CN103772400A - 反式-5-氯-2,3,3a,12b-四氢-1H-二苯并[2,3:6,7]氧杂卓并[4,5-c]吡咯的制备方法 - Google Patents
反式-5-氯-2,3,3a,12b-四氢-1H-二苯并[2,3:6,7]氧杂卓并[4,5-c]吡咯的制备方法 Download PDFInfo
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- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical compound OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 claims description 2
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 claims description 2
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 claims description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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Abstract
本发明属于药物化学领域，提供了一种Asenapine(阿塞那平)关键杂质(Ⅳ)即反式-5-氯-2,3,3a,12b-四氢-1H-二苯并[2,3:6,7]氧杂卓并[4,5-c]吡咯的制备方法。以反式-5-氯-2,3,3a,12b-四氢-2-甲基-1H-二苯并[2,3:6,7]氧杂卓并[4,5-c]吡咯为起始原料制备而成，此杂质是合成Asenapine非常关键的一个杂质，也是控制Asenapine终产物质量标准的一个重要中间体。
Description
技术领域
本发明涉及药物化学领域，具体涉及反式-5-氯-2,3,3a,12b-四氢-1H-二苯并[2,3:6,7]氧杂卓并[4,5-c]吡咯 [Asenapine关键杂质(Ⅳ)]的制备新方法。
背景技术
新型非典型抗精神病药Asenapine (中文名阿塞那平), 化学名为反式-5-氯-2,3,3a,12b-四氢-2-甲基-1H-二苯并[2,3:6,7]氧杂卓并[4,5-c]吡咯。是由欧加农公司研发，后经先灵葆雅公司对该药物进行申请上市。2009年8月14日美国FDA批准其上市请求。它是一种多靶点的非典型抗精神病药物，主要用于治疗成年人精神分裂症、狂躁症与双向情感障碍混合发作的紧急治疗。其结构式如下Ⅰ：
反式-5-氯-2,3,3a,12b-四氢-1H-二苯并[2,3:6,7]氧杂卓并[4,5-c]吡咯[Asenapine杂质(Ⅳ)]是合成Asenapine非常关键的一个杂质，也是控制Asenapine终产物质量标准的一个重要中间体。
由于其结构的特殊性，现有报道的制备Asenapine杂质(Ⅳ)的方法较少，如专利EP2468751中公开的合成方法，采用10步合成目标物，过程繁琐，且涉及原料及中间体众多。另一个例子如Kuethe J.T.报道了此杂质制备方法(J. Label Compd. Radiopharm 2012, 55 180-185)，该文给出的方法以1-氯乙基氯甲酸酯为酯化剂，在乙醇/二氯甲烷体系回流制备，但1-氯乙基氯甲酸酯为高剧毒性，且为受管制药品。综上，文献报道的路线较繁琐并涉及使用剧毒品，设计一条新的路线制备反式-5-氯-2,3,3a,12b-四氢-2-甲基-1H-二苯并[2,3:6,7]氧杂卓并[4,5-c]吡咯并且避免使用剧毒品是很必要的。
发明内容
本发明提供了一套制备抗精神病药Asenapine关键杂质化合物反式-5-氯-2,3,3a,12b-四氢-1H-二苯并[2,3:6,7]氧杂卓并[4,5-c]吡咯(Ⅳ)的方法。其制备方法是以反式-5-氯-2,3,3a,12b-四氢-2-甲基-1H-二苯并[2,3:6,7]氧杂卓并[4,5-c]吡咯(Ⅰ)为起始原料，常压回流采用酯化剂对其端位甲基酯化，常压回流经无机酸水解脱去酯化基团成盐，再经无机碱常压回流解盐制得Asenapine杂质(Ⅳ)，该方法所用试剂简单易得，反应时间短，后处理简单，副产物少，产品纯度高。合成路线如下：
其中酯化阶段化合物(Ⅰ)制备化合物(Ⅱ)采用的酯化剂包括氯甲酸甲酯、氯甲酸乙酯、氯甲酸苯酯、氯甲酸卞酯、1-氯乙基氯甲酸酯，其中优选氯甲酸乙酯。反应溶剂为甲醇、乙醇、二氯甲烷、甲苯，其中优选甲苯。所需控制的反应温度为0℃至回流温度，其中优选90℃-110℃，整个反应过程在常压下进行。
其中酯化物经酸水解阶段化合物(Ⅱ)制备化合物(Ⅲ)，无机酸为40%氢溴酸、浓硫酸、浓盐酸，其中优选40%氢溴酸。所需控制反应温度为0℃至回流温度，其中优选80℃-100℃，整个反应在常压下进行。
其中解盐阶段化合物(Ⅲ)制备化合物(Ⅳ)即目标Asenapine杂质C中无机碱为氢氧化钾、氢氧化钠、碳酸钾、碳酸钠，其中优选碳酸钠。反应温度为0℃至回流温度，其中优选80℃-100℃，整个反应在常压水相中进行。
具体实施实例
以下的实施例在于详细说明本发明，但是不应该构成对本发明的限制。
实施实例一：化合物(Ⅱ)的合成：
向100 mL三口瓶中加入反式-5-氯-2,3,3a,12b-四氢-2-甲基-1H-二苯并[2,3:6,7]氧杂卓并[4,5-c]吡咯, 加入15.0 mL甲苯与0.74g碳酸钠，搅拌30min使之充分溶解。向其中加入0.76g氯甲酸乙酯与5.0 mL甲苯的共混物, 以恒压滴液漏斗缓慢滴入。待滴毕，升温反应液至110℃回流。通过TLC监测原料反应完全，以20.0 mL水淬灭，以20.0 mL乙酸乙酯萃取，后分液，有机相以20.0 mL水洗2次，再以饱和食盐水20.0 mL洗涤两次，以无水硫酸钠干燥4 h。抽滤除去滤饼，滤饼以乙酸乙酯洗涤，滤液旋干得棕红色油状物0.7 g，收率58.18%。1H-NMR (CDCl3) δ 1.26 (t, 3H, J = 7.2 Hz), 3.57~3.58 (m, 4H), 4.00~4.08 (m, 2H), 4.15 (q, 2H, J = 7.2 Hz), 7.01~7.19 (m, 7H). MS (m/z)：[M+H]+ 344.0.
实施实例二：化合物(Ⅲ)的合成：
向50 mL三口瓶中加入化合物(Ⅱ)100 mg, 量取5.0 mL40%氢溴酸加入恒压滴液漏斗，使之缓慢滴入。待滴毕，升温反应液至80℃回流。通过TLC监测原料反应完全，旋干反应液，得红色固体。以10.0 mL乙酸乙酯打浆30 min，抽滤，以少量乙酸乙酯冲洗滤饼。收集滤饼送40℃鼓风烘干。得白色固体88.1 mg，收率85.89%。1H-NMR (DMSO-d 6 ) δ 3.43 (m, 2H), 3.66 (m, 2H), 3.90 (m, 2H), 7.14~7.36 (m, 7H), 9.69 (brs, 2H). MS (m/z)：[M+H]+ 272.0.
实施实例三：Asenapine杂质C，即化合物(Ⅳ) 反式-5-氯-2,3,3a,12b-四氢-1H-二苯并[2,3:6,7]氧杂卓并[4,5-c]吡咯的合成：
向50 mL三口瓶中加入化合物(Ⅲ) 50 mg, 加入5 mL 水和45 mg碳酸钠，升温搅拌至回流，反应2 h。监测pH为8.0-11.0，加入 二氯甲烷10 mL萃取。后分液，有机相以5.0 mL水洗2次，再以饱和食盐水5.0 mL洗涤两次，以无水硫酸钠干燥4 h。抽滤除去滤饼，滤饼以少量 二氯甲烷洗涤。滤液旋干，得白色固体35.1g，收率91.12%。
Claims (8)
1.一种 Asenapine (阿塞那平)关键杂质(Ⅳ)的制备方法，其特征在于使用化合物反式-5-氯-2,3,3a,12b-四氢-2-甲基-1H-二苯并[2,3:6,7]氧杂卓并[4,5-c]吡咯(Ⅰ)为起始原料，在酯化试剂下对其端位甲基酯化生成化合物(Ⅱ)，化合物(Ⅱ)经无机酸水解制备化合物(Ⅲ)，化合物(Ⅲ)经无机碱水解制得阿塞那平杂质(Ⅳ)，
2.根据权利要求1的方法，其中化合物(Ⅰ)制备化合物(Ⅱ)的酯化试剂是氯甲酸甲酯、氯甲酸乙酯、氯甲酸苯酯、氯甲酸卞酯、1-氯乙基氯甲酸酯；反应溶剂是甲醇、乙醇、二氯甲烷、甲苯；反应温度是0℃至反应体系的回流温度。
3. 根据权利要求2的方法，其中酯化试剂为氯甲酸乙酯，反应溶剂为甲苯。
4. 根据权利要求1的方法，化合物(Ⅱ)制备化合物(Ⅲ)的无机酸为40%氢溴酸、浓硫酸、浓盐酸，反应温度是0℃至反应体系的回流温度。
5. 根据权利要求4的方法，无机酸为40%氢溴酸。
6. 根据权利要求1的方法，化合物(Ⅲ)制备化合物(Ⅳ)的无机碱为氢氧化钾、氢氧化钠、碳酸钾、碳酸钠。
7. 根据权利要求6的方法，无机碱为碳酸钠。
8. 根据权利要求1的方法，化合物(Ⅰ)与酯化试剂的用量摩尔比为1:1.5至1:2.5之间；化合物(Ⅱ)与无机酸的用量固液比为1:3至1:10之间；化合物(Ⅲ)与无机碱的用量摩尔比为1:2至1:3之间。
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105566336A (zh) * | 2016-01-08 | 2016-05-11 | 万特制药(海南)有限公司 | 一种制备阿塞那平去甲基杂质的新方法 |
| US10898449B2 (en) | 2016-12-20 | 2021-01-26 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
| US11033512B2 (en) | 2017-06-26 | 2021-06-15 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer |
| US11337932B2 (en) | 2016-12-20 | 2022-05-24 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene |
| US11648213B2 (en) | 2018-06-20 | 2023-05-16 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
| US12329862B2 (en) | 2018-06-20 | 2025-06-17 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
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| US10980753B2 (en) | 2016-12-20 | 2021-04-20 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
| US11337932B2 (en) | 2016-12-20 | 2022-05-24 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene |
| US12138353B2 (en) | 2016-12-20 | 2024-11-12 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
| US11033512B2 (en) | 2017-06-26 | 2021-06-15 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer |
| US11648213B2 (en) | 2018-06-20 | 2023-05-16 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
| US12329862B2 (en) | 2018-06-20 | 2025-06-17 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
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