CN102942532A - Preparation method of 1,4,7,10-tetraazadodecane - Google Patents
Preparation method of 1,4,7,10-tetraazadodecane Download PDFInfo
- Publication number
- CN102942532A CN102942532A CN2012105004283A CN201210500428A CN102942532A CN 102942532 A CN102942532 A CN 102942532A CN 2012105004283 A CN2012105004283 A CN 2012105004283A CN 201210500428 A CN201210500428 A CN 201210500428A CN 102942532 A CN102942532 A CN 102942532A
- Authority
- CN
- China
- Prior art keywords
- preparation
- teteaazacyclododecane
- molar ratio
- salt
- isosorbide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Abstract
The invention relates to a preparation method of 1,4,7,10-tetraazadodecane, which comprises the following steps: (1) reacting triethylenetetramine and N,N-dimethylformamide dimethyl acetal in a solvent benzene at 75-85 DEG C to generate diimidazoline; (2) in the presence of potassium carbonate, reacting the diimidazoline with 1,2-ethylene dibromide in a solvent ethanol to prepare the amber semisolid bromine salt intermediate; and (3) reacting the bromine salt intermediate with sodium hydroxide in a solvent water to generate the 1,4,7,10-tetraazadodecane. The technical process is simple and convenient to operate; the total yield of the target product exceeds 60%; and thus, the invention is suitable for industrial large-scale production.
Description
Technical field
The present invention relates to a kind of Isosorbide-5-Nitrae, the preparation method of 7,10-teteaazacyclododecane.
Background technology
Isosorbide-5-Nitrae, 7,10-teteaazacyclododecane; CAS:294-90-6 molecular formula: C
8H
20N
4, molecular weight: 172.28, be white crystals.Isosorbide-5-Nitrae, 7,10-teteaazacyclododecane are the precursors of the macrocyclic chelants of synthetic metal ion.
1 of present bibliographical information, the synthetic method of 4,7,10-teteaazacyclododecane mainly contains legal four kinds of Stetter method, Richman-Atkins method, Weisman method and Yi Er Quan Shrink, wherein use acetal legal system standby 1,4,7,10-teteaazacyclododecane, raw material is easy to get, mild condition, easy to operate, be laboratory and the comparatively desirable method of production.
The open CN1343203A of Chinese invention patent discloses a kind of preparation formula (I) compound, Isosorbide-5-Nitrae, and the method for 7,10-teteaazacyclododecane, it takes following route:
Wherein: in the step a), Triethylenetetramine (TETA) (TETA) and oxalic dialdehyde condenses are in water or water-soluble solvent or its mixture, and in 0 ~ 5 ℃, condensation in the presence of stoichiometry or excessive calcium hydroxide obtains the compound of formula (IV); In the step b), the compound of formula (IV) and consumption are 1 of 1 to 5mol/mol compound (IV), the 2-ethylene dichloride, in N,N-DIMETHYLACETAMIDE (DMAC) and at consumption, be under the sodium carbonates' presence of 5 to 10mol/mol compounds (IV), the Sodium Bromide reaction that adds 0.1 to 2mol/mol compound (IV), temperature of reaction is 25 to 150 ℃, obtain formula (III) compound, formula (III) compound is with the isolated in form of the acid of inorganic salt; In the step c), under inert atmosphere or air, by in water, under the temperature of pH5 to 9 and 90-120 ℃, in the presence of 5-10mol diethylenetriamine/mol compound (III), reacted 12-48 hour with diethylenetriamine (DETA), compound (III) hydrolysis is converted into compound (II); In the step d), quantitatively discharge alkali, obtain the compound of formula (I).This patented method is by making formula (III) compound change into four hydrochloride forms of compound (I), four hydrochloride form Quantitative yield with compound (I) are the mode of compound (I) again, effectively avoided the larger loss (when directly conversion purify again, the yield of purification step only be 70%) of crude product in purification process of direct preparation compound (I).Although the method has improved the yield of target,, simultaneously also so that operation steps becomes more loaded down with trivial details, the production cycle is elongated, and the finished product yield still is not very desirable, and cost does not descend.
Summary of the invention
Technical problem to be solved by this invention is to overcome the deficiencies in the prior art, provides a kind of yield high, and cost is low, is suitable for the Isosorbide-5-Nitrae of suitability for industrialized production, the preparation method of 7,10-teteaazacyclododecane.
For solving above technical problem, the present invention takes following technical scheme:
A kind of Isosorbide-5-Nitrae, the preparation method of 7,10-teteaazacyclododecane, the method comprises the steps:
(1), the preparation of bi-imidazoline: in the reaction vessel that reflux exchanger, thermometer, drying tube, agitator are housed, add Triethylenetetramine (TETA) (TETA), N, dinethylformamide dimethylacetal, solvent benzol, be heated to 75 ~ 85 ℃, constantly steam the methyl alcohol that reaction generates, refluxed 1.5 ~ 3 hours, decompression steams an amount of benzene, cooling, crystallization, filter, get white crystals, be bi-imidazoline, wherein, the molar ratio of Triethylenetetramine (TETA) and DMF Er Jia Shrink aldehyde is 1:2 ~ 3;
(2), ring expansion prepares bromine salt intermediate: reflux exchanger is being housed, thermometer, in the reaction vessel of agitator, add salt of wormwood, etoh solvent, heating is also stirred, at 75 ~ 85 ℃ of lower step (1) gained bi-imidazolines that slowly drip, 1, the mixed liquid of 2-ethylene dibromide and ethanol reacted after 1.5 ~ 3 hours, was cooled to below 50 ℃, elimination salt of wormwood, pressure reducing and steaming ethanol gets amber semisolid, is bromine salt intermediate, next step usefulness is dissolved in water, wherein, bi-imidazoline, the molar ratio of glycol dibromide and salt of wormwood is 1:1 ~ 1.1:2 ~ 2.5;
(3), Isosorbide-5-Nitrae, 7, the preparation of 10-teteaazacyclododecane: reflux exchanger is being housed, thermometer, in the reaction vessel of agitator and voltage stabilizing dropping funnel, add entry, stirring heating, reflux, drip simultaneously the aqueous solution of step (2) preparation and the aqueous sodium hydroxide solution of 20wt% ~ 35wt%, drip and finish, refluxed 2 ~ 3 hours, filtered while hot, filtrate is changed in the matrass, and decompression steams water, cools off to get white crystals, filter, crude product, crude product gets white crystal and is 1 with the toluene recrystallization that dewaters, 4,7,10-teteaazacyclododecane, wherein the molar ratio of the bromine salt intermediate of sodium hydroxide and step (2) preparation is 5 ~ 8:1.
Preferably, in the step (1), the molar ratio of Triethylenetetramine (TETA) and DMF Er Jia Shrink aldehyde is 1:2 ~ 2.2.
Preferably, in the step (2), the molar ratio of bi-imidazoline, glycol dibromide and salt of wormwood is 1:1:2.
The structural formula of the described bromine salt of step of the present invention (2) intermediate is as follows:
Because the enforcement of above technical scheme, the present invention compared with prior art has following advantage:
Technological process of the present invention is simple, and is easy to operate, and the total recovery of target product is suitable for commercial scale production above 60%.
Embodiment
The present invention will be further described in detail below in conjunction with specific embodiment.
The preparation of embodiment 1 bi-imidazoline
In the four-hole boiling flask that reflux exchanger, thermometer, drying tube, agitator are housed, add TETA14.6g (0.1mol), DMF Er Jia Shrink aldehyde (95%) 25g (0.2mol), benzene 60ml is heated to 80 ℃, and constantly steams the methyl alcohol that reaction generates, refluxed 2 hours, decompression steams an amount of benzene, cooling, crystallization, filter, get white crystals 15g, yield: 90.4%, fusing point: 107-108 ℃.
Embodiment 2 prepares bromine salt intermediate by the bi-imidazoline ring expansion
In the four-hole boiling flask that reflux exchanger, thermometer, agitator are housed, add salt of wormwood 11g (0.08mol), ethanol 100ml, heating is also stirred, and at 80 ℃, slowly drips bi-imidazoline 6.6g(0.04mol), the mixed liquid of glycol dibromide 7.6g (0.04mol) and ethanol 200ml reacts after 2 hours, be cooled to 50 ℃, elimination salt of wormwood, pressure reducing and steaming ethanol, get amber semi-solid 8.4g, be bromine salt intermediate, add next step usefulness of 300ml water dissolution, productive rate 78.7%.
Embodiment 31,4,7, the preparation of 10-teteaazacyclododecane
In the four-hole boiling flask that reflux exchanger, thermometer, agitator and voltage stabilizing dropping funnel are housed, add 76g water, stirring heating refluxes.Drip simultaneously the aqueous solution 310 grams according to the bromine salt intermediate of embodiment 2 methods preparations (the about 8.4g of brominated salt intermediate wherein, 0.03mol) and 30%NaOH aqueous solution 32g(contain sodium hydroxide 2.4mol), drip and finish, refluxed 2 hours, filtered while hot adds filtrate in the matrass, decompression steams water, cool off to get white crystals, filter, get crude product.Crude product gets white crystal 4.6g with the toluene recrystallization that dewaters, and is Isosorbide-5-Nitrae, 7,10-teteaazacyclododecane, GC content 99%, productive rate 83.9%.Fusing point: 111-113 ℃.
Above-described embodiment only is explanation technical conceive of the present invention and characteristics; its purpose is to allow the personage who is familiar with technique can understand content of the present invention and according to this enforcement; can not limit protection scope of the present invention with this; all equivalences that spirit is done according to the present invention change or modify, and all should be encompassed within protection scope of the present invention.
Claims (3)
1. Isosorbide-5-Nitrae, the preparation method of 7,10-teteaazacyclododecane is characterized in that: the method comprises the steps:
(1), the preparation of bi-imidazoline: in the reaction vessel that reflux exchanger, thermometer, drying tube, agitator are housed, add Triethylenetetramine (TETA), DMF Er Jia Shrink aldehyde, solvent benzol, be heated to 75 ~ 85 ℃, constantly steam the methyl alcohol that reaction generates, refluxed 1.5 ~ 3 hours, decompression steams an amount of benzene, cooling, crystallization, filter, get white crystals, be bi-imidazoline, wherein, the molar ratio of Triethylenetetramine (TETA) and DMF Er Jia Shrink aldehyde is 1:2 ~ 3;
(2), ring expansion prepares bromine salt intermediate: reflux exchanger is being housed, thermometer, in the reaction vessel of agitator, add salt of wormwood, etoh solvent, heating is also stirred, at 75 ~ 85 ℃ of lower step (1) gained bi-imidazolines that slowly drip, 1, the mixed liquid of 2-ethylene dibromide and ethanol reacted after 1.5 ~ 3 hours, was cooled to below 50 ℃, elimination salt of wormwood, pressure reducing and steaming ethanol gets amber semisolid, is bromine salt intermediate, next step usefulness is dissolved in water, wherein, bi-imidazoline, the molar ratio of glycol dibromide and salt of wormwood is 1:1 ~ 1.1:2 ~ 2.5;
(3), Isosorbide-5-Nitrae, 7, the preparation of 10-teteaazacyclododecane: reflux exchanger is being housed, thermometer, in the reaction vessel of agitator and voltage stabilizing dropping funnel, add entry, stirring heating, reflux, drip simultaneously the aqueous solution of step (2) preparation and the aqueous sodium hydroxide solution of 20wt% ~ 35wt%, drip and finish, refluxed 2 ~ 3 hours, filtered while hot, filtrate is changed in the matrass, and decompression steams water, cools off to get white crystals, filter, crude product, crude product gets white crystal and is 1 with the toluene recrystallization that dewaters, 4,7,10-teteaazacyclododecane, wherein the molar ratio of the bromine salt intermediate of sodium hydroxide and step (2) preparation is 5 ~ 8:1.
2. Isosorbide-5-Nitrae according to claim 1, the preparation method of 7,10-teteaazacyclododecane is characterized in that: in the step (1), the molar ratio of Triethylenetetramine (TETA) and DMF Er Jia Shrink aldehyde is 1:2 ~ 2.2.
3. Isosorbide-5-Nitrae according to claim 1, the preparation method of 7,10-teteaazacyclododecane is characterized in that: in the step (2), the molar ratio of bi-imidazoline, glycol dibromide and salt of wormwood is 1:1:2.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012105004283A CN102942532A (en) | 2012-11-29 | 2012-11-29 | Preparation method of 1,4,7,10-tetraazadodecane |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012105004283A CN102942532A (en) | 2012-11-29 | 2012-11-29 | Preparation method of 1,4,7,10-tetraazadodecane |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102942532A true CN102942532A (en) | 2013-02-27 |
Family
ID=47725548
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2012105004283A Pending CN102942532A (en) | 2012-11-29 | 2012-11-29 | Preparation method of 1,4,7,10-tetraazadodecane |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102942532A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104892534A (en) * | 2015-05-18 | 2015-09-09 | 武汉利宝瑞医药科技有限公司 | Technology for synthesizing intermediate of cycleanine of gadolinium contrast agent |
| CN108794416A (en) * | 2018-07-02 | 2018-11-13 | 成都药云科技有限公司 | A kind of cycleanine production purification process |
| CN110669020A (en) * | 2019-10-28 | 2020-01-10 | 西南化工研究设计院有限公司 | Preparation method of cycleanine |
| CN111808039A (en) * | 2020-08-13 | 2020-10-23 | 扬州市荣晶工业助剂有限公司 | Novel synthesis method of 1,4,7, 10-tetranitrogen cyclododecane |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5587451A (en) * | 1993-11-26 | 1996-12-24 | The Dow Chemical Company | Process for preparing polyazamacrocycles |
-
2012
- 2012-11-29 CN CN2012105004283A patent/CN102942532A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5587451A (en) * | 1993-11-26 | 1996-12-24 | The Dow Chemical Company | Process for preparing polyazamacrocycles |
Non-Patent Citations (1)
| Title |
|---|
| 张娟: "用酰胺缩醛合成1,4,7,10-四氮杂十二烷的研究", 《现代化工》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104892534A (en) * | 2015-05-18 | 2015-09-09 | 武汉利宝瑞医药科技有限公司 | Technology for synthesizing intermediate of cycleanine of gadolinium contrast agent |
| CN108794416A (en) * | 2018-07-02 | 2018-11-13 | 成都药云科技有限公司 | A kind of cycleanine production purification process |
| CN108794416B (en) * | 2018-07-02 | 2021-09-28 | 成都药云科技有限公司 | Method for producing and purifying cycleanine |
| CN110669020A (en) * | 2019-10-28 | 2020-01-10 | 西南化工研究设计院有限公司 | Preparation method of cycleanine |
| CN111808039A (en) * | 2020-08-13 | 2020-10-23 | 扬州市荣晶工业助剂有限公司 | Novel synthesis method of 1,4,7, 10-tetranitrogen cyclododecane |
| CN111808039B (en) * | 2020-08-13 | 2022-04-26 | 扬州市荣晶工业助剂有限公司 | Novel synthesis method of 1,4,7, 10-tetranitrogen cyclododecane |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101891649B (en) | Novel 3-cyano methyl benzoate preparing method | |
| CN102942532A (en) | Preparation method of 1,4,7,10-tetraazadodecane | |
| CN103724279B (en) | One step to form the loop prepares the convenient synthetic method of 2-methyl-4-amino-5-amino methylpyrimidine | |
| CN101870653B (en) | Synthesis method of 2 - methyl -3 - fluoride - 6 -nitrobenzoic acid | |
| CN103965125A (en) | Synthetic method of 3,3'-binitro-5,5'-di-1,2,4-triazole | |
| CN102911119B (en) | Preparation methods of 3,4-dimethyl pyrazole and 3,4-dimethyl pyrazole phosphate | |
| CN103396318A (en) | Synthetic process for 2,4-dinitroanisole | |
| CN101955415B (en) | Method for preparing 2-hydroxyl biphenyl compound | |
| CN102757390B (en) | Method for preparing 2-methoxy-4-diazanyl-5-fluoropyrimidine | |
| CN102675148B (en) | Preparation method of hydroxybenzyl cyanide | |
| CN101704788B (en) | Improved preparation process of 2-Butyl-1,3-diazapira[4,4]nonane-1-en-4-one | |
| CN102993088A (en) | 4-hydroxy-2-pyridone preparation method | |
| CN107118088A (en) | A kind of preparation method of m-hydroxy acetophenone | |
| CN102010325A (en) | Method for synthesizing p-hydroxyphenylacetic acid | |
| CN103319382B (en) | The preparation method of 2-(amino) ethyl-methyl sulfone salt and intermediate thereof | |
| CN106478422A (en) | A kind of preparation method of paranitrophenylacetic acid | |
| CN101781212B (en) | Method for synthesizing 2-hydroxymethyl acrylate compound | |
| CN101367762B (en) | Preparation method of midbody 7-chloroquinaldine | |
| CN103588638B (en) | A kind of 4-(benzene butoxy) benzoic synthetic method | |
| CN104211652A (en) | Method for preparing plerixafor | |
| CN105294408B (en) | Cation light initiator（2 hydroxy-tetradecyl oxygen phenyl）The preparation method of benzene iodine hexafluoro antimonate | |
| CN105669770A (en) | Method for synthesizing syn-dichloro double(triphenylphosphine)platinum | |
| CN104892608A (en) | 1-(3-hydroxymethylpyridine-2-yl)-4-methyl-2-phenylpiperazine synthesis method | |
| CN105732375A (en) | Method for synthesizing methyl 3,4,5-trimethoxybenzoate from gallic acid | |
| CN105152946A (en) | Method for efficiently and rapidly synthesizing o-amino benzaldehyde |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20130227 |