CN103613557A - Preparation method for magnetic resonance imaging contrast medium gadobutrol - Google Patents
Preparation method for magnetic resonance imaging contrast medium gadobutrol Download PDFInfo
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- ZPDFIIGFYAHNSK-CTHHTMFSSA-K 2-[4,10-bis(carboxylatomethyl)-7-[(2r,3s)-1,3,4-trihydroxybutan-2-yl]-1,4,7,10-tetrazacyclododec-1-yl]acetate;gadolinium(3+) Chemical compound [Gd+3].OC[C@@H](O)[C@@H](CO)N1CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC1 ZPDFIIGFYAHNSK-CTHHTMFSSA-K 0.000 title claims abstract description 32
- 229960003411 gadobutrol Drugs 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 239000002872 contrast media Substances 0.000 title abstract description 11
- 238000002595 magnetic resonance imaging Methods 0.000 title abstract 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 28
- CMIHHWBVHJVIGI-UHFFFAOYSA-N gadolinium(iii) oxide Chemical compound [O-2].[O-2].[O-2].[Gd+3].[Gd+3] CMIHHWBVHJVIGI-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000000047 product Substances 0.000 claims abstract description 18
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000012043 crude product Substances 0.000 claims abstract description 12
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000002904 solvent Substances 0.000 claims abstract description 9
- 229910000104 sodium hydride Inorganic materials 0.000 claims abstract description 8
- 230000007062 hydrolysis Effects 0.000 claims abstract description 7
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 7
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000012312 sodium hydride Substances 0.000 claims abstract description 6
- 238000009833 condensation Methods 0.000 claims abstract description 4
- 230000005494 condensation Effects 0.000 claims abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 29
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 238000010511 deprotection reaction Methods 0.000 claims description 12
- 239000002405 nuclear magnetic resonance imaging agent Substances 0.000 claims description 12
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- 125000000707 boryl group Chemical group B* 0.000 claims description 8
- 238000006467 substitution reaction Methods 0.000 claims description 6
- 230000004913 activation Effects 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 4
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- 238000010612 desalination reaction Methods 0.000 claims description 2
- 238000007670 refining Methods 0.000 claims description 2
- -1 boron-protected 1, 4, 7, 10-tetraazacyclododecane Chemical class 0.000 abstract description 5
- 238000007142 ring opening reaction Methods 0.000 abstract description 4
- 238000000746 purification Methods 0.000 abstract description 3
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 230000003213 activating effect Effects 0.000 abstract 1
- 229940106681 chloroacetic acid Drugs 0.000 abstract 1
- 238000011033 desalting Methods 0.000 abstract 1
- 229940075613 gadolinium oxide Drugs 0.000 abstract 1
- 229910001938 gadolinium oxide Inorganic materials 0.000 abstract 1
- 238000000034 method Methods 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- 229910052688 Gadolinium Inorganic materials 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 10
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- 235000019441 ethanol Nutrition 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 229910052761 rare earth metal Inorganic materials 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000012535 impurity Substances 0.000 description 5
- 210000003734 kidney Anatomy 0.000 description 5
- 238000001035 drying Methods 0.000 description 4
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 4
- 150000002910 rare earth metals Chemical class 0.000 description 4
- 206010016654 Fibrosis Diseases 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000004761 fibrosis Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 3
- 239000004593 Epoxy Substances 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 229910017053 inorganic salt Inorganic materials 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 230000005311 nuclear magnetism Effects 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 229910001948 sodium oxide Inorganic materials 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000004580 weight loss 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
- 206010067484 Adverse reaction Diseases 0.000 description 1
- RPNUMPOLZDHAAY-UHFFFAOYSA-N Diethylenetriamine Chemical compound NCCNCCN RPNUMPOLZDHAAY-UHFFFAOYSA-N 0.000 description 1
- 238000012307 MRI technique Methods 0.000 description 1
- CEVRHGVQRGAUIR-UHFFFAOYSA-N [K].BrCC(=O)O Chemical compound [K].BrCC(=O)O CEVRHGVQRGAUIR-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009692 acute damage Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000002019 anti-mutation Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 229910052729 chemical element Inorganic materials 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 210000000750 endocrine system Anatomy 0.000 description 1
- 125000003700 epoxy group Chemical group 0.000 description 1
- 230000003176 fibrotic effect Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- OCDAWJYGVOLXGZ-VPVMAENOSA-K gadobenate dimeglumine Chemical compound [Gd+3].CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.OC(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC(O)=O)C(C([O-])=O)COCC1=CC=CC=C1 OCDAWJYGVOLXGZ-VPVMAENOSA-K 0.000 description 1
- ZPDFIIGFYAHNSK-UHFFFAOYSA-K gadobutrol Chemical compound [Gd+3].OCC(O)C(CO)N1CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC1 ZPDFIIGFYAHNSK-UHFFFAOYSA-K 0.000 description 1
- HZHFFEYYPYZMNU-UHFFFAOYSA-K gadodiamide Chemical compound [Gd+3].CNC(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC(=O)NC HZHFFEYYPYZMNU-UHFFFAOYSA-K 0.000 description 1
- LGMLJQFQKXPRGA-VPVMAENOSA-K gadopentetate dimeglumine Chemical compound [Gd+3].CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.OC(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O LGMLJQFQKXPRGA-VPVMAENOSA-K 0.000 description 1
- RYHQMKVRYNEBNJ-BMWGJIJESA-K gadoterate meglumine Chemical compound [Gd+3].CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.OC(=O)CN1CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC1 RYHQMKVRYNEBNJ-BMWGJIJESA-K 0.000 description 1
- 229940016115 gadoterate meglumine Drugs 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- SDWBRBLWPQDUQP-UHFFFAOYSA-N n-boranyl-n-methylmethanamine Chemical compound BN(C)C SDWBRBLWPQDUQP-UHFFFAOYSA-N 0.000 description 1
- DRKHJSDSSUXYTE-UHFFFAOYSA-L oxidanium;2-[bis[2-[carboxylatomethyl-[2-(2-methoxyethylamino)-2-oxoethyl]amino]ethyl]amino]acetate;gadolinium(3+) Chemical compound [OH3+].[Gd+3].COCCNC(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC(=O)NCCOC DRKHJSDSSUXYTE-UHFFFAOYSA-L 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
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- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
A preparation method for magnetic resonance imaging contrast medium gadobutrol comprises the following steps: taking THF as a solvent, taking boron-protected 1, 4, 7, 10-tetraazacyclododecane (I) and 4, 4-dimehtyl-3, 5, 8-trioxabicyclo[5.1.0]octane (II) as raw materials, activating the raw materials by sodium hydride and performing ring-opening condensation to obtain an intermediate (III), performing mild hydrolysis to obtain an intermediate (IV), then successively reacting the intermediate (IV) with chloroacetic acid or bromoacetic acid and gadolinium oxide to prepare gadobutrol, performing desalting on the crude product, recrystallizing to obtain gadobutrol pure product. The preparation method comprises the beneficial effects of being mild in reaction condition, high in selectivity, relatively low in apparatus requirement, simple in technological operation, high in total yield, high in product purity, simple in purification, low in environment protection pressure, and relatively suitable for industrial production.
Description
Technical field
The present invention relates to a kind of preparation method of magnetic resonance imaging contrast agent gadobutrol.
Background technology
Rare earth (rare earth) is lanthanon in the periodic table of chemical element, comprises altogether 17 kinds of elements.Since the sixties in last century, rare earth compound is found to have a series of special drug actions successively, in recent years, people are at antitumor, the anti-mutation, antibacterial, antiviral of rare earth and rare earth compounding, with and the research of the aspects such as effect of offseting system and endocrine system all make great progress.Up to the present, most widely used is that one of rare earth element is metal gadolinium clinically, title complex class target mr techniques centered by gadolinium has become in recent years the core of the Novel magnetic resonance imaging technique producing, and to FDA at the beginning of 2013, has ratified to comprise that Magnevist, Prohance, Omniscan, Optimark, Multihance, Gadavist and gadoterate meglumine 7 kinds are containing gadolinium contrast medium.
Containing gadolinium contrast medium, become and applied clinically maximum M R I contrast medium, in worldwide, used over 200,000,000 times.But along with to the Fibrotic continuous report of kidney source property systematicness, increasing evidence shows that the property systematicness fibrosis morbidity of kidney source has close ties with the use of gadolinium contrast medium.
Gadobutrol is the 6th and obtains FDA approval and take gadolinium as basic contrast medium for central nervous system nuclear magnetic resonance, identical containing gadolinium contrast medium with other, gadobutrol also likely causes some untoward reactions such as kidney source property systematicness fibrosis, but think at present gadobutrol be kidney source property systematicness fibrosis risk lower take gadolinium as basic contrast medium, and to be that acute injury of kidney or chronic, serious renal disease patient are also operable a kind ofly take gadolinium as basic contrast medium.Because better tolerance, the toxicity of gadobutrol is low, imaging effect good, its high concentrate formulation is unique advantage in the nuclear magnetic resonance of a large amount of contrast medium of need, and clinical trial proves, its rate of adverse reactions is low, therefore, gadobutrol has a good application prospect, and develops especially urgent that more synthesis technique of practicality also becomes.
Platzek, J. etc. are at patent DE4009119, EP0448191, US2002176823, shown in the following reaction equation of gadobutrol synthetic route of reporting in US6399043: with 1, 4, 7, 3 amino that 10-tetraazacyclododecanand reacts with benzene sulfonyl chloride on prepared ring are protected compound (1) by benzene sulfonyl, with 4, 4-dimethyl-3, 5, 8-trioxa two rings [5, 1, 0] octane (2) generation epoxy group(ing) ring-opening reaction obtains compound (3), compound (3) carries out benzenesulfonyl deprotection and obtains mono-substituted compound (4) under strong alkaline condition, (4) carry out substitution reaction with bromoacetic acid potassium, then carry out acid hydrolysis and obtain the ketal protection that compound is sloughed glycol, react with Gadolinium trioxide again and obtain target compound gadobutrol (5).
The ring-opening reaction of this synthetic route the first step is carried out at 170 ℃; reaction conditions is violent; impurity complexity is wayward, and benzenesulfonyl deprotection under the highly basic condition of second step, because three alkylsulfonyl reactions are incomplete; easily generating portion list is de-; two de-impurity, and these impurity physicochemical property are very approaching, bring very large challenge to product separation purifying; for one, foreign matter content is required and the production of strict injection bulk drug this technological feasibility limited.
Argese, M. etc. are at patent EP0998476, JP2002511884, in WO9905145, with bridging macrocylc compound (A) and piperazine, in hydrochloric acid, reflux and obtain compound (B), compound (B) again with the monobromo-acetic acid of two equivalents alkaline condition next time stream carry out the basic hydrolysis of substitution reaction and acid amides, then reactant obtains compound (C) through hydrochloric acid neutralization, compound (C) is again with 4, 4-dimethyl-3, 5, 8-trioxa two rings [5, 1, 0] octane generation epoxy group(ing) ring-opening reaction then, the ketal group deprotection that carries out glycol under acidic conditions obtains compound (D), compound (D) reacts with Gadolinium trioxide and obtains target compound gadobutrol (5).
This synthetic route relatively and Platzek, J. no matter route is that reaction conditions or selectivity all have suitable improvement, but reaction conditions is also harsher, comprise that hydrochloric acid soln refluxes, sodium hydroxide solution backflow etc., and compound (C) and 4,4-dimethyl-3,5,8-trioxa, two rings [5,1,0] reaction process of octane generation epoxy group(ing) ring-opening reaction is because the existence of (C) three carboxylic acids makes 3,3-dimethyl-3,5,7-trioxa-l-phosphabicyclo ［ 3.1.0 ］ heptane decomposes in reaction, wayward.
Gries, H. etc. are at patent DE4218744; In WO9324469, synthetic route used adopts without 1 of protection; 4; 7,10-tetraazacyclododecanand (i) with 4,4-dimethyl-3; 5; the open loop in propyl carbinol of 8-trioxa two ring [5,1,0] octanes (2) generates intermediate (4); intermediate (4) passes through similar Platzek again, and the method that the people such as J. use at US2002176823 has been synthesized target compound gadobutrol (5).
The method due to four amino (i) going up all can with compound (2) on epoxy ethyl generation open loop condensation reaction, chemo-selective is very undesirable, the intermediate obtaining (4) purity is very low, to such an extent as to causes last a few step final product gadobutrol (5) purifying and quality control to be difficult to carry out.
Gries, H. and Platzek, J. is at DE4237943; Selective problems to above-mentioned technique in EP0596586 patent is improved; 1 of three amido protectings have been adopted; 4; 7; 10-tetraazacyclododecanand (a) makes compound intermediate (b) with the epoxy ethyl on compound (2) 120 ℃ of generation ring-opening reactions; intermediate (b) generates intermediate (4) through deprotection, and intermediate (4) passes through similar Platzek again, and the method that the people such as J. use at US2002176823 has been synthesized target compound gadobutrol (5).
The method is compared with Gries; H. method used in WO9324469; owing to having adopted free amino group protection and deprotection; selectivity is greatly improved; product process control and quality control are also relatively easily carried out, however the open loop condition of 120 ℃, and the reaction conditions of formyl radical deprotection is all very harsh; easily produce impurity, the purification condition of intermediate and product is loaded down with trivial details.
Blaszkiewicz, the people such as P. are at patent DE10064467; WO0248119; DE19724186; US5994536; WO9855467 has mentioned with lithium chloride activation 4,4-dimethyl-3, the epoxy ethyl of 5,8-trioxa, two ring [5,1,0] octanes (2), the improvement of relatively high selection the selective problems running in WO9324469.
But the method do not solve completely four free amino groups that compound (i) goes up all can with compound (2) on the selection problem of epoxy ethyl generation open loop condensation reaction, the intermediate obtaining (4) although purity compared with the product of method described in WO9324469, make moderate progress, but by product still exists, finally cause equally end product gadobutrol (5) to be difficult to the problems such as purifying.
The people such as the Zhu Quan of Guangzhou Consun Medicine R & D Co., Ltd. have reported in patent CN102399199A take diethylenetriamine as raw material; by seven step synthetic routes, prepare the method for gadobutrol (5); the method reactions steps all increases compared with other techniques; and alkylsulfonyl deprotection condition is harsh; reaction not exclusively; post-reaction treatment has also adopted weakly acidic cation-exchange resin to carry out purifying, and purifying process solvent-oil ratio is large, is unfavorable for industrial production.
Patent CN102933562A has announced the inventive method of the J of Bayer Intellectual Property Limited Liability Company pula plan gram, although simplified the synthetic method of EP0596586 in the method operation, still could not change ring-opening reaction temperature high, the drawbacks such as acyl hydrolase condition harshness.
Summary of the invention
Technical problem to be solved by this invention is for above-mentioned prior art, to provide a kind of reaction conditions gentle, selectivity is high, plant and instrument requires lower, technological operation is simple, total recovery is high, environmental protection pressure is little, is more suitable for being suitable for the preparation method of the large magnetic resonance imaging contrast agent gadobutrol of producing of industry.
The present invention solves the problems of the technologies described above adopted technical scheme: a kind of preparation method of magnetic resonance imaging contrast agent gadobutrol, is characterized in that operating according to the following steps:
Take THF as solvent, the Isosorbide-5-Nitrae of boryl protection; 7; 10-tetraazacyclododecanand (I) and 4,4-dimethyl-3,5; 8-trioxa two ring [5.1.0] octanes (II) are raw material; through sodium hydride activation open loop condensation, gained intermediate (III) obtains intermediate (IV) through mild hydrolysis, and intermediate (IV) in succession reacts and prepares gadobutrol with Mono Chloro Acetic Acid or bromoacetic acid and Gadolinium trioxide again; crude product is through desalination, and recrystallization makes gadobutrol sterling.
Press such scheme, the Isosorbide-5-Nitrae of boryl protection, the concentration of 7,10-tetraazacyclododecanand in THF is 0.8M-1.5M.
Press such scheme; count in molar ratio; 1 of boryl protection; 4; 7,10-tetraazacyclododecanand (I): sodium hydride: 4,4-dimethyl-3; 5,8-trioxa, two ring [5.1.0] octanes (II): Mono Chloro Acetic Acid or bromoacetic acid: sodium hydroxide or lithium hydroxide or potassium hydroxide: Gadolinium trioxide=1.0:1.1-1.5:1.0-1.3:3.2-4.0:5.0-10.0:0.5-0.6.
Press such scheme, the Isosorbide-5-Nitrae of boryl protection, 7,10-tetraazacyclododecanand (I) and 4,4-dimethyl-3, the temperature of reaction of 5,8-trioxa, two ring [5.1.0] octanes (II) is 20-30 ℃; The hydrolysis deprotection reaction temperature of intermediate (III) is 20-30 ℃; Described intermediate (IV) is 40-70 ℃ with the substitution reaction temperature that Mono Chloro Acetic Acid or bromoacetic acid prepare intermediate (V) under alkaline condition; 4 of intermediate (V), the temperature of reaction that 4-dimethyl ketal group deprotection under hydrochloric acid condition obtains product (VI) is 40-50 ℃.
Press such scheme, intermediate (IV) is 50-60 ℃ with Mono Chloro Acetic Acid or the substitution reaction temperature of bromoacetic acid under alkaline condition.
Press such scheme, 4 of intermediate (V), pH when 4-dimethyl ketal group carries out deprotection is 0.5-1.5; It is 1.0-3.0 that deprotection obtains the pH that product (VI) reacts with Gadolinium trioxide, and reaction solvent for use is ethanol, solvent temperature 60-80 ℃; Crude product refining solvent for use is 95% ethanol, and crude product quality and ethanol volume ratio be, 1Kg:4L-1Kg:8L.
Magnetic resonance imaging contrast agent gadobutrol of the present invention operates according to the following steps: by 1, 4, 7, the compound (I) of 10-tetraazacyclododecanand and three (dimethylamino) boron reaction preparation is (according to Chuburu, F. wait at document Tetrahedron, 2001, 57, the methods of 2385 reports are synthetic) after sodium hydride activation with 4, 4-dimethyl-3, 5, two ring [5.1.0] octane (II) the open loop condensations in tetrahydrofuran (THF) under room temperature of 8-trioxa, generate midbody compound (III), after reaction solution adds water without purification process, stirring at room generates intermediate (IV), in the reaction solution of intermediate (IV) and Mono Chloro Acetic Acid (or bromoacetic acid) and sodium hydroxide (or lithium hydroxide or potassium hydroxide) aqueous solution, in 50-70 ℃, there is substitution reaction and after hcl acidifying deprotection, generate N-(1-hydroxymethyl-2, 3-dihydroxypropyl)-1, 4, 7-tricarboxylic ylmethyl-1, 4, 7, 10-tetraazacyclododecanand, this acid is reacted with three gadolinium sesquioxides and is obtained magnetic resonance imaging contrast agent gadobutrol product again.
Beneficial effect of the present invention is: reaction conditions is gentle, and selectivity is high, and plant and instrument requires lower, and technological operation is simple, and total recovery is high, and product purity is high, and purification process is easy, and environmental protection pressure is little, is more suitable for being suitable for the large production of industry.
Accompanying drawing explanation
Fig. 1 is infrared absorption spectrum (the IR spectrum test instrument: Bruker VECTOR-22, test condition: KBr compressing tablet) of the embodiment of the present invention 1 products therefrom.
Embodiment
Below in conjunction with specific embodiment, further illustrate the present invention.Should be understood that these embodiment are only not used in and limit the scope of the invention for the present invention is described.
Embodiment 1:
The Isosorbide-5-Nitrae of compound boryl protection, 7, 10-tetraazacyclododecanand (I) 180.2g(1.0mol) be dissolved in 800mL anhydrous tetrahydro furan, under ice-water bath is cooling, add 45g NaH(60%, 1.12mol), be warmed up to stirring at room reaction 0.5h, add 4,4-dimethyl-3 in batches, 5, 8-trioxa two ring [5.1.0] octane (II) 151g(1.05mol), the about 4h(TLC of room temperature reaction detects to raw material (I) disappearance, developing solvent CH
2cl
2: MeOH=10:1), in gained reaction mixture intermediate (III), slowly add 300mL water, stir 30min and obtain intermediate (IV) to complete hydrolysis, in mixed system, add sodium hydroxide 243g (6.0mol) and Mono Chloro Acetic Acid 311g(3.31mmol) in 60 ℃ of reaction 6h, obtain intermediate (V), reaction is down to room temperature and is regulated pH to 1-1.5 with concentrated hydrochloric acid, then in 50 ℃ of heated and stirred 3h to 4 of intermediate (V), 4-dimethyl ketal group is sloughed completely, to obtaining slowly adding Gadolinium trioxide 200g(0.55mol in product (VI) reaction system) stirring at room 2h, add concentrated hydrochloric acid to regulate pH to 2, heated and stirred 4h, then reaction solution is bathed and is cooled to 0 ℃ with cryosel, mixture separatory, the organic phase tetrahydrofuran (THF) that contains impurity is recycled, water regulates pH to 7.0 with 5.0M concentration hydrogen sodium oxide again and stirs 1h and becomes settled solution to suspension, concentrating under reduced pressure goes most of water to thick, add 2.0L ethanol to be heated to 70 ℃ of stirring and dissolving 3.0h, after being cooled to room temperature, filter out sodium-chlor and other inorganic salt, concentrated the separating out after crude product 28g crude product is separated out in gadobutrol crude product 545g contracting again of ethanol mother liquor used 95% ethyl alcohol recrystallization, product drying under reduced pressure at 60 ℃ obtains sterling 536g, productive rate 88.6%.Product mass spectrum and nuclear-magnetism are consistent with the structure of appointment, and it is 98.9% that HPLC analyzes its purity, weight loss on drying 1.37%.
The infrared absorption of products obtained therefrom of the present invention is as accompanying drawing (KBr, cm-1): 3560,3280,2980,2975,2940,2920,2880,2870,1650,1600,1380. and document Inorganic Chemistry, 36, it is in full accord that 1997,6086-6093 reports, and HRMS and NMR also consistent with the structure of appointment.
Embodiment 2:
The Isosorbide-5-Nitrae of compound boryl protection, 7, 10-tetraazacyclododecanand (I) 180.2g(1.0mol) be dissolved in 1000mL anhydrous tetrahydro furan, under ice-water bath is cooling, add 45g NaH(60%, 1.12mol), be warmed up to stirring at room reaction 1.0h, add 4,4-dimethyl-3 in batches, 5, 8-trioxa two ring [5.1.0] octane (II) 155g(1.1mol), the about 4h(TLC of room temperature reaction detects to raw material (I) disappearance, developing solvent CH
2cl
2: MeOH=10:1), in gained reaction mixture intermediate (III), slowly add 500mL water, stir 30min and obtain intermediate (IV) to complete hydrolysis, in mixed system, add sodium hydroxide 243g (6.0mol) and Mono Chloro Acetic Acid 311g(3.31mol) in 70 ℃ of reaction 6h, obtain intermediate (V), reaction is down to room temperature and is regulated pH to 1-1.5 with concentrated hydrochloric acid, then in 50 ℃ of heated and stirred 3h to 4 of intermediate (V), 4-dimethyl ketal group is sloughed completely, to obtaining slowly adding Gadolinium trioxide 200g(0.55mol in product (VI) reaction system) stirring at room 2h, add concentrated hydrochloric acid to regulate pH to 2, heated and stirred 4h, then reaction solution is bathed and is cooled to 0 ℃ with cryosel, mixture separatory, the organic phase tetrahydrofuran (THF) that contains impurity is recycled, water regulates pH to 7.0 with 5.0M concentration hydrogen sodium oxide again and stirs 1h and becomes settled solution to suspension, concentrating under reduced pressure goes most of water to thick, add 2.0L ethanol to be heated to 70 ℃ of stirring and dissolving 2.0h, after being cooled to room temperature, filter out sodium-chlor and other inorganic salt, concentrated the separating out after crude product 48g crude product is separated out in gadobutrol crude product 515g contracting again of ethanol mother liquor used 95% ethyl alcohol recrystallization, product drying under reduced pressure at 60 ℃ obtains sterling 518g, productive rate 85.6%.Product mass spectrum and nuclear-magnetism are consistent with the structure of appointment, and it is 99.2% that HPLC analyzes its purity, weight loss on drying 1.26%.
Claims (6)
1. the preparation method of a magnetic resonance imaging contrast agent gadobutrol; it is characterized in that operating according to the following steps: take THF as solvent; 1 of boryl protection; 4; 7; 10-tetraazacyclododecanand (I) and 4; 4-dimethyl-3; 5,8-trioxa, two ring [5.1.0] octanes (II) are raw material, through sodium hydride activation open loop condensation; gained intermediate (III) obtains intermediate (IV) through mild hydrolysis; intermediate (IV) in succession reacts and prepares gadobutrol with Mono Chloro Acetic Acid or bromoacetic acid and Gadolinium trioxide again, and crude product is through desalination, and recrystallization makes gadobutrol sterling.
2. the preparation method of magnetic resonance imaging contrast agent gadobutrol according to claim 1, is characterized in that: the Isosorbide-5-Nitrae of boryl protection, the concentration of 7,10-tetraazacyclododecanand in THF is 0.8M-1.5M.
3. the preparation method of magnetic resonance imaging contrast agent gadobutrol according to claim 1 and 2; it is characterized in that: count in molar ratio; 1 of boryl protection; 4; 7,10-tetraazacyclododecanand (I): sodium hydride: 4,4-dimethyl-3; 5,8-trioxa, two ring [5.1.0] octanes (II): Mono Chloro Acetic Acid or bromoacetic acid: sodium hydroxide or lithium hydroxide or potassium hydroxide: Gadolinium trioxide=1.0:1.1-1.5:1.0-1.3:3.2-4.0:5.0-10.0:0.5-0.6.
4. the preparation method of magnetic resonance imaging contrast agent gadobutrol according to claim 3, is characterized in that: the Isosorbide-5-Nitrae of boryl protection, 7,10-tetraazacyclododecanand (I) and 4,4-dimethyl-3, the temperature of reaction of 5,8-trioxa, two ring [5.1.0] octanes (II) is 20-30 ℃; The hydrolysis deprotection reaction temperature of intermediate (III) is 20-30 ℃; Described intermediate (IV) is 40-70 ℃ with the substitution reaction temperature that Mono Chloro Acetic Acid or bromoacetic acid prepare intermediate (V) under alkaline condition; 4 of intermediate (V), the temperature of reaction that 4-dimethyl ketal group deprotection under hydrochloric acid condition obtains product (VI) is 40-50 ℃.
5. the preparation method of magnetic resonance imaging contrast agent gadobutrol according to claim 4, is characterized in that: intermediate (IV) is 50-60 ℃ with Mono Chloro Acetic Acid or the substitution reaction temperature of bromoacetic acid under alkaline condition.
6. the preparation method of magnetic resonance imaging contrast agent gadobutrol according to claim 4, is characterized in that: 4 of intermediate (V), and pH when 4-dimethyl ketal group carries out deprotection is 0.5-1.5; It is 1.0-3.0 that deprotection obtains the pH that product (VI) reacts with Gadolinium trioxide, and reaction solvent for use is ethanol, solvent temperature 60-80 ℃; Crude product refining solvent for use is 95% ethanol.
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| CN106967083A (en) * | 2017-04-26 | 2017-07-21 | 穆云 | The process of preparing of Gadobutrol epoxy side chain intermediate |
| CN107001294A (en) * | 2014-12-26 | 2017-08-01 | St制药株式会社 | A kind of method for preparing Gadobutrol |
| CN108047151A (en) * | 2018-01-03 | 2018-05-18 | 广州康瑞泰药业有限公司 | A kind of preparation method of Gadobutrol in high yield |
| KR20200022648A (en) * | 2018-08-23 | 2020-03-04 | 에스티팜 주식회사 | A method for preparing gadobutrol |
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| CN106967083A (en) * | 2017-04-26 | 2017-07-21 | 穆云 | The process of preparing of Gadobutrol epoxy side chain intermediate |
| CN106967083B (en) * | 2017-04-26 | 2020-09-15 | 穆云 | Preparation process method of gadobutrol epoxy side chain intermediate |
| CN108047151A (en) * | 2018-01-03 | 2018-05-18 | 广州康瑞泰药业有限公司 | A kind of preparation method of Gadobutrol in high yield |
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| WO2020141723A1 (en) * | 2019-01-02 | 2020-07-09 | 동국생명과학 주식회사 | Method for preparing calcobutrol |
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