JP2006342105A5 - - Google Patents
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- JP2006342105A5 JP2006342105A5 JP2005169511A JP2005169511A JP2006342105A5 JP 2006342105 A5 JP2006342105 A5 JP 2006342105A5 JP 2005169511 A JP2005169511 A JP 2005169511A JP 2005169511 A JP2005169511 A JP 2005169511A JP 2006342105 A5 JP2006342105 A5 JP 2006342105A5
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- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 claims description 37
- 238000004519 manufacturing process Methods 0.000 claims description 31
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- 239000000243 solution Substances 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 18
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 18
- BWFPGXWASODCHM-UHFFFAOYSA-N Copper monosulfide Chemical compound [Cu]=S BWFPGXWASODCHM-UHFFFAOYSA-N 0.000 claims description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 150000002500 ions Chemical class 0.000 claims description 12
- 229910052751 metal Inorganic materials 0.000 claims description 12
- 239000002184 metal Substances 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 11
- 239000011259 mixed solution Substances 0.000 claims description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 8
- RWSOTUBLDIXVET-UHFFFAOYSA-N dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 claims description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 8
- 229910000037 hydrogen sulfide Inorganic materials 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid group Chemical group S(O)(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- ORTQZVOHEJQUHG-UHFFFAOYSA-L Copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- QMMRZOWCJAIUJA-UHFFFAOYSA-L Nickel(II) chloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 claims description 5
- 238000004587 chromatography analysis Methods 0.000 claims description 5
- -1 -tert-butyl DTPA Chemical compound 0.000 claims description 4
- GVPFVAHMJGGAJG-UHFFFAOYSA-L Cobalt(II) chloride Chemical compound [Cl-].[Cl-].[Co+2] GVPFVAHMJGGAJG-UHFFFAOYSA-L 0.000 claims description 4
- QTMDXZNDVAMKGV-UHFFFAOYSA-L Copper(II) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 claims description 4
- XTVVROIMIGLXTD-UHFFFAOYSA-N Copper(II) nitrate Chemical compound [Cu+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O XTVVROIMIGLXTD-UHFFFAOYSA-N 0.000 claims description 4
- ARUVKPQLZAKDPS-UHFFFAOYSA-L Copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 4
- RPNUMPOLZDHAAY-UHFFFAOYSA-N DETA Chemical compound NCCNCCN RPNUMPOLZDHAAY-UHFFFAOYSA-N 0.000 claims description 4
- NMCUIPGRVMDVDB-UHFFFAOYSA-L Iron(II) chloride Chemical compound Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 claims description 4
- RLJMLMKIBZAXJO-UHFFFAOYSA-N Lead(II) nitrate Chemical compound [O-][N+](=O)O[Pb]O[N+]([O-])=O RLJMLMKIBZAXJO-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 239000012300 argon atmosphere Substances 0.000 claims description 4
- 230000005591 charge neutralization Effects 0.000 claims description 4
- 229910000365 copper sulfate Inorganic materials 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 229960002089 ferrous chloride Drugs 0.000 claims description 4
- 239000008079 hexane Substances 0.000 claims description 4
- 230000001264 neutralization Effects 0.000 claims description 4
- 238000006386 neutralization reaction Methods 0.000 claims description 4
- 239000001184 potassium carbonate Substances 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- MRMBZUFUXAUVPR-UHFFFAOYSA-M 2-chloro-3,3-dimethylbutanoate Chemical compound CC(C)(C)C(Cl)C([O-])=O MRMBZUFUXAUVPR-UHFFFAOYSA-M 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 229940089960 Chloroacetate Drugs 0.000 claims 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
- 230000003197 catalytic Effects 0.000 claims 1
- 238000006555 catalytic reaction Methods 0.000 claims 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-M chloroacetate Chemical compound [O-]C(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-M 0.000 claims 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- 229960003330 Pentetic Acid Drugs 0.000 description 28
- 229910052739 hydrogen Inorganic materials 0.000 description 16
- 229910052757 nitrogen Inorganic materials 0.000 description 12
- 238000010586 diagram Methods 0.000 description 10
- 229910052799 carbon Inorganic materials 0.000 description 8
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 238000001819 mass spectrum Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 230000002194 synthesizing Effects 0.000 description 4
- 238000000921 elemental analysis Methods 0.000 description 3
- 238000005886 esterification reaction Methods 0.000 description 3
- 239000011724 folic acid Substances 0.000 description 3
- OXBLHERUFWYNTN-UHFFFAOYSA-M Copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- LGMLJQFQKXPRGA-VPVMAENOSA-K gadopentetate dimeglumine Chemical compound [Gd+3].CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.OC(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O LGMLJQFQKXPRGA-VPVMAENOSA-K 0.000 description 2
- 230000003301 hydrolyzing Effects 0.000 description 2
- 238000009206 nuclear medicine Methods 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- NPRHUCJECACQPL-NZHWIVLNSA-J 2-[2-[[2-[2-[[(4S)-4-[[4-[(2-amino-4-oxo-1H-pteridin-6-yl)methylamino]benzoyl]amino]-4-carboxybutanoyl]amino]ethylamino]-2-oxoethyl]-(carboxylatomethyl)amino]ethyl-[2-[bis(carboxylatomethyl)amino]ethyl]amino]acetate;indium-111 Chemical compound [111In].C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(=O)NCCNC(=O)CN(CCN(CCN(CC([O-])=O)CC([O-])=O)CC([O-])=O)CC([O-])=O)C(O)=O)C=C1 NPRHUCJECACQPL-NZHWIVLNSA-J 0.000 description 1
- RAZLJUXJEOEYAM-UHFFFAOYSA-N 2-[bis[2-(2,6-dioxomorpholin-4-yl)ethyl]azaniumyl]acetate Chemical compound C1C(=O)OC(=O)CN1CCN(CC(=O)O)CCN1CC(=O)OC(=O)C1 RAZLJUXJEOEYAM-UHFFFAOYSA-N 0.000 description 1
- JQOAQUXIUNVRQW-UHFFFAOYSA-N CCCCCC.CCCCCC Chemical compound CCCCCC.CCCCCC JQOAQUXIUNVRQW-UHFFFAOYSA-N 0.000 description 1
- 229940039231 CONTRAST MEDIA Drugs 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000002872 contrast media Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 238000002595 magnetic resonance imaging Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006011 modification reaction Methods 0.000 description 1
- PCJGZPGTCUMMOT-UHFFFAOYSA-N neurotensin Chemical class C1CCN(C(=O)C(CCCNC(N)=N)NC(=O)C(CCCNC(N)=N)NC(=O)C2N(CCC2)C(=O)C(CCCCN)NC(=O)C(CC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C2NC(=O)CC2)C1C(=O)NC(C(=O)NC(C(C)CC)C(=O)NC(CC(C)C)C(O)=O)CC1=CC=C(O)C=C1 PCJGZPGTCUMMOT-UHFFFAOYSA-N 0.000 description 1
- 239000002405 nuclear magnetic resonance imaging agent Substances 0.000 description 1
- 230000003287 optical Effects 0.000 description 1
- DMTUQTRZIMTUQV-UHFFFAOYSA-N potassium;ethenylideneazanide Chemical compound [K+].[CH2-]C#N DMTUQTRZIMTUQV-UHFFFAOYSA-N 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000002441 reversible Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Description
本発明は、DTPA誘導体の製造方法に関し、特に、ペンタ-アルキル基-DTPA（penta-alkyl
DTPA）を作製して、金属イオンを触媒剤として、選択的に加水分解することにより、テトラ-アルキル基-DTPA（tetra-alkyl DTPA）を作製でき、即ち、造影剤や医療及び化学産業に応用できる、シングルの活性であるDTPA誘導体を作製できるものに関する。
The present invention relates to a method for producing a DTPA derivative, and in particular, penta-alkyl group-DTPA (penta-alkyl).
DTPA) can be prepared by selective hydrolysis using metal ions as a catalyst agent. Tetra-alkyl DTPA (tetra-alkyl DTPA) can be produced, that is, applied to contrast media and medical and chemical industries. It is possible to produce a single active DTPA derivative.
DTPA（Diethylene
triamine pentaacetic acid）は、二つの官能基であるキレートであり、ペプチドやタンパク質とカップリングした後、放射性同位元素にラベルされ、核医学薬品や磁気共鳴造影（MRI）及び光学造影システム（optical imaging）に応用でき、従来のDTPA誘導体の製造方法は、インジウム-111-DTPA-葉酸（111In-DTPA-folate）やテクネチウム-99ｍ-DTPA-葉酸（99mTc-DTPA-folate）、イットリウム-90DTPA-D-フェニル基アラニン-オクトレ オチド（90Y-DTPA-D-Phe-Octreotide）或いはインジウム-111-DTPA-D-フェニル基アラニン-オクトレオチド（111In-DTPA-D-Phe-Octreotide）を標的性の核医学薬品とすることができ、或いは、ガドリニウム-DTPA（Gd-DTPA）をニューロテンシン（neurotensin）誘導体に連結して、磁気共鳴造影剤とすることができる。
DTPA (Diethylene
Triamine pentaacetic acid) is a chelate that is two functional groups, coupled with peptides and proteins, then labeled with radioisotopes, nuclear medicine, magnetic resonance imaging (MRI), and optical imaging systems. The conventional methods for producing DTPA derivatives are indium-111-DTPA-folic acid (111In-DTPA-folate), technetium-99m-DTPA-folic acid (99mTc-DTPA-folate), and yttrium-90DTPA-D-phenyl. Alanine-octreotide (90Y-DTPA-D-Phe-Octreotide) or Indium-111-DTPA-D-phenyl-alanine-octreotide (111In-DTPA-D-Phe-Octreotide) as a targeted nuclear medicine Alternatively, gadolinium-DTPA (Gd-DTPA) can be linked to a neurotensin derivative to form a magnetic resonance contrast agent.
標的分子（例えば、ペプチド、タンパク質）が、DTPAのようなジアンヒドリド類（DTPA dianhydride）とカップリング反応することにより、生成物が得られるだけでなく、DTPAが二つの標的分子と結合する副生成物が得られ、また、上記の工程は、面倒な分離工程が必要し、そして、生産率が低いという欠点があるため、実用上に不足である。 A target molecule (eg, peptide, protein) can be coupled with a DTPA dianhydride such as DTPA to produce a product, as well as a by-product of DTPA binding to two target molecules. In addition, the above process requires a troublesome separation process and has a disadvantage that the production rate is low.
そのため、本発明の主な目的は、工程が簡単で、生産率が高いDTPA誘導体の製造方法を提供する。 Therefore, a main object of the present invention is to provide a method for producing a DTPA derivative with a simple process and a high production rate.
本発明は、上記の目的を達成するためのDTPA誘導体の製造方法であり、DTPA（Diethylene triamine pentaacetic acid）をアルコール溶液と混合してから、触媒剤として硫酸を添加してエステル化反応を行い、そして、24時間の向流反応を行い、溶剤を除去し、そして、飽和炭酸水素ナトリウム水溶液で酸中和を行うと、ペンタ-エチル基-DTPA（penta-ethyl
DTPA）が得られ、当該ペンタ-エチル基-DTPAを、金属イオンと水溶液を混合して攪拌し、そして、アルカリ溶液を添加して攪拌してから、硫化水素（H2S）を導入して硫化銅を含有する混合液が形成され、当該硫化銅を含有する混合液について、ろ紙で硫化銅をろ過し、そして、管柱により純化すると、テトラ-エチル基-DTPA（tetra-ethyl
DTPA）が得られる。
The present invention is a method for producing a DTPA derivative for achieving the above object, and after mixing DTPA (Diethylene triamine pentaacetic acid) with an alcohol solution, an esterification reaction is performed by adding sulfuric acid as a catalyst agent, Then, the countercurrent reaction was performed for 24 hours, the solvent was removed, and acid neutralization was performed with a saturated aqueous solution of sodium hydrogen carbonate. Then, penta-ethyl group-DTPA (penta-ethyl
DTPA) is obtained, and the penta-ethyl group-DTPA is mixed with a metal ion and an aqueous solution and stirred. Then, an alkali solution is added and stirred, and then hydrogen sulfide (H 2 S) is introduced. A mixed liquid containing copper sulfide is formed. When the mixed liquid containing copper sulfide is filtered with a filter paper and purified with a tube column, tetra-ethyl group-DTPA (tetra-ethyl group) is obtained.
DTPA) is obtained.
また、本発明は、もう一つのDTPA誘導体の製造方法を提供し、アルゴン雰囲気下で、ジエチレントリアミン（Diethylenetriamine）を、炭酸カリウムとアセトニトリル（acetonitrile）と攪拌混合してから、アセトニトリルに溶けられたtert-ブチルクロロ酢酸塩（tert-butyl chloroacetate）を添加して、室温下で24時間の反応を行ってから、溶液を除去し粉末をろ過し、また、エーテルとヘキサン（hexane）とを混合して、溶液でクロマトグラフィの管柱により分離純化すると、ペンタ-tert-ブチル-DTPA（penta-tert-butyl
DTPA）が得られ、当該ペンタ-tert-ブチル-DTPAを、金属イオンと水溶液を混合して攪拌し、水酸化ナトリウムや水酸化カリウムであるアルカリ溶液を添加して攪拌してから、硫化水素（H2S）を導入して硫化銅を含有する混合液を形成し、そして、当該硫化銅を含有する混合液をろ紙でろ過し、また、管柱により純化すると、テトラ-tert-ブチル-DTPA（tetra-tert-butyl
DTPA）が得られる。
The present invention also provides another method for producing a DTPA derivative. In an argon atmosphere, diethylenetriamine is stirred and mixed with potassium carbonate and acetonitrile, and then dissolved in acetonitrile. After adding tert-butyl chloroacetate and reacting at room temperature for 24 hours, the solution is removed, the powder is filtered, and ether and hexane are mixed to obtain a solution. And purified by chromatography using a column of chromatography, penta-tert-butyl-DTPA (penta-tert-butyl
DTPA) is obtained, and the penta-tert-butyl-DTPA is mixed with a metal ion and an aqueous solution, stirred, an alkali solution such as sodium hydroxide or potassium hydroxide is added and stirred, and then hydrogen sulfide ( H 2 S) is introduced to form a mixed solution containing copper sulfide, and the mixed solution containing copper sulfide is filtered through a filter paper and purified by a tube column to obtain tetra-tert-butyl-DTPA. (Tetra-tert-butyl
DTPA) is obtained.
本発明のDTPA誘導体の製造方法によれば、まず、ペンタ-アルキル基-DTPA（penta-alkyl
DTPA）を作製して、当該ペンタ-アルキル基-DTPAを、金属イオンを触媒剤として、選択的に加水分解すると、テトラ-アルキル基-DTPA（tetra-alkyl
DTPA）が得られ、即ち、上記の二つの反応工程で、シングルの活性であるDTPA誘導体を作製できることにより、工程が簡単で、生産率が少なくとも51％以上である。
According to the method for producing a DTPA derivative of the present invention, first, a penta-alkyl group-DTPA (penta-alkyl)
DTPA), and then selectively hydrolyzing the penta-alkyl group-DTPA using a metal ion as a catalyst, a tetra-alkyl group-DTPA (tetra-alkyl)
DTPA) is obtained, that is, a single active DTPA derivative can be prepared in the above two reaction steps, so that the process is simple and the production rate is at least 51% or more.
本発明のDTPA誘導体の製造方法は、DTPA（Diethylene triamine pentaacetic acid）溶液を、アルコール溶液と一緒に脱水装置に混合してから、触媒剤として硫酸を添加し、エステル化反応を行って混合溶液を形成した後、当該混合溶液について、24時間の向流反応を行い、当該混合溶液の溶剤を除去し、そして、飽和炭酸水素ナトリウム水溶液で酸中和を行うと、淡褐色のゼリー状の液体であるペンタ-エチル基-DTPA（penta-ethyl
DTPA）が得られ、当該ペンタ-エチル基-DTPAを、塩化銅や臭化銅、硫酸銅、硝酸銅、硝酸鉛、塩化第一鉄、塩化コバルト或いは塩化ニッケルの金属イオンと水溶液を混合して攪拌し、そして、水酸化ナトリウムや水酸化カリウムであるアルカリ溶液を2時間攪拌してから、硫化水素（H2S）を導入して硫化銅を含有する混合液を形成し、当該硫化銅を含有する混合液について、ろ紙でろ過し、そして、管柱により純化すると、テトラ-エチル基-DTPA（tetra-ethyl
DTPA）が得られ、当該テトラ-エチル基-DTPAの構造は、次のようである。
DTPA) is obtained, and the penta-ethyl group-DTPA is mixed with an aqueous solution of metal ions of copper chloride, copper bromide, copper sulfate, copper nitrate, lead nitrate, ferrous chloride, cobalt chloride or nickel chloride. The mixture is stirred, and an alkali solution such as sodium hydroxide or potassium hydroxide is stirred for 2 hours, and then hydrogen sulfide (H 2 S) is introduced to form a mixed solution containing copper sulfide. The mixed liquid contained is filtered with a filter paper and purified with a tube column. Tetra-ethyl group-DTPA (tetra-ethyl)
DTPA) is obtained, and the structure of the tetra-ethyl group-DTPA is as follows.
また、本発明は、もう一つのDTPA誘導体の製造方法を提供し、アルゴン雰囲気下で、ジエチレントリアミン（Diethylenetriamine）と炭酸カリウムを反応瓶に入込んで、アセトニトリル（acetonitrile）を攪拌混合してから、アセトニトリルに溶けられたtert-ブチルクロロ酢酸塩（tert-butyl chloroacetate）を、当該反応瓶に添加し、当該反応瓶を室温下で24時間の反応をさせてから、溶液の除去と粉末のろ過をし、混合割合が1:10であるエーテルとヘキサン（hexane）の混合溶液で、クロマトグラフィの管柱により分離純化すると、ペンタ-tert-ブチル-DTPA（penta-tert-butyl DTPA）が得られ、当該ペンタ-tert-ブチル-DTPAを、金属イオン（例えば、塩化銅や臭化銅、硫酸銅、硝酸銅、硝酸鉛、塩化第一鉄、塩化コバルト或いは塩化ニッケル）と水溶液を混合して攪拌し、水酸化ナトリウムや水酸化カリウムであるアルカリ溶液を2時間攪拌してから、硫化水素（H2S）を導入して硫化銅を含有する混合液を形成し、そして、当該硫化銅を含有する混合液をろ紙でろ過し、また、管柱により純化すると、テトラ-tert-ブチル-DTPA（tetra-tert-butyl
DTPA）が得られ、当該テトラ-tert-ブチル-DTPAの構造は、次のようである。
DTPA) is obtained, and the structure of the tetra-tert-butyl-DTPA is as follows.
本発明のDTPA誘導体の製造方法によれば、まず、ペンタ-アルキル基-DTPA（penta-alkyl
DTPA）を作製して、金属イオンを触媒剤として、選択的に加水分解し、テトラ-アルキル基-DTPA（tetra-alkyl DTPA）が得られ、上記の二つの反応工程で、シングルの活性であるDTPA誘導体を作製できることにより、工程が簡単で、生産率が高い。
According to the method for producing a DTPA derivative of the present invention, first, a penta-alkyl group-DTPA (penta-alkyl)
DTPA) and selectively hydrolyzed using metal ions as catalyst to give tetra-alkyl DTPA (tetra-alkyl DTPA), which is a single activity in the above two reaction steps Since DTPA derivatives can be produced, the process is simple and the production rate is high.
以下、複数のより良い実施例により、本発明を説明する。 The invention will now be described by means of several better embodiments.
ペンタ-エチル基-DTPAの合成 Synthesis of penta-ethyl group-DTPA
図１、２は、本発明のDTPAの構造概念図と、本発明のペンタ-エチル基-DTPAの構造概念図である。図のように、4グラム（g）、0.01モル（mole）のDTPA１と100ミリリットル（ml）のアルコールを混合し、そして、少しずつ、1.5ミリリットルの硫酸を滴下して触媒させ、エステル化反応が、水が存在スル場合、可逆反応（reversible reaction）であるため、Dean-Stark脱水装置により行い、24時間の向流反応させた後、当該脱水装置の溶剤を汲み出し、飽和炭酸水素ナトリウム水溶液で酸中和を行い、4.86グラム、生産率91％、淡褐色ゼリー状液体であるペンタ-エチル基-DTPA２が得られる。 1 and 2 are a conceptual diagram of the structure of the DTPA of the present invention and a conceptual diagram of the structure of the penta -ethyl group- DTPA of the present invention. As shown in the figure, 4 grams (g), 0.01 moles of DTPA1 and 100 milliliters (ml) of alcohol were mixed, and then 1.5 milliliters of sulfuric acid was added dropwise to catalyze the esterification reaction. When water is present, it is a reversible reaction. Therefore, the reaction is carried out with a Dean-Stark dehydrator, and after 24 hours of countercurrent reaction, the solvent of the dehydrator is pumped out and acidified with a saturated aqueous sodium bicarbonate solution. Neutralization yields 4.86 grams, yield 91%, and a light brown jelly-like liquid penta-ethyl group-DTPA2.
水素核磁気共鳴スペクトル（1H NMR） (CDCl3/δppm)
δ1.16〜1.23 （15H 5× -CH3）
δ2.78〜2.84 （8H 2× -N-CH2-CH2-N）
δ3.43〜3.53 （10H 5× -N-CH2-CO ）
δ4.03〜4.33 （10H 5× -O-CH2）
Hydrogen nuclear magnetic resonance spectrum ( 1 H NMR) (CDCl 3 / δppm)
δ1.16-1.23 (15H 5 × -CH 3 )
δ2.78 ~ 2.84 (8H 2 × -N-CH 2 -CH 2 -N)
δ3.43 ~ 3.53 (10H 5 × -N-CH 2 -CO)
δ4.03-4.33 (10H 5 × -O-CH 2 )
炭素核磁気共鳴スペクトル（13C NMR）（CDCl3/δppm）
δ 41.07 δ 128.33
δ 48.85 δ 128.56
δ 50.66 δ 135.57
δ 55.96 δ 169.61
δ 57.08 δ 171.02
δ 66.29
Carbon nuclear magnetic resonance spectrum ( 13 C NMR) (CDCl 3 / δppm)
δ 41.07 δ 128.33
δ 48.85 δ 128.56
δ 50.66 δ 135.57
δ 55.96 δ 169.61
δ 57.08 δ 171.02
δ 66.29
電子イオン化法質量スペクトル（EIMS）（m/e ％）
(MH+) =534
Electron ionization mass spectrum (EIMS) (m / e%)
(MH + ) = 534
元素分析 （Elemental Analyzer、EA）（C、H、N ％）
算出値：C：54.02％ H：8.12％ N：7.87％
実験値：C：53.74％ H：8.20％ N：8.26％
Elemental Analyzer (EA) (C, H, N%)
Calculated value: C: 54.02% H: 8.12% N: 7.87%
Experimental value: C: 53.74% H: 8.20% N: 8.26%
テトラ-エチル基-DTPAの合成 Synthesis of tetra-ethyl group-DTPA
図３は、本発明のテトラ-エチル基-DTPAの構造概念図である。図のように、上記のペンタ-エチル基-DTPA２（1グラム、1.87ミリモル）と、0.318グラム、1.87ミリモルの塩化銅（CuCl2・2H2O）とを、34ミリリットルの水溶液の中で混合攪拌し、そして、少しずつ、0.49ミリリットルの水酸化ナトリウム（0.089グラム、2.244ミリモル）水溶液を滴下し、２時間攪拌し、反応させて硫化銅を含有する混合液を形成し、そして、硫化水素（H2S）を導入して、ろ紙で硫化銅をろ過して除去し、最後に、管柱により純化すると、0.58グラム、生産率61％、ゼリー状のテトラ-エチル基-DTPA３が得られ、当該塩化銅の代わりに塩化ニッケルを利用すると、当該テトラ-エチル基-DTPA３の生産率が56%になり、当該水酸化ナトリウムの代わりに水酸化カリウムを利用すると、当該テトラ-エチル基-DTPA３の生産率が58%になる。 FIG. 3 is a conceptual diagram of the structure of the tetra-ethyl group-DTPA of the present invention. As shown in the figure, the above penta-ethyl group-DTPA 2 (1 gram, 1.87 mmol) and 0.318 gram, 1.87 mmol of copper chloride (CuCl 2 · 2H 2 O) were mixed in 34 ml of aqueous solution. Stir and, in small portions, 0.49 milliliters of aqueous sodium hydroxide (0.089 grams, 2.244 millimoles) in water are added dropwise, stirred for 2 hours, reacted to form a mixture containing copper sulfide, and hydrogen sulfide ( H 2 S) is introduced, and copper sulfide is removed by filtration with a filter paper. Finally, when purified by a tube column, 0.58 g, a production rate of 61%, a jelly-like tetra-ethyl group-DTPA3 is obtained, When nickel chloride is used instead of copper chloride, the production rate of the tetra-ethyl group-DTPA3 is 56%, and when potassium hydroxide is used instead of the sodium hydroxide, the tetra-ethyl group-DTPA3 production rate is increased. The production rate will be 58%.
水素核磁気共鳴スペクトル（CDCl3/δppm）
δ1.10〜1.16 （m 12H 4× -CH3）
δ2.75〜2.82 （8H 2× -N-CH2-CH2-N）
δ3.37〜3.49 （q 10H 5× -N-CH2-CO）
δ3.98〜4.05 （8H 4× -O-CH2）
δ10.33 （S 1H -OH）
Hydrogen nuclear magnetic resonance spectrum (CDCl 3 / δppm)
δ 1.10 to 1.16 (m 12H 4 × -CH 3 )
δ2.75-2.82 (8H 2 × -N-CH 2 -CH 2 -N)
δ3.37-3.49 (q 10H 5 × -N-CH 2 -CO)
δ3.98 ~ 4.05 (8H 4 × -O-CH 2 )
δ10.33 (S 1H -OH)
炭素核磁気共鳴スペクトル（CDCl3/δppm）
δ 14.10 δ
55.06 δ 170.56
δ 51.03 δ
56.90 δ 170.97
δ 51.45 δ
60.49 δ 173.53
δ 51.94 δ
60.72
δ 53.39 δ
60.83
δ 54.82 δ
170.06
Carbon nuclear magnetic resonance spectrum (CDCl 3 / δppm)
δ 14.10 δ
55.06 δ 170.56
δ 51.03 δ
56.90 δ 170.97
δ 51.45 δ
60.49 δ 173.53
δ 51.94 δ
60.72
δ 53.39 δ
60.83
δ 54.82 δ
170.06
電子イオン化法質量スペクトル（m/e ％）
(MH+) =506
Electron ionization mass spectrum (m / e%)
(MH + ) = 506
元素分析（C、H、N ％）
算出値：C：52.27％ H：7.78％ N：8.31％
実験値：C：51.54％ H：7.84％ N：7.92％
Elemental analysis (C, H, N%)
Calculated value: C: 52.27% H: 7.78% N: 8.31%
Experimental value: C: 51.54% H: 7.84% N: 7.92%
ペンタ-tert-ブチル-DTPAの合成 Synthesis of penta-tert-butyl-DTPA
図４は、本発明のペンタ-tert-ブチル-DTPAの構造概念図である。図のように、アルゴン雰囲気下で、ジエチレントリアミン（2グラム、9.69ミリモル）と炭酸カリウム（6.7グラム）と70ミリリットルのアセトニトリルを反応瓶に入込んで攪拌し、10ミリリットルのアセトニトリルに溶けられるtert-ブチルクロロ酢酸塩（8.32ミリリットル、58.16ミリモル）を少しずつ当該反応瓶に添加し、室温下で24時間の反応をさせた後、粉末のろ過と溶液の除去を行い、そして、混合割合が1:10であるエーテルとヘキサン（hexane）の混合溶液で、クロマトグラフィの管柱により分離純化すると、4.0グラム、生産率61％のペンタ-tert-ブチル-DTPA４が得られる。 FIG. 4 is a structural conceptual diagram of penta-tert-butyl-DTPA of the present invention. As shown in the figure, diethylenetriamine (2 grams, 9.69 mmol), potassium carbonate (6.7 grams) and 70 milliliters of acetonitrile are placed in a reaction bottle and stirred in an argon atmosphere, and tert-butylchloro dissolved in 10 milliliters of acetonitrile. Acetate (8.32 ml, 58.16 mmol) was added to the reaction bottle little by little, and after 24 hours of reaction at room temperature, the powder was filtered and the solution was removed, and the mixing ratio was 1:10 Separation and purification with a mixed column of ether and hexane with a column of chromatography gives 4.0 gram of penta -tert-butyl-DTPA4 with a production rate of 61%.
水素核磁気共鳴スペクトル（CDCl3/δppm）
δ1.36（45H 5× -O-C-（CH3）3 ）
δ2.71（S 8H 2× -N-CH2-CH2-N）
δ3.27〜3.45（10H 5× -N-CH2-CO ）
Hydrogen nuclear magnetic resonance spectrum (CDCl 3 / δppm)
δ1.36 (45H 5 × -OC- (CH 3 ) 3 )
δ2.71 (S 8H 2 × -N-CH 2 -CH 2 -N)
δ 3.27-3.45 (10H 5 × -N-CH 2 -CO)
炭素核磁気共鳴スペクトル（CDCl3/δppm）
δ 28.06 δ 55.97 δ80.72
δ 52.09 δ 76.61 δ70.55
δ 52.68 δ 77.03
δ 55.67 δ 77.46
Carbon nuclear magnetic resonance spectrum (CDCl 3 / δppm)
δ 28.06 δ 55.97 δ80.72
δ 52.09 δ 76.61 δ70.55
δ 52.68 δ 77.03
δ 55.67 δ 77.46
電子イオン化法質量スペクトル（m/e ％）
(MH+) =676
Electron ionization mass spectrum (m / e%)
(MH + ) = 676
元素分析（C、H、N ％）
算出値：C：60.60％ H：9.42％ N：8.31％
実験値：C：61.72％ H：9.51％ N：8.09％
Elemental analysis (C, H, N%)
Calculated value: C: 60.60% H: 9.42% N: 8.31%
Experimental value: C: 61.72% H: 9.51% N: 8.09%
テトラ-tert-ブチル-DTPAの合成 Synthesis of tetra-tert-butyl-DTPA
図５は、本発明のテトラ-tert-ブチル-DTPAの構造概念図である。図のように、上記のペンタ-tert-ブチル-DTPA４と、0.318グラム、1.87ミリモルの塩化銅（CuCl2・2H2O）とを、34ミリリットルの水溶液の中で混合攪拌してから、少しずつ0.49ミリリットルの水酸化ナトリウム（0.089グラム、2.244ミリモル）水溶液を添加し、２時間攪拌して、反応させて硫化銅を含有する混合液を形成し、そして、硫化水素（H2S）を導入し、ろ紙で硫化銅をろ過して除去し、最後に、管柱により純化すると、生産率が51％のブチル-tert-ブチル-DTPA５が得られる。 FIG. 5 is a structural conceptual diagram of tetra-tert-butyl-DTPA of the present invention. As shown in the figure, the above penta-tert-butyl-DTPA 4 and 0.318 grams of 1.87 mmol of copper chloride (CuCl 2 · 2H 2 O) were mixed and stirred in 34 ml of aqueous solution, and then a little. 0.49 milliliters of sodium hydroxide (0.089 grams, 2.244 mmol) aqueous solution was added in portions, stirred for 2 hours, reacted to form a mixture containing copper sulfide, and hydrogen sulfide (H 2 S) was introduced Then, copper sulfide is removed by filtration with a filter paper, and finally purified with a tube column, butyl-tert-butyl-DTPA5 having a production rate of 51% is obtained.
水素核磁気共鳴スペクトル（CDCl3/δppm）
δ1.24〜1.29（36H 4× -O-C-（CH3）3）
δ2.72〜2.82（8H 2× -N-CH2-CH2-N）
δ3.25〜3.40（q 10H 5× -N-CH2-CO）
δ9.33（S 1H
-OH）
Hydrogen nuclear magnetic resonance spectrum (CDCl 3 / δppm)
δ1.24 to 1.29 (36H 4 × -OC- (CH 3 ) 3 )
δ2.72 ~ 2.82 (8H 2 × -N-CH 2 -CH 2 -N)
δ 3.25-3.40 (q 10H 5 × -N-CH 2 -CO)
δ9.33 (S 1H
-OH)
炭素核磁気共鳴スペクトル（CDCl3/δppm）
δ 27.92 δ 54.48 δ 81.79
δ 50.95 δ 55.64 δ 169.09
δ 51.11 δ 56.42 δ 169.47
δ 51.44 δ 56.78 δ 170.32
δ 51.74 δ 81.08 δ 173.16
Carbon nuclear magnetic resonance spectrum (CDCl 3 / δppm)
δ 27.92 δ 54.48 δ 81.79
δ 50.95 δ 55.64 δ 169.09
δ 51.11 δ 56.42 δ 169.47
δ 51.44 δ 56.78 δ 170.32
δ 51.74 δ 81.08 δ 173.16
電子イオン化法質量スペクトル（m/e ％）
(MH+) =618
Electron ionization mass spectrum (m / e%)
(MH + ) = 618
元素分析（C、H、N ％）
算出値：C：58.33％ H：9.00％ N：6.80％
実験値：C：57.87％ H：9.12％ N：6.62％
Elemental analysis (C, H, N%)
Calculated value: C: 58.33% H: 9.00% N: 6.80%
Experimental value: C: 57.87% H: 9.12% N: 6.62%
以上のように、本発明のDTPA誘導体の製造方法は、主として、「金属イオンを触媒剤として、アルカリ溶液を添加して選択的に加水分解すること」であり、有効的に、従来の各欠点を解消できるため、工程が簡単で、生産率が高い方法であり、故に、法に従って特許請求を出願する。 As described above, the production method of the DTPA derivative of the present invention is mainly “selectively hydrolyzing by adding an alkaline solution using a metal ion as a catalyst agent”, and effectively, each conventional defect Therefore, the process is simple and the production rate is high. Therefore, a patent request is filed according to the law.
上記の説明は、ただ、本発明のより良い実施例であり、本発明の特許請求の範囲は、それによって制限されるものではなく、本発明の特許請求の範囲や明細書の内容に従って、等価の変更や修正は、全てが本発明の特許請求の範囲に含まれる。 The above descriptions are merely preferred embodiments of the present invention, and the scope of the claims of the present invention is not limited thereby, and is equivalent according to the scope of the claims of the present invention and the contents of the specification. All such changes and modifications are within the scope of the claims of the present invention.
１ DTPA
２ ペンタ-エチル基-DTPA
３ テトラ-エチル基-DTPA
４ ペンタ-tert-ブチル-DTPA
５ テトラ-tert-ブチル-DTPA
1 DTPA
2 Penta-ethyl group-DTPA
3 Tetra-ethyl-DTPA
4 Penta-tert-butyl-DTPA
5 Tetra-tert-butyl-DTPA
Claims (13)
（ａ）DTPA溶液と溶液を脱水装置の中で混合して、触媒剤を添加して触媒反応を行って混合溶液を形成し、
（ｂ）当該混合溶液に対して、24時間の向流反応をしてから、当該混合溶液の溶剤を除去し、そして、飽和炭酸水素ナトリウム水溶液で酸中和をすると、ペンタ-エチル基-DTPA（penta-ethyl
DTPA）が得られ、
（ｃ）当該ペンタ-エチル基-DTPAと金属イオンと水溶液を混合攪拌し、更にアルカリ溶液を添加して2時間攪拌した後、硫化水素（H2S）を導入して、硫化銅を含有する混合液を形成し、
（ｄ）当該硫化銅を含有する混合液をろ紙でろ過してから、管柱により純化すると、テトラ-エチル基-DTPA（tetra-ethyl DTPA）が得られる、
ことを特徴とするテトラ-エチル基-DTPAの製造方法。 There are at least the following steps,
(A) A DTPA solution and a solution are mixed in a dehydrator, and a catalytic agent is added to perform a catalytic reaction to form a mixed solution.
(B) The mixture solution is subjected to a countercurrent reaction for 24 hours, then the solvent of the mixture solution is removed, and acid neutralization with a saturated aqueous sodium hydrogen carbonate solution is performed to obtain a penta-ethyl group-DTPA. (Penta-ethyl
DTPA)
(C) Mixing and stirring the penta-ethyl group-DTPA, metal ions and an aqueous solution, adding an alkaline solution and stirring for 2 hours, introducing hydrogen sulfide (H 2 S) to contain copper sulfide Forming a mixture,
(D) When the mixed liquid containing copper sulfide is filtered with a filter paper and then purified with a tube column, tetra-ethyl group-DTPA (tetra-ethyl DTPA) is obtained.
A process for producing a tetra-ethyl group-DTPA , characterized in that
（ａ）アルゴン雰囲気下で、ジエチレントリアミン（Diethylenetriamine）と炭酸カリウムを反応瓶の中に入込んで、アセトニトリル（acetonitrile）と攪拌混合してから、アセトニトリルに溶けられたtert-ブチルクロロ酢酸塩（tert-butyl chloroacetate）を、当該反応瓶に添加し、
（ｂ）当該反応瓶を、室温下で24時間反応させて、当該反応瓶に対して、溶液の除去と粉末のろ過を行い、そして、エーテルとヘキサン（hexane）の混合溶液でクロマトグラフィの管柱により分離して純化すると、ペンタ-tert-ブチル-DTPA（penta-tert-butyl DTPA）が得られ、
（ｃ）当該ペンタ-tert-ブチル-DTPAと金属イオンと水溶液を混合攪拌してから、アルカリ溶液を添加して2時間攪拌した後、硫化水素（H2S）を導入して硫化銅を含有する混合液を形成し、
（ｄ）当該硫化銅を含有する混合液をろ紙でろ過し、管柱により純化すると、テトラ-tert-ブチル-DTPA（tetra-tert-butyl DTPA）が得られる、
ことを特徴とするテトラ-エチル基-DTPAの製造方法。 There are at least the following steps,
(A) Under an argon atmosphere, diethylenetriamine and potassium carbonate are placed in a reaction bottle, stirred and mixed with acetonitrile, and then tert-butyl chloroacetate (tert-butyl) dissolved in acetonitrile. chloroacetate) to the reaction bottle,
(B) The reaction bottle is reacted at room temperature for 24 hours, the solution is removed from the reaction bottle and the powder is filtered, and a column of chromatography is mixed with a mixed solution of ether and hexane. To separate and purify to yield penta-tert-butyl-DTPA (penta-tert-butyl DTPA)
(C) After mixing and stirring the penta-tert-butyl-DTPA, metal ions, and an aqueous solution, adding an alkali solution and stirring for 2 hours, then introducing hydrogen sulfide (H 2 S) to contain copper sulfide To form a mixture
(D) When the mixed liquid containing copper sulfide is filtered with a filter paper and purified with a tube column, tetra-tert-butyl-DTPA (tetra-tert-butyl DTPA) is obtained.
A process for producing a tetra-ethyl group-DTPA , characterized in that
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