CN113549025B - Preparation method of 1,4,7, 10-tetraazacyclododecane-1, 4, 7-triacetic acid and sodium salt thereof - Google Patents
Preparation method of 1,4,7, 10-tetraazacyclododecane-1, 4, 7-triacetic acid and sodium salt thereof Download PDFInfo
- Publication number
- CN113549025B CN113549025B CN202110795378.5A CN202110795378A CN113549025B CN 113549025 B CN113549025 B CN 113549025B CN 202110795378 A CN202110795378 A CN 202110795378A CN 113549025 B CN113549025 B CN 113549025B
- Authority
- CN
- China
- Prior art keywords
- tetraazacyclododecane
- sodium
- formula
- triacetate
- aqueous solution
- 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.)
- Active
Links
- HHLZCENAOIROSL-UHFFFAOYSA-N 2-[4,7-bis(carboxymethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetic acid Chemical compound OC(=O)CN1CCNCCN(CC(O)=O)CCN(CC(O)=O)CC1 HHLZCENAOIROSL-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 159000000000 sodium salts Chemical class 0.000 title abstract description 5
- 238000000034 method Methods 0.000 claims abstract description 20
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims abstract description 13
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 12
- 239000011734 sodium Substances 0.000 claims abstract description 12
- 239000002904 solvent Substances 0.000 claims abstract description 8
- 230000002378 acidificating effect Effects 0.000 claims abstract description 6
- -1 -tert-butyl triacetate Chemical compound 0.000 claims abstract description 4
- 125000006239 protecting group Chemical group 0.000 claims abstract description 3
- 230000003113 alkalizing effect Effects 0.000 claims abstract 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 36
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 32
- 239000007864 aqueous solution Substances 0.000 claims description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 21
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- OKHVSTSMWHWVMK-UHFFFAOYSA-K trisodium;2-[4,7-bis(carboxylatomethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CN1CCNCCN(CC([O-])=O)CCN(CC([O-])=O)CC1 OKHVSTSMWHWVMK-UHFFFAOYSA-K 0.000 claims description 12
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 10
- 239000003444 phase transfer catalyst Substances 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 238000007363 ring formation reaction Methods 0.000 claims description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims 1
- ILJSQTXMGCGYMG-UHFFFAOYSA-N triacetic acid Chemical compound CC(=O)CC(=O)CC(O)=O ILJSQTXMGCGYMG-UHFFFAOYSA-N 0.000 abstract description 8
- 239000002699 waste material Substances 0.000 abstract description 3
- 239000000203 mixture Substances 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 229910017053 inorganic salt Inorganic materials 0.000 description 10
- 239000000243 solution Substances 0.000 description 8
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- 238000001728 nano-filtration Methods 0.000 description 5
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical group [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 239000002994 raw material Substances 0.000 description 4
- XWNXEWLCHSLQOI-UHFFFAOYSA-K trisodium;triacetate Chemical compound [Na+].[Na+].[Na+].CC([O-])=O.CC([O-])=O.CC([O-])=O XWNXEWLCHSLQOI-UHFFFAOYSA-K 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 241000700141 Rotifera Species 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- QBPPRVHXOZRESW-UHFFFAOYSA-N 1,4,7,10-tetraazacyclododecane Chemical compound C1CNCCNCCNCCN1 QBPPRVHXOZRESW-UHFFFAOYSA-N 0.000 description 2
- 150000001242 acetic acid derivatives Chemical class 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- ZPDFIIGFYAHNSK-CTHHTMFSSA-K 2-[4,10-bis(carboxylatomethyl)-7-[(2r,3s)-1,3,4-trihydroxybutan-2-yl]-1,4,7,10-tetrazacyclododec-1-yl]acetate;gadolinium(3+) Chemical compound [Gd+3].OC[C@@H](O)[C@@H](CO)N1CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC1 ZPDFIIGFYAHNSK-CTHHTMFSSA-K 0.000 description 1
- ANOXEUSGZWSCQL-LOYHVIPDSA-N Cycleanine Chemical compound C([C@H]1N(C)CCC=2C=C(C(=C(OC3=CC=C(C=C3)C[C@H]3N(C)CCC=4C=C(OC)C(OC)=C(C3=4)O3)C=21)OC)OC)C1=CC=C3C=C1 ANOXEUSGZWSCQL-LOYHVIPDSA-N 0.000 description 1
- PEVPVMCJEMVCAS-UHFFFAOYSA-N Cycleanine Natural products COc1cc2CCN(C)C3Cc4ccc(Oc5cccc6CCN(C)C(Cc7ccc(Oc(c1OC)c23)cc7)c56)cc4 PEVPVMCJEMVCAS-UHFFFAOYSA-N 0.000 description 1
- RPNUMPOLZDHAAY-UHFFFAOYSA-N Diethylenetriamine Chemical compound NCCNCCN RPNUMPOLZDHAAY-UHFFFAOYSA-N 0.000 description 1
- ANOXEUSGZWSCQL-UHFFFAOYSA-N O-Methyl-isochondodendrin Natural products O1C(C2=3)=C(OC)C(OC)=CC=3CCN(C)C2CC(C=C2)=CC=C2OC(C=23)=C(OC)C(OC)=CC=2CCN(C)C3CC2=CC=C1C=C2 ANOXEUSGZWSCQL-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical class [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229960003411 gadobutrol Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002405 nuclear magnetic resonance imaging agent Substances 0.000 description 1
- 239000013110 organic ligand Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
- LMYRWZFENFIFIT-UHFFFAOYSA-N toluene-4-sulfonamide Chemical compound CC1=CC=C(S(N)(=O)=O)C=C1 LMYRWZFENFIFIT-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a preparation method of 1,4,7, 10-tetraazacyclododecane-1, 4, 7-triacetic acid and sodium salt thereof, which is characterized in that N, N-di-p-toluenesulfonic acid ethyl ester-p-toluenesulfonamideWith N- (2-aminoethyl) -ethylenediamine-1, 4, 7-tert-butyl triacetate in the presence of a base in a solvent to produce an intermediate:then removing the protective group from the intermediate under an acidic condition to prepare 1,4,7, 10-tetraazacyclododecane-1, 4, 7-triacetic acid, and alkalizing to prepare 1,4,7, 10-tetraazacyclododecane-1, 4, 7-sodium triacetate; the process is simple, high in yield, high in purity, relatively lower in cost, less in three wastes and suitable for industrial application.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of 1,4,7, 10-tetraazacyclododecane-1, 4, 7-triacetic acid and sodium salt thereof.
Background
Sodium 1,4,7, 10-tetraazacyclododecane-1, 4, 7-triacetate is an important intermediate for many metal organic ligands such as gadobutrol and the like, which coordinate with many metal ions such as Gd, eu, mn and Fe to form metal complexes, which are all potential magnetic resonance imaging contrast agents (Inorganic Chemistry 2013,52,3268-3279;New Journal of Chemistry 2016,40, 4606-4616).
The existing method for preparing 1,4,7, 10-tetraazacyclododecane-1, 4, 7-sodium triacetate basically takes the cyclen as a raw material, for example, (1) the cyclen is adopted as the raw material to react with tert-butyl bromoacetate to generate a trisubstituted acetate derivative, and the trisubstituted acetate derivative is subjected to acidic deprotection and alkalization processes to obtain a final product (Molecular Pharmaceutics,2006,3 (5), 507-515.Journal of the Chemical Society,Dalton Transactions,2002,48-54), and the yield is about 58%; (2) The method adopts the cycleanine as a raw material, and directly reacts with bromoacetic acid to generate trisubstituted sodium acetate derivatives (European Journal of Inorganic Chemistry, 2005,19,3918-3927;PCT Int.Appl.9905145) with the yield of about 69%; however, on the one hand, commercial rotifer is expensive, the yield is basically below 70% if self-made rotifer is adopted (i.e. the overall yield is basically below 50% if self-made rotifer is adopted), and three wastes are more in the preparation process; on the other hand, the selectivity of the trisubstituted products of the two routes is not high, and the yield is not ideal.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide an improved method for preparing 1,4,7, 10-tetraazacyclododecane-1, 4, 7-triacetic acid, which has the advantages of high yield, less three wastes and lower cost.
The invention also provides an intermediate for preparing the 1,4,7, 10-tetraazacyclododecane-1, 4, 7-triacetic acid.
The invention also provides a preparation method of the 1,4,7, 10-tetraazacyclododecane-1, 4, 7-sodium triacetate.
In order to achieve the above purpose, the invention adopts a technical scheme that:
a process for the preparation of a compound of formula (i), which comprises: cyclizing N, N-ethyl-p-toluenesulfonate-p-toluenesulfonamide shown in a formula (II) and N- (2-aminoethyl) -ethylenediamine-1, 4, 7-tert-butyl triacetate shown in a formula (III) in a solvent in the presence of a base to generate a compound shown in the formula (I); wherein the alkali is one or a combination of more selected from NaOH, KOH, sodium methoxide and NaH, and the solvent is N, N-dimethylformamide or toluene aqueous solution containing a phase transfer catalyst;
according to some preferred aspects of the invention, the molar ratio of the N, N-ethyl-p-toluenesulfonate-p-toluenesulfonamide represented by the formula (II), the N- (2-aminoethyl) -ethylenediamine-1, 4, 7-triacetate-tert-butyl ester represented by the formula (III) and the base is 1:1-1.1:3-6.
According to some preferred aspects of the invention, the temperature of the cyclization reaction is 70-120 ℃. In some embodiments of the invention, the temperature of the cyclization reaction is 70-110 ℃.
According to some specific aspects of the invention, the cyclization reaction has a reaction time of 12-24 hours.
According to some preferred aspects of the invention, the phase transfer catalyst is tetrabutylammonium bromide in an aqueous toluene solution containing the phase transfer catalyst, and the volume ratio of toluene to water is 2-5:1.
In some embodiments of the invention, the aqueous toluene solution containing a phase transfer catalyst comprises 0.5 to 2.0% by mass of the phase transfer catalyst.
In some embodiments of the invention, when the base is sodium methoxide or NaH or a combination of both, the solvent is N, N-dimethylformamide.
According to the present invention, N-ethyl-p-toluenesulfonate-p-toluenesulfonamide represented by formula (II) and tert-butyl N- (2-aminoethyl) -ethylenediamine-1, 4, 7-triacetate represented by formula (III) are commercially available or prepared according to conventional methods in the art.
Further, N-ethyl-p-toluenesulfonate-p-toluenesulfonamide shown in the formula (II) can be synthesized by one-step reaction of diethanolamine and p-toluenesulfonamide, and N- (2-aminoethyl) -ethylenediamine-1, 4, 7-tert-butyl triacetate shown in the formula (III) can be synthesized by one-step reaction of diethylenetriamine (reference documents: european Journal of Inorganic Chemistry 2019, 3354-3365), the yield can reach 90% or even more than 95%, and the purity is high, and the preparation is convenient.
The invention provides another technical scheme that: an intermediate for the preparation of 1,4,7, 10-tetraazacyclododecane-1, 4, 7-triacetic acid, said intermediate having a structure according to formula (i):
the invention provides another technical scheme that: a process for the preparation of 1,4,7, 10-tetraazacyclododecane-1, 4, 7-triacetic acid, the process comprising: preparing a compound shown in a formula (I) by adopting the method, and then removing a tert-butyl protecting group from the compound shown in the formula (I) under an acidic condition to generate 1,4,7, 10-tetraazacyclododecane-1, 4, 7-triacetic acid shown in a formula (IV);
according to some specific and preferred aspects of the invention, the acidic condition is formed by adding an aqueous sulfuric acid solution having a concentration of sulfuric acid of 1-3mol/L.
According to some specific and preferred aspects of the invention, the reaction to remove the tertiary butyl protecting group is carried out at a temperature of 90-120 ℃ for a period of 24-48 hours.
The invention provides another technical scheme that: a process for preparing sodium 1,4,7, 10-tetraazacyclododecane-1, 4, 7-triacetate, the process comprising: 1,4,7, 10-tetraazacyclododecane-1, 4, 7-triacetic acid represented by formula (IV) is prepared by the method described above, and then alkalization is performed by adding an aqueous solution of an inorganic base containing sodium to produce sodium 1,4,7, 10-tetraazacyclododecane-1, 4, 7-triacetate represented by formula (V);
according to some specific aspects of the invention, the sodium-containing inorganic base may be sodium hydroxide or the like.
Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:
based on the defects of low yield, high cost and the like of the existing method for preparing 1,4,7, 10-tetraazacyclododecane-1, 4, 7-triacetic acid and sodium salt thereof, the invention innovatively provides a compound shown in the formula (I) by cyclizing N, N-di-p-toluenesulfonic acid ethyl p-toluenesulfonamide shown in the formula (II) and N- (2-aminoethyl) -ethylenediamine-1, 4, 7-triacetic acid tert-butyl ester shown in the formula (III) as raw materials, and the compound shown in the formula (I) is obtained by simply deprotection and alkalization of the intermediate, so that 1,4,7, 10-tetraazacyclododecane-1, 4, 7-triacetic acid sodium salt is obtained.
Drawings
FIG. 1 is a nuclear magnetic spectrum of sodium 1,4,7, 10-tetraazacyclododecane-1, 4, 7-triacetate prepared in example 1 of the present invention.
Detailed Description
The above-described aspects are further described below in conjunction with specific embodiments; it should be understood that these embodiments are provided to illustrate the basic principles, main features and advantages of the present invention, and that the present invention is not limited by the scope of the following embodiments; the implementation conditions employed in the examples may be further adjusted according to specific requirements, and the implementation conditions not specified are generally those in routine experiments.
All starting materials are commercially available or prepared by methods conventional in the art, not specifically described in the examples below.
TBAB: tetrabutylammonium bromide; DMF: n, N-dimethylformamide.
Example 1:
tert-butyl N- (2-aminoethyl) -ethylenediamine-1, 4, 7-triacetate (10 mmol,4.45 g) and sodium hydroxide (30 mmol,1.20 g) were dissolved in 20mL of a 0.5wt.% TBAB toluene/water mixture (toluene: water volume ratio 5:1) and mixed uniformly in the reactor, and N, N-ethyl-p-toluenesulfonate-p-toluenesulfonamide (10 mmol,5.67 g) was added and the reaction was continued for 16h after heating to 110 ℃. After the reaction, the temperature was lowered, the mixture was filtered and washed, 20mL of a 1M aqueous sulfuric acid solution was added, and the mixture was reacted at 100℃for 48 hours. After the reaction is completed and the temperature is reduced, 2.81g of 1,4,7, 10-tetraazacyclododecane-1, 4, 7-triacetic acid is obtained through filtration, water washing and drying, and the yield is 81 percent and the purity is 98 percent.
Finally, the sodium triacetate is reacted with 20mL of NaOH aqueous solution to generate 1,4,7, 10-tetraazacyclododecane-1, 4, 7-sodium triacetate, nanofiltration (150D filter membrane) is carried out, small molecular inorganic salt is removed by water permeation, macromolecular products are left, aqueous solution of the products (containing a small amount of inorganic salt) is obtained, and the aqueous solution is concentrated and cooled for crystallization.
Example 2:
n- (2-aminoethyl) -ethylenediamine-1, 4, 7-triacetate (10 mmol,4.45 g) and NaH (30 mmol,0.72 g) were dissolved in 20mL DMF and mixed uniformly in a reactor, and N, N-ethyl-p-toluenesulfonate-p-toluenesulfonamide (10 mmol,5.67 g) was added thereto, and the reaction was continued for 16 hours after the temperature was raised to 70 ℃. After the reaction, the temperature was lowered, the mixture was filtered and washed, 20mL of a 1M aqueous sulfuric acid solution was added, and the mixture was reacted at 100℃for 48 hours. After the reaction is completed and the temperature is reduced, 2.46g of 1,4,7, 10-tetraazacyclododecane-1, 4, 7-triacetic acid is obtained through filtration, water washing and drying, the yield is 71 percent, and the purity is 98 percent.
Finally, the sodium triacetate is reacted with 20mL of NaOH aqueous solution to generate 1,4,7, 10-tetraazacyclododecane-1, 4, 7-sodium triacetate, nanofiltration (150D filter membrane) is carried out, small molecular inorganic salt is removed by water permeation, macromolecular products are left, aqueous solution of the products (containing a small amount of inorganic salt) is obtained, and the aqueous solution is concentrated and cooled for crystallization.
Example 3:
n- (2-aminoethyl) -ethylenediamine-1, 4, 7-triacetate (10 mmol,4.45 g) and sodium methoxide (30 mmol,1.62 g) were dissolved in 20mL of DMF and mixed uniformly in a reactor, and N, N-ethyl-p-toluenesulfonate-p-toluenesulfonamide (10 mmol,5.67 g) was added thereto, and the reaction was continued for 16 hours after the temperature was raised to 110 ℃. After the reaction, the temperature was lowered, the mixture was filtered and washed, 20mL of a 1M aqueous sulfuric acid solution was added, and the mixture was reacted at 100℃for 48 hours. After the reaction is completed and the temperature is reduced, 2.95g of 1,4,7, 10-tetraazacyclododecane-1, 4, 7-triacetic acid is obtained through filtration, water washing and drying, the yield is 85%, and the purity is 96%.
Finally, the sodium triacetate is reacted with 20mL of NaOH aqueous solution to generate 1,4,7, 10-tetraazacyclododecane-1, 4, 7-sodium triacetate, nanofiltration (150D filter membrane) is carried out, small molecular inorganic salt is removed by water permeation, macromolecular products are left, aqueous solution of the products (containing a small amount of inorganic salt) is obtained, and the aqueous solution is concentrated and cooled for crystallization.
Comparative example 1:
n- (2-aminoethyl) -ethylenediamine-1, 4, 7-triacetic acid tert-butyl ester (10 mmol,4.45 g), K 2 CO 3 (30 mmol, 4.14 g) was dissolved in 20mL of a 0.5wt.% TBAB toluene/water mixture (volume ratio 5:1) and placed in a reactor and mixed well, N-ethyl-p-toluenesulfonate-p-toluenesulfonamide (10 mmol,5.67 g) was added, and the reaction was continued for 16h after heating to 110 ℃. After the reaction, the temperature was lowered, the mixture was filtered and washed, 20mL of a 1M aqueous sulfuric acid solution was added, and the mixture was reacted at 100℃for 48 hours. After the reaction is completed and the temperature is reduced, 1.31g of 1,4,7, 10-tetraazacyclododecane-1, 4, 7-triacetic acid is obtained through filtration, water washing and drying, the yield is 38 percent, and the purity is 81 percent.
Finally, the sodium triacetate is reacted with 20mL of NaOH aqueous solution to generate 1,4,7, 10-tetraazacyclododecane-1, 4, 7-sodium triacetate, nanofiltration (150D filter membrane) is carried out, small molecular inorganic salt is removed by water permeation, macromolecular products are left, aqueous solution of the products (containing a small amount of inorganic salt) is obtained, and the aqueous solution is concentrated and cooled for crystallization.
Comparative example 2:
n- (2-aminoethyl) -ethylenediamine-1, 4, 7-triacetate (10 mmol,4.45 g) and NaOH (30 mmol,1.20 g) were dissolved in 20mL THF and mixed uniformly in the reactor, and N, N-ethyl-p-toluenesulfonate-p-toluenesulfonamide (10 mmol,5.67 g) was added thereto, and the reaction was continued after heating to 70℃for 16 hours. After the reaction, the temperature was lowered, the mixture was filtered and washed, 20mL of a 1M aqueous sulfuric acid solution was added, and the mixture was reacted at 100℃for 48 hours. After the reaction is completed and the temperature is reduced, 0.93g of 1,4,7, 10-tetraazacyclododecane-1, 4, 7-triacetic acid is obtained through filtration, water washing and drying, the yield is 27 percent, and the purity is 78 percent.
Finally, 10mmol of 1,4,7, 10-tetraazacyclododecane-1, 4, 7-triacetic acid (3.46 g) is reacted with 20mL of 2M NaOH aqueous solution to generate 1,4,7, 10-tetraazacyclododecane-1, 4, 7-sodium triacetate, nanofiltration (150D filter membrane) is carried out, small molecular inorganic salt is removed by water permeation, macromolecular products are left, aqueous solution of the products (a small amount of inorganic salt is also contained) is obtained, and the product is concentrated and cooled for crystallization.
The above embodiments are provided to illustrate the technical concept and features of the present invention and are intended to enable those skilled in the art to understand the content of the present invention and implement the same, and are not intended to limit the scope of the present invention. All equivalent changes or modifications made in accordance with the spirit of the present invention should be construed to be included in the scope of the present invention.
The endpoints and any values of the ranges disclosed herein are not limited to the precise range or value, and are understood to encompass values approaching those ranges or values. For numerical ranges, one or more new numerical ranges may be found between the endpoints of each range, between the endpoint of each range and the individual point value, and between the individual point value, in combination with each other, and are to be considered as specifically disclosed herein.
Claims (6)
1. A process for the preparation of sodium 1,4,7, 10-tetraazacyclododecane-1, 4, 7-triacetate, the process comprising:
(1) Cyclizing N, N-ethyl-p-toluenesulfonate-p-toluenesulfonamide shown in a formula (II) and N- (2-aminoethyl) -ethylenediamine-1, 4, 7-tert-butyl triacetate shown in a formula (III) in a solvent in the presence of a base to generate a compound shown in the formula (I);
wherein the alkali is NaOH or sodium methoxide or NaH or a combination of the two, and the solvent is N, N-dimethylformamide or toluene aqueous solution containing a phase transfer catalyst;
when the alkali is NaOH, the solvent is toluene aqueous solution containing a phase transfer catalyst, wherein the mass percentage of the phase transfer catalyst in the toluene aqueous solution containing the phase transfer catalyst is 0.5-2.0%, and the volume ratio of toluene to water is 2-5:1;
when the base is sodium methoxide or NaH or a combination of both, the solvent is N, N-dimethylformamide;
(2) Removing tert-butyl protecting groups from a compound shown in a formula (I) under an acidic condition to generate 1,4,7, 10-tetraazacyclododecane-1, 4, 7-triacetic acid shown in a formula (IV); the acidic condition is formed by adding sulfuric acid aqueous solution, and the concentration of sulfuric acid in the sulfuric acid aqueous solution is 1-3mol/L;
(3) Alkalizing 1,4,7, 10-tetraazacyclododecane-1, 4, 7-triacetic acid represented by formula (iv) to produce sodium 1,4,7, 10-tetraazacyclododecane-1, 4, 7-triacetate represented by formula (v), wherein the alkalization is performed by adding an aqueous solution of an inorganic base containing sodium;
2. the process for producing sodium 1,4,7, 10-tetraazacyclododecane-1, 4, 7-triacetate according to claim 1, wherein in the step (1), the molar ratio of the N, N-ethyl-p-toluenesulfonate-p-toluenesulfonamide represented by the formula (II), the t-butyl N- (2-aminoethyl) -ethylenediamine-1, 4, 7-triacetate represented by the formula (III) and the base is 1:1 to 1.1:3 to 6.
3. The process for producing sodium 1,4,7, 10-tetraazacyclododecane-1, 4, 7-triacetate according to claim 1, wherein the temperature of the cyclization reaction in step (1) is 70 to 120 ℃.
4. The process for producing sodium 1,4,7, 10-tetraazacyclododecane-1, 4, 7-triacetate according to claim 1, wherein the reaction time of the cyclization reaction in the step (1) is 12 to 24 hours.
5. The process for the preparation of sodium 1,4,7, 10-tetraazacyclododecane-1, 4, 7-triacetate according to claim 1, wherein in step (2), the reaction for removing the tertiary butyl protecting group is carried out at a temperature of 90 to 120 ℃ for a time of 24 to 48 hours.
6. The process for producing sodium 1,4,7, 10-tetraazacyclododecane-1, 4, 7-triacetate according to claim 1, wherein in the step (3), the sodium-containing inorganic base is sodium hydroxide.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110795378.5A CN113549025B (en) | 2021-07-14 | 2021-07-14 | Preparation method of 1,4,7, 10-tetraazacyclododecane-1, 4, 7-triacetic acid and sodium salt thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110795378.5A CN113549025B (en) | 2021-07-14 | 2021-07-14 | Preparation method of 1,4,7, 10-tetraazacyclododecane-1, 4, 7-triacetic acid and sodium salt thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113549025A CN113549025A (en) | 2021-10-26 |
| CN113549025B true CN113549025B (en) | 2023-07-25 |
Family
ID=78131757
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110795378.5A Active CN113549025B (en) | 2021-07-14 | 2021-07-14 | Preparation method of 1,4,7, 10-tetraazacyclododecane-1, 4, 7-triacetic acid and sodium salt thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113549025B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115894395A (en) * | 2023-02-13 | 2023-04-04 | 康化（上海）新药研发有限公司 | A kind of preparation method of cylindrine derivative |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1292130B1 (en) * | 1997-06-11 | 1999-01-25 | Bracco Spa | PROCESS FOR THE PREPARATION OF 1,4,7,10-TETRAAZACYCLODODECAN -1,4,7-TRIACETIC ACID AND ITS DERIVATIVES |
| IT1292131B1 (en) * | 1997-06-11 | 1999-01-25 | Bracco Spa | PROCESS FOR THE PREPARATION OF 5H, 9BH-2A, 4A, 7,9A-OTTAIDROTETRAAZA- CICLOOTTA (CD) PENTALENE |
| CN102399199B (en) * | 2010-09-19 | 2014-01-08 | 广州康臣药物研究有限公司 | Preparation method of magnetic resonance imaging contrast agent |
| CN102898392B (en) * | 2012-09-06 | 2015-08-12 | 中国工程物理研究院核物理与化学研究所 | N-acetyl oxygen benzyl-3-[-three tertiary fourth oxygen formyl radical-tetraazacyclododecanand bases] intermediate and preparation method thereof |
| CN108047151B (en) * | 2018-01-03 | 2020-08-04 | 广州康瑞泰药业有限公司 | Preparation method of gadobutrol with high yield |
| CN110835326B (en) * | 2018-08-15 | 2023-04-14 | 正大天晴药业集团股份有限公司 | Process for the preparation of macrocyclic chelants and intermediates therefor |
-
2021
- 2021-07-14 CN CN202110795378.5A patent/CN113549025B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN113549025A (en) | 2021-10-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108047151A (en) | A kind of preparation method of Gadobutrol in high yield | |
| CN101646492A (en) | Dmc catalysts, method for the production thereof and use thereof | |
| CN102510774B (en) | Method for producing bridged manganese complexes of triazacyclononane | |
| CN113549025B (en) | Preparation method of 1,4,7, 10-tetraazacyclododecane-1, 4, 7-triacetic acid and sodium salt thereof | |
| CN101792463B (en) | Nitrogen-containing aryl hypophosphite metal salt and preparation method thereof | |
| CN109879813A (en) | A kind of new process synthetic method of 2- sulfydryl -5- methoxybenzimidazol | |
| KR101971435B1 (en) | Gadobutrol intermediate and method for preparing gadobutrol using the same | |
| CN102791677A (en) | Preparation method of 4-aminomethylbenzoic acid | |
| CN102731422A (en) | Preparation method of 6-(N,N-dihydroxyethyl)amino-2,4-dichloro-1,3,5-triazine | |
| CN108752217B (en) | Synthesis method of dolutegravir key intermediate 2, 4-difluorobenzylamine | |
| CN111253272B (en) | Method for preparing benzamide compound | |
| CN117143105A (en) | A method for synthesizing hexabenzylhexaazaisowurtzitane using an ionic liquid catalyst | |
| CN111018782B (en) | Preparation method of 9-aminoacridine and derivatives thereof | |
| CN110002403A (en) | A kind of boron hydronitrogen sodium salt Na [BH3NH2BH3] synthetic method | |
| CN113072452B (en) | Method for catalytically synthesizing o-aminophenol | |
| CN109225323B (en) | Sulfonic acid functionalized organic/inorganic double cation-vanadium-doped heteropolyacid anion composite hybrid and its synthesis and application | |
| CN114478216A (en) | Novel synthesis method of 1-acetyl-1-chlorocyclopropane | |
| CN109589998B (en) | Novel ZnO/Se/SiO2Preparation method of composite material and application of composite material in preparation of phthalide | |
| CN1101817C (en) | Process for prepn. of tetraazamacrocycles | |
| JP5019086B2 (en) | Manufacturing method of near infrared absorber | |
| CN101379031B (en) | Improved method for preparing stable nitroxyl radicals | |
| CN110642789A (en) | Continuous synthesis method of 2-chloropyrimidine-4-formic acid compound | |
| KR20210112910A (en) | Method for manufacturing calcobutrol to gadovist excipient | |
| CN112300198B (en) | Synthesis method of cefixime and cefixime ester | |
| JP2005145896A (en) | Method for producing metal phthalocyanine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |