JP2023055797A - 非イオン性造影剤の調製に有用な中間体の調製プロセス - Google Patents
非イオン性造影剤の調製に有用な中間体の調製プロセス Download PDFInfo
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Abstract
Description
(i)図1に表現された化学式III、IV、V及び/またはVIのいずれかの化合物を生産する、または
(ii)図2に表現された化学式IX、X、XI、XII及び/またはイオパミドールのいずれかの化合物を生産する、または
(iii)イオジキサノールを生産する
といった多段階化学合成を含むことができる。
(i)アミド化、水素化によるニトロ基の還元、ヨウ素化、アシル化及び選択的な加水分解、または
(ii)水素化によるニトロ基の還元、ヨウ素化、求核アシル基置換及びアシル化。
パートA:連続的なアミド化及び水素化(装置セットアップの実施例として図3参照)。
・化合物Iの1-アミノプロパンジオールに対するモル比: 1:2から1:3
・化合物Iのメタノールに対するモル比: 1:30から1:50
・アミド化温度: 100から130℃
・アミド化圧力: 2から10bar
・アミド化の流動速度: 6から11mL min-1
・水素の流動速度: 170から220mL min-1
・水素化温度: 100から130℃
・水素化圧力: 5から20bar。
・ヨウ素のメタノールに対するモル比: 1:30から1:50
・ヨウ素酸カリウムの硫酸に対するモル比: 1:0.1から1:1
・ヨウ素酸カリウムの水に対するモル比: 1:30から1:50
・供給物Aの供給物Bに対する供給比: 1:1.1から1:10
・供給物Aの供給物Cに対する供給比: 1:0.5から1:1.5
・温度: 60から140℃
・圧力: 5から15bar
・流速: 1から6mL min-1。
・化合物IVの無水酢酸に対するモル比: 1:6から1:25
・化合物IVの酢酸に対するモル比: 1:50から1:80
・化合物IVの硫酸に対するモル比: 1:0.05から1:1
・温度: 80から130℃
・圧力: 2から10bar
・流動速度: 0.01から0.06mL min-1。
・化合物Vのメタノールに対するモル比: 1:100から1:150
・水酸化ナトリウムの水に対するモル比: 1:25から1:50
・供給物Dの供給物Eに対する供給比: 1:0.5から1:2
・温度: 22から75℃
・圧力: 1から10bar
・流動速度: 0.01から0.2mL min-1
Claims (28)
- 非イオン性造影剤の調製に有用な1以上の中間体化合物の調製プロセスであって、2以上の逐次化学反応を含む多段階化学合成の実行を含み、前記各逐次化学反応は2以上の前記中間体化合物の少なくとも1つの前記調製につながり、2以上の前記逐次化学反応が1以上の連続フロー反応器中で実行され、2以上の前記逐次化学反応の少なくとも2つが中断なく連続的に実行され、2以上の前記逐次化学反応は以下の連続フロー(i)または連続フロー(ii)から選択されたいずれかであって、
連続フロー(i)
i-a) アミド化、
i-b) 水素化によるニトロ基の還元、
i-c) ヨウ素化、
i-d) アシル化及び
i-e) 選択的な加水分解、または
連続フロー(ii)
ii-a) 水素化によるニトロ基の還元、
ii-b) ヨウ素化、
ii-c) 求核アシル基置換及び
ii-d) アシル化
前記非イオン性造影剤は、1以上のイオヘキソールおよびイオジキサノールであり、
前記非イオン性造影剤の調整に有用な前記中間体化合物は、化学式II、III、IV、VおよびVIに示される1以上の化合物であるか、
前記非イオン性造影剤は、イオパミドールであり、
前記非イオン性造影剤の調整に有用な前記中間体化合物は、化学式VIII、IX、X、XIおよびXIIに示される1以上の化合物である、
- 前記1以上の連続フロー反応器は、パイプ形反応器、プラグ流反応器、管形反応器、ピストン流れ反応器または2以上の反応器の組合せを含む請求項1に記載の調製プロセス。
- 各反応は、1以上の前記連続フロー反応器の個別の前記連続フロー反応器内で実行される請求項1または2に記載の調製プロセス。
- 前記調製プロセスより生ずる中間体化合物は非イオン性造影剤の調製に使用される請求項1乃至3のいずれか1項に記載の調製プロセス。
- 前記連続フロー(i)において、
前記化学反応ステップi-a)の前記生成物は、第2の中間体化合物を製造するための前記化学反応ステップi-b)の反応物として使用される第1の中間体化合物であり、
このフローは、
前記第2の中間体化合物が、第3の中間体化合物を製造するための前記化学反応ステップi-c)の反応物として使用される反応ステップ、
前記第3の中間体化合物が、第4の中間体化合物を製造するための前記化学反応ステップi-d)の反応物として使用される反応ステップ、および
前記第4の中間体化合物が、第5の中間体化合物を製造するための前記化学反応ステップi-e)の反応物として使用される反応ステップ
でも同じように繰り返される請求項1に記載の調製プロセス。 - 前記調製プロセスの最終中間体化合物が所望された場合を除き、前記調製プロセスはいずれの中間体化合物の単離または精製をすることなく実行される請求項1乃至5のいずれか1項に記載の調製プロセス。
- 中断は単離または精製のステップを含む請求項1乃至6のいずれか1項に記載の調製プロセス。
- 前記調製プロセスは、以下の
(i)1以上の洗浄ステップ
(ii)1以上の精製ステップ
(iii)1以上の単離ステップ
(iv)1以上の溶媒の使用、任意に1以上の溶媒変性ステップ及び/または溶媒切替ステップ
の1以上を含む請求項1乃至7のいずれか1項に記載の調製プロセス。 - 前記1以上の連続フロー反応器中で、さらに条件を制御する請求項1乃至8のいずれか1項に記載の調整プロセス。
- 条件の制御は、以下に示す1以上の条件の調整または変更を含む請求項1乃至9のいずれか1項に記載の調整プロセス。
(i)1以上の連続フロー反応器内の温度、
(ii)1以上の連続フロー反応器内の圧力、
(iii)1以上の連続フロー反応器内の溶媒または溶媒系の使用、
(iv)1以上の連続フロー反応器内の流動速度、
(v)1以上の連続フロー反応器に入る供給物中の反応物の濃度 - 前記1以上の連続フロー反応器を通る試剤の流動速度は、実行される前記化学反応に応じて、制御、変更または調整される請求項1乃至10のいずれか1項に記載の調製プロセス。
- 前記試剤の流動速度は、前記1以上の連続フロー反応器の1以上の選択された距離に従って異なっており、任意の前記1以上の選択された距離は重複していない請求項1乃至11のいずれか1項に記載の調製プロセス。
- 化学反応ステッ10プに関連する前記試剤の流動速度は、次の化学反応ステップに関連する前記流動速度に影響する請求項1乃至12のいずれか1項に記載の調製プロセス。
- 試剤は前記1以上の連続フロー反応器の選択された距離に従って異なる移動速度で移行する請求項1乃至13のいずれか1項に記載の調製プロセス。
- 前記1以上の連続フロー反応器を通る前記試剤の流動速度は、ポンプ、隣接する流速計及び制御弁を利用して制御、調整または変更される請求項1乃至14のいずれか1項に記載の調製プロセス。
- ステップii-c)の求核アシル基置換は以下の
(a)ハロゲン化物のアルコール官能基への置換、
(b)アミン官能基のハロゲン化物への置換、または
(c)アミド化
の1以上を含む請求項1に記載の調製プロセス。 - ステップii-c)の前記求核アシル基置換反応の収率は、アミド化反応の収率が少なくとも95%であるアミド化反応の形態である請求項1に記載の調製プロセス。
- ステップi-c)またはステップii-b)のいずれかにおいて、前記ヨウ素化反応の前記収率は、少なくとも85%である請求項1に記載の調製プロセス。
- ステップi-d)またはステップii-d)のいずれかにおいて、前記アシル化反応の前記収率は、少なくとも74%である請求項1に記載の調製プロセス。
- ステップi-e)の前記選択された加水分解反応の前記収率は、少なくとも97%である請求項1に記載の調製プロセス。
- 前記1以上の非イオン性造影剤の前記調製に有用な前記中間体化合物は、前記化学式VIの化合物または前記化学式XIIの化合物である請求項1に記載の調製プロセス。
- 前記1以の連続フロー反応器は、1以上の静的混合装置を含む請求項1乃至21のいずれか1項に記載の調製プロセス。
- 前記1以上の連続フロー反応器は、ガラス、炭化ケイ素、ステンレス鋼及び/または1以上の高性能合金を含む請求項1乃至22のいずれか1項に記載の調製プロセス。
- 撹拌タンク反応器(CSTRs)または保留タンクの前記使用を含まない請求項1乃至23のいずれか1項に記載の調製プロセス。
- 前記中間体化合物は、化学式VIの化合物である請求項1に記載の調製プロセス。
- 前記中間体化合物は、化学式XIIの化合物である請求項1に記載の調製プロセス。
- 各反応は、不均一または均一の環境内で実行される請求項1乃至26のいずれか1項に記載の調製プロセス。
- 前記連続フロー(ii)において、
前記化学反応ステップii-a)の前記生成物は、第2の中間体化合物を製造するための前記化学反応ステップii-b)の反応物として使用される第1の中間体化合物であり、
このフローは、
前記第2の中間体化合物が、第3の中間体化合物を製造するための前記化学反応ステップii-c)の反応物として使用される反応ステップ、および
前記第3の中間体化合物が、第4の中間体化合物を製造するための前記化学反応ステップii-d)の反応物として使用される反応ステップ
でも同じように繰り返される請求項1に記載の調製プロセス。
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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 |
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CA2881707C (en) | 2012-11-12 | 2021-01-12 | Ge Healthcare As | Preparation of intermediates of x-ray contrast agents |
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US20180169607A1 (en) | 2018-06-21 |
CN116730858A (zh) | 2023-09-12 |
PT108524A (pt) | 2016-12-02 |
US11059021B2 (en) | 2021-07-13 |
IL256044B (en) | 2021-04-29 |
IL256044A (en) | 2018-01-31 |
AU2016272537B2 (en) | 2020-11-12 |
EP3300499A1 (en) | 2018-04-04 |
KR20180034339A (ko) | 2018-04-04 |
JP2018517705A (ja) | 2018-07-05 |
CA2987720A1 (en) | 2016-12-08 |
PT108524B (pt) | 2017-12-15 |
EP3300499B1 (en) | 2023-10-04 |
CN107848951A (zh) | 2018-03-27 |
WO2016193740A1 (en) | 2016-12-08 |
JP2021102628A (ja) | 2021-07-15 |
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EP3300499C0 (en) | 2023-10-04 |
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