CN114555603A - 制备作为食欲素受体调节剂的(2h-1,2,3-三唑-2-基)苯基化合物的改进的合成方法 - Google Patents
制备作为食欲素受体调节剂的(2h-1,2,3-三唑-2-基)苯基化合物的改进的合成方法 Download PDFInfo
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- CN114555603A CN114555603A CN202080070355.1A CN202080070355A CN114555603A CN 114555603 A CN114555603 A CN 114555603A CN 202080070355 A CN202080070355 A CN 202080070355A CN 114555603 A CN114555603 A CN 114555603A
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- nmr
- fluoro
- dmso
- triazol
- fluorophenyl
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- -1 (2H-1,2, 3-triazol-2-yl) phenyl compounds Chemical class 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 108050000742 Orexin Receptor Proteins 0.000 title abstract description 5
- 102000008834 Orexin receptor Human genes 0.000 title abstract description 5
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- 150000001875 compounds Chemical class 0.000 claims abstract description 41
- 238000000034 method Methods 0.000 claims abstract description 39
- 230000008569 process Effects 0.000 claims abstract description 13
- YESCPKTWTUCNTK-UHFFFAOYSA-N 2-fluoro-6-(triazol-2-yl)benzaldehyde Chemical compound FC1=C(C(=CC=C1)N1N=CC=N1)C=O YESCPKTWTUCNTK-UHFFFAOYSA-N 0.000 claims abstract description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 35
- 238000006243 chemical reaction Methods 0.000 claims description 29
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 claims description 20
- NTPOZDBAGMLNQA-UHFFFAOYSA-N 2-fluoro-6-(triazol-2-yl)benzoic acid Chemical compound OC(=O)C1=C(F)C=CC=C1N1N=CC=N1 NTPOZDBAGMLNQA-UHFFFAOYSA-N 0.000 claims description 18
- RPTIYJUGBYNDAB-UHFFFAOYSA-N 2-(3-fluorophenyl)triazole Chemical compound Fc1cccc(c1)-n1nccn1 RPTIYJUGBYNDAB-UHFFFAOYSA-N 0.000 claims description 17
- SQOCEMCKYDVLMM-UHFFFAOYSA-N [2-(4,6-dimethylpyrimidin-2-yl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]-[2-fluoro-6-(triazol-2-yl)phenyl]methanone Chemical compound CC1=CC(C)=NC(N2CC3CN(CC3C2)C(=O)C=2C(=CC=CC=2F)N2N=CC=N2)=N1 SQOCEMCKYDVLMM-UHFFFAOYSA-N 0.000 claims description 15
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 13
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Abstract
本发明描述了用于制备(((3aR,6aS)‑5‑(4,6‑二甲基嘧啶‑2‑基)六氢吡咯并[3,4‑c]吡咯‑2(1H)‑基)(2‑氟‑6‑(2H‑1,2,3‑三唑‑2‑基)苯基)甲酮
Description
相关申请的交叉引用
本申请要求于2019年8月7日提交的美国临时专利申请62/883,857和2020年2月7日提交的美国临时专利申请62/971,265的权益,这些专利申请全部以引用方式并入本文。
技术领域
本发明涉及制备(((3aR,6aS)-5-(4,6-二甲基嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(2-氟-6-(2H-1,2,3-三唑-2-基)苯基)甲酮(赛托雷生(Seltorexant))的合成方法,该化合物可用于调节食欲素受体并用于治疗由食欲素受体活性介导的疾病状态、障碍和病症。
背景技术
食欲素(或下视丘分泌素)信号传导由两种受体和两种肽激动剂介导。下文称为食欲素的两种食欲素肽(食欲素A和食欲素B)与称为食欲素-1和食欲素-2受体的两种高亲和力受体结合。食欲素-1受体选择性地更倾向于结合食欲素A,而食欲素-2受体以类似的亲和力结合两种食欲素。食欲素是相同基因—前增食欲素原的裂解产物。在表达前增食欲素原的中枢神经系统神经元中,产生食欲素的前体存在于穹隆周围核、背侧下丘脑和外侧下丘脑(C.Peyron等人,《神经科学杂志》(J.Neurosci.),1998年,第18卷第23期,第9996-10015页)中。这些核中的促食欲素细胞突出到脑的许多区域,在喙部延伸到嗅球并在尾部延伸到脊髓(van den Pol,A.N.等人,《神经科学杂志》(J.Neurosci.),1999年,第19卷第8期,第3171-3182页)。
对本文参考文献的引用不应理解为承认此类参考文献是本发明的现有技术。本文提及的所有出版物全文以引用方式并入。
取代的二氮杂双环化合物已被报道为用于治疗认知损害(WO2008067121,2008年6月5日)和用于改善认知(WO 2006124897,2006年11月23日和US20060258672,2006年11月16日)的中枢神经系统活性剂(国际公布WO2001081347,2001年11月1日;US2002/0019388,2002年2月14日)、α7乙酰胆碱受体调节剂(US2005/101602,2005年5月12日;US2005/0065178,2005年3月24日和Frost等人,《药物化学杂志》(Journal of MedicinalChemistry),2006年,第49卷第26期,第7843-7853页)、脯氨酸转运蛋白抑制剂,被报道为用于治疗包括癌症在内的雄性激素受体相关病症(WO2009081197,2009年7月2日)的雄性激素受体配体,以及被报道为用于治疗癌症、神经退行性疾病和自身免疫性疾病的组蛋白脱乙酰酶抑制剂(WO20060123121,2006年11月23日)。
在所开发的化合物中,发现(((3aR,6aS)-5-(4,6-二甲基嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(2-氟-6-(2H-1,2,3-三唑-2-基)苯基)甲酮充当食欲素-2受体的抑制剂并且可用于治疗睡眠障碍和重度抑郁疾病(US 8,653,263B2)。如以下方案1中所示,由两种关键构成原料(building block)组建化合物:
方案1
初始合成采用直接苯基-三唑偶联。如以下方案2中所示,由与三唑上不同氮原子的非选择性偶联产生产物的混合物。
方案2
2-芳基三唑的独有合成可以通过Cu(II)介导的双腙环化来完成,如方案3所示。然而,该方法的原子经济性较差,因为苯肼与乙二醛的双加成导致50%的芳基构成原料转化为苯胺副产物(参见例如《有机化学杂志》(J.Org.Chem.)1948,13,815;有关二腙方法的最新改进,参见《俄罗斯有机化学杂志》(Russian Journal of Organic Chemistry)2009,45,1683;和《杂环化合物化学》(Chemistry of Heterocyclic Compounds)2010,46,79)。
方案3
已经报道了制备2取代的三唑的其他尝试(Tomé,A.C《合成科学》(Science ofSynthesis)2004,第13.13.2节,第528-540页;Topics Heterocycl.Chem.2015,40,51;Org.Let.2009,11,5026;OPRD 2019,23,234;Angew.Chem.Int.Ed.2011,50,8944;和Heterocycles 1980,14,1279。)但在所有情况下,当三唑环的4位和5位未被取代时,通过中间体环化成2-芳基三唑衍生物的方法具有低收率。
本发明的目的是提供一种用于制备(((3aR,6aS)-5-(4,6-二甲基嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(2-氟-6-(2H-1,2,3-三唑-2-基)苯基)甲酮的方法,该方法利用排他性N2-芳基三唑生产以便减少浪费,以消除分离不期望的偶联产物的需要,并且降低制造成本。
发明内容
本发明包括一种制备(((3aR,6aS)-5-(4,6-二甲基嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(2-氟-6-(2H-1,2,3-三唑-2-基)苯基)甲酮的方法。
所述方法包括下述步骤:
式I的腙的环化,以在单个步骤中得到式II的2-苯基-2H-1,2,3-三唑
其中
R1为-H、-CO2H或-CO2C(1-4)烷基;
X为-OH、-OC(1-4)烷基、-OCH2Ph、-OPh、-OC(O)CH3、-OSO2CH3、-N(CH3)2、哌啶-1-基、-NHC(O)CH3、-NHSO2PhCH3或-N(CH3)3I。
具体实施方式
本发明包括一种制备(((3aR,6aS)-5-(4,6-二甲基嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(2-氟-6-(2H-1,2,3-三唑-2-基)苯基)甲酮的方法。
所述方法包括下述步骤:
式I的肼的环化,以在单个步骤中得到式II的2-苯基-2H-1,2,3-三唑
其中
R1为-H、-CO2H或-CO2C(1-4)烷基;
X为-OH、-OC(1-4)烷基、-OCH2Ph、-OPh、-OC(O)CH3、-OSO2CH3、-N(CH3)2、哌啶-1-基、-NHC(O)CH3、-NHSO2PhCH3或-N(CH3)3I。
在本发明的另一个实施方案中:
本发明包括一种制备(((3aR,6aS)-5-(4,6-二甲基嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(2-氟-6-(2H-1,2,3-三唑-2-基)苯基)甲酮的方法。
所述方法包括下述步骤:
式I的肼的环化,以在单个步骤中得到式II的2-苯基-2H-1,2,3-三唑
其中
R1为-H或-CO2CH3;
X为-OC(1-2)烷基、-OC(CH3)3、-OCH2Ph、-N(CH3)2或-N(CH3)3I。
在本发明的另一个实施方案中:
本发明包括一种制备(((3aR,6aS)-5-(4,6-二甲基嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(2-氟-6-(2H-1,2,3-三唑-2-基)苯基)甲酮的方法。
所述方法包括下述步骤:
a)式I的肼的环化,以在单个步骤中得到式II的2-苯基-2H-1,2,3-三唑
其中
R1为-H;
X为-OC(1-2)烷基、-OC(CH3)3、-OCH2Ph、-N(CH3)2或-N(CH3)3I。
b)2-(3-氟苯基)-2H-1,2,3-三唑的羧化,以得到2-氟-6-(2H-1,2,3-三唑-2-基)苯甲酸,
其中所述羧化的特征在于使用异丙基-MgCl和CO2。
在本发明的另一个实施方案中:
本发明包括一种制备(((3aR,6aS)-5-(4,6-二甲基嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(2-氟-6-(2H-1,2,3-三唑-2-基)苯基)甲酮的方法。
所述方法包括下述步骤:
a)式I的肼的环化,以在单个步骤中得到式II的2-苯基-2H-1,2,3-三唑
其中
R1为-H;
X为-OC(1-2)烷基、-OC(CH3)3、-OCH2Ph、-N(CH3)2或-N(CH3)3I;
b)2-(3-氟苯基)-2H-1,2,3-三唑的羧化,以得到2-氟-6-(2H-1,2,3-三唑-2-基)苯甲酸,
其中所述羧化的特征在于使用异丙基-MgCl和CO2;
c)2-氟-6-(2H-1,2,3-三唑-2-基)苯甲酸与(3aR,6aS)-2-(4,6-二甲基嘧啶-2-基)八氢吡咯并[3,4-c]吡咯反应以形成(((3aR,6aS)-5-(4,6-二甲基嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(2-氟-6-(2H-1,2,3-三唑-2-基)苯基)甲酮
其中所述反应的特征在于使用SOCl2。
在本发明的另一个实施方案中:
本发明包括一种制备(((3aR,6aS)-5-(4,6-二甲基嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(2-氟-6-(2H-1,2,3-三唑-2-基)苯基)甲酮的方法。
所述方法包括下述步骤:
a)式I的肼的环化,以在单个步骤中得到式II的2-苯基-2H-1,2,3-三唑
其中
R1为-H;
X为-OC(1-2)烷基、-OC(CH3)3、-OCH2Ph、-N(CH3)2或-N(CH3)3I;
b)2-(3-氟苯基)-2H-1,2,3-三唑的羧化,以得到2-氟-6-(2H-1,2,3-三唑-2-基)苯甲酸,
其中所述羧化的特征在于使用LiCl、异丙基-MgCl和CO2;
c)2-氟-6-(2H-1,2,3-三唑-2-基)苯甲酸与(3aR,6aS)-2-(4,6-二甲基嘧啶-2-基)八氢吡咯并[3,4-c]吡咯反应以形成(((3aR,6aS)-5-(4,6-二甲基嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(2-氟-6-(2H-1,2,3-三唑-2-基)苯基)甲酮
其中所述反应的特征在于使用SOCl2。
本发明还包括一种制备式I的化合物的方法
所述方法包括:
(3-氟苯基)肼盐酸盐与乙二醛在水和/或甲醇的存在下反应,以形成(E)-2-(2-(3-氟苯基)亚肼基)乙醛,收率超过90%;
其中
R1为H、CO2H或-CO2C(1-4)烷基;
并且
X为-OH、-OC(1-4)烷基、-OCH2Ph、-OPh、-OAc、-N(CH3)2、哌啶基、-NHC(O)CH3、-NHSO2PhCH3或-N(CH3)3I。
本发明的另一个实施方案为式I的化合物:
其中
R1为H、CO2H或-CO2C(1-4)烷基。
本发明的另一个实施方案是选自由以下组成的组的化合物:
本发明的另一个实施方案是选自由以下组成的组的化合物:
本发明的另一个实施方案是选自由以下组成的组的化合物:
通过参考以下描述,包括以下术语表和结论性实施例,可更完全地理解本发明。为简明起见,将本说明书所引用的出版物(包括专利)的公开内容以引用的方式并入本文中。
如本文所用,术语“包括”、“含有”和“包含”在本文中是以其开放的、非限制性的意思使用。
定义
术语“(((3aR,6aS)-5-(4,6-二甲基嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(2-氟-6-(2H-1,2,3-三唑-2-基)苯基)甲酮”意指
本说明书中所述的化学反应的产物可直接与另外的试剂反应,或者可在后续反应之前分离。术语“分离的”意指反应产物与反应容器中的其他材料部分或完全分离。这些其他材料包括但不限于溶剂、未反应的原料、反应中使用的试剂、副产物、杂质和反应中使用的试剂产品。
术语“制备”意指通过化学方法合成。
另外,本文给出的任何式旨在还指这类化合物的水合物、溶剂化物和多晶型物、以及它们的混合物,即使这些形式没有明确列出。
本文给定的任何式还旨在表示化合物的未标记形式以及同位素标记形式。同位素标记的化合物具有本文给出式所描绘的结构,不同的是一个或多个原子被具有选定的原子量或质量数的原子所代替。可掺入本发明的化合物中的同位素的示例包括氢、碳、氮、氧、磷、氟和氯的同位素,诸如分别为2H、3H、11C、13C、14C、15N、18O、17O。此类同位素标记的化合物可用于代谢研究(优选用14C)、反应动力学研究(例如用2H或3H)、检测或成像技术[如正电子发射断层扫描术(PET)或单光子发射电子计算机断层扫描术(SPECT)],包括药物或底物的组织分布测定法,或者可用于患者的放射治疗。此外,用较重的同位素如氘(即2H)进行置换可以提供由更大的代谢稳定性所带来的某些治疗优势,例如体内半衰期延长或需要的剂量减少。同位素标记的本发明的化合物及其前药,通常可以通过用容易获得的同位素标记的试剂替代非同位素标记的试剂以执行下文描述的方案中或实施例和制备中所公开的程序来制备。
本领域技术人员将认识到,本发明的化合物可以作为立体异构体存在,该化合物中存在至少一个双键。本发明考虑了(E)和(Z)立体异构体及其所有混合物。
本领域的技术人员将认识到,用于本发明的反应中的化合物和试剂可作为盐存在。本发明设想使用本文所例示的反应中使用的任何化合物的所有盐。
盐的示例包括但不限于硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、氯化物、溴化物、碘化物、乙酸盐、丙酸盐、癸酸盐、辛酸盐、丙烯酸盐、甲酸盐、异丁酸盐、己酸盐、庚酸盐、丙炔酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、癸二酸盐、富马酸盐、马来酸盐、丁炔-1,4-二酸盐、己炔-1,6-二酸盐、苯甲酸盐、氯代苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、邻苯二甲酸盐、磺酸盐、二甲苯磺酸盐、苯乙酸盐、苯丙酸盐、苯丁酸盐、柠檬酸盐、乳酸盐、γ-羟丁酸盐、乙醇酸盐、酒石酸盐、甲磺酸盐、丙磺酸盐、萘-1-磺酸盐、萘-2-磺酸盐和扁桃酸盐。
当用于本发明的反应中的化合物或试剂含有碱性氮时,盐可通过本领域可用的任何合适的方法制备,例如,用下述酸处理游离碱:无机酸,诸如盐酸、氢溴酸、硫酸、氨基磺酸、硝酸、硼酸、磷酸等;或者有机酸,诸如乙酸、苯乙酸、丙酸、硬脂酸、乳酸、抗坏血酸、马来酸、羟基马来酸、羟乙磺酸、琥珀酸、戊酸、延胡索酸、丙二酸、丙酮酸、草酸、乙醇酸、水杨酸、油酸、棕榈酸、月桂酸、吡喃糖苷酸(诸如葡萄糖醛酸或半乳糖醛酸)、α-羟基酸(诸如扁桃酸、柠檬酸或酒石酸)、氨基酸(诸如天冬氨酸、戊二酸或谷氨酸)、芳族酸(诸如苯甲酸、2-乙酰氧基苯甲酸、萘甲酸或肉桂酸)、磺酸(诸如月桂基磺酸、对甲苯磺酸、甲磺酸、乙磺酸)、诸如本文作为示例给出的那些酸的任何相容混合物,以及根据本技术领域的普通技能水平视为等同物或可接受替代物的任何其他酸及其混合物。
本领域的技术人员将认识到,许多试剂可用于酯的皂化并且那些试剂既是多种多样的,又是熟练的从业者已知的。本发明设想使用所有常见的酯转化成羧酸的方法,包括由T.W.Green和P.G.M.Wuts编写的“Protective Groups in Organic Synthesis”,Wiley-Interscience,New York,1999年,第579-580、744-747页中所述的那些。
现在将参考示例性合成方案来描述可用于本发明的方法中的示例性反应,以用于下文的它们的一般性制备和后面的具体实施例。本领域的技术人员将认识到,反应可在任何合适的溶剂中进行。本领域的技术人员还将认识到,除非明确限制,否则反应可在宽泛的温度范围内进行。除非另外指明,否则反应可在溶剂的熔点和回流温度之间进行,并且优选在介于0℃和溶剂的回流温度之间进行。可采用常规加热或微波加热来加热反应。反应还可在密闭压力容器中在高于溶剂的正常回流温度下进行。
缩写
在本文以及整个说明书中,可使用以下缩写:
缩写 | 术语 |
Ac | 乙酰基 |
ACN | 乙腈 |
Bn | 苄基 |
DCM | 二氯甲烷 |
DMSO | 二甲亚砜 |
EG | 乙二醇 |
EtOAc或EA | 乙酸乙酯 |
Et | 乙基 |
HPLC | 高效液相色谱法 |
iPr或<sup>i</sup>Pr | 异丙基 |
LC | 液相色谱法 |
Me | 甲基 |
nBu或<sup>n</sup>Bu | 正丁基 |
OAc | 乙酸盐 |
OTf | 三氟甲烷磺酸盐(=三氟甲烷磺酰基) |
Ph | 苯基 |
tBu或<sup>t</sup>Bu | 叔丁基 |
THF | 四氢呋喃 |
Ts | 甲苯磺酰基(=对甲苯磺酰基) |
实施例
在获得下文实施例中描述的化合物和相应的分析数据时,除非另外指明,否则遵循以下实验和分析方案。
除非另外指明,否则在室温(rt)和氮气气氛下搅拌反应混合物。在将混合物、溶液和提取物“浓缩”的情况下,它们通常进行减压浓缩。微波照射条件下的反应是在BiotageInitiator或CEM Discover仪器中进行的。
正相快速柱层析(FCC)使用预封装的萃取小柱在硅胶(SiO2)上进行,用指定的溶剂洗脱。
除非另外指明,否则质谱(MS)使用电喷雾电离(ESI)以正模式在Bruker QTOF、Waters QTOF Ultima仪器上获得,或使用电子冲击(EI)在Waters GC-TOF上获得。计算的质量(calcd.)对应于精确质量。
核磁共振(NMR)谱是在Bruker光谱仪上获得的。以下1H NMR数据的格式是:在四甲基硅烷参照物的低场的化学位移(单位为ppm)(多重度,耦合常数J(单位为Hz),积分)。
化学名称使用ChemDraw Ultra 6.0.2(CambridgeSoft Corp.,Cambridge,MA)或ACD/Name第9版(Advanced Chemistry Development,Toronto,Ontario,Canada)产生。
常规方案
苯肼III或相应的盐在乙酸钠的存在下可以与乙二醛和水或水-甲醇反应以形成亚肼基乙醛IV。本发明使用苯肼微溶于其中的水-乙二醛混合物,以用相对少量过量的乙二醛完成所需的单缩合。所需的单缩合产物可以通过适当的溶剂(诸如水或者甲醇和水的混合物)以高收率获得,这使溶液中的肼起始材料的浓度最小化,并且还允许单缩合产物的产物在形成时从溶液中沉淀析出。
与H2N-X缩合得到腙I。产物被形成为E/Z立体异构体的混合物,这些立体异构体在加热时相互转化;无需将立体异构体彼此分开。腙混合物的环化在I的单个步骤中得到2-苯基-2H-1,2,3-三唑II。
2-苯基-2H-1,2,3-三唑II的合成是当R1为-CO2C(1-4)烷基时通过皂化,或者当R1为H时通过羧化来完成的,得到2-氟-6-(2H-1,2,3-三唑-2-基)苯甲酸。将LiCl加入到反应混合物中减少了不期望的-CO2的双加成。
产物2-氟-6-(2H-1,2,3-三唑-2-基)苯甲酸使用亚硫酰氯或任何合适的活化剂活化,并使其与(3aR,6aS)-2-(4,6-二甲基嘧啶-2-基)八氢吡咯并[3,4-c]吡咯反应,以形成((3aR,6aS)-5-(4,6-二甲基嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(2-氟-6-(2H-1,2,3-三唑-2-基)苯基)甲酮。
实施例1:式IV的酰肼乙醛的合成
实施例1a:(E)-2-(2-(3-氟苯基)亚肼基)乙醛的合成。
将40w/w%的乙二醛的水溶液(613g,4.22mol)加入到177g(1.06mol)(3-氟苯基)肼(盐酸盐)于1.24L水中的悬浮液中,然后在2小时内加入129.9g(1.58mol)乙酸钠于708mL水中的溶液。在室温下搅拌几小时后,过滤悬浮液,并用0.89L水洗涤滤饼,并真空干燥,以提供172.8g(95%收率)黄色固体状标题化合物。
mp 118℃-119℃。
1H NMR(DMSO-d6)δ:11.80(br s,1H),9.49(d,J=7.7Hz,1H),7.36(d,J=7.9Hz,1H),7.32-7.39(m,1H),6.96-7.03(m,2H),6.75-6.83(m,1H)。13C NMR(DMSO-d6)δ:190.4,163.0(br d,J=242.7Hz),144.7(br d,J=10.8Hz),136.3,131.2(d,J=10.0Hz),110.0(d,J=2.3Hz),108.5(d,J=21.6Hz),100.6(d,J=27.0Hz)。19F NMR(DMSO-d6)δ:-111.72。
HRMS(EI-TOF)m/z:C8H8FN2O的[M+H]+计算值为167.0621;实测值为167.0611。
实施例1b:(E)-2-氟-6-(2-(2-氧代亚乙基)肼基)苯甲酸甲酯的合成
在10℃下在10分钟内,将2-氟-6-肼基苯甲酸甲酯(17.65g,0.08mol)于甲醇-水(90ml+180ml)中的溶液加入到40w%乙二醛水溶液(58.04g,0.8mol)、水(100ml)和乙酸钠(9.85g,0.12mol)的混合物中。然后将混合物搅拌约1.5小时,然后过滤。将滤饼用水(2×50mL)洗涤并真空干燥。将干燥的固体(16.12g)在50℃下重新溶解于乙酸乙酯(50ml)中,然后通过缓慢加入庚烷(200ml)并且冷却至5℃来进行结晶。将所得固体过滤,用庚烷(2×15ml)冲洗并真空干燥。获得黄色固体状期望的产物(13.33g,74%收率)。mp 110.8℃。
1H NMR(DMSO-d6)δ:11.74(s,1H),9.41(d,1H),7.49(m,2H),7.19(d,1H),6.92(m,1H),3.84(s,3H)。
MS(ESI-TOF)m/z:225.1([M+H]+)。
实施例1c:(E)-2-氟-6-(2-(2-氧代亚乙基)肼基)苯甲酸的合成
使2-氟-6-肼基苯甲酸与过量的乙二醛水溶液反应,以提供黄色固体状所需化合物2-氟-6-(2-(2-氧代亚乙基)肼基)苯甲酸,收率为64%。该化合物原样用于下一步骤中。
实施例2:式I的肼的合成
实施例2a:(1E,2E)-2-(2-(3-氟苯基)亚肼基)乙醛O-甲基肟的合成。
在1.5小时内将59.7g(715mmol)的甲氧胺盐酸盐和58.6g(715mmol)乙酸钠于210mL水中的溶液加入到70g(408mmol)的(E)-2-(2-(3-氟苯基)亚肼基)乙醛于350mL甲醇中的溶液中,然后加入210mL水。在室温下搅拌2小时后,将悬浮液冷却至0℃并在此温度下搅拌过夜,然后过滤。用70L水洗涤滤饼,并真空干燥,以提供77.4g(92%收率)黄色固体状标题化合物。NMR分析显示存在2种异构体(约1/1比率)。
异构体的分离。
10g实施例2a的反应产物的异构体通过超临界流体色谱法(SFC-洗脱液:超临界CO2中的等度7%乙腈),以得到6g(63%收率)的异构体1(E,E)和2.7g(28%收率)的异构体2(E,Z)。
异构体1(E,E):
mp:90℃。
1H NMR(DMSO-d6)δ:10.89(s,1H),7.83(d,J=8.8Hz,1H),7.54(dd,J=8.8,0.7Hz,1H),7.20-7.28(m,1H),6.74-6.83(m,2H),6.54-6.62(m,1H),3.84(s,3H)。13C NMR(DMSO-d6)δ:163.2(br d,J=241.2Hz),148.3,146.1((br d,J=10.8Hz),132.8,130.8(d,J=10.0Hz),108.4(d,J=2.3Hz),105.9(d,J=21.6Hz),98.9(d,J=27.0Hz),61.7。19F NMR(DMSO-d6)δ:-112.30。
HRMS(EI-TOF)m/z:C9H11FN3O的[M+H]+计算值为196.0881;实测值为196.0876。
异构体2(E,Z):
mp 114℃。
1H NMR(DMSO-d6)δ:11.04(s,1H),7.96(dd,J=8.6,0.9Hz,1H),7.25(d,J=8.4Hz,1H),7.21-7.29(m,1H),6.78-6.86(m,2H),6.59-6.66(m,1H),3.85(s,3H)。13C NMR(DMSO-d6)δ=163.2(br d,J=242.0Hz),145.8(br d,J=10.8Hz),145.4,130.8(d,J=10.0Hz),127.9,108.8(d,J=2.3Hz),106.6(d,J=21.6Hz),99.3(d,J=26.2Hz),61.7。19F NMR(DMSO-d6)δ:-112.18。
HRMS(EI-TOF)m/z:C9H11FN3O的[M+H]+计算值为196.0881;实测值为196.0876。
实施例2b:由化合物(3-氟苯基)肼(盐酸盐)、乙二醛和甲氧胺盐酸在不干燥(E)-2-(2-(3-氟苯基)亚肼基)乙醛的情况下替代性合成(1E,2E)-2-(2-(3-氟苯基)亚肼基)乙醛O-甲基肟。
向第一反应器中装入4.5kg(3-氟苯基)肼(盐酸盐)和36L水。将悬浮液在65℃下搅拌1小时。向第二反应器中装入6.15kg乙二醛和4.6L水,并且冷却至10℃。在2小时内将(3-氟苯基)肼(盐酸盐)的水溶液从第一反应器转移到第二反应器。将反应混合物进一步搅拌3小时,然后过滤并用水洗涤固体(E)-2-(2-(3-氟苯基)亚肼基)乙醛。将湿滤饼与18kg甲醇一起再装入反应器中。然后在有效搅拌下加入3.77kg盐酸羟胺、3.7kg乙酸钠和9kg水。将悬浮液搅拌30分钟-60分钟,加入18kg水,并将最终混合物冷却至5℃并搅拌1小时-2小时。将产物(1E,2E)-2-(2-(3-氟苯基)亚肼基)乙醛O-甲基肟和(1E,2Z)-2-(2-(3-氟苯基)亚肼基)乙醛O-甲基肟的混合物过滤,用水洗涤并真空干燥,以提供5.01kg黄色固体(收率:93%),纯度>99%。
实施例2c:由(E)-2-(2-(3-氟苯基)亚肼基)乙醛和X-NH2合成式I的化合物。
除非提及,否则式I的化合物(其中R1为H)由(E)-2-(2-(3-氟苯基)亚肼基)乙醛和X-NH2按照实施例2a的程序或非常相似的程序制备,并且使用粗产物或者通过结晶或通过色谱法纯化。结果报告于表1中。
表1
黄色固体。mp 135℃。
异构体1(主要):1H NMR(400MHz,DMSO-d6)δ=11.33(s,1H),10.70(s,1H),7.77(d,J=8.6Hz,1H),7.59(dd,J=0.4,8.8Hz,1H),7.27-7.17(m,1H),6.80-6.76(m,1H),6.75(d,J=1.5Hz,1H),6.59-6.51(m,1H)。13C NMR(101MHz,DMSO-d6)δ=163.24(br d,J=241.2Hz),147.88,146.46(br d,J=10.8Hz),134.44,130.74(d,J=10.0Hz),108.29(d,J=2.3Hz),105.56(d,J=21.6Hz),98.71(d,J=26.2Hz)。19F NMR(377MHz,DMSO-d6)δ=-112.36。
HRMS(EI-TOF)m/z:C8H9FN3O的[M+H]+计算值为182.0730;实测值为182.0726。
异构体2(次要):1H NMR(400MHz,DMSO-d6)δ=11.28(s,1H),10.90(s,1H),8.06(dd,J=0.7,8.4Hz,1H),7.27-7.17(m,2H),6.83-6.80(m,1H),6.80-6.76(m,1H),6.63-6.59(m,1H)。13C NMR(101MHz,DMSO-d6)δ=163.21(br d,J=241.2Hz),146.16(br d,J=10.8Hz),144.96,130.82(d,J=10.0Hz),128.71,108.65(d,J=2.3Hz),106.14(d,J=21.6Hz),99.09(d,J=26.2Hz)。19F NMR(377MHz,DMSO-d6)δ=-112.26。
HRMS(EI-TOF)m/z:C8H9FN3O的[M+H]+计算值为182.0730;实测值为182.0727。
黄色固体。mp:82.7℃和101.7℃(异构体的混合物)。
异构体1(主要):1H NMR(400MHz,DMSO-d6)δ=10.88(s,1H),7.82(d,J=8.6Hz,1H),7.56(d,J=8.8Hz,1H),7.29-7.18(m,1H),6.85-6.73(m,2H),6.61-6.52(m,1H),4.10(q,J=7.0Hz,2H),1.22(t,J=7.0Hz,3H)。13C NMR(101MHz,DMSO-d6)δ=163.21(br d,J=241.2Hz),148.02,146.20(br d,J=10.8Hz),133.08,130.73(d,J=10.0Hz),108.40(d,J=2.3Hz),105.84(d,J=20.8Hz),98.86(d,J=26.2Hz),69.24,14.31。19F NMR(377MHz,DMSO-d6)δ=-112.34。
HRMS(EI-TOF)m/z:C10H13FN3O的[M+H]+计算值为210.1043;实测值为210.1035。
异构体2(次要):1H NMR(400MHz,DMSO-d6)δ=11.05(s,1H),8.00(d,J=8.6Hz,1H),7.29-7.18(m,2H),6.85-6.73(m,2H),6.66-6.58(m,1H),4.11(q,J=7.0Hz,2H),1.22(br t,J=7.0Hz,3H)。13C NMR(101MHz,DMSO-d6)δ=163.16(br d,J=241.2Hz),145.86(brd,J=11.6Hz),145.17,130.80(br d,J=10.0Hz),128.15,108.78(d,J=2.3Hz),106.46(d,J=21.6Hz),99.25(d,J=27.0Hz),69.20,14.38。19F NMR(377MHz,DMSO-d6)δ=-112.22。
HRMS(EI-TOF)m/z:C10H13FN3O的[M+H]+计算值为210.1043;实测值为210.1035。
(1E,2E)-2-(2-(3-氟苯基)亚肼基)乙醛O-(叔丁基)肟
黄色固体。mp:93.8℃(异构体的混合物)。
异构体1:1H NMR(400MHz,DMSO-d6)δ=10.80(s,1H),7.80(d,J=8.6Hz,1H),7.60(d,J=9.0Hz,1H),7.29-7.18(m,1H),6.84-6.75(m,2H),6.60–6.53(m,1H),1.28(s,9H)。13CNMR(101MHz,DMSO-d6)δ=163.23(br d,J=241.2Hz),147.19,146.33(br d,J=10.8Hz),133.76,130.63(d,J=10.0Hz),108.35(d,J=2.3Hz),105.66(d,J=21.6Hz),98.84(d,J=26.2Hz),78.78,27.18。19F NMR(377MHz,DMSO-d6)δ=-112.36。
HRMS(EI-TOF)m/z:C12H17FN3O的[M+H]+计算值为238.1356;实测值为238.1351。
异构体2:1H NMR(400MHz,DMSO-d6)δ=11.02(s,1H),8.03(d,J=9.0Hz,1H),7.29-7.18(m,2H),6.84-6.75(m,2H),6.60–6.53(m,1H),1.29(s,9H)。13C NMR(101MHz,DMSO-d6)δ=163.18(br d,J=242.0Hz),146.01(br d,J=10.8Hz),144.37,130.69(br d,J=10.0Hz),128.56,108.70(d,J=2.3Hz),99.17(d,J=26.2Hz),78.40,27.18。19F NMR(377MHz,DMSO-d6)δ=-112.29。
HRMS(EI-TOF)m/z:C12H17FN3O的[M+H]+计算值为238.1356;实测值为238.1351。
异构体3:1H NMR(400MHz,DMSO-d6)δ=10.93(s,1H)7.80(m,1H),6.89(m,1H),7.29-7.18(m,1H),6.84-6.75(m,2H),6.60–6.53(m,1H),1.34(s,9H)。13C NMR(101MHz,DMSO-d6)δ=163.30(br d,J=241.2Hz),146.66(d,J=11.6Hz),141.90,137.58,130.69(br d,J=10.0Hz,1C),130.63(d,J=10.0Hz,1C),130.56(d,J=10.0Hz,1C),128.56,127.44,108.13(d,J=2.3Hz),105.04(d,J=21.6Hz),98.49(d,J=26.2Hz),79.63,27.11。19F NMR(377MHz,DMSO-d6)δ=-112.16。
HRMS(EI-TOF)m/z:C12H17FN3O的[M+H]+计算值为238.1356;实测值为238.1351。
异构体4:1H NMR(400MHz,DMSO-d6)δ=11.35(s,1H),8.28(d,J=6.8Hz,1H),7.29-7.18(m,1H),6.84-6.75(m,3H),6.60–6.53(m,1H),1.27(s,9H)。13C NMR(101MHz,DMSO-d6–检测到的信号)δ=163.30(br d,J=241.2Hz,1C),163.23(br d,J=241.2Hz,1C),163.18(br d,J=242.0Hz,1C),144.28,127.44,108.86(d,J=2.3Hz),106.56(d,J=21.6Hz),99.38(br d,J=26.2Hz),27.06。19F NMR(377MHz,DMSO-d6)δ=-112.22。
(1E,2E)-2-(2-(3-氟苯基)亚肼基)乙醛O-苄基肟
黄色固体。mp:105.6℃(异构体的混合物)。
异构体1(主要):1H NMR(400MHz,DMSO-d6)δ=10.91(s,1H),7.94(d,J=8.8Hz,1H),7.56(d,J=9.0Hz,1H),7.42-7.27(m,5H),7.27-7.19(m,1H),6.87-6.76(m,2H),6.62-6.54(m,1H),5.13(s,1H)。13C NMR(101MHz,DMSO-d6)δ=163.20(d,J=241.2Hz),148.86,146.13(br d,J=10.8Hz,1C),137.43,132.71,130.74(d,J=9.2Hz),128.25,128.00,127.74,108.46(d,J=2.3Hz),105.96(d,J=21.6Hz),98.95(d,J=26.2Hz),75.51。19F NMR(377MHz,DMSO-d6)δ=-112.23。
HRMS(EI-TOF)m/z:C15H15FN3O的[M+H]+计算值为272.1199;实测值为272.1198。
异构体2(次要):1H NMR(400MHz,DMSO-d6)δ=11.08(s,1H),8.06(d,J=9.0Hz,1H),7.56(d,J=9.0Hz,1H),7.42-7.27(m,5H),7.27-7.19(m,1H),6.87-6.76(m,2H),6.66-6.62(m,1H),5.14(br s,1H)。13C NMR(101MHz,DMSO-d6)δ=163.16(br d,J=241.2Hz),145.94,137.50,108.83(d,J=2.3Hz),106.58(d,J=21.6Hz),99.31(d,J=26.2Hz)75.56。19FNMR(377MHz,DMSO-d6)δ=-112.12。
HRMS(EI-TOF)m/z:C15H15FN3O的[M+H]+计算值为272.1199;实测值为272.1199。
异构体3:HRMS(EI-TOF)m/z:C15H15FN3O的[M+H]+计算值为272.1199;实测值为272.1200。
(1E,2E)-2-(2-(3-氟苯基)亚肼基)乙醛O-苯基肟
黄色固体。mp:93.4℃(异构体的混合物)。
异构体1(主要):1H NMR(400MHz,DMSO-d6)δ=11.17(s,1H),8.28(d,J=8.6Hz,1H),7.70(d,J=8.8Hz,1H),7.45-7.32(m,2H),7.32-7.23(m,1H),7.18(d,J=7.9Hz,2H),7.09-7.01(m,1H),6.93-6.81(m,2H),6.64(dt,J=2.2,8.6Hz,1H)。13C NMR(101MHz,DMSO-d6)δ=163.17(br d,J=241.2Hz),158.61,151.99,145.82(br d,J=11.6Hz),131.57,130.87(d,J=9.2Hz),129.44,122.43,114.18,108.72(d,J=2.3Hz),106.48(d,J=21.6Hz),99.62(d,J=26.2Hz)。19F NMR(377MHz,DMSO-d6)δ=-112.13。
HRMS(EI-TOF)m/z:C14H13FN3O的[M+H]+计算值为258.1043;实测值为258.1038。
异构体2(次要):1H NMR(400MHz,DMSO-d6)δ=11.38(s,1H),8.19(d,J=8.6Hz,1H),7.69(br d,J=8.4Hz,1H),7.45-7.32(m,2H),7.32-7.23(m,1H),7.18(d,J=7.9Hz,2H),7.09-7.01(m,1H),6.93-6.81(m,2H),6.69(dt,J=2.2,8.6Hz,1H)。13C NMR(101MHz,DMSO-d6)δ=163.13(br d,J=242.0Hz),158.66,148.82,145.47(br d,J=10.8Hz),130.95(d,J=10.0Hz),129.44,127.23,122.33,114.21,109.14(d,J=2.3Hz),107.14(d,J=21.6Hz),99.62(d,J=26.2Hz)。19F NMR(377MHz,DMSO-d6)δ=-112.02。
HRMS(EI-TOF)m/z:C14H13FN3O的[M+H]+计算值为258.1043;实测值为258.1038。
(1E,2E)-2-(2-(3-氟苯基)亚肼基)乙醛O-乙酰基肟
将1.16ml的50w%羟胺水溶液(19mmol)加入到3g(18mmol)的化合物(E)-2-(2-(3-氟苯基)亚肼基)乙醛于15ml甲醇中的溶液中。在室温下搅拌过夜后,分两次加入3.6ml(19mmol)乙酸酐。搅拌过夜后,加入15ml水以完成沉淀。过滤该所需化合物,用几毫升水洗涤,并真空干燥,以提供2.6g(65%收率)黄色固体。
黄色固体。mp:100.8℃(异构体的混合物)。
异构体1:
1H NMR(400MHz,DMSO-d6)δ=11.31(br s,1H),8.20(d,J=8.8Hz,1H),7.63(d,J=8.8Hz,1H),7.36-7.22(m,1H),6.93-6.79(m,2H),6.78-6.60(m,1H),2.15(s,3H)。13C NMR(101MHz,DMSO-d6)δ=167.88,163.15(br d,J=242.0Hz),155.53,145.54(br d,J=10.8Hz),131.12(d,J=10.0Hz),130.58,108.93(d,J=2.3Hz),106.94(d,J=21.6Hz),99.44(d,J=26.2Hz),19.25。19F NMR(377MHz,DMSO-d6)δ=-112.07。
HRMS(EI-TOF)m/z:C10H11FN3O2的[M+H]+计算值为224.0835;实测值为224.0835。
异构体2:
1H NMR(400MHz,DMSO-d6,visible signals)δ=11.46(br s,1H),7.36-7.22(m,1H),6.99(s,1H),6.93-6.79(m,2H),6.78-6.60(m,1H),1.91(s,3H)。13C NMR(101MHz,DMSO-d6)δ=171.93,163.02(br d,J=242.7Hz),151.84,144.63(br d,J=10.8Hz),130.95(d,J=10.0Hz),130.97,109.45(d,J=2.3Hz),108.23(d,J=21.6Hz),100.16(d,J=26.2Hz),21.00。19F NMR(377MHz,DMSO-d6)δ=-111.71。
HRMS(EI-TOF)m/z:C10H11FN3O2的[M+H]+计算值为224.0835;实测值为224.0836。
异构体3:
1H NMR(400MHz,DMSO-d6)δ=11.85(br s,1H),7.97(d,J=8.4Hz,1H),7.74(d,J=8.4Hz,1H),7.36-7.22(m,1H),6.93-6.79(m,2H),6.78-6.60(m,1H),2.17(s,3H)。13C NMR(101MHz,DMSO-d6)δ=167.91,163.11(br d,J=242.0Hz),155.53,145.20(br d,J=10.0Hz),131.66(d,J=9.3Hz),126.80,109.35(d,J=2.3Hz),107.57(d,J=21.6Hz),99.85(d,J=27.0Hz),19.37。19F NMR(377MHz,DMSO-d6)δ=-111.95。
(E)-2-((E)-2-(2-(3-氟苯基)亚肼基)亚乙基)-1,1-二甲基肼
黄色固体。mp:134.4℃(单一异构体)。
1H NMR(400MHz,DMSO-d6)δ=10.27(s,1H),7.58(d,J=7.9Hz,1H),7.23-7.13(m,1H),7.02(d,J=8.1Hz,1H),6.77-6.67(m,2H),6.52-6.42(m,1H),2.89(s,6H)。13C NMR(101MHz,DMSO-d6)δ=163.33(br d,J=240.4Hz),147.21(d,J=10.8Hz),139.63,130.69,130.55(d,J=10.0Hz),107.80(d,J=1.5Hz),104.33(d,J=21.6Hz),98.06(d,J=26.2Hz),42.24。19F NMR(377MHz,DMSO-d6)δ=-112.61。
HRMS(EI-TOF)m/z:C10H14FN4的[M+H]+计算值为209.1202;实测值为209.1200。
(1E,2E)-2-(2-(3-氟苯基)亚肼基)-N-(哌啶-1-基)乙-1-亚胺
黄色固体。mp:155.4℃(单一异构体)。
1H NMR(400MHz,DMSO-d6)δ=10.36(s,1H),7.58(d,J=8.1Hz,1H),7.31(d,J=7.9Hz,1H),7.25-7.08(m,1H),6.83-6.62(m,2H),6.48(dt,J=2.3,8.5Hz,1H),3.06(br t,J=5.4Hz,4H),1.81-1.52(m,4H),1.52-1.23(m,2H)。13C NMR(101MHz,DMSO-d6)δ=163.31(d,J=240.4Hz,1C),147.05(d,J=10.8Hz,1C),139.45,132.82,130.55(br d,J=10.0Hz,1C),107.88(br d,J=2.3Hz,1C),104.54(d,J=21.6Hz,1C),98.17(br d,J=26.2Hz,1C),51.14,24.43,23.48。19F NMR(377MHz,DMSO-d6)δ=-112.59。
HRMS(EI-TOF)m/z:C13H18FN4的[M+H]+计算值为249.1515;实测值为249.1518。
N'-((1E,2E)-2-(2-(3-氟苯基)亚肼基)亚乙基)乙酰肼
黄色固体。mp:265.1℃(异构体的混合物)。
异构体1(旋转体1,主要):
1H NMR(400MHz,DMSO-d6)δ=11.22(s,1H),10.85(s,1H),7.75(d,J=8.4Hz,1H),7.57(d,J=8.6Hz,1H),7.25(q,J=7.8Hz,1H),6.93-6.73(m,2H),6.59(br t,J=7.8Hz,1H),2.13(s,3H)。13C NMR(101MHz,DMSO-d6)δ=190.43,171.62,163.26(d,J=241.2Hz,1C),146.20(br d,J=10.8Hz,1C),142.49,136.15,130.79(d,J=10.0Hz,1C),108.44(d,J=2.3Hz,1C),105.84(br d,J=21.6Hz,1C),98.86(br d,J=26.2Hz,1C),20.07。19F NMR(377MHz,DMSO-d6)δ=-112.21。
异构体1(旋转体2,次要):
1H NMR(400MHz,DMSO-d6)δ=11.37(s,1H),10.92(s,1H),7.87(d,J=8.4Hz,1H),7.62(d,J=8.4Hz,1H),7.25(q,J=7.8Hz,1H),6.93-6.73(m,2H),6.59(br t,J=7.8Hz,1H),1.96(s,3H)。13C NMR(101MHz,DMSO-d6)δ=190.43,165.52,163.26(d,J=241.2Hz,1C),146.17(br d,J=10.8Hz,1C),145.05,136.32,130.79(d,J=10.0Hz,1C),108.48(brd,J=2.3Hz,1C),105.91(br d,J=21.6Hz,1C),98.89(br d,J=26.2Hz,1C),21.56。19FNMR(377MHz,DMSO-d6)δ=-112.21。
HRMS(EI-TOF)m/z:C10H12FN4O的[M+H]+计算值为223.0995;实测值为223.0994。
N'-((1E,2E)-2-(2-(3-氟苯基)亚肼基)亚乙基)-4-甲基苯磺酰肼
黄色固体。mp:146.7℃(单一异构体)。
1H NMR(400MHz,DMSO-d6)δ=11.48(s,1H),10.84(s,1H),7.71(d,J=8.4Hz,2H),7.61(d,J=8.4Hz,1H),7.42(br d,J=8.6Hz,1H),7.41(br d,J=8.1Hz,2H),7.27-7.17(m,1H),6.79-6.70(m,2H),6.63-6.52(m,1H),2.37(s,3H)。13C NMR(101MHz,DMSO-d6)δ=163.18(br d,J=241.2Hz),146.37,145.99(br d,J=10.8Hz),143.46,136.07,135.31,130.83(d,J=10.0Hz),129.68,127.05,108.52(d,J=2.3Hz),106.07(d,J=21.6Hz),98.92(d,J=26.2Hz),20.96。19F NMR(377MHz,DMSO-d6)δ=-112.20。
HRMS(EI-TOF)m/z:C15H16FN4O2S的[M+H]+计算值为335.0978;实测值为335.0982。
在25℃下,向(E)-2-(2-(3-氟苯基)亚肼基)乙醛(1mmol,1.0当量)和NaOAc(1.5mmol,1.5当量)于MeOH(3mL)中的溶液中一次性加入1,1-二甲基肼盐酸盐(1.2mmol,1.2当量)。在起始材料消耗完后(约30分钟),将水(3mL)加入到反应混合物中。然后将悬浮液过滤,并用水洗涤滤饼。将中间体二腙(E)-2-((E)-2-(2-(3-氟苯基)亚肼基)亚乙基)-1,1-二甲基肼在50℃下真空干燥3小时。在25℃下,向如此获得的(E)-2-((E)-2-(2-(3-氟苯基)亚肼基)亚乙基)-1,1-二甲基肼(1.0mmol,1.0当量)(分离的或非分离的中间体)在ACN(2mL)中的溶液中一次性加入MeI(5.0mmol,5.0当量)。在搅拌过夜或直到起始材料消耗完后,将EtOAc(3mL)加入到悬浮液中。将悬浮液过滤,并用EtOAc洗涤滤饼。将肼盐(E)-2-((E)-2-(2-(3-氟苯基)亚肼基)亚乙基)-1,1,1-三甲基肼-1-碘化物在30℃下真空干燥,以提供315mg黄色固体(收率:90%)。
mp:166.8℃。
1H NMR(400MHz,DMSO-d6):δ11.82(s,1H),8.73(d,J=8.0Hz,1H),7.63(d,J=8.1Hz,1H),7.35(dd,J=15.1,8.2Hz,1H),6.99–6.90(m,2H),6.82–6.71(m,1H),3.47(s,9H)。13C NMR(101MHz,DMSO-d6):δ164.73,163.18,162.32,145.32,145.22,131.81,131.72,131.12,110.01,108.77,108.56,100.55,100.29,55.52,55.46。
HRMS(ESI):C11H16FN4 +的计算值[M+]:223.1359,实测值:223.1348。M.P.:166.8℃。
实施例2d:2-氟-6-(2-(2-(甲氧基亚氨基)亚乙基)肼基)苯甲酸甲酯的合成
将甲氧胺盐酸盐(3.61g,43.2mmol)和乙酸钠(3.55g,43.2mmol)于水(80ml)中的溶液加入到(E)-2-氟-6-(2-(2-氧代亚乙基)肼基)苯甲酸甲酯(8.07g,36.0mmol)于甲醇(40ml)中的溶液中。在室温下搅拌过夜后,将标题化合物过滤,用水(2×15ml)冲洗并真空干燥。获得黄色固体状所需产物(7.85g,79%收率)。NMR显示存在几种异构体。mp 90.0℃。
1H NMR(DMSO-d6–主要异构体)δ:10.87(s,1H),7.76(m,2H),7.40(m,1H),7.11(m,1H),6.72(m,1H),3.86(s,3H),3.83(s,3H)。
MS(ESI-TOF)m/z:254.2([M+H]+)。
将1,1-二甲基肼盐酸盐(0.76g,7.9mmol)和乙酸钠(0.74g,9.0mmol)于甲醇(10ml)中的悬浮液缓慢加入到(E)-2-氟-6-(2-(2-氧代亚乙基)肼基)苯甲酸甲酯(1.68g,7.5mmol)于甲苯-甲醇(25ml+6ml)中的溶液中。在室温下搅拌1小时后,将混合物真空浓缩,并将残余物在水和乙酸乙酯(10ml+20ml)之间分配。在相分离之后,将水层用乙酸乙酯(20ml)萃取,并将合并的有机层真空浓缩。通过色谱法(硅胶,洗脱液:乙酸乙酯-庚烷,1/8)纯化所得油,并且获得黄色固体状中间体二腙(1.8g)。然后将中间体(1.6g)重新溶解于乙腈(12ml)中,加入碘甲烷(5.11g,36.0mmol),并将反应混合物在36℃下搅拌8小时。冷却至室温后,将固体过滤,用乙腈(2×20ml)冲洗,并真空干燥,以提供黄色固体状所需化合物(2.0g,总收率65%)。mp:177.5℃。
1H NMR(DMSO-d6)δ:11.51(s,1H),8.57(d,1H),7.84(m,2H),7.50(m,1H),7.25(m,1H),6.88(m,1H),3.86(s,3H),3.45(s,9H)。19F NMR(DMSO-d6)δ:-111.49。
MS(ESI-TOF)m/z:281.1([肼离子]+)。
实施例2f:2-氟-6-(2-((1E,2E)-2-(甲氧基亚氨基)亚乙基)肼基)苯甲酸的合成
使2-氟-6-(2-(2-氧代亚乙基)肼基)苯甲酸与甲氧胺盐酸盐和乙酸钠在水-甲醇中反应,以提供黄色固体状2-氟-6-(2-((1E,2E)-2-(甲氧基亚氨基)亚乙基)肼基)苯甲酸,收率为52%。该所需化合物原样用于下一步骤中。
实施例3:式II的2-苯基-2-H-1,2,3-三唑的合成
实施例3a:2-(3-氟苯基)-2-H-1,2,3-三唑的合成,其中X为-N+Me3I-。
在25℃下,向肼盐(E)-2-((E)-2-(2-(3-氟苯基)亚肼基)亚乙基)-1,1,1-三甲基肼-1-碘化物(X=-N+Me3I--1.0mmol,1.0当量)于DMF(3mL)中的溶液中一次性加入K2CO3或KHCO3(2.0mmol,2.0当量)。将悬浮液加热至50℃。搅拌2小时后或直到起始材料消耗完为止,将反应物冷却至25℃并用H2O和EtOAc处理。将有机层分配并用EtOAc萃取两次。将合并的有机物用盐水洗涤,经Na2SO4干燥,过滤并真空浓缩。通过快速柱色谱法使用庚烷/乙酸乙酯作为洗脱剂纯化得到2-(3-氟苯基)-2H-1,2,3-三唑,收率为87%。
当用KHCO3代替K2CO3时,收率提高到96%。
实施例3b:使用其它-X基团合成2-(3-氟苯基)-2H-1,2,3-三唑。
对于各种-X离去基团,可以按照以下程序由式I的化合物(其中R1为H)合成2-(3-氟苯基)-2H-1,2,3-三唑:
5mmol的式I的化合物(其中R1为H)和0.25mmol五水合硫酸铜或甲磺酸铜水合物于5mL至7mL正丁醇或乙二醇(EG)中的溶液/悬浮液在110℃下搅拌数小时,然后冷却至室温,用7.5ml的1M HCl水溶液洗涤,并且通过LC分析2-(3-氟苯基)-2H-1,2,3-三唑。
下表2说明在所列条件下针对每个-X离去基团获得的收率。反应条件没有优化,本发明考虑了每个-X基团的反应条件,以及其明显的变体。可以用于任何-X离去基团的反应优化的各种筛选条件的示例示于实施例3c(其中-X为-OCH3)中。
表2
实施例3c:由(1E,2E)-2-(2-(3-氟苯基)亚肼基)乙醛O-甲基肟合成2-(3-氟苯基)-2H-1,2,3-三唑(条件的筛选)。
将(1E,2E)-2-(2-(3-氟苯基)亚肼基)乙醛O-甲基肟(1当量)和催化剂于溶剂中的溶液在110℃-120℃下加热20分钟,过夜,然后冷却至室温,并LC分析2-(3-氟苯基)-2H-1,2,3-三唑。反应条件和收率总结在表3中。
表3
实施例3d:由(1E,2E)-2-(2-(3-氟苯基)亚肼基)乙醛O-甲基肟形成和分离2-(3-
氟苯基)-2H-1,2,3-三唑。
将反应器中装入0.31kg五水合硫酸铜和26.8kg EG,使其呈惰性并在搅拌下加热至120℃-130℃。分5份加入4.8kg的(1E,2E)-2-(2-(3-氟苯基)亚肼基)乙醛O-甲基肟。在120℃-130℃下搅拌1小时后,真空蒸馏反应混合物的一部分。馏出物(13L,2-(3-氟苯基)-2H-1,2,3-三唑+EG)在3.3kg庚烷和4.8kg 2w/w%HCl水溶液之间分配。分离两层,并用3.3kg庚烷萃取极性一层。将两个庚烷层合并,用4.8kg水洗涤并真空浓缩,以提供3.09kg无色至浅黄色油状2-(3-氟苯基)-2H-1,2,3-三唑(收率:77%)。
1H NMR(400MHz,DMSO-d6)δ=8.14(s,2H),7.87(dd,J=1.3,8.1Hz,1H),7.79(td,J=2.2,10.1Hz,1H),7.60(dt,J=6.4,8.3Hz,1H),7.26(ddt,J=0.9,2.5,8.5Hz,1H)。13CNMR(101MHz,DMSO-d6)δ=162.38(br d,J=244.3Hz),140.32(d,J=1.5Hz),136.88,131.63(d,J=9.2Hz),114.34(d,J=3.1Hz),114.37(d,J=20.8Hz),105.79(d,J=27.7Hz)。19F NMR(377MHz,DMSO-d6)δ=-110.88。
HRMS(EI-TOF)m/z:C8H6FN3的[M]+℃计算值为163.0546;实测值为163.0521。
实施例3e部分1:由2-氟-6-(2-(2-(甲氧基亚氨基)亚乙基)肼基)苯甲酸甲酯合成
2-氟-6-(2H-1,2,3-三唑-2-基)苯甲酸甲酯
将2-氟-6-(2-(2-(甲氧基亚氨基)亚乙基)肼基)苯甲酸甲酯(4.05g,16mmol)分四份加入到五水合硫酸铜(250mg,1.0mmol)于乙二醇(25ml)中的溶液中,保持在125℃下。将所得混合物在125℃下搅拌3小时以上,然后冷却至60℃。加入水(60ml)、庚烷(30ml)和乙酸乙酯(20ml),并且分离各层。在有机层浓缩并且通过柱色谱法(硅胶,庚烷-乙酸乙酯8/1)纯化残余物后获得1.3g(37%收率)所需产物。mp 56.9℃。
当首先在室温下将2-氟-6-(2-(2-(甲氧基亚氨基)亚乙基)肼基)苯甲酸甲酯(633mg,2.50mmol)和五水合硫酸铜(31mg,0.125mmol)在乙二醇(5ml)中混合时,然后加热至120℃(加热时,化学物质得到完全溶解)持续约4小时,然后冷却至室温,用水稀释,用乙酸异丙酯萃取并通过柱色谱法纯化时,2-氟-6-(2H-1,2,3-三唑-2-基)苯甲酸甲酯的收率提高到54%。当用1.00mmol起始材料、0.05mmol五水合硫酸铜于10ml乙二醇中的溶液重复上述程序,且加热时间为约8小时时,获得57%收率的收率。
1H NMR(DMSO-d6)δ:8.18(s,2H),7.87(d,1H),7.75(m,1H),7.48(t,1H),3.78(s,3H)。13C NMR(DMSO-d6)δ:163.68,159.40(d),137.63,137.6(d),133.27(d),118.00(d),115.86(d),115.8(d),53.28。19F NMR(DMSO-d6)δ:-114.28。
实施例3e部分2:由2-氟-6-(2H-1,2,3-三唑-2-基)苯甲酸甲酯合成2-氟-6-(2H-
1,2,3-三唑-2-基)苯甲酸
将2-氟-6-(2H-1,2,3-三唑-2-基)苯甲酸甲酯(360mg)和氢氧化锂水合物(66mg,10.2mmol)于THF-水(各2ml)中的溶液搅拌直至完全转化。在中和以及分离后,获得所需产物,收率为86%。
将来自(E)-2-((E)-2-(2-(3-氟苯基)亚肼基)亚乙基)-1,1,1-三甲基肼-1-碘化物的2-氟-6-(2H-1,2,3-三唑-2-基)苯甲酸甲酯(0.61g,1.5mmol)和碳酸氢钾(0.75g,7.5mmol)于DMF(10ml)中的溶液在56℃下搅拌1小时,然后真空浓缩。将残余物在庚烷和水(15ml+6ml)之间分配。在相分离后,用庚烷(15ml)萃取水层,并将合并的有机层真空浓缩,以提供黄色粉末状所需产物(0.27g,81%收率)。
实施例3g:由2-氟-6-(2-((1E,2E)-2-(甲氧基亚氨基)亚乙基)肼基)苯甲酸合成
2-氟-6-(2H-1,2,3-三唑-2-基)苯甲酸
使2-氟-6-(2-((1E,2E)-2-(甲氧基亚氨基)亚乙基)肼基)苯甲酸在热乙二醇中在五水合硫酸铜的存在下反应,以提供2-氟-6-(2H-1,2,3-三唑-2-基)苯甲酸,收率为约25%。
实施例4:由2-(3-氟苯基)-2H-1,2,3-三唑合成2-氟-6-(2H-1,2,3-三唑-2-基)苯
甲酸
实施例4a:碱和添加剂的筛选
将碱加入到化合物2-(3-氟苯基)-2H-1,2,3-三唑的溶液中,并且搅拌混合物,然后鼓泡CO2气体直至阴离子完全淬灭和酸性处理。通过LC分析所得混合物,并在完成处理后分离2-氟-6-(2H-1,2,3-三唑-2-基)苯甲酸。结果报告于下表4中。
表4
实施例4b:2-氟-6-(2H-1,2,3-三唑-2-基)苯甲酸的合成和分离
将2M异丙基氯化镁溶液于THF(735mL,1.47mol)中的溶液加入到加热(35℃-40℃)的200g(1.23mol)2-(3-氟苯基)-2H-1,2,3-三唑和25.98g(0.61mol)氯化锂于一升THF中的溶液中。将所得混合物在35℃-40℃下搅拌6小时,然后冷却至-5℃。以不允许反应温度超过10℃的速率向混合物中鼓泡CO2气体(67.44g,1.53mol)。通过加入800mL甲苯、800mL水和144mL浓HCl溶液来淬灭反应混合物。不溶性颗粒溶解后,分离两层,弃去水层。将有机层通过木炭过滤并真空浓缩,然后将残余物重新溶解于1.80L甲苯和800mL水中;将两相混合物加热至回流几分钟,冷却至75℃-80℃,加入晶种,并且进一步冷却至10℃。结晶后,通过过滤分离产物,用几毫升水和甲苯洗涤,并真空干燥,以获得白色至浅黄色固体状2-氟-6-(2H-1,2,3-三唑-2-基)苯甲酸(212g-217g,83%-85%收率)。
mp 153℃-155℃。
1H NMR(400MHz,DMSO-d6)δ=13.70(br s,1H),8.14(s,2H),7.79(d,J=8.1Hz,1H),7.66(dt,J=6.1,8.3Hz,1H),7.42(ddd,J=1.0,8.4,9.3Hz,1H)。13C NMR(101MHz,DMSO-d6)δ=164.09,158.90(br d,J=247.4Hz),136.97,136.77(br d,J=6.2Hz),131.82(d,J=9.2Hz),118.03(d,J=3.1Hz),117.25(br d,J=23.1Hz),115.48(d,J=22.3Hz)。19FNMR(377MHz,DMSO-d6)δ=-114.93。
HRMS(EI-TOF)m/z:C9H7FN3O2的[M+H]+计算值为208.0517;实测值为208.0517。
实施例5:(((3aR,6aS)-5-(4,6-二甲基嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2
(1H)-基)(2-氟-6-(2H-1,2,3-三唑-2-基)苯基)甲酮的合成
将亚硫酰氯(60mmol,4.3mL)加入到2-氟-6-(2H-1,2,3-三唑-2-基)苯甲酸(9.5g,46mmol)于甲苯(110mL)中的悬浮液中,并加热至55℃持续2.5小时。将反应物真空浓缩至约100mL的残留体积(约20ml的蒸馏的溶剂)并且加入到充分搅拌的(3aR,6aS)-2-(4,6-二甲基嘧啶-2-基)八氢吡咯并[3,4-c]吡咯(10.2g,45.7mmol)于甲苯(44mL)和碳酸钠水溶液(44mL,68.5mmol)中的两相混合物中。将所得双相混合物在30℃下搅拌3.5小时,然后加热至70℃。将有机层用57mL水洗涤两次,并真空浓缩至约64mL的残留体积。将浓缩的混合物加热至90℃以获得溶液,然后冷却至室温并添加环己烷(64mL)。将所得悬浮液搅拌过夜,过滤,用环己烷(12mL)洗涤,用水(11mL)洗涤,并真空干燥,以得到固体状(((3aR,6aS)-5-(4,6-二甲基嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(2-氟-6-(2H-1,2,3-三唑-2-基)苯基)甲酮(18.1g,97%收率)。1H NMR(400MHz,吡啶-d5)δppm 2.33(s,12H)2.81-2.97(m,4H)3.27(dd,J=10.6,5.0Hz,1H)3.33(dd,J=10.5,4.7Hz,1H)3.57(br t,J=7.1Hz,1H)3.59(br t,J=7.0Hz,1H)3.67(dd,J=11.7,4.5Hz,1H)3.70-3.75(m,1H)3.75-3.82(m,2H)3.82-3.98(m,7H)4.11(dd,J=12.4,7.6Hz,1H)6.29(s,1H)6.29(s,1H)7.19(td,J=8.7,1.0Hz,1H)7.26(td,J=8.6,0.9Hz,1H)7.46(td,J=8.3,6.2Hz,1H)7.46(td,J=8.3,6.0Hz,1H)7.90(dt,J=8.2,0.8Hz,1H)7.90(s,2H)7.98(dt,J=8.2,0.8Hz,1H)8.04(s,2H)。13C NMR(101MHz,吡啶-d5)δppm 24.47,24.48,41.74,41.82,42.71,42.93,50.76,50.82,50.90,51.03,51.43,51.62,51.87,52.06,109.27,109.44,115.88(br d,J=22.4Hz),115.89(br d,J=22.4Hz),118.82(br d,J=3.3Hz),118.97(br d,J=3.3Hz),120.48(d,J=24.9Hz),120.55(d,J=24.6Hz),131.53(br d,J=9.2Hz),131.54(d,J=9.2Hz),137.33,137.47,138.04(d,J=7.0Hz),138.07(br d,J=7.0Hz),159.71(d,J=245.8Hz),159.81(d,J=245.4Hz),161.53,161.61,162.99(d,J=7.3Hz),162.99(d,J=7.3Hz),167.61,167.63。高分辨率MS(ES,m/z):C21H23FN7O(M+H)+的计算值:408.1943;实测值:408.1946。
尽管上述说明通过提供的实施例进行说明来指出了本发明的原理,但应当理解,本发明的实践涵盖以下权利要求书及其等同形式的范围内的所有一般变型形式、改变形式和/或修改形式。
本文引用的所有文献均以引用方式并入本文。
Claims (10)
2.根据权利要求1所述的方法,其中:
R1为-H或-CO2CH3;
X为-OC(1-2)烷基、-OC(CH3)3、-OCH2Ph、-N(CH3)2或-N(CH3)3I。
4.根据权利要求3所述的方法,
所述方法包括下述步骤:
a)式I的肼的环化,以在单个步骤中得到式II的2-苯基-2H-1,2,3-三唑
其中
R1为-H;
X为-OC(1-2)烷基、-OC(CH3)3、-OCH2Ph、-N(CH3)2或-N(CH3)3I;
b)2-(3-氟苯基)-2H-1,2,3-三唑的羧化,以得到2-氟-6-(2H-1,2,3-三唑-2-基)苯甲酸,
其中所述羧化的特征在于使用异丙基-MgCl和CO2;
c)2-氟-6-(2H-1,2,3-三唑-2-基)苯甲酸与(3aR,6aS)-2-(4,6-二甲基嘧啶-2-基)八氢吡咯并[3,4-c]吡咯反应以形成(((3aR,6aS)-5-(4,6-二甲基嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(2-氟-6-(2H-1,2,3-三唑-2-基)苯基)甲酮
其中所述反应的特征在于使用SOCl2。
5.根据权利要求4所述的方法,
所述方法包括下述步骤:
a)式I的肼的环化,以在单个步骤中得到式II的2-苯基-2H-1,2,3-三唑
其中
R1为-H;
X为-OC(1-2)烷基、-OC(CH3)3、-OCH2Ph、-N(CH3)2或-N(CH3)3I;
b)2-(3-氟苯基)-2H-1,2,3-三唑的羧化,以得到2-氟-6-(2H-1,2,3-三唑-2-基)苯甲酸,
其中所述羧化的特征在于使用LiCl、异丙基-MgCl和CO2;
c)2-氟-6-(2H-1,2,3-三唑-2-基)苯甲酸与(3aR,6aS)-2-(4,6-二甲基嘧啶-2-基)八氢吡咯并[3,4-c]吡咯反应以形成(((3aR,6aS)-5-(4,6-二甲基嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(2-氟-6-(2H-1,2,3-三唑-2-基)苯基)甲酮
其中所述反应的特征在于使用SOCl2。
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US4826833A (en) * | 1984-01-30 | 1989-05-02 | Pfizer Inc. | 6-(Substituted)methylene-penicillanic and 6-(substituted)hydroxymethylpenicillanic acids and derivatives thereof |
US20110313003A1 (en) * | 2010-06-16 | 2011-12-22 | Metabolex, Inc. | Gpr120 receptor agonists and uses thereof |
CN102781942A (zh) * | 2009-10-23 | 2012-11-14 | 詹森药业有限公司 | 用作食欲肽受体调节剂的二取代八氢吡咯并[3, 4-c]吡咯 |
WO2015150252A1 (en) * | 2014-04-01 | 2015-10-08 | Bayer Cropscience Ag | Use of heterocyclic compounds for controlling nematodes |
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US4826833A (en) * | 1984-01-30 | 1989-05-02 | Pfizer Inc. | 6-(Substituted)methylene-penicillanic and 6-(substituted)hydroxymethylpenicillanic acids and derivatives thereof |
CN102781942A (zh) * | 2009-10-23 | 2012-11-14 | 詹森药业有限公司 | 用作食欲肽受体调节剂的二取代八氢吡咯并[3, 4-c]吡咯 |
US20110313003A1 (en) * | 2010-06-16 | 2011-12-22 | Metabolex, Inc. | Gpr120 receptor agonists and uses thereof |
WO2015150252A1 (en) * | 2014-04-01 | 2015-10-08 | Bayer Cropscience Ag | Use of heterocyclic compounds for controlling nematodes |
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