CN105524001B - A kind of N, N ＇ carbonic acyl radicals are double（The dioxygen ethylene imine of 4 ethyl 2,3）Preparation method - Google Patents

A kind of N, N ＇ carbonic acyl radicals are double（The dioxygen ethylene imine of 4 ethyl 2,3）Preparation method Download PDF

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CN105524001B
CN105524001B CN201510110290.XA CN201510110290A CN105524001B CN 105524001 B CN105524001 B CN 105524001B CN 201510110290 A CN201510110290 A CN 201510110290A CN 105524001 B CN105524001 B CN 105524001B
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ethyl
preparation
dioxygen ethylene
dioxygen
ethylene imine
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CN105524001A (en
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高爱红
冯维春
张剑文
纪晓红
刘丽秀
刘茂岭
王立芹
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Jinan Ift Science & Technology Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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

Abstract

The invention discloses a kind of N, N' carbonic acyl radicals are double（The dioxygen ethylene imine of 4 ethyl 2,3）Preparation method, with the dioxygen ethylene imine of 4 ethyl 2,3 for raw material, itself and metallic sodium are reacted into obtain the dioxygen ethylene imine sodium salt of 4 ethyl 2,3, gained sodium salt reacts with triphosgene in the presence of a catalyst, obtains N, and N' carbonic acyl radicals are double（The dioxygen ethylene imine of 4 ethyl 2,3）.Dioxygen ethylene imine, for raw material, is changed into sodium salt by the present invention using metallic sodium with the dioxygen ethylene imine of 4 ethyl 2,3 as stripping hydrogen reagent, the use of trim,ethylchlorosilane is prevented completely, side reaction is few, and product purity is high, does not produce a large amount of silicon-containing wastewaters, post processing cost is saved, disposal of waste gas, water and industrial residue cost is greatly reduced, simple to operate, route is succinct, meet cleanly production objective, be more suitable for industrialization.

Description

A kind of N, N ＇-carbonic acyl radical-bis--（4- ethyl -2,3- dioxygen ethylene imines）Preparation method
Technical field
The present invention relates to a kind of preparation method of HO-EPCP intermediates, and in particular to and a kind of N, N'- carbonic acyl radical-bis--（4- Ethyl -2,3- dioxygen ethylene imines）Preparation method, belong to technical field of organic synthesis.
Background technology
Cynnematin is the representative of third generation cephalosporin analog antibiotic, broad-spectrum antiseptic, is the first-line drug of anti Bacillus pyocyaneu Flugge, International and national all has huge market, N, and N'- carbonic acyl radicals-bis--（4- ethyl -2,3- dioxygen ethylene imines）With D (-)-to hydroxyl Phenylglycine condensation can prepare cefoperazone（Cefobid）, avocin important intermediate HO-EPCP.On HO- EPCP synthesis is more with N- ethyl -2,3- dioxygen ethylene imine acyl chlorides（It is abbreviated as EOCP）Route report it is in the majority, as CN101508679B, CN1446807A, JP59036668A, DE215194001, GB15008062 are reported with N- ethyls dioxygen ethylene imine and triphosgene For raw material, formylation reaction preparation N- ethyl dioxygen ethylene imine acyl chlorides occurs in the presence of trim,ethylchlorosilane, triethylamine（Following letter Claim dioxygen ethylene imine acyl chlorides）, then with D-pHPG be condensed HO-EPCP process, process route is as follows：
Problems be present in above-mentioned route：1st, the use of substantial amounts of triphosgene and trim,ethylchlorosilane is raw material, dioxygen ethylene imine Acyl chlorides facile hydrolysis is, it is necessary to which operating environment is strictly anhydrous；2nd, dioxygen ethylene imine acyl chlorides is unstable and active relatively strong, therefore reaction need to be low Temperature is carried out；3rd, dioxygen ethylene imine acyl chlorides is difficult to separation and Extraction, causes by-product to increase, and adds the corresponding equipment of post processing and power is set Apply.
Research finds N, N'- carbonic acyl radicals-bis--（4- ethyl -2,3- dioxygen ethylene imines）It is anti-with D (-)-D-pHPG When should prepare HO-EPCP, the one of dioxygen ethylene imine being connected on carbonic acyl radical is easy to leave away, and property is compared with dioxygen ethylene imine acyl chlorides Matter is stable, it is not necessary to and anhydrous condition, product purity are high, therefore N, N'- carbonic acyl radical-bis--（4- ethyl -2,3- dioxygen ethylene imines）It is ratio The more outstanding HO-EPCP intermediates of dioxygen ethylene imine acyl chlorides.
At present on N, N'- carbonic acyl radicals-bis--（4- ethyl -2,3- dioxygen ethylene imines）Report is with 4- ethyl -2,3- dioxygens Piperazine is reacted to prepare under trim,ethylchlorosilane protection with phosgene or its substitute triphosgene（Reaction is as follows）, such as EP0317484, this method equally use a large amount of trim,ethylchlorosilanes, produce the largely waste water containing rule, the advantage compared with acid chloride route Unobvious.
The content of the invention
For the deficiency of existing preparation method, the invention provides a kind of N, N'- carbonic acyl radicals-bis--（4- ethyls -2,3- is double Oxygen piperazine）Preparation method, this method is simple to operate, and route is succinct, and three wastes yield is small, suitable for industrialized production.
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 imines）Preparation method, with 4- ethyl -2,3- dioxygens Piperazine is raw material, and it reacts to obtain with metallic sodium to 4- ethyl -2,3- dioxygen ethylene imine sodium salts, gained sodium salt in the presence of a catalyst with Triphosgene is reacted, and obtains N, and N'- carbonic acyl radicals-bis--（4- ethyl -2,3- dioxygen ethylene imines）.
The present invention, as raw material, using metallic sodium as stripping hydrogen reagent, makes 4- second first with 4- ethyls -2,3- dioxygen ethylene imine Base -2,3- dioxygen ethylene imine forms sodium salt, and the sodium salt is then reacted into generation bisamide directly with triphosgene under catalyst action, By-product only has sodium chloride.The process route avoids the drawbacks of being brought using trim,ethylchlorosilane, and side reaction is few, and the three wastes are few, institute It is high to obtain product purity.Either from atom utilization, production cost, or in terms of " three wastes " yield, the inventive method Dioxygen ethylene imine acyl trim,ethylchlorosilane technique is superior to, with more industrialization advantage.
Reaction equation of the present invention is as follows：
In above-mentioned preparation method, the ratio of the amount of the material of metallic sodium and 4- ethyl -2,3- dioxypiperazine piperazines for 0.95~ 1：1, preferably:1：1.
In above-mentioned preparation method, 4- ethyls -2,3- dioxygen ethylene imine is reacted in organic solvent with metallic sodium.It is described molten Agent is glycol dimethyl ether, dioxane or toluene.
In above-mentioned preparation method, organic solvent provides metallic sodium and the environment of 4- ethyls -2,3- dioxygen ethylene imine reaction, and it is used Amount can be adjusted according to being actually needed.
In above-mentioned preparation method, 4- ethyls -2,3- dioxygen ethylene imine is reacted with metallic sodium at 25~83 DEG C, reaction Temperature is higher, and the reaction time is shorter, is preferably reacted under solvent reflux temperature, and backflow can promote 4- ethyl -2,3- dioxygens Piperazine and the progress of metallic sodium stripping hydrogen reaction, shorten process cycle.When from optimal organic solvent glycol dimethyl ether, return It is 83 DEG C to flow temperature.
In above-mentioned preparation method, 4- ethyl -2,3- dioxygen ethylene imine sodium salts and the catalyst of triphosgene reaction are imidazoles or three Ethamine, preferably imidazoles.
In above-mentioned preparation method, the ratio of the amount of the material of catalyst and 4- ethyl -2,3- dioxypiperazine piperazines for 0.01~ 0.1:1, it is contemplated that integrated cost, preferably 0.01:1.
In above-mentioned preparation method, the ratio of triphosgene and the amount of the material of 4- ethyl -2,3- dioxypiperazine piperazines is 1:6~ 6.6, preferably 1:6.
In above-mentioned preparation method, it is contemplated that the problems of dissolution of triphosgene, first triphosgene is dissolved into glycol dimethyl ether Wiring solution-forming, then add in reaction system.
In above-mentioned preparation method, for controlling reaction temperature, triphosgene is preferably added portionwise.
In above-mentioned preparation method, 4- ethyl -2,3- dioxygen ethylene imine sodium salts are reacted with triphosgene at -15~15 DEG C, It is preferred that reacted at 5 DEG C.
In above-mentioned preparation method, following steps are specifically included：4- ethyl -2,3- dioxygen ethylene imines are added to organic solvent In, metallic sodium is then added, reaction temperature is warming up to and is reacted；System is cooled to -15~15 DEG C after completion of the reaction, added The ethylene glycol dimethyl ether solution and catalyst of triphosgene, react to obtain N at this temperature, and N'- carbonic acyl radicals-bis--（4- ethyls -2,3- Dioxygen ethylene imine）.
In above-mentioned preparation method, after reaction terminates, end reaction liquid is subjected to following handle：Reaction solution concentration removing is had Solvent, add recrystallization reagent and dissolve again, be filtered to remove insoluble matter（Byproduct sodium chloride and unreacted 4- ethyls -2,3- Dioxygen ethylene imine）, then by filtrate activated carbon decolorizing, crystallization is concentrated after decolouring, crystal, drying is collected, produces N, N'- phosphinylidynes Base-bis--（4- ethyl -2,3- dioxygen ethylene imines）Product.
In above-mentioned preparation method, recrystallization reagent is ethanol, isopropanol, preferably isobutanol, isopropanol.
The present invention, for raw material, is become dioxygen ethylene imine as stripping hydrogen reagent using metallic sodium with 4- ethyls -2,3- dioxygen ethylene imine For sodium salt, the use of trim,ethylchlorosilane is prevented completely, side reaction is few, and product purity is high, does not produce a large amount of silicon-containing wastewaters, saves About post processing cost, greatly reduces disposal of waste gas, water and industrial residue cost, simple to operate, route is succinct, meets cleanly production ancestor Purport, it is more suitable for industrialization.
Embodiment
The present invention is further elaborated below by embodiment, it should be appreciated that, the description below is merely to solution The present invention is released, its content is not limited.
Raw material used in the present invention can commercially be bought.
Embodiment 1
Triphosgene solution configures：9.9g triphosgenes are dissolved into 100ml glycol dimethyl ethers, and add 0.7g imidazoles, Stir to complete molten stand-by.
Glycol dimethyl ether 500ml, 4- ethyl -2,3- dioxygen ethylene imine 28.4g is sequentially added in 1L three-necked flasks, is stirred Uniformly, metallic sodium 4.6g is added, is heated to flowing back, after reacting 10h, 5 DEG C is cooled to, three light configured is added portionwise under stirring Gasoloid, controlling reaction temperature are no more than 10 DEG C, finish and continue stirring reaction 10h, are concentrated in vacuo, and remove solvent, add 300ml Isopropanol, 30min to be stirred, is filtered to remove solid, filtrate adds activated carbon decolorizing, is filtered to remove activated carbon, filter vacuum is spin-dried for, Dry, obtain white solid, as N, N'- carbonic acyl radicals-bis--（4- ethyl -2,3- dioxygen ethylene imines）59.6g, it is double with 4- ethyls -2,3- Oxygen piperazine rate of collecting is that 96.1%, HPLC determines purity 98.1%.
Embodiment 2
Preparation method with embodiment 1, unlike：Metallic sodium amount used is 4.4g, gained N, N'- carbonic acyl radical-bis--（4- Ethyl -2,3- dioxygen ethylene imines）53.1g, with 4- ethyl -2,3- dioxygen ethylene imines rate of collecting for 85.6%.HPLC determines purity 91.6%.
Embodiment 3
Preparation method with embodiment 1, unlike：Triphosgene amount used is 9g, gained N, N'- carbonic acyl radical-bis--（4- second Base -2,3- dioxygen ethylene imines）53.0g, using triphosgene rate of collecting as 95.1%.HPLC determines purity 98.3%.
Embodiment 4
Preparation method with embodiment 1, unlike：Triphosgene amount is 11.8g, gained N, N'- carbonic acyl radical-bis--（4- second Base -2,3- dioxygen ethylene imines）49g, with 4- ethyl -2,3- dioxygen ethylene imines rate of collecting for 79.0%.HP LC determine purity 79.6%.
Embodiment 5
Preparation method with embodiment 1, unlike：Dioxygen ethylene imine sodium salt is -15 DEG C, gained N with triphosgene reaction temperature, N'- carbonic acyl radicals-bis--（4- ethyl -2,3- dioxygen ethylene imines）59g, with 4- ethyl -2,3- dioxygen ethylene imines rate of collecting for 95%.HPLC is surveyed Determine purity 98.5%.
Embodiment 6
Preparation method with embodiment 1, unlike：Used solvent is dioxane, gained N, N'- carbonic acyl radical-bis-- （4- ethyl -2,3- dioxygen ethylene imines）56.8g, with 4- ethyl -2,3- dioxygen ethylene imines rate of collecting for 91.6%.HPLC determines purity 97.1%。
Embodiment 7
Preparation method with embodiment 1, unlike：Dioxygen ethylene imine sodium salt is 15 DEG C, gained N with triphosgene reaction temperature, N'- carbonic acyl radicals-bis--（4- ethyl -2,3- dioxygen ethylene imines）52.5g, with 4- ethyl -2,3- dioxygen ethylene imines rate of collecting for 84.6%. HPLC determines purity 89.7%.
Embodiment 8
Preparation method with embodiment 1, unlike：Catalyst is 1.5ml triethylamines, N obtained by gained, N'- carbonic acyl radicals- Double-（4- ethyl -2,3- dioxygen ethylene imines）58.6g, with 4- ethyl -2,3- dioxygen ethylene imines rate of collecting for 95%.HPLC determines purity 95.9%。
Embodiment 9
Preparation method with embodiment 1, unlike：Dioxygen ethylene imine sodium salt and triphosgene reaction time are 3h.Gained N, N'- Carbonic acyl radical-bis--（4- ethyl -2,3- dioxygen ethylene imines）39.6g, with 4- ethyl -2,3- dioxygen ethylene imines rate of collecting for 63.8%.HPLC Determine purity 93.9%.
Embodiment 10
Preparation method is with embodiment 1, the difference is that post processing solvent for use is absolute ethyl alcohol, gained N, N'- carbonic acyl radical- Double-（4- ethyl -2,3- dioxygen ethylene imines）32.1g, with 4- ethyl -2,3- dioxygen ethylene imines rate of collecting for 52.1%.HPLC determines purity 93.6%。
Embodiment 11
Preparation method is with embodiment 1, the difference is that post processing solvent for use is isobutanol, gained N, N'- carbonic acyl radical-bis-- （4- ethyl -2,3- dioxygen ethylene imines）57g, with 4- ethyl -2,3- dioxygen ethylene imines rate of collecting for 92.3%.HPLC determines purity 98.0%。
Embodiment 12
Preparation method is with embodiment 1, the difference is that post processing solvent for use is tetrahydrofuran, gained N, N'- carbonic acyl radical- Double-（4- ethyl -2,3- dioxygen ethylene imines）32.2g, with 4- ethyl -2,3- dioxygen ethylene imines rate of collecting for 51.9%.HPLC determines purity 93.5%。

Claims (17)

1. a kind of N, N'- carbonic acyl radical-bis--（4- ethyl -2,3- dioxygen ethylene imines）Preparation method, it is characterized in that：With 4- ethyl -2, 3- dioxygen ethylene imines are raw material, it is reacted with metallic sodium 4- ethyl -2,3- dioxygen ethylene imine sodium salts, gained sodium salt are deposited in catalyst Reacted lower with triphosgene, obtain N, N'- carbonic acyl radicals-bis--（4- ethyl -2,3- dioxygen ethylene imines）.
2. preparation method according to claim 1, it is characterized in that：The thing of metallic sodium and 4- ethyl -2,3- dioxypiperazine piperazines The ratio of the amount of matter is 0.95~1：1.
3. preparation method according to claim 2, it is characterized in that：The thing of metallic sodium and 4- ethyl -2,3- dioxypiperazine piperazines The ratio of the amount of matter is 1：1.
4. preparation method according to claim 1, it is characterized in that：4- ethyl -2,3- dioxygen ethylene imines are with metallic sodium organic Reacted in solvent.
5. preparation method according to claim 4, it is characterized in that：The organic solvent is glycol dimethyl ether, dioxy six Ring or toluene.
6. according to the preparation method any one of claim 1-5, it is characterized in that：4- ethyl -2,3- dioxygen ethylene imines and gold Category sodium is reacted at 25~83 DEG C.
7. preparation method according to claim 6, it is characterized in that：4- ethyl -2,3- dioxygen ethylene imines are with metallic sodium at 83 DEG C Under reacted.
8. preparation method according to claim 1, it is characterized in that：Triphosgene and the thing of 4- ethyl -2,3- dioxypiperazine piperazines The ratio of the amount of matter is 1:6~6.6.
9. preparation method according to claim 1, it is characterized in that：The thing of catalyst and 4- ethyl -2,3- dioxypiperazine piperazines The ratio of the amount of matter is 0.01~0.1:1.
10. preparation method according to claim 9, it is characterized in that：Catalyst and 4- ethyl -2,3- dioxypiperazine piperazines The ratio of the amount of material is 0.01:1.
11. according to the preparation method described in claim 1,9 or 10, it is characterized in that：The catalyst is imidazoles or triethylamine.
12. preparation method according to claim 11, it is characterized in that：The catalyst is imidazoles.
13. according to the preparation method any one of claim 1-5, it is characterized in that：4- ethyl -2,3- dioxygen ethylene imine sodium Salt is reacted with triphosgene at -15~15 DEG C.
14. preparation method according to claim 13, it is characterized in that：4- ethyls -2,3- dioxygen ethylene imines sodium salt and triphosgene Reacted at 5 DEG C.
15. according to the preparation method any one of claim 1-5, it is characterized in that：4- ethyl -2,3- dioxygen ethylene imine sodium salts Reaction solution reacted with triphosgene carries out following post-process：Reaction solution is concentrated and removes organic solvent, adds recrystallization reagent Dissolving, insoluble matter is filtered to remove, gained filtrate is dried with crystallization, gained crystal is concentrated after activated carbon decolorizing, obtains N, N'- phosphinylidynes Base-bis--（4- ethyl -2,3- dioxygen ethylene imines）.
16. preparation method according to claim 15, it is characterized in that：The recrystallization reagent is ethanol, isopropanol, isobutyl Alcohol or tetrahydrofuran.
17. preparation method according to claim 16, it is characterized in that：The recrystallization reagent is isopropanol.
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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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