Preparation method of iohexol impurity I

A technology of iohexol and impurities, applied in the field of preparation of iohexol impurity I, can solve the problem of high cost, and achieve the effects of low cost, easily available raw materials, and controllable reaction conditions

Inactive Publication Date: 2020-08-14
浙江海昌药业股份有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] At present, the iohexol impurity I is obtained by preparing the liquid phase and purifying the crude product obtained in the synthesis of iohexol from the hydrolyzate. Since the amount of impurities generated in the synthesis is small, it is necessary to prepare a large amount of the liquid phase and purify it, costing very high

Method used

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  • Preparation method of iohexol impurity I
  • Preparation method of iohexol impurity I
  • Preparation method of iohexol impurity I

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preparation example Construction

[0023] The present invention provides a method for preparing iohexol impurity I, comprising the following steps: (1) using iohexol I-1' as a raw material, an intramolecular coupling reaction occurs under alkaline conditions to form compound I', The synthetic route is

[0024]

[0025] where the R 1 and R 2 Each is independently a hydroxyl protecting group, and the hydroxyl protecting group is selected from an alkyl group, a cycloalkyl group, an acyl group, a silyl group, an aryl group and a heteroaryl group; or, R 1 and R 2 together form a heterocyclic group;

[0026] (2) Removal of R 1 and R 2 Hydroxyl protecting group, to form iohexol impurity I, synthetic route is

[0027]

[0028] Preferably, the base of the alkaline condition is at least one of alkali metal alcoholate, alkali metal carbonate, alkali metal hydroxide, alkaline earth metal carbonate and alkaline earth metal hydroxide, preferably tert-butanol At least one of sodium, potassium tert-butoxide, sodiu...

Embodiment 1

[0040]Under nitrogen protection, add iohexol (8.2g, 0.01mol) and sodium hydroxide aqueous solution (12.0g, 0.03mol) in the reaction flask of 100ml, stir reaction at room temperature for 12 hours, TLC detects raw material iohexol reaction completely, Adjust the pH to 5 with hydrochloric acid, concentrate, add ethyl acetate to dissolve, filter, and the filtrate is subjected to column chromatography to obtain 5.2 g of the product, with a yield of 80%, ESI (+) MSm / z 651.96 (M+H).

Embodiment 2

[0042] Under the protection of nitrogen, add iohexol (8.2g, 0.01mol) and sodium hydroxide aqueous solution (10.0g, 0.03mol) to a 100ml reaction flask, heat up to 100°C and stir for 12 hours, TLC detects the raw material iohexol After the reaction was complete, adjust the pH to 5 with hydrochloric acid, concentrate, add ethyl acetate to dissolve, filter, and the filtrate was subjected to column chromatography to obtain 5.2 g of the product, with a yield of 80%, ESI (+) MSm / z 651.96 (M+H).

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Abstract

The invention discloses a preparation method of an iohexol impurity I. The preparation method comprises the following steps: (1) subjecting iohexol I-1'as a raw material to an intramolecular couplingreaction under an alkaline condition to form a compound I', the synthetic route being shown in the specification, with R1 and R2 being respectively independent hydroxyl protecting groups, and the hydroxyl protecting group being one of alkyl, cycloalkyl, acyl, silyl, aryl and heteroaryl; or R1 and R2 together forming a heterocyclic group; (2) removing the R1 and R2 hydroxyl protecting groups to form the iohexol impurity I. The synthesis route is shown in the specification.

Description

technical field [0001] The invention relates to a preparation method of iohexol impurity I. Background technique [0002] Iohexol (Iohexol) 5-(N-2,3-dihydroxypropylacetamido)-2,4,6-triiodo-N,N-bis(2,3-dihydroxypropyl)isophthalein Amide is a non-ionic X-CT contrast agent launched by Norwegian Nycomyn Co., Ltd. in the 1980s. It can be widely used in cardiovascular angiography, urography, arteriography, venography, and endoscopic pancreatography. With many advantages such as good safety, high contrast, low osmotic pressure and low toxicity to the human body, iohexol has become the best-selling contrast agent in the international market in one fell swoop, and has become the "golden standard" on which various X-ray contrast agents are evaluated in the medical field. standard". [0003] However, serious adverse reactions still occur from time to time, and the occurrence of adverse reactions is not only related to the pharmacological activity of iohexol itself, but also has a lot...

Claims

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Application Information

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IPC IPC(8): C07D265/36
CPCC07D265/36Y02P20/55
Inventor 刘成荡刘颖平吴涛
Owner 浙江海昌药业股份有限公司
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