CN107021921A - 一种茚达特罗中间体的盐及其制备方法 - Google Patents
一种茚达特罗中间体的盐及其制备方法 Download PDFInfo
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- 229960004078 indacaterol Drugs 0.000 title claims abstract description 27
- QZZUEBNBZAPZLX-QFIPXVFZSA-N indacaterol Chemical compound N1C(=O)C=CC2=C1C(O)=CC=C2[C@@H](O)CNC1CC(C=C(C(=C2)CC)CC)=C2C1 QZZUEBNBZAPZLX-QFIPXVFZSA-N 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- -1 benzo cycloalkyl Chemical group 0.000 claims description 17
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 15
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 11
- LPNBBFKOUUSUDB-UHFFFAOYSA-N p-toluic acid Chemical compound CC1=CC=C(C(O)=O)C=C1 LPNBBFKOUUSUDB-UHFFFAOYSA-N 0.000 claims description 11
- KGVIJLMNQNSQHB-UHFFFAOYSA-N 5,6-diethyl-2,3-dihydro-1h-inden-2-amine Chemical compound C1=C(CC)C(CC)=CC2=C1CC(N)C2 KGVIJLMNQNSQHB-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- 239000000376 reactant Substances 0.000 claims description 6
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 5
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
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- 235000011090 malic acid Nutrition 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- 235000006408 oxalic acid Nutrition 0.000 claims description 5
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
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- 238000006467 substitution reaction Methods 0.000 claims description 4
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims description 4
- XRHGYUZYPHTUJZ-UHFFFAOYSA-N 4-chlorobenzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C=C1 XRHGYUZYPHTUJZ-UHFFFAOYSA-N 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 3
- 150000002170 ethers Chemical class 0.000 claims description 3
- 125000001188 haloalkyl group Chemical group 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- WPOPWLXGDCLQNP-UHFFFAOYSA-N chlorobenzene formic acid Chemical compound C(=O)O.ClC1=CC=CC=C1 WPOPWLXGDCLQNP-UHFFFAOYSA-N 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 150000002825 nitriles Chemical class 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 150000003457 sulfones Chemical class 0.000 claims description 2
- 150000003462 sulfoxides Chemical class 0.000 claims description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 7
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- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
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- 239000003795 chemical substances by application Substances 0.000 description 2
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- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical class [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
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- 229910021529 ammonia Inorganic materials 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 201000009267 bronchiectasis Diseases 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
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- 235000002906 tartaric acid Nutrition 0.000 description 1
- WFRBDWRZVBPBDO-UHFFFAOYSA-N tert-hexyl alcohol Natural products CCCC(C)(C)O WFRBDWRZVBPBDO-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/24—Oxygen atoms attached in position 8
- C07D215/26—Alcohols; Ethers thereof
-
- 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
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
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- 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
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
本发明涉及一种茚达特罗中间体的盐及其制备方法。本发明的茚达特罗中间体的盐的制备方法操作简单,成本低廉,重现性好,易于实现,适合工业化生产。
Description
技术领域
本发明涉及一种茚达特罗中间体的盐及其制备方法。
背景技术
茚达特罗(Indacaterol,商品名),结构如式(VI)所示:
茚达特罗是具有有效的支气管扩张活性的β-选择性肾上腺素受体激动剂,可用于治疗哮喘和慢性阻塞性肺病(COPD)。2009年以来已在全球70多个国家和地区上市,2012年6月经国家药监局批准在中国上市,是国内首个获批用于治疗COPD的长效β2受体激动剂。
茚达特罗是由(R)-5-[2-[(5,6-二乙基-2,3-二氢-1H-茚-2-基)氨基]-1-羟基乙基]-8-(取代氧基)-2(1H)-喹啉酮[式(II)]脱去保护基得到的,因此,式(II)是制备茚达特罗的关键中间体。而制备式(II)的方法,是通过使8-取代氧基-5-(R)-环氧乙烷基-(1H)-喹啉-2-酮[式(I)]与2-氨基-(5,6-二乙基)-茚满反应,形成所需的中间体式(II),但是该反应不具有区域选择性,反应液中生成了不同量的区域异构体式(III)和二聚体式(IV)。
一般而言,此反应仅含有60%至80%所需的式(II)的中间体,且目前对式(II)的中间体通过结晶法进行纯化收率非常低,而采用硅胶柱层析进行纯化虽然收率高但又不适合工业化生产。
专利CN100363349公开了使用苯甲酸、马来酸、琥珀酸、富马酸、酒石酸对上述反应液进行成盐处理,得到的式(II)的相应的盐来进行分离纯化,但所达到的产率和纯度仍然不够理想。因此,有必要开发更有效的制备式(II)中间体或盐的方法,使之有更高的化学纯度和收率,更适合工业化生产要求。
发明内容
本发明的目的是提供一种茚达特罗中间体的盐,有如下结构:
其中HA为酸,选自苹果酸、草酸、丙二酸、对甲基苯甲酸、对氯苯甲酸。R为羟基保护基。
进一步的,R选自烷基、芳基、烷氧基、链烯基、环烷基、苯并环烷基、环烷基烷基、芳烷基、杂环基、杂芳烷基、卤代烷基和取代的甲硅烷基。优选苄基、叔丁基二甲基甲硅烷基或三苯甲基。
本发明同时提供了一种操作简单、产率高、适合大规模工业化生产的茚达特罗中间体的盐的制备方法,包括如下步骤:
1)在溶剂存在下,使式(I)的8-取代氧基-5-(R)-环氧乙烷基-(1H)-喹啉-2-酮
与2-氨基-(5,6-二乙基)-茚满反应,得到含有式(II)、(III)和(IV)化合物的反应混合物:
其中R为保护基;
1)用酸处理步骤1)中制备的反应混合物,得到相应的盐;
2)将步骤2)中得到的盐结晶分离即得到式(V)的盐,即得(R)-5-[2-[(5,6-二乙基-2,3-二氢-1H-茚-2-基)氨基]-1-羟基乙基]-8-(取代氧基)-2(1H)-喹啉酮盐。
其中HA为酸,选自苹果酸、草酸、丙二酸、丁二酸、对甲基苯甲酸、对氯苯甲酸。
进一步的,R为保护基,选自烷基、芳基、烷氧基、链烯基、环烷基、苯并环烷基、环烷基烷基、芳烷基、杂环基、杂芳烷基、卤代烷基和取代的甲硅烷基。更进一步的,保护基优选苄基、叔丁基二甲基甲硅烷基或三苯甲基。
进一步的,步骤1)中所述的溶剂选自水、醇类、醚类、酮类、酯类、腈类、酰胺类、砜或亚砜中的一种或多种,优选醇类和醚类,更优选地,溶剂为二乙二醇二甲醚或丁醇。
进一步的,所述的式(I)的8-取代氧基-5-(R)-环氧乙烷基-(1H)-喹啉-2-酮与溶剂的重量比为1:1~1:100,与酸的摩尔比为1:0.1~1:10。
进一步的,步骤1)中的温度优选10~150℃,更优选90~130℃。
又,步骤2)中的温度优选10~150℃,更优选50~120℃。
又,步骤3)中的温度优选-10~70℃,更优选0~30℃。
本发明同时提供由式(V)茚达特罗中间体的盐制备茚达特罗或其盐的用途。
用本发明的制备方法制备式(V)的茚达特罗中间体的盐,收率均在60%以上,纯度均在98%以上。用这种纯度的茚达特罗中间体可以方便的制备得到高纯度的茚达特罗或其盐。本发明的茚达特罗中间体的盐的制备方法操作简单,成本低廉,重现性好,易于实现,适合工业化生产。
具体实施方式
以下结合具体实施例对本发明作进一步说明,但本发明的保护范围不受以下实施例的限制。
实施例1
(R)-5-[2-[(5,6-二乙基-2,3-二氢-1H-茚-2-基)氨基]-1-羟基乙基]-8-(苄氧基)-2(1H)-喹啉酮苹果酸盐的制备:
将8-苄氧基-5-(R)-环氧乙烷基-(1H)-喹啉-2-酮(1.2克)与2-氨基-(5,6-二乙基)-茚满(1.1克)加入到二乙二醇二甲醚中,加热至110℃,并在该温度下反应48小时,将所得混悬液降温至70℃,加入乙醇(70毫升),随后加入苹果酸(0.6克),将溶液降温至20~30℃,加入晶种,将所得混悬液降温至0~5℃,过滤分离出固体,真空干燥,收率64%,HPLC纯度98.4%。
实施例2
(R)-5-[2-[(5,6-二乙基-2,3-二氢-1H-茚-2-基)氨基]-1-羟基乙基]-8-(苄氧基)-2(1H)-喹啉酮草酸盐的制备:
将8-苄氧基-5-(R)-环氧乙烷基-(1H)-喹啉-2-酮(1.2克)与2-氨基-(5,6-二乙基)-茚满(1.1克)加入到正丁醇中,加热至120℃,并在该温度下反应48小时,将所得混悬液降温至70℃,加入草酸(0.5克),将溶液降温至20~30℃,加入晶种,将所得混悬液降温至0~5℃,过滤分离出固体,真空干燥,收率65%,HPLC纯度98.6%。
实施例3
(R)-5-[2-[(5,6-二乙基-2,3-二氢-1H-茚-2-基)氨基]-1-羟基乙基]-8-(三苯甲基氧基)-2(1H)-喹啉酮丙二酸盐的制备:
将8-三苯甲基氧基-5-(R)-环氧乙烷基-(1H)-喹啉-2-酮(1.2克)与2-氨基-(5,6-二乙基)-茚满(1.1克)加入到二乙二醇二甲醚中,加热至110℃,并在该温度下反应48小时,将所得混悬液降温至70℃,加入丙二酸(0.7克),将溶液降温至20~30℃,加入晶种,将所得混悬液降温至0~5℃,过滤分离出固体,真空干燥,收率68%,HPLC纯度99.0%。。
实施例4
(R)-5-[2-[(5,6-二乙基-2,3-二氢-1H-茚-2-基)氨基]-1-羟基乙基]-8-(叔丁基二甲基甲硅烷基氧基)-2(1H)-喹啉酮对氯苯甲酸盐的制备:
将8-叔丁基二甲基甲硅烷基氧基-5-(R)-环氧乙烷基-(1H)-喹啉-2-酮(1.2克)与2-氨基-(5,6-二乙基)-茚满(1.1克)加入到二乙二醇二甲醚中,加热至110℃,并在该温度下反应48小时,将所得混悬液降温至70℃,加入对氯苯甲酸(0.7克),将溶液降温至20~30℃,加入晶种,将所得混悬液降温至0~5℃,过滤分离出固体,真空干燥,收率65%,HPLC纯度98.2%。
实施例5
(R)-5-[2-[(5,6-二乙基-2,3-二氢-1H-茚-2-基)氨基]-1-羟基乙基]-8-(苄氧基)-2(1H)-喹啉酮对甲基苯甲酸盐的制备:
将8-苄氧基-5-(R)-环氧乙烷基-(1H)-喹啉-2-酮(1.2克)与2-氨基-(5,6-二乙基)-茚满(1.1克)加入到二乙二醇二甲醚中,加热至110℃,并在该温度下反应48小时,将所得混悬液降温至70℃,加入乙醇(70毫升),随后加入对甲基苯甲酸(0.5克),将溶液降温至20~30℃,加入晶种,将所得混悬液降温至0~5℃,过滤分离出固体,真空干燥,收率67%HPLC纯度98.0%。
实施例6
茚达特罗草酸盐的制备:
将实施例2得到的(R)-5-[2-[(5,6-二乙基-2,3-二氢-1H-茚-2-基)氨基]-1-羟基乙基]-8-(苄氧基)-2(1H)-喹啉酮草酸盐(1.0克)加入到乙醇(100毫升)中,随后加入10%的钯碳(0.1克,含水50%),将反应物在20~30℃下进行氢化12小时,直至完全转化为茚达特罗,过滤,滤液中加入草酸(0.3克),加热至50℃,搅拌2小时后降温至0~5℃,析出固体,过滤,得到茚达特罗草酸盐0.82克,纯度99.6%。
用本发明的制备方法制备式(V)的茚达特罗中间体的盐,收率均在60%以上,纯度均在98%以上。用本发明的制备方法制备茚达特罗的中间体可以方便的制备得到高纯度的茚达特罗或其盐。
Claims (8)
1.一种茚达特罗中间体的盐,结构如式(V)所示:
其中HA为酸,选自苹果酸、草酸、丙二酸、对甲基苯甲酸、对氯苯甲酸,R为羟基保护基。
2.根据权利要求1所述的盐,其特征在于,R选自烷基、芳基、烷氧基、链烯基、环烷基、苯并环烷基、环烷基烷基、芳烷基、杂环基、杂芳烷基、卤代烷基和取代的甲硅烷基。优选苄基、叔丁基二甲基甲硅烷基和三苯甲基。
3.一种制备式(V)的盐的方法,其特征在于包含以下步骤:
1)在溶剂的存在下,使式(I)的8-取代氧基-5-(R)-环氧乙烷基-(1H)-喹啉-2-酮与2-氨基-(5,6-二乙基)-茚满反应,得到含有式(II)、(III)和(IV)化合物的反应混合物,其中R为羟基保护基;
2)用酸HA处理步骤1)中制备的反应混合物,得到相应的盐;
3)将步骤2)中的得到的盐结晶并分离得到式(V)的盐。其中HA为酸,选自苹果酸、草酸、丙二酸、对甲基苯甲酸、对氯苯甲酸。R为羟基保护基。
4.根据权利要求3所述的制备方法,R选自烷基、芳基、烷氧基、链烯基、环烷基、苯并环烷基、环烷基烷基、芳烷基、杂环基、杂芳烷基、卤代烷基和取代的甲硅烷基。优选苄基、叔丁基二甲基甲硅烷基和三苯甲基。
5.根据权利要求3所述的制备方法,其特征在于,步骤1)中所述的溶剂选自水、C1-C10的醇类、醚类、酮类、酯类、腈类、酰胺类、砜或亚砜中的一种或多种。
6.根据权利要求3-5所述的制备方法,其特征在于,所述式(I)的8-取代氧基-5-(R)-环氧乙烷基-(1H)-喹啉-2-酮与溶剂的重量比为1:1~1:100,与酸的摩尔比为1:0.1~1:10。
7.根据权利要求3-6所述的制备方法,其特征在于,步骤1)中的温度为10~150℃,步骤2)中的温度为10~150℃,步骤3)中的温度为-10~70℃。
8.由式(V)的茚达特罗中间体的盐制备茚达特罗或其盐的用途。
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