CN108299322A - A method of preparing high-purity Gadobutrol - Google Patents
A method of preparing high-purity Gadobutrol Download PDFInfo
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- CN108299322A CN108299322A CN201810124932.5A CN201810124932A CN108299322A CN 108299322 A CN108299322 A CN 108299322A CN 201810124932 A CN201810124932 A CN 201810124932A CN 108299322 A CN108299322 A CN 108299322A
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- gadobutrol
- purity
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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 41
- 229960003411 gadobutrol Drugs 0.000 title claims abstract description 41
- 238000000034 method Methods 0.000 title claims abstract description 32
- 238000006243 chemical reaction Methods 0.000 claims abstract description 45
- RJOJUSXNYCILHH-UHFFFAOYSA-N gadolinium(3+) Chemical compound [Gd+3] RJOJUSXNYCILHH-UHFFFAOYSA-N 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims description 38
- 239000002585 base Substances 0.000 claims description 29
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 229910052688 Gadolinium Inorganic materials 0.000 claims description 11
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 claims description 11
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- 238000002425 crystallisation Methods 0.000 claims description 8
- 230000008025 crystallization Effects 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 229940075613 gadolinium oxide Drugs 0.000 claims description 3
- 229910001938 gadolinium oxide Inorganic materials 0.000 claims description 3
- CMIHHWBVHJVIGI-UHFFFAOYSA-N gadolinium(iii) oxide Chemical group [O-2].[O-2].[O-2].[Gd+3].[Gd+3] CMIHHWBVHJVIGI-UHFFFAOYSA-N 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 2
- 239000000920 calcium hydroxide Substances 0.000 claims description 2
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- MEANOSLIBWSCIT-UHFFFAOYSA-K gadolinium trichloride Chemical compound Cl[Gd](Cl)Cl MEANOSLIBWSCIT-UHFFFAOYSA-K 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- ARXKVVRQIIOZGF-UHFFFAOYSA-N 1,2,4-butanetriol Chemical class OCCC(O)CO ARXKVVRQIIOZGF-UHFFFAOYSA-N 0.000 abstract description 13
- 238000002360 preparation method Methods 0.000 abstract description 10
- REXUYBKPWIPONM-UHFFFAOYSA-N 2-bromoacetonitrile Chemical compound BrCC#N REXUYBKPWIPONM-UHFFFAOYSA-N 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 239000000413 hydrolysate Substances 0.000 abstract description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 31
- 235000019441 ethanol Nutrition 0.000 description 19
- 239000000047 product Substances 0.000 description 17
- 238000003756 stirring Methods 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 230000007062 hydrolysis Effects 0.000 description 9
- 238000006460 hydrolysis reaction Methods 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 239000000463 material Substances 0.000 description 8
- 238000001914 filtration Methods 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000011347 resin Substances 0.000 description 6
- 229920005989 resin Polymers 0.000 description 6
- -1 dihydroxy hydroxymethyl propyl tetraazacyclododecane Chemical compound 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000000921 elemental analysis Methods 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- ILJSQTXMGCGYMG-UHFFFAOYSA-N triacetic acid Chemical compound CC(=O)CC(=O)CC(O)=O ILJSQTXMGCGYMG-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000001273 butane Substances 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 3
- 239000004744 fabric Substances 0.000 description 3
- 150000003840 hydrochlorides Chemical class 0.000 description 3
- 238000011031 large-scale manufacturing process Methods 0.000 description 3
- FQTCUKQMGGJRCU-UHFFFAOYSA-N n,n-diacetylacetamide Chemical compound CC(=O)N(C(C)=O)C(C)=O FQTCUKQMGGJRCU-UHFFFAOYSA-N 0.000 description 3
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 3
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- FDRCDNZGSXJAFP-UHFFFAOYSA-M sodium chloroacetate Chemical compound [Na+].[O-]C(=O)CCl FDRCDNZGSXJAFP-UHFFFAOYSA-M 0.000 description 3
- QBPPRVHXOZRESW-UHFFFAOYSA-N 1,4,7,10-tetraazacyclododecane Chemical compound C1CNCCNCCNCCN1 QBPPRVHXOZRESW-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 0 CCCN(CCN(CC*C)CCN(CCNCC#N)CC#N)C(CO)C(CO)O Chemical compound CCCN(CCN(CC*C)CCN(CCNCC#N)CC#N)C(CO)C(CO)O 0.000 description 2
- ANOXEUSGZWSCQL-LOYHVIPDSA-N Cycleanine Chemical compound C([C@H]1N(C)CCC=2C=C(C(=C(OC3=CC=C(C=C3)C[C@H]3N(C)CCC=4C=C(OC)C(OC)=C(C3=4)O3)C=21)OC)OC)C1=CC=C3C=C1 ANOXEUSGZWSCQL-LOYHVIPDSA-N 0.000 description 2
- PEVPVMCJEMVCAS-UHFFFAOYSA-N Cycleanine Natural products COc1cc2CCN(C)C3Cc4ccc(Oc5cccc6CCN(C)C(Cc7ccc(Oc(c1OC)c23)cc7)c56)cc4 PEVPVMCJEMVCAS-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- ANOXEUSGZWSCQL-UHFFFAOYSA-N O-Methyl-isochondodendrin Natural products O1C(C2=3)=C(OC)C(OC)=CC=3CCN(C)C2CC(C=C2)=CC=C2OC(C=23)=C(OC)C(OC)=CC=2CCN(C)C3CC2=CC=C1C=C2 ANOXEUSGZWSCQL-UHFFFAOYSA-N 0.000 description 2
- JZNZSKXIEDHOBD-UHFFFAOYSA-N OCC(C(CO)O)N1CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC1 Chemical compound OCC(C(CO)O)N1CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC1 JZNZSKXIEDHOBD-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 239000002872 contrast media Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 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 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- SYZRZLUNWVNNNV-UHFFFAOYSA-N 2-bromoacetyl chloride Chemical compound ClC(=O)CBr SYZRZLUNWVNNNV-UHFFFAOYSA-N 0.000 description 1
- PILXSQCNYFRTOB-UHFFFAOYSA-N C(C)(=O)O.C(C)(=O)O.C(C)(=O)O.CCCCCCCCCCCC Chemical compound C(C)(=O)O.C(C)(=O)O.C(C)(=O)O.CCCCCCCCCCCC PILXSQCNYFRTOB-UHFFFAOYSA-N 0.000 description 1
- BIRXWRKZBYACHU-UHFFFAOYSA-N C=C(CCN(CC#N)CCN(CC#N)CC1)CCN1C(CO)C(CO)O Chemical compound C=C(CCN(CC#N)CCN(CC#N)CC1)CCN1C(CO)C(CO)O BIRXWRKZBYACHU-UHFFFAOYSA-N 0.000 description 1
- CDRDWQOZPCIHSV-UHFFFAOYSA-N NC(CN(CCN(CC(N)=O)CC1)CCN(CC(N)=O)CCN1C(CO)C(CO)O)=O Chemical compound NC(CN(CCN(CC(N)=O)CC1)CCN(CC(N)=O)CCN1C(CO)C(CO)O)=O CDRDWQOZPCIHSV-UHFFFAOYSA-N 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 238000006701 autoxidation reaction Methods 0.000 description 1
- 150000001538 azepines Chemical class 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-M chloroacetate Chemical compound [O-]C(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-M 0.000 description 1
- 229940089960 chloroacetate Drugs 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- DDTBPAQBQHZRDW-UHFFFAOYSA-N cyclododecane Chemical compound C1CCCCCCCCCCC1 DDTBPAQBQHZRDW-UHFFFAOYSA-N 0.000 description 1
- 230000002498 deadly effect Effects 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000002595 magnetic resonance imaging Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 239000002405 nuclear magnetic resonance imaging agent Substances 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- CHWRSCGUEQEHOH-UHFFFAOYSA-N potassium oxide Chemical compound [O-2].[K+].[K+] CHWRSCGUEQEHOH-UHFFFAOYSA-N 0.000 description 1
- 229910001950 potassium oxide Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000002633 protecting effect Effects 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003643 water by type Substances 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a kind of methods preparing high-purity Gadobutrol, this method uses 3 (1,4,7,10 tetraazacyclododecanand, 1 base) butane 1,2,4 triols are reacted with bromoacetonitrile or acetbromamide, obtained intermediate is hydrolyzed under alkaline condition, and hydrolysate carries out complex reaction with gadolinium ion source, obtains the Gadobutrol of high-purity.This method preparation process is simply mild, is suitble to big technique productions.
Description
Technical field
The present invention relates to a kind of methods preparing high-purity Gadobutrol.
Background technology
In the field of the contrast agent containing gadolinium, Gadobutrol (gadobutrol) with trade name add happy aobvious (Gadovist) or
Gadavist is in commercial distribution from all parts of the world.It is a kind of novel potent magnetic resonance imaging contrast agent, is approved for people
The Contrast enhanced magnetic resonance imaging (CE-MRI) at the multiple positions of body diagnoses, including brain, spinal cord, blood vessel, liver and kidney.In addition, gadolinium cloth
Alcohol contains the ionic state T1- relaxivities of high concentration.In view of its high concentration and high relaxation efficiency, shown in all contrast medium containing gadolinium
Every milliliter of highest short T1 efficiency is shown.This makes it possess excellent picture quality, and has the smaller practicality of dosage
Advantage.
The Gadobutrol indicated by following formula 1 is one kind by gadolinium (III) and macrocyclic ligand dihydroxy hydroxymethyl propyl tetraazacyclododecane
The nonionic complex of dodecane triacetic acid composition.
[formula 1]
In CN102933562A using DMF acetals by three amido protectings of cycleanine, then again with dimethyl -3 4,4-,
5,8- trioxa, two ring [5.1.0] octane reacts, after hydrolysising protection base again with chloroacetate reaction.The route can improve selection
Property.But the cycleanine due to the use of the protection of DMF acetals is extremely unstable, hydrolysis is easy, it is difficult to control impurity；In alkylation step
The monoxone used is deadly poisonous compound, dangerous higher.
CN107001294A discloses a kind of method preparing Gadobutrol, is reacted using bromo-acetic acid tert-butyl, then
Carry out sour water solution.However, the more difficult purifying of product after bromo-acetic acid tert-butyl reaction, and in lower one-step hydrolysis, concentrated acid need to be used
It carries out under the high temperature conditions, reaction is slow；On the one hand the tertiary butyl that hydrolysis is fallen can form C in acid condition+Ion, C+Ion
It can migrate to hydroxyl group, generate one and be difficult to the impurity removed, which can take in finished product always, can not remove；
On the other hand, due to being reacted for a long time under concentrated acid and high temperature, chloro and elimination reaction can occur for the hydroxyl in product, generate new
Impurity.
Inorg.Chem.1997 discloses the schemes of three kinds of synthesis Gadobutrols in 36,6086-6093, wherein scheme 1 needs
It is largely used to the resin of purifying, it is very unfavorable for using production equipment to be purified, cause unit cost to increase, is not suitable for
In large-scale production；Scheme 2 then has the shortcomings that low-yield and low-purity；The route of scheme 3 is appropriate only for reality due to its low output
It tests room scale and is not suitable for large-scale production.
International standard (such as ICH guides) suggests impurity content as 0.1% hereinafter, it is therefore preferable that preparing for being used as medicine
The ultra-high purity Gadobutrol that the purity of object sale is 99.9% or more.However, the method disclosed in the bibliography of reference is multiple
It is miscellaneous, it cannot thus prepare the Gadobutrol of high-purity.Therefore a kind of new preparation method is needed, can simply and efficiently prepared high-purity
Spend Gadobutrol.
Invention content
Passing through the simple method for preparing high-purity Gadobutrol with mild technique the object of the present invention is to provide a kind of.
The purpose for preparing high-purity Gadobutrol is realized through the invention, and the method includes using 3- (Isosorbide-5-Nitrae, 7,10- tetra- nitrogen
- 1 base of triazacyclododecane) butane -1,2,4- triols react with bromoacetonitrile or acetbromamide, then carry out water under alkaline condition
Solution, hydrolysate carry out complex reaction with gadolinium ion source, and products obtained therefrom obtains higher degree and the gadolinium of good yield by purifying
Cloth alcohol.
The method of high-purity Gadobutrol produced according to the present invention comprising：
(1) compound for reacting formula 3 is alkylated with 5 compound of formula using the compound or its salt of formula 2；
(2) carry out the compound of formula 4 using the compound of the formula 3；
(3) carry out the Gadobutrol of formula 1 using the compound of the formula 4；
[formula 1]
[formula 2]
[formula 3]
[formula 4]
[formula 5]
Wherein, X is halogen, TsO- or MsO-.
Specifically, step (1), alkylated reaction
It is alkylated and is reacted and 3 compound of formula with 5 compound of formula by using 2 compound or its salt of formula；
5 compound of formula is：
Wherein, X is halogen, TsO- or MsO-；
In certain embodiments of the present invention, the salt of 2 compound of formula is the hydrochloride of formula 2-1, wherein n 1-4, it is excellent
4 hydrochlorides or 3 hydrochlorides are selected as, it is highly preferred that the salt of 2 compound of the formula is 4 hydrochlorides of formula 2-1.
[formula 2-1]
In addition, in certain embodiments of the present invention, the compound of the formula 5 can be the compound of following formula 5-1,
Middle X is Br；
[formula 5-1]
In step (1), alkylated reaction is carried out in the solvent for being usually used in alkylated reaction.Preferably, described molten
Agent can be H2O, C2-C11 nitriles, C4-C11 ethers, C2-C5 alcohol or their mixture, and it is highly preferred that the solvent can be with
It is acetonitrile, however, the present invention is not limited thereto.
In addition, the reaction can carry out in the presence of base, it is preferable that the alkali can be potassium carbonate, sodium carbonate, hydrogen
Potassium oxide, sodium hydroxide, 1,8- diazabicylos, 11 carbon -7- alkene (DBU) or their mixture, and it is highly preferred that institute
It is potassium carbonate, however, the present invention is not limited thereto to state alkali.
Reaction in step (1) can be at 40 DEG C to 80 DEG C, preferably at 50 DEG C to 60 DEG C, and more preferably at 50 DEG C
It is carried out to 55 DEG C, however, the present invention is not limited thereto.
According to certain embodiments of the present invention, step (1) can further comprise the crystallization process of the compound of formula 3.
Solvent for crystallization process can be C2-C8 alcohol, C3-C8 ketone or their mixture, and it is preferable to use second
The mixture of alcohol.97% or more, preferably 98% or more, and more preferable 99% or more high-purity can be generated by step (1)
The formula 3 compound.
Step (2), hydrolysis
The chemical combination of the formula 4 of high-purity is prepared by making 3 compound of formula of the high-purity of step (1) generation carry out basic hydrolysis
Object.
The alkali includes lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide etc., preferably lithium hydroxide.
The hydrolysis can be carried out by using the General reactions condition of basic hydrolysis.Preferably, the basic hydrolysis can be with
It is carried out by being added to lithium hydroxide solution in 3 compound of formula.
In addition, the hydrolysis can be at 70 DEG C to 100 DEG C, preferably at 70 DEG C to 80 DEG C, more preferably at 75 DEG C to 80
It is carried out at DEG C, however, the present invention is not limited thereto.
In certain embodiments of the present invention, step (2) may include the purifying of the compound of the formula 4 by using resin
Process.And since resin usage amount is low, production cost can be reduced.
In addition, according to certain embodiments of the present invention, step (2) can further comprise the crystallization process of 4 compound of formula.
Solvent for the crystallization process can be ethyl alcohol, methanol, acetone or their mixture, and it is preferable to use
Alcohol solvent.
85% or more can be generated by step (2), the compound of the formula 4 of preferably 90% or more high-purity.
Step (3), the formation of gadolinium complex
The gadolinium as gadolinium complex is prepared by so that the compound of the formula 4 prepared in step (2) is reacted with gadolinium ion source
Cloth alcohol.
The gadolinium ion source can be any compound for being capable of providing gadolinium ion.For example, the gadolinium ion source can be selected
Autoxidation gadolinium, gadolinium and gadolinium chloride.Preferably, the gadolinium ion source is gadolinium oxide, however, the present invention is not limited thereto.
Reaction in step (3) can carry out at 80 DEG C to 100 DEG C, preferably be carried out at 85 DEG C to 95 DEG C, more preferably
It is carried out at 87 DEG C to 93 DEG C, but the invention is not restricted to this.
Step (3) can further comprise the crystallization process of Gadobutrol.
The solvent of crystallization can be alcohol or ketone, preferably absolute ethyl alcohol, isopropanol, acetone etc..
99% or more, preferably 99.5% or more, the institute of more preferable 99.9% or more high-purity can be generated by step (3)
State the Gadobutrol of formula 1.
The present invention is using 2 compound of formula (that is, 3- (Isosorbide-5-Nitrae, -1 base of 7,10- tetraazacyclododecanand) butane -1,2,4- tri-
Alcohol) and bromoacetonitrile or acetbromamide reaction, reaction condition is mild, can react at room temperature；Wherein mesosome easily purifies, purity pole
High (98% or more), yield all increase compared with monoxone and bromo-acetic acid tert-butyl.And in further hydrolytic process, use
Alkaline condition hydrolyzes, and reacts mild quick, the not generation of by-product.The Gadobutrol made by bromoacetonitrile route, purity reach
To 99.9% or more.
The present invention avoids using toxic articles monoxone, reduces security risk, environmentally friendly.
The Gadobutrol preparation process of the present invention is simply mild, is very suitable for mass producing.
Specific implementation mode
Hereinafter, it will be described in the preparation method of Gadobutrol of the present invention.
Its synthetic route of the preparation method of Gadobutrol according to the present invention is as follows：
The preparation of embodiment Gadobutrol
Step 1：2,2', 2 "-(10- (1,3,4- trihydroxybutane -2- bases)-Cyclen -1,
Tri- bases of 4,7-) three acetonitriles preparation
(1) bromoacetonitrile is used
500mL acetonitriles are added in 1000ml reaction bulbs, lower addition 50g (0.1184mol) 3- into reaction bulb of stirring (1,
4,7,10- tetraazacyclododecanand -1- bases) butane -1,2,163g is added in 4 hydrochloride of 4- triols into reaction bulb at room temperature
(1.184mol) potassium carbonate, and it is slowly added to 42.6g (0.3552mol) bromoacetonitrile thereto.It, will be in reaction bulb after adding material
Temperature of charge is heated to 50 DEG C to 55 DEG C, and this temperature is maintained to be stirred to react.After reaction terminating, filtering, filtrate decompression concentration,
Concentration terminates the ethyl alcohol that 250ml is added into concentrate bottle, is heated to flowing back by temperature of charge after adding ethyl alcohol and maintains reflux temperature
Degree stirring 3 hours, room temperature is down to by temperature of charge, is filtered, and filter cake washs and is evacuated to 50mL ethyl alcohol no efflux, obtains product
Filtered crystal is dried in a vacuum in wet product, product under 50 DEG C of internal temperature, obtains the 2,2' of 41.94g, 2 "-(10- (1,
3,4- trihydroxybutane -2- bases)-three bases of Cyclen -1,4,7-) three acetonitriles.Yield：90%, it is pure
Degree：98%.
1HNMR(400MHz,MeOD,ppm):2.49-2.92(m,19H),3.46-3.81(m,12H).
(2) acetbromamide is used
500mL acetonitriles are added in 1000ml reaction bulbs, lower addition 50g (0.1184mol) 3- into reaction bulb of stirring (1,
4,7,10- tetraazacyclododecanand -1- bases) butane -1,2,163g is added in 4 hydrochloride of 4- triols into reaction bulb at room temperature
(1.184mol) potassium carbonate, and 50.65g (0.3671mol) bromoacetyl chloride is added thereto.It, will be in reaction bulb after adding material
Temperature of charge is heated to 50 DEG C to 55 DEG C, and this temperature is maintained to be stirred to react.After reaction terminating, filtering, filtrate decompression concentration,
Concentration terminates the ethyl alcohol that 200ml is added into concentrate bottle, is heated to flowing back by temperature of charge after adding ethyl alcohol and maintains reflux temperature
Degree stirring 3 hours, room temperature is down to by temperature of charge, is filtered, and filter cake washs and is evacuated to 50mL ethyl alcohol no efflux, obtains product
Filtered crystal is dried in a vacuum in wet product, product under 50 DEG C of internal temperature, obtains the 2,2' of 48.75g, 2 "-(10- (1,
3,4- trihydroxybutane -2- bases)-three bases of Cyclen -1,4,7-) triacetamide.Yield：92%, it is pure
Degree：97.5%.
Step 2：2,2', 2 "-(10- (1,3,4- trihydroxybutane -2- bases)-Cyclen -1,
Tri- bases of 4,7-) triacetic acid preparation
(1) use 2,2', 2 "-(10- (1,3,4- trihydroxybutane -2- bases)-Cyclen -1,
Tri- bases of 4,7-) three acetonitriles
The purified water of 30ml and 10mL methanol are added in 250ml there-necked flasks, 10g is added into reaction bulb under stiring
The 2,2' of (0.025mol), 2 "-(10- (1,3,4- trihydroxybutane -2- bases)-Cyclen -1,4,
Tri- bases of 7-) three acetonitriles, lithium hydroxide 6.1g (0.254mol) is added into reaction bulb at room temperature, general down is stirred after adding material
Temperature of charge is heated to 75 DEG C~80 DEG C and this temperature is maintained to react in reaction bulb, determines after reaction, by reaction solution
Temperature is cooled to room temperature, and for the lower resin cation that is added into reaction bulb of stirring to material pH=3.5-4.5, filtering is dense by filtrate
Contracting, concentration terminate, and the ethyl alcohol of 40ml is added into reaction bulb and is heated to flowing back, cooling after maintaining reflux temperature to stir 4 hours
To 10 DEG C~20 DEG C, filtering, filter cake is washed with 20ml ethyl alcohol and is filtered to no efflux, internal temperature of the gained wet product at 50 DEG C
Under filtered crystal is dried in a vacuum, obtain the 2,2' of 10.1g, 2 "-(10- (1,3,4- trihydroxybutane -2- bases) -1,
Three bases of 4,7,10- tetraazacyclododecanands -1,4,7-) triacetic acid.Yield：88.2%, purity：90%.
1HNMR(400MHz,D2O,ppm):3.08-3.34(m,16H),3.53-3.78(m,12H).
(2) use 2,2', 2 "-(10- (1,3,4- trihydroxybutane -2- bases)-Cyclen -1,
Tri- bases of 4,7-) triacetamide
30ml purified waters and 10mL methanol are added in 250ml reaction bulbs, stirring is lower, and 10g is added into reaction bulb
The 2,2' of (0.0223mol), 2 "-(10- (1,3,4- trihydroxybutane -2- bases)-Cyclen -1,4,
Tri- bases of 7-) triacetamide, lithium hydroxide (4.28g, 0.1787mol) is added into reaction bulb at room temperature, charging terminates, stirring
It is lower that temperature of charge in reaction bulb is heated to 75 DEG C~80 DEG C and insulation reaction, it determines after reaction, by material in reaction bulb
Temperature is cooled to room temperature.For the lower resin cation that is added into reaction bulb of stirring to material pH=3.5-4.5, filtering is dense by filtrate
Contracting, concentration terminate, and the ethyl alcohol of 36ml is added into reaction bulb and is heated to flowing back, cooling after maintaining reflux temperature to stir 4 hours
To 10 DEG C~20 DEG C, filtering, filter cake is washed with 20ml ethyl alcohol and is filtered to no efflux, internal temperature of the gained wet product at 50 DEG C
Under be dried in a vacuum dry product 9.1g 2,2', 2 "-(four azepines of 10- (1,3,4- trihydroxybutane -2- bases) -1,4,7,10-
Three bases of cyclododecane -1,4,7-) triacetic acid.Yield：91%, purity：91%.
Step 3：10- (2,3- dihydroxy -1- (methylol) propyl)-Cyclen -1,4,7- three
The preparation of the gadolinium complex (Gadobutrol) of acetic acid
The purified water of 15ml is added in 100ml reaction bulbs, stirring is lower, and 15.4g is added into reaction bulb
The 2,2' of (0.0342mol), 2 "-(10- (1,3,4- trihydroxybutane -2- bases)-Cyclen -1,4,
Tri- bases of 7-) triacetic acid, and 6.2g (0.0171mol) gadolinium oxide is added thereto, charging finishes, by object in reaction bulb under stirring
Material temperature degree is heated to 90 DEG C, and this temperature is maintained to be stirred to react, and when determining after reaction, filters while hot, at filtrate resin
No efflux is concentrated into after reason.The purified water of 7.7ml is added into concentrate bottle, after adding water, by temperature of charge in bottle under stirring
It is heated to 75 DEG C and maintains material dissolved clarification in this temperature to bottle, the ethyl alcohol of 160ml is added into bottle and is heated to flowing back, maintain back
Temperature is flowed to stir 3 hours.Temperature of charge in bottle is cooled to 20-25 DEG C under stirring, and this temperature is maintained to stir 1 hour, filtering.
Gained wet product is dry in 50 DEG C or less vacuum, obtains 10- (2,3- dihydroxy -1- (methylol) propyl)-Isosorbide-5-Nitrae of dry product 15.5g,
7,10- tetraazacyclododecanand -1,4,7- triacetic acid gadoliniums.Yield：74.6%, purity：99.99%.
Gadobutrol high resolution mass spec (HRMS) the results are shown in Table 1.
Table 1
Gadobutrol elemental analysis
Gadobutrol elemental analysis (to water amendment), this batch products loss on drying result are 3.05%, and etoh solvent is remaining
It is not detected.After being corrected to water, elemental analysis the results are shown in Table 2.
Table 2
| % | C | H | N |
| Theoretical value | 34.66 | 5.35 | 8.99 |
| Measured value | 34.44 | 5.38 | 8.89 |
| Absolute error | 0.22 | 0.03 | 0.10 |
Conclusion：C, the absolute error of H and N is both less than 0.3%, therefore the elemental analysis result and calculated value of this batch products
Unanimously.
The preparation process of the present invention is simply mild, and can obtain higher degree and the Gadobutrol of good yield, very
It is suitble to large-scale production.
Claims (10)
1. a kind of method preparing high-purity Gadobutrol comprising：
(1) compound for carrying out formula 3 is reacted with 5 compound of formula using the compound or its salt of formula 2；
(2) carry out the compound of formula 4 using the compound of the formula 3；
(3) carry out the Gadobutrol of formula 1 using the compound of the formula 4；
[formula 1]
[formula 2]
[formula 3]
[formula 4]
[formula 5]
Wherein, X is halogen, TsO- or MsO-.
2. the method according to claim 1 for preparing high-purity Gadobutrol, wherein in step (1),
The compound of formula 5 is the compound of following formula 5-1,
[formula 5-1]
3. the method according to claim 2 for preparing high-purity Gadobutrol, wherein
The salt of 2 compound of formula is the hydrochloride of formula 2-1, wherein n is 3 or 4,
[formula 2-1]
4. the method according to claim 2 for preparing high-purity Gadobutrol, wherein
Reaction carries out in the presence of base, and the alkali is selected from potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, 1,8- phenodiazines
It is one or more in 11 carbon -7- alkene of miscellaneous two ring.
5. the method according to claim 1 for preparing high-purity Gadobutrol, wherein in step (2),
3 compound of formula is hydrolyzed to obtain the compound of formula 4 under alkaline condition.
6. the method according to claim 5 for preparing high-purity Gadobutrol, wherein
The alkali is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide and calcium hydroxide.
7. the method according to claim 5 for preparing high-purity Gadobutrol, wherein
Step (2) further comprises the crystallization process of 4 compound of formula.
8. the method according to claim 1 for preparing high-purity Gadobutrol, wherein in step (3),
It is reacted come the Gadobutrol of formula 1 with gadolinium ion source by the compound of formula 4.
9. the method according to claim 8 for preparing high-purity Gadobutrol, wherein
The gadolinium ion source is selected from gadolinium oxide, gadolinium and gadolinium chloride.
10. the method according to claim 8 for preparing high-purity Gadobutrol, wherein
Step (3) further comprises the crystallization process of the Gadobutrol of formula 1.
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| CN111039885A (en) * | 2019-12-06 | 2020-04-21 | 广州康瑞泰药业有限公司 | Method for preparing high-purity combretastatin |
| CN112585121A (en) * | 2018-08-23 | 2021-03-30 | St制药株式会社 | Method for preparing gadobutrol |
| CN113527223A (en) * | 2021-06-22 | 2021-10-22 | 安徽普利药业有限公司 | Gadobutrol refining method |
| CN113880850A (en) * | 2021-10-18 | 2022-01-04 | 苏州百灵威超精细材料有限公司 | Gadobutrol intermediate, preparation method and application in gadobutrol preparation |
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| CN112585121A (en) * | 2018-08-23 | 2021-03-30 | St制药株式会社 | Method for preparing gadobutrol |
| CN112585121B (en) * | 2018-08-23 | 2023-11-21 | St制药株式会社 | Process for the preparation of gadobutrol |
| CN111039885A (en) * | 2019-12-06 | 2020-04-21 | 广州康瑞泰药业有限公司 | Method for preparing high-purity combretastatin |
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| CN113527223A (en) * | 2021-06-22 | 2021-10-22 | 安徽普利药业有限公司 | Gadobutrol refining method |
| CN113880850A (en) * | 2021-10-18 | 2022-01-04 | 苏州百灵威超精细材料有限公司 | Gadobutrol intermediate, preparation method and application in gadobutrol preparation |
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