Synthesis method of iomeprol

Abstract

The invention relates to a preparation method of iomeprol. The iomeprol is a non-ionic X-ray contrast agent with excellent safety and contrast effect. The invention relates to a synthesis method of iomeprol, which is characterized in that 5-amino-N, N '-bis (2, 3-dihydroxy propyl)-2, 4, 6-triiodo-1, 3-benzene dicarboxamide (compound II) is used as an initial raw material, chloroacetylation, methylation, hydrolysis and hydroxylation reactions are sequentially carried out to synthesize an iomeprol product, and the synthesis route is as follows. The chemical method for preparing iomeprol is realized through the following steps: acylation reaction, methylation reaction, hydrolysis reaction and hydroxylation reaction. The preparation method disclosed by the invention is stable in quality, high in yield, low in cost, small in pollution and easy to realize industrial production.

Description

technical field

[0001] The invention belongs to the technical field of chemical synthesis, in particular to a synthesis method of iomeprol. Background technique

[0002] Iomeprol, English general name Iomeprol, the trade name of its preparation is Iomeron (iomyron), is a kind of non-ionic X-ray contrast agent developed by Italy Bracco company, respectively in May 1993 in Italy, 1992 It was approved for listing in the UK in December. Compared with the same type of non-ionic X-ray contrast agents (such as iopamidol, ioversol and iohexol, etc.), iomeprol has the lowest osmotic pressure and lower viscosity at the same concentration, and can be made into A high-concentration preparation with an iodine content of 400mg / mL. Its structural formula (I) is as follows

[0003]

[0004] European Patent EP0026281A1 first discloses two synthetic methods of iomeprol, which are:

[0005] The first synthesis method is to use 5-amino-2,4,6-triiodoisophthalic acid as the starting materi...

Examples

Embodiment 1

[0047] A synthetic method for iomeprol, the synthetic method is based on 5-amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzene Diformamide (compound II) is the starting material, and the chloroacetylation, methylation, hydrolysis and hydroxylation reactions are carried out successively to synthesize the iomeprol product, and its synthetic route is as follows:

[0048]

[0049] , the specific process is 4 reaction steps:

[0050] S1. Chloroacetylation reaction (5-(2-chloroacetylamino)-2,4,6-triiodo-N,N'-bis(2,3-bis(2-chloroacetoxy)propyl)- The preparation of isophthalamide):

[0051] Dissolve 12g of 5-amino-N.N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide in 24g of N,N-dimethylacetamide, Stir at room temperature to dissolve. Control the temperature below 60°C and add 12g of chloroacetyl chloride. After the addition, keep warm at 50-60°C and stir for 4 hours. After the reaction is complete, concentrate to dryness below 65°C in vacuum. 36 ml of ethyl ac...

Embodiment 2

[0059] S1. Chloroacetylation reaction (5-(2-chloroacetylamino)-2,4,6-triiodo-N,N'-bis(2,3-bis(2-chloroacetoxy)propyl)- The preparation of isophthalamide):

[0060] Dissolve 500g of 5-amino-N.N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide in 1000g of N,N-dimethylacetamide at room temperature Stir to dissolve. Control the temperature below 60°C, and add 500g of chloroacetyl chloride. After the addition, keep warm at 50-60°C and stir for 4 hours. After the reaction is complete, concentrate to dryness below 65°C in vacuum. Add 1500ml of ethyl acetate and 1500ml of 5% aqueous sodium bicarbonate solution to the concentrated solution for extraction. Add 480 ml of ethyl acetate to the aqueous layer after liquid separation for secondary extraction. After the extracted organic solution was mixed, 650 ml of 5% brine was added, washed, and after recovering the organic solution layer, magnesium sulfate was added to remove water, filtered, and vacuum distillation was carried ou...

technical field

[0001] The invention belongs to the technical field of chemical synthesis, in particular to a synthesis method of iomeprol. Background technique

[0002] Iomeprol, English general name Iomeprol, the trade name of its preparation is Iomeron (iomyron), is a kind of non-ionic X-ray contrast agent developed by Italy Bracco company, respectively in May 1993 in Italy, 1992 It was approved for listing in the UK in December. Compared with the same type of non-ionic X-ray contrast agents (such as iopamidol, ioversol and iohexol, etc.), iomeprol has the lowest osmotic pressure and lower viscosity at the same concentration, and can be made into A high-concentration preparation with an iodine content of 400mg / mL. Its structural formula (I) is as follows

[0003]

[0004] European Patent EP0026281A1 first discloses two synthetic methods of iomeprol, which are:

[0005] The first synthesis method is to use 5-amino-2,4,6-triiodoisophthalic acid as the starting materi...

Examples

Embodiment 1

[0047] A synthetic method for iomeprol, the synthetic method is based on 5-amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzene Diformamide (compound II) is the starting material, and the chloroacetylation, methylation, hydrolysis and hydroxylation reactions are carried out successively to synthesize the iomeprol product, and its synthetic route is as follows:

[0048]

[0049] , the specific process is 4 reaction steps:

[0050] S1. Chloroacetylation reaction (5-(2-chloroacetylamino)-2,4,6-triiodo-N,N'-bis(2,3-bis(2-chloroacetoxy)propyl)- The preparation of isophthalamide):

[0051] Dissolve 12g of 5-amino-N.N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide in 24g of N,N-dimethylacetamide, Stir at room temperature to dissolve. Control the temperature below 60°C and add 12g of chloroacetyl chloride. After the addition, keep warm at 50-60°C and stir for 4 hours. After the reaction is complete, concentrate to dryness below 65°C in vacuum. 36 ml of ethyl ac...

Embodiment 2

[0059] S1. Chloroacetylation reaction (5-(2-chloroacetylamino)-2,4,6-triiodo-N,N'-bis(2,3-bis(2-chloroacetoxy)propyl)- The preparation of isophthalamide):

[0060] Dissolve 500g of 5-amino-N.N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide in 1000g of N,N-dimethylacetamide at room temperature Stir to dissolve. Control the temperature below 60°C, and add 500g of chloroacetyl chloride. After the addition, keep warm at 50-60°C and stir for 4 hours. After the reaction is complete, concentrate to dryness below 65°C in vacuum. Add 1500ml of ethyl acetate and 1500ml of 5% aqueous sodium bicarbonate solution to the concentrated solution for extraction. Add 480 ml of ethyl acetate to the aqueous layer after liquid separation for secondary extraction. After the extracted organic solution was mixed, 650 ml of 5% brine was added, washed, and after recovering the organic solution layer, magnesium sulfate was added to remove water, filtered, and vacuum distillation was carried ou...

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