CN113527168A - Purification method of vildagliptin - Google Patents
Purification method of vildagliptin Download PDFInfo
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- CN113527168A CN113527168A CN202010304990.3A CN202010304990A CN113527168A CN 113527168 A CN113527168 A CN 113527168A CN 202010304990 A CN202010304990 A CN 202010304990A CN 113527168 A CN113527168 A CN 113527168A
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- 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
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Abstract
The invention discloses a vildagliptin purification method, which simplifies a vildagliptin purification process, avoids repeated recrystallization, can control vildagliptin disubstituted impurities to be below 0.1 percent, can control the yield of 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)3 ,7]Decan-1-yl) amino]Acetyl pyrrolidine-2-carbonitrile having the structural formula shown in formula III:
dipeptidyl peptidase-IV (DPP-IV) inhibitors for oral administration for the treatment of type II diabetes. Day 28, 9, 2007, on the market in 27 eu countries and norway and ireland, day 16, 8, 2011, "jiaweile" (vildagliptin) was approved for marketing in china.
At present, various preparation and purification processes of related vildagliptin are reported in literatures. Document CN1329593A discloses that compounds L-prolinamide and chloroacetyl chloride are used as starting materials, tetrahydrofuran is used as a solvent to obtain an intermediate, the intermediate is filtered and dried, the next reaction is directly performed, trifluoroacetic anhydride is used for dehydration to obtain a key intermediate (2S) -N-chloroacetyl-2-cyano tetrahydropyrrole, the key intermediate is subjected to condensation reaction with 3-amino-1-adamantanol, and the target product vildagliptin is obtained through three steps of reactions.
Patent document CN104326961A, taking compound N-fluorenylmethyloxycarbonyl-L-prolinamide as starting material, dehydrating amide to nitrile group with trifluoroacetic anhydride, removing Fmoc-protecting group, performing N-acetylation with chloroacetyl chloride under alkaline condition to obtain key intermediate (2S) -N-chloroacetyl-2-cyanotetrahydropyrrole, and performing condensation reaction with 3-amino-1-adamantanol to obtain the target product vildagliptin.
In patent document WO2014020462a1, L-prolinamide is used as a starting material, amino is protected by di-tert-butyl dicarbonate, dehydration reaction is performed by cyanuric chloride, protecting groups are removed by methanesulfonic acid, the amino is reacted with chloroacetyl chloride to obtain a key intermediate (2S) -N-chloroacetyl-2-cyano tetrahydropyrrole, and finally condensation reaction is performed with 3-amino-1-adamantanol to obtain the target product vildagliptin.
The literature Synthesis of (S) -1- (2-chloroacetyl) pyrolidine-2-carbonitrile: a key intermediate for a dipeptidyl peptidase IV inhibitors [ J ].Beilstein J Org Chem2008, 4 (20): 1-5. the compound uses L-proline and chloroacetyl chloride as starting materials to carry out N-acylation reaction to obtain an intermediate, then uses DCC to activate carboxyl and then converts the carboxyl to generate an amide group, uses trifluoroacetic anhydride TFAA to carry out dehydration reaction to generate a key intermediate (2S) -N-chloroacetyl-2-cyano tetrahydropyrrole, then carries out condensation reaction and one-step refining with 3-amino-1-adamantanol, and finally synthesizes vildagliptin through four-step reaction.
Patent document WO2013083326a1 discloses a process scheme for synthesizing vildagliptin by a three-step reaction of a condensation reaction of L-prolinamide and chloroacetic acid as starting materials to obtain an intermediate, a condensation reaction of the intermediate with 3-amino-1-adamantanol and a phosphorus oxychloride dehydration reaction, and a repeated experiment verifies the process, and finds that the solubility of the intermediate amide is extremely poor, the reaction is difficult to complete, the yield is only 20%, and in addition, the reaction system is disordered under the phosphorus oxychloride dehydration condition, and the purification is difficult.
Patent document CN107033054A discloses a method for synthesizing vildagliptin by using L-prolinamide as a starting material, firstly protecting an active amino group, then performing dehydration reaction and removing a protecting group to obtain a key intermediate, performing condensation reaction and ester hydrolysis on another starting material, namely 3-amino-1-adamantanol, and ethyl chloroacetate to obtain another key intermediate, and performing condensation reaction on the two key intermediates under the conditions of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (edc.hcl) and 1-Hydroxybenzotriazole (HOBT), and finally performing six-step reaction. The reaction steps of the process are complicated, the post-treatment is troublesome, the water content is strictly controlled in the dehydration reaction and the final butt-joint reaction, and the process is not beneficial to industrial production.
Compared with the synthetic routes in the literature, the synthesis of vildagliptin mainly comprises the condensation reaction of a compound (2S) -N-chloroacetyl-2-cyanotetrahydropyrrole (formula I) and 3-amino-1-adamantanol (formula II), the synthetic process is a conventional process for synthesizing vildagliptin, the yield is high, the operation is simple and convenient, but the synthetic method cannot avoid generating a byproduct vildagliptin disubstituted compound (formula IV), repeated experiments show that disubstituted impurities are difficult to control in the reaction process, and the disubstituted impurities can reach below 0.15% by refining for many times in the post-treatment process. Other synthetic routes for avoiding the formation of the disubstituted impurity by the vildagliptin cannot realize industrialization due to the reasons of 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 the key for effectively removing the byproduct vildagliptin disubstituted impurity (formula IV) and ensuring the yield is 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 vildagliptin disubstituted impurities are difficult to remove.
In order to achieve the purpose, the purification method adopted by the invention comprises the following steps:
(1) carrying out condensation reaction on (2S) -N-chloroacetyl-2-cyano tetrahydropyrrole (formula I) and 3-amino-1-adamantanol (formula II) to obtain a vildagliptin (formula III) crude product;
(2) dissolving the crude product in the step (1) by using an acidic aqueous solution, adding an isovolumetric organic solvent for extraction and liquid separation treatment, retaining the vildagliptin disubstituted impurity (formula IV) in an organic phase by extraction, transferring vildagliptin to a water phase, and collecting the water phase;
(3) adjusting the pH value of the water phase obtained in the step (2) by using an alkaline reagent, adding an organic solvent for extraction, and keeping an organic phase;
(4) and (4) combining the organic phases obtained in the step (3), drying, and concentrating under reduced pressure to obtain the vildagliptin pure product.
The vildagliptin disubstituted impurity (formula IV) content in the vildagliptin pure product obtained by the purification method is less than 0.1%, and the purification process yield is more than 90%.
Wherein the mass-to-volume ratio of the crude product to the acidic aqueous solution in the step (1) is about 1: 10-1 ': 30, further, in some embodiments, the mass-to-volume ratio of the crude product to the acidic aqueous solution is about 1: 15-1': 25, and in some embodiments, the mass-to-volume ratio of the crude product to the acidic aqueous solution 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 plurality of times, and in certain 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 certain embodiments, step (2) is performed at least 1 time.
Step (3) of the present invention may be repeated a plurality of times, and in certain 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 certain embodiments, step (3) is performed at least 1 time.
The volume ratio of the organic solvent to the aqueous phase added in step (3) 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, 1.2, 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, in the step (2) or the organic solvent is chloralkane or alkyl acetate, wherein the chloralkane can be 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 chloroalkane. In certain embodiments, the organic solvent described in step (2) is an alkyl acetate.
Wherein, in the step (3) or the organic solvent is chloralkane or alkyl acetate, wherein the chloralkane can be dichloromethane or trichloromethane, and the alkyl acetate is any one selected from methyl acetate, ethyl acetate, butyl acetate and isopropyl acetate. In certain embodiments, the organic solvent in step (3) is a chloroalkane. 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, potassium dihydrogen phosphate aqueous solution, sodium dihydrogen phosphate aqueous solution or potassium hydrogen sulfate aqueous solution.
The pH range of the acidic aqueous solution in the step (2) is 3-5, if the pH of the aqueous phase is lower than the control range, vildagliptin disubstituted impurities cannot be removed, and if the pH of the aqueous phase is higher than the control range, partial products can remain in the organic phase.
Wherein in the step (3), an alkaline reagent is used for adjusting the pH value of the water phase, and the alkaline reagent is a sodium bicarbonate aqueous solution or a sodium carbonate aqueous solution. After the water phase adjusts the alkali, the pH range is 7-9, vildagliptin can be degraded when the pH is too high, and the extraction efficiency is reduced when the pH is too low.
The beneficial results of the invention are as follows:
firstly, the vildagliptin finished product obtained by the purification method can control the vildagliptin double-substituted impurity to be below 0.10%. Secondly, the purification method provided by the patent avoids repeated recrystallization refining, greatly improves the yield, and the yield is more than 90%.
Detailed Description
The present invention will be further described with reference to the following examples. It should be noted that the following examples are given solely for the purpose of illustration and are not to be construed as limitations on the scope of the invention, as many insubstantial modifications and variations of the invention may be made by those skilled in the art in light of the above teachings.
Example 1
Weighing 50g of vildagliptin crude product, adding 1.0L of 10% potassium dihydrogen phosphate aqueous solution, dissolving, transferring to a separating funnel, adding trichloromethane, washing for 2 times (1.0L of 1,500ml of 1), collecting a water phase, adjusting the pH of the water phase to 7.5 by using a saturated sodium bicarbonate solution, adding dichloromethane, extracting for 3 times, collecting an organic phase, drying by using anhydrous sodium sulfate, and concentrating under reduced pressure to obtain vildagliptin solid 9.55g, wherein the yield is 95.5%.
Example 2
Weighing 50g of vildagliptin crude product, adding 1.0L of water to dissolve the solid, adjusting the pH to 4.0 by using 1N hydrochloric acid, transferring the adjusted vildagliptin crude product into a separating funnel, adding ethyl acetate to wash for 3 times (1.0L 1,500ml 2), collecting a water phase, adjusting the pH of the water phase to 7.5 by using a 5% sodium carbonate solution, adding dichloromethane to extract for 3 times, collecting an organic phase, drying by using anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 9.38g of vildagliptin solid with the yield of 93.8%.
Example 3
Weighing 50g of vildagliptin crude product, adding 1.0L of water to dissolve the solid, adjusting the pH to 4.0 by using 1N concentrated sulfuric acid solution, transferring the adjusted vildagliptin crude product into a separating funnel, adding isopropyl acetate to wash for 3 times (1.0L of 1,500ml of 2), collecting a water phase, adjusting the pH of the water phase to 8.0 by using saturated sodium bicarbonate solution, adding dichloromethane to extract for 3 times, collecting an organic phase, drying by using anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 9.39g of vildagliptin solid with the yield of 93.9%.
Example 4
Weighing 50g of vildagliptin crude product, adding 1.0L of water to dissolve the solid, adding potassium bisulfate solid under stirring to adjust the pH to 4.0, transferring the mixture to a separating funnel after the adjustment is finished, adding methyl acetate to wash for 3 times (1.0L 1,500ml 2), collecting a water phase, adjusting the pH of the water phase to 8.0 by using a saturated sodium bicarbonate solution, adding dichloromethane to extract for 3 times, collecting an organic phase, drying by using anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 9.30g of vildagliptin solid with the yield of 93.0%.
Example 5
Weighing 50g of vildagliptin crude product, adding 1.0L of 10% sodium dihydrogen phosphate aqueous solution, dissolving, transferring to a separating funnel, adding dichloromethane, washing for 2 times (1.0L of 1,500ml of 1), collecting a water phase, adjusting the pH of the water phase to 8.0 by using a saturated sodium bicarbonate solution, adding dichloromethane, extracting for 3 times, collecting an organic phase, drying by using anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 9.55g of vildagliptin solid with the yield of 95.5%.
Example 6
Weighing 50g of vildagliptin crude product, adding 1.0L of water to dissolve the solid, adding citric acid solid under a stirring state to adjust the pH value to 4.0, transferring the mixture to a separating funnel after the adjustment is finished, adding butyl acetate to wash for 3 times (1.0L 1,500ml 2), collecting a water phase, adjusting the pH value of the water phase to 8.0 by using a saturated sodium bicarbonate solution, adding dichloromethane to extract for 3 times, collecting an organic phase, drying by using anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 9.36g of vildagliptin solid with the yield of 93.6%.
Example 7
The purification methods of the above examples were compared with different organic solvents for the efficiency of removing vildagliptin disubstituted impurities, and the results are shown in table 1.
TABLE 1 comparison table of extraction efficiency
Note: n.d indicates no detection.
Claims (10)
1. A purification method of vildagliptin, which comprises the following steps:
(1) carrying out condensation reaction on (2S) -N-chloroacetyl-2-cyano tetrahydropyrrole (formula I) and 3-amino-1-adamantanol (formula II) to obtain a vildagliptin (formula III) crude product;
(2) dissolving the crude product in the step (1) by using 20 times (mass-volume ratio) of acidic aqueous solution, adding an isovolumetric organic solvent for extraction and liquid separation treatment, so that vildagliptin disubstituted impurity (formula IV) is retained in an organic phase, vildagliptin is transferred to a water phase, and collecting the water phase;
(3) adjusting the pH value of the water phase obtained in the step (2) by using an alkaline reagent, adding an organic solvent for extraction, and keeping an organic phase;
(4) combining the organic phases obtained in the step (3), drying, and concentrating under reduced pressure to obtain a vildagliptin pure product;
wherein the pH of the acidic aqueous solution in step (2) is 3 to 5;
wherein the pH value of the water phase after alkali adjustment in the step (3) is 7-9;
the content of vildagliptin disubstituted impurities in the vildagliptin pure product obtained in the step (4) is less than 0.1%, and the yield of the vildagliptin pure product is more than 90%.
2. The purification method according to claim 1, wherein the mass-to-volume ratio of the crude product and the acidic aqueous solution in step (1) is about 1:10 to 1: 30.
3. The purification process according to claim 1, wherein the volume ratio of the organic solvent to the aqueous phase added in step (3) is about 2:1 to about 1: 4.
4. The purification process according to claim 1, wherein step (2) is performed in a plurality of repetitions and step (3) is performed in a plurality of repetitions.
5. The purification process according to claim 1, characterized in that the organic solvent of step (2) is a chlorinated alkane or an alkyl acetate.
6. The purification process according to claim 1, characterized in that the organic solvent of step (3) is a chlorinated alkane or an alkyl acetate.
7. The purification process according to any one of claims 1 to 5, wherein the chlorinated alkane is dichloromethane or trichloromethane.
8. The purification process according to any one of claims 1 to 5, wherein the alkyl acetate is selected from any one of methyl acetate, ethyl acetate, butyl acetate, isopropyl acetate.
9. The purification method according to claim 1, wherein the acidic aqueous solution in the step (2) is one or more of an aqueous citric acid solution, an aqueous hydrochloric acid solution, an aqueous sulfuric acid solution, an aqueous potassium dihydrogen phosphate solution, an aqueous sodium dihydrogen phosphate solution, or an aqueous potassium hydrogen sulfate solution.
10. Purification process according to claim 1, characterized in that in step ((3) the pH of the aqueous phase is adjusted using an alkaline agent which is an aqueous solution of sodium bicarbonate or sodium carbonate.
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Citations (5)
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|---|---|---|---|---|
| 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 |
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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 |
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| 司旭等: "维格列汀的合成研究进展", 《国际药学研究杂志》 * |
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