CN111548297A - Synthetic method of vildagliptin - Google Patents
Synthetic method of vildagliptin Download PDFInfo
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- CN111548297A CN111548297A CN202010548195.9A CN202010548195A CN111548297A CN 111548297 A CN111548297 A CN 111548297A CN 202010548195 A CN202010548195 A CN 202010548195A CN 111548297 A CN111548297 A CN 111548297A
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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
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Abstract
The invention discloses a synthesis method of vildagliptin, which comprises the steps of taking glycolic acid and (S) -pyrrolidine-2-carbonitrile as raw materials, carrying out condensation reaction under the action of a condensing agent to prepare (S) -1- (2-hydroxyacetyl) pyrrolidine-2-carbonitrile, carrying out substitution reaction on the (S) -1- (2-hydroxyacetyl) pyrrolidine-2-carbonitrile and thionyl chloride, removing small molecular compounds only by reduced pressure distillation to obtain a relatively pure carbon tetrachloride solution containing the (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile, finally adding 3-amino-1-adamantanol hydrate and cesium carbonate into the solution, and carrying out substitution reaction only for 4-5h, after the crude product is recrystallized by ethanol, the purity of the crude product reaches up to 99.85 percent, a high-efficiency synthetic route is provided for the synthesis of high-purity vildagliptin, and the method has good practicability.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a synthetic method of vildagliptin.
Background
Vildagliptin (vildagliptin) is yet another orally administered dipeptidyl peptidase-IV (DPP-IV) inhibitor following sitagliptin (sitagliptin), approved for marketing in the european union in 2008 by Novartis (Novartis) pharmaceuticals ltd, switzerland, for the treatment of type 2 diabetes. Vildagliptin is a representative drug of dipeptidyl peptidase inhibitors, and shows good anti-diabetic effect and tolerance in clinical research whether being used alone or being combined with metformin and insulin.
The existing synthetic route of vildagliptin has more steps, generates more types of byproducts and is difficult to remove.
Disclosure of Invention
The invention aims to provide a synthetic method of vildagliptin.
The purpose of the invention can be realized by the following technical scheme:
a synthetic method of vildagliptin specifically comprises the following steps:
firstly, adding 51-52mmol of glycollic acid, 50-53mmol of EDCI/HOBT, a base catalyst and 250-150 ml of solvent anhydrous tetrahydrofuran into a reaction bottle, putting the reaction bottle into a salt bath, stirring for 15-20min, adding 10mmol of (S) -pyrrolidine-2-carbonitrile into the reaction bottle at low temperature every half an hour, adding 50mmol of (S) -pyrrolidine-2-carbonitrile into the reaction bottle, taking the reaction bottle out after the addition is finished, placing the reaction bottle in a room temperature environment, stirring for 2-3h, placing the reaction bottle into a heating jacket for heating, keeping the temperature and stirring for 1.5-2h after the temperature is raised, naturally cooling to room temperature after the reaction is finished, filtering, rotationally evaporating to remove the solvent, adding 100-150ml of saturated saline water into a concentrate, stirring and mixing for 15-20min, adding 100-150ml of ethyl acetate into the concentrate for extraction, after the liquid separation, the organic phase is rotated and evaporated to remove the solvent, thus obtaining (S) -1- (2-hydroxyacetyl) pyrrolidine-2-carbonitrile; the reaction formula is as follows:
secondly, adding 20mmol (S) -1- (2-hydroxyacetyl) pyrrolidine-2-carbonitrile and 100ml dry carbon tetrachloride into a reaction bottle, slowly heating to 50-55 ℃, dropwise adding 20.5-21mmol thionyl chloride, heating to 60-65 ℃ after dropwise adding, keeping the temperature and stirring, after the reaction is finished, naturally cooling to room temperature, and removing small molecular compounds by reduced pressure distillation to obtain a carbon tetrachloride solution containing (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile; the reaction formula is as follows:
step three, adding 20mmol of 3-amino-1-adamantanol hydrate and 8-10g of cesium carbonate into the solution obtained in the step two, heating while stirring, keeping the temperature and stirring for reaction, naturally cooling to room temperature after the reaction is finished, removing the solvent by rotary evaporation, and recrystallizing by using ethanol to obtain vildagliptin; the reaction formula is as follows:
further, in the first step, the alkali catalyst is cesium carbonate, and the addition amount of the cesium carbonate is 18-20 g.
Further, in the first step, the temperature of the heat preservation is 50-55 ℃.
Further, in the second step, the heat preservation and stirring time is 40-60 min.
Further, in the third step, the temperature of heat preservation is 50-55 ℃.
Further, in the third step, the reaction time is 4-5h under heat preservation and stirring.
The invention has the beneficial effects that:
the invention provides a synthesis method of vildagliptin, which comprises the steps of taking glycolic acid and (S) -pyrrolidine-2-carbonitrile as raw materials, carrying out condensation reaction under the action of a condensing agent to prepare (S) -1- (2-hydroxyacetyl) pyrrolidine-2-carbonitrile, carrying out substitution reaction on the (S) -1- (2-hydroxyacetyl) pyrrolidine-2-carbonitrile and thionyl chloride, removing small molecular compounds only by reduced pressure distillation to obtain a relatively pure carbon tetrachloride solution containing the (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile, finally adding 3-amino-1-adamantanol hydrate and cesium carbonate into the solution, and carrying out substitution reaction only for 4-5h, after the crude product is recrystallized by ethanol, the purity of the crude product reaches up to 99.85 percent, a high-efficiency synthetic route is provided for the synthesis of high-purity vildagliptin, and the method has good practicability.
Of course, it is not necessary for any product in which the invention is practiced to achieve all of the above-described advantages at the same time.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
A synthetic method of vildagliptin specifically comprises the following steps:
step one, adding 51mmol of glycollic acid, 50mmol of EDCI/HOBT, 20g of cesium carbonate and 300ml of solvent anhydrous tetrahydrofuran into a reaction bottle, putting the reaction bottle into a ice salt bath, stirring for 20min, adding 10mmol (S) -pyrrolidine-2-carbonitrile into the reaction flask at low temperature every half an hour, adding 50mmol (S) -pyrrolidine-2-carbonitrile, taking out the reaction flask, standing at room temperature, stirring for 2h, placing into a heating jacket, heating to 55 deg.C, stirring for 2h, after reaction, naturally cooling to room temperature, filtering, rotary evaporating to remove solvent, adding 150ml saturated saline solution into the concentrate, stirring and mixing for 15min, adding 150ml ethyl acetate to extract, separating, rotary evaporating organic phase to remove solvent, thus obtaining (S) -1- (2-hydroxyacetyl) pyrrolidine-2-carbonitrile; the yield is 91.6%;
the mass spectrum result of (S) -1- (2-hydroxyacetyl) pyrrolidine-2-carbonitrile is: HRMS M/z (M + H)+)：155.351。
Secondly, adding 20mmol (S) -1- (2-hydroxyacetyl) pyrrolidine-2-carbonitrile and 100ml dry carbon tetrachloride into a reaction bottle, slowly heating to 55 ℃, dropwise adding 20.5mmol thionyl chloride, heating to 60 ℃ after dropwise adding, preserving heat, stirring, reacting for 60min, naturally cooling to room temperature after the reaction is finished, and removing small molecular compounds by reduced pressure distillation to obtain a carbon tetrachloride solution containing (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile;
the mass spectrum result of (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile is：HRMS m/z(M+H+)：173.064。
And step three, adding 20mmol of 3-amino-1-adamantanol hydrate and 10g of cesium carbonate into the solution obtained in the step two, heating to 55 ℃ while stirring, preserving heat, stirring, reacting for 4 hours, naturally cooling to room temperature after the reaction is finished, removing the solvent by rotary evaporation, recrystallizing by using ethanol to obtain vildagliptin, detecting the purity of the vildagliptin by using HPLC (high performance liquid chromatography), wherein the reaction formula is as follows:
the mass spectrum result of vildagliptin is: HRMS M/z (M + H)+)：303.976。
The foregoing is merely exemplary and illustrative of the principles of the present invention and various modifications, additions and substitutions of the specific embodiments described herein may be made by those skilled in the art without departing from the principles of the present invention or exceeding the scope of the claims set forth herein.
Claims (6)
1. A synthetic method of vildagliptin is characterized by comprising the following steps: the method specifically comprises the following steps:
firstly, adding 51-52mmol of glycollic acid, 50-53mmol of EDCI/HOBT, a base catalyst and 250-150 ml of solvent anhydrous tetrahydrofuran into a reaction bottle, putting the reaction bottle into a salt bath, stirring for 15-20min, adding 10mmol of (S) -pyrrolidine-2-carbonitrile into the reaction bottle at low temperature every half an hour, adding 50mmol of (S) -pyrrolidine-2-carbonitrile into the reaction bottle, taking the reaction bottle out after the addition is finished, placing the reaction bottle in a room temperature environment, stirring for 2-3h, placing the reaction bottle into a heating jacket for heating, keeping the temperature and stirring for 1.5-2h after the temperature is raised, naturally cooling to room temperature after the reaction is finished, filtering, rotationally evaporating to remove the solvent, adding 100-150ml of saturated saline water into a concentrate, stirring and mixing for 15-20min, adding 100-150ml of ethyl acetate into the concentrate for extraction, after the liquid separation, the organic phase is rotated and evaporated to remove the solvent, thus obtaining (S) -1- (2-hydroxyacetyl) pyrrolidine-2-carbonitrile; the reaction formula is as follows:
secondly, adding 20mmol (S) -1- (2-hydroxyacetyl) pyrrolidine-2-carbonitrile and 100ml dry carbon tetrachloride into a reaction bottle, slowly heating to 50-55 ℃, dropwise adding 20.5-21mmol thionyl chloride, heating to 60-65 ℃ after dropwise adding, keeping the temperature and stirring, after the reaction is finished, naturally cooling to room temperature, and removing small molecular compounds by reduced pressure distillation to obtain a carbon tetrachloride solution containing (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile; the reaction formula is as follows:
step three, adding 20mmol of 3-amino-1-adamantanol hydrate and 8-10g of cesium carbonate into the solution obtained in the step two, heating while stirring, keeping the temperature and stirring for reaction, naturally cooling to room temperature after the reaction is finished, removing the solvent by rotary evaporation, and recrystallizing by using ethanol to obtain vildagliptin; the reaction formula is as follows:
2. the method for synthesizing vildagliptin according to claim 1, wherein the method comprises the following steps: in the first step, the alkali catalyst is cesium carbonate, and the addition amount of the cesium carbonate is 18-20 g.
3. The method for synthesizing vildagliptin according to claim 1, wherein the method comprises the following steps: in the first step, the temperature of the heat preservation is 50-55 ℃.
4. The method for synthesizing vildagliptin according to claim 1, wherein the method comprises the following steps: in the second step, the heat preservation and stirring time is 40-60 min.
5. The method for synthesizing vildagliptin according to claim 1, wherein the method comprises the following steps: in the third step, the temperature of the heat preservation is 50-55 ℃.
6. The method for synthesizing vildagliptin according to claim 1, wherein the method comprises the following steps: in the third step, the reaction time is kept for 4-5h by stirring.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1237176A (en) * | 1996-09-13 | 1999-12-01 | 先灵公司 | Tricyclic compounds useful as FPT inhibitors |
| JP2008290969A (en) * | 2007-05-24 | 2008-12-04 | Kyorin Pharmaceut Co Ltd | Method for producing aminoacetylpyrrolidine derivative |
| WO2013083326A1 (en) * | 2011-12-06 | 2013-06-13 | Chemelectiva S.R.L. | New process and intermediates for the synthesis of vildagliptin |
| CN103435526A (en) * | 2013-08-22 | 2013-12-11 | 天津速研医药科技有限公司 | Synthesis method of vildagliptin |
| CN106966947A (en) * | 2017-03-30 | 2017-07-21 | 河北医科大学 | A kind of preparation method of vildagliptin |
-
2020
- 2020-06-16 CN CN202010548195.9A patent/CN111548297A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1237176A (en) * | 1996-09-13 | 1999-12-01 | 先灵公司 | Tricyclic compounds useful as FPT inhibitors |
| JP2008290969A (en) * | 2007-05-24 | 2008-12-04 | Kyorin Pharmaceut Co Ltd | Method for producing aminoacetylpyrrolidine derivative |
| WO2013083326A1 (en) * | 2011-12-06 | 2013-06-13 | Chemelectiva S.R.L. | New process and intermediates for the synthesis of vildagliptin |
| CN103435526A (en) * | 2013-08-22 | 2013-12-11 | 天津速研医药科技有限公司 | Synthesis method of vildagliptin |
| CN106966947A (en) * | 2017-03-30 | 2017-07-21 | 河北医科大学 | A kind of preparation method of vildagliptin |
Non-Patent Citations (1)
| Title |
|---|
| MARIE S. T. MORIN ET AL.: "Intramolecular rhodium-catalyzed activation of a-amino C–H bonds: decisive influence of conformational factors in the synthesis of bicyclic aminals from N-sulfamoyloxyacetyl azacycloalkanes", 《TETRAHEDRON LETTERS》 * |
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Application publication date: 20200818 |