CN105524001A - Preparation method of N, N'-carbonyl-bis-(4-ethyl-2, 3-dioxopiperazine) - Google Patents
Preparation method of N, N'-carbonyl-bis-(4-ethyl-2, 3-dioxopiperazine) Download PDFInfo
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- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
- C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
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Abstract
The invention discloses a preparation method of N, N'-carbonyl-bis-(4-ethyl-2, 3-dioxopiperazine). 4-ethyl-2, 3-dioxopiperazine as a raw material and metallic sodium undergo a reaction to produce a sodium salt of 4-ethyl-2, 3-dioxopiperazine and the sodium salt and triphosgene undergo a reaction in the presence of a catalyst to produce N, N'-carbonyl-bis-(4-ethyl-2, 3-dioxopiperazine). 4-ethyl-2, 3-dioxopiperazine as a raw material and metallic sodium as a hydrogen removal reagent undergo a reaction to produce a sodium salt of 4-ethyl-2, 3-dioxopiperazine so that trimethylchlorosilane use is avoided, side reactions are less, product purity is high, a large amount of siliceous waste water is not produced, a post-treatment cost is saved and a three-waste treatment cost is greatly reduced. The preparation method has simple processes and a simple route, satisfies clean production requirements and is suitable for industrialization.
Description
Technical field
The present invention relates to a kind of preparation method of HO-EPCP intermediate, be specifically related to the preparation method of a kind of N, N'-carbonic acyl radical-bis--(4-ethyl-2,3-dioxygen ethylene imine), belong to technical field of organic synthesis.
Background technology
Cynnematin is the representative of third generation cephalosporin analog antibiotic; broad-spectrum antimicrobial; for the first-line drug of anti Bacillus pyocyaneu Flugge; international and domestic all there is huge market; N; N'-carbonic acyl radical-bis--(4-ethyl-2,3-dioxygen ethylene imine) and D (-)-D-pHPG condensation can prepare the important intermediate HO-EPCP of cefoperazone (cefobid), piperacillin sodium.About HO-EPCP synthesis mainly with N-ethyl-2; 3-dioxygen ethylene imine acyl chlorides (being abbreviated as EOCP) route report is in the majority; as CN101508679B, CN1446807A, JP59036668A, DE215194001, GB15008062 all report with N-ethyl dioxygen ethylene imine and triphosgene as raw material; there is formylation reaction under existing prepare N-ethyl dioxygen ethylene imine acyl chlorides (hereinafter referred to as dioxygen ethylene imine acyl chlorides) at trimethylchlorosilane, triethylamine; obtain the processing method of HO-EPCP with D-pHPG condensation again, operational path is as follows:
There are problems in above-mentioned route: 1, uses a large amount of triphosgene and trimethylchlorosilane to be raw material, dioxygen ethylene imine acyl chlorides facile hydrolysis, need operating environment strictly anhydrous; 2, dioxygen ethylene imine acyl chlorides instability and activity are comparatively strong, and therefore reaction needs low temperature to carry out; 3, dioxygen ethylene imine acyl chlorides is difficult to separation and Extraction, causes by-product to increase, and adds the corresponding equipment of aftertreatment and power facility.
Research finds N; N'-carbonic acyl radical-bis--(4-ethyl-2; 3-dioxygen ethylene imine) with D (-)-D-pHPG react prepare HO-EPCP time; one of them dioxygen ethylene imine that carbonic acyl radical is connected is easy to leave away; and character comparatively dioxygen ethylene imine acyl chlorides stable in properties, do not need anhydrous condition, product purity high, therefore N; N'-carbonic acyl radical-bis--(4-ethyl-2,3-dioxygen ethylene imine) is the HO-EPCP intermediate more outstanding than dioxygen ethylene imine acyl chlorides.
At present about N; N'-carbonic acyl radical-bis--(4-ethyl-2; 3-dioxygen ethylene imine) report all with 4-ethyl-2; 3-dioxygen ethylene imine reacts to prepare (reacting as follows) with phosgene or its surrogate triphosgene under trimethylchlorosilane protection; as EP0317484; the method uses a large amount of trimethylchlorosilane equally, and produce a large amount of containing rule waste water, advantage is not obvious compared with acid chloride route.
Summary of the invention
For the deficiency of existing preparation method, the invention provides the preparation method of a kind of N, N'-carbonic acyl radical-bis--(4-ethyl-2,3-dioxygen ethylene imine), the method is simple to operate, and route is succinct, and three wastes generation is little, is suitable for suitability for industrialized production.
The concrete technical scheme of the present invention is as follows:
A kind of N; N'-carbonic acyl radical-bis--(4-ethyl-2; 3-dioxygen ethylene imine) preparation method, with 4-ethyl-2,3-dioxygen ethylene imine for raw material; itself and sodium Metal 99.5 are reacted to obtain 4-ethyl-2; 3-dioxygen ethylene imine sodium salt, gained sodium salt reacts with triphosgene in the presence of a catalyst, obtains N; N'-carbonic acyl radical-bis--(4-ethyl-2,3-dioxygen ethylene imine).
The present invention with 4-ethyl-2,3-dioxygen ethylene imine as raw material, using sodium Metal 99.5 as stripping hydrogen reagent, first 4-ethyl-2 is made, 3-dioxygen ethylene imine forms sodium salt, and then this sodium salt is direct and triphosgene is reacted and generated bisamide under catalyst action, and by-product only has sodium-chlor.This operational path avoids the drawback using trimethylchlorosilane to bring, and side reaction is few, and the three wastes are few, and products obtained therefrom purity is high.No matter be from atom utilization, production cost, or from " three wastes " generation aspect, the inventive method is all better than dioxygen ethylene imine acyl trimethylchlorosilane technique, has more industrialization advantage.
Reaction equation of the present invention is as follows:
In above-mentioned preparation method, the ratio of the amount of substance of sodium Metal 99.5 and 4-ethyl-2,3-dioxypiperazine piperazine is 0.95 ~ 1:1, preferably: 1:1.
In above-mentioned preparation method, 4-ethyl-2,3-dioxygen ethylene imine and sodium Metal 99.5 react in organic solvent.Described solvent is glycol dimethyl ether, dioxane or toluene.
In above-mentioned preparation method, organic solvent provides the environment of sodium Metal 99.5 and the reaction of 4-ethyl-2,3-dioxygen ethylene imine, and its consumption can adjust according to actual needs.
In above-mentioned preparation method, 4-ethyl-2,3-dioxygen ethylene imine and sodium Metal 99.5 react at 25 ~ 83 DEG C, temperature of reaction is higher, reaction times is shorter, preferably reacts under solvent reflux temperature, and backflow can promote 4-ethyl-2, the carrying out of H-H reaction shelled by 3-dioxygen ethylene imine and sodium Metal 99.5, shortens process cycle.When selecting optimum organic solvent glycol dimethyl ether, reflux temperature is 83 DEG C.
In above-mentioned preparation method, the catalyzer that 4-ethyl-2,3-dioxygen ethylene imine sodium salt and triphosgene are reacted is imidazoles or triethylamine, preferred imidazoles.
In above-mentioned preparation method, the ratio of the amount of substance of catalyzer and 4-ethyl-2,3-dioxypiperazine piperazine is 0.01 ~ 0.1:1, considers comprehensive cost, preferred 0.01:1.
In above-mentioned preparation method, the ratio of the amount of substance of triphosgene and 4-ethyl-2,3-dioxypiperazine piperazine is 1:6 ~ 6.6, preferred 1:6.
In above-mentioned preparation method, consider the problems of dissolution of triphosgene, first triphosgene is dissolved into wiring solution-forming in glycol dimethyl ether, and then adds in reaction system.
In above-mentioned preparation method, in order to control temperature of reaction, triphosgene preferably adds in batches.
In above-mentioned preparation method, 4-ethyl-2,3-dioxygen ethylene imine sodium salt and triphosgene are reacted at-15 ~ 15 DEG C, preferably react at 5 DEG C.
In above-mentioned preparation method, specifically comprise the following steps: 4-ethyl-2,3-dioxygen ethylene imine is joined in organic solvent, then adds sodium Metal 99.5, be warming up to temperature of reaction and react; After completion of the reaction system is cooled to-15 ~ 15 DEG C, adds ethylene glycol dimethyl ether solution and the catalyzer of triphosgene, react to obtain N, N'-carbonic acyl radical-bis--(4-ethyl-2,3-dioxygen ethylene imine) at this temperature.
In above-mentioned preparation method; after reaction terminates, end reaction liquid is carried out following process: by reaction solution concentrated removing organic solvent, add recrystallization reagent and again dissolve; cross and filter insolubles (byproduct sodium chloride and unreacted 4-ethyl-2; 3-dioxygen ethylene imine), then by filtrate activated carbon decolorizing, concentrated crystallization after decolouring; collect crystal, drying; obtain N, N'-carbonic acyl radical-bis--(4-ethyl-2,3-dioxygen ethylene imine) product.
In above-mentioned preparation method, recrystallization reagent is ethanol, Virahol, isopropylcarbinol, preferred Virahol.
The present invention for raw material, adopts sodium Metal 99.5, as stripping hydrogen reagent, dioxygen ethylene imine is become sodium salt with 4-ethyl-2,3-dioxygen ethylene imine, stop the use of trimethylchlorosilane completely, side reaction is few, and product purity is high, does not produce a large amount of silicon-containing wastewater, save aftertreatment cost, greatly reduce disposal of waste gas, water and industrial residue cost, simple to operate, route is succinct, meet cleanly production aim, be more suitable for industrialization.
Embodiment
Below by embodiment, the present invention being further elaborated, it is to be understood that following explanation is only to explain the present invention, its content not being limited.
The present invention's raw material used all can commercially be buied.
embodiment 1
Triphosgene solution configures: 9.9g triphosgene be dissolved in 100ml glycol dimethyl ether, and add 0.7g imidazoles, be stirred to complete molten stand-by.
Glycol dimethyl ether 500ml is added successively in 1L there-necked flask, 4-ethyl-2, 3-dioxygen ethylene imine 28.4g, stir, add sodium Metal 99.5 4.6g, be heated to backflow, after reaction 10h, be cooled to 5 DEG C, add the triphosgene solution configured under stirring in batches, control temperature of reaction and be no more than 10 DEG C, finish and continue stirring reaction 10h, vacuum concentration, except desolventizing, add 300ml Virahol, stir 30min, solids removed by filtration, filtrate adds activated carbon decolorizing, cross and filter gac, filter vacuum is spin-dried for, dry, obtain white solid, be N, N'-carbonic acyl radical-bis--(4-ethyl-2, 3-dioxygen ethylene imine) 59.6g, with 4-ethyl-2, the 3-dioxygen ethylene imine rate of collecting is 96.1%, HPLC measures purity 98.1%.
embodiment 2
Preparation method with embodiment 1, unlike: sodium Metal 99.5 amount used is 4.4g, and gained N, N'-carbonic acyl radical-bis--(4-ethyl-2,3-dioxygen ethylene imine) 53.1g, with 4-ethyl-2, the 3-dioxygen ethylene imine rate of collecting for 85.6%.HPLC measures purity 91.6%.
embodiment 3
Preparation method with embodiment 1, unlike: triphosgene amount used is 9g, and gained N, N'-carbonic acyl radical-bis--(4-ethyl-2,3-dioxygen ethylene imine) 53.0g, with the triphosgene rate of collecting for 95.1%.HPLC measures purity 98.3%.
embodiment 4
Preparation method with embodiment 1, unlike: triphosgene amount is 11.8g, and gained N, N'-carbonic acyl radical-bis--(4-ethyl-2,3-dioxygen ethylene imine) 49g, with 4-ethyl-2, the 3-dioxygen ethylene imine rate of collecting for 79.0%.HPLC measures purity 79.6%.
embodiment 5
Preparation method with embodiment 1, unlike: dioxygen ethylene imine sodium salt and triphosgene temperature of reaction are-15 DEG C, and gained N, N'-carbonic acyl radical-bis--(4-ethyl-2,3-dioxygen ethylene imine) 59g, with 4-ethyl-2, the 3-dioxygen ethylene imine rate of collecting for 95%.HPLC measures purity 98.5%.
embodiment 6
Preparation method with embodiment 1, unlike: use solvent for dioxane, gained N, N'-carbonic acyl radical-bis--(4-ethyl-2,3-dioxygen ethylene imine) 56.8g, with 4-ethyl-2, the 3-dioxygen ethylene imine rate of collecting for 91.6%.HPLC measures purity 97.1%.
embodiment 7
Preparation method with embodiment 1, unlike: dioxygen ethylene imine sodium salt and triphosgene temperature of reaction are 15 DEG C, and gained N, N'-carbonic acyl radical-bis--(4-ethyl-2,3-dioxygen ethylene imine) 52.5g, with 4-ethyl-2, the 3-dioxygen ethylene imine rate of collecting for 84.6%.HPLC measures purity 89.7%.
embodiment 8
Preparation method with embodiment 1, unlike: catalyzer is 1.5ml triethylamine, gained gained N, and N'-carbonic acyl radical-bis--(4-ethyl-2,3-dioxygen ethylene imine) 58.6g, with 4-ethyl-2, the 3-dioxygen ethylene imine rate of collecting for 95%.HPLC measures purity 95.9%.
embodiment 9
Preparation method with embodiment 1, unlike: dioxygen ethylene imine sodium salt and triphosgene reaction times are 3h.Gained N, N'-carbonic acyl radical-bis--(4-ethyl-2,3-dioxygen ethylene imine) 39.6g, with 4-ethyl-2, the 3-dioxygen ethylene imine rate of collecting for 63.8%.HPLC measures purity 93.9%.
embodiment 10
Preparation method, with embodiment 1, is dehydrated alcohol unlike aftertreatment solvent for use, and gained N, N'-carbonic acyl radical-bis--(4-ethyl-2,3-dioxygen ethylene imine) 32.1g, with 4-ethyl-2, the 3-dioxygen ethylene imine rate of collecting for 52.1%.HPLC measures purity 93.6%.
embodiment 11
Preparation method, with embodiment 1, is isopropylcarbinol unlike aftertreatment solvent for use, and gained N, N'-carbonic acyl radical-bis--(4-ethyl-2,3-dioxygen ethylene imine) 57g, with 4-ethyl-2, the 3-dioxygen ethylene imine rate of collecting for 92.3%.HPLC measures purity 98.0%.
embodiment 12
Preparation method, with embodiment 1, is tetrahydrofuran (THF) unlike aftertreatment solvent for use, and gained N, N'-carbonic acyl radical-bis--(4-ethyl-2,3-dioxygen ethylene imine) 32.2g, with 4-ethyl-2, the 3-dioxygen ethylene imine rate of collecting for 51.9%.HPLC measures purity 93.5%.
Claims (10)
1. a N; N'-carbonic acyl radical-bis--(4-ethyl-2; 3-dioxygen ethylene imine) preparation method, it is characterized in that: with 4-ethyl-2,3-dioxygen ethylene imine for raw material; itself and sodium Metal 99.5 are reacted to obtain 4-ethyl-2; 3-dioxygen ethylene imine sodium salt, gained sodium salt reacts with triphosgene in the presence of a catalyst, obtains N; N'-carbonic acyl radical-bis--(4-ethyl-2,3-dioxygen ethylene imine).
2. preparation method according to claim 1, is characterized in that: the ratio of the amount of substance of sodium Metal 99.5 and 4-ethyl-2,3-dioxypiperazine piperazine is 0.95 ~ 1:1, preferably: 1:1.
3. preparation method according to claim 1, is characterized in that: 4-ethyl-2,3-dioxygen ethylene imine and sodium Metal 99.5 react in organic solvent.
4. preparation method according to claim 3, is characterized in that: described organic solvent is glycol dimethyl ether, dioxane or toluene.
5. the preparation method according to any one of claim 1-4, is characterized in that: 4-ethyl-2,3-dioxygen ethylene imine and sodium Metal 99.5 react at 25 ~ 83 DEG C, preferably react at 83 DEG C.
6. preparation method according to claim 1, is characterized in that: the ratio of the amount of substance of triphosgene and 4-ethyl-2,3-dioxypiperazine piperazine is 1:6 ~ 6.6.
7. preparation method according to claim 1, is characterized in that: the ratio of the amount of substance of catalyzer and 4-ethyl-2,3-dioxypiperazine piperazine is 0.01 ~ 0.1:1, preferred 0.01:1.
8. the preparation method according to claim 1,6 or 7, is characterized in that: described catalyzer is imidazoles or triethylamine, preferred imidazoles.
9. the preparation method according to claim 1,6 or 7, is characterized in that: 4-ethyl-2,3-dioxygen ethylene imine sodium salt and triphosgene are reacted at-15 ~ 15 DEG C, preferably react at 5 DEG C.
10. the preparation method according to any one of claim 1-9, it is characterized in that: 4-ethyl-2,3-dioxygen ethylene imine sodium salt and the reacted reaction solution of triphosgene carry out following aftertreatment: remove organic solvent by concentrated for reaction solution, add recrystallization agent dissolves, cross and filter insolubles, concentrated crystallization after gained filtrate activated carbon decolorizing, gained crystal is dry, obtain N, N'-carbonic acyl radical-bis--(4-ethyl-2,3-dioxygen ethylene imine); Described recrystallization reagent is ethanol, Virahol, isopropylcarbinol or tetrahydrofuran (THF), is preferably Virahol.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112379012A (en) * | 2020-10-27 | 2021-02-19 | 山东鑫泉医药有限公司 | High performance liquid chromatography determination method of 4-ethyl-2, 3-dioxopiperazinoyl chloride |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112379012A (en) * | 2020-10-27 | 2021-02-19 | 山东鑫泉医药有限公司 | High performance liquid chromatography determination method of 4-ethyl-2, 3-dioxopiperazinoyl chloride |
| CN112379012B (en) * | 2020-10-27 | 2022-08-02 | 山东鑫泉医药有限公司 | High performance liquid chromatography determination method of 4-ethyl-2, 3-dioxopiperazinoyl chloride |
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