CN113527168B - Purification method of vildagliptin - Google Patents
Purification method of vildagliptin Download PDFInfo
- Publication number
- CN113527168B CN113527168B CN202010304990.3A CN202010304990A CN113527168B CN 113527168 B CN113527168 B CN 113527168B CN 202010304990 A CN202010304990 A CN 202010304990A CN 113527168 B CN113527168 B CN 113527168B
- Authority
- CN
- China
- Prior art keywords
- vildagliptin
- collecting
- phase
- aqueous solution
- crude product
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- 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 discloses a method for purifying vildagliptin, which simplifies the process for purifying the vildagliptin, avoids repeated recrystallization, can control the disubstituted impurity of the vildagliptin to be below 0.1 percent, can control the yield of the vildagliptin to be above 90 percent, and is more suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a purification method of a vildagliptin crude product.
Background
Vildagliptin, english name: vildagliptin, chemical name: (2S) -1- { [ (3-hydroxytricyclo [ 3.3.1.1.1) 3 ,7 ]Decan-1-yl) amino]Acetyl } pyrrolidine-2-carbonitrile, having a structural formula shown in formula III:
dipeptidyl peptidase-IV (DPP-IV) inhibitors, which are orally administered, are useful in the treatment of type II diabetes. 28, 9 in 2007, on 27 eu countries, norway and irish, 16, 8 in 2011, "Jiavele" (vildagliptin) is approved for marketing in china.
At present, a plurality of relevant vildagliptin preparation and purification processes are reported in the literature. Document CN1329593a discloses that the target product vildagliptin is obtained by taking compound L-prolinamide and chloroacetyl chloride as starting materials, using tetrahydrofuran as a solvent to obtain an intermediate, filtering and drying the intermediate, directly performing the next reaction, dehydrating the intermediate by trifluoroacetic anhydride to obtain a key intermediate (2S) -N-chloroacetyl-2-cyano tetrahydropyrrole, and performing condensation reaction with 3-amino-1-adamantanol.
In patent document CN104326961A, a compound N-fluorenylmethoxycarbonyl-L-prolinamide is taken as an initial raw material, trifluoroacetic anhydride is adopted to dehydrate the amide into nitrile groups, fmoc-protecting groups are removed, the nitrile groups and chloroacetyl chloride are subjected to an N-acetylation reaction under an alkaline condition to prepare a key intermediate (2S) -N-chloroacetyl-2-cyano tetrahydropyrrole, and the key intermediate and 3-amino-1-adamantanol are subjected to a condensation reaction to obtain the target product vildagliptin.
Patent document WO2014020462A1 uses L-prolinamide as a starting material, and uses di-tert-butyl dicarbonate to protect amino, uses cyanuric chloride to carry out dehydration reaction, uses methanesulfonic acid to remove protecting group, then uses the obtained product to react with chloroacetyl chloride to obtain a key intermediate (2S) -N-chloroacetyl-2-cyano tetrahydropyrrole, and finally uses the obtained product to carry out condensation reaction with 3-amino-1-adamantanol to obtain the target product vildagliptin.
The literature Synthesis of (S) -1- (2-chloroacetyl) pyrrosidine-2-carbonidazole a key intermediate for dipeptidyl peptidase IV inhibitors [ J ].Beilstein J Org ChemAnd 2008,4 (20) performing N-acylation reaction on the compound by taking L-proline and chloroacetyl chloride as starting raw materials to obtain an intermediate, activating carboxyl, then converting the carboxyl into an amide group, performing TFAA dehydration reaction on trifluoroacetic anhydride to obtain a key intermediate (2S) -N-chloroacetyl-2-cyano tetrahydropyrrole, performing condensation reaction and one-step refining on the key intermediate and 3-amino-1-adamantanol, and performing four-step reaction to synthesize vildagliptin.
Patent document WO2013083326A1 uses L-prolinamide and chloroacetic acid as starting materials to perform condensation reaction to obtain an intermediate, and performs condensation reaction with 3-amino-1-adamantanol and phosphorus oxychloride dehydration reaction, and the process scheme of synthesizing vildagliptin through three steps of reactions is adopted, and repeated experiments prove that the intermediate of the amide has extremely poor solubility, is difficult to completely react, has the yield of only 20%, and has the defects that the reaction system becomes disordered under the phosphorus oxychloride dehydration condition, and the refining and purification are difficult.
In patent document CN107033054a, an active amino group is protected by using L-prolinamide as a starting material, then a key intermediate is obtained by dehydration reaction and removal of a protecting group, another starting material 3-amino-1-adamantanol is condensed with ethyl chloroacetate, and ester hydrolysis is performed to obtain another key intermediate, and the two key intermediates are subjected to condensation reaction under the conditions of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (edc.hcl) and 1-Hydroxybenzotriazole (HOBT), so as to synthesize vildagliptin through six steps. The process has complicated reaction steps and troublesome post-treatment, and the dehydration reaction and the final butt joint reaction are strictly controlled on the water content, so that the industrial production is not facilitated.
Through comparison of synthetic routes in the literature, the synthesis of the vildagliptin mainly comprises the condensation reaction of a compound (2S) -N-chloroacetyl-2-cyano-pyrrolidine (formula I) and 3-amino-1-adamantanol (formula II), the synthesis process is a conventional process for synthesizing the vildagliptin, the yield is high, the operation is simple and convenient, but the synthesis method cannot avoid the generation of a byproduct vildagliptin disubstituted compound (formula IV), the repeated experiment shows that the disubstituted impurity is difficult to control in the reaction process, and the process needs repeated refining in the post-treatment process to reach less than 0.15%. Other synthetic routes for avoiding the generation of disubstituted impurities of vildagliptin cannot realize industrialization due to reasons such as yield, cost, operability and the like, so that the purification process of the vildagliptin crude product directly influences the yield of the whole synthetic process, and how to effectively remove the byproduct vildagliptin disubstituted impurities (formula IV) and ensure the yield is a key point of the development of the whole process.
Disclosure of Invention
The invention aims to provide a purification method of a vildagliptin crude product, namely a purification process for effectively removing vildagliptin disubstituted impurities and ensuring yield, and solves the technical problem that the vildagliptin disubstituted impurities are difficult to remove.
In order to achieve the above object, the purification method adopted by the present invention comprises the steps of:
(1) Condensing (2S) -N-chloroacetyl-2-cyano tetrahydropyrrole (formula I) with 3-amino-1-adamantanol (formula II) to obtain a crude vildagliptin (formula III);
(2) Dissolving the crude product in the step (1) by using an acidic aqueous solution, adding an equal volume of organic solvent for extraction and liquid separation treatment, and preserving the vildagliptin disubstituted impurities (formula IV) into an organic phase by extraction, transferring the vildagliptin into a water phase, and collecting the water phase;
(3) Then using an alkaline reagent to adjust the pH value of the water phase obtained in the step (2), adding an organic solvent for extraction, and preserving an organic phase;
(4) And (3) merging the organic phases obtained in the step (3), and drying and concentrating under reduced pressure to obtain the pure vildagliptin.
The content of the vildagliptin disubstituted impurity (formula IV) in the vildagliptin pure product obtained by the purification method is less than 0.1%, and the yield of the purification process is more than 90%.
Wherein the ratio of the crude product to the acidic aqueous solution in step (1) is about 1:10 to about 1 ':30, further, in some embodiments, the ratio of the crude product to the acidic aqueous solution in step (1) is about 1:15 to about 1':25, and in some embodiments, the ratio of the crude product to the acidic aqueous solution in step (1) is about 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:23, or 1:24.
Step (2) of the present invention may be repeated a number of times, and in some embodiments, step (2) is performed at least 5 times. In certain embodiments, step (2) is performed at least 4 times. Further, in certain embodiments, step (2) is performed at least 3 times, in some embodiments, step (2) is performed at least 2 times, and in some embodiments, step (2) is performed at least 1 time.
Step (3) of the present invention may be repeated a number of times, and in some embodiments, step (3) is performed at least 5 times. In certain embodiments, step (3) is performed at least 4 times. Further, in certain embodiments, step (3) is performed at least 3 times, in some embodiments, step (3) is performed at least 2 times, and in some embodiments, step (3) is performed at least 1 time.
The volume ratio of the organic solvent to the aqueous phase added in step (3) of the present invention is about 2:1 to about 1:4, further, in some embodiments, the volume ratio of the organic solvent to the aqueous phase added is about 1:1 to about 1:2, and in some embodiments, the volume ratio of the organic solvent to the aqueous phase added is about 1:1, 1.1, 1:1, 1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, or 1:2.
Wherein the step (2) or the organic solvent is chloralkane or alkyl acetate, wherein the chloralkane can be selected from dichloromethane or trichloromethane, and the alkyl acetate is selected from any one of methyl acetate, ethyl acetate, butyl acetate and isopropyl acetate. In certain embodiments, the organic solvent in step (2) is a chlorinated alkane. In certain embodiments, the organic solvent described in step (2) is an alkyl acetate.
Wherein the step (3) or the organic solvent is chloralkane or alkyl acetate, wherein the chloralkane can be selected from dichloromethane or trichloromethane, and the alkyl acetate is selected from any one of methyl acetate, ethyl acetate, butyl acetate and isopropyl acetate. In certain embodiments, the organic solvent in step (3) is a chlorinated alkane. In certain embodiments, the organic solvent described in step (3) is an alkyl acetate.
Wherein the acidic aqueous solution in the step (2) is one or more of citric acid aqueous solution, hydrochloric acid aqueous solution, sulfuric acid aqueous solution, monopotassium phosphate aqueous solution, sodium dihydrogen phosphate aqueous solution and potassium hydrogen sulfate aqueous solution.
The pH of the acidic aqueous solution in the step (2) ranges from 3 to 5, if the pH of the aqueous phase is lower than the control range, the vildagliptin disubstituted impurities cannot be removed, and if the pH is higher than the control range, part of the product remains in the organic phase.
Wherein in the step (3), an alkaline reagent is used for adjusting the pH of the water phase, and the alkaline reagent is sodium bicarbonate water solution or sodium carbonate water solution. The pH range of the aqueous phase is 7-9 after alkali adjustment, the pH value is Gao Weige, the statin can be degraded, and the extraction efficiency is reduced too low.
The beneficial results of the invention are:
firstly, the vildagliptin finished product obtained by the purification method can control the vildagliptin double-substituted impurity below 0.10%. Secondly, the purification method avoids repeated recrystallization refining, greatly improves the yield, and has the yield of more than 90 percent.
Detailed Description
The invention will be further described with reference to examples of the invention. It is noted herein that the following examples are given solely for the purpose of further illustration of the present invention and are not to be construed as limiting the scope of the invention, as many insubstantial modifications and variations of the invention will become apparent to those skilled in the art in light of the above disclosure.
Example 1
50g of vildagliptin crude product is weighed, 1.0L of 10% potassium dihydrogen phosphate aqueous solution is added, dissolved and transferred to a separating funnel, chloroform is added for washing for 2 times (1.0L is 1,500ml is 1), water phase is collected, pH of the water phase is adjusted to 7.5 by saturated sodium bicarbonate solution, dichloromethane is added for 3 times, organic phase is collected, anhydrous sodium sulfate is dried, reduced pressure concentration is carried out, and 9.55g of vildagliptin solid is obtained, and the yield is 95.5%.
Example 2
Weighing 50g of vildagliptin crude product, adding 1.0L of water to dissolve solid, regulating pH to 4.0 by using 1N hydrochloric acid, transferring to a separating funnel after regulating, adding ethyl acetate to wash for 3 times (1.0L is 1,500ml is 2), collecting water phase, regulating pH of the water phase to 7.5 by using 5% sodium carbonate solution, adding dichloromethane to extract for 3 times, collecting organic phase, drying by using anhydrous sodium sulfate, concentrating under reduced pressure to obtain 9.38g of vildagliptin solid, and obtaining 93.8% of yield.
Example 3
50g of crude vildagliptin is weighed, 1.0L of water is added to dissolve solid, the pH is regulated to 4.0 by using 1N concentrated sulfuric acid solution, the mixture is transferred to a separating funnel after the regulation is finished, isopropyl acetate is added to wash 3 times (1.0L of 1,500ml of 2), water phase is collected, the pH of the water phase is regulated to 8.0 by using saturated sodium bicarbonate solution, dichloromethane is added to extract 3 times, organic phase is collected, anhydrous sodium sulfate is dried, reduced pressure concentration is carried out, 9.39g of vildagliptin solid is obtained, and the yield is 93.9%.
Example 4
Weighing 50g of vildagliptin crude product, adding 1.0L of water to dissolve solid, adding potassium bisulfate solid to adjust the pH to 4.0 under stirring, transferring to a separating funnel after the adjustment is finished, adding methyl acetate to wash 3 times (1.0L of 1,500ml of 2), collecting water phase, adjusting the pH of the water phase to 8.0 by using saturated sodium bicarbonate solution, adding dichloromethane to extract 3 times, collecting organic phase, drying by anhydrous sodium sulfate, concentrating under reduced pressure to obtain 9.30g of vildagliptin solid, and obtaining the yield of 93.0%.
Example 5
50g of crude vildagliptin is weighed, 1.0L of 10% sodium dihydrogen phosphate aqueous solution is added, dissolved and transferred to a separating funnel, dichloromethane is added for washing for 2 times (1.0L is 1,500ml is 1), water phase is collected, the pH of the water phase is adjusted to 8.0 by using saturated sodium bicarbonate solution, dichloromethane is added for extraction for 3 times, organic phase is collected, anhydrous sodium sulfate is dried, reduced pressure concentration is carried out, and 9.55g of vildagliptin solid is obtained, and the yield is 95.5%.
Example 6
Weighing 50g of vildagliptin crude product, adding 1.0L of water to dissolve solid, adding citric acid solid to adjust the pH to 4.0 under stirring, transferring to a separating funnel after adjustment, adding butyl acetate to wash 3 times (1.0L is 1,500ml is 2), collecting water phase, adjusting the pH of the water phase to 8.0 by using saturated sodium bicarbonate solution, adding dichloromethane to extract 3 times, collecting organic phase, drying by anhydrous sodium sulfate, concentrating under reduced pressure to obtain 9.36g of vildagliptin solid, and obtaining the yield of 93.6%.
Example 7
The purification process of the above example, the efficiency of the different organic solvents for removal of vildagliptin disubstituted impurities was compared and the results are shown in table 1.
TABLE 1 comparative extraction efficiency Table
Note that: N.D represents undetected.
Claims (2)
1. A method for purifying vildagliptin comprises the steps of weighing 50g of vildagliptin crude product, adding 1.0L of 10% potassium dihydrogen phosphate aqueous solution, transferring to a separating funnel after dissolution, adding chloroform for washing for 2 times, collecting aqueous phase, adjusting pH of the aqueous phase to 7.5 by using saturated sodium bicarbonate solution, adding dichloromethane for extraction for 3 times, collecting organic phase, drying by anhydrous sodium sulfate, and concentrating under reduced pressure to obtain vildagliptin solid.
2. A method for purifying vildagliptin comprises the steps of weighing 50g of vildagliptin crude product, adding 1.0L of 10% sodium dihydrogen phosphate aqueous solution, transferring to a separating funnel after dissolution, adding dichloromethane to wash for 2 times, collecting aqueous phase, adjusting pH of the aqueous phase to 8.0 by using saturated sodium bicarbonate solution, adding dichloromethane to extract for 3 times, collecting organic phase, drying by using anhydrous sodium sulfate, and concentrating under reduced pressure to obtain vildagliptin solid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010304990.3A CN113527168B (en) | 2020-04-17 | 2020-04-17 | Purification method of vildagliptin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010304990.3A CN113527168B (en) | 2020-04-17 | 2020-04-17 | Purification method of vildagliptin |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113527168A CN113527168A (en) | 2021-10-22 |
| CN113527168B true CN113527168B (en) | 2023-05-09 |
Family
ID=78093478
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010304990.3A Active CN113527168B (en) | 2020-04-17 | 2020-04-17 | Purification method of vildagliptin |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113527168B (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103992257A (en) * | 2014-05-16 | 2014-08-20 | 苏州天马精细化学品股份有限公司 | Purification method of vildagliptin crude product |
| CN105085360A (en) * | 2015-09-10 | 2015-11-25 | 南京理工大学 | Preparation method of high-purity vildagliptin |
| CN105153004A (en) * | 2015-04-16 | 2015-12-16 | 北京凯瑞科德药物技术研究有限公司 | Improved industrialization technology for preparing Vildagliptin |
| CN106966947A (en) * | 2017-03-30 | 2017-07-21 | 河北医科大学 | A kind of preparation method of vildagliptin |
| CN110092738A (en) * | 2019-04-24 | 2019-08-06 | 深圳市第二人民医院 | The preparation method of vildagliptin |
-
2020
- 2020-04-17 CN CN202010304990.3A patent/CN113527168B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103992257A (en) * | 2014-05-16 | 2014-08-20 | 苏州天马精细化学品股份有限公司 | Purification method of vildagliptin crude product |
| CN105153004A (en) * | 2015-04-16 | 2015-12-16 | 北京凯瑞科德药物技术研究有限公司 | Improved industrialization technology for preparing Vildagliptin |
| CN105085360A (en) * | 2015-09-10 | 2015-11-25 | 南京理工大学 | Preparation method of high-purity vildagliptin |
| CN106966947A (en) * | 2017-03-30 | 2017-07-21 | 河北医科大学 | A kind of preparation method of vildagliptin |
| CN110092738A (en) * | 2019-04-24 | 2019-08-06 | 深圳市第二人民医院 | The preparation method of vildagliptin |
Non-Patent Citations (1)
| Title |
|---|
| 维格列汀的合成研究进展;司旭等;《国际药学研究杂志》;20150430;第42卷(第2期);156-159 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113527168A (en) | 2021-10-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109336892B (en) | Preparation method of tofacitinib impurity | |
| CN111574461A (en) | Salt forming purification method of oxalagogrel intermediate and obtained refined oxalagogrel intermediate | |
| CN102875451A (en) | Improved method for synthesis process of manidipine hydrochloride | |
| CN105348172A (en) | Preparation of (S)-1-(4-methoxy-3-ethoxy)phenyl-2-methylsulfonyl ethylamine and preparation method of apremilast | |
| CN112028806B (en) | Synthetic method of vildagliptin intermediate | |
| CN113527168B (en) | Purification method of vildagliptin | |
| US5616727A (en) | Process for purifying 1-[N2 -((S)-ethoxycarbonyl)-3-phenylpropyl)-N6 -trifluoroacetyl]-l-lysyl-l-proline (lisinopril (TFA) ethyl ester | |
| CN102093444A (en) | Method for preparing isepamicin and salts thereof | |
| WO2014191426A1 (en) | Process for the purification of melphalan | |
| WO2013131978A1 (en) | Process for the preparation of intermediates useful in the preparation of a viral protease inhibitor | |
| US20120123128A1 (en) | Process for production of optically active nipecotamide | |
| CN110698335A (en) | Synthesis method of terbutaline intermediate | |
| RU2340603C1 (en) | Method of obtaining 2-(2-methylaminoethyl)pyridine salts | |
| CN111518861B (en) | Novel process for preparing D-calcium pantothenate | |
| CN114014835A (en) | Glycolide purification process | |
| CN109824687B (en) | Novel synthetic method of xylofuranose derivative | |
| CN109970620B (en) | Method for preparing saxagliptin intermediate | |
| CN109879780B (en) | Preparation method of (2-methylamine-ethyl) -tert-butyl carbamate | |
| CN106083833B (en) | Purification method of trityl olmesartan medoxomil | |
| CN111116503A (en) | Preparation method of high-purity micafungin intermediate | |
| CN104650048B (en) | Purification method of olmesartan medoxomil condensation compound | |
| CN108373442B (en) | Method for recovering abamectin intermediate isomer | |
| CN110590618A (en) | Preparation method of avibactam intermediate | |
| CN106866626A (en) | A kind of preparation method of dabigatran etexilate intermediate | |
| US6320061B1 (en) | Solvent exchange process |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |