CN108440362A - A kind of preparation method of vildagliptin intermediate - Google Patents
A kind of preparation method of vildagliptin intermediate Download PDFInfo
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- CN108440362A CN108440362A CN201810212339.6A CN201810212339A CN108440362A CN 108440362 A CN108440362 A CN 108440362A CN 201810212339 A CN201810212339 A CN 201810212339A CN 108440362 A CN108440362 A CN 108440362A
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- 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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Abstract
The invention belongs to medicine intermediate fields, and in particular to a kind of preparation method of vildagliptin intermediate.The present invention reacts raw material L proline and chloracetyl chloride, it is not necessary that other solvents are added when reaction, avoids introducing other impurity, improve purity, be added acid binding agent, can in time neutralization reaction generate hydrochloric acid, shorten the reaction time, and improve yield, product is easy to purify, securely and reliably, the present invention is not necessarily to a large amount of solvents, and react at room temperature compared with conventional method, energy consumption is reduced, and environmentally friendly.
Description
Technical field
The invention belongs to medicine intermediate fields, and in particular to a kind of preparation method of vildagliptin intermediate.
Background technology
Vildagliptin, English name Vildagliptin, chemical name：(S) -1- [[(3- hydroxyl -1- adamantyls) amino]
Acetyl group] -2- cyano tetrahydro pyrrolidines.It is the pyrrolidines for a kind of substitution developed by Novartis Co., Ltd of Switzerland (Novartis)
Object is closed, is with selectivity, competitive, two reversible peptidyl enzyme IV (DPP-IV) inhibitor.The drug by with DPP-IV knot
The activity for forming DPP-IV compound and inhibiting the enzyme is closed, GLP-1 (glucagon-like-peptide-1) concentration is being improved, is promoting pancreas islet
While B cell generates insulin, Glucagon concentrations are reduced, to reduce blood glucose, and weight are had no significant effect.It can use
It treats diabetes B, either independent medication or is used in combination with other antidiabetic medicines, can significantly reduce glycosyl
Change hemoglobin level, there is good tolerance and be a glycosuria with applications well foreground without notable adverse reaction
Sick new drug.In September, 2007 ratifies low dosage medication by European Union, has also gone through in Brazil and Mexico.Row spit of fland class medicine at present
Object is still in the starting stage of clinical application in China, but achieves the progress advanced by leaps and bounds in recent years, and market application prospect is wide
It is wealthy.
Wherein, 1- (2- chloracetyls) proline is the key intermediate for preparing vildagliptin, at present 1- (2- chloracetyls
Base) proline is all high temperature reflux reacts to be carried out under solvent and alkaline condition, instead using L-PROLINE and chloracetyl chloride as raw material
Should after obtain 1- (2- chloracetyls) proline, reaction needs a large amount of solvents, and consume is serious, and unfriendly to environment, therefore,
Develop easy to operate, reaction condition is mild, and low energy consumption, and yield is high, and it is completely necessary to be suitble to the method for large-scale production.
Invention content
The technical problems to be solved by the invention：It is required for for vildagliptin intermediate 1- (2- chloracetyls) proline
High temperature reflux reacts are carried out under solvent condition, reaction needs a large amount of solvents, and consume is serious, and, yield unfriendly to environment
Low problem provides a kind of preparation method of vildagliptin intermediate.
In order to solve the above technical problems, the technical solution adopted by the present invention is：
Synthetic route of the present invention is as follows：
Specific synthesis step is as follows：
(1) in molar ratio 1:10~15, L-PROLINE and chloracetyl chloride are weighed, is added in three-necked flask, stirs at room temperature
Mix mixing；
(2) acid binding agent is added into three-necked flask after being stirred 5~10min, 3~5h of reaction is stirred at room temperature, instead
Should after be evaporated under reduced pressure the extra chloracetyl chloride of recycling, reaction solution is poured into ethyl acetate and distilled water, is stirred rear stratification,
Collected organic layer, vacuum distillation recycling ethyl acetate, you can obtain vildagliptin intermediate 1- (2- chloracetyls) proline.
The molar ratio of the acid binding agent and L-PROLINE is 2~3:1, acid binding agent is triethylamine, sodium acetate, 4- diformazan ammonia
It is a kind of in yl pyridines.
Compared with other methods, advantageous effects are the present invention：
(1) present invention reacts raw material L-PROLINE and chloracetyl chloride, it is not necessary that other solvents, chloroethene is added when reaction
Acyl chlorides serves not only as raw material and participates in reaction, is also used as solvent use, can be conducive to reaction and more fully carry out, and avoid
Introduce other impurity, acid binding agent be added, can the hydrochloric acid that generates of neutralization reaction in time, shorten the reaction time, and improve yield, produce
Product are easy to purify, securely and reliably；
(2) present invention is not necessarily to a large amount of solvents, and react at room temperature compared with conventional method, reduces energy consumption, and
And it is environmentally friendly, the reaction condition of synthesis 1- (2- chloracetyls) proline is optimized, to 1- (2- chloracetyls) proline
Synthesis be of great significance.
Description of the drawings
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of 1- (2- chloracetyls) proline.
Fig. 2 is the carbon-13 nmr spectra figure of 1- (2- chloracetyls) proline.
Specific implementation mode
In molar ratio 1:10~15, L-PROLINE and chloracetyl chloride are weighed, is added in three-necked flask, is stirred at room temperature mixed
It closes；It is stirred after 5~10min and acid binding agent is added into three-necked flask, the molar ratio of acid binding agent and L-PROLINE is 2~3:1,
3~5h of reaction is stirred at room temperature, the extra chloracetyl chloride of vacuum distillation recycling, ethyl acetate and steaming are poured by reaction solution after reaction
Distilled water is stirred rear stratification, collected organic layer, vacuum distillation recycling ethyl acetate, you can obtain among vildagliptin
Body 1- (2- chloracetyls) proline.Acid binding agent is a kind of in triethylamine, sodium acetate, 4-dimethylaminopyridine.
Example 1
In molar ratio 1:10, L-PROLINE and chloracetyl chloride are weighed, is added in three-necked flask, mixing is stirred at room temperature；
It is stirred after 5min to be added into three-necked flask and ties up triethylamine, the molar ratio of triethylamine and L-PROLINE is 2:1, at room temperature
It is stirred to react 3h, reaction solution is poured into ethyl acetate and distilled water by the extra chloracetyl chloride of vacuum distillation recycling after reaction, and stirring is mixed
Stratification after conjunction, collected organic layer, vacuum distillation recycling ethyl acetate, you can obtain vildagliptin intermediate 1- (2- chloroethenes
Acyl group) proline, fusing point is 112.3 DEG C, purity 99.89%, yield 92.5%.
Example 2
In molar ratio 1:12, L-PROLINE and chloracetyl chloride are weighed, is added in three-necked flask, mixing is stirred at room temperature；
It is stirred after 7min and sodium acetate is added into three-necked flask, the molar ratio of sodium acetate and L-PROLINE is 2.5:1, at room temperature
It is stirred to react 4h, reaction solution is poured into ethyl acetate and distilled water by the extra chloracetyl chloride of vacuum distillation recycling after reaction, and stirring is mixed
Stratification after conjunction, collected organic layer, vacuum distillation recycling ethyl acetate, you can obtain vildagliptin intermediate 1- (2- chloroethenes
Acyl group) proline, fusing point is 112.7 DEG C, purity 99.92%, yield 93.0%.
Example 3
In molar ratio 1:15, L-PROLINE and chloracetyl chloride are weighed, is added in three-necked flask, mixing is stirred at room temperature；
4-dimethylaminopyridine, mole of 4-dimethylaminopyridine and L-PROLINE are added into three-necked flask after being stirred 10min
Than being 3:1, reaction 5h is stirred at room temperature, the extra chloracetyl chloride of vacuum distillation recycling, acetic acid second is poured by reaction solution after reaction
Ester and distilled water are stirred rear stratification, collected organic layer, vacuum distillation recycling ethyl acetate, you can obtain Wei Gelie
Spit of fland intermediate 1- (2- chloracetyls) proline, fusing point are 113.1 DEG C, purity 99.92%, yield 94.8%.
Claims (2)
1. a kind of preparation method of vildagliptin intermediate, it is characterised in that specifically preparation process is：
(1) in molar ratio 1:10~15, L-PROLINE and chloracetyl chloride are weighed, is added in three-necked flask, is stirred at room temperature mixed
It closes；
(2) acid binding agent is added into three-necked flask after being stirred 5~10min, 3~5h of reaction is stirred at room temperature, after reaction
Extra chloracetyl chloride is recycled in vacuum distillation, and reaction solution is poured into ethyl acetate and distilled water, is stirred rear stratification, collects
Organic layer, vacuum distillation recycling ethyl acetate, you can obtain vildagliptin intermediate 1- (2- chloracetyls) proline.
2. a kind of preparation method of vildagliptin intermediate according to claim 1, it is characterised in that：The acid binding agent
Molar ratio with L-PROLINE is 2~3:1, acid binding agent is a kind of in triethylamine, sodium acetate, 4-dimethylaminopyridine.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201810212339.6A CN108440362A (en) | 2018-03-15 | 2018-03-15 | A kind of preparation method of vildagliptin intermediate |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201810212339.6A CN108440362A (en) | 2018-03-15 | 2018-03-15 | A kind of preparation method of vildagliptin intermediate |
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| CN108440362A true CN108440362A (en) | 2018-08-24 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110590632A (en) * | 2019-09-29 | 2019-12-20 | 浙江国邦药业有限公司 | Preparation method of vildagliptin intermediate |
| 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 |
-
2018
- 2018-03-15 CN CN201810212339.6A patent/CN108440362A/en not_active Withdrawn
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110590632A (en) * | 2019-09-29 | 2019-12-20 | 浙江国邦药业有限公司 | Preparation method of vildagliptin intermediate |
| 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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Application publication date: 20180824 |