Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Method for preparing loxilan intermediate

The technology of an intermediate, ioxilan, is applied in the field of preparation of non-ionic X-ray contrast agents, can solve the problems of high price of iodine monochloride, high reaction cost, long reaction steps and the like, and achieves low cost, high product purity, The effect of short reaction steps

Active Publication Date: 2011-01-19
CHIA TAI TIANQING PHARMA GRP CO LTD
View PDF4 Cites 4 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In the reaction of above-mentioned synthetic compound I, just carry out reductive iodination reaction at the initial stage of reaction step, because the raw material iodine monochloride price required for iodination is expensive, generates 5-amino-N-(2-hydroxyethyl)- After 2,4,6-triiodo-m-formamide benzoic acid, it is necessary to carry out acylation reaction, acyl chloride reaction and amidation reaction to obtain compound I. The reaction steps are long and the loss is large, so the whole reaction cost is higher

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Method for preparing loxilan intermediate
  • Method for preparing loxilan intermediate
  • Method for preparing loxilan intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Synthesis of 5-nitro-N-(2-hydroxyethyl)-m-carboxamidobenzoic acid methyl ester:

[0020] In a flask equipped with a stirrer and a reflux condenser, add 51 g (0.2 mol) of 5-nitro-N-(2-hydroxyethyl)-m-carboxamidobenzoic acid and 200 ml of methanol at room temperature, stir evenly, and add Sulfuric acid 2ml, heated to 70°C and refluxed for 24 hours to end the reaction, evaporated the methanol under reduced pressure, added the solid to water to form a suspension, adjusted the pH value to about 8 with saturated sodium carbonate solution, stood still for 24 hours, and filtered the solid , washed with distilled water, and dried to obtain 46.5 g of the product, with a yield of 86.7%, and mp: 147-150°C. HPLC detection content: 98.8% (detection conditions: chromatographic column: amino column (250 × 4.6mm, 5 μm); mobile phase: acetonitrile-water solution (87:13); temperature is 30 ° C; flow rate: 1.0mL / min; detection wavelength : 245nm).

Embodiment 2

[0022] Synthesis of 5-nitro-N-(2,3-dihydroxypropyl)-N'-(2-hydroxyethyl)-1,3-benzenedicarboxamide:

[0023] In a flask equipped with a stirrer and a reflux condenser, add 53.6 g (0.2 mol) of methyl 5-nitro-N-(2-hydroxyethyl)-m-formamide benzoate and 200 ml of methanol at room temperature, and stir evenly Finally, add 20g (0.22mol) of 3-amino-1,2-propanediol, heat up to 70°C and reflux for 48 hours to complete the reaction, cool the reaction solution to 4°C, precipitate a solid, filter, wash with a small amount of methanol, and dry to obtain the product 62.9g, yield 96.2%, mp: 142-144°C. 1 H-NMR (DMSO-D 6 , 400MHzδ(ppm): 3.17~3.73(m, 9H, 4×CH 2 , 1×CH), 4.55~4.84(m, 3H, 3×OH), 8.76~8.81(m, 3H, 3×Ar-H), 8.86~8.93(t, 2H, 2×ArCONH); MS: m / z(%): 328.1(M + +H, 100). HPLC detection content: 99.1% (detection conditions: chromatographic column: amino column (250 × 4.6mm, 5 μm); mobile phase: acetonitrile-water solution (87:13); temperature is 30 ° C; flow rate: 1.0mL / min; detectio...

Embodiment 3

[0026] Synthesis of 5-amino-N-(2,3-dihydroxypropyl)-N'-(2-hydroxyethyl)-2,4,6-triiodo-1,3-benzenedicarboxamide:

[0027]In a flask equipped with a stirrer and a reflux condenser, 5-nitro-N-(2,3-dihydroxypropyl)-N'-(2-hydroxyethyl)-1,3-benzene Dissolve 65.4g (0.2mol) of diformamide in 250ml of water, add 5ml of hydrochloric acid and heat up to 80°C, add 56g (1mol) of iron powder in 5 times, continue to stir for one hour after the addition, filter, wash the filter cake with distilled water, Combine the filtrate and washing liquid, adjust the pH value to 1 with concentrated hydrochloric acid, raise the temperature to 80°C, add 107g (0.66mol) of iodine monochloride dropwise, react at 90°C for 3 hours to complete the reaction, and cool the reaction solution to 4°C , precipitated a solid, filtered, washed with a small amount of ethanol, and dried to obtain 110.8 g of the product, with a yield of 82.1%, mp: 220-225°C. 1 H-NMR (DMSO-D 6 , 400MHz) δ (ppm): 3.18~3.76 (m, 9H, 4×CH 2 ,...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention discloses a method for preparing a loxilan intermediate. 5-nitro-N-(2-hydroxyethyl)-m-formamide benzoic acid serving as an initial raw material is subjected to methyl esterification reaction with methanol, amidation reaction with 3-amino-1,2-propylene glycol in methanol solution, iodination reaction with iodine monochlorde in aqueous solution after the product of amidation reaction is reduced with ferric acid, acetylation reaction with acetic anhydride and hydrolysis in aqueous ammonia to obtain 5-acetamido-N-(2,3-dihydroxypropyl)-N-(2-hydroxyethyl)-2,4,6-triiodo-1,3-phthalic amide. The target compound can be obtained by acylation and hydrolysis reaction after the iodination reaction; the use of the expensive iodine monochlorde is avoided at the initial stage of the reactionsteps, so the cost of the whole reaction is greatly reduced; and the reaction condition is mild and the purity of the product is high because the aqueous ammonia is used in the hydrolysis reaction.

Description

technical field [0001] The invention discloses a preparation method of an ioxilan intermediate, which belongs to the technical field of non-ionic X-ray contrast agent preparation, and in particular relates to a preparation method of a non-ionic X-ray contrast agent ioxilan intermediate. Background technique [0002] Ioxilan (Ioxilan, trade name is Oxilan) is a non-ionic X-ray contrast agent developed by Cooking Contrast Agent Company of the United States and Chugai Pharmaceutical Co., Ltd., with a chemical name of 5-[acetyl (2,3-dihydroxypropyl) Amino]-N-(2,3-dihydroxypropyl)-N'-(2-hydroxyethyl)-2,4,6-triiodo-1,3-benzenedicarboxamide (chemical II) . Ioxilan has low osmotic pressure and viscosity due to its asymmetric structure in the molecule and the hydrophobic region formed between molecules, so it has better systemic tolerance and good contrast performance. Ioxilan has relatively stable chemical properties and can withstand high-temperature sterilization. It is made int...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
IPC IPC(8): C07C237/46C07C231/02
Inventor 刘娅灵邹霈谢敏浩罗世能何拥军王洪勇吴军
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com