CN111548297A - A kind of synthetic method of vildagliptin - Google Patents
A kind of synthetic method of vildagliptin Download PDFInfo
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- 229960001254 vildagliptin Drugs 0.000 title claims abstract description 22
- SYOKIDBDQMKNDQ-XWTIBIIYSA-N vildagliptin Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC(=O)N1CCC[C@H]1C#N SYOKIDBDQMKNDQ-XWTIBIIYSA-N 0.000 title claims abstract description 22
- 238000010189 synthetic method Methods 0.000 title claims description 10
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims abstract description 16
- HOAXAMIXIJSFGP-LURJTMIESA-N (2S)-1-(2-hydroxyacetyl)pyrrolidine-2-carbonitrile Chemical compound OCC(=O)N1CCC[C@H]1C#N HOAXAMIXIJSFGP-LURJTMIESA-N 0.000 claims abstract description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 10
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims abstract description 10
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims abstract description 10
- 229910000024 caesium carbonate Inorganic materials 0.000 claims abstract description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical group ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 10
- ALSCEGDXFJIYES-YFKPBYRVSA-N (2s)-pyrrolidine-2-carbonitrile Chemical compound N#C[C@@H]1CCCN1 ALSCEGDXFJIYES-YFKPBYRVSA-N 0.000 claims abstract description 8
- 238000004821 distillation Methods 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 33
- 238000003756 stirring Methods 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 239000000243 solution Substances 0.000 claims description 9
- 238000002390 rotary evaporation Methods 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 5
- 238000009413 insulation Methods 0.000 claims description 5
- 238000004321 preservation Methods 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 3
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 claims description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 3
- DWPIPTNBOVJYAD-UHFFFAOYSA-N 3-aminoadamantan-1-ol Chemical compound C1C(C2)CC3CC1(N)CC2(O)C3 DWPIPTNBOVJYAD-UHFFFAOYSA-N 0.000 claims description 3
- 239000012141 concentrate Substances 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 239000012074 organic phase Substances 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- YCWRPKBYQZOLCD-UHFFFAOYSA-N 1-(2-chloroacetyl)pyrrolidine-2-carbonitrile Chemical compound ClCC(=O)N1CCCC1C#N YCWRPKBYQZOLCD-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- -1 small molecule compound Chemical class 0.000 claims description 2
- YCWRPKBYQZOLCD-LURJTMIESA-N (2s)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile Chemical compound ClCC(=O)N1CCC[C@H]1C#N YCWRPKBYQZOLCD-LURJTMIESA-N 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000000034 method Methods 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 238000006467 substitution reaction Methods 0.000 abstract description 3
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- 239000003795 chemical substances by application Substances 0.000 abstract description 2
- 238000006482 condensation reaction Methods 0.000 abstract description 2
- 239000012043 crude product Substances 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 238000001819 mass spectrum Methods 0.000 description 3
- 102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 description 2
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 102000003779 Dipeptidyl-peptidases and tripeptidyl-peptidases Human genes 0.000 description 1
- 108090000194 Dipeptidyl-peptidases and tripeptidyl-peptidases Proteins 0.000 description 1
- 102100023915 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 229940122344 Peptidase inhibitor Drugs 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- 229960003105 metformin Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 229960004034 sitagliptin Drugs 0.000 description 1
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
Abstract
本发明公开了一种维达列汀的合成方法，以乙醇酸和(S)‑吡咯烷‑2‑甲腈为原料，在缩合剂的作用下，发生缩合反应，制备得到了(S)‑1‑(2‑羟基乙酰基)吡咯烷‑2‑甲腈，接着，(S)‑1‑(2‑羟基乙酰基)吡咯烷‑2‑甲腈与二氯亚砜发生取代反应，仅需要减压蒸馏除去小分子化合物，即可得到较纯的含有(S)‑1‑(2‑氯乙酰基)吡咯烷‑2‑甲腈的四氯化碳溶液，最后向溶液中加入3‑氨基‑1‑金刚烷醇水合物和碳酸铯，仅需要4‑5h进行取代反应，粗产物经乙醇重结晶后，纯度高达99.85％，为高纯度维达列汀的合成提供了一条高效率的合成路线，具有良好的实用性。The invention discloses a method for synthesizing vildagliptin. Glycolic acid and (S)-pyrrolidine-2-carbonitrile are used as raw materials, and under the action of a condensing agent, a condensation reaction occurs to prepare (S)- 1-(2-hydroxyacetyl)pyrrolidine-2-carbonitrile, then, (S)-1-(2-hydroxyacetyl)pyrrolidine-2-carbonitrile is substituted with thionyl chloride, only need Underpressure distillation to remove small molecular compounds, a relatively pure carbon tetrachloride solution containing (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile can be obtained, and finally 3-amino is added to the solution ‑1‑adamantanol hydrate and cesium carbonate only need 4‑5h to carry out the substitution reaction. After the crude product is recrystallized from ethanol, the purity is as high as 99.85%, which provides a high-efficiency synthesis for the synthesis of high-purity vildagliptin. route, with good practicality.
Description
技术领域technical field
本发明属于药物技术领域，具体涉及一种维达列汀的合成方法。The invention belongs to the technical field of medicine, and in particular relates to a method for synthesizing vildagliptin.
背景技术Background technique
维达列汀(vildagliptin)是继西他列汀(sitagliptin)后的又一个口服给药的二肽基肽酶-IV(DPP-IV)抑制剂，由瑞士诺华(Novartis)制药有限公司，2008年获准在欧盟上市，用于治疗2-型糖尿病。维格列汀是二肽基肽酶抑制剂的一个代表药物，在临床研究中无论单独用药还是联合二甲双胍和胰岛素用药，均显示了良好的抗糖尿病作用以及耐受性。Vildagliptin is another orally administered dipeptidyl peptidase-IV (DPP-IV) inhibitor after sitagliptin. Approved in the European Union for the treatment of type 2 diabetes. Vildagliptin is a representative drug of dipeptidyl peptidase inhibitor. It has shown good anti-diabetic effect and tolerance in clinical studies, whether alone or in combination with metformin and insulin.
现有的维达列汀的合成路线步骤较多，且产生的副产物种类较多，且难以去除。The existing synthetic route of vildagliptin has many steps, and produces many types of by-products, which are difficult to remove.
发明内容SUMMARY OF THE INVENTION
本发明的目的在于提供一种维达列汀的合成方法。The object of the present invention is to provide a kind of synthetic method of vildagliptin.
本发明的目的可以通过以下技术方案实现：The object of the present invention can be realized through the following technical solutions:
一种维达列汀的合成方法，具体包括以下步骤：A kind of synthetic method of vildagliptin, specifically comprises the following steps:
第一步、在反应瓶中加入51-52mmol乙醇酸、50-53mmol EDCI/HOBT、碱催化剂以及250-300ml溶剂无水四氢呋喃，将反应瓶放入冰盐浴中，搅拌15-20min后，在低温下每隔半小时加入10mmol(S)-吡咯烷-2-甲腈,共加入50mmol(S)-吡咯烷-2-甲腈，加入完毕后，将反应瓶取出放置在室温环境中，搅拌2-3h，放入加热套中进行加热，升温后保温搅拌1.5-2h，反应结束后，自然冷却到室温，过滤，旋转蒸发除去溶剂，向浓缩物中加入100-150ml饱和食盐水，搅拌混合15-20min后，加入100-150ml乙酸乙酯进行萃取，分液后，有机相旋转蒸发除去溶剂，即得到(S)-1-(2-羟基乙酰基)吡咯烷-2-甲腈；反应式如下：The first step, add 51-52mmol glycolic acid, 50-53mmol EDCI/HOBT, base catalyst and 250-300ml solvent anhydrous tetrahydrofuran in the reaction flask, put the reaction flask into the ice-salt bath, after stirring for 15-20min, in the 10mmol (S)-pyrrolidine-2-carbonitrile was added every half hour at low temperature, and 50mmol (S)-pyrrolidine-2-carbonitrile was added in total. After the addition, the reaction flask was taken out and placed in a room temperature environment and stirred. 2-3h, put it into a heating mantle for heating, heat up and keep stirring for 1.5-2h, after the reaction, cool to room temperature naturally, filter, remove the solvent by rotary evaporation, add 100-150ml of saturated brine to the concentrate, stir and mix After 15-20min, 100-150ml ethyl acetate was added for extraction, and after liquid separation, the organic phase was rotary evaporated to remove the solvent to obtain (S)-1-(2-hydroxyacetyl)pyrrolidine-2-carbonitrile; reaction The formula is as follows:
第二步、在反应瓶中加入20mmol(S)-1-(2-羟基乙酰基)吡咯烷-2-甲腈和100ml干燥的四氯化碳，缓慢升温至50-55℃，逐滴滴加20.5-21mmol二氯亚砜，滴加完毕后，升温至60-65℃，保温搅拌，反应结束后，自然冷却到室温，减压蒸馏除去小分子化合物，即得到含有(S)-1-(2-氯乙酰基)吡咯烷-2-甲腈的四氯化碳溶液；反应式如下：The second step, add 20mmol (S)-1-(2-hydroxyacetyl)pyrrolidine-2-carbonitrile and 100ml dry carbon tetrachloride to the reaction flask, slowly heat up to 50-55°C, drop by drop Add 20.5-21 mmol of thionyl chloride, after the dropwise addition is completed, the temperature is raised to 60-65 ° C, and the temperature is maintained and stirred. After the reaction is completed, it is naturally cooled to room temperature, and the small molecule compound is removed by distillation under reduced pressure to obtain (S)-1- The carbon tetrachloride solution of (2-chloroacetyl) pyrrolidine-2-carbonitrile; Reaction formula is as follows:
第三步、向第二步的溶液中加入20mmol 3-氨基-1-金刚烷醇水合物和8-10g碳酸铯，边搅拌边加热升温，保温搅拌反应，反应结束后，自然冷却到室温，旋转蒸发除去溶剂，采用乙醇重结晶即得到维达列汀；反应式如下：The 3rd step, in the solution of the second step, add 20mmol 3-amino-1-adamantanol hydrate and 8-10g cesium carbonate, heat up while stirring, heat preservation and stirring reaction, after the reaction finishes, naturally cool to room temperature, The solvent is removed by rotary evaporation, and vildagliptin is obtained by recrystallization from ethanol; the reaction formula is as follows:
进一步，第一步中，所述的碱催化剂为碳酸铯，碳酸铯的加入量为18-20g。Further, in the first step, the alkali catalyst is cesium carbonate, and the addition of cesium carbonate is 18-20g.
进一步，第一步中，所述的保温的温度为50-55℃。Further, in the first step, the temperature of the heat preservation is 50-55°C.
进一步，第二步中，所述的保温搅拌的时间为40-60min。Further, in the second step, the time of described heat preservation and stirring is 40-60min.
进一步，第三步中，所述的保温的温度为50-55℃。Further, in the third step, the temperature of the heat preservation is 50-55°C.
进一步，第三步中，所述的保温搅拌反应的时间为4-5h。Further, in the third step, the time of the described thermal insulation stirring reaction is 4-5h.
本发明的有益效果：Beneficial effects of the present invention:
本发明提供的一种维达列汀的合成方法，以乙醇酸和(S)-吡咯烷-2-甲腈为原料，在缩合剂的作用下，发生缩合反应，制备得到了(S)-1-(2-羟基乙酰基)吡咯烷-2-甲腈，接着，(S)-1-(2-羟基乙酰基)吡咯烷-2-甲腈与二氯亚砜发生取代反应，仅需要减压蒸馏除去小分子化合物，即可得到较纯的含有(S)-1-(2-氯乙酰基)吡咯烷-2-甲腈的四氯化碳溶液，最后向溶液中加入3-氨基-1-金刚烷醇水合物和碳酸铯，仅需要4-5h进行取代反应，粗产物经乙醇重结晶后，纯度高达99.85％，为高纯度维达列汀的合成提供了一条高效率的合成路线，具有良好的实用性。The invention provides a method for synthesizing vildagliptin. Glycolic acid and (S)-pyrrolidine-2-carbonitrile are used as raw materials, and under the action of a condensing agent, a condensation reaction occurs to prepare (S)- 1-(2-hydroxyacetyl)pyrrolidine-2-carbonitrile, followed by (S)-1-(2-hydroxyacetyl)pyrrolidine-2-carbonitrile substitution reaction with thionyl chloride, only need Decompression distillation to remove small molecular compounds to obtain a relatively pure carbon tetrachloride solution containing (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile, and finally add 3-amino to the solution -1-adamantanol hydrate and cesium carbonate, only need 4-5h for the substitution reaction, the crude product is recrystallized from ethanol, the purity is as high as 99.85%, which provides a high-efficiency synthesis for the synthesis of high-purity vildagliptin route, with good practicality.
当然，实施本发明的任一产品并不一定需要同时达到以上所述的所有优点。Of course, it is not necessary for any product embodying the present invention to achieve all of the above-described advantages simultaneously.
具体实施方式Detailed ways
下面将对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其它实施例，都属于本发明保护的范围。The technical solutions in the embodiments of the present invention will be described clearly and completely below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.
一种维达列汀的合成方法，具体包括以下步骤：A kind of synthetic method of vildagliptin, specifically comprises the following steps:
第一步、在反应瓶中加入51mmol乙醇酸、50mmol EDCI/HOBT、20g碳酸铯以及300ml溶剂无水四氢呋喃，将反应瓶放入冰盐浴中，搅拌20min后，在低温下每隔半小时加入10mmol(S)-吡咯烷-2-甲腈,共加入50mmol(S)-吡咯烷-2-甲腈，加入完毕后，将反应瓶取出放置在室温环境中，搅拌2h，放入加热套中，升温至55℃，保温搅拌2h，反应结束后，自然冷却到室温，过滤，旋转蒸发除去溶剂，向浓缩物中加入150ml饱和食盐水，搅拌混合15min后，加入150ml乙酸乙酯进行萃取，分液后，有机相旋转蒸发除去溶剂，即得到(S)-1-(2-羟基乙酰基)吡咯烷-2-甲腈；收率为91.6％；The first step, add 51mmol glycolic acid, 50mmol EDCI/HOBT, 20g cesium carbonate and 300ml solvent anhydrous tetrahydrofuran in the reaction flask, put the reaction flask into the ice-salt bath, after stirring 20min, add every half hour at low temperature 10mmol (S)-pyrrolidine-2-carbonitrile, a total of 50mmol (S)-pyrrolidine-2-carbonitrile was added, after the addition, the reaction flask was taken out and placed at room temperature, stirred for 2h, and put into a heating mantle , heat up to 55°C, keep stirring for 2h, after the reaction, cool to room temperature naturally, filter, remove the solvent by rotary evaporation, add 150ml of saturated brine to the concentrate, stir and mix for 15min, add 150ml of ethyl acetate for extraction, separate After the liquid, the solvent was removed by rotary evaporation of the organic phase to obtain (S)-1-(2-hydroxyacetyl)pyrrolidine-2-carbonitrile; the yield was 91.6%;
(S)-1-(2-羟基乙酰基)吡咯烷-2-甲腈的质谱结果为：HRMS m/z(M+H+)：155.351。The mass spectrum of (S)-1-(2-hydroxyacetyl)pyrrolidine-2-carbonitrile was: HRMS m/z (M+H + ): 155.351.
第二步、在反应瓶中加入20mmol(S)-1-(2-羟基乙酰基)吡咯烷-2-甲腈和100ml干燥的四氯化碳，缓慢升温至55℃，逐滴滴加20.5mmol二氯亚砜，滴加完毕后，升温至60℃，保温搅拌反应60min，反应结束后，自然冷却到室温，减压蒸馏除去小分子化合物，即得到含有(S)-1-(2-氯乙酰基)吡咯烷-2-甲腈的四氯化碳溶液；In the second step, add 20mmol (S)-1-(2-hydroxyacetyl)pyrrolidine-2-carbonitrile and 100ml of dry carbon tetrachloride to the reaction flask, slowly heat up to 55°C, and dropwise add 20.5 mmol thionyl chloride, after the dropwise addition, the temperature was raised to 60°C, and the reaction was kept under stirring for 60 min. After the reaction was completed, it was naturally cooled to room temperature, and the small molecular compound was distilled off under reduced pressure to obtain (S)-1-(2- chloroacetyl)pyrrolidine-2-carbonitrile in carbon tetrachloride;
(S)-1-(2-氯乙酰基)吡咯烷-2-甲腈的质谱结果为：HRMS m/z(M+H+)：173.064。The mass spectrum of (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile was: HRMS m/z (M+H + ): 173.064.
第三步、向第二步的溶液中加入20mmol 3-氨基-1-金刚烷醇水合物和10g碳酸铯，边搅拌边升温至55℃，保温搅拌反应4h，反应结束后，自然冷却到室温，旋转蒸发除去溶剂，采用乙醇重结晶即得到维达列汀，采用HPLC检测其纯度为99.85％，反应式如下：The third step, add 20mmol of 3-amino-1-adamantanol hydrate and 10g of cesium carbonate to the solution of the second step, heat up to 55°C while stirring, keep stirring for 4h, and after the reaction is finished, naturally cool to room temperature , the solvent was removed by rotary evaporation, and vildagliptin was obtained by recrystallization from ethanol, and its purity was 99.85% detected by HPLC, and the reaction formula was as follows:
维达列汀的质谱结果为：HRMS m/z(M+H+)：303.976。The mass spectrum result of vildagliptin was: HRMS m/z (M+H + ): 303.976.
以上内容仅仅是对本发明的构思所作的举例和说明，所属本技术领域的技术人员对所描述的具体实施例做各种各样的修改或补充或采用类似的方式替代，只要不偏离发明的构思或者超越本权利要求书所定义的范围，均应属于本发明的保护范围。The above contents are only examples and descriptions of the concept of the present invention. Those skilled in the art can make various modifications or supplements to the described specific embodiments or replace them in similar ways, as long as they do not deviate from the concept of the invention. Or beyond the scope defined by the claims, all belong to the protection scope of the present invention.
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