CN106986789A - 对苯二酚类化合物及其制备方法与在抗肿瘤或免疫调节中的应用 - Google Patents

对苯二酚类化合物及其制备方法与在抗肿瘤或免疫调节中的应用 Download PDF

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CN106986789A
CN106986789A CN201610037849.5A CN201610037849A CN106986789A CN 106986789 A CN106986789 A CN 106986789A CN 201610037849 A CN201610037849 A CN 201610037849A CN 106986789 A CN106986789 A CN 106986789A
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tert
metoxyphenols
butyl group
ester
acid
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CN201610037849.5A
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CN106986789B (zh
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张学敏
何新华
周涛
刘正刚
李涛
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Institute of Pharmacology and Toxicology of AMMS
Biomedical Analysis Center of AMMS
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Institute of Pharmacology and Toxicology of AMMS
Biomedical Analysis Center of AMMS
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Priority to CN201610037849.5A priority Critical patent/CN106986789B/zh
Application filed by Institute of Pharmacology and Toxicology of AMMS, Biomedical Analysis Center of AMMS filed Critical Institute of Pharmacology and Toxicology of AMMS
Priority to EP17741124.6A priority patent/EP3398934A4/en
Priority to PCT/CN2017/074386 priority patent/WO2017125093A1/zh
Priority to RU2018111766A priority patent/RU2708464C2/ru
Priority to AU2017209362A priority patent/AU2017209362B2/en
Priority to JP2018506216A priority patent/JP6659828B2/ja
Priority to US16/069,814 priority patent/US10786481B2/en
Publication of CN106986789A publication Critical patent/CN106986789A/zh
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Publication of CN106986789B publication Critical patent/CN106986789B/zh
Priority to US16/988,525 priority patent/US11738000B2/en
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    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
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Abstract

本发明公开了一种对苯二酚类化合物及其制备方法与在抗肿瘤或免疫调节中的应用。所述对苯二酚类化合物的结构式如式Ⅰ所示，式Ⅰ中，X为C＝O或CH2；Y为NH、O或不存在；R选自下述基团中任一种：至少1个碳原子的取代或未取代的烷基、至少3个碳原子的取代或未取代的环烷基、至少2个碳原子的取代或未取代的烯基或炔基；和至少含有4个碳原子的取代或未取代的芳基或杂芳基。本发明提供的化合物可以在体内缓释释放2-叔丁基-4-甲氧基苯酚，克服2-叔丁基-4-甲氧基苯酚直接给药体内半衰期短的缺点(T1/2＝0.5～1h)，保持平稳的2-叔丁基-4-甲氧基苯酚血药浓度(T1/2＝12～24h)。本发明提供的化合物保护了2-叔丁基-4-甲氧基苯酚的酚羟基，避免了在环境中的氧化作用，提高了药物的环境稳定性。

Description

对苯二酚类化合物及其制备方法与在抗肿瘤或免疫调节中的应用
技术领域
本发明涉及一种对苯二酚类化合物及其制备方法与在抗肿瘤或免疫调节中的应用。
背景技术
实体肿瘤中除癌细胞外，还包括成纤维细胞、内皮细胞、多种免疫细胞和大量细胞外基质等。其中，免疫细胞在肿瘤侵袭、转移和免疫逃逸的过程中均发挥了关键作用，其中肿瘤相关巨噬细胞(tumor-associated macrophages，TAMs)在肿瘤间质细胞中占有相当大的比例，它们大部分由外周血单核细胞迁移、分化，并在肿瘤细胞及其微环境的影响下发育成熟。TAMs可以分泌多种生长因子、细胞因子、免疫抑制介质和蛋白水解酶以促进肿瘤的进展和转移。
肿瘤相关巨噬细胞(TAMs)可以极化为M1和M2两种表型：M1型巨噬细胞，又称为经典活化型巨噬细胞，具有很强的促炎和病原体杀伤作用，并可促进IL12、IL23等炎性因子介导的Th1型细胞应答；M2型巨噬细胞，也称为非经典活化型巨噬细胞，具有免疫调节、组织重塑、促血管生成等作用。越来越多的证据表明，肿瘤相关巨噬细胞(TAMs)在恶性肿瘤的发生发展中发挥着“双刃剑”的关键作用：M1能杀伤胖瘤细胞，而M2则表现为促进胖瘤发生、发展和转移(Cell 2010，141:39-51.)。TAMs的极化与肿瘤微环境密切相关，且在恶性胖瘤中通常呈现M2样极化状态。因此，调节肿瘤的微环境，抑制TAMs的M2型极化可以改变肿瘤细胞的微环境，促进肿瘤细胞的死亡，从而抑制肿瘤的发生、发展和转移。
最近研究表明2-叔丁基-4-甲氧基苯酚(BHA)，Apocynin,TEMPO和NAC等抗氧剂可以通过抑制活性氧自由基ROS的产生，从而抑制单核细胞向M2巨噬细胞的分化，进而抑制K-rasLA2模型小鼠肺癌的发生(Cell Research 2013,23:898-914.)但是，也有不少研究表明抗氧剂会加速肿瘤的生长，这与2-叔丁基-4-甲氧基苯酚的体内抗肿瘤活性不相符，因此，抑制ROS的产生是2-叔丁基-4-甲氧基苯酚抑制TAMs的M2极化一个因素，而不是全部，BHA抑制TAMs的M2极化，进而抑制肿瘤发生、发展还存在其他机制(Cancer Res.1986,46,165-168；Cancer Res.,1985，45:1-8.)。然而，与此相矛盾的是，在早期的研究中，有证据表明2-叔丁基-4-甲氧基苯酚具有致癌作用(Archives of Biochemistry and Biophysics 449(2006)171–177；Regulatory Toxicology and Pharmacology 47(2007)68–77；Food and ChemicalToxicology 38(2000)1075±1084)。
文献(Cell Research 2013,23:898-914.)用含量0.75％饲料给药，可以完全抑制K-rasLA2模型小鼠肺癌的发生。但是，按体表面积和种属差异，该剂量折合成60kg体重的人的剂量约为7.5g/天。该剂量显然大大超过欧盟和美国规定的的每天0.5mg/kg体重的摄入量，也超过我国对2-叔丁基-4-甲氧基苯酚在食品中的添加限量0.2g/kg。因此，2-叔丁基-4-甲氧基苯酚无法成为直接可用的肿瘤治疗药物。
因此，需要进一步研究评估2-叔丁基-4-甲氧基苯酚的肿瘤治疗作用。
发明内容
本发明的目的是提供一种对苯二酚类化合物及其制备方法与在抗肿瘤或免疫调节中的应用。
本发明所提供的对苯二酚类化合物的结构式如式Ⅰ所示，其药学上可接受的盐、水合物或溶剂合物也是本发明保护的范围，
式Ⅰ中，X为C＝O或CH2，R选自下述基团中任一种：至少1个碳原子的取代或未取代的烷基、至少含有3个碳原子的取代或未取代的环烷基、至少2个碳原子数的取代或未取代的烯基或炔基和取代或未取代的芳基或杂芳基；
式Ⅰ中，Y为NH、O或不存在；
R中的取代基为卤素、氨基、硝基、酯基、羰基、氨基酸衍生物、天然黄酮、天然生物碱、聚乙二醇、多聚谷氨酸或多糖。
式Ⅰ中，所述烷基的碳原子个数可为1～40，优选为1～30，再优选为1～25；所述环烷基的碳原子个数可为3～40，优选为3～30，再优选为3～25；所述烯基或炔基的碳原子个数可为2～40，优选为2～30，再优选为2～25。
式Ⅰ中，所述芳基或杂芳基具体可为萘环、吲哚、苯环、吡啶、嘌呤、嘧啶、咪唑、呋喃、吡咯或苯并杂环等。
式Ⅰ中，X和Y的选择如下述1)-3)中任一种：
1)当X为C＝O时，Y为NH；
2)当X为CH2时，Y为O；
3)X为C＝O或CH2，Y不存在。
式Ⅰ所示化合物包括但不限于下述1)-66)化合物中任一种：
1)(N-苄基)氨基甲酸-(2-叔丁基-4-甲氧基苯酚)酯，
2)(N-正丁基)氨基甲酸(2-叔丁基-4-甲氧基苯酚)酯，
3)(N-异丙基)氨基甲酸(2-叔丁基-4-甲氧基苯酚)酯，
4)(N-环己基)氨基甲酸(2-叔丁基-4-甲氧基苯酚)酯，
5)(N-苯乙基)氨基甲酸(2-叔丁基-4-甲氧基苯酚)酯，
6)特戊酰(2-叔丁基-4-甲氧基苯酚氧基)甲基酯；
7)苯甲酸-2-叔丁基-4-甲氧基苯酚酯，
8)乙酸-2-叔丁基-4-甲氧基苯酚酯，
9)烟酸-2-叔丁基-4-甲氧基苯酚酯，
10)异烟酸-2-叔丁基-4-甲氧基苯酚酯，
11)环己烯甲酸-2-叔丁基-4-甲氧基苯酚酯，
12)丙酸-2-叔丁基-4-甲氧基苯酚酯，
13)丙烯酸-2-叔丁基-4-甲氧基苯酚酯，
14)3,4-二甲氧基苯乙酸(2-叔丁基-4-甲氧基苯酚)-酯，
15)丁炔酸-2-叔丁基-4-甲氧基苯酚酯，
16)2,2‘-联苯二甲酸双(2-叔丁基-4-甲氧基苯酚)酯，
17)2-氯-5-三氟甲基苯甲酸(2-叔丁基-4-甲氧基苯酚)酯，
18)3-氟苯乙酸(2-叔丁基-4-甲氧基苯酚)酯，
19)(1H-吲哚-3基)乙酸(2-叔丁基-4-甲氧基苯酚)酯，
20)3-(4-氟苯基)-丙酸-(2-叔丁基-4-甲氧基苯酚)酯，
21)N-叔定氧羰基哌啶-3-甲酸(2-叔丁基-4-甲氧基苯酚)酯，
22)对苯二甲酸二(2-叔丁基-4-甲氧基苯酚)酯，
23)3-(3-硝基苯基)丙酸(2-叔丁基-4-甲氧基苯酚)酯，
24)4-苯基苯甲酸(2-叔丁基-4-甲氧基苯酚)酯，
25)4-甲基吡啶-3-甲酸(2-叔丁基-4-甲氧基苯酚)酯，
26)4-甲氧基吡啶-3-甲酸(2-叔丁基-4-甲氧基苯酚)酯，
27)十六酸-2-叔丁基-4-甲氧基苯酚酯，
28)N-叔丁氧羰基甘氨酸(2-叔丁基-4-甲氧基苯酚)酯，
29)3-氟-4-氯苯甲酸(2-叔丁基-4-甲氧基苯酚)酯，
30)N-叔丁氧羰基四氢吡咯、苯并杂环-3-甲酸(2-叔丁基-4-甲氧基苯酚)酯，
31)3-氰基苯甲酸(2-叔丁基-4-甲氧基苯酚)酯，
32)N-叔丁氧羰基丙氨酸(2-叔丁基-4-甲氧基苯酚)酯，
33)2-萘甲酸(2-叔丁基-4-甲氧基苯酚)酯，
34)丙二酸二(2-叔丁基-4-甲氧基苯酚)酯，
35)3,6-二氯哒嗪-4-甲酸(2-叔丁基-4-甲氧基苯酚)酯，
36)1-甲基环丙甲酸(2-叔丁基-4-甲氧基苯酚)酯，
37)2-吲哚甲酸(2-叔丁基-4-甲氧基苯酚)酯，
38)2-氯-3-吡啶甲酸(2-叔丁基-4-甲氧基苯酚)酯，
39)2-噻吩乙酸(2-叔丁基-4-甲氧基苯酚)酯，
40)3-(4-甲基苯基)-丙酸(2-叔丁基-4-甲氧基苯酚)酯，
41)丙炔酸(2-叔丁基-4-甲氧基苯酚)酯，
42)2-苯基丙酸(2-叔丁基-4-甲氧基苯酚)酯，
43)2-氟丙酸(2-叔丁基-4-甲氧基苯酚)酯，
44)环己乙酸(2-叔丁基-4-甲氧基苯酚)酯，
45)环戊甲酸(2-叔丁基-4-甲氧基苯酚)酯，
46)金刚烷乙酸(2-叔丁基-4-甲氧基苯酚)酯，
47)环丙基乙酸(2-叔丁基-4-甲氧基苯酚)酯，
48)N-叔丁氧羰基哌啶-4-甲酸(2-叔丁基-4-甲氧基苯酚)酯，
49)辛酸(2-叔丁基-4-甲氧基苯酚)酯，
50)7-氧代辛酸(2-叔丁基-4-甲氧基苯酚)酯，
51)环己-2-烯甲酸(2-叔丁基-4-甲氧基苯酚)酯，
52)2,4,5-三氟苯乙酸(2-叔丁基-4-甲氧基苯酚)酯，
53)2-溴-5-碘苯甲酸(2-叔丁基-4-甲氧基苯酚)酯，
54)2-氟-4-硝基苯甲酸(2-叔丁基-4-甲氧基苯酚)酯，
55)N-叔丁氧羰基哌啶-3-甲酸(2-叔丁基-4-甲氧基苯酚)酯，
56)对苯二乙酸二(2-叔丁基-4-甲氧基苯酚)酯，
57)4-苯甲酰丁酸(2-叔丁基-4-甲氧基苯酚)酯，
58)3,5-二甲氧基苯并烯酸(2-叔丁基-4-甲氧基苯酚)酯，
59)4-氯吡啶-2-甲酸(2-叔丁基-4-甲氧基苯酚)酯，
60)N-甲基哌啶-3-甲酸(2-叔丁基-4-甲氧基苯酚)酯，
61)、N-叔丁氧羰基-6-氨基戊酸(2-叔丁基-4-甲氧基苯酚)酯，
62)3,3,3-三氟丙酸(2-叔丁基-4-甲氧基苯酚)酯，
63)吗啉-4-基乙酸(2-叔丁基-4-甲氧基苯酚)酯，
64)3-(3,5-二叔丁基-4-羟基-苯基)丙酸-(2-叔丁基-4-甲氧基苯酚)酯，
65)己二酸二(2-叔丁基-4-甲氧基苯酚)酯；
66)2-(2-叔丁基-4-甲氧基苯氧基)乙酸乙酯。
本发明进一步提供了式Ⅰ所示化合物的制备方法，包括如下(1)、(2)、(3)或(4)的步骤：
(1)当X为C＝O时，Y为NH时，包括如下步骤：
RCH2与三光气进行反应得到R-N＝C＝O；R-N＝C＝O与2-叔丁基-4-甲氧基苯酚经缩合反应即得式Ⅰ所示化合物；
式Ⅰ、RCH2和R-N＝C＝O中，R选自下述基团中任一种：至少1个碳原子的取代或未取代的烷基、至少3个碳原子的取代或未取代的环烷基、至少2个碳原子数为的取代或未取代的烯基或炔基和取代或未取代的芳基或杂芳基；
R中取代基为卤素、氨基、硝基、酯基、羰基、氨基酸衍生物、天然黄酮、天然生物碱、聚乙二醇、多聚谷氨酸或多糖；
式Ⅰ中，X为C＝O，Y为NH；
(2)当X为CH2时，Y为O时，包括如下步骤：
2-叔丁基-4-甲氧基苯酚钠与式1所示化合物经缩合反应即得式Ⅰ所示化合物；
式Ⅰ和式1中，R选自下述基团中任一种：至少1个碳原子的取代或未取代的烷基、至少3个碳原子的取代或未取代的环烷基、至少2个碳原子的取代或未取代的烯基或炔基和取代或未取代的芳基或杂芳基；
R中取代基为卤素、氨基、硝基、酯基、羰基、氨基酸衍生物、天然黄酮、天然生物碱、聚乙二醇、多聚谷氨酸或多糖；
式Ⅰ中，X为CH2，Y为O；
(3)X为C＝O，Y不存在时，即为式Ⅱ所示化合物，包括如下1)或2)的步骤：
1)2-叔丁基-4-甲氧基苯酚钠与式2所示酰氯经缩合即得式Ⅱ所示化合物；
式Ⅱ和式2中，R选自下述基团中任一种：至少1个碳原子的取代或未取代的烷基、至少3个碳原子的取代或未取代的环烷基、至少2个碳原子的取代或未取代的烯基或炔基和取代或未取代的芳基或杂芳基；
R中取代基为卤素、氨基、硝基、酯基、羰基、氨基酸衍生物、天然黄酮、天然生物碱、聚乙二醇、多聚谷氨酸或多糖；
式Ⅱ中，X为C＝O；
2)2-叔丁基-4-甲氧基苯酚钠与式3所示羧酸经缩合即得式Ⅱ所示化合物；
式Ⅱ和式3中，R选自下述基团中任一种：至少1个碳原子的取代或未取代的烷基、至少3个碳原子的取代或未取代的环烷基、至少2个碳原子的取代或未取代的烯基或炔基和取代或未取代的芳基或杂芳基；
R中取代基为卤素、氨基、硝基、酯基、羰基、氨基酸衍生物、天然黄酮、天然生物碱、聚乙二醇、多聚谷氨酸或多糖；
式Ⅱ中，X为C＝O；
(4)当X为CH2，Y不存在时，即式Ⅱ所示化合物，包括如下步骤：
2-叔丁基-4-甲氧基苯酚钠与式4所示化合物经缩合反应即得式Ⅱ所示化合物；
式Ⅱ和式4中，R选自下述基团中任一种：至少1个碳原子的取代或未取代的烷基、至少3个碳原子的取代或未取代的环烷基、至少2个碳原子的取代或未取代的烯基或炔基和取代或未取代的芳基或杂芳基；
R中取代基为卤素、氨基、硝基、酯基、羰基、氨基酸衍生物、天然黄酮、天然生物碱、聚乙二醇、多聚谷氨酸或多糖；
X为CH2。
上述制备方法中，所述缩合反应可在常规的反应条件，如室温、加热、回流或者冰浴等条件下进行。
式Ⅰ所示化合物、其药学上可接受的盐、其水合物或其溶剂合物可应用于抗肿瘤或免疫调节，即利用式Ⅰ所示化合物在体内能够释放为2-叔丁基-4-甲氧基苯酚.
本发明验证了2-叔丁基-4-甲氧基苯酚(BHA)能够抑制巨噬细胞M2极化的作用，并在Her2乳腺癌小鼠模型上证实了2-叔丁基-4-甲氧基苯酚的抗肿瘤转移作用；HER2小鼠模型，2-叔丁基-4-甲氧基苯酚剂量(50-1000mg/kg BW)分次给药显示明显的抗肿瘤作用。
本发明优势在于：1)本发明提供的化合物可以在体内缓释释放2-叔丁基-4-甲氧基苯酚，克服2-叔丁基-4-甲氧基苯酚直接给药体内半衰期短的缺点(T1/2＝0.5～1h)，保持平稳的2-叔丁基-4-甲氧基苯酚血药浓度(T1/2＝12～24h)。2)本发明提供的化合物等效剂量更低，达到相同血药浓度和类似药时曲线(AUC)，本发明化合物的给药剂量仅为2-叔丁基-4-甲氧基苯酚直接给药剂量的1/100～1/5000，避免高剂量的2-叔丁基-4-甲氧基苯酚所致的毒性作用；3)本发明提供的化合物与2-叔丁基-4-甲氧基苯酚相比细胞毒性更小，部分化合物小鼠急性毒性(LD50>1200mg/kg)，比2-叔丁基-4-甲氧基苯酚(LD50＝1100mg/kg)；4)本发明提供的化合物保护了2-叔丁基-4-甲氧基苯酚的酚羟基，避免了在环境中的氧化作用，提高了药物的环境稳定性。
附图说明
图1为2-叔丁基-4-甲氧基苯酚抑制巨噬细胞M2极化作用的示意图。
图2为BHA在小鼠体内代谢的实验结果。
图3为本发明化合物在人体血浆中释放BHA的曲线。
图4为本发明化合物在小鼠体内释放BHA的曲线。
具体实施方式
下述实施例中所使用的实验方法如无特殊说明，均为本专业领域常规方法。
下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
本发明首先验证了2-叔丁基-4-甲氧基苯酚(BHA)抑制巨噬细胞M2极化的作用，并在Her2乳腺癌小鼠模型上证实了2-叔丁基-4-甲氧基苯酚的抗肿瘤转移作用，如图1所示，在乳腺癌Her发瘤模型上，BHA给药组小鼠肿瘤未见转移头部(左图)，空白对照组小鼠头部转移明显，以致双目失明(右图)。同时，通过药物代谢试验发现BHA在体内的半衰期很短只有30-60分钟，如图2所示。此外，本发明进行毒理学实验，发现小鼠600mg/kg给药，仅见部分“宿醉”状的中枢作用，半小时后可以恢复，1100mg/kg半数小鼠致死，存活的小鼠在30-60分钟后，毒性反应症状消失；低剂量小鼠长期给药2年未见毒性作用；因此，结合文献2-叔丁基-4-甲氧基苯酚的代谢产物(具有DNA损伤作用，Food and Chemical Toxicology 1999，37:1027-1038)研究结果，本发明推断2-叔丁基-4-甲氧基苯酚本身具有抗肿瘤作用，其代谢产物tert-butylhydroquinone(TBHQ)与DNA的作用可能是其副作用产生的原因。
深入分析发现，2-叔丁基-4-甲氧基苯酚口服吸收和代谢都很快(达峰时间5min，小鼠T1/2＝20min)，每次给药的血药浓度都是一个时间跨度很小的“脉冲”，在药物浓度峰值远远高于最低有效药物浓度，不仅不利于疗效的发挥，而且导致不必要的毒副作用。
因此，如能控制2-叔丁基-4-甲氧基苯酚的释放，使之保持平稳的血药浓度，不仅可以在实现增效减毒的作用，而且可以有效降低2-叔丁基-4-甲氧基苯酚的剂量。同时，由于2-叔丁基-4-甲氧基苯酚是一种抗氧剂，易被氧化，因此环境稳定性和在肝脏中代谢(首过效应严重)也是其成为药物的直接障碍。本发明为了控制2-叔丁基-4-甲氧基苯酚的释放、提高环境稳定性和尽量减少首过效应、提高药物安全性，提供了2-叔丁基-4-甲氧基苯酚前药，并验证了它们在体外、体内的释放特性，细胞毒性以及体内安全性。
实施例1、苯甲酸-2-叔丁基-4-甲氧基苯酚酯的制备(XH2005)
将2-叔丁基-4-甲氧基苯酚(0.9g，5mmol)溶于无水四氢呋喃(20mL)中，滴加到0-5℃的氢化钠(220mg，5.5mmol)/无水四氢呋喃混合液(10mL)中，加毕，保温反应1小时。将苯甲酰氯(0.58mL，5mmol)/二氯甲烷(10mL)滴加到上步所得的反应液中，加毕保温反应2小时，然后室温反应3小时。减压除去溶剂，残余物加入乙酸乙酯(30mL)和冰水(10mL)，搅拌澄清，分液，取有机层，水洗10mL×3，无水硫酸钠干燥过夜，柱层析(展开剂乙酸乙酯:石油醚＝4：1)得到白色固体1.14g。收率80％。1H NMR(400MHz,DMSO-d6)δ:1.30(s,9H),3.78(s,3H),6.86-6.92(m,2H),7.09-7.11(d,J＝8.4Hz,1H),7.62-7.66(m,2H),7.75-7.79(m,1H),8.15-8.17(d,J＝7.2Hz,2H)；13C NMR(100MHz,DMSO-d6)δ:29.8,34.2,55.3,111.1,113.1,125.2,129.2,129.3,129.7,134.1,141.9,142.3,156.6,165.0.
实施例2、乙酸-2-叔丁基-4-甲氧基苯酚酯的制备(XH2006)
按照实施例1中的方法进行制备，2-叔丁基-4-甲氧基苯酚与氢化钠反应后，再与乙酰氯反应，制备实施例2所述化合物，经乙醇重结晶纯化，收率90％。1H NMR(400MHz,CDCl3)δ:1.33(s,9H),2.32(s,3H),3.79(s,3H),6.72-6.75(m,1H),6.91-6.93(m,2H).13C NMR(100MHz,CDCl3)δ:21.6,30.1,34.6,55.6,110.6,113.9,124.6,142.4,142.7,156.9,170.2.
实施例3、烟酸-2-叔丁基-4-甲氧基苯酚酯(XH2010)
将烟酸(0.62g，5mmol)加入到二甲基甲酰胺(20mL)中，加入二环己基碳二亚胺(1200mg，6mmol)，搅拌5分钟，加入2-叔丁基-4-甲氧基苯酚(900mg，5mmol)，保温35-40℃反应过夜。减压除去二甲基甲酰胺，残余物加入乙酸乙酯(50mL)和水(2mL)，搅拌20分钟，抽滤，滤液经柱层析(洗脱剂位乙酸乙酯:石油醚＝3:1)纯化得到产物。收率73％。1H NMR(400MHz,CDCl3)δ:1.34(s,9H),3.81(s,3H),6.76-6.81(m,1H),6.97-7.03(m,2H),7.46-7.49(m,1H),8.44-8.47(dt,J1＝8.4Hz,J2＝2.0Hz,1H),8.84-8.86(dd,J1＝4.8Hz,J2＝1.6Hz,1H),9.41-9.42(d,J＝2.0Hz,1H)；13C NMR(100MHz,CDCl3)δ:30.2,34.7,55.6,110.8,114.1,123.7,124.7,125.9,137.7,142.5,142.7,151.5,154.1,157.3,164.6.
实施例4、异烟酸-2-叔丁基-4-甲氧基苯酚酯(XH2011)
制备方法与实施例3相同。异烟酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率75％。1H NMR(400MHz,CDCl3)δ:1.33(3,9H),3.81(s,3H),6.76-6.80(m,1H),6.97-7.01(m,2H),8.00-8.02(d,J＝6.2Hz,2H),8.86-8.87(d,J＝6.2Hz,2H).13C NMR(100MHz,CDCl3)δ:30.4,34.9,55.6,110.8,114.3,123.5,124.5,137.0,142.4,151.0,157.4,164.9.
实施例5、环己烯甲酸-2-叔丁基-4-甲氧基苯酚酯的制备(XH2015)
制备方法与实施例3相同。环己烯甲酸与2-叔丁基-4-甲氧基苯酚酯缩合，收率75％。1H NMR(400MHz,CDCl3)δ(ppm):1.32(s,9H),1.83-1.87(m,1H),2.16-2.23(m,3H),2.43-2.45(m,2H),2.81-2.84(m,1H),3.79(s,3H),5.75(d,J＝1.1Hz,2H),6.71-6.74(m,1H),6.85-6.87(d,J＝8.8Hz,1H),6.92-6.93(d,J＝3.0Hz,1H).13C NMR(100MHz,CDCl3)δ(ppm):24.5,24.9,27.4,30.0,34.5,39.9,55.4,110.5,113.7,124.4,125.0,126.8,142.2,142.9,156.7,174.8.
实施例6、丙酸-2-叔丁基-4-甲氧基苯酚酯(XH2016)
制备方法与实施例3相同。丙酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率85％。1H NMR(400MHz,CDCl3)δ:1.27-1.32(m,12H),2.59-2.63(q,J＝3.56Hz,2H),3.79(s,3H),6.77-6.75(m,1H),6.89-6.93(m,2H).13C NMR(100MHz,CDCl3)δ(ppm):9.0,28.3,30.1,34.6,55.5,110.5,113.8,124.5,142.3,142.8,156.8,173.4.
实施例7、丙烯酸-2-叔丁基-4-甲氧基苯酚酯(XH2017)
制备方法与实施例3相同。丙烯酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率55％。1H NMR(400MHz,CDCl3)δ(ppm):6.94-6.97(m,2H),6.77-6.75(m,1H),6.60(m,1H),6.36(m,1H),6.03-6.06(d,J＝24Hz,1H),3.81(s,3H),1.33(s,9H)13C NMR(100MHz,CDCl3)δ(ppm):156.8,142.5,132.6,128.5,124.5,113.9,110.5,55.5,34.6,30.0.
实施例8、3,4-二甲氧基苯乙酸(2-叔丁基-4-甲氧基苯酚)-酯(XH2018)
制备方法与实施例3相同。3,4-二甲氧基苯乙酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率83％。1H NMR(400MHz,CDCl3)δ(ppm):6.92-6.84(m,5H),6.72-6.68(m,1H),3.88(s,6H),3.82(s,2H),3.78(s,3H),1.27(s,9H).13C NMR(100MHz,CDCl3)δ(ppm):170.8,157.0,149.1,148.4,142.9,142.5,125.7,124.5,122.0,113.9,112.7,111.3,110.6,56.1,56.0,55.6,41.8,34.6,30.0.
实施例9、丁炔酸-2-叔丁基-4-甲氧基苯酚酯(XH2019)
制备方法与实施例3相同。丁炔酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率41％。1H NMR(400MHz,CDCl3)δ:1.35(s,9H),2.07(s,3H),3.82(s,3H),6.77-6.75(m,1H),6.94-6.97(m,2H).13C NMR(100MHz,CDCl3)δ(ppm):29.5,30.2,34.7,55.6,72.6,88.1,110.6,114.0,124.5,142.1,142.7,153.0,157.3.
实施例10、2,2’-联苯二甲酸双(2-叔丁基-4-甲氧基苯酚)酯(XH2020)
制备方法与实施例3相同。2,2’-联苯二甲酸与2-叔丁基-4-甲氧基苯酚按照摩尔比为1:2的投料比反应，收率62％。1H NMR(400MHz,CDCl3)δ(ppm):1.26(s,9H),3.76(s,6H),6.65-6.68(m,2H),6.77-6.79(m,2H),6.87-6.88(m,2H),7.26-7.29(m,2H),7.45-7.48(m,2H),7.55-7.58(m,2H),8.19-8.21(dd,J1＝7.8Hz,J2＝1.4Hz,2H).13CNMR(100MHz,CDCl3)δ(ppm):28.8,33.2,54.2,109.2,112.4,123.2,126.2,127.6,129.1,130.7,141.3,141.5,142.8,155.4,164.4.
实施例11、2-氯-5-三氟甲基苯甲酸(2-叔丁基-4-甲氧基苯酚)酯(XH2021)
制备方法与实施例3相同。2-氯-5-三氟甲基苯甲酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率74％。1H NMR(400MHz,CDCl3)δ(ppm):1.38(s,9H),3.83(s,3H),6.80-6.82(m,1H),6.99(m,1H),7.06-7.08(m,1H),7.60-7.64(m,1H),7.74-7.78(m,1H),8.32(s,1H),13C NMR(100MHz,CDCl3)δ(ppm):30.2,34.7,55.6,110.8,114.1,124.5,128.8,129.7,130.5,132.3,138.5,142.6,157.4,163.5.
实施例12、3-氟苯乙酸(2-叔丁基-4-甲氧基苯酚)酯(XH2022)
制备方法与实施例3相同。3-氟苯乙酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率80％。1H NMR(400MHz,CDCl3)δ(ppm):1.23(s,9H),3.78(s,3H),3.88(s,2H),6.68-6.71(m,1H),6.81-6.85(m,2H),6.90-7.10(m,1H),7.12-7.18(m,1H),7.32-7.38(m,1H),13C NMR(100MHz,CDCl3)δ(ppm):29.9,34.5,41.7,55.5,110.5,113.8,114.3,114.5,116.6,124.3,125.3,130.1,130.2,135.3,135.4,142.3,142.6,156.9,161.9,164.1,169.8.
实施例13、(1H-吲哚-3基)乙酸(2-叔丁基-4-甲氧基苯酚)酯(XH2023)
制备方法与实施例3相同。1H-吲哚-3乙酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率65％。1H NMR(400MHz,CDCl3)δ(ppm):1.32(s,9H),3.81(s,3H),6.66-6.70(m,2H),6.78-6.82(m,1H),6.85-6.90(m,1H),7.12-7.42(m,2H),7.67(m,1H),8.32(s,1H),13C NMR(100MHz,CDCl3)δ(ppm):30.0,32.1,34.7,55.7,107.9,110.6,111.0,111.5,113.9,114.2,119.0,119.9,122.4,123.6,124.6,124.7,132.5,143.2,143.7,157.0,157.5,163.7,171.2.
实施例14、3-(4-氟苯基)-丙酸-(2-叔丁基-4-甲氧基苯酚)酯(XH2024)
制备方法与实施例3相同。3-(4-氟苯基)-丙酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率64％。1H NMR(400MHz,CDCl3)δ(ppm):1.28(s,9H),2.88(m,2H),3.06(m,2H),3.82(s,3H),6.52(m,1H),6.79(m,1H),6.91(m,1H),6.99(m,2H),7.25(m,2H).13C NMR(100MHz,CDCl3)δ(ppm):30.0,34.4,36.6,55.4,110.5,111.7,113.7,115.2,115.4,124.4,129.9,135.7,142.2,142.5,156.8,160.3,162.8,171.6.
实施例15、N-叔定氧羰基哌啶-3-甲酸(2-叔丁基-4-甲氧基苯酚)酯(XH2025)
制备方法与实施例3相同。N-叔定氧羰基哌啶-3-甲酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率60％。1H NMR(400MHz,CDCl3)δ(ppm):1.32(s,9H),1.47(s,9H),1.76-1.82(m,2H),2.22-2.26(m,1H),2.79(m,1H),2.84-2.88(m,1H),3.16-3.20(m,1H),3.82(s,3H),3.97-4.02(m,1H),4.33-4.36(m,1H),6.68(m,1H),6.83(m,1H),6.92(m,1H),13C NMR(100MHz,CDCl3)δ(ppm):24.4,27.5,28.6,29.7,30.2,34.8,42.1,55.7,110.8,113.9,124.6,142.8,154.8,157.1,172.6.
实施例16、对苯二甲酸二(2-叔丁基-4-甲氧基苯酚)酯(XH2026)
制备方法与实施例3相同。对苯二甲酸(5mmol)与2-叔丁基-4-甲氧基苯酚(10mmol)缩合，收率55％。1H NMR(400MHz,CDCl3)δ(ppm):1.37(s,18H),3.83(s,6H),6.80-6.83(m,2H),7.00-7.05(m,4H),8.38(s,4H),13C NMR(100MHz,CDCl3)δ(ppm):30.1,34.6,55.5,110.7,113.9,124.5,130.4,134.1,142.5,142.6,157.1,164.5.
实施例17、3-(3-硝基苯基)丙酸(2-叔丁基-4-甲氧基苯酚)酯(XH2028)
制备方法与实施例3相同。3-(3-硝基苯基)丙酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率70％。1H NMR(400MHz,CDCl3)δ(ppm):1.33(s,9H),2.94-2.99(t,J＝7.2Hz,2H),3.14-3.20(t,J＝7.2Hz,2H),3.78(s,3H),6.69-6.73(m,1H),6.80-6.83(d,J＝8.8Hz,1H),6.89-6.90(d,J＝2.1Hz,1H),7.45-7.50(m,1H),7.61-7.64(m,1H),8.08-8.11(m,1H),8.14-8.16(m,1H).13C NMR(100MHz,CDCl3)δ(ppm):30.2,34.5,36.0,55.7,110.7,114.1,121.9,123.5,124.6,129.7,135.2,142.3,142.6,148.5,157.1,171.4.
实施例18、4-苯基苯甲酸(2-叔丁基-4-甲氧基苯酚)酯(XH2029)
制备方法与实施例3相同。4-苯基苯甲酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率80％。1H NMR(400MHz,CDCl3)δ(ppm):1.38(s,9H),3.80(s,3H),6.78-6.80(m,1H),6.98-7.04(m,2H),7.18-7.22(m,2H),7.63-7.65(m,2H),7.72-7.74(m,2H),8.28-8.30(m,2H).13C NMR(100MHz,CDCl3)δ(ppm):30.1,34.6,55.5,110.6,113.8,124.7,127.3,128.3,128.5,130.7,139.8,142.6,142.8,146.3,156.9,165.6.
实施例19、4-甲基吡啶-3-甲酸(2-叔丁基-4-甲氧基苯酚)酯(XH2030)
制备方法与实施例3相同。4-甲基吡啶-3-甲酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率80％。1H NMR(400MHz,CDCl3)δ(ppm):1.38(s,9H),2.68(s,3H),3.82(s,3H),6.78-6.81(m,1H),6.98-6.99(m,1H),7.02-7.04(m,1H),7.33-7.35(m,1H),8.34-8.36(m,1H),9.31-9.32(d,J＝1.68Hz,1H),13C NMR(100MHz,CDCl3)δ:24.9,30.2,55.5,110.7,114.0,123.4,124.7,138.0,150.4,156.4,157.1,164.0,164.7.
实施例20、4-甲氧基吡啶-3-甲酸(2-叔丁基-4-甲氧基苯酚)酯(XH2031)
制备方法与实施例3相同。4-甲氧基吡啶-3-甲酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率75％。由于邻位甲氧基的影响，NMR可见手性面所致的立体异构体的成对峰的出现，2个异构体的比例为1:2。1H NMR(400MHz,CDCl3)δ:1.33(s,9H),3.81(s,3H),3.82&4.00(s,3H),6.76-6.81(m,1H),6.97-7.01(m,2H),7.47-7.48&8.04-8.05(m,1H),7.55-7.58&7.93-7.95(m,1H),8.35-8.37&8.63-8.64(m,1H).13C NMR(100MHz,CDCl3)δ:30.0,34.5,53.8,55.3,110.5,111.6,113.8,115.9,124.3,139.9,142.3,147.9,150.8,152.6,157.1,157.3,163.1,164.1,164.8.
实施例21、十六酸-2-叔丁基-4-甲氧基苯酚酯(XH2033)
制备方法与实施例3相同。十六酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率75％。1H NMR(400MHz,CDCl3)δ(ppm):0.88(m,3H),1.25-1.33(m,34H),1.71-1.79(m,2H),2.55-2.59(m,2H),3.78(s,3H),6.71-6.74(m,1H),6.88-6.93(m,2H).13C NMR(100MHz,CDCl3)δ(ppm):14.3,22.8,24.9,29.3,29.5,29.6,29.7,29.8,,30.1,32.034.8,35.0,55.5,110.5,113.9,124.6,142.3,142.8,156.8,172.9.
实施例22、N-叔丁氧羰基甘氨酸(2-叔丁基-4-甲氧基苯酚)酯(XH2034)
制备方法与实施例3相同。N-叔丁氧羰基甘氨酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率45％。1H NMR(400MHz,CDCl3)δ(ppm):1.30(s,9H),1.46(s,9H),3.83(s,3H),4.20(s,2H),5.2(br s,1H),6.71-6.73(m,1H),6.92-6.94(m,2H),13C NMR(100MHz,CDCl3)δ(ppm):28.2,30.0,34.4,42.9,55.4,80.0,110.4,113.8,124.2,142.2,155.5,156.9,169.5.
实施例23、3-氟-4-氯苯甲酸(2-叔丁基-4-甲氧基苯酚)酯(XH2035)
制备方法与实施例3相同。3-氟-4-氯苯甲酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率78％。1H NMR(400MHz,CDCl3)δ(ppm):1.34(s,9H),3.82(s,3H),6.71-6.73(m,1H),6.98-7.00(m,2H),7.56-7.60(m,1H),7.96-7.97(m,2H).13C NMR(100MHz,CDCl3)δ:30.2,34.7,55.6,110.8,114.1,118.4,124.6,126.6,130.4,131.2,142.6,156.9,157.3,159.4,164.1.
实施例24、N-叔丁氧羰基四氢吡咯、苯并杂环-3-甲酸(2-叔丁基-4-甲氧基苯酚)酯(XH2036-1)
制备方法与实施例3相同。N-叔丁氧羰基四氢吡咯、苯并杂环-3-甲酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率70％。1H NMR(400MHz,CDCl3)δ(ppm):1.32(s,9H),1.46(s,9H),2.30-2.32(m,2H),3.28-3.34(m,1H),3.38-3.44(m,1H),3.52-3.58(m,1H),3.72-3.82(m,2H),3.82(s,3H),6.70-6.74(m,1H),6.85-6.88(m,1H),6.92-6.93(m,2H).13C NMR(100MHz,CDCl3)δ(ppm):28.4,30.0,34.5,43.4,45.1,47.8,55.5,79.5,110.5,113.8,124.3,142.1,142.5,154.2,156.9,172.0.
实施例25、3-氰基苯甲酸(2-叔丁基-4-甲氧基苯酚)酯(XH2036-2)
制备方法与实施例3相同。3-氰基苯甲酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率70％。1H NMR(400MHz,CDCl3)δ(ppm):1.35(s,9H),3.82(s,3H),6.78-6.81(m,1H),6.99-7.01(m,2H),7.67-7.71(t,J＝3.84Hz,1H),7.92-7.95(m,1H),8.44-8.47(m,2H),8.50(s,1H).13C NMR(100MHz,CDCl3)δ(ppm):30.1,34.5,55.6,110.7,113.3,113.9,117.7,124.4,129.8,131.1,133.7,134.1,136.5,142.4,157.2,163.9.
实施例26、N-叔丁氧羰基丙氨酸(2-叔丁基-4-甲氧基苯酚)酯(XH2036-3)
制备方法与实施例3相同。N-叔丁氧羰基丙氨酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率37％。1H NMR(400MHz,CDCl3)1.32(s,9H),1.40(s,9H),1.43(d,2H),3.73(s,3H),4.61(m,1H),6.99-7.01(m,2H),6.78-6.81(m,1H).
实施例27、2-萘甲酸(2-叔丁基-4-甲氧基苯酚)酯(XH2036-4)
制备方法与实施例3相同。2-萘甲酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率77％。1H NMR(400MHz,CDCl3)δ(ppm):1.32(s,9H),3.73(s,3H),6.84(m,1H),6.88-6.89(m,2H),7.46-7.49(m,3H),7.82-7.85(m,4H).13C NMR(100MHz,CDCl3)δ(ppm):30.0,34.6,42.4,55.5,110.6,113.9,124.5,126.4,127.6,127.8,128.6,130.7,131.7,133.6,142.4,142.9,157.0,170.5.
实施例28、丙二酸二(2-叔丁基-4-甲氧基苯酚)酯(XH2037)
制备方法与实施例3相同。丙二酸(5mmol)与2-叔丁基-4-甲氧基苯酚(10mmol)缩合反应制备，收率70％。1H NMR(400MHz,CDCl3)δ(ppm):1.35(s,18H),3.80(s,6H),3.88(s,2H),6.75(m,2H),6.94(m,2H),6.99-7.01(m,2H).13C NMR(100MHz,CDCl3)δ(ppm):30.2,34.7,42.6,55.5,110.8,114.0,124.4,142.5,142.6,157.3,165.4.
实施例29、3,6-二氯哒嗪-4-甲酸(2-叔丁基-4-甲氧基苯酚)酯(XH2038-1)
制备方法与实施例3相同。3,6-二氯哒嗪-4-甲酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率77％。1H NMR(400MHz,CDCl3)δ(ppm):1.36(s,9H),3.82(s,3H),6.76-6.79(m,1H),6.97-7.02(m,2H),7.99(s,1H).13C NMR(100MHz,CDCl3)δ(ppm):30.2,34.7,55.6,110.8,114.1,124.4,131.5,137.8,138.8,142.3,142.6,157.5,158.0,161.4.
实施例30、1-甲基环丙甲酸(2-叔丁基-4-甲氧基苯酚)酯(XH2038-2)
制备方法与实施例1相同。1-甲基环丙甲酸与氯化亚砜反应，再与2-叔丁基-4-甲氧基苯酚钠缩合反应制备，收率87％。1H NMR(400MHz,CDCl3)δ(ppm):0.83-0.85(m,2H),1.33(s,9H),1.40-1.42(m,2H),1.46(s,3H),3.78(s,3H),6.72-6.73(m,1H),6.84-6.87(m,1H),6.90-6.92(m,1H),13C NMR(100MHz,CDCl3)δ(ppm):17.3,19.1,19.7,30.1,34.6,55.6,110.6,113.7,124.7,142.4,143.2,156.7,175.2.
实施例31、2-吲哚甲酸(2-叔丁基-4-甲氧基苯酚)酯(XH2038-3)
制备方法与实施例3相同。2-吲哚甲酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率67％。1H NMR(400MHz,CDCl3)δ(ppm):1.33(s,3H),3.77(s,3H),7.08-7.11(m,1H),7.16-7.20(m,1H),7.32-7.40(m,2H),7.43-7.44(m,1H),7.74-7.77(m,1H),9.36(s,1H),13C NMR(100MHz,CDCl3)δ(ppm):30.1,34.6,55.5,109.9,110.5,112.1,113.9,121.0,122.7,124.6,125.8,126.8,127.4,137.3,142.3,142.7,157.0,161.3.
实施例32、2-氯-3-吡啶甲酸(2-叔丁基-4-甲氧基苯酚)酯(XH2038-4)
制备方法与实施例3相同。2-氯-3-吡啶甲酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率87％。1H NMR(400MHz,CDCl3)δ(ppm):1.34(s,9H),3.83(s,3H),6.79-6.82(m,1H),6.98-6.99(m,1H),7.05-7.07(m,1H),7.43(m,1H),8.37-8.39(m,1H),8.61(s,1H).13C NMR(100MHz,CDCl3)δ(ppm):30.2,34.7,55.6,110.9,114.1,122.4,124.5,126.7,140.5,142.5,142.6,150.7,152.5,157.4,163.7.
实施例33、2-噻吩乙酸(2-叔丁基-4-甲氧基苯酚)酯(XH2038-5)
制备方法与实施例3相同。2-噻吩乙酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率70％。1H NMR(400MHz,CDCl3)δ(ppm):1.27(s,9H),3.78(s,3H),4.10(s,2H),6.70-6.73(m,1H),6.87(m,1H),6.90-.92(m,2H),6.98-7.07(m,1H),7.04-7.06(m,2H),7.24(m,1H).13C NMR(100MHz,CDCl3)δ(ppm):30.1,34.6,36.1,55.5,110.6,113.9,124.4,125.4,127.1,127.5,134.2,142.4,142.8,157.0,169.4.
实施例34、3-(4-甲基苯基)-丙酸(2-叔丁基-4-甲氧基苯酚)酯(XH2039-1)
制备方法与实施例3相同。3-(4-甲基苯基)-丙酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率65％。1H NMR(400MHz,CDCl3)δ(ppm):1.29(s,9H),2.32(s,3H),2.88-2.90(t,J＝8.2Hz,2H),3.03-3.05(t,J＝8.2Hz,2H),3.78(s,3H),6.69-6.72(m,1H),6.81-6.84(m,1H),6.90-.92(m,1H),7.12-7.15(m,4H).13C NMR(100MHz,CDCl3)δ(ppm):21.0,30.3,34.5,36.6,55.4,110.4,113.7,124.4,128.3,129.2,135.8,137.0,142.2,142.6,156.7,171.8.
实施例35、2-苯基丙酸(2-叔丁基-4-甲氧基苯酚)酯(XH2039-3)
制备方法与实施例3相同。2-苯基丙酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率65％。1H NMR(400MHz,CDCl3)δ(ppm):1.16(s,9H),1.63-1.67(d,J＝8.8Hz,3H),3.76(s,3H),3.93-3.97(q,J＝8.8Hz,1H),6.68-6.70(m,2H),6.75-6.77(m,1H),6.87-6.88(m,1H),7.20-7.45(m,5H).13C NMR(100MHz,CDCl3)δ(ppm):18.1,29.7,34.4,46.1,55.4,110.4,113.6,124.1,127.4,127.8,128.7,139.5,142.3,142.9,156.7,173.3.
实施例36、2-氟丙酸(2-叔丁基-4-甲氧基苯酚)酯(XH2039-4)
制备方法与实施例3相同。2-氟丙酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率60％。1H NMR(400MHz,CDCl3)δ(ppm):1.33(s,9H),1.72-1.80(m,3H),3.80(s,3H),5.19-5.31(m,1H),6.73-6.76(m,1H),6.92-6.95(m,2H).13C NMR(100MHz,CDCl3)δ(ppm):18.0,18.2,29.9,34.6,55.4,84.9,86.7,110.5,113.9,123.9,142.0,142.3,157.1,169.4.
实施例37、环己乙酸(2-叔丁基-4-甲氧基苯酚)酯(XH2039-5)
制备方法与实施例3相同。环己乙酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率68％。1H NMR(400MHz,CDCl3)δ(ppm):1.00-1.20(m,3H),1.20-1.40(m,11H),1.63-1.76(m,3H),1.90-2.00(m,1H),1.83-1.87(m,2H),2.44-2.46(m,2H),3.77(s,3H),6.70-6.73(m,1H),6.88-6.92(m,2H).13C NMR(100MHz,CDCl3)δ(ppm):26.0,26.1,30.0,33.1,34.5,34.6,42.6,55.4,110.4,113.7,124.5,142.2,142.7,156.6,171.9.
实施例38、环戊甲酸(2-叔丁基-4-甲氧基苯酚)酯(XH2039-6)
制备方法与实施例3相同。环戊甲酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率78％。1H NMR(400MHz,CDCl3)δ(ppm):1.33(s,9H),1.63-1.70(m,2H),1.74-1.82(m,2H),1.93-2.07(m,4H),3.78(s,3H),6.71-6.73(m,1H),6.86-6.88(d,J＝8.8Hz,1H),6.91-6.92(d,J＝2.8Hz,1H).13C NMR(100MHz,CDCl3)δ(ppm):25.7,29.9,34.5,44.4,55.4,110.4,113.6,124.4,142.2,142.9,156.6,175.6.
实施例39、金刚烷乙酸(2-叔丁基-4-甲氧基苯酚)酯(XH2040-1)
制备方法与实施例3相同。金刚烷乙酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率70％。1H NMR(400MHz,CDCl3)δ(ppm):1.32(s,9H),1.66-1.76(m,12H),2.01(brs,3H),2.32(s,2H),3.79(s,3H),6.71-6.74(m,1H),6.91-6.94(m,2H).13C NMR(100MHz,CDCl3)δ(ppm):28.7,30.1,33.3,34.6,36.8,42.6,49.2,55.6,110.5,113.8,124.6,142.4,142.7,156.8,170.8.
实施例40、环丙基乙酸(2-叔丁基-4-甲氧基苯酚)酯(XH2040-2)
制备方法与实施例3相同。环丙基乙酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率73％。1H NMR(400MHz,CDCl3)δ(ppm):0.25-0.29(m,2H),0.61-0.66(m,2H),1.19-1.23(m,1H),1.33(s,9H),2.47-2.49(d,J＝7.2Hz,2H),3.79(s,3H),6.72-6.75(m,1H),6.91-6.93(m,2H).13C NMR(100MHz,CDCl3)δ(ppm):4.77,6.92,30.1,40.2,55.6,110.6,113.9,124.7,142.4,142.9,156.9,172.2.
实施例41、N-叔丁氧羰基哌啶-4-甲酸(2-叔丁基-4-甲氧基苯酚)酯(XH2040-3)
制备方法与实施例3相同。N-叔丁氧羰基哌啶-4-甲酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率73％。1H NMR(400MHz,CDCl3)δ(ppm):1.32(s,9H),1.47(s,9H),1.73-1.84(m,2H),2.05-2.10(m,2H),2.66-2.73(m,1H),2.85-2.93(m,2H),3.79(s,3H),4.11-4.16(m,2H),6.71-6.74(m,1H),6.82-6.84(d,J＝8.8Hz,1H),6.92-6.93(d,J＝3.2Hz,1H).13C NMR(100MHz,CDCl3)δ(ppm):28.0,28.5,30.1,34.7,41.8,43.4,55.6,79.8,110.7,113.8,124.5,142.3,142.8,154.7,156.9,173.7.
实施例42、辛酸(2-叔丁基-4-甲氧基苯酚)酯(XH2040-4)
制备方法与实施例3相同。辛酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率63％。1H NMR(400MHz,CDCl3)δ(ppm):0.87-0.91(m,3H),1.27-1.43(m,18H),1.73-1.81(m,2H),2.55-2.59(t,J＝7.6Hz,2H),6.71-6.74(m,1H),6.88-6.90(d,J＝8.8Hz,1H),6.92-6.93(d,J＝3.2Hz,1H).13C NMR(100MHz,CDCl3)δ(ppm):14.2,22.7,24.9,29.0,29.3,30.1,31.8,34.7,35.0,55.6,110.5,113.8,124.6,142.3,142.8,156.8,172.9.
实施例43、7-氧代辛酸(2-叔丁基-4-甲氧基苯酚)酯(XH2040-5)
制备方法与实施例3相同。7-氧代辛酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率60％。1H NMR(400MHz,CDCl3)δ(ppm):1.30-1.44(m,13H),1.60-1.66(m,2H),1.74-1.80(m,2H),2.16(s,3H),2.45-2.49(t,J＝7.2Hz,2H),2.57-2.60(t,J＝7.6Hz,2H),3.79(s,3H),6.71-6.74(m,1H),6.88-6.90(d,J＝8.8Hz,1H),6.92-6.93(d,J＝3.2Hz,1H).13C NMR(100MHz,CDCl3)δ(ppm):23.4,24.6,28.7,29.5,30.1,34.6,34.7,43.5,55.6,110.6,111.8,124.6,142.3,142.7,156.8,172.6,209.0.
实施例44、环己-2-烯甲酸(2-叔丁基-4-甲氧基苯酚)酯(XH2041-1)
制备方法与实施例3相同。环己-2-烯甲酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率57％。1H NMR(400MHz,CDCl3)δ(ppm):1.31(s,9H),2.78-2.86(m,4H),3.36-3.41(m,1H),3.79(s,3H),5.72(s,2H),6.71-6.74(m,1H),6.88-6.90(d,J＝8.8Hz,1H),6.92-6.93(d,J＝3.2Hz,1H).13C NMR(100MHz,CDCl3)δ(ppm):30.1,34.6,36.2,42.4,55.6,110.6,113.8,124.5,129.1,142.3,143.1,156.8,175.1.
实施例45、2,4,5-三氟苯乙酸(2-叔丁基-4-甲氧基苯酚)酯(XH2041-2)
制备方法与实施例3相同。2,4,5-三氟苯乙酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率77％。1H NMR(400MHz,CDCl3)δ(ppm):1.27(s,9H),3.78(s,3H),3.87(s,2H),6.71-6.74(m,1H),6.88-6.91(m,2H),6.95-7.01(m,1H),7.19-7.25(m,1H).13C NMR(100MHz,CDCl3)δ(ppm):29.8,34.4,55.4,105.4,105.6,105.7,105.9,110.5,113.8,119.1,119.3,124.2,142.2,142.5,157.0,168.7.
实施例46、2-溴-5-碘苯甲酸(2-叔丁基-4-甲氧基苯酚)酯(XH2041-3)
制备方法与实施例3相同。2-溴-5-碘苯甲酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率87％。1H NMR(400MHz,CDCl3)δ(ppm):1.34(s,9H),3.82(s,3H),6.78-6.80(m,1H),6.97-6.98(d,J＝2.8Hz,1H),7.05-7.07(d,J＝8.8Hz,1H),7.45-7.47(d,J＝8.4Hz,1H),7.69-7.71(dd,J1＝8.4Hz,J2＝2.0Hz,1H),8.28(d,J＝2.0Hz,1H).13CNMR(100MHz,CDCl3)δ(ppm):30.4,34.8,55.7,92.1,110.9,114.2,122.4,124.5,133.7,136.5,140.3,142.1,142.8,157.4,164.1.
实施例47、2-氟-4-硝基苯甲酸(2-叔丁基-4-甲氧基苯酚)酯(XH2041-4)
制备方法与实施例3相同。2-氟-4-硝基苯甲酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率85％。1H NMR(400MHz,CDCl3)δ(ppm):1.32(s,9H),3.83(s,3H),6.78-6.81(dd,J1＝8.4Hz,J2＝3.2Hz,1H),6.98-6.99(d,J＝3.2Hz,1H),7.02-7.05(d,J＝8.4Hz,1H),8.09-8.12(dd,J1＝9.6Hz,J2＝2.0Hz,1H),8.15-8.18(m,1H),8.30-8.34(m,1H).13C NMR(100MHz,CDCl3)δ(ppm):30.0,34.5,55.5,110.7,113.1,113.4,114.0,119.1,123.9,124.0,124.3,133.7,142.2,142.4,151.3,157.3,160.3,162.0,163.0.
实施例48、N-叔丁氧羰基哌啶-3-甲酸(2-叔丁基-4-甲氧基苯酚)酯(XH2041-5)
制备方法与实施例3相同。N-叔丁氧羰基哌啶-3-甲酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率65％。1H NMR(400MHz,CDCl3)δ(ppm):1.32(s,9H),1.47(s,9H),1.50-1.67(m,2H),1.76-1.82(m,2H),2.22-2.26(m,1H),2.67-2.73(m,1H),2.82-2.89(m,1H),3.10-3.16(m,1H),3.79(s,3H),3.98-4.01(m,1H),4.33(br s,1H),6.71-6.74(dd,J1＝8.8Hz,J2＝2.8Hz,1H),6.83-6.85(d,J＝8.8Hz,1H),6.91-6.92(d,J＝2.8Hz,1H).13CNMR(100MHz,CDCl3)δ(ppm):14.1,24.2,27.2,28.3,29.4,30.1,34.5,41.8,55.4,79.8,110.5,113.7,124.4,142.2,142.6,154.6,156.8,172.4.
实施例49、对苯二乙酸二(2-叔丁基-4-甲氧基苯酚)酯(XH2042)
制备方法与实施例3相同。对苯二乙酸(5mmol)与2-叔丁基-4-甲氧基苯酚(10mmol)缩合反应制备，收率65％。1H NMR(400MHz,CDCl3)δ(ppm):1.23(s,18H),3.74(s,6H),6.67–6.71(dd,J1＝8.8Hz,J2＝3.2Hz,2H),6.83-6.86(d,J＝8.8Hz,2H),6.89-6.90(d,J＝3.2Hz,2H),7.39(s,4H).13C NMR(100MHz,CDCl3)δ(ppm):30.1,34.6,41.9,55.6,110.7,114.0,124.6,130.1,132.5,142.5,142.9,157.1,170.5.
实施例50、4-苯甲酰丁酸(2-叔丁基-4-甲氧基苯酚)酯(XH2043-1)
制备方法与实施例3相同。4-苯甲酰丁酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率75％。1H NMR(400MHz,CDCl3)δ(ppm):1.32(s,9H),2.20-2.23(m,2H),2.71-2.75(t,J＝8.8Hz,2H),3.14-3.17(t,J＝7.0Hz,2H),3.79(s,3H),6.72-6.75(m,1H),6.91-6.93(m,2H),7.44-7.49(m,2H),7.55-7.59(m,1H),7.97-7.99(m,2H).13C NMR(100MHz,CDCl3)δ(ppm):19.4,30.2,34.1,34.7,37.6,55.7,110.7,114.0,124.7,128.2,128.9,133.4,136.9,142.4,142.8,157.0,172.5,199.6.
实施例51、3,5-二甲氧基苯丙烯酸(2-叔丁基-4-甲氧基苯酚)酯(XH2043-2)
制备方法与实施例3相同。3,5-二甲氧基苯丙烯酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率60％。1H NMR(400MHz,CDCl3)δ(ppm):1.35(s,9H),3.81(s,3H),6.53-6.54(t,J＝2.3Hz,1H),6.61-6.65(d,J＝16Hz,1H),6.73-6.78(m,3H),6.95-7.00(m,2H),7.77-7.81(d,J＝16Hz,1H).13C NMR(100MHz,CDCl3)δ(ppm):30.3,34.8,55.7,103.1,106.4,110.7,114.0,118.4,124.8,136.2,142.7,146.8,157.1,161.3,166.2.
实施例52、4-氯吡啶-2-甲酸(2-叔丁基-4-甲氧基苯酚)酯(XH2043-3)
制备方法与实施例3相同。4-氯吡啶-2-甲酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率65％。1H NMR(400MHz,CDCl3)δ(ppm):1.36(s,9H),3.82(s,3H),6.78-6.81(dd,J1＝9.2Hz,J2＝3.0Hz,1H),6.98-6.99(d,J＝3.0Hz,1H),7.04-7.06(d,J＝9.2Hz,1H),7.56-7.58(dd,J1＝5.2Hz,J2＝2.3Hz,1H),8.27-8.28(m,1H),8.75-8.76(d,J＝5.2Hz,1H).13C NMR(100MHz,CDCl3)δ(ppm):30.4,34.9,55.7,110.9,114.2,124.6,126.4,127.7,142.8,145.8,149.3,151.3,157.4,163.7.
实施例53、N-甲基哌啶-3-甲酸(2-叔丁基-4-甲氧基苯酚)酯(XH2043-4)
制备方法与实施例3相同。N-甲基哌啶-3-甲酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率60％。1H NMR(400MHz,CDCl3)δ(ppm):1.34(s,9H),1.51-1.61(m,1H),1.65-1.74(m,1H),1.80-1.85(m,1H),1.99-2.05(m,1H),2.13-2.18(m,1H),2.24-2.31(m,1H),2.34(s,3H),2.79-2.92(m,2H),3.14-3.16(br d,1H),3.78(s,3H),6.70-6.74(dd,J1＝8.4Hz,J2＝3.2Hz,1H),6.84-6.86(d,J＝8.4Hz,1H).13C NMR(100MHz,CDCl3)δ(ppm):24.6,26.3,29.9,34.5,42.3,46.4,55.4,55.5,57.1,110.5,113.7,124.4,142.2,142.6,156.7,172.9.
实施例54、N-叔丁氧羰基-6-氨基戊酸(2-叔丁基-4-甲氧基苯酚)酯(XH2043-5)
制备方法与实施例3相同。N-叔丁氧羰基-6-氨基戊酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率60％。1H NMR(400MHz,CDCl3)δ(ppm):1.32(s,9H),1.45(s,9H),1.57-1.65(m,2H),1.75-1.83(m,2H),2.59(t,J＝7.6Hz,2H),3.16-3.19(t,J＝6.8Hz,2H),3.79(s,3H),6.71-6.74(dd,J1＝8.8Hz,J2＝2.8Hz,1H),6.87-6.89(d,J＝8.8Hz,1H),6.92-6.93(d,J＝2.8Hz,1H).13C NMR(100MHz,CDCl3)δ(ppm):22.1,28.6,29.8,30.2,34.6,34.8,40.4,55.7,110.7,114.0,124.7,142.5,142.9,156.2,157.0,172.6.
实施例55、3,3,3-三氟丙酸(2-叔丁基-4-甲氧基苯酚)酯(XH2044-1)
制备方法与实施例3相同。3,3,3-三氟丙酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率60％。1H NMR(400MHz,CDCl3)δ(ppm):1.33(s,9H),3.41-3.48(q,J＝19.9Hz,2H),3.79(s,3H),6.72-6.75(m,1H),6.91-6.94(m,2H).13C NMR(100MHz,CDCl3)δ(ppm):30.2,34.8,40.3,55.7,110.9,114.2,124.4,142.5,157.5,163.5.
实施例56、吗啉-4-基乙酸(2-叔丁基-4-甲氧基苯酚)酯(XH2044-2)
制备方法与实施例3相同。吗啉-4-基乙酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率68％。1H NMR(400MHz,CDCl3)δ:1.30(s,9H),2.65-2.68(t,J＝4.4Hz,4H),3.47(s,2H),3.75-3.79(m,7H),6.70-6.73(m,1H),6.89-6.92(m,2H).13C NMR(100MHz,CDCl3)δ(ppm):30.3,34.7,53.5,55.7,60.2,67.0,110.7,114.1,124.6,142.4,157.1,169.2.
实施例57、3-(3,5-二叔丁基-4-羟基-苯基)丙酸-(2-叔丁基-4-甲氧基苯酚)酯(XH2045-2)
制备方法与实施例3相同。3-(3,5-二叔丁基-4-羟基-苯基)丙酸与2-叔丁基-4-甲氧基苯酚缩合反应制备，收率68％。1H NMR(400MHz,CDCl3)δ(ppm):1.29(s,9H),1.45(s,18H),2.86-2.90(m,2H),2.99-3.03(m,2H),3.78(s,3H),5.10(br s,1H),6.69-6.72(m,1H),6.80-6.83(d,J＝8.8Hz,1H),6.90-6.91(d,J＝3.0Hz,1H),7.06(s,2H).13CNMR(100MHz,CDCl3)δ(ppm):30.0,30.2,30.8,34.2,34.5,37.0,55.4,110.4,113.7,124.5,124.9,130.7,135.9,142.2,142.7,152.3,156.7,172.1.
实施例58、己二酸二(2-叔丁基-4-甲氧基苯酚)酯(XH2046-3)
制备方法与实施例3相同。己二酸(5mmol)与2-叔丁基-4-甲氧基苯酚(10mmol)缩合反应制备，收率65％。1H NMR(400MHz,CDCl3)δ(ppm):1.32(s,18H),1.89-1.93(m,4H),2.64-2.68(m,4H),3.79(s,6H),6.71-6.74(m,2H),6.89-6.93(m,4H).13C NMR(100MHz,CDCl3)δ(ppm):24.3,30.1,34.6,55.6,110.6,113.9,124.6,142.4,142.7,156.9,172.3.
实施例59、碳酸-(2-叔丁基-4-甲氧基苯酚氧基)甲酯异丙酯(XJP2005)
2-叔丁基-4-甲氧基苯酚(5mmol)溶于四氢呋喃(15mL)，再滴加到氢化钠(5.5mmol)/四氢呋喃(10mL)的溶液中，加毕，搅拌30分钟。滴加氯甲基碳酸异丙酯(5mmol)，加毕，室温反应24小时。柱层析纯化(乙酸乙酯:石油醚＝1:9)，得到无色油状物，收率75％。1H-NMR(CDCl3)δ(ppm):(ppm)1.32(s,9H),1.35(d,J＝6.4Hz,6H),3.78(s,3H),4.31(m,1H),5.26(s,2H),6.71-6.74(m,1H),6.90-6.91(d,J＝3.0Hz,1H),6.96-6.97(d,J＝8.6Hz,1H).
实施例60、N-(2-叔丁基-4-甲氧基苯酚氧羰基)甘氨酸乙酯(XJP2006)
甘氨酸乙酯(5.10mmol)溶于100mL二氯甲烷中，加入的饱和碳酸氢钠溶液，冰水浴搅拌5min。然后加入三光气(530mg,1.786mmol)，剧烈搅拌15min。二氯甲烷萃取四次，无水Na2SO4干燥1h，减压浓缩蒸干，得到D-天冬氨酸苄酯异氰酸酯(1-1)，备用。将2-叔丁基-4-甲氧基苯酚(1.28mmol)加入到100mL无水四氢呋喃中，加入三乙胺(386mg,3.83mmol)，室温搅拌30min，将上述制备的异氰酸酯(1-1)用2mL二氯甲烷溶解，加入到反应液中，升温至40℃，搅拌过夜。结束反应，直接加入硅胶蒸干，经硅胶柱层析纯化(乙酸乙酯:石油醚＝1:3)，得到，收率56.8％。1H-NMR(CDCl3)δ(ppm):(ppm)1.28-1.32(t,J＝7.0Hz,3H),1.34(s,9H),3.79(s,3H),4.06-4.08(d,J＝5.3Hz,2H),4.22-4.28(q,J＝7.0Hz,2H),5.53-5.56(t,J＝5.3Hz,1H),6.71-6.74(m,1H),6.90-6.91(d,J＝3.0Hz,1H),6.96-6.97(d,J＝8.6Hz,1H).
实施例61、2-(2-叔丁基-4-甲氧基苯氧基)乙酸乙酯(XJP1005)
2-叔丁基-4-甲氧基苯酚(5mmol)溶于四氢呋喃(15mL)，再滴加到氢化钠(5.5mmol)/四氢呋喃(10mL)的溶液中，加毕，搅拌30分钟。滴加溴乙酸乙酯(5mmol)，加毕，室温反应24小时。柱层析纯化(乙酸乙酯:石油醚＝1:9)，得到无色油状物，收率75％。1H-NMR(CDCl3)δ:(ppm)1.28-1.32(t,J＝7.2Hz,3H),1.40(s,9H),3.77(s,3H),4.24-4.30(q,J＝7.2Hz,2H),4.59(s,2H),6.65-6.66(m,2H),6.88-6.91(m,1H).
实施例62、(N-苄基)氨基甲酸-(2-叔丁基-4-甲氧基苯酚)酯制备(ZXY1025-2)
2-叔丁基-4-甲氧基苯酚(0.9g，5mmol)溶于二氯甲烷(15mL)，加入三乙胺(0.1mL)，滴加苄基异氰酸酯(5mmol)/二氯甲烷溶液(10mL)，加毕，搅拌反应4-10小时，水洗，柱层析得到白色固体，收率85％。1H-NMR(CDCl3)δ(ppm)1.32(s,3H),3.78(s,3H),4.47-4.48(d,J＝2.2Hz,2H),5.32-5.34(br t,J＝2.2Hz,1H),6.71-6.74(m,1H),6.89-6.90(d,J＝3.2Hz,1H),6.98-7.01(d,J＝8.4Hz,1H),7.30-7.38(m,5H).
实施例63、(N-正丁基)氨基甲酸(2-叔丁基-4-甲氧基苯酚)酯制备(ZXY1025-3)
制备方法同实施例62，由2-叔丁基-4-甲氧基苯酚与丁基异氰酸酯反应制备，收率90％。1H-NMR(CDCl3)δ(ppm)0.92-0.95(t,J＝8.0Hz,3H),1.32-1.41(m,11H),1.51-1.58(m,2H),3.25-3.30(q,J＝6.8Hz,2H),3.78(s,3H),4.99(br t,1H),6.70-6.73(m,1H),6.88-6.89(d,J＝3.2Hz,1H),6.94-6.97(d,J＝8.8Hz,1H).
实施例64、(N-异丙基)氨基甲酸(2-叔丁基-4-甲氧基苯酚)酯(ZXY1025-4)
制备方法同实施例62，收率85％。1H-NMR(CDCl3)δ(ppm)1.21-1.23(d,J＝6.4Hz,6H),1.32(s,9H),3.78(s,3H),3.88-3.93(m,1H),4.82-4.84(br d,J＝8.0Hz,1H),6.70-6.73(m,1H),6.88-6.89(d,J＝3.2Hz,1H),6.94-6.97(d,J＝8.8Hz,1H).
实施例65、(N-环己基)氨基甲酸(2-叔丁基-4-甲氧基苯酚)酯(ZXY1025-5)
制备方法同实施例62，收率87％。1H-NMR(CDCl3)δ(ppm)1.13-1.25(m,2H),1.32-1.42(m,12H),1.60-1.64(m,1H),1.72-1.75(m,2H),1.99-2.03(m,2H),3.54-3.61(m,1H),3.78(s,3H),4.87-4.89(d,J＝8.4Hz,1H),6.70-6.73(m,1H),6.88-6.89(d,J＝2.0Hz,1H),6.95-6.97(d,J＝8.4Hz,1H).
实施例66、(N-苯乙基)氨基甲酸(2-叔丁基-4-甲氧基苯酚)酯(ZXY1025-6)
制备方法同实施例62，收率87％。1H-NMR(CDCl3)δ(ppm)1.30(s,9H),2.87-2.90(t,J＝6.4Hz,2H),3.52-3.57(m,2H),3.77(s,3H),5.03(m,1H),6.69-6.72(m,1H),6.88-6.94(m,2H),7.22-7.25(m,3H),7.30-7.34(m,2H).
实施例67、特戊酰(2-叔丁基-4-甲氧基苯酚氧基)甲基酯(XJP1041)
2-叔丁基-4-甲氧基苯酚(5mmol)溶于四氢呋喃(15mL)，再滴加到氢化钠(5.5mmol)/四氢呋喃(10mL)的溶液中，加毕，搅拌30分钟。滴加特戊酰氯甲酯(5mmol)，加毕，室温反应24小时。柱层析纯化(乙酸乙酯:石油醚＝1:9)，得到类白色固体，收率75％。1H-NMR(CDCl3)δ(ppm)1.24(s,9H),1.32(s,9H),3.78(s,3H),5.30(s,2H),6.69-6.72(m,1H),6.88-6.94(m,2H).
实施例69、化合物体外释放评价
1、分析条件
流动相：梯度洗脱；A：水；B：甲醇；
色谱柱：CAPCEL PAK MF PH-1；
检测仪器：TQ-S；离子源：APCI；离子检测模式：MRM；
2、目标化合物在PBS缓冲溶液(pH＝7.4)中的释放试验
将一定质量的化合物溶于PBS缓冲液中，涡旋混匀，按照每份0.3mL等分出10等份，于37℃孵育，在不同的时间(0h、1h、2h、6h、12h、24h和48h等)取样，HPLC检测。以0h时目标化合物峰面积为标准，其它时间点化合物峰面积与标准峰面积相比，计算药物释放度。实验结果发现所有实施例化合物在水溶液中均保持稳定，未见BHA释放。
3、目标化合物在人血浆中释放实验
用DMSO溶解目标化合物，然后用0.9％的生理盐水稀释至5μg/mL。分装后的人空白血浆在-70℃保存，使用时在4℃冰箱解冻。取空白血浆20μL，加入20μL上述配置的目标化合物溶液，涡旋15s，置37℃水浴，分别于5min，20min，40min，1.5h，3h，6h，9h时间点取样，每个时间点平行三份样品，再向不同水浴时间点的样本中加入100μL甲醇，沉淀蛋白，涡旋1min，13000r·min-1低温离心15min，取上清进样，进样体积为10μL。
结果显示所有化合物均能释放BHA，但是释放速率和持续时间不同，如图3所示。
实施例69、小鼠体内药物代谢实验
1、实验方法
180-200g大鼠，灌胃给药；给药剂量：100mg/kg；给药溶液：2.5mg/mL(溶酶是玉米油)；给药前禁食12h，自由饮水。取不同采血点的大鼠血浆20μL，加入20μL的去离子水，然后加入100μL甲醇，涡旋1min，13000rpm转速下离心15min，取10μL进样，进行LC-MS/MS分析。共11个取血点:0min、5min、20min、40min、1h、1.5h、2h、4h、8h、12h、24h。
2、分析测试条件
流动相：A：水；B：甲醇，(二元梯度)；
洗脱条件如表1中所示：
表1洗脱条件
离子源：APCI；离子检测模式：MRM.
3、代表性化合物实验结果
根据血浆BHA释放实验结果，本发明选取代谢性质量好的化合物进行体内代谢实验，结果显示本发明涉及的前药可以在体内持续释放BHA(图4)，血药浓度可以平稳维持12小时。
实施例70、细胞毒活性测试
以MTS方法检测化合物对永生化的小鼠骨髓巨噬细胞(IBMM)、小鼠胚胎成纤维细胞(NIH3t3)和人源胚胎肾细胞(HEK293)细胞的毒性实验，结果显示实施例化合物细胞毒性均较轻微，IC50均在20毫摩尔以上，尤其对巨噬细胞毒性较小，调控巨噬细胞分化的药物安全窗较大(SI>1000)，亦可以证明本实施例化合物的抗肿瘤作用与细胞毒无关系，与现有的抗肿瘤药的机制完全不同。结果见下表2。
表2部分化合物的细胞毒性试验结果
实施例71、小鼠急性毒性试验
1、实验方法
采用上下法测定部分化合物的急性毒性。20～22g小鼠，灌胃给药；溶酶为玉米油，给药前禁食12h，自由饮水。
2、实验结果
结果如表3中所示，由表3中的数据可知，与细胞毒性试验结果相一致，本发明制备的代表性化合物XH2006,XH2010,XH2011,XH2044-2的急性毒性均小于2-叔丁基-4-甲氧基苯酚氧基(BHA)，显示了更优的安全性。
表3部分化合物的小鼠急性毒性试验结果

Claims (9)

1.式Ⅰ所示化合物、其药学上可接受的盐、其水合物或其溶剂合物，
式Ⅰ中，X为C＝O或CH2；Y为NH、O或不存在；R选自下述基团中任一种：至少1个碳原子的取代或未取代的烷基、至少3个碳原子的取代或未取代的环烷基、至少2个碳原子的取代或未取代的烯基或炔基；和至少含有4个碳原子的取代或未取代的芳基或杂芳基。
2.根据权利要求1所述的化合物、盐、水合物或溶剂合物，其特征在于：R中取代基为卤素、氨基、硝基、酯基、羰基、氨基酸衍生物、天然黄酮、天然生物碱、聚乙二醇、多聚谷氨酸或多糖。
3.根据权利要求1或2所述的化合物、盐、水合物或溶剂合物，其特征在于：式Ⅰ中，X和Y的选择如下述1)-3)中任一种：
1)当X为C＝O时，Y为NH；
2)当X为CH2时，Y为O；
3)X为C＝O或CH2，Y不存在。
4.根据权利要求3所述的化合物、盐、水合物或溶剂合物，其特征在于：式Ⅰ所示化合物包括但不限于下述1)-66)化合物中任一种：
1)(N-苄基)氨基甲酸-(2-叔丁基-4-甲氧基苯酚)酯，
2)(N-正丁基)氨基甲酸(2-叔丁基-4-甲氧基苯酚)酯，
3)(N-异丙基)氨基甲酸(2-叔丁基-4-甲氧基苯酚)酯，
4)(N-环己基)氨基甲酸(2-叔丁基-4-甲氧基苯酚)酯，
5)(N-苯乙基)氨基甲酸(2-叔丁基-4-甲氧基苯酚)酯，
6)特戊酰(2-叔丁基-4-甲氧基苯酚氧基)甲基酯，
7)苯甲酸-2-叔丁基-4-甲氧基苯酚酯，
8)乙酸-2-叔丁基-4-甲氧基苯酚酯，
9)烟酸-2-叔丁基-4-甲氧基苯酚酯，
10)异烟酸-2-叔丁基-4-甲氧基苯酚酯，
11)环己烯甲酸-2-叔丁基-4-甲氧基苯酚酯，
12)丙酸-2-叔丁基-4-甲氧基苯酚酯，
13)丙烯酸-2-叔丁基-4-甲氧基苯酚酯，
14)3,4-二甲氧基苯乙酸(2-叔丁基-4-甲氧基苯酚)-酯，
15)丁炔酸-2-叔丁基-4-甲氧基苯酚酯，
16)2,2‘-联苯二甲酸双(2-叔丁基-4-甲氧基苯酚)酯，
17)2-氯-5-三氟甲基苯甲酸(2-叔丁基-4-甲氧基苯酚)酯，
18)3-氟苯乙酸(2-叔丁基-4-甲氧基苯酚)酯，
19)(1H-吲哚-3基)乙酸(2-叔丁基-4-甲氧基苯酚)酯，
20)3-(4-氟苯基)-丙酸-(2-叔丁基-4-甲氧基苯酚)酯，
21)N-叔定氧羰基哌啶-3-甲酸(2-叔丁基-4-甲氧基苯酚)酯，
22)对苯二甲酸二(2-叔丁基-4-甲氧基苯酚)酯，
23)3-(3-硝基苯基)丙酸(2-叔丁基-4-甲氧基苯酚)酯，
24)4-苯基苯甲酸(2-叔丁基-4-甲氧基苯酚)酯，
25)4-甲基吡啶-3-甲酸(2-叔丁基-4-甲氧基苯酚)酯，
26)4-甲氧基吡啶-3-甲酸(2-叔丁基-4-甲氧基苯酚)酯，
27)十六酸-2-叔丁基-4-甲氧基苯酚酯，
28)N-叔丁氧羰基甘氨酸(2-叔丁基-4-甲氧基苯酚)酯，
29)3-氟-4-氯苯甲酸(2-叔丁基-4-甲氧基苯酚)酯，
30)N-叔丁氧羰基四氢吡咯、苯并杂环-3-甲酸(2-叔丁基-4-甲氧基苯酚)酯，
31)3-氰基苯甲酸(2-叔丁基-4-甲氧基苯酚)酯，
32)N-叔丁氧羰基丙氨酸(2-叔丁基-4-甲氧基苯酚)酯，
33)2-萘甲酸(2-叔丁基-4-甲氧基苯酚)酯，
34)丙二酸二(2-叔丁基-4-甲氧基苯酚)酯，
35)3,6-二氯哒嗪-4-甲酸(2-叔丁基-4-甲氧基苯酚)酯，
36)1-甲基环丙甲酸(2-叔丁基-4-甲氧基苯酚)酯，
37)2-吲哚甲酸(2-叔丁基-4-甲氧基苯酚)酯，
38)2-氯-3-吡啶甲酸(2-叔丁基-4-甲氧基苯酚)酯，
39)2-噻吩乙酸(2-叔丁基-4-甲氧基苯酚)酯，
40)3-(4-甲基苯基)-丙酸(2-叔丁基-4-甲氧基苯酚)酯，
41)丙炔酸(2-叔丁基-4-甲氧基苯酚)酯，
42)2-苯基丙酸(2-叔丁基-4-甲氧基苯酚)酯，
43)2-氟丙酸(2-叔丁基-4-甲氧基苯酚)酯，
44)环己乙酸(2-叔丁基-4-甲氧基苯酚)酯，
45)环戊甲酸(2-叔丁基-4-甲氧基苯酚)酯，
46)金刚烷乙酸(2-叔丁基-4-甲氧基苯酚)酯，
47)环丙基乙酸(2-叔丁基-4-甲氧基苯酚)酯，
48)N-叔丁氧羰基哌啶-4-甲酸(2-叔丁基-4-甲氧基苯酚)酯，
49)辛酸(2-叔丁基-4-甲氧基苯酚)酯，
50)7-氧代辛酸(2-叔丁基-4-甲氧基苯酚)酯，
51)环己-2-烯甲酸(2-叔丁基-4-甲氧基苯酚)酯，
52)2,4,5-三氟苯乙酸(2-叔丁基-4-甲氧基苯酚)酯，
53)2-溴-5-碘苯甲酸(2-叔丁基-4-甲氧基苯酚)酯，
54)2-氟-4-硝基苯甲酸(2-叔丁基-4-甲氧基苯酚)酯，
55)N-叔丁氧羰基哌啶-3-甲酸(2-叔丁基-4-甲氧基苯酚)酯，
56)对苯二乙酸二(2-叔丁基-4-甲氧基苯酚)酯，
57)4-苯甲酰丁酸(2-叔丁基-4-甲氧基苯酚)酯，
58)3,5-二甲氧基苯并烯酸(2-叔丁基-4-甲氧基苯酚)酯，
59)4-氯吡啶-2-甲酸(2-叔丁基-4-甲氧基苯酚)酯，
60)N-甲基哌啶-3-甲酸(2-叔丁基-4-甲氧基苯酚)酯，
61)、N-叔丁氧羰基-6-氨基戊酸(2-叔丁基-4-甲氧基苯酚)酯，
62)3,3,3-三氟丙酸(2-叔丁基-4-甲氧基苯酚)酯，
63)吗啉-4-基乙酸(2-叔丁基-4-甲氧基苯酚)酯，
64)3-(3,5-二叔丁基-4-羟基-苯基)丙酸-(2-叔丁基-4-甲氧基苯酚)酯，
65)己二酸二(2-叔丁基-4-甲氧基苯酚)酯；
66)2-(2-叔丁基-4-甲氧基苯氧基)乙酸乙酯。
5.式Ⅰ所示化合物的制备方法，包括如下(1)、(2)、(3)或(4)的步骤：
(1)当X为C＝O时，Y为NH时，包括如下步骤：
RCH2与三光气进行反应得到R-N＝C＝O；R-N＝C＝O与2-叔丁基-4-甲氧基苯酚经缩合反应即得式Ⅰ所示化合物；
式Ⅰ、RCH2和R-N＝C＝O中，R选自下述基团中任一种：至少1个碳原子的取代或未取代的烷基、至少3个碳原子的取代或未取代的环烷基、至少2个碳原子的取代或未取代的烯基或炔基和取代或未取代的芳基或杂芳基，
R中取代基为卤素、氨基、硝基、酯基、羰基、氨基酸衍生物、天然黄酮、天然生物碱、聚乙二醇、多聚谷氨酸或多糖；
式Ⅰ中，X为C＝O，Y为NH；
(2)当X为CH2时，Y为O时，包括如下步骤：
2-叔丁基-4-甲氧基苯酚钠与式1所示化合物经缩合反应即得式Ⅰ所示化合物；
式Ⅰ和式1中，R选自下述基团中任一种：至少1个碳原子的取代或未取代的烷基、至少3个碳原子的取代或未取代的环烷基、至少2个碳原子的取代或未取代的烯基或炔基和取代或未取代的芳基或杂芳基；
R中取代基为卤素、氨基、硝基、酯基、羰基、氨基酸衍生物、天然黄酮、天然生物碱、聚乙二醇、多聚谷氨酸或多糖；
式Ⅰ中，X为CH2，Y为O；
(3)X为C＝O，Y不存在时，即为式Ⅱ所示化合物，包括如下1)或2)的步骤：
1)2-叔丁基-4-甲氧基苯酚钠与式2所示酰氯经缩合即得式Ⅱ所示化合物；
式Ⅱ和式2中，R选自下述基团中任一种：至少1个碳原子的取代或未取代的烷基、至少3个碳原子的取代或未取代的环烷基、至少2个碳原子的取代或未取代的烯基或炔基和取代或未取代的芳基或杂芳基；
R中取代基为卤素、氨基、硝基、酯基、羰基、氨基酸衍生物、天然黄酮、天然生物碱、聚乙二醇、多聚谷氨酸或多糖；
式Ⅱ中，X为C＝O；
2)2-叔丁基-4-甲氧基苯酚钠与式3所示羧酸经缩合即得式Ⅱ所示化合物；
式Ⅱ和式3中，R选自下述基团中任一种：至少1个碳原子的取代或未取代的烷基、至少3个碳原子的取代或未取代的环烷基、至少2个碳原子的取代或未取代的烯基或炔基和取代或未取代的芳基或杂芳基；
R中取代基为卤素、氨基、硝基、酯基、羰基、氨基酸衍生物、天然黄酮、天然生物碱、聚乙二醇、多聚谷氨酸或多糖；
式Ⅱ中，X为C＝O；
(4)当X为CH2，Y不存在时，即为式Ⅱ所示化合物，包括如下步骤：
2-叔丁基-4-甲氧基苯酚钠与式4所示化合物经缩合反应即得式Ⅱ所示化合物；
式Ⅱ和式4中，R选自下述基团中任一种：至少1个碳原子的取代或未取代的烷基、至少3个碳原子的取代或未取代的环烷基、至少2个碳原子的取代或未取代的烯基或炔基和取代或未取代的芳基或杂芳基；
R中取代基为卤素、氨基、硝基、酯基、羰基、氨基酸衍生物、天然黄酮、天然生物碱、聚乙二醇、多聚谷氨酸或多糖；
X为CH2。
6.式Ⅰ所示化合物、其药学上可接受的盐、其水合物或其溶剂合物在制备抗肿瘤或免疫调节的药物中的应用。
7.根据权利要求6所述的应用，其特征在于：式Ⅰ所示化合物释放2-叔丁基-4-甲氧基苯酚。
8.式Ⅰ所示化合物、其药学上可接受的盐、其水合物或其溶剂合物在制备释放2-叔丁基-4-甲氧基苯酚的前药中的应用。
9.一种抗肿瘤药物或免疫调节药物，其活性成分为式Ⅰ所示化合物、其药学上可接受的盐、其水合物、其溶剂合物或者药物组合物。
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