CN113801089B - 一种克立硼罗中间体的制备方法 - Google Patents
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- SURBAJYBTYLRMQ-UHFFFAOYSA-N dioxido(propan-2-yloxy)borane Chemical compound CC(C)OB([O-])[O-] SURBAJYBTYLRMQ-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/18—Radicals substituted by singly bound oxygen or sulfur atoms
- C07D317/22—Radicals substituted by singly bound oxygen or sulfur atoms etherified
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/18—Radicals substituted by singly bound oxygen or sulfur atoms
- C07D317/20—Free hydroxyl or mercaptan
Abstract
本发明属于药物合成技术领域,具体涉及一种克立硼罗中间体的制备方法。以MED代替现有技术中的乙二醇进行缩醛保护,可显著降低反应温度以及分水器的使用,简化了反应操作,减少能耗。本发明的制备工艺,相较于现有技术所得产品收率及纯度均较高,更适合工业化生产。
Description
技术领域
本发明属于药物合成技术领域,具体涉及一种克立硼罗中间体的制备方法。
背景技术
克立硼罗(Crisaborole)由安纳考尔(Anacor)医药公司开发,是一种磷酸二酯酶4(PDE4)抑制剂,这种抑制导致细胞内环磷酸腺苷(cAMP)水平增高,用于2岁及以上患者的轻度至中度过敏性皮炎的局部治疗,具有广阔前景。2016年12月14日,经美国食品药品管理局(FDA)批准上市,商品名Eucrisa,其化学结构式如下:
克立硼罗的制备方法已有研究报道,CN109456347A、IN201821000974、WO2019138422A1、US2019241585A1、WO2019120637A1、IN201741016807、CN109517003A、CN108864160A、WO2018224923A1、WO2018216032A1、WO2018207216A1、CN108659024A、WO2018150327A1、WO2018115362A1、CN108047261A、CN107759625A、US20170305936A1、CN106928264A、US20070286822A1、WO2009111676A2、WO2007095638A2、WO2007078340A2等专利中均有报道。
其中,CN102014927A公开了合成路线以2-溴-5-羟基苯甲醛为起始原料,先使用乙二醇进行醛基保护,然后与卤代甲腈类物质反应后在酸性条件下脱除乙二醇保护基得到关键中间体,再经Miyaura偶联反应引入硼原子,经硼氢化钠还原等反应得到克立硼罗,合成路线如下:
X=F,Cl;Y,Z=CH,N;R1=H,卤素。
CN108659025A中则采用原甲酸三乙酯或乙二醇先对醛基进行保护,然后在异丙基氯化镁的存在下与硼酸酯(2-烷氧基-4,4,5,5-四甲基-1,3,2-二氧硼戊环、硼酸三异丙酯或硼酸三甲酯)反应,最后与碱金属硼氢化物接触反应,得到克立硼罗。合成路线如下:
Tsutomu Akama等人在Bioorganic&Medicinal Chemistry Letters,19(2009)2129-2132中则以二氢吡喃代替MOM-Cl对苄醇进行保护后在正丁基锂条件下引入硼酸异丙酯后环合制得目标产品的方法。合成路线如下:
硕士论文《克立硼罗合成工艺及质量标准研究》中则采用上述策略制得4-(4-溴-3-(羟甲基)苯氧基)苄腈,醇经乙酰基保护后,在苯环上引入硼酸频哪醇酯,最后在酸性条件下环合制得目标产品。合成路线如下:
综上可知,为避免醛基羟基自身缩合导致反应难以进行的问题,缩醛保护策略在克立硼罗相关中间体的制备中应用较多,而实验证明乙二缩醛保护基较二烷基缩醛保护基优势明显,如4-(4-溴-3-(1,3-二氧戊环-2-基)苯氧基)苄腈及4-溴-3-(1,3-二氧戊环-2-基)苯酚在多条制备工艺中被公开用作制备克立硼罗的关键中间体。其化学结构式如下:
硕士论文《克立硼罗合成工艺及质量标准研究》中参照4-溴-3-(1,3-二氧戊环-2-基)苯酚在文献Bioorganic&Medicinal Chemistry Letters,19(2009)2129-2132中4-溴-3-甲酰基苯酚和乙二醇在p-TsOH的催化作用下,以甲苯为溶剂回流反应6h,加水淬灭后使用乙酸乙酯进行萃取,合并上层有机相,水洗涤3次,加入无水Na2SO4干燥1h,减压浓缩至干的方法,所得产品收率为90%。但是经预实验后发现,反应产率很低,有大量原料剩余,且反应后有大量黑色油状物产生,不利于后处理脱色。通过分析该反应机理,发现反应中有水产生,若不能及时将水除掉,会影响反应的进行,进而影响反应的进程。为使甲苯将反应中产生的水带出,反应温度会对产率产生很大影响,而甲苯的沸点为110℃,经实验验证,当反应温度设为120℃时,产率仅为52.3%。反应过程中有水产生,影响反应进行,应进一步升温使甲苯将反应中产生的水除去,提高产率,这无疑大大增加了反应能耗,同时操作也极不方便。
CN108659025A虽然公开了4-(4-溴-3-(1,3-二氧戊环-2-基)苯氧基)苄腈化合物,但未公开其制备方法,同时参照上述方法以4-(4-溴-3-甲酰基苯氧基)苄腈为起始物料与乙二醇在酸性条件下高温长时间反应制备4-(4-溴-3-(1,3-二氧戊环-2-基)苯氧基)苄腈时除上述问题外,仍存在少量氰基水解杂质,难以精制。
综上,目前克立硼罗制备工艺中的相关乙二缩醛中间体的制备方法在产品纯度、收率和试验操作等方面存在许多不足,因此,研究寻找一条反应条件温和,操作过程简便,产品收率高、纯度高的适合工业化生产乙二缩醛保护中间体的制备方法仍是目前需要解决的问题。
发明内容
针对目前克立硼罗制备工艺中的乙二缩醛类中间体的制备技术存在的问题,本发明提供了一种新的醛基保护制备中间体的方法。该方法反应条件温和,操作过程简便,所制得的目标产品具有较高的纯度、收率。
本发明的具体技术方案如下:
一种克立硼罗乙二缩醛类中间体的制备方法,具体包括以下步骤:
室温,将SM-1、丁酮乙二醇缩酮(MED)、催化剂加入干燥的反应溶剂中,控温至反应结束后,经后处理制得目标化合物。
优选方案,所述的催化剂为对甲苯磺酸、樟脑磺酸、α-萘磺酸、β-萘磺酸中的一种或其组合,其中特别优选对甲苯磺酸;其中樟脑磺酸可为消旋物或1R-(-)-10-樟脑磺酸、1S-(+)-10-樟脑磺酸中的单一异构体或其混合物。
优选方案,所述的反应溶剂为苯、甲苯、二甲苯、二氯甲烷、氯仿中的一种或其组合,其中特别优选二氯甲烷。
优选方案,所述的SM-1与MED、催化剂的投料摩尔比为1:1.1~2.0:3.0%~10.0%,其中特别优选1:1.3:5.0%。
优选方案,所述的反应温度为0~40℃,其中特别优选20~25℃。
优选方案,所述的后处理方法为:反应结束后加入饱和碳酸氢钠溶液后分液取有机层,纯化水洗涤,饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩至干即为目标化合物。
本发明中,所述的干燥的溶剂的方法是指通过分子筛除水或者精馏等常规手段获得的。
本发明的有益效果:
1.本发明提供了一种新的制备克立硼罗相关乙二缩醛中间体方法,以MED代替乙二醇进行缩醛保护,室温下几乎定量得到相关中间体,可显著降低反应温度以及分水器的使用,简化了反应操作,减少能耗。
2.在含有氰基的相关乙二缩醛中间体的制备过程中可有效降低氰基水解的含量,提高产品收率及纯度。
3.本发明的制备工艺,相较于现有技术所得产品收率及纯度均较高,更适合工业化生产。
具体实施方式
下面通过实施例来进一步说明本发明,应该正确理解的是:本发明的实施例仅仅是用于说明本发明,而不是对本发明的限制,所以,在本发明的方法前提下对本发明的简单改进均属于本发明要求保护的范围。
4-溴-3-(1,3-二氧戊环-2-基)苯酚结构确证数据:ESI-HRMS(m/z):243.9728[M+H]+;1H NMR(400MHz,DMSO-d6)δ:8.24(s,1H),7.38(d,J=8.4Hz,1H),6.94(d,J=2.6Hz,1H),6.72(d,J=8.2Hz,1H),5.93(s,1H),4.14~3.86(m,4H);13C NMR(101MHz,DMSO-d6)δ:153.21,139.67,134.46,118.14,117.91,111.33,104.20,67.28。
4-(4-溴-3-(1,3-二氧戊环-2-基)苯氧基)苄腈结构确证数据:ESI-HRMS(m/z):345.0006[M+H]+;1HNMR(400MHz,DMSO-d6)δ:7.88~7.74(m,3H),7.53(d,J=2.8Hz,1H),7.48~7.32(m,2H),7.28~7.08(m,1H),5.93(s,1H),4.06~4.13(m,4H);13C NMR(101MHz,DMSO-d6)δ:159.58,153.11,140.18,133.31,131.56,120.28,120.01,119.12,117.57,117.20,109.84,104.20,67.28。
以下各实施例中,未详细描述的各种过程和方法是本领域中公知的常规方法。
实施例1
室温,将2-溴-5-羟基苯甲醛(SM-1,20.10g,0.10mol)、丁酮乙二醇缩酮(MED,15.10g,0.13mol),对甲苯磺酸(0.86g,0.005mol)加入干燥的二氯甲烷(300ml)中,控温20~25℃至反应结束后,加入饱和碳酸氢钠溶液(150ml)搅拌10~15min后分液取有机层,纯化水(150ml×3)洗涤,饱和食盐水(150ml)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩至干即为4-溴-3-(1,3-二氧戊环-2-基)苯酚,收率97.5%,纯度99.83%。
实施例2
室温,将2-溴-5-羟基苯甲醛(SM-1,20.10g,0.10mol)、MED(12.78g,0.11mol),1R-(-)-10-樟脑磺酸(1.16g,0.005mol)加入干燥的二氯甲烷(300ml)中,控温20~25℃至反应结束后,加入饱和碳酸氢钠溶液(150ml)搅拌10~15min后分液取有机层,纯化水(150ml×3)洗涤,饱和食盐水(150ml)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩至干即为4-溴-3-(1,3-二氧戊环-2-基)苯酚,收率96.9%,纯度99.79%。
实施例3
室温,将2-溴-5-羟基苯甲醛(SM-1,20.10g,0.10mol)、MED(11.62g,0.10mol),1S-(+)-10-樟脑磺酸(1.16g,0.005mol)加入干燥的二氯甲烷(300ml)中,控温20~25℃至反应结束后,加入饱和碳酸氢钠溶液(150ml)搅拌10~15min后分液取有机层,纯化水(150ml×3)洗涤,饱和食盐水(150ml)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩至干即为4-溴-3-(1,3-二氧戊环-2-基)苯酚,收率96.7%,纯度99.77%。
实施例4
室温,将2-溴-5-羟基苯甲醛(SM-1,20.10g,0.10mol)、MED(23.23g,0.20mol),α-萘磺酸(1.04g,0.005mol)加入干燥的二氯甲烷(300ml)中,控温20~25℃至反应结束后,加入饱和碳酸氢钠溶液(150ml)搅拌10~15min后分液取有机层,纯化水(150ml×3)洗涤,饱和食盐水(150ml)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩至干即为4-溴-3-(1,3-二氧戊环-2-基)苯酚,收率96.5%,纯度99.78%。
实施例5
室温,将2-溴-5-羟基苯甲醛(SM-1,20.10g,0.10mol)、MED(24.39g,0.21mol),β-萘磺酸(1.04g,0.005mol)加入干燥的二氯甲烷(300ml)中,控温20~25℃至反应结束后,加入饱和碳酸氢钠溶液(150ml)搅拌10~15min后分液取有机层,纯化水(150ml×3)洗涤,饱和食盐水(150ml)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩至干即为4-溴-3-(1,3-二氧戊环-2-基)苯酚,收率96.6%,纯度99.76%。
实施例6
室温,将2-溴-5-羟基苯甲醛(SM-1,20.10g,0.10mol)、MED(15.10g,0.13mol),对甲苯磺酸(0.52g,0.003mol)加入干燥的氯仿(300ml)中,控温30~35℃至反应结束后,加入饱和碳酸氢钠溶液(150ml)搅拌10~15min后分液取有机层,纯化水(150ml×3)洗涤,饱和食盐水(150ml)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩至干即为4-溴-3-(1,3-二氧戊环-2-基)苯酚,收率96.5%,纯度99.78%。
实施例7
室温,将2-溴-5-羟基苯甲醛(SM-1,20.10g,0.10mol)、MED(15.10g,0.13mol),对甲苯磺酸(0.34g,0.002mol)加入干燥的苯(300ml)中,控温35~40℃至反应结束后,加入饱和碳酸氢钠溶液(150ml)搅拌10~15min后分液取有机层,纯化水(150ml×3)洗涤,饱和食盐水(150ml)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩至干即为4-溴-3-(1,3-二氧戊环-2-基)苯酚,收率96.1%,纯度99.76。
实施例8
室温,将2-溴-5-羟基苯甲醛(SM-1,20.10g,0.10mol)、MED(15.10g,0.13mol),对甲苯磺酸(1.72g,0.01mol)加入干燥的二氯甲烷(300ml)中,控温10~15℃至反应结束后,加入饱和碳酸氢钠溶液(250ml)搅拌10~15min后分液取有机层,纯化水(150ml×3)洗涤,饱和食盐水(150ml)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩至干即为4-溴-3-(1,3-二氧戊环-2-基)苯酚,收率97.7%,纯度99.73%。
实施例9
室温,将2-溴-5-羟基苯甲醛(SM-1,20.10g,0.10mol)、MED(15.10g,0.13mol),对甲苯磺酸(1.89g,0.011mol)加入干燥的二甲苯(300ml)中,控温0~5℃至反应结束后,加入饱和碳酸氢钠溶液(300ml)搅拌10~15min后分液取有机层,纯化水(150ml×3)洗涤,饱和食盐水(150ml)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩至干即为4-溴-3-(1,3-二氧戊环-2-基)苯酚,收率97.6%,纯度99.70%。
实施例10
室温,将4-(4-溴-3-甲酰基苯氧基)苄腈(SM-1,30.21g,0.10mol)、MED(13.94g,0.12mol),对甲苯磺酸(0.86g,0.005mol)加入干燥的二氯甲烷(300ml)中,控温20~25℃至反应结束后,加入饱和碳酸氢钠溶液(150ml)后分液取有机层,纯化水(150ml×3)洗涤,饱和食盐水(150ml)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩至无溶剂流出即得4-(4-溴-3-(1,3-二氧戊环-2-基)苯氧基)苄腈,收率97.9%,纯度99.87%。
Claims (2)
1.一种克立硼罗中间体的制备方法,其特征在于,以式SM-1化合物与MED催化反应得到目标化合物,路线如下:
;
具体包括以下步骤:室温,将SM-1、丁酮乙二醇缩酮即MED、催化剂加入干燥的反应溶剂中,控温至反应结束后,经后处理制得目标化合物;
所述的催化剂为对甲苯磺酸、樟脑磺酸、α-萘磺酸、β-萘磺酸中的一种或其组合;
所述的反应溶剂为苯、甲苯、二甲苯、二氯甲烷、氯仿中的一种或其组合;
所述的控温温度为0~40℃。
2.如权利要求1所述的制备方法,其特征在于,所述的SM-1与MED、催化剂的投料摩尔比为1:1.1~2.0:3.0%~10.0%。
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