JP2002510296A - 大環状キレート化剤の製造方法およびその常磁性金属イオンとのキレート化合物 - Google Patents
大環状キレート化剤の製造方法およびその常磁性金属イオンとのキレート化合物Info
- Publication number
- JP2002510296A JP2002510296A JP50149799A JP50149799A JP2002510296A JP 2002510296 A JP2002510296 A JP 2002510296A JP 50149799 A JP50149799 A JP 50149799A JP 50149799 A JP50149799 A JP 50149799A JP 2002510296 A JP2002510296 A JP 2002510296A
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- JP
- Japan
- Prior art keywords
- formula
- compound
- reaction
- acid
- paramagnetic metal
- Prior art date
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- Granted
Links
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- 229910021645 metal ion Inorganic materials 0.000 title description 5
- 238000000034 method Methods 0.000 claims abstract description 82
- 150000003839 salts Chemical class 0.000 claims abstract description 29
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 26
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- 229910052751 metal Inorganic materials 0.000 claims abstract description 18
- 239000002184 metal Substances 0.000 claims abstract description 18
- 238000001914 filtration Methods 0.000 claims abstract description 11
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims abstract description 11
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- -1 cycloocta [cd] pentalene Chemical compound 0.000 claims abstract description 8
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- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000005804 alkylation reaction Methods 0.000 claims abstract description 7
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- 150000001875 compounds Chemical class 0.000 claims description 45
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- 150000002500 ions Chemical class 0.000 claims description 18
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- 238000005342 ion exchange Methods 0.000 claims description 17
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- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims description 13
- 229910052688 Gadolinium Inorganic materials 0.000 claims description 13
- 230000002378 acidificating effect Effects 0.000 claims description 12
- 150000001768 cations Chemical class 0.000 claims description 10
- 238000002955 isolation Methods 0.000 claims description 10
- 150000002924 oxiranes Chemical class 0.000 claims description 10
- 150000001450 anions Chemical class 0.000 claims description 8
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 claims description 6
- 239000003377 acid catalyst Substances 0.000 claims description 6
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 6
- 238000011097 chromatography purification Methods 0.000 claims description 6
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- 239000002904 solvent Substances 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 5
- 229910052692 Dysprosium Inorganic materials 0.000 claims description 4
- 229910052769 Ytterbium Inorganic materials 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical group OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- GUVXZFRDPCKWEM-UHFFFAOYSA-N pentalene Chemical compound C1=CC2=CC=CC2=C1 GUVXZFRDPCKWEM-UHFFFAOYSA-N 0.000 claims description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 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 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
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- DDTBPAQBQHZRDW-UHFFFAOYSA-N cyclododecane Chemical compound C1CCCCCCCCCCC1 DDTBPAQBQHZRDW-UHFFFAOYSA-N 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
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- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
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- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 claims 1
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- QBPPRVHXOZRESW-UHFFFAOYSA-N 1,4,7,10-tetraazacyclododecane Chemical compound C1CNCCNCCNCCN1 QBPPRVHXOZRESW-UHFFFAOYSA-N 0.000 abstract description 3
- 238000010668 complexation reaction Methods 0.000 abstract description 3
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- 150000002118 epoxides Chemical class 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 239000000047 product Substances 0.000 description 21
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- 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 11
- 229960003411 gadobutrol Drugs 0.000 description 11
- DPNNNPAKRZOSMO-UHFFFAOYSA-K gadoteridol Chemical compound [Gd+3].CC(O)CN1CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC1 DPNNNPAKRZOSMO-UHFFFAOYSA-K 0.000 description 11
- 229960005451 gadoteridol Drugs 0.000 description 11
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 description 9
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- 239000000543 intermediate Substances 0.000 description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 description 5
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- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
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- GEKNCWQQNMEIMS-UHFFFAOYSA-N 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane Chemical compound C1OC(C)(C)OCC2OC21 GEKNCWQQNMEIMS-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 238000010268 HPLC based assay Methods 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
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- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 3
- 239000002250 absorbent Substances 0.000 description 3
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- 229910001938 gadolinium oxide Inorganic materials 0.000 description 3
- CMIHHWBVHJVIGI-UHFFFAOYSA-N gadolinium(iii) oxide Chemical compound [O-2].[O-2].[O-2].[Gd+3].[Gd+3] CMIHHWBVHJVIGI-UHFFFAOYSA-N 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 3
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 description 2
- 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 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- 102100024167 C-C chemokine receptor type 3 Human genes 0.000 description 2
- 101710149862 C-C chemokine receptor type 3 Proteins 0.000 description 2
- 150000000921 Gadolinium Chemical class 0.000 description 2
- 229910003317 GdCl3 Inorganic materials 0.000 description 2
- IQUHNCOJRJBMSU-UHFFFAOYSA-N H3HP-DO3A Chemical compound CC(O)CN1CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC1 IQUHNCOJRJBMSU-UHFFFAOYSA-N 0.000 description 2
- 101100340769 Homo sapiens ILF2 gene Proteins 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
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- 102000049951 Nuclear Factor 45 Human genes 0.000 description 2
- 108700031302 Nuclear Factor 45 Proteins 0.000 description 2
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 2
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- 238000010494 dissociation reaction Methods 0.000 description 2
- 230000005593 dissociations Effects 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- MEANOSLIBWSCIT-UHFFFAOYSA-K gadolinium trichloride Chemical compound Cl[Gd](Cl)Cl MEANOSLIBWSCIT-UHFFFAOYSA-K 0.000 description 2
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- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 2
- GYPCWHHQAVLMKO-XXKQIVDLSA-N (7s,9s)-7-[(2r,4s,5s,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-[(e)-n-[(1-hydroxy-2,2,6,6-tetramethylpiperidin-4-ylidene)amino]-c-methylcarbonimidoyl]-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydrochloride Chemical group Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\N=C1CC(C)(C)N(O)C(C)(C)C1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 GYPCWHHQAVLMKO-XXKQIVDLSA-N 0.000 description 1
- HHLZCENAOIROSL-UHFFFAOYSA-K 2-[4,7-bis(carboxylatomethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetate Chemical compound [O-]C(=O)CN1CCNCCN(CC([O-])=O)CCN(CC([O-])=O)CC1 HHLZCENAOIROSL-UHFFFAOYSA-K 0.000 description 1
- DPNNNPAKRZOSMO-UHFFFAOYSA-N 2-[4,7-bis(carboxymethyl)-10-(2-hydroxypropyl)-1,4,7,10-tetrazacyclododec-1-yl]acetic acid;gadolinium(3+) Chemical compound [Gd+3].CC(O)CN1CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC1 DPNNNPAKRZOSMO-UHFFFAOYSA-N 0.000 description 1
- 101100515517 Arabidopsis thaliana XI-I gene Proteins 0.000 description 1
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- 230000005526 G1 to G0 transition Effects 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000012455 biphasic mixture Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
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- 239000000706 filtrate Substances 0.000 description 1
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- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000005291 magnetic effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
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- PIOSEDPFJPAJKQ-UHFFFAOYSA-M sodium;toluene;hydroxide Chemical compound [OH-].[Na+].CC1=CC=CC=C1 PIOSEDPFJPAJKQ-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- VIOLGJHDEHCJFA-UHFFFAOYSA-N sulfo hydrogen sulfate;1,4,7,10-tetrazacyclododecane Chemical compound OS(=O)(=O)OS(O)(=O)=O.C1CNCCNCCNCCN1 VIOLGJHDEHCJFA-UHFFFAOYSA-N 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
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- GBRLMXHJWQWYSY-UHFFFAOYSA-N tert-butyl 2-[7-formyl-4,10-bis[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]-1,4,7,10-tetrazacyclododec-1-yl]acetate Chemical compound CC(C)(C)OC(=O)CN1CCN(CC(=O)OC(C)(C)C)CCN(C=O)CCN(CC(=O)OC(C)(C)C)CC1 GBRLMXHJWQWYSY-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- HRJSZZAKOGKNGM-UHFFFAOYSA-K trisodium 2-[4,10-bis(carboxylatomethyl)-7-formyl-1,4,7,10-tetrazacyclododec-1-yl]acetate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CN1CCN(CC([O-])=O)CCN(CCN(CC([O-])=O)CC1)C=O HRJSZZAKOGKNGM-UHFFFAOYSA-K 0.000 description 1
- 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 description 1
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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)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
Description
Claims (1)
- 【特許請求の範囲】 1.式(XII): (式中、 R1およびR2は、独立して、水素原子;酸素原子1〜10個を含有する(C1〜 C20)アルキル;または非置換であるか、(C1〜C5)アルキルもしくはヒドロ キシ、(C1〜C5)アルコキシ、カルバモイルもしくはカルボキシル基によって 置換されていることもできる、フェニル、フェニルオキシ、フェニルジオキシ基 であり; Me3+は、常磁性金属の三価イオンである) で示される、大環状キレート化剤と常磁性金属の三価イオンとの錯体の製造方法 であって、 以下の反応式:(式中、R1、R2およびMeは、上記に定義した意味を有する) a)溶剤の非存在下、かつ酸触媒の存在下で、1,4,7,10−テトラアザ シクロドデカンをオルトギ酸トリエチルと高温で反応させて、式(III)の5H ,9bH−2a,4a,7,9a−オクタヒドロテトラアザシクロオクタ[cd ]ペンタレンを得る工程; b)化合物(III)を、水中で、塩基性条件で、ハロ酢酸によってカルボキシ メチル化反応させて、単離することなく後続の工程c)の加水分解反応に付す、 式(IX)の中間体を得る工程; c)中間体(IX)を、塩基性条件で、工程b)で加えたものと同じ塩基の添加 によって加水分解反応させて、単離することなく後続の工程d)に付す、式(X )の塩の水溶液を得る工程; d)既知の方法によって、式(XI)のエポキシドを用いて水中でアルキル化し て、単離することなく工程e)に付す、化合物(I)の対応する塩を得る工程; e)既知の方法により、20〜31、42、43、44、49および50〜5 7の範囲の原子番号を有する常磁性金属の塩の添加によって、水中で錯体化する 工程; f)化合物(XII)の水溶液を、場合によってはクロマトグラフィー精製工程 によって親油性不純物を除去した後、ろ別によって精製して大部分の塩および低 分子量不純物を除去し、水溶液をイオン交換樹脂上で最終的に脱塩する工程;な らびに g)化合物(XII)の結晶化または回収する工程 で示される工程を含む方法。 2.工程a)において、オルトギ酸トリエチルを、化学量論的量の105〜20 0%の範囲の量で使用する、請求項1記載の方法。 3.工程a)において、反応温度が、110〜150℃の範囲であり、反応時間 が、5〜24時間の範囲である、請求項1または2記載の方法。 4.工程a)において、酸触媒が、少なくとも3個の炭素原子を有するカルボン 酸である、請求項1〜3のいずれか1項記載の方法。 5.工程b)において、化合物(IX)の塩が、ナトリウム、カリウムおよびカル シウムから選択される、請求項1〜4のいずれか1項記載の方法。 6.工程b)のカルボキシメチル化反応を、化合物(III)に対するハロ酢酸の モル比3〜5mol/molで、アルカリまたはアルカリ土類金属の水酸化物の添加に よる9.5〜12.5のpHにおいて、7〜50℃で3〜48時間実施する、請 求項1〜5のいずれか1項記載の方法。 7.工程b)において、化合物(III)に対するハロ酢酸のモル比が、3.2〜 4.5であり、pHが、10〜12である、請求項6記載の方法。 8.工程c)において、反応を、12.5よりも高いpH、6〜100℃で5〜 48時間実施する、請求項1〜7のいずれか1項記載の方法。 9.工程b)におけるハロ酢酸が、ブロモ酢酸である、請求項1〜8のいずれか 1項記載の方法。 10.常磁性金属が、Gd、Dy、Ybから選択される、請求項1〜9のいずれ か1項記載の方法。 11.工程f)において、4個のイオン交換床のユニットを使用し、第一のイオ ン交換床が、炭酸水素塩形の強塩基性アニオン交換体からなり、第二のイオン交 換床が、H+形の弱酸性カチオン交換体からなり、第三のイオン交換床が、OH- 形の強塩基性アニオン交換体からなり、第四のイオン交換床が、H+形の弱酸性 カチオン交換体からなる、請求項1〜10のいずれか1項記載の方法。 12.工程f)において、小径粒子の樹脂を使用する、請求項1〜11のいずれ か1項記載の方法。 13.工程f)において、強塩基性イオン交換体が、タイプIまたはタイプIIの 、ゲルまたはマクロ孔質マトリックス樹脂からなる群より選択される、請求項1 〜12のいずれか1項記載の方法。 14.工程f)において、弱酸性イオン交換体が、ゲルマトリックス樹脂からな る群より選択される、請求項1〜12のいずれか1項記載の方法。 15.工程f)が、ろ別工程の前に親油性不純物を除去するためのクロマトグラ フィー精製を含む、請求項1〜14のいずれか1項記載の方法。 16.式(XII)において、R1が、メチルであり;R2が、水素であり;Me3+ が、Gd3+であり;式(XI)のエポキシドが、プロピレンオキシドである、請求 項1〜15のいずれか1項記載の方法。 17.式(XII)において、R1およびR2が、ヒドロキシメチルであり;Me3+ が、Gd3+であり;式(XI)のエポキシドが、4,4−ジメチル−3,5,8− トリオキサビシクロ[5.1.0]オクタンである、請求項1〜15のいずれか 1項記載の方法。
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IT97MI001371A IT1292128B1 (it) | 1997-06-11 | 1997-06-11 | Processo per la preparazione di chelanti macrociclici e loro chelati con ioni metallici paramagnetici |
IT97A001371 | 1997-06-11 | ||
PCT/EP1998/003308 WO1998056775A1 (en) | 1997-06-11 | 1998-06-03 | A process for the preparation of macrocyclic chelants and the chelates thereof with paramagnetic metal ions |
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IL (1) | IL133394A (ja) |
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JP2021528361A (ja) * | 2019-01-28 | 2021-10-21 | フーベイ ティアンシュ ファーマシューティカル カンパニー リミテッドHubei Tianshu Pharmaceutical Co., Ltd | ガドリニウム系イオン性造影剤の中間体の調製方法及びその応用 |
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JP2014522387A (ja) * | 2011-04-21 | 2014-09-04 | バイエル・インテレクチュアル・プロパティ・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング | 高純度ガドブトロールの製造 |
JP2017031220A (ja) * | 2011-04-21 | 2017-02-09 | バイエル・インテレクチュアル・プロパティ・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツングBayer Intellectual Property GmbH | 高純度ガドブトロールの製造 |
JP2018188477A (ja) * | 2011-04-21 | 2018-11-29 | バイエル・インテレクチュアル・プロパティ・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツングBayer Intellectual Property GmbH | 高純度ガドブトロールの製造 |
JP2021528361A (ja) * | 2019-01-28 | 2021-10-21 | フーベイ ティアンシュ ファーマシューティカル カンパニー リミテッドHubei Tianshu Pharmaceutical Co., Ltd | ガドリニウム系イオン性造影剤の中間体の調製方法及びその応用 |
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ATE308528T1 (de) | 2005-11-15 |
EP0988294A1 (en) | 2000-03-29 |
CN1166649C (zh) | 2004-09-15 |
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IL133394A (en) | 2004-02-08 |
DK0988294T3 (da) | 2006-02-13 |
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DE69832170T2 (de) | 2006-07-13 |
US5925752A (en) | 1999-07-20 |
WO1998056775A1 (en) | 1998-12-17 |
ITMI971371A0 (ja) | 1997-06-11 |
NO313140B1 (no) | 2002-08-19 |
ITMI971371A1 (it) | 1998-12-11 |
AU8110098A (en) | 1998-12-30 |
US6046324A (en) | 2000-04-04 |
IL133394A0 (en) | 2001-04-30 |
IT1292128B1 (it) | 1999-01-25 |
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EP0988294B1 (en) | 2005-11-02 |
IN185469B (ja) | 2001-01-27 |
ES2252845T3 (es) | 2006-05-16 |
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