CN116589422A - Total synthesis and purification method of high-purity MRI (magnetic resonance imaging) contrast agent intermediate - Google Patents
Total synthesis and purification method of high-purity MRI (magnetic resonance imaging) contrast agent intermediate Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 35
- 238000000746 purification Methods 0.000 title claims description 21
- 238000006257 total synthesis reaction Methods 0.000 title claims description 13
- 238000002595 magnetic resonance imaging Methods 0.000 title description 10
- 239000002872 contrast media Substances 0.000 title description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 202
- 238000001914 filtration Methods 0.000 claims abstract description 30
- 238000002425 crystallisation Methods 0.000 claims abstract description 14
- 230000008025 crystallization Effects 0.000 claims abstract description 14
- 239000002616 MRI contrast agent Substances 0.000 claims abstract description 12
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 claims abstract description 12
- 230000001105 regulatory effect Effects 0.000 claims abstract description 10
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims abstract description 8
- 238000005406 washing Methods 0.000 claims abstract description 7
- 239000012043 crude product Substances 0.000 claims description 87
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 81
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 81
- 238000006243 chemical reaction Methods 0.000 claims description 77
- 239000003960 organic solvent Substances 0.000 claims description 62
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 58
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 42
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 39
- 239000002904 solvent Substances 0.000 claims description 38
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 34
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 32
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 27
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 25
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- 239000003513 alkali Substances 0.000 claims description 20
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 20
- 239000003208 petroleum Substances 0.000 claims description 17
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 16
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 16
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 16
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 15
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 15
- 239000007864 aqueous solution Substances 0.000 claims description 14
- 239000002585 base Substances 0.000 claims description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 13
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 12
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 10
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 10
- 235000011181 potassium carbonates Nutrition 0.000 claims description 10
- 238000000605 extraction Methods 0.000 claims description 9
- 239000012046 mixed solvent Substances 0.000 claims description 9
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 9
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 9
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 8
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 8
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 claims description 8
- 235000011056 potassium acetate Nutrition 0.000 claims description 8
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 8
- 230000007062 hydrolysis Effects 0.000 claims description 7
- 238000006460 hydrolysis reaction Methods 0.000 claims description 7
- 230000009471 action Effects 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 6
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 6
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 6
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 6
- 235000011009 potassium phosphates Nutrition 0.000 claims description 6
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 claims description 5
- 229910000343 potassium bisulfate Inorganic materials 0.000 claims description 5
- 238000003786 synthesis reaction Methods 0.000 claims description 5
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 4
- 239000005695 Ammonium acetate Substances 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- 235000019257 ammonium acetate Nutrition 0.000 claims description 4
- 229940043376 ammonium acetate Drugs 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 238000006264 debenzylation reaction Methods 0.000 claims description 4
- 239000011736 potassium bicarbonate Substances 0.000 claims description 4
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 4
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 4
- 239000001632 sodium acetate Substances 0.000 claims description 4
- 235000017281 sodium acetate Nutrition 0.000 claims description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 235000011007 phosphoric acid Nutrition 0.000 claims description 3
- 235000017550 sodium carbonate Nutrition 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 2
- 229910000404 tripotassium phosphate Inorganic materials 0.000 claims description 2
- 235000019798 tripotassium phosphate Nutrition 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 35
- 238000004128 high performance liquid chromatography Methods 0.000 abstract description 11
- 230000003321 amplification Effects 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 238000003199 nucleic acid amplification method Methods 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 239000012535 impurity Substances 0.000 abstract 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 abstract 1
- 238000013421 nuclear magnetic resonance imaging Methods 0.000 abstract 1
- 238000010791 quenching Methods 0.000 abstract 1
- 230000000171 quenching effect Effects 0.000 abstract 1
- 239000012074 organic phase Substances 0.000 description 44
- 239000000243 solution Substances 0.000 description 31
- 238000003756 stirring Methods 0.000 description 26
- 238000001035 drying Methods 0.000 description 17
- 239000011259 mixed solution Substances 0.000 description 15
- 238000006467 substitution reaction Methods 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 238000012544 monitoring process Methods 0.000 description 8
- 238000004090 dissolution Methods 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 239000000203 mixture Substances 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 239000013522 chelant Substances 0.000 description 4
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical group COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000003759 clinical diagnosis Methods 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- JHVLLYQQQYIWKX-UHFFFAOYSA-N benzyl 2-bromoacetate Chemical compound BrCC(=O)OCC1=CC=CC=C1 JHVLLYQQQYIWKX-UHFFFAOYSA-N 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000005865 ionizing radiation Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
-
- 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
Abstract
The invention provides a preparation method of a high-purity compound with a formula (IV): the method comprises the following steps: 1) Nucleophilic substitution reaction is carried out on the compound shown in the formula 1 and tert-butyl bromoacetate, and the compound shown in the formula (II) is obtained through quenching, filtering, washing and crystallization; 2) The compound shown in the formula (II) reacts with nucleophilic substitution, and the compound shown in the formula (III) with high purity is obtained through washing, concentration and crystallization; 3) The compound of the formula (III) is hydrolyzed or catalytically hydrogenated, and the pH is regulated, extracted and crystallized to obtain the high-purity nuclear magnetic resonance imaging drug intermediate compound shown in the formula (IV). The method adopted by the invention can obtain the high-purity MRI contrast agent with the HPLC purity more than or equal to 99.8 percent and single impurity less than 0.1 percent, and can be applied to kilogram scale amplification production.
Description
Technical Field
The invention relates to the technical field of organic synthesis of medical intermediates, in particular to a full synthesis and purification method of a high-purity MRI contrast agent intermediate.
Background
Nuclear magnetic resonance technology (MRI) can obtain high-resolution images without using ionizing radiation, and thus is widely used in clinical diagnosis and research, particularly in screening and diagnosis of tumor tissues. A series of derivatives synthesized by taking the compound shown in the formula (I) as a raw material can form stable chelate with Gd (III) ions, and the stable chelate is used as a contrast agent for nuclear magnetic resonance scanning technology to enhance the sensitivity and resolution of the stable chelate, so that the purposes of reducing the scanning time, completing the clinical diagnosis more quickly and accurately can be achieved, and the stable chelate has important practical application value. DOTA-tri-t-Butyl ester (a compound of formula (VI)) has received considerable attention as a primary intermediate in the preparation of such Magnetic Resonance Imaging (MRI) contrast agents, particularly in terms of quality, especially formula purity and content. The chinese name of DOTA-tri-t-Butyl ester formula (VI) is: 1,4,7, 10-tetraazacyclododecane-1, 4, 7-tri-tert-butyl triacetate-10-acetic acid has the following structural formula:
according to various literature disclosures, (see J.am. Soc.2011,133,16346-16349, chem. Sci.,2015,6,6256, chem. Eur. J.2019,25,10895-10906 and org. Biomol. Chem.,2021,19,2186), the compound of formula (IV) is prepared from the compound of formula (I) by a three-step reaction, but most of them are purified by column purification or cation exchange resin, which is expensive, cumbersome to handle and not suitable for large scale production. Patent publication No. CN113999185A describes a method for providing a compound of the formula (IV) in high purity, but only the final reaction and post-treatment purification operation are involved, and there is no purification method for the key intermediates involved, so that it is necessary to find a method for obtaining a compound of the formula (IV) in high purity simply and efficiently for efficient mass production. The invention comprises taking the material of the compound shown as formula (I) as the initial material, carrying out three steps of reactions, and purifying each step of reaction, thus not only obtaining the compound shown as the formula (II) and the formula (III) with higher purity, but also comprising the novel method of obtaining the compound shown as the formula (IV) with ultrahigh purity by the last step of reaction and purification.
Disclosure of Invention
(one) solving the technical problems
The invention aims to provide a full synthesis and purification method of a high-purity Magnetic Resonance Imaging (MRI) contrast agent, which has the advantages of simple process, convenient operation and convenient amplification.
(II) technical scheme
In order to achieve the above purpose, the present invention provides the following technical solutions: a full synthesis and purification method of high-purity Magnetic Resonance Imaging (MRI) contrast agent has the following reaction formula:
the method comprises the following steps:
1) Under the action of alkali, a compound of formula (I) and tert-butyl bromoacetate undergo nucleophilic substitution reaction in an organic solvent;
2) After the nucleophilic substitution reaction in the step 1) is completed, adjusting the pH to 8-10 by using an aqueous solution of alkali at low temperature, and filtering to obtain a wet crude product of the compound shown in the formula (II);
3) Dissolving the wet crude product shown in the formula (II) obtained in the step 2) by using an organic solvent, and washing, concentrating and crystallizing to obtain a high-purity compound shown in the formula (II);
4) Heating the compound of the formula (II) and the compound of the formula (V) obtained in the step 3) in an organic solvent under the action of alkali to perform nucleophilic substitution reaction, filtering and concentrating to obtain a crude product of the compound of the formula (III);
5) The crude product of the compound shown in the formula (III) obtained in the step 4) is washed and crystallized by an organic solvent to obtain the compound shown in the formula (III) with high purity;
6) When R is methyl, ethyl or benzyl, the compound shown in the formula (III) obtained in the step 5) can be hydrolyzed in a mixed solvent under the action of alkali to obtain a compound shown in the formula (IV); when R is benzyl, the compound shown in the formula (IV) can be obtained through catalytic hydrogenation debenzylation;
7) And (3) after the compound shown in the formula (III) in the step (6) is subjected to hydrolysis or catalytic hydrogenation debenzylation, regulating the pH value to 5-8 in water, and extracting, concentrating and crystallizing by using an organic solvent to obtain the compound shown in the formula (IV) with high purity.
Preferably, the base used in step 1) is potassium acetate, sodium acetate or ammonium acetate in an amount equivalent to the compound of formula (1) of 4:1 or 5:1, the equivalent ratio of the ethyl bromoacetate to the compound shown in the formula (I) is as follows: 3.1-4:1.
preferably, the reaction organic solvent used in step 1) is N, N-dimethylformamide or N, N-dimethylacetamide in an amount such that the ratio to the compound of formula (I) is 3:1 to 4:1.
preferably, the reaction temperature used in step 1) is from 0℃to 20 ℃.
Preferably, in the step 1), the compound of formula (I) and the base are added to the reaction solvent in the order of addition, and ethyl bromoacetate is added dropwise to the reaction solution.
Preferably, step 2) adjusts the pH temperature in the range of 0 ℃ to 30 ℃.
Preferably, the base used in step 2) is sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate or potassium phosphate.
Preferably, the volume ratio of the amount of water used in step 2) to the organic solvent used in step 1) is 3:1-5:1.
preferably, the organic solvent used to dissolve the crude product in step 3) is chloroform, dichloroethane or dichloromethane.
Preferably, the crystallization solvent in the step 3) is one or more of dichloromethane, chloroform, petroleum ether, n-hexane, n-heptane, ethyl acetate or tert-butyl methyl ether, and the ratio of the compound shown in the formula (I) to the crystallization solvent is 1g:10-15mL.
Preferably, the base used in step 4) is potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium methoxide or sodium ethoxide.
Preferably, the equivalent ratio of base used in step 4) to compound of formula (II) is from 1.2 to 2:1.
preferably, the organic solvent used in step 4) is methanol, ethanol, acetonitrile or tetrahydrofuran.
Preferably, the reaction temperature in step 4) is 40-80 ℃, the higher the reaction temperature, the faster the reaction speed.
Preferably, the organic solvent used for dissolving the crude product in step 5) is ethyl acetate, dichloromethane, chloroform or dichloroethane, and the ratio of the solvent used to the compound of formula (II) in step 4) is 5mL:1g.
Preferably, the solvent used in the crystallization in the step 5) is one or more of normal hexane, petroleum ether, ethyl acetate, methylene dichloride and methyl tertiary butyl ether, and the volume weight ratio of the crystallization solvent to the compound shown in the formula (II) is 5mL:1g.
Preferably, the base used in the hydrolysis in step 6) is lithium hydroxide, potassium hydroxide or sodium hydroxide.
Preferably, the ratio of the base used for the hydrolysis in step 6) to the compound of formula (III) is 1.1:1-3:1, the higher the alkali proportion, the faster the reaction rate.
Preferably, the mixed solvent used in the hydrolysis in the step 6) is water and methanol, ethanol, tetrahydrofuran or acetonitrile, and the volume ratio of water to organic solvent is 5:1-20:1, the ratio of solvent used to compound of formula (III) is 5:1-10:1.
preferably, in step 6) when R is benzyl, the catalyst used for the catalytic hydrogenation is Pd/C (10%) and is used in an amount of 5% by weight of the compound of formula (III).
Preferably, in step 6), when R is benzyl, the solvent for catalytic hydrogenation reaction is one or more of water, methanol, ethanol, tetrahydrofuran or acetonitrile, and the ratio of the solvent to the compound of formula (iii) is 10mL:1g.
Preferably, in step 6), when R is benzyl, the catalytic hydrogenation reaction temperature is room temperature.
Preferably, the acid used in step 7) to a pH of 5-8 is hydrochloric acid, sulfuric acid, sodium dihydrogen phosphate, potassium dihydrogen phosphate, phosphoric acid or potassium hydrogen sulfate.
Preferably, the organic solvent used for extraction in step 7) is ethyl acetate, dichloromethane or chloroform, and the ratio of the solvent used to the compound of formula (III) used in step 4) is 10mL:1g.
Preferably, the solvent used for crystallization in the step 7) is one or more of normal hexane, petroleum ether, diethyl ether, ethyl acetate, dichloromethane and dichloroethane, and the ratio of the solvent used for crystallization to the compound shown in the formula (IV) is 3-5mL:1g.
(III) beneficial effects
Compared with the prior art, the invention provides a total synthesis and purification method of a high-purity Magnetic Resonance Imaging (MRI) contrast agent, which has the following beneficial effects:
the method of the invention can obtain the compound shown in the formula (IV) with high purity through three steps of reaction and purification, and the structure is confirmed by HNNR and MS, and the HPLC purity is more than 99.8 and is 99.97 percent at most.
Description of the drawings:
FIG. 1 is a HNMR spectrum of compound 1 of formula (IV);
FIG. 2 is an HPLC chart of the compound represented by the formula (IV).
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The invention provides a total synthesis and purification method of a high-purity Magnetic Resonance Imaging (MRI) contrast agent, which has the following reaction formula:
the method comprises the following steps:
1) Synthesizing a compound shown in a formula (II): placing a compound shown in a formula (I) in a container, and adding a proper amount of organic solvent, wherein the solvent comprises N, N-dimethylformamide or N, N-dimethylacetamide, and the volume-mass ratio of the solvent to the compound shown in the formula (I) is 3mL:1g-4mL:1g, stirring and dissolving completely, and then adding a proper amount of alkali, wherein the alkali comprises potassium acetate, sodium acetate or ammonium acetate, and the equivalent ratio of the alkali to the compound shown in the formula (I) is 3.1:1-5:1. and then dropwise adding tert-butyl bromoacetate at a proper temperature, wherein the proper temperature is 0-20 ℃, and the equivalent ratio of the tert-butyl bromoacetate to the compound shown in the formula (I) is 3.1:1-4:1. After the addition was completed, the reaction was continued and monitored by HPLC or TLC until the reaction was completed. After the reaction is completed, the pH is adjusted to 8-10 by using an aqueous alkali solution, wherein the alkali comprises sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate or potassium phosphate, and the volume ratio of the water consumption to the volume ratio of the organic solvent used in the reaction is 3:1-5:1. the system was then filtered and the filter cake was dissolved in an appropriate amount of organic solvents, including chloroform, dichloroethane or dichloromethane, in a volume to weight ratio to the compound of formula (I) of 10mL:1g. Washing the organic solvent with water, and concentrating to obtain crude product. Crystallizing the crude product with a proper amount of solvent, wherein the solvent comprises one or more of dichloromethane, chloroform, petroleum ether, n-hexane, n-heptane, ethyl acetate or tert-butyl methyl ether, and the volume weight ratio of the organic solvent for crystallization to the compound shown in the formula (1) is 10-15mL:1g. And filtering and drying to obtain the compound shown in the formula (II) with high purity.
2) Synthesizing a compound shown in a formula (III): placing a compound shown in a formula (II) in a container, and adding a proper amount of organic solvent, wherein the organic solvent comprises methanol, ethanol, acetonitrile or tetrahydrofuran, and the volume weight ratio of the organic solvent to the compound shown in a formula (III) is 5mL to 1g. After stirring and fully dissolving, adding a proper amount of alkali, wherein the alkali comprises potassium carbonate, sodium carbonate, cesium carbonate, tripotassium phosphate, sodium methoxide or sodium ethoxide, and the equivalent ratio of the alkali dosage to the compound shown in the formula (III) is 1.2-2:1. then adding a proper amount of a compound shown in a formula (V), wherein the equivalent ratio of the compound shown in the formula (V) to the compound shown in a formula (III) is 1.1-2:1. then the reaction solution is heated to a proper temperature for reaction, and the reaction temperature is 40-80 ℃. Monitoring by HPLC or TLC until the reaction is finished, cooling the reaction liquid, filtering, and concentrating to obtain a crude product. The crude product is dissolved by an appropriate amount of organic solvent, wherein the organic solvent comprises ethyl acetate, dichloromethane, chloroform or dichloroethane, and the volume weight ratio of the organic solvent to the compound shown in the formula (III) is 5mL:1g. The organic phase is washed with water and concentrated to obtain crude product. Crystallizing the crude product by using a proper and proper amount of solvent, wherein the organic solvent comprises one or more of normal hexane, petroleum ether, ethyl acetate, dichloromethane and dichloroethane, and the volume weight ratio of the organic solvent to the compound shown in the formula (II) is 5mL to 1g. And then filtering and drying to obtain the compound shown in the formula (III) with high purity.
3) When the R group is methyl, ethyl or benzyl, the compound shown in the formula (IV) is synthesized by hydrolysis: placing a compound shown in a formula (III) in a container, and adding a proper amount of an organic solvent, wherein the organic solvent comprises methanol, ethanol, tetrahydrofuran or acetonitrile. The volume weight ratio of the organic solvent to the compound shown in the formula (III) is 0.25-1 mL/1 g. Then adding a proper amount of aqueous solution of alkali, wherein the alkali comprises lithium hydroxide, potassium hydroxide or sodium hydroxide, and the equivalent ratio of the alkali to the compound shown in the formula (III) is 1.1-3:1, the volume weight ratio of the water consumption to the compound shown in the formula (III) is 5-20mL:1g. After completion of the reaction, the reaction mixture was adjusted to pH 5-8 with an acid selected from the group consisting of hydrochloric acid, sulfuric acid, sodium dihydrogen phosphate, potassium dihydrogen phosphate and potassium hydrogen sulfate. Then extracting the reaction liquid with a proper amount of organic solvent, wherein the organic solvent for extraction comprises ethyl acetate, dichloromethane or chloroform, and the volume weight ratio of the organic solvent to the compound shown in the formula (III) is 10mL:1g. Washing the organic solvent with water, and concentrating to obtain crude product. Crystallizing the crude product with an appropriate amount of organic solvent, wherein the organic solvent comprises one or more of n-hexane, petroleum ether, methyl tertiary butyl ether, ethyl acetate and dichloromethane, and the volume weight ratio of the amount of the organic solvent for crystallization to the compound shown in the formula (III) is 3-5mL:1g. And then filtering and drying to obtain the compound shown in the formula (IV) with high purity.
4) When the R group is benzyl, the compound shown in the formula (IV) is synthesized by catalytic hydrogenation reduction of a trivia compound shown in the formula (III): placing a compound shown in a formula (III) in a container, adding a proper amount of organic solvent, wherein the organic solvent comprises one or more of methanol, ethanol, tetrahydrofuran and acetonitrile, and the volume weight ratio of the organic solvent to the compound shown in the formula (III) is 10 mL/1 g. After nitrogen substitution three times, 5% by weight of wet palladium carbon was added, nitrogen substitution was again performed three times, and then hydrogen substitution was again performed three times, and the catalytic hydrogenation reaction was started to be performed at room temperature. The reaction is monitored to be finished by HPLC or TLC, and the reaction solution is filtered and concentrated until the volume weight ratio of the residual organic solvent to the compound shown in the formula (III) is as follows: 0.25-1mL:1g. Adding a proper amount of water, wherein the volume weight ratio of the water amount to the compound shown in the formula (III) is 5-20mL:1g, the reaction solution is adjusted to pH 5-8 with an acid, which includes hydrochloric acid, sulfuric acid, sodium dihydrogen phosphate, potassium dihydrogen phosphate, phosphoric acid or potassium hydrogen sulfate. Then extracting the reaction liquid with a proper amount of organic solvent, wherein the organic solvent for extraction comprises ethyl acetate, dichloromethane or chloroform, and the volume weight ratio of the organic solvent to the compound shown in the formula (III) is 10mL:1g. Washing the organic solvent with water, and concentrating to obtain crude product. Crystallizing the crude product with an appropriate amount of organic solvent, wherein the organic solvent comprises one or more of n-hexane, petroleum ether, methyl tertiary butyl ether, ethyl acetate and dichloromethane, and the volume weight ratio of the organic solvent to the compound shown in the formula (III) is as follows: 3-5mL:1g. And then filtering and drying to obtain the compound shown in the formula (IV) with high purity.
Embodiment one:
1) Preparation of Compounds of formula (II)
172g of a compound shown in a formula (I) is placed in a three-mouth bottle, 520mL of N, N-dimethylformamide is added, 254g of sodium acetate is added after stirring and complete dissolution, 605g of tert-butyl bromoacetate is dropwise added under stirring, after stirring and reaction for 12h, 2000g of 20% sodium carbonate aqueous solution is slowly dropwise added, the pH is regulated to 8.0, solids are separated out, and a wet crude product is obtained after filtration. The wet crude was dissolved with 1720mL of dichloromethane and the organic phase was washed once with 1000mL of water. The organic phase is separated and concentrated to obtain a crude product, the crude product is crushed and added into 2600mL of normal hexane, the mixture is stirred for 1h, filtered and dried to obtain 476g of a compound shown in a formula (II), and the yield is 80%.
2) Preparation of the Compound (R=ethyl) of formula (III)
476g of the compound of formula (II) was placed in a three-necked flask, 2500mL of methanol was added, 51.8g of sodium methoxide and 147g of ethyl bromoacetate were added with stirring, the temperature was raised to 40℃and the reaction was stirred for 1 hour, after the completion of the TLC monitoring, the reaction solution was cooled to room temperature, filtered and concentrated to be solvent-free. The crude product is dissolved by 2500mL of ethyl acetate, 1000mL of water is washed once, the organic phase is concentrated to be free of solvent, the crude product is recrystallized by 2500mL of normal hexane, and 456g of the compound shown in the formula (III) is obtained after filtration and drying, and the yield is 95%.
3) Preparation of Compounds of formula (IV)
456g of the compound of formula (iii) (r=ethyl) were placed in a three-necked flask, 114mL of methanol was added, 2500g of a 2.3% aqueous lithium hydroxide solution was added, the reaction was carried out at room temperature for 6 hours, the reaction was monitored by hplc, the pH was adjusted to 7.2 with a 10% aqueous hydrochloric acid solution, and then extracted once with 4500mL of ethyl acetate, and the organic phase was washed twice with 2000mL of water each time. The organic phase is concentrated to obtain a crude product, 2700mL of normal hexane is used for recrystallization, and 304g of a compound shown in a formula (IV) is obtained after filtration and drying, and the yield is 70%.
Embodiment two:
1) Preparation of Compounds of formula (II)
172g of a compound shown in a formula (I) is placed in a three-necked flask, 680mL of N, N-dimethylacetamide is added, 392g of potassium acetate is added after stirring and complete dissolution, 686g of tert-butyl bromoacetate is dropwise added under stirring, 2000g of 25% potassium carbonate aqueous solution is slowly dropwise added after stirring and reaction for 12h, pH is regulated to 8.3, solid is separated out, and a wet crude product is obtained after filtration. The wet crude was dissolved with 1720mL of dichloroethane and the organic phase was washed once with 1000mL of water. The organic phase is separated and concentrated to obtain a crude product, the crude product is crushed and added into 2600mL of petroleum ether, the mixture is stirred for 1h, filtered and dried to obtain 456g of a compound shown as a formula (II), and the yield is 77%.
2) Preparation of the Compound (R=ethyl) of formula (III)
456g of the compound of formula (II) is placed in a three-necked flask, 2300mL of ethanol is added, 63g of sodium ethoxide and 154g of ethyl bromoacetate are added under stirring, the temperature is raised to 80 ℃ and the reaction is stirred for 1h, after TLC monitoring is finished, the reaction solution is cooled to room temperature, filtered and concentrated to be free of solvent. The crude product is dissolved by 2000mL of dichloromethane, 1000mL of dichloromethane is washed once, the organic phase is concentrated until no solvent exists, the crude product is recrystallized by 2000mL of petroleum ether, and 434g of the compound shown in the formula (III) is obtained after filtration and drying, and the yield is 94%.
3) Preparation of Compounds of formula (IV)
434g of the compound of formula (iii) (r=ethyl) was placed in a three-necked flask, 440mL of ethanol was added, 4300g of 1% aqueous potassium hydroxide solution was added, the reaction was carried out at room temperature for 12 hours, hplc was monitored to be complete, pH was adjusted to 6.7 with 10% aqueous sulfuric acid solution, and then extraction was carried out once with 4500mL of dichloromethane, and the organic phase was washed twice with 2000mL of water each time. The organic phase is concentrated to obtain a crude product, the crude product is recrystallized by 2700mL of petroleum ether, and 274g of a compound shown in a formula (IV) is obtained after filtration and drying, and the yield is 66%.
Embodiment III:
1) Preparation of Compounds of formula (II)
172g of a compound shown in a formula (I) is placed in a three-necked flask, 680mL of N, N-dimethylformamide is added, 385g of ammonium acetate is added after stirring and complete dissolution, 784g of tert-butyl bromoacetate is dropwise added under stirring and reaction is carried out for 12h, 2000g of 30% potassium bicarbonate aqueous solution is slowly dropwise added, pH is regulated to 9.0, solid is separated out, and wet crude product is obtained after filtration. The wet crude product was dissolved with 1720mL of chloroform and the organic phase was washed once with 1000mL of water. The organic phase is separated and concentrated to obtain a crude product, the crude product is crushed and added into 2600mL of n-heptane, the mixture is stirred for 1h, filtered and dried to obtain 462g of a compound shown as a formula (II), and the yield is 78%.
2) Preparation of the Compound (R=ethyl) of formula (III)
462g of the compound of formula (II) was placed in a three-necked flask, 2300mL of acetonitrile was added, 165g of sodium carbonate and 261g of ethyl bromoacetate were added under stirring, the temperature was raised to 80℃and the reaction was stirred for 1h, after the completion of the TLC monitoring reaction, the reaction solution was cooled to room temperature, filtered and concentrated to be solvent-free. The crude product is dissolved by 2300mL of chloroform, 1000mL of chloroform is washed once, the organic phase is concentrated until no solvent exists, the crude product is recrystallized by 250mL of mixed solvent of methyl tertiary butyl ether and 2250mL of petroleum ether, 397g of compound shown in formula (III) is obtained after filtration and drying, and the yield is 85%.
3) Preparation of Compounds of formula (IV)
397g of the compound of formula (iii) (r=ethyl) were placed in a three-necked flask, 800mL of tetrahydrofuran was added, 2000g of 3.3% aqueous sodium hydroxide solution was added, the reaction was carried out at room temperature for 12 hours, hplc was monitored to be complete, pH was adjusted to 5.0 with 10% aqueous sodium dihydrogen phosphate solution, then extraction was carried out once with 4000mL of chloroform, and the organic phase was washed twice with 2000mL of water each time. The organic phase is concentrated to obtain a crude product, the crude product is recrystallized by using 50mL of mixed solution of dichloromethane and 950mL of petroleum ether, and the crude product is filtered and dried to obtain 190g of a compound shown in a formula (IV) with a yield of 50%.
Experimental example four:
1) Preparation of Compounds of formula (II)
172g of a compound shown in a formula (I) is placed in a three-necked flask, 680mL of N, N-dimethylformamide is added, 392g of potassium acetate is added after stirring and complete dissolution, 605g of tert-butyl bromoacetate is dropwise added under stirring and reaction is carried out for 12h, 2000g of 20% cesium carbonate aqueous solution is slowly dropwise added, pH is regulated to 8.6, solid is separated out, and the wet crude product is obtained after filtration. The wet crude product was dissolved with 1720mL of chloroform and the organic phase was washed once with 1000mL of water. The organic phase is separated and concentrated to obtain a crude product, the crude product is crushed and added into a mixed solution of 350mL of dichloromethane and 1400mL of normal hexane, the mixed solution is stirred for 1h, filtered and dried to obtain 416g of a compound shown in a formula (II), and the yield is 70%.
2) Preparation of the Compound (R=ethyl) of formula (III)
416g of the compound of formula II is placed in a three-necked flask, 2200mL of tetrahydrofuran is added, 296g of potassium phosphate and 175g of ethyl bromoacetate are added under stirring, the temperature is raised to 70 ℃ and the reaction is stirred for 1h, after the TLC monitoring reaction is finished, the reaction solution is cooled to room temperature, filtered and concentrated until no solvent exists. The crude product is dissolved by 2200mL of dichloroethane, 1000mL of the solution is washed once, the organic phase is concentrated until no solvent exists, the crude product is recrystallized by 250mL of mixed solvent of ethyl acetate and 2250mL of petroleum ether, 378g of the compound shown in the formula (III) is obtained after filtration and drying, and the yield is 90%.
3) Preparation of Compounds of formula (IV)
378g of the compound of formula (III) (R=ethyl) are placed in a three-necked flask, 800mL of acetonitrile is added, 2000g of 2.5% aqueous sodium hydroxide solution is added, the reaction is carried out at room temperature for 12 hours, the reaction is monitored by HPLC, the pH is adjusted to 7.5 by 10% aqueous potassium hydrogen sulfate solution, then the mixture is extracted once by 4000mL of chloroform, and the organic phase is washed twice with 2000mL of water each time. The organic phase is concentrated to obtain a crude product, the crude product is recrystallized by using 400mL of mixed solution of methyl tertiary butyl ether and 1600mL of normal hexane, and 238g of a compound shown in a formula (IV) is obtained after filtering and drying, and the yield is 66%.
Fifth embodiment:
1) Preparation of Compounds of formula (II)
172g of a compound shown in a formula (I) is placed in a three-mouth bottle, 680mL of N, N-dimethylformamide is added, 392g of potassium acetate is added after stirring and complete dissolution, 605g of tert-butyl bromoacetate is dropwise added under stirring, 2000g of 30% potassium phosphate aqueous solution is slowly dropwise added after stirring and reaction for 12h, the pH is regulated to 9.4, solids are separated out, and a wet crude product is obtained after filtration. The wet crude product was dissolved with 1720mL of chloroform and the organic phase was washed once with 1000mL of water. The organic phase is separated and concentrated to obtain a crude product, the crude product is crushed and added into a mixed solution of 350mL of chloroform and 1400mL of normal hexane, the mixed solution is stirred for 1h, filtered and dried to obtain 386g of a compound shown as a formula (II), and the yield is 65%.
2) Preparation of the Compound (R=ethyl) of formula (III)
386g of the compound represented by the formula (II) is placed in a three-necked flask, 2000mL of ethanol is added, 422g of cesium carbonate and 130g of ethyl bromoacetate are added under stirring, the temperature is raised to 80 ℃ and the reaction is stirred for 1h, after the TLC monitoring reaction is finished, the reaction solution is cooled to room temperature, filtered and concentrated to be free of solvent. The crude product is dissolved by 2000mL of ethyl acetate, 1000mL of water is washed once, the organic phase is concentrated to be free of solvent, the crude product is recrystallized by using a mixed solvent of 250mL of dichloromethane and 2250mL of petroleum ether, 273g of a compound shown in a formula (III) is obtained after filtration and drying, and the yield is 70%.
3) Preparation of Compounds of formula (IV)
273g of the compound of formula (iii) (r=ethyl) are placed in a three-necked flask, 300mL of ethanol is added, 2000g of 1.8% aqueous sodium hydroxide solution is added, the reaction is carried out at room temperature for 12 hours, hplc is monitored to be complete, the pH is adjusted to 5.8 with 10% aqueous potassium dihydrogen phosphate solution, then extraction is carried out once with 4000mL of dichloromethane, and the organic phase is washed twice with 2000mL of water each time. The organic phase is concentrated to obtain a crude product, the crude product is recrystallized by using a mixed solution of 50mL of ethyl acetate and 950mL of petroleum ether, and the crude product is filtered and dried to obtain 130g of a compound shown in a formula (IV) with a yield of 50%.
Example six
1) Preparation of Compounds of formula (II)
172g of a compound shown in a formula (I) is placed in a three-necked flask, 680mL of N, N-dimethylformamide is added, 392g of potassium acetate is added after stirring and complete dissolution, 605g of tert-butyl bromoacetate is dropwise added under stirring and reaction is carried out for 12h, 2000g of 25% potassium carbonate aqueous solution is slowly dropwise added, pH is regulated to 8.6, solid is separated out, and the wet crude product is obtained after filtration. The wet crude product was dissolved with 1720mL of chloroform and the organic phase was washed once with 1000mL of water. The organic phase is separated and concentrated to obtain a crude product, the crude product is crushed and added into a mixed solution of 500mL of ethyl acetate and 2000mL of methyl tertiary butyl ether, the mixture is stirred for 1h, filtered and dried, 376g of a compound shown in a formula (II) is obtained, and the yield is 63%.
2) Preparation of Compound (R=methyl) of formula (III)
376g of the compound of formula (II) was placed in a three-necked flask, 2000mL of methanol was added thereto, 41g of sodium methoxide and 116g of methyl bromoacetate were added thereto with stirring, the temperature was raised to 40℃and the reaction was stirred for 1 hour, after the completion of the TLC monitoring, the reaction solution was cooled to room temperature, filtered and concentrated to be solvent-free. The crude product is dissolved by 1800mL of ethyl acetate, 1000mL of water is washed once, the organic phase is concentrated to be free of solvent, the crude product is recrystallized by a mixed solvent of 250mL of ethyl acetate and 2250mL of normal hexane, and 234g of a compound (R=methyl) shown in a formula (III) is obtained after filtration and drying, and the yield is 62%.
3) Preparation of Compounds of formula (IV)
234g of the compound of formula (iii) (r=methyl) are placed in a three-necked flask, 250mL of methanol is added, 1500g of 2% aqueous sodium hydroxide solution is added, the reaction is carried out at room temperature for 12 hours, hplc is monitored to be complete, the pH is adjusted to 8.0 with 10% aqueous phosphoric acid solution, then extraction is carried out once with 4000mL of chloroform, and the organic phase is washed twice with 2000mL of water each time. The organic phase is concentrated to obtain a crude product, the crude product is recrystallized by using 400mL of mixed solution of methyl tertiary butyl ether and 1600mL of n-hexane, and 136g of a compound shown in a formula (IV) is obtained by filtering and drying, and the yield is 61%.
Example seven
1) Preparation of Compounds of formula (II)
172g of a compound shown in a formula (I) is placed in a three-necked flask, 680mL of N, N-dimethylformamide is added, 392g of potassium acetate is added after stirring and complete dissolution, 605g of tert-butyl bromoacetate is dropwise added under stirring and reaction is carried out for 12h, 2000g of 25% potassium carbonate aqueous solution is slowly dropwise added, pH is regulated to 8.6, solid is separated out, and the wet crude product is obtained after filtration. The wet crude product was dissolved with 1720mL of chloroform and the organic phase was washed once with 1000mL of water. The organic phase is separated and concentrated to obtain a crude product, the crude product is crushed and added into a mixed solution of 500mL of ethyl acetate and 2000mL of n-heptane, the mixture is stirred for 1h, filtered and dried to obtain 428g of a compound shown in a formula (II), and the yield is 72%.
2) Preparation of the Compound (R=benzyl) of formula (III)
428g of the compound of formula (II) is placed in a three-necked flask, 2100mL of acetonitrile is added, 196g of potassium carbonate and 198g of benzyl bromoacetate are added under stirring, the temperature is raised to 80 ℃ and the reaction is stirred for 1h, after TLC monitoring the reaction, the reaction solution is cooled to room temperature, filtered and concentrated until no solvent exists. The crude product is dissolved by 2100mL of ethyl acetate, 1000mL of water is washed once, the organic phase is concentrated to be free of solvent, the crude product is recrystallized by a mixed solvent of 250mL of methyl tertiary butyl ether and 2250mL of n-hexane, and 438g of a compound (R=benzyl) shown in a formula (III) is obtained after filtration and drying, and the yield is 92%.
3) Preparation of Compounds of formula (IV)
438g of the compound of formula (iii) (r=benzyl) was placed in a three-necked flask, 800mL of ethanol was added, 2000g of 2.6% aqueous sodium hydroxide solution was added, the reaction was carried out at room temperature for 12 hours, hplc was monitored to be complete, pH was adjusted to 6.7 with 10% aqueous potassium dihydrogen phosphate solution, then extraction was carried out once with 4000mL of chloroform, and the organic phase was washed twice with 2000mL of water each time. The organic phase is concentrated to obtain a crude product, the crude product is recrystallized by using 400mL of mixed solution of methyl tertiary butyl ether and 1600mL of n-hexane, and the crude product is filtered and dried to obtain 262g of a compound shown in a formula (IV) with the yield of 69%.
Example eight
1) Preparation of Compounds of formula (II)
The procedure is as in step 1) of example 7 to give 400g of the compound of formula (II) in 67% yield
2) Preparation of the Compound (R=benzyl) of formula (III)
The procedure is as in example 7, step 2) to give 399g of the compound of formula (III) (R=benzyl) in 90% yield.
3) Preparation of Compounds of formula (IV)
399g of the compound represented by formula (iii) (r=benzyl) were placed in a three-necked flask, 4000mL of methanol was added, after three substitutions of N2, 20g of wet palladium on carbon (10% content, 63% water) was added, nitrogen was again substituted three times, then hydrogen was substituted three times, and after the reaction was performed at room temperature, HPLC was monitored for completion of the reaction. The reaction solution was filtered, concentrated to a weight of about 900g, 2000mL of water was added, then the pH was adjusted to 5.3 with 10% sodium dihydrogen phosphate aqueous solution, then extracted once with 4000mL of chloroform, and the organic phase was washed twice with 2000mL of water each time. The organic phase is concentrated to obtain a crude product, the crude product is recrystallized by using 400mL of mixed solution of methyl tertiary butyl ether and 1600mL of normal hexane, and 294g of a compound shown in a formula (IV) is obtained by filtering and drying, and the yield is 85%.
Example nine
1) Preparation of Compounds of formula (II)
The procedure is as in step 1) of example 7 to give 400g of the compound of formula (II) in a yield of 60%
2) Preparation of the Compound (R=benzyl) of formula (III)
The procedure is as in step 2) of example 7 to give 399g of the compound of formula (III) (R=benzyl) in 92% yield.
3) Preparation of Compounds of formula (IV)
365g of the compound of formula (iii) (r=benzyl) was placed in a three-necked flask, 3650mL of ethanol was added, after three substitutions of N2, 18.3g of wet palladium on carbon (10% content, 63% water) was added, three substitutions of nitrogen were performed again, and after three substitutions of hydrogen, the reaction was performed at room temperature, and HPLC monitored that the reaction was completed. The reaction solution was filtered, concentrated to a weight of about 700g, 2000mL of water was added, then the pH was adjusted to 5.5 with 10% sodium dihydrogen phosphate aqueous solution, then extracted once with 4000mL of chloroform, and the organic phase was washed twice with 2000mL of water each time. The organic phase is concentrated to obtain a crude product, the crude product is recrystallized by using 400mL of mixed solution of methyl tertiary butyl ether and 1600mL of normal hexane, and the crude product is filtered and dried to obtain 237g of a compound shown in a formula (IV) with a yield of 75%.
Examples ten
1) Preparation of Compounds of formula (II)
The procedure is as in step 1) of example 7 to give 400g of the compound of formula (II) in 64% yield
2) Preparation of the Compound (R=benzyl) of formula (III)
The procedure is as in step 2) of example 7 to give 399g of the compound of formula (III) (R=benzyl) in 95% yield.
3) Preparation of Compounds of formula (IV)
402g of the compound of formula (iii) (r=benzyl) was placed in a three-necked flask, 4000mL of acetonitrile was added, after three substitutions of N2, 20g of wet palladium on carbon (10% content, 63% water) was added, nitrogen was again substituted three times, then hydrogen was substituted three times, and after the reaction was performed at room temperature, HPLC was monitored for completion of the reaction. The reaction solution was filtered, concentrated to a weight of about 900g, 2000mL of water was added, then the pH was adjusted to 5.3 with 10% sodium dihydrogen phosphate aqueous solution, then extracted once with 4000mL of chloroform, and the organic phase was washed twice with 2000mL of water each time. The organic phase is concentrated to obtain a crude product, the crude product is recrystallized by using 400mL of mixed solution of methyl tertiary butyl ether and 1600mL of normal hexane, and 348g of compound shown in a formula (IV) is obtained after filtering and drying, and the yield is 81%.
Example eleven
1) Preparation of Compounds of formula (II)
The procedure is as in step 1) of example 7 to give 400g of the compound of formula (II) in 63% yield
2) Preparation of the Compound (R=benzyl) of formula (III)
The procedure is as in step 2) of example 7 to give 399g of the compound of formula (III) (R=benzyl) in 88% yield.
3) Preparation of Compounds of formula (IV)
367g of the compound represented by formula (iii) (r=benzyl) was placed in a three-necked flask, 3700mL of tetrahydrofuran was added, after three substitutions of N2, 18.3g of wet palladium on carbon (10% content, 63% water) was added, three substitutions of nitrogen were performed again, and after three substitutions of hydrogen, the reaction was performed at room temperature, and HPLC monitored for completion of the reaction. The reaction solution was filtered, concentrated to a weight of about 750g, 2000mL of water was added, then the pH was adjusted to 6.3 with 10% sodium dihydrogen phosphate aqueous solution, then extracted once with 4000mL of chloroform, and the organic phase was washed twice with 2000mL of water each time. The organic phase is concentrated to obtain a crude product, the crude product is recrystallized by using 400mL of mixed solution of methyl tertiary butyl ether and 1600mL of normal hexane, and then the crude product is filtered and dried to obtain 235g of a compound shown in a formula (IV), and the yield is 74%.
Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made therein without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (10)
1. A full synthesis and purification method of a high-purity MRI contrast agent intermediate is characterized in that the reaction formula is as follows:
comprises the following steps:
1) Under the action of alkali, a compound of the formula (I) and tert-butyl bromoacetate react with organic solvent in a nucleophilic substitution way at low temperature;
2) After the nucleophilic substitution reaction in the step 1) is completed, adjusting the pH to 8-10 by using an aqueous solution of alkali at low temperature, and filtering to obtain a wet crude product of the compound shown in the formula (II);
3) Dissolving the wet crude product shown in the formula (II) obtained in the step 2) by using an organic solvent, and washing, concentrating and crystallizing to obtain a high-purity compound shown in the formula (II);
4) Heating the compound of the formula (II) and the compound of the formula (V) obtained in the step 3) in an organic solvent under the action of alkali to perform nucleophilic substitution reaction, filtering and concentrating to obtain a crude product of the compound of the formula (III);
5) The crude product of the compound shown in the formula (III) obtained in the step 4) is washed and crystallized by an organic solvent to obtain the compound shown in the formula (III) with high purity;
6) When R is methyl, ethyl or benzyl, the compound shown in the formula (III) obtained in the step 5) can be hydrolyzed in a mixed solvent under the action of alkali to obtain a compound shown in the formula (IV); when R is benzyl, the compound shown in the formula (IV) can be obtained through catalytic hydrogenation debenzylation;
7) And 6) after the compound shown in the formula (III) is subjected to hydrolysis or catalytic hydrogenation debenzylation, regulating the pH value to 5-8 in water, and extracting, concentrating and crystallizing by using an organic solvent to obtain the compound shown in the formula (IV) with high purity.
2. The method for total synthesis and purification of a high purity MRI contrast agent intermediate according to claim 1, characterized in that: as shown in step 1), the base used is potassium acetate, sodium acetate or ammonium acetate, and the equivalent ratio of the amount used to the compound of formula (1) is 3.1-4:1, the equivalent ratio of the ethyl bromoacetate to the compound shown in the formula (I) is as follows: 3.1-4:1, the reaction organic solvent is N, N-dimethylformamide or N, N-dimethylacetamide, and the ratio of the reaction organic solvent to the compound shown in the formula (I) is 3:1 to 4:1, the reaction temperature is 0-20 ℃.
3. The method for total synthesis and purification of a high purity MRI contrast agent intermediate according to claim 1, characterized in that: as shown in step 2), the temperature range at pH is 0 ℃ to 30 ℃, the base used is sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate or potassium phosphate, the volume ratio of water used to the organic solvent used in step 1) is 1:3.
4. the method for total synthesis and purification of a high purity MRI contrast agent intermediate according to claim 1, characterized in that: as shown in the step 3), dissolving the wet crude product by using an organic solvent, wherein the organic solvent is chloroform, dichloroethane or dichloromethane, the crystallization solvent is one or more of dichloromethane, chloroform, petroleum ether, n-hexane, n-heptane, ethyl acetate or tert-butyl methyl ether, and the ratio of the compound shown in the formula (I) to the crystallization solvent is 1g:10-15mL.
5. The method for total synthesis and purification of a high purity MRI contrast agent intermediate according to claim 1, characterized in that: as shown in step 4), the base is potassium carbonate, sodium carbonate, cesium carbonate, tripotassium phosphate, sodium methoxide or sodium ethoxide, and the equivalent ratio of the base to the compound of formula (ii) is 1.2-2:1, wherein the organic solvent is methanol, ethanol, acetonitrile or tetrahydrofuran, and the volume weight ratio of the organic solvent to the compound shown in the formula (II) is 5mL:1g, the reaction heating temperature is 40-80 ℃.
6. The method for total synthesis and purification of a high purity MRI contrast agent intermediate according to claim 1, characterized in that: as shown in step 5), the organic solvent used for dissolving the crude compound of formula (iii) is ethyl acetate, dichloromethane, chloroform or dichloroethane, and the ratio of the solvent used to the compound of formula (ii) in step 4 is 5mL:1g of a solvent used for crystallizing the compound shown in the formula (III) is one or more of normal hexane, petroleum ether, diethyl ether, ethyl acetate and methylene dichloride, and the ratio of the compound shown in the formula (III) to the crystallization solvent is 1g:3-6mL.
7. The method for total synthesis and purification of a high purity MRI contrast agent intermediate according to claim 1, characterized in that: in step 6), the base used for the hydrolysis of the compound of formula (III) is lithium hydroxide, potassium hydroxide or sodium hydroxide, the ratio of the amount of base to the compound of formula (III) being 1.1-3:1.
8. the method for total synthesis and purification of a high purity MRI contrast agent intermediate according to claim 1, characterized in that: in the step 6), the organic solvent of the mixed solvent used for hydrolyzing the compound of the formula (III) is water and methanol, ethanol, tetrahydrofuran or acetonitrile, and the ratio of water to the organic solvent is 5:1-10:1, the volume ratio of the solvent to the compound shown in the formula (III) is 5:1-10:1, when R is benzyl, the solvent for catalytic hydrogenation reaction is one or more of water, methanol, ethanol, tetrahydrofuran or acetonitrile, and the ratio of the solvent to the compound of formula (III) is 10mL:1g, the catalytic hydrogenation reaction temperature is room temperature, the catalyst used in the catalytic hydrogenation is Pd/C (10%), and the amount used is 5% of the weight of the compound represented by the formula (III).
9. The method for total synthesis and purification of a high purity MRI contrast agent intermediate according to claim 1, characterized in that: in step 7), the acid used for adjusting the pH to 5-8 is hydrochloric acid, sulfuric acid, sodium dihydrogen phosphate, potassium dihydrogen phosphate, phosphoric acid or potassium hydrogen sulfate.
10. The method for total synthesis and purification of a high purity MRI contrast agent intermediate according to claim 1, characterized in that: after the pH is adjusted to 5-8 as shown in the step 7), the organic solvent for extraction is ethyl acetate, dichloromethane or chloroform, and the ratio of the solvent to the compound shown in the formula (III) used in the step 4) is 10mL:1g, the solvent for obtaining the high-purity compound shown in the formula (IV) is one or more of normal hexane, methyl tertiary butyl ether, ethyl acetate and methylene dichloride, and the ratio of the solvent for crystallization to the compound shown in the formula (IV) is 3-5mL:1g.
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