CN110698419A - Preparation method of cycleanine - Google Patents
Preparation method of cycleanine Download PDFInfo
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- CN110698419A CN110698419A CN201910919416.6A CN201910919416A CN110698419A CN 110698419 A CN110698419 A CN 110698419A CN 201910919416 A CN201910919416 A CN 201910919416A CN 110698419 A CN110698419 A CN 110698419A
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- cyclen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
Abstract
The invention provides a preparation method of cycleanine, which comprises the steps of taking triethylene tetramine (TETA) as a raw material, refining the raw material, reacting the refined raw material with methylglyoxal to obtain an intermediate 2, closing the ring of the intermediate 2 and glyoxal, reducing the closed ring by using sodium borohydride to obtain a cyclized intermediate 3, performing acid hydrolysis and ring opening, and adjusting the pH value by using an alkali solution to dissociate cycleanine.
Description
Technical Field
The invention relates to a preparation method of cycleanine.
Background
Cyclen (1,4,7, 10-tetraazacyclododecane, cyclen) is a very important intermediate for the synthesis of therapeutic drugs for diagnostic kits. The cyclocyclen and the derivatives thereof are used for removing stones in a human body and inhibiting loss caused by myocardial ischemia reperfusion, and particularly show extremely important application values in the aspects of manufacturing contrast agents of medical imaging technologies such as nuclear Magnetic Resonance Imaging (MRI), X-ray CT, ultrasonic imaging and the like and radiotherapy medicines of malignant tumors. The complex which is used as a precursor of a macrocyclic chelating agent for synthesizing metal ions can form a very stable complex with ions, particularly a complex formed with paramagnetic metal ions such as gadolinium ions, is applied to the field of medical diagnosis, does not have high toxicity caused by free ions, and has the safety characteristic. At present, the aging is more and more serious in the world, the dosage of cyclen is more and more, but only a few manufacturers produce cyclen at present, and the prospect is very wide.
At present, the synthesis methods of cycleanine mainly comprise the following steps:
stetter, h.; mayer, K. -H. [ J ]. chem.Ber.1961,94:1410, using ethylenediamine as raw material, making TsCl protection, then making it react with methyl bromoacetate, hydrolyzing and reacting with thionyl chloride to obtain intermediate containing acyl chloride, then making it undergo the process of cyclization with two molecules of ethylenediamine, finally making reduction and Ts-removal to obtain cyclen.
Richman,J.E.；Atkins,T.J.[J]J.Am.chem.Soc.1974,96:2268, preparing disodium salt from diethylenetriamine after TsCl protection, and closing a ring with Ts-protected diethanolamine; using concentrated sulfuric acid to perform deprotection at 100 ℃ to obtain sulfate; finally reacting with concentrated hydrochloric acid to obtain cyclen 4 HCl. Meuneier. [ J ]]Can.J. chem.1995,73:685, TETA protected by TsCl to make disodium salt, and other operations were the same. The resulting cyclen 4HCl was neutralized with 30% caustic soda lye to pH 12 and then with CH3And (5) extracting Cl to obtain cyclen.
Weisman,G.R.；Reed,D.P.Additions and Corrections,[J]Chem.1996,61:5186, using dithiooxamide with an excess of CH3CHBr is alkylated by S to obtain dithioimine ester salt, then reacted with TETA to obtain cyclon precursor tricyclic diamidine, and finally subjected to double reduction by DIBALH (diisobutylaluminum hydride) to expand the ring to obtain the cyclon.
WO96/28432, WO97/49691 and WO98/45296 use polyamine and glyoxal (or ethanedisulfonic acid sodium salt) to condense in aqueous solution, then to combine with alkylating reagent to form ring, then to oxidize with oxidant in aqueous phase or aqueous two-phase solvent to obtain mixture of multiple oxidation products, finally to hydrolyze in acid to obtain cyclen.
Weijunfa et al 1997 reported diethyl oxalate/methanol mixed liquor in the college and chemistry institute of higher school, and dripped into methanol solution of TETA to condense into ring under stirring in ice water bath, consisting of KBH4Preparation B2H6To reduce ketone carbonyl to obtain product cyclen.
In WO95/14726, TETA and dried DMFDMA are heated to directly react to obtain diimidazole, then the diimidazole reacts with 1, 2-dibromoethane to obtain a cyclized intermediate, and then the cyclized intermediate is subjected to reflux hydrolysis under an alkaline condition to obtain cyclen, wherein the yield is 65-70%.
However, the above-mentioned round of synthetic cyclorotenine has disadvantages in that:
the Stetter synthesis method is pioneering for the synthesis of cyclen, the first four steps of the method are relatively conventional, but the subsequent operation steps are more, and the final reduction and deprotection steps require high-price raw materials and low total yield, so the method is rarely used.
The improved Richman-Atkins method is a classical synthesis method, but the method has the disadvantages of long reaction time, more steps, large reagent consumption and difficult operation, and needs to prepare the disulfonamide disodium salt first and filter the disulfonamide disodium salt under the nitrogen environment to take out the sodium salt, so the operation can not be carried out in a common laboratory, and the method has a lot of inconvenience in industrial production.
The Weisman method is characterized in that dithiooxamide is salified, then reacts with triethylene tetramine, and then is hydrolyzed to obtain a target product. Although the method has only three steps and low yield, the raw materials dithiooxamide and DIBALH are expensive and generate toxic gas H2S, and DIBALH is extremely sensitive to water (violent exotherm, evolution of H)2) And therefore limited to laboratory trials.
The linear polyamine and glyoxal method does not need to protect polyamine, has less steps, mild conditions and easy separation of products. But the yield of each step is not high, and if the yield of two steps of condensation and oxidative ring opening can be improved, the method has certain utilization value.
The diethyl oxalate method has the advantages of simple and easily obtained raw materials, few steps and mild conditions, but the yields in the two steps are respectively 39% and 56%, and diborane is unstable, easy to decompose and explode when meeting moisture, and is not suitable for large-scale production.
The laboratory production effect of the Tao's route method is better, but the used solvent has high price, is easy to absorb water, has more side reactions and greatly reduces the amplification yield.
Disclosure of Invention
The invention provides a preparation method of cycleanine, which has the advantages of easily obtained raw materials, mild reaction conditions and high product yield.
According to the preparation method of cyclen, triethylene tetramine (TETA) is used as a raw material, and is refined to react with methylglyoxal to obtain an intermediate 2, the intermediate 2 is subjected to ring closure with glyoxal and is reduced by sodium borohydride to obtain a cyclized intermediate 3, and finally, the cyclized intermediate is hydrolyzed by hydrochloric acid to open a ring, and the pH value is adjusted by an alkali solution to dissociate cyclen. The synthetic route is as follows:
(1) refining the compound TETA to obtain an intermediate 1;
(2) reacting the intermediate 1 with methylglyoxal to obtain an intermediate 2;
(3) the intermediate 2 and glyoxal are subjected to ring closure reaction and then are reduced to obtain an intermediate 3;
(4) hydrolyzing the intermediate 3 under hydrochloric acid to obtain an intermediate 4;
(5) intermediate 4 is liberated under basic conditions to yield cyclen (cyclen).
In the step (1), triethylene tetramine (TETA) is refined in water and toluene solution to obtain an intermediate 1, wherein the purity can reach more than 99%.
In the step (2), the intermediate 1 and methylglyoxal react to obtain an intermediate 2, the reaction is carried out under a nitrogen atmosphere, the temperature is kept at-10-5 ℃, and the reaction solvent can be selected from methanol, ethanol, cyclohexane, tetrahydrofuran, acetone and the like.
The intermediate 2 prepared by using the methylglyoxal has better stability and reaction selectivity.
Intermediate 2 can be used without isolation to prepare intermediate 3 directly.
In step (3), intermediate 2 undergoes a ring closure reaction with glyoxal, followed by reduction with a reducing agent to give cyclized intermediate 3.
The reducing agent may be sodium borohydride, lithium aluminum hydride, or the like.
Benzotriazole can be used in the ring-closing reaction, so that the stability of the intermediate state during the synthesis of the intermediate 3 from the intermediate 2 can be improved.
In step (4), the intermediate 3 is hydrolyzed under hydrochloric acid to obtain an intermediate 4, i.e., hydrochloric acid salt of cyclen.
In step (5), the pH of the solution is adjusted by an aqueous solution of a base, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, etc., to precipitate crystals.
After filtration, recrystallization from a solvent gives cyclen (cyclen). The crystallization solvent can be selected from benzene, toluene, dichloromethane, etc.
The invention has the advantages of
1. The raw materials of the route are cheap and easy to obtain, so that the production cost is greatly reduced;
2. the intermediate 2 is prepared by using the methylglyoxal, so that the stability is better, and the reaction selectivity is better;
3. the stability of the intermediate state is improved when the intermediate compound 3 is synthesized from the intermediate 2 by using benzotriazole;
4. firstly, preparing cyclen hydrochloride, and then dissociating cyclen by using alkali to obtain high-purity cyclen;
5. mild reaction conditions, safe reagents and considerable reaction yield, and is suitable for large-scale production.
Detailed Description
The preparation method of cyclen according to the present invention is specifically described below by way of examples.
The synthetic route of cyclen according to the invention is as follows:
examples
The first step is as follows: purification of TETA
Adding 1.0kg of triethylene tetramine (TETA) and 0.17kg of water into a reaction container, controlling the temperature to be 20-50 ℃, adding a small amount of seed crystal, then dropwise adding 1.5-2.0 kg of toluene, controlling the temperature to be 20-50 ℃, cooling to 0-20 ℃ after dropwise adding is finished, keeping the temperature and stirring for 2-4 hours, then filtering, collecting a filter cake, and drying to obtain 850g of water with the purity of 99%.
1H-NMR(400MHz,CDCl3,ppm)δ:2.92(s,4H),2.56(m,12H),2.49(m,6H).
The second step is that: preparation of intermediate 2
Adding 350g of the compound 1 into a reaction container, adding 3-4L of absolute ethyl alcohol, cooling to-10-5 ℃, dropwise adding 40% methylglyoxal (347-520 g) ethanol (1.5-2.0L) solution under nitrogen atmosphere, keeping the temperature and stirring for 2-4 hours, monitoring the completion of the reaction by TLC, and directly using the product for the next reaction without separation.
The third step: preparation of intermediate 3
And (3) directly adding 460-690 g of Benzotriazole (BTA) into the reaction product obtained in the second step, dropwise adding an ethanol (175ml) solution of 40% glyoxal (280-560 g), keeping the temperature, stirring for 2 hours, then adding 150-350 g of sodium borohydride, stirring for 12 hours, filtering, and concentrating the filtrate to obtain 884g of a crude intermediate product 3.
MS:209.2[M+].
1H-NMR(400MHz,CDCl3,ppm)δ:3.05-2.80(m,14H),2.64(s,1H),2.48(t,2H),1.23(s,3H).
The fourth step: preparation of cyclen 4HCl
Adding 884g of the intermediate 3 crude product into a reaction container, adding 1.3-1.5L of concentrated hydrochloric acid, heating to 80-100 ℃ for reaction for 3-5 hours, monitoring whether the raw materials are completely reacted by TLC (thin layer chromatography), adding 500-600 mL of methanol after the reaction is finished, stirring for half an hour, filtering, concentrating the filtrate under reduced pressure to dryness, adding 400-600 mL of pure water, adding 20-30 g of activated carbon, refluxing for 1 hour, filtering out the activated carbon, adding 100-200 mL of concentrated hydrochloric acid into the filtrate at 80-100 ℃, cooling to 40-60 ℃, dropwise adding 300-500 mL of concentrated hydrochloric acid, cooling to 0-5 ℃ by ice bath, filtering, washing the filter cake with acid water, collecting the filter cake, and performing vacuum drying to obtain 301g of a white solid with purity of 99.98% and yield of 49.2%.
1H-NMR(400MHz,CDCl3,ppm)δ:8.84(s,8H),3.21(s,16H).
The fifth step: preparation of cyclen
Adding 174g of cyclen 4 hydrochloride into a reaction container, adding 100-200 ml of pure water, heating to 80-100 ℃, dropwise adding a KOH (150-200 g) water (150-200 ml) solution, stirring for 1-3 hours under heat preservation, cooling to room temperature, separating out crystals, further cooling to 0-10 ℃ in an ice water bath, stirring for 1 hour, filtering, washing a filter cake with mother liquor, refluxing and dewatering the filter cake with toluene (500-800 ml), filtering while hot, and recrystallizing the filter cake with toluene (200-300 ml) to obtain 86g of white crystalline solid, wherein the purity is 99.98%, and the yield is 91.3%.
1H-NMR(400MHz,CDCl3,ppm)δ:2.68(s,16H),1.98(s,4H).
According to the preparation method of cyclen, the raw materials are easy to obtain, the reaction conditions are mild, and cyclen with high yield and high purity can be obtained.
Claims (7)
1. A preparation method of cycleanine comprises the following steps:
(1) refining the compound TETA to obtain an intermediate 1;
(2) reacting the intermediate 1 with methylglyoxal to obtain an intermediate 2;
(3) the intermediate 2 and glyoxal are subjected to ring closure reaction and then are reduced to obtain an intermediate 3;
(4) hydrolyzing the intermediate 3 under hydrochloric acid to obtain an intermediate 4;
(5) dissociating the intermediate 4 under an alkaline condition to obtain cyclen;
2. a method for preparing cyclen according to claim 1, wherein TETA is purified in water and toluene solution in step (1) to obtain intermediate 1.
3. A method for preparing cyclen according to claim 1, wherein the reaction is performed in step (2) under a nitrogen atmosphere, and the temperature is maintained at-10 to 5 ℃.
4. The method for preparing cyclen according to claim 1, wherein benzotriazole is further added in the ring closing reaction in step (3).
5. A method for preparing cyclen according to claim 1, wherein the reducing agent used in step (3) is sodium borohydride.
6. A method for preparing cyclen according to claim 1, wherein in step (4), intermediate 3 is hydrolytically opened under concentrated HCl to give intermediate 4.
7. The method for preparing cyclen according to claim 1, wherein the pH of the solution is adjusted with an aqueous solution of potassium hydroxide in the step (5) to obtain cyclen.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060217548A1 (en) * | 2003-06-13 | 2006-09-28 | Boschetti Frederic | Method of preparing cis-8b-methyldecahydro-2a,4a,6a,8a-tetraazacyclopenta[fg] acenaphthylene, cis-decahydro-2a,4a,6a,8a-tetraazacyclopenta[fg] acenaphthylene, cyclene and functionalised cyclenes |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060217548A1 (en) * | 2003-06-13 | 2006-09-28 | Boschetti Frederic | Method of preparing cis-8b-methyldecahydro-2a,4a,6a,8a-tetraazacyclopenta[fg] acenaphthylene, cis-decahydro-2a,4a,6a,8a-tetraazacyclopenta[fg] acenaphthylene, cyclene and functionalised cyclenes |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
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