ml acetone, to be slowly added dropwise in reaction bulb, and stirring reaction 1 hour is filtered, will filtered while hot Liquid is spin-dried for, and adds the dissolving of 200ml water, adds the extraction of 200ml dichloromethane, 200ml water washings are added to by organic, will be organic Mutually drying is spin-dried for, and obtains compound 2.
The preparation of embodiment 3-dimensional Ge Lieting diketopiperazines
33.6g is added in equipped with mechanical agitation, condenser pipe, thermometer, the 1000ml four-hole bottles of heater (0.1mol) compound 2, adds 13.8g (0.1mol) potassium carbonate and 200mlDMF, 50 DEG C of stirring reactions 3 hours, filtering, plus Enter 300ml water and 200ml dichloromethane extracting and demixings, by organic phase 200ml water washings, organic phase is dried and is spin-dried for by layering, Obtain vildagliptin diketopiperazine, yield 80%.
The preparation of the vildagliptin diketopiperazine of embodiment 4
33.6g is added in equipped with mechanical agitation, condenser pipe, thermometer, the 1000ml four-hole bottles of heater (0.1mol) compound 2, adds 13.8g (0.1mol) potassium carbonate and 200m tetrahydrofurans, 50 DEG C of stirring reactions 3 hours, mistake Filter, adds 300ml water and 200ml dichloromethane extracting and demixings, and by organic phase 200ml water washings, organic phase is dried in layering It is spin-dried for, obtains vildagliptin diketopiperazine, yield 60%.
The preparation of the vildagliptin diketopiperazine of embodiment 5
33.6g is added in equipped with mechanical agitation, condenser pipe, thermometer, the 1000ml four-hole bottles of heater (0.1mol) compound 2, adds 2.4g (0.1mol) sodium hydrides and 200m tetrahydrofurans, 50 DEG C of stirring reactions 3 hours, mistake Filter, adds 300ml water and 200ml dichloromethane extracting and demixings, and by organic phase 200ml water washings, organic phase is dried in layering It is spin-dried for, obtains vildagliptin diketopiperazine, yield 70%.
HPLC (99.2%)
ESI(m/z):305.3[M+1]
1HNMR (CDCl3,600M) 1.53 (d, 1H, J=12Hz), 1.59 (d, 1H, J=12Hz), 1.70 (t, 4H, J= 12Hz), 1.86-1.94 (m, 1H), 1.97-2.21 (m, 9H), 2.29-2.35 (m, 3H), 3.51-3.61 (m, 2H), 3.88 (d, 1H, J=16Hz), 4.02 (t, 1H, J=6Hz), 4.11 (d, 1H, J=16Hz).
13CNMR (CDCl3,150M) 22.9,28.8,30.9,31.0,34.7,38.4 (2), 43.8 (2), 44.9,47.3, 47.9,60.5,61.5,69.4,164.1,168.6.

Claims (9)

1. a kind of preparation method of vildagliptin impurity, it is characterised in that：Comprise the following steps：
(1) L-PROLINE methyl esters reacts generation compound 1 in the basic conditions with chloracetyl chloride：Chloracetyl chloride is added into solvent In, L-PROLINE methyl esters, triethylamine or/and n-butylamine or/and pyridine reagent are added in solvent, dissolving chloracetyl chloride is added dropwise to Solvent in, stirring reaction, add water extracting and demixing, be then washed with water and wash organic phase, organic phase is dried, obtain compound 1； Described solvent is dichloromethane or/and THF or/and ethyl acetate or/and butyl acetate or/and 1,2- dichloroethanes；
(2) compound 1 generates compound 2 with the condensation reaction of 3- amino-1-adamantane alcohols：Compound 1 is added into acetone or/and 2- In butanone or/and methyl tertbutyl ketone, the solution of compound 1 is made, by 3- amino-1-adamantane alcohols, potassium carbonate or/and carbonic acid Sodium, KI or/and sodium iodide are added in acetone, are heated to reflux, and instill the solution of compound 1, stirring reaction, while hot mistake Filter, filtrate is spin-dried for, and adds water dissolving, adds dichloromethane extraction, water washing is added to by organic, organic phase is dried and revolved It is dry, obtain compound 2；
(3) compound 2 occur in the basic conditions self-condensation reaction obtain vildagliptin diketopiperazine：By compound 2 and alkali Add in reaction dissolvent, reaction temperature is 30~100 DEG C, stirring reaction, filtering adds water and dichloromethane, volume ratio is 3： 2, organic phase is washed with water extracting and demixing, layering, and organic phase is dried and is spin-dried for, vildagliptin diketopiperazine is obtained；
2. preparation method as claimed in claim 1, it is characterised in that：The compound 2 of described step (3) prepares vildagliptin The reaction dissolvent of diketopiperazine is methanol, ethanol, DMF, DMA, acetonitrile, tetrahydrofuran, 2- methyltetrahydrofurans, ether, dichloro One or more in methane, chloroform, dioxane.
3. the preparation method as described in right wants 1, it is characterised in that：Described step (3), the alkali used is triethylamine, carbonic acid One or more in potassium, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, hydrofining, Sodamide.
4. the preparation method as described in claims 1 to 3 is any, it is characterised in that：The compound 2 and alkali of described step (3) Mol ratio be 1:1 to 1:10.
5. preparation method as claimed in claim 4, it is characterised in that：Described step (1) is：
Chloracetyl chloride is added in dichloromethane, then L-PROLINE methyl esters and triethylamine are dissolved in dichloromethane, are added dropwise to In the dichloromethane for dissolving chloracetyl chloride, stirring reaction 1 hour adds water extracting and demixing, is then washed with water and washs organic phase, will Organic phase is dried, and obtains compound 1, wherein chloracetyl chloride：L-PROLINE methyl esters：The mol ratio of triethylamine is 1.5：1：1.
6. preparation method as claimed in claim 4, it is characterised in that：Described step (2) is：
Compound 1 is added in acetone, the solution of compound 1 is made, 3- amino-1-adamantane alcohols, potassium carbonate, KI are added Enter in acetone, be heated to reflux, and instill the solution of compound 1, stirring reaction 1 hour filters, filtrate is spin-dried for while hot, add Water is dissolved, and adds dichloromethane extraction, water washing is added to by organic, and organic phase drying decompression is spin-dried for, compound 2 is obtained, Wherein, compound 1：3- amino-1-adamantane alcohols：Potassium carbonate：The mol ratio of KI is：1：1.5：1.：0.05.
7. preparation method as claimed in claim 4, it is characterised in that：Described step (3) is：
It is 1 by mol ratio：1 compound 2 and potassium carbonate are added in DMF, 50 DEG C of stirring reactions 3 hours, and filtering adds water and two Chloromethanes, volume ratio is 3：2, organic phase is washed with water extracting and demixing, layering, and organic phase is dried and is spin-dried for, vildagliptin is obtained Diketopiperazine.
8. preparation method as claimed in claim 4, it is characterised in that：Described step (3) is：
It is 1 by mol ratio：1 compound 2 and potassium carbonate are added in tetrahydrofuran, 60 DEG C of stirring reactions 3 hours, are filtered, are added Water and dichloromethane, volume ratio are 3：2, organic phase is washed with water extracting and demixing, layering, and organic phase is dried and is spin-dried for, must be tieed up Ge Lieting diketopiperazines.
9. preparation method as claimed in claim 4, it is characterised in that：Described step (3) is：
It is 1 by mol ratio：1 compound 2 and sodium hydride are added in tetrahydrofuran, 50 DEG C of stirring reactions 4 hours, are filtered, are added Water and dichloromethane, volume ratio are 3：2, organic phase is washed with water extracting and demixing, layering, and organic phase is dried and is spin-dried for, must be tieed up Ge Lieting diketopiperazines.
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CN108329322B (en) * 2018-05-10 2020-02-21 上海医药集团青岛国风药业股份有限公司 Preparation method of vildagliptin cyclic amidine impurity
CN113527309A (en) * 2021-07-20 2021-10-22 重庆医科大学附属大学城医院 Vildagliptin diketopiperazine and preparation method thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101143852A (en) * 2006-09-13 2008-03-19 深圳市翰宇生物工程有限公司 Method for preparing cyclodipeptide cyclo(L-Asp-L-Pro)
CN103787944A (en) * 2012-11-01 2014-05-14 天津药物研究院 Preparation method of 1-(2-chloroacetyl)-2-(S)-nitrile pyrrolidine
CN104311467A (en) * 2014-09-11 2015-01-28 青岛国风药业股份有限公司 Method and device for continuous preparation of Vildagliptin by tubular reaction
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

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CZ2008512A3 (en) * 2008-08-26 2010-03-10 Zentiva, A. S Process for preparing extremely pure vildagliptin

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101143852A (en) * 2006-09-13 2008-03-19 深圳市翰宇生物工程有限公司 Method for preparing cyclodipeptide cyclo(L-Asp-L-Pro)
CN103787944A (en) * 2012-11-01 2014-05-14 天津药物研究院 Preparation method of 1-(2-chloroacetyl)-2-(S)-nitrile pyrrolidine
CN104311467A (en) * 2014-09-11 2015-01-28 青岛国风药业股份有限公司 Method and device for continuous preparation of Vildagliptin by tubular reaction
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

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"1-[[(3-Hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine: A Potent,Selective, and Orally Bioavailable Dipeptidyl Peptidase IV Inhibitor with Antihyperglycemic Properties";Edwin B. Villhauer等，;《J. Med. Chem.》;20030524;第46卷;第2774-2789页 *

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