CN113480546A - 巴瑞克替尼及其衍生物的制备 - Google Patents
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- 229950000971 baricitinib Drugs 0.000 title abstract description 14
- -1 compound 2- (1- (ethylsulfonyl) -3- (4- (7-substituted-7H-pyrrolo [2,3-d ] pyrimidine-4-yl) -1H-pyrazol-1-yl) azetidin-3-yl) acetonitrile Chemical class 0.000 claims abstract description 15
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- C—CHEMISTRY; METALLURGY
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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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
- C07F7/0803—Compounds with Si-C or Si-Si linkages
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- C07F7/083—Syntheses without formation of a Si-C bond
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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
本发明涉及巴瑞克替尼及其衍生物的合成，具体为(4‑(1,3‑二氧戊环‑2‑基)‑7‑取代‑7H‑吡咯[2,3‑d]嘧啶在溶剂存在下和2‑(1‑(乙基磺酰基)‑3‑肼基氮杂环丁‑3‑基)乙腈、(氯亚甲基)二甲基氯化铵发生反应，实现化合物2‑(1‑(乙基磺酰基)‑3‑(4‑(7‑取代‑7H‑吡咯并[2,3‑d]嘧啶‑4‑基)‑1H‑吡唑‑1‑基)氮杂环丁‑3‑基)乙腈的制备。
Description
技术领域
本发明属于化学药物合成领域，具体涉及巴瑞克替尼及其衍生物的制备。
背景技术
巴瑞克替尼(Baricitinib,LY3009104或INCB028050)，商品名：Olumiant，是由EliLilly与Incyte公司合作研发的一种选择性、可逆性Janus激酶JAK1和JAK2抑制剂，IC50分别为5.9nM和5.7nM。目前临床上开发用于多种炎症性疾病和自身免疫性疾病的治疗，包括类风湿性关节炎(RA)、强直性脊柱炎(AS)、银屑病、特应性皮炎、系统性红斑狼疮、溃疡性肠炎(UC)和斑秃等。2017年2月，巴瑞克替尼获得欧盟批准，作为一种单药或联合甲氨蝶呤，用于对一种或多种疾病修饰抗风湿药物(DMARD)缓解不足或不耐受的中度至重度活动性类风湿性关节炎成人患者的治疗。这也是欧盟批准治疗类风湿性关节炎的首个JAK抑制剂。2018年6月，美国FDA批准了巴瑞克替尼上市，用于治疗罹患中度至重度类风湿关节炎。
另外，2020年2月，《柳叶刀》发布通讯文章，指出巴瑞替尼可以作为2019-nCoV急性呼吸系统疾病的潜在治疗方案。2020年10月，礼来制药与因赛特医疗共同宣布，最新数据显示巴瑞替尼联合瑞德西韦对比瑞德西韦单药，缩短了2019新型冠状病毒肺炎(COVID-19)患者的恢复时间、提高了临床获益。2020年11月，美国食品药品监督管理局(FDA)批准礼来制药的巴瑞替尼的EUA(紧急使用授权)，与瑞德西韦联用后用于成年住院患者、2岁及以上的儿童住院患者，这些患者为疑似或实验室确诊的2019新型冠状病毒肺炎(COVID-19)病例并需要辅助供氧、侵入性机械通气或体外膜氧合(ECMO)。
巴瑞克替尼化学英文名为：1-(Ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-azetidineacetonitril e,中文名称：1-(乙基磺酰基)-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]-3-氮杂环丁烷乙腈。CAS：1187594-09-7，分子式为C16H17N7O2S，该药物分子中含有吡咯并嘧啶、吡唑、氮杂环丁烷核心结构片段和拥有一个季碳中心，其结构式如下：
2007年Incyte公司首次报道巴瑞克替尼的合成方法(US20070135461/WO2009114512)，并对巴瑞克替尼的结构进行专利保护，如下：
其中，L＝SO2或CO；R1＝(非)取代烷基、环状烷基、苯基、5，6-元杂芳香基、吲哚基等。从N-叔丁氧羰基-4-哌啶酮和氰甲基磷酸二乙酯出发经过一系列反应，包括：Wittig-Horner反应，Suzuki偶联反应，Michael加成反应以及保护及的脱除及保护等步骤合成巴瑞克替尼。具体路线如下：
2016年，有文献(Journal of Chemical Research,2016,40,205-208.)报道对原研专利合成路线进行优化，优化路线以N-叔丁氧羰基-4-哌啶酮为起始物料，依次经过Wittig-Horner(维蒂希－霍纳尔)反应、N-Boc保护基脱除、磺酰胺化、吡唑-4-硼酸频哪醇酯的Michael加成反应，最后再和4-氯吡咯并嘧啶通过Suzuki偶联反应制备巴瑞克替尼。在合成路线中省去了对4-氯吡咯并嘧啶的SEM硅基保护和脱保护基等步骤，合成路线比较简短，总产率可以达到49％。
2016年，Eli Lilly(WO 2016205487)提出一种合成巴瑞克替尼及其关键中间体的方法。主要合成步骤包括：吡唑-4-硼酸频哪醇酯对2-[1-(乙基磺酰基)-3-氮杂环丁亚基]乙腈的Michael加成反应，然后再与4-氯吡咯并嘧啶-7-羧酸叔丁酯经过金属催化的交叉偶联反应制备巴瑞克替尼，该合成路线如下：
2017年，Egis公司(WO 2017109524A1)报道了(4-(1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate和2-[1-(乙基磺酰基)-3-氮杂环丁亚基]乙腈的Michael加成反应，得到的中间体在酸性条件下脱除Boc保护基，再经乙基磺酰胺化反应等步骤制备巴瑞克替尼，其专利合成路线如下：
另外，还有其它许多专利对巴瑞克替尼的各个片段的合成方法(如CN108129482合成吡咯环及氮杂环丁酮)等，不同的保护基(如CN106946917用BOC保护吡咯嘧啶，CN107176955用苯磺酰基保护吡咯嘧啶，WO 2016088094A1用SEM保护吡咯嘧啶)以及片段之间的连接顺序(CN106496195A)进行优化组合等等。
本发明提供一条制备巴瑞克替尼及其衍生物的新方法，旨在规避目前制备巴瑞克替尼的专利壁垒和规避现有合成路线的缺陷。
发明内容
本发明的目的在于提供一条制备巴瑞克替尼及其衍生物的方法。
研究发现，化合物式I(4-(1,3-二氧戊环-2-基)-7-取代-7H-吡咯[2,3-d]嘧啶)在溶剂存在下和化合物式II(2-(1-(乙基磺酰基)-3-肼基氮杂环丁-3-基)乙腈)、化合物式III((氯亚甲基)二甲基氯化铵)发生反应，可以制备得到化合物式IV(2-(1-(乙基磺酰基)-3-(4-(7-取代-7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)氮杂环丁-3-基)乙腈)。反应式如下：
反应所使用的溶剂为CHCl3,CH2Cl2,DMF,Dioxane,CH3CN，DMSO,2-Me-THF。
化合物式I中，R为SEM(2-(2-三甲基硅烷基)-乙氧甲基),POM(特戊酰基氧甲基),Ts,Ac,Boc,H。
化合物式IV中，R为SEM(2-(2-三甲基硅烷基)-乙氧甲基),POM(特戊酰基氧甲基),Ts,Ac,Boc,H。
反应温度为30-100℃。
具体实施方式
以下典型实施例用来说明本发明，在本领域内的技术人员对本发明所做的简单替换和改进等均属于本发明所保护的技术方案之内。
实施例一:2-(1-(乙基磺酰基)-3-(4-(7-乙酰基-7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)氮杂环丁-3-基)乙腈的制备
三口烧瓶中，氮气保护下向反应瓶中加入(氯亚甲基)二甲基氯化铵(25.6g,200mmol)的CHCl3(100mL)的溶液，反应体系升温至50℃；然后通过滴液漏斗向反应体系中加入4-(1,3-二氧戊环-2-基)-7-乙酰基-7H-吡咯并[2,3-d]嘧啶(23.4g,100.3mmol)的CHCl3(50mL)溶液，加入完毕后体系升温至60℃搅拌反应1小时；然后减压去除反应体系的CHCl3，随后向反应体系中加入2-(1-(乙基磺酰基)-3-肼基氮杂环丁-3-基)乙腈(24.1g,110.3mmol)的CHCl3(100mL)溶液；加入完毕后体系升温至65℃搅拌反应2小时。体系自然降温至室温，反应体系加入水(100mL),搅拌后静置，分出有机相。水相使用CH2Cl2萃取(2×50mL)。合并有机相，减压去除溶剂，残余物柱层析纯化(CH2Cl2/MeOH＝40:1)得2-(1-(乙基磺酰基)-3-(4-(7-乙酰基-7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)氮杂环丁-3-基)乙腈(类白色固体，28.1g,67.8％)。1H NMR(600MHz,DMSO-D6)δ1.25(t，J＝5.1Hz,3H),3.01(s,3H),3.27(q,J＝6.0Hz,2H),3.70(s,1H),4.26(d,J＝9.0Hz,2H),4.63(d,J＝9.0Hz,2H),7.43(d,J＝9.0Hz,2H),8.14(d,J＝4.2Hz,1H),8.50(s,1H),8.97(d,J＝5.4Hz,1H),9.01(s,1H)。
实施例二:(4-(1-(3-(腈基甲基)-1-(乙基磺酰基)氮杂环丁-3-基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-7-基)甲基特戊酸酯的制备
三口烧瓶中，氮气保护下向反应瓶中加入(氯亚甲基)二甲基氯化铵(26.0g,203.1mmol)的无水2-Me-THF(100mL)的溶液，反应体系升温至50-55℃；然后通过滴液漏斗向反应体系中加入(4-(1,3-二氧戊环-2-基)-7H-吡咯并[2,3-d]嘧啶-7-基)甲基特戊酸酯(30.6g,100.2mmol)的无水2-Me-THF(60mL)溶液，加入完毕后体系升温至60-65℃搅拌反应1.5小时；然后减压去除反应体系的2-Me-THF，随后向反应体系中加入2-(1-(乙基磺酰基)-3-肼基氮杂环丁-3-基)乙腈(25.0g,114.5mmol)的无水2-Me-THF(120mL)溶液；加入完毕后体系升温至60-65℃搅拌反应3小时。体系自然降温至室温，反应体系加入水(150mL)和CH2Cl2萃取(200mL),搅拌后静置，分出有机相。水相使用CH2Cl2萃取(2×80mL)。合并有机相，减压去除溶剂，残余物柱层析纯化(CH2Cl2/MeOH＝30:1)得(4-(1-(3-(腈基甲基)-1-(乙基磺酰基)氮杂环丁-3-基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-7-基)甲基特戊酸酯(白色固体，29.95g,61.6％)。1H NMR(600MHz,CDCl3)δ1.20(s,9H),1.40(t，J＝9.0Hz,3H),3.10(q，J＝9.0Hz,2H),3.42(s,2H),4.25(d,J＝9.6Hz,2H),4.61(d,J＝9.0Hz,2H),6.25(s,2H),6.77(d,J＝4.2Hz,1H),7.51(d,J＝4.2Hz,1H),8.38(s,1H),8.44(s,1H),8.88(s,1H)。
Claims (5)
1.制备巴瑞克替尼及其衍生物的方法，具体为化合物式I(4-(1,3-二氧戊环-2-基)-7-取代-7H-吡咯[2,3-d]嘧啶)在溶剂存在下和化合物式II(2-(1-(乙基磺酰基)-3-肼基氮杂环丁-3-基)乙腈)、化合物式III((氯亚甲基)二甲基氯化铵)发生反应，实现化合物式IV(2-(1-(乙基磺酰基)-3-(4-(7-取代-7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)氮杂环丁-3-基)乙腈)的制备。反应式如下：
2.如权利要求1所示的反应，反应所使用的溶剂为CHCl3,CH2Cl2,DMF,Dioxane,CH3CN，DMSO，2-Me-THF。
3.如权利要求1所示的反应，化合物式I中R为SEM(2-(2-三甲基硅烷基)-乙氧甲基),POM(特戊酰基氧甲基),Ts,Ac,Boc,H。
4.如权利要求1所示的反应，化合物式IV中，R为SEM(2-(2-三甲基硅烷基)-乙氧甲基),POM(特戊酰基氧甲基),Ts,Ac,Boc,H。
5.如权利要求1所示的反应，反应温度为30-100℃。
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115124537A (zh) * | 2022-07-13 | 2022-09-30 | 山东大学 | 一种jak抑制剂巴瑞替尼的制备方法 |
| CN115417876A (zh) * | 2022-09-20 | 2022-12-02 | 山东新时代药业有限公司 | 一种巴瑞替尼中间体化合物 |
| WO2023288197A1 (en) * | 2021-07-12 | 2023-01-19 | Incyte Corporation | Process and intermediates for preparing baricitinib |
| US11897889B2 (en) | 2020-08-18 | 2024-02-13 | Incyte Corporation | Process and intermediates for preparing a JAK1 inhibitor |
| US11905292B2 (en) | 2020-08-18 | 2024-02-20 | Incyte Corporation | Process and intermediates for preparing a JAK inhibitor |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11897889B2 (en) | 2020-08-18 | 2024-02-13 | Incyte Corporation | Process and intermediates for preparing a JAK1 inhibitor |
| US11905292B2 (en) | 2020-08-18 | 2024-02-20 | Incyte Corporation | Process and intermediates for preparing a JAK inhibitor |
| WO2023288197A1 (en) * | 2021-07-12 | 2023-01-19 | Incyte Corporation | Process and intermediates for preparing baricitinib |
| CN115124537A (zh) * | 2022-07-13 | 2022-09-30 | 山东大学 | 一种jak抑制剂巴瑞替尼的制备方法 |
| CN115417876A (zh) * | 2022-09-20 | 2022-12-02 | 山东新时代药业有限公司 | 一种巴瑞替尼中间体化合物 |
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