CN117024375A - 一种噻二唑类组蛋白去乙酰化酶抑制剂化合物的制备方法及其用途 - Google Patents
一种噻二唑类组蛋白去乙酰化酶抑制剂化合物的制备方法及其用途 Download PDFInfo
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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Abstract
本发明涉及药物化学领域，提供了一类新型的含有噻二唑结构的异羟肟酸类HDACi，包括其药学上可接受的盐、代谢物、异构体以及前药等；同时也公布了该化合物的制备方法，以及其作为新型的HDACi的应用；在噻二唑结构基础上引入异羟肟酸结构骨架，设计和合成了一类新型的含噻二唑结构的异羟肟酸类化合物，该类化合物结合了噻二唑和异羟肟酸结构的优势，作为组蛋白去乙酰化酶抑制剂可应用在预防和治疗癌症或炎症放入药物中；还可用于诱发获得性耐药导致化疗失败后的抗肿瘤治疗的药物中；其结构如下所示：
Description
技术领域
本发明属于生物与医药领域，具体涉及一种含噻二唑结构的异羟肟酸类化合物的合成方法及其用途。
背景技术
癌症目前仍然是致死率较高的恶性疾病，是一种由调节细胞增殖与分裂的关键激酶或蛋白异常而引起的疾病。究其本质就是基因的表达失控，一类是基因突变，另一类是表观遗传修饰。在表观遗传学中，组蛋白去乙酰化酶（HDAC）与组蛋白乙酰转移酶（HAT）之间的关系是正常调节基因表达的一个重要因素。HDAC表达异常会引起两者之间的平衡关系失衡，引发各种疾病。因此，HDAC与肿瘤的发生发展有着密不可分的关系。HDACi（组蛋白去乙酰化酶抑制剂）对肿瘤具有强大疗效。此外，已证明HDACi通过多种机制在肿瘤发展过程中发挥作用，如促进肿瘤细胞侵袭和迁移、促进肿瘤组织新生血管生成、增强肿瘤细胞对药物的耐药性、抑制肿瘤细胞分化凋亡等。
到目前为止，在哺乳动物中已经鉴定出18种HDAC酶，根据它们与酵母细胞HDACs的相似性分为4类。在所有已知的HDAC酶类中，I、II和IV类HDAC酶是金属酶(依赖锌离子)，需要锌离子来激活其生物活性。目前已经有五个组蛋白去乙酰化酶抑制剂（HDACis）药物批准上市：SAHA、PXD-101、LBH589、FK-228和CS055，分别用于治疗皮肤T细胞淋巴瘤、多发性骨髓瘤或外周T细胞淋巴瘤。但目前上市的HDACis大多是针对血液系统癌症，对实体瘤的效果比较差，因此研发针对实体肿瘤效果好的HDACis是十分必要的。
大部分的HDACis的结构都由三个结构模块组成：表面结合区域(CAP)，延伸进入通道内的连接区(Linker)，位于催化中心的锌离子结合区域(ZBG)。CAP区被认为是鉴定HDACi与不同亚型的HDAC进行表面相互作用的关键部分。因此，建立新的CAP区基团是提高HDACi选择性和药效的重要研究方向。
发明内容
本发明提供了一种含噻二唑类组蛋白去乙酰化酶抑制剂及其合成方法，在异羟肟酸的基础上引入苯连噻二唑结构；还提供了该类化合物的应用，通过抑制组蛋白去乙酰化酶的活性来治疗恶性肿瘤。
为实现上述目的，本发明采用如下技术方案
一类含噻二唑结构的异羟肟酸类化合物结构式如式（Ⅰ）所示：
（Ⅰ）
式（Ⅰ）中，R为以下基团：-H，-CH3，-OCH3，-Cl，-Br。
上述化合物合成方法以下：
化合物1和氯乙酰氯在无水四氢呋喃或甲苯溶液中生成化合物2；化合物2在N,N-二甲基甲酰胺中与对甲氧基苯胺反应得化合物3；化合物3在1,4-二氧六环或四氢呋喃溶液中加热得化合物4；化合物4在适当的溶剂如二氯甲烷或甲醇或二氯亚砜中酯化生成化合物5；化合物5在甲醇中与盐酸羟胺反应，分离提纯得目标产物6。
上述化合物药学上可接受的盐。优选的，所述盐为酸加成盐。更优选的，所述酸为琥珀酸、马来酸、水杨酸、氢溴酸、盐酸、硫酸、磷酸、乙酸、酒石酸、柠檬酸、乳酸、甲磺酸、对甲苯磺酸或丙酮酸。
上述化合物及其药学上可接受的盐作为组蛋白去乙酰化酶抑制剂的应用。具体的，可作为预防和治疗因组蛋白乙酰化调控失衡导致的癌症、恶性肿瘤或炎症的药物；还可作为诱发获得性耐药导致化疗失败后的抗肿瘤药物。
本发明的有益成果：
本发明提供的含有噻二唑结构的异羟肟酸类组蛋白去乙酰化酶抑制剂，对于HDAC1有很好的抑制活性，其抑制活性优于SAHA；该系列化合物结合了噻二唑和异羟肟酸的优势，获得的化合物作为组蛋白去乙酰化酶抑制剂可应用在预防和治疗癌症或炎症药物中；还可用于诱发获得性耐药导致化疗失败后的抗肿瘤治疗的药物中。
附图说明
图1为本发明中化合物对HDAC1的抑制率结果图。
实施方式
下面结合实施例和附图对本发明做进一步说明，但本发明不受下述实施例的限制。在不背离发明构思的精神和范围下，本领域技术人员能够想到的变化都被包括在本发明中，并以所附的权利要求书为保护范围。
噻二唑类异羟肟酸化合物的合成与表征。
本实施例中，1H-NMR用Bruker AVANCE Ⅲ HD 600兆核磁共振波谱仪测定；MS用Agilent 6440 Triple Quad LC/MS型仪测定，除注明外均为ESI方式；所有溶剂在使用前均经过重新蒸馏，所使用的无水溶剂均是按标准方法干燥处理获得；除说明外，所有反应均是在氩气保护下进行并用TLC跟踪，后处理时均经饱和食盐水洗涤和无水硫酸钠干燥过程；产品的纯化除说明外均使用硅胶(200-300目)的柱色谱法；所使用的硅胶，包括200-300目和GF254为青岛海浪硅胶干燥剂有限公司生产。
实施例1-1化合物N1-羟基-N7-（4-甲氧基苯基）-N7-（5-对甲苯基）-1，3，4-噻二唑-2-甲基）庚二酰胺（WX-468B）的具体合成步骤如下：
（1）取4-甲基苯甲酰肼（2000mg, 13.3mmol）溶于15ml无水四氢呋喃中，0℃，氮气保护下加入氯乙酰氯（2ml，25.2mmol），常温反应一小时，再加入劳森试剂（6310mg，15.6mmol）搅拌回流4h，蒸干溶剂，萃取纯化得白色固体化合物；
（2）取对甲氧基苯胺（2911mg，23.7mmol）溶于8ml N,N-二甲基甲酰胺中，加入碳酸铯（7711mg，23.7mmol）常温搅拌30min后加入步骤（1）中的化合物, 40℃搅拌过夜，萃取、分离纯化得黄色油状化合物（2663.8mg，53%）；
（3）将步骤（2）中获得的化合物与庚二酸酐（1643mg，10.3mmol）溶于20ml1,4-二氧六环中，回流搅拌过夜，蒸干溶剂萃取得黄色固体粗产品；
（4）将步骤（3）中获得的化合物溶于15ml甲醇中，滴加5滴二氯亚砜，搅拌回流3h，减压蒸馏除去溶剂和催化剂，分离萃取获得黄色油状化合物（546mg，30%）；
（5）盐酸羟胺（4061mg，58.4mmol）溶解于20ml甲醇中，缓慢加入氢氧化钾（3276mg，58.4mmol），40℃反应1h后抽滤，取滤液与步骤（4）中的化合物混合，加入氢氧化钾（328mg，5.8mmol），在常温下搅拌反应6h，蒸干萃取后在二氯甲烷/甲醇体系下过硅胶柱纯化得目标化合物HR-468-1（430mg，78%）。
1H NMR (600 MHz, DMSO-d6) δ 10.30 (br s, 1H), 8.64 (br s, 1H), 7.85(d, J = 7.8 Hz, 2H), 7.35 (d, J = 7.8 Hz, 2H), 7.19 (d, J = 6.6 Hz, 2H), 6.97(d, J = 9.0 Hz, 2H), 5.14 (s, 2H), 3.76 (s, 3H), 2.37 (s, 3H), 2.04 (t, J =7.8 Hz, 2H), 1.88 (t, J = 7.8 Hz, 2H), 1.50 – 1.44 (m, 2H), 1.41 – 1.34 (m,2H), 1.16 - 1.12 (m, 2H).
13C NMR (150 MHz, DMSO) δ 172.48, 169.27, 169.01, 165.78, 158.76,141.44, 134.29, 130.01, 129.23, 127.59, 126.89, 114.89, 55.36, 48.04, 33.08,32.12, 28.14, 24.89, 24.47, 21.03.
实施例1-2化合物N1-羟基-N7-（4-甲氧基苯基）-N7-（5-（4-甲氧基苯基）-1，3，4-噻二唑-2-甲基）庚二酰胺（WX-484B）的制备
将4-甲基苯甲酰肼换成3-甲氧基苯甲酰肼。1H NMR (600 MHz, DMSO-d6) δ10.31 (br s, 1H), 8.65 (br s, 1H), 7.91 (d, J = 9.0 Hz, 2H), 7.18 (d, J = 9.0Hz, 2H), 7.09 (d, J = 9.0 Hz, 2H), 6.97 (d, J = 8.4 Hz, 2H), 5.13 (s, 2H),3.83 (s, 3H), 3.76 (s, 3H), 2.04 (t, J = 7.2 Hz, 2H), 1.88 (t, J = 7.2 Hz,2H), 1.49 – 1.44 (m, 2H), 1.41 – 1.35 (m, 2H), 1.16 – 1.10 (m, 2H).
13C NMR (150 MHz, DMSO-d6) δ 172.46 , 169.02 , 168.96 , 165.26 ,161.64 , 158.76 , 134.29 , 129.32 , 129.23 , 122.12 , 114.89 , 114.84 , 55.51, 55.36 , 48.01 , 33.08 , 32.12 , 28.14 , 24.90 , 24.48 .
实施例1-3化合物N1-羟基-N7-（4-甲氧基苯基）-N7-（5-（3-甲氧基苯基）-1，3，4-噻二唑-2-甲基）庚二酰胺（WX-484）的制备
将4-甲基苯甲酰肼换成4-甲氧基苯甲酰肼。1H NMR (600 MHz, DMSO-d6) δ10.30 (br s, 1H), 8.64 (br s, 1H), 7.53 (d, J= 7.8 Hz, 2H), 7.49 (s, 1H),7.46 (dd, J = 8.4, 8.4 Hz, 1H), 7.14 (d, J = 6.6 Hz, 1H), 6.97 (d, J = 9.0Hz, 2H), 5.16 (s, 2H), 3.84 (s, 3H), 3.76 (s, 3H), 2.04 (t, J = 7.2 Hz, 2H),1.88 (t, J = 7.2 Hz, 2H), 1.49 – 1.44 (m, 2H), 1.40 – 1.35 (m, 2H), 1.15 –1.10 (m, 2H).
13C NMR (150 MHz, DMSO-d6) δ 172.48 , 169.06 , 168.97 , 166.31 ,159.72 , 158.76 , 134.26 , 130.78 , 130.70 , 129.22 , 120.28 , 117.43 ,114.88 , 112.05 , 55.43 , 55.35 , 48.04 , 33.07 , 32.11 , 28.13 , 24.88 ,24.45 .
实施例1-4化合物N1-（5-（4-氯苯基）-1，3，4-噻二唑-2-基甲基）-N7-羟基-N1-（4-甲氧基苯基）庚二酰胺（WX-488B）的制备
将4-甲基苯甲酰肼换成3-氯苯甲酰肼。1H NMR (600 MHz, DMSO-d6) δ 10.30(br s, 1H), 8.64 (br s, 1H), 8.00 (d, J = 7.8 Hz, 2H), 7.62 (d, J = 8.4 Hz,2H), 7.19 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 8.4 Hz, 2H), 5.15 (s, 2H), 3.76(s, 3H), 2.04 (t, J = 7.2 Hz, 2H), 1.88 (t, J = 7.2 Hz, 2H), 1.49 – 1.44 (m,2H), 1.40 – 1.35 (m, 2H), 1.15 – 1.10 (m, 2H).
13C NMR (151 MHz, DMSO-d6) δ 172.52 , 168.99 , 168.11 , 166.61 ,158.77 , 136.00 , 134.27 , 129.53 , 129.39 , 129.21 , 128.43 , 114.90 , 55.36, 48.09 , 33.04 , 32.10 , 28.12 , 24.88 , 24.46 .
实施例1-5化合物N1-（5-（2-氯苯基）-1，3，4-噻二唑-2-基）甲基）-N7-羟基-N1-（4-甲氧基苯基）庚二酰胺（WX-488A）的制备
将4-甲基苯甲酰肼换成2-氯苯甲酰肼。1H NMR (600 MHz, DMSO-d6) δ 10.30(br s, 1H), 8.64 (br s, 1H), 8.14 (d, J = 7.8 Hz, 1H), 7.71 (d, J = 8.4 Hz,1H), 7.60 (dd, J = 7.8, 7.8 Hz, 1H), 7.55 (dd, J = 7.2, 7.2 Hz, 1H), 7.20 (d,J = 8.4 Hz, 2H), 6.98 (d, J = 8.4 Hz, 2H), 5.21 (s, 2H), 3.77 (s, 3H), 2.05(t, J = 7.2 Hz, 2H), 1.87 (t, J = 7.2 Hz, 2H), 1.49 – 1.44 (m, 2H), 1.40 –1.35 (m, 2H), 1.16 – 1.10 (m, 2H).
13C NMR (150 MHz, DMSO-d6) δ 172.54 , 168.97 , 167.52 , 164.55 ,158.76 , 134.32 , 132.45 , 131.51 , 131.06 , 130.71 , 129.21 , 128.30 ,127.99 , 114.89 , 55.36 , 47.90 , 33.04 , 32.11 , 28.11 , 24.89 , 24.46 .
实施例1-6化合物N1-（5-（3-氯苯基）-1，3，4-噻二唑-2-基）甲基）-N7-羟基-N1-（4-甲氧基苯基）庚二酰胺（WX-488C）的制备
将4-甲基苯甲酰肼换成3-氯苯甲酰肼。1H NMR (600 MHz, Chloroform-d) δ10.30 (br s, 1H), 8.65 (br s, 1H), 8.02 (s, 1H), 7.94 (d, J = 7.4 Hz, 1H),7.63 (d, J = 7.9 Hz, 1H), 7.57 (t, J = 7.9 Hz, 1H), 7.20 (d, J = 8.5 Hz, 2H),6.97 (d, J = 8.5 Hz, 2H), 5.16 (s, 2H), 3.76 (s, 3H), 2.04 (t, J = 7.4 Hz,2H), 1.88 (t, J = 7.4 Hz, 2H), 1.47 (m, J = 7.5 Hz, 2H), 1.38 (m, J = 7.5 Hz,2H), 1.13 (m, J = 7.0, 6.4 Hz, 2H).
13C NMR (150 MHz, DMSO-d6) δ 172.52 , 168.97 , 167.78 , 166.95 ,134.26 , 134.07 , 131.45 , 131.40 , 131.11 , 129.22 , 126.91 , 126.54 ,114.89 , 55.35 , 39.52 , 33.06 , 32.10 , 28.12 , 24.88 , 24.45 .
实施例1-7化合物N1-（5-（4-氟苯基）-1，3，4-噻二唑-2-基）甲基）-N7-羟基-N1-（4-甲氧基苯基）庚二酰胺（WX-472B）的制备
将4-甲基苯甲酰肼换成4-氟苯甲酰肼。1H NMR (600 MHz, DMSO-d6) δ 10.30(s, 1H), 8.64 (s, 1H), 8.01 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H),7.19 (d, J = 9.0 Hz, 2H), 6.97 (d, J = 9.0 Hz, 2H), 5.15 (s, 2H), 3.76 (s,3H), 2.04 (t, J = 7.2 Hz, 2H), 1.88 (t, J = 7.2 Hz, 2H), 1.49 – 1.44 (m, 2H),1.40 – 1.35 (m, 2H), 1.15 – 1.10 (m, 2H).
13C NMR (150 MHz, DMSO-d6) δ 172.51 , 168.97 , 168.10 , 166.60 ,135.99 , 134.27 , 129.53 , 129.38 , 129.21 , 128.42 , 114.89 , 55.35 , 48.08, 33.04 , 32.10 , 28.11 , 24.87 , 24.45 .
实施例1-8化合物N1-（5-（2-氟苯基）-1，3，4-噻二唑-2-基甲基）-N7-羟基-N1-（4-甲氧基苯基）庚二酰胺（WX-472A）的制备
将4-甲基苯甲酰肼换成2-氟苯甲酰肼。1H NMR (600 MHz, DMSO-d6) δ 10.30(br s, 1H), 8.63 (br s, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.46 (dd, J = 9.0, 7.8Hz, 2H), 7.43 (d, J = 7.2 Hz, 1H), 7.37 (dd, J = 7.2, 7.8 Hz,1H), 7.22 (d, J= 8.4 Hz, 2H), 6.99 (d, J = 8.4 Hz, 2H), 3.78 (s, 3H), 3.34 (s, 3H), 2.06 (t,J = 7.8 Hz, 2H), 1.88 (t, J = 7.8 Hz, 2H), 1.49 – 1.45 (m, 2H), 1.41 – 1.36(m, 2H), 1.18 – 1.12 (m, 2H).
13C NMR (151 MHz, DMSO-d6) δ 172.45 , 168.96 , 166.55 , 158.74 ,136.48 , 134.31 , 131.56 , 130.54 , 129.24 , 126.53 , 114.86 , 55.34 , 47.92, 33.05 , 32.09 , 28.11 , 24.86 , 24.45.
实施例1-9化合物N1-（5-（3-氟苯基）-1，3，4-噻二唑-2-基甲基）-N7-羟基-N1-（4-甲氧基苯基）庚二酰胺（WX-472C）的制备
将4-甲基苯甲酰肼换成3-氟苯甲酰肼。1H NMR (600 MHz, DMSO-d6) δ 10.31(br s, 1H), 8.65 (br s, 1H), 7.83 (d, J = 7.2 Hz, 2H), 7.60 (dd, J = 7.8, 7.8Hz, 1H), 7.43 (dd, J = 7.2, 7.2 Hz 1H), 7.20 (d, J = 9.0 Hz, 2H), 6.98 (d, J= 9.0 Hz 2H), 5.17 (s, 2H), 3.77 (s, 3H), 2.04 (t, J = 7.2 Hz, 2H), 1.88 (t,J = 7.2 Hz, 2H), 1.50 – 1.45 (m, 2H), 1.41 – 1.36 (m, 2H), 1.14 – 1.11 (m,2H).
13C NMR (151 MHz, DMSO-d6) δ 172.52 , 168.99 , 167.96 , 161.52 ,158.78 , 134.27 , 131.72 , 131.66 , 129.22 , 124.12 , 124.10 , 118.28 ,118.13 , 114.90 , 114.17 , 114.01 , 55.35 , 48.08 , 33.06 , 32.11 , 28.13 ,24.89 , 24.46 .
实施例1-10化合物N1-（5-（4-溴苯基）-1，3，4-噻二唑-2-基）甲基）-N7-羟基-N1-（4-甲氧基苯基）庚二酰胺（WX-533B）的制备
将4-甲基苯甲酰肼换成4-溴苯甲酰肼。1H NMR (600 MHz, DMSO-d6) δ 10.30(br s, 1H), 8.64 (br s, 1H), 7.93 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 9.0 Hz,2H), 7.19 (d, J = 9.0 Hz, 2H), 6.97 (d, J = 9.0 Hz, 2H), 5.15 (s, 2H), 3.76(s, 3H), 2.04 (t, J = 7.2 Hz, 2H), 1.88 (t, J = 7.2 Hz, 2H), 1.49 – 1.44 (m,2H), 1.40 – 1.35 (m, 2H), 1.15 – 1.10 (m, 2H).
13C NMR (150 MHz, DMSO-d6) δ 172.52 , 168.98 , 168.23 , 166.62 ,158.77 , 134.27 , 132.45 , 129.54 , 129.21 , 128.76 , 124.82 , 114.89 , 55.35, 48.09 , 33.04 , 32.10 , 28.12 , 24.87 , 24.45 .
实施例2 本发明化合物对HDAC1酶活性的抑制
以Ac-Lys-Tyr-Lys(Ac)-AMC为底物，采用荧光检测法，在96孔或384孔平底微孔板中检测酶活性：底物Ac-Lys-Tyr-Lys(Ac)-AMC经HDAC1去乙酰化后，利用胰酶水解得到的产物AMC经荧光检测仪在355 nm激发下发射460 nm荧光。加入抑制剂后会影响荧光的强弱，通过检测荧光信号随时间的变化，计算得到反应初速度，并计算IC50，以SAHA为阳性对照，结果见图1，从图1可以看出本发明化合物对于HDAC1都有一定的抑制活性，且显著优于SAHA，特别是WX-488C的抑制活性相比SAHA提高了约14倍。
Claims (6)
1.一类含噻二唑结构的异羟肟酸类小分子有机化合物，其特征在于，包括化合物I及其衍生物，所述化合物I的结构如下：
（Ⅰ）式（Ⅰ）中R选自下列基团：-CH3、-OCH3、-F、-Cl、-Br。
2.根据权利要求1所述的化合物其特征在于，所述的衍生物，包括化合物I与酸形成的酸加成盐；其中，所述酸为氢溴酸、盐酸、硫酸、磷酸、乙酸、水杨酸、酒石酸、甲磺酸、柠檬酸、乳酸、对甲苯磺酸、琥珀酸、马来酸、丙酮酸。
3.根据权利要求1所述的化合物其特征在于，所述的衍生物，包括化合物I的水合物或药学上可接受的盐：
N1-羟基-N7-（4-甲氧基苯基）-N7-（5-对甲苯基）-1，3，4-噻二唑-2-甲基）庚二酰胺
N1-羟基-N7-（4-甲氧基苯基）-N7-（5-（4-甲氧基苯基）-1，3，4-噻二唑-2-甲基）庚二酰胺
N1-羟基-N7-（4-甲氧基苯基）-N7-（5-（3-甲氧基苯基）-1，3，4-噻二唑-2-甲基）庚二酰胺
N1-（5-（4-氯苯基）-1，3，4-噻二唑-2-基甲基）-N7-羟基-N1-（4-甲氧基苯基）庚二酰胺
N1-（5-（2-氯苯基）-1，3，4-噻二唑-2-基）甲基）-N7-羟基-N1-（4-甲氧基苯基）庚二酰胺
N1-（5-（3-氯苯基）-1，3，4-噻二唑-2-基）甲基）-N7-羟基-N1-（4-甲氧基苯基）庚二酰胺
N1-（5-（4-氟苯基）-1，3，4-噻二唑-2-基）甲基）-N7-羟基-N1-（4-甲氧基苯基）庚二酰胺
N1-（5-（2-氟苯基）-1，3，4-噻二唑-2-基甲基）-N7-羟基-N1-（4-甲氧基苯基）庚二酰胺
N1-（5-（3-氟苯基）-1，3，4-噻二唑-2-基甲基）-N7-羟基-N1-（4-甲氧基苯基）庚二酰胺
N1-（5-（4-溴苯基）-1，3，4-噻二唑-2-基）甲基）-N7-羟基-N1-（4-甲氧基苯基）庚二酰胺。
4.一种权利要求1或2所述的化合物的应用，其特征在于，作为组蛋白去乙酰化酶抑制剂通过抑制组蛋白乙酰化酶途径，应用在预防和治疗组蛋白乙酰化调控失衡导致的各种血液肿瘤和实体瘤中，还可用于诱发获得性耐药导致化疗失败后的抗肿瘤治疗的药物中。
5.一种权利要求1所述化合物的制备方法，其特征在于，R选自下列基团：-CH3、-OCH3、-F、-Cl、-Br，包括以下步骤：
化合物1和氯乙酰氯在溶剂A中中生成化合物2；化合物2在溶剂B中与对甲氧基苯胺反应得化合物3；化合物3在溶剂C中加热得化合物4；化合物4在溶剂D中适当的溶剂如二氯甲烷或甲醇或二氯亚砜中酯化生成化合物5；化合物5在溶剂E中与盐酸羟胺反应，分离提纯得目标产物6。
6.根据权利要求所述的制备方法，其特征在于，所述溶剂A为无水四氢呋喃，乙醇或甲苯溶液；所述溶剂B为N,N-二甲基甲酰胺或吡啶；所述溶剂C为1,4-二氧六环或四氢呋喃溶液；所述溶剂D为二氯甲烷或甲醇或二氯亚砜；所述溶剂E为甲醇、乙醇、甲苯或二氯甲烷。
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