CN105820102A - Oxiracetam synthesis technology - Google Patents
Oxiracetam synthesis technology Download PDFInfo
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- CN105820102A CN105820102A CN201610303419.3A CN201610303419A CN105820102A CN 105820102 A CN105820102 A CN 105820102A CN 201610303419 A CN201610303419 A CN 201610303419A CN 105820102 A CN105820102 A CN 105820102A
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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
- C07D207/18—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 one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—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 one double bond between ring members or between a ring member and a non-ring member 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones 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 other ring carbon atoms
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Abstract
The invention belongs to the field of pharmaceutical chemicals and particularly relates to an oxiracetam synthesis technology, ethyl acetoacetate and glycine are taken as the raw materials, the ethyl acetoacetate is changed into 4-halogeneated ethyl acetoacetate by halogenation reaction, the 4-halogeneated ethyl acetoacetate and glycine ester formed by the glycine are cyclized to form 2,4-dioxo-1-pyrrolidine acetate, and 4-hydroxy-2-oxo-1-pyrrolidineacetamide is obtained after hydrolysis and aminolysis. According to the oxiracetam synthesis technology, the related raw materials are easy to obtain, and the synthesis technology is simple and has good industrial values.
Description
Technical field
The invention belongs to field of medicine and chemical technology, be specifically related to the synthesis technique of oxiracetam.
Background technology
Oxiracetam, chemical entitled Esomeprazole, is the ring of a kind of hydroxy-amino-butyric acid (GABOB)
Shape derivant, for a new generation's nootropic agents, can promote Phosphorylcholine and phosphatidyl ethanolamine synthesis, promote brain metabolism, pass through
Blood brain barrier has stimulation to specificity nervus centralis road, improves intelligence and memory, is primarily adapted for use in treatment clinically forgetful
Disease, alzheimer disease, vascular dementia etc..Its structural formula is as follows:
In the synthetic route of the oxiracetam reported at present, patent CN1513836A is with 4-haloacetyl acetogenin for rising
Beginning raw material, the most hydrogenated after carrying out condensation reaction with the azide of alkali metal or alkaline-earth metal, cyclization, ammonification obtain target chemical combination
Thing.This route restores the raw material azide price into using in the method for amino after using Azide higher, explosive, is giving birth to
Product exists bigger potential safety hazard, and the hydroxyl of the intermediate after cyclization is without hydroxyl protection meeting when reacting with ethyl chloroacetate
Produce O-hydrocarbonylation by-product, make productivity reduce.Its synthetic route is as follows:
Patent JP53101367, with 4-amino-3 hydroxybutyric acid as initiation material, carries out hydroxyl with amino protecting agent hexamethyl two silicon nitrogen
Carry out ring-closure reaction after base protection, then after deprotection, ammonolysis reaction, obtain target product after the replacement of 2-bromoacetate.Should
One side initiation material in route is not easy to obtain, and amino protecting agent used is expensive, and production cost is higher；On the other hand
The protection of this route increase and the step of deprotection, make yield reduce.Its synthetic route is as follows:
Summary of the invention
Problem to be solved by this invention is to provide the synthesis technique processed of a kind of oxiracetam for above-mentioned prior art, for former
There is the route methods of preparation, it is proposed that a new synthetic route.
The present invention solves the synthesis technique of the technical scheme is that oxiracetam of above-mentioned technical problem, according to following technique road
Line is carried out:
1) ethyl acetoacetate III is mixed homogeneously with organic solvent, add halide reagent, low temperature halogenating reaction 2～8h, be passed through
The nitrogen 1～2h being dried, after being evaporated to constant weight, distills to obtain compound IV through decompression；
2) being mixed homogeneously with acylating reagent by alkylol, add glycine I, the system of finishing is warming up to 70 ± 5 DEG C of reactions 5～7h,
Concentrating under reduced pressure removes unnecessary solvent, and residue adds acetone stirring, filters, and filter cake is vacuum dried to obtain compound II；
3) previous step gained compound II is dissolved in organic solvent, control temperature-5～5 DEG C, adds acid binding agent stirring 1h,
Adding compound IV, be warming up to 60～120 DEG C, controlling pH is alkalescence, back flow reaction 6～12h, filtered while hot, filtrate decompression
Adding dichloromethane after being spin-dried for, wash with water for several times, organic facies anhydrous sodium sulfate is dried, and filters, is concentrated to give compound V；
4) control temperature-5～15 DEG C, previous step gained compound V is dissolved in alcohol, after adding hydroborating reagent, react 3h, reaction
With dilute hydrochloric acid tune pH to neutral after end, filtering, filtrate is directly dissolved in methanol after concentrating, control temperature 0～25 DEG C, is passed through
Reacting 4～5h after ammonia, concentrate, residue solvent recrystallization i.e. obtains compound VI；
Above-mentioned steps 1)-4) reaction equation is as follows:
In formula, R is C1-4Alkyl, X is Cl or Br.
By such scheme, step 1) described organic solvent is dichloromethane, chloroform, carbon tetrachloride, ether, benzene or petroleum ether
In any one；Described halide reagent is Cl2, bromine, any one in NBS or NCS.
By such scheme, step 1) mol ratio of described ethyl acetoacetate and halide reagent is 1:1.1～1.2.
By such scheme, step 1) described halogenating reaction controls temperature-5～5 DEG C.
By such scheme, step 2) mol ratio of described glycine and acylating reagent is 1:3, described acylating reagent and alkylol
Mass volume ratio is 1g:2.5～3ml.
By such scheme, step 2) described alkylol and acylating reagent incorporation time be 0.5～1.5h, controls temperature-5～5 DEG C, point
2～4 batches add glycine；Described residue mixing time in acetone is 5～8h.
By such scheme, step 3) described organic solvent is any in methanol, ethanol, acetone, toluene, DMF or acetonitrile
A kind of.
By such scheme, step 3) described acid binding agent be alkali metal or the carbonate of alkaline-earth metal, Feldalat NM, sodium hydroxide,
One or more mixing in triethylamine or pyridine；Controlling pH scope is 8-10.
By such scheme, step 3) mol ratio of described compound II and acid binding agent is 1:1.2～2.2, described compound II and change
The mol ratio of compound IV is 1:1.2～1.5.
By such scheme, step 4) described hydroborating reagent is alkali-metal boron hydride or lithium aluminium hydride reduction.
By such scheme, step 4) described recrystallization solvent is acetone, ethanol water or methanol aqueous solution.
The invention has the beneficial effects as follows: with ethyl acetoacetate and glycine as raw material, ethyl acetoacetate is 4-through halogenating reaction
Haloacetyl ethyl acetate, the glycinate cyclization formed with glycine generates 2, through hydrolysis after 4-dioxy-1-pyrrolidine acetic acid ester
Esomeprazole is obtained with ammonolysis, its route optimization process conditions, simple to operate, the raw material that relates to
Simple and easy to get, cost is relatively low, finally gives Esomeprazole through cyclization, hydrolysis and ammonolysis, has very
Good industrial value.
Detailed description of the invention
Below in conjunction with embodiment, the present invention will be further described.
Embodiment 1
A kind of preparation of Esomeprazole
1) preparation of 4-ethyl bromoacetoacetate: control temperature-5～5 DEG C, by ethyl acetoacetate 26.03g and dichloromethane 15mL
Mix homogeneously, dropwise dropping bromine 35.16g, insulation reaction 2h, be passed through dry nitrogen 1h, after being evaporated to constant weight, warp
Oil pump decompression distillation is collected the fraction of 85 DEG C and is obtained transparent oily liquid 4-ethyl bromoacetoacetate 38.69g, yield 92.54%；
2) preparation of glycine methyl ester hydrochloride: control temperature-5～5 DEG C, dropwise drops to absolute methanol by chloroacetic chloride 23.56g
In 60ml, dripping off rear insulation reaction 1h, point 2 crowdes of addition glycine 7.51g, the system of finishing is warming up to 70 DEG C of reaction 5h, decompression
Concentrating and remove unnecessary solvent, residue adds acetone 30ml and stirs 5h, filters, and filter cake is vacuum dried to obtain glycine methyl ester
Hydrochlorate 11.39g, yield 90.68%, fusing point 174-176 DEG C；
3) preparation of 2,4-dioxo-1-methyl pyrrolidineacetate: control temperature-5～5 DEG C, by step 2) the sweet ammonia of gained compound
Acid methyl ester hydrochloride salt 7.54g is dissolved in 25mL methanol, adds potassium carbonate powder 9.97g being dried, insulation reaction 1h, dropping step
Rapid 1) gained compound 4-bromo-acetoacetic ester 15.07g, controls pH 9, is gradually heating to 78 DEG C, back flow reaction 8h,
Filtered while hot, filtrate decompression adds 20mL dichloromethane after being spin-dried for, washs 3 times with water (20mL*3), and organic facies is with anhydrous
Sodium sulfate is dried, and filters, and filtrate is concentrated to give 2,4-dioxo-1-methyl pyrrolidineacetate 7.38g, yield 71.87%；
4) preparation of Esomeprazole: control temperature-5～5 DEG C, by step 3) gained compound 2,4-
Dioxo-1-methyl pyrrolidineacetate 6.85g is dissolved in 15mL methanol, reacts 3h, reaction knot after adding 1.51g sodium borohydride
Adjusting pH to neutral after bundle, filter, filtrate is directly dissolved in 15mL methanol after concentrating, and controls temperature 20 DEG C, is passed through ammonia extremely
Saturated, react 4h, concentrate and remove solvent, residue acetone recrystallization i.e. obtains compound 4-hydroxy base-2-OXo-1-pyrrolidine second
Amide 4.55g, yield 71.92%, fusing point 166-168 DEG C.
Embodiment 2
A kind of preparation of Esomeprazole
1) preparation of 4-ethyl bromoacetoacetate: control temperature-5～5 DEG C, by ethyl acetoacetate 30.03g and dichloromethane 15mL
Mix homogeneously, dropwise dropping bromine 44.24g, insulation reaction 2h, be passed through dry nitrogen 1h, after being evaporated to constant weight, warp
Oil pump decompression distillation is collected the fraction of 85 DEG C and is obtained transparent oily liquid 4-ethyl bromoacetoacetate 38.69g, yield 92.66%.
2) preparation of glycine ethyl ester: control temperature-5～5 DEG C, dropwise drops to chloroacetic chloride 23.56g in dehydrated alcohol 70ml,
Dripping off rear insulation reaction 1h, point 2 crowdes of addition glycine 7.51g, the system of finishing is warming up to 70 DEG C of reaction 5h, and concentrating under reduced pressure removes
Unnecessary solvent, residue adds acetone 40ml and stirs 5h, filters, and filter cake is vacuum dried to obtain glycine ethyl ester hydrochloride
12.42g, yield 88.98%, fusing point 142-144 DEG C.
3) preparation of 2,4-dioxo-1-pyrrolidine acetic acid ethyl ester: control temperature 0 ± 5 DEG C, by step 2) gained compound glycine
Carbethoxy hydrochloride 8.27g and sodium hydroxide 2.4g mix and blend 1h in methanol solution, adds compound 4-ethyl bromoacetoacetate
18.57g, adds the Feldalat NM 3.79g of brand-new, stirs 1h, is warming up to 60～120 DEG C, back flow reaction 6～12h, filtered while hot,
Filtrate decompression adds 20mL ethyl acetate after being spin-dried for, and washs 3 times with water (20mL*3), and organic facies anhydrous sodium sulfate is dried,
Filter, be concentrated to give compound 2,4-dioxo-1-pyrrolidine acetic acid ethyl ester 7.6g, yield 68.40%, fusing point 84-88 DEG C
4) preparation of Esomeprazole: control temperature-5～15 DEG C, by step 3) gained compound 2,4-
Dioxo-1-pyrrolidine acetic acid ethyl ester 7.40g is dissolved in 15mL methanol, reacts 3h, reaction knot after adding lithium aluminium hydride reduction 1.52g
Adjusting pH to neutral after bundle, filter, filtrate is directly dissolved in 15mL methanol after concentrating, and controls temperature 25 DEG C, after being passed through ammonia
Reaction 4h, concentrates, and residue ethanol water (ethanol: water=8:1) solution recrystallization i.e. obtains compound 4-hydroxy base-2-oxo-1-
Pyrrolidine acetamide 4.25g, yield 67.18%, fusing point 164-167 DEG C.
Claims (11)
1. the synthesis technique of oxiracetam, is carried out according to following process route:
1) ethyl acetoacetate III is mixed homogeneously with organic solvent, add halide reagent, low temperature halogenating reaction 2～8h, be passed through
The nitrogen 1～2h being dried, after being evaporated to constant weight, distills to obtain compound IV through decompression；
2) being mixed homogeneously with acylating reagent by alkylol, add glycine I, the system of finishing is warming up to 70 ± 5 DEG C of reactions 5～7h,
Concentrating under reduced pressure removes unnecessary solvent, and residue adds acetone stirring, filters, and filter cake is vacuum dried to obtain compound II；
3) previous step gained compound II is dissolved in organic solvent, control temperature-5～5 DEG C, adds acid binding agent stirring 1h,
Adding compound IV, be warming up to 60～120 DEG C, controlling pH is alkalescence, back flow reaction 6～12h, filtered while hot, filtrate decompression
Adding dichloromethane after being spin-dried for, wash with water for several times, organic facies anhydrous sodium sulfate is dried, and filters, is concentrated to give compound V；
4) control temperature-5～15 DEG C, previous step gained compound V is dissolved in alcohol, after adding hydroborating reagent, react 3h, reaction
With dilute hydrochloric acid tune pH to neutral after end, filtering, filtrate is directly dissolved in methanol after concentrating, control temperature 0～25 DEG C, is passed through
Reacting 4～5h after ammonia, concentrate, residue solvent recrystallization i.e. obtains compound VI；
Above-mentioned steps 1)-4) reaction equation is as follows:
In formula, R is C1-4Alkyl, X is Cl or Br.
Synthesis technique the most according to claim 1, it is characterised in that step 1) described organic solvent is dichloromethane, chlorine
Any one in imitative, carbon tetrachloride, ether, benzene or petroleum ether；Described halide reagent is Cl2, bromine, NBS or NCS
In any one.
Synthesis technique the most according to claim 1, it is characterised in that step 1) described ethyl acetoacetate and halide reagent
Mol ratio be 1:1.1～1.2.
Synthesis technique the most according to claim 1, it is characterised in that step 1) described halogenating reaction controls temperature-5～5 DEG C.
Synthesis technique the most according to claim 1, it is characterised in that step 2) described glycine and acylating reagent mole
It is 1g:2.5～3ml than the mass volume ratio for 1:3, described acylating reagent and alkylol.
Synthesis technique the most according to claim 1, it is characterised in that step 2) described alkylol is when mixing with acylating reagent
Between be 0.5～1.5h, control temperature-5～5 DEG C, points 2～4 batches add glycine；Described residue mixing time in acetone is 5～8h.
Synthesis technique the most according to claim 1, it is characterised in that step 3) described organic solvent be methanol, ethanol,
Any one in acetone, toluene, DMF or acetonitrile.
Synthesis technique the most according to claim 1, it is characterised in that step 3) described acid binding agent be alkali metal or alkaline earth gold
One or more mixing in the carbonate, Feldalat NM, sodium hydroxide, triethylamine or the pyridine that belong to；Control pH scope
For 8-10.
Synthesis technique the most according to claim 1, it is characterised in that step 3) described compound II and acid binding agent mole
It is 1:1.2～1.5 than the mol ratio for 1:1.2～2.2, described compound II and compound IV.
Synthesis technique the most according to claim 1, it is characterised in that step 4) described hydroborating reagent is alkali-metal boron
Hydride or lithium aluminium hydride reduction.
11. synthesis techniques according to claim 1, it is characterised in that step 4) described recrystallization solvent is acetone, second
Alcohol-water solution or methanol aqueous solution.
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| CN201610303419.3A CN105820102A (en) | 2016-05-10 | 2016-05-10 | Oxiracetam synthesis technology |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106349144A (en) * | 2016-08-30 | 2017-01-25 | 山东默得森生物制药有限公司 | Preparation method of (S)-oxiracetam intermediate |
| CN106366031A (en) * | 2016-08-30 | 2017-02-01 | 山东默得森生物制药有限公司 | Preparation method of (S)-4-hydroxy-2-oxo-1-pyrrolidinyl acetamide |
| CN111348992A (en) * | 2020-04-13 | 2020-06-30 | 北京富百科生物技术有限公司 | Novel method for synthesizing 1-bromo-2, 2-dimethoxypropane |
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| US4118396A (en) * | 1975-08-13 | 1978-10-03 | I.S.F. S.P.A. | Pyrrolidine derivatives |
| US4824966A (en) * | 1985-09-24 | 1989-04-25 | Lonza Ltd. | Process for the production of 4-hydroxy-2-oxo-pyrrolidin-1-yl acetamide |
| US5276164A (en) * | 1990-06-26 | 1994-01-04 | Lonza Ltd. | Process for the production of 4-hydroxy-2-oxopyrrolidin-1-yl-acetamide |
| CN102134212A (en) * | 2010-01-27 | 2011-07-27 | 重庆圣华曦药业股份有限公司 | Preparation method of Oxiracetam |
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| CN104725294A (en) * | 2015-03-25 | 2015-06-24 | 浙江工业大学 | Novel method for synthesizing oxiracetam key intermediate ethyl 2-(2, 4-dioxopyrrolidine-1-yl) acetate |
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| US4118396A (en) * | 1975-08-13 | 1978-10-03 | I.S.F. S.P.A. | Pyrrolidine derivatives |
| US4824966A (en) * | 1985-09-24 | 1989-04-25 | Lonza Ltd. | Process for the production of 4-hydroxy-2-oxo-pyrrolidin-1-yl acetamide |
| US5276164A (en) * | 1990-06-26 | 1994-01-04 | Lonza Ltd. | Process for the production of 4-hydroxy-2-oxopyrrolidin-1-yl-acetamide |
| CN102134212A (en) * | 2010-01-27 | 2011-07-27 | 重庆圣华曦药业股份有限公司 | Preparation method of Oxiracetam |
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| 李柏娜 等: "奥拉西坦合成方法研究", 《沈阳化工大学学报》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106349144A (en) * | 2016-08-30 | 2017-01-25 | 山东默得森生物制药有限公司 | Preparation method of (S)-oxiracetam intermediate |
| CN106366031A (en) * | 2016-08-30 | 2017-02-01 | 山东默得森生物制药有限公司 | Preparation method of (S)-4-hydroxy-2-oxo-1-pyrrolidinyl acetamide |
| CN111348992A (en) * | 2020-04-13 | 2020-06-30 | 北京富百科生物技术有限公司 | Novel method for synthesizing 1-bromo-2, 2-dimethoxypropane |
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