CN104557943A - Preparation method of vildagliptin impurities - Google Patents
Preparation method of vildagliptin impurities Download PDFInfo
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- CN104557943A CN104557943A CN201410811679.2A CN201410811679A CN104557943A CN 104557943 A CN104557943 A CN 104557943A CN 201410811679 A CN201410811679 A CN 201410811679A CN 104557943 A CN104557943 A CN 104557943A
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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 impurities. The preparation method comprises the steps of dissolving initial raw materials including (S)-N-chloroacetyl-2-cyanopyrrolidine and 3-amino-1-adamantanol into a solvent, reacting at an alkaline condition by virtue of catalysis of potassium iodide to prepare an intermediate product, namely (S)-1-[[(3-hydroxyadamantane)amino]acetyl]-2-cyanopyrrolidine, and preparing the vildagliptin impurities from the intermediate product by virtue of catalysis of lewis acid. The preparation method has the beneficial effects that the process is simple, the operation is easy and convenient, and the preparation efficiency is beneficially improved.
Description
Technical field
The present invention relates to a kind of preparation of medicine, particularly a kind of preparation of Oral anti-diabetic new drug Vildagliptin impurity.
Background technology
Vildagliptin (Vildagliptin) a kind ofly has selectivity, competitiveness, reversible DPP-4 (IV type dipeptidyl peptidase) inhibitor; its chemistry (2S)-1-by name [[(3-hydroxyadamantane) is amino] ethanoyl]-2-Cyanopyrolidine; mixture can be formed thus the activity suppressing DDP-4 by being combined with DPP-4; improve the concentration of the important hormone GLP-1 maintaining glucose sugar concentration in body; B cell is impelled to produce Regular Insulin; reduce the concentration of hyperglycemic-glycogenolytic factor simultaneously, thus reduce blood sugar.On September 28th, 2007, the Oral anti-diabetic new drug (trade(brand)name: Galvus) using Vildagliptin as activeconstituents obtains EU Committee's approval, goes on the market with Ireland in 27 European Union member countries and Norway.In November, 2011, SFDA ratifies it in Discussion on Chinese Listed.
Be below the structure of Vildagliptin impurity:
Summary of the invention
The invention discloses a kind of new preparation method of Vildagliptin impurity; react obtained intermediate product in the basic conditions by starting raw material (S)-N-chloracetyl-2-Cyanopyrolidine and 3-amino-1-adamantane alcohol, intermediate product is obtained Vildagliptin impurity under lewis acidic catalysis again.
The present invention first proposed a kind of preparation method of Vildagliptin impurity, comprises the following steps:
1) starting raw material (S)-N-chloracetyl-2-Cyanopyrolidine (I) is dissolved in solvent with 3-amino-1-adamantane alcohol (II), thereafter in the basic conditions, through the catalysis of potassiumiodide, be obtained by reacting intermediate product (S)-1-[[(3-hydroxyadamantane) is amino] ethanoyl]-2-Cyanopyrolidine (III);
2) intermediate product (S)-1-[[(3-hydroxyadamantane) is amino] ethanoyl]-2-Cyanopyrolidine (III), under the lewis acidic catalysis of process contaminants, obtains Vildagliptin impurity T.M.;
Be understandable that, in above-mentioned basic step, can be added other for the additional step of collecting product, improve productive rate, improve product purity, remove impurity etc. simultaneously, as filtered, repeatedly concentrated, the washing of filtrate, extraction, the common supplementary means such as dry.
The present invention proposes a kind of preferred implementation of above preparation method simultaneously, i.e. step 1) in dissolve the solvent of starting raw material and be selected from tetrahydrofuran (THF), methylene dichloride, chloroform, ethyl acetate or isopropyl acetate.Wherein most preferably tetrahydrofuran (THF).
The mol ratio of (S) in addition preferably: step 1)-N-chloracetyl-2-Cyanopyrolidine and described 3-amino-1-adamantane alcohol is 1:1 ~ 1:1.5.
Further preferably step 1) described in the mol ratio of (S)-N-chloracetyl-2-Cyanopyrolidine and described 3-amino-1-adamantane alcohol be 1:1.1.
For above preparation method, the present invention proposes another kind of preferred implementation simultaneously, i.e. step 1) to carry out in a heated condition, Heating temperature is 25 ~ 80 DEG C.
Whether the reaction of this step, to react completely as end condition, judges the content that can be detected starting raw material (S)-N-chloracetyl-2-Cyanopyrolidine by TLC completely to reaction.
The present invention proposes another kind of preferred implementation simultaneously, i.e. step 1) described in alkaline condition, thered is provided by the alkaline matter added in starting raw material, one or more for being selected from triethylamine, N, N-diethyl methyl amine, salt of wormwood, sodium carbonate or cesium carbonate of described alkaline matter.
The present invention proposes another kind of preferred implementation simultaneously; i.e. step 1) also comprise intermediate product (S)-1-[[(3-hydroxyadamantane) amino] ethanoyl] recrystallization of-2-Cyanopyrolidine; the step of recrystallization is: in intermediate product, add good solvent; heated and stirred makes it clearly molten; thereafter reflux; filtered while hot after backflow, at room temperature stirs filtrate thereafter, crystallize out.
For above-mentioned recrystallization, be further preferably described good solvent be selected from acetone, butanone, methylene dichloride, ethyl acetate, isopropyl acetate, toluene, dimethylbenzene, ethanol one or more.Further preferably good solvent is butanone.
For above preparation method, the invention also proposes another kind of preferred implementation, i.e. step 2) to carry out in a heated condition, Heating temperature is 25 ~ 50 DEG C.
Intermediate product S in addition preferably: step 2))-1-[[(3-hydroxyadamantane) amino] ethanoyl]-2-Cyanopyrolidine and lewis acidic mol ratio be 1:1.0 ~ 1:1.5.
In addition preferably: step 2) described Lewis acid is Aluminum chloride anhydrous.
The present invention, by the enforcement of above technical scheme, provides a kind of process simple, the preparation method of Vildagliptin impurity easy and simple to handle.
Embodiment
After starting raw material (S)-N-chloracetyl-2-Cyanopyrolidine (I) is dissolved in solvent with 3-amino-1-adamantane alcohol (II), in the basic conditions, obtained intermediate product (the S)-1-of reaction [[(3-hydroxyadamantane) is amino] ethanoyl]-2-Cyanopyrolidine (III), process contaminants Lewis acid is added in its backward intermediate product (S)-1-[[(3-hydroxyadamantane) is amino] ethanoyl]-2-Cyanopyrolidine (III), namely Vildagliptin impurity (T.M.) is obtained after reaction under lewis acidic catalysis.
Dissolve the optional tetrahydrofuran (THF) of solvent, methylene dichloride, chloroform, ethyl acetate, the isopropyl acetate of starting raw material, wherein preferred tetrahydrofuran (THF).In the process preparing intermediate product (III), reaction can be carried out under the heating condition of 25-80 DEG C, and alkaline condition can by additional alkaline matter, as triethylamine, N, N-diethyl methyl amine, salt of wormwood, sodium carbonate or cesium carbonate provide, preferred salt of wormwood; (S) the optional 1:1 ~ 1:1.5 of the mol ratio of-N-chloracetyl-2-Cyanopyrolidine and 3-amino-1-adamantane alcohol, preferred 1:1.1; Obtained intermediate product (III) is for ensureing that purity can carry out recrystallization further.
In the process preparing end product Vildagliptin impurity (T.M.); intermediate product (S)-1-[[(3-hydroxyadamantane) is amino] ethanoyl]-2-Cyanopyrolidine and the optional 1:1.0 ~ 1:1.5 of lewis acidic mol ratio; Lewis acid can select Aluminum chloride anhydrous, and reaction can be carried out under the condition of Heating temperature 25 ~ 50 DEG C.
Below in conjunction with embodiments of the invention, the invention will be further elaborated.
Embodiment 1: the preparation of intermediate product (S) 1-[[(3-hydroxyadamantane) is amino] ethanoyl]-2-Cyanopyrolidine:
100g (0.58mol) (S)-N-chloracetyl-2-Cyanopyrolidine and 1L tetrahydrofuran (THF) are added in 2L round-bottomed flask, stirring makes it clearly molten, then 107g (0.64mol) 3-amino-1-adamantane alcohol is added, 240g (1.74mol) salt of wormwood, 9.96g (0.06mol) potassiumiodide, stirring is warming up to 66 DEG C of backflows, react 6 hours, TLC detects (S)-N-chloracetyl-2-Cyanopyrolidine and reacts completely, to liquid filtered while hot in the flask completing reaction, by the filter cake 0.5L tetrahydrofuran (THF) washing produced after filtration, and washings and filtrate are merged, then be evaporated to dry at 40 DEG C.
2L saturated sodium bicarbonate solution is added in remaining material in concentrated rear flask, stirring makes solid clearly molten, thereafter 4 extractions are divided with each 1L of methylene dichloride, undertaken merging by extracting the organic phase obtained and use saturated aqueous common salt to carry out once washing, collect the organic phase after washing, and carry out drying 2 hours in wherein adding anhydrous sodium sulphate, thereafter filter, filter the filter cake produced to wash with q. s. methylene chloride again, filtrate is evaporated to dry at 40 DEG C simultaneously, 520mL butanone is added in enriched material, stir molten clear and keep backflow 5 minutes at 80 DEG C, thereafter filtered while hot, crystal within 6 hours, is made to separate out completely in stirred at ambient temperature filtrate, thereafter crystal is leached, filter cake uses the butanone that volume ratio is 1:1 to wash with the mixed solution that methyl tertiary butyl ether mixes mutually, after washing and crystal be incorporated in 60 DEG C at vacuum-drying 6 hours, namely intermediate product (S) 1-[[(3-hydroxyadamantane) is amino] ethanoyl]-2-Cyanopyrolidine 68.4g is obtained, its yield is 38.9%, the characterization result of the intermediate product of gained is:
m.p.：143-145℃；
m/z：303(M+)；
1H-NMR(CDC1
3,400MHz):1.52-1.69(m,12H),1.96(m,2H),2.09-2.33(m,4H),3.41-3.42(m,2H),3.34-3.64(m,2H),4.75-4.89(dd,1H)。
Embodiment 2: the preparation of Vildagliptin impurity:
(S) 1-[[(3-hydroxyadamantane) is amino] the ethanoyl]-2-Cyanopyrolidine prepared by embodiment 1 by 50g (0.165mol) and 250mL acetonitrile add in 1L round-bottomed flask, stirring makes it clearly molten, then under agitation slowly adds 22g (0.165mol) AlCl
3, the mixing liquid obtained is reacted 4h at 40 DEG C, add 2mol/L hcl acidifying, add 5g activated carbon decolorizing again 1 hour, thereafter mixed solution is cooled to room temperature, filter, add in filtrate mass concentration be 30% sodium hydroxide solution 110ml be adjusted to alkalescence, thereafter extract at twice with each 250ml of chloroform, the organic phase that extraction obtains is carried out merging and carried out drying by adding anhydrous sodium sulphate, filter after drying, gained filtrate is evaporated to dry at 35 DEG C, obtain faint yellow mashed prod, column chromatography purification (eluent is methylene dichloride and the methyl alcohol of volume ratio 30:1) is carried out to it, obtain white crystal formation solid 30.6g, be Vildagliptin impurity, its productive rate is 61.2%, characterization result is:
m/z：303(M+)；
1H-NMR(CDC1
3,400MHz):1.51-1.65(m,12H),1.95(m,2H),2.13-2.33(m,4H),3.51-3.52(m,2H),3.55-3.65(m,2H),4.55-4.69(m,1H)。
Although above in conjunction with the embodiments to invention has been detailed description, it will be appreciated by those skilled in the art that under the prerequisite not departing from present inventive concept, within the scope of the claims, can also to carry out above-described embodiment and more or change etc.
Claims (10)
1. a preparation method for Vildagliptin impurity, is characterized in that: comprise the following steps:
1) starting raw material (S)-N-chloracetyl-2-Cyanopyrolidine (I) is dissolved in solvent with 3-amino-1-adamantane alcohol (II), thereafter in the basic conditions, through the catalysis of potassiumiodide, be obtained by reacting intermediate product (S)-1-[[(3-hydroxyadamantane) is amino] ethanoyl]-2-Cyanopyrolidine (III);
2) intermediate product (S)-1-[[(3-hydroxyadamantane) is amino] ethanoyl]-2-Cyanopyrolidine (III), under the lewis acidic catalysis of process contaminants, obtains Vildagliptin impurity T.M.;
2. the preparation method of Vildagliptin impurity according to claim 1, is characterized in that: step 1) in dissolve the described solvent of starting raw material and be selected from tetrahydrofuran (THF), methylene dichloride, chloroform, ethyl acetate or isopropyl acetate.
3. the preparation method of Vildagliptin impurity according to claim 1, is characterized in that: step 1) described in the mol ratio of (S)-N-chloracetyl-2-Cyanopyrolidine and described 3-amino-1-adamantane alcohol be 1:1 ~ 1:1.5.
4. the preparation method of Vildagliptin impurity according to claim 1, is characterized in that: step 1) to carry out in a heated condition, Heating temperature is 25 ~ 80 DEG C.
5. the preparation method of Vildagliptin impurity according to claim 1, it is characterized in that: step 1) described in alkaline condition, thered is provided by the alkaline matter added in described starting raw material, one or more for being selected from triethylamine, N, N-diethyl methyl amine, salt of wormwood, sodium carbonate or cesium carbonate of described alkaline matter.
6. the preparation method of Vildagliptin impurity according to claim 1; it is characterized in that: step 1) also comprise described intermediate product (S)-1-[[(3-hydroxyadamantane) amino] ethanoyl] recrystallization of-2-Cyanopyrolidine; the step of recrystallization is: in intermediate product, add good solvent; heated and stirred makes it clearly molten; thereafter reflux; filtered while hot after backflow, at room temperature stirs filtrate thereafter, crystallize out.
7. the preparation method of Vildagliptin impurity according to claim 6, is characterized in that: described good solvent is be selected from one or more in acetone, butanone, methylene dichloride, ethyl acetate, isopropyl acetate, toluene, ethanol.
8. the preparation method of Vildagliptin impurity according to claim 1, is characterized in that: step 2) to carry out in a heated condition, Heating temperature is 25 ~ 50 DEG C.
9. the preparation method of Vildagliptin impurity according to claim 1, is characterized in that: step 2) described in intermediate product (S)-1-[[(3-hydroxyadamantane) amino] ethanoyl]-2-Cyanopyrolidine and described lewis acidic mol ratio be 1:1.0 ~ 1:1.5.
10. the preparation method of Vildagliptin impurity according to claim 1, is characterized in that: step 2) described in Lewis acid be Aluminum chloride anhydrous.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN108329322A (en) * | 2018-05-10 | 2018-07-27 | 上海医药集团青岛国风药业股份有限公司 | A kind of preparation method of vildagliptin ring amidine impurity |
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| CN103370064A (en) * | 2010-09-03 | 2013-10-23 | 百时美施贵宝公司 | Drug formulations using water soluble antioxidants |
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| WO2005117841A1 (en) * | 2004-05-28 | 2005-12-15 | Bristol-Myers Squibb Company | Coated tablet formulation and method |
| CN103370064A (en) * | 2010-09-03 | 2013-10-23 | 百时美施贵宝公司 | Drug formulations using water soluble antioxidants |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN108329322A (en) * | 2018-05-10 | 2018-07-27 | 上海医药集团青岛国风药业股份有限公司 | A kind of preparation method of vildagliptin ring amidine impurity |
| 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 |
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