CN114163372A - Continuous preparation method of vildagliptin key intermediate - Google Patents
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- CN114163372A CN114163372A CN202111574210.8A CN202111574210A CN114163372A CN 114163372 A CN114163372 A CN 114163372A CN 202111574210 A CN202111574210 A CN 202111574210A CN 114163372 A CN114163372 A CN 114163372A
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Abstract
The invention discloses a continuous preparation method of vildagliptin key intermediate(s) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile, belonging to the technical field of organic synthesis; taking L-proline as an initial raw material, preparing Boc-L-prolinamide by using a one-pot method, then performing dehydration reaction with cyanuric chloride, adding a solvent and thionyl chloride for deprotection and salt formation crystallization to obtain(s) -pyrrolidine-2-carbonitrile hydrochloride, and finally adding chloroacetyl chloride for reaction to obtain(s) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile. The method of the invention combines a one-pot method and a continuous preparation method, saves the step of intermediate crystallization, has the yield of more than 60 percent and the purity of 99.7 percent, has simple whole reaction process, is easy to operate and is suitable for industrial production.
Description
Technical Field
The invention relates to a method for synthesizing a vildagliptin key intermediate(s) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile, belonging to the technical field of organic synthesis.
Background
Vildagliptin (Vildagliptin), formula (2S) -1- {2- [ ((3-hydroxy-1-adamantyl) amino ] acetyl } -pyrrolidine-2 carbonitrile, clinical drug is orally administered dipeptidyl peptidase-iv (DPP-iv), originally developed by norwalk pharmaceutical limited, switzerland, approved for marketing in the european union in 2008, (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile (1) is a key intermediate in the synthesis of Vildagliptin, the structural formula of which is as follows:
the current synthetic routes of the intermediate are mainly divided into two types:
the first kind of technological process represented by primary patents WO2000034241 and WO2010022690 takes L-prolinamide (compound II) as initial material, and directly performs chloroacetylation and cyanation dehydration to obtain a key intermediate I through three-step reaction, wherein the technological synthetic route is as follows:
the starting material L-prolinamide of the process is usually prepared from L-proline (compound IV), and the high activity of the amino group on the pyrrole ring of L-proline leads to low yield in the amidation process and high price of L-prolinamide, and the high price of trifluoroacetic anhydride (TFAA) as a dehydrating agent used in the cyanation process leads to high cost of the whole process. Patents WO2006100181, WO20080167479 and the like report that directly taking L-proline as a starting material, firstly reacting chloroacetyl chloride with amino, and then performing amidation and cyanation to prepare a key intermediate i, wherein the process synthetic route is as follows:
the method has simple steps, avoids the problem of impurities caused by the activity of amino, but the chloracetyl is easy to be partially aminolyzed in the amidation process, and trifluoroacetic anhydride (TFAA) is still used as a dehydrating agent, so that the process yield is only about 40%, the product impurities are more, and the yield and the purity of the final product are greatly influenced along with the expansion of the production scale.
The second method is that the imino group of L-prolinamide is protected, then dehydration and deprotection are carried out, finally chloroacetylation is carried out to prepare an intermediate I, and the route technological synthetic route is as follows:
the route effectively reduces process impurities through the protection of amino, uses the cheap cyanuric chloride as a dehydrating agent, and is convenient for industrial production. However, the route still uses expensive L-prolinamide as a starting material, and the subsequent deprotection process uses methanesulfonic acid, and sulfonic acid belongs to genotoxic impurities, so that the potential risk of genotoxic residues exists in the final product, and the safety of the medicine is not facilitated. If the L-proline is calculated, the process is more complex, and a large amount of yield loss is caused by repeated product crystallization and purification, so that the method has no industrial condition.
At present, a synthesis process of(s) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile which has high yield, high quality and low cost and is suitable for industrialization is in urgent need of development.
Disclosure of Invention
Aiming at the technical problems in the prior art, the invention aims to solve the technical problems of providing a synthetic method of vildagliptin intermediate (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile, finding out through experiments that after the amino group of the pyrrole ring in L-proline is protected, the reaction in each step has higher conversion rate, and the by-products in each step can be removed by extraction and distillation methods, developing a method for synthesizing Boc-L-prolinamide (compound VII) by using L-proline as a starting material and adopting a direct one-pot method, greatly simplifying the preparation process of Boc-L-prolinamide (compound VII), and directly synthesizing the intermediate I without an intermediate crystallization purification process; a method for efficiently removing the boc protecting group in a dichloromethane system is also developed, so that the process is further simplified, and introduction of sulfonic acid impurities is avoided. The product obtained by the method has less impurities, the purity is as high as 99.7%, the yield can reach more than 60% (calculated by L-proline), and the method is suitable for industrial production.
The technical scheme adopted by the invention is as follows: a continuous preparation method of a vildagliptin key intermediate comprises the following steps:
1) preparation of Boc-L-prolinamide: under the protection of nitrogen, adding L-proline and dichloromethane into a reaction container until the L-proline is completely dissolved, adding alkali, stirring and controlling the temperature to be 0-20 ℃, dropwise adding di-tert-butyl dicarbonate until the system is clear, continuously controlling the temperature to be 0-20 ℃, dropwise adding ethyl chloroformate, quickly stirring, dropwise adding ammonia water until the system is clear, continuously reacting for 3-5 hours, adding concentrated hydrochloric acid to adjust the system to be neutral, separating out an organic phase, drying with anhydrous sodium sulfate, and evaporating the solvent to obtain Boc-L-prolinamide;
2) preparation of(s) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile: adding dimethylformamide into Boc-L-prolinamide obtained in the step (1) until the Boc-L-prolinamide is completely dissolved, adding cyanuric chloride, continuously reacting for 1-3h after a large amount of the system is separated out, cooling to 0-20 ℃, adding sodium bicarbonate to adjust the system to be neutral, filtering out solid, evaporating the solvent in vacuum, adding dichloromethane until the dichloromethane is completely dissolved, adding deprotection solvent, controlling the temperature to be 0-20 ℃, dropwise adding thionyl chloride, reacting for 0.5-2h, adding purified water until the system is clear, adding sodium carbonate to adjust the system to be neutral, separating to obtain an organic phase and a water phase, reversely extracting the water phase, adding triethylamine into the organic phase, controlling the temperature to be 0-10 ℃, dropwise adding chloroacetyl chloride, stirring until the reaction is complete, sequentially washing the organic phase by using 3-8% sodium bicarbonate water solution and purified water, the solvent is distilled off, and ethyl acetate and cyclohexane are added for recrystallization to obtain(s) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile.
The process route is as follows:
the alkali in the step (1) is sodium hydroxide or triethylamine, the dosage of the alkali is 1-2 times of the molar weight of the L-proline, and the temperature is preferably controlled to be 10-15 ℃.
The using amount of the ethyl chloroformate in the step (1) is 1-2 times of the molar weight of the L-proline, preferably, the temperature is controlled to be 10-15 ℃, and the reaction time is 4 hours.
In the step (2), the mass ratio of the cyanuric chloride to the L-proline is 0.4-0.8: 1, preferably, the temperature is controlled to be 10-15 ℃, and the reaction time is 1 h.
The mass ratio of the volume of the dichloromethane to the L-proline in the step (2) is 7-10:1, and the dosage of the thionyl chloride is 0.9-1.5 times of the molar weight of the L-proline.
The deprotection solvent is methanol, ethanol and/or butanol.
The dosage of the deprotection solvent is 1 to 3 times of the molar weight of the thionyl chloride, and the temperature is preferably 0 to 10 ℃ before the thionyl chloride is added; the reaction time after adding thionyl chloride is preferably 1 h.
The dosage of triethylamine in the step (2) is 1-2 times of the molar weight of L-proline, and the molar weight of chloroacetyl chloride L-proline is 0.8-1.2 times.
In the step (2), 15-30g of L-proline is added into each 100mL of the mixed solution of ethyl acetate and cyclohexane, wherein the weight ratio of ethyl acetate: the volume ratio of cyclohexane is 1: 4.
The innovation points of the invention are as follows:
1. the method for synthesizing Boc-L-prolinamide (compound VII) by using a one-pot method and taking L-proline as a starting material greatly simplifies the preparation process of Boc-L-prolinamide (compound VII), does not need an intermediate crystallization and purification process, and can be directly synthesized into an intermediate I.
2. A method for efficiently removing the boc protecting group in a dichloromethane system is developed, so that the process is further simplified, and introduction of sulfonic acid impurities is avoided.
The invention has the beneficial effects that:
1. the intermediate I is continuously prepared from the L-proline, so that process impurities are obviously reduced, the purity is over 99.5 percent, the total yield is over 60 percent, and the yield and quality advantages are obvious.
2. The raw materials in the process are low in price, the process operation is simple, the conditions are mild, and the method is suitable for industrial amplification.
3. A cheap thionyl chloride system is adopted in the deprotection process, and no gene toxic impurities are introduced, so that the safety risk of downstream medicines is avoided.
Drawings
FIG. 1 is an HPLC chart of(s) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile (compound I) of example 1.
Detailed Description
The present invention is further illustrated by the following specific examples, but it should be understood by those skilled in the art that the specific examples of the present invention are not intended to limit the present invention in any way, and any equivalents based on the present invention are within the scope of the present invention.
Example 1:
under the protection of nitrogen, 100ml of dichloromethane, 23g L-proline and 8.8g of sodium hydroxide are sequentially added into a round-bottom flask, the temperature is controlled to 10-15 ℃ by stirring, 48g of di-tert-butyl dicarbonate is dropwise added until the system is clear, the temperature is continuously controlled to 10-15 ℃ and 26g of ethyl chloroformate is dropwise added, 42g of 25% ammonia water is dropwise added under rapid stirring, the reaction is continuously carried out for 4 hours after the system is clear, concentrated hydrochloric acid is added to adjust the system to be neutral, an organic phase is separated out and dried by anhydrous sodium sulfate, and the solvent is evaporated to dryness, so that 37.7g of colorless oily boc-L-prolinamide is obtained.
Adding 100ml of dimethylformamide into the obtained boc-L-prolinamide, adding 14.8g of cyanuric chloride at room temperature, continuously reacting for 2 hours after a large amount of system is separated out, cooling to 0-10 ℃, adding sodium bicarbonate to neutralize the system, filtering out solids, evaporating the solvent in vacuum, adding 200ml of dichloromethane to dissolve, adding 13g of methanol, controlling the temperature to 0-10 ℃, dropwise adding 24g of thionyl chloride, reacting for 1 hour, adding 100ml of purified water until the system is clear, adding sodium carbonate at low temperature to adjust the pH of the system to 7-7.5, separating and back-extracting a water phase, adding 24g of triethylamine into a dichloro phase, controlling the temperature to 5-10 ℃, dropwise adding 14g of chloroacetyl chloride, controlling the temperature to stir for 2 hours until the reaction is complete, washing an organic phase by using 5% of sodium bicarbonate aqueous solution and purified water in sequence, evaporating to remove the solvent, adding 20ml of ethyl acetate and 80ml of cyclohexane to recrystallize, and obtaining 21g of white solid(s) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile Purity 99.7% (see fig. 1), yield 61% (based on L-proline).
Example 2:
under the protection of nitrogen, sequentially adding 100ml of dichloromethane, 23g L-proline and 22.3g of triethylamine into a round-bottom flask, stirring and controlling the temperature to be 5-10 ℃, dropwise adding 48g of di-tert-butyl dicarbonate until the system is clear, continuously controlling the temperature to be 10-15 ℃, dropwise adding 26g of ethyl chloroformate, quickly stirring and dropwise adding 42g of 25% ammonia water, continuously reacting for 4 hours after the system is clear, adding concentrated hydrochloric acid to adjust the system to be neutral, separating out an organic phase, drying with anhydrous sodium sulfate, and evaporating the solvent to dryness to obtain 37.7g of colorless oily boc-L-prolinamide.
Adding 100ml of dimethylformamide into the obtained boc-L-prolinamide, adding 14.8g of cyanuric chloride at room temperature, continuously reacting for 2 hours after a large amount of system is separated out, cooling to 0-10 ℃, adding sodium bicarbonate to neutralize the system, filtering out solids, evaporating the solvent in vacuum, adding 200ml of dichloromethane to dissolve, adding 13g of methanol, controlling the temperature to 0-10 ℃, dropwise adding 24g of thionyl chloride, reacting for 1 hour, adding 100ml of purified water until the system is clear, adding sodium carbonate at low temperature to adjust the pH of the system to 7-7.5, separating and back-extracting a water phase, adding 24g of triethylamine into a dichloro phase, controlling the temperature to 5-10 ℃, dropwise adding 14g of chloroacetyl chloride, controlling the temperature to stir for 2 hours until the reaction is complete, washing an organic phase by using 5% of sodium bicarbonate aqueous solution and purified water in sequence, evaporating to remove the solvent, adding 20ml of ethyl acetate and 80ml of cyclohexane to recrystallize, and obtaining 20.7g of white solid(s) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile Purity 99.5% and yield 60% (based on L-proline).
Example 3:
under the protection of nitrogen, 100ml of dichloromethane, 23g L-proline and 8.8g of sodium hydroxide are sequentially added into a round-bottom flask, the temperature is controlled to 10-15 ℃ by stirring, 48g of di-tert-butyl dicarbonate is dropwise added until the system is clear, the temperature is continuously controlled to 10-15 ℃, 22.3g of ethyl chloroformate is dropwise added, 42g of 25% ammonia water is dropwise added under rapid stirring, the reaction is continuously carried out for 3 hours after the system is clear, concentrated hydrochloric acid is added to adjust the system to be neutral, an organic phase is separated out and dried by anhydrous sodium sulfate, and the solvent is evaporated to dryness, so that 37.7g of colorless oily boc-L-prolinamide is obtained.
Adding 100ml of dimethylformamide into the obtained boc-L-prolinamide, adding 14.8g of cyanuric chloride at room temperature, continuously reacting for 2 hours after a large amount of system is separated out, cooling to 0-10 ℃, adding sodium bicarbonate to neutralize the system, filtering out solids, evaporating the solvent in vacuum, adding 200ml of dichloromethane to dissolve, adding 13g of methanol, controlling the temperature to 0-10 ℃, dropwise adding 24g of thionyl chloride, reacting for 1 hour, adding 100ml of purified water until the system is clear, adding sodium carbonate at low temperature to adjust the pH of the system to 7-7.5, separating and back-extracting a water phase, adding 24g of triethylamine into a dichloro phase, controlling the temperature to 5-10 ℃, dropwise adding 14g of chloroacetyl chloride, controlling the temperature to stir for 2 hours until the reaction is complete, washing an organic phase by using 5% of sodium bicarbonate aqueous solution and purified water in sequence, evaporating to remove the solvent, adding 20ml of ethyl acetate and 80ml of cyclohexane to recrystallize, and obtaining 19.3g of white solid(s) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile Purity 99.7% and yield 56% (based on L-proline).
Claims (9)
1. A continuous preparation method of a vildagliptin key intermediate is characterized by comprising the following steps:
1) preparation of Boc-L-prolinamide: under the protection of nitrogen, adding L-proline and dichloromethane into a reaction container until the L-proline is completely dissolved, adding alkali, stirring and controlling the temperature to be 0-20 ℃, dropwise adding di-tert-butyl dicarbonate until the system is clear, continuously controlling the temperature to be 0-20 ℃, dropwise adding ethyl chloroformate, quickly stirring, dropwise adding ammonia water until the system is clear, continuously reacting for 3-5 hours, adding concentrated hydrochloric acid to adjust the system to be neutral, separating out an organic phase, drying with anhydrous sodium sulfate, and evaporating the solvent to obtain Boc-L-prolinamide;
2) preparation of(s) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile: adding dimethylformamide into Boc-L-prolinamide obtained in the step (1) until the Boc-L-prolinamide is completely dissolved, adding cyanuric chloride, continuously reacting for 1-3h after a large amount of the system is separated out, cooling to 0-20 ℃, adding sodium bicarbonate to adjust the system to be neutral, filtering out solid, evaporating the solvent in vacuum, adding dichloromethane until the dichloromethane is completely dissolved, adding deprotection solvent, controlling the temperature to be 0-20 ℃, dropwise adding thionyl chloride, reacting for 0.5-2h, adding purified water until the system is clear, adding sodium carbonate to adjust the system to be neutral, separating to obtain an organic phase and a water phase, reversely extracting the water phase, adding triethylamine into the organic phase, controlling the temperature to be 0-10 ℃, dropwise adding chloroacetyl chloride, stirring until the reaction is complete, sequentially washing the organic phase by using 3-8% sodium bicarbonate water solution and purified water, the solvent is distilled off, and ethyl acetate and cyclohexane are added for recrystallization to obtain(s) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile.
2. The continuous preparation method of vildagliptin key intermediate as claimed in claim 1, wherein the base in step (1) is sodium hydroxide or triethylamine, and the amount of the base is 1-2 times of the molar amount of L-proline.
3. The continuous preparation method of vildagliptin key intermediate as claimed in claim 1, wherein the amount of ethyl chloroformate used in step (1) is 1-2 times the molar amount of L-proline.
4. The continuous preparation method of vildagliptin key intermediate according to claim 1, wherein the mass ratio of cyanuric chloride to L-proline in step (2) is 0.4-0.8: 1.
5. the continuous preparation method of vildagliptin key intermediate, according to claim 1, wherein the amount of thionyl chloride used in step (2) is 0.9-1.5 times the molar amount of L-proline.
6. The continuous preparation method of vildagliptin key intermediate as claimed in claim 1, wherein the deprotection solvent is methanol, ethanol and/or butanol.
7. The continuous preparation method of vildagliptin key intermediate, according to claim 1, wherein the amount of the deprotection solvent is 1-3 times of the molar amount of thionyl chloride.
8. The continuous preparation method of vildagliptin key intermediate as claimed in claim 1, wherein the amount of triethylamine in step (2) is 1-2 times of the molar amount of L-proline, and the molar amount of chloroacetyl chloride L-proline is 0.8-1.2 times.
9. The continuous preparation method of vildagliptin key intermediate as claimed in claim 1, wherein in the step (2), 15-30g l-proline is added per 100mL of mixed solution of ethyl acetate and cyclohexane, wherein the ratio of ethyl acetate: the volume ratio of cyclohexane is 1: 4.
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| CN112028806A (en) * | 2020-08-25 | 2020-12-04 | 河北合佳医药科技集团股份有限公司 | Synthetic method of vildagliptin intermediate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112028806A (en) * | 2020-08-25 | 2020-12-04 | 河北合佳医药科技集团股份有限公司 | Synthetic method of vildagliptin intermediate |
Non-Patent Citations (4)
| Title |
|---|
| JIANG WANG ET AL.: "Synthesis and biological evaluation of pyrrolidine-2-carbonitrile and 4-fluoropyrrolidine-2-carbonitrile derivatives as dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes", 《BIOORGANIC & MEDICINAL CHEMISTRY》, vol. 21, pages 7420 * |
| PRAMOD KUMAR ET AL.: "Chiral Mn-salalen and -salan Complexes Derived from (S)-Pyrrolidin-2-ylmethanamine and Their Catalytic Activity in the Asymmetric Strecker Reaction", 《EUR.J.INORG.CHEM》, pages 5078 * |
| RAM N. KUSHWAHA ET AL.: "Design, Synthesis, Biological Screening, and Molecular Docking Studies of Piperazine-Derived Constrained Inhibitors of DPP-IV for the Treatment of Type 2 Diabetes", 《CHEM BIOL DRUG DES》, vol. 85, pages 443 * |
| ZIWEN WANG ET AL.: "Design, Synthesis, and Antiviral Activity Evaluation of Phenanthrene-Based Antofine Derivatives", 《J. AGRIC. FOOD CHEM.》, vol. 60, pages 8544 * |
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