CN108341750B - Synthetic method of impurities generated in preparation of iodinated contrast medium intermediate - Google Patents
Synthetic method of impurities generated in preparation of iodinated contrast medium intermediate Download PDFInfo
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- 239000012535 impurity Substances 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 238000010189 synthetic method Methods 0.000 title abstract description 3
- 239000000193 iodinated contrast media Substances 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 132
- 238000006243 chemical reaction Methods 0.000 claims abstract description 50
- 239000002872 contrast media Substances 0.000 claims abstract description 14
- 238000006722 reduction reaction Methods 0.000 claims abstract description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 4
- 230000002083 iodinating effect Effects 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 177
- 239000000243 solution Substances 0.000 claims description 82
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- 238000003756 stirring Methods 0.000 claims description 21
- 239000000047 product Substances 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 18
- 238000001816 cooling Methods 0.000 claims description 16
- 238000001914 filtration Methods 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 13
- 239000007787 solid Substances 0.000 claims description 13
- 230000002194 synthesizing effect Effects 0.000 claims description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 11
- 239000012074 organic phase Substances 0.000 claims description 10
- 239000000725 suspension Substances 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 9
- 238000000746 purification Methods 0.000 claims description 7
- 239000000706 filtrate Substances 0.000 claims description 6
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 claims description 6
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 4
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 3
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 3
- 239000011259 mixed solution Substances 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 239000012065 filter cake Substances 0.000 claims description 2
- 238000005984 hydrogenation reaction Methods 0.000 claims description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 abstract description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- 238000004809 thin layer chromatography Methods 0.000 description 10
- 238000010438 heat treatment Methods 0.000 description 9
- 239000002994 raw material Substances 0.000 description 9
- KJJPLEZQSCZCKE-UHFFFAOYSA-N 2-aminopropane-1,3-diol Chemical compound OCC(N)CO KJJPLEZQSCZCKE-UHFFFAOYSA-N 0.000 description 6
- MQDLKAADJTYKRH-UHFFFAOYSA-N 1-aminopropane-1,2,3-triol Chemical compound NC(O)C(O)CO MQDLKAADJTYKRH-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 238000004949 mass spectrometry Methods 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- NBDAHKQJXVLAID-UHFFFAOYSA-N 5-nitroisophthalic acid Chemical compound OC(=O)C1=CC(C(O)=O)=CC([N+]([O-])=O)=C1 NBDAHKQJXVLAID-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 2
- AMDBBAQNWSUWGN-UHFFFAOYSA-N Ioversol Chemical compound OCCN(C(=O)CO)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I AMDBBAQNWSUWGN-UHFFFAOYSA-N 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229960004359 iodixanol Drugs 0.000 description 2
- NBQNWMBBSKPBAY-UHFFFAOYSA-N iodixanol Chemical compound IC=1C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C(I)C=1N(C(=O)C)CC(O)CN(C(C)=O)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I NBQNWMBBSKPBAY-UHFFFAOYSA-N 0.000 description 2
- 229960001025 iohexol Drugs 0.000 description 2
- NTHXOOBQLCIOLC-UHFFFAOYSA-N iohexol Chemical compound OCC(O)CN(C(=O)C)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I NTHXOOBQLCIOLC-UHFFFAOYSA-N 0.000 description 2
- 229960004537 ioversol Drugs 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- MRJNWRZZFGDDBA-UHFFFAOYSA-N NC(O)C(O)CO.NCC(CO)O Chemical compound NC(O)C(O)CO.NCC(CO)O MRJNWRZZFGDDBA-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/14—Preparation of carboxylic acid amides by formation of carboxamide groups together with reactions not involving the carboxamide groups
Abstract
The invention discloses a synthetic method of an impurity shown in a formula (I) generated in the preparation of a contrast agent intermediate, which comprises the following steps: (1) compounds (II) and R2NH2The reaction is carried out to obtain a compound (III),
wherein R is1Lower alkyl group of 1 to 4 carbon atoms, R2is-CH2CH(OH)CH2(OH) or-CH (CH2OH)2Any one of the above; (2) compounds (III) and R3NH2Reacting under alkaline condition to obtain compound (IV),
wherein R is2is-CH2CH(OH)CH2(OH) is R3is-CH (CH2OH)2Wherein R is2is-CH (CH2OH)2When R is3is-CH2CH(OH)CH2(OH). (3) Carrying out nitro reduction reaction on the compound (IV) to obtain a compound (V),
(4) compound (V) is prepared by adopting an iodinating reagent to obtain compound (I),
Description
Technical Field
The invention relates to a preparation method of a compound, in particular to a synthesis method of an impurity for preparing an iodinated contrast medium intermediate, belonging to the field of medicinal chemistry.
Background
The compound of formula (VI) is used as a key intermediate for the preparation of iohexol, ioversol and iodixanol, which determines the quality of the final product. During the synthesis of the intermediate, the main raw material of amino glycerol (H)2NCH(CH2OH)2) Will contain a small amount of H2NCH2CH(OH)CH2(OH) produces an impurity of formula (I) during the reaction, and the byproduct is similar to the product of formula (VI) in nature and is difficult to separate by HPLC analysis.
Therefore, if a method for synthesizing the compound shown in the formula (I) with high product purity and good selectivity can be provided, the compound is taken as a reference, the purity of the intermediate of the compound shown in the formula (VI) can be improved, and the preparation of high-purity iodinated contrast medium products such as iohexol, ioversol, iodixanol and the like can be facilitated.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a method for synthesizing the compound impurity shown in the formula (I) generated in the preparation of the key intermediate of the iodinated contrast agent, and the impurity product synthesized by the method has high purity and good selectivity.
In order to solve the technical problem, the invention discloses a method for synthesizing impurities shown in formula (I) generated in the preparation of a contrast agent intermediate, which comprises the following steps:
(1) a compound of formula (II) with R2NH2Reacting to prepare the compound shown in the formula (III),
wherein R is1Represents a lower alkyl group having 1 to 4 carbon atoms, R2Is selected from-CH2CH(OH)CH2(OH) or-CH (CH2OH)2Any one of the above;
(2) the compound shown as the formula (III) obtained in the step (1) and R3NH2Reacting under alkaline condition to prepare the compound shown in the formula (IV),
wherein R is2is-CH2CH(OH)CH2(OH) is R3is-CH (CH2OH)2，
Wherein R is2is-CH (CH2OH)2When R is3is-CH2CH(OH)CH2(OH)。
(3) Carrying out nitro reduction reaction on the compound shown in the formula (IV) obtained in the step (2) to prepare a compound shown in a formula (V),
(4) preparing the compound shown in the formula (V) obtained in the step (3) by using an iodinating reagent to obtain a compound shown in the formula (I),
further, in the step (1), the compound represented by the formula (II) and methanol are added to a reaction vessel, and stirred at room temperature to obtain a suspension, and R is added2NH2After completely dissolving with methanol, slowly dropwise adding into the suspension, after dropwise adding, carrying out reflux reaction on the mixed solution at 30-65 ℃ (preferably 55-65 ℃), detecting by TLC until products do not change obviously, stopping the reaction, cooling the reaction solution to room temperature, adjusting the pH of the solution to 6-7 with acetic acid, then adding pure water into the reaction solution while stirring, filtering, drying and recovering a filter cake, extracting the filtrate with ethyl acetate or dichloromethane or chloroform, washing an organic phase with water, concentrating under reduced pressure, and drying to obtain a white solid, namely the compound shown in formula (III), wherein the purity is higher than 98%.
Further, the compound shown in the formula (II) in the step (1) and R2NH2The molar ratio of (1): 1 to 1.5, preferably 1: 1.2.
further, the mass-to-volume ratio of the compound shown in the formula (II) in the step (1) to the methanol is 1 g: 6-10 mL, preferably 1 g: 8 mL; r2NH2The mass-to-volume ratio of the methanol to the methanol is 1 g: 2-5 mL, preferably 1 g: 3.5 mL.
Further, in the step (1), R is dropwise added2NH2The time of the methanol solution is 2 to 6 hours, preferably 4 hours.
Further, the volume usage ratio of pure water added to the reaction liquid in the step (1) to methanol used is 0.8-2: 1, preferably 1: 1.
further, in the step (2), the compound shown in the formula (III) is dissolved in methanol, absolute ethyl alcohol or isopropanol, and sodium methoxide or sodium ethoxide and R are added3NH2And (3) carrying out reaction at 35-40 ℃, detecting that the compound shown in the formula (III) basically disappears completely by TLC, stopping the reaction, cooling the solution to room temperature, adjusting the pH of the solution to 6-7 by using acetic acid to obtain a solution of the compound shown in the formula (IV), and directly carrying out the next reaction without purification.
Further, the compound represented by the formula (III) in the step (2) and R3NH2The molar ratio of (1): 1.2 to 2.0, preferably 1: 1.5, the molar ratio of the sodium methoxide or sodium ethoxide to the compound shown in the formula (III) is 0.05-0.15: 1.
further, the mass-to-volume ratio of the compound shown in the formula (III) in the step (2) to methanol, absolute ethyl alcohol or isopropanol is 1 g: 6-10 mL, preferably 1 g: 8 mL.
Further, in the step (3), the methanol solution of the compound shown in the formula (IV) obtained in the step (2) is placed in a reaction vessel, a palladium-carbon (Pd/C) or Raney nickel catalyst is added, hydrogenation reduction is carried out at 30-35 ℃ under the pressure of 0.3-0.4 MPa until the end, the catalyst is removed by filtration to obtain the methanol solution of the compound shown in the formula (V), the molar weight of the compound shown in the formula (V) is calculated according to the complete reaction, and the next reaction is directly carried out without purification;
in the step (4), the methanol solution of the compound represented by the formula (V) obtained in the step (3) is placed in a reaction vessel, and fresh ICl or IHSO is added dropwise at room temperature4Using the solution as an iodinating reagent, and reacting the compound of formula (V) with ICl or IHSO4In a molar ratio of 1: 3.05 to 3.3, reacting for 3 to 4 hours at the temperature of between 60 and 65 ℃, reducing the solution to room temperature after TLC detection reaction is finished, adding sodium hydrosulfite (namely sodium hydrosulfite) to remove excessive iodine, adjusting the pH of the solution to be 6 to 7 by using a solution with the mass concentration of 30 percent NaOH, concentrating the reaction solution to remove methanol, stirring the residual solution at the temperature of between 5 and 10 ℃ for crystallization to obtain a light brown product, and recrystallizing by using pure water to obtain a white-like solid, namely the compound shown in the formula (I), wherein the purity of the compound is high>98％。
The invention is provided withThe compound (5-nitroisophthalate) shown in the formula (II) is used as a raw material to obtain a compound shown in the formula (V), and then the compound shown in the formula (I) is further obtained. Among these, the synthesis of the compound of formula (III) is a key step in the preparation of the compound of formula (I) and also constitutes an important feature of the present invention. The inventor finds that the compound shown as the formula (II) and RNH through experimental research2[ R represents-CH2CH(OH)CH2(OH) or-CH (CH2OH)2In the absence of other alkalis, the reaction selectivity is good, the compound shown in the formula (III) with high purity can be synthesized, and simultaneously, the raw material (5-nitroisophthalate) which is not completely reacted can be recovered in the post-treatment process, so that the utilization rate of the raw material and the product yield are improved. In the whole reaction process, each intermediate does not need further treatment and purification, the next reaction can be directly carried out, the intermediate loss is less, the operation is simple, the impurity product purity is high, the reaction selectivity is high, the raw material utilization rate is high (the raw material which is not completely reacted can be recycled), the method is simple and convenient, and the method has a referential significance for preparing the intermediate of the high-purity iodinated contrast agent.
Detailed Description
The present invention will be described more specifically with reference to examples. The practice of the present invention is not limited to the following examples, and any modification or variation of the present invention is within the scope of the present invention.
Example 1:
(1) synthesis of Compound represented by the formula (III)
71.7g (0.3mol) of the compound (R) of the formula (II)1is-CH3) Placing the mixture into a reaction bottle, adding 610mL of methanol, stirring to obtain a white suspension, heating the mixture in an oil bath to 60-65 ℃, dissolving 33g (0.36mol) of serinol (2-amino-1, 3-propanediol) into 99mL of methanol, slowly dropwise adding the mixture into the suspension, after 4 hours of dropwise addition, reacting at a constant temperature for 20 hours, detecting that a product does not obviously change after TLC (thin layer chromatography) detection, cooling the solution to room temperature, adjusting the pH of the solution to 6-7 with acetic acid, adding 710mL of pure water, stirring for a plurality of minutes (or adding the pure water while stirring), filtering, recovering solids, extracting the filtrate with ethyl acetate (300mL multiplied by 5 times), combining organic phases, and performing water-assisted extraction on the organic phasesWashed (200 mL. times.2 times), the organic phase was dried over anhydrous magnesium sulfate overnight, filtered, and concentrated under reduced pressure to give 65g of a white powdery product (i.e., the compound represented by formula (III)), yield 75.3%, HPLC>98％，m/z：【M+H】＝299.1。
(2) Synthesis of Compound represented by the formula (IV)
Weighing 12g (0.04mol, 1.0eq) of the white powdery product obtained in the step (1), placing the white powdery product in a reaction bottle, adding 96mL of methanol, stirring at room temperature for complete dissolution, sequentially adding 5.46g (0.06mol, 1.5eq) of amino glycerol (3-amino-1, 2-propanediol) and 0.22g of sodium methoxide (0.004mol), heating the solution to 35-40 ℃ for reaction, tracking and detecting by TLC (thin layer chromatography) until the compound shown in the formula (III) basically disappears, cooling to room temperature, adjusting the pH of the solution to 6-7 by using acetic acid, obtaining a methanol solution of the compound shown in the formula (III), directly using the methanol solution of the compound shown in the formula (III) for the next step without treatment, wherein the molar weight of the compound shown in the formula (IV) is calculated by the compound shown in the formula (III), and obtaining 0.04mol of the methanol solution of the compound shown in. A small amount of methanol solution of the compound shown in the formula (IV) is taken, concentrated and subjected to mass spectrometry, and the mass spectrometry is matched with the experimental result: m/z: [ M + H ] 358.1, [ M + Na ]+380，【M-17】340.1。
(3) Synthesis of Compound represented by the formula (V)
And (3) putting the methanol solution of the compound (0.04mol) shown in the formula (IV) obtained in the step (2) into a reactor, adding 0.7g of Pd/C (the mass content of active substances can be 10% or 5%), replacing the reactor for 3 times by nitrogen, replacing for 2 times by hydrogen, keeping the pressure in the reactor at 0.3-0.4 MPa, heating to 30-35 ℃ for reaction for 2 hours, detecting the complete disappearance of the compound IV by TLC, filtering the solution to obtain the methanol solution of the compound V, concentrating to 1/3, directly using the methanol solution for the next reaction without purification, and obtaining the methanol solution of the compound shown in the formula (V) of 0.04mol in total according to the compound shown in the formula (IV). Taking a small amount of methanol solution of the compound shown as the formula (V), concentrating, and performing mass spectrometry: m/z: [ M + H ] 328, [ M + Na ]+350。
(4) Synthesis of Compound represented by the formula (I)
Placing the methanol solution of the compound (0.04mol) shown in the formula (V) obtained in the step (3) into a reaction bottle, and slowly dropwise adding a new ICl solutionAnd (b) the molar ratio of ICl to the compound represented by the formula (V) in the solution is 3.1: 1, reacting for 4 hours at room temperature to 60-65 ℃, detecting that the compound V basically completely disappears by HPLC, cooling the solution to room temperature, adding sodium hydrosulfite (sodium hydrosulfite) to remove excessive iodine, adjusting the pH of the solution to 6-7 by using a NaOH solution with the mass concentration of 30%, concentrating the reaction solution to remove methanol, cooling the rest solution in an ice bath to 5-10 ℃, stirring overnight, filtering to obtain light brown solid, recrystallizing by using pure water to obtain 18g of white solid with the yield of 63.8% (calculated by the compound shown in the formula (IV)), and performing HPLC>98％，m/z：【M+H】705.8，【M+Na】+727.8。
Example 2:
synthesis of Compound represented by the formula (III)
71.7g (0.3mol) of the compound (R) of the formula (II)1is-CH3) Placing the mixture into a reaction bottle, adding 617mL of methanol, stirring to obtain a white suspension, heating the mixture in an oil bath to 60-65 ℃, dissolving 32.7g (0.36mol, 1.2eq) of amino glycerol into 100mL of methanol, slowly dropwise adding the mixture into the solution, dropwise adding the mixture for 4.5 hours, reacting at a constant temperature for 20 hours, detecting that a product does not change obviously, cooling the solution to room temperature, adjusting the pH of the solution to 6-7 with acetic acid, adding 717mL of pure water, stirring for several minutes (or adding pure water while stirring), filtering, recovering a solid, drying to obtain 12.3g of a solid, extracting the filtrate with ethyl acetate (200mL multiplied by 4 times), combining organic phases, washing with water (200mL multiplied by 3 times), drying the organic phase with anhydrous magnesium sulfate overnight, filtering, and concentrating under reduced pressure to obtain 41.4g of a white powdery product (namely the compound shown in the formula (III)), wherein the yield is 56%, and HPLC (>98％，m/z：【M+Na】+321.1。
In this example, R3NH2The other raw materials, the amounts and the steps of serinol are the same as those in example 1, which are not described again, and HPLC still exists in the obtained product>98％。
Example 3:
12g (0.05mol) of the compound (R) of the formula (II) at room temperature1is-CH3) Placing the mixture into a reaction bottle, adding 80mL of methanol, stirring to obtain a white suspension, heating the suspension to 60-65 ℃ in an oil bath, dissolving 6.8(0.075mol, 1.5eq) serinol into 30mL of methanol, and slowly dropwise adding the mixture until the serinol is dissolvedIn the solution, after dropwise addition for 2 hours, reacting at constant temperature for 20 hours, detecting by TLC that the product does not change obviously, cooling the solution to room temperature, adjusting the pH to 6-7 with acetic acid, adding 100mL of pure water, stirring for several minutes (or adding pure water while stirring), filtering, recovering the solid, drying to obtain 1.3g, extracting the filtrate with ethyl acetate (50mL multiplied by 4 times), combining the organic phases, washing with water (50mL multiplied by 3 times), drying the organic phase with anhydrous magnesium sulfate overnight, filtering, concentrating under reduced pressure to obtain 9g of a white powdery product (namely the compound shown in the formula (III)), obtaining a yield of 67.6%, and performing HPLC (high performance liquid chromatography)>98％。
9g (0.03mol) of the compound represented by the formula (III) obtained in this example were dissolved in 90ml of isopropyl alcohol, and the other raw materials, the amounts of the raw materials and the steps were the same as those in example 1, and thus, the details thereof are omitted.
Example 4:
(1) synthesis of Compound represented by the formula (III)
23.9g (0.1mol) of the compound (R) of the formula (II)1is-CH3) Placing the mixture into a reaction bottle, adding 191.2mL of methanol, stirring to obtain a white suspension, heating the mixture in an oil bath to 60-65 ℃, dissolving 10.9g (0.12mol) of serinol into 38.1mL, slowly dropwise adding the mixture into the solution, after 4.5 hours of dropwise adding, reacting at a constant temperature for 20 hours, detecting that a product does not change obviously, cooling the solution to room temperature, adjusting the pH of the solution to be 6-7 by using acetic acid, adding 250mL of pure water, stirring for a plurality of minutes (or adding pure water under stirring), filtering, recovering a solid, extracting the filtrate by using ethyl acetate (150mL multiplied by 4 times), combining organic phases, washing by water (200mL multiplied by 2 times), drying the organic phases by using anhydrous magnesium sulfate overnight, filtering, concentrating under reduced pressure to obtain a white powdery product (namely the compound shown in the formula (III)) 42.1g, wherein the yield is 65.2%, and performing HPLC>98％。
(2) Synthesis of Compound represented by the formula (IV)
Weighing 14.9g (0.05mol, 1.0eq) of the compound shown in the formula (III) obtained in the step (1), placing the compound into a reaction bottle, adding 89.4mL of methanol, stirring at room temperature to completely dissolve the compound, sequentially adding 9.1g (0.1mol, 2.0eq) of amino glycerol and 0.27g of sodium methoxide (0.005mol), heating the solution to 35-40 ℃ for reaction, tracking and detecting by TLC (thin layer chromatography) until the compound shown in the formula (III) basically completely disappears, cooling to room temperature, adjusting the pH of the solution to 6-7 by using acetic acid to obtain a methanol solution of the compound shown in the formula (IV), and directly using the methanol solution of the compound shown in the formula (IV) for the next step without treatment, wherein the molar weight of the compound shown in the formula (IV) is calculated by the compound shown in the formula (III) to obtain 0.05mol of the methanol solution.
(3) Synthesis of Compound represented by the formula (V)
And (3) putting the methanol solution of the compound (0.05mol) shown in the formula (IV) obtained in the step (2) into a reactor, adding 0.9g of Raney nickel catalyst, replacing the reactor with nitrogen for 3 times, replacing with hydrogen for 2 times, keeping the pressure in the reactor at 0.3-0.4 MPa, heating to 30-35 ℃ for reacting for 2-3 hours, detecting the complete disappearance of the compound IV by TLC, filtering the solution to obtain the methanol solution of the compound V, concentrating to 1/3, directly using the methanol solution for the next step without purification, and obtaining the methanol solution of the compound shown in the formula (V) with the molar weight of the compound shown in the formula (V) being calculated as the compound shown in the formula (IV) and 0.05mol of the compound shown in the formula (V).
(4) Synthesis of Compound represented by the formula (I)
Placing the methanol solution of the compound (0.05mol) shown in the formula (V) obtained in the step (3) into a reaction bottle, and slowly dropwise adding fresh IHSO4Solution of IHSO4The molar ratio to the compound represented by the formula (V) is 3.2: 1, reacting for 3.5 hours at the temperature of between room temperature and 60 and 65 ℃, detecting that a compound V basically completely disappears by HPLC, cooling the solution to the room temperature, adding sodium hydrosulfite to remove excessive iodine, adjusting the pH of the solution to be between 6 and 7 by using 30 percent NaOH, concentrating the reaction solution to remove methanol, cooling the residual solution to be between 5 and 10 ℃ in an ice bath, stirring for 12 to 16 hours, filtering to obtain brown solid, recrystallizing by using pure water to obtain 21.5g of off-white solid with the yield of 61 percent (calculated according to the compound shown in the formula (IV), and performing HPLC to detect that the compound V basically completely disappears>98％。
Example 5:
synthesis of Compound represented by the formula (IV)
Weighing 18.8g (0.06mol, 1.0eq) of the compound shown in the formula (III) synthesized in the example 1, placing the compound into a reaction bottle, adding 150mL of methanol, stirring at room temperature to completely dissolve the compound, sequentially adding 8.3g (0.09mol, 1.5eq) of amino glycerol and 0.24g (0.0035mol) of sodium ethoxide, heating the solution to 35-40 ℃ for reaction, tracking and detecting by TLC (thin layer chromatography) until the compound shown in the formula (III) basically completely disappears, cooling to room temperature, adjusting the pH of the solution to 6-7 by using acetic acid to obtain a methanol solution of the compound shown in the formula (IV), directly using the methanol solution of the compound shown in the formula (IV) for the next reaction without treatment, wherein the molar weight of the compound shown in the formula (IV) is calculated by the compound shown in the formula (III) and the total amount of the methanol solution of the compound.
The rest of the reaction steps are the same as example 1 and are not repeated.
Claims (10)
1. A method for synthesizing an impurity represented by formula (I) generated in the preparation of an intermediate of a contrast agent, characterized in that: the method comprises the following steps:
(1) a compound of formula (II) with R2NH2Reacting to prepare the compound shown in the formula (III),
wherein R is1Represents a lower alkyl group having 1 to 4 carbon atoms, R2Is selected from-CH2CH(OH)CH2(OH) or-CH (CH)2OH)2Any one of the above;
(2) the compound shown as the formula (III) obtained in the step (1) and R3NH2Reacting under alkaline condition to prepare the compound shown in the formula (IV),
wherein R is2is-CH2CH(OH)CH2(OH) is R3is-CH (CH)2OH)2，
Wherein R is2is-CH (CH)2OH)2When R is3is-CH2CH(OH)CH2(OH)；
(3) Carrying out nitro reduction reaction on the compound shown in the formula (IV) obtained in the step (2) to prepare a compound shown in a formula (V),
(4) preparing the compound shown in the formula (V) obtained in the step (3) by using an iodinating reagent to obtain a compound shown in the formula (I),
2. the method for synthesizing an impurity represented by formula (I) generated when preparing an intermediate of a contrast medium according to claim 1, wherein: in the step (1), a compound represented by the formula (II) and methanol are added into a reaction vessel, the mixture is stirred at room temperature to obtain a suspension, and R is added2NH2And (2) after completely dissolving with methanol, slowly dropwise adding into the suspension, after dropwise adding, carrying out reflux reaction on the mixed solution at 30-65 ℃ until the mixed solution is completely reacted, stopping the reaction, cooling the reaction solution to room temperature, adjusting the pH of the solution to 6-7 with acetic acid, then adding pure water into the reaction solution while stirring, filtering, drying a filter cake, recovering, extracting the filtrate, washing the obtained organic phase with water, concentrating under reduced pressure, and drying to obtain a white solid, namely the compound shown in the formula (III).
3. The method for synthesizing an impurity represented by the formula (I) generated when preparing a contrast medium intermediate according to claim 1 or 2, wherein: the compound shown in the formula (II) in the step (1) and R2NH2The molar ratio of (1): 1 to 1.5.
4. The method for synthesizing an impurity represented by formula (I) generated in the preparation of an intermediate for a contrast medium according to claim 3, wherein: the mass-to-volume ratio of the compound shown in the formula (II) in the step (1) to methanol is 1 g: 6-10 mL; r2NH2The mass-to-volume ratio of the methanol to the methanol is 1 g: 2-5 mL.
5. The method for synthesizing an impurity represented by formula (I) generated in the preparation of an intermediate for a contrast medium according to claim 2, wherein: in the step (1), R is dropwise added2NH2The time of the methanol solution is 2-6 hours.
6. The method for synthesizing an impurity represented by formula (I) generated in the preparation of an intermediate for a contrast medium according to claim 2, wherein: the volume total dosage ratio of pure water added into the reaction liquid in the step (1) to methanol used in the step is 0.8-2: 1.
7. the method for synthesizing an impurity represented by formula (I) generated when preparing an intermediate of a contrast medium according to claim 1, wherein: in the step (2), the compound shown in the formula (III) is dissolved in methanol, absolute ethyl alcohol or isopropanol, and then one of sodium methoxide or sodium ethoxide and R are added3NH2And (3) completely reacting at 35-40 ℃, cooling the solution to room temperature, adjusting the pH of the solution to 6-7 by using acetic acid to obtain a solution of the compound shown in the formula (IV), and directly carrying out the next reaction without purification.
8. The method for synthesizing an impurity of formula (I) produced in the preparation of an intermediate for a contrast agent according to claim 7, wherein: a compound shown in the formula (III) in the step (2) and R3NH2The molar ratio of (1): 1.2-2.0, wherein the molar use ratio of sodium methoxide or sodium ethoxide to the compound shown in the formula (III) is 0.05-0.15: 1.
9. the method for synthesizing an impurity of formula (I) produced in the preparation of an intermediate for a contrast agent according to claim 7, wherein: the mass-to-volume ratio of the compound shown in the formula (III) in the step (2) to the methanol, the absolute ethyl alcohol or the isopropanol for dissolving is 1 g: 6-10 mL.
10. The method for synthesizing an impurity represented by formula (I) generated when preparing an intermediate of a contrast medium according to claim 1, wherein:
in the step (3), the methanol solution of the compound shown in the formula (IV) obtained in the step (2) is placed in a reaction container, a palladium-carbon or Raney nickel catalyst is added, hydrogenation reduction is carried out at the temperature of 30-35 ℃ under the pressure of 0.3-0.4 MPa until the end, the catalyst is removed by filtration to obtain the methanol solution of the compound shown in the formula (V), the molar weight of the compound shown in the formula (V) is calculated according to the complete reaction, and the next reaction is directly carried out without purification;
in the step (4), the methanol solution of the compound represented by the formula (V) obtained in the step (3) is placed in a reaction vessel, and fresh ICl or IHSO is added dropwise at room temperature4Solution of a compound of the formula (V) with IClOrIHSO4In a molar ratio of 1: 3.05 to 3.3, reacting at the temperature of between 60 and 65 ℃ for 3 to 4 hours, cooling the solution to room temperature after the reaction is finished, adding sodium hydrosulfite to remove excessive iodine, adjusting the pH of the solution to be between 6 and 7 by using a NaOH solution with the mass concentration of 30 percent, concentrating the reaction solution to remove methanol, stirring the residual solution at the temperature of between 5 and 10 ℃ for crystallization to obtain a light brown product, and recrystallizing by using pure water to obtain a white-like solid, namely the compound shown in the formula (I).
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| WO2000029372A1 (en) * | 1998-11-16 | 2000-05-25 | Nycomed Imaging As | Preparation of 5-amino-isophthalamides |
| CN1436095A (en) * | 2000-04-28 | 2003-08-13 | 准确聚合物公司 | Simulated activity of protein A displayed by ligands attached to cellulose bead surface |
| WO2009106551A2 (en) * | 2008-02-27 | 2009-09-03 | Ge Healthcare As | Contrast agents |
| CN101687051A (en) * | 2007-07-12 | 2010-03-31 | 通用电气医疗集团股份有限公司 | Contrast agents |
| 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 |
| CN105294472A (en) * | 2015-11-17 | 2016-02-03 | 浙江海洲制药有限公司 | Synthetic method of iopamidol impurity C |
| CN105461581A (en) * | 2015-11-17 | 2016-04-06 | 浙江海洲制药有限公司 | Synthetic methods of an impurity A and an impurity B of iopamidol |
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2017
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Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2000029372A1 (en) * | 1998-11-16 | 2000-05-25 | Nycomed Imaging As | Preparation of 5-amino-isophthalamides |
| CN1436095A (en) * | 2000-04-28 | 2003-08-13 | 准确聚合物公司 | Simulated activity of protein A displayed by ligands attached to cellulose bead surface |
| CN101687051A (en) * | 2007-07-12 | 2010-03-31 | 通用电气医疗集团股份有限公司 | Contrast agents |
| WO2009106551A2 (en) * | 2008-02-27 | 2009-09-03 | Ge Healthcare As | Contrast agents |
| 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 |
| CN105294472A (en) * | 2015-11-17 | 2016-02-03 | 浙江海洲制药有限公司 | Synthetic method of iopamidol impurity C |
| CN105461581A (en) * | 2015-11-17 | 2016-04-06 | 浙江海洲制药有限公司 | Synthetic methods of an impurity A and an impurity B of iopamidol |
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