Iobitridol preparation method and iobitridol intermediate and preparation method thereof
An intermediate, iodine ratio alcohol technology, applied in the preparation of carboxylic acid amides, chemical instruments and methods, preparation of organic compounds, etc., can solve the problems of low reaction route efficiency, high comprehensive cost, and difficulty in achieving satisfactory results.
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[0095] According to one embodiment of the present invention, the first aspect of the present invention provides a novel intermediate M1 (5-(2-isopropyl-1,3-dioxane-5- carbonyl)-2,4,6-triiodoisophthalic acid), which has the following structure:
[0096]
[0097] With bisformyl chloride intermediate 5-(2-isopropyl-1,3-dioxane-5-carboxamido)-2,4,6-triiodoisophthaloyl chloride ( Compound M2, shown below) is different in that the substituent corresponding to the acid chloride of this intermediate is formic acid. The intermediate M2 in the prior art is prepared from 5-amino-2,4,6-triiodoisophthaloyl chloride (compound A) as a starting material.
[0098]
[0099] However, the present inventors found that in this reaction system, M2 is unstable and prone to degradation. In addition, after the reaction, unreacted compound A and product M2 are difficult to separate, resulting in the mixture containing compound A and M2 undergoing the next step of acyl chloride amidation substitu...
Embodiment 1
[0161] Preparation of intermediate M1: 5-(2-isopropyl-1,3-dioxane-5-carboxamido)-2,4,6-triiodoisophthalic acid, the reaction formula is:
[0162]
[0163] Add SM2 (2-isopropyl-1,3-dioxane-5-carboxylic acid) (261.28g, 2.5eq) and DMAc (500ml) into the reaction flask, start stirring, and use an ice bath to reduce the temperature of the system to below 0°C. Subsequently, triphosgene (178.05g, 1.0eq) was dissolved in dichloromethane (500ml), and slowly dropped into the reaction flask. During the dropwise addition, an ice bath was used to keep the temperature of the system below 0°C. After the dropwise addition, the reaction was carried out for 30 minute. Then, SM1-A (5-amino-2,4,6-triiodoisophthalic acid) (335.30 g, 1.0 eq) was added into the reaction flask at one time, the temperature of the system was raised to 50° C., and the reaction was carried out for 16 hours. Subsequently, the solution was cooled to below 0° C. using an ice bath, and aqueous sodium hydroxide solution (...
Embodiment 2
[0167] Preparation of intermediate M1: 5-(2-isopropyl-1,3-dioxane-5-carboxamido)-2,4,6-triiodoisophthalic acid)
[0168] From SM1-B(R 1 =R 2 = methyl) synthetic M0, reaction formula is:
[0169]
[0170] Add SM2 (2-isopropyl-1,3-dioxane-5-carboxylic acid) (31.35g, 3.0eq) and 100ml DMAc into the reaction flask, start stirring, and use an ice bath to lower the system temperature to below 0 degrees . Dissolve triphosgene (21.37g, 1.2eq) in 60ml of dichloromethane, and slowly drop it into the reaction flask. During the dropping process, keep the system temperature within 0°C. After the dropping, react for 30 minutes. Add SM1-B (5-amino-2,4,6-triiodoisophthalic acid methyl ester) (35.21g, 1.0eq) into the reaction flask at one time, raise the temperature of the system to 50 degrees, and react for 16 hours .
[0171] The reaction solution was washed three times with 100 ml of water, and the organic phase was evaporated to dryness. The resulting crude product was subjected to ...
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