CN113354594A - 制备考布曲钙的方法 - Google Patents
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- LGZKGOGODCLQHG-CYBMUJFWSA-N 5-[(2r)-2-hydroxy-2-(3,4,5-trimethoxyphenyl)ethyl]-2-methoxyphenol Chemical compound C1=C(O)C(OC)=CC=C1C[C@@H](O)C1=CC(OC)=C(OC)C(OC)=C1 LGZKGOGODCLQHG-CYBMUJFWSA-N 0.000 title claims abstract description 17
- LGZKGOGODCLQHG-UHFFFAOYSA-N combretastatin Natural products C1=C(O)C(OC)=CC=C1CC(O)C1=CC(OC)=C(OC)C(OC)=C1 LGZKGOGODCLQHG-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 238000000034 method Methods 0.000 title claims description 29
- 239000011575 calcium Substances 0.000 title claims description 19
- 229910052791 calcium Inorganic materials 0.000 title claims description 19
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 title claims description 18
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims abstract description 20
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229910001424 calcium ion Inorganic materials 0.000 claims abstract description 12
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229940106681 chloroacetic acid Drugs 0.000 claims abstract description 10
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims abstract description 7
- QBPPRVHXOZRESW-UHFFFAOYSA-N 1,4,7,10-tetraazacyclododecane Chemical compound C1CNCCNCCNCCN1 QBPPRVHXOZRESW-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000002156 mixing Methods 0.000 claims abstract description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 9
- 238000002425 crystallisation Methods 0.000 claims description 7
- 230000008025 crystallization Effects 0.000 claims description 7
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 6
- 239000007983 Tris buffer Substances 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- LVDKZNITIUWNER-UHFFFAOYSA-N Bronopol Chemical compound OCC(Br)(CO)[N+]([O-])=O LVDKZNITIUWNER-UHFFFAOYSA-N 0.000 claims description 4
- 229960003168 bronopol Drugs 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 2
- 239000001110 calcium chloride Substances 0.000 claims description 2
- 229910001628 calcium chloride Inorganic materials 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
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000006243 chemical reaction Methods 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 229910052688 Gadolinium Inorganic materials 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 239000008213 purified water Substances 0.000 description 7
- 239000007858 starting material Substances 0.000 description 7
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 6
- 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 description 6
- 150000001924 cycloalkanes Chemical class 0.000 description 6
- 229960003411 gadobutrol Drugs 0.000 description 6
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 5
- 239000011347 resin Substances 0.000 description 5
- 229920005989 resin Polymers 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- 239000003456 ion exchange resin Substances 0.000 description 4
- 229920003303 ion-exchange polymer Polymers 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- -1 gadolinium cations Chemical class 0.000 description 3
- 238000001728 nano-filtration Methods 0.000 description 3
- 235000006408 oxalic acid Nutrition 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- ILJSQTXMGCGYMG-UHFFFAOYSA-N triacetic acid Chemical compound CC(=O)CC(=O)CC(O)=O ILJSQTXMGCGYMG-UHFFFAOYSA-N 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000003729 cation exchange resin Substances 0.000 description 2
- 239000002872 contrast media Substances 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 230000000694 effects 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
- 239000012044 organic layer Substances 0.000 description 2
- 239000000126 substance Substances 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
- FYFSGGAVTBSKBV-UHFFFAOYSA-N 3-(1,4,7,10-tetrazacyclododec-1-yl)butane-1,2,4-triol;tetrahydrochloride Chemical compound Cl.Cl.Cl.Cl.OCC(O)C(CO)N1CCNCCNCCNCC1 FYFSGGAVTBSKBV-UHFFFAOYSA-N 0.000 description 1
- YLZOPXRUQYQQID-UHFFFAOYSA-N 3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]propan-1-one Chemical compound N1N=NC=2CN(CCC=21)CCC(=O)N1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F YLZOPXRUQYQQID-UHFFFAOYSA-N 0.000 description 1
- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 239000002616 MRI contrast agent Substances 0.000 description 1
- 239000003957 anion exchange resin Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- AKHMHYGTZRJYBS-UHFFFAOYSA-N bicyclo[5.1.0]octane Chemical compound C1CCCCC2CC21 AKHMHYGTZRJYBS-UHFFFAOYSA-N 0.000 description 1
- 229960004436 budesonide Drugs 0.000 description 1
- 150000001669 calcium Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- UZUODNWWWUQRIR-UHFFFAOYSA-L disodium;3-aminonaphthalene-1,5-disulfonate Chemical compound [Na+].[Na+].C1=CC=C(S([O-])(=O)=O)C2=CC(N)=CC(S([O-])(=O)=O)=C21 UZUODNWWWUQRIR-UHFFFAOYSA-L 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 239000011147 inorganic material Substances 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- 238000001223 reverse osmosis Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/101—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals
- A61K49/106—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being cyclic, e.g. DOTA
- A61K49/108—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being cyclic, e.g. DOTA the metal complex being Gd-DOTA
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- C07D—HETEROCYCLIC COMPOUNDS
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2123/00—Preparations for testing in vivo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
Description
相关申请的交叉引用
本申请要求于2020年3月6日提交的韩国专利申请第10-2020-0028549号的优先权,其全部内容通过引用并入本文。
技术领域
本发明涉及一种制备考布曲钙的方法,更具体地,涉及一种制备在制备MRI造影剂钆布醇注射剂中使用的考布曲钙的方法。
背景技术
在世界各地的含钆的造影剂领域中,钆布醇以商品名Gadovist或Gadavist进行销售。
在这种含钆造影剂的情况下,发现以钙络合物的形式施用过量的络合物形成配体是有利的。在此,钙络合物的作用是防止制备后从钆布醇中释放出游离的钆,从而解决由钆阳离子的毒性引起的肾病性全身纤维化(NSF)的安全性问题。
考布曲钙的合成方法在文献(无机化学(Inorg.Chem.)1997,36,6086-6093)中有详细描述。然而,尽管可以通过上述文献的方法获得纯度为90-95%的材料,但这没有达到配制所需的纯度。
采用离子交换树脂通过布醇的两性离子纯化来进一步纯化2,2,2-(10-1,3,4-三羟基丁烷-2-基)-1,4,7,10-四氮杂环十二烷-1,4,7-三基)三乙酸(下文中为“布醇(butrol)”)是不易的,并且无法通过pH调节进行结晶,因此也无法通过结晶进行纯化。
在终止反应并通过离子交换柱纯化后,可通过结晶获得高纯度(>99.6%)的中性钆络合物钆布醇,但由于残留的酸性官能团,使得考布曲钙的纯化问题难以解决。因此,从纯度角度上,已知直接由布醇制备考布曲钙的方法是不合适的。
根据拜耳(Bayer)注册的韩国专利第10-1057939号,已知已经获得的钆布醇被选择为起始原料并被络合,然后除去游离的钆以制备高纯度的布醇,然后与钙络合制备考布曲钙,以制备高纯度的考布曲钙。然而,在上述方法中使用的用于分解的草酸是有毒的,因此其使用受到限制。另外,通过在阳离子交换树脂上吸附和解吸附布醇的过程,除去其他杂质以获得高纯度的布醇,然后使其与钙离子反应以获得考布曲钙。这一系列过程不经济,并且过程也很复杂。
根据ST制药株式会社(ST Pharm Co.,Ltd.)已注册的韩国专利第10-1693400号,已知将钆布醇中间体3-(1,4,7,10-四氮杂环十二烷-1-基)丁烷-1,2,4-三醇四盐酸盐用作起始原料,并将其引入溴乙酸叔丁酯中。在脱保护处理后,通过树脂纯化获得高纯度的布醇,然后通过与钙离子反应获得考布曲钙。然而,在上述方法中使用溴乙酸叔丁酯的情况下,对人体有害并且价格很高。另外,由于添加了脱保护剂工艺,因此并不经济,且该工艺变得复杂。
因此,需要开发一种生产考布曲钙的方法,该方法对人体的危害较小且对环境无害,通过去除树脂纯化和脱保护过程而经济,并且通过简化的方法获得高纯度。
发明内容
技术目的
因此,本发明的目的是通过使用环烷(其是比常规原料更便宜的原料)作为起始原料、通过纳米过滤器(纳米过滤)工艺进行纯化而具有高纯度。整个制备过程简单,且可以经济地生产考布曲钙。
本发明的另一目的是相比于使用钆布醇作为起始原料的通常已知方法而言是经济的。本发明不使用对人体有害的材料,例如草酸,因此提供了一种更安全地制备考布曲钙的方法。
技术方案
为了实现上述目的,本发明提供了一种生产考布曲钙的方法,该方法包括:将氯化锂和4,4-二甲基-3,5,8-三双环[5,1,0]辛烷与由下式1表示的1,4,7,10-四氮杂环十二烷反应,以得到由下式2表示的考布曲钙中间体;将由式2表示的考布曲钙中间体与氯乙酸反应,以得到由下式3表示的布醇;将由式3表示的布醇与钙离子反应,以得到由下式4表示的考布曲钙。
[式1]
[式2]
[式3]
[式4]
本发明的技术效果
如上所述,根据本发明的制备考布曲钙的方法通过使用环烷(其是廉价的原料)作为起始原料是经济的。由于不使用草酸等对人体有害的材料,因此可以更安全地制备。另外,可以通过纳米过滤器(纳米过滤)工艺进行纯化来制备高纯度的考布曲钙。
具体实施方式
在下文中,将更详细地描述本发明。
本发明公开了一种制备考布曲钙的方法,如以下方案1中所示,该方法使用环烷作为起始原料来制备考布曲钙。
[方案1]
在环烷中使用氯化锂和DTCO制备中间体之后,使用氯乙酸、氢氧化钠和盐酸,然后使用纳米过滤器和离子交换树脂获得高纯度的布醇。其中碳酸钙用于提供钙离子并结晶从而以高收率制备高纯度的考布曲钙。
具体地,为了制备根据本发明的考布曲钙,首先,通过将由下式1表示的1,4,7,10-四氮杂环十二烷(以下称为“环烷”)作为起始原料进行反应,制备环烷-氯化锂络合物。然后,使4,4-二甲基-3,5,8-三双环[5,1,0]辛烷反应以获得由下式2表示的N-(6-羟基-2,2-二甲基-1,3-二氧基苯-5-基)-1,4,7,10-四氮杂环十二烷-氯化锂络合物(以下称为“考布曲钙中间体”)。
[式1]
[式2]
反应可以在诸如异丙醇、纯净水、甲醇和乙醇的溶剂中进行,并且反应温度通常为75至100℃。相对于1当量的环烷,使用的氯化锂的量为0.8至1.5当量,优选为1.05至1.2当量。如果氯化锂的量太少,则存在纯度降低的问题,而如果氯化锂的量过多,则存在氯化物的量增加的问题。
基于环烷-氯化锂络合物,使用的4,4-二甲基-3,5,8-三双环[5,1,0]辛烷的量为1.0至1.5当量,优选为1.2至1.4当量。如果4,4-二甲基-3,5,8-三双环[5,1,0]辛烷的量太少,则存在由于未反应的物质而导致的降低收率的问题,如果过多,则存在通过热解副产物降低纯度和收率的问题。
接下来,将由式2表示的考布曲钙中间体与氯乙酸反应,得到由式3表示的2,2,2-((10-1,3,4-三羟基丁烷-2-基)-1,4,7,10-四氮杂环十二烷-1,4,7-三基)三乙酸(以下称为“布醇”)。
[式3]
该反应可以在碱性水溶剂中进行。例如,作为反应的溶剂,将氢氧化钠(NaOH)滴加到水中以形成pH为8至12,优选为9至10的碱性介质。该反应通常可以在75℃至85℃的温度下进行。在反应中,基于由式2表示的考布曲钙中间体,所使用的氯乙酸的量为3.0至4.5当量,优选为3.4至4.0当量。其中,如果氯乙酸的量太少,则存在降低未反应产物的收率和纯度的问题,并且如果氯乙酸的量太大,则存在除去未反应产物和分解产物的问题。
将反应产物浓缩并在酸性条件下过滤,特别是使用纳米过滤器纯化。纳米过滤器系统作为反渗透设备可以通过有机层分离和纯化具有盐和其他分子量的无机材料,该反渗透设备设计用于过滤或浓缩摩尔质量为200至300道尔顿或更多的螺旋型有机层中的物质。通过纳米过滤器纯化的滤液可以通过离子交换树脂工艺进一步纯化,并且离子交换树脂可以级联方式用作阳离子交换树脂柱和阴离子交换树脂柱。当再次过滤包括从反应中产生的盐的反应产物时,可以除去剩余的解络剂和副产物。将纯化的滤液浓缩时,可获得纯度为99.7%以上的布醇。
接下来,使由式3表示的布醇与钙离子反应并结晶以获得由式4表示的2,2,2-(10-1,3,4-三羟基丁烷-2-基)-1,4,7,10-四氮杂环十二烷-1,4,7-三基)三乙酸钙络合物(以下称为考布曲钙)
[式4]
反应使用纯净水。钙离子源可包括碳酸钙、氢氧化钙、氯化钙等,并且优选使用碳酸钙。基于(相对于)1.0当量的布醇,使用的钙离子源的量为0.95至1.05当量,优选为1.0当量。其中,如果钙源的量太少,则形成的络合物较少,导致收率降低;如果钙源的量太大,则会形成布醇与钙的含量比为2:3的络合物。
反应温度通常在80至90℃的温度下进行,如果温度太低,则由于未反应的产物而导致收率降低,而如果温度太高,则可能会出现产物质量问题。另外,布醇和钙离子的反应时间为1小时至2小时,如果反应时间短,则在结晶过程中可能会出现问题,并且未反应的产物会降低收率,而如果反应时间太长,则会出现质量问题,例如可能会形成相关物质。
将反应产物浓缩后,可将其溶于纯净水中并结晶,并用结晶溶剂分离。作为结晶溶剂,可以使用甲醇、乙醇、异丙醇和丙酮等有机溶剂,优选使用丙酮。具体而言,母液可以在纯净水-丙酮条件下通常在45至55℃下结晶。将结晶的混合物干燥以获得纯度为99.0%或更高的考布曲钙。
在下文中,将通过实施例更详细地描述本发明,但是本发明不受以下实施例的限制。
实施例1:由式3表示的布醇的制备
将1,4,7,10-四氮杂环十二烷(100g,1当量)、氯化锂(29.55g,1.14当量)、4,4-二甲基-3,5,8-三双环[5.1.0]辛烷(83.75g,1当量)和异丙醇(219.6g,2.2体积)加入反应器中,并将温度升至85-95℃以进行反应。反应完成后,加入830.49g的甲基叔丁基醚,在20至25℃下搅拌1小时,然后过滤。然后,用79.56g的甲基叔丁基醚洗涤。在减压下浓缩滤液,然后加入642.5g纯净水。将温度升至50℃并加入氯乙酸(139.1g,3.7当量)。滴加40%NaOH,并在75至85℃下加热并搅拌,同时保持pH 9至10,然后终止反应。加入14.83g盐酸,然后在减压下浓缩。通过添加128.5g甲醇过滤盐,并进行纳米过滤。此后,将650g弱碱性树脂和弱酸性树脂分别放入树脂柱中,将反应溶液处理10次,然后在减压下浓缩,以获得100g透明液体布醇(收率38.26wt%,纯度99.8%,水分11.2%)。
实施例2-1:使用丙酮制备考布曲钙(固体)
将50.0g实施例1中制备的布醇、9.87g碳酸钙和200ml纯净水加入到反应器中。然后,将温度升至75℃,搅拌3小时,冷却并过滤。将其浓缩,然后加入50ml纯净水。将温度升至40℃,并加入600ml丙酮。当形成晶体时,将混合物冷却至20℃,并将所得晶体过滤并干燥,以获得46.12g白色考布曲钙固体(收率85.0%)。
实施例2-2:使用无水乙醇制备考布曲钙(固体)
将50.0g实施例1中制备的布醇、9.87g碳酸钙和200ml纯净水添加到反应器中。将温度升至75℃,搅拌3小时,冷却并过滤。将其浓缩,并将温度升至60℃,然后加入200ml无水乙醇。当形成固体时,将其浓缩并加入无水乙醇直至水分为3%,然后进一步浓缩。当水分含量达到3%时,将所得晶体冷却至20℃并过滤。干燥,得到49.37g(收率91.0%)的白色考布曲钙固体。
Claims (7)
2.根据权利要求1所述的方法,其中,当制备布醇时,pH为8至12。
3.根据权利要求1所述的方法,其中,使用纳米过滤器纯化布醇。
4.根据权利要求1所述的方法,其中,所述钙离子选自由碳酸钙、氢氧化钙、氯化钙及其混合物组成的组,并且基于布醇钙离子的含量为0.95至1.05当量。
5.根据权利要求1所述的方法,其中,基于考布曲钙中间体,所使用的氯乙酸的量为3.0至4.5当量。
7.根据权利要求1所述的方法,其中,在获得考布曲钙的步骤中,使用选自由甲醇、乙醇、异丙醇和丙酮组成的组中的结晶溶剂进行结晶。
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CN106187930A (zh) * | 2016-07-12 | 2016-12-07 | 嘉实(湖南)医药科技有限公司 | 高纯度考布曲钙的制备方法 |
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CN106187930A (zh) * | 2016-07-12 | 2016-12-07 | 嘉实(湖南)医药科技有限公司 | 高纯度考布曲钙的制备方法 |
WO2020012372A1 (en) * | 2018-07-10 | 2020-01-16 | Biophore India Pharmaceuticals Pvt. Ltd | Process for the preparation of 2,2',2''-(10-((2r,3s)-1,3,4-trihydroxy butan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid and its complexes |
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