CN103772307A - Preparation method of DOTA.2HCl - Google Patents
Preparation method of DOTA.2HCl Download PDFInfo
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- CN103772307A CN103772307A CN201210407810.XA CN201210407810A CN103772307A CN 103772307 A CN103772307 A CN 103772307A CN 201210407810 A CN201210407810 A CN 201210407810A CN 103772307 A CN103772307 A CN 103772307A
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- dota2hcl
- tetraazacyclododecanand
- nitrae
- isosorbide
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- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- WDLRUFUQRNWCPK-UHFFFAOYSA-N Tetraxetan Chemical compound OC(=O)CN1CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC1 WDLRUFUQRNWCPK-UHFFFAOYSA-N 0.000 title abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 36
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 20
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000002994 raw material Substances 0.000 claims abstract description 7
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 claims abstract description 5
- 230000007062 hydrolysis Effects 0.000 claims abstract description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 4
- 230000002378 acidificating effect Effects 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 66
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 23
- JMANVNJQNLATNU-UHFFFAOYSA-N glycolonitrile Natural products N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 claims description 14
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 10
- 239000003513 alkali Substances 0.000 claims description 4
- 239000000376 reactant Substances 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 3
- 239000000047 product Substances 0.000 abstract description 13
- -1 cyanomethylene Chemical group 0.000 abstract description 4
- QBPPRVHXOZRESW-UHFFFAOYSA-N 1,4,7,10-tetraazacyclododecane Chemical compound C1CNCCNCCNCCN1 QBPPRVHXOZRESW-UHFFFAOYSA-N 0.000 abstract description 3
- 239000006227 byproduct Substances 0.000 abstract description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 17
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000009413 insulation Methods 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 5
- 239000008098 formaldehyde solution Substances 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- 229910017053 inorganic salt Inorganic materials 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-O oxonium Chemical compound [OH3+] XLYOFNOQVPJJNP-UHFFFAOYSA-O 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 238000010907 mechanical stirring Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- VUKOLUDZTXFTAM-UHFFFAOYSA-N CCC(CN)C=C Chemical compound CCC(CN)C=C VUKOLUDZTXFTAM-UHFFFAOYSA-N 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000002872 contrast media Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 230000000694 effects Effects 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
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000003127 radioimmunoassay Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000003579 shift reagent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention discloses a preparation method of DOTA.2HCl. According to the preparation method, 1,4,7,10-tetraazacyclododecane, formaldehyde, and sodium cyanide are taken as raw materials; 1,4,7,10-tetra(cyanomethylene)-N-tetraazacyclododecane is obtained via reaction at a temperature of 0 to 3 DEG C under acidic conditions; hydrolysis of 1,4,7,10-tetra(cyanomethylene)-N-tetraazacyclododecane is performed under alkaline conditions, and obtained products are reacted with hydrochloric acid so as to obtain DOTA.2HCl. The preparation method possesses following advantages: the raw materials are easily available; operation is safe; by-product is less; and the preparation method is friendly to the environment.
Description
Technical field
The present invention relates to the synthetic of chemical substance, the particularly preparation method of a kind of DOTA2HCl.
Background technology
DOTA2HCl (1,4,7,10-tetraazacyclododecanand-1,4,7,10-tetraacethyl) be the polynitrogen heterocycle alkane that typical N replaces, its complex compound can be used for contrast medium, (NMR) shift reagent and radioimmunoassay development and the treatment etc. of medical diagnosis nuclear magnetic resonance technique (MRI), has noticeable development prospect.So synthetic DOTA2HCl tool is of great significance.
The structural formula of DOTA2HCl is:
molecular formula is C
16h
20n
4o
8c
12, molecular weight is 477.
The method of existing synthetic DOTA2HCl, comprising:
As document (synthesizing of some tetraacethyl tetraazacyclododecane alkane, complex compound, chemical reagent, 18,168,1996) disclosed content, with alkali as acid binding agent, Isosorbide-5-Nitrae, there is N-carboxymethylation reaction in 7,10-tetraazacyclododecanand and halogen acetic acid, generates DOTA2HCl.The method reaction conditions is strict, and reaction process is wayward, affected by pH value, is unfavorable for large-scale industrialization production; Meanwhile, compound purity prepared by the method is limited, conventionally need to could obtain product through the column chromatography separation method that raw material consumption is large, cost is higher.
As document (selectivity one-step synthesis Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand three substituted alkyl compounds, Tetrahedron, 60,5595,2004) disclosed content, under alkali effect, bromo-acetic acid tert-butyl and Isosorbide-5-Nitrae, 7, the reaction of 10-tetraazacyclododecanand, generates Isosorbide-5-Nitrae, 7,10-tetra-(tertiary butyloxycarbonyl methylene)-N-tetraazacyclododecanand, and then be hydrolyzed to obtain DOTA2HCl.Obtain a small amount of target product, major part is trisubstitution product.The method cost is higher simultaneously, is not suitable for suitability for industrialized production.
Summary of the invention
For the existing weak point of prior art preparation method, the invention provides the preparation method of a kind of DOTA2HCl, its reaction scheme is as follows:
Said method comprising the steps of:
(1) with Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand, formaldehyde, sodium cyanide are raw material, under acidic conditions, obtain Isosorbide-5-Nitrae in 0-3 ℃ of reaction, 7,10-tetra-(cyanogen methylene radical)-N-tetraazacyclododecanand;
(2), under alkaline condition, described step (1) product is hydrolyzed, and obtains described DOTA2HCl with hydrochloric acid reaction.
In described step (1), by Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand is dissolved in water, regulate pH to 4-5, be chilled to 0-3 ℃, add formaldehyde, sodium cyanide, regulate pH to 4.5-6.0 to react, obtain described Isosorbide-5-Nitrae, 7,10-tetra-(cyanogen methylene radical)-N-tetraazacyclododecanand.
In step (1), the mol ratio of reactant is Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand: formaldehyde: sodium cyanide=1: 5-6: 5-6.
In described step (2), under alkaline condition, by described Isosorbide-5-Nitrae, 7,10-tetra-(cyanogen methylene radical)-N-tetraazacyclododecanand through hydrolysis, obtains DOTA2HCl with hydrochloric acid reaction at 80-90 ℃.
In step (2), the mol ratio of reactant is Isosorbide-5-Nitrae, 7,10-tetra-(cyanogen methylene radical)-N-tetraazacyclododecanand: alkali (as: LiOHH2O)=1: 11-13.In step (2), take water and methyl alcohol as mixed solvent, volume ratio is methyl alcohol: water=1: 3-5.
In step of the present invention (1) reaction process, the nucleophilicity of the cyanide ion in sodium cyanide is stronger, and sterically hindered less, is easy to replace Isosorbide-5-Nitrae, all H ions of the upper N of 7,10-tetraazacyclododecanand (cyclen).In step (2), under alkaline condition, remove cyano group completely through hydrolysis and obtain target product.The advantage of this reaction is simple to operate, mild condition, and raw material easily obtains, and by product is less, and synthetic reaction product yield is high, is easy to purifying, can be used for suitability for industrialized production.
The present invention compared with prior art has raw material and easily obtains, and has production cost lower, operational safety, the advantage such as by product is few, environmentally friendly.
Embodiment
In conjunction with following specific embodiment, the present invention is described in further detail.Implement process of the present invention, condition, reagent, experimental technique etc., except the content of mentioning specially below, be universal knowledege and the common practise of this area, the present invention is not particularly limited content.
The preparation method of DOTA2HCl of the present invention, comprises the following steps:
(1) Isosorbide-5-Nitrae, the preparation of 7,10-tetra-(cyanogen methylene radical)-N-tetraazacyclododecanand
By 1, 4, 7, 10-tetraazacyclododecanand (cyclen) is dissolved in water, regulate pH to 4-5, be chilled to 0-3 ℃, first drip a part of formaldehyde solution, two mixed solution and sodium cyanide solutions that drip formaldehyde and acetic acid again, after the mixed solution of formaldehyde and acetic acid drips off, remaining sodium cyanide solution continues to drip, drip acetum to maintain between pH=4.5-6.0 simultaneously, more than dripping off 0-3 ℃ of insulation reaction 8h, filter gained solid soluble in water, a small amount of 10% NaOH is adjusted to PH and is greater than 10, stir half an hour, filter gained solid acetone thermosol, heat filtering is removed inorganic salt, backflow boils off after the acetone of half, coolingly make product fully separate out rear filtration to make intermediate 1, 4, 7, 10-tetra-(cyanogen methylene radical)-N-tetraazacyclododecanand.
(2) preparation of DOTA2HCl:
Two hydronium(ion) oxidation lithiums are joined in water and methanol mixed solvent, be warming up to 80 ℃ of left and right, uncovered lower one side drips step (1) gained intermediate in batches, drip methyl alcohol on one side in batches, about 4-5 hour drips, and then, 80-90 ℃ of lower open mouth reaction, within later every 3-4 hour, drips a methyl alcohol, divide and drip for three times, altogether more than insulation reaction 50h.The basic water to the greatest extent that steams of decompression, adds after methyl alcohol band water evaporate to dryness, then adds methyl alcohol, is neutralized to about pH=3.5 with the methanol solution of hydrochloric acid, then adds acetone, coolingly makes product fully separate out rear filtration to obtain target product DOTA2HCl.
Embodiment 1
(1) Isosorbide-5-Nitrae, the preparation of 7,10-tetra-(cyanogen methylene radical)-N-tetraazacyclododecanand
In the four-hole bottle of 1000ml, disposable 250ml and 1 of adding water, 4, 7, 10-tetraazacyclododecanand 34.4g (0.2mol), under mechanical stirring, use concentrated hydrochloric acid (about 42ml, 0.4mol) adjust PH=4-5, bathe and control reaction solution at 0-3 ℃ with cryosel, about 10min drips approximately 1 equivalent (16g, formaldehyde solution (massfraction 37%) 0.2mol), remaining formaldehyde solution 81.3g (1.0mol) mixes with about acetic acid 66g (0.9mol), be 0-3 ℃ of dropping at reaction solution, drip this mixed solution and sodium cyanide solution 196g (massfraction is 30% simultaneously, 1.2mol), approximately 4 hours, the acetum of formaldehyde dropwises, at this moment sodium cyanide also approximately remains 1 equivalent (33g, 0.2mol), when continuing to drip sodium cyanide, the acetic acid that drips again about 13-15g is to keep in whole dropping process pH value between 4.5-6, after all dripping off, continue to make reaction solution about 0-3 ℃ insulation 8 hours.In above reaction process, if there is a small amount of solid to separate out, sodium cyanide approximately drips a half, adds the acetone of 100-150ml in reaction solution, increases solubleness, reaction is carried out more thorough.
Aftertreatment:
1., after reaction finishes, filter, frozen water drip washing solid, after draining, without drying solid suspension in 150ml water, a small amount of 10% NaOH adjusts PH > 10, fully stirs after 0.5 hour and filters, and ethyl acetate drip washing is dried.
2. crude product ebuillition of heated in acetone (1: 12) solution dissolves, and filtered while hot is removed inorganic salt, and backflow step-down boils off after the acetone of half, be chilled to 5-10 ℃, insulation is greater than 2h makes product fully separate out rear filtration, a small amount of acetone drip washing, dry, survey fusing point 158-160 ℃.Yield 80%, HPLC content 99%.1H-NMR(CDCl
3)δ：2.60(16H，s)，3.67(8H，s)。
(2) DOTA2HCl's is synthetic
In the there-necked flask of 2000ml, disposable water 1200ml, methyl alcohol 60ml and the two hydronium(ion)s oxidation lithium 39g (0.93mol) of adding, be warming up to 80 ℃ of left and right, uncovered lower one side drips DOTA intermediate 1 in batches, 4,7,10-tetra-(cyanogen methylene radical)-N-tetraazacyclododecanand (2.5*10 time=25g), drip methyl alcohol (18*10 time=180ml) on one side in batches, about 4-5 hour drips, and then, 80-90 ℃ of lower open mouth reaction, within later every 3-4 hour, drips a methyl alcohol, divide and drip (20ml*3 time) three times, altogether more than insulation reaction 50h.
Aftertreatment:
The basic water (interior temperature is no more than 90 ℃) to the greatest extent that steams of decompression, add after 2 band water evaporates to dryness of 50ml methyl alcohol *, add again 60ml methyl alcohol, be neutralized to about Ph=3.5 (interior temperature is no more than 20 ℃) with the methanol solution (mass concentration is more than 30%) of hydrochloric acid, add again 300ml acetone, then more than being chilled to about 5 ℃ maintenance 1h, filter a small amount of acetone drip washing, drain (easily water suction), the 50 ℃ of oven dry of reducing pressure, DOTA2HCl product 34g, fusing point > 300 spends, yield 93%, HPLC content 97.7%.1H-NMR(D
2O)δ：2.73(16H，s)，3.65(8H，s)。
Embodiment 2
(1) Isosorbide-5-Nitrae, the preparation of 7,10-tetra-(cyanogen methylene radical)-N-tetraazacyclododecanand
In the four-hole bottle of 250ml, disposable 50ml and 1 of adding water, 4, 7, 10-tetraazacyclododecanand 6.44g (0.04mol), under mechanical stirring, use concentrated hydrochloric acid (about 8.2ml, 0.08mol) adjust PH=4-5, bathe and control reaction solution at 0-2 ℃ with cryosel, about 10min drips approximately 1 equivalent (3.2g, formaldehyde solution (massfraction 37%) 0.04mol), remaining formaldehyde solution 14.6g (0.18mol) mixes with about acetic acid 11.8g (0.16mol), be 0-2 ℃ of dropping at reaction solution, drip this mixed solution and sodium cyanide solution 36.0g (massfraction is 30% simultaneously, 0.22mol), approximately 4 hours, the acetum of formaldehyde dropwises, at this moment sodium cyanide also approximately remains 1 equivalent (6.6g, 0.04mol), when continuing to drip sodium cyanide, the acetic acid that drips again about 1.3-1.5g is to keep in whole dropping process pH value between 4.5-6, after all dripping off, continue to make reaction solution about 0-2 ℃ insulation 8 hours.(note: be that sodium cyanide approximately drips a half if there is a small amount of solid to separate out in reaction process, add the acetone of 20-30ml in reaction solution, increase solubleness, reaction is carried out more thorough)
Aftertreatment:
1., after reaction finishes, filter, frozen water drip washing solid, after draining, without drying solid suspension in 30ml water, a small amount of 10% NaOH adjusts PH > 10, fully stirs after 0.5 hour and filters, and ethyl acetate drip washing is dried.
2. crude product ebuillition of heated in acetone (1: 12) solution dissolves, and filtered while hot is removed inorganic salt, and backflow step-down boils off after the acetone of half, be chilled to 5-10 ℃, insulation is greater than 2h makes product fully separate out rear filtration, a small amount of acetone drip washing, dry, survey fusing point 158-160 ℃.Yield 76%, HPLC content 98%.1H-NMR(CDCl3)δ：2.60(16H，s)，3.67(8H，s)。
(2) DOTA2HCl's is synthetic
In the there-necked flask of 500ml, disposable water 260ml, methyl alcohol 15ml and the two hydronium(ion)s oxidation lithium 7.5g (0.18mol) of adding, be warming up to 80 ℃ of left and right, uncovered lower one side drips DOTA intermediate 1 in batches, 4,7,10-tetra-(cyanogen methylene radical)-N-tetraazacyclododecanand (0.5*10 time=5g), drip methyl alcohol (5*10 time=50ml) on one side in batches, about 4-5 hour drips, and then, 80-90 ℃ of lower open mouth reaction, within later every 3-4 hour, drips a methyl alcohol, divide and drip (5ml*3 time) three times, altogether more than insulation reaction 50h.
Aftertreatment:
The basic water (interior temperature is no more than 90 ℃) to the greatest extent that steams of decompression, add after 2 band water evaporates to dryness of 10ml methyl alcohol *, add again 10ml methyl alcohol, be neutralized to about Ph=3.5 (interior temperature is no more than 20 ℃) with the methanol solution (mass concentration is more than 30%) of hydrochloric acid, add again 60ml acetone, then more than being chilled to about 5 ℃ maintenance 1h, filter a small amount of acetone drip washing, drain (easily water suction), the 50 ℃ of oven dry of reducing pressure, product 6.4g, fusing point > 300 spends, yield 87%, HPLC content 95.6%.1H-NMR(D2O)δ：2.73(16H，s)，3.65(8H，s)。
Protection content of the present invention is not limited to above embodiment.Do not deviating under the spirit and scope of inventive concept, variation and advantage that those skilled in the art can expect are all included in the present invention, and take appending claims as protection domain.
Claims (6)
1. a preparation method of DOTA2HCl, is characterized in that, shown in following reaction equation:
Said method comprising the steps of:
(1) with Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand, formaldehyde, sodium cyanide are raw material, under acidic conditions, obtain Isosorbide-5-Nitrae in 0-3 ℃ of reaction, 7,10-tetra-(cyanogen methylene radical)-N-tetraazacyclododecanand;
(2), under alkaline condition, described step (1) product is hydrolyzed, and obtains described DOTA2HCl with hydrochloric acid reaction.
2. the preparation method of DOTA2HCl as claimed in claim 1, is characterized in that, in described step (1), by Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand is dissolved in water, regulates pH to 4-5, is chilled to 0-3 ℃, add formaldehyde, sodium cyanide, regulate pH to 4.5-6.0 to react, obtain described Isosorbide-5-Nitrae, 7,10-tetra-(cyanogen methylene radical)-N-tetraazacyclododecanand.
3. the preparation method of DOTA2HCl as claimed in claim 1, is characterized in that, in step (1), the mol ratio of reactant is Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand: formaldehyde: sodium cyanide=1: 5-6: 5-6.
4. the preparation method of DOTA2HCl as claimed in claim 1, it is characterized in that, in described step (2), under alkaline condition, by described Isosorbide-5-Nitrae, 7,10-tetra-(cyanogen methylene radical)-N-tetraazacyclododecanand through hydrolysis, obtains DOTA2HCl with hydrochloric acid reaction at 80-90 ℃.
5. the preparation method of DOTA2HCl as claimed in claim 1, is characterized in that, in described step (2), the mol ratio of reactant is Isosorbide-5-Nitrae, 7,10-tetra-(cyanogen methylene radical)-N-tetraazacyclododecanand: alkali=1: 11-13.
6. the preparation method of DOTA2HCl as claimed in claim 1, is characterized in that, in described step (2), take water and methyl alcohol as mixed solvent, volume ratio is methyl alcohol: water=1: 3-5.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5428156A (en) * | 1993-04-02 | 1995-06-27 | Associated Universities, Inc. | Synthesis of macrocyclic polyaminocarboxylates and their use for preparing stable radiometal antibody immunoconjugates for therapy, spect and pet imaging |
| CN102659702A (en) * | 2012-04-09 | 2012-09-12 | 武汉工程大学 | Purifying process of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetracetic acid (DOTA) |
-
2012
- 2012-10-18 CN CN201210407810.XA patent/CN103772307A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5428156A (en) * | 1993-04-02 | 1995-06-27 | Associated Universities, Inc. | Synthesis of macrocyclic polyaminocarboxylates and their use for preparing stable radiometal antibody immunoconjugates for therapy, spect and pet imaging |
| CN102659702A (en) * | 2012-04-09 | 2012-09-12 | 武汉工程大学 | Purifying process of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetracetic acid (DOTA) |
Non-Patent Citations (1)
| Title |
|---|
| 扈艳红等: "微波辐射技术在1,4,7,10-四氮杂环十二烷四乙酸合成中的应用", 《合成化学》, vol. 15, no. 4, 31 August 2007 (2007-08-31), pages 491 - 493 * |
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Application publication date: 20140507 |