CN106045891A - Process for preparing (S)-1-(2-chloroacetyl chloride)-2-nitrile pyrrolidine - Google Patents
Process for preparing (S)-1-(2-chloroacetyl chloride)-2-nitrile pyrrolidine Download PDFInfo
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- CN106045891A CN106045891A CN201610519176.7A CN201610519176A CN106045891A CN 106045891 A CN106045891 A CN 106045891A CN 201610519176 A CN201610519176 A CN 201610519176A CN 106045891 A CN106045891 A CN 106045891A
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- Prior art keywords
- acetonitrile
- itrile group
- chloracetyl chloride
- pyrrolidine
- technique
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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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Chemical & Material Sciences (AREA)
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- Pyrrole Compounds (AREA)
Abstract
The invention discloses a process for preparing (S)-1-(2-chloroacetyl chloride)-2-nitrile pyrrolidine. Acetonitrile is used as a main solvent system, or solvent systems comprise acetonitrile and toluene combinations and acetonitrile and DMF (dimethyl formamide) combinations or acetonitrile and THF (tetrahydrofuran) combinations; carbonate is used as an acid binding agent; trifluoro acetic anhydride (TFAA) or phosphorus oxychloride is used as a dehydrating agent. The process includes preparing (S)-1-(2-chloroacetyl chloride)-2-nitrile pyrrolidine intermediates from L-prolinamide via two-step reaction by the aid of a one-pot method. The process has the advantages of convenience, speediness and high yield.
Description
Technical field
The present invention relates to pharmaceutical technology field, particularly relate to one and prepare (S)-1-(2-chloracetyl chloride)-2-itrile group pyrrole
The technique coughing up alkane.
Background technology
Diabetes are the metabolic syndromes jointly being acted on initiation by h and E factor, and human insulin can be caused absolute
With relative hyposecretion, causing internal sugar, protein, the metabolism disorder such as fat, is a kind of to the biggest slow of human health risk
Property disease.
Vildagliptin (English: Vildagliptin), it is happy that trade name is preferred dimension, be one have selectivity, competitiveness, can
Inverse DPP-4 (dipeptidyl peptidase-4) inhibitor class oral antidiabetic, is used for treating type ii diabetes.It it is unique a kind of nothing
Opinion can the material of glucagon suppression when hyperglycemia or hypoglycemia.
On JIUYUE 28th, 2007, the vildagliptin (vildagliptin, trade name: Galvus) of Novartis Co., Ltd obtains European Union
Committee ratifies, and lists with Ireland in 27 European Union member countries and Norway.
Within 2011, approval is at China's import vildagliptin tablet and vildagliptin and the compound preparation of metformin.
Galvus is that in same types of drug, unique one can be with metformin, the medicine that the antidiabetic drug such as thiazole two alkanone is used in combination.
Vildagliptin is that the researcher DdwinB.Villhauer of Novartis was when research adamantane derivative in 1998
Find.Chemistry entitled (S)-1-[[(3-hydroxyl-1-amantadine) amino] acetyl group] tetrahydro pyrrolidine-2-of vildagliptin
Formonitrile HCN, molecular formula C17H25N3O2, relative molecular mass is 303.4.
Containing a hand-type carbon atom in the chemical constitution of vildagliptin, what its study on the synthesis worked focuses on skeleton
Build and the introducing of hand-type carbon atom.Theoretical according to reverse reaction, vildagliptin can be divided into two fragments synthesize: (S)-1-
(2-chloracetyl chloride)-2-itrile group pyrrolidine (compound 1) and 3-amino-1-adamantane alcohol (compound 2), reaction equation is as follows:
Summary of the invention
It is an object of the invention to for technological deficiency present in prior art, and provide one to prepare (S)-1-(2-chlorine
Chloroacetic chloride) technique of-2-itrile group pyrrolidine.
Be the technical scheme is that one prepares (S)-1-(2-chloracetyl chloride)-2-nitrile by realizing the purpose of the present invention
The technique of base pyrrolidine, it is characterised in that comprise the following steps:
(1) by L-prolineamide, acid binding agent, join in dicyandiamide solution, control temperature and at 0-15 DEG C and stir, slowly drip
Add chloracetyl chloride；
(2), after dropping, recover to room temperature and continuously stirred；After the reaction completely of TLC point plate, sucking filtration, obtain filtrate；
(3) filtrate is stirred under the temperature conditions of 0-15 DEG C, is simultaneously added dropwise dehydrant；Continue at 25 DEG C after dropping
Stirring；
(4) after the reaction completely of TLC point plate, it is spin-dried for, is subsequently adding ethyl acetate, continue rotation steaming and take unnecessary dehydration out of
Agent；The most repeated multiple times, dissolve the residue in ethyl acetate, be 8 with sodium carbonate liquor regulation pH value, organic facies saturated common salt
Water washs, and is dried with anhydrous sodium sulfate, filters, is spin-dried for, obtains grease；
(5) grease stands overnight, and obtains brown solid after solidification, is (S)-1-(2-chloracetyl chloride)-2-itrile group
Pyrrolidine crude product.
Dicyandiamide solution in described step (1) is acetonitrile, acetonitrile and toluene combination, acetonitrile and DMF combination or acetonitrile and THF
Combination；
Preferably, described dicyandiamide solution is acetonitrile.
Described acid binding agent is potassium carbonate, sodium carbonate or cesium carbonate.
Preferably, described acid binding agent is potassium carbonate.
Described dehydrant is trifluoroacetic anhydride (TFAA) or phosphorus oxychloride.
Preferably, described dehydrant is trifluoroacetic anhydride (TFAA).
The technique of preparation (S)-1-(2-the chloracetyl chloride)-2-itrile group pyrrolidine that the present invention provides use acetonitrile as master
Want dicyandiamide solution, or use acetonitrile and toluene combination, acetonitrile and DMF combination or acetonitrile and the dicyandiamide solution of THF combination；Carbonate
As acid binding agent；Trifluoroacetic anhydride (TFAA) or phosphorus oxychloride are as dehydrant；Set out with L-prolineamide for raw material, through two steps
Reacting, (S)-1-(2-chloracetyl chloride)-2-itrile group pyrrolidine intermediate is somebody's turn to do in one kettle way preparation, and technique is convenient, and yield is high.
Present invention also offers the purification process of one (S)-1-(2-chloracetyl chloride)-2-itrile group pyrrolidine crude product, it is special
Levy and be, operate according to following steps:
Above-mentioned (S)-1-(2-chloracetyl chloride)-2-itrile group pyrrolidine solid is joined with esters as solute, ethers or hydrocarbon
Class is in the solution of solvent, raises solution temperature, and (S)-1-(2-chloracetyl chloride)-2-itrile group pyrrolidine solid is dissolved；Reduce
Temperature, has solid to separate out in solution, sucking filtration, is dried, obtains white solid and be (S)-1-(2-chloracetyl chloride)-2-nitrile after purification
Base pyrrolidine.
Described esters is ethyl acetate, propyl acetate or n-butyl acetate.
Described ethers is ether, methyl tertiary butyl ether(MTBE) or petroleum ether.
Described hydro carbons is normal hexane or normal heptane.
Preferably, described esters be solute, ethers or hydro carbons be the solution of solvent be ethyl acetate and methyl tertiary butyl ether(MTBE)
Solution.
Further, the volume ratio of described ethyl acetate and methyl tertiary butyl ether(MTBE) is 10:1-1:10.
Further, the volume ratio of described ethyl acetate and methyl tertiary butyl ether(MTBE) is 1:4.
The inventive principle of this purifying process is: use esters be solute, ethers or hydro carbons be that the solution system of solvent is carried out
Purification, on the premise of ensureing (S)-1-(2-chloracetyl chloride)-2-itrile group pyrrolidine yield, improves product purity further；Should
Purifying process on the premise of holistic cost reduces, can improve the quality of vildagliptin crude drug indirectly, reduces cost.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is described in further detail.Should be appreciated that described herein specifically
Embodiment only in order to explain the present invention, is not intended to limit the present invention.
The technique that one prepares (S)-1-(2-chloracetyl chloride)-2-itrile group pyrrolidine, it is characterised in that comprise the following steps:
(1) by L-prolineamide, acid binding agent, join in dicyandiamide solution, control temperature and at 0-15 DEG C and stir, slowly drip
Add chloracetyl chloride；
(2), after dropping, recover to room temperature and continuously stirred；After the reaction completely of TLC point plate, sucking filtration, obtain filtrate；
(3) filtrate is stirred under the temperature conditions of 0-15 DEG C, is simultaneously added dropwise dehydrant；Continue at 25 DEG C after dropping
Stirring；
(4) after the reaction completely of TLC point plate, it is spin-dried for, is subsequently adding ethyl acetate, continue rotation steaming and take unnecessary dehydration out of
Agent；The most repeated multiple times, dissolve the residue in ethyl acetate, be 8 with sodium carbonate liquor regulation pH value, organic facies saturated common salt
Water washs, and is dried with anhydrous sodium sulfate, filters, is spin-dried for, obtains grease；
(5) grease stands overnight, and obtains brown solid after solidification, is (S)-1-(2-chloracetyl chloride)-2-itrile group
Pyrrolidine crude product.
Dicyandiamide solution in described step (1) is acetonitrile, acetonitrile and toluene combination, acetonitrile and DMF combination or acetonitrile and THF
Combination；
Preferably, described dicyandiamide solution is acetonitrile.
Described acid binding agent is potassium carbonate, sodium carbonate or cesium carbonate.
Preferably, described acid binding agent is potassium carbonate.
Described dehydrant is trifluoroacetic anhydride (TFAA) or phosphorus oxychloride.
Preferably, described dehydrant is trifluoroacetic anhydride (TFAA).
The technique of preparation (S)-1-(2-the chloracetyl chloride)-2-itrile group pyrrolidine that the present invention provides use acetonitrile as master
Want dicyandiamide solution, or use acetonitrile and toluene combination, acetonitrile and DMF combination or acetonitrile and the dicyandiamide solution of THF combination；Carbonate
As acid binding agent；Trifluoroacetic anhydride (TFAA) or phosphorus oxychloride are as dehydrant；Set out with L-prolineamide for raw material, through two steps
Reacting, (S)-1-(2-chloracetyl chloride)-2-itrile group pyrrolidine intermediate is somebody's turn to do in one kettle way preparation, and technique is convenient, and yield is high.
Embodiment:
One prepares the technique of (S)-1-(2-chloracetyl chloride)-2-itrile group pyrrolidine, comprises the following steps: by L-prolyl
Amine (20g, 0.175mol), potassium carbonate (48g, 0.348mol) join in 400mL acetonitrile, are slowly added dropwise under 0-15 DEG C of stirring
16mL (0.21mol) chloracetyl chloride (time for adding 2-3 hour), after dropping, recovers stirred overnight at room temperature, and TLC point plate is anti-
Should completely after, sucking filtration, filtrate 0-15 DEG C stirring under drip 13.4mL (0.094mol) TFAA, after dropping, at 25 DEG C stir
Overnight, after the reaction completely of TLC point plate, it is spin-dried for, is subsequently adding the continuation rotation steaming of 20mL ethyl acetate and takes unnecessary TFAA out of, the most instead
Multiple 3 times, residue is dissolved in 150mL ethyl acetate, is 8 with sodium carbonate liquor regulation pH value, and organic facies saturated aqueous common salt washs,
Anhydrous sodium sulfate is dried, and filters, is spin-dried for, obtains grease, stand overnight, and solidification (if do not solidified, can add slightly before standing
Crystal seed), brown solid (compound 2) 12.2g, yield 92%.
Present invention also offers the purification process of one (S)-1-(2-chloracetyl chloride)-2-itrile group pyrrolidine crude product, according to
Following steps operate:
Above-mentioned (S)-1-(2-chloracetyl chloride)-2-itrile group pyrrolidine solid is joined with esters as solute, ethers or hydrocarbon
Class is in the solution of solvent, raises solution temperature, and (S)-1-(2-chloracetyl chloride)-2-itrile group pyrrolidine solid is dissolved；Reduce
Temperature, has solid to separate out in solution, sucking filtration, is dried, obtains white solid and be (S)-1-(2-chloracetyl chloride)-2-nitrile after purification
Base pyrrolidine.
Described esters is ethyl acetate, propyl acetate or n-butyl acetate.
Described ethers is ether, methyl tertiary butyl ether(MTBE) or petroleum ether.
Described hydro carbons is normal hexane or normal heptane.
Preferably, described esters be solute, ethers or hydro carbons be the solution of solvent be ethyl acetate and methyl tertiary butyl ether(MTBE)
Solution.
Further, the volume ratio of described ethyl acetate and methyl tertiary butyl ether(MTBE) is 10:1-1:10.
Further, the volume ratio of described ethyl acetate and methyl tertiary butyl ether(MTBE) is 1:4.
The inventive principle of this purifying process is: use esters be solute, ethers or hydro carbons be that the solution system of solvent is carried out
Purification, on the premise of ensureing (S)-1-(2-chloracetyl chloride)-2-itrile group pyrrolidine yield, improves product purity further；Should
Purifying process on the premise of holistic cost reduces, can improve the quality of vildagliptin crude drug indirectly, reduces cost.
Embodiment:
The purification process of a kind of (S)-1-(2-chloracetyl chloride)-2-itrile group pyrrolidine crude product, according to following operation: by above-mentioned
(S)-1-(2-chloracetyl chloride)-2-itrile group pyrrolidine crude product, i.e. brown solid 10g, join ethyl acetate and methyl-tert fourth
In the mixed solution of base ether, ethyl acetate, the volume ratio of methyl tertiary butyl ether(MTBE) are 1:4, and under 65 degrees Celsius, solid is dissolved；Fall
After low temperature, product is had to separate out, sucking filtration, it is dried, obtains white solid and be (S)-1-(2-chloracetyl chloride)-2-itrile group after purification
Pyrrolidine.After weighing, white solid quality is 8.5g, crystallization yield 85%.
The above is only the preferred embodiment of the present invention, it is noted that for the common skill of the art
For art personnel, under the premise without departing from the principles of the invention, it is also possible to make some improvements and modifications, these improvements and modifications
Also should be regarded as protection scope of the present invention.
Claims (7)
1. the technique preparing (S)-1-(2-chloracetyl chloride)-2-itrile group pyrrolidine, it is characterised in that comprise the following steps:
(1) by L-prolineamide, acid binding agent, join in dicyandiamide solution, control temperature and at 0-15 DEG C and stir, be slowly added dropwise chlorine
Chloroacetic chloride；
(2), after dropping, recover to room temperature and continuously stirred；After the reaction completely of TLC point plate, sucking filtration, obtain filtrate；
(3) filtrate is stirred under the temperature conditions of 0-15 DEG C, is simultaneously added dropwise dehydrant；Persistently stir at 25 DEG C after dropping
Mix；
(4) after the reaction completely of TLC point plate, it is spin-dried for, is subsequently adding ethyl acetate, continue rotation steaming and take unnecessary dehydrant out of；As
This is repeated multiple times, dissolves the residue in ethyl acetate, is 8 with sodium carbonate liquor regulation pH value, and organic facies saturated common salt is washed
Wash, be dried with anhydrous sodium sulfate, filter, be spin-dried for, obtain grease；
(5) grease stands overnight, and obtains brown solid after solidification, is (S)-1-(2-chloracetyl chloride)-2-itrile group pyrroles
Alkane crude product.
One the most according to claim 1 prepares the technique of (S)-1-(2-chloracetyl chloride)-2-itrile group pyrrolidine, its feature
The dicyandiamide solution being in described step (1) is acetonitrile, acetonitrile and toluene combination, acetonitrile and DMF combination or acetonitrile and THF group
Close.
One the most according to claim 1 prepares the technique of (S)-1-(2-chloracetyl chloride)-2-itrile group pyrrolidine, its feature
It is that described dicyandiamide solution is acetonitrile.
One the most according to claim 1 prepares the technique of (S)-1-(2-chloracetyl chloride)-2-itrile group pyrrolidine, its feature
It is that described acid binding agent is potassium carbonate, sodium carbonate or cesium carbonate.
One the most according to claim 1 prepares the technique of (S)-1-(2-chloracetyl chloride)-2-itrile group pyrrolidine, its feature
It is that described acid binding agent is potassium carbonate.
One the most according to claim 1 prepares the technique of (S)-1-(2-chloracetyl chloride)-2-itrile group pyrrolidine, its feature
It is that described dehydrant is trifluoroacetic anhydride or phosphorus oxychloride.
One the most according to claim 1 prepares the technique of (S)-1-(2-chloracetyl chloride)-2-itrile group pyrrolidine, its feature
It is that described dehydrant is trifluoroacetic anhydride.
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| CN201610519176.7A CN106045891A (en) | 2016-07-05 | 2016-07-05 | Process for preparing (S)-1-(2-chloroacetyl chloride)-2-nitrile pyrrolidine |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110563627A (en) * | 2019-09-24 | 2019-12-13 | 沧州那瑞化学科技有限公司 | Preparation method of (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile |
| CN113264863A (en) * | 2021-04-25 | 2021-08-17 | 合肥利夫生物科技有限公司 | Preparation method of (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile with high chiral purity |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105367470A (en) * | 2015-12-15 | 2016-03-02 | 天津民祥生物医药科技有限公司 | Method for preparing vildagliptin |
| CN105523985A (en) * | 2015-12-18 | 2016-04-27 | 天津民祥生物医药股份有限公司 | Preparation method of vildagliptin |
-
2016
- 2016-07-05 CN CN201610519176.7A patent/CN106045891A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105367470A (en) * | 2015-12-15 | 2016-03-02 | 天津民祥生物医药科技有限公司 | Method for preparing vildagliptin |
| CN105523985A (en) * | 2015-12-18 | 2016-04-27 | 天津民祥生物医药股份有限公司 | Preparation method of vildagliptin |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110563627A (en) * | 2019-09-24 | 2019-12-13 | 沧州那瑞化学科技有限公司 | Preparation method of (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile |
| CN113264863A (en) * | 2021-04-25 | 2021-08-17 | 合肥利夫生物科技有限公司 | Preparation method of (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile with high chiral purity |
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