CN103058880B - The preparation method of Visipaque 320 and synthetic intermediate thereof - Google Patents
The preparation method of Visipaque 320 and synthetic intermediate thereof Download PDFInfo
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Abstract
The invention discloses the preparation method of a kind of Visipaque 320 and two (kharophen)-N, the N ' of synthetic intermediate 1,3--bis-[3,5-two (chloroformyl)-2,4,6-phenyl triiodide base]-2-propanol acetate thereof.This preparation method avoids with 5-acetylaminohydroxyphenylarsonic acid N, N '-bis-(2,3-dihydroxypropyl)-2,4, two polycondensation reaction of 6-tri-iodo isophtalamide, as final step, effectively improve the content of Visipaque 320 in product, and the purity of the Visipaque 320 crude product obtained is greater than 90%, and single assorted most high-content is lower than 2%, reduces the difficulty of purified product.
Description
Technical field
The invention belongs to medicinal chemistry art; relate to Visipaque 320 (formula II) and intermediate 1 thereof; two (the kharophen)-N of 3-; N '-bis-[3; two (chloroformyl)-2 of 5-; 4,6-phenyl triiodide base] preparation method of-2-propanol acetate (formula I).
Background technology
Visipaque 320 (Iodixanol, commodity are called Visipaque) is a kind of non-ionic type, the water miscible x-ray contrast agent developed by Nycomed company of Norway, in listing in 1993, and in a large amount of production; Two (acetamido)-N, N ' of its chemistry 1,3-by name-bis-[two (2,3-dihydroxypropyl aminocarbonyl)-2,4, the 6-phenyl triiodide bases of 3,5-]-2-hydroxy propane.
Visipaque 320 is the representative of dimer non-ionic type Iodine contrast medium, compares with traditional ionic contrast agent, and its infiltration is forced down, and viscosity is low, good hydrophilic property, and the probability that side effect occurs significantly reduces, and has very good market outlook.The production of Visipaque 320 comprises the production (i.e. primary productoin) of medicinal chemicals and the production (namely secondary is produced) of pharmaceutical preparation.Because nonionic X-ray contrast agent is injected directly in human vas, and consumption is with a high standard, therefore has very high requirement to its bulk drug quality.But for suitability for industrialized production medical compounds, the high efficiency of its primary productoin and economy are important too, therefore the chemosynthesis of Visipaque 320 and the advance of purifying process very crucial.
Bibliographical information has a lot about the method preparing Visipaque 320.They comprise the chemical synthesis process of multi-step, and the purification process of chromatogram and non-chromatogram.
The Article 1 synthetic route (NO161358) of Visipaque 320 is as follows:
Its final step obtains Visipaque 320 by the iodo-isophtalamide of two polycondensation 5-acetylaminohydroxyphenylarsonic acid N, N '-two (2,3-dihydroxypropyl)-2,4,6-tri-(hereinafter referred to as " compd A ").This step is the former committed step of grinding in route of Visipaque 320, and what existing document (EP108638, WO0047549, CN1340042 and CN101830825) adopted is also with compd A is raw material, obtains Visipaque 320 by dimerization reaction.According to prior art, the compd A of 40% ~ 60% is converted into Visipaque 320 by this step usually, the crude product purity obtained is about 80%, and containing more than 2% almost inexpungible impurity, in order to reach qualified purity, need to be purified to pharmaceutical purity by preparative liquid chromatography (EP108638) or continuous crystallization method (CN101293855 repeats crystallization 4 ~ 5 times), purifying cost is high, becomes the defect that Visipaque 320 is prepared in industry.
The Article 2 synthetic route of Visipaque 320 is as follows, by 5-amino-2,4,6-triiodo m-phthalic acid is converted into its dichloride (WO 96/37459), be converted into compd A (US 5705692) again, finally obtain Visipaque 320 by two polycondensation reaction of compd A again.This method is different from the approach of Article 1 route synthetic compound A, but have employed two polycondensation reaction of compd A equally, therefore there is identical defect with Article 1 reaction scheme.
KR 20050006367A, KR 20050024944A report the Article 3 synthetic route of Visipaque 320; that compd A is first reacted with hydroxy protecting agent; dimerization reaction again; last deprotection obtains Visipaque 320; add two-step reaction, have no it and improve yield and the report reducing the by products such as alkoxy compound.
The people such as Priebe had once delivered article (the Acta Radiol.36 (1995) attempting improving Visipaque 320 chemosynthesis yield, Suppi.399,21-31), the synthetic route of this section of article description can avoid the dimerization reaction described in Article 1 synthetic route, but does not report corresponding synthetic reaction condition and yield.
Organic Process Research & Development 2002,6,113-119 describes a kind of method being prepared Visipaque 320 by intermediate (formula I), the dimerization reaction in Article 1 synthetic route can be avoided equally, but in product containing content be about 6% list mix.
Summary of the invention
The invention provides the method that one prepares two (kharophen)-N, the N ' of Visipaque 320 intermediate 1,3--bis-[3,5-two (chloroformyl)-2,4,6-phenyl triiodide base]-2-propanol acetate.
Intermediate-1 for the preparation of Visipaque 320 (Iodixanol) provided by the invention; two (kharophen)-N, N ' of 3--bis-[two (chloroformyl)-2 of 3,5-; 4,6-phenyl triiodide base]-2-propanol acetate obtains by following methods:
The synthetic method of two (kharophen)-N, N ' of 1,3--bis-[3,5-two (chloroformyl)-2,4,6-phenyl triiodide base]-2-propanol acetate, its concrete steps are:
A) with amino-2,4, the 6-tri-iodo m-phthalic acid (formula 1) of 5-for starting raw material, at 20 DEG C ~ 90 DEG C, react 0.5 ~ 24 hour with aceticanhydride, obtain 5-acetylaminohydroxyphenylarsonic acid 2,4,6-triiodo m-phthalic acid (formula 2);
B) by steps A) intermediate (formula 2) that obtains is dissolved in polar solvent, under alkaline environment, 16 ~ 54 hours are reacted in 0 DEG C ~ 60 DEG C with dimerisation reagents, after reaction terminates, acidifying, separate out 1, two (kharophen)-N, N ' of 3--bis-(two carboxyl-2 of 3,5-, 4,6-phenyl triiodide base)-2-propyl alcohol (formula 3);
C) by step B) intermediate (formula 3) that obtains is under catalyst, 6 ~ 18 hours are reacted in 20 DEG C ~ 90 DEG C with acetylation reagent, generate 1, two (the kharophen)-N of 3-, N '-bis-(3, two carboxyl-2,4, the 6-phenyl triiodide base of 5-)-2-propanol acetate (formula 4);
D) by step C) intermediate (formula 4) that obtains is dissolved in organic solvent; through organic base catalytic; 3 ~ 12 hours are reacted in 40 DEG C ~ 90 DEG C with chloride reagent; generate 1; two (kharophen)-N, N ' of 3--bis-[two (chloroformyl)-2 of 3,5-; 4,6-phenyl triiodide base]-2-propanol acetate (formula I).
Each step of this synthetic method specifically describes as follows:
Steps A): amino-2,4, the 6-tri-iodo m-phthalic acid (formula 1) of 5-and aceticanhydride generation acylation reaction, obtain 5-acetylaminohydroxyphenylarsonic acid 2,4,6-tri-iodo m-phthalic acid (formula 2); Wherein, the ratio of raw material (formula)/aceticanhydride is that every g of compound adds 0.25 ~ 1.5 milliliter of aceticanhydride, preferably 0.8 ~ 1.2 milliliter; Acylation reaction temperature is 20 DEG C ~ 90 DEG C, and preferable reaction temperature is 60 DEG C ~ 80 DEG C; The acylation reaction time is 0.5 ~ 24 hour, and the preferred reaction time is 16 ~ 24 hours.
Step B): intermediate (formula 2) is dissolved in polar solvent, under alkaline environment, react with dimerisation reagents, after reaction terminates, two (the kharophen)-N of dimer 1,3-is separated out in acidifying, N '-bis-(3, two carboxyl-2,4, the 6-phenyl triiodide base of 5-)-2-propyl alcohol (formula 3); Wherein, polar solvent is selected from 1-methoxy-2-propanol, ethylene glycol monomethyl ether, methyl alcohol, propylene glycol, water, N,N-DIMETHYLACETAMIDE or 2-methyl cellosolve, preferred 1-methoxy-2-propanol, ethylene glycol monomethyl ether, propylene glycol or water; The pH of alkaline environment is preferably pH 10 ~ 13, most preferably is pH 11.5 ~ 12.5; The alkali regulating pH to adopt is alkali metal hydroxide or alkalimetal hydride, preferred sodium hydroxide, potassium hydroxide or sodium hydride; Dimerisation reagents is selected from 1,3-bis-chloro-2-propyl alcohol, 1,3-bis-bromo-2-propyl alcohol, glycerin α-diiodohydrin or Epicholorohydrin, preferably 1,3-bis-chloro-2-propyl alcohol or Epicholorohydrin; Intermediate (formula 2) and dimerisation reagents molar ratio be 1.0: 0.5 ~ 0.7, preferred feed ratio scope is 1.0: 0.6; Temperature of reaction is 0 DEG C ~ 60 DEG C, and preferable reaction temperature is 10 DEG C ~ 20 DEG C; Reaction times is 16 ~ 54 hours, and the preferred reaction time is 24 ~ 48 hours; The acid that acidifying adopts is the acid of hydrochloric acid, sulfuric acid or its mixture, preferred hydrochloric acid; Be acidified to pH 0 ~ 1.
Step C): intermediate (formula 3) is dissolved in acetylation reagent, adds catalyst reaction, generates 1, two (kharophen)-N, N ' of 3--bis-[two (carboxyl)-2 of 3,5-, 4,6-phenyl triiodide base]-2-propanol acetate (formula 4); Wherein, acetylation reagent is aceticanhydride or Acetyl Chloride 98Min., preferred aceticanhydride; The ratio of intermediate (formula 3)/acetylation reagent is that every g of compound adds 1.5 ~ 5 milliliters of acetylation reagents, preferably 2 ~ 3 milliliters; Catalyzer is DMAP, 4-pyrollidinopyridine, P (MeNCH2CH2) 3N or tributylphosphine, preferred DMAP; Acylation reaction temperature is 20 DEG C ~ 90 DEG C, and preferable reaction temperature is 60 DEG C ~ 70 DEG C; The acylation reaction time is 6 ~ 18 hours, and the preferred reaction time is 9 ~ 12 hours.
Step D): intermediate (formula 4) and chloride reagent are in organic solvent through organic base catalytic; be obtained by reacting 1; two (the kharophen)-N of 3-; N '-bis-[3; two (chloroformyl)-2 of 5-; 4,6-phenyl triiodide base]-2-propanol acetate (formula I).Wherein, chloride reagent is selected from thionyl chloride, phosphorus trichloride, phosphorus pentachloride, oxalyl chloride, Cynuric Chloride or triphosgene, preferred thionyl chloride; Organic bases is acid amides, Tetramethyl Ethylene Diamine, DMA, pyridine or DMAP, preferred DMF; The charging capacity of organic bases is catalytic amount; Organic solvent is selected from methylene dichloride, thionyl chloride, glycol dimethyl ether or tetrahydrofuran (THF), preferred thionyl chloride; Temperature of reaction is 40 DEG C ~ 90 DEG C, and preferable reaction temperature is 70 DEG C ~ 80 DEG C; Reaction times is 3 ~ 12 hours, and the preferred reaction time is 3 ~ 6 hours.
Another object of the present invention is to provide a kind of method preparing Visipaque 320:
This reaction scheme gives the synthetic method of Visipaque 320, and its concrete steps are:
A) with amino-2,4, the 6-tri-iodo m-phthalic acid (formula 1) of 5-for starting raw material, at 20 DEG C ~ 90 DEG C, react 0.5 ~ 24 hour with aceticanhydride, obtain 5-acetylaminohydroxyphenylarsonic acid 2,4,6-triiodo m-phthalic acid (formula 2);
B) by steps A) intermediate (formula 2) that obtains is dissolved in polar solvent, under alkaline environment, 16 ~ 54 hours are reacted in 0 DEG C ~ 60 DEG C with dimerisation reagents, after reaction terminates, acidifying, separate out 1, two (kharophen)-N, N ' of 3--bis-(two carboxyl-2 of 3,5-, 4,6-phenyl triiodide base)-2-propyl alcohol (formula 3);
C) by step B) intermediate (formula 3) that obtains is under catalyst, 6 ~ 18 hours are reacted in 20 DEG C ~ 90 DEG C with acetylation reagent, generate 1, two (the kharophen)-N of 3-, N '-bis-(3, two carboxyl-2,4, the 6-phenyl triiodide base of 5-)-2-propanol acetate (formula 4);
D) by step C) intermediate (formula 4) that obtains is dissolved in organic solvent; through organic base catalytic; 3 ~ 12 hours are reacted in 40 DEG C ~ 90 DEG C with chloride reagent; generate 1; two (kharophen)-N, N ' of 3--bis-[two (chloroformyl)-2 of 3,5-; 4,6-phenyl triiodide base]-2-propanol acetate (formula I).
E) by step D) there is ammonolysis reaction with amino-glycerol in-10 DEG C ~ 10 DEG C in the intermediate (formula I) that obtains, using alkali as acid binding agent, react 16 ~ 32 hours, generate two (kharophen)-N, the N '-bis-[3 of 1,3-, 5-two (2,3-dihydroxypropyl aminocarbonyl)-2,4,6-phenyl triiodide bases]-2-propanol acetate (formula 5);
F) by step e) intermediate (formula 5) that obtains is hydrolyzed 0.5 ~ 12 hour under acid or alkaline conditions, obtains the product removing ethanoyl, through nanofiltration, macroporous resin or obtain Visipaque 320 crude product through ion exchange resin;
Each step of this Visipaque 320 synthetic method specifically describes as follows:
Steps A): amino-2,4, the 6-tri-iodo m-phthalic acid (formula 1) of 5-and aceticanhydride generation acylation reaction, obtain 5-acetylaminohydroxyphenylarsonic acid 2,4,6-tri-iodo m-phthalic acid (formula 2); Wherein, the ratio of raw material (formula 1)/aceticanhydride is that every g of compound adds 0.25 ~ 1.5 milliliter of aceticanhydride, preferably 0.8 ~ 1.2 milliliter; Acylation reaction temperature is 20 DEG C ~ 90 DEG C, and preferable reaction temperature is 60 DEG C ~ 80 DEG C; The acylation reaction time is 0.5 ~ 24 hour, and the preferred reaction time is 16 ~ 24 hours.
Step B): intermediate (formula 2) is dissolved in polar solvent, under alkaline environment, react with dimerisation reagents, after reaction terminates, two (the kharophen)-N of dimer 1,3-is separated out in acidifying, N '-bis-(3, two carboxyl-2,4, the 6-phenyl triiodide base of 5-)-2-propyl alcohol (formula 3); Wherein, polar solvent is selected from 1-methoxy-2-propanol, ethylene glycol monomethyl ether, methyl alcohol, propylene glycol, water, N,N-DIMETHYLACETAMIDE or 2-methyl cellosolve, preferred 1-methoxy-2-propanol, ethylene glycol monomethyl ether, propylene glycol or water; The pH of alkaline environment is preferably pH 10 ~ 13, most preferably pH 11.5 ~ 12.5; The alkali regulating pH to adopt is alkali metal hydroxide or alkalimetal hydride, preferred sodium hydroxide, potassium hydroxide or sodium hydride; Dimerisation reagents is 1,3-bis-chloro-2-propyl alcohol, 1,3-bis-bromo-2-propyl alcohol, glycerin α-diiodohydrin or Epicholorohydrin, preferably 1,3-bis-chloro-2-propyl alcohol or Epicholorohydrin; Intermediate (formula 2) and dimerisation reagents molar ratio be 1.0: 0.5 ~ 0.7, preferred feed ratio scope is 1.0: 0.6; Temperature of reaction is 0 DEG C ~ 60 DEG C, and preferable reaction temperature is 10 DEG C ~ 20 DEG C; Reaction times is 16 ~ 54 hours, and the preferred reaction time is 24 ~ 48 hours; The acid that acidifying adopts is the acid of hydrochloric acid, sulfuric acid or its mixture, preferred hydrochloric acid; Be acidified to pH 0 ~ 1.
Step C): intermediate (formula 3) is dissolved in acetylation reagent, adds catalyst reaction, generates 1, two (kharophen)-N, N ' of 3--bis-[two (carboxyl)-2 of 3,5-, 4,6-phenyl triiodide base]-2-propanol acetate (formula 4); Wherein, acetylation reagent is aceticanhydride or Acetyl Chloride 98Min., preferred aceticanhydride; The ratio of intermediate (formula 3)/acetylation reagent is that every g of compound adds 1.5 ~ 5 milliliters of acetylation reagents, preferably 2 ~ 3 milliliters; Catalyzer is DMAP, 4-pyrollidinopyridine, P (MeNCH2CH2) 3N or tributylphosphine, preferred DMAP; Acylation reaction temperature is 20 DEG C ~ 90 DEG C, and preferable reaction temperature is 60 DEG C ~ 70 DEG C; The acylation reaction time is 6 ~ 18 hours, and the preferred reaction time is 9 ~ 12 hours.
Step D): intermediate (formula 4) and chloride reagent are in organic solvent through organic base catalytic; be obtained by reacting 1; two (the kharophen)-N of 3-; N '-bis-[3; two (chloroformyl)-2 of 5-; 4,6-phenyl triiodide base]-2-propanol acetate (formula I).Wherein, chloride reagent is thionyl chloride, phosphorus trichloride, phosphorus pentachloride, oxalyl chloride, Cynuric Chloride or triphosgene, preferred thionyl chloride; Organic bases is acid amides, Tetramethyl Ethylene Diamine, N, methylphenylamine, pyridine or DMAP, preferred DMF; The charging capacity of organic bases is catalytic amount; Organic solvent is selected from methylene dichloride, thionyl chloride, glycol dimethyl ether or tetrahydrofuran (THF), preferred thionyl chloride; Temperature of reaction is 40 DEG C ~ 90 DEG C, and preferable reaction temperature is 70 DEG C ~ 80 DEG C; Reaction times is 3 ~ 12 hours, and the preferred reaction time is 3 ~ 6 hours.
Step e): intermediate (formula I) and amino-glycerol generation ammonolysis reaction, generate 1, two (the kharophen)-N of 3-, N '-bis-[3,5-two (2,3-dihydroxypropyl aminocarbonyl)-2,4,6-phenyl triiodide bases]-2-propanol acetate (formula 5).Wherein, the solvent that ammonolysis reaction adopts is selected from tetrahydrofuran aqueous solution, DMF, dimethyl sulfoxide (DMSO), glycol dimethyl ether or tetrahydrofuran (THF), preferred tetrahydrofuran aqueous solution; Acid binding agent is selected from conventional alkaline reagent as sodium hydroxide, sodium carbonate, ammoniacal liquor etc.; Reaction times is 16 ~ 32 hours, preferably 16 ~ 20 hours; Temperature of reaction is-10 DEG C ~ 10 DEG C, preferably-5 DEG C ~ 5 DEG C.
Step F): intermediate (formula 5) is hydrolyzed 0.5 ~ 12 hour under acid or alkaline conditions, obtains the product removing ethanoyl, through nanofiltration, macroporous resin or obtain Visipaque 320 crude product through ion exchange resin.Wherein, acidic conditions is pH 0 ~ 2, preferably 0 ~ 1; For the mixing acid regulating the acid of pH to be selected from hydrochloric acid, sulfuric acid, phosphoric acid, boric acid or above-mentioned acid, preferred hydrochloric acid; Wherein, alkaline condition is pH 9 ~ 13; For regulating the alkali of pH to be alkali-metal oxyhydroxide, alkali-metal hydride, salt of wormwood or ammoniacal liquor, preferred sodium hydroxide, potassium hydroxide or sodium hydride; Reaction times is 0.5 ~ 12 hour, preferably 4 ~ 8 hours.
The common technology in starting raw material of the present invention (formula 1) available this area obtains, including, but not limited to method disclosed in Publication about Document:
WO 9637458
EP 2243767
WO 2010121904
Raw material (formula 1) involved in present disclosure refers to 5-amino-2,4,6-tri-iodo m-phthalic acid; Intermediate (formula 2) refers to 5-acetylaminohydroxyphenylarsonic acid 2,4,6-triiodo m-phthalic acid; Intermediate (formula 3) refers to two (kharophen)-N, the N ' of 1,3--bis-(two carboxyl-2,4, the 6-phenyl triiodide base of 3,5-)-2-propyl alcohol; Intermediate (formula 4) refers to two (kharophen)-N, the N ' of 1,3--bis-(two carboxyl-2,4, the 6-phenyl triiodide base of 3,5-)-2-propanol acetate; Intermediate (formula I) refers to two (kharophen)-N, the N ' of 1,3--bis-[3,5-two (chloroformyl)-2,4,6-phenyl triiodide base]-2-propanol acetate; Intermediate (formula 5) refers to two (kharophen)-N, the N ' of 1,3--bis-[two (2,3-dihydroxypropyl aminocarbonyl)-2,4, the 6-phenyl triiodide bases of 3,5-]-2-propanol acetate; Visipaque 320 (formula II) refers to two (acetamido)-N, the N ' of 1,3--bis-[two (2,3-dihydroxypropyl aminocarbonyl)-2,4, the 6-phenyl triiodide bases of 3,5-]-2-hydroxy propane.
The invention has the advantages that: present invention, avoiding with 5-acetylaminohydroxyphenylarsonic acid N, N '-bis-(2, 3-dihydroxypropyl)-2, 4, two polycondensation reaction of 6-tri-iodo isophtalamide are as final step, effectively improve the content of Visipaque 320 in product, the purity of the Visipaque 320 crude product obtained is greater than 90%, wherein single assorted most high-content is lower than 2%, in product, other single assorted content is all less than 1% simultaneously, reduce the difficulty of purified product, only need to refine secondary with 4 times amount methanol eddy crystallizatioies, just the Visipaque 320 of qualified purity can be obtained, single crystallization yield is greater than 80%, and in the present invention, midbody product need not be refined further, just can drop into next step and use, can product loss be reduced, and reduce the requirement to production unit, be applicable to suitability for industrialized production, be conducive to improving industrial production efficiency.
Embodiment
Can be conducted further description the present invention by the following examples, but scope of the present invention is not limited to following embodiment.
the synthesis of embodiment 1,5-acetylaminohydroxyphenylarsonic acid 2,4,6-triiodo m-phthalic acid (formula 2)
In reaction flask, add 5-amino-2,4,6-tri-iodo m-phthalic acid (1) 500g, aceticanhydride 500mL successively, be warming up to 80 DEG C, insulated and stirred reaction 18h, after reaction terminates, removes solvent under reduced pressure, obtains off-white color solid 505g, yield 90%.
the synthesis of two (kharophen)-N, N ' of embodiment 2,1,3--bis-(two carboxyl-2,4, the 6-phenyl triiodide base of 3,5-)-2-propyl alcohol (formula 3)
method one
Intermediate (formula 2) 500g, 1-methoxy-2-propanol 3000mL directly obtained by embodiment 1 is added in reaction flask successively, add sodium hydroxide and be adjusted to pH value of solution 12, drip 1,3-bis-chloro-2-propyl alcohol 64g, reaction 24h ~ 48h, after reaction terminates, add concentrated hydrochloric acid and be acidified to pH 0 ~ 1, separate out off-white color solid, filter, dry filter cake, obtain off-white color solid 310g, yield 59%.
method two
Intermediate (formula 2) 500g, 1-methoxy-2-propanol 3000mL directly obtained by embodiment 1 is added in reaction flask successively, add potassium hydroxide and be adjusted to pH value of solution 12, drip 1,3-bis-chloro-2-propyl alcohol 64g, reaction 24h ~ 48h, after reaction terminates, add concentrated hydrochloric acid, separate out off-white color solid, filter, dry filter cake, obtain off-white color solid 305g, yield 58%.
method three
Intermediate (formula 2) 500g, 1-methoxy-2-propanol 3000mL directly obtained by embodiment 1 is added in reaction flask successively, add potassium hydroxide and be adjusted to pH value of solution 12, drip Epicholorohydrin 47g, reaction 24h ~ 48h, after reaction terminates, add concentrated hydrochloric acid, separate out off-white color solid, filter, dry filter cake, obtain off-white color solid 290g, yield 55%.
method four
Intermediate (formula 2) 500g, the water 3000mL that are obtained by embodiment 1 are added in reaction flask successively, add potassium hydroxide and be adjusted to pH value of solution 12, drip 1,3-bis-chloro-2-propyl alcohol 64g, reaction 24h ~ 48h, after reaction terminates, add concentrated hydrochloric acid, separate out off-white color solid, filter, dry filter cake, obtain off-white color solid masses 250g, yield 48%.
the synthesis of two (kharophen)-N, N ' of embodiment 3,1,3--bis-(two carboxyl-2,4, the 6-phenyl triiodide base of 3,5-)-2-propanol acetate (formula 4)
Intermediate (formula 3) 500g directly obtained by embodiment 2, aceticanhydride 1000mL and DMAP 2g adds in reaction flask successively, is warming up to 70 DEG C, and reaction 12h, removes solvent under reduced pressure, obtain off-white color solid 510g.
the synthesis of two (kharophen)-N, N ' of embodiment 4,1,3--bis-[3,5-two (chloroformyl)-2,4,6-phenyl triiodide base]-2-propanol acetate (formula I)
Intermediate (formula 4) 500g directly obtained by embodiment 3 is dissolved in methylene dichloride 500mL, stirring and dissolving, drips thionyl chloride 200mL, add the DMF of catalytic amount, back flow reaction 4h, remove solvent and excessive thionyl chloride under reduced pressure, obtain off-white color solid 490g.
the synthesis of two (kharophen)-N, N ' of embodiment 5,1,3--bis-[two (2,3-dihydroxypropyl aminocarbonyl)-2,4, the 6-phenyl triiodide bases of 3,5-]-2-propanol acetate (formula 5)
Intermediate (formula I) 500g directly obtained by embodiment 4, tetrahydrofuran (THF) 500mL and water 250mL adds in reaction flask, stirring and dissolving, add triethylamine 200g, drip amino-glycerol 300g, at 0 DEG C, react 16h, after reaction terminates, isolate organic phase.
the synthesis of two (kharophen)-N, N ' of embodiment 6,1,3--bis-[two (2,3-dihydroxypropyl aminocarbonyl)-2,4, the 6-phenyl triiodide bases of 3,5-]-2-hydroxy propane (formula II)
The intermediate (formula 5) obtained by embodiment 5 adds 1000mL water, and adopts sodium hydroxide to be adjusted to pH 11, stirs hydrolysis 4h.Gained reaction solution, through macroporous resin desalination, removes solvent under reduced pressure, obtains off-white color solid 536g, yield 95%.
the recrystallization of embodiment 7, Visipaque 320
With methyl alcohol heating for dissolving Visipaque 320 crude product (V/W=4), add activated carbon decolorizing, 80 DEG C of reflux 2 hours, filtering gac; Filtrate backflow 2 ~ 3 days, crystallization, filters; Continuous crystallisation twice, obtains the satisfactory Visipaque 320 of purity.
the detection method of embodiment 8, Visipaque 320 content
HPLC method is adopted to detect the content of Visipaque 320 crude product and Visipaque 320 standard substance (purchased from GE Healthcare AS) respectively, sample adopts water-acetonitrile (30: 70) to dissolve, concentration is 1mg/mL, each sample size is 10 μ L, the chromatographic column adopted is Agilent Zorbax NH2 specification is 250mm × 4.6mm, particle diameter 5 μm, determined wavelength is 254nm, column temperature 25 DEG C, carry out gradient elution, the acetonitrile gradient of elution flow phase is be reduced to 5% by 85%, flow velocity 1.5mL/min in 0 ~ 55min.Shown in the following list lattice of result, wherein table 1 is the content detection result of Visipaque 320 standard substance; Table 2 is the content detection result of Visipaque 320 crude product.
The detection of table 1 Visipaque 320 standard substance content
| Retention time (min) | 17.612 | 18.214 | 19.071 |
| % area | 62.14 | 34.85 | 2.40 |
The detection of table 2 Visipaque 320 crude product content
From the above results, in table 2,17.504min, 18.085min, 19.042min tri-peaks are the peak of Visipaque 320, and in crude product, the content of Visipaque 320 is 92.87% as calculated; And the highest list content of mixing is 1.56% in crude product.
Claims (3)
1. a method for the Visipaque 320 shown in preparation formula II, is characterized in that, comprises the steps:
A) with amino-2,4,6-tri-iodo of the 5-shown in formula 1 m-phthalic acid for starting raw material, react with aceticanhydride, obtain the intermediate shown in formula 2; Wherein, the ratio of the raw material/aceticanhydride shown in formula 1 is that every g of compound adds 0.8 ~ 1.2 milliliter of aceticanhydride; Acylation reaction temperature is 60 DEG C ~ 80 DEG C; The acylation reaction time is 16 ~ 24 hours;
B) by steps A) intermediate shown in formula 2 that obtains is dissolved in polar solvent, and under alkaline environment, react with dimerisation reagents, after reaction terminates, acidifying, separates out the intermediate shown in formula 3; Wherein, polar solvent is selected from 1-methoxy-2-propanol, ethylene glycol monomethyl ether, methyl alcohol, propylene glycol or water; The pH scope of alkaline environment is pH 11.5 ~ 12.5; The alkali regulating pH to adopt is selected from sodium hydroxide, potassium hydroxide or sodium hydride; Dimerisation reagents is selected from the chloro-2-propyl alcohol of 1,3-bis-or Epicholorohydrin; Intermediate shown in formula 2 and dimerisation reagents molar ratio be 1.0:0.6; Temperature of reaction is 10 DEG C ~ 20 DEG C; Reaction times is 24 ~ 48 hours; The acid that acidifying adopts is hydrochloric acid; Be acidified to pH 0 ~ 1;
C) by step B) intermediate shown in formula 3 that obtains under catalyst, react with acetylation reagent, the intermediate shown in production 4; Wherein, the ratio of the intermediate/acetylation reagent shown in formula 3 is that every g of compound adds 2 ~ 3 milliliters of acetylation reagents; Acetylation reagent used is aceticanhydride; Used catalyst is DMAP; Acylation reaction temperature is 60 DEG C ~ 70 DEG C; The acylation reaction time is 9 ~ 12 hours;
D) by step C) intermediate shown in formula 4 that obtains is dissolved in organic solvent, through organic base catalytic, reacts 3 ~ 12 hours, the intermediate shown in production I with chloride reagent in 40 DEG C ~ 90 DEG C; Wherein, chloride reagent used is selected from thionyl chloride, phosphorus trichloride, phosphorus pentachloride, oxalyl chloride, Cynuric Chloride or triphosgene; Organic bases used is selected from acid amides, Tetramethyl Ethylene Diamine, DMA, pyridine or DMAP; The charging capacity of organic bases is catalytic amount; Organic solvent is selected from methylene dichloride, thionyl chloride, glycol dimethyl ether or tetrahydrofuran (THF);
E) by step D) there is ammonolysis reaction in-10 DEG C ~ 10 DEG C in the intermediate shown in formula I that obtains and amino-glycerol, using alkali as acid binding agent, react 16 ~ 32 hours, the intermediate shown in production 5; Wherein, the solvent that ammonolysis reaction adopts is selected from tetrahydrofuran aqueous solution, DMF, dimethyl sulfoxide (DMSO), glycol dimethyl ether or tetrahydrofuran (THF); Acid binding agent is selected from sodium hydroxide, sodium carbonate, ammoniacal liquor or triethylamine;
F) by step e) intermediate shown in formula 5 that obtains is hydrolyzed under acid or alkaline conditions, obtains the product removing ethanoyl, through nanofiltration, macroporous resin or obtain Visipaque 320 crude product through ion exchange resin; Wherein, acidic conditions is pH 0 ~ 1, is hydrochloric acid for regulating the acid of pH; Alkaline condition is pH 9 ~ 13, is sodium hydroxide, potassium hydroxide or sodium hydride for regulating the alkali of pH; Reaction times is 4 ~ 8 hours
2. preparation method according to claim 1, is characterized in that step D) in, chloride reagent used is thionyl chloride; Organic bases used is DMA; Organic solvent is thionyl chloride; Temperature of reaction is 70 DEG C ~ 80 DEG C; Reaction times is 3 ~ 6 hours.
3. preparation method according to claim 1, is characterized in that step e) in, the solvent that ammonolysis reaction adopts is tetrahydrofuran aqueous solution; Reaction times is 16 ~ 20 hours; Temperature of reaction Wei ?5 DEG C ~ 5 DEG C.
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