CN110903275A - Process for producing iobitridol, intermediate therefor, and process for producing the same - Google Patents
Process for producing iobitridol, intermediate therefor, and process for producing the same Download PDFInfo
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Abstract
The invention discloses a method for preparing iobitridol, an intermediate thereof and a preparation method thereof. In particular to an intermediate M15- (2-isopropyl-1, 3-dioxane-5-carbonyl acyl) -2,4, 6-triiodoisophthalic acid for preparing ioditol. In addition, the invention also discloses a preparation method of the intermediate M1 and a method for preparing the iobitridol from the intermediate. The intermediate has high activity and easy preparation, and the method for synthesizing the iobitridol from the intermediate has short time, simple synthesis method, low comprehensive cost and high yield and purity of reaction targets, thereby being suitable for industrial production.
Description
Technical Field
The invention relates to a contrast agent ioditol, an intermediate thereof and a preparation method thereof.
Background
Iobitrido1 was the first developed by gabor corporation of france (Guerbet) as a non-ionic iodine-containing contrast agent under the trade name of the third generation developer (xentix). Compared with alcohol, iobitriol has the advantages of high water solubility, low viscosity, low osmotic pressure and the like, so that the iobitriol is widely applied to urinary tract venography, artery angiography, vein blood vessel digital subtraction, skull and whole body computed tomography to assist in diagnosing target tissues or organs.
The standard designation for iobitridol is 5- (3-hydroxy-2-hydroxymethyl-propionamido) -N ", N" -dimethyl-N', N "-bis- (2, 3-dihydroxypropyl) -2,4, 6-triiodo-isophthalamide, having the following structural formula:
because of the great difficulty in synthesizing the iobitridol, no imitation drugs exist in the world at present, and few publications and reports are made on a route for synthesizing the iobitridol.
Chinese patent CN 89103735.7 of gabor, france discloses several methods for synthesizing iobitol analogs. Example 1 a derivative of iodobitrol, 5- (3-hydroxy-2- (hydroxymethyl) -N- (2, 3-dihydroxypropyl) propionamido) -N', N "-bis (2-hydroxyethyl) -2,4, 6-triiodoisophthalamide, was synthesized as follows:
example 1
In this example, 5-amino-2, 4, 6-triiodoisophthaloyl chloride was reacted for four days starting from 5-amino-2, 4, 6-triiodoisophthaloyl chloride to give the amidated product 5- (2-isopropyl-1, 3-dioxane-5-carboxamido) -2,4, 6-triiodoisophthaloyl chloride in only 64% yield.
The 5-amino-2, 4, 6-triiodoisophthaloyl dichloride has extremely low reactivity of the 5-amino, and although the compound is used as an initiator, the cost of raw materials is low, the reaction time of the first step is too long, the yield is not ideal, so that the overall reaction route has low efficiency and low yield, and the satisfactory effect is difficult to achieve.
Example 5 of US equivalent patent US 5,043,152 from gabor, france discloses a method for the synthesis of iobitol.
In the method, the 5- (2-isopropyl-1, 3-dioxane-5-formamido) -2,4, 6-triiodoisophthaloyl dichloride is used for synthesizing the iobitridol. Although this example does not disclose how to obtain the starting material, example 1 of this patent is the same as example 1 of the above-mentioned chinese patent, and therefore, if iobitridol is prepared from the same starting material, there is also a problem that the reaction activity using 5-amino-2, 4, 6-triiodoisophthaloyl dichloride as a starting material is too low.
In addition, the method purifies the final product by column chromatography, and thus, is difficult to be industrially applied.
Chinese patent CN103254095B also discloses a synthetic method of iobitridol, which comprises the following synthetic route:
the synthesis method takes 5- (2-isopropyl-1, 3-dioxane-5-formamido) -2,4, 6-triiodoisophthaloyl dichloride as a starting material to synthesize the iobitridol. The process does not disclose how to obtain the starting material. The process is carried out in a first step with an excess of methylaminopropylene glycol, which is subsequently freed by the introduction of hydrogen chloride gas to salify the excess methylaminopropylene glycol and then to precipitate it. However, this method requires cooling and filtration several times to remove unreacted raw materials as much as possible, and the effect of desalting is not thorough. In addition, the intermediate polyhydroxy compound 5- (2-isopropyl-1, 3-dioxane-5-formamido) -N ', N' -dimethyl-N ', N' -bis- (dihydroxypropyl) -2,4, 6-triiodoisophthalamide is sticky and is not beneficial to subsequent operation.
In addition, the second step of removing the hydroxyl protection is carried out under strong acid conditions such as hydrochloric acid, sulfuric acid and the like, then the acid is neutralized by alkali, after water is evaporated, the viscous substance is dissolved in ethanol to remove inorganic salts, and finally the ethanol is removed to obtain a crude product. In this step, since the acid removal step cannot completely remove the acid, whereas iobitridol is a polyhydroxy compound and is liable to absorb moisture in the presence of a small amount of acid, the crude product obtained is viscous. After deprotection with strong inorganic acid, in order to further purify the iodobitrol, it is necessary to use ion exchange resins of the hydrogen ion type and the hydroxide ion type to completely remove the inorganic salts. If the ion exchange resin is to be recycled, the resin also needs to be regenerated. Therefore, the method also has the problems of complex operation, high comprehensive cost and difficult large-scale production.
Disclosure of Invention
In view of the above, it is an object of the present invention to provide a method for synthesizing iobitridol which overcomes at least one of the above disadvantages.
In order to achieve the purpose of the invention, the invention discloses an intermediate 5- (2-isopropyl-1, 3-dioxane-5-carbonyl acyl) -2,4, 6-triiodoisophthalic acid for preparing ioditol, which has the following structural formula:
the invention also discloses a method for preparing the intermediate M1, wherein the intermediate M1 is 5- (2-isopropyl-1, 3-dioxane-5-carbonyl acyl) -2,4, 6-triiodoisophthalic acid, and the method comprises the step of carrying out amidation reaction on a compound shown as a formula SM1 and a compound shown as a formula SM2 in the presence of an acyl chlorination reagent:
wherein, in the formula SM1, R1、R2May independently be H, C1～C4An alkyl group, wherein,
when R is1、R2When the intermediate is H, the intermediate M1 is directly generated;
when R is1、R2When the H is not simultaneously generated, a compound shown as a formula M0 is generated, and then M1 is generated through hydrolysis reaction, wherein the acyl chlorination reagent is at least one selected from the group consisting of triphosgene, thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride and phosphorus oxychloride.
Further, the compound represented by formula SM2 was previously dissolved in an organic solvent, which was dimethylacetamide DMAc or dimethylformamide DMF.
Further, wherein the solution of the acid chlorination reagent is added dropwise to the solution of the compound represented by formula SM2 to perform acid chlorination reaction, and then the compound represented by formula SM1 is added at a temperature of room temperature to 70 ℃ to perform amidation reaction.
In some embodiments, the dropping and the acyl chlorination reaction are carried out at 0 ℃ or less, and the amidation reaction is preferably carried out at a temperature of 40 ℃ to 60 ℃.
The invention also discloses a method for preparing the ioditol, which comprises the step of preparing a compound M2 from an intermediate M1 through an acylchlorination reaction, wherein the compound M2 is 5- (2-isopropyl-1, 3-dioxane-5-carbonyl acyl) -2,4, 6-triiodoisophthaloyl dichloride, and the reaction formula is as follows:
wherein, the acyl chlorination reagent used in the acyl chlorination reaction is at least one selected from the group consisting of triphosgene, thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride and phosphorus oxychloride.
Further, compound M1 is dissolved in an organic solvent in advance, and the organic solvent is dimethylacetamide DMAc or dimethylformamide DMF.
Further, the solution of the acid chlorination reagent was added dropwise to the solution of intermediate M1 to perform the acid chlorination reaction to form compound M2.
In some embodiments, the method further comprises the step of preparing the compound of formula M3 or formula M3 'from compound M2 and the compound of formula SM3 or formula SM 3' by amidation in the presence of an organic base, wherein the reaction formula is:
wherein Q is1、Q2Independently selected from H, and optionally substituted by one or more R3Substituted of the following groups: c1～C10Saturated or unsaturated chain hydrocarbon group and C6～C12Aryl, wherein R3Independently selected from halogen, C1～C6Alkyl radical, C1～C6An alkoxy group; or Q1、Q2Forming a 5 or 6 membered cyclic hydrocarbyl group;
wherein Q is3May be the same or different, preferably the same, and is selected from the group optionally substituted by one or more R4Substituted C1～C10Saturated or unsaturated chain hydrocarbon group and C6～C12Aryl, wherein R4Independently selected from halogen, C1～C6Alkyl radical, C1～C6An alkoxy group.
Wherein the organic base may be at least one selected from the group consisting of triethylamine, pyridine, methylimidazole, collidine and DIPEA.
Further, the method further comprises a step of deprotecting the compound represented by formula M3 or formula M3' in the presence of an acid to obtain iodobitrol, which has the reaction formula:
further, the acid is strong inorganic acid or solid acid; preferably, the inorganic strong acid is hydrochloric acid or sulfuric acid; preferably, the solid strong acid is a strongly acidic ion exchange resin.
The invention also discloses an intermediate M3 for preparing the iobitridol, which has the following structural formula:
wherein Q is1、Q2Independently selected from H, and optionally substituted by one or more R3Substituted of the following groups: c1～C10Saturated or unsaturated chain hydrocarbon group and C6～C12Aryl, wherein R3Independently selected from halogen, C1～C6Alkyl radical, C1～C6An alkoxy group; or Q1、Q2Forming a 5 or 6 membered cyclic hydrocarbyl group.
The invention also discloses a method for preparing the intermediate compound shown as the formula M3, which comprises the step of preparing the compound shown as the formula M3 by amidation reaction of M2 and the compound shown as the formula SM3 in the presence of organic base, wherein the reaction formula is as follows:
wherein Q is1、Q2Independently selected from H, and optionally substituted by one or more R3Substituted of the following groups: c1～C10Saturated or unsaturated chain hydrocarbon group and C6～C12Aryl, wherein R3Independently selected from halogen, C1～C6Alkyl radical, C1～C6An alkoxy group; or Q1、Q2Forming a 5 or 6 membered cyclic hydrocarbyl group.
Further, wherein the organic base may be at least one selected from the group consisting of triethylamine, pyridine, methylimidazole, collidine and DIPEA.
Further, the method comprises a step of preparing a compound M2 from an intermediate M1 through an acyl chlorination reaction, wherein the compound M2 is 5- (2-isopropyl-1, 3-dioxane-5-carbonyl acyl) -2,4, 6-triiodoisophthaloyl dichloride, and the reaction formula is as follows:
further, the acyl chlorination reaction uses an acyl chlorination reagent selected from at least one of the group consisting of triphosgene, thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride and phosphorus oxychloride.
Further, the intermediate M1 was previously dissolved in an organic solvent, which was dimethylacetamide DMAc or dimethylformamide DMF.
Further, a solution of an acylchlorinating agent was added dropwise to the solution of intermediate M1 to conduct an acylchlorination reaction to give compound M2.
In some embodiments, the method comprises the step of preparing intermediate M1 from a compound of formula SM1 and a compound of formula SM2 by an amidation reaction in the presence of an acylchlorinating agent:
wherein, in the formula SM1, R1、R2May independently be H, C1～C4An alkyl group, wherein,
when R is1、R2When the intermediate is H, the intermediate M1 is directly generated;
when R is1、R2When not being H, firstly generating a compound shown as a formula M0, then generating M1 through hydrolysis reaction,
wherein the acylchlorinating agent is selected from at least one of the group consisting of triphosgene, thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride and phosphorus oxychloride.
Further, the compound represented by formula SM2 was previously dissolved in an organic solvent, which was dimethylacetamide DMAc or dimethylformamide DMF.
Further, the solution of the acid chlorination reagent is added dropwise to the solution of the compound represented by formula SM2 to perform acid chlorination reaction, and then the compound represented by formula SM1 is added at a temperature of room temperature to 70 ℃ to perform amidation reaction.
In some embodiments, the dropping and the acyl chlorination reaction are carried out at 0 ℃ or less, and the amidation reaction is preferably carried out at a temperature of 40 ℃ to 60 ℃.
The invention also discloses a step of obtaining the ioditol by deprotecting the compound shown as the formula M3 in the presence of acid, wherein the reaction formula is as follows:
wherein Q is1、Q2Independently selected from H, and optionally substituted by one or more R3Substituted of the following groups: c1～C10Saturated or unsaturated chain hydrocarbon group and C6～C12Aryl, wherein R3Independently selected from halogen, C1～C6Alkyl radical, C1～C6An alkoxy group; or Q1、Q2Forming a 5 or 6 membered cyclic hydrocarbyl group;
further, the acid is strong inorganic acid or solid acid; preferably, the inorganic strong acid is hydrochloric acid or sulfuric acid; preferably, the solid strong acid is a strongly acidic ion exchange resin.
In some embodiments, the method further comprises the step of preparing a compound represented by formula M3 by reacting compound M2 with a compound represented by formula SM3 in the presence of an organic base:
further, the organic base may be at least one selected from the group consisting of triethylamine, pyridine, methylimidazole, collidine and DIPEA.
Further, the method further comprises a step of preparing a compound M2 from the intermediate M1 through an acylchlorination reaction, wherein the compound M2 is 5- (2-isopropyl-1, 3-dioxane-5-carbonyl) -2,4, 6-triiodoisophthaloyl chloride, and the reaction formula is as follows:
wherein, the acyl chlorination reagent used in the acyl chlorination reaction is at least one selected from the group consisting of triphosgene, thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride and phosphorus oxychloride.
Further, compound M1 was dissolved in an organic solvent in advance, which was dimethylacetamide DMAc or dimethylformamide DMF.
Further, the solution of the acid chlorination reagent was added dropwise to the solution of intermediate M1 to perform the acid chlorination reaction to form compound M2.
In some embodiments, wherein the method comprises the step of amidation of a compound of formula SM1 with a compound of formula SM 2:
wherein, in the formula SM1, R1、R2May independently be H, C1～C4An alkyl group, wherein,
when R is1、R2When the intermediate is H, the intermediate M1 is directly generated;
when R is1、R2When not being H, firstly generating a compound shown as a formula M0, then generating M1 through hydrolysis reaction,
wherein the acylchlorinating agent is selected from at least one of the group consisting of triphosgene, thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride and phosphorus oxychloride.
Further, the compound represented by formula SM2 was previously dissolved in an organic solvent, which was dimethylacetamide DMAc or dimethylformamide DMF.
Further, a solution of an acylchlorinating agent is added dropwise to a solution of a compound represented by the formula SM2 to perform an acylchlorination reaction, and then an amidation reaction is performed with a compound represented by the formula SM1 at a temperature of room temperature to 70 ℃.
In some embodiments, the dropping and the acyl chlorination reaction are carried out at 0 ℃ or less, and the amidation reaction is preferably carried out at a temperature of 40 ℃ to 60 ℃.
The invention has the beneficial effects that the method for synthesizing the iobitridol has short reaction time, higher reaction activity and higher yield of reaction intermediates in each step, is simple to operate, has low comprehensive cost, and has environmental protection property, thereby being applicable to industrial production.
Detailed Description
The technical solutions in the embodiments of the present invention will be described clearly and completely below with reference to the preferred embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention.
Throughout the specification, unless otherwise specifically noted, terms used herein should be understood as having meanings as commonly used in the art. Accordingly, unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. If there is a conflict, the present specification will control.
As used herein, "alkyl" refers to straight or branched chain alkyl groups, including, for example, "C1-C6Alkyl group "," C1-C4Alkyl group "," C1-C3Alkyl "and the like, specific examples include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-dimethylbutyl3-dimethylbutyl, 2-ethylbutyl, 1, 2-dimethylpropyl, and the like.
As used herein, "alkenyl" refers to a straight or branched chain alkenyl group containing at least one double bond, including, for example, "C2-C6Alkenyl group "," C2-4Alkenyl groups "and the like. Examples include, but are not limited to: vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1, 3-butadienyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1, 3-pentadienyl, 1, 4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1, 4-hexadienyl.
As used herein, "alkynyl" refers to straight or branched chain alkynyl groups containing at least one triple bond, including, for example, "C2-C6Alkynyl and C2-4Alkynyl groups "and the like. Examples include, but are not limited to: ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1, 3-butadiynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 1, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1, 4-hexynyl.
As used herein, "alkenyl" refers to straight or branched chain saturated alkyl, straight or branched chain unsaturated alkenyl, or alkynyl groups, with the alkyl, alkenyl, and alkynyl groups being as defined above. E.g. "C1～C10Saturated or unsaturated chain hydrocarbon group "," C1～C6Saturated or unsaturated chain hydrocarbon group "," C1～C3Saturated or unsaturated chain hydrocarbon radicals "and the like, including but not limited to" C1-C6Alkyl group "," C1-C4Alkyl group "," C1-C3Alkyl group "," C2-C6Alkenyl group "," C2-C4Alkenyl group "," C2-C6Alkynyl and C2-C4Alkynyl radicals ".
As used herein, "aryl" refers to a monocyclic or polycyclic hydrocarbon group having aromatic character, such as C6～C12Aryl radical, C6～C10Aryl radical, C5～C8Aryl, and the like. Specific examples include, but are not limited to, phenyl, naphthaleneAnd (4) a base.
As used herein, "halogen" includes chlorine, fluorine, bromine, iodine.
As used herein, "alkoxy" refers to a group having the structure alkyl-O-, wherein alkyl is as previously defined. Specific examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, pentyloxy, hexyloxy, and the like.
As used herein, "cycloalkyl" refers to a saturated or unsaturated, but not aromatic, cyclic group, including, for example, "5-6 membered cycloalkyl", specific examples include, but are not limited to: cyclopentyl, cyclohexyl.
According to one embodiment of the present invention, a first aspect of the present invention provides a novel intermediate M1(5- (2-isopropyl-1, 3-dioxane-5-carbonyl) -2,4, 6-triiodoisophthalic acid) for the synthesis of iodobitrol, having the following structure:
unlike the bis-formyl chloride intermediate 5- (2-isopropyl-1, 3-dioxane-5-carboxamide) -2,4, 6-triiodo isophthaloyl chloride (compound M2, shown below) of the prior art, the substituent of the corresponding acyl chloride of this intermediate is formic acid. The intermediate M2 in the prior art is prepared by taking 5-amino-2, 4, 6-triiodoisophthaloyl dichloride (compound A) as a starting material.
However, the present inventors found that M2 is unstable in this reaction system and is easily degraded. In addition, after the reaction is finished, the unreacted compound a and the product M2 are difficult to separate, so that the mixture containing the compound a and M2 is subjected to the next acid chloride amination substitution reaction, and the reaction yield and purity are further reduced.
Accordingly, a second aspect of the present invention provides a process for the preparation of intermediate M1. The method takes 5-amino-2, 4, 6-triiodoisophthalic acid or ester thereof (a compound shown as a formula SM 1) as a starting material, and 2-isopropyl-1, 3-dioxane-5-formic acid (a compound shown as a formula SM2) react with an acyl chlorination reagent to generate an intermediate M1. The reaction route is as follows:
wherein R in SM11、R2The groups may independently be H, C1～C4The alkyl group is preferably both H or methyl, more preferably both H.
The inventor creatively finds that after SM1 is used for replacing the raw material A in the prior art in the reaction, the yield and purity of the intermediate M1 can be obviously improved, and the intermediate M1 can be well separated from the compound SM1 in the post-treatment operation, and has no degradation problem, so that the intermediate is a better intermediate and plays a key role in reducing the preparation cost and improving the yield and purity of the product iopamidol. Also, the starting material SM1 is also relatively easy to obtain, so that no additional cost is added.
According to a specific embodiment, in the above reaction, compound SM2 is first acid chlorinated by addition of an acid chlorinating reagent and then amidated with a compound of formula SM1 to form intermediate M1.
Conventional acid chlorination reagents may be used in the present invention. Specific examples are, for example, triphosgene, thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride and the like or any combination thereof, preferably triphosgene.
According to the invention, SM2 is dissolved beforehand in an organic solvent, which is dimethylacetamide DMAc or dimethylformamide DMF, preferably dimethylacetamide DMAc.
According to the invention, the solution of the acylating chlorination reagent is added dropwise to the solution of the compound represented by the formula SM2 for acylating chlorination reaction, and then the compound represented by the formula SM1 is added at a temperature of room temperature to 70 ℃ for amidation reaction.
According to a preferred embodiment, after the formation of the acid chloride from compound SM2, a one-pot reaction with compound SM1 gives intermediate M1. Specifically, triphosgene was dissolved in an organic solvent and added dropwise to a DMAc solution of compound SM2 to form an acid chloride solution, followed by direct addition of compound SM1 to raise the reaction temperature for reaction. The organic solvent for triphosgene is not particularly limited, and any conventional solvent can be used as long as it is inert and does not cause side reactions. Specific examples are methylene chloride, chloroform, toluene, tetrahydrofuran, chlorobenzene and 2-methyltetrahydrofuran.
Preferably, the temperature is controlled below 0 ℃ when the triphosgene solution is added dropwise to the SM2 solution. When the temperature of acyl chlorination is controlled below 0 ℃, side reaction can be reduced, and the amount of impurities is controlled to be lower.
The amidation of the above-mentioned compound SM1 is carried out at a temperature of from room temperature to 70 ℃, preferably at a temperature of from 40 ℃ to 60 ℃, more preferably at 50 ℃.
In the case of using M0 as a starting material, the one-step acidification hydrolysis reaction may be continued to obtain intermediate M1.
According to an embodiment of the present invention, the reaction time is reduced to less than 24 hours from the 4 days reaction time (CN 89103735.7) required for M2 to be prepared from M-bis-formyltriiodoaniline (compound a), and can be completed within about 20 hours, even about 15 hours under the preferred reaction conditions. Moreover, when the preferable acyl chlorination reagent is adopted in the reaction for preparing the M1, the yield of the reaction is up to about 95 percent, and the reaction efficiency of the step is greatly improved, so that the preparation efficiency of the iobitridol is integrally improved.
According to a third aspect of the present invention, there is provided a process for the preparation of iobitridol from intermediate M1, based on intermediate M1.
The process of the present invention for the preparation of iodobitrol comprises at least the step a) of preparing compound M2 from intermediate M1, i.e. the step of acylating intermediate M1(5- (2-isopropyl-1, 3-dioxane-5-carbonyl) -2,4, 6-triiodoisophthalic acid) to compound M2(5- (2-isopropyl-1, 3-dioxane-5-carbonyl) -2,4, 6-triiodoisophthaloyl chloride).
In the acid chlorination reaction, the acid chlorination reagent may be selected from the group consisting of triphosgene, thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, and the like, and combinations thereof, and is preferably triphosgene. According to a preferred embodiment of the invention, the acylating and chlorinating reagent is dimethylacetamide DMAc or dimethylformamide DMF as solvent, preferably dimethylacetamide DMAc. According to a preferred embodiment, the acylchlorinating agent is triphosgene and dimethylacetamide (DMAc) is used as the solvent.
According to a preferred embodiment, triphosgene is dissolved in an organic solvent to form an acid chloride solution and added dropwise to a DMAc solution of compound M1. The organic solvent for triphosgene is not particularly limited, and any conventional solvent can be used as long as it is inert and does not cause side reactions. Specific examples are methylene chloride, chloroform, toluene, tetrahydrofuran, chlorobenzene and 2-methyltetrahydrofuran.
Preferably, the temperature is controlled below 0 ℃ during the dropwise addition, so as to reduce side reactions and control the amount of impurities to be lower.
This step is relatively easy to carry out, and in the best mode, intermediate M1 can even reach close to 100% conversion. After the reaction is finished, the purity of the product M2 in the reaction liquid can be as high as more than 95%, and the purification is convenient.
After the reaction is completed, the compound M2 can be easily obtained as a solid by extraction with an organic solvent and recrystallization, and the post-reaction and the subsequent operations are facilitated. The organic solvent used for extraction of compound M2 may be methyltetrahydrofuran, tetrahydrofuran, ethanol, isopropanol, preferably methyltetrahydrofuran. The solvent used for recrystallization may be n-heptane, n-hexane, cyclohexane, preferably n-heptane.
After obtaining compound M2, the reaction can be carried out according to known methods (such as those disclosed in US 5,043,152 or CN 103254095B) to obtain iobitridol.
According to a preferred embodiment of the present invention, there is provided a step of preparing compound M3 or M3' from M2.
The step comprises the step of preparing M3 or M3 'from M2 and SM3 or SM 3' through amidation reaction in the presence of organic base. The reaction formula is as follows:
wherein Q is1、Q2Independently selected from H, optionally substituted by one or more R3Substituted of the following groups: c1～C10Saturated or unsaturated chain hydrocarbon group, C6～C12Aryl, wherein R3Independently selected from halogen, C1～C6Alkyl radical, C1～C6An alkoxy group; or Q1、Q2Forming a 5 or 6 membered cyclic hydrocarbyl group;
preferably, Q1、Q2Independently selected from H, optionally substituted by one or more R3Substituted of the following groups: c1～C6Alkyl radical, C1～C6Alkenyl radical, C6～C10Aryl radical, said R3Independently selected from Cl, Br, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy; or Q1、Q2Forming a 5 or 6 membered cyclic hydrocarbyl group;
more preferably, Q1、Q2Independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, phenyl, p-methoxyphenyl, 2, 4-dimethoxyphenyl, vinyl, or, Q1、Q2Together form cyclohexane.
Most preferably, Q1、Q2Are all methyl. When Q is1、Q2When the methyl is adopted, the raw material SM3 is easy to obtain, and the production cost can be reduced.
Wherein Q is3May be the same or different, preferably the same, and is selected from the group optionally substituted by one or more R4Substituted C1～C10Saturated or unsaturated chain hydrocarbon group, C6～C12Aryl radical, R4Independently selected from halogen, C1～C6Alkyl radical, C1～C6An alkoxy group. Preferably, Q3Are identical and are selected from the group optionally substituted by one or more R4Substituted C1～C6Alkyl radical, C1～C6Alkenyl radical, C6～C10Aryl radical, R4Independently selected from halogen, C1～C6Alkyl radical, C1～C6Alkoxy, more preferably, said R4Independently selected from Cl, Br, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy.
More particularly, Q3Likewise, it may be selected from methyl, ethyl, chloroethyl, dichloroethyl, trichloroethyl, methoxyethyl, methoxymethyl, p-chlorophenylethyl, phenethyl, diphenylethyl, phenylpropyl, 4-pentenyl, 4-acetylpropyl, neopentyl, benzyl and 2,4, 6-trimethylbenzyl groups.
Wherein the organic base may be at least one selected from the group consisting of triethylamine, pyridine, methylimidazole, collidine, and DIPEA. Preferably, the organic base is triethylamine.
The reaction is carried out under conventional conditions, and the product is obtained by recrystallization in a conventional manner, without particular limitation. The reaction in this step is easy to occur, and the yield of M3 or M3' converted from M2 can reach more than 75%, even more than 80%.
The compound M3 or M3 'is a precursor compound of the ioditol, and the hydroxyl groups in the ioditol are all protected in the form of ether in M3 or M3'. Because no hydroxyl exists in M3 or M3', the problem of moisture absorption does not exist, the solid is easy to purify, and the subsequent reaction and operation are convenient.
According to a preferred embodiment of the present invention, the compound M3 or M3' is deprotected to obtain lopbitol. Deprotection can be carried out in the presence of a strong acid. The strong acid may be any mineral acid used in the art, such as hydrochloric acid or sulfuric acid, of the formula:
in the above reaction, the strong acid is a catalyst for the reaction and is not consumed in the reaction. After the reaction is completed, neutralization is carried out by adding a base such as sodium hydroxide, and the salt thus formed is removed by adding an organic solvent such as ethanol to obtain a crude product, and further, the residual inorganic ions are completely removed by using an ion exchange resin, and purified iobitridol is obtained.
The method has the disadvantage that when the ioditol is purified, inorganic cations and inorganic anions are respectively removed by using hydrogen ion type ion exchange resin and hydroxide ion type ion exchange resin, so that a pure product can be obtained. In the step, the ion exchange resin can be recycled after regeneration, the process is complex, the cost is high, and a large amount of waste liquid can be generated.
Therefore, the conventional purification process of iobitridol described above is not suitable for industrialization. Therefore, the present invention further provides a deprotection step suitable for industrial production. In the step, the acid source adopts strong acid ion exchange resin to replace conventional inorganic acid, so that the separation difficulty of the iobitridol and the inorganic salt is reduced, the complex regeneration process of the ion exchange resin after a precipitation method is adopted is avoided, the cost is obviously reduced, and the generation of regeneration waste liquid is also avoided.
The strongly acidic ion exchange resin is not particularly limited as a hydrogen ion source, as long as it can provide sufficient hydrogen ions in the reaction. For example, the strongly acidic ion exchange resins useful in the present invention may be Dow chemical AMBERLYST35, AMBERLYST 36, AMBERLYST 40, Dowex Mac-3 resin, and type 732 strongly acidic ion exchange resins.
The deprotection reaction is carried out in alcohol or alcohol-water mixed solvent. The reaction temperature is 50-90 deg.C, preferably 60-80 deg.C, and most preferably 70 deg.C. The reaction usually lasts for about 48 to 72 hours. Stirring is continuously carried out during the reaction period, so that the ion exchange resin is fully contacted with the solution.
The present invention creatively uses a strongly acidic ion exchange resin as an acid source for the acid catalyst. Because the resin is insoluble in solution, is a catalyst in the reaction and does not consume hydrogen ions, the resin is directly filtered after the reaction is finished, and residual acid does not exist in the filtrate, so that a solid ioditol product can be easily obtained by removing the solvent. The ion exchange resin can be recycled without regeneration and waste liquid. The strong acid ion exchange resin is used as an acid catalyst to solve the problems of difficult purification and high cost after the deprotection of the iobitridol, so that the method is easy to industrialize.
According to the intermediate M1, the synthesis method thereof and the method for preparing the iobitridol from M1, the invention has the outstanding advantages that the intermediate M1 with the bisformic acid substituent is prepared by taking the compound SM1 with the bisformic acid substituent as a starting material, and the compound M2 is obtained from the intermediate M1 through an easily-occurring acyl chlorination reaction. The method avoids the problem that the traditional compound A with the dibenzoyl chloride substituent as the starting material is difficult to separate from the product M2 with the dibenzoyl chloride substituent, and improves the overall reaction efficiency.
In addition, when the intermediate M1 is prepared by taking SM1 as a starting material, an acyl chlorination reagent and a solvent are adopted, so that the amino reaction activity of the starting material SM1 aniline is greatly improved, the reaction time is greatly shortened, the reaction efficiency is improved, and the possibility is provided for the industrial production of the ioditol.
The invention further avoids generating polyhydroxy compounds in the whole reaction route, and takes the compound M3/M3' as a precursor compound of the ioditol, so that products in each step are easy to purify to obtain solids, and the whole process is simplified.
The invention has the further advantages that the last deprotection step adopts strong acid ion exchange resin as an acid source, the acid removal step in the purification of the iobitol is greatly simplified, no waste liquid is generated, and the ion exchange resin can be recycled without regeneration, so that the industrial production of the iobitol becomes possible.
According to another embodiment of the present invention, there is provided a fourth aspect of the present invention, an intermediate M3 for the preparation of iopbitol:
wherein Q1And Q2As defined above.
A fifth aspect of the invention provides a process for the preparation of intermediate M3. The process comprises the step of obtaining M3 from compound M2 via amidation, the reaction formula being:
the reaction conditions were as described above.
The process for the preparation of intermediate M3 further comprises the step of preparing compound M2. Compound M2 can be prepared by methods known in the art, for example starting from 5-amino-2, 4, 6-triiodoisophthaloyl dichloride by conventional methods as described above. M2 may also be prepared by acid chlorination of intermediate M1 as previously described. The preparation method of the intermediate M1 is as described above and is not described in detail herein.
Accordingly, a sixth aspect of the present invention provides a process for the preparation of iopbitol, which comprises the step of deprotecting intermediate M3 to obtain iopbitol.
Intermediate M3 was deprotected under acidic conditions as previously described. Inorganic strong acids, such as hydrochloric acid, sulfuric acid, and the like, can be used as the acid source. However, the present invention preferably uses a strongly acidic ion exchange resin as the acid source. The reaction is as described above and will not be described in detail here.
According to the intermediate M3, the synthesis method thereof and the method for preparing the iobitridol from M3, the invention has the outstanding advantages that polyhydroxy compounds are not used as intermediates, so that the intermediates which are easy to purify to obtain solids are obtained, and the whole process is simplified.
The invention has the further advantages that the strong acid ion exchange resin is adopted as an acid source in the step of deprotection by M3, the step of removing acid in the purification of the ioditol is greatly simplified, no waste liquid is generated, and the ion exchange resin can be recycled without regeneration, so that the industrial production of the ioditol becomes possible.
In addition, the route provided by the invention for preparing M3 through M1 takes the compound SM1 with a biscarboxylate substituent as a starting material to prepare an intermediate M1 with the biscarboxylate substituent, and then the compound M2 is obtained from the intermediate M1 through an easily-occurring acyl chlorination reaction. The method avoids the problem that the traditional compound A with the dibenzoyl chloride substituent as the starting material is difficult to separate from the product M2 with the dibenzoyl chloride substituent, and improves the overall reaction efficiency.
In addition, the invention adopts the acyl chlorination reagent with energy when the intermediate M1 is prepared by taking SM1 as the starting material, thereby greatly improving the amino reaction activity of the starting material SM1 aniline, greatly shortening the reaction time, further improving the reaction efficiency and providing possibility for the industrial production of the ioditol.
The invention is further illustrated by the following examples.
Example 1
Preparation of intermediate M1: 5- (2-isopropyl-1, 3-dioxane-5-formamido) -2,4, 6-triiodo isophthalic acid, the reaction formula is as follows:
SM2 (2-isopropyl-1, 3-dioxane-5-carboxylic acid) (261.28g,2.5eq) and DMAc (500ml) were added to a reaction flask, stirring was turned on, and the temperature of the system was lowered to below 0 ℃ using an ice bath. Triphosgene (178.05g,1.0eq) was then dissolved in dichloromethane (500ml) and slowly added dropwise into the reaction flask, while maintaining the system temperature below 0 ℃ using an ice bath, and after completion of the addition, the reaction was carried out for 30 minutes. Then, SM1-A (5-amino-2, 4, 6-triiodoisophthalic acid) (335.30g,1.0eq) was added in one portion to the reaction flask, and the temperature of the system was raised to 50 ℃ for 16 hours. Then the solution was cooled to below 0 ℃ using an ice bath, and aqueous sodium hydroxide (600ml, 40%) was slowly added dropwise while maintaining the temperature of the system within 25 ℃. After the addition was complete, the layers were separated, the organic phase was discarded and the aqueous phase was washed twice with dichloromethane (500 ml). The aqueous phase was filtered to remove suspended matter. The aqueous phase was transferred to a reaction flask and heated to 70 ℃. Concentrated hydrochloric acid (540ml) was slowly added dropwise, and after completion of the addition, the temperature was maintained at 70 ℃ for 2 hours. Then, after the reaction solution was cooled to room temperature by stopping heating, the reaction solution was filtered by suction and the filter cake was collected, and the filter cake was washed twice with water (500ml) and air-dried at 40 ℃ to obtain the target product M1(410.61g) in a yield of 95.7% and a purity of 97.6%.
LC-MS：[M+H]+＝715.8[2M-H]-＝1428.4
1HNMR(DMSO-d6):10.33(s,2H),8.80(s,1H),4.41-4.30(m,2H),3.97-3.86(t,1H),3.64-3.51(m,2H),3.09-3.01(m,1H),1.80-1.61(m,1H),0.92-0.87(d,6H)。
Example 2
Preparation of intermediate M1: 5- (2-isopropyl-1, 3-dioxane-5-carboxamido) -2,4, 6-triiodo isophthalic acid)
From SM1-B (R)1＝R2Methyl) to M0, the reaction formula is:
SM2 (2-isopropyl-1, 3-dioxane-5-carboxylic acid) (31.35g, 3.0eq) and 100ml DMAc were added to the reaction flask, stirring was turned on, and the temperature of the system was lowered to below 0 ℃ using an ice bath. Triphosgene (21.37g,1.2eq) was dissolved in 60ml of dichloromethane and slowly dropped into the reaction flask, and during the dropping process, the temperature of the system was kept within 0 ℃, and the dropping was completed, and the reaction was carried out for 30 minutes. SM1-B (methyl 5-amino-2, 4, 6-triiodoisophthalate) (35.21g,1.0eq) was added to the reaction flask all at once, and the temperature of the system was raised to 50 ℃ for 16 hours.
The reaction mixture was washed three times with 100ml of water, the organic phase was evaporated to dryness and the crude product was subjected to column chromatography (petroleum ether-ethyl acetate) to give 39.18g of the target product M0 in 87.9% yield and 98.1% purity.
Preparation of M1 from M0:
m0(7.43g, 1.0eq), 50ml of tetrahydrofuran were added to the flask, the stirring was turned on, and the temperature of the system was lowered below 0 ℃ using an ice bath. Lithium hydroxide (0.50g, 2.10eq) was dissolved in 50ml of water, slowly dropped into the reaction flask, and after completion of the dropping, reacted at room temperature for 2 hours.
80ml of methylene chloride was added to the reaction solution, and liquid separation was performed to collect the aqueous phase, and then the aqueous phase was washed twice with 50ml of methylene chloride. Slowly dropwise adding 1mol/L dilute hydrochloric acid into the obtained water phase until the pH value is about 1.0, filtering, and collecting a filter cake. The filter cake was dried by air blowing to give 7.05g of the desired product M1 in 98.6% yield.
M1 data were obtained in the same manner as in example 1
Example 3
Preparation of M2: 5- (2-isopropyl-1, 3-dioxane-5-formamido) -2,4, 6-triiodo isophthaloyl dichloride, the reaction formula is as follows:
m1(286.00g,1.0eq) prepared in example 1 and DMAc (550ml) were charged into a reaction flask, and the temperature of the system was lowered to below 0 ℃ using an ice bath. Triphosgene (237.40g,2.0eq) was dissolved in dichloromethane (700ml) and slowly added dropwise to the reaction flask with the internal temperature controlled below 0 ℃ using an ice bath during the addition. After the end of the dropwise addition, the reaction was carried out for 2 hours using an ice bath. Then, the reaction mixture was added to a mixture of methyltetrahydrofuran (700ml) and water (2000ml), and the mixture was allowed to stand for liquid separation. The organic phase was collected and washed twice with water (2000 ml). After the solvent was removed by rotary evaporation at 45 ℃, the resulting solid was dissolved in methyltetrahydrofuran (500ml), and n-heptane (2000ml) was added dropwise to the above solution to form crystals. The filter cake was then collected by suction filtration and washed twice with n-heptane (200ml) and then air-dried at 40 ℃ to give the desired product M2(254.16g) in 84.5% yield and 98.9% purity.
LC-MS:[M+H]+＝751.6,[M-H]-＝749.6
Example 4
Preparation M3-A: 5- (2-isopropyl-1, 3-dioxane-5-carboxamide) -N ', N "-dimethyl-N', N" -bis (2, 2-dimethyl-1, 3-dioxolan-4-yl) -2,4, 6-triiodo-isophthalamide, reaction formula:
m2(180.46g,1.0eq) obtained in example 3 and methylene chloride (750ml) were charged into a reaction flask, and the temperature of the system was reduced to 0 ℃ or lower using an ice bath. SM3-A (1- (2, 2-dimethyl-1, 3-dioxolan-4-yl) -N-methyl methylamine) (74.67g,2.2eq) and triethylamine (53.43g,2.2eq) were dissolved in dichloromethane (250ml), and slowly dropped into a reaction flask, during dropping, the temperature of the system was maintained below 0 ℃ using an ice bath, and after dropping, the reaction was carried out for 1 hour. Then, an aqueous solution of sodium hydroxide (1000ml, 1%) was added to the reaction solution, and after liquid separation, the organic phase was collected. The organic phase was washed twice with water (1000ml) and the solvent was removed by spin-off. The resulting solid was dissolved in ethyl acetate (400ml) and n-heptane (1600ml) was slowly added dropwise to form crystals. Then, the cake was collected by suction filtration, washed twice with n-heptane (200ml), and air-dried at 35 ℃ to obtain the aimed product M3-A (190.78g) in 82.0% yield and 99.6% purity.
LC-MS:[M+H]+＝969.9[M+NH4]+＝986.9
1HNMR(DMSO-d6):8.33(s,1H),4.51-4.38(m,2H),4.36-4.22(m,4H),4.18(s,1H),3.96-3.80(m,4H),3.62-3.54(m,1H),3.24-3.08(m,2H),2.96-2.77(m,4H),1.82-1.70(t,3H),1.48-1.35(m,4H),1.33-1.19(m,10H),0.92-0.87(d,6H).
Example 5
Preparing iobitridol: 5- (3-hydroxy-2-hydroxymethyl-propionamido) -N ', N "-dimethyl-N', N" -bis- (2, 3-dihydroxypropyl) -2,4, 6-triiodo isophthalamide, the reaction formula is as follows:
M3-A (174.49g) obtained in example 4, a strongly acidic ion exchange resin (150.00g, Dow chemical AMBERLYST 40), ethanol (350ml) and water (350ml) were charged into a reaction flask and reacted at 70 ℃ for 60 hours. After the reaction is finished, after the reaction solution is cooled to room temperature, the reaction solution is filtered by using filter paper and a 0.45-micrometer filter membrane in sequence. After the reaction solution was concentrated to dryness, the resulting solid was dissolved in methanol (350 ml). To the above methanol solution was added dropwise dichloromethane (700ml) to crystallize. Suction filtration was carried out, the filter cake was collected, washed twice with methylene chloride (200ml), and vacuum-dried at 35 ℃ to obtain the target product iodipamol (120.36g) in 80.0% yield and 99.5% purity.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the scope of the present invention, and all equivalent changes or modifications, or direct/indirect applications in other related fields under the inventive concept of the present invention are included in the scope of the present invention.
Claims (14)
1. An intermediate 5- (2-isopropyl-1, 3-dioxane-5-carbonyl) -2,4, 6-triiodoisophthalic acid for preparing iobitridol, having the following structural formula:
2. a process for the preparation of intermediate M1, intermediate M1 being 5- (2-isopropyl-1, 3-dioxane-5-carbonyl) -2,4, 6-triiodoisophthalic acid, comprising the step of carrying out an amidation reaction between a compound of formula SM1 and a compound of formula SM2 in the presence of an acylchlorinating agent:
wherein, in the formula SM1, R1、R2Independently H, C1～C4An alkyl group, wherein,
when R is1、R2When the intermediate is H, the intermediate M1 is directly generated;
when R is1、R2When not being H, firstly generating a compound shown as a formula M0, then generating M1 through hydrolysis reaction,
wherein the acylchlorinating agent is selected from at least one of the group consisting of triphosgene, thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride and phosphorus oxychloride; preferably, the compound of formula SM2 is dissolved in an organic solvent, which is dimethylacetamide DMAc or dimethylformamide DMF beforehand.
3. The method of claim 2, wherein the solution of the acylating chlorination reagent is added dropwise to the solution of the compound of formula SM2 for acylating chlorination reaction, followed by amidation reaction with the addition of the compound of formula SM1 at a temperature of room temperature to 70 ℃; preferably, the dropwise addition and the acylchlorination reaction are carried out at 0 ℃ or less, and the amidation reaction is preferably carried out at a temperature of 40 to 60 ℃.
4. A process for the preparation of iodobitrol comprising the step of acylating chlorination of intermediate M1 to produce compound M2, compound M2 being 5- (2-isopropyl-1, 3-dioxane-5-carbonyl) -2,4, 6-triiodoisophthaloyl chloride of the formula:
preferably, the acyl chlorination reaction uses an acyl chlorination reagent selected from at least one of the group consisting of triphosgene, thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride and phosphorus oxychloride;
more preferably, compound M1 is dissolved in an organic solvent in advance, which is dimethylacetamide DMAc or dimethylformamide DMF;
further preferably, the solution of the acid chlorination reagent is added dropwise to the solution of intermediate M1 to perform the acid chlorination reaction to form compound M2.
5. The process of claim 4, wherein the process further comprises the step of preparing the compound of formula M3 or formula M3 'from compound M2 and the compound of formula SM3 or formula SM 3' by amidation in the presence of an organic base, according to the reaction scheme:
wherein Q is1、Q2Independently selected from H, and optionally substituted by one or more R3Substituted of the following groups: c1～C10Saturated or unsaturated chain hydrocarbon group and C6～C12Aryl, wherein R3Independently selected from halogen, C1～C6Alkyl radical, C1～C6An alkoxy group; or Q1、Q2Forming a 5 or 6 membered cyclic hydrocarbyl group;
wherein Q is3May be the same or different, preferably the same, and is selected from the group optionally substituted by one or more R4Substituted C1～C10Saturated or unsaturated chain hydrocarbon group and C6～C12Aryl, wherein R4Independently selected from halogen, C1～C6Alkyl radical, C1～C6An alkoxy group;
preferably, the organic base is at least one selected from the group consisting of triethylamine, pyridine, methylimidazole, collidine and N, N-Diisopropylethylamine (DIPEA).
6. The process of claim 5, wherein the process further comprises the step of deprotecting the compound of formula M3 or formula M3' in the presence of an acid to afford lopamidol according to the reaction formula:
preferably, the acid is a strong inorganic acid or a strong solid acid; more preferably, the strong inorganic acid is hydrochloric acid or sulfuric acid; more preferably, the solid strong acid is a strongly acidic ion exchange resin.
7. An intermediate M3 for the preparation of iobitridol, having the following structural formula:
wherein Q is1、Q2Independently selected from H, andoptionally substituted by one or more R3Substituted of the following groups: c1～C10Saturated or unsaturated chain hydrocarbon group and C6～C12Aryl, wherein R3Independently selected from halogen, C1～C6Alkyl radical, C1～C6An alkoxy group; or Q1、Q2Forming a 5 or 6 membered cyclic hydrocarbyl group.
8. A process for the preparation of an intermediate compound of formula M3, comprising the step of preparing a compound of formula M3 from M2 and a compound of formula SM3 by amidation in the presence of an organic base, wherein the reaction is as follows:
wherein Q is1、Q2Independently selected from H, and optionally substituted by one or more R3Substituted of the following groups: c1～C10Saturated or unsaturated chain hydrocarbon group and C6～C12Aryl, wherein R3Independently selected from halogen, C1～C6Alkyl radical, C1～C6An alkoxy group; or Q1、Q2Forming a 5 or 6 membered cyclic hydrocarbyl group;
preferably, the organic base is at least one selected from the group consisting of triethylamine, pyridine, methylimidazole, collidine and N, N-Diisopropylethylamine (DIPEA).
9. The method of claim 8, further comprising,
a step of preparing a compound M2 from an intermediate M1 through an acylchlorination reaction, wherein the compound M2 is 5- (2-isopropyl-1, 3-dioxane-5-carbonyl acyl) -2,4, 6-triiodoisophthaloyl dichloride, and the reaction formula is as follows:
preferably, the acyl chlorination reaction uses an acyl chlorination reagent selected from at least one of the group consisting of triphosgene, thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride and phosphorus oxychloride;
more preferably, the intermediate M1 is dissolved in an organic solvent in advance, the organic solvent being dimethylacetamide DMAc or dimethylformamide DMF; further preferably, a solution of the acid chlorination reagent is added dropwise to the solution of intermediate M1 to effect the acid chlorination reaction to produce compound M2.
10. The process of claim 9, further comprising the step of amidating a compound of formula SM1 and a compound of formula SM2 in the presence of an acylchlorinating agent to produce intermediate M1:
wherein, in the formula SM1, R1、R2Independently H, C1～C4An alkyl group, wherein,
when R is1、R2When the intermediate is H, the intermediate M1 is directly generated;
when R is1、R2When not being H, firstly generating a compound shown as a formula M0, then generating M1 through hydrolysis reaction,
wherein the acylchlorinating agent is selected from at least one of the group consisting of triphosgene, thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride and phosphorus oxychloride;
preferably, the compound represented by formula SM2 is dissolved in an organic solvent in advance, wherein the organic solvent is dimethylacetamide DMAc or dimethylformamide DMF;
more preferably, the solution of the acyl chlorination reagent is dripped into the solution of the compound shown in the formula SM2 for acyl chlorination reaction, and then the compound shown in the formula SM1 is added at the temperature of room temperature to 70 ℃ for amidation reaction; further preferably, the dropping and the acylchlorination reaction are carried out at 0 ℃ or lower, and the amidation reaction is preferably carried out at a temperature of 40 to 60 ℃.
11. A process for the preparation of iopbitol, comprising the step of deprotecting a compound represented by the formula M3 in the presence of an acid to give iopbitol according to the reaction formula:
wherein Q is1、Q2Independently selected from H, and optionally substituted by one or more R3Substituted of the following groups: c1～C10Saturated or unsaturated chain hydrocarbon group and C6～C12Aryl, wherein R3Independently selected from halogen, C1～C6Alkyl radical, C1～C6An alkoxy group; or Q1、Q2Forming a 5 or 6 membered cyclic hydrocarbyl group;
preferably, the acid is a strong inorganic acid or a strong solid acid; more preferably, the strong inorganic acid is hydrochloric acid or sulfuric acid; more preferably, the solid strong acid is a strongly acidic ion exchange resin.
12. The process of claim 11, wherein the process further comprises a step of preparing a compound represented by formula M3 by reacting the compound M2 with a compound represented by formula SM3 in the presence of an organic base:
preferably, the organic base is at least one selected from the group consisting of triethylamine, pyridine, methylimidazole, collidine and N, N-Diisopropylethylamine (DIPEA).
13. The method of claim 12, wherein the method further comprises,
a step of preparing a compound M2 from an intermediate M1 through an acylchlorination reaction, wherein the compound M2 is 5- (2-isopropyl-1, 3-dioxane-5-carbonyl acyl) -2,4, 6-triiodoisophthaloyl dichloride, and the reaction formula is as follows:
preferably, the acyl chlorination reaction uses an acyl chlorination reagent selected from at least one of the group consisting of triphosgene, thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride and phosphorus oxychloride;
more preferably, compound M1 is dissolved in an organic solvent in advance, which is dimethylacetamide DMAc or dimethylformamide DMF; further preferably, the solution of the acid chlorination reagent is added dropwise to the solution of intermediate M1 to perform the acid chlorination reaction to form compound M2.
14. The process according to claim 13, wherein the process comprises a step of amidation reaction of a compound of formula SM1 with a compound of formula SM 2:
wherein, in the formula SM1, R1、R2Independently H, C1～C4An alkyl group, wherein,
when R is1、R2When the intermediate is H, the intermediate M1 is directly generated;
when R is1、R2When not being H, firstly generating a compound shown as a formula M0, then generating M1 through hydrolysis reaction,
wherein the acyl chlorination reagent is at least one selected from the group consisting of triphosgene, thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride and phosphorus oxychloride;
preferably, the compound represented by formula SM2 is dissolved in an organic solvent in advance, wherein the organic solvent is dimethylacetamide DMAc or dimethylformamide DMF;
more preferably, a solution of the acyl chlorination reagent is dripped into a solution of the compound shown in the formula SM2 to carry out acyl chlorination reaction, and then amidation reaction is carried out with the compound shown in the formula SM1 at the temperature of room temperature to 70 ℃; further preferably, the dropping and the acylchlorination reaction are carried out at 0 ℃ or lower, and the amidation reaction is preferably carried out at a temperature of 40 to 60 ℃.
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