CN110054571A - The different peptide chloride derivative of 5- amino -2,4,6- triiodo and its application in synthesis Iopamidol impurity - Google Patents
The different peptide chloride derivative of 5- amino -2,4,6- triiodo and its application in synthesis Iopamidol impurity Download PDFInfo
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- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to an acyclic carbon atom of a hydrocarbon radical substituted by oxygen atoms
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Abstract
The present invention relates to a kind of production method of Iopamidol impurity, in particular to a kind of 5- amino -2,4, the different peptide chloride derivative of 6- triiodo and its synthesis Iopamidol impurity in application, belong to pharmaceutical technology field.A kind of 5- amino -2,4, the different peptide chloride derivative of 6- triiodo, the structural formula of the compound are shown in formula 1:
Description
Technical field
The present invention relates to a kind of production method of Iopamidol impurity, in particular to a kind of 5- amino -2,4, the different peptide of 6- triiodo
Chloride derivative and its application in synthesis Iopamidol impurity, belong to pharmaceutical technology field.
Background technique
Iopamidol is one of the nonionic x-ray contrast agent being most widely used at present, impurity D, impurity F, impurity G
Control is required in European Pharmacopoeia and United States Pharmacopeia with impurity J within 0.1%, self-structure difference is as follows:
During synthesizing Iopamidol, 2 compound of formulaThere are 1 and 3 two in the structure
Acid chloride groups, therefore, in subsequent reaction process, 1 and 3 acyl chlorides can generate by-product because of access different structure,
These by-products form corresponding impurity D, F, G and J by subsequent removing acetyl group.These types of impurity is in the synthesis process
It is difficult to control, and is difficult to completely remove in subsequent purification process, therefore can remain in Iopamidol product and influence product quality.
So specification ground carries out miscellaneous Quality Research, and controlled within a safety, reasonable limits, will be directly related to
The quality and safety of Iopamidol.Significant for the synthesis of Iopamidol impurity, it can be used for impurity in Iopamidol production
Qualitative and quantitative analysis provide important finger so as to improve the quality standard of Iopamidol for people's masses'safety medication
Lead meaning.
Summary of the invention
The purpose of the present invention is to provide a kind of 5- amino -2,4, the different peptide chloride derivative of 6- triiodo is with the compound
Starting material can be used for synthesizing Iopamidol impurity D, impurity F, impurity G or impurity J.
The technical solution adopted by the present invention to solve the technical problems is:
A kind of 5- amino -2,4, the different peptide chloride derivative of 6- triiodo, the structural formula of the compound are shown in formula 1:Formula 1.The present invention is synthesized by starting material of 5- amino -1,3- hexichol list formyl chloride
1 compound of key intermediate formula prepares Iopamidol impurity D, impurity by the intermediate and different material aminolysis or hydrolysis
F, impurity G, impurity J.
A kind of 5- amino -2,4, the synthetic method of the different peptide chloride derivative of 6- triiodo, this method is with 5- amino -
1,3- phthalyl chloride (formula 2) and 2 (S) -2- acetoxyl group propionyl chlorides (formula 5) are that raw material prepares 3 compound of intermediate formula, formula 3
Compound is reacted with serinol (formula 6) again is made 4 compound of formula, and 4 compound of formula reacts to obtain 1 compound of formula through aceticanhydride, above-mentioned
The synthetic route of reaction is
Preferably, this method comprises the following steps:
(1) 3 compound of formula is synthesized
The iodo- 1,3- phthalyl chloride of 5- amino -2,4,6- three is placed in a reaction flask with anhydrous DMAC N,N' dimethyl acetamide
It is uniformly mixed, ice bath is cooled to 0-5 DEG C, and 2 (S) -2- acetoxyl group propionyl chlorides are slowly added dropwise, protect at 15-20 DEG C after dripping
Temperature reaction, methylene chloride is added after reaction, successively washes, and saturated common salt washing separates organic phase, is concentrated to give 3 chemical combination of formula
Object；
(2) 4 compound of formula is synthesized
3 compound of formula is added in reaction flask, sequentially adds n,N-dimethylacetamide and methylene chloride, 5-10 DEG C is stirred
It mixes, triethylamine is added, serinol is dissolved in n,N-dimethylacetamide solution, is slowly added dropwise into reaction solution, is dripped, instead
It answers liquid to be warming up to 20-30 DEG C and continues stirring 20-30 hours, reaction is finished, and with sulfuric acid tune pH, water washing collects organic phase, it is concentrated,
Obtain 4 compound concentrate of formula；
(3) 1 compound of formula is synthesized
4 compound of formula is added in reaction flask, ethyl acetate and 4-dimethylaminopyridine (DMAP) are sequentially added, vinegar is added dropwise
Acid anhydride is warming up to 60-80 DEG C of reaction, and reaction finishes, is cooled to 20-30 DEG C and is washed with water, and collects organic phase, and dry, cooling crystallization obtains
1 compound solid of formula.
Preferably, 5- amino -2,4 in step (1), iodo- 1, the 3- phthalyl chloride of 6- tri- and anhydrous N, N- dimethyl
The mass volume ratio of acetamide is 1g:2.0~2.5ml, 5- amino -2,4, iodo- 1, the 3- phthalyl chloride of 6- tri- and 2 (S) -2- second
The molar ratio of acyloxy propionyl chloride is 1.0:2.0~2.5；The volume ratio of the methylene chloride and anhydrous DMAC N,N' dimethyl acetamide
Are as follows: 1:2~3.
3 compound of formula and the mass volume ratio of DMAC N,N' dimethyl acetamide and methylene chloride in the step (2) are
1g:0.5~1.0ml:3.0~4.0ml；The mass volume ratio of the serinol and DMAC N,N' dimethyl acetamide be 1g:10~
15ml；The molar ratio of formula 3 compound and triethylamine are as follows: 1:0.8~1.0.
The mass volume ratio of 4 compound of formula and ethyl acetate in the step (3) is 1g:2.0~3.0ml；It is described
The dosage of DMAP is the 0.05%~0.1% of 4 compound quality of formula；The molar ratio of formula 4 compound and aceticanhydride are as follows: 1:2.5
~3.0.
The different peptide chloride derivative of 5- amino -2,4,6- triiodo described in a kind of is in synthesis Iopamidol impurity D, impurity F, impurity
Application in G or impurity J.
A kind of synthetic method of Iopamidol impurity D, this method are using 1 compound of formula as raw material, after reacting with sodium hydroxide
Acyl chlorides is hydrolyzed into carboxylic acid, and acetoxyl group is hydrolyzed into hydroxyl, and resin separation purification obtains Iopamidol impurity D.
Preferably, comprising the concrete steps that: pure water, 1 compound of formula and two is added in 1 compound of formula after dissolving in methylene chloride
The mass volume ratio of chloromethanes and pure water be 1g:3~5ml:3~5ml, be added dropwise 20% sodium hydroxide solution, 1 compound of formula with
The molar ratio of sodium hydroxide is 1:4~4.5, keeps the temperature 20-30 DEG C of reaction, and it is 6-7 with 10% hydrochloric acid tune pH that reaction, which is finished, and layering obtains
Impurity D is obtained after resin cation and resin anion (R.A.) desalination to water layer.
Synthetic route is
A kind of synthetic method of Iopamidol impurity F (9 compound of formula), this method is first passed through using 1 compound of formula as raw material
Then 8 compound intermediate of amidation process production generates Iopamidol impurity F by hydrolysis；It comprises the concrete steps that:
(1) 8 compound of formula is synthesized
N,N-dimethylacetamide solution and triethylamine is added into reaction flask in 1 compound of addition formula, and ice bath cools down,
Keep the temperature 0-10 DEG C of 40% dimethylamine agueous solution of dropwises addition, the molar ratio of 1 compound of formula and dimethylamine is 1:1.0~1.5, drip off it is complete,
It is warming up to 20-30 DEG C of reaction, HPLC detects end of reaction, and filtering is added isopropanol after filtrate decompression concentration, flows back 2-4 hours
After be cooled to 20-30 DEG C, be slowly added dropwise acetone, the volume ratio of acetone and isopropanol is 1.5~2.5:1,20-30 DEG C of stirring 1-2
Hour, filtering, dry 8 compound of formula；
(2) 9 compound of formula is synthesized
8 compound of addition formula is added methylene chloride and dissolution is stirred at room temperature, add pure water, be added dropwise 50% into reaction flask
Sodium hydroxide, the mass volume ratio of 8 compound of formula and methylene chloride and pure water is 1g:3~5ml:3~5ml, 8 chemical combination of formula
The molar ratio of object and sodium hydroxide is 1:3~3.5, and 20-30 DEG C of reaction is added dropwise, and HPLC tracing detection end of reaction is used
10% hydrochloric acid tune pH is 6-7, and layering obtains water layer, after resin cation and resin anion (R.A.) desalination, is concentrated under reduced pressure, adds
Enter pure water recrystallization, obtains white solid impurity F；
Synthetic route is
A kind of synthetic method of Iopamidol impurity G (11 compound of formula), this method is first passed through using 1 compound of formula as raw material
Superamideization reacts 10 compound intermediate of production, then generates Iopamidol impurity G by hydrolysis；It comprises the concrete steps that:
(1) 10 compound of formula is synthesized
1 compound of formula is added in reaction flask, n,N-dimethylacetamide solution and triethylamine is added, ice bath cools down,
The mass volume ratio for keeping the temperature 0-10 DEG C of dropwise addition amino-glycerol, 1 compound of formula and n,N-dimethylacetamide and triethylamine is 1g:
The molar ratio of 0.8~1.0ml:1~3ml, 1 compound of formula and amino-glycerol is 1:1~1.5, drips off complete, is warming up to 20-30 DEG C
Reaction, HPLC detect end of reaction, and after filtrate decompression concentration, isopropanol is added in filtering, and reflux was cooled to 20-30 after 2-4 hours
DEG C, 20-30 DEG C stirring 1-2 hours, filtering, dry 10 compound solid of formula；
(2) 11 compound of formula is synthesized
10 compound of formula is added in reaction flask, methylene chloride is added, dissolution is stirred at room temperature, add pure water, be added dropwise 50%
Sodium hydroxide, the mass volume ratio of 10 compound of formula and methylene chloride and pure water is 1g:3~5ml:3~5ml, and formula 10 is changed
The molar ratio for closing object and sodium hydroxide is 1:3~3.5, and 20-30 DEG C of reaction is added dropwise, and HPLC tracing detection end of reaction is used
10% hydrochloric acid tune pH is 5-6, and layering obtains water layer, after resin cation and resin anion (R.A.) desalination, is concentrated under reduced pressure, it obtains
To white solid impurity G；
Synthetic route is
A kind of synthetic method of Iopamidol impurity J (Formula 13), this method comprises the following steps:
(1) 12 compound of formula is synthesized
1 compound of formula is added in reaction flask, the triethylamine in n,N-dimethylacetamide solution is added, ice bath cools down,
The mass volume ratio for keeping the temperature 0-10 DEG C of dropwise addition ethanol amine, 1 compound of formula and n,N-dimethylacetamide and triethylamine is 1g:
The molar ratio of 0.8~1.0ml:1~3ml, 1 compound of formula and ethanol amine is 1:1~1.5, drip off it is complete, be warming up to 20-30 DEG C it is anti-
It answers, HPLC detects end of reaction, and after filtrate decompression concentration, isopropanol is added in filtering, and reflux was cooled to 20-30 after 2-4 hours
DEG C, 20-30 DEG C stirring 1-2 hours, filtering, dry 12 compound of formula；
(2) 13 compound of formula is synthesized
12 compound of formula is added in reaction flask, methylene chloride is added, dissolution is stirred at room temperature, add pure water, be added dropwise 50%
Sodium hydroxide, the mass volume ratio of 12 compound of formula and methylene chloride and pure water is 1g:3~5ml:3~5ml, and formula 12 is changed
The molar ratio for closing object and sodium hydroxide is 1:3~3.5, and 20-30 DEG C of reaction is added dropwise, and HPLC tracing detection end of reaction is used
10% hydrochloric acid tune pH is 5-6, and layering obtains water layer, after resin cation and resin anion (R.A.) desalination, is concentrated under reduced pressure, obtains
To white solid impurity J.
Synthetic route:
The beneficial effects of the present invention are: 5- amino -2,4 of the present invention, the different peptide chloride derivative of 6- triiodo, with the change
Closing object is that starting material can be used for synthesizing Iopamidol impurity D, impurity F, impurity G or impurity J, so that the quality for Iopamidol controls
Qualified reference substance is provided.
Specific embodiment
Below by specific embodiment, technical scheme of the present invention will be further explained in detail.It should be appreciated that this hair
Bright implementation is not limited by the following examples, and the accommodation in any form made to the present invention and/or changed will all be fallen
Enter the scope of the present invention.
In the present invention, if not refering in particular to, all parts, percentage are unit of weight, used equipment and raw material etc.
It is commercially available or commonly used in the art.Method in following embodiments is unless otherwise instructed the normal of this field
Rule method.
Embodiment 1: the synthesis of 1 compound of formula
(1) (the change of formula 3 of the iodo- 1,3- phthalyl chloride of 5- [(2 (S) -2- acetoxyl group propionyl) amino] -2,4,6- three is synthesized
Close object)
It is 1 according to the iodo- 1,3- phthalyl chloride of 5- amino -2,4,6- three and 2 (S) -2- acetoxyl group propionyl cl molar ratios:
2, by 30g 5- amino -2,4, iodo- 1, the 3- phthalyl chloride of 6- tri- is placed in the reaction flask of 250ml, is added under nitrogen protection
60mL n,N-dimethylacetamide is stirred at room temperature to being completely dissolved, and is cooled to 0-5 DEG C and keeps the temperature, and 15g 2 (S)-is slowly added dropwise
2- acetoxyl group propionyl chloride, is added dropwise, and warms naturally to 15-20 DEG C of insulation reaction 30-40 hours, and 150mL dichloromethane is added
Alkane stirs 3-5 minutes, three times, then with each 200mL saturated common salt water washing 2 times with the water washing of each 300mL, has separated
Machine phase, is concentrated to dryness, and 90mL isopropanol stirring and crystallizing is added, and filters, dry, obtains 32g off-white color 5- [(2 (S) -2- acetyl
Oxygroup propionyl) amino] -2,4,6- tri- iodo- 1,3- phthalyl chlorides, yield 91%, HPLC detection purity 95%.
(2) 1- [2- hydroxyl -1- (methylol) ethyl] -3- [chlorobenzoyl chloride] -5- [(2 (S) -2- acetoxyl groups third are synthesized
Acyl) amino] three iodo- benzamide (4 compound of formula) of -2,4,6-
According to the iodo- 1,3- phthalyl chloride of 5- [(2 (S) -2- acetoxyl group propionyl) amino] -2,4,6- three and triethylamine,
The molar ratio 1:1:0.9 of serinol, by 15g 5- [(2 (S) -2- acetoxyl group propionyl) amino] -2,4,6- tri- iodo- 1,3- benzene two
Formyl chloride is placed in 250mL reaction flask, sequentially adds 11mL n,N-dimethylacetamide and the methylene chloride of 60mL, and 5-10 DEG C
2.4g triethylamine is added in stirring, and 2.1g serinol is dissolved in 30mLN, in N- dimethylacetamide solution, is slowly added dropwise to reaction
It in liquid, drips, reaction solution rises 20-30 DEG C and continues stirring 20-30 hours, and HPLC detects end of reaction, with sulfuric acid tune pH to 1-
3, each 200mL is washed twice, and collects organic phase, is concentrated under reduced pressure, is obtained a 1- [2- hydroxyl -1- (methylol) ethyl] -3- [benzene first
Acyl chlorides] -5- [(2 (S) -2- water 200mL wash acetoxyl group propionyl) amino] -2,4,6- tri- iodo- benzamide liquid, for next
Step reaction.
(3) 1- [2- glycolyl -1- (hydroxyl acetonyl) ethyl] -3- [chlorobenzoyl chloride] -5- [(2 (S) -2- acetyl are synthesized
Oxygroup propionyl) amino] three iodo- benzamide (1 compound of formula) of -2,4,6-
According to 1- [2- hydroxyl -1- (methylol) ethyl] -3- [chlorobenzoyl chloride] -5- [(2 (S) -2- acetoxyl group propionyl) ammonia
Base] -2,4,6- tri- iodo- benzamides and aceticanhydride molar ratio be 1:3, by 15g1- [2- hydroxyl -1- (methylol) ethyl] -3-
The iodo- benzamide of [chlorobenzoyl chloride] -5- [(2 (S) -2- acetoxyl group propionyl) amino] -2,4,6- three is placed in 250mL reaction flask
In, 60mL ethyl acetate and 0.2gDMAP are sequentially added, 10-30 DEG C is added dropwise to 6g aceticanhydride, keeps the temperature 30 minutes, is warming up to 60-80
DEG C, it reacts 20-40 hours, HPLC detects raw material end of reaction, stops reaction, is cooled to 20-30 DEG C, each 200mL water washing
Twice, it collects organic phase to be cooled to 0-10 DEG C after dry and precipitate crystal, obtains 1- [2- glycolyl -1- (hydroxyl acetyl after dry
Methyl) ethyl] three iodo- benzamide solid of -3- [chlorobenzoyl chloride] -5- [(2 (S) -2- acetoxyl group propionyl) amino] -2,4,6-
(9.73g, yield 54.08%, HPLC purity 99.1%).
Obtained solid product is analyzed by mass spectrometry, MS (m/z): ES is obtained+847.9[M+Na+].1H-NMR: δ H
(300MHz, DMSO-d6) 1.52 (d, J=6.9,3H), 1.58 (S, 3H), 2.01 (S, 3H), 4.34 (m, 2H), 4.78 (m,
2H), 5.08 (S, 1H), 8.0 (1H).
Embodiment 2: the synthesis of Iopamidol impurity D
According to 1- [2- glycolyl -1- (hydroxyl acetonyl) ethyl] -3- [chlorobenzoyl chloride] -5- [(2 (S) -2- acetyl oxygen
Base propionyl) amino] -2,4,6- tri- iodo- benzamides and sodium hydroxide molar ratio be 1:5, by 15g1- [2- glycolyl -1-
(hydroxyl acetonyl) ethyl] three iodo- benzene first of -3- [chlorobenzoyl chloride] -5- [(2 (S) -2- acetoxyl group propionyl) amino] -2,4,6-
Amide is put into 250mL reaction flask, 60mL methylene chloride is added, dissolution is stirred at room temperature, add 60mL pure water, 17.7mL is added dropwise
20% sodium hydroxide, is added dropwise 20-30 DEG C of reaction, and HPLC tracing detection end of reaction is 6- with 10% hydrochloric acid tune pH
7, layering obtains water layer, after resin cation and resin anion (R.A.) desalination, obtains impurity D, yield 70%, HPLC detection
Purity 97.4%.
Embodiment 3: the synthesis of Iopamidol impurity F
(1) according to 1 compound of formula and triethylamine, molar ratio 1:1.2:1.6, the 1 compound 18g of formula of addition of dimethylamine,
20mLN is added, the triethylamine of 3.3mL in N- dimethylacetamide solution, ice bath cooling keeps the temperature 0-10 DEG C of dropwise addition 3.6g40% bis-
Methylamine water solution, drips off complete, is warming up to 20-30 DEG C of reaction, HPLC detects end of reaction, and filtering is added after filtrate decompression concentration
30mL isopropanol, reflux are cooled to 20-30 DEG C after 2-4 hours, are slowly added dropwise 60mL acetone, 20-30 DEG C stirring 1-2 hours, mistake
Filter, dry 12g N- [N, N '-dimethyl]-N '-[2- glycolyl -1- (hydroxyl acetonyl) ethyl] -5- [(2 (S) -2- second
Acyloxy propionyl) amino] three iodo- 1,3- benzenedicarboxamide of -2,4,6-.
(2) according to N- [N, N '-dimethyl]-N '-[2- glycolyl -1- (hydroxyl acetonyl) ethyl] -5- [(2 (S) -2-
Acetoxyl group propionyl) amino] -2,4,6- tri- iodo- 1,3- benzenedicarboxamides and sodium hydroxide molar ratio be 1:4, by 15g N- [N,
N '-dimethyl]-N '-[2- glycolyl -1- (hydroxyl acetonyl) ethyl] -5- [(2 (S) -2- acetoxyl group propionyl) amino] -
In 2,4,6- tri- iodo- 1,3- benzenedicarboxamides investment 250mL reaction flasks, 60mL methylene chloride is added and is stirred at room temperature dissolution, then plus
Enter 60mL pure water, the sodium hydroxide of 14mL 50% is added dropwise, is added dropwise 20-30 DEG C of reaction, HPLC tracing detection end of reaction,
It is 6-7 with 10% hydrochloric acid tune pH, layering obtains water layer, after resin cation and resin anion (R.A.) desalination, it is concentrated under reduced pressure,
30mL pure water recrystallization is added, obtains 12g white solid impurity F, yield 87%, HPLC detects purity 97.3%.
Embodiment 4: Iopamidol impurity G synthesis
(1) according to the molar ratio 1:1.2:1.3 of 1 compound of formula and triethylamine, amino-glycerol, 1 compound of formula of addition
20mLN is added in 18g, the triethylamine of 3.3mL in N- dimethylacetamide solution, and ice bath cooling keeps the temperature 0-10 DEG C of dropwise addition 2.5g ammonia
Base glycerol, drips off complete, is warming up to 20-30 DEG C of reaction, HPLC detects end of reaction, and 40mL is added after filtrate decompression concentration in filtering
Isopropanol, reflux are cooled to 20-30 DEG C after 2-4 hour, 20-30 DEG C stirring 1-2 hours, filter, dry 13g N- [N, N '-
Dimethyl]-N '-[2- glycolyl -1- (hydroxyl acetonyl) ethyl] -5- [(2 (S) -2- acetoxyl group propionyl) amino] -2,4,
Iodo- 1, the 3- benzenedicarboxamide of 6- tri-, yield 82%.
(2) according to N- [2,3- dihydroxypropyl]-N '-[2- glycolyl -1- (hydroxyl acetonyl) ethyl] -5- [(2
(S) -2- acetoxyl group propionyl) amino] -2,4,6- tri- iodo- 1,3- benzenedicarboxamides and sodium hydroxide molar ratio be 1:4, by 15g
N- [2,3- dihydroxypropyl]-N '-[2- glycolyl -1- (hydroxyl acetonyl) ethyl] -5- [(2 (S) -2- acetoxyl groups third
Acyl) amino] in -2,4,6- tri- iodo- 1,3- benzenedicarboxamides investment 250mL reaction flasks, 60mL methylene chloride is added and is stirred at room temperature
Dissolution adds 60mL pure water, and the sodium hydroxide of 14mL 50% is added dropwise, 20-30 DEG C of reaction, HPLC tracing detection is added dropwise
End of reaction is 5-6 with 10% hydrochloric acid tune pH, and layering obtains water layer, after resin cation and resin anion (R.A.) desalination,
It is concentrated under reduced pressure, obtains 10.3g white solid impurity G, yield 73%, HPLC detects purity 95.6%.
Embodiment 5: Iopamidol impurity J synthesis
(1) according to 1 compound of formula and triethylamine, molar ratio 1:1.2:1.3, the 1 compound 18g of formula of addition of ethanol amine,
20mLN is added, the triethylamine of 3.3mL in N- dimethylacetamide solution, ice bath cooling keeps the temperature 0-10 DEG C of dropwise addition 1.7g ethyl alcohol
Amine, drips off complete, is warming up to 20-30 DEG C of reaction, HPLC detects end of reaction, and 40mL isopropyl is added after filtrate decompression concentration in filtering
Alcohol, reflux are cooled to 20-30 DEG C after 2-4 hour, 20-30 DEG C stirring 1-2 hours, filter, dry 9.5g N- [2- hydroxyl second
Amine]-N '-[2- glycolyl -1- (hydroxyl acetonyl) ethyl] -5- [(2 (S) -2- acetoxyl group propionyl) amino] -2,4,6- three
Iodo- 1,3- benzenedicarboxamide, yield 60%.
(2) according to N- [colamine]-N '-[2- glycolyl -1- (hydroxyl acetonyl) ethyl] -5- [(2 (S) -2- second
Acyloxy propionyl) amino] -2,4,6- tri- iodo- 1,3- benzenedicarboxamides and sodium hydroxide molar ratio be 1:4, by 15g N- [2- hydroxyl
Ethamine]-N '-[2- glycolyl -1- (hydroxyl acetonyl) ethyl] -5- [(2 (S) -2- acetoxyl group propionyl) amino] -2,4,6-
In three iodo- 1,3- benzenedicarboxamide investment 250mL reaction flasks, 60mL methylene chloride is added, dissolution is stirred at room temperature, add 60mL
Pure water is added dropwise the sodium hydroxide of 14mL 50%, 20-30 DEG C of reaction, HPLC tracing detection end of reaction, with 10% is added dropwise
Hydrochloric acid tune pH be 5-6, layering, obtain water layer, after resin cation and resin anion (R.A.) desalination, be concentrated under reduced pressure, obtain 10g
White solid impurity J, yield 71%, HPLC detect purity 95.8%.
Embodiment 6: the synthesis of 1 compound of formula
(1) (the change of formula 3 of the iodo- 1,3- phthalyl chloride of 5- [(2 (S) -2- acetoxyl group propionyl) amino] -2,4,6- three is synthesized
Close object)
It is 1 according to the iodo- 1,3- phthalyl chloride of 5- amino -2,4,6- three and 2 (S) -2- acetoxyl group propionyl cl molar ratios:
2.2, by 30g 5- amino -2,4, iodo- 1, the 3- phthalyl chloride of 6- tri- is placed in the reaction flask of 250ml, is added under nitrogen protection
60mL n,N-dimethylacetamide is stirred at room temperature to being completely dissolved, and is cooled to 0-5 DEG C and keeps the temperature, and 16.5g 2 is slowly added dropwise
(S) -2- acetoxyl group propionyl chloride, is added dropwise, and warms naturally to 15-20 DEG C of insulation reaction 30-40 hours, and 150mL bis- is added
Chloromethanes stirs 3-5 minute, three times with the water washing of each 300mL, then with each 200mL saturated common salt water washing 2 times, divides
Organic phase out is concentrated to dryness, and 90mL isopropanol stirring and crystallizing is added, and is filtered, dry, obtains 32g off-white color 5- [(2 (S) -2-
Acetoxyl group propionyl) amino] -2,4,6- tri- iodo- 1,3- phthalyl chlorides, yield 92.3%, HPLC detection purity 95%.
(2) 1- [2- hydroxyl -1- (methylol) ethyl] -3- [chlorobenzoyl chloride] -5- [(2 (S) -2- acetoxyl groups third are synthesized
Acyl) amino] three iodo- benzamide (4 compound of formula) of -2,4,6-
According to the iodo- 1,3- phthalyl chloride of 5- [(2 (S) -2- acetoxyl group propionyl) amino] -2,4,6- three and triethylamine,
The molar ratio 1:1:0.85 of serinol, by 15g 5- [(2 (S) -2- acetoxyl group propionyl) amino] -2,4,6- tri- iodo- 1,3- benzene
Dimethyl chloride is placed in 250mL reaction flask, sequentially adds 11mL n,N-dimethylacetamide and the methylene chloride of 60mL, 5-10
DEG C stirring, is added 2.4g triethylamine, 1.98g serinol is dissolved in 30mLN, in N- dimethylacetamide solution, be slowly added dropwise to
It in reaction solution, drips, reaction solution rises 20-30 DEG C and continues stirring 20-30 hours, and HPLC detects end of reaction, with sulfuric acid tune pH
To 1-3, each 200mL is washed twice, and collects organic phase, is concentrated under reduced pressure, is obtained a 1- [2- hydroxyl -1- (methylol) ethyl] -3-
[chlorobenzoyl chloride] -5- [(2 (S) -2- water 200mL wash acetoxyl group propionyl) amino] -2,4,6- tri- iodo- benzamide liquid are used
It is reacted in next step.
(3) 1- [2- glycolyl -1- (hydroxyl acetonyl) ethyl] -3- [chlorobenzoyl chloride] -5- [(2 (S) -2- acetyl are synthesized
Oxygroup propionyl) amino] three iodo- benzamide (1 compound of formula) of -2,4,6-
According to 1- [2- hydroxyl -1- (methylol) ethyl] -3- [chlorobenzoyl chloride] -5- [(2 (S) -2- acetoxyl group propionyl) ammonia
Base] -2,4,6- tri- iodo- benzamides and aceticanhydride molar ratio be 1:3, by 15g1- [2- hydroxyl -1- (methylol) ethyl] -3-
The iodo- benzamide of [chlorobenzoyl chloride] -5- [(2 (S) -2- acetoxyl group propionyl) amino] -2,4,6- three is placed in 250mL reaction flask
In, 60mL ethyl acetate and 0.2gDMAP are sequentially added, 10-30 DEG C is added dropwise to 6g aceticanhydride, keeps the temperature 30 minutes, is warming up to 60-80
DEG C, it reacts 20-40 hours, HPLC detects raw material end of reaction, stops reaction, is cooled to 20-30 DEG C, each 200mL water washing
Twice, it collects organic phase to be cooled to 0-10 DEG C after dry and precipitate crystal, obtains 1- [2- glycolyl -1- (hydroxyl acetyl after dry
Methyl) ethyl] three iodo- benzamide solid of -3- [chlorobenzoyl chloride] -5- [(2 (S) -2- acetoxyl group propionyl) amino] -2,4,6-
(9.86g, yield 54.78%, HPLC purity 99.0%).
Above-mentioned embodiment is only a preferred solution of the present invention, not the present invention is made in any form
Limitation, there are also other variations and modifications on the premise of not exceeding the technical scheme recorded in the claims.
Claims (10)
1. a kind of 5- amino -2,4, the different peptide chloride derivative of 6- triiodo, it is characterised in that the structural formula of the compound is shown in formula 1:
2. a kind of 5- amino -2,4 described in claim 1, the synthetic method of the different peptide chloride derivative of 6- triiodo, feature exist
In: this method is with 5- amino -1,3- phthalyl chloride (formula 2) and 2 (S) -2- acetoxyl group propionyl chlorides (formula 5) for raw material preparation
3 compound of intermediate formula, 3 compound of formula is reacted with serinol (formula 6) again is made 4 compound of formula, and 4 compound of formula is reacted through aceticanhydride
1 compound of formula is obtained, the synthetic route of above-mentioned reaction is
3. synthetic method according to claim 2, it is characterised in that this method comprises the following steps:
(1) 3 compound of formula is synthesized
The iodo- 1,3- phthalyl chloride of 5- amino -2,4,6- three is placed in a reaction flask with anhydrous DMAC N,N' dimethyl acetamide and is mixed
Uniformly, ice bath is cooled to 0-5 DEG C, and 2 (S) -2- acetoxyl group propionyl chlorides are slowly added dropwise, and keeps the temperature at 15-20 DEG C after dripping anti-
It answers, methylene chloride is added after reaction, successively washes, saturated common salt washing separates organic phase, is concentrated to give 3 compound of formula；
(2) 4 compound of formula is synthesized
3 compound of formula is added in reaction flask, n,N-dimethylacetamide and methylene chloride are sequentially added, 5-10 DEG C of stirring adds
Enter triethylamine, serinol is dissolved in n,N-dimethylacetamide solution, is slowly added dropwise into reaction solution, is dripped, reaction solution
It is warming up to 20-30 DEG C and continues stirring 20-30 hours, reaction is finished, and with sulfuric acid tune pH, water washing collects organic phase, and concentration obtains formula 4
Compound concentrate；
(3) 1 compound of formula is synthesized
4 compound of formula is added in reaction flask, ethyl acetate and 4-dimethylaminopyridine (DMAP) are sequentially added, aceticanhydride is added dropwise,
It is warming up to 60-80 DEG C of reaction, reaction finishes, is cooled to 20-30 DEG C and is washed with water, and collects organic phase, and dry, cooling crystallization obtains formula 1
Compound solid.
4. synthetic method according to claim 3, it is characterised in that:
The mass body of 5- amino -2,4,6- three iodo- 1,3- phthalyl chloride and anhydrous DMAC N,N' dimethyl acetamide in step (1)
Product is than being 1g:2.0~2.5ml, 5- amino -2,4,6- tri- iodo- 1,3- phthalyl chloride and 2 (S) -2- acetoxyl group propionyl chlorides
Molar ratio is 1.0:2.0~2.5；The volume ratio of the methylene chloride and anhydrous DMAC N,N' dimethyl acetamide are as follows: 1:2~3.
The mass volume ratio of 3 compound of formula and DMAC N,N' dimethyl acetamide and methylene chloride in the step (2) is 1g:
0.5~1.0ml:3.0~4.0ml；The mass volume ratio of the serinol and DMAC N,N' dimethyl acetamide is 1g:10~15ml；
The molar ratio of formula 3 compound and triethylamine are as follows: 1:0.8~1.0.
The mass volume ratio of 4 compound of formula and ethyl acetate in the step (3) is 1g:2.0~3.0ml；The DMAP's
Dosage is the 0.05%~0.1% of 4 compound quality of formula；The molar ratio of formula 4 compound and aceticanhydride are as follows: 1:2.5~3.0.
5. a kind of different peptide chloride derivative of 5- amino -2,4,6- triiodo described in claim 1 is in synthesis Iopamidol impurity D, miscellaneous
Application in matter F, impurity G or impurity J.
6. a kind of synthetic method of Iopamidol impurity D, it is characterised in that: this method is using 1 compound of formula as raw material, with hydroxide
Acyl chlorides is hydrolyzed into carboxylic acid after sodium reaction, and acetoxyl group is hydrolyzed into hydroxyl, and resin separation purification obtains Iopamidol impurity D.
7. synthetic method according to claim 6, it is characterised in that comprise the concrete steps that: 1 compound of formula is in methylene chloride
The mass volume ratio that pure water, 1 compound of formula and methylene chloride and pure water are added after dissolution is 1g:3~5ml:3~5ml, is added dropwise
The molar ratio of 20% sodium hydroxide solution, 1 compound of formula and sodium hydroxide is 1:4~4.5, keeps the temperature 20-30 DEG C of reaction, reaction
Finish, be 6-7 with 10% hydrochloric acid tune pH, layering obtains water layer, after resin cation and resin anion (R.A.) desalination, obtains impurity
D。
Synthetic route is
8. a kind of synthetic method of Iopamidol impurity F (9 compound of formula), it is characterised in that: this method is with 1 compound of formula for original
Material, first passes through 8 compound intermediate of amidation process production, then generates Iopamidol impurity F by hydrolysis；Specific step
Suddenly it is:
(1) 8 compound of formula is synthesized
N,N-dimethylacetamide solution and triethylamine, ice bath cooling, heat preservation is added into reaction flask in 1 compound of addition formula
The molar ratio of 0-10 DEG C of 40% dimethylamine agueous solution of dropwise addition, 1 compound of formula and dimethylamine is 1:1.0~1.5, drips off complete, heating
It is reacted to 20-30 DEG C, HPLC detects end of reaction, and after filtrate decompression concentration, isopropanol is added in filtering, and reflux is dropped after 2-4 hours
Acetone is slowly added dropwise to 20-30 DEG C in temperature, and the volume ratio of acetone and isopropanol is 1.5~2.5:1,20-30 DEG C stirring 1-2 hours,
Filtering, dry 8 compound of formula；
(2) 9 compound of formula is synthesized
8 compound of addition formula is added methylene chloride and dissolution is stirred at room temperature, add pure water, 50% hydrogen is added dropwise into reaction flask
The mass volume ratio of sodium oxide molybdena, 8 compound of formula and methylene chloride and pure water is 1g:3~5ml:3~5ml, 8 compound of formula with
The molar ratio of sodium hydroxide is 1:3~3.5, and 20-30 DEG C of reaction, HPLC tracing detection end of reaction, with 10% is added dropwise
Hydrochloric acid tune pH is 6-7, and layering obtains water layer, after resin cation and resin anion (R.A.) desalination, is concentrated under reduced pressure, pure water is added
Recrystallization, obtains white solid impurity F；
Synthetic route is
9. a kind of synthetic method of Iopamidol impurity G (11 compound of formula), it is characterised in that: this method is to be with 1 compound of formula
Raw material first passes through 10 compound intermediate of amidation process production, then generates Iopamidol impurity G by hydrolysis；Tool
Body step is:
(1) 10 compound of formula is synthesized
1 compound of formula is added in reaction flask, n,N-dimethylacetamide solution and triethylamine, ice bath cooling, heat preservation is added
The mass volume ratio of 0-10 DEG C of dropwise addition amino-glycerol, 1 compound of formula and n,N-dimethylacetamide and triethylamine is 1g:0.8
The molar ratio of~1.0ml:1~3ml, 1 compound of formula and amino-glycerol is 1:1~1.5, drip off it is complete, be warming up to 20-30 DEG C it is anti-
It answers, HPLC detects end of reaction, and after filtrate decompression concentration, isopropanol is added in filtering, and reflux was cooled to 20-30 after 2-4 hours
DEG C, 20-30 DEG C stirring 1-2 hours,
Filtering, dry 10 compound solid of formula；
(2) 11 compound of formula is synthesized
10 compound of formula is added in reaction flask, methylene chloride is added, dissolution is stirred at room temperature, add pure water, 50% hydrogen is added dropwise
The mass volume ratio of sodium oxide molybdena, 10 compound of formula and methylene chloride and pure water is 1g:3~5ml:3~5ml, 10 compound of formula
Molar ratio with sodium hydroxide is 1:3~3.5, and 20-30 DEG C of reaction, HPLC tracing detection end of reaction, with 10% is added dropwise
Hydrochloric acid tune pH be 5-6, layering, obtain water layer, after resin cation and resin anion (R.A.) desalination, be concentrated under reduced pressure, obtain white
Color solid impurity G；
Synthetic route is
10. a kind of synthetic method of Iopamidol impurity J (Formula 13), it is characterised in that this method comprises the following steps:
(1) 12 compound of formula is synthesized
1 compound of formula is added in reaction flask, the triethylamine in n,N-dimethylacetamide solution, ice bath cooling, heat preservation is added
The mass volume ratio of 0-10 DEG C of dropwise addition ethanol amine, 1 compound of formula and n,N-dimethylacetamide and triethylamine be 1g:0.8~
The molar ratio of 1.0ml:1~3ml, 1 compound of formula and ethanol amine is 1:1~1.5, drips off complete, is warming up to 20-30 DEG C of reaction,
HPLC detects end of reaction, and after filtrate decompression concentration, isopropanol is added in filtering, and reflux was cooled to 20-30 DEG C after 2-4 hours,
20-30 DEG C stirring 1-2 hours, filtering, dry 12 compound of formula；
(2) 13 compound of formula is synthesized
12 compound of formula is added in reaction flask, methylene chloride is added, dissolution is stirred at room temperature, add pure water, 50% hydrogen is added dropwise
The mass volume ratio of sodium oxide molybdena, 12 compound of formula and methylene chloride and pure water is 1g:3~5ml:3~5ml, 12 compound of formula
Molar ratio with sodium hydroxide is 1:3~3.5, and 20-30 DEG C of reaction, HPLC tracing detection end of reaction, with 10% is added dropwise
Hydrochloric acid tune pH be 5-6, layering, obtain water layer, after resin cation and resin anion (R.A.) desalination, be concentrated under reduced pressure, obtain white
Color solid impurity J.
Synthetic route:
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114716340A (en) * | 2022-05-10 | 2022-07-08 | 杭州微流汇科技有限公司 | Preparation method of iopromide intermediate |
| CN116003277A (en) * | 2023-01-03 | 2023-04-25 | 安庆朗坤药业有限公司 | Preparation method of contrast agent intermediate iodide |
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| CN102746184A (en) * | 2012-07-09 | 2012-10-24 | 浙江司太立制药股份有限公司 | Preparation method of iohexol impurity |
| CN102816085A (en) * | 2012-08-20 | 2012-12-12 | 浙江司太立制药股份有限公司 | Preparation method of iohexol impurity |
| CN103382160A (en) * | 2012-05-02 | 2013-11-06 | 上海海神化学生物科技有限公司 | Synthesis of iopamidol and preparation of iopamidol synthesis intermediate |
| CN105272899A (en) * | 2015-11-17 | 2016-01-27 | 浙江海洲制药有限公司 | Novel compound and method for synthesizing iopamidol impurity D, impurity F, impurity G and impurity J by means of novel compound |
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2019
- 2019-04-30 CN CN201910361819.3A patent/CN110054571A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103382160A (en) * | 2012-05-02 | 2013-11-06 | 上海海神化学生物科技有限公司 | Synthesis of iopamidol and preparation of iopamidol synthesis intermediate |
| CN102746184A (en) * | 2012-07-09 | 2012-10-24 | 浙江司太立制药股份有限公司 | Preparation method of iohexol impurity |
| CN102816085A (en) * | 2012-08-20 | 2012-12-12 | 浙江司太立制药股份有限公司 | Preparation method of iohexol impurity |
| CN105272899A (en) * | 2015-11-17 | 2016-01-27 | 浙江海洲制药有限公司 | Novel compound and method for synthesizing iopamidol impurity D, impurity F, impurity G and impurity J by means of novel compound |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
| CN116003277A (en) * | 2023-01-03 | 2023-04-25 | 安庆朗坤药业有限公司 | Preparation method of contrast agent intermediate iodide |
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