CN111138334A - Preparation method of vildagliptin - Google Patents
Preparation method of vildagliptin Download PDFInfo
- Publication number
- CN111138334A CN111138334A CN202010029575.1A CN202010029575A CN111138334A CN 111138334 A CN111138334 A CN 111138334A CN 202010029575 A CN202010029575 A CN 202010029575A CN 111138334 A CN111138334 A CN 111138334A
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- China
- Prior art keywords
- chloracetyl
- preparing
- pyrrolidine
- prolinamide
- vildagliptin
- Prior art date
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- 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 21
- 229960001254 vildagliptin Drugs 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims abstract description 14
- VLJNHYLEOZPXFW-BYPYZUCNSA-N L-prolinamide Chemical compound NC(=O)[C@@H]1CCCN1 VLJNHYLEOZPXFW-BYPYZUCNSA-N 0.000 claims abstract description 13
- DWPIPTNBOVJYAD-BQKDNTBBSA-N (5s,7r)-3-aminoadamantan-1-ol Chemical compound C([C@H](C1)C2)[C@@H]3CC2(N)CC1(O)C3 DWPIPTNBOVJYAD-BQKDNTBBSA-N 0.000 claims abstract description 9
- YCWRPKBYQZOLCD-LURJTMIESA-N (2s)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile Chemical compound ClCC(=O)N1CCC[C@H]1C#N YCWRPKBYQZOLCD-LURJTMIESA-N 0.000 claims abstract description 8
- YKDRUBGIBPCRBH-YFKPBYRVSA-N (2s)-1-(2-chloroacetyl)pyrrolidine-2-carboxamide Chemical compound NC(=O)[C@@H]1CCCN1C(=O)CCl YKDRUBGIBPCRBH-YFKPBYRVSA-N 0.000 claims abstract description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 8
- 230000035484 reaction time Effects 0.000 claims abstract description 7
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229910017604 nitric acid Inorganic materials 0.000 claims abstract description 4
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 7
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 4
- 238000004821 distillation Methods 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 239000006227 byproduct Substances 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000001308 synthesis method Methods 0.000 abstract description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 6
- 239000008103 glucose Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- 102000051325 Glucagon Human genes 0.000 description 4
- 108060003199 Glucagon Proteins 0.000 description 4
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 4
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 4
- 229960004666 glucagon Drugs 0.000 description 4
- 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 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 2
- 229960003105 metformin Drugs 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 108010004460 Gastric Inhibitory Polypeptide Proteins 0.000 description 1
- 102100039994 Gastric inhibitory polypeptide Human genes 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000009229 glucose formation Effects 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- MGXWVYUBJRZYPE-YUGYIWNOSA-N incretin Chemical class C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)[C@@H](C)O)[C@@H](C)CC)C1=CC=C(O)C=C1 MGXWVYUBJRZYPE-YUGYIWNOSA-N 0.000 description 1
- 239000000859 incretin Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 231100000682 maximum tolerated dose Toxicity 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyrrole Compounds (AREA)
Abstract
The invention discloses a preparation method of vildagliptin, which comprises the following steps: l-prolinamide is acylated by chloracetyl chloride to obtain (S) -N-chloracetyl-2-carbamoyl pyrrolidine, is dehydrated to obtain (S) -N-chloracetyl-2-cyano pyrrolidine, and then undergoes nucleophilic substitution reaction with 3-amino-1-adamantanol to obtain 1- [2- (3-hydroxyadamantan-1-ylamino) acetyl group]Pyrrolidine-2 (S) -carbonitrile; the preparation formula is as follows:
Description
Technical Field
The invention relates to the field of vildagliptin preparation, in particular to a vildagliptin preparation method.
Background
Vildagliptin (English name: Vildagliptin), which is chemically named as (-) - (2S) -1- [ [ (3-hydroxytricyclo [3.3.1.1[3,7] ] decan-1-yl) amino ] acetyl ] pyrrolidine-2-carbonitrile, is a selective dipeptide-peptidase-4 (DPP-4) inhibitor marketed by Novartis, 2008, and can rapidly inhibit DPP-4 activity after administration, so that the levels of endogenous glucagon GLP-1 (glucagon polypeptide-1) and GLP (glucose-dependent insulinotropic polypeptide) are increased after fasting eating, thereby increasing the sensitivity of B cells to glucose, promoting the secretion of glucose-dependent insulin, and increasing the level of endogenous GLP-1 by increasing Vildagliptin can also increase the sensitivity of A cells to glucose, the degree of engagement between glucose levels and the amount of glucagon secretion is increased. During hyperglycemia, vildagliptin increases the ratio of insulin to glucagon by increasing the level of incretin, resulting in a decrease in hepatic glucose production after fasting eating, thereby lowering blood glucose, and is suitable for treating type 2 diabetes. Metformin is used in combination with metformin when it is used as monotherapy until the maximum tolerated dose is still ineffective in controlling blood glucose.
Regarding the synthetic method of vildagliptin, the methods reported in the literature mainly include: in WO2011101861A1, potassium carbonate is used as an alkali, potassium iodide is used as a catalyst, and (S) -1- (2-chloroacetyl) pyrrole-2-carbonitrile and 3-amino-1-adamantanol react in a tetrahydrofuran solution at 60-65 ℃ for 5h to obtain a product after recrystallization from ethyl acetate and methanol, wherein the yield is about 60%. In the final butt-joint reaction in the step, the selectivity of mono-substituted products and di-substituted impurities on nitrogen atoms of adamantane is difficult to control, so that very harsh control conditions are required for realizing the selectivity, the crude product is difficult to purify, and the purification yield is less than 30%. Meanwhile, the synthetic route of the key intermediate (S) -1- (2-chloroacetyl) pyrrole-2-carbonitrile is long, and the yield is not high; the by-products are difficult to remove, and the purity index of the final product is not high; complicated operation procedures and the like.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a preparation method of vildagliptin, which has the advantages of simple and convenient steps, high yield, less byproduct amount and the like, and can also obviously reduce the production cost.
In order to achieve the aim of the invention, the invention adopts the specific scheme that:
a preparation method of vildagliptin comprises the following steps: the L-prolinamide is acylated by chloracetyl chloride to obtain (S) -N-chloracetyl-2-carbamyl pyrrolidine, and the (S) -N-chloracetyl-2-cyano pyrrolidine is obtained by dehydrationThen the obtained product and 3-amino-1-adamantanol are subjected to nucleophilic substitution reaction to obtain 1- [2- (3-hydroxyadamantan-1-ylamino) acetyl]Pyrrolidine-2 (S) -carbonitrile; the preparation formula is as follows:
when preparing (S) -N-chloracetyl-2-carbamoylpyrrolidine, the feeding ratio of L-prolinamide to chloracetyl chloride is 1: 3, when preparing (S) -N-chloroacetyl-2-cyanopyrrolidine, the reaction time is 8h, and when preparing 3-amino-1-adamantanol, the dosage of 98 percent sulfuric acid and 68 percent nitric acid is 3: 1.
further, when the chloroacetyl chloride is used in a small amount, the reaction of L-prolinamide is incomplete and the L-prolinamide is difficult to separate from the product, and the excess chloroacetyl chloride can be removed by distillation under reduced pressure.
Further, in the preparation of 1- [2- (3-hydroxyadamantan-1-ylamino) acetyl ] pyrrolidine-2 (S) -carbonitrile, THF was used as a solvent, the reaction temperature was 60 ℃ and the reaction time was 6h, methyl tert-butyl ether was used as a precipitant in the post-treatment, and a solid was precipitated within 10 min.
The invention has the beneficial effects that:
the synthesis method has the advantages of simple steps, high yield, less byproduct amount and the like, can obviously reduce the production cost, and can avoid the generation of disubstituted impurities on the nitrogen atom of the adamantane under the condition of not using a protecting group on the amino group.
Detailed Description
The present invention is further described below by way of specific examples, but the present invention is not limited to only the following examples. Variations, combinations, or substitutions of the invention, which are within the scope of the invention or the spirit, scope of the invention, will be apparent to those of skill in the art and are within the scope of the invention.
A preparation method of vildagliptin comprises the following steps: l-prolinamide is acylated by chloracetyl chloride to obtain (S) -N-chloracetyl-2-carbamoyl pyrrolidine, is dehydrated to obtain (S) -N-chloracetyl-2-cyano pyrrolidine, and then undergoes nucleophilic substitution reaction with 3-amino-1-adamantanol to obtain 1- [2- (3-hydroxy adamantane)-1-ylamino) acetyl]Pyrrolidine-2 (S) -carbonitrile; the preparation formula is as follows:
when preparing (S) -N-chloracetyl-2-carbamoylpyrrolidine, the feeding ratio of L-prolinamide to chloracetyl chloride is 1: 3, when preparing (S) -N-chloroacetyl-2-cyanopyrrolidine, the reaction time is 8h, and when preparing 3-amino-1-adamantanol, the dosage of 98 percent sulfuric acid and 68 percent nitric acid is 3: 1.
further, when the chloroacetyl chloride is used in a small amount, the reaction of L-prolinamide is incomplete and the L-prolinamide is difficult to separate from the product, and the excess chloroacetyl chloride can be removed by distillation under reduced pressure.
Further, in the preparation of 1- [2- (3-hydroxyadamantan-1-ylamino) acetyl ] pyrrolidine-2 (S) -carbonitrile, THF was used as a solvent, the reaction temperature was 60 ℃ and the reaction time was 6h, methyl tert-butyl ether was used as a precipitant in the post-treatment, and a solid was precipitated within 10 min.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the present invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (3)
1. A preparation method of vildagliptin is characterized by comprising the following steps: l-prolinamide is acylated by chloracetyl chloride to obtain (S) -N-chloracetyl-2-carbamoyl pyrrolidine, is dehydrated to obtain (S) -N-chloracetyl-2-cyano pyrrolidine, and then undergoes nucleophilic substitution reaction with 3-amino-1-adamantanol to obtain 1- [2- (3-hydroxyadamantan-1-ylamino) acetyl group]Pyrrolidine-2 (S) -carbonitrile; the preparation formula is as follows:
when preparing (S) -N-chloracetyl-2-carbamoylpyrrolidine, the feeding ratio of L-prolinamide to chloracetyl chloride is 1: 3, when preparing (S) -N-chloroacetyl-2-cyanopyrrolidine, the reaction time is 8h, and when preparing 3-amino-1-adamantanol, the dosage of 98 percent sulfuric acid and 68 percent nitric acid is 3: 1.
2. the method for preparing vildagliptin according to claim 1, wherein the chloroacetyl chloride is used in a small amount, the reaction of L-prolinamide is incomplete and the product is difficult to separate, and the excess chloroacetyl chloride can be removed by distillation under reduced pressure.
3. The method for preparing vildagliptin according to claim 1, wherein when 1- [2- (3-hydroxyadamantan-1-ylamino) acetyl ] pyrrolidine-2 (S) -carbonitrile is prepared, THF is used as a solvent, the reaction temperature is 60 ℃, the reaction time is 6h, methyl tert-butyl ether is used as a precipitant for post-treatment, and a solid is precipitated within 10 min.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112939837A (en) * | 2021-02-03 | 2021-06-11 | 海南通用三洋药业有限公司 | Method for preparing vildagliptin through multiphase compound continuous production |
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2020
- 2020-01-13 CN CN202010029575.1A patent/CN111138334A/en active Pending
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| CN103641761A (en) * | 2013-11-22 | 2014-03-19 | 沈阳化工大学 | Vildagliptin preparation method |
| CN104326961A (en) * | 2014-11-20 | 2015-02-04 | 海南中和药业有限公司 | Synthetic process of 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 |
| CN104945299A (en) * | 2015-05-28 | 2015-09-30 | 烟台万润药业有限公司 | Efficient synthesis method of 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 |
| CN107501154A (en) * | 2017-09-13 | 2017-12-22 | 浙江普洛康裕制药有限公司 | (S) synthetic method of the formonitrile HCN of 1 (2 chloracetyl) pyrrolidines 2 |
| CN110642769A (en) * | 2019-11-01 | 2020-01-03 | 烟台万润药业有限公司 | Preparation method of vildagliptin |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112939837A (en) * | 2021-02-03 | 2021-06-11 | 海南通用三洋药业有限公司 | Method for preparing vildagliptin through multiphase compound continuous production |
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