CN103787944A - Preparation method of 1-(2-chloroacetyl)-2-(S)-nitrile pyrrolidine - Google Patents
Preparation method of 1-(2-chloroacetyl)-2-(S)-nitrile pyrrolidine Download PDFInfo
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- CN103787944A CN103787944A CN201210429886.2A CN201210429886A CN103787944A CN 103787944 A CN103787944 A CN 103787944A CN 201210429886 A CN201210429886 A CN 201210429886A CN 103787944 A CN103787944 A CN 103787944A
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- RJDQTISEHDHUEK-ZETCQYMHSA-N CCC(N(CCC1)[C@@H]1C#N)=O Chemical compound CCC(N(CCC1)[C@@H]1C#N)=O RJDQTISEHDHUEK-ZETCQYMHSA-N 0.000 description 1
- YDLOXOLNRWYAJM-QMMMGPOBSA-N NC([C@H]1N(CCCCCl)CCC1)=O Chemical compound NC([C@H]1N(CCCCCl)CCC1)=O YDLOXOLNRWYAJM-QMMMGPOBSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Abstract
The invention provides a preparation method of 1-(2-chloroacetyl)-2-(S)-nitrile pyrrolidine which is a key intermediate of vildagliptin, a new drug for treating diabetes. The method of the invention adopts 1-(2-chloroacetyl)-2-(S)-pyrrolidine methanamide (V) as a raw material, adopts N,N-dimethyl formamide (DMF), tetrahydrofuran, 1,4-dioxane or dichloromethane, chloroform, and the like as solvents, adopts phosphorus oxychloride or trifluoroacetic anhydride as a dehydrating agent, adopts triethylamine, pyridine or N,N-dimethyl formamide as acid binding agents, and obtains the target product of 1-(2-chloroacetyl)-2-(S)-nitrile pyrrolidine (II) with high purity. The method of the invention solves the problem that the purification of drug vildagliptin is difficult because of low purity and more impurities of products in the past. The structural formulae of the compounds (II) and (V) are shown in the description.
Description
Technical field
The invention belongs to medical technical field, be specifically related to the preparation method of a kind of antidiabetic thing dipeptidyl peptidase 4 (DPP-4) inhibitor Vildagliptin intermediate.
Background technology
Vildagliptin is specificity dipeptide amido peptidase TV (DPP-4) inhibitor of being developed by Novartis, is mainly used in treating type II diabetes.On September 28th, 2007, obtains EU Committee's approval, in 27 European Union member countries and Norway and Ireland listing.Vildagliptin chemical name: (-)-(2S)-1-[[(3-hydroxyl three encircles [3.3.1.1[3,7]] decane-1-yl) amino] ethanoyl] tetramethyleneimine-2-formonitrile HCN (I) chemical structural formula:
Formula I
The key intermediate of synthetic this compound is 1-(2-chloracetyl)-2-(S)-itrile group tetramethyleneimine (II)
Formula II
At document Beiletein Jouenal of Organic Chemistry, 2008, in 4:20-22, report the preparation method of 1-(2-chloracetyl)-2-(S)-itrile group tetramethyleneimine, take L-PROLINE (III) as starting raw material, react with chloroacetyl chloride and generate 1-(2-chloracetyl)-2-(S)-pyrrolidinecarboxylic acid (IV), obtain 1-(2-chloracetyl)-2-(S)-pyrrolidine formamide (V) through aminating reaction, obtain key intermediate 1-(2-chloracetyl)-2-(S)-itrile group tetramethyleneimine (II) through trifluoroacetic anhydride (TFAA) dehydration again.
The reaction that obtains 1-(2-chloracetyl)-2-(S)-itrile group tetramethyleneimine (II) due to 1-(2-chloracetyl)-2-(S)-pyrrolidine formamide (V) through trifluoroacetic anhydride dehydration in the method is carried out not exclusively; cause the purity of product low; impurity is many, makes the purifying of medicine Vildagliptin very difficult.
Summary of the invention
The present invention is directed to 1-(2-chloracetyl)-2-(S)-pyrrolidine formamide (V) obtains the reaction existence of 1-(2-chloracetyl)-2-(S)-itrile group tetramethyleneimine (II) problem through trifluoroacetic anhydride dehydration; provide that a kind of raw materials cost is low, simple to operate, gained finished product purity is high, be more suitable for the method for preparing 1-(2-chloracetyl)-2-(S)-itrile group tetramethyleneimine (II) of suitability for industrialized production.
Present method is take 1-(2-chloracetyl)-2-(S)-pyrrolidine formamide (V) as raw material; DMF (DMF), tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane or methylene dichloride, chloroform etc. are solvent; Phosphorus oxychloride or trifluoroacetic anhydride are dewatering agent; Triethylamine, pyridine or DMF are acid binding agent; Obtain highly purified target product 1-(2-chloracetyl)-2-(S)-itrile group tetramethyleneimine (II).
The mol ratio of phosphorus oxychloride or trifluoroacetic anhydride and raw material (V) is 1～10: 1, preferably 2～5: 1.
The mol ratio of acid binding agent and dewatering agent is 1～5: 1, preferably 1～2: 1(is when DMF is simultaneously as except solvent and acid binding agent).
The solvent using is DMF, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane or methylene dichloride, chloroform etc.Preferably DMF, tetrahydrofuran (THF) or Isosorbide-5-Nitrae-dioxane.
Temperature of reaction is 0～60 ℃, preferably 0～30 ℃.
Reaction times is 1～6 hour, preferably 3～4 hours.
Accompanying drawing explanation
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of 1-(2-chloracetyl)-2-(S)-itrile group tetramethyleneimine.
Embodiment
With example, the present invention is described in further detail below, certainly can not thinks that the present invention only limits to this example
embodiment 1
In reaction flask, add 40ml dry DMF, be cooled to 0 ℃, slowly drip 12ml phosphorus oxychloride (0.13mol), dropwise and keep 0 ~ 5 ℃, stirring reaction 30 minutes.Add subsequently 1-(2-chloracetyl)-2-(S)-pyrrolidine formamide 5g(0.026mol in batches), reinforced be completely warming up to 40 ℃, stirring reaction 3 hours.TLC monitoring has been reacted.Add frozen water 400ml, saturated sodium bicarbonate aqueous solution is adjusted pH value 8 ~ 9, with 150ml ethyl acetate extractive reaction liquid, by organic layer washing, after anhydrous sodium sulfate dehydration is dry, concentrating under reduced pressure, raffinate adds mixed solvent (ethyl acetate: isopropyl ether=1: 3) stir 20 minutes, leave standstill crystallization, obtain white or light yellow solid powder 4.1g, yield: 91%.mp.54~57℃，
1HNMR，δppm（CDC
3）:2.10-2.40（m，4H,2，3-CH
2）,3.54-3.73(m，2H,4-CH
2)，4.03-4.21(m，2H,5-CH
2)，4.76-4.86(m，1H,1-CH)。
embodiment 2
In reaction flask, add 1-(2-chloracetyl)-2-(S)-pyrrolidine formamide 5g(0.026mol); triethylamine 10ml(0.072mol) and tetrahydrofuran (THF) 40ml; stirring is cooled to 0 ~ 3 ℃, drips trifluoroacetic acid 7.5ml(0.053mol), approximately drip 45 minutes.Be incubated 0 ~ 5 ℃ of stirring reaction 30 minutes, rise to 30 ℃ of reaction 4hr, TLC monitoring has been reacted.By reaction solution evaporated under reduced pressure, raffinate adds methylene dichloride 200ml to dissolve, and washes once with saturated sodium bicarbonate solution 30ml, washes secondary (40ml × 2), anhydrous sodium sulfate drying.Remove solvent under reduced pressure, raffinate adds mixed solvent (ethyl acetate: isopropyl ether=1: 3) stir 20 minutes, leave standstill crystallization, obtain white or light yellow solid powder 4.3g, yield: 94%.mp.54~57℃，
1HNMR，δppm（CDC
3）:2.10-2.40（m，4H,2，3-CH
2）,3.54-3.73(m，2H,4-CH
2)，4.03-4.21(m，2H,5-CH
2)，4.76-4.86(m，1H,1-CH)。
embodiment 3
In reaction flask, add 1-(2-chloracetyl)-2-(S)-pyrrolidine formamide 5g(0.026mol); pyridine 8.5ml(0.106mol) and Isosorbide-5-Nitrae-dioxane 50ml, stir and be cooled to 0 ~ 3 ℃; drip trifluoroacetic acid 15ml(0.106mol), approximately drip 45 minutes.Be incubated 0 ~ 5 ℃ of stirring reaction 30 minutes, rise to room temperature (20 ~ 25 ℃) reaction 6hr, TLC monitoring has been reacted.By reaction solution evaporated under reduced pressure, raffinate adds chloroform 200ml to dissolve, wash once with saturated sodium bicarbonate solution 30ml, washing secondary (40ml × 2), anhydrous sodium sulfate drying, removes solvent under reduced pressure, raffinate adds mixed solvent (ethyl acetate: isopropyl ether=1: 3) stir 20 minutes, leave standstill crystallization, obtain white or light yellow solid powder 4.0g, yield: 89%.mp.54~57℃，
1HNMR，δppm（CDC
3）:2.10-2.40（m，4H,2，3-CH
2）,3.54-3.73(m，2H,4-CH
2)，4.03-4.21(m，2H,5-CH
2)，4.76-4.86(m，1H,1-CH)。
embodiment 4
In reaction flask, add 50ml methylene dichloride, 30ml dry DMF (0.39mol), be cooled to 0 ℃, slowly drip 12ml phosphorus oxychloride (0.13mol), dropwise and keep 0 ~ 5 ℃, stirring reaction 30 minutes.Add subsequently 1-(2-chloracetyl)-2-(S)-pyrrolidine formamide 5g(0.026mol in batches), reinforced be completely warming up to 50 ℃, stirring reaction 5 hours.TLC monitoring has been reacted.Add frozen water 400ml, saturated sodium bicarbonate aqueous solution is adjusted pH value 8 ~ 9, with 200ml ethyl acetate extractive reaction liquid, by organic layer washing, after anhydrous sodium sulfate dehydration is dry, concentrating under reduced pressure, raffinate adds mixed solvent (ethyl acetate: isopropyl ether=1: 3) stir 20 minutes, leave standstill crystallization, obtain white or light yellow solid powder 3.9g, yield: 86.6%.mp.54~57℃，
1HNMR，δppm（CDC
3）:2.10-2.40（m，4H,2，3-CH
2）,3.54-3.73(m，2H,4-CH
2)，4.03-4.21(m，2H,5-CH
2)，4.76-4.86(m，1H,1-CH)。
In reaction flask, add 1-(2-chloracetyl)-2-(S)-pyrrolidine formamide 5g(0.026mol); triethylamine 14.8ml(0.106mol) and chloroform 60ml; stirring is cooled to 0 ~ 3 ℃, drips trifluoroacetic acid 7.5ml(0.053mol), approximately drip 45 minutes.Be incubated 0 ~ 5 ℃ of stirring reaction 30 minutes, rise to 60 ℃ of reaction 1hr, TLC monitoring has been reacted.By reaction solution evaporated under reduced pressure, raffinate adds methylene dichloride 200ml to dissolve, and washes once with saturated sodium bicarbonate solution 30ml, washes secondary (40ml × 2), anhydrous sodium sulfate drying.Remove solvent under reduced pressure, raffinate adds mixed solvent (ethyl acetate: isopropyl ether=1: 3) stir 20 minutes, leave standstill crystallization, obtain white or light yellow solid powder 3.8g, yield: 84.4%.mp.54~57℃，
1HNMR，δppm（CDC
3）:2.10-2.40（m，4H,2，3-CH
2）,3.54-3.73(m，2H,4-CH
2)，4.03-4.21(m，2H,5-CH
2)，4.76-4.86(m，1H,1-CH)。
Claims (8)
1. prepare the method for Vildagliptin key intermediate 1-(2-chloracetyl)-2-(S)-itrile group tetramethyleneimine (II) for one kind, it is characterized in that, in organic solvent, take 1-(2-chloracetyl)-2-(S)-pyrrolidine formamide as raw material, under dewatering agent and acid binding agent effect, obtain target product;
2. method according to claim 1, is characterized in that, described organic solvent is DMF, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, methylene dichloride, chloroform; Preferably DMF, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane.
3. preparation method according to claim 1, is characterized in that, described dewatering agent is phosphorus oxychloride or trifluoroacetic anhydride.
4. preparation method according to claim 1, is characterized in that, described acid binding agent is triethylamine, pyridine or DMF.
5. according to the preparation method described in claim 1-4 any one, it is characterized in that, the mol ratio of described dewatering agent and raw material 1-(2-chloracetyl)-2-(S)-pyrrolidine formamide is 1～10: 1, preferably 2～5: 1.
6. according to the preparation method described in claim 1-4 any one, it is characterized in that, the mol ratio of described acid binding agent and dewatering agent is 1～5: 1, preferably 1～2: 1.
7. according to the preparation method described in claim 1-4 any one, it is characterized in that, temperature of reaction is 0～60 ℃, preferably 0～30 ℃.
8. according to the preparation method described in claim 1-4 any one, it is characterized in that, the reaction times is 1～6 hour, preferably 3～4 hours.
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| CN201210429886.2A CN103787944A (en) | 2012-11-01 | 2012-11-01 | Preparation method of 1-(2-chloroacetyl)-2-(S)-nitrile pyrrolidine |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006100181A2 (en) * | 2005-03-22 | 2006-09-28 | F. Hoffmann-La Roche Ag | New salt and polymorphs of a dpp-iv inhibitor |
| WO2008066083A1 (en) * | 2006-11-29 | 2008-06-05 | Mitsubishi Tanabe Pharma Corporation | Process for production of n-(n'-substituted-glycyl)- 2-cyanopyrrolidine derivative |
| WO2010022690A2 (en) * | 2008-08-26 | 2010-03-04 | Zentiva, K.S. | A method of preparation of highly pure vildagliptin |
| CN102491928A (en) * | 2011-12-13 | 2012-06-13 | 临海天宇药业有限公司 | Method for preparing (2S)-N-chloracetyl-2-cyano-group pyrrolidine |
-
2012
- 2012-11-01 CN CN201210429886.2A patent/CN103787944A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006100181A2 (en) * | 2005-03-22 | 2006-09-28 | F. Hoffmann-La Roche Ag | New salt and polymorphs of a dpp-iv inhibitor |
| WO2008066083A1 (en) * | 2006-11-29 | 2008-06-05 | Mitsubishi Tanabe Pharma Corporation | Process for production of n-(n'-substituted-glycyl)- 2-cyanopyrrolidine derivative |
| WO2010022690A2 (en) * | 2008-08-26 | 2010-03-04 | Zentiva, K.S. | A method of preparation of highly pure vildagliptin |
| CN102491928A (en) * | 2011-12-13 | 2012-06-13 | 临海天宇药业有限公司 | Method for preparing (2S)-N-chloracetyl-2-cyano-group pyrrolidine |
Non-Patent Citations (1)
| Title |
|---|
| SANTOSH K. SINGH等: "Synthesis of (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile: A key intermediate for dipeptidyl peptidase IV inhibitors", 《BEILSTEIN JOURNAL OF ORGANIC CHEMISTRY》, vol. 4, no. 20, 12 June 2008 (2008-06-12), pages 1 - 5, XP002714153, DOI: 10.3762/bjoc.4.20 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN105153165B (en) * | 2015-07-30 | 2017-08-29 | 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 impurity |
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Application publication date: 20140514 |