CN112441864B - 一种hiv蛋白酶抑制剂中间体化合物的合成方法 - Google Patents
一种hiv蛋白酶抑制剂中间体化合物的合成方法 Download PDFInfo
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Abstract
本发明适用于药物合成技术领域,提供了一种HIV蛋白酶抑制剂中间体化合物的合成方法,包括:在氩气保护下,将化合物1a在反应溶剂中,加入催化剂和氢源混合物进行不对称转移氢化反应,得到HIV蛋白酶抑制剂中间体化合物2a、2a’,其合成路线如下所示:
Description
技术领域
本发明属于药物合成技术领域,尤其涉及一种HIV蛋白酶抑制剂中间体化合物的合成方法。
背景技术
艾滋病是世界上最难治愈的疾病之一。在过去的几十年里,艾滋病的治疗已经取得了重大的进步,HIV蛋白酶抑制剂是目前最有前景的治疗技术,但是高昂的药物价格使得很多艾滋病人放弃治疗,所以发展一种高效廉价的HIV蛋白酶抑制剂中间体的合成方法至关重要,目前常见的HIV蛋白酶抑制剂及其中间体的结构如下所示:
现有技术中主要采用酶催化以及不对称氢化方法合成该中间体,其中,采用手性氨基醛为原料采用化学方法合成该中间体,需要大量化学试剂NaBH4进行还原,得到的产物立体选择性控制较差,必须通过重结晶得到单一构型的产物;2001年,B.Moon Kim小组报道了一种以天然手性源为起始原料,经过多步复杂过程合成该中间体;2013年,IoannisN.Houpis分别用不对称氢化和酶催化的方法合成了该中间体,虽然有比较好的立体控制性,但是催化的活性较差,大多数情况下不能够转化完全,原料损耗较大,酶的用量也很大。
由此可见,现有合成HIV蛋白酶抑制剂中间体的方法存在立体选择性控制较差、反应活性低、原料损耗大以及合成工艺过程复杂的问题。
发明内容
本发明实施例提供一种HIV蛋白酶抑制剂中间体化合物的合成方法,旨在解决现有合成HIV蛋白酶抑制剂中间体的方法存在立体选择性控制较差、反应活性低、原料损耗大以及合成工艺过程复杂的问题。
本发明实施例是这样实现的,一种HIV蛋白酶抑制剂中间体化合物的合成方法,包括:
将化合物1a在反应溶剂中,加入催化剂和氢源混合物进行不对称转移氢化反应,得到HIV蛋白酶抑制剂中间体化合物2a、2a’,其合成路线如下所示:
所述基团R为叔丁氧羰基、苄氧羰基、对甲苯磺酰基、乙酰基、苯甲酰基中的一种。
本发明实施例提供的HIV蛋白酶抑制剂中间体化合物的合成方法,利用不对称转移氢化技术,所合成的HIV蛋白酶抑制剂中间体化合物与现有的类似中间体相比,其立体选择性和收率能够大幅提高,产物的非对映选择性比例达到 94:6;另外,催化剂用量少且催化效率高,改善了反应活性,原料损耗少,整体工艺快速简便、成本大幅下降。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合具体实施例,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅用以解释本发明,并不用于限定本发明。
本发明实施例提供的HIV蛋白酶抑制剂中间体化合物的合成方法,在氩气保护下,将化合物1a在反应溶剂中,加入催化剂和氢源混合物进行不对称转移氢化反应,得到HIV蛋白酶抑制剂中间体化合物2a、2a’,其合成路线如下所示:
化合物1a的命名:
tert-butyl(S)-(4-chloro-3-oxo-1-phenylbutan-2-yl)carbamate。
HIV蛋白酶抑制剂中间体化合物的命名:
2a:tert-butyl((2S,3R)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate;
2a’:tert-butyl((2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate。
在本发明实施例中,所述基团R为叔丁氧羰基(Boc)、苄氧羰基(CBz)、对甲苯磺酰基(Ts)、乙酰基(Ac)、苯甲酰基(Bz)中的一种。
在本发明实施例中,所用催化剂在转移氢化过程中的结构如下所示:
在本发明实施例中,催化剂与化合物1a的摩尔比为1:100~5000;化合物1a 在反应体系的浓度为0.1M~0.5M。
在本发明实施例中,不对称转移氢化反应是在氩气或氮气保护下进行。
在本发明实施例中,所用的反应溶剂为甲醇、四氢呋喃、异丙醇、邻二氯乙烷、二氯甲烷、甲苯、水、N,N-二甲基甲酰胺中的一种或几种。
在本发明实施例中,所述反应溶剂还可以为体积比1:1的四氢呋喃与水的混合液、体积比1:1的异丙醇与水的混合液、体积比1:1的N,N-二甲基甲酰胺与水的混合液中的一种。
在本发明实施例中,氢源为甲酸三乙胺(5:2)共沸混合物、甲酸钠中的一种或两种。
在本发明实施例中,所述不对称转移氢化反应的反应时间为2~16h,其中,体系在不同反应溶剂或不同氢源的情况下,所用反应时间不同,当所用氢源为甲酸三乙胺,反应溶剂分别为四氢呋喃、异丙醇、邻二氯乙烷、二氯甲烷、甲苯时对应的反应时间优选为2h;当所用氢源为甲酸三乙胺,反应溶剂为甲醇时对应的反应时间优选为12h;当所用氢源为甲酸钠,反应溶剂分别为水、四氢呋喃与水的混合液、异丙醇与水的混合液、N,N-二甲基甲酰胺与水的混合液时对应的反应时间为16h。
在本发明实施例中,不对称转移氢化反应的反应温度为25℃;当反应温度高于30℃,加热体系会变得复杂,故本发明实施例都是在25℃下进行。
本发明实施例提供的HIV蛋白酶抑制剂中间体化合物的合成方法,利用不对称转移催化技术,所合成的HIV蛋白酶抑制剂中间体化合物与现有的类似中间体相比,其立体选择性和收率能够大幅提高,产物的非对映选择性比例达到 94:6;另外,催化剂用量少且催化效率高,改善了反应活性,原料损耗少,整体工艺快速简便、成本大幅下降。
以下通过具体实施例对本发明的HIV蛋白酶抑制剂中间体化合物的合成方法的技术效果做进一步的说明。
实施例1
在温度为25℃下,在氩气保护下,将化合物1a(0.2mmol)在甲醇(2mL) 中,加入催化剂cat.1和甲酸三乙胺(5:2)(40uL)混合物(催化剂是0.002M 的甲醇溶液取用100uL),进行不对称转移氢化反应16h,,得到HIV蛋白酶抑制剂中间体化合物2a、2a’,其合成路线如下所示:
实施例2-18
本发明为考察不对称转移氢化反应所用催化剂的种类对HIV蛋白酶抑制剂中间体化合物的转化率(conv.)以及非对映异构体的比例(dr)的影响,在实施例1 的基础上,将催化剂cat.1依次替换为cat.2、cat.3、cat.4、cat.5、cat.6、cat.7、 cat.8、cat.9、cat.10、cat.11、cat.12、(R,R)-cat.13和(S,S)-cat.13、cat.14、cat.15、 cat.16、cat.17。
实施例1-18中不同催化剂对HIV蛋白酶抑制剂中间体化合物的转化率以及 dr值的影响结果见下表1所示;其中,转化率由LC测得(反相C18柱),dr 值由LC和核磁共振氢谱及碳谱所确定。
表1
综上,从表1中可知,催化剂的种类决定了反应整体的立体选择性。实施例1-18分别使用了不同催化剂,反应的非对映选择性很大,同时活性的差别也比较大,相对于最优催化剂cat.13活性的差别可能是其他催化剂结构比较分散,容易在催化循环中被小分子捕获而失活,选择性差的原因可能是分散的手性催化剂对该类底物不能够提供一个比较优秀的手性口袋,而cat.13的链式结构可以提供。
进一步,经研究发现催化剂在不同的溶剂环境中的表现不一,为考察不对称转移氢化反应所用反应溶剂的种类对HIV蛋白酶抑制剂中间体化合物的转化率以及非对映异构体的比例的影响,在实施例13的基础上,反应时间为3h, S/C=1000,并依次将反应溶剂甲醇替换为四氢呋喃(THF)、异丙醇(IPA)、邻二氯乙烷(DCE)、二氯甲烷(DCM)、甲苯(toluene)、甲醇(MeOH),其他组分、含量,工艺条件均不变,进行实施例19-24;以及在实施例14的基础上,其合成路线如下所示:
不同反应溶剂种类对HIV蛋白酶抑制剂中间体化合物的转化率以及dr值的影响结果见下表2所示。
表2
反应溶剂种类 | conv.(%) | dr(2a:2a’) | |
实施例19 | THF | >99 | 90:10 |
实施例20 | IPA | >99 | 91:9 |
实施例21 | DCE | >99 | 93:7 |
实施例22 | DCM | >99 | 91:9 |
实施例23 | toluene | >99 | 91:9 |
实施例24 | MeOH | >99 | 94:6 |
综上,从表2可知,在实施例13的基础上,反应时间为2h,S/C=1000,并依次将反应溶剂甲醇替换为四氢呋喃(THF)、异丙醇(IPA)、邻二氯乙烷(DCE)、二氯甲烷(DCM)、甲苯(toluene)、甲醇(MeOH),对HIV蛋白酶抑制剂中间体化合物的转化率影响较小,对dr值影响较大;其中,实施例19-24中HIV 蛋白酶抑制剂中间体化合物的转化率均高于99%,实施例24所得HIV蛋白酶抑制剂中间体化合物中非对映异构体的比例为94:6,即相对现有技术提高了反应的立体控制能力。
进一步,为获得非对映异构体比例更高的HIV蛋白酶抑制剂中间体化合物,在实施例13的基础上,将氢源甲酸三乙胺替换为甲酸钠HCOONa(6eq.),反应时间16h,S/C=1000,反应溶剂依次替换为水、体积比1:1的四氢呋喃与水的混合液H2O/THF(1:1)、体积比1:1的异丙醇与水的混合液H2O/IPA(1:1),进行以下实施例25-27,对HIV蛋白酶抑制剂中间体化合物的转化率以及dr值的影响结果见下表3所示。
表3
氢源 | 反应溶剂 | conv.(%) | dr(2a:2a’) | |
实施例25 | HCOONa(6eq.) | H<sub>2</sub>O | 20 | 83:17 |
实施例26 | HCOONa(6eq.) | H<sub>2</sub>O/THF(1:1) | 90 | 92:8 |
实施例27 | HCOONa(6eq.) | H<sub>2</sub>O/IPA(1:1) | >99 | 89:11 |
综上,从表3可知,当氢源选用甲酸钠时,反应溶剂种类的选择对HIV蛋白酶抑制剂中间体化合物的转化率以及非对映异构体的比例影响显著,其中,反应溶剂为水时,转化率与立体控制性均较差,说明在S/C=1000时,实施例25-27 所得HIV蛋白酶抑制剂中间体化合物的转化率以及非对映异构体的比例均不如氢源选用甲酸三乙胺的实施例。
进一步,为考察不对称转移氢化反应中不同R基团对HIV蛋白酶抑制剂中间体化合物的转化率以及非对映异构体的比例的影响,在实施例13-14的基础上,S/C=1000,反应溶剂为DCM,改变底物,将底物化合物I的R基团依次变为Boc、Bz、Ac、Ts、CBz基团,其合成路线如下所示:
对HIV蛋白酶抑制剂中间体化合物的转化率以及dr值的影响结果见下表4 所示。
表4
综上,从表4可知,催化剂的手性构型决定了产物的手性构型,即S,S构型的催化剂的到SS构型的底物R,R构型的催化剂的到S,R构型的底物;催化剂对不同N保护基团的底物有很好的兼容性,有非常优异的非对映选择性,其中当氮上的保护基团是苯甲酰基的时候可以得到最佳的非对映选择性,>99:1dr。另外,当氮上的保护基团是叔丁氧羰或者苄氧羰基的时候,S,S构型的催化剂比 R,R构型催化剂的非对映选择性略高一点。这可能是底物本身是S构型,在与 SS催化剂进行反应的时候,手性口袋匹配度更高一些。。
进一步,底物中R基团为苯甲酰基,以最佳催化剂cat.13作为催化剂、以 DCM作为反应溶剂,以甲酸三乙胺(5:2)作为氢源,分别改变氢源用量、反应时间、底物在反应体系中浓度等,合成路线如下所示:
对HIV蛋白酶抑制剂中间体化合物的转化率以及dr值的影响结果见下表5 所示。
表5
综上,从表5中可知,在S/C=5000的时候,甲酸三乙胺的量从1eq~100eq 的改变对反应的转化率的影响不大,但是大大过量的氢源会使产物的dr值略微降低。另外,在0.1M~0.5M的浓度范围,反应体系中底物的浓度对反应的影响比较小,所以在小量反应的时候用0.1M的浓度,放大反应的时候采用0.5M的浓度。
综上,本发明实施例提供的HIV蛋白酶抑制剂中间体化合物的合成方法,利用不对称转移氢化技术,所合成的HIV蛋白酶抑制剂中间体化合物与现有的类似中间体相比,其立体选择性和收率能够大幅提高,产物的非对映选择性比例达到94:6;另外,催化剂用量少且催化效率高,改善了反应活性,原料损耗少,整体工艺快速简便、成本大幅下降。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等,均应包含在本发明的保护范围之内。
Claims (4)
1.一种HIV蛋白酶抑制剂中间体化合物的合成方法,其特征在于,包括:
将化合物1a在反应溶剂中,加入催化剂和氢源混合物进行不对称转移氢化反应,得到HIV蛋白酶抑制剂中间体化合物2a、2a’,其合成路线如下所示:
所述基团R为叔丁氧羰基、苄氧羰基、对甲苯磺酰基、乙酰基、苯甲酰基中的一种;
所述催化剂为(R,R)-cat.13、(S,S)-cat.13、cat.14、cat.15、cat.16、cat.17中的一种:
所述氢源为甲酸三乙胺、甲酸钠中的一种;
所述氢源为甲酸钠时,所述反应溶剂为体积比1:1的四氢呋喃与水的混合液、体积比1:1的异丙醇与水的混合液中的一种;
所述氢源为甲酸三乙胺时,所述反应溶剂为甲醇、四氢呋喃、异丙醇、邻二氯乙烷、二氯甲烷、甲苯中的一种;
所述不对称转移氢化反应在氩气或者氮气氛围下进行;
所述化合物1a在反应体系的浓度为0.1M~0.5M。
2.如权利要求1所述的HIV蛋白酶抑制剂中间体化合物的合成方法,其特征在于,所述催化剂与化合物1a的摩尔比为1:1000~5000。
3.如权利要求1所述的HIV蛋白酶抑制剂中间体化合物的合成方法,其特征在于,所述不对称转移氢化反应的反应时间为2~48h。
4.如权利要求1所述的HIV蛋白酶抑制剂中间体化合物的合成方法,其特征在于,所述不对称转移氢化反应的反应温度为25℃。
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