CN106366015B - A kind of Preparation Method And Their Intermediate of Iopromide - Google Patents

A kind of Preparation Method And Their Intermediate of Iopromide Download PDF

Info

Publication number
CN106366015B
CN106366015B CN201510434615.XA CN201510434615A CN106366015B CN 106366015 B CN106366015 B CN 106366015B CN 201510434615 A CN201510434615 A CN 201510434615A CN 106366015 B CN106366015 B CN 106366015B
Authority
CN
China
Prior art keywords
preparation
formula
compound
solvent
reaction
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201510434615.XA
Other languages
Chinese (zh)
Other versions
CN106366015A (en
Inventor
郭猛
胡明通
高大志
王笃政
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Chia Tai Tianqing Pharmaceutical Group Co Ltd
Original Assignee
Chia Tai Tianqing Pharmaceutical Group Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Chia Tai Tianqing Pharmaceutical Group Co Ltd filed Critical Chia Tai Tianqing Pharmaceutical Group Co Ltd
Priority to CN201510434615.XA priority Critical patent/CN106366015B/en
Publication of CN106366015A publication Critical patent/CN106366015A/en
Application granted granted Critical
Publication of CN106366015B publication Critical patent/CN106366015B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Abstract

The present invention relates to a kind of Preparation Method And Their Intermediates of Iopromide; it is starting material that the method, which is specifically included by VIII compound of formula, and the Iopromide of formula I is prepared through acylation reaction, further acylation reaction, dilactone reaction, reduction reaction, iodide reaction, again acylation reaction and final hydrolysis.Wherein III compound of introduction-type and V compound of formula are as intermediate, by introducing the intermediate, the generation of bismer by-product is avoided, V compound dilactoneization of formula is complete, and dilactone ring is not easy open loop removing during iodide reaction, while the intermediate introduced is easily isolated purifying.Therefore, the present invention can prepare the Iopromide of higher degree with higher yields.

Description

A kind of Preparation Method And Their Intermediate of Iopromide
Technical field
The present invention relates to organic syntheses and field of medicinal chemistry, specifically, the present invention relates to N, bis- (2, the 3- dihydroxies of N'- Propyl) -2,4,6- three iodo- 5- [(Methoxyacetyl) amino]-N- methyl-1, the preparation method of 3- benzenedicarboxamide and wherein Mesosome.
Background technique
Iopromide (Iopromide) is the non-ionic Iodine contrast medium of German Schering Plough company research and development, chemical name Bis- (2,3- the dihydroxypropyl) -2,4,6- three of referred to as N, N'- iodo- 5- [(Methoxyacetyl) amino]-N- methyl-1,3- benzene diformazan Amide, for structure as shown in formula I, Iopromide is widely used in x-ray contrast agent field.
United States Patent (USP) US4364921 discloses the preparation method of three kinds of Iopromides, and reaction route is as follows:
Route one:
Route two:
In above-mentioned route one, by 2 preparation of compounds of formula of formula, 3 compound during, be easy production 18 shown in two acyls Change by-product (bismer)；
Above-mentioned route two can be avoided the generation of two acylated by-products shown in formula 18, but by 7 preparation of compounds of formula 8 of formula During compound, it is easy to generate the endless full acetylated product of four hydroxyls, and be difficult to isolate and purify, to reduce subsequent The purity of intermediate and finished product；And by the iodide reaction of 9 preparation of compounds of formula of formula, 10 compound during, Acetyl Protecting Groups It is easily taken off, to reduce yield, improves cost, be unfavorable for industrialized production.
Above-mentioned route three equally can be to avoid the generation of two acylated by-products shown in formula 18, but iodide reaction process In, the acetyl group of 13 compound of formula is equally easily taken off.
The present invention is intended to provide the preparation method suitable for industrialized production that a kind of Iopromide is new.
Summary of the invention
On the one hand, the present invention provides a kind of preparation methods of Iopromide, characterized by comprising:
Acylation reaction occurs for III compound of formula and methoxyacetyl chloride, obtains II compound of formula；Water occurs for II compound of formula Solution reaction, obtains Iopromide；
Wherein, X is carbon or sulphur.
In some embodiments, above-mentioned acylation reaction can carry out in a solvent, and the solvent includes but is not limited to four Hydrogen furans, acetonitrile, n,N-dimethylacetamide or n,N-Dimethylformamide, preferably n,N-dimethylacetamide or N, N- diformazan Base formamide, most preferably n,N-dimethylacetamide；In some embodiments, above-mentioned acylation reaction can at 0-50 DEG C into Row, preferably 20-30 DEG C, most preferably 25-30 DEG C；In some embodiments, above-mentioned III compound of acylation reaction formula and methoxyl group The molar ratio of chloroacetic chloride is 1:1.5-3, preferably 1:1.5-2, most preferably 1:2.
In some embodiments, above-mentioned hydrolysis can carry out in the presence of alkali and solvent, and the solvent includes But it one of is not limited to water, isopropanol, 1,4- dioxane, acetonitrile, tetrahydrofuran, methanol or ethyl alcohol or a variety of mixing is molten The mixed solvent of agent, preferably water or water and methanol, most preferably water；The alkali includes but is not limited to sodium carbonate, potassium carbonate, bicarbonate Sodium, sodium hydroxide or potassium hydroxide, preferably sodium hydroxide or potassium hydroxide, most preferably sodium hydroxide.In some embodiments, Above-mentioned hydrolysis can carry out at 0-50 DEG C, preferably 20-30 DEG C, most preferably 25-30 DEG C.
In another aspect, the present invention provides II compounds of a kind of formula III and formula:
Wherein, X is carbon or sulphur.
On the other hand, the present invention provides a kind of formulas III and II compound of formula to prepare the purposes in Iopromide.
On the other hand, the present invention provides a kind of preparation methods of III compound of formula, characterized by comprising:
Under the action of reducing agent reduction reaction occurs for V compound of formula, obtains IV compound of formula；IV compound of formula and iodine Change reagent and iodination reaction occurs, obtains III compound of formula；
Wherein, X is carbon or sulphur.
In some embodiments, above-mentioned reduction reaction can carry out in the presence of reducing agent and solvent, the reducing agent Including but not limited to Raney-Ni, Pd/C, zinc powder, iron powder, stannous chloride, vulcanized sodium, FeOOH/ hydrazine hydrate, FeOOH/ activity Charcoal/hydrazine hydrate, FeCl3/ hydrazine hydrate or FeCl3/ active carbon/hydrazine hydrate, preferably Pd/C or zinc powder；The solvent includes but unlimited In one of N,N-dimethylformamide, 1,4- dioxane, acetonitrile, tetrahydrofuran, water, methanol or ethyl alcohol or a variety of mixing Solvent, preferably methanol or tetrahydrofuran, most preferably methanol；In some embodiments, above-mentioned reduction reaction can be in 3-5MPa Lower progress, preferably 4MPa；In some embodiments, above-mentioned reduction reaction can carry out at 25-40 DEG C, and preferably 25-35 DEG C, Most preferably 25-30 DEG C；In some embodiments, the inventory of above-mentioned 10% Pd/C is the mass fraction of V compound of formula 4%-10%, preferably 4%-6%, most preferably 5%；In some embodiments, above-mentioned zinc powder rubs with feeding intake for V compound of formula You are than being 4-10:1, preferably 4-6:1, most preferably 5:1.
In some embodiments, above-mentioned iodination reaction can carry out in the presence of iodination reagent and solvent, the iodine Changing reagent includes but is not limited to elemental iodine, acid iodide, N-iodosuccinimide or NaICl2, preferably NaICl2Or acid iodide, most preferably NaICl2；The solvent includes but is not limited to water, C1-C4Lower alcohol, acetonitrile, tetrahydrofuran, in 1,4- dioxane or acetic acid One or more mixed solvents, the preferably mixed solvent of water or water and methanol, most preferably water；In some embodiments, on Stating iodination reaction can carry out under catalyst, and the catalyst includes but is not limited to sulfuric acid, phosphoric acid or concentrated hydrochloric acid, preferably Concentrated hydrochloric acid；In some embodiments, above-mentioned iodination reaction can carry out at 50-85 DEG C, preferably 70-85 DEG C, most preferably 75- 80℃；In some embodiments, above-mentioned IV compound of iodination reaction formula and NaICl2Molar ratio be 1:3.1-3.5, It is preferred that 1-1:3.1-3.3, most preferably 1:3.2.
On the other hand, the present invention provides IV compounds of a kind of formula V and formula:
Wherein, X is carbon or sulphur.
On the other hand, the present invention provides a kind of formula V and IV compound of formula are in III compound of preparation formula and to prepare iodine general Purposes in sieve amine.
In some embodiments, V compound of formula can be prepared by the generation dilactoneization reaction of VI compound of formula；
Wherein, X is carbon or sulphur.
In some embodiments, above-mentioned dilactoneization reaction can carry out in the presence of condensing agent and solvent, the contracting Mixture includes but is not limited to CDI, triphosgene, thionyl chloride, ethyl chloroformate, preferably CDI, triphosgene or thionyl chloride；It is described Solvent includes but is not limited to acetonitrile, tetrahydrofuran, methylene chloride, chloroform or DMF, preferably DMF or chloroform, most preferably DMF；One In a little embodiments, above-mentioned dilactoneization reaction can carry out at 10-50 DEG C, preferably 10-30 DEG C, most preferably 10-20 DEG C；? In some embodiments, the molar ratio of above-mentioned VI compound of dilactone reaction equation and condensing agent is 1:2.5-4, preferably 1: 2.5-3.5 most preferably 1:3.
In some embodiments, VI compound of formula is referred to method disclosed in US4364921 and is prepared；One In a little embodiments, VI compound of formula can also be for example, by: VIII compound of formula and chlorination reagent generate acyl chlorides through chlorination reaction, Then acyl chlorides is prepared into VII compound of formula through acylation reaction；VII compound further occurrence acylation reaction of formula, is prepared formula VI Compound；
R1For methyl or hydrogen.
In some embodiments, R1For methyl, VI compound of formula is generated by VIII compound of formula and chlorination reagent reaction Acyl chlorides, then acylation reaction occurs for acyl chlorides and 3- methylamino -1,2-PD, is prepared into VII compound of formula；VII compound of formula is again Acylation reaction occurs with 3- amino -1,2-PD, VI compound of formula is prepared.In some embodiments, R1For hydrogen, formula VI compound generates acyl chlorides by VIII compound of formula and chlorination reagent reaction, and then acyl chlorides and 3- amino -1,2-PD occur Acylation reaction is prepared into VII compound of formula；Acylation reaction, preparation occur with 3- methylamino -1,2-PD again for VII compound of formula Obtain VI compound of formula.
In some embodiments, above-mentioned chlorination reaction in the presence of chlorination reagent and solvent can carry out, the chlorine Changing reagent includes but is not limited to thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride or triphosgene, preferably oxalyl Chlorine or thionyl chloride, most preferably oxalyl chloride；The solvent include but is not limited to methylene chloride, tetrahydrofuran, 1,4- dioxane, Ethyl acetate or chloroform, preferably methylene chloride or chloroform, most preferably methylene chloride；In some embodiments, above-mentioned chlorination is anti- It can should be carried out at 0-40 DEG C, preferably 20-30 DEG C, most preferably 25-30 DEG C.
In some embodiments, the above-mentioned acylation reaction by VII compound of acyl chlorides preparation formula can in the presence of solvent into Row, the solvent includes but is not limited to methylene chloride, DMF or ethyl acetate, preferably methylene chloride or DMF, most preferably dichloromethane Alkane；In some embodiments, above-mentioned acylation reaction can carry out at -10-10 DEG C, preferably -5-5 DEG C, most preferably -5-0 DEG C.
In some embodiments, the above-mentioned acylation reaction by VII preparation of compounds of formula of formula, VI compound can be deposited in solvent In lower progress, the solvent includes but is not limited to tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, n,N-dimethylacetamide or DMF, preferably DMF or n,N-dimethylacetamide, most preferably DMF；In some embodiments, above-mentioned acylation reaction can be at 60-100 DEG C It carries out, preferably 65-85 DEG C, most preferably 70-80 DEG C.
On the other hand, the present invention provides a kind of preparation method of Iopromide, include the following steps:
Dilactoneization reaction occurs for VI compound of formula, and V compound of formula is prepared；Work of V compound of formula in reducing agent With raw reduction reaction is issued, IV compound of formula is obtained；Iodination reaction occurs for IV compound of formula and iodination reagent, obtains III chemical combination of formula Object；Acylation reaction occurs for III compound of formula and methoxyacetyl chloride, obtains II compound of formula；It is anti-that hydrolysis occurs for II compound of formula It answers, obtains Iopromide；
Wherein, X is carbon or sulphur.
In some embodiments, X is carbon；In some embodiments, X is sulphur.
In some embodiments, above-mentioned dilactoneization reaction can carry out in the presence of condensing agent and solvent, the contracting Mixture includes but is not limited to CDI, triphosgene, thionyl chloride, ethyl chloroformate, preferably CDI, triphosgene or thionyl chloride；It is described Solvent includes but is not limited to acetonitrile, tetrahydrofuran, methylene chloride, chloroform or DMF, preferably DMF or chloroform, most preferably DMF；One In a little embodiments, above-mentioned dilactoneization reaction can carry out at 10-50 DEG C, preferably 10-30 DEG C, most preferably 10-20 DEG C；? In some embodiments, the molar ratio of above-mentioned VI compound of dilactone reaction equation and condensing agent is 1:2.5-4, preferably 1: 2.5-3.5 most preferably 1:3.
In some embodiments, above-mentioned reduction reaction can carry out in the presence of reducing agent and solvent, the reducing agent Including but not limited to Raney-Ni, Pd/C, zinc powder, iron powder, stannous chloride, vulcanized sodium, FeOOH/ hydrazine hydrate, FeOOH/ activity Charcoal/hydrazine hydrate, FeCl3/ hydrazine hydrate or FeCl3/ active carbon/hydrazine hydrate, preferably Pd/C or zinc powder；The solvent includes but unlimited In one of N,N-dimethylformamide, 1,4- dioxane, acetonitrile, tetrahydrofuran, water, methanol or ethyl alcohol or a variety of mixing Solvent, preferably methanol or tetrahydrofuran, most preferably methanol；In some embodiments, above-mentioned reduction reaction can be in 3-5MPa Lower progress, preferably 4MPa；In some embodiments, above-mentioned reduction reaction can carry out at 25-40 DEG C, and preferably 25-35 DEG C, Most preferably 25-30 DEG C；In some embodiments, the inventory of above-mentioned 10% Pd/C is the mass fraction of V compound of formula 4%-10%, preferably 4%-6%, most preferably 5%；In some embodiments, above-mentioned zinc powder rubs with feeding intake for V compound of formula You are than being 4-10:1, preferably 4-6:1, most preferably 5:1.
In some embodiments, above-mentioned iodination reaction can carry out in the presence of iodination reagent and solvent, the iodine Changing reagent includes but is not limited to elemental iodine, acid iodide, N-iodosuccinimide or NaICl2, preferably NaICl2Or acid iodide, most preferably NaICl2；The solvent includes but is not limited to water, C1-C4Lower alcohol, acetonitrile, tetrahydrofuran, in 1,4- dioxane or acetic acid One or more mixed solvents, the preferably mixed solvent of water or water and methanol, most preferably water；In some embodiments, on Stating iodination reaction can carry out under catalyst, and the catalyst includes but is not limited to sulfuric acid, phosphoric acid or concentrated hydrochloric acid, preferably Concentrated hydrochloric acid；In some embodiments, above-mentioned iodination reaction can carry out at 50-85 DEG C, preferably 70-85 DEG C, most preferably 75- 80℃；In some embodiments, above-mentioned IV compound of iodination reaction formula and NaICl2Molar ratio be 1:3.1-3.5, It is preferred that 1-1:3.1-3.3, most preferably 1:3.2.
In some embodiments, above-mentioned acylation reaction can carry out in a solvent, and the solvent includes but is not limited to four Hydrogen furans, acetonitrile, n,N-dimethylacetamide or n,N-Dimethylformamide, preferably n,N-dimethylacetamide or N, N- diformazan Base formamide, most preferably n,N-dimethylacetamide；In some embodiments, above-mentioned acylation reaction can at 0-50 DEG C into Row, preferably 20-30 DEG C, most preferably 25-30 DEG C；In some embodiments, above-mentioned III compound of acylation reaction formula and methoxyl group The molar ratio of chloroacetic chloride is 1:1.5-3, preferably 1:1.5-2, most preferably 1:2.
In some embodiments, above-mentioned hydrolysis can carry out in the presence of alkali and solvent, and the solvent includes But it one of is not limited to water, isopropanol, 1,4- dioxane, acetonitrile, tetrahydrofuran, methanol or ethyl alcohol or a variety of mixing is molten The mixed solvent of agent, preferably water or water and methanol, most preferably water；The alkali includes but is not limited to sodium carbonate, potassium carbonate, bicarbonate Sodium, sodium hydroxide or potassium hydroxide, preferably sodium hydroxide or potassium hydroxide, most preferably sodium hydroxide.In some embodiments, Above-mentioned hydrolysis can carry out at 0-50 DEG C, preferably 20-30 DEG C, most preferably 25-30 DEG C.
In some embodiments, the preparation of III compound of formula can also include further purification, the purification item Part includes but is not limited to ethyl alcohol or recrystallisation from isopropanol, preferably isopropanol.
In some embodiments, VI compound of formula is referred to method disclosed in US4364921 and is prepared；One In a little embodiments, VI compound of formula can be for example, by: VIII compound of formula and chlorination reagent reaction generate acyl chlorides, then acyl chlorides Through acylation reaction, it is prepared into VII compound of formula；VII compound further occurrence acylation reaction of formula, is prepared VI compound of formula；
R1For methyl or hydrogen.
In some embodiments, R1For methyl, VI compound of formula is generated by VIII compound of formula and chlorination reagent reaction Acyl chlorides, then acylation reaction occurs for acyl chlorides and 3- methylamino -1,2-PD, is prepared into VII compound of formula；VII compound of formula is again Acylation reaction occurs with 3- amino -1,2-PD, VI compound of formula is prepared.In some embodiments, R1For hydrogen, formula VI compound generates acyl chlorides by VIII compound of formula and chlorination reagent reaction, and then acyl chlorides and 3- amino -1,2-PD occur Acylation reaction is prepared into VII compound of formula；Acylation reaction, preparation occur with 3- methylamino -1,2-PD again for VII compound of formula Obtain VI compound of formula.
In some embodiments, above-mentioned chlorination reaction in the presence of chlorination reagent and solvent can carry out, the chlorine Changing reagent includes but is not limited to thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride or triphosgene, preferably oxalyl Chlorine or thionyl chloride, most preferably oxalyl chloride；The solvent include but is not limited to methylene chloride, tetrahydrofuran, 1,4- dioxane, Ethyl acetate or chloroform, preferably methylene chloride or chloroform, most preferably methylene chloride；In some embodiments, above-mentioned chlorination is anti- It can should be carried out at 0-40 DEG C, preferably 20-30 DEG C, most preferably 25-30 DEG C.
In some embodiments, the above-mentioned acylation reaction by VII compound of acyl chlorides preparation formula can in the presence of solvent into Row, the solvent includes but is not limited to methylene chloride, DMF or ethyl acetate, preferably methylene chloride or DMF, most preferably dichloromethane Alkane；In some embodiments, above-mentioned acylation reaction can carry out at -10-10 DEG C, preferably -5-5 DEG C, most preferably -5-0 DEG C.
In some embodiments, the above-mentioned acylation reaction by VII preparation of compounds of formula of formula, VI compound can be deposited in solvent In lower progress, the solvent includes but is not limited to tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, n,N-dimethylacetamide or DMF, preferably DMF or n,N-dimethylacetamide, most preferably DMF；In some embodiments, above-mentioned acylation reaction can be at 60-100 DEG C It carries out, preferably 65-85 DEG C, most preferably 70-80 DEG C.
The present invention also provides II -1 compound of formula and II -2 compounds；
The present invention also provides III -1 compound of formula and III -2 compounds；
The present invention also provides IV -1 compound of formula and IV -2 compounds；
The present invention also provides V -2 compounds of V -1 compound of formula and formula；
The present invention also provides VII -1 compounds；
The present invention also provides II -1 compound of formula, II -2 compound, III -1 compound, III -2 compound, IV -1 chemical combination Object, IV -2 compound, V -1 compound of formula, V -2 compound of formula and VII -1 compound are preparing the purposes in Iopromide.
In the present invention, unless otherwise indicated,
Term " DMF " refers to N,N-dimethylformamide；
Term " CDI " refers to N, N- carbonyl dimidazoles；
Term " room temperature " refers to 25-30 DEG C.
It is provided by the invention by VI compound of formula occur dilactoneization reaction V compound of preparation formula when, the reaction time compared with Short, dilactone fully reacting can obtain V compound of formula of high-purity without silica gel chromatograph column separating purification, advantageously reduce Cost improves subsequent intermediates purity；When V compound of formula is through reduction reaction, iodide reaction III compound of preparation formula, due to iodine When generation reaction, dilactone ring is not easy open loop removing, and III compound of formula is easily isolated purifying, therefore effectively increases reaction and receive Rate, and III compound of high-purity is obtained, to improve the yield and purity of subsequent intermediates and final product；The present invention provides The preparation method of Iopromide be extremely applicable to industrialized production.
Specific embodiment
Following embodiment is further non-limitingly described in detail technical solution of the present invention.They should not be considered as It limits the scope of the present invention, and only exemplary illustration and Typical Representative of the invention.Solvent used in the present invention, examination Agent and raw material etc. be commercially available chemistry it is pure or analysis net product.
Embodiment one: 3- ((2,3- dihydroxypropyl) carbamoyl) -5- nitrobenzene methyl (formula VII -1)
3- methoxycarbonyl group -5- nitrobenzoic acid (formula VIII) (50g, 0.222mol) is added in reaction flask, adds 400mL dichloromethane Alkane is dissolved, and oxalyl chloride (28.5mL, 0.335mol) is added dropwise at room temperature, continues stirring 1-2 hours after being added dropwise, and then will Reaction solution concentration, is redissolved concentrate with methylene chloride (125mL), and reaction solution is cooled to 0 DEG C hereinafter, 3- amino -1,2- is added dropwise Propylene glycol (48.5g, 0.53mol), the entire process that is added dropwise are maintained 4 hours, are stirred 0.5 hour after being added dropwise, reaction solution water It washes, organic layer is dried, filtered with anhydrous sodium sulfate, is concentrated to get 3- ((2,3- dihydroxypropyl) carbamoyl) -5- nitro Methyl benzoate (formula VII -1).
MS m/z[ESI]:298.1[M+1]+。
Embodiment two: N1,N3Double-(2,3- dihydroxypropyl)-N1Methyl-5-nitro isophthaloyl amine (formula VI)
3- ((2,3- dihydroxypropyl) carbamoyl) -5- nitrobenzene methyl (formula VII-that embodiment one is obtained 1) (29.8g, 0.1mol), 3- methylamino -1,2-PD (15g, 0.14mol) are dissolved in DMF (30mL), 70-80 DEG C of reaction 5h, reaction solution measure HPLC purity >=95%.
Embodiment three: 3- ((2,3- dihydroxypropyl) methyl-carbamoyl) -5- nitrobenzene methyl (formula VII -2)
3- methoxycarbonyl group -5- nitrobenzoic acid (formula VIII) (50g, 0.222mol) is added in reaction flask, adds 400mL dichloromethane Alkane is dissolved, and oxalyl chloride (28.5mL, 0.335mol) is added dropwise at room temperature, continues stirring 1-2 hours after being added dropwise, and then will Reaction solution concentration, concentrate is redissolved with methylene chloride (125mL), reaction solution be cooled to 0 DEG C hereinafter, be added dropwise methylamino -1 3-, 2- propylene glycol (55.7g, 0.53mol), the entire process that is added dropwise maintain 4 hours, and reaction in 0.5 hour is stirred after being added dropwise to be terminated, Reaction solution is washed with water, and organic layer is dried, filtered with anhydrous sodium sulfate, is concentrated to get 3- ((2,3- dihydroxypropyl) methylamino first Acyl group) -5- nitrobenzene methyl (formula VII -2).
Example IV: N1,N3Double-(2,3- dihydroxypropyl)-N1Methyl-5-nitro isophthaloyl amine (formula VI)
3- ((2,3- dihydroxypropyl) methyl-carbamoyl) -5- nitrobenzene methyl (formula that embodiment three is obtained VII -2) (50g, 0.16mol), 3- amino -1,2-PD (29.1g, 0.32mol) are dissolved in DMF (30mL), and 70-80 DEG C anti- It answers 6 hours, reaction solution measures HPLC purity >=95%.
Embodiment five: N1Methyl-5-nitro-N1,N3Double-((2- oxo -1,3- dioxolanes -4- base) methyl) different phthalein Amide (formula V -1)
The reaction solution (formula VI) that embodiment two or example IV obtain is stirred at 10-20 DEG C, is slowly added into CDI (48.6g, 0.3mol).It finishes, stirs 15 minutes, then reaction solution is added drop-wise in dilute hydrochloric acid (500mL) at 0-10 DEG C, is stirred Mix crystallization.Filtering, filter cake are washed with water, and obtain white solid N1Methyl-5-nitro-N1,N3Double-((2- oxo -1,3- dioxy Penta ring -4- base) methyl) isophthaloyl amine (formula V -1) (57.6g), yield 85%, HPLC purity >=92%.
MS m/z[ESI]:424.1[M+1]+。
Embodiment six: N1Methyl-5-nitro-N1,N3Double-((2- oxo -1,3- dioxolanes -4- base) methyl) different phthalein Amide (formula V -1)
The reaction solution (formula VI) that embodiment two or example IV obtain is stirred at 10-20 DEG C, triethylamine is added (40.4g, 0.4mol), is then slowly added dropwise tetrahydrofuran (150mL) solution of triphosgene (29.7g, 0.1mol), and reaction 1 is small When.Reaction solution is slowly added in 500mL ice water, stirring and crystallizing.Filtering, filter cake are washed with water 2-3 times, obtain white solid N1Methyl-5-nitro-N1,N3Double-((2- oxo -1,3- dioxolanes -4- base) methyl) isophthaloyl amine (formula V -1) (30.1g), yield 90%, HPLC purity >=90%.
MS m/z[ESI]:424.1[M+1]+。
Embodiment seven: N1Methyl -5- amino-N1,N3Double-((2- oxo -1,3- dioxolanes -4- base) methyl) different phthalein Amide (formula IV -1)
By N1Methyl-5-nitro-N1,N3Double-((2- oxo -1,3- dioxolanes -4- base) methyl) isophthaloyl amine (formula V -1) (42.3g, 0.1mol) is dissolved in 1L methanol, and 10% Pd/C (2g) is added in reaction solution, reacts 5- under room temperature 4MPa 6 hours.Then Pd/C is filtered to remove, filtrate concentration obtains solid N1Methyl -5- amino-N1,N3Double-((oxo -1 2-, 3- dioxolanes -4- base) methyl) isophthaloyl amine (formula IV -1) (38.5g), yield 98%, HPLC purity >=95%.
MS m/z[ESI]:393.1[M+1]+。
Eight: 5- amino-2,4,6-triiodo-N of embodiment1Methyl-N1,N3Double-((2- oxo -1,3- dioxolanes -4- Base) methyl) isophthaloyl amine (formula III -1)
By N1Methyl -5- amino-N1,N3Double-((2- oxo -1,3- dioxolanes -4- base) methyl) isophthaloyl amine (formula IV -1) (39.3g, 0.1mol), 393mL water, 9mL concentrated hydrochloric acid stir dissolved clarification at room temperature, and previously prepared NaICl is then added dropwise2 Reaction solution after being added dropwise, is warming up to 80 DEG C, maintains reaction 3-4 hours by (51.9g ICl, 18.7g NaCl, 200mL water). Then sodium sulfite (6.3g, 0.05mol) quenching reaction is added, filtering obtains white solid 5- amino -2,4, the iodo- N of 6- tri-1- Methyl-N1,N3The crude product of double-((2- oxo-1,3-dioxolanes -4- base) methyl) isophthaloyl amine (formula III -1), crude yield It is 96% for 85%, HPLC purity.
Above-mentioned crude product is recrystallized with isopropanol (250mL), obtains white solid 5- amino -2,4, the iodo- N of 6- tri-1First Base-N1,N3The highly finished product (69.4g) of double-((2- oxo-1,3-dioxolanes -4- base) methyl) isophthaloyl amine (formula III -1), essence Product yield is 90%, HPLC purity >=98%.
MS m/z[ESI]:771.8[M+1]+。
Embodiment nine: 2,4,6- tri- iodo- 5- (2- methoxyacetyl amino)-N1Methyl-N1,N3Double-((2- oxo -1,3- Dioxolanes -4- base) methyl) isophthaloyl amine (formula II -1)
By 5- amino-2,4,6-triiodo-N1Methyl-N1,N3Double-((2- oxo -1,3- dioxolanes -4- base) methyl) Isophthaloyl amine (formula III -1) (77.1g, the 0.1mol) DMAc of 150mL dissolves, 0-10 DEG C of dropwise addition methoxyacetyl chlorine (21.7g, 0.2mol), after being added dropwise, it is warmed to room temperature reaction 10 hours.Reaction solution is poured into 500mL ice water, crystallization precipitating, filtering, Filter cake is washed with water, and obtains 2,4,6- tri- iodo- 5- (2- methoxyacetyl amino)-N1Methyl-N1,N3Double-((2- oxo -1,3- Dioxolanes -4- base) methyl) isophthaloyl amine (formula II -1) (73.3g), yield 87%, HPLC purity >=98%.
MS m/z[ESI]:843.8[M+1]+。
Embodiment ten: N, bis- (2,3- the dihydroxypropyl) -2,4,6- three of N'- iodo- 5- [(Methoxyacetyl) amino]-N- first Base -1,3- benzenedicarboxamide (formula I)
By the iodo- 5- of 2,4,6- tri- (2- methoxyacetyl amino)-N1Methyl-N1,N3Double-((2- oxo -1,3- dioxy penta Ring -4- base) methyl) isophthaloyl amine (formula II -1) (84.3g, 0.1mol) and 5% sodium hydroxide (400mL) be stirred at room temperature 3 together Hour obtains Iopromide crude product, and crude product obtains Iopromide (formula I) sterling (63.3g) through resin column desalination after spray drying, Yield is 80%, HPLC purity >=99%.
MS m/z[ESI]:791.9[M+1]+。1H-NMR(500MHz,DMSO-d6): δ=10.07,10.03,9.97, 9.90(4s,1H)；8.66,8.57,8.52(3t,1H)；4.76-4.74(m,1H)；4.72,4.67(2t,1H)；4.59-4.58 (m,1H)；4.54-4.44(m,1H)；4.00(s,2H)；3.89-3.88(m,1H)；3.69-3.68(m,2H)；3.47(s,3H)； 3.44-3.38(m,4H)；3.23-3.17(m,3H)；2.85-2.83(4s,3H).
Embodiment 11: N1Methyl-5-nitro-N1,N3Double-((penta ring -4- base of 2- oxo -1,3,2- dioxy thia) first Base) isophthaloyl amine (formula V -2)
The reaction solution (formula VI) that embodiment two or example IV obtain is stirred at 10-20 DEG C, is slowly added into chlorination Sulfoxide (35.7g, 0.3mol), adds that the reaction was continued 2 hours, and then reaction solution is slowly added in 500mL ice water, stirring analysis It is brilliant.Filtering, filter cake are washed with water 2-3 times, obtain white solid N1Methyl-5-nitro-N1,N3Double-((2- oxo -1,3,2- Penta ring -4- base of dioxy thia) methyl) isophthaloyl amine (formula V -2) (39.4g), yield 85%, HPLC purity >=95%.
MS m/z[ESI]:464.0[M+1]+。
Embodiment 12: N1Methyl -5- amino-N1,N3Double-((penta ring -4- base of 2- oxo -1,3,2- dioxy thia) first Base) isophthaloyl amine (formula IV -2)
By N1Methyl-5-nitro-N1,N3Double-((penta ring -4- ylmethyl of 2- oxo -1,3,2- dioxy thia) isophthaloyl Amine (formula V -2) (46.3g, 0.1mol) 500mL methanol dissolves, and zinc powder (33g, 0.5mol) then is added, and stirs 10 minutes, Ammonium chloride (54g, 1mol) is added dropwise under low temperature, the reaction was continued at room temperature after dripping off 5 hours.Then it is filtered to remove zinc powder, filtrate is dense Contracting removes methanol, obtains N1Methyl -5- amino-N1,N3Double-((penta ring -4- base of 2- oxo -1,3,2- dioxy thia) methyl) The aqueous solution of isophthaloyl amine (formula IV -2).
MS m/z[ESI]:434.1[M+1]+。
13: 5- amino-2,4,6-triiodo-N of embodiment1Methyl-N1,N3Double-((2- oxo -1,3,2- dioxy thia Penta ring -4- base) methyl) isophthaloyl amine (formula III -2)
The N that embodiment 13 is obtained1Methyl -5- amino-N1,N3Double-((penta ring of 2- oxo -1,3,2- dioxy thia - 4- yl) methyl) aqueous solution, 393mL water, the 9mL concentrated hydrochloric acid of isophthaloyl amine (formula IV -2) (43.3g, 0.1mol) stir at room temperature Then previously prepared NaICl is added dropwise in dissolved clarification2(51.9g ICl, 18.7g NaCl, 200mL water), after being added dropwise, will react Liquid is warming up to 80 DEG C, maintains reaction 3-4 hours.Then sodium sulfite (6.3g, 0.05mol) quenching reaction is added, filtering obtains White solid 5- amino-2,4,6-triiodo-N1Methyl-N1,N3Double-((penta ring -4- base of 2- oxo -1,3,2- dioxy thia) first Base) isophthaloyl amine (formula III -2) crude product, crude yield 78%, HPLC purity be 95%.
Above-mentioned crude product is recrystallized with isopropanol (250mL), obtains white solid 5- amino -2,4, the iodo- N of 6- tri-1First Base-N1,N3The highly finished product of double-((penta ring -4- base of 2- oxo -1,3,2- dioxy thia) methyl) isophthaloyl amine (formula III -2) (52.7g), highly finished product yield are 83.3%, HPLC purity >=97%.
MS m/z[ESI]:811.7[M+1]+。
Embodiment 14: 2,4,6- tri- iodo- 5- (2- methoxyacetyl amino)-N1Methyl-N1,N3Double-((oxo -1 2-, Penta ring -4- base of 3,2- dioxy thia) methyl) isophthaloyl amine (formula II -2)
By 5- amino-2,4,6-triiodo-N1Methyl-N1,N3Double-((penta ring -4- base of 2- oxo -1,3,2- dioxy thia) Methyl) isophthaloyl amine (formula III -2) (81.1g, the 0.1mol) DMAc of 150mL dissolves, 0-10 DEG C of dropwise addition methoxyacetyl chlorine (21.7g, 0.2mol) after being added dropwise, is warmed to room temperature reaction 10 hours.Reaction solution is poured into 500mL ice water, crystallization is heavy It forms sediment, filtering, filter cake is washed with water, and obtains 2,4,6- tri- iodo- 5- (2- methoxyacetyl amino)-N1Methyl-N1,N3Double-((2- oxygen Generation penta ring -4- base of -1,3,2- dioxy thia) methyl) isophthaloyl amine (formula II -2) (75g), yield 85%, HPLC purity >= 95%.
MS m/z[ESI]:883.8[M+1]+。
Embodiment 15: N, bis- (2,3- the dihydroxypropyl) -2,4,6- three of N'- iodo- 5- [(Methoxyacetyl) amino]-N- Methyl-1,3- benzenedicarboxamide (formula I)
By the iodo- 5- of 2,4,6- tri- (2- methoxyacetyl amino)-N1Methyl-N1,N3Double-((2- oxo -1,3,2- sulphur dioxide Miscellaneous penta ring -4- base) methyl) isophthaloyl amine (formula II -2) (88.3g, 0.1mol) stirs with 5% sodium hydroxide (400mL) together room temperature It mixes and obtains within 3 hours Iopromide crude product, crude product obtains Iopromide (formula I) sterling through resin column desalination after spray drying (59.3g), yield 75%, HPLC purity >=99%.
MS m/z[ESI]:791.9[M+1]+。1H-NMR(500MHz,DMSO-d6): δ=10.07,10.03,9.97, 9.90(4s,1H)；8.66,8.57,8.52(3t,1H)；4.76-4.74(m,1H)；4.72,4.67(2t,1H)；4.59-4.58 (m,1H)；4.54-4.44(m,1H)；4.00(s,2H)；3.89-3.88(m,1H)；3.69-3.68(m,2H)；3.47(s,3H)； 3.44-3.38(m,4H)；3.23-3.17(m,3H)；2.85-2.83(4s,3H).

Claims (62)

1. a kind of preparation method of Iopromide (type I compound), which is characterized in that pass through following steps:
Step 5: dilactoneization reaction occurs in the presence of condensing agent and solvent for VI compound of formula, obtains V compound of formula；
Step 3: in the presence of reducing agent and solvent reduction reaction occurs for V compound of formula, obtains IV compound of formula；
Step 4: in the presence of iodination reagent, catalysts and solvents iodination reaction occurs for IV compound of formula, obtains III chemical combination of formula Object；
III compound of formula further recrystallizes the sterling for obtaining purification through organic solvent；
Condensing agent described in step 5 is CDI, triphosgene, thionyl chloride or ethyl chloroformate；
Step 1: with methoxyacetyl chloride acylation reaction occurs for III compound of formula in the presence of solvent, obtains II compound of formula；
Step 2: in the presence of alkali and solvent hydrolysis occurs for II compound of formula, obtains Iopromide；
Wherein, X is carbon or sulphur.
2. preparation method according to claim 1, which is characterized in that solvent described in step 1 is tetrahydrofuran, second Nitrile, DMAC N,N' dimethyl acetamide or N,N-dimethylformamide.
3. preparation method according to claim 2, which is characterized in that solvent described in step 1 is N, N- dimethyl second Amide or N,N-dimethylformamide.
4. preparation method according to claim 3, which is characterized in that solvent described in step 1 is N, N- dimethyl second Amide.
5. preparation method according to claim 1, which is characterized in that III compound of step 1 Chinese style and methoxyacetyl chloride Molar ratio be 1:1.5-3.
6. preparation method according to claim 5, which is characterized in that III compound of step 1 Chinese style and methoxyacetyl chloride Molar ratio be 1:1.5-2.
7. preparation method according to claim 6, which is characterized in that III compound of step 1 Chinese style and methoxyacetyl chloride Molar ratio be 1:2.
8. preparation method according to claim 1, which is characterized in that alkali described in step 2 be sodium carbonate, potassium carbonate, Sodium bicarbonate, sodium hydroxide or potassium hydroxide.
9. preparation method according to claim 8, which is characterized in that alkali described in step 2 is sodium hydroxide or hydrogen-oxygen Change potassium.
10. preparation method according to claim 9, which is characterized in that alkali described in step 2 is sodium hydroxide.
11. preparation method according to claim 1, which is characterized in that solvent described in step 2 be water, isopropanol, One of 1,4- dioxane, acetonitrile, tetrahydrofuran, methanol or ethyl alcohol or a variety of mixed solvents.
12. preparation method according to claim 11, which is characterized in that solvent described in step 2 is water or water and first The mixed solvent of alcohol.
13. preparation method according to claim 12, which is characterized in that solvent described in step 2 is water.
14. preparation method according to claim 1, which is characterized in that reducing agent described in step 3 be Raney-Ni, Pd/C, zinc powder, iron powder, stannous chloride, vulcanized sodium, FeOOH/ hydrazine hydrate, FeOOH/ active carbon/hydrazine hydrate, FeCl3/ hydrazine hydrate Or FeCl3/ active carbon/hydrazine hydrate.
15. preparation method according to claim 14, which is characterized in that reducing agent described in step 3 is Pd/C or zinc Powder.
16. preparation method according to claim 15, which is characterized in that reducing agent described in step 3 is 10%Pd/ C accounts for the 4%-10% of V compound quality score of formula.
17. preparation method according to claim 16, which is characterized in that reducing agent described in step 3 is 10%Pd/ C accounts for the 4%-6% of V compound quality score of formula.
18. preparation method according to claim 17, which is characterized in that reducing agent described in step 3 is 10%Pd/ C accounts for the 5% of V compound quality score of formula.
19. preparation method according to claim 15, which is characterized in that reducing agent described in step 3 is zinc powder, with V compound molar ratio of formula is 4-10:1.
20. preparation method according to claim 19, which is characterized in that reducing agent described in step 3 is zinc powder, with V compound molar ratio of formula is 4-6:1.
21. preparation method according to claim 20, which is characterized in that reducing agent described in step 3 is zinc powder, with V compound molar ratio of formula is 5:1.
22. preparation method according to claim 1, which is characterized in that solvent described in step 3 is N, N- dimethyl One of formamide, 1,4- dioxane, acetonitrile, tetrahydrofuran, water, methanol or ethyl alcohol or a variety of mixed solvents.
23. preparation method according to claim 22, which is characterized in that solvent described in step 3 is methanol or tetrahydro Furans.
24. preparation method according to claim 23, which is characterized in that solvent described in step 3 is methanol.
25. preparation method according to claim 1, which is characterized in that iodination reagent described in step 4 be elemental iodine, Acid iodide, N-iodosuccinimide or NaICl2。
26. preparation method according to claim 25, which is characterized in that iodination reagent described in step 4 is NaICl2 Or acid iodide.
27. preparation method according to claim 26, which is characterized in that iodination reagent described in step 4 is NaICl2。
28. preparation method according to claim 27, which is characterized in that IV compound of formula described in step 4 and iodate Reagent N aICl2Molar ratio be 1:3.1-3.5.
29. preparation method according to claim 28, which is characterized in that IV compound of formula described in step 4 and iodate Reagent N aICl2Molar ratio be 1:3.1-3.3.
30. preparation method according to claim 29, which is characterized in that IV compound of formula described in step 4 and iodate Reagent N aICl2Molar ratio be 1:3.2.
31. preparation method according to claim 1, which is characterized in that catalyst described in step 4 is sulfuric acid, phosphoric acid Or concentrated hydrochloric acid.
32. preparation method according to claim 31, which is characterized in that catalyst described in step 4 is concentrated hydrochloric acid.
33. preparation method according to claim 1, which is characterized in that solvent described in step 4 is water, C1-C4It is low One of grade alcohol, acetonitrile, tetrahydrofuran, 1,4- dioxane or acetic acid or a variety of mixed solvents.
34. preparation method according to claim 33, which is characterized in that solvent described in step 4 is water or water and first The mixed solvent of alcohol.
35. preparation method according to claim 34, which is characterized in that solvent described in step 4 is water.
36. preparation method according to claim 1, which is characterized in that purification condition described in step 4 be ethyl alcohol or Recrystallisation from isopropanol.
37. preparation method according to claim 36, which is characterized in that purification condition described in step 4 is isopropanol Recrystallization.
38. preparation method according to claim 1, which is characterized in that condensing agent described in step 5 is CDI, three light Gas or thionyl chloride.
39. preparation method according to claim 1, which is characterized in that VI compound of formula described in step 5 and condensation The molar ratio of agent is 1:2.5-4.
40. preparation method according to claim 39, which is characterized in that VI compound of formula described in step 5 and condensation The molar ratio of agent is 1:2.5-3.5.
41. preparation method according to claim 40, which is characterized in that VI compound of formula described in step 5 and condensation The molar ratio of agent is 1:3.
42. preparation method according to claim 1, which is characterized in that solvent described in step 5 is acetonitrile, tetrahydro furan It mutters, methylene chloride, chloroform or DMF.
43. preparation method according to claim 42, which is characterized in that solvent described in step 5 is DMF or chloroform.
44. preparation method according to claim 43, which is characterized in that solvent described in step 5 is DMF.
45. preparation method according to claim 1 further includes the preparation method of VI compound of formula, which is characterized in that pass through Following steps:
Step 6: chlorination reaction occurs in the presence of solvent and generates acyl chlorides for VIII compound of formula and chlorination reagent, then further by Acylation reaction occurs in the presence of solvent for acyl chlorides, obtains VII compound of formula；
Step 7: VII compound of formula further occurrence acylation reaction in the presence of solvent obtains VI compound of formula；
Wherein, R1For H or methyl.
46. preparation method according to claim 45, which is characterized in that chlorination reagent described in step 6 is protochloride Sulfone, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride or triphosgene.
47. preparation method according to claim 46, which is characterized in that chlorination reagent described in step 6 is oxalyl chloride Or thionyl chloride.
48. preparation method according to claim 47, which is characterized in that chlorination reagent described in step 6 is oxalyl Chlorine.
49. preparation method according to claim 45, which is characterized in that the solvent in chlorination reaction described in step 6 For methylene chloride, tetrahydrofuran, 1,4- dioxane, ethyl acetate or chloroform.
50. preparation method according to claim 49, which is characterized in that the solvent in chlorination reaction described in step 6 For methylene chloride or chloroform.
51. preparation method according to claim 50, which is characterized in that the solvent in chlorination reaction described in step 6 For methylene chloride.
52. preparation method according to claim 45, which is characterized in that the solvent in acylation reaction described in step 6 For methylene chloride, DMF or ethyl acetate.
53. preparation method according to claim 52, which is characterized in that the solvent in acylation reaction described in step 6 For methylene chloride or DMF.
54. preparation method according to claim 53, which is characterized in that the solvent in acylation reaction described in step 6 For methylene chloride.
55. preparation method according to claim 45, which is characterized in that the solvent in acylation reaction described in step 7 For tetrahydrofuran, 1,4- dioxane, DMAC N,N' dimethyl acetamide or DMF.
56. preparation method according to claim 55, which is characterized in that the solvent in acylation reaction described in step 7 For DMF or DMAC N,N' dimethyl acetamide.
57. preparation method according to claim 56, which is characterized in that the solvent in acylation reaction described in step 7 For DMF.
58. II compound of formula:
Wherein X is carbon or sulphur.
59. III compound of formula:
Wherein X is carbon or sulphur.
60. IV compound of formula:
Wherein X is carbon or sulphur.
61. V compound of formula:
Wherein X is carbon or sulphur.
62. prepared by II compound of formula, III compound of formula described in claim 58-61, IV compound of formula and V compound of formula Purposes in Iopromide.
CN201510434615.XA 2015-07-22 2015-07-22 A kind of Preparation Method And Their Intermediate of Iopromide Active CN106366015B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201510434615.XA CN106366015B (en) 2015-07-22 2015-07-22 A kind of Preparation Method And Their Intermediate of Iopromide

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201510434615.XA CN106366015B (en) 2015-07-22 2015-07-22 A kind of Preparation Method And Their Intermediate of Iopromide

Publications (2)

Publication Number Publication Date
CN106366015A CN106366015A (en) 2017-02-01
CN106366015B true CN106366015B (en) 2019-01-25

Family

ID=57879743

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201510434615.XA Active CN106366015B (en) 2015-07-22 2015-07-22 A kind of Preparation Method And Their Intermediate of Iopromide

Country Status (1)

Country Link
CN (1) CN106366015B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114716340B (en) * 2022-05-10 2023-11-14 杭州微流汇科技有限公司 Preparation method of iopromide intermediate

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4364921A (en) * 1979-03-08 1982-12-21 Schering, Aktiengesellschaft Novel triiodinated isophthalic acid diamides as nonionic X-ray contrast media
CN1178522A (en) * 1995-03-16 1998-04-08 舍林股份公司 Radiographic contrasting agent for computerised tomography and urography
CN1069633C (en) * 1994-09-23 2001-08-15 尼科梅德成像有限公司 Iodinated X-ray contrast media
CN1478068A (en) * 2000-12-01 2004-02-25 Process for preparation of iopamidol and new intermediates therein
CN102015624A (en) * 2008-04-30 2011-04-13 株式会社Lg生命科学 Novel process for preparation of iopromide

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015067601A1 (en) * 2013-11-05 2015-05-14 Bracco Imaging Spa Process for the preparation of iopamidol

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4364921A (en) * 1979-03-08 1982-12-21 Schering, Aktiengesellschaft Novel triiodinated isophthalic acid diamides as nonionic X-ray contrast media
CN1069633C (en) * 1994-09-23 2001-08-15 尼科梅德成像有限公司 Iodinated X-ray contrast media
CN1178522A (en) * 1995-03-16 1998-04-08 舍林股份公司 Radiographic contrasting agent for computerised tomography and urography
CN1478068A (en) * 2000-12-01 2004-02-25 Process for preparation of iopamidol and new intermediates therein
CN102015624A (en) * 2008-04-30 2011-04-13 株式会社Lg生命科学 Novel process for preparation of iopromide

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
碘普罗胺合成路线图解;赵文龙;《淮海工学院学报》;20130930;第22卷(第3期);第50-52页
碘普罗胺的合成;王哲 等;《中国医药工业杂志》;20121231;第43卷(第7期);第527-529页

Also Published As

Publication number Publication date
CN106366015A (en) 2017-02-01

Similar Documents

Publication Publication Date Title
CN113563363B (en) Ruugeli intermediate, preparation method thereof and preparation method of Ruugeli
CN103570580B (en) Preparation method of high-purity iopromide
KR101098553B1 (en) Novel Process for Preparation of Iopromide
EP0839056B1 (en) Process for producing ioversol
CN106496187A (en) A kind of synthetic method for preparing PARP inhibitor Niraparib
CN107353222A (en) The method for preparing 2 amino Ns (2,2,2 trifluoroethyl) acetamide
CN106366015B (en) A kind of Preparation Method And Their Intermediate of Iopromide
CN112543751B (en) One-pot preparation method of intermediate organic iodinated compound for synthesizing ioversol
ES2549060T3 (en) Manufacture of a triiodinated contrast agent
CN110078636B (en) Method for preparing iopromide intermediate
CN110267937B (en) Method for producing organic iodinated compound by one-pot method
CN106366016B (en) A kind of Preparation Method And Their Intermediate of Iopromide
CN115160172A (en) Preparation process of iopromide
KR101520187B1 (en) A method for preparation of an intermediate of iopromide
CN110015972A (en) A kind of preparation method of Iopromide intermediate
CN105001114B (en) Prepare the new method of Iopromide
CN107253917A (en) The preparation method of Iopromide and the purposes of intermediate
CN103804123B (en) The synthetic method of a kind of fingolimod hydrochloride and intermediate thereof
CN114716340B (en) Preparation method of iopromide intermediate
KR100286639B1 (en) Process for preparing iopromide
KR100567449B1 (en) Process for preparing Iodixanol
JPH09511242A (en) Method for producing carboxyarene sulfonic acid and carboxylic acid derivative thereof
CN108997316A (en) A kind of preparation process of dabigatran etcxilate
KR960007801B1 (en) Preparation of unionic iodine-containing x-ray contrast agents
KR100511102B1 (en) Improved process for preparing Iodixanol

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant