CN114478373B - 一种氨基磺酸酯的制备方法 - Google Patents
一种氨基磺酸酯的制备方法 Download PDFInfo
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- CN114478373B CN114478373B CN202011254756.0A CN202011254756A CN114478373B CN 114478373 B CN114478373 B CN 114478373B CN 202011254756 A CN202011254756 A CN 202011254756A CN 114478373 B CN114478373 B CN 114478373B
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- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 229950010588 pevonedistat Drugs 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000001749 primary amide group Chemical group 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 description 1
- 229960004134 propofol Drugs 0.000 description 1
- 229960004604 propranolol hydrochloride Drugs 0.000 description 1
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol hydrochloride Natural products C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003334 secondary amides Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- QAHVHSLSRLSVGS-UHFFFAOYSA-N sulfamoyl chloride Chemical compound NS(Cl)(=O)=O QAHVHSLSRLSVGS-UHFFFAOYSA-N 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 150000003511 tertiary amides Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- YWBFPKPWMSWWEA-UHFFFAOYSA-O triazolopyrimidine Chemical compound BrC1=CC=CC(C=2N=C3N=CN[N+]3=C(NCC=3C=CN=CC=3)C=2)=C1 YWBFPKPWMSWWEA-UHFFFAOYSA-O 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
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Abstract
本发明涉及一种氨基磺酸酯的制备方法。具体地，本发明公开了一种氨基磺酰化试剂，具有廉价易得、溶解度好、高稳定性等优点。使用所述试剂可高选择性地实现对羟基的氨基磺酰化修饰，反应条件温和，操作简单，可放大量。所得产物具有收率高、副产物少、纯度高等优势。
Description
技术领域
本发明涉及有机合成和药物化学领域，具体地涉及氨基磺酸酯化合物的高效制备及其在药物分子合成上的应用。
背景技术
氨基磺酸酯具有独特的化学和生物学性质，在有机化学、药物化学等领域都有重要的应用。在合成反应中，氨基磺酸酯既是交叉偶联反应前体(J.Am.Chem.Soc.2009,131,17748)，又是碳氢活化体系中氨基供体(Org.Lett.2020,22,168)。另一方面，作为药效基团，氨基磺酸酯是磺酸酯和磷酸酯的等排类似物，在生理环境下为电中性，独特的相互作用模式使其在药物分子中常常作为调整生物活性和生物利用度的重要基团(J.Med.Chem.2003,46,2197)。
到目前为止，从醇/酚出发直接制备氨基磺酰酯的合成方法还非常有限。最常见的策略是以氨基磺酰氯(H2NSO2Cl)为亲电试剂的取代反应，然而H2NSO2Cl却存在价格贵(百灵威售价：12903元/100g)、不稳定、多羟基选择性差的缺点。
2012年，Zhu课题组开发了一种氨基磺酰化试剂t-Bu/DABCO Burgess-typeReagent，并应用到了NAE抑制剂MLN4924的合成工艺上。但该试剂在高溶解性的大极性溶剂(如DMAc、DMF)中稳定性差，而在能稳定存在的溶剂(如MeCN)中却表现出很差的溶解性，经NMR测试其在室温下氘代乙腈中的饱和溶解浓度为0.06mol/L，这使得大规模反应时搅拌困难，且不得不加热，(ACS Symposium Series，2016,1240,13-62.)这制约了该磺酰化反应的可操作性、底物普适性和选择性。另一方面，该试剂须使用0.2eq～0.4eq的HCl作为添加剂来促进反应的进行，这导致与醇反应时存在氯代副产物(Org.Lett.2020,14,2626)。
2020年，Leahy和Miller等人报道了N-甲基咪唑催化的以活泼氨基磺酸酯PCPS为试剂的磺酰化反应。然而该试剂有较大的毒性，毒性来源于分解物五氯苯酚，大鼠经口急毒测试LD50＝50mg/kg。另外其官能团兼容性较差，且制备是仍需要使用过量的H2NSO2Cl。(Org.Lett.2020,22,168)。
对于含有多羟基的复杂分子的氨基磺酰化反应，选择性是需要考察的重要方向。例如，在NAE抑制剂MLN4924的合成中，后期对于伯醇和仲醇的选择性氨基磺酰化是抑制剂制备过程中的难点和关键步骤。Zhu课题组使用t-Bu/DABCO Burgess-type Reagent作为反应试剂时(Org.Process Res.Dev.2015,19,1299)，原料转化率仅有63％，且与伯醇氨基磺酰化产物相伴也得到了相当比例的仲醇取代副产物以及双羟基取代副产物(52:7:3)。Leahy和Miller等人利用活泼氨基磺酸酯PCPS为氨基磺酰化试剂时，仅以38％的收率得到目标产物，(Org.Lett.2020,22,168)且伴随得到大量仲醇取代和双取代副产物(4.7:1.0:1.1)。
基于以上背景，开发一种高效实用的新型氨基磺酰化试剂，并探索出条件温和、操作便捷、选择性高、官能团兼容性好的氨基磺酸酯制备方法具有重要的意义。
发明内容
本发明的目的在于提供一种廉价易得，高效稳定的磺酰化试剂，并开发其在氨基磺酸酯合成上的应用。
本发明的第一方面，提供了一种氨基磺酰化试剂，所述试剂包含式I所示化合物和式II所示化合物，
其中，R1选自下组：取代或未取代的C1-10烷基、取代或未取代的C2-10烯基、取代或未取代的C2-10炔基、取代或未取代的C6-10芳基、取代或未取代的C6-10芳基-(CH2)m-、取代或未取代的芴基-(CH2)m-；
各m独立地选自下组：0、1、2、3、4、5；
R2-R6各自独立地选自下组：H、取代或未取代的C1-10烷基、取代或未取代的C2-10烯基、取代或未取代的C2-10炔基、取代或未取代的C1-10酰胺基、取代或未取代的C1-10羰基、卤素、取代或未取代的苯基、取代或未取代的C1-10烷氧基、-COOC1-10烷基、-S-C1-10烷基、-C＝COOC1-10烷基、硝基、氰基、羟基、羧基；
所述取代指被选自下组的一个或多个取代基取代：卤素、羟基、硝基、氰基、醛基、酯基、羧基、C1-10烷基、C1-10氟烷基、C1-10环烷基、C1-10烷氧基、C2-10烯基、C2-10炔基、苯基；
所述试剂中，所述式I所示化合物和所述式II所示化合物的摩尔比为1：0.5-1.5。
在另一优选例中，所述式I所示化合物和所述式II所示化合物的摩尔比为1:1。
在另一优选例中，R1选自下组：C1-10烷基、C2-10烯基、C2-10炔基、C6-10芳基、C6-10芳基-(CH2)m-、芴基-(CH2)m-；
m为1；
R2-R6各自独立地选自下组：H、C1-10烷基、C2-10烯基、C2-10炔基、C1-10酰胺基、C1-10羰基、卤素、苯基、C1-10烷氧基、-COOC1-10烷基、-S-C1-10烷基、-C＝COOC1-10烷基、硝基、氰基、羟基、羧基。
在另一优选例中，R1选自下组：C1-6烷基、C2-6烯基、C2-6炔基、C6-10芳基、C6-10芳基-(CH2)m-、芴基-(CH2)m-。
在另一优选例中，R2-R6各自独立地选自下组：H、C1-6烷基。
在另一优选例中，m＝1。
在另一优选例中，式I所示化合物和式II所示化合物中，各R2-R6相同。
在另一优选例中，所述试剂选自下组：
本发明的第二方面，提供了一种本发明第一方面所述试剂的制备方法，包括步骤：
1)将化合物A与R1OH反应，得到化合物B；
2)将化合物B与化合物C反应，得到试剂D，即本发明第一方面所述试剂；
其中，R1-R6如本发明第一方面所定义。
在另一优选例中，步骤2)中，化合物C与R1OH的摩尔比为2-4。
在另一优选例中，步骤1)中，R1OH和化合物A的摩尔比为1-1.5，优选1.1。
在另一优选例中，步骤2)中，化合物C与R1OH的摩尔比为2-2.5。
本发明的第三方面，提供了一种本发明第一方面所述试剂的用途，用于制备氨基磺酸酯。
本发明的第四方面，提供了一种氨基磺酸酯的制备方法，包括步骤：
i)将化合物E与本发明第一方面所述试剂反应，得到化合物F，即氨基磺酸酯；
其中，
R选自下组：取代或未取代的C1-10烷基、取代或未取代的C2-10烯基、取代或未取代的C2-10炔基、取代或未取代的苯基、取代或未取代的吡啶基、取代或未取代的呋喃基、取代或未取代的噻吩基、取代或未取代的噻唑基、取代或未取代的吡咯基、取代或未取代的萘基、取代或未取代的蒽基、取代或未取代的苯并基团；
所述取代指被选自下组的一个或多个取代基取代：卤素、羟基、硝基、氰基、羧基、C1-10烷基、C1-10亚烷基、取代的C1-10亚烷基、C1-10烷氧基、C2-10烯基、C2-10炔基、苯基、苯氧基、苯基-(C＝O)-、＝O、/> 萘基；
R1如本发明第一方面所定义。
在另一优选例中，所述苯并基团具有选自下组的结构：
本发明的第五方面，提供了一种药物分子氨基磺酰化的方法，包括步骤：
使用本发明第一方面所述氨基磺酰化试剂对前体药物进行单羟基修饰，以得到氨基磺酰化的药物分子；
所述前体药物包含2-10个羟基。
在另一优选例中，所述前体药物包含2-6个羟基，较佳地2-4个，更佳地2个。
在另一优选例中，所述方法中，本发明第一方面所述氨基磺酰化试剂与所述前体药物的摩尔比为2-5，较佳地2-3。
在另一优选例中，所述方法在选自下组的溶剂中进行：乙腈、二氯甲烷、或其组合。
在另一优选例中，所述氨基磺酰化的药物分子具有选自下组的结构：
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过长期而深入的研究，意外地制备了一种溶解性好、稳定性好、廉价易得、无氯代副产物、反应易操作、条件温和、底物普适性好、便于药物后期修饰、多羟基选择性好的新型的氨基磺酰化试剂，并将所述氨基磺酰化试剂应用到了多羟基复杂分子的氨基磺酰化，具有多羟基选择性好、总收率高、副产物少、纯度高等优势。在此基础上，发明人完成了本发明。
术语
在本发明中，除非特别指出，所用术语具有本领域技术人员公知的一般含义。
在本发明中，术语“卤素”指F、Cl、Br或I。
在本发明中，“C1-6烷基”是指包括1-6个碳原子的直链或支链的烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、新戊基、特戊基、或类似基团。术语“C1-10烷基”具有类似含义。
在本发明中，术语“C2-6烯基”是指具有2-6个碳原子的含有一个双键的直链或支链烯基，非限制性地包括乙烯基、丙烯基、丁烯基、异丁烯基、戊烯基和己烯基等。术语“C2-10烯基”具有类似含义。
在本发明中，术语“C2-6炔基”是指具有2-6个碳原子的含有一个三键的直链或支链炔基，非限制性地包括乙炔基、丙炔基、丁炔基、异丁炔基、戊炔基和己炔基等。术语“C2-10炔基”具有类似含义。
在本发明中，术语“C1-6烷氧基”是指具有1-6个碳原子的直链或支链烷氧基，非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。优选为C1-C4烷氧基。术语“C1-10烷氧基”具有类似含义。
在本发明中，术语“C1-10酰胺基”是指具有1-10个碳原子的含有一个酰胺键的一级、二级或三级酰胺。
在本发明中，术语“C1-10羰基”是指具有1-10个碳原子的含有一个碳氧双键的羰基。
在本发明中，术语“芳环”或“芳基”具有相同的含义，优选为“C6-10芳基”。术语“C6-10芳基”是指在环上不含杂原子的具有6-10个碳原子的芳香族环基，如苯基、萘基等。
在本发明中，术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限于)：卤素、羟基、羧基(-COOH)、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-至12元杂环基、芳基、杂芳基、C1-C8醛基、C2-C10酰基、C2-C10酯基、氨基、C1-C6烷氧基、C1-C10磺酰基等。
在本发明中，术语“多个”指1、2、3、4、5或6个。其他类似术语具有类似含义。
氨基磺酰化试剂及其制备
本发明人开发了一种新型氨基磺酰化试剂(D)，在稳定存在的溶剂(如DCM，MeCN)中表现出良好的溶解性，经NMR测试其在室温下氘代乙腈中的饱和溶解浓度为0.35mol/L，且无需添加剂、无氯代副产物，可由廉价易得原料(氯磺酰异氰酸酯百灵威售价：251元/100g)方便制备。与醇/酚的氨基磺酰化反应操作简单、底物范围广、可大量合成，已成功应用于多种药物分子的后期结构修饰。与此同时，对于多羟基复杂化合物体现出了良好的选择性，以MLN4924的合成为例，该方法可以以两步84％的总收率高效制备目标化合物，且几乎无仲醇取代及双取代副产物，使得纯化更加方便。
现有氨基磺酰化试剂和本发明氨基磺酰化试剂的特点概述如下表1所示。
表1
本发明所述氨基磺酰化试剂是如下制备的：
将反应物氯磺酰异氰酸酯(A)与醇试剂R1OH用溶剂混合，氮气保护下反应，后加入2倍量(取代)吡啶(C)，反应后经重结晶、快速过滤、干燥后得试剂D。其中：
1)R1为叔丁基、苄基、烯丙基、芴甲基。
2)R2～R6独立地选自下组：氢、取代或未取代的C1-10烷基、C2-10烯基、C2-10炔基、C1-10酰胺基、C1-10羰基、卤素、取代或未取代的苯基、C1-10烷氧基、-COOC1-10烷基、-S-C1-10烷基、-C＝COOC1-10烷基、硝基、氰基、羟基、羧基。
3)式D中，n为1.5～0.5，通常为1.0。
4)步骤1和步骤2的溶剂选自下组：四氢呋喃、二甲基乙二醚、1,4-二氧六环、甲苯、二氯甲烷、1,2-二氯乙烷、乙腈。
5)步骤1中，醇试剂与反应物A的摩尔比为1.0-2.0:1，优选1.1倍量。反应温度为0-30℃，优选0℃。反应时间为0.1-5小时，优选1小时。
6)步骤2中，反应物C与反应物A的摩尔比为2.0-4.0:1，优选2.2倍量。反应温度为0-30℃，优选0℃。逐渐升温到室温(25-40℃)。反应时间为0.1-48小时，优选3小时。
氨基磺酸酯及其制备
采用本发明所述氨基磺酰化试剂通过如下路线制备了氨基磺酸酯：
将反应底物醇/酚(E)与氨基磺酰化试剂(D)用溶剂混合反应，后处理后柱层析纯化，得产物F。其中：
1)R选自下组：取代或未取代的C1-10烷基、C2-10烯基、C2-10炔基、取代或未取代的苯基、取代或未取代的吡啶基、取代或未取代的呋喃基、取代或未取代的噻吩基、取代或未取代的噻唑基、取代或未取代的吡咯基、取代或未取代的萘基、取代或未取代的蒽基、取代或未取代的苯并基团。
2)步骤3中，反应物D与醇/酚试剂的摩尔比为1.0-5.0:1。反应温度为0-30℃，通常为室温。反应时间为0.1-48小时。
3)步骤3的溶剂选自下组：四氢呋喃、二甲基乙二醚、1,4-二氧六环、二氯甲烷、1,2-二氯乙烷、乙腈。
与现有技术相比，本发明具有以下主要优点：
(1)所述氨基磺酰化试剂具有如下优点：溶解性好、稳定性好、廉价易得、无氯代副产物、反应易操作、条件温和、底物普适性好、便于药物后期修饰；
(2)使用所述氨基磺酰化试剂对多羟基复杂分子进行氨基磺酰化的反应具有多羟基选择性好、总收率高、副产物少、纯度高等优势。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
实施例1：氨基磺酰化试剂D1的制备。
氮气保护条件下，向250mL的反应瓶中加入叔丁醇(44mmol，3260mg)，干燥的甲苯60mL，冰浴降温至0℃，滴加氯磺酰异氰酸酯(40mmol，5660mg)，0℃下搅拌一小时，滴加入吡啶(88mmol，6960mg)后，升至室温继续搅拌3小时，有白色固体析出。快速抽滤，用乙醚洗一遍，固体转移至100mL烧瓶中，真空干燥20分钟后得白色固体产物D1，无需纯化，收率92％。1H NMR(400MHz,CDCl3)δ8.92(dd,J＝6.6,1.5Hz,4H),8.48(tt,J＝7.8,1.6Hz,2H),8.01(dd,J＝7.8,6.6Hz,4H),7.40(s,1H),1.41(s,9H).
实施例2：氨基磺酰化试剂D2的制备。
氮气保护条件下，向250mL的反应瓶中加入叔丁醇(44mmol，3260mg)，干燥的甲苯60mL，冰浴降温至0℃，滴加氯磺酰异氰酸酯(40mmol，5660mg)，0℃下搅拌一小时，滴加入4-甲基吡啶(88mmol，8195mg)后，升至室温继续搅拌3小时，有白色固体析出。快速抽滤，用乙醚洗一遍，固体转移至100mL烧瓶中，真空干燥20分钟后得白色固体产物D2，无需纯化，收率90％。1H NMR(400MHz,CDCl3)δ8.71(d,J＝6.6Hz,4H),7.73(d,J＝6.2Hz,4H),2.65(s,6H),1.41(s,9H).
实施例3：氨基磺酰化试剂D3的制备。
氮气保护条件下，向250mL的反应瓶中加入9-芴甲醇(44mmol，8634mg)，干燥的甲苯60mL，冰浴降温至0℃，滴加氯磺酰异氰酸酯(40mmol，5660mg)，0℃下搅拌一小时，滴加入吡啶(88mmol，6960mg)后，升至室温继续搅拌3小时，有白色固体析出。快速抽滤，用乙醚洗一遍，固体转移至100mL烧瓶中，真空干燥20分钟后得白色固体产物D1，无需纯化，收率85％。1H NMR(400MHz,CDCl3)δ8.85(d,J＝5.3Hz,4H),8.39(t,J＝7.8Hz,2H),7.92(dd,J＝7.5,6.7Hz,4H),7.76–7.66(m,2H),7.64–7.53(m,2H),7.35(t,J＝7.5Hz,2H),7.26(t,J＝7.3Hz,2H),4.40–4.10(m,3H).
实施例4：氨基磺酸酯F1的合成。
向10mL的反应瓶中加入苯乙醇(0.2mmol，24.4mg)、氨基磺酰化试剂D1(0.4mmol，150mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F1，无色油状物，50mg，收率84％。1H NMR(400MHz,Chloroform-d)δ7.32–7.19(m,5H),4.47(t,J＝7.1Hz,2H),3.03(t,J＝7.1Hz,2H),1.43(s,9H).
实施例5：氨基磺酸酯F2的合成。
向10mL的反应瓶中加入1-苯基-2-丙醇(0.2mmol，27.2mg)、氨基磺酰化试剂D1(0.4mmol，150mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F2，无色油状物，56.8mg，收率90％。1H NMR(400MHz,Chloroform-d)δ7.36–7.03(m,5H),5.05(q,J＝6.4Hz,1H),3.12(dd,J＝13.6,5.2Hz,1H),2.87(dd,J＝13.6,7.9Hz,1H),1.46(s,9H),1.32(d,J＝6.2Hz,3H).
实施例6：氨基磺酸酯F3的合成。
方法1)：向10mL的反应瓶中加入2-萘乙醇(0.2mmol，34.2mg)、氨基磺酰化试剂D1(0.4mmol，150mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F3，白色固体，56.2mg，收率80％。
方法2)：向10mL的反应瓶中加入2-萘乙醇(0.2mmol，34.2mg)、氨基磺酰化试剂D2(0.4mmol，160mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F3，白色固体，52.7mg，收率75％。
1H NMR(400MHz,Chloroform-d)δ7.83–7.73(m,3H),7.65(t,J＝1.3Hz,1H),7.50–7.40(m,2H),7.32(dd,J＝8.5,1.8Hz,1H),4.57(t,J＝7.1Hz,2H),3.20(t,J＝7.1Hz,2H),1.39(s,9H).
实施例7：氨基磺酸酯F4的合成。
向10mL的反应瓶中加入2-萘酚(0.2mmol，28.8mg)、氨基磺酰化试剂D1(0.4mmol，150mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F4，白色固体，48.5mg，收率75％。1H NMR(400MHz,Chloroform-d)δ7.78–7.71(m,4H),7.46–7.39(m,3H),1.40(s,9H).
实施例8：氨基磺酸酯F5的合成。
向10mL的反应瓶中加入4-甲氧基-1-萘酚(0.2mmol，34.8mg)、氨基磺酰化试剂D1(0.4mmol，150mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F5，白色固体，58.0mg，收率82％。1H NMR(400MHz,Methanol-d4)δ8.29–8.17(m,2H),7.58–7.38(m,3H),6.85(d,J＝8.5Hz,1H),3.99(s,3H),1.40(s,9H).
实施例9：氨基磺酸酯F6的合成。
向10mL的反应瓶中加入4-苯氧基苯酚(0.2mmol，37.2mg)、氨基磺酰化试剂D1(0.4mmol，150mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F6，无色油状物，61.4mg，收率84％。1H NMR(400MHz,CDCl3)δ7.38(dd,J＝8.6,7.5Hz,2H),7.27(d,J＝9.1Hz,2H),7.17(t,J＝7.4Hz,1H),7.07–6.99(m,4H),1.54(s,9H).
实施例10：氨基磺酸酯F7的合成。
向10mL的反应瓶中加入4-溴苯酚(0.2mmol，34.6mg)、氨基磺酰化试剂D1(0.4mmol，150mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F7，白色固体，47.9mg，收率68％。1H NMR(400MHz,Methanol-d4)δ7.52(d,J＝8.9Hz,2H),7.22(d,J＝8.9Hz,2H),1.45(s,9H).
实施例11：氨基磺酸酯F8的合成。
向10mL的反应瓶中加入4-叔丁基苯酚(0.2mmol，30.0mg)、氨基磺酰化试剂D1(0.4mmol，150mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F8，无色油状物，48.1mg，收率73％。1H NMR(400MHz,Chloroform-d)δ7.36(d,J＝8.8Hz,2H),7.20(d,J＝8.8Hz,2H),1.46(s,9H),1.29(s,9H).
实施例12：氨基磺酸酯F9的合成。
向10mL的反应瓶中加入对氰基苯酚(0.2mmol，23.8mg)、氨基磺酰化试剂D1(0.4mmol，150mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F9，白色固体，44.7mg，收率75％。1H NMR(400MHz,CD3OD)δ7.84(d,J＝8.9Hz,2H),7.46(d,J＝8.9Hz,2H),1.46(s,9H).
实施例13：氨基磺酸酯F10的合成。
向10mL的反应瓶中加入4-羟基-二苯甲酮(0.2mmol，39.6mg)、氨基磺酰化试剂D1(0.4mmol，150mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F10，无色油状物，46.8mg，收率62％。1H NMR(400MHz,Chloroform-d)δ7.72(dd,J＝21.5,8.0Hz,4H),7.55(t,J＝7.6Hz,1H),7.46–7.33(m,4H),1.41(s,9H).
实施例14：氨基磺酸酯F11的合成。
向10mL的反应瓶中加入雌酚酮(0.2mmol，54.0mg)、氨基磺酰化试剂D1(0.4mmol，150mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F11，无色油状物，75.5mg，收率84％。1H NMR(400MHz,Chloroform-d)δ7.22(d,J＝8.6Hz,1H),7.03(d,J＝8.7Hz,1H),6.98(s,1H),2.86–2.82(m,2H),2.48(dd,J＝19.0,8.6Hz,1H),2.38–2.29(m,1H),2.26–1.92(m,5H),1.88(d,J＝9.4Hz,1H),1.63–1.33(m,14H),0.83(s,3H).
实施例15：氨基磺酸酯F12的合成。
向10mL的反应瓶中加入睾酮(0.2mmol，57.6mg)、氨基磺酰化试剂D1(0.4mmol，150mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F12，无色油状物，69.2mg，收率74％。1H NMR(400MHz,Chloroform-d)δ5.72(s,1H),4.51(dd,J＝9.2,7.7Hz,1H),2.43–2.33(m,3H),2.31–2.14(m,3H),2.05–1.88(m,3H),1.83(ddd,J＝9.9,4.9,2.9Hz,2H),1.73–1.61(m,3H),1.57(ddd,J＝14.2,7.5,3.7Hz,2H),1.47(s,9H),1.41–1.33(m,2H),1.17(s,3H),1.07–0.97(m,1H),0.87(s,3H).
实施例16：氨基磺酸酯F13的合成。
向10mL的反应瓶中加入表雄酮(0.2mmol，58.0mg)、氨基磺酰化试剂D1(0.4mmol，150mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F13，无色油状物，85.5mg，收率91％。1H NMR(400MHz,Chloroform-d)δ4.68(dq,J＝10.8,5.5,5.0Hz,1H),2.49–2.35(m,1H),2.09(m,1H),2.02(m,2H),1.95–1.88(m,1H),1.84–1.74(m,5H),1.73–1.67(m,1H),1.54(m,4H),1.48(s,9H),1.34–1.30(m,2H),1.22(m,3H),1.01(m,2H),0.83(d,J＝2.6Hz,6H).
实施例17：氨基磺酸酯F14的合成。
向10mL的反应瓶中加入二氢胆固醇(0.2mmol，77.7mg)、氨基磺酰化试剂D1(0.4mmol，150mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F14，无色油状物，90.9mg，收率80％。1H NMR(400MHz,Chloroform-d)δ4.70(dt,J＝11.5,6.0Hz,1H),1.97(m,2H),1.85–1.70(m,5H),1.70–1.56(m,5H),1.50(s,9H),1.41–1.29(m,6H),1.17–0.97(m,12H),0.91–0.83(m,12H),0.65(d,J＝5.8Hz,4H).
实施例18：氨基磺酸酯F15的合成。
向10mL的反应瓶中加入盐酸普萘洛尔(0.2mmol，59.2mg)、氨基磺酰化试剂D1(0.4mmol，150mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F15，白色固体，66.7mg，收率76％。1H NMR(400MHz,dmso)δ9.07(s,2H),8.29(d,J＝8.2Hz,1H),7.88(d,J＝7.7Hz,1H),7.53(dd,J＝15.7,7.6Hz,3H),7.42(t,J＝7.9Hz,1H),6.97(d,J＝7.6Hz,1H),5.12–5.01(m,1H),4.36(ddd,J＝24.1,10.6,4.8Hz,2H),3.51–3.37(m,3H),1.37(s,9H),1.31(dd,J＝12.3,6.4Hz,6H).
实施例19：氨基磺酸酯F16的合成。
向10mL的反应瓶中加入艾地苯醌(0.2mmol，67.6mg)、氨基磺酰化试剂D1(0.4mmol，150mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F16，黄色油状物，72.5mg，收率70％。1H NMR(400MHz,Chloroform-d)δ4.30(t,J＝6.5Hz,2H),3.96(d,J＝1.7Hz,6H),2.41(t,J＝7.4Hz,2H),1.98(s,3H),1.72(dd,J＝8.3,6.5Hz,2H),1.47(s,9H),1.41–1.22(m,14H).
实施例20：氨基磺酸酯F17的合成。
向10mL的反应瓶中加入托吡卡胺(0.2mmol，56.8mg)、氨基磺酰化试剂D1(0.4mmol，150mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F17，白色固体，60.3mg，收率65％。1H NMR(400MHz,CD3OD)δ8.41(d,J＝5.8Hz,2H),7.44–7.25(m,5H),7.19(dd,J＝24.0,6.0Hz,2H),4.76(td,J＝9.4,7.2Hz,1H),4.71–4.62(m,2H),4.56(dd,J＝9.4,5.0Hz,1H),4.32–4.15(m,1H),3.48(dtd,J＝36.6,14.2,7.2Hz,2H),1.43(d,J＝5.2Hz,9H),1.05(dt,J＝20.6,7.1Hz,3H).
实施例21：氨基磺酸酯F18的合成。
向10mL的反应瓶中加入甲硝唑(0.2mmol，34.2mg)、氨基磺酰化试剂D1(0.4mmol，150mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F18，白色固体，51.9mg，收率74％。1H NMR(400MHz,CD3OD)δ7.98(s,1H),4.74–4.70(m,2H),4.65–4.61(m,2H),2.51(s,3H),1.38(s,9H).
实施例22：氨基磺酸酯F19的合成。
向10mL的反应瓶中加入美索巴莫(0.2mmol，48.2mg)、氨基磺酰化试剂D1(0.4mmol，150mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F19，无色油状物，50.4mg，收率60％。1H NMR(400MHz,CDCl3)δ6.96–6.72(m,4H),5.51(s,2H),5.14–5.05(m,1H),4.40(ddd,J＝18.3,12.4,4.7Hz,2H),4.25–4.19(m,1H),4.13(dd,J＝10.6,5.6Hz,1H),3.82(s,3H),1.29(s,9H).
实施例23：氨基磺酸酯F20的合成。
向10mL的反应瓶中加入4'-羟基黄烷酮(0.2mmol，48.0mg)、氨基磺酰化试剂D1(0.6mmol，224mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F20，无色油状物，76.3mg，收率91％。1H NMR(400MHz,Chloroform-d)δ7.87(d,J＝7.9Hz,1H),7.54–7.39(m,3H),7.38–7.31(m,2H),7.08–6.92(m,2H),5.40(d,J＝12.5Hz,1H),3.06–2.72(m,2H),1.45(s,9H).
实施例24：氨基磺酸酯F21的合成。
向10mL的反应瓶中加入丙泊酚(0.2mmol，35.7mg)、氨基磺酰化试剂D1(0.6mmol，224mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F21，无色油状物，55.8mg，收率78％。1H NMR(400MHz,Methanol-d4)δ7.19(m,3H),3.52(m,2H),1.52(s,9H),1.21(d,J＝6.9Hz,12H).
实施例25：氨基磺酸酯F22的合成。
向10mL的反应瓶中加入CBZ-L-酪氨酸甲酯(0.2mmol，65.9mg)、氨基磺酰化试剂D1(0.6mmol，224mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F22，无色油状物，71.2mg，收率70％。1H NMR(400MHz,CDCl3)δ7.36–7.25(m,5H),7.18(d,J＝8.3Hz,2H),7.05(d,J＝8.1Hz,2H),5.44(d,J＝8.2Hz,1H),5.04(s,2H),4.58(dd,J＝13.4,6.0Hz,1H),3.66(s,3H),3.01(ddd,J＝20.3,13.7,6.1Hz,2H),1.40(s,9H).
实施例26：氨基磺酸酯F23的合成。
向10mL的反应瓶中加入2-萘乙醇(0.2mmol，34.2mg)、氨基磺酰化试剂D3(0.4mmol，198.4mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F23，无色油状物，62.5mg，收率66％。1H NMR(400MHz,CDCl3)δ7.61(t,J＝5.7Hz,3H),7.55(t,J＝7.5Hz,2H),7.43(d,J＝7.8Hz,3H),7.30(dd,J＝6.2,3.3Hz,2H),7.27–7.22(m,2H),7.12(t,J＝7.0Hz,3H),4.41(t,J＝7.1Hz,2H),4.19(d,J＝6.9Hz,2H),3.98(t,J＝7.0Hz,1H),2.99(t,J＝7.0Hz,2H).
实施例27：Pevonedistat的合成。
向10mL的反应瓶中加入底物原料E1(0.2mmol，73.2mg)、氨基磺酰化试剂D1(0.4mmol，150mg)、干燥的乙腈1.5mL，干燥的二氯甲烷1.5mL，室温下搅拌1小时后，补加D1(0.1mmol，37.4mg)，继续搅拌1小时，TLC监控原料反应完全。加入12M浓盐酸0.5mL，室温搅拌1小时后，加饱和碳酸氢钠水溶液调pH到中性。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、饱和NaCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，HPLC分析伯醇氨基磺酰化产物、剩余原料、仲醇取代副产物以及双羟基取代副产物的比例为：20:1：0.15:1)，反应选择性明显优于已报到方法。硅胶柱层析分离得产物G1，白色固体，74.5mg，收率84％。1HNMR(600MHz,MeOD)δ8.17(s,1H),7.25(t,J＝6.2Hz,2H),7.22–7.12(m,3H),6.63(d,J＝3.6Hz,1H),5.85(t,J＝7.7Hz,1H),5.45(qd,J＝8.8,5.0Hz,1H),4.49(t,J＝3.6Hz,1H),4.38(dd,J＝9.7,7.6Hz,1H),4.20(dd,J＝9.7,7.4Hz,1H),3.05(ddd,J＝15.6,8.7,3.2Hz,1H),2.97–2.88(m,1H),2.84–2.75(m,1H),2.63(dtd,J＝11.1,7.8,3.3Hz,1H),2.34(ddd,J＝13.5,7.9,1.1Hz,1H),2.25(ddd,J＝19.6,11.3,7.0Hz,2H),2.08–1.97(m,2H).
实施例28：三唑并嘧啶类NAE抑制剂G2的合成。
向250mL的反应瓶中加入底物原料E2(2.0mmol，792mg)、干燥的乙腈15mL，室温下缓慢滴加氨基磺酰化试剂D1(5.0mmol，1870mg)的乙腈溶液(25mL，0.2M)，室温下搅拌5小时。加入12M浓盐酸5mL，室温搅拌1小时后，加饱和碳酸氢钠水溶液调pH到中性。加入250mL乙酸乙酯，先后用饱和碳酸氢钠溶液、饱和NaCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后得黄色油状物粗品760mg。加入100mL乙醚，室温搅拌3小时，有灰白色固体析出，过滤，固体用乙酸乙酯溶解、活性炭吸附、重结晶后得产物G2，白色固体，570mg，收率60％。1H NMR(400MHz,Methanol-d4)δ8.45(s,1H),7.36–7.14(m,4H),6.00(d,J＝5.4Hz,1H),5.61(s,1H),4.57(s,1H),4.44–4.31(m,2H),4.23(dd,J＝9.8,7.3Hz,1H),3.38(d,J＝7.9Hz,3H),3.17(qd,J＝16.4,4.3Hz,2H),2.91(s,1H),2.61(dt,J＝12.7,5.7Hz,1H),2.46(ddd,J＝12.7,7.8,4.5Hz,1H),2.33(t,J＝7.2Hz,2H).MS(ESI)：[M+H]+m/z 476.4
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (9)
1.一种氨基磺酰化试剂，其特征在于，所述试剂包含式I所示化合物和式II所示化合物，
其中，R1选自下组：C1-10烷基、C6-10芳基-(CH2)m-、芴基-(CH2)m-；
各m独立地选自下组：0、1、2、3、4、5；
R2-R6各自独立地选自下组：H、C1-10烷基；
所述试剂中，所述式I所示化合物和所述式II所示化合物的摩尔比为1：0.5-1.5。
2.如权利要求1所述的试剂，其特征在于，
R1选自下组：C1-10烷基、C6-10芳基-(CH2)m-、芴基-(CH2)m-；
m为1；
R2-R6各自独立地选自下组：H、甲基。
3.如权利要求1所述的试剂，其特征在于，式I所示化合物和式II所示化合物中，各R2-R6相同。
4.如权利要求1所述的试剂，其特征在于，所述试剂选自下组：
5.一种权利要求1所述试剂的制备方法，其特征在于，包括步骤：
1)将化合物A与R1OH反应，得到化合物B；
2)将化合物B与化合物C反应，得到试剂D，即权利要求1所述试剂；
其中，R1-R6如权利要求1所定义。
6.如权利要求5所述的方法，其特征在于，步骤2)中，化合物C与R1OH的摩尔比为2-4。
7.一种氨基磺酸酯的制备方法，其特征在于，包括步骤：
i)将化合物E与权利要求1所述试剂反应，得到化合物F，即氨基磺酸酯；
其中，
R选自下组：取代或未取代的C1-10烷基、取代或未取代的苯基、取代或未取代的吡啶基、取代或未取代的呋喃基、取代或未取代的噻吩基、取代或未取代的噻唑基、取代或未取代的吡咯基、取代或未取代的萘基、取代或未取代的蒽基、取代或未取代的苯并基团；
所述苯并基团具有选自下组的结构：
所述取代指被选自下组的一个或多个取代基取代：卤素、羟基、硝基、氰基、羧基、C1-10烷基、C1-10烷氧基、C2-10烯基、C2-10炔基、苯基、苯氧基、苯基-(C＝O)-、萘基；
R1如权利要求1所定义。
8.一种权利要求1所述试剂的用途，其特征在于，用于制备如权利要求7中化合物F所示的氨基磺酸酯，其中，R、R1如权利要求7所定义。
9.一种药物分子氨基磺酰化的方法，其特征在于，包括步骤：
使用权利要求1所述氨基磺酰化试剂对前体药物进行单羟基修饰，以得到氨基磺酰化的药物分子；所述氨基磺酰化的药物分子具有选自下组的结构：
所述前体药物包含2-10个羟基。
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