CN109485664B - 一种抗真菌药物他伐硼罗的制备工艺 - Google Patents
一种抗真菌药物他伐硼罗的制备工艺 Download PDFInfo
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Abstract
本发明涉及一种抗真菌药物他伐硼罗(Tavaborole)的制备工艺,反应步骤如下:以2‑溴‑5‑氟苯甲醛为起始物料,在钯催化剂和溶剂存在下,与频哪醇硼酸酯反应,生成2‑频哪醇硼基‑5‑氟苯甲醛(TAV‑A),再经还原、关环,生成产物他伐硼罗,后处理使用稀碱液调节反应液PH值,即可析出他伐硼罗。该制备工艺反应步骤短,条件温和安全,易于操作,收率高,对环境友好,适宜于工业化生产。
Description
技术领域
本发明涉及一种抗真菌药物他伐硼罗的制备工艺,属于药物合成领域。
背景技术
甲癣,俗称“灰指甲”,是指皮癣菌侵犯甲板或甲下所引起的疾病,也称甲真菌病。甲真菌病是由皮癣菌、酵母菌及非皮癣菌等真菌引起的甲感染,是皮肤癣菌病中最顽固难治的一种。甲真菌病除影响美观,患者容易产生异常心理障碍,对某些职业和日常生活正常一点影响外,还可引起疼痛和不适,易引发甲沟炎、甲床炎、手指脓皮病等并发症,是手足癣、体股癣、丹毒等严重皮肤病和阴部证据感染的传染源。它的危害不可小觑。
口服抗真菌药物伊曲康唑、氟康唑等,靶向性差,治愈率不足50%,且不良反应较为严重,可能导致肝脏损伤,有些口服药物与其他药物可能发生严重的相互作用。因此,治疗甲癣一般使用外用抗真菌药物。目前临床常用的局部治疗药物有5%阿莫罗芬搽剂、8%环吡酮甲涂剂、复方酮康唑搽剂、特比萘芬乳剂等,临床治愈率不高,不能满足患者需求。
Tavaborole(本文译作他伐硼罗)是2014年FDA批准上市的一种全新机理的抗真菌药,商品名Kerydin®,适用于由红色毛癣菌或须癣毛癣菌引起的趾甲真菌病的局部治疗。他伐硼罗为氧硼戊环类抗真菌药物,作用机理为抑制真菌蛋白合成的关键酶—亮酰胺转移RNA合成酶,从而阻断真菌蛋白质合成。该药物安全性高,优于现有药物;外用涂抹,患者依从性高;不需要清创,患者痛苦小;其全新的药理机制更可有效预防复发,是一种较好的治疗甲癣的外用药物。
他伐硼罗的化学名为5-氟-1,3-二氢-1-羟基-2,1-苯并氧杂硼,结构如下:
他伐硼罗(Tavaborole)
目前,文献报道的他伐硼罗的合成路线主要有以下几条:
路线1(J Label Compd Radiopharm 2007;50:245–250)以胺代化合物为起始原料,经过重氮化、取代、氧化、还原,保护,水解等五步反应制备终产物,该条路线较长,整体工艺难度较高,并且用到了剧毒化合物氰化钾,实验的危险性大,第二步的温度也相对较高,不易操作。路线1如下所示:
路线2(J. Med. Chem. 2006,49,4447-4450)选用苯甲酸类化合物为起始原料,经过还原、保护、水解等三步反应制备终产物,该条路线整体工艺难度较低,但第一步还原所用的硼烷相对较贵,最后一步使用丁基锂和硼酸三异丙酯,反应条件苛刻,危险度较高。路线2如下所示:
路线3(US2005261277)的两条路线分别选用甲酸类化合物和苄醇类化合物为起始原料,分别经过保护、溴代、水解;保护、脱溴、水解各三步反应制备终产物,两条路线整体工艺难度较低,但溴代会产生较多异构体,后处理复杂,制备成本高。路线3如下所示:
以上路线在最后一步中,均使用丁基锂,使得该步反应条件苛刻、危险度提高,并且上述路线反应都较长,总收率降低,不利于工业化生产。因此,有必要开发一种条件温和安全,易于操作,原料易得,收率高,对环境友好,适宜于工业化生产的路线。
发明内容
针对现有技术中存在的问题,本发明的发明人经过大量的条件实验,开发出一条全新的路线,以2-溴-5-氟苯甲醛为起始物料,经取代、硼氢化还原、关环等反应过程,生成产物他伐硼罗,只需经过2步反应,并且后处理使用稀碱液调节反应液PH值,即可析出纯品,整条路线简单易行,终产物纯度达到99.9%以上,整条路线收率达到70%以上。该路线如下:
本发明的抗真菌药物他伐硼罗(Tavaborole,缩写为TAV)的制备工艺,包含以下步骤:
a)以2-溴-5-氟苯甲醛为起始物料,在钯催化剂和溶剂存在下,与频哪醇硼酸酯反应,生成2-频哪醇硼基-5-氟苯甲醛(TAV-A);
b)TAV-A经还原剂还原、关环,生成产物他伐硼罗;
c)使用稀碱液调节反应液pH值,析晶,即得纯品他伐硼罗。
如本发明所述的他伐硼罗的制备工艺,进一步地,所述步骤a)中的钯催化剂选自PdCl2、Pd(OAc)2、Pd(PPh3)4、Pd(dppf)Cl2、Pd2(dba)3中的一种。
如本发明所述的他伐硼罗的制备工艺,进一步地,所述钯催化剂的含量为0.5-10%。
如本发明所述的他伐硼罗的制备工艺,进一步地,所述步骤a)中的溶剂选自水、甲醇、四氢呋喃、二氧六环、乙醇、DMSO中的1种或2种。
如本发明所述的他伐硼罗的制备工艺,进一步地,所述步骤a)中的反应条件中还可以含有碱。
如本发明所述的的他伐硼罗的制备工艺,进一步地,所述碱选自碳酸锂、碳酸钠、醋酸钠、碳酸钾、醋酸钾、碳酸铯、磷酸钾、磷酸二氢钾中的一种。
如本发明所述的他伐硼罗的制备工艺,进一步地,所述步骤b)的还原剂选自硼氢化钠、硼氢化钾、硼氢化钙、醋酸硼氢化钠中的一种。
如本发明所述的他伐硼罗的制备工艺,进一步地,所述步骤c)的中的稀碱液为无机碱溶液。
如本发明所述的他伐硼罗的制备工艺,进一步地,所述步骤c)的反应液的pH值为6-8。
本发明的他伐硼罗的制备工艺,具有如下优点:首先,该路线短,只需2步,大大节省了工艺时间;其次,反应条件温和,不需要使用丁基锂,避免了-78℃低温的苛刻条件反应;再次,避免了氰化物、丁基锂等剧毒、易燃物的使用,避免了对人体危害性较强的溶剂的使用,大大提高了反应的安全性;并且,该条路线操作简便,收率很高,对环境友好,非常适合工业化生产。
附图说明
图1为经本发明的制备工艺所制得的他伐硼罗的HPLC图谱。
图2为经本发明的制备工艺所制得的他伐硼罗的H-NMR图谱。
图3经本发明的制备工艺所制得的他伐硼罗的13C-NMR图谱。
具体实施方式
以下结合具体实施例对本发明进行进一步的阐释。本发明的内容包括但不限于以下实施例。
实施例1 TAV-A的合成工艺1
100L反应釜中加入起始物料2-溴-5-氟苯甲醛(3.045kg,15mol,1 eq),Pin2B2(4.572kg,18mol,1.2 eq),醋酸钾(4.41kg,45mol,3.0 eq)和50L二氧六环溶剂,氮气保护下,加入Pd(dppf)Cl2(550g,0.75mol,0.05 eq)。搅拌升温至95℃,反应约18小时。TLC监测反应完毕,倾入50L水中淬灭,用乙酸乙酯萃取(3×20L),合并有机相,有机相加入饱和食盐水(30L)洗涤,分液,无水硫酸钠干燥过夜,减压蒸干,回收乙酸乙酯,得到棕黄色油状物TAV-A(3.189kg,收率85%)。
实施例2 TAV-A的合成工艺2
100L反应釜中加入起始物料2-溴-5-氟苯甲醛(3.045kg,15mol,1 eq),Pin2B2(4.572kg,18mol,1.2 eq),碳酸钠(4.77kg,45mol,3.0 eq),50L乙醇(95%)溶剂,氮气保护下,加入Pd2(dba)3(274.7g,0.3mol,0.02eq)。搅拌升温至回流,反应约18小时。TLC监测反应完毕,倾入30L水中淬灭,用乙酸乙酯萃取(3×20L),合并有机相,有机相加入饱和食盐水(30L)洗涤,分液,无水硫酸钠干燥过夜,减压蒸干,回收乙酸乙酯,得到棕黄色油状物TAV-A(3.112kg,收率83%)。
实施例3 TAV-A的合成工艺3
100L反应釜中加入起始物料2-溴-5-氟苯甲醛(3.045kg,15mol,1 eq),Pin2B2(4.572kg,18mol,1.2 eq),碳酸铯(9.77kg,30mol,2.0 eq),50L水和DMSO(体积比3:2)的混合溶剂,氮气保护下,加入Pd(OAc)2(336g,1.5mol,0.1 eq)。搅拌升温至100℃,反应约16小时。TLC监测反应完毕,倾入30L水中淬灭,用乙酸乙酯萃取(3×20L),合并有机相,有机相加入饱和食盐水(30L)洗涤,分液,无水硫酸钠干燥过夜,减压蒸干,回收乙酸乙酯,得到棕黄色油状物TAV-A(3.264kg,收率87%)。
实施例4 TAV-A的合成工艺4
100L反应釜中加入起始物料2-溴-5-氟苯甲醛(3.045kg,15mol,1 eq),Pin2B2(4.572kg,18mol,1.2 eq),醋酸钠(3.69kg,45mol,3.0 eq),50L甲醇和四氢呋喃(体积比4:1)的混合溶剂,氮气保护下,加入Pd(PPh3)4(173.3g,0.15mol,0.01 eq)。搅拌升温至90℃,反应约18小时。TLC监测反应完毕,倾入30L水中淬灭,用乙酸乙酯萃取(3×20L),合并有机相,有机相加入饱和食盐水(30L)洗涤,分液,无水硫酸钠干燥过夜,减压蒸干,回收乙酸乙酯,得到棕黄色油状物TAV-A(3.0kg,收率80%)。
实施例5 TAV-A的合成工艺5
100L反应釜中加入起始物料2-溴-5-氟苯甲醛(3.045kg,15mol,1 eq),Pin2B2(4.572kg,18mol,1.2 eq),碳酸锂(1.85kg,25mol,1.7 eq),50L二氧六环和水(体积比4:1)的混合溶剂,氮气保护下,加入Pd(dppf)Cl2(550g,0.75mol,0.05 eq)。搅拌升温至95℃,反应约18小时。TLC监测反应完毕,倾入30L水中淬灭,用乙酸乙酯萃取(3×20L),合并有机相,有机相加入饱和食盐水(30L)洗涤,分液,无水硫酸钠干燥过夜,减压蒸干,回收乙酸乙酯,得到棕黄色油状物TAV-A(3.03kg,收率81%)。
实施例6 TAV-A的合成工艺6
100L反应釜中加入起始物料2-溴-5-氟苯甲醛(3.045kg,15mol,1 eq),Pin2B2(4.572kg,18mol,1.2 eq),磷酸钾(5.53kg,25mol,1.7 eq),50L甲醇和水(体积比9:1)的混合溶剂,氮气保护下,加入Pd2(dba)3(686.8g,0.75mol,0.05eq)。搅拌升温至回流,反应约18小时。TLC监测反应完毕,倾入30L水中淬灭,用乙酸乙酯萃取(3×20L),合并有机相,有机相加入饱和食盐水(30L)洗涤,分液,无水硫酸钠干燥过夜,减压蒸干,回收乙酸乙酯,得到棕黄色油状物TAV-A(2.9kg,收率78%)。
实施例7 他伐硼罗的合成工艺1
取TAV-A(3kg,12mol,1 eq)溶解于30L无水甲醇中,5℃下,分批加入硼氢化钠(454g,12mol,1 eq),加完室温搅拌反应1小时。TLC监测原料消失。向反应液中加入2mol/L的稀盐酸(约18L),调节pH值到2,室温下搅拌反应1小时。TLC监测中间体消失。加入20L水淬灭,减压将甲醇蒸干,回收甲醇。接着向剩下的水溶液中慢慢滴加1mol/L氢氧化钠水溶液,调节pH=6-8,即析出固体,搅拌2h,过滤,常温干燥至恒重,得白色固体他伐硼罗(1.66kg,收率91%)。
HPLC:100%,见说明书附图图1。
MS:170.1[M+H2O]+、175.0[M+Na]+、153.1[M+H]+
H-NMR(500MHz,DMSO-d6):4.961(s,2H),7.158(td,1H),7.242(d,1H),7.743(dd,1H),9.230(s,1H)。见说明书附图图2。
13C-NMR(500MHz,DMSO-d6):165.22-163.26,156.85,156.78,132.68,114.54,108.53,69.58。见说明书附图图3。
实施例8他伐硼罗的合成工艺2
取TAV-A(3kg,12mol,1 eq)溶解于30L无水甲醇中,5℃下,分批加入硼氢化钾(648g,12mol,1 eq),加完室温搅拌反应1小时。TLC监测原料消失。向反应液中加入2mol/L的稀盐酸(约18L),调节pH值到2,室温下搅拌反应1小时。TLC监测中间体消失。加入20L水淬灭,减压将甲醇蒸干,回收甲醇。接着向剩下的水溶液中慢慢滴加1mol/L氢氧化钾水溶液,调节pH=6-8,即析出固体,搅拌2h,过滤,常温干燥至恒重,得白色固体他伐硼罗(1.64kg,收率90%)。
实施例9他伐硼罗的合成工艺3
取TAV-A(3kg,12mol,1 eq)溶解于30L无水甲醇中,5℃下,分批加入醋酸硼氢化钠(3.05g,14.4mol,1.2 eq),加完室温搅拌反应1小时。TLC监测原料消失。向反应液中加入2mol/L的稀盐酸(约18L),调节pH值到2,室温下搅拌反应1小时。TLC监测中间体消失。加入20L水淬灭,减压将甲醇蒸干,回收甲醇。接着向剩下的水溶液中慢慢滴加1mol/L氢氧化钾水溶液,调节pH=6-8,即析出固体,搅拌2h,过滤,常温干燥至恒重,得白色固体他伐硼罗(1.61kg,收率88%)。
对所公开的实施例的上述说明,使本领域的专业技术人员能够实现或者使用本发明。但在本发明的基础上可以对之做进一步修改或改进,这对本领域专业技术人员来说是显而易见的。因此,在不偏离本发明的基础上所做的修改或者改进,均属于保护的范围。
Claims (1)
1.一种抗真菌药物他伐硼罗的制备工艺,其特征在于,所述制备工艺的反应式为:
制备步骤如下:
(1)制备TAV-A
100L反应釜中加入起始物料2-溴-5-氟苯甲醛3.045kg,Pin2B2 4.572kg,碳酸铯9.77kg,体积比3:2的50L水和DMSO的混合溶剂,氮气保护下,加入Pd(OAc)2 336g,搅拌升温至100℃,反应16小时;TLC监测反应完毕,倾入30L水中淬灭,用乙酸乙酯萃取,合并有机相,有机相加入饱和食盐水洗涤,分液,无水硫酸钠干燥过夜,减压蒸干,回收乙酸乙酯,得到棕黄色油状物TAV-A;
(2)制备他伐硼罗TAV
取TAV-A 3kg溶解于30L无水甲醇中,5℃下,分批加入硼氢化钠454g,加完室温搅拌反应1小时;TLC监测原料消失,向反应液中加入2mol/L的稀盐酸,调节pH值到2,室温下搅拌反应1小时,TLC监测中间体消失;加入20L水淬灭,减压将甲醇蒸干,回收甲醇;接着向剩下的水溶液中滴加1mol/L氢氧化钠水溶液,调节pH=6-8,析出固体,搅拌2h,过滤,常温干燥至恒重,得白色固体他伐硼罗。
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