JP2009518325A - Method for recovery of iopromide from mother liquor suitable for pharmaceutical purposes - Google Patents
Method for recovery of iopromide from mother liquor suitable for pharmaceutical purposes Download PDFInfo
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- JP2009518325A JP2009518325A JP2008543678A JP2008543678A JP2009518325A JP 2009518325 A JP2009518325 A JP 2009518325A JP 2008543678 A JP2008543678 A JP 2008543678A JP 2008543678 A JP2008543678 A JP 2008543678A JP 2009518325 A JP2009518325 A JP 2009518325A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B63/00—Purification; Separation; Stabilisation; Use of additives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/46—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having carbon atoms of carboxamide groups, amino groups and at least three atoms of bromine or iodine, bound to carbon atoms of the same non-condensed six-membered aromatic ring
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- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
本発明は、反応器における母液又は二次結晶体の熱処理及び続く結晶化による、医薬目的のために適切なイオプロミドの回収方法を記載する。 The present invention describes a process for the recovery of iopromide suitable for pharmaceutical purposes by heat treatment and subsequent crystallization of the mother liquor or secondary crystals in the reactor.
Description
本発明は、反応器における母液、又は溶解された二次結晶体の熱処理及び続く結晶化による、医薬目的のために適切なイオプロミド（iopromide）の回収方法に関する。
イオプロミド、すなわち５−メトキシアセチルアミノ−２，４，６−トリヨード−イソフタル酸−[（２，３−ジヒドロキシ−N−メチル−プロピル）−（２，３−ジヒドロキシプロピル）]−ジアミド（DE19641178C及びEP0015867B）は、下記化学構造式を有するヨウ素含有X−線対比媒体である：
The present invention relates to a process for the recovery of iopromide suitable for pharmaceutical purposes by heat treatment and subsequent crystallization of the mother liquor or dissolved secondary crystals in the reactor.
Iopromide, ie 5-methoxyacetylamino-2,4,6-triiodo-isophthalic acid-[(2,3-dihydroxy-N-methyl-propyl)-(2,3-dihydroxypropyl)]-diamide (DE19641178C and EP0015867B ) Is an iodine-containing X-ray contrast medium having the following chemical structural formula:
粗大ヨウ素原子は、芳香環と、N−メチル基の存在によりジヒドロキシプロピル−メチルアミノ基を有するアミド基との間での、前記構造式において１により同定される結合の自由回転をかなりの程度、妨げる。そのようなアトロプ異性体は、"Recent Advances in Atropisomerism" by M. Oki in the journal "Topics in Stereochemistry", 1983, Vol. 14, Pages. 1-81 and Tetrahedron Letters No. 38, Pages 4593 - 4598, 1966に記載されている。１つのアトロプ異性体の場合、置換された窒素原子が環平面上に存在し；他の異性体に関しては、それは環平面下に存在する。２種のアトロプ異性体化合物（異性体１及び２）は、それらの物質において、特に水及び有機溶媒におけるそれらの溶解性において異なる。それらのアトロプ異性体に関する一定の組成物中のイオプロミドのみがX−線対比媒として可能である（40〜51％の異性体１及び49〜60％の異性体２）。 The coarse iodine atom has a considerable degree of free rotation of the bond identified by 1 in the above structural formula between the aromatic ring and the amide group having a dihydroxypropyl-methylamino group due to the presence of the N-methyl group, Hinder. Such atropisomers are described in "Recent Advances in Atropisomerism" by M. Oki in the journal "Topics in Stereochemistry", 1983, Vol. 14, Pages. 1-81 and Tetrahedron Letters No. 38, Pages 4593-4598, 1966. In the case of one atropisomer, the substituted nitrogen atom is on the ring plane; for the other isomer it is below the ring plane. The two atropisomeric compounds (isomers 1 and 2) differ in their solubility, especially in water and organic solvents. Only iopromide in certain compositions with respect to their atropisomers is possible as X-ray contrast medium (40-51% isomer 1 and 49-60% isomer 2).
医薬目的のためのイオプロミドは、エタノールからの結晶化により得られる。これに関しては、約48％の異性体１及び約52％の異性体２から成る混合物は規則的に蓄積する。母液は、約60％での異性体１及び約40％までの異性体２を含む。この理由のために、アトロプ異性体に関する誤った組成を含む二次結晶体は、母液（多構造異性体を含む）から回収され得る。 Iopromide for pharmaceutical purposes is obtained by crystallization from ethanol. In this regard, a mixture consisting of about 48% isomer 1 and about 52% isomer 2 accumulates regularly. The mother liquor contains about 60% isomer 1 and up to about 40% isomer 2. For this reason, secondary crystals containing the wrong composition for atropisomers can be recovered from the mother liquor (including multi-structural isomers).
イオプロミドの生成においては、アルコールから成る最終結晶化が行われる。これに関しては、約10％のイオプロミドの割合が母液に溶解された形で存続し、これは収率の損失として明らかに成る。 In the production of iopromide, a final crystallization consisting of alcohol is performed. In this regard, a proportion of about 10% iopromide persists in dissolved form in the mother liquor, which manifests itself as a yield loss.
蓄積する母液から二次結晶化により追加のイオンプロミドを結晶化し、そして従って、収率を高めるための初期試験は、母液から回収されるイオプロミドK2が、アトロプ異性体比に関して、規格に従っていないので、失敗した。この挙動性は、一定のアトロプ異性体が好ましくは、母液に蓄積する事実に寄与する。 The initial test to crystallize additional ionic promide from the accumulating mother liquor by secondary crystallization, and thus increase the yield, failed because the iopromide K2 recovered from the mother liquor does not comply with the standard with respect to the atropisomer ratio did. This behavior contributes to the fact that certain atropisomers preferably accumulate in the mother liquor.
本発明の目的：
従来技術から知られているイオプロミドについての生成方法は、収率の高い損失が許容されるべきである欠点を示し、そしてアトロプ異性体比に関しての規格に従って存在し、そして従って医薬目的のために使用され得るイオプロミドの母液からの回収を可能にする技術方法は存在しない。
Objects of the invention :
The production methods for iopromide known from the prior art show the disadvantages that a high yield loss should be tolerated and exist according to the specifications for the atropisomer ratio and are therefore used for pharmaceutical purposes There is no technical method that allows recovery of iopromide from the mother liquor that can be made.
本発明の解決：
上記欠点は、最初に、K2がイオプロミド、すなわち純粋な母液から、適切な二次結晶化により回収され、次に存在する物質の有意な分解を伴わないで、適切な熱処理により、規格に従って連続管状流反応器において異性体化されることにおいて、驚くべきことには十分に解決され得る。従って、本発明は、二次及び続く結晶体の溶液の管状流反応器における100〜300℃、好都合には200〜220℃での熱処理、及び次に、室温へのすばやい冷却及び結晶化による、医薬目的のために適切なイオプロミド及びイオプロミド母液の回収方法を包含する。管状流反応器における熱処理は好都合には１〜60分の流体力学的滞留時間で水溶液において行われる。この特定の態様は、特許請求の範囲に引用されている。イオプロミドの合計収率は、本発明の方法により有意に高められ、その結果、経済的効率が上昇する。さらに、ハロゲン含有廃棄物の蓄積が少なくなる。
Solution of the present invention :
The above disadvantages are that K2 is first recovered from iopromide, i.e. pure mother liquor, by appropriate secondary crystallization and then by continuous heat treatment without any significant decomposition of the substances present, according to the specifications. Surprisingly enough can be solved in the isomerization in the flow reactor. Thus, the present invention involves heat treatment at 100-300 ° C., conveniently 200-220 ° C. in a tubular flow reactor of a secondary and subsequent crystalline solution, and then rapid cooling and crystallization to room temperature. Methods for recovering iopromide and iopromide mother liquor suitable for pharmaceutical purposes are included. The heat treatment in the tubular flow reactor is conveniently carried out in aqueous solution with a hydrodynamic residence time of 1 to 60 minutes. This particular embodiment is cited in the claims. The total yield of iopromide is significantly increased by the process of the present invention, resulting in an increase in economic efficiency. Furthermore, the accumulation of halogen-containing waste is reduced.
本発明の詳細な記載：
第１に、二次結晶体は、２〜16倍に蒸発により濃縮され、そして高温でアルコールに溶解されたエタノール性母液により、イオプロミド、すなわち純粋な母液から回収される。適切なアルコールの例は、アルコール、例えばメタノール、エタノール、１−プロパノール、２−プロパノール、１−ブタノール及び２−ブタノールである。この溶液からの結晶化は特にすばやく且つ完全に生じ、そして従って経済的であるので、エタノール、１−プロパノール、及び２−プロパノール、特に好ましくは１−プロパノールが使用される。結晶化を達成するためには、それはイオプロミドにより完全に接種され得る。次に、K2結晶体が、既知方法に従って、単離され、洗浄され、そして乾燥される。
Detailed description of the invention:
First, the secondary crystals are concentrated from iopromide, a pure mother liquor, by an ethanolic mother liquor that is concentrated 2 to 16 times by evaporation and dissolved in alcohol at high temperature. Examples of suitable alcohols are alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol and 2-butanol. Since crystallization from this solution occurs particularly quickly and completely and is therefore economical, ethanol, 1-propanol and 2-propanol, particularly preferably 1-propanol, are used. To achieve crystallization, it can be completely inoculated with iopromide. The K2 crystals are then isolated, washed and dried according to known methods.
例１：K2結晶体の生成：
12,000gのイオプロミド、すなわち純粋母液（約6.2％の固形分）を、真空下での蒸発により濃縮し、892gの粘性油状物を形成した。877gのこの残留物を、適切な反応容器において65℃の槽温度で439mlの１−プロパノールと共に、撹拌しながら混合する。0.73gのイオプロミドによる接種の後、それを65℃の槽温度で、さらに48時間、十分に撹拌する。次に、結晶懸濁液を20℃に冷却し、この温度で１時間、撹拌し、そして吸引フィルターを通して吸引する。110mlのエタノールを４回にわけて、それぞれにより洗浄した後、二次結晶体を真空乾燥オーブンにおいて40℃で乾燥する。
収量：363.8g（実験の約52％）
母液から得られる二次結晶体は、次のアトロープ異性体比を有する：
Example 1 : Production of K2 crystals :
12,000 g of iopromide, ie pure mother liquor (about 6.2% solids), was concentrated by evaporation under vacuum to form 892 g of a viscous oil. 877 g of this residue is mixed with 439 ml of 1-propanol at 65 ° C. bath temperature in a suitable reaction vessel with stirring. After inoculation with 0.73 g of iopromide, it is stirred thoroughly at a bath temperature of 65 ° C. for a further 48 hours. The crystal suspension is then cooled to 20 ° C., stirred at this temperature for 1 hour and sucked through a suction filter. After washing 110 ml of ethanol in 4 portions, each washed, the secondary crystals are dried at 40 ° C. in a vacuum drying oven.
Yield: 363.8g (about 52% of the experiment)
The secondary crystals obtained from the mother liquor have the following atropisomer ratio:
次に、回収された二次結晶体を溶液にし、すなわち水に溶解し、そして適切に企画された耐圧性連続解放管反応器において熱−異性体化する。これに関して、１〜60分、好ましくは１〜30分、特に好ましくは１〜10分の流体力学的滞留間が、100〜300℃、好ましくは150〜250℃、好ましくは180〜230℃、特に好ましくは200〜220℃の温度で設定される。次に下流の熱交管器において、熱処理されたイオプロミドK2溶液を、室温に急冷却する。 The recovered secondary crystals are then brought into solution, i.e. dissolved in water and thermo-isomerized in a suitably designed pressure-resistant continuous open tube reactor. In this connection, the hydrodynamic residence between 1 and 60 minutes, preferably 1 to 30 minutes, particularly preferably 1 to 10 minutes, is 100 to 300 ° C., preferably 150 to 250 ° C., preferably 180 to 230 ° C., in particular Preferably, it is set at a temperature of 200 to 220 ° C. Next, in the downstream heat exchanger, the heat-treated iopromide K2 solution is rapidly cooled to room temperature.
例２：イオプロミド二次結晶体の熱−異性体化：
280gの例１からのイオプロミド−K2を、520gの水に溶解する。次に、その溶液を、208〜209℃で20バールの圧力弁を備えた流動パイプを通して3ml/分の容積流量で供給する。使用される流動パイプは、1.7526mmの内径及び5.5mの加熱される長さを有する（図１を参照のこと）。
Example 2 : Thermo-isomerization of iopromide secondary crystals :
280 g of iopromide-K2 from Example 1 is dissolved in 520 g of water. The solution is then fed at a volumetric flow rate of 3 ml / min through a flow pipe equipped with a 20 bar pressure valve at 208-209 ° C. The flow pipe used has an inner diameter of 1.7526 mm and a heated length of 5.5 m (see FIG. 1).
次に、異性体化されたイオプロミド二次結晶体の溶液を、イオン交換カラムを通して精製し、そしてエタノールから結晶化する。
エタノールから結晶化されるイオプロミドの収率は、イオン化に使用される二次結晶体に関する実験の約80％である。
結晶体は、HPLC（標準方法）の後、外部標準に対して97.5％以上の含有率を示し、そして次のアトロプ異性体比を有する：
Next, a solution of the isomerized iopromide secondary crystal is purified through an ion exchange column and crystallized from ethanol.
The yield of iopromide crystallized from ethanol is about 80% of the experiments on secondary crystals used for ionization.
The crystals, after HPLC (standard method), show a content of over 97.5% with respect to the external standard and have the following atropisomer ratio:
原文に記載なし No description in the original text
Claims (8)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE200510059191 DE102005059191B4 (en) | 2005-12-05 | 2005-12-05 | Process for the recovery of pharmaceutically acceptable iopromide from mother liquors |
| US74817505P | 2005-12-08 | 2005-12-08 | |
| PCT/EP2006/010943 WO2007065534A1 (en) | 2005-12-05 | 2006-11-10 | Method for recovering iopromide suitable for pharmaceutical purposes from mother liquors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JP2009518325A true JP2009518325A (en) | 2009-05-07 |
Family
ID=37773154
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2008543678A Pending JP2009518325A (en) | 2005-12-05 | 2006-11-10 | Method for recovery of iopromide from mother liquor suitable for pharmaceutical purposes |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP1960348A1 (en) |
| JP (1) | JP2009518325A (en) |
| KR (1) | KR20080073369A (en) |
| CA (1) | CA2630413C (en) |
| WO (1) | WO2007065534A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2012510510A (en) * | 2008-12-05 | 2012-05-10 | ダエウン ファーマシューティカル カンパニー リミテッド | Method for selectively crystallizing the Z isomer of iopromide |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS55153755A (en) * | 1979-03-08 | 1980-11-29 | Schering Ag | Triiodoisophthalic acid diamide derivative* its manufacture and x ray contrast agent containing it |
| JP2001519320A (en) * | 1997-10-02 | 2001-10-23 | ニユコメド・イメージング・アクシエセルカペト | Method for crystallizing sterically hindered compounds |
-
2006
- 2006-11-10 WO PCT/EP2006/010943 patent/WO2007065534A1/en active Application Filing
- 2006-11-10 JP JP2008543678A patent/JP2009518325A/en active Pending
- 2006-11-10 EP EP06818545A patent/EP1960348A1/en not_active Withdrawn
- 2006-11-10 KR KR1020087016311A patent/KR20080073369A/en not_active Application Discontinuation
- 2006-11-10 CA CA2630413A patent/CA2630413C/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS55153755A (en) * | 1979-03-08 | 1980-11-29 | Schering Ag | Triiodoisophthalic acid diamide derivative* its manufacture and x ray contrast agent containing it |
| JP2001519320A (en) * | 1997-10-02 | 2001-10-23 | ニユコメド・イメージング・アクシエセルカペト | Method for crystallizing sterically hindered compounds |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2012510510A (en) * | 2008-12-05 | 2012-05-10 | ダエウン ファーマシューティカル カンパニー リミテッド | Method for selectively crystallizing the Z isomer of iopromide |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1960348A1 (en) | 2008-08-27 |
| CA2630413A1 (en) | 2007-06-14 |
| WO2007065534A1 (en) | 2007-06-14 |
| CA2630413C (en) | 2013-06-25 |
| KR20080073369A (en) | 2008-08-08 |
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