CN108299322B - Method for preparing gadobutrol - Google Patents
Method for preparing gadobutrol Download PDFInfo
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- CN108299322B CN108299322B CN201810124932.5A CN201810124932A CN108299322B CN 108299322 B CN108299322 B CN 108299322B CN 201810124932 A CN201810124932 A CN 201810124932A CN 108299322 B CN108299322 B CN 108299322B
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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 45
- 229960003411 gadobutrol Drugs 0.000 title claims abstract description 45
- 238000000034 method Methods 0.000 title claims abstract description 30
- 238000006243 chemical reaction Methods 0.000 claims abstract description 44
- 238000002360 preparation method Methods 0.000 claims abstract description 21
- 150000001875 compounds Chemical class 0.000 claims description 38
- -1 gadolinium ions Chemical class 0.000 claims description 19
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 18
- 229910052688 Gadolinium Inorganic materials 0.000 claims description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- 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
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 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 4
- 229910001938 gadolinium oxide Inorganic materials 0.000 claims description 4
- CMIHHWBVHJVIGI-UHFFFAOYSA-N gadolinium(iii) oxide Chemical compound [O-2].[O-2].[O-2].[Gd+3].[Gd+3] CMIHHWBVHJVIGI-UHFFFAOYSA-N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-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
- MEANOSLIBWSCIT-UHFFFAOYSA-K gadolinium trichloride Chemical compound Cl[Gd](Cl)Cl MEANOSLIBWSCIT-UHFFFAOYSA-K 0.000 claims description 2
- LYQGMALGKYWNIU-UHFFFAOYSA-K gadolinium(3+);triacetate Chemical compound [Gd+3].CC([O-])=O.CC([O-])=O.CC([O-])=O LYQGMALGKYWNIU-UHFFFAOYSA-K 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- REXUYBKPWIPONM-UHFFFAOYSA-N 2-bromoacetonitrile Chemical compound BrCC#N REXUYBKPWIPONM-UHFFFAOYSA-N 0.000 abstract description 6
- NXHUAYWRBFCZOA-UHFFFAOYSA-N 3-(1,4,7,10-tetrazacyclododec-1-yl)butane-1,2,4-triol Chemical compound OCC(O)C(CO)N1CCNCCNCCNCC1 NXHUAYWRBFCZOA-UHFFFAOYSA-N 0.000 abstract description 5
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 5
- JUIKUQOUMZUFQT-UHFFFAOYSA-N 2-bromoacetamide Chemical compound NC(=O)CBr JUIKUQOUMZUFQT-UHFFFAOYSA-N 0.000 abstract description 4
- RJOJUSXNYCILHH-UHFFFAOYSA-N gadolinium(3+) Chemical compound [Gd+3] RJOJUSXNYCILHH-UHFFFAOYSA-N 0.000 abstract description 3
- 239000000413 hydrolysate Substances 0.000 abstract description 2
- 230000003301 hydrolyzing effect Effects 0.000 abstract description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 31
- 238000003756 stirring Methods 0.000 description 19
- 239000000463 material Substances 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 239000000047 product Substances 0.000 description 11
- 238000010992 reflux Methods 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 8
- 230000007062 hydrolysis Effects 0.000 description 8
- 238000006460 hydrolysis reaction Methods 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000005804 alkylation reaction Methods 0.000 description 6
- 238000001816 cooling Methods 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
- JZNZSKXIEDHOBD-UHFFFAOYSA-N 2-[4,10-bis(carboxymethyl)-7-(1,3,4-trihydroxybutan-2-yl)-1,4,7,10-tetrazacyclododec-1-yl]acetic acid Chemical compound OCC(O)C(CO)N1CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC1 JZNZSKXIEDHOBD-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 4
- 229940106681 chloroacetic acid Drugs 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 239000002253 acid Substances 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000000921 elemental analysis Methods 0.000 description 3
- 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 3
- 239000007788 liquid Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000000746 purification Methods 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
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 2
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 125000002091 cationic group Chemical group 0.000 description 2
- 239000002872 contrast media Substances 0.000 description 2
- 238000004896 high resolution mass spectrometry Methods 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
- 238000005086 pumping Methods 0.000 description 2
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 2
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 description 1
- SXNRJXPFKZHLFP-UHFFFAOYSA-N 2-[4,5-bis(carboxymethyl)-1,12-dihydroxy-2-(hydroxymethyl)-3-propyl-1,2,3,4-tetrazacyclododec-5-yl]acetic acid Chemical compound CCCN1N(CO)N(O)C(O)CCCCCCC(CC(O)=O)(CC(O)=O)N1CC(O)=O SXNRJXPFKZHLFP-UHFFFAOYSA-N 0.000 description 1
- SYZRZLUNWVNNNV-UHFFFAOYSA-N 2-bromoacetyl chloride Chemical compound ClC(=O)CBr SYZRZLUNWVNNNV-UHFFFAOYSA-N 0.000 description 1
- GEKNCWQQNMEIMS-UHFFFAOYSA-N 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane Chemical compound C1OC(C)(C)OCC2OC21 GEKNCWQQNMEIMS-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 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
- 238000005660 chlorination reaction Methods 0.000 description 1
- 230000009918 complex formation Effects 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 239000012467 final product Substances 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
- 230000007774 longterm Effects 0.000 description 1
- 238000002595 magnetic resonance imaging 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
- 239000002405 nuclear magnetic resonance imaging agent Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 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
- 231100000331 toxic Toxicity 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- ILJSQTXMGCGYMG-UHFFFAOYSA-N triacetic acid Chemical compound CC(=O)CC(=O)CC(O)=O ILJSQTXMGCGYMG-UHFFFAOYSA-N 0.000 description 1
- 230000004580 weight loss Effects 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a method for preparing high-purity gadobutrol, which comprises the steps of reacting 3- (1,4,7, 10-tetraazacyclododecane-1-yl) butane-1, 2, 4-triol with bromoacetonitrile or bromoacetamide, hydrolyzing the obtained intermediate under alkaline conditions, and carrying out complex reaction on the hydrolysate and a gadolinium ion source to obtain high-purity gadobutrol. The method has simple and mild preparation process, and is suitable for large-scale production.
Description
Technical Field
The invention relates to a method for preparing high-purity gadobutrol.
Background
In the field of gadolinium-containing contrast agents, gadobutrol (gadobutrol) is commercially sold worldwide under the trade name Gadovist (Gadovist) or Gadovist. It is a new type of powerful magnetic resonance imaging contrast agent approved for contrast enhanced magnetic resonance imaging (CE-MRI) diagnosis of multiple parts of the human body, including the brain, spinal cord, blood vessels, liver and kidney. In addition, gadobutrol contains a high concentration of ionic T1-relaxation potency. The highest short T1 potency per ml was shown in all gadolinium-containing contrast agents in view of their high concentration and high relaxation potency. This makes it possible to have excellent image quality and to have the practical advantage of using smaller doses.
Gadobutrol, represented by the following formula 1, is a nonionic complex consisting of gadolinium (iii) and the macrocyclic ligand dihydroxyhydroxymethylpropyltetraazacyclododecanetriacetic acid.
[ formula 1]
In CN102933562A, three amino groups of cyclen are protected by DMF acetal, and then reacted with 4, 4-dimethyl-3, 5, 8-trioxabicyclo [5.1.0] octane, and after hydrolysis of the protecting group, reacted with chloroacetic acid. This route may improve selectivity. However, the cyclen protected by DMF acetal is extremely unstable and easy to hydrolyze, and impurities are difficult to control; chloroacetic acid used in the alkylation step is a highly toxic compound and has a high risk.
CN107001294A discloses a method for preparing gadobutrol by using bromoacetic acid tert-butylThe butyl esters are reacted and then acid hydrolyzed. However, the product obtained after the reaction of the tert-butyl bromoacetate is difficult to purify, and in the next hydrolysis step, concentrated acid is needed to be used under the high-temperature condition, so that the reaction is slow; on the one hand, the tert-butyl group which is hydrolyzed off will form C under acidic conditions+Ion, C+The ions migrate to the hydroxyl groups, forming an impurity that is difficult to remove, which is carried over to the final product and cannot be removed; on the other hand, due to the long-term reaction under concentrated acid and high temperature, hydroxyl in the product can generate chlorination and elimination reaction, and new impurities are generated.
Three schemes for synthesizing gadobutrol are disclosed in Inorg. chem. 1997, 36, 6086-6093, wherein scheme 1 requires a large amount of resin for purification, is very disadvantageous for purification using production equipment, leads to increased unit cost and is not suitable for large-scale production; scheme 2 suffers from low yield and low purity; the route of scheme 3 is only suitable for laboratory scale and not for large scale production due to its low yield.
International standards (such as ICH guidelines etc.) recommend impurity levels below 0.1% and therefore it is preferred to prepare ultra-high purity gadobutrol with a purity above 99.9% for sale as a pharmaceutical. However, the process disclosed in the cited reference is complicated and does not allow the preparation of gadobutrol therefrom in high purity. Therefore, a new preparation method is needed, which can simply and efficiently prepare high-purity gadobutrol.
Disclosure of Invention
The invention aims to provide a method for preparing high-purity gadobutrol by a simple and mild process.
The purpose of preparing the high-purity gadobutrol is realized by the invention, the method comprises the steps of reacting 3- (1,4,7, 10-tetraazacyclododecane-1-yl) butane-1, 2, 4-triol with bromoacetonitrile or bromoacetamide, then hydrolyzing under alkaline conditions, carrying out complexation reaction on a hydrolysate and a gadolinium ion source, and purifying the obtained product to obtain the gadobutrol with higher purity and good yield.
The process for preparing high-purity gadobutrol according to the invention comprises:
(1) preparing a compound of formula 3 by alkylation of a compound of formula 2 or a salt thereof with a compound of formula 5;
(2) using the compound of formula 3 to prepare a compound of formula 4;
(3) preparing gadobutrol of formula 1 using the compound of formula 4;
[ formula 1]
[ formula 2]
[ formula 3]
[ formula 4]
[ formula 5]
Wherein X is halogen, TsO-or MsO-.
Specifically, step (1), alkylation reaction
Preparing a compound of formula 3 by alkylation reaction of a compound of formula 2 or a salt thereof with a compound of formula 5;
the compounds of formula 5 are:
wherein X is halogen, TsO-or MsO-;
in some embodiments of the invention, the salt of the compound of formula 2 is a hydrochloride salt of formula 2-1, wherein n is 1-4, preferably 4 hydrochloride or 3 hydrochloride, more preferably the salt of the compound of formula 2 is 4 hydrochloride of formula 2-1.
[ formula 2-1]
Further, in some embodiments of the present invention, the compound of formula 5 may be a compound of the following formula 5-1, wherein X is Br;
[ formula 5-1]
In step (1), the alkylation reaction is carried out in a solvent which is commonly used in alkylation reactions. Preferably, the solvent may be H2O, C2-C11 nitrile, C4-C11 ether, C2-C5 alcohol, or a mixture thereof, and more preferably, the solvent may be acetonitrile, but the present invention is not limited thereto.
Further, the reaction may be carried out in the presence of a base, preferably, the base may be potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, 1, 8-diazabicycloundec-7-ene (DBU), or a mixture thereof, and more preferably, the base is potassium carbonate, but the present invention is not limited thereto.
The reaction in step (1) may be performed at 40 to 80 ℃, preferably at 50 to 60 ℃, and more preferably at 50 to 55 ℃, but the present invention is not limited thereto.
According to some embodiments of the present invention, step (1) may further comprise a crystallization process of the compound of formula 3.
The solvent used in the crystallization process may be a C2-C8 alcohol, a C3-C8 ketone, or a mixture thereof, and preferably a mixture of ethanol is used. The compound of formula 3 may be produced in a high purity of 97% or more, preferably 98% or more, and more preferably 99% or more by the step (1).
Step (2), hydrolysis
Preparing a compound of formula 4 with high purity by subjecting the compound of formula 3 with high purity produced in step (1) to alkaline hydrolysis.
The base includes lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, etc., preferably lithium hydroxide.
The hydrolysis may be carried out by using general reaction conditions of alkaline hydrolysis. Preferably, the basic hydrolysis may be performed by adding a lithium hydroxide solution to the compound of formula 3.
Further, the hydrolysis may be performed at 70 to 100 ℃, preferably at 70 to 80 ℃, more preferably at 75 to 80 ℃, but the present invention is not limited thereto.
In some embodiments of the present invention, step (2) may comprise a purification process of the compound of formula 4 by using a resin. And because the using amount of the resin is low, the production cost can be reduced.
Furthermore, according to some embodiments of the present invention, step (2) may further include a crystallization process of the compound of formula 4.
The solvent used for the crystallization process may be ethanol, methanol, acetone or a mixture thereof, and an ethanol solvent is preferably used.
The compound of formula 4 can be produced in a high purity of 85% or more, preferably 90% or more, by step (2).
Step (3), gadolinium Complex formation
Gadobutrol as a gadolinium complex is prepared by reacting the compound of formula 4 prepared in step (2) with a source of gadolinium ions.
The source of gadolinium ions may be any compound capable of providing gadolinium ions. For example, the source of gadolinium ions may be selected from gadolinium oxide, gadolinium acetate and gadolinium chloride. Preferably, the source of gadolinium ions is gadolinium oxide, but the invention is not limited thereto.
The reaction in the step (3) may be carried out at 80 to 100 ℃, preferably at 85 to 95 ℃, more preferably at 87 to 93 ℃, but the present invention is not limited thereto.
The step (3) can further comprise a crystallization process of gadobutrol.
The solvent for crystallization may be alcohol or ketone, preferably absolute ethanol, isopropanol, acetone, etc.
The gadobutrol of formula 1 can be produced in a high purity of 99% or more, preferably 99.5% or more, more preferably 99.9% or more by step (3).
The compound of formula 2 (namely, 3- (1,4,7, 10-tetraazacyclododecane-1-yl) butane-1, 2, 4-triol) is used for reacting with bromoacetonitrile or bromoacetamide, the reaction condition is mild, and the reaction can be carried out at room temperature; the intermediate is easy to purify, the purity is extremely high (more than 98 percent), and the yield is improved compared with chloroacetic acid and tert-butyl bromoacetate. In the further hydrolysis process, alkaline conditions are used for hydrolysis, the reaction is mild and rapid, and no by-product is generated. The purity of the gadobutrol prepared by a bromoacetonitrile route reaches more than 99.9 percent.
The invention avoids using highly toxic chloroacetic acid, reduces the safety risk and is environment-friendly.
The gadobutrol preparation process is simple and mild, and is very suitable for large-scale production.
Detailed Description
Hereinafter, the process for the preparation of gadobutrol according to the invention will be described in detail.
The synthesis route of the preparation method of gadobutrol according to the invention is as follows:
EXAMPLES preparation of gadobutrol
Step 1: preparation of 2,2',2' ' - (10- (1,3, 4-trihydroxybutan-2-yl) -1,4,7, 10-tetraazacyclododecane-1, 4, 7-triyl) trisacetonitrile
(1) Using bromoacetonitrile
500 mL of acetonitrile was charged into a 1000mL reaction flask, 50g (0.1184 mol) of 3- (1,4,7, 10-tetraazacyclododecan-1-yl) butane-1, 2, 4-triol 4 hydrochloride was added to the reaction flask with stirring, 163g (1.184 mol) of potassium carbonate was added to the reaction flask at room temperature, and 42.6g (0.3552 mol) of bromoacetonitrile was slowly added thereto. After the materials are added, the temperature of the materials in the reaction bottle is heated to 50 ℃ to 55 ℃, and the temperature is maintained to be stirred for reaction. After the reaction is terminated, filtering, concentrating the filtrate under reduced pressure, adding 250mL of ethanol into a concentration bottle after the concentration is finished, heating the material to reflux after the ethanol is added, maintaining the reflux temperature and stirring for 3 hours, cooling the material to room temperature, filtering, washing a filter cake by 50mL of ethanol, and pumping till no effluent liquid exists to obtain a wet product, and drying the filtered crystal in vacuum at the internal temperature of 50 ℃ to obtain 41.94g of 2,2',2' ' - (10- (1,3, 4-trihydroxybutane-2-yl) -1,4,7, 10-tetraazacyclododecane-1, 4, 7-triyl) acetonitrile. Yield: 90%, purity: 98 percent.
1HNMR (400 MHz, MeOD, ppm): 2.49-2.92 (m, 19H), 3.46-3.81 (m, 12H).
(2) Using bromoacetamide
500 mL of acetonitrile was charged into a 1000mL reaction flask, 50g (0.1184 mol) of 3- (1,4,7, 10-tetraazacyclododecan-1-yl) butane-1, 2, 4-triol 4 hydrochloride was added to the reaction flask with stirring, 163g (1.184 mol) of potassium carbonate was added to the reaction flask at room temperature, and 50.65g (0.3671 mol) of bromoacetyl chloride was added thereto. After the materials are added, the temperature of the materials in the reaction bottle is heated to 50 ℃ to 55 ℃, and the temperature is maintained to be stirred for reaction. After the reaction is terminated, filtering, concentrating the filtrate under reduced pressure, adding 200mL of ethanol into a concentration bottle after the concentration is finished, heating the material to reflux after the ethanol is added, maintaining the reflux temperature and stirring for 3 hours, cooling the material to room temperature, filtering, washing a filter cake by 50mL of ethanol, and pumping till no effluent liquid exists to obtain a wet product, and drying the filtered crystal in vacuum at the internal temperature of 50 ℃ to obtain 48.75g of 2,2',2' ' - (10- (1,3, 4-trihydroxybutane-2-yl) -1,4,7, 10-tetraazacyclododecane-1, 4, 7-triyl) triethylamine. Yield: 92%, purity: 97.5 percent.
Step 2: preparation of 2,2',2' ' - (10- (1,3, 4-trihydroxybutan-2-yl) -1,4,7, 10-tetraazacyclododecane-1, 4, 7-triyl) triacetic acid
(1) Using 2,2',2' ' - (10- (1,3, 4-trihydroxybutan-2-yl) -1,4,7, 10-tetraazacyclododecane-1, 4, 7-triyl) triacetonitrile
Adding 30mL of purified water and 10mL of methanol into a 250mL three-neck flask, adding 10g (0.025 mol) of 2,2',2' ' - (10- (1,3, 4-trihydroxybutane-2-yl) -1,4,7, 10-tetraazacyclododecane-1, 4, 7-triyl) acetonitrile into the reaction flask under stirring, adding 6.1g (0.254 mol) of lithium hydroxide into the reaction flask at room temperature, heating the material in the reaction flask to 75-80 ℃ under stirring after the material is added, maintaining the temperature for reaction, cooling the reaction solution to room temperature after the reaction is finished, adding cationic resin into the reaction flask under stirring until the material pH =3.5-4.5, filtering, concentrating the filtrate, finishing the concentration, adding 40mL of ethanol into the reaction flask, heating to reflux, maintaining the reflux temperature for stirring for 4 hours, cooling to 10-20 ℃, filtering, washing the filter cake with 20ml of ethanol and filtering until no effluent is present, drying the filtered crystals in vacuo at an internal temperature of 50 ℃ to obtain 10.1g of 2,2',2 ″ - (10- (1,3, 4-trihydroxybutane-2-yl) -1,4,7, 10-tetraazacyclododecane-1, 4, 7-triyl) triacetic acid. Yield: 88.2%, purity: 90 percent.
1HNMR (400 MHz, D2O, ppm): 3.08-3.34 (m, 16H), 3.53-3.78 (m, 12H).
(2) 2,2',2' ' - (10- (1,3, 4-trihydroxybutan-2-yl) -1,4,7, 10-tetraazacyclododecane-1, 4, 7-triyl) triethylamine is used
Adding 30mL of purified water and 10mL of methanol into a 250mL reaction bottle, adding 10g (0.0223 mol) of 2,2',2' ' - (10- (1,3, 4-trihydroxybutane-2-yl) -1,4,7, 10-tetraazacyclododecane-1, 4, 7-triyl) triethylamine into the reaction bottle under stirring, adding lithium hydroxide (4.28 g, 0.1787 mol) into the reaction bottle at room temperature, heating the materials in the reaction bottle to 75-80 ℃ under stirring after the addition is finished, preserving the temperature for reaction, and cooling the materials in the reaction bottle to room temperature after the reaction is determined to be finished. Adding cationic resin into a reaction bottle under stirring till the material pH is =3.5-4.5, filtering, concentrating the filtrate, finishing the concentration, adding 36ml of ethanol into the reaction bottle, heating to reflux, maintaining the reflux temperature, stirring for 4 hours, cooling to 10-20 ℃, filtering, washing a filter cake by using 20ml of ethanol, performing suction filtration till no effluent liquid exists, and drying the obtained wet product in vacuum at the internal temperature of 50 ℃ to obtain a dry product of 9.1g of 2,2',2' ' - (10- (1,3, 4-trihydroxybutane-2-yl) -1,4,7, 10-tetraazacyclododecane-1, 4, 7-triyl) triacetic acid. Yield: 91%, purity: 91 percent.
And step 3: preparation of gadolinium complex of 10- (2, 3-dihydroxy-1- (hydroxymethyl) propyl) -1,4,7, 10-tetraazacyclododecane-1, 4, 7-triacetic acid (gadobutrol)
15 ml of purified water are introduced into a 100ml reaction flask, 15.4g (0.0342 mol) of 2,2',2' ' - (10- (1,3, 4-trihydroxybutan-2-yl) -1,4,7, 10-tetraazacyclododecane-1, 4, 7-triyl) triacetic acid are added to the flask with stirring, 6.2g (0.0171 mol) of gadolinium oxide are added to the flask, the contents are heated to 90 ℃ with stirring and the reaction is maintained at this temperature with stirring, and when the end of the reaction is established, the mixture is filtered while hot, and the filtrate is concentrated to no effluent after treatment with a resin. Adding 7.7ml of purified water into the concentration bottle, heating the material in the bottle to 75 ℃ under stirring after the water is added, maintaining the temperature until the material in the bottle is dissolved, adding 160ml of ethanol into the bottle, heating to reflux, and stirring for 3 hours under the reflux temperature. The contents were cooled to 20-25 ℃ with stirring and maintained at this temperature for 1 hour of stirring and filtered. The wet product was dried at 50 ℃ or lower under vacuum to obtain 15.5g of 10- (2, 3-dihydroxy-1- (hydroxymethyl) propyl) -1,4,7, 10-tetraazacyclododecane-1, 4, 7-gadolinium triacetate as a dry product. Yield: 74.6%, purity: 99.99 percent.
Gadobutrol High Resolution Mass Spectrometry (HRMS) results are shown in table 1.
TABLE 1
Gadobutrol elemental analysis
Gadobutrol element analysis (corrected for water), the drying weight loss result of the batch of products is 3.05%, and the solvent ethanol residue is not detected. The results of elemental analysis after correction for water are shown in table 2.
TABLE 2
And (4) conclusion: C. the absolute errors of H and N are less than 0.3%, so the elemental analysis result of the batch of products is consistent with the calculated value.
The preparation process is simple and mild, and gadobutrol with higher purity and good yield can be obtained, so that the method is very suitable for large-scale production.
Claims (10)
1. A process for the preparation of gadobutrol, comprising:
(1) reacting a compound of formula 2 or a salt thereof with a compound of formula 5 to prepare a compound of formula 3;
(2) using the compound of formula 3 to prepare a compound of formula 4;
(3) preparing gadobutrol of formula 1 using the compound of formula 4;
[ formula 1]
[ formula 2]
[ formula 3]
[ formula 4]
[ formula 5]
Wherein X is halogen, TsO-or MsO-.
2. A process for the preparation of gadobutrol according to claim 1, wherein, in step (1),
the compound of formula 5 is a compound of the following formula 5-1,
[ formula 5-1]
3. A process for the preparation of gadobutrol according to claim 2, wherein,
the salt of the compound of formula 2 is a hydrochloride salt of formula 2-1, wherein n is 3 or 4,
[ formula 2-1]
4. A process for the preparation of gadobutrol according to claim 2, wherein, in step (1),
the reaction is carried out in the presence of a base, which is one or more selected from potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, 1, 8-diazabicycloundecen-7-ene.
5. A process for the preparation of gadobutrol according to claim 1, wherein, in step (2),
the compound of formula 3 is hydrolyzed under basic conditions to give the compound of formula 4.
6. A process for the preparation of gadobutrol according to claim 5, wherein,
the base is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide and calcium hydroxide.
7. A process for the preparation of gadobutrol according to claim 5, wherein,
step (2) further comprises a crystallization process of the compound of formula 4.
8. A process for the preparation of gadobutrol according to claim 1, wherein, in step (3),
gadobutrol of formula 1 is prepared by reacting a compound of formula 4 with a source of gadolinium ions.
9. A process for the preparation of gadobutrol according to claim 8, wherein,
the source of gadolinium ions is selected from gadolinium oxide, gadolinium acetate and gadolinium chloride.
10. A process for the preparation of gadobutrol according to claim 8, wherein,
the step (3) further comprises a crystallization process of gadobutrol of formula 1.
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| CN103497117A (en) * | 2013-09-25 | 2014-01-08 | 河北诚信有限责任公司 | Production technology of ethylenediamine tetraacetic acid (EDTA) |
| CN104130146A (en) * | 2014-07-31 | 2014-11-05 | 苏州昊帆生物科技有限公司 | Preparation method of (4S)-3, 6, 9-triaza-3, 6, 9-tri(carboxymethyl)-4-(4-ethoxy benzyl)undecanedioic acid |
| CN107001294A (en) * | 2014-12-26 | 2017-08-01 | St制药株式会社 | A kind of method for preparing Gadobutrol |
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| CN103497117A (en) * | 2013-09-25 | 2014-01-08 | 河北诚信有限责任公司 | Production technology of ethylenediamine tetraacetic acid (EDTA) |
| CN104130146A (en) * | 2014-07-31 | 2014-11-05 | 苏州昊帆生物科技有限公司 | Preparation method of (4S)-3, 6, 9-triaza-3, 6, 9-tri(carboxymethyl)-4-(4-ethoxy benzyl)undecanedioic acid |
| CN107001294A (en) * | 2014-12-26 | 2017-08-01 | St制药株式会社 | A kind of method for preparing Gadobutrol |
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