CN107253917A - The preparation method of Iopromide and the purposes of intermediate - Google Patents
The preparation method of Iopromide and the purposes of intermediate Download PDFInfo
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- CN107253917A CN107253917A CN201710459413.XA CN201710459413A CN107253917A CN 107253917 A CN107253917 A CN 107253917A CN 201710459413 A CN201710459413 A CN 201710459413A CN 107253917 A CN107253917 A CN 107253917A
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- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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Abstract
The present invention relates to a kind of preparation method of Iopromide.In order to solve to prepare the Methods For Purification difficulty height of Iopromide, complex steps, the technical problem for polluting environment present in existing technology.The present invention provides a kind of preparation method of Iopromide and the purposes of intermediate, comprises the following steps：Step a. methoxyacetic anhydrides are protected：The compound of formula (10) obtains the compound of formula (11) with methoxyacetic acid anhydride reactant；The compound of step b. formulas (11) and the propane diols of 3 methylamino 1,2 react, product through hydrolysis, after purification, obtain the compound of formula (12)；The compound of step c. formulas (12) and the Iopromide that formula (1) is obtained after iodo reagent reacting.The compound of formula (10), formula (11) or formula (12) prepares the purposes of Iopromide.The preparation method of the Iopromide of the present invention reduces the pollution to environment；Shorten the reaction time, save energy consumption；Post processing is simple, so that cost-effective, makes that reaction is more environmentally friendly, cost is lower.
Description
Technical field
The present invention relates to a kind of preparation method of Iopromide, in particular it relates to a kind of preparation method of Iopromide and
The purposes of intermediate.
Background technology
Current Iopromide is widely used in angiogram, renal arteriography, IVU, the inspection of CT Contrast enhanceds, body
Chamber such as shows at the x-ray contrast agent.As water soluble contrast material, its good water solubility, viscosity is low, better tolerance, is injected intravenously toxicity
It is low, it is a kind of comparatively ideal CT enhancings scanning contrast agent.The preparation method of the relevant Iopromide of document report is disclosed in patent
Number for US4364921, CN201110205473 and CN201210279515 patent document in.Patent (US4364921) is open
Its reactions steps of the preparation method of Iopromide are as follows：
Reaction scheme 1：
Reaction scheme 2：
According to above-mentioned reaction scheme 1, the Iopromide of formula (1) is made by the steps：In DMF solvent, formula
(2) 5- amino -2,4,6- triiodo isophthaloyl chlorine reacts with methoxyacetyl chloride, production (3) 5- methoxyacetamido -2,
4,6- triiodo isophthaloyl chlorine；Again using triethylamine etc. as alkali in DMF solvent, by the compound of formula (3) successively with 3- amino -1,
2- propane diols and the reaction of 3- methylamino -1,2- propane diols obtain Iopromide.
Understood via above-mentioned reaction scheme 2, the compound of formula (3) successively with 3- amino -1,2-PD and 3- methylaminos -
1,2-PD reacts, due to the presence of double acyl chlorides, and it is difficult formula (5) accessory substance 5- methoxyl group acetyl ammonia removed that will generate
Double (2,3- the dihydroxypropyls) -2,4,6- triiodoisophthal amides of base-N, N'-.Therefore the Iopromide of high-purity is obtained, according to anti-
Answer the method for route 1 to be accomplished by removing the accessory substance of formula (5) by a large amount of solvent purifications, finally may result in reaction scheme 1
Yield it is relatively low, post-process it is cumbersome a series of problems, such as.
It is as follows that patent CN201110205473 discloses the preparation method of Iopromide its reactions steps：
Reaction scheme 3：
According to above-mentioned reaction scheme 3, the Iopromide of formula (1) is made by the steps：In chloroform solvent,
DMF makees catalyst, the compound of formula (6) is obtained the compound of formula (8) with methoxyacetyl chloride reaction, after basic hydrolysis,
The compound of formula (8), which is added in substantial amounts of thionyl chloride, carries out the compound that chloride obtains formula (4), the compound of formula (4)
Iopromide is obtained with the reaction of 3- methylamino -1,2- propane diols.
Above-mentioned reaction scheme 3, although avoid formula (5) accessory substance in reaction scheme 1, but be the introduction of more reaction steps
Suddenly, and the thionyl chloride of substantial amounts of high pollution has been used, has added environmental treatment, reaction treatment is more cumbersome, so that yield is low,
Increase cost.
The preparation method reactions steps that patent CN201210279515 discloses Iopromide are as follows：
Reaction scheme 4：
According to above-mentioned reaction scheme 4, although pass through the compound of purifying formula (9) to reduce purifying difficulty, but exist
The problem of patent (US4364921), and reactions steps are also add, make route more cumbersome, yield is lower, so that cost is carried
It is high.
The content of the invention
It is an object of the invention to solve technical problem present in above prior art at least one of, for above-mentioned existing
With the presence of all multi-methods for preparing Iopromide shortcoming, the present invention provides a kind of new reaction scheme, reaction more rationally, production
The purposes of the preparation method and intermediate of rate and the higher Iopromide of purity, so that it is lower to react more environmentally friendly, cost.
The purpose of the present invention is achieved through the following technical solutions：
A kind of preparation method of Iopromide, comprises the following steps：
Step a. methoxyacetic anhydrides are protected：The compound of formula (10) obtains the change of formula (11) with methoxyacetic acid anhydride reactant
Compound；
The compounds of step b. formulas (11) is reacted with 3- methylaminos -1,2-PD, product through hydrolysis, after purification, obtain
The compound of formula (12)；
The compound of step c. formulas (12) and the Iopromide that formula (1) is obtained after iodo reagent reacting；
Reaction equation is as follows：
Further, when the compound of the step a Chinese styles (10) is with methoxyacetic acid anhydride reactant, methoxyacetic acid is added
Catalyst is used as with the concentrated sulfuric acid；Compound, methoxyacetic anhydride, methoxyacetic acid and the concentrated sulfuric acid of the step a Chinese styles (10)
Mass ratio be 80:240:150:3.
Further, the compound of the step a Chinese styles (10) and methoxyacetic acid anhydride reactant are comprised the following steps that：Will
Compound 3- amino -5- (the 2,3- hydroxyl n-propylamine bases of 150g methoxyacetic acids, 240g methoxyacetic anhydrides and 80g formulas (10)
Formoxyl)-methyl benzoate is heated with stirring to 40-65 DEG C, and the 3g concentrated sulfuric acids are added, 12h is reacted at this temperature, formula is obtained
(11) compound.
Further, the solvent of the step b Chinese styles (11) and 3- methylaminos -1,2-PD reaction for absolute methanol or
Absolute ethyl alcohol, catalyst is sodium methoxide, natrium carbonicum calcinatum or Anhydrous potassium carbonate；The compound and 3- methylaminos -1,2- of formula (11)
The mol ratio of propane diols sum is 1:1.1~1.5.
Further, catalyst is sodium methoxide in the step b；3- methylaminos -1,2- the propane diols and sodium methoxide
Mass ratio is 40.7:1.5；The compound of formula (11) and the mol ratio of 3- methylamino -1,2- propane diols sums are 1:1.3.
Further, the step b is：By compound 300mL absolute methanols or the nothing of the formula (11) obtained in step a
Water-ethanol dissolves, and then adds 40.7g 3- methylaminos -1,2-PD and 1.5g sodium methoxides, heating reflux reaction 6h, reaction
After finishing, less than 30 DEG C are cooled to, the aqueous solution for adding alkali is added dropwise, is warming up to after 50-65 DEG C of reaction 3-5h, is cooled to after dripping off
Room temperature, PH is adjusted to 2-3 with concentrated hydrochloric acid, be concentrated under reduced pressure into it is near dry, add after the dissolving of ethanol agitating and heating slow cooling to 5 DEG C with
Lower crystallization 8h, filter, be dried in vacuo formula (12) compound；The aqueous solution of the alkali is sodium hydrate aqueous solution, sodium carbonate
The aqueous solution or wet chemical；When the aqueous solution of alkali is sodium hydrate aqueous solution, the concentration of sodium hydrate aqueous solution is
10mol/L, the volume of addition is 180mL.
Further, the iodo reagent in the step c is iodine monochloride；The compound of the step c Chinese styles (12) with
The solvent of iodine monochloride reaction is water, and the compound of the formula (12) and the mol ratio of iodine monochloride are 1:3.1~3.3.
Further, the compound of the formula (12) and the mol ratio of iodine monochloride are 1:3.15.
Further, the step c is：The compound of 50g formulas (12) is dissolved in 150g pure water, is heated with stirring to 70-80
DEG C, it is added dropwise and adds 63.3g iodine monochlorides, 85-90 DEG C of reaction 3-5h is warming up to after dripping off, after completion of the reaction, is cooled to 50 DEG C, use
The aqueous solution of alkali adjusts PH to 8-9, and be concentrated under reduced pressure 120mL water, adds 165g ethanol, and stirred crystallization obtains the compound of formula (1)
Iopromide, the aqueous solution of the alkali is sodium hydrate aqueous solution or ammoniacal liquor；When the aqueous solution of alkali is sodium hydrate aqueous solution,
The concentration of sodium hydrate aqueous solution is 10mol/L.
The compound of formula (10), formula (11) or formula (12) prepares the purposes of Iopromide.
The present invention is relative to the beneficial effect of prior art：The preparation method of the Iopromide of the present invention, by using
Formula (11) is as reaction raw materials, and reactions steps are few, and the design of its reaction scheme is more reasonable；According to the preparation of the Iopromide of the present invention
Yield and purity prepared by method is higher；In addition, the preparation method selection of the present invention uses more environmentally friendly reaction reagent, reduce
Pollution to environment；Shorten the reaction time, save energy consumption；Post processing is simple, so that cost-effective, makes that reaction is more environmentally friendly, cost
It is lower, it is to avoid to pollute environment, low yield, the high defect of purification difficulty, with stronger practical value in the prior art.
Embodiment
Technical scheme is described in detail below in conjunction with embodiment, so that those skilled in the art
Can be sufficiently complete on the basis of description of the invention has been read realize technical scheme, and solve institute of the present invention
The technical problem to be solved.It should be noted that following is only the preferred embodiment of the present invention, for the common skill of this area
For art personnel, without departing from the concept of the premise of the invention, various modifications and improvements can be made, these should be all
Belong to protection scope of the present invention.The technical characteristic of embodiments of the invention mutually it is reconcilable in the case of independent assortment, group
The technical scheme obtained after conjunction still falls within the scope of protection of the invention.
A kind of preparation method of Iopromide, comprises the following steps：
Step a. methoxyacetic anhydrides are protected：The compound of formula (10) obtains the change of formula (11) with methoxyacetic acid anhydride reactant
Compound；
The compounds of step b. formulas (11) is reacted with 3- methylaminos -1,2-PD, product through hydrolysis, after purification, obtain
The compound of formula (12)；
The compound of step c. formulas (12) and the Iopromide that formula (1) is obtained after iodo reagent reacting；
Reaction equation is as follows：
Specifically, reaction equation is as follows：
Further, when the compound of the step a Chinese styles (10) is with methoxyacetic acid anhydride reactant, methoxyacetic acid is added
Catalyst is used as with the concentrated sulfuric acid；Compound, methoxyacetic anhydride, methoxyacetic acid and the concentrated sulfuric acid of the step a Chinese styles (10)
Mass ratio be 80:240:150:3.
Further, the compound of the step a Chinese styles (10) and methoxyacetic acid anhydride reactant are comprised the following steps that：Will
Compound 3- amino -5- (the 2,3- hydroxyl n-propylamine bases of 150g methoxyacetic acids, 240g methoxyacetic anhydrides and 80g formulas (10)
Formoxyl)-methyl benzoate is heated with stirring to 40-65 DEG C, and the 3g concentrated sulfuric acids are added, 12h is reacted at this temperature, formula is obtained
(11) compound.
Further, the solvent of the step b Chinese styles (11) and 3- methylaminos -1,2-PD reaction for absolute methanol or
Absolute ethyl alcohol, catalyst is sodium methoxide, natrium carbonicum calcinatum or Anhydrous potassium carbonate；The compound and 3- methylaminos -1,2- of formula (11)
The mol ratio of propane diols sum is 1:1.1~1.5.
Further, catalyst is sodium methoxide in the step b；3- methylaminos -1,2- the propane diols and sodium methoxide
Mass ratio is 40.7:1.5；The compound of formula (11) and the mol ratio of 3- methylamino -1,2- propane diols sums are 1:1.3.
Further, the step b is：By compound 300mL absolute methanols or the nothing of the formula (11) obtained in step a
Water-ethanol dissolves, and then adds 40.7g 3- methylaminos -1,2-PD and 1.5g sodium methoxides, heating reflux reaction 6h, reaction
After finishing, less than 30 DEG C are cooled to, the aqueous solution for adding alkali is added dropwise, is warming up to after 50-65 DEG C of reaction 3-5h, is cooled to after dripping off
Room temperature, PH is adjusted to 2-3 with concentrated hydrochloric acid, be concentrated under reduced pressure into it is near dry, add after the dissolving of ethanol agitating and heating slow cooling to 5 DEG C with
Lower crystallization 8h, filter, be dried in vacuo formula (12) compound；The aqueous solution of the alkali is sodium hydrate aqueous solution, sodium carbonate
The aqueous solution or wet chemical；When the aqueous solution of alkali is sodium hydrate aqueous solution, the concentration of sodium hydrate aqueous solution is
10mol/L, the volume of addition is 180mL.
Further, the iodo reagent in the step c is iodine monochloride；The compound of the step c Chinese styles (12) with
The solvent of iodine monochloride reaction is water, and the compound of the formula (12) and the mol ratio of iodine monochloride are 1:3.1~3.3.
Further, the compound of the formula (12) and the mol ratio of iodine monochloride are 1:3.15.
Further, the step c is：The compound of 50g formulas (12) is dissolved in 150g pure water, is heated with stirring to 70-80
DEG C, it is added dropwise and adds 63.3g iodine monochlorides, 85-90 DEG C of reaction 3-5h is warming up to after dripping off, after completion of the reaction, is cooled to 50 DEG C, use
The aqueous solution of alkali adjusts PH to 8-9, and be concentrated under reduced pressure 120mL water, adds 165g ethanol, and stirred crystallization obtains the compound of formula (1)
Iopromide, the aqueous solution of the alkali is sodium hydrate aqueous solution or ammoniacal liquor；When the aqueous solution of alkali is sodium hydrate aqueous solution,
The concentration of sodium hydrate aqueous solution is 10mol/L.
The compound of formula (10), formula (11) or formula (12) prepares the purposes of Iopromide.
The preparation method of the Iopromide of the present invention is with 3- amino -5- (the 2,3- hydroxyl n-propylamine base formyls of formula (10)
Base)-methyl benzoate is that raw material is protected by methoxyacetic anhydride, amidatioon, the reaction such as dehydroxylation protection are made formula (12)
5- methoxyacetamidos-M-phthalic acid [(2,3- dihydroxy-N- methyl-propyls)-(2,3- dihydroxypropyls)] diamides
Intermediate, Iopromide is finally made by the intermediate by the reaction such as iodo.Therefore, each intermediate of the invention and original
Material, can be used as and be used as synthesis Iopromide.
Embodiment 1
Step one：150g methoxyacetic acids, 240g methoxyacetic anhydrides, 80g are added in four-hole boiling flask clean 500mL
Compound 3- amino -5- (2,3- hydroxyl n-propylamine base formoxyl)-methyl benzoate of formula (10), is heated with stirring to 40 DEG C, plus
Enter the 3g concentrated sulfuric acids, 12h is reacted at this temperature, obtain the compound of formula (11)；
Step 2：It is above-mentioned to depressurize after completion of the reaction and boil off solvent, then dissolved with 300mL absolute methanols, add 40.7g3-
Methylamino -1,2-PD, 1.5g sodium methoxides, heating reflux reaction 6h after completion of the reaction, are cooled to 30 DEG C, are added dropwise and add
180mL 10mol/L sodium hydrate aqueous solutions, are warming up to after 50 DEG C of reaction 3h after dripping off, are cooled to room temperature, are adjusted with concentrated hydrochloric acid
PH is concentrated under reduced pressure near dry to 2, adds after the dissolving of 174g ethanol agitating and heating slow cooling to 5 DEG C of crystallization 8h, filtering, vacuum
The compound 98g of dry formula (12)；
Step 3：50g formulas (12) are dissolved in 150g pure water, 70 DEG C are heated with stirring to, is added dropwise and adds iodine monochloride solution
(iodine monochloride addition is 0.39mol), is warming up to 85 DEG C of reaction 3h after dripping off, after completion of the reaction, be cooled to 50 DEG C, use
10mol/L sodium hydrate aqueous solution adjusts PH to 8, and be concentrated under reduced pressure 120mL water, adds 165g ethanol, and stirred crystallization is dried
Obtain the compound Iopromide of 82.3g formulas (1).
Embodiment 2
Step one：30kg methoxyacetic acids, 48kg methoxyacetic anhydrides, 16kg formulas are added in reactor clean 100L
(10) compound 3- amino -5- (2,3- hydroxyl n-propylamine base formoxyl)-methyl benzoate, is heated with stirring to 65 DEG C, addition
The 600g concentrated sulfuric acids, react 12h at this temperature, obtain the compound of formula (11)；
Step 2：It is above-mentioned to depressurize after completion of the reaction and boil off solvent, then dissolved with 48kg absolute methanols, add 8.2kg3- first
Amino -1,2-PD, 300g sodium methoxides, heating reflux reaction 6h after completion of the reaction, are cooled to 30 DEG C, are added dropwise and add
36L10mol/L sodium hydrate aqueous solution, is warming up to after 50 DEG C of reaction 3h after dripping off, is cooled to room temperature, PH is adjusted with concentrated hydrochloric acid
To 2, it is concentrated under reduced pressure near dry, adds after the dissolving of 34kg ethanol agitating and heating that slow cooling is to 5 DEG C of crystallization 8h, filtering, vacuum are done
The dry compound 19.5kg for obtaining formula (12)；
Step 3：30kg pure water is added in 100L reactors, stirring is lower to add 10kg formulas (12), is heated with stirring to 70
DEG C, it is added dropwise and adds iodine monochloride solution (iodine monochloride addition is 78mol), 85 DEG C of reaction 3h is warming up to after dripping off, have been reacted
Bi Hou, is cooled to 50 DEG C, adjusts PH to 8 with 10mol/L sodium hydrate aqueous solution, be concentrated under reduced pressure 24L water, adds 30kg second
Alcohol, stirred crystallization it is dry 16.5kg formulas (1) compound Iopromide.
Embodiment 3
Step one：Added in reactor clean 1000L 300kg methoxyacetic acids, 480kg methoxyacetic anhydrides,
Compound 3- amino -5- (2,3- hydroxyl n-propylamine base formoxyl)-methyl benzoate of 160kg formulas (10), is heated with stirring to 50
DEG C, the 6kg concentrated sulfuric acids are added, 12h is reacted at this temperature, the compound of formula (11) is obtained；
Step 2：It is above-mentioned that decompression boils off solvent, then is dissolved with 480kg absolute methanols or absolute ethyl alcohol after completion of the reaction, plus
Enter 82kg3- methylaminos -1,2-PD, 3kg sodium methoxides, heating reflux reaction 6h after completion of the reaction, is cooled to 20 DEG C, dropwise addition
360L 10mol/L sodium hydrate aqueous solutions are added, is warming up to after dripping off after 50 DEG C of reaction 3h, is cooled to room temperature, uses concentrated hydrochloric acid
PH is adjusted to 2, is concentrated under reduced pressure near dry, slow cooling is added after the dissolving of 340kg ethanol agitating and heating to 3 DEG C of crystallization 8h, filtering,
Be dried in vacuo formula (12) compound 196kg；
Step 3：300kg pure water is added in 1000L reactors, stirring is lower to add 100kg formulas (12), is heated with stirring to
70 DEG C, addition iodine monochloride solution is added dropwise, and ((iodine monochloride addition is 780mol) is warming up to 85 DEG C of reaction 3h, instead after dripping off
After should finishing, 50 DEG C are cooled to, PH is adjusted to 8 with 10mol/L sodium hydrate aqueous solution, be concentrated under reduced pressure 240L water, adds
300kg ethanol, stirred crystallization it is dry 167kg formulas (1) compound Iopromide.
Embodiment 4
Step one：150g methoxyacetic acids, 240g methoxyacetic anhydrides, 80g are added in four-hole boiling flask clean 500mL
Compound 3- amino -5- (2,3- hydroxyl n-propylamine base formoxyl)-methyl benzoate of formula (10), is heated with stirring to 55 DEG C, plus
Enter the 3g concentrated sulfuric acids, 12h is reacted at this temperature, obtain the compound of formula (11)；
Step 2：It is above-mentioned that decompression boils off solvent, then is dissolved with 300mL absolute methanols or absolute ethyl alcohol after completion of the reaction, plus
Enter 40.7g3- methylaminos -1,2-PD, 2g Anhydrous potassium carbonates, heating reflux reaction 6h after completion of the reaction, is cooled to 15 DEG C,
It is 25% ammoniacal liquor to be added dropwise and add 200mL mass percent, is warming up to after dripping off after 55 DEG C of reaction 3.5h, is cooled to room temperature,
PH is adjusted to 2.5 with concentrated hydrochloric acid, is concentrated under reduced pressure near dry, adds after the dissolving of 174g ethanol agitating and heating slow cooling to 4 DEG C of knots
Brilliant 8h, filter, be dried in vacuo formula (12) compound 94.5g；
Step 3：50g formulas (12) are dissolved in 150g pure water, 75 DEG C are heated with stirring to, is added dropwise and adds iodine monochloride solution
(iodine monochloride addition is 0.39mol), is warming up to 87 DEG C of reaction 4h, after completion of the reaction, is cooled to 50 DEG C, uses quality after dripping off
The ammoniacal liquor of percentage 25% adjusts PH to 8, and be concentrated under reduced pressure 120mL water, adds 165g absolute ethyl alcohols, and stirred crystallization obtains 81.9g
The compound Iopromide of formula (1).
Embodiment 5
A kind of preparation method of Iopromide, comprises the following steps：
Step a. methoxyacetic anhydrides are protected：150g methoxyacetic acids, 240g are added in four-hole boiling flask clean 500mL
Compound 3- amino -5- (2,3- hydroxyl n-propylamine base formoxyl)-methyl benzoate of methoxyacetic anhydride, 80g formulas (10), is stirred
Mix and be heated to 55 DEG C, add the 3g concentrated sulfuric acids, 12h is reacted at this temperature, the compound of formula (11) is obtained；
Step b. is above-mentioned after completion of the reaction, and decompression boils off solvent, then is dissolved with 300mL absolute methanols or absolute ethyl alcohol, presses
The compound of illuminated (11) and the mol ratio of 3- methylamino -1,2- propane diols sums are 1:1.1, add 3- methylaminos -1,2- the third two
Alcohol and 2g sodium methoxides, heating reflux reaction 6h after completion of the reaction, are cooled to 15 DEG C, the 10mol/L hydrogen-oxygens for adding 180mL are added dropwise
Change sodium water solution, be warming up to after dripping off after 55 DEG C of reaction 3.5h, be cooled to room temperature, adjusted PH to 2.5 with concentrated hydrochloric acid, be concentrated under reduced pressure
To near dry, slow cooling is added after the dissolving of 174g ethanol agitating and heating to 4 DEG C of crystallization 8h, filter, be dried in vacuo to obtain formula (12)
Compound 94.5g；
50g formulas (12) are dissolved in 150g pure water by step c., are heated with stirring to 75 DEG C, according to the compound and one of formula (12)
The mol ratio of lodine chloride is 1:3.1, it is added dropwise and adds iodine monochloride, 87 DEG C of reaction 4h, after completion of the reaction, cooling is warming up to after dripping off
To 50 DEG C, PH is adjusted to 8 with the ammoniacal liquor of mass percent 25%, be concentrated under reduced pressure 120mL water, add 165g absolute ethyl alcohols, stir
Mix crystallize formula (1) compound Iopromide.
Embodiment 6
A kind of preparation method of Iopromide, comprises the following steps：
Step a. methoxyacetic anhydrides are protected：150g methoxyacetic acids, 240g are added in four-hole boiling flask clean 500mL
Compound 3- amino -5- (2,3- hydroxyl n-propylamine base formoxyl)-methyl benzoate of methoxyacetic anhydride, 80g formulas (10), is stirred
Mix and be heated to 55 DEG C, add the 3g concentrated sulfuric acids, 12h is reacted at this temperature, the compound of formula (11) is obtained；
Step b. is above-mentioned after completion of the reaction, and decompression boils off solvent, then is dissolved with 300mL absolute methanols or absolute ethyl alcohol, presses
The compound of illuminated (11) and the mol ratio of 3- methylamino -1,2- propane diols sums are 1:1.5, add 3- methylaminos -1,2- the third two
Alcohol and 2g sodium methoxides, heating reflux reaction 6h after completion of the reaction, are cooled to 15 DEG C, the 10mol/L hydrogen-oxygens for adding 180mL are added dropwise
Change sodium water solution, be warming up to after dripping off after 55 DEG C of reaction 3.5h, be cooled to room temperature, adjusted PH to 2.5 with concentrated hydrochloric acid, be concentrated under reduced pressure
To near dry, slow cooling is added after the dissolving of 174g ethanol agitating and heating to 4 DEG C of crystallization 8h, filter, be dried in vacuo to obtain formula (12)
Compound 94.5g；
50g formulas (12) are dissolved in 150g pure water by step c., are heated with stirring to 75 DEG C, according to the compound and one of formula (12)
The mol ratio of lodine chloride is 1:3.3, it is added dropwise and adds iodine monochloride, 87 DEG C of reaction 4h, after completion of the reaction, cooling is warming up to after dripping off
To 50 DEG C, PH is adjusted to 8 with the ammoniacal liquor of mass percent 25%, be concentrated under reduced pressure 120mL water, add 165g absolute ethyl alcohols, stir
Mix crystallize formula (1) compound Iopromide.
Embodiment 7
A kind of preparation method of Iopromide, comprises the following steps：
Step a. methoxyacetic anhydrides are protected：150g methoxyacetic acids, 240g are added in four-hole boiling flask clean 500mL
Compound 3- amino -5- (2,3- hydroxyl n-propylamine base formoxyl)-methyl benzoate of methoxyacetic anhydride, 80g formulas (10), is stirred
Mix and be heated to 55 DEG C, add the 3g concentrated sulfuric acids, 12h is reacted at this temperature, the compound of formula (11) is obtained；
Step b. is above-mentioned after completion of the reaction, and decompression boils off solvent, then is dissolved with 300mL absolute methanols or absolute ethyl alcohol, presses
The compound of illuminated (11) and the mol ratio of 3- methylamino -1,2- propane diols sums are 1:1.3, add 3- methylaminos -1,2- the third two
Alcohol and 2g natrium carbonicum calcinatums, heating reflux reaction 6h after completion of the reaction, are cooled to 15 DEG C, the 10mol/L for adding 180mL are added dropwise
Sodium hydrate aqueous solution, is warming up to after 55 DEG C of reaction 3.5h after dripping off, is cooled to room temperature, PH to 2.5, decompression are adjusted with concentrated hydrochloric acid
It is concentrated into and closely does, adds slow cooling after the dissolving of 174g ethanol agitating and heating and, to 4 DEG C of crystallization 8h, filter, be dried in vacuo to obtain formula
(12) compound 94.5g；
50g formulas (12) are dissolved in 150g pure water by step c., are heated with stirring to 75 DEG C, according to the compound and one of formula (12)
The mol ratio of lodine chloride is 1:3.15 are added dropwise addition iodine monochloride, and 87 DEG C of reaction 4h, after completion of the reaction, cooling are warming up to after dripping off
To 50 DEG C, PH is adjusted to 8 with the ammoniacal liquor of mass percent 25%, be concentrated under reduced pressure 120mL water, add 165g absolute ethyl alcohols, stir
Mix crystallize formula (1) compound Iopromide.
Embodiment 8
A kind of preparation method of Iopromide, comprises the following steps：
Step a. methoxyacetic anhydrides are protected：150g methoxyacetic acids, 240g are added in four-hole boiling flask clean 500mL
Compound 3- amino -5- (2,3- hydroxyl n-propylamine base formoxyl)-methyl benzoate of methoxyacetic anhydride, 80g formulas (10), is stirred
Mix and be heated to 55 DEG C, add the 3g concentrated sulfuric acids, 12h is reacted at this temperature, the compound of formula (11) is obtained；
Step b. is above-mentioned after completion of the reaction, and decompression boils off solvent, then is dissolved with 300mL absolute methanols or absolute ethyl alcohol, presses
The compound of illuminated (11) and the mol ratio of 3- methylamino -1,2- propane diols sums are 1:1.25, add 3- methylaminos -1,2- the third two
Alcohol and 2g sodium methoxides, heating reflux reaction 6h after completion of the reaction, are cooled to 15 DEG C, and the mass percent that addition 200mL is added dropwise is
25% ammoniacal liquor, is warming up to after 55 DEG C of reaction 3.5h after dripping off, is cooled to room temperature, adjust PH to 2.5 with concentrated hydrochloric acid, be concentrated under reduced pressure
To near dry, slow cooling is added after the dissolving of 174g ethanol agitating and heating to 4 DEG C of crystallization 8h, filter, be dried in vacuo to obtain formula (12)
Compound 94.5g；
50g formulas (12) are dissolved in 150g pure water by step c., are heated with stirring to 75 DEG C, according to the compound and one of formula (12)
The mol ratio of lodine chloride is 1:3.2, it is added dropwise and adds iodine monochloride, 87 DEG C of reaction 4h, after completion of the reaction, cooling is warming up to after dripping off
To 50 DEG C, PH is adjusted to 8 with the ammoniacal liquor of mass percent 25%, be concentrated under reduced pressure 120mL water, add 165g absolute ethyl alcohols, stir
Mix crystallize formula (1) compound Iopromide.
Embodiment 9
A kind of preparation method of Iopromide, comprises the following steps：
Step a. methoxyacetic anhydrides are protected：150g methoxyacetic acids, 240g are added in four-hole boiling flask clean 500mL
Compound 3- amino -5- (2,3- hydroxyl n-propylamine base formoxyl)-methyl benzoate of methoxyacetic anhydride, 80g formulas (10), is stirred
Mix and be heated to 55 DEG C, add the 3g concentrated sulfuric acids, 12h is reacted at this temperature, the compound of formula (11) is obtained；
Step b. is above-mentioned after completion of the reaction, and decompression boils off solvent, then is dissolved with 300mL absolute methanols or absolute ethyl alcohol, presses
The compound of illuminated (11) and the mol ratio of 3- methylamino -1,2- propane diols sums are 1:1.4, add 3- methylaminos -1,2- the third two
Alcohol and 2g natrium carbonicum calcinatums, heating reflux reaction 6h after completion of the reaction, are cooled to 15 DEG C, the quality percentage for adding 200mL are added dropwise
Number is 25% ammoniacal liquor, is warming up to after dripping off after 55 DEG C of reaction 3.5h, is cooled to room temperature, PH to 2.5, decompression are adjusted with concentrated hydrochloric acid
It is concentrated into and closely does, adds slow cooling after the dissolving of 174g ethanol agitating and heating and, to 4 DEG C of crystallization 8h, filter, be dried in vacuo to obtain formula
(12) compound 94.5g；
50g formulas (12) are dissolved in 150g pure water by step c., are heated with stirring to 75 DEG C, according to the compound and one of formula (12)
The mol ratio of lodine chloride is 1:3.2, it is added dropwise and adds iodine monochloride, 87 DEG C of reaction 4h, after completion of the reaction, cooling is warming up to after dripping off
To 50 DEG C, PH is adjusted to 8 with the ammoniacal liquor of mass percent 25%, be concentrated under reduced pressure 120mL water, add 165g absolute ethyl alcohols, stir
Mix crystallize formula (1) compound Iopromide.
Technical scheme can preferably be realized according to the record of this specification.
Claims (10)
1. a kind of preparation method of Iopromide, it is characterised in that comprise the following steps：
Step a. methoxyacetic anhydrides are protected：The compound of formula (10) obtains the chemical combination of formula (11) with methoxyacetic acid anhydride reactant
Thing；
The compounds of step b. formulas (11) is reacted with 3- methylaminos -1,2-PD, product through hydrolysis, after purification, obtain formula
(12) compound；
The compound of step c. formulas (12) and the Iopromide that formula (1) is obtained after iodo reagent reacting；
Reaction equation is as follows：
2. the preparation method of Iopromide according to claim 1, it is characterised in that the change of the step a Chinese styles (10)
When compound is with methoxyacetic acid anhydride reactant, adds methoxyacetic acid and the concentrated sulfuric acid is used as catalyst；The step a Chinese styles (10)
Compound, methoxyacetic anhydride, the mass ratio of methoxyacetic acid and the concentrated sulfuric acid are 80:240:150:3.
3. the preparation method of Iopromide according to claim 2, it is characterised in that the change of the step a Chinese styles (10)
Compound is comprised the following steps that with methoxyacetic acid anhydride reactant：By 150g methoxyacetic acids, 240g methoxyacetic anhydrides and 80g formulas
(10) compound 3- amino -5- (2,3- hydroxyl n-propylamine base formoxyl)-methyl benzoate is heated with stirring to 40-65 DEG C, then
The 3g concentrated sulfuric acids are added, 12h is reacted at this temperature, the compound of formula (11) is obtained.
4. the preparation method of Iopromide according to claim 3, it is characterised in that the step b Chinese styles (11) and 3-
The solvent of methylamino -1,2-PD reaction is absolute methanol or absolute ethyl alcohol, and catalyst is sodium methoxide, natrium carbonicum calcinatum or nothing
Aqueous carbonate potassium；The compound of formula (11) and the mol ratio of 3- methylamino -1,2- propane diols sums are 1:1.1~1.5.
5. the preparation method of Iopromide according to claim 4, it is characterised in that catalyst is first in the step b
Sodium alkoxide；The mass ratio of the 3- methylaminos -1,2- propane diols and sodium methoxide is 40.7:1.5；The compound and 3- first ammonia of formula (11)
The mol ratio of base -1,2- propane diols sums is 1:1.3.
6. the preparation method of Iopromide according to claim 5, it is characterised in that the step b is：By in step a
The compound of obtained formula (11) is dissolved with 300mL absolute methanols or absolute ethyl alcohol, then adds 40.7g 3- methylaminos -1,2-
Propane diols and 1.5g sodium methoxides, heating reflux reaction 6h after completion of the reaction, are cooled to less than 30 DEG C, are added dropwise and add the water-soluble of alkali
Liquid, is warming up to after 50-65 DEG C of reaction 3-5h after dripping off, is cooled to room temperature, PH is adjusted to 2-3 with concentrated hydrochloric acid, be concentrated under reduced pressure near
It is dry, add after the dissolving of ethanol agitating and heating slow cooling to 5 DEG C of crystallization below 8h, filter, be dried in vacuo formula (12) chemical combination
Thing；The aqueous solution of the alkali is sodium hydrate aqueous solution, aqueous sodium carbonate or wet chemical；When the aqueous solution of alkali is hydrogen
During aqueous solution of sodium oxide, the concentration of sodium hydrate aqueous solution is 10mol/L, and the volume of addition is 180mL.
7. the preparation method of Iopromide according to claim 6, it is characterised in that the iodo reagent in the step c
For iodine monochloride；The compound of the step c Chinese styles (12) is water, the chemical combination of the formula (12) with the solvent that iodine monochloride reacts
The mol ratio of thing and iodine monochloride is 1:3.1~3.3.
8. the preparation method of Iopromide according to claim 7, it is characterised in that the compound and one of the formula (12)
The mol ratio of lodine chloride is 1:3.15.
9. the preparation method of Iopromide according to claim 8, it is characterised in that the step c is：50g formulas (12)
Compound be dissolved in 150g pure water, be heated with stirring to 70-80 DEG C, be added dropwise and add 63.3g iodine monochlorides, be warming up to after dripping off
85-90 DEG C of reaction 3-5h, after completion of the reaction, is cooled to 50 DEG C, adjusts PH to 8-9 with the aqueous solution of alkali, be concentrated under reduced pressure 120mL
Water, adds 165g ethanol, and stirred crystallization obtains the compound Iopromide of formula (1), and the aqueous solution of the alkali is water-soluble for sodium hydroxide
Liquid or ammoniacal liquor；When the aqueous solution of alkali is sodium hydrate aqueous solution, the concentration of sodium hydrate aqueous solution is 10mol/L.
10. the compound of formula (10), formula (11) or formula (12) prepares the purposes of Iopromide.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110028419A (en) * | 2019-04-30 | 2019-07-19 | 台州学院 | A kind of preparation method of Iopromide |
| CN116041201A (en) * | 2022-12-30 | 2023-05-02 | 黑龙江迪诺医药有限公司 | Preparation method of ioversol intermediate |
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| US4364921A (en) * | 1979-03-08 | 1982-12-21 | Schering, Aktiengesellschaft | Novel triiodinated isophthalic acid diamides as nonionic X-ray contrast media |
| CN102351735A (en) * | 2011-07-21 | 2012-02-15 | 浙江司太立制药股份有限公司 | Preparation method of Iopromide |
| CN102964269A (en) * | 2012-11-29 | 2013-03-13 | 浙江海昌药业有限公司 | Novel preparation method of iopromide |
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| US4364921A (en) * | 1979-03-08 | 1982-12-21 | Schering, Aktiengesellschaft | Novel triiodinated isophthalic acid diamides as nonionic X-ray contrast media |
| CN102351735A (en) * | 2011-07-21 | 2012-02-15 | 浙江司太立制药股份有限公司 | Preparation method of Iopromide |
| CN102964269A (en) * | 2012-11-29 | 2013-03-13 | 浙江海昌药业有限公司 | Novel preparation method of iopromide |
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| CN110028419A (en) * | 2019-04-30 | 2019-07-19 | 台州学院 | A kind of preparation method of Iopromide |
| CN110028419B (en) * | 2019-04-30 | 2022-01-21 | 台州学院 | Preparation method of iopromide |
| CN116041201A (en) * | 2022-12-30 | 2023-05-02 | 黑龙江迪诺医药有限公司 | Preparation method of ioversol intermediate |
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