CN116354842A - Improved preparation method of iomeprol and application of iomeprol in preparation - Google Patents
Improved preparation method of iomeprol and application of iomeprol in preparation Download PDFInfo
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- CN116354842A CN116354842A CN202111561385.5A CN202111561385A CN116354842A CN 116354842 A CN116354842 A CN 116354842A CN 202111561385 A CN202111561385 A CN 202111561385A CN 116354842 A CN116354842 A CN 116354842A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 229960000780 iomeprol Drugs 0.000 title abstract description 21
- NJKDOADNQSYQEV-UHFFFAOYSA-N iomeprol Chemical compound OCC(=O)N(C)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I NJKDOADNQSYQEV-UHFFFAOYSA-N 0.000 title abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 31
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 22
- -1 2, 3-dihydroxypropyl Chemical group 0.000 claims abstract description 21
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims abstract description 14
- 238000006136 alcoholysis reaction Methods 0.000 claims abstract description 4
- 238000007112 amidation reaction Methods 0.000 claims abstract description 4
- 238000006640 acetylation reaction Methods 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 43
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 21
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 12
- KQIGMPWTAHJUMN-UHFFFAOYSA-N 3-aminopropane-1,2-diol Chemical compound NCC(O)CO KQIGMPWTAHJUMN-UHFFFAOYSA-N 0.000 claims description 9
- 230000008569 process Effects 0.000 claims description 9
- 239000011347 resin Substances 0.000 claims description 9
- 229920005989 resin Polymers 0.000 claims description 9
- HZDNNJABYXNPPV-UHFFFAOYSA-N (2-chloro-2-oxoethyl) acetate Chemical compound CC(=O)OCC(Cl)=O HZDNNJABYXNPPV-UHFFFAOYSA-N 0.000 claims description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 150000008064 anhydrides Chemical class 0.000 claims description 5
- CZZBBYONDSOYKL-UHFFFAOYSA-N 3-n-(2,3-dihydroxypropyl)-5-[(3-hydroxy-2-oxopropyl)amino]-2,4,6-triiodobenzene-1,3-dicarboxamide Chemical compound NC(=O)C1=C(I)C(NCC(=O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I CZZBBYONDSOYKL-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- IGXXLDZJIBEORC-UHFFFAOYSA-N [2-acetyloxy-3-[[3-(2,3-diacetyloxypropylcarbamoyl)-2,4,6-triiodobenzoyl]amino]propyl] acetate Chemical compound CC(=O)OCC(OC(C)=O)CNC(=O)C1=C(I)C=C(I)C(C(=O)NCC(COC(C)=O)OC(C)=O)=C1I IGXXLDZJIBEORC-UHFFFAOYSA-N 0.000 claims description 4
- 125000002091 cationic group Chemical group 0.000 claims description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 239000007810 chemical reaction solvent Substances 0.000 claims description 3
- 238000005660 chlorination reaction Methods 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- NNIGNXCBAHWYLI-UHFFFAOYSA-N 5-(2,3-dihydroxypropyl)-2,4,6-triiodobenzene-1,3-dicarboxamide Chemical compound NC(=O)C1=C(I)C(CC(O)CO)=C(I)C(C(N)=O)=C1I NNIGNXCBAHWYLI-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- LSPOLJMWTKCACL-UHFFFAOYSA-N [2-acetyloxy-3-(3,5-dicarbamoyl-2,4,6-triiodophenyl)propyl] acetate Chemical compound CC(=O)OCC(OC(C)=O)CC1=C(I)C(C(N)=O)=C(I)C(C(N)=O)=C1I LSPOLJMWTKCACL-UHFFFAOYSA-N 0.000 claims description 2
- 230000009435 amidation Effects 0.000 claims description 2
- 238000005815 base catalysis Methods 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims 2
- YIPGLACOACNFML-UHFFFAOYSA-N 1-n,3-n-bis(2,3-dihydroxypropyl)-2,4,6-triiodobenzene-1,3-dicarboxamide Chemical compound OCC(O)CNC(=O)C1=C(I)C=C(I)C(C(=O)NCC(O)CO)=C1I YIPGLACOACNFML-UHFFFAOYSA-N 0.000 claims 1
- 125000003277 amino group Chemical group 0.000 claims 1
- JIKUXBYRTXDNIY-UHFFFAOYSA-N n-methyl-n-phenylformamide Chemical compound O=CN(C)C1=CC=CC=C1 JIKUXBYRTXDNIY-UHFFFAOYSA-N 0.000 claims 1
- 229910000027 potassium carbonate Inorganic materials 0.000 claims 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims 1
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 claims 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 1
- 229910000029 sodium carbonate Inorganic materials 0.000 claims 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 238000005580 one pot reaction Methods 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 150000001263 acyl chlorides Chemical class 0.000 abstract description 2
- 125000000350 glycoloyl group Chemical group O=C([*])C([H])([H])O[H] 0.000 abstract description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000012535 impurity Substances 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 5
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
- 239000002872 contrast media Substances 0.000 description 3
- 238000011033 desalting Methods 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000001632 sodium acetate Substances 0.000 description 3
- 235000017281 sodium acetate Nutrition 0.000 description 3
- JEZJSNULLBSYHV-UHFFFAOYSA-N 5-amino-2,4,6-triiodobenzene-1,3-dicarboxylic acid Chemical compound NC1=C(I)C(C(O)=O)=C(I)C(C(O)=O)=C1I JEZJSNULLBSYHV-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 238000007792 addition Methods 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000006192 iodination reaction Methods 0.000 description 2
- 238000007069 methylation reaction Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 230000026045 iodination Effects 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 229960001025 iohexol Drugs 0.000 description 1
- 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 1
- 229960004647 iopamidol Drugs 0.000 description 1
- XQZXYNRDCRIARQ-LURJTMIESA-N iopamidol Chemical compound C[C@H](O)C(=O)NC1=C(I)C(C(=O)NC(CO)CO)=C(I)C(C(=O)NC(CO)CO)=C1I XQZXYNRDCRIARQ-LURJTMIESA-N 0.000 description 1
- 229960004537 ioversol Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000006462 rearrangement reaction Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/14—Preparation of carboxylic acid amides by formation of carboxamide groups together with reactions not involving the carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
-
- 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
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to an improved N, N ， -bis (2, 3-dihydroxypropyl) -5- [ (hydroxyacetyl) methylamino]Preparation method of (E) -2,4, 6-triiodo-1, 3-benzenedicarboxamide (I-Mei-Pr) comprises acyl chloride reaction, chloroacetylation reaction, amidation reaction, acetylation reaction and alcoholysis reaction to obtain I-Mei-Pr
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to an improved preparation method of a nonionic X-ray contrast agent iomeprol.
Background
Iomeprol is a non-ionic X-ray contrast agent developed by the braicco company in italy and is widely used for intravascular, subarachnoid and intra-coelomic imaging, and is approved for marketing in italy and in the uk at month 5 in 1993 and at month 12 in 1992, respectively. Compared with the non-ionic contrast agents (such as iohexol, iopamidol and ioversol) of the same type on the market, the iomeprol has the lowest osmotic pressure and lower viscosity at the same concentration, can be prepared into a high-concentration preparation of up to 400mg (I)/ml, has more excellent contrast effect, and therefore, the iomeprol has wide potential application market. Because the high-concentration preparation of the iomeprol is used, the dosage of raw material medicines is large, and the quality requirement is high, the requirements on the preparation method and the purity are high.
There are two main types of methods for the synthesis of iomeprol.
European patent EP0026281A1 discloses two methods:
method 1: taking 5-amino-2, 4, 6-triiodo isophthalic acid as a raw material, firstly carrying out nitrogen methylation reaction, then generating diacyl chloride, then carrying out acylation reaction with acetoxyacetyl chloride, then carrying out amidation reaction with 3-amino-1, 2-propanediol, and finally carrying out hydrolysis reaction with sodium hydroxide to obtain the iomeprol, wherein the synthetic route is as follows:
the synthetic route is short, the reaction condition is simple, but each step of intermediate is required to be treated to carry out the next reaction, both the compound (3) and the compound (4) are unstable bisacyl chloride structures, and the compound (3) and the compound (4) are easy to decompose and inconvenient to store in the post-treatment process; the compound (4) has good water solubility after reacting with 3-amino-1, 2-propanediol, salt generated by the reaction and excessive 3-amino-1, 2-propanediol are not easy to separate, and only the solvent can be distilled out for direct hydrolysis, the obtained iomeprol aqueous solution contains more organic impurities and inorganic salts, anion-cation resin for removing salt and macroporous adsorption resin for removing impurities are needed, the operation is complicated, the yield is low, and the industrial mass production is not facilitated.
Method 2: similarly, 5-amino-2, 4, 6-triiodo isophthalic acid is taken as a raw material, diacyl chloride is firstly generated by reaction, then the diacyl chloride and acetoxyacetyl chloride are subjected to acylation reaction, then the acidylation reaction is carried out with 3-amino-1, 2-propanediol, then the hydrolysis reaction is carried out with sodium hydroxide, and finally the azomethine reaction is carried out, so that the iomeprol is prepared, and the synthetic route is as follows:
the method 2 also has the problems of unstable intermediates and difficult purification of the iomeprol, the last step of methylation reaction uses expensive methyl iodide, the yield is not high (77%), and the method 2 is not suitable for industrial mass production.
Chinese patent CN102363600B optimizes the above route, replaces the acetoxyacetyl chloride with chloroacetyl chloride, and finally, hydroxylates with sodium acetate to obtain iomeprol, the synthetic route is as follows:
the method also needs to separate an unstable intermediate containing the diacyl chloride (the yield of the step is 84.9%), and finally, the hydroxylation reaction with sodium acetate needs a long-time (24 h) high-temperature reflux reaction, so that impurities are increased, a large amount of sodium acetate (3-6 times of molar ratio) is added, and the post-treatment needs anion-cation resin desalting, so that the post-treatment cost is increased.
International patent WO2000032561A1 describes another route for the synthesis of iomeprol by iodination and Smiles ， Rearrangement is a key reaction step, and the route is as follows:
the route avoids the formation of a diacyl chloride intermediate, but the overall synthetic route is longer, the iodination reaction has high toxicity and serious environmental pollution; the intermediate has a plurality of alcoholic hydroxyl groups, has good water solubility, and can not effectively remove water-soluble impurities and inorganic salts; the final step of rearrangement reaction is carried out under the alkaline condition in water, 1-2% of unrearranged impurities can be generated, refining and removal are difficult, a large amount of inorganic salts are still brought, anion-cation resin is needed for desalting, the operation process is complex, and the equipment investment is large.
In view of the above, the existing method for preparing iomeprol fails to achieve a satisfactory large production effect, and has to be improved in terms of reaction operability, cost, yield and purity.
Disclosure of Invention
Aiming at the defects of the prior art, an improved method for preparing the iomeprol is provided through the research on reaction mechanism and a large amount of experimental exploration. The preparation route is as follows:
the preparation method of the invention comprises the following steps:
step 1: performing acyl chlorination reaction on a compound of formula (2) 5-methylamino-2, 4, 6-triiodo-1, 3-phthalic acid and thionyl chloride in an organic solvent to obtain a compound of formula (3) 5-methylamino-2, 4, 6-triiodo-1, 3-phthaloyl chloride; continuously adding acetoxyacetyl chloride into the reaction liquid of the compound of the formula (3) to carry out chloroacetylation reaction, and distilling off the reaction solvent to obtain the compound of the formula (4) 5- [ (acetoxyacetyl) methylamino ] -2,4, 6-triiodo-1, 3-phthaloyl chloride.
Step 2: amidation of a compound of formula (4) with 3-amino-1, 2-propanediol in an organic solvent under the catalysis of a base to obtain a compound of formula (5) 5- [ (acetoxyacetyl) methylamino]-N,N ， -bis (2, 3-dihydroxypropyl) -2,4, 6-triiodo-1, 3-benzenedicarboxamide; continuously adding anhydride and the compound of formula (5) for acetylation reaction, adding water and filtering to obtain the compound of formula (6) 5- [ (acetoxyacetyl) methylamino ]]-N，N ’ Bis (2, 3-diacetoxypropyl) -2,4, 6-triiodo-1, 3-benzenedicarboxamide.
Step 3: dissolving the compound of formula (6) in methanol, performing alcoholysis reaction under base catalysis, adding H-type cationic resin, filtering, and distilling the filtrate to remove methanol to obtain compound N, N of formula (1) ， -bis (2, 3-dihydroxypropyl) -5- [ (hydroxyacetyl) methylamino]-2,4, 6-triiodo-1, 3-benzenedicarboxamide.
The invention has the following technical characteristics:
1. the method combines the two steps of acyl chlorination reaction and chloracetyl reaction into one step operation by adopting a one-pot braising mode, thereby omitting a complex post-treatment process; the compounds of the formula (3) and the formula (4) are not separated independently, so that the damage of the acyl chloride intermediate in the post-treatment process is avoided, and the reaction yield is high; the reaction solvent and the excessive thionyl chloride can be recycled after distillation recovery.
2. The compound of the formula (4) and 3-amino-1, 2-propanediol continue to react with anhydride after the reaction is completed, and the two-step reaction is also carried out in a one-pot mode, so that the operation is simple; the prepared compound of the formula (6) has strong fat solubility, and the solvent, inorganic salt and water-soluble impurities are removed by washing with water after the reaction is finished, thereby being beneficial to separation and purification.
3. The catalytic amount of alkali is used for catalyzing alcoholysis reaction in methanol, the reaction condition is mild, and the side reaction is very few; after the reaction is finished, a small amount of H-type cationic resin is used for neutralizing alkali, so that the use of inorganic acid to generate salt which is not easy to separate from the compound of the formula (1) is avoided, the process of desalting by an anion-cation resin column is omitted, and the investment of equipment is reduced.
The improved method for preparing the iomeprol has the characteristics of few operation steps, mild reaction conditions and simple post-treatment; the obtained iomeprol has stable quality, high yield and good purity (HPLC purity is more than 99.2%), and can improve the quality and medication safety of the preparation product; the material is fed twice in a one-pot braised mode, so that the flow and the operation are further simplified; through process optimization, the investment of a large amount of equipment and personnel is saved, and the method is suitable for continuous industrial mass production.
The specific embodiment is as follows:
example 1: synthesis of 5- [ (acetoxyacetyl) methylamino ] -2,4, 6-triiodo-1, 3-benzenedicarboxyl chloride as Compound of formula (4)
100g of 5-methylamino-2, 4, 6-triiodo-1, 3-phthalic acid and 88g of thionyl chloride are dissolved in 500ml of dichloroethane, and the mixture is heated and refluxed for 2 hours; then 54kg of acetoxyacetyl chloride is added, and the reflux reaction is continued for 2 hours. The dichloroethane and excess thionyl chloride were distilled off to give 122g of the compound 5- [ (acetoxyacetyl) methylamino ] -2,4, 6-triiodo-1, 3-benzenedicarboxyl chloride of formula (4) in 98% yield and 98.2% purity.
Example 2: compound 5- [ (acetoxyacetyl) methylamino of formula (6)]-N，N ’ Synthesis of bis (2, 3-diacetoxypropyl) -2,4, 6-triiodo-1, 3-benzenedicarboxamide
122g of the compound of formula (4) 5- [ (acetoxyacetyl) methylamino)]2,4, 6-triiodo-1, 3-benzenedicarboxyl chloride was dissolved in 244ml of N, N-dimethylacetamide, followed by addition of 56ml of triethylamine and 36.6g of 3-amino-1, 2-propanediol, and reaction was carried out at 20℃for 1.5 hours with heat preservation. 91.5g acetic anhydride was added and the reaction was continued at 25℃for 2h. Adding the reaction solution into 1000ml ice water, stirring for crystallization for 2h after the addition, filtering, and drying to obtain 162g of compound 5- [ (acetoxyacetyl) methylamino of formula (6)]-N，N ’ -bis (2, 3-diacetoxypropyl) -2,4, 6-triiodo-1, 3-benzenedicarboxamide in 95.3% yield and 99% purity.
Example 3: compounds of formula (1) N, N ， -bis (2, 3-dihydroxypropyl) -5- [ (hydroxyacetyl) methylamino]Synthesis of (E) -2,4, 6-triiodo-1, 3-benzenedicarboxamide
162g of the compound of formula (6) 5- [ (acetoxyacetyl) methylamino)]-N，N ’ Bis (2, 3-diacetoxypropyl) -2,4, 6-triiodo-1, 3-benzenedicarboxamide was dissolved in 1200ml of methanol, and 0.4g of sodium methoxide was added thereto to react at 25℃for 2 hours. Adding 5g H type cationic resin, stirring for 1 hr, vacuum filtering, and distilling the filtrate to remove methanol to obtain 125g of compound N, N of formula (1) ， -bis (2, 3-dihydroxypropyl) -5- [ (hydroxyacetyl) methylamino]-2,4, 6-triiodo-1, 3-benzenedicarboxamide in 9 yield8% and the purity is 99.3%. 1 H-NMR (800MHz，DMSO-d 6 ) δ(ppm): 8.47-8.60 (m，2H)， 4.89-4.90 (s，1H)，4.71-4.75 (m，2H)，4.50-4.56 (m，2H)，3.69-3.73 (d，2H)， 3.67-3.69 (m，2H)， 3.30-3.48 (m，4H)，3.00-3.20 (m，4H), 2.50(s，3H)。HRMS-ESI (m/z): 799.8432 [M+Na] + 。
Although the technical scheme of the invention has been described in detail by using specific embodiments in the specification, some modifications or improvements made by those skilled in the art according to the inventive concept in the specific embodiments and application scope are within the scope of the invention as claimed. Therefore, the description herein should not be construed as limiting the invention.
Claims (6)
1. An improved preparation method of a compound shown in a formula (1) is characterized by comprising the following reaction steps:
step 1: performing acyl chlorination reaction on a compound of formula (2) 5-methylamino-2, 4, 6-triiodo-1, 3-phthalic acid and thionyl chloride in an organic solvent to obtain a compound of formula (3) 5-methylamino-2, 4, 6-triiodo-1, 3-phthaloyl chloride; continuously adding acetoxyacetyl chloride into the reaction liquid of the compound shown in the formula (3) to carry out chloroacetylation reaction, and distilling off a reaction solvent to obtain a compound shown in the formula (4) 5- [ (acetoxyacetyl) methylamino ] -2,4, 6-triiodo-1, 3-phthaloyl chloride;
step 2: amidation of a compound of formula (4) with 3-amino-1, 2-propanediol in an organic solvent under the catalysis of a base to obtain a compound of formula (5) 5- [ (acetoxyacetyl) methylamino]-N,N ， -bis (2, 3-dihydroxypropyl) -2,4, 6-triiodo-1, 3-benzenedicarboxamide; continuously adding anhydride and the compound of formula (5) for acetylation reaction, adding water and filtering to obtain the compound of formula (6) 5- [ (acetoxyacetyl) methyl)Amino group]-N，N ’ -bis (2, 3-diacetoxypropyl) -2,4, 6-triiodo-1, 3-benzenedicarboxamide;
step 3: dissolving the compound of formula (6) in methanol, performing alcoholysis reaction under base catalysis, adding H-type cationic resin, filtering, and distilling the filtrate to remove methanol to obtain compound N, N of formula (1) ， -bis (2, 3-dihydroxypropyl) -5- [ (hydroxyacetyl) methylamino]-2,4, 6-triiodo-1, 3-benzenedicarboxamide.
2. Process for the preparation of the compound 5-methylamino-2, 4, 6-triiodo-1, 3-phthaloyl chloride according to claim 1, characterized in that the molar ratio of 5-methylamino-2, 4, 6-triiodo-1, 3-phthalic acid to thionyl chloride in step 1 is 1: 1-3; the organic solvent is chloroform, dichloroethane, toluene or ethyl acetate, and the reaction temperature is 60-120 ℃; the reaction time is 1-10 h.
3. Process for the preparation of the compound 5- [ (acetoxyacetyl) methylamino ] -2,4, 6-triiodo-1, 3-phthaloyl chloride according to claim 1, characterized in that the molar ratio of 5-methylamino-2, 4, 6-triiodo-1, 3-phthalic acid to acetoxyacetyl chloride in step 1 is 1: 1-3; the reaction temperature is 60-120 ℃; the reaction time is 1-12 h.
4. A compound of formula (5) according to claim 1, 5- [ (acetoxyacetyl) methylamino]-N,N ， -a process for the preparation of bis (2, 3-dihydroxypropyl) -2,4, 6-triiodo-1, 3-benzenedicarboxamide, characterized in that the organic solvent in step 2 is N, N-dimethylformamide, N-phenyl-N-methylformamide or N, N-dimethylacetamide; the base is triethylamine, pyridine, diazabicyclo (DBU), potassium carbonate or sodium carbonate; 5- [ (acetoxyacetyl) methylamino]The molar ratio of the 2,4, 6-triiodo-1, 3-phthaloyl chloride to the 3-amino-1, 2-propanediol is 1: 2-3; the reaction temperature is 0-30 ℃; the reaction time is 1-5 h.
5. A compound of formula (6) according to claim 1, 5- [ (acetoxyacetyl) methylamino]-N，N ’ -a process for the preparation of bis (2, 3-diacetoxypropyl) -2,4, 6-triiodo-1, 3-benzenedicarboxamide, characterized in that the anhydride in step 2 is acetic anhydride or propionic anhydride; 5- [ (acetoxyacetyl) methylamino]The molar ratio of 2,4, 6-triiodo-1, 3-phthaloyl chloride to anhydride is 1: 4-6; the reaction temperature is 0-40 ℃; the reaction time is 1-5 h.
6. The compound N, N of formula (1) according to claim 1 ， -bis (2, 3-dihydroxypropyl) -5- [ (hydroxyacetyl) methylamino]-2,4, 6-triiodo-1, 3-benzenedicarboxamide, characterized in that the base in step 3 is sodium methoxide, sodium ethoxide or potassium tert-butoxide; 5- [ (acetoxyacetyl) methylamino]-N，N ’ -bis (2, 3-diacetoxypropyl) -2,4, 6-triiodo-1, 3-benzenedicarboxamide to base molar ratio 1:0.01 to 0.1; the reaction temperature is 10-40 ℃; the reaction time is 1-4 h.
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| KR20180073981A (en) * | 2016-12-23 | 2018-07-03 | 엠에프씨 주식회사 | preparation method of contrast agent |
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