JP2016539147A - 非イオン性x線造影剤の合成における代替アセチル化方法 - Google Patents
非イオン性x線造影剤の合成における代替アセチル化方法 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
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Abstract
Description
(i)5−アミノ−N,N’−ビス(2,3−ジヒドロキシプロピル)−2,4,6−トリヨードイソフタルアミド(「化合物B」)を無水酢酸/酢酸の混合物と反応させて、スラリーを形成する工程と、
(ii)スラリーを約60℃に加熱する工程と、
(iii)反応温度が約65〜85℃の温度範囲で維持されるような速度で、スラリーに酸触媒(好ましくは、パラトルエンスルホン酸(PTSA))を添加する工程と
を含む方法を提供する。
(i)5−アミノ−N,N’−ビス(2,3−ジヒドロキシプロピル)−2,4,6−トリヨードイソフタルアミド(「化合物B」)を無水酢酸/酢酸の混合物と反応させて、スラリーを形成する工程と、
(ii)スラリーを約60℃に加熱する工程と、
(iii)反応温度が約65〜85℃の温度範囲で維持されるような速度で、スラリーに酸触媒(好ましくは、パラトルエンスルホン酸(PTSA))を添加し、過剰アセチル化化合物Aを形成する工程と、
(iv)過剰アセチル化化合物Aを脱アセチル化し、化合物Aを形成する工程と
を含む工業的規模の方法も提供する。
(i)5−アミノ−N,N’−ビス(2,3−ジヒドロキシプロピル)−2,4,6−トリヨードイソフタルアミド(「化合物B」)を無水酢酸/酢酸の混合物と反応させて、スラリーを形成する工程と、
(ii)スラリーを約60℃に加熱する工程と、
(iii)反応温度が約65〜85℃の温度範囲で維持されるような速度で、スラリーに酸触媒(好ましくは、パラトルエンスルホン酸(PTSA))を添加し、過剰アセチル化化合物Aを形成する工程と、
(iv)過剰アセチル化化合物Aを脱アセチル化し、化合物Aを形成する工程と、
(v)化合物Aを分離する工程と
を含む工業的規模の方法も提供する。
アセチル化:例1及び例2の両方について、化合物B(200g)を無水酢酸(191.8mL)及び酢酸(103.3mL)の混合物に添加した。スラリーを約60℃に加熱し、PTSA粉末(1.0g)を一度に添加した。発熱反応により、温度が約120〜125℃に急激に上昇した。
アセチル化:例3及び例4のそれぞれについて、化合物B(200g)を無水酢酸(150.4mL)及び酢酸(141.6mL)の混合物に添加し、スラリーを形成した。PTSA(1.6g)を少量の無水酢酸(3.0mL)に別々に溶解した。このスラリーを、約60℃まで加熱し、約2時間かけてPTSA溶液を添加し、過剰アセチル化化合物Aを形成し、その後、化合物Aを形成するための次の脱アセチル化方法の工程に進んだ。
Claims (9)
- 以下の工程:
(i)5−アミノ−N,N’−ビス(2,3−ジヒドロキシプロピル)−2,4,6−トリヨードイソフタルアミド(「化合物B」)を無水酢酸/酢酸の混合物と反応させて、スラリーを形成する工程と、
(ii)スラリーを約60℃に加熱する工程と、
(iii)反応温度が約65〜85℃の温度範囲で維持されるような速度で、スラリーに酸触媒を添加する工程と
を含む方法。 - 工程(iii)の反応混合物に脱アセチル化剤を添加する工程(iv)をさらに含む、請求項1に記載の方法。
- 工程(iv)の反応混合物を精製する工程(v)をさらに含む、請求項2に記載の方法。
- 精製工程が結晶化工程である、請求項3に記載の方法。
- 結晶化工程が化合物Aの添加によって達成される、請求項4に記載の方法。
- 酸触媒が硫酸である、請求項1乃至請求項5のいずれか1項に記載の方法。
- 酸触媒がパラトルエンスルホン酸(PTSA)である、請求項6に記載の方法。
- PTSAが固体として触媒量で添加される、請求項7に記載の方法。
- PTSAが、少量の無水酢酸に溶解されたPTSAの溶液として触媒量で添加される、請求項7に記載の方法。
Applications Claiming Priority (5)
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US201361912794P | 2013-12-06 | 2013-12-06 | |
US61/912,794 | 2013-12-06 | ||
US201461969932P | 2014-03-25 | 2014-03-25 | |
US61/969,932 | 2014-03-25 | ||
PCT/EP2014/076885 WO2015082719A1 (en) | 2013-12-06 | 2014-12-08 | Alternative acetylation process in the synthesis of non-ionic xray contrast agents |
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JP2019125133A Division JP2019206536A (ja) | 2013-12-06 | 2019-07-04 | 非イオン性x線造影剤の合成における代替アセチル化方法 |
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JP2016539147A true JP2016539147A (ja) | 2016-12-15 |
JP2016539147A5 JP2016539147A5 (ja) | 2020-09-24 |
JP6783140B2 JP6783140B2 (ja) | 2020-11-11 |
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JP2019125133A Pending JP2019206536A (ja) | 2013-12-06 | 2019-07-04 | 非イオン性x線造影剤の合成における代替アセチル化方法 |
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US (1) | US9688614B2 (ja) |
EP (1) | EP3077366B1 (ja) |
JP (2) | JP6783140B2 (ja) |
CN (1) | CN105764882B (ja) |
ES (1) | ES2638645T3 (ja) |
WO (1) | WO2015082719A1 (ja) |
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CN109912445A (zh) * | 2019-02-26 | 2019-06-21 | 兄弟科技股份有限公司 | 碘海醇杂质f的合成方法及其在碘海醇杂质g、杂质h和杂质m合成中的应用 |
GB202004773D0 (en) | 2020-03-31 | 2020-05-13 | Ge Healthcare As | Continuous crystallisation method |
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EP2277851A1 (en) * | 2009-07-21 | 2011-01-26 | GE Healthcare AS | Acetylation using reduced volume of acetic acid anhydride for synthesizing non-ionic X-ray contrast agents |
EP2277859A1 (en) * | 2009-07-21 | 2011-01-26 | GE Healthcare AS | Acetylation using reduced concentration of acetic acid anhydride for synthesizing non-ionic X-ray contrast agents |
US20110021821A1 (en) * | 2009-07-21 | 2011-01-27 | Ge Healthcare As | Continuous acetylation process in synthesis of non-ionic x-ray contrast agents |
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US7863484B1 (en) * | 2009-07-21 | 2011-01-04 | Ge Healthcare As | Method for reducing aminoisophthalic acid bisamide related impurities in preparation of non-ionic X-ray contrast agents |
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- 2014-12-08 ES ES14809013.7T patent/ES2638645T3/es active Active
- 2014-12-08 EP EP14809013.7A patent/EP3077366B1/en active Active
- 2014-12-08 US US15/100,683 patent/US9688614B2/en active Active
- 2014-12-08 JP JP2016536235A patent/JP6783140B2/ja active Active
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Patent Citations (10)
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JPS5321137A (en) * | 1976-06-11 | 1978-02-27 | Serukapeto | Xxray contrast medium |
JPH0672927A (ja) * | 1992-08-28 | 1994-03-15 | Sumitomo Chem Co Ltd | 末端アセチレン化合物およびその製造法 |
CN1132743A (zh) * | 1995-11-20 | 1996-10-09 | 江苏省原子医学研究所 | 一种碘海醇的制备方法 |
WO2002014278A1 (fr) * | 2000-08-08 | 2002-02-21 | Daiichi Pharmaceutical Co., Ltd. | Procedes de preparation de composes bicycliques et intermediaires de mise en oeuvre |
US7754920B1 (en) * | 2009-07-21 | 2010-07-13 | Ge Healthcare As | Solvent reduction in crystallisation of intermediate for non-ionic X-ray contrast agents |
EP2277851A1 (en) * | 2009-07-21 | 2011-01-26 | GE Healthcare AS | Acetylation using reduced volume of acetic acid anhydride for synthesizing non-ionic X-ray contrast agents |
EP2277859A1 (en) * | 2009-07-21 | 2011-01-26 | GE Healthcare AS | Acetylation using reduced concentration of acetic acid anhydride for synthesizing non-ionic X-ray contrast agents |
US20110021821A1 (en) * | 2009-07-21 | 2011-01-27 | Ge Healthcare As | Continuous acetylation process in synthesis of non-ionic x-ray contrast agents |
US20110021822A1 (en) * | 2009-07-21 | 2011-01-27 | Ge Healthcare As | continuous deacetylation and purification process in synthesis of non-ionic x-ray contrast agents |
CN101962342A (zh) * | 2009-07-21 | 2011-02-02 | 通用电气医疗集团股份有限公司 | 非离子x射线造影剂的合成中的连续脱乙酰化和纯化工艺 |
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US20160304438A1 (en) | 2016-10-20 |
ES2638645T3 (es) | 2017-10-23 |
JP2019206536A (ja) | 2019-12-05 |
US9688614B2 (en) | 2017-06-27 |
EP3077366B1 (en) | 2017-08-09 |
JP6783140B2 (ja) | 2020-11-11 |
WO2015082719A1 (en) | 2015-06-11 |
CN105764882B (zh) | 2018-03-30 |
EP3077366A1 (en) | 2016-10-12 |
CN105764882A (zh) | 2016-07-13 |
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