CN108822122A - A method of efficiently preparation 4,4- dimethyl -3,5,8- trioxa-l-phosphabicyclo [5,1,0] octane - Google Patents
A method of efficiently preparation 4,4- dimethyl -3,5,8- trioxa-l-phosphabicyclo [5,1,0] octane Download PDFInfo
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- CN108822122A CN108822122A CN201810968902.2A CN201810968902A CN108822122A CN 108822122 A CN108822122 A CN 108822122A CN 201810968902 A CN201810968902 A CN 201810968902A CN 108822122 A CN108822122 A CN 108822122A
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- phosphabicyclo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
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Abstract
The invention discloses a kind of efficiently preparation 4,4- dimethyl -3,5, the method of 8- trioxa-l-phosphabicyclo [5,1,0] octane, with 4,7- dihydro -2,2- dimethyl -1,3- dioxane hept- 5- alkene is raw material, and in the presence of catalyst and hydrogen peroxide, reaction generates 4,4- dimethyl -3,5,8- trioxa-l-phosphabicyclo [5,1,0] octane, the catalyst are selected from phosphomolybdic acid, phosphotungstic acid, sodium tungstate and vanadyl acetylacetonate.Reaction temperature can be significantly reduced according to the method for the present invention, avoids the generation of a large amount of wastes, greatly improve the purity of product.
Description
Technical field
The present invention relates to a kind of methods for efficiently preparing 4,4- dimethyl -3,5,8- trioxa-l-phosphabicyclo [5,1,0] octane.
Background technique
4,4- dimethyl -3,5,8- trioxa-l-phosphabicyclo [5,1,0] octane are the important intermediate for producing Gadobutrol, structure
As shown in Equation 1.
Synthesis 4,4- dimethyl -3,5 at present, the method for 8- trioxa-l-phosphabicyclo [5,1,0] octane generally use compound 3
(2- butene-1,4- glycol) is raw material, generates (4,7- dihydro -2,2- dimethyl -1, the 3- dioxies of compound 2 after protecting double hydroxyls
Heterocycle hept- 5- alkene), 4,4- dimethyl -3,5 shown in 2 epoxidation production 1 of compound, 8- trioxa-l-phosphabicyclo [5,1,0] is pungent
Alkane, synthetic route are as follows：
The difference of existing synthetic method is mainly process for epoxidation difference.For example, CN103351396A discloses one
Kind 4,4- dimethyl -3,5, the preparation method of 8- trioxa-l-phosphabicyclo [5,1,0] octane, using metachloroperbenzoic acid oxidizing process.
CN103896885A discloses a kind of preparation process of epoxide, and alkene and halogenating agent is anti-in water or in the mixed solvent
It answers, arrives epoxide, shown halogenating agent such as N-bromosuccinimide (NBS) etc..CN106967083A discloses one kind
The preparation process of Gadobutrol epoxy side chain intermediate, using hydrogen peroxide oxidation method.
But there is the danger of synthesis road in above-mentioned preparation 4,4- dimethyl -3,5, the method for 8- trioxa-l-phosphabicyclo [5,1,0] octane,
A series of difficult points such as more than solid waste, so that market at prices is high.
For example, method disclosed in CN103351396A and CN103896885A generates solid waste when suffering from amplification production
More disadvantages, method reaction temperature disclosed in CN106967083A is high, so that production danger coefficient is high, and the miscellaneous mistake of product list
Height, purity are low；These disadvantages seriously hinder the further life of 4,4- dimethyl -3,5,8- trioxa-l-phosphabicyclo [5,1,0] octane
Produce application and development.
Therefore, the process route that exploitation one can amplify safely and product purity is high will have great practical value.
Summary of the invention
The present invention provides a kind of efficiently preparation 4,4- dimethyl -3,5, the method for 8- trioxa-l-phosphabicyclo [5,1,0] octane,
Reaction temperature is significantly reduced, the generation of a large amount of wastes is avoided, greatly improves the purity of product.
A kind of efficiently preparation 4,4- dimethyl -3,5, the method for 8- trioxa-l-phosphabicyclo [5,1,0] octane, including：
Compound 2 is in catalyst and hydrogen peroxide (H2O2) in the presence of reaction generate 4,4- dimethyl -3,5,8- trioxa
Bicyclic [5,1,0] octane 1；
Wherein, the catalyst is selected from phosphomolybdic acid, phosphotungstic acid, sodium tungstate and vanadyl acetylacetonate.
The dosage of catalyst is the 0.1-1%, preferably 0.2-0.8% of 2 weight of compound.
The molar ratio of compound 2 and hydrogen peroxide is 1:1.2-1.6.
The concentration of hydrogen peroxide is 27-35%, it is preferable to use the hydrogen peroxide that concentration is 30%.
Preparation method of the invention can carry out at low temperature, for example, reaction temperature is 40-60 DEG C.
The pH value of reaction controls in the range of 8-10, and NaOH solution can be used to adjust the pH value of solution.
Reaction can be carried out in the mixed solvent, for example, using the mixed solvent being made of methanol, acetonitrile and water, it is each molten
There is no limit however, the present invention is not limited theretos for the mixed proportion of agent.
After the reaction was completed, can be used sodium sulfite aqueous solution hydrogen peroxide is quenched, it is preferable to use 20% sodium sulfite
Aqueous solution.
Preparation method according to the present invention, can also by be added phosphate come the pH value of regulation system, such as using
Na2HPO4。
Preparation method according to the present invention, wherein (4,7- dihydro -2,2- dimethyl -1,3- dioxane hept- of compound 2
5- alkene) it can be prepared by any method disclosed in the prior art.As an example, 2- butene-1 can be used, 4- glycol is
Raw material synthesizes compound 2.For example, make 2- butene-1,4- glycol and 2,2-dimethoxypropane depositing in the catalyst concentrated sulfuric acid
Compound 2 is obtained in lower generation cyclization reaction.
Beneficial effect
1, the present invention can significantly be dropped using the catalyst for being selected from phosphomolybdic acid, phosphotungstic acid, sodium tungstate and vanadyl acetylacetonate
Low reaction temperatures, reaction can carry out in a low temperature of 40-60 DEG C.
2, preparation method according to the present invention can be avoided the generation of debirs, greatly improve the purity of product.
Gas chromatographic detection is the results show that the purity of product prepared according to the methods of the invention reaches 99.62% or more.
3, preparation method of the invention is easy to operate, highly-safe, is easy to amplify production, advantageously reduces production cost.
Detailed description of the invention
Fig. 1 is the gas chromatographic analysis result of the product of 1 preparation according to embodiments of the present invention.
Fig. 2 is the gas chromatographic analysis result of the product of 2 preparation according to embodiments of the present invention.
Fig. 3 is the gas chromatographic analysis result of the product of 3 preparation according to embodiments of the present invention.
Specific embodiment
Below by by embodiment come the preparation 4,4- dimethyl -3,5,8- trioxa-l-phosphabicyclo that the present invention will be described in detail [5,
1,0] method of octane.
Embodiment 1
Successively put into reaction flask methanol (90g, 2.81mol), acetonitrile (100g, 2.44mol), pure water (100g,
5.56mol)、Na2HPO4(1g, 0.007mol) and phosphomolybdic acid (0.3g) is placed in heating stirring in oil bath pan, and it is molten that 1M NaOH is added dropwise
The pH of liquid regulation system is 8-10, and Weigh Compound 2 (100g, 0.78mol) is put into reaction flask, when reaction solution is heated to 50 DEG C
When, H is slowly added dropwise2O2(128g, 1.13mol), reaction temperature are controlled at 40-60 DEG C；Completion of dropwise addition, insulation reaction 3h or so are former
Material residue≤1%.Post-processing：Be quenched hydrogen peroxide with the sodium sulfite aqueous solution of 125g 20%, be added 100g saturated salt solution and
After 300g methylene chloride (DCM) sufficiently oscillation, liquid separation, water phase extracts (150g*2) with DCM again.Merge organic phase, then uses nothing
Aqueous sodium persulfate is dry.Concentration removes organic solvent and obtains crude product 109g.Then it is evaporated under reduced pressure, obtains 4,4- dimethyl -3,5,
8- trioxa-l-phosphabicyclo [5,1,0] octane product.
Fig. 1 is the gas chromatogram of the product prepared according to embodiment 1, and the purity of product is 99.62% as the result is shown.
Embodiment 2
Successively put into reaction flask methanol (90g, 2.81mol), acetonitrile (100g, 2.44mol), pure water (100g,
5.56mol)、Na2HPO4(1g, 0.007mol), phosphotungstic acid (0.5g) is placed in heating stirring in oil bath pan, and it is molten that 1M NaOH is added dropwise
The pH of liquid regulation system is 8-10, and Weigh Compound 2 (100g, 0.78mol) is put into reaction flask, when reaction solution is heated to 50 DEG C
When, H is slowly added dropwise2O2(128g, 1.13mol), reaction temperature control maintenance system pH in 40-60 DEG C, reaction process is 8-
10；Completion of dropwise addition, insulation reaction 3h or so, starting material left≤1%.Post-processing：It is quenched with the sodium sulfite aqueous solution of 125g 20%
Go out hydrogen peroxide, is added after 100g saturated salt solution and 300g DCM sufficiently vibrate, liquid separation, water phase is again with DCM extraction (150g*2).
Merge organic phase, it is then dry with anhydrous sodium sulfate.Concentration removes organic solvent and obtains crude product 109g.Then it is evaporated under reduced pressure,
Obtain product.
Fig. 2 is the gas chromatogram of the product prepared according to embodiment 2, and the purity of product is 99.66% as the result is shown.
Embodiment 3
Successively put into reaction flask methanol (90g, 2.81mol), acetonitrile (100g, 2.44mol), pure water (100g,
5.56mol)、Na2HPO4(1g, 0.007mol), sodium tungstate (0.6g) is placed in heating stirring in oil bath pan, and it is molten that 1M NaOH is added dropwise
The pH of liquid regulation system is 8-10, and Weigh Compound 2 (100g, 0.78mol) is put into reaction flask, when reaction solution is heated to 50 DEG C
When, H is slowly added dropwise2O2(128g, 1.13mol), reaction temperature are controlled at 40-60 DEG C；Maintenance system pH is 8- in reaction process
10；Completion of dropwise addition, insulation reaction 3h or so, starting material left≤1%.Post-processing：It is quenched with the sodium sulfite aqueous solution of 125g 20%
Go out hydrogen peroxide, is added after 100g saturated salt solution and 300g DCM sufficiently vibrate, liquid separation, water phase is again with DCM extraction (150g*2).
Merge organic phase, it is then dry with anhydrous sodium sulfate.Concentration removes organic solvent and obtains crude product 109g.Then it is evaporated under reduced pressure,
Obtain product.
Fig. 3 is the gas chromatogram of the product prepared according to embodiment 3, and the purity of product is 99.65% as the result is shown.
Preparation 4,4- dimethyl -3,5 according to the present invention, the method for 8- trioxa-l-phosphabicyclo [5,1,0] octane, in catalyst
In the presence of, using hydrogen peroxide oxidation compound 2, reaction can carry out in a low temperature of 40-60 DEG C, significantly reduce reaction temperature
Degree, avoids the generation of debirs, greatly improves the purity of product.
Claims (6)
1. a kind of efficiently preparation 4,4- dimethyl -3,5, the method for 8- trioxa-l-phosphabicyclo [5,1,0] octane, including：
Compound 2 reacted in the presence of catalyst and hydrogen peroxide generate 4,4- dimethyl -3,5,8- trioxa-l-phosphabicyclo [5,1,
0] octane 1；
Wherein, the catalyst is selected from phosphomolybdic acid, phosphotungstic acid, sodium tungstate and vanadyl acetylacetonate.
2. according to the method described in claim 1, wherein, the dosage of catalyst is the 0.1-1% of 2 weight of compound.
3. according to the method described in claim 1, wherein, the molar ratio of compound 2 and hydrogen peroxide is 1:1.2-1.6.
4. according to the method described in claim 1, wherein, reaction temperature is 40-60 DEG C.
5. according to the method described in claim 1, wherein, the pH value for controlling reaction is 8-10.
6. according to the method described in claim 1, wherein, reacting the in the mixed solvent formed in methanol, acetonitrile and water and carrying out.
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| CN201810968902.2A CN108822122A (en) | 2018-08-23 | 2018-08-23 | A method of efficiently preparation 4,4- dimethyl -3,5,8- trioxa-l-phosphabicyclo [5,1,0] octane |
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| CN201810968902.2A CN108822122A (en) | 2018-08-23 | 2018-08-23 | A method of efficiently preparation 4,4- dimethyl -3,5,8- trioxa-l-phosphabicyclo [5,1,0] octane |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999041296A1 (en) * | 1998-02-11 | 1999-08-19 | Rensselaer Polytechnic Institute | Photopolymerizable compositions containing cycloaliphatic epoxyalcohol monomers |
| US5972563A (en) * | 1996-07-29 | 1999-10-26 | Ciba Specialty Chemicals Corp. | Liquid, radiation-curable composition, especially for stereolithography |
| CN101175739A (en) * | 2005-05-16 | 2008-05-07 | 昭和电工株式会社 | Process for the preparation of difunctional epoxy monomers by selective oxidation of diene compounds |
| CN103896885A (en) * | 2014-03-13 | 2014-07-02 | 广州康瑞泰药业有限公司 | Preparation process of epoxy compound |
-
2018
- 2018-08-23 CN CN201810968902.2A patent/CN108822122A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5972563A (en) * | 1996-07-29 | 1999-10-26 | Ciba Specialty Chemicals Corp. | Liquid, radiation-curable composition, especially for stereolithography |
| WO1999041296A1 (en) * | 1998-02-11 | 1999-08-19 | Rensselaer Polytechnic Institute | Photopolymerizable compositions containing cycloaliphatic epoxyalcohol monomers |
| CN101175739A (en) * | 2005-05-16 | 2008-05-07 | 昭和电工株式会社 | Process for the preparation of difunctional epoxy monomers by selective oxidation of diene compounds |
| CN103896885A (en) * | 2014-03-13 | 2014-07-02 | 广州康瑞泰药业有限公司 | Preparation process of epoxy compound |
Non-Patent Citations (1)
| Title |
|---|
| A. E. MESHECHKINA，等: "Efficiency of Phase-Transfer Catalysis in Cyclopentene Epoxidation with Hydrogen Peroxide", 《RUSSIAN JOURNAL OF APPLIED CHEMISTRY》 * |
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