CN105001114A - New method for preparing iopromide - Google Patents
New method for preparing iopromide Download PDFInfo
- Publication number
- CN105001114A CN105001114A CN201410158535.1A CN201410158535A CN105001114A CN 105001114 A CN105001114 A CN 105001114A CN 201410158535 A CN201410158535 A CN 201410158535A CN 105001114 A CN105001114 A CN 105001114A
- Authority
- CN
- China
- Prior art keywords
- formula
- amino
- compound
- methoxyacetyl
- iopromide
- 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.)
- Granted
Links
Abstract
The present invention relates to iopromide preparation methods, and provides three new iopromide preparation methods, wherein the method 1 comprises that a compound represented by a formula II is adopted as a starting raw material and reacts with allylamine to obtain a compound represented by a formula III, the compound represented by the formula III reacts with N-methyl allylamine to obtain a compound represented by a formula IV, the compound represented by the formula IV reacts with methoxyacetyl chloride to obtain a compound represented by a formula V, and the compound represented by the formula V is oxidized to obtain the iopromide represented by a formula I, the method 2 comprises that the compound represented by the formula II is adopted as a starting raw material and reacts with allylamine to obtain the compound represented by the formula III, the compound represented by the formula III reacts with methoxyacetyl chloride to obtain a compound represented by a formula IV-1, the compound represented by the formula IV-1 reacts with N-methyl allylamine to obtain the compound represented by the formula V, and the compound represented by the formula V is oxidized to obtain the iopromide represented by the formula I, the method 3 comprises that the compound represented by the formula II is adopted as a starting raw material and reacts with allylamine to obtain the compound represented by the formula III, the compound represented by the formula III reacts with methoxyacetyl chloride to obtain the compound represented by the formula IV-1, the compound represented by the formula IV-1 reacts with 3-methylamino-1,2-propanediol to obtain a compound represented by a formula V-1, and the compound represented by the formula V-1 is oxidized to obtain the iopromide represented by the formula I, and the method 4 comprises that the compound represented by the formula II is adopted as a starting raw material and reacts with methoxyacetyl chloride obtain a compound represented by a formula III-1, the compound represented by the formula III-1 reacts with allylamine to obtain the compound represented by the formula IV-1, the compound represented by the formula IV-1 reacts with N-methyl allylamine to obtain the compound represented by the formula V, and the compound represented by the formula V is oxidized to obtain the iopromide represented by the formula I.
Description
Technical field:
The present invention relates to the preparation method of Iopromide, provide the novel method that three are prepared Iopromide: method one: with formula II for starting raw material, formula III is obtained by reacting with allylamine, formula III and N-methyl allyl amine are obtained by reacting formula IV, formula IV and methoxyacetyl chloride are obtained by reacting formula V, and formula V obtains Iopromide formula I through peroxidation; Method two: with formula II for starting raw material, is obtained by reacting formula III with allylamine, and formula III and methoxyacetyl chloride are obtained by reacting formula IV-1, and formula IV-1 and N-methyl allyl amine are obtained by reacting formula V, and formula V obtains Iopromide formula I through peroxidation; Method three: with formula II for starting raw material, is obtained by reacting formula III with allylamine, and formula III and methoxyacetyl chloride are obtained by reacting formula IV-1, and formula IV-1 and 3-methylamino--1,2-PD are obtained by reacting formula V-1, and formula V-1 obtains Iopromide formula I through peroxidation; Method four: with formula II for starting raw material, is obtained by reacting formula III-1 with methoxyacetyl chloride, and formula III-1 and allyl amine are obtained by reacting formula IV-1, and formula IV-1 and N-methacrylic amine are obtained by reacting formula V, and formula V obtains Iopromide formula I through peroxidation.
According to the present invention, by simple crystallization formula III intermediate, the bismer by product causing Iopromide purity drop produced in the preparation process of Iopromide can be removed easily, and do not need the other bismer by product described in purification step removing, finally can obtain highly purified Iopromide by high yield.
Background technology
Iopromide (formula I) is widely used as x-ray contrast agent clinically.Current bibliographical information be published in patent US4364921 about its preparation method, in CN200980115336.X, CN201110205473.1, CN201210497200.3.
Patent US4364921 discloses the preparation method of three kinds of Iopromides.Method one is as follows:
Method one:
According to the preparation method of method one, in the process by 2 preparations 3, inevitably produce and a large amount of twoly replace by product, i.e. compounds 3 ', and due to compound 3 ' and 3 polarity too large, very difficult purifying, therefore there is the shortcoming that productive rate is low, purity is low in this step.
Method two:
Method three:
Although method two and method three can avoid two generation replacing by product, all there is the shortcoming that reactions steps is many, aftertreatment bothers, the production cycle is long, productive rate is low.
Korean Patent CN200980115336.X improves technique subsequently, and synthetic method is as shown in method four:
Method four:
Method four, by introducing intermediate 17, reduces the polarity of compound, and the removing of employing crystallization mode is two replaces by product, although can remove two replacement by product, owing to introducing, removing protecting group, adds reactions steps, reduces production efficiency.
Chinese patent CN201110205473.1, also improves technique, and synthetic method is as shown in method five:
Method five:
Method five also can avoid two generation replacing by product, but because raw material 18 is expensive, be difficult to obtain, so method production cost is higher.
Chinese patent CN201210497200.3, by introducing new protecting group, improve its synthesis technique, synthetic method is as shown in method six:
Method six:
Method six, by the protection of Methoxyacetyl, reduces the polarity of compound, and then is removed by the mode of crystallization and twoly replace by product, although this method decreases reactions steps, have that starting raw material is more expensive, protecting group more greatly, the not easily shortcoming such as Deprotection.
In sum; there is two replacement shortcomings such as by product not easily removes, reactions steps is many, introduce protecting group, expensive starting materials is not easy to obtain in current synthesis technique; therefore develop one can effectively remove two replace by product, reactions steps few, do not introduce protecting group, cheaper starting materials is easy to get, the technique that high yield, high purity prepare Iopromide is significant.
Summary of the invention
Technical purpose: the present invention adopts new synthetic method and new intermediate to prepare Iopromide.
Technique means: the preparation method that the present invention relates to Iopromide, provide the novel method that three are prepared Iopromide: method one: with formula II for starting raw material, formula III is obtained by reacting with allylamine, formula III and N-methyl allyl amine are obtained by reacting formula IV, formula IV and methoxyacetyl chloride are obtained by reacting formula V, and formula V obtains Iopromide formula I through peroxidation; Method two: with formula II for starting raw material, is obtained by reacting formula III with allylamine, and formula III and methoxyacetyl chloride are obtained by reacting formula IV-1, and formula IV-1 and N-methyl allyl amine are obtained by reacting formula V, and formula V obtains Iopromide formula I through peroxidation; Method three: with formula II for starting raw material, is obtained by reacting formula III with allylamine, and formula III and methoxyacetyl chloride are obtained by reacting formula IV-1, and formula IV-1 and 3-methylamino--1,2-PD are obtained by reacting formula V-1, and formula V-1 obtains Iopromide formula I through peroxidation.Method four: with formula II for starting raw material, is obtained by reacting formula III-1 with methoxyacetyl chloride, and formula III-1 and allyl amine are obtained by reacting formula IV-1, and formula IV-1 and N-methacrylic amine are obtained by reacting formula V, and formula V obtains Iopromide formula I through peroxidation.
Article four, method uses 5-amino-3-allyl amino formyl radical-2, 4, 6-phenyl triiodide formyl chloride (formula III), 5-Amino-N-methyl-N, N '-diallyl-2, 4, 6-triiodo isophtalamide (formula IV), 5-methoxyacetyl Amino-N-methyl-N, N '-diallyl-2, 4, 6-triiodo isophtalamide (formula V), 5-methoxyacetyl amino-3-allyl amino formyl radical-2, 4, 6-phenyl triiodide formyl chloride (formula IV-1) and 5-methoxyacetyl amino-2, 4, 6-triiodo m-phthalic acid [(allyl amino)-(2, 3-dihydroxyl-N-methyl-propyl)] diamide (formula V-1) is as intermediate.
Synthetic method is as follows:
Method one:
Method two:
Method three:
Method four:
Technique effect: by simple crystallization formula III intermediate, the bismer by product causing Iopromide purity drop produced in the preparation process of Iopromide can be removed easily, and do not need the other bismer by product described in purification step removing, finally can obtain highly purified Iopromide by high yield.
Embodiments of the invention only for illustration of the present invention, and can not cause restriction to other invention scope.
Embodiment
The synthesis of embodiment 1:5-amino-3-allyl amino formyl radical-2,4,6-phenyl triiodide formyl chloride (formula III):
Method one: by 5-amino-2,4,6-triiodo m-phthalic acid dichloride (formula II) (100.0g, 0.17mol) be dissolved in 500mlTHF, cryosel bath is cooled to less than 0 DEG C, drips allylamine (30.5g, the 0.53mol) solution that 500mlTHF dissolves, drip and finish, less than 0 DEG C is reacted 10h.Reaction is finished, and suction filtration, filtrate evaporate to dryness, obtains faint yellow white powder, and crude product methylene dichloride is pulled an oar, suction filtration, and filtrate evaporate to dryness obtains beige white powder 62.1g, molar yield 60%.
Method two: adopt DMF as reaction solvent, allylamine (10.96g, 0.19mol), operates the same, in room temperature reaction 8h, product yield 61%.
Method two: adopt DMF as reaction solvent, allylamine (10.96g, 0.19mol), operates the same, in room temperature reaction 12h, product yield 63%.
The synthesis of embodiment 2:5-methoxyl acetamide base-2,4,6-triiodo m-phthaloyl chloride (formula III-1):
Be dissolved in by methoxyacetyl chloride (54.6g, 0.50mol) in the DMA of 100mL drying, temperature control 10 DEG C drips 5-amino-2, the DMA solution 300mL of 4,6-triiodo m-phthalic acid dichloride (formula II) (100.0g, 0.17mol), drip and finish, room temperature reaction 24 hours.Reaction is finished, and is poured into by reaction solution in frozen water, and adularescent solid is separated out immediately, and stir 15min, suction filtration, is dissolved in filter cake in methylene dichloride, uses saturated NaHCO successively
3solution, saturated NaCl solution respectively wash twice, and organic layer is as adding a small amount of anhydrous Na in refrigerator
2sO
4dried overnight, desolventizing obtains white solid 101.1g, and molar yield is 90.2%.
Embodiment: 3:5-Amino-N-methyl-N, the synthesis of N '-diallyl-2,4,6-triiodo isophtalamide (formula IV):
Method one: room temperature; by N-methyl allyl amine (20.76g; 0.29mol) be dissolved in 180mlTHF; be added dropwise to 5-amino-3-allyl amino formyl radical-2; in the 420mlTHF of 4,6-phenyl triiodide formyl chloride (formula III) (60.0g, 0.10mol); drip and finish, room temperature reaction.Reaction is finished, and suction filtration, filtrate evaporate to dryness obtains white powder 62.7g, molar yield 99%.
Method two: adopt DMF as reaction solvent, operate the same, in room temperature reaction 10h, product yield 95%.
Method two: adopt DMF as reaction solvent, operate the same, in room temperature reaction 14h, product yield 97%.
The preparation of embodiment 4:5-methoxyacetyl amino-3-allyl amino formyl radical-2,4,6-phenyl triiodide formyl chloride (formula IV-1):
Method one: room temperature; by methoxyacetyl chloride (31.7g; 0.29mol) be dissolved in 300mlTHF; be added dropwise to 5-amino-3-allyl amino formyl radical-2; in the 300mlTHF of 4,6-phenyl triiodide formyl chloride (formula III) (60.0g, 0.10mol); drip and finish, room temperature reaction.Reaction is finished, and evaporated under reduced pressure, obtains white powder 65.0g, molar yield 97%.
Method two: adopt DMF as reaction solvent, operate the same, product yield 95%.
Method two: adopt DMF as reaction solvent, operate the same, product yield 97%.
Method four: adopt acetonitrile as reaction solvent, add triethylamine (29.0g, 0.29mol), reaction is finished, and suction filtration, reaction solution evaporated under reduced pressure obtains product, product yield 96%.
Method five: adopt toluene as reaction solvent, operate same method four, product yield 93%.
Embodiment 5:5-methoxyacetyl Amino-N-methyl-N, the synthesis of N '-diallyl-2,4,6-triiodo isophtalamide (formula V):
Method one: room temperature, by methoxyacetyl chloride (30.0g, 0.28mol) be dissolved in 300mlTHF, be added dropwise to 5-Amino-N-methyl-N, N '-diallyl-2,4,6-triiodo isophtalamide (formula IV) (60.0g, in 300mlTHF 0.09mol), drip and finish, room temperature reaction about 40h.Reaction is finished, and evaporated under reduced pressure, adds methylene dichloride 300ml and dissolve, and use saturated sodium bicarbonate, water (washing 1 time), saturated aqueous common salt respectively to wash twice successively, evaporated under reduced pressure obtains white powder 64.6g, molar yield 97%.
Method two: by 5-methoxyl acetamide base-3-allyl amino formyl radical-2,4,6-phenyl triiodide formyl chloride (formula IV-1) (30.0g; 0.04mol) be dissolved in 300mLTHF, under room temperature, drip N-methacrylic amine (3.4g, 0.05mol); finish, be warming up to 45 DEG C of reactions.React complete, reaction solution is poured in a large amount of water.Suction filtration, filtrate extracts with DCM, anhydrous Na
2sO
4dried overnight, boils off DCM, obtains a pale yellow oil, pulls an oar with a small amount of anhydrous diethyl ether, can obtain white solid powder 21.7g, and molar yield is 68.9%.
The preparation of embodiment 6:5-methoxyacetyl amino-2,4,6-triiodo m-phthalic acid [(allyl amino)-(2,3-dihydroxyl-N-methyl-propyl)] diamide (formula V-1):
Room temperature; by 3-methylamino--1; 2-propylene glycol (18.3g; 0.17mol) be dissolved in 180ml acetonitrile-dioxane (v/v=1:1), be added dropwise to 5-methoxyacetyl amino-3-allyl amino formyl radical-2,4; 6-phenyl triiodide formyl chloride (formula IV-1) (60.0g; in 420ml acetonitrile-dioxane (v/v=1:1) 0.09mol), drip and finish, room temperature reaction.Reaction is finished, suction filtration, filtrate evaporate to dryness, and ethanol is pulled an oar, and suction filtration obtains white solid 60.0g, molar yield 91%.
Embodiment 7: the preparation of Iopromide (formula I):
By 5-methoxyacetyl Amino-N-methyl-N, N '-diallyl-2,4,6-triiodo isophtalamide (formula V) (60.0g, 0.08mol) is dissolved in 900mlAcetone:H
20(3:1), add NMO (23.4g, 0.18mol), OsO successively
4(110ml, 0.003mol, 1%), room temperature reaction 13h.Reaction is finished, and pressure reducing and steaming acetone, adds a small amount of water in resistates, adds appropriate Sulfothiorine, stirs 0.5h, and the separation of reaction solution macroporous adsorbent resin, purifying are obtained black solid, with methanol activity charcoal backflow 1h decolouring.Obtain beige white powder 55.8g, molar yield 85%.
Claims (34)
1. prepare a novel method for Iopromide (formula I), reaction formula is as follows:
It is characterized in that, comprise the following steps:
Step (a
1): amino-2,4,6-triiodo m-phthalic acid dichloride (formula II) of 5-is obtained by reacting 5-amino-3-allyl amino formyl radical-2,4,6-phenyl triiodide formyl chloride (formula III) with allylamine;
Step (b
1): 5-amino-3-allyl amino formyl radical-2,4,6-phenyl triiodide formyl chloride (formula III) and N-methyl allyl amine are obtained by reacting 5-Amino-N-methyl-N, N '-diallyl-2,4,6-triiodo isophtalamide (formula IV);
Step (c
1): 5-Amino-N-methyl-N, N '-diallyl-2,4,6-triiodo isophtalamide (formula IV) and methoxyacetyl chloride are obtained by reacting 5-methoxyacetyl Amino-N-methyl-N, N '-diallyl-2,4,6-triiodo isophtalamide (formula V);
Step (d
1): 5-methoxyacetyl Amino-N-methyl-N, N '-diallyl-2,4,6-triiodo isophtalamide (formula V) obtains Iopromide (formula I) through peroxidation.
2. method according to claim 1, is characterized in that: step (a
1) in, the compound of formula II and the allylamine of 0.6-6.0 equivalent react.
3. method according to claim 2, is characterized in that: step (a
1) in, the compound of formula II and the allylamine of 0.6-3.0 equivalent react.
4. method according to claim 1, is characterized in that: step (a
1) in, the solvent of use be selected from DMF, N,N-dimethylacetamide, tetrahydrofuran (THF), acetone, ethyl acetate, toluene, N-Methyl pyrrolidone, acetonitrile, dioxane, dimethyl sulfoxide (DMSO) one or more.
5. method according to claim 1, is characterized in that: step (a
1) in, by the formula II compound recirculation of reclaiming in formula III compound purge process.
6. method according to claim 1, is characterized in that: step (b
1) in, the compound of formula III and the N-methyl allyl amine of 1.0-6.0 equivalent react.
7. method according to claim 1, is characterized in that: step (b
1) in, the solvent of use be selected from DMF, N,N-dimethylacetamide, tetrahydrofuran (THF), acetone, toluene, N-Methyl pyrrolidone, dioxane, ethyl acetate, acetonitrile, dimethyl sulfoxide (DMSO) one or more.
8. method according to claim 1, is characterized in that: step (b
1) in, reaction system is not added alkali or interpolation and is selected from one or more alkali in triethylamine, tri-n-butyl amine, pyridine, DIPEA, sodium carbonate, sodium bicarbonate, salt of wormwood, saleratus.
9. method according to claim 1, is characterized in that: step (c
1) in, the compound of formula IV and the methoxyacetyl chloride of 1.0-6.0 equivalent react.
10. method according to claim 1, is characterized in that: step (c
1) in, the solvent of use be selected from DMF, N,N-dimethylacetamide, tetrahydrofuran (THF), acetone, toluene, N-Methyl pyrrolidone, dioxane, ethyl acetate, acetonitrile, dimethyl sulfoxide (DMSO) one or more.
11. methods according to claim 1, is characterized in that: step (c
1) in, reaction system not volume exogenously added alkali or interpolation is selected from one or more alkali in organic bases and mineral alkali.
12. methods according to claim 11, is characterized in that: step (c
1) in, the alkali added in reaction system be selected from triethylamine, pyridine, tri-n-butyl amine, DIPEA, sodium carbonate, sodium bicarbonate, salt of wormwood, saleratus one or more.
13. methods according to claim 1, is characterized in that: step (d
1) in, the oxygenant of use is selected from perosmic anhydride, starve in sour potassium, potassium permanganate, hydrogen peroxide, metachloroperbenzoic acid, peroxyformic acid, Peracetic Acid, peroxy trifluoroacetic acid, peroxy tert-butyl alcohol, sodium periodate, OXONE, ruthenium trichloride, oxygen one or more.
14. methods according to claim 1, is characterized in that: step (a
1) in, by product formula VI compound of generation, the purifying removing of through type III compound,
15. 1 kinds of novel methods preparing Iopromide (formula I), it is characterized in that, reaction formula is as follows:
Comprise the following steps:
Step (a
2): amino-2,4,6-triiodo m-phthalic acid dichloride (formula II) of 5-is obtained by reacting 5-amino-3-allyl amino formyl radical-2,4,6-phenyl triiodide formyl chloride (formula III) with allylamine;
Step (b
2): 5-amino-3-allyl amino formyl radical-2,4,6-phenyl triiodide formyl chloride (formula III) and methoxyacetyl chloride are obtained by reacting 5-methoxyacetyl amino-3-allyl amino formyl radical-2,4,6-phenyl triiodide formyl chloride (formula IV-1);
Step (c
2): 5-methoxyacetyl amino-3-allyl amino formyl radical-2,4,6-phenyl triiodide formyl chloride (formula IV-1) and N-methyl allyl amine are obtained by reacting 5-methoxyacetyl Amino-N-methyl-N, N '-diallyl-2,4,6-triiodo isophtalamide (formula V);
Step (d
2): 5-methoxyacetyl Amino-N-methyl-N, N '-diallyl-2,4,6-triiodo isophtalamide (formula V) obtains Iopromide (formula I) through peroxidation.
16. methods according to claim 15, is characterized in that: step (b
2) in, the compound of formula III and the methoxyacetyl chloride of 1.0-6.0 equivalent react.
17. methods according to claim 15, is characterized in that: step (b
2) in, the solvent used is selected from N, one or more in dinethylformamide, N,N-dimethylacetamide, tetrahydrofuran (THF), acetone, toluene, N-Methyl pyrrolidone, dioxane, ethyl acetate, methylene dichloride, chloroform, acetonitrile, dimethyl sulfoxide (DMSO).
18. methods according to claim 15, is characterized in that: step (c
2) in, the compound of formula IV-1 and the N-methyl allyl amine of 1.0-6.0 equivalent react.
19. methods according to claim 15, is characterized in that: step (c
2) in, the solvent used is selected from N, one or more in dinethylformamide, N,N-dimethylacetamide, tetrahydrofuran (THF), acetone, toluene, N-Methyl pyrrolidone, dioxane, ethyl acetate, acetonitrile, methylene dichloride, chloroform, dimethyl sulfoxide (DMSO).
20. 1 kinds of novel methods preparing Iopromide (formula I), it is characterized in that, reaction formula is as follows:
Comprise the following steps:
Step (a
3): amino-2,4,6-triiodo m-phthalic acid dichloride (formula II) of 5-is obtained by reacting 5-amino-3-allyl amino formyl radical-2,4,6-phenyl triiodide formyl chloride (formula III) with allylamine;
Step (b
3): 5-amino-3-allyl amino formyl radical-2,4,6-phenyl triiodide formyl chloride (formula III) and methoxyacetyl chloride are obtained by reacting 5-methoxyacetyl amino-3-allyl amino formyl radical-2,4,6-phenyl triiodide formyl chloride (formula IV-1);
Step (c
3): 5-methoxyacetyl amino-3-allyl amino formyl radical-2,4,6-phenyl triiodide formyl chloride (formula IV-1) and 3-methylamino--1,2-propylene glycol is obtained by reacting 5-methoxyacetyl amino-2,4,6-triiodo m-phthalic acid [(allyl amino)-(2,3-dihydroxyl-N-methyl-propyl)] diamide (formula V-1);
Step (d
3): 5-methoxyacetyl amino-2,4,6-triiodo m-phthalic acid [(allyl amino)-(2,3-dihydroxyl-N-methyl-propyl)] diamide (formula V-1) obtains Iopromide (formula I) through peroxidation.
21. methods according to claim 20, is characterized in that: step (c
3) in, the compound of formula IV-1 and the 3-methylamino--1,2-PD of 1.0-6.0 equivalent react.
22. methods according to claim 20, is characterized in that: step (c
3) in, the solvent used is selected from N, one or more in dinethylformamide, N,N-dimethylacetamide, tetrahydrofuran (THF), acetone, toluene, N-Methyl pyrrolidone, dioxane, ethyl acetate, methylene dichloride, chloroform, acetonitrile, dimethyl sulfoxide (DMSO).
23. methods according to claim 20, is characterized in that: step (d
3) in, the oxygenant of use is selected from perosmic anhydride, starve in sour potassium, potassium permanganate, hydrogen peroxide, Peracetic Acid, metachloroperbenzoic acid, peroxyformic acid, peroxy trifluoroacetic acid, peroxy tert-butyl alcohol, sodium periodate, OXONE, ruthenium trichloride, oxygen one or more.
24. 1 kinds of novel methods preparing Iopromide (formula I), it is characterized in that, reaction formula is as follows:
Through following steps:
Step (a
4): 5-methoxyl acetamide base-2,4,6-triiodo m-phthaloyl chloride (formula II) and methoxyacetyl chloride are obtained by reacting 5-methoxyl acetamide base-2,4,6-triiodo m-phthaloyl chloride (formula III-1);
Step (b
4): 5-methoxyl acetamide base-2,4,6-triiodo m-phthaloyl chloride (formula III-1) and allyl amine are obtained by reacting 5-methoxyl acetamide base-3-allyl amino formyl radical-2,4,6-phenyl triiodide formyl chloride (formula IV-1);
Step (c
4): 5-methoxyacetyl amino-3-allyl amino formyl radical-2,4,6-phenyl triiodide formyl chloride (formula IV-1) and N-methacrylic amine are obtained by reacting 5-methoxyacetamido-N-methyl-N, N '-diallyl-2,4,6-triiodo isophtalamide (formula V);
Step (d
4): 5-methoxyacetyl Amino-N-methyl-N, N '-diallyl-2,4,6-triiodo isophtalamide (formula V) obtains Iopromide (formula I) through peroxidation.
25. methods according to claim 24, is characterized in that: step (b
4) in, the compound of formula III-1 and the allyl amine of 0.5-3.5 equivalent react.
26. methods according to claim 25, is characterized in that: step (b
4) in, the compound of formula III-1 and the allyl amine of 0.5-2.5 equivalent react.
27. methods according to claim 24, is characterized in that: step (b
4) in, the solvent of use is selected from methylene dichloride, chloroform, ethyl acetate, toluene, DMF, N,N-dimethylacetamide, one or more in tetrahydrofuran (THF), acetone, acetonitrile, dioxane, dimethyl sulfoxide (DMSO).
28. methods according to claim 24, is characterized in that: step (b
4) in, additionally interpolation alkali or interpolation are selected from one or more alkali in triethylamine, tri-n-butyl amine, pyridine, DIPEA, sodium carbonate, sodium bicarbonate, salt of wormwood, saleratus to reaction system.
29. methods according to claim 24, is characterized in that: step (b
4) in, will in step (b
4) by product formula VII compound that produces, the purifying removing of through type IV-1 compound,
The compound of 30. formulas III is preparing the application in Iopromide,
The compound of 31. formulas IV is preparing the application in Iopromide,
The compound of 32. formulas V is preparing the application in Iopromide,
The compound of 33. formulas IV-1 is preparing the application in Iopromide,
The compound of 34. formulas V-1 is preparing the application in Iopromide,
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410158535.1A CN105001114B (en) | 2014-04-18 | 2014-04-18 | Prepare the new method of Iopromide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410158535.1A CN105001114B (en) | 2014-04-18 | 2014-04-18 | Prepare the new method of Iopromide |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105001114A true CN105001114A (en) | 2015-10-28 |
| CN105001114B CN105001114B (en) | 2018-11-20 |
Family
ID=54374029
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410158535.1A Expired - Fee Related CN105001114B (en) | 2014-04-18 | 2014-04-18 | Prepare the new method of Iopromide |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105001114B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106699594A (en) * | 2016-12-29 | 2017-05-24 | 山东诚汇双达药业有限公司 | Preparation method of iopromide |
| CN114716340A (en) * | 2022-05-10 | 2022-07-08 | 杭州微流汇科技有限公司 | Preparation method of iopromide intermediate |
Citations (7)
| 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 |
| WO2007094683A1 (en) * | 2006-02-15 | 2007-08-23 | Ge Healthcare As | Contrast agents |
| WO2008123779A1 (en) * | 2007-04-04 | 2008-10-16 | Ge Healthcare As | Trisubstituted triazamacrocycli c compounds and their use as contrast agents |
| US20080260651A1 (en) * | 2007-04-17 | 2008-10-23 | Ge Healthcare As | Contrast agents |
| CN101842120A (en) * | 2007-10-30 | 2010-09-22 | 通用电气医疗集团股份有限公司 | Contrast agents |
| CN102964269A (en) * | 2012-11-29 | 2013-03-13 | 浙江海昌药业有限公司 | Novel preparation method of iopromide |
| CN103570580A (en) * | 2012-08-08 | 2014-02-12 | 北京京卫信康医药科技发展有限公司 | Preparation method of high-purity iopromide |
-
2014
- 2014-04-18 CN CN201410158535.1A patent/CN105001114B/en not_active Expired - Fee Related
Patent Citations (7)
| 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 |
| WO2007094683A1 (en) * | 2006-02-15 | 2007-08-23 | Ge Healthcare As | Contrast agents |
| WO2008123779A1 (en) * | 2007-04-04 | 2008-10-16 | Ge Healthcare As | Trisubstituted triazamacrocycli c compounds and their use as contrast agents |
| US20080260651A1 (en) * | 2007-04-17 | 2008-10-23 | Ge Healthcare As | Contrast agents |
| CN101842120A (en) * | 2007-10-30 | 2010-09-22 | 通用电气医疗集团股份有限公司 | Contrast agents |
| CN103570580A (en) * | 2012-08-08 | 2014-02-12 | 北京京卫信康医药科技发展有限公司 | Preparation method of high-purity iopromide |
| CN102964269A (en) * | 2012-11-29 | 2013-03-13 | 浙江海昌药业有限公司 | Novel preparation method of iopromide |
Non-Patent Citations (2)
| Title |
|---|
| 王哲等: "碘普罗胺的合成", 《中国医药工业杂志》 * |
| 赵文龙: "碘普罗胺合成路线图解", 《淮海工学院学报（自然科学版）》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106699594A (en) * | 2016-12-29 | 2017-05-24 | 山东诚汇双达药业有限公司 | Preparation method of iopromide |
| CN114716340A (en) * | 2022-05-10 | 2022-07-08 | 杭州微流汇科技有限公司 | Preparation method of iopromide intermediate |
| CN114716340B (en) * | 2022-05-10 | 2023-11-14 | 杭州微流汇科技有限公司 | Preparation method of iopromide intermediate |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105001114B (en) | 2018-11-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102295672B (en) | Synthetic method for tylosin | |
| CN106349245B (en) | A kind of phosphoric acid Xi Gelieting impurity and its preparation method and application | |
| CN100528839C (en) | Ionic liquid of alkyl guanidine salt and its preparation process | |
| CN105753888A (en) | Preparation method for free-state edoxaban | |
| CN103382160B (en) | The synthesis of Iopamidol and its preparation of synthetic intermediate | |
| CN105056991B (en) | The chiral phosphazene catalyst of the spirocyclic ring scaffold based on chiral diamine, preparation method and applications | |
| CN103864898A (en) | Preparation method of kyprolis | |
| CN102351735B (en) | Preparation method of Iopromide | |
| CN104650142A (en) | Preparation method of fosaprepitant dimeglumine | |
| CN105254721B (en) | Purification and salt conversion method of micafungin | |
| CN105001114A (en) | New method for preparing iopromide | |
| CN104592081B (en) | A kind of synthetic method of aztreonam main ring | |
| CN107056722A (en) | A kind of method for preparing Parecoxib Sodium | |
| CN106279175A (en) | A kind of preparation method of Ertapenem Sodium | |
| CN105859747B (en) | A kind of preparation method of cefepime Hydrochloride suitable for industrialized production | |
| CN106699604A (en) | Sacubitril and preparation method of midbody of sacubitril | |
| CN103864889A (en) | Epoxy ketone compound, preparation method thereof and preparation method of kyprolis | |
| CN105017062A (en) | New method for preparing iopromide | |
| CN105968040A (en) | Preparation method of ledipasvir intermediate | |
| CN114409727A (en) | Preparation method of anti-coronavirus 3CLPRO inhibitor | |
| CN100390180C (en) | Clopidogrel and its salt preparing method | |
| CN109836360B (en) | Preparation method of edoxaban tosylate intermediate and intermediate compound | |
| CN106632594A (en) | Pidotimod synthesis method | |
| AU2021297767A1 (en) | Preparation method for aromatic ether compound | |
| CN106977543A (en) | The preparation technology of improved Suo Feibuwei intermediates |
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 | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20181120 Termination date: 20210418 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |