CN109071489A - 吲唑的合成 - Google Patents
吲唑的合成 Download PDFInfo
- Publication number
- CN109071489A CN109071489A CN201780026130.4A CN201780026130A CN109071489A CN 109071489 A CN109071489 A CN 109071489A CN 201780026130 A CN201780026130 A CN 201780026130A CN 109071489 A CN109071489 A CN 109071489A
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- Prior art keywords
- formula
- compound
- indazole
- methyl
- mixture
- Prior art date
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Abstract
本发明涉及一种新的制备以下结构(I)的2‑取代吲唑的方法:
Description
本发明涉及一种制备具有以下结构的2-取代的吲唑的新方法
涉及所述2-取代的吲唑的新的多晶B形式,涉及中间体化合物,并涉及中间体化合物用于制备所述2-取代的吲唑的用途。
本发明涉及抑制白细胞介素-1受体相关激酶4(IRAK4)的式(I)的取代的吲唑的制备。
人IRAK4(白细胞介素-1受体相关激酶4)在免疫系统的激活中起关键作用。因此,该激酶是用于开发炎症抑制物质的重要治疗靶分子。IRAK4由许多细胞表达并介导以下受体的信号转导:Toll样受体(TLR)(除TLR3之外),以及由IL-1R(受体)、IL-18R、IL-33R和IL-36R组成的白细胞介素(IL)-1β家族的受体(Janeway and Medzhitov,Annu.Rev.Immunol.,2002;Dinarello,Annu.Rev.Immunol.,2009;Flannery and Bowie,BiochemicalPharmacology,2010)。
IRAK4基因敲除小鼠和来自缺失IRAK4的患者的人细胞均对TLR(除TLR3之外)和IL-1β家族的刺激不起反应(Suzuki,Suzuki等人,Nature,2002;Davidson,Currie等人,TheJournal of Immunology,2006;Ku,von Bernuth等人,JEM,2007;Kim,Staschke等人,JEM,2007)。
TLR配体或IL-1β家族的配体与各自受体的结合导致MyD88[髓样分化因子初次应答基因(88)]募集并结合至受体。从而,MyD88与IRAK4相互作用,导致形成活性复合物,所述活性复合物与激酶IRAK1或IRAK2相互作用并将其激活(Kollewe,Mackensen等人,Journalof Biological Chemistry,2004;Precious等人,J.Biol.Chem.,2009)。由此,将NF(核因子)-kB信号传导途径和MAPK(促分裂原活化蛋白激酶)信号传导途径激活(Wang,Deng等人,Nature,2001)。NF-kB信号传导途径和MAPK信号传导途径两者的激活产生与不同免疫过程相关的过程。例如,多种炎症信号分子和酶(如细胞因子、趋化因子和COX-2(环加氧酶-2))的表达增加,并且炎症相关基因(例如COX-2、IL-6、IL-8)的mRNA稳定性增强(Holtmann,Enninga等人,Journal of Biological Chemistry,2001;Datta,Novotny等人,TheJournal of Immunology,2004)。此外,这些过程可与特定细胞类型(例如单核细胞、巨噬细胞、树突细胞、T细胞和B细胞)的增殖和分化相关(Wan,Chi等人,Nat Immunol,2006;McGettrick and J.O′Neill,British Journal of Haematology,2007)。
IRAK4在各种炎症性病症的病理学中的核心作用已通过直接比较野生型(WT)小鼠与具有激酶失活形式的IRAK4(IRAK4 KDKI)的遗传修饰动物而示出。在多发性硬化、动脉粥样硬化、心肌梗死和阿尔茨海默氏病的动物模型中,IRAK4 KDKI动物具有改善的临床表现(Rekhter,Staschke等人,Biochemical and Biophysical Research Communication,2008;Maekawa,Mizue等人,Circulation,2009;Staschke,Dong等人,The Journal ofImmunology,2009;Kim,Febbraio等人,The Journal of Immunology,2011;Cameron,Tse等人,The Journal of Neuroscience,2012)。此外,发现,动物模型中IRAK4的缺失通过改善抗病毒反应并同时降低全身炎症而防止病毒诱导的心肌炎(Valaperti,Nishii等人,Circulation,2013)。还已表明IRAK4的表达与伏格特-小柳-原田综合征(Vogt-Koyanagi-Harada syndrome)的程度相关(Sun,Yang等人,PLoS ONE,2014)。
除了IRAK4在先天性免疫中的关键作用,也存在这样的暗示:IRAK4影响所谓的Th17T细胞——适应性免疫的组分——的分化。在没有IRAK4激酶活性的情况下,与WT小鼠相比,有较少的IL-17-生成T细胞(Th17T细胞)产生。因此,抑制IRAK4适于预防和/或治疗动脉粥样硬化、1型糖尿病、类风湿性关节炎、脊椎关节炎、红斑狼疮、银屑病、白癜风、慢性炎性肠病和病毒性病症,例如HIV(人免疫缺陷病毒)、肝炎病毒(Staschke等人,The Journal0f Immunology,2009;Zambrano-Zaragoza等人,International Journal ofInflammation,2014)。
由于IRAK4在TLR(除TLR3之外)和IL-1受体家族的MyD88-介导的信号级联中的核心作用,抑制IRAK4可以用于预防和/或治疗由所述受体介导的病症。TLR以及IL-1受体家族的组分与以下疾病的发病机理相关:类风湿性关节炎、代谢综合征、糖尿病、骨关节炎、合格伦综合征( syndrome)和败血症(Scanzello,Plaas等人,Curr Opin Rheumatol,2008;Roger,Froidevaux等人,PNAS,2009;Gambuzza,Licata等人,Journal ofNeuroimmunology,2011;Fresno,Archives Of Physiology And Biochemistry,2011;Volin and Koch,J Interferon Cytokine Res,2011;Akash,Shen等人,Journal ofPharmaceutical Sciences,2012;Goh and Midwood,Rheumatology,2012;Dasu,Ramirez等人,Clinical Science,2012;Ramirez and Dasu,Curr Diabetes Rev,2012;Li,Wang等人,Pharmacology&Therapeutics,2013;Sedimbi,Hagglof等人,Cell Mol Life Sci,2013;Talabot-Aye等人,Cytokine,2014)。皮肤病如银屑病、特应性皮炎、Kindler综合征、变应性接触性皮炎、反常性痤疮(acne inversa)和寻常痤疮(acne vulgaris)与IRAK4介导的TLR信号传导途径有关(Gilliet,Conrad等人,Archives of Dermatology,2004;Niebuhr,Langnickel等人,Allergy,2008;Miller,Adv Dermatol,2008;Terhorst,Kalali等人,Am JClin Dermatol,2010;Viguier,Guigue等人,Annals of Internal Medicine,2010;Cevikbas,Steinhoff,J Invest Dermatol,2012;Minkis,Aksentijevich等人,Archivesof Dermatology,2012;Dispenza,W0lpert等人,J Invest Dermatol,2012;Minkis,Aksentijevich等人,Archives of Dermatology,2012;Gresnigt and van deVeerdonk,Seminars in Immunology,2013;Selway,Kurczab等人,BMCDermatology,2013;Sedimbi,Hagglof等人,Cell Mol Life Sci,2013;Wollina,Koch等人,Indian Dermatol Online,2013;Foster,Baliwag等人,The Journal of Immunology,2014)。
肺部病症如肺纤维化、阻塞性肺病(COPD)、急性呼吸窘迫综合征(ARDS)、急性肺损伤(ALI)、间质性肺病(ILD)、结节病和肺动脉高压也显示与多种TLR介导的信号传导途径相关。肺部病症的发病机理可能为感染介导的或非感染介导的过程(Ramirez Cruz,Maldonado Bernal等人,Rev Alerg Mex,2004;Jeyaseelan,Chu等人,Infection andImmunity,2005;Seki,Tasaka等人,Innammation Research,2010;Xiang,Fan等人,Mediators of Inflammation,2010;Margaritopoulos,Antoniou等人,Fibrogenesis&Tissue Repair,2010;Hilberath,Carlo等人,The FASEB Journal,2011;Nadigel,Prefontaine等人,Respiratory Research,2011;Kovach and Standiford,InternationalImmunopharmacology,2011;Bauer,Shapiro等人,Mol Med,2012;Deng,Yang等人,PLoSOne,2013;Freeman,Martinez等人,Respiratory Research,2013;Dubaniewicz,A.,HumanImmunology,2013)。TLR以及IL-1R家族成员还参与其他炎症性病症如贝切特氏病(Beheet′s disease)、痛风、红斑狼疮、成人斯蒂尔氏病(adult-onset Still’s disease)和慢性炎性肠病如溃疡性结肠炎和克罗恩氏病(Crohn’s disease)以及移植排斥的发病机理,因此,此处,抑制IRAK4是合适的治疗方法(Liu-Bryan,Scott等人,Arthritis&Rheumatism,2005;Christensen,Shupe等人,Immunity,2006;Cario,Inflammatory Bowel Diseases,2010;Nickerson,Christensen等人,The Journal of Immunology,2010;Rakoff-Nahoum,Hao等人,Immunity,2006;Heimesaat,Fischer等人,PLoS ONE,2007;Kobori,Yagi等人,JGastroenterol,2010;Shi,Mucsi等人,Immunological Reviews,2010;Leventhal andSchroppel,Kidney Int,2012;Chen,Lin等人,Arthritis Res Ther,2013;Hao,Liu等人,Curr Opin Gastroenterol,2013;Kreisel and Goldstein,Transplant International,2013;Li,Wang等人,Pharmacology&Therapeutics,2013;Walsh,Carthy等人,Cytokine&Growth Factor Reviews,2013;Zhu,Jiang等人,Autoimmunity,2013;Yap and Lai,Nephrology,2013)。由于式(I)的化合物的作用机理,它们还适于TLR和IL-1R家族介导的病症子宫内膜异位症和动脉粥样硬化的预防性和/或治疗性应用(Akoum,Lawson等人,HumanReproduction,2007;Allhorn,Boing等人,Reproductive Biology and Endocrinology,2008;Lawson,Bourcier等人,Journal of Reproductive Immunology,2008;Seneviratne,Sivagurunathan等人,Clinica Chimica Acta,2012;Sikora,Mielczarek-Palacz等人,American Journal of Reproductive Immunology,2012;Falck-Hansen,Kassiteridi等人,International Journal of Molecular Sciences,2013;Khan,Kitajima等人,Journalof Obstetrics and GynaecologyResearch,2013;Santulli,Borghese等人,HumanReproduction,2013;Sedimbi,Hagglof等人,Cell Mol Life Sci,2013)。
除了已经提及的病症外,在眼部病症的发病机理中也记载了IRAK4介导的TLR过程,所述眼部病症如视网膜缺血、角膜炎、变应性结膜炎、干燥性角结膜炎、黄斑变性和葡萄膜炎(Kaarniranta and Salminen,J MolMed(Berl),2009;Sun and Pearlman,Investigative Ophthalmology&Visual Science,2009;Redfernand McDermott,ExperimentalEyeResearch,2010;Kezic,Taylor等人,J Leukoc Biol,2011;Chang,McCluskey等人,Clinical&Experimental Ophthalmology,2012;Guo,Gao等人,ImmunolCell Biol,2012;Lee,Hattori等人,Investigative Ophthalmology&Visual Science,2012;Qi,Zhao等人,InvestigativeOphthalmology&Visual Science,2014)。
由于IRAK4在TLR介导的过程中的核心作用,抑制IRAK4还能够治疗和/或预防心血管病症和神经病症,例如心肌再灌注损伤、心肌梗死、高血压(Oyama,Blais等人,Circulation,2004;Timmers,Sluijter等人,Circulation Research,2008;Fang and Hu,Med Sci Monit,2011;Bijani,International Reviews of Immunology,2012;Bomfim,DosSantos等人,Clin Sci(Lond),2012;Christia and Frangogiannis,European Journal ofClinical Investigation,2013;Thompson and Webb,Clin Sci(Lond),2013;),以及阿尔茨海默氏病、中风、颅脑创伤和帕金森氏病(Brough,Tyrrell等人,Trends inPharmacological Sciences,2011;Carty and Bowie,Biochemical Pharmacology,2011;Denes,Kitazawa,Cheng等人,The Journal of Immunology,2011;Lim,Kou等人,TheAmerican Journal of Pathology,2011;Béraud and Maguire-Zeiss,Parkinsonism&Related Disorders,2012;Denes,Wilkinson等人,Disease Models&Mechanisms,2013;Noelker,Morel等人,Sci.Rep.,2013;Wang,Wang等人,Stroke,2013)。
由于在瘙痒和疼痛(例如癌症疼痛、手术后疼痛、炎症引发的疼痛和慢性疼痛)的情况中涉及经由IRAK4的TLR信号和IL-1受体家族介导的信号,因此可以假定通过抑制IRAK4在所述适应症中具有治疗作用(Wolf,Livshits等人,Brain,Behavior,andImmunity,2008;Kim,Lee等人,Toll-like Receptors:Roles in Infection andNeuropathology,2009;del Rey,Apkarian等人,Annals of the New York Academy ofSciences,2012;Guerrero,Cunha等人,European Journal of Pharmacology,2012;Kwok,Hutchinson等人,PLoS ONE,2012;Nicotra,Loram等人,Experimental Neurology,2012;Chopra and Cooper,J Neuroimmune Pharmacol,2013;David,Ratnayake等人,Neurobiology of Disease,2013;Han,Zhao等人,Neuroscience,2013;Liu and Ji,Pflugers Arch.,2013;Stokes,Cheung等人,Journal of Neuroinflammation,2013;Zhao,Zhang等人,Neuroscience,2013;Liu,Zhang等人,Cell Research,2014)。
这也适用于一些肿瘤病症。特定淋巴瘤如ABC-DLBCL(活化B细胞弥漫性大细胞B细胞淋巴瘤)、套细胞淋巴瘤和瓦尔登斯特伦氏病( disease),以及慢性淋巴性白血病、黑色素瘤和肝细胞癌的特征在于MyD88的突变或MyD88活性的变化,它们可通过IRAK4抑制剂进行治疗(Ngo,Young等人,Nature,2011;Puente,Pinyol等人,Nature,2011;Srivastava,Geng等人,Cancer Research,2012;Treon,Xu等人,New EnglandJournal of Medicine,2012;Choi,Kim等人,Human Pathology,2013;(Liang,Chen等人,Clinical Cancer Research,2013)。此外,MyD88在ras-依赖性肿瘤中起重要作用,因此IRAK4抑制剂也适于治疗ras-依赖性肿瘤(Kfoury,A.,K.L.Corf等人,Journal of theNational Cancer Institute,2013)。
炎症性病症如CAPS(冷吡啉相关周期性综合征(cryopyrin-associated periodicsyndromes)),包括FCAS(家族性寒冷型自身炎症综合征(familial coldautoinflammatory syndrome))、MWS(Muckle-Wells综合征)、NOMID(新生儿多系统炎症性疾病(neonatal-onset multisystem inflammatory disease))和CONCA(慢性婴儿神经皮肤关节(chronic infantile,neurological,cutaneous,and articular)综合征);FMF(家族性地中海热)、HIDS(高-IgD综合征)、TRAPS(肿瘤坏死因子受体1相关周期性综合征)、幼年特发性关节炎(juvenile idiopathic arthritis)、成人斯蒂尔氏病、亚-贝二氏综合征(disease)、类风湿性关节炎、骨关节炎、干燥性角结膜炎和合格伦综合征,通过阻断IL-1信号传导途径来治疗;因此,此处,IRAK4抑制剂也适于治疗所述疾病(Narayanan,Corrales等人,Cornea,2008;Henderson and Goldbach-Mansky,ClinicalImmunology,2010;Dinarello,European Journal of Immunology,2011;Gul,Tugal-Tutkun等人,Ann Rheum Dis,2012;Pettersson,Annals of MedicinePetterson,2012;Ruperto,Brunner等人,New England Journal of Medicine,2012;Knight等人,The Journal of Rheumatology,2012;Vijmasi,Chen等人,Mol Vis,2013;Yamada,Arakaki等人,Opinion on Therapeutic Targets,2013)。IL-33R的配体IL-33与急性肾衰竭的发病机理特别相关,因此,将IRAK4的抑制用于预防和/或治疗是合适的治疗方法(Akcay,Nguyen等人,Journal of the Amcrican Society of Nephrology,2011)。IL-1受体家族的组分与心肌梗死、不同的肺部病症(如哮喘、COPD、特发性间质性肺炎、变应性鼻炎、肺纤维化和急性呼吸窘迫综合征(ARDS))相关,因此,在所述适应症中,通过抑制IRAK4,预计有预防性和/或治疗性作用(Kang,Homer等人,The Journal of Immunology,2007;Imaoka,Hoshino等人,European Respiratory Journal,2008;Couillin,Vasscur等人,TheJournal of Immunology,2009;Abbate,Kontos等人,The Amcrican Journal ofCardiology,2010;Lloyd,Current Opinion in Immunology,2010;Pauwels,Bracke等人,European Respiratory Journal,2011;Haenuki,Matsushita等人,Journal of Allergyand Clinical Immunology,2012;Yin,Li等人,Clinical&Experimental Immunology,2012;Abbate,Van Tassell等人,The American Journal of Cardiology,2013;Alexander-Brett等人,The Journal of Clinical Investigation,2013;Bunting,Shadie等人,BioMed Research International,2013;Byers,Alexander-Brett等人,The Journalof Clinical Investigation,2013;Kawayama,Okamoto等人,J Interferon CytokineRes,2013;Martinez-González,Roca等人,American Journal of Respiratory Cell andMolecular Biology,2013;Nakanishi,Yamaguchi等人,PLoS ONE,2013;Qiu,Li等人,Immunology,2013;Li,Guabiraba等人,Journal of Allergy and Clinical Immunology,2014;Saluja,Ketelaar等人,MolecularImmunology,2014)。
现有技术公开了许多IRAK4抑制剂(参见,例如,Annual Reports in MedicinalChemistry(2014),49,117-133)。
US8293923和US20130274241公开了具有3-取代的吲唑结构的IRAK4抑制剂。没有记载2-取代的吲唑。
WO2013/106254和WO2011/153588公开了2,3-二取代的吲唑衍生物。
WO2007/091107记载了2-取代的吲唑衍生物,其用于治疗杜兴肌营养不良(Duchenne muscular dystrophy)。所公开的化合物没有6-羟基烷基取代。
WO2015/091426记载了吲唑,其2位的烷基被甲酰胺结构取代。
WO2015/104662公开了在治疗上可用作激酶抑制剂、特别是IRAK4抑制剂的式(I)的吲唑化合物
以及其可用于治疗和预防疾病或病症的药学上可接受的盐或立体异构体,特别是它们在由激酶、特别是IRAK4酶介导的疾病或病症中的用途。
在本申请的优先权日之后公布的WO2016/083433记载了具有下式的新的取代的吲唑
其制备方法,其单独或组合用于治疗和/或预防疾病的用途,以及其用于制备用于治疗和/或预防疾病、特别是用于治疗和/或预防以下疾病的药物的用途:子宫内膜异位症以及与子宫内膜异位症相关的疼痛和其他与子宫内膜异位症相关的症状如痛经、交媾困难、排尿困难和大便困难,淋巴瘤,类风湿性关节炎,脊椎关节炎(特别是牛皮癣性脊椎关节炎和别赫捷列夫氏病(Bekhterev’s disease)),红斑狼疮,多发性硬化,黄斑变性,COPD,痛风,脂肪肝疾病,胰岛素抗性,肿瘤疾病和银屑病。
新的IRAK4抑制剂应尤其适于治疗和预防以反应过度的免疫系统为特征的增殖性和炎症性病症。在本文中应特别提及炎症性皮肤病症、心血管病症、肺部病症、眼部病症、自身免疫性病症、妇科病症(尤其是子宫内膜异位症)和癌症。
将公开一种方法,其使得可以在工业规模上制备吲唑(I),其中尤其关注以下需求:
·制备过程的按比例放大/可扩展性
·在N2-烷基化反应中的高区域选择性
·避免色谱分离和纯化步骤
·经由结晶的最终处理
·使用3类溶剂对多晶型物进行最终调整(根据FDA指南)。
引人注目地,可公开一种满足上述所有需求的方法。
本发明描述了经由N2上的出人意料地高选择性烷基化的化合物(I)的制备:
N2-取代的吲唑的制备先前已在文献中有所记载。然而,这些方法具有相当多的缺点,使得它们不适于工业规模。可以通过合成步骤的复杂顺序选择性地制备N2-取代的吲唑,所述合成步骤不涉及直接烷基化步骤。然而,这些顺序冗长且繁琐并且涉及相当大的损失,最终导致低的总产率。因此,可由1H-吲唑前体通过在N2处的直接和选择性烷基化而直接制备N2-取代的吲唑的合成路线是最令人感兴趣的。在尝试对通式(II)的1H-吲唑前体进行直接烷基化时,通常得到由N1-烷基化区域异构体(IIIa)和N2-烷基化区域异构体(III)构成的混合物。
吲唑及其衍生物,一类典型的芳香族N-杂环,已由于其多样的生物活性而在合成化学和药物化学中引起显著的兴趣。此外,可由吲唑衍生的N-杂环卡宾获得多种杂环结构。在吲唑中,N1/N2-取代的吲唑广泛用作抗癌药、抗炎药、抗HIV药和抗微生物药。通常,N2-取代的吲唑的合成涉及各种起始物料的环化步骤。不幸的是,一般方法学在文献中仍很少见。其中,仅获得中等产率。
关于当前的技术状态,已知若干出版物,其将在以下部分论述。所公开的方法都没有描写使用甲基乙烯基砜作为烷化剂导致直接N2-选择性烷基化的反应条件。没有观察到转化或选择性和产率低。现有技术方法的问题在于使用不含不稳定官能团的相对简单的烷化剂。这些试剂主要通过其卤化物、甲苯磺酸酯、三氟甲磺酸酯或甲磺酸酯的亲核取代而连接至1H-吲唑。当使用更多官能化的部分时,产率和选择性显著降低。在以下部分中,说明了为什么这些现有技术方法不适于目前挑战的原因:
1.WO 2011/043479:反应在THF中在回流下进行(参见方案2)。这不适于目前的情况(甲基乙烯基砜)。由例如醇制备相应的三氟甲磺酸酯是不可能的,因为其立即发生分解。此外,其仅使用在侧链中没有官能团的简单底物。
2.S.R.Baddam,N.U.Kumar,A.P.Reddy,R.Bandichhor,Tetrahedron Lett.2013,54,1661:在反应中仅使用没有官能团的简单吲唑。仅使用三氯乙酰亚胺酸甲酯作为烷化剂。将酸催化的条件转移至通过与甲基乙烯基砜反应而在吲唑核心结构的N2位上选择性引入甲基乙基砜侧链的尝试失败了。该方法不能轻易扩大规模。
3.Q.Tian,Z.Cheng,H.H.Yajima,S.J.Savage,K.L.Green,T.Humphries,M.E.Reynolds,S.Babu,F.Gosselin,D.Askin,Org.Process Res.Dev.2013,17,97:提出了优选用于吲唑的N2的THP-醚的制备。该反应通过不同的机理进行,且不代表一般方法,因为THP-醚产物不能容易地进一步转化。此外,提出了在酸性条件下使用对甲氧基苄基衍生物保护吲唑的选择性方法。将这些条件转移至通过与甲基乙烯基砜反应而在吲唑核心结构的N2位上选择性引入甲基乙基砜侧链的尝试失败了。
4.D.J.Slade,N.F.Pelz,W.Bodnar,J.W.Lampe,P.S.Watson,J.Org.Chem.2009,74,6331:使用酸性条件的THP-醚和PMB-保护(PPTS:吡啶鎓对甲苯磺酸盐),参见方案2;将这些条件转移至通过与甲基乙烯基砜反应而在吲唑核心结构的N2位上选择性引入甲基乙基砜侧链的尝试失败了。
5.M.Cheung,A.Boloor,J.A.Stafford,J.Org.Chem.2003,68,4093:使用高反应性和高致癌性的Meerwein盐作为烷化剂(参见方案2)。该方法仅包含简单的非官能化的乙基和甲基Meerwein盐。反应在环境温度下在极性乙酸乙酯中进行。这些条件不能转移至通过与甲基乙烯基砜反应而在吲唑核心结构的N2位上选择性引入甲基乙基砜侧链。
方案1:1H-吲唑的N-烷基化
方案2:由现有技术已知的吲唑的N-烷基化方法
6.M.-H.Lin,H.-J.Liu,W.-C.Lin,C.-K.Kuo,T.-H.Chuang,Org.Biomol.Chem.2015,13,11376:方法是N2选择性的;然而,其不能采用在化学计量的量下使用的Ga和Al金属来扩大规模。在所述反应条件下,形成布朗斯台德酸(Broenstedacid),其与相应的金属反应得到氢气。其仅使用相对简单的底物作为烷化剂(没有砜基团)。当使用更多的官能化的底物时,观察到产率显著降低。将这些条件转移至通过与甲基乙烯基砜反应而在吲唑核心结构的N2位上选择性引入甲基乙基砜侧链的尝试失败了。
7.G.Luo,L.Chen,G.Dubowchick,J.Org.Chem.2006,71,5392:使用2-(三甲基甲硅烷基)乙氧基甲基氯化物(SEM-Cl)在THF中在吲唑的N2上进行取代。将这些条件转移至通过与甲基乙烯基砜反应而在吲唑核心结构的N2位上选择性引入甲基乙基砜侧链的尝试失败。该出版物中记载的相应产物为醚,并且与我们的目标分子无关。使用高致癌性的2-(三甲基甲硅烷基)乙氧基甲基氯化物(SEM-Cl)以及苄氧基甲基氯化物(BOM-Cl)不代表用于获得目标化合物的可扩大的选择。
8.A.E.Shumeiko,A.A.Afon‘kin,N.G.Pazumova,M.L.Kostrikin,Russ.J.Org.Chem.2006,42,294:在该方法中仅使用非常简单的底物。未报道显著的选择性。观测到在吲唑上N1-烷基化的轻微偏好。
9.G.A.Jaffari,A.J.Nunn,J.Chem.Soc.Perkin 1 1973,2371:使用非常简单的底物,并且仅使用甲基化试剂。更复杂的底物,例如,甲醛与质子化甲醇的结合物仅产生N1-取代的产物(醚)。
10.V.G.Tsypin et al.,Russ.J.Org.Chem.2002,38,90:反应在硫酸和氯仿中进行。仅记载了使用金刚烷醇(adamanthyl alcohol)作为唯一烷化剂的简单吲唑的转化。这些条件不能转移到通过与甲基乙烯基砜反应在吲唑核心结构的N2位上选择性引入甲基乙基砜侧链。
11.S.K.Jains等人,RSC Advances 2012,2,8929:该出版物的特征是吲唑的N-苄基化的实例,其对N1取代具有低选择性。该KF-/铝催化的方法不能有效地用于合成N2-取代的吲唑。将这些条件转移到通过与甲基乙烯基砜的反应在吲唑核心结构的N2位上选择性引入甲基乙基砜侧链的尝试失败了。
12.L.Gavara等人,Tetrahedron 2011,67,1633:仅使用相对简单的底物。所描述的酸性THP-醚形成和在回流THF中的苄基化不适用于我们的底物。将这些条件转移到通过与甲基乙烯基砜的反应在吲唑核心结构的N2位上选择性引入甲基乙基砜侧链的尝试失败了。
13.M.Chakrabarty等人,Tetrahedron 2008,64,6711:观察到N2-烷基化,但是优选获得N1-烷基化产物。在THF中使用氢氧化钠水溶液和相转移催化剂的所述条件不适用于2-取代的吲唑。将这些条件转移到我们的系统(甲基乙烯基砜)的尝试失败了。
14.M.T.Reddy等人,Der Pharma Chemica 2014,6,411:反应在作为溶剂的相应的烷化剂中进行。仅记载了使用高活性的溴乙酸乙酯作为烷化剂。没有关于选择性的数据。这些条件不适用于N2-取代的吲唑的选择性合成。将这些条件转移到通过与甲基乙烯基砜的反应在吲唑核心结构的N2-位上选择性引入甲基乙基砜侧链的尝试失败了。
15.S.N.Haydar等人,J.Med.Chem.2010,53,2521:仅记载了简单的非官能化烷基(甲基、异丙基、异丁基)。碳酸铯用作碱,并且反应产生N1-和N2-烷基化产物的混合物。这些条件不适用于2-吲唑的化合物。将这些条件转移到通过与甲基乙烯基砜的反应在吲唑核心结构的N2-位上选择性引入甲基乙基砜侧链的尝试失败了。
16.Zh.V.Chirkova等人,Russ.J.Org.Chem.2012,48,1557:在该方法中,相对简单的底物在DMF中用碳酸钾作为碱来转化。获得N1-和N2-烷基化产物的混合物。该条件不适用于N2-取代的吲唑的选择性合成。将这些条件转移到通过与甲基乙烯基砜的反应在吲唑核心结构的N2-位上选择性引入甲基乙基砜侧链的尝试失败了。
17.C.Marminon等人,Tetrahedron 2007,63,735:吲唑中7位的邻位取代基R通过屏蔽N1免受亲电子攻击而将烷基化引向N2。在THF中氢化钠作为碱的条件不适用于N2-取代的吲唑的选择性合成,因为它们优选在吲唑的7位上没有取代基的情况下在N1位进行烷基化。将这些条件转移到通过与甲基乙烯基砜的反应在吲唑核心结构的N2-位上选择性引入甲基乙基砜侧链的尝试失败了。
18.D.A.Nicewicz等人,Angew.Chem.Int.Ed.2014,53,6198:仅使用简单底物。该方法记载了不容易按比例放大的光化学反应,并且不适用于N2-取代的吲唑的一般选择性合成。在自由基反应条件下使用非常特定的苯乙烯衍生物。将这些条件转移到通过与甲基乙烯基砜的反应在吲唑核心结构的N2-位选择性地引入甲基乙基砜侧链的尝试失败了。
19.A.Togni等人,Angew.Chem.Int.Ed.2011,50,1059:该出版物仅记载了一种具体类型的取代基(高价碘作为三氟甲基化试剂与乙腈的结合)。这种特殊情况不适用于N2-取代的吲唑的一般选择性合成。
20.L.Salerno等人,European J.Med.Chem.2012,49,118:该出版物记载了α-溴酮熔体中吲唑的转化。该反应条件不能转移到N2-取代的吲唑的选择性合成中。将这些条件转移到通过与甲基乙烯基砜的反应在吲唑核心结构的N2-位上选择性引入甲基乙基砜侧链的尝试失败了。
21.K.W.Hunt,D.A.Moreno,N.Suiter,C.T.Clark,G.Kim,Org.Lett.2009,11,5054:该出版物本质上记载了添加不同的碱的N1-选择性烷基化的方法。使用简单的底物。将这些条件转移到通过与甲基乙烯基砜的反应在吲唑核心结构的N2-位上选择性引入甲基乙基砜侧链的尝试失败了。
22.J.Yang等人,Synthesis 2016,48,48,1139:该出版物记载了N1-选择性碱催化的氮杂迈克尔反应(aza-Michael reaction)。未观测到N2上的取代。将这些条件转移到通过与甲基乙烯基砜的反应在吲唑核心结构的N2-位上选择性引入甲基乙基砜侧链的尝试失败了。
23.P.R.Kym等人,J.Med.Chem.2006,49,2339:本质上记载了N1-烷基化。将这些条件转移到通过与甲基乙烯基砜的反应在吲唑核心结构的N2-位上选择性引入甲基乙基砜侧链的尝试失败了。
24.A.J.Souers等人,J.Med.Chem.2005,48,1318:该出版物还记载了使用碳酸钾作为碱。该方法主要优选进行在N1处取代,因此不适用于N2取代的吲唑的选择性合成。将这些条件转移到通过与甲基乙烯基砜的反应在吲唑核心结构的N2-位上选择性引入甲基乙基砜侧链的尝试失败了。
25.P.Bethanamudi等人,E-Journal of Chemistry 2012,9,1676:使用离子液体以及碳酸钾作为碱以低产率得到N1-和N2-烷基化吲唑的混合物。选择性示出了向N1处取代的趋势。不能将离子液体的使用转移至我们体系中。将这些条件转移到通过与甲基乙烯基砜的反应在吲唑核心结构的N2-位上选择性引入甲基乙基砜侧链的尝试失败了。
26.S.Palit等人,Synthesis 2015,3371:本文所述的反应基本上是非选择性的,略微优先进行在吲唑的N1处的取代。仅使用简单的非官能化的烷基。使用氢化钠和类似的强碱。将这些条件转移到通过与甲基乙烯基砜的反应在吲唑核心结构的N2-位上选择性引入甲基乙基砜侧链的尝试失败了。
已表明,式(I)的化合物可以类似于先前在文献中公开的方法,通过例如使用2-溴乙基甲基砜直接烷基化来合成。然而,获得N1-和N2-烷基化产物的混合物,优选N1-位置异构体(regioisomer)(N1∶N2=约2∶1)。如在本申请的优先权日之后公开的WO2016/083433中所述,还可通过以下反应过程以非常低的产率获得所期望的式(I)的N2-烷基化吲唑:
将160mg(0.44mmol)N-[6-(2-羟基丙-2-基)-1H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲甲酰胺(中间体5-1)以及182mg碳酸钾和36mg碘化钾一同悬浮于1.0ml DMF中,并将混合物在室温下搅拌15min。然后,加入123mg2-溴乙基甲基砜并将混合物在室温下搅拌过夜。添加水,用乙酸乙酯将混合物萃取两次,并用饱和氯化钠水溶液洗涤萃取物,通过疏水性过滤器进行过滤并浓缩。通过制备型HPLC纯化残余物得到20mg(9.7%产率)标题化合物。
已证实消耗性制备型HPLC对于有效分离N1-位置异构体/N2-位置异构体是不可或缺的。该新发明的方法的目的在于避免HPLC分离,其通过在有利于在N2处取代的反应中实现更高的选择性、随后进行新发明的重结晶过程。
本发明提供由通式(II)的化合物制备通式(III)的化合物的方法
其中
R12-(甲基磺酰基)乙基;
R4为二氟甲基、三氟甲基或甲基;且
R5为氢或氟;
其中优选R4=三氟甲基且R5=H:
出乎意料地,我们发现在反应中甲基乙烯基砜(IX)可替换相应的烷基卤化物。出乎意料的是,将乙烯基砜用于吲唑在N2处的烷基化是前所未有的,因此是具有高度创造性的。当将通式(II)的化合物与甲基乙烯基砜在甲苯中反应,任选地添加有机碱(例如N,N-二异丙基乙胺或三乙胺)时,就可以以非常高的选择性获得所期望的式(III)和(I)的N2-异构体。发现反应混合物中的选择性为8∶1至10∶1,以有利于N2-烷基化产物(III)以及(I)的方式。在反应混合物的后处理后,不期望的N1-取代的副产物主要残留在母液中(结晶后大多<2%)。
反应在不使用额外的碱的情况下进行。将通式(II)或(V)的化合物置于反应容器中。加入1-2当量的甲基乙烯基砜并将反应混合物在甲苯中回流加热(约110℃的内部温度)。反应可使用相对于原材料(II)或(V)的量5至30体积的甲苯进行。优选地,反应使用8至15体积以及最佳使用10体积的甲苯进行。反应时间跨越12至100h。优选在48至72h之间进行。在一些情况下,已证实有利地是,将甲基乙烯基砜逐份加入反应混合物中,例如以1当量开始,然后在24h后添加0.3当量,并在48h之后再添加0.3当量。
任选地,反应在催化量的有机助剂碱(例如N,N-二异丙基乙胺)下进行。将通式(II)或(V)的化合物以及溶剂(甲苯或二甲苯)和催化量的有机碱一同置于反应容器中。
可添加0.01至1当量的量的助剂有机碱,例如N,N-二异丙基乙胺、N,N-二环己基胺或三乙胺。反应用0.01至0.1当量的碱进行。
值得关注且确实出乎意料的是,在相同的反应温度下使用氯苯或乙苯作为溶剂或在较高反应温度下使用二甲苯作为溶剂,可通过消除水而以更高的量获得烯烃(IV)。引人注目的是,当使用甲苯作为溶剂时,仅以非常少的量观察到这种消除。因此,必须将甲苯视为对于这种特定反应具有独特且完全未预料到的性质的创造性的溶剂。还发现(IV)的形成取决于(V)的质量。当使用具有高于通常水含量的(V)(1重量%而不是<0.5重量%)时,在反应中获得更显著量的(IV)。值得注意的是,通过与甲苯共沸蒸馏从(V)中除去过量的水并加入催化量的有机碱,特别是N,N-二异丙基乙胺,可有效地抑制消除产物(VI)的形成。
分离过程:在反应完成之后,可从反应混合物中蒸馏出部分甲苯。然后,可将第二溶剂,例如甲基叔丁基醚(MTBE)或二异丙基醚(优选甲基叔丁基醚)加入到反应混合物中。在加入各溶剂时,就从混合物中几乎定量地沉淀出产物。在某些情况下,证明将混合物用少量晶体接种以获得可重复的结晶作用是有用的。冷却并长时间搅拌所得悬浮液后,通过过滤、用溶剂洗涤并在50至60℃下真空干燥来分离产物,通常产率为59至67%。粗产物的纯度通常为95至97%(面积),其中N1-位置异构体少于2%(面积)。
必须强调地是,取代的乙烯基砜用于定向高度选择性地制备N2-官能化吲唑的反应是新颖的,在文献中没有先例,因此其是一项制备这类取代类型的科学上高度重要的发明。
GMP材料——其还将用于临床试验中——的制备需要额外的纯化步骤。此外,由于活性药物成分将用于制备药物组合物,例如片剂,则需要可重复供给完全相同的晶癖的方法。出乎意料地,这可以用乙醇或异丙醇作为重结晶溶剂来实现。乙醇是优选的溶剂。因此,首先将化合物溶解在丙酮中,然后通过颗粒过滤器(GMP过滤)。然后,通过蒸馏进行从丙酮到乙醇的溶剂交换。继续蒸馏直到达到相对于投料乙醇的6至7体积的最终体积。当已经达到乙醇的沸点(约77-78℃)确保所有的丙酮已被蒸馏出时取消蒸馏。然后将混合物冷却、搅拌,并将结晶的产物通过过滤分离并在高温下真空干燥。结晶的产率通常>90%。从该结晶方法获得的产物具有制备药物组合物(例如片剂)所需的期望多晶型性质。该产品表现出了非常高的纯度和非常高的含量。表1中给出了典型批料最重要的分析数据:
表1:如表7中所示的批料实施例的分析数据
通过上述结晶方法获得的多晶型物在存储期间显示良好的稳定性。其还可易于微粒化而不丧失其晶体性质。
通式(II)以及(V)的化合物的制备记载于WO 2015/091426中。该新发明的方法集中于式(V)所示的化合物:
在已公开的专利申请WO 2015/091426中,式(V)的化合物通过使用甲基溴化镁的二乙基醚溶液而使式(VI)的甲基醚化合物反应来制备:
在后处理之后,对粗产物进行柱色谱纯化,得到产率为45%的式(V)的化合物。
在本申请的优先权日之后公开的WO2016/083433记载了用于制备式(V)的化合物的合成途径,其同样始于式(VI)的化合物通过格式反应(Grignard reaction)使用合适的烷基卤化镁(例如甲基氯化镁或甲基溴化镁)在THF中或在二乙醚中或在THF和二乙醚的混合物中进行。
该方法由于以下缺点而不适用于在工业规模上制备式(V)的化合物:
·由于乙醚的低燃点和高爆炸潜在性而必须避免使用。
·使用相对昂贵的甲基溴化镁代替更易于生产的更常见的甲基氯化镁。
·在工业规模上应当避免色谱分离,因为它们通常需要大量的不经济的消耗有机溶剂。
·未描述结晶过程。根据研究实验室中的常规实践,蒸发式(V)的化合物直至干燥。该操作在工业规模上不可行。
·产率令人不满意:出于工业目的,应当获得至少75%的产率。
令人惊奇的是,已发现当使用甲基氯化镁和氯化锂(2∶1)的THF溶液代替时,可以以显著更高的产率制备式(V)的化合物。反应以较少的副产物进行,所述副产物使用WO2015/091426和WO2016/083433中描述的方法也必须通过繁琐的柱色谱法除去。发现该反应最好用THF作为溶剂进行。将6至10当量的甲基氯化镁(约3M的THF溶液)和3至5当量的氯化锂搅拌并保持在-10至0℃下。在1至3h,优选2h内,将式(VI)的化合物作为于THF中的溶液滴加至混合物中。将反应混合物在所示的温度范围(-10℃至0℃)下搅拌5至30min,然后通过倒入水中来淬灭。将所得的混合物剧烈搅拌。然后通过添加无机或有机酸(优选柠檬酸)将混合物的pH调节至约4,并加入乙酸乙酯。分离各相,将有机相用盐水(氯化钠水溶液)洗涤数次。通过蒸馏使所得有机溶液与甲苯进行溶剂交换。在此过程中,式(V)的化合物开始结晶并可通过过滤分离。将沉淀物在升高的温度(50-60℃)下真空干燥。通常,此阶段的产率为80至96%,纯度为95至99面积%(HPLC)。
为了制备具有现行良好生产规范(cGMP)质量的材料,最终在异丙醇/水(1∶1,相对于投料2至10体积)的混合物中搅拌该产品被证明是有益的。将该材料搅拌1至5h,优选3h。然后将其过滤并用少量1∶1的异丙醇/水混合物洗涤两次。将产物在升高的温度(50-60℃)下真空干燥。通常,得到的产率>90%且纯度>97面积%(HPLC)。
在实验部分的以下实施例中,还描述了一种变形(参见实施例#2,变形#3),其中在用活性炭处理后,直接进行溶剂交换,交换成异丙醇。通过加入水使产物结晶。以这种方式,直接获得具有非常高纯度的产物。
式(VI)的化合物的制备还记载于专利申请WO 2015/091426中。因此,使用1-[双(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物六氟磷酸盐(CAS号:148893-10-1)作为偶联剂使6-(三氟甲基)吡啶-2-甲酸(VII)(CAS号:21190-87-4)与式(VIII)的苯胺类化合物(5-氨基-1H-吲唑-6甲酸甲酯;CAS号:1000373-79-4)偶联。以84%的产率获得酰胺(VI)。
由于工艺安全性的原因,由于基于脲鎓的偶联剂具有爆炸可能性,不可能对其扩大规模。因此,必须寻找另一种偶联方法。
用于制备式(VI)的酰胺类化合物的安全且可扩大的方法基于使用T3P(2,4,6-三丙基-1,3,5,2,4,6-三氧杂三磷杂环己烷-2,4,6-三氧化物;CAS号:68957-94-8)作为偶联剂。
反应平稳进行并以高产率得到式(VI)的酰胺类化合物。在一锅法中,将式(VII)的羧酸类化合物(最好以相对于苯胺(VIII)稍微不足来使用,约0.90-0.95当量)与1.5当量N,N-二异丙基乙胺一同置于16倍体积的THF中。随后,在0至5℃下缓慢加入2当量T3P(50重量%的乙酸乙酯溶液)。将反应混合物在0至5℃下再搅拌2至4小时,优选搅拌2小时。
然后将混合物用水淬灭,用碳酸钠水溶液调节其pH至约7.4,并大量地蒸馏出THF/乙酸乙酯混合物(200mbar,内部温度45-50℃)。随后,加入水和乙醇并通过加入碳酸钠水溶液将pH调节至约7.0。将混合物在50℃下搅拌1至5h,优选1至2h,然后冷却至20至25℃并搅拌10至30min。将产物通过过滤分离,随后用乙醇和水的混合物洗涤,最后在45℃下真空干燥。通过该方法,通常获得95至96%的非常高的产率。在所有情况下纯度均>98面积%(HPLC)。
在一些情况下,特别是当使用光学品质差(例如深棕色)的式(VIII)的苯胺类化合物作为原料时,证明用活性炭进行处理是有用的。以下部分描述了此过程:
将粗酰胺(VI)溶于甲醇和THF的混合物(2∶1)中并加入活性炭。将混合物加热至60至65℃,保持1至1.5h。过滤出活性炭,并将滤液浓缩(降低至相对于投料2倍体积),加入水并使产物沉淀,过滤,洗涤并在55至60℃下(在真空下)干燥。
式(VII)和(VIII)的化合物的合成已记载在文献中,并且两者均可大量商购。
对于式(VII)的化合物:Cottet,Fabrice;Marull,Marc;Lefebvre,Olivier;Schlosser,Manfred,European Journal of Organic Chemistry,2003,8第1559-1568页;Carter,Percy H.;Cherney,Robert J.;Batt,Douglas G.;Duncia,John V.;Gardner,Daniel S.;Ko,Soo S.;Srivastava,Anurag S.;Yang,Michael G.Patent:US2005/54627A1,2005;Ashimori;Ono;Uchida;Ohtaki;Fukaya;Watanabe;Yokoyama Chemical andPharmaceutical Bulletin,1990,第38卷,9第2446-2458页。
对于式(VIII)的化合物:Nissan Chemical Industries,Ltd.;CHUGAI SEIYAKUKABUSHIKI KAISHA,EP2045253A1,2009。
总方法的评估:
方案2示出由式(VIII)的苯胺类化合物得到纯的式(I)的产物的总合成。获得的式(I)的产物的纯度>99面积%(HPLC)。当用每一步获得的最佳产率计算时,获得50%的总产率。这还包括最终的晶型的形成。
方案2:由式(VIII)的苯胺类化合物得到纯的式(I)的产物的总合成
当将该总产率与公开的现有技术数据对比时:℃
1.酰胺偶联(式(VI)的化合物的制备):产率84%;
2.格氏反应,然后进行色谱纯化:产率45%;
3.用2-溴乙基甲基砜进行烷基化,类似于文献中已知的方法,然后进行色谱纯化:产率9.68%;
新工艺的优势变得非常明显:
利用现有技术中已知的方法并如上所述,可以得到仅3.7%的总产率,其中不包括最终的晶型的形成。
总之,与现有技术相比,新发明的方法提供了总产率高>13倍的式(I)的化合物。此外,新发明的方法包括用于制备药物组合物(例如片剂)的目标多晶型物的定向和可重复的制备。
必须强调的是,取代的乙烯基砜用于N2-官能化的吲哚的定向高选择性制备的反应是新颖的,在文献中没有先例,因此是制备这种取代模式的具有高度显著意义的发明。
因此,在第一方面,本发明涉及通过反应方案IA中所示的以下步骤制备式(I)的化合物的方法,如下:
方案IA:由作为原材料的式(VIII)的化合物制备式(I)的化合物
其中R表示烷基,例如甲基、乙基或正丙基,或芳基,例如苯基;芳烃溶剂是溶剂,例如甲苯或二甲苯。
在第一方面的一个实施方案中,本发明涉及通过反应方案I中所示的以下步骤制备式(I)的化合物的方法,如下:
方案I:由作为原材料的式(VIII)的化合物制备式(I)的化合物
在第一方面的一个实施方案中,本发明涉及制备式(I)的化合物的方法:
其包括以下步骤(A):
其中任选地在芳族烃溶剂例如甲苯或二甲苯中,优选在所述溶剂的回流温度下使式(V)的化合物:
与式(IX’)的乙烯基砜化合物反应,从而得到所述式(I)的化合物:
其中R代表烷基,例如甲基、乙基或正丙基;或芳基,例如苯基。
在第一方面的一个实施方案中,本发明涉及制备如上所述式(I)的化合物的方法,其中所述芳族烃溶剂是甲苯。
在第一方面的一个实施方案中,本发明涉及制备如上所述式(I)的化合物的方法,其中所述式(V)的化合物:
通过以下步骤(B)制备:
其中任选地在碱金属卤化物例如氯化锂存在下,使式(VI)的化合物:
与还原性甲基化试剂例如甲基金属试剂,例如甲基卤化镁,例如甲基氯化镁反应,从而获得所述式(V)的化合物。
在第一方面的一个实施方案中,本发明涉及制备如上所述式(I)的化合物的方法,其中所述式(VI)的化合物:
通过以下步骤(C)制备:
其中任选地在有机碱,特别是弱有机碱例如叔胺,例如N,N-二异丙基乙胺存在下,
任选地在偶联剂例如2,4,6-三丙基-1,3,5,2,4,6-三氧杂三磷杂环己烷2,4,6-三氧化物(T3P)存在下,
使式(VIII)的化合物:
与式(VII)的化合物反应:
从而获得所述式(VI)的化合物。
在第一方面的另一个实施方案中,本发明涉及制备如上所述式(I)的化合物的方法,其中所述式(I)的化合物通过结晶纯化,特别是从溶剂如乙醇或异丙醇中结晶纯化。
在第一方面的所述另一个实施方案的变形中,所述溶剂是乙醇。
在第一方面的所述另一个实施方案的变形中,所述溶剂是异丙醇。
在第一方面的一个实施方案中,本发明涉及制备如上所述的式(I)的化合物的方法,其中所述式(I)的化合物为多晶型物(B)的形式。
根据第二方面,本发明涉及通过上述方法制备的式(I)的化合物的多晶型物(B):
根据第三方面,本发明涉及式(I)的化合物的多晶型物(B):
根据第三方面的实施方案,本发明涉及如上所述的所述多晶型物(B),其XRPD峰最大值[°2θ](铜(Cu))如下:
表2:化合物(I)的多晶型物B的XRPD
图1示出了多晶型物B中式(I)的化合物的X射线粉末衍射图(在25℃下且用Cu-Kα1作为放射源)。
根据第四方面,本发明涉及选自以下的化合物:
用于通过上述方法制备如上所述的式(I)的化合物或式(I)的化合物的多晶型物B的用途,
根据第五方面,本发明涉及式(IX’)的乙烯基砜化合物:
其中R代表烷基,例如甲基、乙基或正丙基;或芳基,例如苯基;
用于制备如上所述的式(I)的化合物或式(I)的化合物的多晶型物B的用途,
在第五方面的一个实施方案中,本发明涉及其中所述式(IX’)的乙烯基化合物是甲基乙烯基砜的用途。
方法
HPLC
方法A
设备:Agilent Technologie 1260Infinity,其配有1290InfinitySampler&Agilent 1100Series
Zorbax SB-AQ,50*4.6mm,1,5μm
缓冲液:磷酸二氢铵pH:2.4
乙腈
0min.5%缓冲液
8.3min 80%缓冲液
11min.80%缓冲液
210nm/4nm
1.2ml/min.
方法B
GC-HS
通过顶空气相色谱法(GC-HS)进行残留溶剂分析
Agilent 6890气相色谱仪,配有分流进样和FID(柱:Restek Rxi Sil MS;长度:20m;内径:0.18mm;df=1μm)。进样器温度160℃,流速1.2ml/min(H2)分流比18,箱温40℃(4.5min)-14℃/min-70℃-90℃/min-220℃(1.69min)。检测器:温度300℃,400ml/min(合成气),40ml/min(H2),30ml/min(N2),比率20Hz。
Perkin Elmer Turbomatrix 40顶空进样器:恒温箱80℃,针150℃,传输线160℃,系统压力140kPa,平衡时间32min,加压4.0min,进样时间0.04min(进样器)0.05min(GC)。
样品浓度:20mg物质于2ml DMF中
X-射线结晶学:测量条件:
工作实施例
以下实施例举例说明本发明。
N-{6-(2-羟基丙-2-基)-2-[2-(甲基磺酰基)乙基]-2H-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲酰胺(I)的制备
实施例#1
5-({[6-(三氟甲基)吡啶-2-基]羰基}氨基)-1H-吲唑-6甲酸甲酯(VI)
将2000g(10.46mol)5-氨基-1H-吲唑-6-甲酸甲酯、1899g(9.94mol)6-(三氟甲基)吡啶-2-甲酸和2028g(15.69mol)N,N-二异丙基乙胺于14.2kg THF中混合。在0至5℃下,在30min内逐滴加入13.3kgT3P的乙酸乙酯溶液(50重量%)。在相同的温度下继续搅拌2h。
后处理:
将反应混合物加热至环境温度(20℃)。加入3000g水同时将温度保持在20至25℃。继续搅拌10min。使用4N碳酸钠水溶液将pH调节至约7.4(7-8)。继续搅拌10min。如果需要,再次使用4N碳酸钠水溶液将pH调节至约7.4。
将溶剂(THF/乙酸乙酯)在减压条件(约200mbar,45-50℃内部温度)下蒸发直到达到搅拌的极限。添加4.7kg乙醇的和14.0kg水的混合物,并使用4N碳酸钠水溶液将pH再次调节至pH 7.4(7-8)。
将混合物在50℃下搅拌1h,然后冷却至20至25℃。在相同的温度下继续搅拌10min。将沉淀出的晶体过滤,用乙醇和水的混合物(1.3kg乙醇和4kg水)洗涤,并在干燥箱中真空干燥(45℃,N2流,至少12h)。
根据上述方法,在专业实验室中使用2kg原材料(5-氨基-1H-吲唑-6-甲酸甲酯)制备了四批批料:
产率:
批料#1:3476g(95%)
批料#2:3449g(95%)
批料#3:3476g(95%)
批料#4:3494g(96%)
经测定,所有批料的纯度>98面积%(HPLC)。
HPLC(方法A):Rt=6.5min。
MS(ESI pos):m/z=365(M+H)+
1H NMR(500MHz,DMSO-d6):δ[ppm]:3.98(s,3H),8.21(d,1H),8.25(s,1H),8.31(s,1H),8.39(t,1H),8.48(d,1H),9.16(s,1H),12.57(s,1H),13.45(br s,1H)。
1H NMR(300MHz,DMSO-d6):δ[ppm]=3.97(s,3H),8.13-8.27(m,2H),8.30(s,1H),8.33-8.45(m,1H),8.45-8.51(m,1H),9.15(s,1H),12.57(s,1H),13.44(br s,1H)。
实施例#2
N-[6-(2-羟基丙-2-基)-1H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺(V)
在以下部分中,描述了反应过程和后处理的不同变形。这些过程针对各个技术工厂中的给定条件。
使用惰性气体(N2或Ar)在排除水和空气的情况下进行以下实验。
变形#1
将50g(137.255mmol)5-({[6-(三氟甲基)吡啶-2-基]羰基}氨基)-1H-吲唑-6-甲酸甲酯(VI)溶解于800ml THF中。在常压(1atm)下在70℃下蒸馏出约300ml THF。然后将溶液冷却至0至3℃。
将溶液保持在该温度下,并在0至3℃下在120min内逐滴加入到457.5ml(1372.6mmol)于THF中的3M甲基氯化镁和29.1g氯化锂(686.3mmol)的冷却的混合物中。该添加完成之后,从混合物中取样并进行HPLC分析,显示已完全转化。在0至3℃下在25min内将混合物小心地倒入500ml1/2-饱和的氯化钠水溶液中(注意:放热!在第一个50ml过程中观察到温度剧烈升至29℃!)。得到悬浮液,当加入358ml 20重量%的柠檬酸水溶液时(pH从8.08降至4.28),所得悬浮液可溶解。在20至25℃下继续搅拌10min。加入500ml乙酸乙酯并继续搅拌10min。分离各相。将引种(mulm)加入有机相中。将5g活性炭加入有机相中。将混合物加热至78℃(内部温度),在此温度下搅拌30min,然后冷却至50℃(内部温度)。将热溶液通过硅藻土过滤,并用125ml乙酸乙酯洗涤两次。在环境压力(1atm)和110℃下将混合物浓缩至约150ml。加入350ml甲苯并在环境压力(1atm)和110℃下蒸馏出200ml。沉淀出产物。在60℃的内部温度下,在45min内加入200ml正庚烷。将混合物冷却至0至3℃并在该温度下搅拌2h。将产物过滤出,并用50ml甲苯/正庚烷(1∶1)的混合物洗涤两次。将沉淀出的产物在40℃和20mbar的干燥箱中干燥>48h。
产率:39.42g(78.83%,纯度97.84面积%HPLC)
HPLC(方法A):Rt=5.8min。
MS(ESIpos):m/z=365(M+H)+
1H-NMR(400MHz,DMSO-d6):[ppm]=1.63(s,6H),5.99(s,1H),7.50(s,1H),8.06(s,1H),8.17(d,1H),8.37(t,1H),8.46(d,1H),8.78(s,1H),12.33(s,1H),12.97(br s,1H)。
根据变形#1的方法制备13批批料。下表3汇总了各自的产率。就使用5-({[6-(三氟甲基)吡啶-2-基]羰基}氨基)-1H-吲唑-6-甲酸甲酯(VI)作为原材料而言,在1kg的规模下进行所述反应。在大部分情况下,在用活性炭处理之后合并两批批料:
表3:从(VI)合成(V)的批料1至13所获得的产率
*)单个批料
变形#2
将30g(82.4mmol)5-({[6-(三氟甲基)吡啶-2-基]羰基}氨基)-1H-吲唑-6-甲酸甲酯(VI)溶解于480ml THF中。在常压(1atm)下在70℃下蒸馏出约180ml THF。然后将混合物(轻微悬浮)冷却至0至3℃。
将溶液保持在该温度下,并在0至3℃在120min内逐滴加入到274.5ml(823.5mmol)于THF中的3M甲基氯化镁和17.5g氯化锂(411.8mmol)的冷却的混合物中。该添加完成后15min之后,从混合物中取样并进行HPLC分析,显示(VI)已完全转化。在0至3℃下在15min内将混合物小心地倒入300ml水中(注意:放热!在第一个50ml的过程中,观察到温度剧烈上升!)。加入310ml 20重量%的柠檬酸水溶液(pH降至4.05)。继续在20至25℃下搅拌60min。加入300ml乙酸乙酯并继续搅拌30min。分离各相。将引种加入有机相中。将有机相用450ml水洗涤两次。在65℃(内部温度)和环境压力(1atm)下将有机相浓缩至350ml。加入250ml乙酸乙酯。将6g活性炭加入有机相中。将混合物加热至65℃(内部温度),在此温度下搅拌120min,然后冷却至50℃(内部温度)。将热溶液通过硅藻土过滤,并用125ml乙酸乙酯洗涤两次。在环境压力(1atm)和110℃下将混合物浓缩至约150ml。加入300ml甲苯并在环境压力(1atm)和110℃下蒸馏出200ml。沉淀出产物。在60℃内部温度下,在45min内加入200ml正庚烷。将混合物冷却至0-3℃并在该温度下搅拌2h。将产物过滤出,并用50ml甲苯/正庚烷(1∶1)的混合物洗涤两次。将沉淀出的产物在40℃和20mbar的干燥箱中干燥>48h。
产率:24.0g(80%,纯度:95.8面积%HPLC)
HPLC(方法A):Rt=5.8min。
MS(ESI pos):m/z=365(M+H)+
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.63(s,6H),5.99(s,1H),7.50(s,1H),8.06(s,1H),8.17(d,1H),8.37(t,1H),8.46(d,1H),8.78(s,1H),12.33(s,1H),12.97(br s,1H)。
变形#3
将30g(82.4mmol)5-({[6-(三氟甲基)吡啶-2-基]羰基}氨基)-1H-吲唑-6-甲酸甲酯(VI)溶解于600ml THF中。在常压(1atm)下在70℃下蒸馏出约150ml THF。然后将混合物(轻微悬浮)冷却至0-3℃。
将溶液保持在该温度下,并在0-3℃下在120min内逐滴加入到274.5ml(823.5mmol)于THF中3M甲基氯化镁和17.5g(411.8mmol)氯化锂的冷却的混合物中。用10mlTHF冲洗滴液漏斗两次。该添加完成后15min之后,从混合物中取样并进行HPLC分析,显示(VI)已完全转化。在0-3℃下在10min内将混合物小心地倒入300ml水中(注意:放热!在第一个50ml过程中,观察到温度剧烈升至25℃!)。加入250ml 20重量%的柠檬酸水溶液(pH从8降至4)。在20-25℃下继续搅拌30min。加入300ml乙酸乙酯并继续搅拌10min。分离各相。将引种加入有机相中。将有机相用200ml 1重量%的氯化钠水溶液洗涤两次。分离各相。在65℃(内部温度)和环境压力(1atm)下将有机相浓缩至250ml。将150ml乙酸乙酯和6g活性炭加入有机相中。将混合物加热至65℃(内部温度),在此温度下搅拌120min,然后冷却至50℃(内部温度)。将热溶液通过硅藻土过滤,并用50ml乙酸乙酯洗涤两次。在环境压力(1atm)和110℃下将混合物浓缩至约100ml。加入300ml异丙醇。在环境压力(1atm)和110℃下蒸馏出300ml。再次加入300ml异丙醇,并在110℃下蒸馏出(约355ml)。将所得的悬浮液冷却至20-25℃。在45min内加入45ml水。将混合物搅拌1h。将沉淀出的产物过滤并用50ml水/异丙醇(1∶1)混合物洗涤。将沉淀出的产物在50℃和20mbar的干燥箱中干燥>48h。
产率:24.9g(83%,纯度:97.84面积%HPLC)
HPLC(方法A):Rt=5.8min。
MS(ESI pos):m/z=365(M+H)+
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.63(s,6H),5.99(s,1H),7.50(s,1H),8.06(s,1H),8.17(d,1H),8.37(t,1H),8.46(d,1H),8.78(s,1H),12.33(s,1H),12.97(br s,1H)。
变形#4
该变形用于在kg规模(>10kg)下制备工业批料(见表4)。
60g(164.7mmol)5-({[6-(三氟甲基)吡啶-2-基]羰基}氨基)-1H-吲唑-6-甲酸甲酯(VI)溶解于1500ml THF中。在常压(1atm)下在70℃下蒸馏出约600ml THF。然后将混合物(黄色溶液)冷却至0-3℃。
将溶液保持在该温度下,并在0-3℃下在120min内逐滴加入到550ml(1647.1mmol)于THF中3M甲基氯化镁和35g(823.5mmol)氯化锂的冷却的混合物中。该添加完成后15min之后,从混合物中取样并进行HPLC分析,显示(VI)已完全转化。在0-3℃下在15min内将混合物小心地倒入600ml水中(注意:放热!在第一个50ml的过程中,观察到温度剧烈上升!)。加入600ml 20重量%的柠檬酸水溶液(pH降至4)。在20-25℃下继续搅拌30min。分离各相。将有机相用400ml 1重量%的氯化钠水溶液洗涤两次。将引种加入有机相中。分离各相。在65℃(内部温度)和环境压力(1atm)下将有机相浓缩至700ml。将500ml乙酸乙酯和12g活性炭加入有机相中。将混合物加热至65℃(内部温度),在此温度下搅拌120min,然后冷却至50℃(内部温度)。将热溶液通过硅藻土过滤,并用200ml乙酸乙酯洗涤两次。在减压(200mbar)下继续浓缩。进行与甲苯的溶剂交换(残余体积约850mL)。将所得的悬浮液冷却至0-3℃。将沉淀出的产物过滤并用50ml甲苯洗涤。将沉淀出的产物在50℃和20mbar的干燥箱中干燥>48h。
产率:51.2g(85.3%,纯度96.51面积%HPLC)
HPLC(方法A):Rt=5.8min。
MS(ESI pos):m/z=365(M+H)+
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.63(s,6H),5.99(s,1H),7.50(s,1H),8.06(s,1H),8.17(d,1H),8.37(t,1H),8.46(d,1H),8.78(s,1H),12.33(s,1H),12.97(br s,1H)。
变形#5
通过在异丙醇/水中搅拌而纯化
根据粗产物的纯度,可以进行通过在异丙醇和水的混合物(优选1∶1)中搅拌的额外的纯化步骤。根据粗产物的纯度,搅拌在粗原料的2-10倍体积范围内进行。以下实施例描述了在3倍体积异丙醇/水中的搅拌:
在20℃下将纯度为95面积%(HPLC)的7.5g N-[6-(2-羟基丙-2-基)-1H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺(V)在22.5ml水和异丙醇的1∶1(体积)混合物中搅拌2h。然后过滤悬浮液,用4ml相同的溶剂混合物洗涤产物。将产物在50℃干燥箱中真空(<100mbar)干燥。
产率:6.8g(90.7%,纯度>98面积%HPLC)
HPLC(方法A):Rt=5.8min。
MS(ESIpos):m/z=365(M+H)+
1H-NMR(400MHz,DMSO-4):δ[ppm]=1.63(s,6H),5.99(s,1H),7.50(s,1H),8.06(s,1H),8.17(d,1H),8.37(t,1H),8.46(d,IH),8.78(s,1H),12.33(s,1H),12.97(br s,1H)。
变形#4和#5的结合在44kg规模下进行(参见下表4)。.
表4:按照变形#4和#5的方案制备式(V)的化合物
实施例#3
N-{6-(2-羟基丙-2-基)-2-[2-(甲基磺酰基)乙基]-2H-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲酰胺(I)
变形#1
该变形用于在kg规模下生产工业批料并遵循WO2016/083433中描述的方案。
将2.5kg(6.86mol)N-[6-(2-羟基丙-2-基)-1H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺(V)悬浮于33l(28.6kg)甲苯中。将混合物加热至回流,并从混合物中蒸馏出约8l甲苯。将混合物冷却至90℃,并将44g(0.34mol)N,N-二异丙基乙胺加入混合物中。在90℃下将混合物再搅拌15min,然后加入1.17kg(10.98mmol)甲基乙烯基砜。将反应混合物保持在112℃(回流甲苯)下,并搅拌至少72h。将混合物冷却至20℃。然后将混合物加热至回流,并从混合物中蒸馏出8l甲苯。然后将混合物冷却至70℃,并在30min内加入12.6kg甲基叔丁基醚(MTBE)。在2h内将混合物冷却至20℃,并在20℃下搅拌过夜。然后将其冷却至0℃并搅拌1h。过滤出沉淀物并用3l冷MTBE洗涤两次。将结晶产物在50℃的烘箱中真空干燥。
产率:2.39kg(73.9%,纯度:97.8面积%HPLC)
HPLC(方法B):Rt=3.07min。
MS(ESI pos):m/z=471(M+H)+
1H NMR(400MHz,DMSO-d6):δ[ppm]=1.63(s,6H),2.90(s,3H),3.85(t,2H),4.86(t,2H),5.97(s,1H),7.59(s,1H),8.13-8.19(m,1H),8.37(s,1H),8.41-8.48(m,2H),8.74(s,1H),12.37(s,1H)。
表5:从(V)到(I)的三批批料的产率和纯度(以%计,在HPLC之后)
*方法B
为了获得具有非常高的纯度且具有确定结晶形式(多晶型物B)的材料,引入了额外的纯化步骤。
在环境温度下将1.85kg粗N-{6-(2-羟基丙-2-基)-2-[2-(甲基磺酰基)乙基]-2H-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲酰胺(I)溶解于36.6kg(46.3l)丙酮中。在2.5h内将所得溶液加入回流的乙醇中。在加入过程中,蒸馏出54l溶剂并达到63℃的内部温度。加入额外的20.8l乙醇,从混合物中蒸馏出27l溶剂。另外,加入10.2l额外的乙醇,从混合物中蒸馏出9.3l。最后,加入另外10.2l额外的乙醇,从混合物中蒸馏出10.2l溶剂。将混合物在3h内冷却至20℃并搅拌过夜。将混合物在1.5h内冷却至0-2℃并在该温度下再搅拌3h。过滤悬浮液,用2x0.93l冷乙醇洗涤沉淀物。将产物在50℃的干燥箱中真空干燥。
产率:1.59kg(85.7%,纯度:99.0面积%HPLC)
HPLC(方法B):Rt=3.07min。
MS(ESI pos):m/z=471(M+H)+
1H NMR(400MHz,DMSO-d6):δ[ppm]=1.63(s,6H),2.90(s,3H),3.85(t,2H),4.86(t,2H),5.97(s,1H),7.59(s,1H),8.16(d,1H),8.37(t,1H),8.41-8.48(m,2H),8.74(s,1H),12.37(s,1H)。
表6:合成后得到的产率和纯度以及从(V)合成的(I)在HPLC后的纯度(%)
变形#2
该变形用于在kg规模下生产工业批料。
将10g(27.448mmol)N-[6-(2-羟基丙-2-基)-1H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺(V)悬浮于100ml甲苯中。加入3.496g(32.937mmol)甲基乙烯基砜。将反应混合物加热至110℃(回流甲苯)并搅拌至少15h。加入额外部分的583mg(5.49mmol)甲基乙烯基砜,并将反应混合物在回流下搅拌7h。再加入583mg(5.49mmol)甲基乙烯基砜,将反应混合物搅拌>15h。根据HPLC分析,2.5%的原材料(V)仍在反应混合物中。N1/N2选择性总计为1:8。蒸馏出30ml甲苯。将混合物冷却至70℃。在此温度下,在5min内将70ml MTBE滴加到混合物中,得到悬浮液。将混合物冷却至20℃过夜。然后将其冷却至0℃并搅拌2h。过滤出沉淀物并用10ml冷MTBE洗涤两次。将结晶产物在干燥箱中在50℃和<100mbar下干燥至少48h。
产率:8.6g(66.6%,纯度:94.7面积%HPLC)
HPLC(方法B):Rt=3.07min。
MS(ESI pos):m/z=471(M+H)+
1H NMR(400MHz,DMSO-d6):δ[ppm]=1.63(s,6H),2.90(s,3H),3.85(t,2H),4.86(t,2H),5.97(s,1H),7.59(s,1H),8.16(d,1H),8.37(t,1H),8.41-8.48(m,2H),8.74(s,1H),12.37(s,1H)。
工业规模的批料:
按照变形#2所描述的过程,制备了原材料(V)规模为3.396kg和1.699kg的批料:
表7:由化合物(V)合成的化合物(I)的产率
为了制备GMP级材料并获得用于制备药物组合物(例如片剂)的确定结晶形式(多晶型物B),引入了额外的纯化步骤。
将1.5kg从如在变形#2下所述的合成中获得的粗N-{6-(2-羟基丙-2-基)-2-[2-(甲基磺酰基)乙基]-2H-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲酰胺(I)溶解于45kg丙酮中并进行澄清过滤(过滤器滤筒:3.0m→GMP-过滤)。将滤液浓缩,并与乙醇进行溶剂交换。由此,在蒸馏过程中同时加入乙醇,直至达到77℃的内部温度。将溶液浓缩至相对于起始体积6-7倍体积的乙醇。将混合物冷却至20℃并在该温度下搅拌12h。然后将其冷却至0℃并再搅拌3h。过滤出产物,用1kg冷乙醇洗涤两次。将产物在60℃的干燥烘箱中在真空(<100mbar)下干燥。
产率:1370g(91.33%)。类似于所述过程,在工业规模上进行了三批批料,参见表7。
表8:由粗(I)通过上述纯化获得的纯化合物(I)的产率
表9:如表8中所示的合并的三批批料的分析数据
纯度(HPLC)* | ≥99%(面积) |
含量(供使用进行的含量测定) | ≥97.7%(重量) |
乙醇 | <0.25%(重量)** |
Pd | <1ppm |
*方法B;**GC-HS
X射线衍射图如图1所示。
Claims (12)
1.制备式(I)的化合物的方法:
其包括以下步骤(A):
其中任选地在芳族烃溶剂例如甲苯中,优选在所述溶剂的回流温度下使式(V)的化合物:
与式(IX’)的乙烯基砜化合物反应,从而得到所述式(I)的化合物,
其中R代表烷基,例如甲基、乙基或正丙基;或芳基,例如苯基。
2.根据权利要求1的方法,其中所述芳族烃溶剂为甲苯。
3.根据权利要求1或2的方法,其中所述式(V)的化合物:
通过以下步骤(B)制备:
其中任选地在碱金属卤化物例如氯化锂存在下,使式(VI)的化合物:
与还原性甲基化试剂例如甲基金属试剂,例如甲基卤化镁,例如甲基氯化镁反应,从而获得所述式(V)的化合物。
4.根据权利要求1、2或3的方法,其中所述式(VI)的化合物:
通过以下步骤(C)制备:
其中任选地在有机碱,特别是弱有机碱例如叔胺,例如N,N-二异丙基乙胺存在下,
任选地在偶联剂例如2,4,6-三丙基-1,3,5,2,4,6-三氧杂三磷杂环己烷2,4,6-三氧化物(T3P)存在下,
使式(VIII)的化合物:
与式(VII)的化合物反应:
从而获得所述式(VI)的化合物。
5.根据权利要求1至4中任一项的方法,其中所述式(I)的化合物通过反应方案IA中所示的以下步骤制备,如下:
方案IA,
其中R和芳族烃溶剂如权利要求1至4中任一项所定义。
6.根据权利要求1至5中任一项的方法,其中所述式(I)的化合物通过反应方案I中所示的以下步骤制备,如下:
方案I。
7.根据权利要求1至6中任一项的方法,其中所述式(I)的化合物通过结晶纯化,特别是从溶剂如乙醇或异丙醇中纯化。
8.根据权利要求7的方法,其中所述溶剂是乙醇。
9.根据权利要求7的方法,其中所述溶剂是异丙醇。
10.选自以下的化合物:
用于制备权利要求1至10中任一项的式(I)的化合物的用途:
11.式(IX’)的乙烯基砜化合物:
其中R代表烷基,例如甲基、乙基或正丙基;或芳基,例如苯基;
用于制备权利要求1至10中任一项的式(I)的化合物的用途:
12.根据权利要求11的用途,其中所述式(IX’)的乙烯基化合物是甲基乙烯基砜。
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