CN103547573B - 高纯度钆布醇的制备 - Google Patents
高纯度钆布醇的制备 Download PDFInfo
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- CN103547573B CN103547573B CN201280024781.7A CN201280024781A CN103547573B CN 103547573 B CN103547573 B CN 103547573B CN 201280024781 A CN201280024781 A CN 201280024781A CN 103547573 B CN103547573 B CN 103547573B
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- Prior art keywords
- gadobutrol
- water
- solution
- ion
- product
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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 title claims abstract description 56
- 229960003411 gadobutrol Drugs 0.000 title claims abstract description 56
- 238000002360 preparation method Methods 0.000 title abstract description 38
- 238000000034 method Methods 0.000 claims abstract description 61
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 69
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 65
- 150000001875 compounds Chemical class 0.000 claims description 36
- 239000004744 fabric Substances 0.000 claims description 28
- 239000000047 product Substances 0.000 claims description 28
- 239000000203 mixture Substances 0.000 claims description 27
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 20
- CMIHHWBVHJVIGI-UHFFFAOYSA-N gadolinium(iii) oxide Chemical compound [O-2].[O-2].[O-2].[Gd+3].[Gd+3] CMIHHWBVHJVIGI-UHFFFAOYSA-N 0.000 claims description 18
- 150000002500 ions Chemical class 0.000 claims description 18
- 125000003158 alcohol group Chemical group 0.000 claims description 17
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 16
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 16
- 238000000746 purification Methods 0.000 claims description 16
- 239000012043 crude product Substances 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 14
- 238000010992 reflux Methods 0.000 claims description 14
- 239000012141 concentrate Substances 0.000 claims description 11
- 230000008569 process Effects 0.000 claims description 9
- 238000001816 cooling Methods 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 8
- 230000029936 alkylation Effects 0.000 claims description 7
- 238000005804 alkylation reaction Methods 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 7
- AIDLAEPHWROGFI-UHFFFAOYSA-N 2-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=C(C(O)=O)C=CC=C1C(O)=O AIDLAEPHWROGFI-UHFFFAOYSA-N 0.000 claims description 6
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 claims description 6
- 238000012805 post-processing Methods 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 5
- FDRCDNZGSXJAFP-UHFFFAOYSA-M sodium chloroacetate Chemical compound [Na+].[O-]C(=O)CCl FDRCDNZGSXJAFP-UHFFFAOYSA-M 0.000 claims description 5
- QBPPRVHXOZRESW-UHFFFAOYSA-N 1,4,7,10-tetraazacyclododecane Chemical compound C1CNCCNCCNCCN1 QBPPRVHXOZRESW-UHFFFAOYSA-N 0.000 claims description 4
- -1 gadolinium (III) ion Chemical class 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 230000001105 regulatory effect Effects 0.000 claims description 2
- ATACSYDDCNWCLV-UHFFFAOYSA-N 2-chloroacetic acid;sodium Chemical compound [Na].OC(=O)CCl ATACSYDDCNWCLV-UHFFFAOYSA-N 0.000 claims 1
- KYEJVSYUPWCUOL-UHFFFAOYSA-N CC1(OCP2OC2CO1)C Chemical compound CC1(OCP2OC2CO1)C KYEJVSYUPWCUOL-UHFFFAOYSA-N 0.000 claims 1
- 230000029219 regulation of pH Effects 0.000 claims 1
- 238000000926 separation method Methods 0.000 claims 1
- 238000002425 crystallisation Methods 0.000 abstract description 14
- 230000008025 crystallization Effects 0.000 abstract description 14
- 229910052688 Gadolinium Inorganic materials 0.000 abstract description 10
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 abstract description 10
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 6
- 239000003795 chemical substances by application Substances 0.000 abstract description 5
- 239000002872 contrast media Substances 0.000 abstract description 5
- 238000002583 angiography Methods 0.000 abstract description 2
- 238000011161 development Methods 0.000 abstract description 2
- 230000018109 developmental process Effects 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 35
- 150000004682 monohydrates Chemical class 0.000 description 29
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000012535 impurity Substances 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 10
- 239000006227 byproduct Substances 0.000 description 10
- 238000004458 analytical method Methods 0.000 description 9
- 238000004455 differential thermal analysis Methods 0.000 description 9
- 238000002441 X-ray diffraction Methods 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000011575 calcium Substances 0.000 description 6
- 229910052791 calcium Inorganic materials 0.000 description 6
- 238000002329 infrared spectrum Methods 0.000 description 6
- 229960004592 isopropanol Drugs 0.000 description 6
- 238000011084 recovery Methods 0.000 description 6
- 230000033228 biological regulation Effects 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- 239000012086 standard solution Substances 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 238000004448 titration Methods 0.000 description 4
- DPEYHNFHDIXMNV-UHFFFAOYSA-N (9-amino-3-bicyclo[3.3.1]nonanyl)-(4-benzyl-5-methyl-1,4-diazepan-1-yl)methanone dihydrochloride Chemical group Cl.Cl.CC1CCN(CCN1Cc1ccccc1)C(=O)C1CC2CCCC(C1)C2N DPEYHNFHDIXMNV-UHFFFAOYSA-N 0.000 description 3
- 229910052782 aluminium Inorganic materials 0.000 description 3
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 239000002158 endotoxin Substances 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 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
- 230000009471 action Effects 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- GCLKDXFGQNCFQW-CTHHTMFSSA-L calcium 2-[4,10-bis(carboxylatomethyl)-7-[(2R,3S)-1,3,4-trihydroxybutan-2-yl]-1,4,7,10-tetrazacyclododec-1-yl]acetate hydron Chemical compound [H+].[Ca+2].OC[C@@H](O)[C@@H](CO)N1CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC1 GCLKDXFGQNCFQW-CTHHTMFSSA-L 0.000 description 2
- 229950006450 calcobutrol Drugs 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000005253 cladding Methods 0.000 description 2
- 239000000356 contaminant Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- RJOJUSXNYCILHH-UHFFFAOYSA-N gadolinium(3+) Chemical compound [Gd+3] RJOJUSXNYCILHH-UHFFFAOYSA-N 0.000 description 2
- GFSTXYOTEVLASN-UHFFFAOYSA-K gadoteric acid Chemical compound [Gd+3].OC(=O)CN1CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC1 GFSTXYOTEVLASN-UHFFFAOYSA-K 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000000634 powder X-ray diffraction Methods 0.000 description 2
- 238000004445 quantitative analysis Methods 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- 231100000027 toxicology Toxicity 0.000 description 2
- JZNZSKXIEDHOBD-HUUCEWRRSA-N 2-[4,10-bis(carboxymethyl)-7-[(2r,3s)-1,3,4-trihydroxybutan-2-yl]-1,4,7,10-tetrazacyclododec-1-yl]acetic acid Chemical group OC[C@@H](O)[C@@H](CO)N1CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC1 JZNZSKXIEDHOBD-HUUCEWRRSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical group CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 101100098216 Caenorhabditis elegans rars-1 gene Proteins 0.000 description 1
- 241000345998 Calamus manan Species 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 238000007476 Maximum Likelihood Methods 0.000 description 1
- 244000061458 Solanum melongena Species 0.000 description 1
- 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 description 1
- ZASZRISNJPOCCF-UHFFFAOYSA-N [O-2].[Li+].O.O.[Li+] Chemical compound [O-2].[Li+].O.O.[Li+] ZASZRISNJPOCCF-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- KFAUAWMNLGGWLP-UHFFFAOYSA-N azacyclododecane Chemical compound C1CCCCCNCCCCC1 KFAUAWMNLGGWLP-UHFFFAOYSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- 238000002059 diagnostic imaging Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000003344 environmental pollutant Substances 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000012216 imaging agent Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 231100000719 pollutant Toxicity 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 235000012950 rattan cane Nutrition 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- VIFBVOSDYUIKIK-UHFFFAOYSA-J sodium;gadolinium(3+);2-[4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetate Chemical compound [Na+].[Gd+3].[O-]C(=O)CN1CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC1 VIFBVOSDYUIKIK-UHFFFAOYSA-J 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000012956 testing procedure Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- ILJSQTXMGCGYMG-UHFFFAOYSA-N triacetic acid Chemical compound CC(=O)CC(=O)CC(O)=O ILJSQTXMGCGYMG-UHFFFAOYSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/003—Compounds containing elements of Groups 3 or 13 of the Periodic Table without C-Metal linkages
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/101—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals
- A61K49/106—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being cyclic, e.g. DOTA
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/101—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals
- A61K49/106—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being cyclic, e.g. DOTA
- A61K49/108—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being cyclic, e.g. DOTA the metal complex being Gd-DOTA
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2123/00—Preparations for testing in vivo
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Radiology & Medical Imaging (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
方法步骤 | 收率 |
轮环藤宁到钆布醇,粗 | 几乎定量(>96%) |
离子交换剂纯化 | 74.1% |
最终结晶 | 96.9% |
总收率(由轮环藤宁开始) | 70% |
多晶型物 | 水中溶解度(g/l) |
一水合物I | 1081±2 |
一水合物II | 922±9 |
分析参数 | 测量值 |
纯度(HPLC) | >99.7%或99.8%或99.9% |
游离Gd3+ | <0.01% |
布醇配体 | <0.03% |
双TOBO配体 | <0.03% |
Gd-DO3A | <0.03% |
未指明杂质 | <0.03% |
含量 | 98%-102% |
内毒素 | <0.5EU |
乙醇溶剂的残留量 | <200ppm |
步骤 | 时间[min] | A[%] | B[%] | 梯度性质 |
1 | 0.0 | 100 | 0 | --- |
2 | 15.0 | 100 | 0 | 等度 |
3 | 30.0 | 75 | 25 | 线性 |
4 | 30.1 | 100 | 0 | 线性 |
5 | 40.0 | 100 | 0 | 平衡 |
编号 | 名称 | RT[min] | RRT |
1 | 双-TOBO配体 | 2.9 | 0.22 |
1b | Gd-双-TOBO | 3.3 | 0.25 |
2 | 布醇配体 | 4.85 | 0.36 |
3 | 钆布醇 | 13.3 | 1.00 |
4 | Gd-DO3A | 15.3 | 1.15 |
5 | GD-DOTA | 30.2 | 2.27 |
Claims (4)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE102011100128.3 | 2011-04-21 | ||
DE102011100128 | 2011-04-21 | ||
PCT/EP2012/057013 WO2012143355A1 (en) | 2011-04-21 | 2012-04-17 | Preparation of high-purity gadobutrol |
Publications (2)
Publication Number | Publication Date |
---|---|
CN103547573A CN103547573A (zh) | 2014-01-29 |
CN103547573B true CN103547573B (zh) | 2016-08-17 |
Family
ID=46208435
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201280024781.7A Active CN103547573B (zh) | 2011-04-21 | 2012-04-17 | 高纯度钆布醇的制备 |
Country Status (34)
Country | Link |
---|---|
US (2) | US10072027B2 (zh) |
EP (2) | EP2699556A1 (zh) |
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PE20141325A1 (es) * | 2011-04-21 | 2014-10-08 | Bayer Ip Gmbh | Preparacion de gadobutrol de alta pureza |
WO2015117911A1 (en) * | 2014-02-06 | 2015-08-13 | Agfa Healthcare | Process for purifying 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid |
KR101693400B1 (ko) * | 2014-09-17 | 2017-01-05 | 에스티팜 주식회사 | 칼코부트롤의 제조방법 |
KR101646211B1 (ko) * | 2014-11-12 | 2016-08-05 | (주)디아이테크 | 자기공명영상용 조영제의 제조방법 |
KR101653064B1 (ko) * | 2014-12-26 | 2016-09-09 | 에스티팜 주식회사 | 가도부트롤의 제조방법 |
IL265536B (en) * | 2016-09-27 | 2022-07-01 | Bayer Pharma AG | A method for the production of a crystalline form of the a modification of calcobuterol |
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