Improvements in crystallization of an intermediate for synthesizing non-ionic x-ray contrast agents

A crystallization and compound technology, applied in the preparation of organic compounds, semi-permeable membrane separation, separation/purification of carboxylic acid amides, etc.

Inactive Publication Date: 2011-02-02
GE HEALTHCARE AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Even small increases in yield can lead to significant savings in large-scale production

Method used

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  • Improvements in crystallization of an intermediate for synthesizing non-ionic x-ray contrast agents
  • Improvements in crystallization of an intermediate for synthesizing non-ionic x-ray contrast agents
  • Improvements in crystallization of an intermediate for synthesizing non-ionic x-ray contrast agents

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Embodiment 1 (comparative example)

[0023] 5-Amino-N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide (452 ​​kg) was triiodated with aqueous iodine chloride in an aqueous reaction medium. Excess iodine chloride was quenched by adding sodium bisulfite. Add 5-amino-N, N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide (compound B) (5.5kg ) seeds. The total amount of water in the mixture is about 3200-3300 liters at this stage. The seeded mixture was cooled slowly to 32°C. Crystal growth was allowed to continue for 12 hours, then filtered and the filter cake washed with water.

Embodiment 2

[0025] 5-Amino-N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide (452 ​​kg) was triiodated with aqueous iodine chloride in an aqueous reaction medium. Excess iodine chloride was quenched by adding sodium bisulfite. Add 5-amino-N, N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide (compound B) (5.5kg ) seeds. The total amount of water in the mixture is about 3200-3300 liters at this stage. The seeded mixture was cooled slowly to 35°C and subjected to nanofiltration followed by diafiltration with water. The mother liquor was decanted from the slurry and concentrated to about 60% of its original volume in a nanofiltration unit before being returned to the crystallization vessel. Crystal growth was allowed to continue for 12 hours, then filtered and the filter cake washed with water. The isolated yield of Compound B was about 3.5% higher than that in Comparative Example 1.

Embodiment 3

[0027] 5-Amino-N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide (452 ​​kg) was triiodated with aqueous iodine chloride in an aqueous reaction medium. Excess iodine chloride was quenched by adding sodium bisulfite. Add 5-amino-N, N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide (compound B) (5.5kg ) seeds. The total amount of water in the mixture is about 3200-3300 liters at this stage. The seeded mixture was cooled slowly to 35°C and subjected to nanofiltration followed by diafiltration with water. The mother liquor was decanted from the slurry and concentrated in a nanofiltration unit before it was returned to the crystallization vessel. This step was repeated twice, resulting in an approximately 50% reduction in the total volume of the mother liquor. Crystal growth was allowed to continue for 12 hours, then filtered and the filter cake washed with water. The isolated yield of Compound B was about 4% higher than that in Comparative Example 1.

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Abstract

This invention relates to the crystallization process of 5-amino-N, N'- bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide (''Compound B''), an iodinated intermediate in the preparation of non-ionic X-ray contrast agents. The instant process utilizes a nanofiltration system to pass through low molecular weight salt, thereby reducing the solubility of Compound B in the retentate. This process increases supersaturation of the mother liquor and improves crystal growth in the crystallization following the initial one. The process of the present invention is useful in increasing the overall crystallization yield of Compound B in an industrial manufacturing process.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of priority under 35 U.S.C. §119(e) of US Provisional Application No. 61 / 227,084, filed July 21, 2009, the entire disclosure of which is incorporated herein by reference. technical field [0003] In general, the present invention relates to non-ionic X-ray contrast agents. The invention also relates to a process for crystallization improvement of intermediates in the synthesis of non-ionic X-ray contrast agents. Specifically, the present invention relates to the use of nanofiltration systems to make 5-amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-phthalamide ("Compound B") was crystallized to increase the crystallization yield. Background of the invention [0004] Nonionic X-ray contrast agents constitute a very important class of mass-produced pharmaceutical compounds. 5-[N-(2,3-dihydroxypropyl)-acetylamino]-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-isophthalamide Amid...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/24C07C231/12C07C237/46
CPCB01D61/027C07C231/24B01D2315/16C07C237/46
Inventor O·E·英沃斯塔德
Owner GE HEALTHCARE AS
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