CN108658882A - A kind of preparation method of Cyclen -1,4,7,10- tetraacethyls - Google Patents
A kind of preparation method of Cyclen -1,4,7,10- tetraacethyls Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- QBPPRVHXOZRESW-UHFFFAOYSA-N 1,4,7,10-tetraazacyclododecane Chemical compound C1CNCCNCCNCCN1 QBPPRVHXOZRESW-UHFFFAOYSA-N 0.000 title claims description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 46
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims abstract description 31
- 229960003194 meglumine Drugs 0.000 claims abstract description 31
- CMIHHWBVHJVIGI-UHFFFAOYSA-N gadolinium(III) oxide Inorganic materials [O-2].[O-2].[O-2].[Gd+3].[Gd+3] CMIHHWBVHJVIGI-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000001953 recrystallisation Methods 0.000 claims abstract description 9
- 239000002253 acid Substances 0.000 claims abstract description 8
- 230000000536 complexating effect Effects 0.000 claims abstract description 3
- GFSTXYOTEVLASN-UHFFFAOYSA-K gadoteric acid Chemical compound [Gd+3].OC(=O)CN1CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC1 GFSTXYOTEVLASN-UHFFFAOYSA-K 0.000 claims description 28
- 229960003823 gadoteric acid Drugs 0.000 claims description 28
- 238000006243 chemical reaction Methods 0.000 claims description 23
- 239000002904 solvent Substances 0.000 claims description 17
- 239000012043 crude product Substances 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 150000001243 acetic acids Chemical class 0.000 claims description 6
- 238000005804 alkylation reaction Methods 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- 150000001298 alcohols Chemical class 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 2
- JDNTWHVOXJZDSN-UHFFFAOYSA-N iodoacetic acid Chemical compound OC(=O)CI JDNTWHVOXJZDSN-UHFFFAOYSA-N 0.000 claims description 2
- BLALBRWEAJQIIL-UHFFFAOYSA-N [Cl].CC(O)=O Chemical compound [Cl].CC(O)=O BLALBRWEAJQIIL-UHFFFAOYSA-N 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 24
- 230000001681 protective effect Effects 0.000 abstract description 2
- WDLRUFUQRNWCPK-UHFFFAOYSA-N Tetraxetan Chemical compound OC(=O)CN1CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC1 WDLRUFUQRNWCPK-UHFFFAOYSA-N 0.000 description 23
- 229910052688 Gadolinium Inorganic materials 0.000 description 19
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 description 19
- 239000000243 solution Substances 0.000 description 16
- 239000011347 resin Substances 0.000 description 11
- 229920005989 resin Polymers 0.000 description 11
- 238000010438 heat treatment Methods 0.000 description 10
- 238000003756 stirring Methods 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000010612 desalination reaction Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 239000003643 water by type Substances 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 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 4
- 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 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 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 4
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 4
- 238000004448 titration Methods 0.000 description 4
- 238000005406 washing Methods 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 compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229910001938 gadolinium oxide Inorganic materials 0.000 description 3
- 229940075613 gadolinium oxide Drugs 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 238000001728 nano-filtration Methods 0.000 description 3
- 238000007670 refining Methods 0.000 description 3
- 235000011121 sodium hydroxide Nutrition 0.000 description 3
- SHWNNYZBHZIQQV-UHFFFAOYSA-J EDTA monocalcium diisodium salt Chemical compound [Na+].[Na+].[Ca+2].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O SHWNNYZBHZIQQV-UHFFFAOYSA-J 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229940087511 calcium disodium versenate Drugs 0.000 description 2
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 2
- 239000002872 contrast media Substances 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical group 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- -1 normal-butyl Chemical group 0.000 description 2
- 230000000269 nucleophilic effect Effects 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 229910001961 silver nitrate Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000002583 angiography Methods 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 239000003183 carcinogenic agent Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 150000001896 cresols Chemical class 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000002595 magnetic resonance imaging Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000002601 radiography Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- YRWWOAFMPXPHEJ-OFBPEYICSA-K sodium L-ascorbic acid 2-phosphate Chemical compound [Na+].[Na+].[Na+].OC[C@H](O)[C@H]1OC(=O)C(OP([O-])([O-])=O)=C1[O-] YRWWOAFMPXPHEJ-OFBPEYICSA-K 0.000 description 1
- 229940048058 sodium ascorbyl phosphate Drugs 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- FDRCDNZGSXJAFP-UHFFFAOYSA-M sodium chloroacetate Chemical compound [Na+].[O-]C(=O)CCl FDRCDNZGSXJAFP-UHFFFAOYSA-M 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000010792 warming Methods 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/003—Compounds containing elements of Groups 3 or 13 of the Periodic Table without C-Metal linkages
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The present invention relates to a kind of preparation methods of 1,4,7,10 tetraazacyclododecanand, 1,4,7,10 tetraacethyl.Specifically, this method selects means re-crystallization to obtain high-purity compound of formula I, further, by meglumine, Gd2O3Gadoteric Acid meglumine can be obtained with compound of formula I complexing, the method is easy to operate, at low cost, environmentally protective, is suitable for mass producing.
Description
Technical field
The invention belongs to medicinal chemistry arts, are related to a kind of Isosorbide-5-Nitrae, 7,10- tetraazacyclododecanands-Isosorbide-5-Nitrae, 7,10- tetrems
Acid and its complex compound preparation method.
Background technology
Gadoteric Acid meglumine (Gadoteric Acid Meglumine), the entitled Isosorbide-5-Nitrae of chemistry, 7,10- tetraazacyclododecanes 12
Alkane-Isosorbide-5-Nitrae, 7,10- tetraacethyl gadolinium meglumines are to be developed and listed by Guerbet, are used as the Magnetic resonance imaging radiography of cancer
Agent.
Gadoteric Acid meglumine is that the ring-like gadolinium preparation of ion belongs to low-risk drug due to its design feature, is being listed
9 kinds of gadolinium contrast agent in, cause the risk of kidney source sexual system fibrosis (NSF) theoretically to be analyzed to be minimum.Compared to other
Gadolinium contrast agent, this product indication is wider, and other than liver, this product can be used for maincenter, whole body and angiography,
Currently, existing literature report discloses the preparation method of a plurality of Gadoteric Acid meglumine, substantially it is summarized as follows：
Wangler et al. (Bioorganic＆Medicinal Chemistry, 16,2606-2616,2008) report with
Cycleanine and ethyl chloroacetate are raw material, and through N- nucleophilic displacement of fluorine, ester hydrolysis is acidified, and is reacted after gadolinium cooperation, then with meglumine
Generate gadoterlc acid meglumine saltlniection.A large amount of sodium chloride are will produce in the reaction process to remove by organic extractant phase method, effect is excessively poor,
Intermediate 2 is not readily passed through refined mode and is purified by design feature in the route simultaneously, and purifying process is cumbersome, uncomfortable
Industrialized production is closed,
US5428156A is reacted by Mannich from torus Teng Ning and generates intermediate 6, is hydrolyzed under LiOH catalysis
Obtain 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (also known as DOTA), then be complexed with gadolinium oxide, finally with
Meglumine reaction generates Gadoteric Acid meglumine.Potassium cyanide is toxic articles in the route, is not suitable for technique productions,
US4963344 is then disclosed using cycleanine as raw material, occurs N- nucleophilic displacement of fluorine through monoxone, acidification, then with Portugal's first
Amine, Gd2O3Complexing, the method that " one kettle way " prepares gadoterlc acid meglumine saltlniection.When technical staff repeats the technique, find due to intermediate
Gadoteric Acid is unstable, and dissociating in finished product Gadoteric Acid meglumine, gadolinium concentrations are exceeded, and process repeatability is poor, is unsuitable for technique and puts
Big production, and needed after obtaining Gadoteric Acid meglumine crude product without salt-removal steps in entire technical process, desalination operation is just carried out,
To aggravate the difficulty and workload of technique desalination, it is not suitable for technique productions,
Meanwhile CN104955822A and CN105939994 disclose the purifying in the way of resin or nanofiltration and prepare gadolinium respectively
Special acid meglumine intermediate DOTA, and utilize gained DOTA further with meglumine, Gd2O3Complexing prepares Gadoteric Acid meglumine
Method.The technique greatest drawback be using resin or nanofiltration purifying intermediate DOTA production capacities it is not high, technique is cumbersome, while also depositing
The risk of unknown impuritie is introduced in purifying resin.
For this purpose, the present invention provides a kind of preparation method of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid,
Preparation is simple for this, environmentally protective, is suitable for the needs that industry produces greatly.
Invention content
The present invention provides a kind of system of Cyclen -1,4,7,10- tetraacethyls (Formulas I) compound
Preparation Method, this method include：Compound of formula I crude product re-crystallization step will be contained.Recrystallization gained compound of formula I purity is not less than
95.0%, in embodiments can be 95.0%, 95.2%, 95.4%, 95.6%, 95.8%, 96.0%, 96.2%,
96.4%, 96.6%, 96.8%, 97.0%, 97.2%, 97.4%, 97.6%, 97.8%, 98.0%, 99.0% or higher,
Meanwhile gained compound of formula I compound of formula H content is not more than 1%.In some embodiments, Formula II chemical combination
Object content can be 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%,
0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01% or smaller, further, the formula
II compounds contents are not more than 0.5%, preferably no greater than 0.2%,
Formula II compound have with Formulas I chemical combination similar structures, chemical polarity is close, during preparation of compounds of formula I, formula
II compounds invariably accompany generation, and are not easy to remove, and in Gadoteric Acid meglumine or Gadoteric Acid finished product, Formula II compound with
The impurity of gadolinium complexing is also extremely not easy to remove.If compound of formula I compound of formula H content is more than 1%, subsequently gadolinium is being prepared
During special acid or Gadoteric Acid meglumine, 0.05% cannot be down to once by resin or nanofiltration purifying, it is difficult to meet ICH
Guideline requirement.
In embodiments, recrystallization solvent of the present invention is selected from least one of water, alcohols solvent, the alcohols
Solvent is C1-6Alkylol can be at least one of methanol, ethyl alcohol, propyl alcohol；Further, the recrystallization solvent is selected from
At least one of water, ethyl alcohol.
Further, when volume-weight ratio of re-crystallization step solvent for use amount of the present invention and compound of formula I crude product
It needs to control in a certain range, such as selects nonelectrolyte mixed aqueous solution, the two ratio can be with 30:1~100:1, it in embodiments, can
Think 30:1、35:1、40:1、45:1、50:1、55:1、60:1、65:1、70:1、75:1、80:1、85:1、90:1、95:1、
100:1。
If single solvent is selected to need, according to the solvent volume-weight ratio suitable to the selection of material dissolution performance, implementing
In scheme, water is selected to be used as refining solvent, volume-weight ratio of solvent dosage and compound of formula I crude product is 1:2~5:1, in reality
It applies in scheme, the two ratio can be 1:2、1:1.9、1:1.8、1:1.7、1:1.6、1:1.5、1:1.4、1:1.3、1:1.2、1:
1.1,1:1、1.4:1、1.6:1、1.8:1、2:1、2.2:1、2.4:1、2.6:1、2.8:1、3:1、3.2:1、3.4:1、3.6:1、
3.8:1、4:1、4.2:1、4.4:1、4.6:1、4.8:1、5.0:1, preferably 1:1~3:1.
During preparing Gadoteric Acid or Gadoteric Acid meglumine, salt content in intermediate DOTA is controlled into a certain range, this
Sample not only can cause yield to reduce to avoid the intermediate exhaustive purification, but also can be to avoid the follow-up Gadoteric Acid of influence or Gadoteric Acid Portugal
The purifying process of methylamine and the quality of subsequent product and yield.Salt content is not more than 20% in compound of formula I of the present invention,
In embodiments can be 20,19,18,17,16,15,14,13,12,11,10,9,8,7,6,5,4,3,2,1% or smaller,
Preferably no greater than 15%.
In embodiments, re-crystallization step of the present invention：
1) compound of formula I crude product is added in suitable solvent, heating stirring dissolving,
2) cooling crystallization is stirred,
3) it filters, washing, dry compound of formula I.
Further, formula Compound I crude product can by Isosorbide-5-Nitrae, 7,10- tetraazacyclododecanands (cycleanine) with
Alkylated reaction obtains halogenated acetic acids under alkaline condition, as described below：
Wherein, X is halogen.
It being described as described in CN104955855, the alkylated reaction can be influenced by several factors, for example, halogen
For the dosage of acetic acid, reaction time, reaction temperature etc..Alkali used in alkylated reaction of the present invention is selected from alkali metal hydroxide
Object, preferably sodium hydroxide or potassium hydroxide.Except this, in embodiments, alkylated reaction also needs to strictly control reactant
PH value in system, the usual alkylation reaction system alkaline pH are not more than 13, and the pair that can control the alkylation process very well is anti-
It answers.Preferably 8~12, can be 8.0,8.2,8.4,8.6,8.8,9.0,9.1,9.2,9.3,9.4,9.5,9.6,9.7,9.8,
9.9、10.0、10.1、10.2、10.3、10.4、10.5、10.6、10.7、10.8、10.9、11.0、11.2、11.4、11.6、
11.8,12.0, more preferably 9.0~11.0.
Further, aforesaid alkylization reaction in halogenated acetic acids used can be iodoacetic acid, bromoacetic acid or chloracetic acid, it is excellent
It is selected as chloracetic acid.
In some embodiments, prepared by 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (Formulas I) compound
Method, including：
It is anti-that Cyclen (cycleanine) a) under alkaline condition to that alkyl occur with halogenated acetic acids
It answers；
B) step a) after reaction, adjusts reaction solution pH to acidity, crystallization filters to obtain compound of formula I crude product；
C) compound of formula I crude product is recrystallized.
Further, the acid pH be not more than 3, in embodiments can be 3.0,2.9,2.8,2.7,2.6,2.5,
2.4,2.3,2.2,2.1,2.0,1.9,1.8,1.7,1.6,1.5,1.4,1.3,1.2,1.1,1.0, preferably 2.0~2.5.
The present invention also provides a kind of preparation method of Gadoteric Acid, this method includes the steps that above-mentioned preparation of compounds of formula I, with
And by Gd2O3With the step of being complexed according to compound of formula I obtained by the preparation method.
The present invention also provides a kind of preparation method of Gadoteric Acid meglumine, this method includes above-mentioned preparation of compounds of formula I
Step, and by Gd2O3, meglumine with being complexed according to compound of formula I obtained by above-mentioned preparation method the step of.
Detailed description of the invention
By the measurement of HPLC, the detection method is as follows for substance " content " of the present invention or " purity "：
2695 Alliance liquid chromatographs of Waters or 1200 liquid chromatographs of Agilent；
It is filler with octadecylsilane chemically bonded silica；It is respectively A, B mobile phase with 0.2% sodium ascorbyl phosphate, acetonitrile, ladder
Degree elution, Detection wavelength 196nm.
Salometry can be by the method for HPLC in the present invention, and the retention time of salt is about 1.9min.May be used also
By in the way of silver nitrate titration, then the content data for obtaining salt in sample can be quantified by simple mathematical calculations.It is described
Silver nitrate titration method is known to those skilled in the art or it was determined that can also refer to the chief editors such as Liao Lifu《Analysisization
It learns》Described in (publishing house of the Central China University of Science and Technology, 2015.8.).
Retention time about 19min in Formula II compound HPLC of the present invention, relative retention time 0.13.
Solvent dosage of the present invention is with volume units, and solid sample dosage is in terms of mass unit.
" volume-weight " of the present invention is stated：Compare between solvent for use volume and refining crude weight.
Free gadolinium assay method of the present invention：
Precision weighs this product 7.6g, sets in 250ml conical flasks, is dissolved in water, and pH to 5.0~7.5 is adjusted, with pyridine and two
For cresols orange solution using the aobvious red of solution, it is in yellow to be titrated to solution with Calcium Disodium Versenate titrating solution.
If any free gadolinium in sample, calculated as the following formula：
Wherein：V is the volume (ml) of the titrating solution of consumption；Cs is the concentration (mol/ of Calcium Disodium Versenate titrating solution
L)；
M is the weight (g) of Gadoteric Acid meglumine test sample；
Quality standard provides Gadoteric Acid meglumine：It is calculated by anhydride, free gadolinium amount must not cross 0.013%.
After the use of resin is all activation in the present invention, the resin activated method is well known to those skilled in the art
Or it is identifiable.For example, D311 is resin activated：Purified water is utilized to impregnate successively, the washing of 5% hydrochloric acid solution purifies water washing
It is not more than 7 to efflux pH value, conductivity is not more than 10 μ/cm.
" alkyl " of the present invention refers to the aliphatic hydrocarbon group of saturation, and alkyl of the choosing containing 1 to 6 carbon atom (can be expressed as
C1-6 alkyl).Non-limiting embodiment includes methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tertiary butyl, Zhong Ding
Base, n-pentyl, 1,1- dimethyl propyls, 1,2- dimethyl propyls, 2,2- dimethyl propyls, 1- ethyl propyls, 2- methyl butyls,
3- methyl butyls, n-hexyl, 1- Ethyl-2-Methyls propyl, 1,1,2- thmethylpropyls, 1,1- dimethylbutyls, 1,2- diformazans
Base butyl, 2,2- dimethylbutyls, 1,3- dimethylbutyls, 2- ethyl-butyls, 2- methyl amyls, 3- methyl amyls.
It is of the present invention to be obtained by commercial sources with reagent.
Specific implementation mode
The present invention is explained in greater detail below with reference to embodiment, the embodiment of the present invention is merely to illustrate the skill of the present invention
Art scheme, the spirit and scope of the invention are not limited thereto.
Embodiment 1
Be added 11.8kg monoxones and 12l purified waters into 100L reaction kettles, stirring and dissolving, be added under ice bath dissolved with
3.2kg cycleanines are suspended in 6l water and are added in reaction by the 15l water of 5kg sodium hydroxides, are warming up to 80~85 DEG C, are added dropwise
Dissolved with the 6L water of 5.2kg sodium hydroxides, for control reaction system pH 10~11, overnight, 10.4l is added dropwise after being cooled to room temperature in reaction
Concentrated hydrochloric acid adjusts pH to 2~2.5, and filter cake is collected by filtration in stirring and crystallizing, dry that DOTA crude product 7.5kg, Formula II compound contain
Amount about 3.1%.
DOTA crude products 7.5kg, 18kg purified water is added in 50L reaction kettles, after heating stirring dissolving, cooling crystallization, mistake
Filter, washing, dry that DOTA 6.21kg, yield 82.7%, wherein content salt amount are 2%, Formula II compounds content is
0.05%.
Embodiment 2：DOTA crude product refining methods are groped
It takes 20g DOTA crude products to be added in reaction bulb, is separately added into the solvent to be screened, after heating for dissolving, cooling and stirring analysis
Crystalline substance filters to obtain DOTA samples, detects respectively, and records under data such as table 1：
Table 1
Note：
A can be detected in solvent screening by TLC (plate layer chromatography plate), after obtaining general evaluation, then through inspections such as HPLC
Survey means further detect；
B is detected through HPLC, and gained DOTA purifying is 96.9%, content salt amount 3.07%, Formula II chemical combination object amount 0.02%；
C is detected through HPLC, and gained DOTA purifying is 95.7, content salt amount 10.27% (titration measurement), Formula II compound
Amount 0.05%；
D is detected through HPLC, and gained DOTA purifying is 95.1, content salt amount 6.11% (titration measurement), Formula II compound
Amount 0.10%；
E TLC testing conditions：Solvent methanol/ammonium hydroxide (10:1), product Rf values 0.5.
Conclusion：
It is not difficult to find out from above-mentioned data, 2,5,6 couples of DOTA of experimental example, which are purified, relatively good effect, and experimental example 1,7
Although poor to DOTA purification effects Deng institute's sample high income.
Embodiment 3：
In 50L purified waters, 1 gained DOTA 5.1kg of embodiment are added, after 40~50 DEG C of heating stirrings dissolve, respectively
Be added meglumine (2.5kg), gadolinium oxide (2.33kg), pH value of solution=7-9, heating reaction 3h, filtering, successively with 001 × 7 and
D311 resin desalinations obtain satisfactory Gadoteric Acid meglumine solution, are concentrated to dryness or are lyophilized and to obtain Gadoteric Acid meglumine 7.46kg,
Yield 78.5%, Formula II content is 0.01% hereinafter, free gadolinium concentrations are less than 0.013% after testing, salt content zero.
Embodiment 4：
In 100mL purified waters, 2 gained DOTA 10g of experimental example are added, after heating stirring dissolving, add 4.7g oxidations
Gadolinium, heating reaction 3h, filtering obtain satisfactory Gadoteric Acid solution successively with 001 × 7 and D311 resin desalinations, 35~40 DEG C
It is concentrated to dryness or is lyophilized and to obtain Gadoteric Acid 9.42g, yield 67.9%, Formula II content is 0.01% hereinafter, free gadolinium concentrations after testing
It is 0.042%, salt content zero.
Embodiment 5：
In 300mL purified waters, 1 gained DOTA 30g of embodiment are added and add 14.1g oxygen after heating stirring dissolving
Change gadolinium, heating reaction 3h, filtering successively with 001 × 7 and D311 resin desalinations, obtains satisfactory Gadoteric Acid solution, is concentrated into
Solution is committed to 200ml, then the solution is rushed into ethyl alcohol, and white solid is precipitated, dry that gadolinium is special at 35~40 DEG C after filtering
Sour 26.4g yields 63.4%, Formula II content is 0.01% hereinafter, free gadolinium concentrations are 0.027% after testing, salt content zero.
Embodiment 6：
In 28mL purified waters, 6 gained DOTA 2.8g of experimental example are added and sequentially add 1.14g after heating stirring dissolving
It is special to obtain satisfactory gadolinium successively with 001 × 7 and D311 resin desalinations for gadolinium oxide, meglumine, reaction solution pH to 7-9, filtering
Sour meglumine solution, 35~40 DEG C are concentrated to dryness or are lyophilized and to obtain Gadoteric Acid meglumine 4.13g, yield 78.8%, after testing Formula II
Content is 0.01% hereinafter, salt content is zero.
Claims (10)
1. a kind of preparation method of compound of formula I, including：The step of compound of formula I crude product recrystallizes, gained compound of formula I is pure
Degree is not less than 95%, wherein the Formula II compounds content is not more than 1%, the preferably described recrystallization solvent is selected from water or alcohols is molten
At least one of agent,
2. preparation method according to claim 1, it is characterised in that the compound of formula I compound of formula H content is little
In 0.5%, preferably no greater than 0.2%.
3. preparation method according to claim 1 or 2, it is characterised in that salt content is not more than in the compound of formula I
20%, preferably no greater than 15%.
4. according to claim 1-3 any one of them preparation methods, it is characterised in that the compound of formula I crude product is by Isosorbide-5-Nitrae, and 7,
Alkylated reaction obtains 10- tetraazacyclododecanands under alkaline condition with halogenated acetic acids.
5. preparation method according to claim 4, which is characterized in that alkali used in alkylation reaction is selected from alkali metal hydroxide
Object, preferably sodium hydroxide, potassium hydroxide.
6. preparation method according to claim 4, it is characterised in that the alkaline pH no more than 13.0, preferably 8.0~
12.0, more preferably 9.0~11.0.
7. preparation method according to claim 4, it is characterised in that the halogenated acetic acids is selected from iodoacetic acid, bromoacetic acid and chlorine
Acetic acid.
8. according to claim 1-7 any one of them preparation methods, which is characterized in that the compound of formula I preparation method packet
It includes：
A) alkylation reaction is occurred under alkaline condition for Cyclen and halogenated acetic acids；
B) step a) after reaction, adjusts reaction solution pH to acidity, crystallization filters to obtain compound of formula I crude product, the preferably described acid
Property pH be not more than 3.0, more preferably 2.0~2.5；
C) by compound of formula I crude product through solvent recrystallization.
9. a kind of preparation method of Gadoteric Acid, including claim 1-8 any one of them preparation process and by Gd2O3With right
It is required that obtained by any one of 1-8 the step of compound of formula I complexing.
10. a kind of preparation method of Gadoteric Acid meglumine, including claim 1-8 any one of them preparation process and general
Gd2O3, compound of formula I obtained by meglumine and any one of claim 1-8 the step of being complexed.
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Cited By (6)
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| CN111375070A (en) * | 2018-12-26 | 2020-07-07 | 江苏恒瑞医药股份有限公司 | Method for preparing contrast agent |
| CN111375071A (en) * | 2018-12-26 | 2020-07-07 | 江苏恒瑞医药股份有限公司 | Method for preparing contrast agent |
| CN113087680A (en) * | 2020-01-08 | 2021-07-09 | 威智医药有限公司 | DOTA crystal form and preparation method thereof |
| CN113527222A (en) * | 2020-04-21 | 2021-10-22 | 威智医药有限公司 | Preparation method of meglumine gadoterate |
| KR20210152656A (en) * | 2020-06-09 | 2021-12-16 | 주식회사 엔지켐생명과학 | Menufacturing of Gadoteric acid as Gadoterate meglumine Intermediate and Gadoterate meglumine |
| CN113801071A (en) * | 2021-09-14 | 2021-12-17 | 安徽普利药业有限公司 | Refining method of meglumine gadoterate |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111375070A (en) * | 2018-12-26 | 2020-07-07 | 江苏恒瑞医药股份有限公司 | Method for preparing contrast agent |
| CN111375071A (en) * | 2018-12-26 | 2020-07-07 | 江苏恒瑞医药股份有限公司 | Method for preparing contrast agent |
| CN111375071B (en) * | 2018-12-26 | 2023-04-07 | 江苏恒瑞医药股份有限公司 | Method for preparing contrast agent |
| CN113087680A (en) * | 2020-01-08 | 2021-07-09 | 威智医药有限公司 | DOTA crystal form and preparation method thereof |
| CN113527222A (en) * | 2020-04-21 | 2021-10-22 | 威智医药有限公司 | Preparation method of meglumine gadoterate |
| CN113527222B (en) * | 2020-04-21 | 2023-06-13 | 威智医药股份有限公司 | Preparation method of gadoteric acid meglumine |
| KR20210152656A (en) * | 2020-06-09 | 2021-12-16 | 주식회사 엔지켐생명과학 | Menufacturing of Gadoteric acid as Gadoterate meglumine Intermediate and Gadoterate meglumine |
| KR102445756B1 (en) * | 2020-06-09 | 2022-09-21 | 주식회사 엔지켐생명과학 | Menufacturing of Gadoteric acid as Gadoterate meglumine Intermediate and Gadoterate meglumine |
| CN113801071A (en) * | 2021-09-14 | 2021-12-17 | 安徽普利药业有限公司 | Refining method of meglumine gadoterate |
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