CN109153626B - 2-羟基-4-(2，3-双取代苄氧基)-5-取代苯甲醛衍生物的制备方法 - Google Patents

2-羟基-4-(2，3-双取代苄氧基)-5-取代苯甲醛衍生物的制备方法 Download PDF

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CN109153626B
CN109153626B CN201780031942.8A CN201780031942A CN109153626B CN 109153626 B CN109153626 B CN 109153626B CN 201780031942 A CN201780031942 A CN 201780031942A CN 109153626 B CN109153626 B CN 109153626B
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derivative
substituted
hydroxy
aryltoluene
reaction
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CN109153626A (zh
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冯志强
陈晓光
杨阳
来芳芳
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Institute of Materia Medica of CAMS
Tianjin Chase Sun Pharmaceutical Co Ltd
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Institute of Materia Medica of CAMS
Tianjin Chase Sun Pharmaceutical Co Ltd
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Abstract

提供了式(I)化合物2‑羟基‑4‑(2，3‑双取代苄氧基)‑5‑取代苯甲醛衍生物的制备方法，包括如下步骤：(1)以2‑取代‑3‑碘甲苯衍生物1和芳基硼酸5或芳基硼酸酯为原料，制备2‑取代‑3‑芳基甲苯衍生物2；(2)以2‑取代‑3‑芳基甲苯衍生物2为原料，制备苄卤衍生物3；(3)以苄卤衍生物3和2，4‑二羟基‑5‑取代苯甲醛6为原料，制备2‑羟基‑4‑(2，3‑双取代苄氧基)‑5‑取代苯甲醛衍生物(I)。

Description

2-羟基-4-(2，3-双取代苄氧基)-5-取代苯甲醛衍生物的制备 方法
技术领域
本发明涉及式(I)化合物即2-羟基-4-(2，3-双取代苄氧基)-5-取代苯甲醛衍生物的制备方法，属于医药技术领域。
背景技术
随着对肿瘤免疫研究的深入，人们发现肿瘤微环境可以保护肿瘤细胞不被机体免疫系统识别和杀伤，肿瘤细胞的免疫逃逸在肿瘤发生、发展中扮演了非常重要的角色。2013年Science杂志将肿瘤免疫治疗列为十大突破之首，再次让免疫治疗成为肿瘤治疗领域的“焦点”。机体免疫细胞的激活或抑制是通过正性信号和负性信号来调节，其中程序性死亡分子1(programmed death 1，PD-1)/PD-1配体(PD-1ligand，PD-L1)便是负性免疫调节信号，抑制了肿瘤特异性CD8+T细胞的免疫活性，介导了免疫逃逸。
肿瘤细胞所具有的逃避免疫系统的能力，是通过在其表面产生的程序性死亡配体(PD-L1)结合到T细胞的PD-1蛋白上实现的。机体内的肿瘤微环境会诱导浸润的T细胞高表达PD-1分子，肿瘤细胞会高表达PD-1的配体PD-L1和PD-L2，导致肿瘤微环境中PD-1通路持续激活，T细胞功能被抑制而不能发现肿瘤以至于不能向免疫系统发出需要攻击肿瘤和杀伤肿瘤细胞的治疗。PD-1抗体是针对PD-1或者PD-L1的一种抗体蛋白，使得前两种蛋白不能发生结合，阻断这一通路，部分恢复T细胞的功能，使这些细胞能够继续杀伤肿瘤细胞。
基于PD1/PDL1的免疫疗法是当前备受瞩目的新一代免疫疗法，旨在利用人体自身的免疫系统抵御肿瘤，通过阻断PD-1/PD-L1信号通路诱导凋亡，具有治疗多种类型肿瘤潜力。最近，一系列令人惊喜的研究结果证实PDI/PD-Ll抑制性抗体对多种肿瘤具有强大的抗瘤活性，格外引人注目。2014年9月4日美国默克的
Figure BDA0001876951330000011
(pembrolizumab)成为FDA批准的首例PD-1单抗用于治疗对其它药物治疗无效的晚期或无法切除的黑色素瘤患者。目前，默沙东正在30多种不同类型的癌症中调查Keytruda的潜力，包括各类血液癌症、肺癌、乳腺癌、膀胱癌、胃癌、头颈部癌症。2014年12月22日，制药巨头百时美施贵宝公司不负重望，率先发力，获得美国食品药品监督管理局(FDA)加速批准，其研发的抗癌免疫疗法药物nivolumab以Opdivo的商品名上市，用于治疗对其它药物没有应答的不可切除的或转移性黑色素瘤患者，是继默沙东Keytruda之后第二个在美国上市的PD-1抑制剂。FDA于2015年3月4日批准了nivolumab用于治疗在经铂为基础化疗期间或化疗后发生疾病进展的转移性鳞性非小细胞肺癌。根据默沙东公布的Keytruda(pembrolizumab)治疗实体瘤的一项Ib期KEYNOTE-028研究数据，Keytruda治疗在25例胸膜间皮瘤(pleuralmesothelioma，PM)患者中取得了28％的总缓解率(ORR)，并有48％的患者病情稳定，疾病控制率达到了76％。对当前任何已获批药物均无治疗反应的晚期霍奇金淋巴瘤(HL)患者，接受默沙东Keytruda和百时美Opdvio治疗后，能够达到完全缓解。在2015AACR年会上，约翰霍普金斯基梅尔癌症中心(Kimmel Cancer Center)的肿瘤内科学副教授Leisha A.Emens,MD,PhD做出的报道指出，罗氏的MPDL3280A这一具有抗PD-L1作用的单克隆抗体，在晚期三阴性乳腺癌中表现出了持久的疗效。
虽然肿瘤免疫治疗被认为是靶向治疗后癌症治疗的革命。但是，单抗治疗药物有其本身的缺陷：易被蛋白酶分解，因而在体内不稳定，不能口服；易产生免疫交叉反应；产品质量不易控制，制作技术要求高；大量制备和纯化比较困难，生产成本高；使用不方便，只能注射或点滴。所以，PDl/PD-Ll相互作用小分子抑制剂是肿瘤免疫治疗的更佳选择。
本发明式(I)所示的2-羟基-4-(2，3-双取代苄氧基)-5-取代苯甲醛衍生物是作用于PDl/PD-Ll的免疫调节剂的重要中间体，该类免疫调节剂主要用于癌症、感染性疾病和自身免疫性疾病；
目前的部分2-羟基-4-(2，3-双取代苄氧基)-5-取代苯甲醛衍生物(I)的制备方法产率不足够高、不宜于工业化生产；
发明内容
本发明要解决的技术问题是提供2-羟基-4-(2，3-双取代苄氧基)-5-取代苯甲醛衍生物(I)作为潜在药物中间体的制备方法。
为实现本发明的目的，采用如下的技术方案制备2-羟基-4-(2，3-双取代苄氧基)-5-取代苯甲醛衍生物(I)：
包括以下步骤：
Figure BDA0001876951330000031
其中：R1＝氟、氯、溴、甲基、氰基；
Figure BDA0001876951330000032
R3＝氢、甲基、乙基、氟、氯、溴；
X选自溴、氯、碘。
优选的路线包括以下步骤：
1)以2-取代-3-碘甲苯衍生物1和芳基硼酸5或芳基硼酸酯为原料，制备2-取代-3-芳基甲苯衍生物2；
Figure BDA0001876951330000033
2)以2-取代-3-芳基甲苯衍生物2为原料，制备苄卤衍生物3；
Figure BDA0001876951330000034
3)以苄卤衍生物3和2，4-二羟基-5-取代苯甲醛6为原料，制备2-羟基-4-(2，3-双取代苄氧基)-5-取代苯甲醛衍生物(I)；
Figure BDA0001876951330000035
R1＝氟、氯、溴、甲基、氰基；
Figure BDA0001876951330000036
R3＝氢、甲基、乙基、氟、氯、溴；
X选自溴、氯、碘。
所用溶剂可按本领域的常规方法干燥备用。
具体而言，本发明的制备的方法如下
步骤1)制备2-取代-3-芳基甲苯衍生物2
步骤1)的原料为2-取代-3-碘甲苯衍生物1和芳基硼酸5或芳基硼酸酯的摩尔比为1∶0.8-1.5；优选是1∶1；
反应在常规的化学反应容器中进行，例如烧瓶或反应釜。优选对反应的容器进行干燥。
反应所用溶剂可选质子溶剂、非质子溶剂、极性溶剂和非极性溶剂，或混合溶剂，以溶解反应物为目的。优选的非质子溶剂选自四氢呋喃，乙醚，二氧六环，二甲亚砜，甲苯，N，N-二甲基甲酰胺；优选的质子溶剂选自乙醇、异丙醇、甲醇、叔丁醇、水、甲酸、乙酸、乙胺；最优选的溶剂选自二氧六环/水，优选的体积比例为1-10:1，最优选5:1。
反应优选的钯催化剂为零价钯和二价钯化合物；更优选三苯膦合钯、四(三苯膦)钯，PdCl2(dppf)；最优选的四(三苯膦)钯。
反应优选的碱可选自碱金属碳酸盐、碱金属醋酸盐、碱金属和碱土金属氢氧化物、碱金属氟化物、碱金属磷酸盐；更优选自碳酸铯、碳酸钾、碳酸钠、醋酸钠、醋酸钾、醋酸铯、氢氧化铯、氢氧化钾、氢氧化锶、氢氧化钡、氟化钾、氟化铯、磷酸钾、磷酸铯、磷酸钠；最优选的是碳酸铯、醋酸铯、氢氧化钡、磷酸铯。
反应条件优选自惰性气体保护，最优选氩气保护；反应条件优选控制反应温度，可控制在室温到120℃之间，优选的反应温度为100℃。反应的温度随溶剂不同而变化。
步骤2)制备卤苄衍生物3；
步骤2)中，以2-取代-3-芳基甲苯衍生物2为原料，制备苄卤衍生物3；
步骤2)中，2-取代-3-芳基甲苯衍生物2与溴化剂在自由基引发条件下反应制备苄卤衍生物3。2-取代-3-芳基甲苯衍生物2与溴化剂的摩尔比为1∶0.8-1.5；最优选是1∶1；溴化剂与自由基引发剂的摩尔比为1∶0.01-0.10；最优选是1∶0.05；
反应优选的溴化剂可为NCS(N-氯代丁二酰亚胺)、NBS(N-溴代丁二酰亚胺)、TBAB(苯基三甲基三溴化铵)、单质溴；最优选的溴化剂为NBS。
反应优选的自由基引发条件是加入自由基引发剂、光照、或兼而有之；更优选加入自由基引发剂；特优选过氧化苯甲酰、间氯过氧苯甲酸；最优选过氧化苯甲酰。
反应在常规的化学反应容器中或光化反应器中进行，例如烧瓶或特制的光化反应器。优选对反应的容器进行干燥。
反应所用溶剂优选自四氯化碳、四溴化碳、乙腈；最优选四氯化碳。
反应条件优选控制反应温度，可控制在50到85℃之间，优选的反应温度为80℃。反应的温度随溶剂不同而变化。
步骤3)以苄卤衍生物3和2，4-二羟基-5-取代苯甲醛6为原料，制备2-羟基-4-(2，3-双取代苄氧基)-5-取代苯甲醛衍生物(I)。；
步骤3)中，苄卤衍生物3和2，4-二羟基-5-取代苯甲醛6在弱碱性条件下选择性制备2-羟基-4-(2，3-双取代苄氧基)-5-取代苯甲醛衍生物(I)。
反应在常规的化学反应容器中进行，例如烧瓶或反应釜。优选对反应的容器进行干燥。
反应中原料苄卤衍生物3和2，4-二羟基-5-取代苯甲醛6摩尔比为1∶0.8-1.5；最优选是1∶1；
反应中优选的弱碱条件是加入碱金属碳酸氢盐，碱金属醋酸盐；更优选的弱碱条件是加入碳酸氢钠或碳酸氢钾；
反应所用溶剂可选非质子极性溶剂，以溶解反应物为目的；优选的非质子溶剂选自乙腈、四氢呋喃、乙醚、二氧六环、二甲亚砜、N，N-二甲基甲酰胺；最优选的溶剂选自乙腈、四氢呋喃、N，N-二甲基甲酰胺；
反应条件优选控制反应温度，可控制在20到85℃之间，优选的反应温度为50-60℃。反应的温度随溶剂不同而变化
有益技术效果：
本发明提供的涉及式(I)化合物即2-羟基-4-(2，3-双取代苄氧基)-5-取代苯甲醛衍生物的制备方法，属于医药技术领域；
2-羟基-4-(2，3-双取代苄氧基)-5-取代苯甲醛衍生物(I)是免疫调节剂的重要中间体；其制备方法具有产率高、易工业化的优点；部分中间体2-羟基-4-(2，3-双取代苄氧基)-5-取代苯甲醛衍生物(I)为新化合物是潜在的医药中间体；
本发明提供的合成路线中：
步骤1)中，以2-取代-3-碘甲苯衍生物1和芳基硼酸5或芳基硼酸酯为原料，制备2-取代-3-芳基甲苯衍生物2的方法，原料易得，不需特殊试剂，简便，易操作，条件温和，高产率，易于工业化。
步骤2)中，2-取代-3-芳基甲苯衍生物2与溴化剂在自由基引发条件下反应制备苄卤衍生物3，或2-取代-3-芳基甲苯衍生物2与溴化剂在光照条件下反应制备苄卤衍生物3，反应条件温和，产率高，后处理容易，不用分离，直接进行下一步反应，易工业化。
步骤3)以苄卤衍生物3和2，4-二羟基-5-取代苯甲醛6为原料，选择性制备2-羟基-4-(2，3-双取代苄氧基)-5-取代苯甲醛衍生物(I)，具有步骤少，易操作，经济实用，易于工业化的优点。
总之：本发明的合成路线原料易得，不需要柱层析分离，不需要低温设备，
不需要保护基团的引入与消除，反应路线短，易操作，经济实用，适于工业化的制备方法。
以本发明的制备方法制备得到的2-羟基-4-(2，3-双取代苄氧基)-5-取代苯甲醛衍生物是一类免疫调节剂的重要中间体，实施例2、4、6、8是该类免疫调节剂的举例说明。可以看出实施例2、4、6、8化合物可显著抑制PD-1与PD-L1的相互作用，是一类新型的免疫调节剂。
术语和简称
THF：四氢呋喃
DMF：N，N-二甲基甲酰胺
NBS：N-溴代邻苯二甲酰亚胺
BPO：过氧化苯甲酰
具体实施方式
实施例1 2-羟基-4-(2-溴-3-苯基苄氧基)-5-氯苯甲醛
2-溴-3-苯基甲苯:
置2-溴-3-碘甲苯(350mg)于50ml单口瓶中，加入二氧六环/水(体积比5/1)搅拌，鼓吹氩气10min排除溶液中溶解的氧气，然后加入苯硼酸(172.65mg)碳酸铯(961.2mg)，三苯基膦合钯(40.91mg)。氩气保护，80-100℃下搅拌12h。停止反应，降至室温，用硅藻土过滤。滤液减压浓缩后，加入水和乙酸乙酯萃取3次。合并有机相，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压蒸干，得到2-溴-3-苯基甲苯无色油状物234mg。产率88％。1HNMR(400MHz,DMSO-d6)，δ7.49–7.29(m,7H,Ar-H),7.14(d,1H,Ar-H),2.42(s,3H,Ar-CH3)。MS(FAB):248(M+1)。
2-溴-3-苯基苄溴；
称取原料2-溴-3-苯基甲苯(234mg)于100ml单口瓶中，加入20ml CCl4,使之溶解完全，搅拌下加入NBS(178mg)，升温至80℃，回流，然后加入过氧化苯甲酰(4mg)，2h后再次加入过氧化苯甲酰(4mg)，继续反应2h，停止反应，冷至室温，加水淬灭反应，然后加入二氯甲烷和水进行萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压蒸干，得到2-溴-3-苯基苄溴黄色油状物262mg。直接用于下一步的反应。
2-羟基-4-(2-溴-3-苯基苄氧基)-5-氯苯甲醛:
Figure BDA0001876951330000071
称取2,4-二羟基-5-氯苯甲醛(73.94mg)置于50ml单口瓶中，以6ml无水乙腈溶解，然后加入碳酸氢钠(98.88mg)。室温搅拌40min后，将2-溴-3-苯基苄溴(192mg)溶于8ml DMF中，用恒压滴液漏斗缓慢加入至反应体系，加热回流至反应完全。降至室温，加入水和乙酸乙酯进行萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压蒸干得到2-羟基-4-(2-溴-3-苯基苄氧基)-5-氯苯甲醛白色固体192mg。产率85％。1H NMR(400MHz,DMSO-d6)δ10.99(s,1H,-OH),10.03(s,1H,-CHO),7.64(d,1H,Ar-H),7.57(d,1H,Ar-H),7.45(m,4H,Ar-H),7.37(d,2H,Ar-H),6.67(d,1H,Ar-H),6.59(s,1H,Ar-H),5.25(s,2H,-CH2-)。MS(FAB):418(M+1)。
实施例2N-乙酰胺乙基-2-(3-氰基苄氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄胺
2-(3-氰基苄氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苯甲醛:
将2-羟基-4-(2-溴-3-苯基苄氧基)-5-氯苯甲醛(100mg)置于50ml单口瓶中，用6ml DMF溶解，加入碳酸铯(127.53mg)。室温搅拌15min后，滴加间氰基苄溴(76.65mg)的DMF(4ml)溶液。在80℃下搅拌2h后停止反应。降至室温，加入水和乙酸乙酯萃取分液，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压蒸干，通过硅胶柱层析得到白色固体103mg。1H NMR(400MHz,DMSO-d6)δ10.26(s,1H,-CHO),8.00(s,1H,Ar-H),7.83(dd,2H,Ar-H),7.72(d,1H,Ar-H),7.61(t,2H,Ar-H),7.55–7.23(m,7H,Ar-H),6.95(s,1H,Ar-H),6.81(d,1H,Ar-H),5.35(s,2H,-CH2-),5.30(s,2H,-CH2-)。MS(FAB):509(M+1)。
N-乙酰胺乙基-2-(3-氰基苄氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄胺:
Figure BDA0001876951330000081
将2-(3-氰基苄氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苯甲醛(50.8mg)溶于5mlDMF中，加入2-乙酰氨基乙胺(31.25mg)，冰醋酸(36.75mg)至反应体系中。室温搅拌20min后，加入氰基硼氢化钠(19.23mg)，25℃下搅拌14h。停止反应，加入水和乙酸乙酯萃取分离。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压蒸干，通过硅胶柱层析得到白色固体55mg。1H NMR(500MHz,DMSO-d6)δ8.00(s,1H,-ArH),7.86(dd,2H,-ArH),7.69–7.62(m,2H,-ArH),7.53(d,2H,-ArH),7.50(d,2H,-ArH),7.46(d,1H,-ArH),7.41(t,3H,-ArH),7.07(s,1H,-ArH),5.33(s,2H,-CH2-),5.32(s,2H,-CH2-),3.89(s,2H,-CH2-),3.25(m,2H,-CH2-),2.74(t,2H,
-CH2-),1.83(s,3H,-COCH3).MS(FAB):620(M+1)。
实施例3 2-羟基-4-(2-溴-3-(3，4-乙二氧基苯基)苄氧基)-5-氯苯甲醛
2-溴-3-(3，4-乙二氧基苯基)甲苯:
用2-(3，4-乙二氧苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷代替苯硼酸，用[1,1'-双(二苯基膦基)二茂铁]二氯化钯代替三苯基膦钯，碳酸钾代替碳酸铯，操作同实施例1，得到化合物2-溴-3-(3，4-乙二氧基苯基)甲苯，淡黄色油状物。1H NMR(400MHz,Chloroform-d)δ7.21(d,2H,-ArH),7.11(m,1H,-ArH),6.90(d,2H,-ArH),6.86(d,1H,-ArH),4.30(m,4H,-OCH2CH2O-),2.48(s,3H,-CH3).
2-羟基-4-(2-溴-3-(3，4-乙二氧基苯基)苄氧基)-5-氯苯甲醛:
Figure BDA0001876951330000091
用2-溴-3-(3，4-乙二氧基苯基)甲苯代替2-溴-3-甲基-1,1'-联苯，操作同实施例1进行溴化反应。得到的产物不经过分离直接与2,4-二羟基-5-氯苯甲醛进行下一步反应，操作同实施例1，得到白色固体。1H NMR(400MHz,DMSO-d6)δ10.91(s,1H,-OH),9.95(s,1H,-CHO),7.57(d,1H,-ArH),7.45(d,1H,-ArH),7.37(t,1H,-ArH),7.25(d,1H,-ArH),6.84(d,1H,-ArH),6.78(s,1H,-ArH),6.74(d,1H,-ArH),6.59(d,1H,-ArH),6.51(s,1H,-ArH),5.16(s,2H,-CH2-),4.20(m,4H,-OCH2CH2O-).MS(FAB):476(M+1)。
实施例4N-(羟乙基)-2-(3-氰基苄氧基)-4-(2-溴-3-(3，4-二甲氧基苯基)苄氧基)-5-氯苄胺
2-(3-氰基苄氧基)-4-(2-溴-3-(3，4-乙二氧基苯基)苄氧基)-5-氯苯甲醛:
用2-羟基-4-(2-溴-3-(3，4-乙二氧基苯基)苄氧基)-5-氯苯甲醛代替2-羟基-4-(2-溴-3-苯基苄氧基)苯甲醛，操作同实施例2得到白色固体。1H NMR(400MHz,DMSO-d6)δ10.28(s,1H,-CHO),8.01(s,1H,-ArH),7.85(dd,2H,-ArH),7.74(d,1H,-ArH),7.63(t,1H,-ArH),7.58(d,1H,-ArH),7.46(t,1H,-ArH),7.35(d,1H,-ArH),6.94(d,2H,-ArH),6.87(s,1H,-ArH),6.82(d,2H,-ArH),5.36(s,2H,-CH2-),5.30(s,2H,-CH2-),4.29(m,4H,-OCH2CH2O-).MS(FAB):567(M+1)。
N-(羟乙基)-2-(3-氰基苄氧基)-4-(2-溴-3-(3，4-二甲氧基苯基)苄氧基)-5-氯苄胺:
Figure BDA0001876951330000092
用2-(3-氰基苄氧基)-4-(2-溴-3-(3，4-乙二氧基苯基)苄氧基)苯甲醛代替2-(3-氰基苄氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苯甲醛，操作同实施例2，得到类白色固体粉末。1H NMR(400MHz,DMSO-d6)δ8.74(s,1H,-NH-),8.14(m,1H,-CONH-),8.00(s,1H,-ArH),7.85(dd,2H,-ArH),7.63(t,1H,-ArH),7.54(d,1H,-ArH),7.50–7.37(m,2H,-ArH),7.33(d,1H,-ArH),6.94(d,1H,-ArH),6.86(s,2H,-ArH),6.82(d,1H,-ArH),6.74(d,1H,-ArH),5.27(s,2H,-CH2-),5.20(s,2H,-CH2-),4.29(m,4H,-OCH2CH2O-),4.13(s,2H,-CH2-),3.34-3.39(m,2H,-CH2-),2.96(m,2H,-CH2-),1.82(s,3H,-COCH3).MS(FAB):678(M+1)。
实施例5 2-羟基-4-(2-甲基-3-(3，4-乙二氧基苯基)苄氧基)-5-氯苯甲醛
Figure BDA0001876951330000101
以2-甲基-3-碘甲苯代替2-溴-3-碘甲苯为原料，操作同实施例1，得到白色固体2-羟基-4-(2-甲基-3-(3，4-乙二氧基苯基)苄氧基)-5-氯苯甲醛。MS(FAB):411(M+1),最后一步产率78％。
实施例6(R)-N-[2-(5-氰基吡啶-3-亚甲氧基)-4-(2-甲基-3-(3，4-乙二氧基苯基)苄氧基)-5-氯苄基]-3-(吡啶-3-基)丙氨酸
Figure BDA0001876951330000102
用5-氰基吡啶-3-亚甲基溴代替间氰基苄溴，天冬酰胺代替2-乙酰氨基乙胺，操作同实施例2得到白色固体(R)-N-[2-(5-氰基吡啶-3-亚甲氧基)-4-(2-甲基-3-(3，4-乙二氧基苯基)苄氧基)-5-氯苄基]-3-(吡啶-3-基)丙氨酸。MS(FAB):678(M+1),产率48％。
实施例7 2-羟基-4-(2-氰基-3-(3，4-乙二氧基苯基)苄氧基)-5-溴苯甲醛
Figure BDA0001876951330000111
以2-氰基-3-碘甲苯代替2-溴-3-碘甲苯为原料，2，4-二羟基-5-溴苯甲醛代替2，4-二羟基-5-氯苯甲醛，操作同实施例1，得到白色固体2-羟基-4-(2-氰基-3-(3，4-乙二氧基苯基)苄氧基)-5-溴苯甲醛。MS(FAB):467(M+1),最后一步产率76％。
实施例8N-(2-乙酰胺基乙基)-2-(3-氰基苄氧基)-4-(2-氰基-3-(3，4-二甲氧基苯基)苄氧基)苄胺
Figure BDA0001876951330000112
以2-羟基-4-(2-氰基-3-(3，4-乙二氧基苯基)苄氧基)-5-溴苯甲醛为原料，操作同实施例2得到白色固体N-(2-乙酰胺基乙基)-2-(3-氰基苄氧基)-4-(2-氰基-3-(3，4-二甲氧基苯基)苄氧基)苄胺。MS(FAB):668(M+1),产率46％。
注：实施例1、3、5、7是中间体2-羟基-4-(2，3-双取代苄氧基)-5-取代苯甲醛衍生物(I)
实施例2、4、6、8分别是在实施例1、3、5、7的基础上制备得到的有免疫调节作用的化合物
实施例5、6、7、8化合物是已知化合物
药理活性
体外活性评价：体外酶学水平的检测方法采用Cisbio公司的HTRF检测试剂盒。
PD-1/PD-L1小分子抑制剂的筛选原理和方法
1、原理：PD-1蛋白带HIS标签，PD-1的配体PD-L1带hFc标签，分别用Eu标记的anti-hFc抗体和XL665标记的anti-HIS抗体与两个标签蛋白结合，激光激发后，能量能够从供体Eu上转移到受体XL665，使得XL665发光，而加入抑制剂(化合物或抗体)后，阻断PD-1与PD-L1的结合，使得Eu和XL665距离较远，能量不能转移，XL665不会发光。
2、实验方法：384孔白色酶标板，每孔加入2μl稀释液或者用稀释液稀释的目标化合物，然后每孔再加入4μl PD-1蛋白和4μl PD-L1蛋白，常温孵育15min，再每孔加入10μlanti-Tag1-Eu3+和anti-Tag2-XL665，室温孵育1h后检测665nm和620nm处的荧光信号。HTRF率＝(665nm/620nm)*104。每个化合物检测8-10个浓度，采用Graphpad软件计算IC50。
3、筛选结果：
实施例 IC<sub>50</sub>(M) 实施例 IC<sub>50</sub>(M)
2 6.23×10<sup>-8</sup> 4 2.68×10<sup>-7</sup>
6 3.5×10<sup>-8</sup> 8 7.12×10<sup>-9</sup>

Claims (1)

1.一种制备2-羟基-4-(2，3-双取代苄氧基)-5-取代苯甲醛衍生物(I)的方法，其特征在于，包括以下步骤：
Figure FDA0003603329150000011
1)以2-取代-3-碘甲苯衍生物1和芳基硼酸5或芳基硼酸酯为原料，制备2-取代-3-芳基甲苯衍生物2；
Figure FDA0003603329150000012
2-取代-3-碘甲苯衍生物1和芳基硼酸5或芳基硼酸酯发生Suzuki-Miyaura偶联反应生成2-取代-3-芳基甲苯衍生物2,是在钯催化和碱作用下进行，其中，所述的钯催化剂选自三苯膦合钯、PdCl2(dppf)，所述的碱选自碳酸铯、碳酸钾；
2)以2-取代-3-芳基甲苯衍生物2为原料，制备卤苄衍生物3；
Figure FDA0003603329150000013
2-取代-3-芳基甲苯衍生物2与卤化剂在自由基引发条件下反应制备卤苄衍生物3，所述的卤化剂为N-溴代丁二酰亚胺，所述的自由基引发条件是加入自由基引发剂，所述的自由基引发剂为过氧化苯甲酰；且2-取代-3-芳基甲苯衍生物2与卤化剂的摩尔比1∶1-1.5；卤化剂与自由基引发剂的摩尔比为1∶0.01-0.10；反应所用溶剂为四氯化碳；反应温度在50到85℃之间；
3)以卤苄衍生物3和2，4-二羟基-5-取代苯甲醛6为原料，制备2-羟基-4-(2，3-双取代苄氧基)-5-取代苯甲醛衍生物(I)；
Figure FDA0003603329150000014
卤苄衍生物3和2，4-二羟基-5-取代苯甲醛6在弱碱性条件下选择性制备2-羟基-4-(2，3-双取代苄氧基)-5-取代苯甲醛衍生物(I)，所述的弱碱条件是加入碱金属碳酸氢盐，所述的碱金属碳酸氢盐为碳酸氢钠；
其中：R1选自溴、甲基、氰基；
R2选自
Figure FDA0003603329150000021
R3选自氯、溴；
X选自溴。
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