CN113272284B - 制备考布曲钙的方法 - Google Patents
制备考布曲钙的方法 Download PDFInfo
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- CN113272284B CN113272284B CN201980087491.9A CN201980087491A CN113272284B CN 113272284 B CN113272284 B CN 113272284B CN 201980087491 A CN201980087491 A CN 201980087491A CN 113272284 B CN113272284 B CN 113272284B
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- CN
- China
- Prior art keywords
- butoxide
- purity
- acid
- exchange resin
- crude
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- 238000000034 method Methods 0.000 title claims abstract description 24
- 239000011575 calcium Substances 0.000 title abstract description 13
- 229910052791 calcium Inorganic materials 0.000 title abstract description 13
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 title abstract description 12
- LGZKGOGODCLQHG-CYBMUJFWSA-N 5-[(2r)-2-hydroxy-2-(3,4,5-trimethoxyphenyl)ethyl]-2-methoxyphenol Chemical compound C1=C(O)C(OC)=CC=C1C[C@@H](O)C1=CC(OC)=C(OC)C(OC)=C1 LGZKGOGODCLQHG-CYBMUJFWSA-N 0.000 title description 18
- LGZKGOGODCLQHG-UHFFFAOYSA-N combretastatin Natural products C1=C(O)C(OC)=CC=C1CC(O)C1=CC(OC)=C(OC)C(OC)=C1 LGZKGOGODCLQHG-UHFFFAOYSA-N 0.000 title description 18
- 229960005235 piperonyl butoxide Drugs 0.000 claims description 47
- FIPWRIJSWJWJAI-UHFFFAOYSA-N Butyl carbitol 6-propylpiperonyl ether Chemical compound C1=C(CCC)C(COCCOCCOCCCC)=CC2=C1OCO2 FIPWRIJSWJWJAI-UHFFFAOYSA-N 0.000 claims description 45
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- 238000002425 crystallisation Methods 0.000 claims description 18
- 238000004519 manufacturing process Methods 0.000 claims description 18
- 230000008025 crystallization Effects 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 238000000746 purification Methods 0.000 claims description 11
- 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 description 6
- QBPPRVHXOZRESW-UHFFFAOYSA-N 1,4,7,10-tetraazacyclododecane Chemical compound C1CNCCNCCNCCN1 QBPPRVHXOZRESW-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 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 claims description 3
- 239000003957 anion exchange resin Substances 0.000 claims description 3
- 239000003729 cation exchange resin Substances 0.000 claims description 3
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 claims description 3
- 229940106681 chloroacetic acid Drugs 0.000 claims description 3
- 239000003456 ion exchange resin Substances 0.000 claims description 3
- 229920003303 ion-exchange polymer Polymers 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- ILJSQTXMGCGYMG-UHFFFAOYSA-N triacetic acid Chemical compound CC(=O)CC(=O)CC(O)=O ILJSQTXMGCGYMG-UHFFFAOYSA-N 0.000 claims description 3
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 2
- JDNTWHVOXJZDSN-UHFFFAOYSA-N iodoacetic acid Chemical compound OC(=O)CI JDNTWHVOXJZDSN-UHFFFAOYSA-N 0.000 claims description 2
- NXHUAYWRBFCZOA-UHFFFAOYSA-N 3-(1,4,7,10-tetrazacyclododec-1-yl)butane-1,2,4-triol Chemical compound OCC(O)C(CO)N1CCNCCNCCNCC1 NXHUAYWRBFCZOA-UHFFFAOYSA-N 0.000 claims 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 1
- 125000004122 cyclic group Chemical group 0.000 claims 1
- 150000003141 primary amines Chemical class 0.000 claims 1
- 125000001453 quaternary ammonium group Chemical group 0.000 claims 1
- 150000003335 secondary amines Chemical class 0.000 claims 1
- 125000000542 sulfonic acid group Chemical group 0.000 claims 1
- 150000003512 tertiary amines Chemical class 0.000 claims 1
- 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
- 230000002194 synthesizing effect Effects 0.000 abstract description 5
- 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 compound 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 abstract description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- 239000013078 crystal Substances 0.000 description 10
- 239000008213 purified water Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 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 7
- 229960003411 gadobutrol Drugs 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- -1 butoxide ester Chemical class 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 239000011347 resin Substances 0.000 description 4
- 229920005989 resin Polymers 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 239000002872 contrast media Substances 0.000 description 3
- ZPDFIIGFYAHNSK-UHFFFAOYSA-K gadobutrol Chemical compound [Gd+3].OCC(O)C(CO)N1CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC1 ZPDFIIGFYAHNSK-UHFFFAOYSA-K 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- XSDQTOBWRPYKKA-UHFFFAOYSA-N amiloride Chemical compound NC(=N)NC(=O)C1=NC(Cl)=C(N)N=C1N XSDQTOBWRPYKKA-UHFFFAOYSA-N 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- SIIVGPQREKVCOP-UHFFFAOYSA-N but-1-en-1-ol Chemical compound CCC=CO SIIVGPQREKVCOP-UHFFFAOYSA-N 0.000 description 2
- 125000002091 cationic group Chemical group 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- CZLVPINBLDRZCJ-UHFFFAOYSA-N 2,3,4,4,5,5,6,6-octachlorocyclohex-2-en-1-one Chemical compound ClC1=C(Cl)C(Cl)(Cl)C(Cl)(Cl)C(Cl)(Cl)C1=O CZLVPINBLDRZCJ-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000001669 calcium Chemical class 0.000 description 1
- 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 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 229950006450 calcobutrol Drugs 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000002595 magnetic resonance imaging Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000001223 reverse osmosis Methods 0.000 description 1
- MBURIAHQXJQKRE-UHFFFAOYSA-M sodium;octane-1-sulfonate;hydrate Chemical compound O.[Na+].CCCCCCCCS([O-])(=O)=O MBURIAHQXJQKRE-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000003325 tomography Methods 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)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2019-0000085 | 2019-01-02 | ||
| KR1020190000085A KR101979836B1 (ko) | 2019-01-02 | 2019-01-02 | 칼코부트롤의 제조방법 |
| PCT/KR2019/015962 WO2020141723A1 (ko) | 2019-01-02 | 2019-11-20 | 칼코부트롤의 제조방법 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113272284A CN113272284A (zh) | 2021-08-17 |
| CN113272284B true CN113272284B (zh) | 2024-06-21 |
Family
ID=66675345
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201980087491.9A Active CN113272284B (zh) | 2019-01-02 | 2019-11-20 | 制备考布曲钙的方法 |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JP7272710B2 (ko) |
| KR (1) | KR101979836B1 (ko) |
| CN (1) | CN113272284B (ko) |
| WO (1) | WO2020141723A1 (ko) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11588339B2 (en) | 2021-02-03 | 2023-02-21 | Jason Watson | Combination charging cable and hair tie assembly |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107108532A (zh) * | 2014-09-17 | 2017-08-29 | St制药株式会社 | 制备考布曲钙的方法 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4218744C2 (de) * | 1992-06-04 | 1997-11-06 | Schering Ag | Verfahren zur Herstellung von N-ß-Hxdroxyalkyl-tri-N-carboxylalkyl-1,4,7,10-tetraazacyclododecan- und N-ß-Hydroxyalkyl-tri-N-carboxyalkyl-1,4,8,11-tetraazacyclotetradecan-Derivaten und deren Metallkomplexe |
| DE102009053171B4 (de) | 2009-11-04 | 2011-07-21 | Bayer Schering Pharma Aktiengesellschaft, 13353 | Verfahren zur Herstellung des Calcium-Komplexes von Dihydroxy-hydroxy-methylpropyl-tetraazacyclododecan-triessigsäure (Calcobutrol) |
| CN103613557B (zh) * | 2013-10-18 | 2015-07-29 | 武汉利宝瑞医药科技有限公司 | 一种磁共振成像对比剂钆布醇的制备方法 |
| KR101653064B1 (ko) * | 2014-12-26 | 2016-09-09 | 에스티팜 주식회사 | 가도부트롤의 제조방법 |
-
2019
- 2019-01-02 KR KR1020190000085A patent/KR101979836B1/ko active IP Right Grant
- 2019-11-20 WO PCT/KR2019/015962 patent/WO2020141723A1/ko active Application Filing
- 2019-11-20 CN CN201980087491.9A patent/CN113272284B/zh active Active
- 2019-11-20 JP JP2021538471A patent/JP7272710B2/ja active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107108532A (zh) * | 2014-09-17 | 2017-08-29 | St制药株式会社 | 制备考布曲钙的方法 |
Non-Patent Citations (2)
| Title |
|---|
| J.Platzek et al..Synthesis and structure of a new macrocylic polyhydroxylated gadolinium chelate used as a contract agent for magnetic resonance imaging.《Inorg. Chem》.1997,第36卷第6086-6093页. * |
| Synthesis and structure of a new macrocylic polyhydroxylated gadolinium chelate used as a contract agent for magnetic resonance imaging;J.Platzek et al.;《Inorg. Chem》;第36卷;第6086-6093页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2022515893A (ja) | 2022-02-22 |
| CN113272284A (zh) | 2021-08-17 |
| KR101979836B1 (ko) | 2019-05-21 |
| WO2020141723A1 (ko) | 2020-07-09 |
| JP7272710B2 (ja) | 2023-05-12 |
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| PB01 | Publication | ||
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| GR01 | Patent grant |