CN105315190A - Method of preparing pyrrolidone acetate - Google Patents
Method of preparing pyrrolidone acetate Download PDFInfo
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- CN105315190A CN105315190A CN201410315197.8A CN201410315197A CN105315190A CN 105315190 A CN105315190 A CN 105315190A CN 201410315197 A CN201410315197 A CN 201410315197A CN 105315190 A CN105315190 A CN 105315190A
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Abstract
The invention discloses a method of preparing pyrrolidone acetate, which includes the following steps: a) performing a condensation reaction to 4-amino butyryl halide and halogenated acetate in a non-polar solvent containing alkali to obtain amino acetate; and b) performing a lactamization cyclization reaction to the amino acetate in a polar aprotic solvent containing alkali to obtain the pyrrolidone acetate. The synthetic route is represented as follows, wherein X is chlorine, bromine or iodine; R is a phenyl group, a benzyl group or a straight-chain alkyl group being 1-3 in carbon number. The method is simple in operations, is mild in reaction conditions, is low in requirement on devices, employs raw material being low in cost and easy to obtain, is low in cost, is easy to carry out in large scale, satisfies production demands of preparing the pyrrolidone acetate industrially and has industrial application value.
Description
Technical field
The present invention relates to a kind of method preparing pyrrolidone acetic ester, belong to technical field of organic chemistry.
Background technology
Pyrrolidone acetic ester is the important intermediate of synthesis piracetam (CAS:7491-74-9), plays decisive role to product piracetam cost.Piracetam; have another name called piracetam, piracetam, Piracetam, Acetamidopyrrolidinone, nootropyl, Piracetam, compare pyrrolidone than ethanamide, acid amides; for the congener of aminobutyric acid; there is activation, protect and repair the effect of brain cell; cerebral anoxia, activation brain cell can be improved, improve ATP/ADP ratio in brain; promote the absorption of amino acid and phosphide, protein synthesis and the utilization of glucose and the storage of energy, promote brain metabolism, increase cerebral blood flow (CBF).Can accelerate through callosal information transmission speed between hemicerebrum, improve the ability of learning and memory and thinking activities.
In prior art, the preparation method about pyrrolidone acetic ester mainly contains following several:
1, pyrrolidone and ethyl chloroacetate synthesis method (Knight, DavidW, JournaloftheChemicalSociety, PerkinTransactions1:OrganicandBio-OrganicChemistry, (22), 3673 ~ 3684; 1998): take pyrrolidone as starting raw material, with ethyl chloroacetate in toluene, add sodium bits and carry out linked reaction.This method need be considered to be worth doing with inflammable sodium, and environmental pollution is comparatively large, and operational hazards, is not suitable for industrialization production requirements.
2, pyrrolidone and ethyl bromoacetate synthesis method (Kramarova, ZhurnalObshcheiKhimii, 58 (5), 1093 ~ 1092; 1988): take pyrrolidone as starting raw material and ethyl bromoacetate at benzene and DMSO as under solvent condition, add potassium hydroxide and carry out linked reaction.This method uses a kind solvent benzene and the higher DMSO of boiling point, and aftertreatment distillation is difficult to operation, and toxicity is excessive, and environmental pollution is comparatively large, and yield is lower, is also not suitable for industrialization production requirements.
3, halogenated pyrrole alkane ketone ethyl acetate grignard hydrolysis method (Hua, WentingandCai, Chaozhong, FamingZhuanliShenqingGongkaiShuomingshu, 1105357,19Jul1995): with halogenated pyrrole alkane ketone ethyl acetate for raw material, exchange hydrolysis again by grignard and obtain pyrrolidone ethyl acetate.This method need preparation more un-come-at-able halogenated pyrrole alkane ketone ethyl acetate, and grignard reaction conditional request is harsher to external world, produce more difficult realization, yield is very low, is more not suitable for industrialization production requirements.
4, pentanedioic acid prepare pyrrolidone again with ethyl bromoacetate synthesis method (Hua, WentingandCai, Chaozhong, ZhuanliShenqingGongkaiShuomingshu, 1105357,19Jul1995): take pentanedioic acid as starting raw material, Pyroglutaric acid is generated with acetic anhydride, react with ammoniacal liquor again and prepare glutarimide, 4-Aminobutanoicacid is obtained again with sodium hydroxide-aqueous sodium hypochlorite solution open loop, finally close ring in reflux in toluene and obtain pyrrolidone, subsequent operations is similar to method 2.This method is higher to equipment requirements, and the total recovery of reaction is too low, is not suitable for suitability for industrialized production.
Summary of the invention
The problems referred to above existed for prior art and defect, the object of this invention is to provide a kind of method preparing pyrrolidone acetic ester, to meet the requirement of preparation of industrialization pyrrolidone acetic ester better.
For achieving the above object, the present invention adopts following technical scheme:
Prepare a method for pyrrolidone acetic ester, comprise the steps:
A) make 4-aminobutyryl halogen and halogenated acetic acids ester carry out condensation reaction in containing the non-polar solvent of alkali, obtain aminoacetate;
B) make aminoacetate carry out lactamize ring closure reaction in containing the polar aprotic solvent of alkali, namely obtain pyrrolidone acetic ester;
Its synthetic route is as follows:
Wherein: X is chlorine, bromine or iodine; R is the straight-chain paraffin base of phenyl, benzyl or C1 ~ C3.
Described 4-aminobutyryl halogen is preferably 4-aminobutyryl chlorine; Described halogenated acetic acids ester is preferably methyl bromoacetate or bromoethyl acetate.
Described non-polar solvent can be methylene dichloride, ethyl acetate or toluene, is preferably methylene dichloride.
Condensation reaction alkali used be selected from metal hydride, metal alkoxide, organic bases any one, can be sodium hydride, hydrolith, sodium methylate, sodium ethylate, triethylamine or pyridine, be preferably triethylamine.
Setting-up point is preferably-5 ~ 0 DEG C.
Described polar aprotic solvent can be tetrahydrofuran (THF), dimethyl formamide, dimethyl sulfoxide (DMSO), N,N-dimethylacetamide or hexamethylphosphoramide, is preferably tetrahydrofuran (THF).
Lactamize ring closure reaction alkali used can be selected from 1,8-diazabicyclo [5.4.0] 11-7-carbene (DBU), DMAP (DMAP), nitrogen methylmorpholine or tetramethyl guanidine (TMG), be preferably DBU.
Lactamize ring closure reaction is preferably back flow reaction.
Compared with prior art, the present invention has following significance progress:
1, simple to operate, reaction conditions is gentle, low for equipment requirements;
2, raw materials used cheap and easy to get, and solvent for use can realize synchronous recovery;
3, environmental pollution is little, and yield is high, is suitable for suitability for industrialized production;
In a word, adopt the inventive method can meet the requirement of industrialized mass production pyrrolidone acetic ester better, there is significance industrial application value.
Embodiment
Do to illustrate in detail, intactly further to technical scheme provided by the invention below in conjunction with embodiment.
Embodiment 1: prepare pyrrolidone ethyl acetate
One, synthesizing amino ethyl acetate
121.6g (1.0mol) 1-aminopropan acyl chlorides, 111.1g (1.1mol) triethylamine and 600mL methylene dichloride is added in the there-necked flask that 1000mL is dry, clean, be stirred to clearly molten, be cooled to-5 ~ 0 DEG C, drip the mixing solutions of ethyl bromoacetate 183.7g (1.1mol) and 200mL methylene dichloride, drip and finish, maintain-5 ~ 0 DEG C of reaction 3 hours, as TLC, to track to 1-aminopropan acyl chloride reaction complete, drip 2N hydrochloric acid soln adjust ph to 6.5 ~ 7.0, be separated organic layer, water layer dichloromethane extraction 2 times, each 200mL; Merge organic layer, add 400mL water washing, organic layer adds 50g anhydrous sodium sulfate drying 2 hours, filters, and in 35 ~ 40 DEG C of underpressure distillation to cutout, namely obtain pale yellow oil: ethyl aminoacetate, be weighed as 163.5g, molar yield is 86.4%.
Two, synthesis of pyrrolidine ketone ethyl acetate
In the there-necked flask that 500mL is dry, clean, add 94.6g ethyl aminoacetate (0.5mol), 60.6g (0.6mol) nitrogen methylmorpholine and 400mL tetrahydrofuran (THF), be warming up to back flow reaction 16 hours; React completely when TLC tracks to ethyl aminoacetate, be evaporated to cutout in 60 DEG C, in the oily matter obtained, add 300mL ethyl acetate and 200mL purified water, stir layering, water layer adds extraction into ethyl acetate 2 times, each 100mL, merges organic layer, add 30g anhydrous sodium sulfate drying 2 hours, filter, be evaporated to dry in 40 ~ 50 DEG C, namely obtain pale yellow oil: pyrrolidone ethyl acetate, be weighed as 71.2g, molar yield is 83.2%.
Embodiment 2: prepare pyrrolidone methyl acetate
One, synthesizing amino methyl acetate
121.6g (1.0mol) 1-aminopropan acyl chlorides, 111.1g (1.1mol) triethylamine and 600mL methylene dichloride is added in the there-necked flask that 1000mL is dry, clean, be stirred to clearly molten, be cooled to-5 ~ 0 DEG C, drip the mixing solutions of methyl bromoacetate 168.3g (1.1mol) and 200mL methylene dichloride, drip and finish, maintain-5 ~ 0 DEG C of reaction 3 hours, as TLC, to track to 1-aminopropan acyl chloride reaction complete, drip 2N hydrochloric acid soln adjust ph to 6.5 ~ 7.0, be separated organic layer, water layer dichloromethane extraction 2 times, each 200mL; Merge organic layer, add 400mL water washing, organic layer adds 50g anhydrous sodium sulfate drying 2 hours, filters, and in 35 ~ 40 DEG C of underpressure distillation to cutout, namely obtain pale yellow oil: methyl aminoacetate, be weighed as 150.3g, molar yield is 85.8%.
Two, synthesis of pyrrolidine ketone methyl acetate
In the there-necked flask that 500mL is dry, clean, add 87.5g methyl aminoacetate (0.5mol), 60.6g (0.6mol) nitrogen methylmorpholine and 400mL tetrahydrofuran (THF), be warming up to back flow reaction 16 hours; React completely when TLC tracks to methyl aminoacetate, be evaporated to cutout in 60 DEG C, in the oily matter obtained, add 300mL ethyl acetate and 200mL purified water, stir layering, water layer adds extraction into ethyl acetate 2 times, each 100mL, merges organic layer, add 30g anhydrous sodium sulfate drying 2 hours, filter, be evaporated to dry in 40 ~ 50 DEG C, namely obtain pale yellow oil: pyrrolidone methyl acetate, be weighed as 65.0g, molar yield is 82.7%.
Finally be necessary described herein:
Above embodiment is only for being described in further detail technical scheme of the present invention; can not be interpreted as limiting the scope of the invention, some nonessential improvement that those skilled in the art's foregoing according to the present invention is made and adjustment all belong to protection scope of the present invention.
Claims (10)
1. prepare a method for pyrrolidone acetic ester, it is characterized in that, comprise the steps:
A) make 4-aminobutyryl halogen and halogenated acetic acids ester carry out condensation reaction in containing the non-polar solvent of alkali, obtain aminoacetate;
B) make aminoacetate carry out lactamize ring closure reaction in containing the polar aprotic solvent of alkali, namely obtain pyrrolidone acetic ester;
Its synthetic route is as follows:
Wherein: X is chlorine, bromine or iodine; R is the straight-chain paraffin base of phenyl, benzyl or C1 ~ C3.
2. the method for claim 1, is characterized in that: described 4-aminobutyryl halogen is 4-aminobutyryl chlorine.
3. the method for claim 1, is characterized in that: described halogenated acetic acids ester is methyl bromoacetate or bromoethyl acetate.
4. the method for claim 1, is characterized in that: described non-polar solvent is methylene dichloride, ethyl acetate or toluene.
5. the method for claim 1, is characterized in that: condensation reaction alkali used be selected from metal hydride, metal alkoxide, organic bases any one.
6. method as claimed in claim 5, is characterized in that: condensation reaction alkali used is sodium hydride, hydrolith, sodium methylate, sodium ethylate, triethylamine or pyridine.
7. the method for claim 1, is characterized in that: setting-up point is-5 ~ 0 DEG C.
8. the method for claim 1, is characterized in that: described polar aprotic solvent is tetrahydrofuran (THF), dimethyl formamide, dimethyl sulfoxide (DMSO), N,N-dimethylacetamide or hexamethylphosphoramide.
9. the method for claim 1, is characterized in that: lactamize ring closure reaction alkali used is selected from 1,8-diazabicyclo [5.4.0] 11-7-carbene, DMAP, nitrogen methylmorpholine or tetramethyl guanidine.
10. the method for claim 1, is characterized in that: lactamize ring closure reaction is back flow reaction.
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| CN201410315197.8A CN105315190A (en) | 2014-07-03 | 2014-07-03 | Method of preparing pyrrolidone acetate |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110386891A (en) * | 2018-04-23 | 2019-10-29 | 新发药业有限公司 | A kind of preparation method of imrecoxib |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1105357A (en) * | 1994-01-13 | 1995-07-19 | 北京大学 | Process for synthesizing alpha-pyrrolidone acetamide |
| CN102459165A (en) * | 2009-04-15 | 2012-05-16 | 雅培制药有限公司 | Anti-viral compounds |
| CN102718691A (en) * | 2012-07-20 | 2012-10-10 | 上海现代哈森（商丘）药业有限公司 | Novel piracetam synthetic method |
| CN103553999A (en) * | 2013-11-06 | 2014-02-05 | 重庆润泽医药有限公司 | Preparation method of (S)-oxiracetam crystal form III |
-
2014
- 2014-07-03 CN CN201410315197.8A patent/CN105315190A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1105357A (en) * | 1994-01-13 | 1995-07-19 | 北京大学 | Process for synthesizing alpha-pyrrolidone acetamide |
| CN102459165A (en) * | 2009-04-15 | 2012-05-16 | 雅培制药有限公司 | Anti-viral compounds |
| CN102718691A (en) * | 2012-07-20 | 2012-10-10 | 上海现代哈森（商丘）药业有限公司 | Novel piracetam synthetic method |
| CN103553999A (en) * | 2013-11-06 | 2014-02-05 | 重庆润泽医药有限公司 | Preparation method of (S)-oxiracetam crystal form III |
Non-Patent Citations (3)
| Title |
|---|
| DANSHU YAO等: "Synthesis and Mesomorphism of Novel Star-shaped Liquid Crystals Containing Donor-Acceptor Groups", 《APPLIED MECHANICS AND MATERIALS》 * |
| PAUL DANIEL SIMONCIC: "Application of Hetero Diels-Alder Methodology Towards the Synthesis of Martinelline 编号：1150011", 《SEL. ORG. REACT. DATABASE》 * |
| 金晓峰等: "奥拉西坦的合成工艺改进", 《化学工程与装备》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110386891A (en) * | 2018-04-23 | 2019-10-29 | 新发药业有限公司 | A kind of preparation method of imrecoxib |
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