CN117924316A - 四氢吡咯并恶嗪酮环的制备方法 - Google Patents
四氢吡咯并恶嗪酮环的制备方法 Download PDFInfo
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Classifications
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明提供了一种四氢吡咯并恶嗪酮环的制备方法,所述四氢吡咯并恶嗪酮环为顺式构型,其结构如式Ⅰ所示:
Description
技术领域
本发明属于化药制备领域,尤其是涉及一种四氢吡咯并恶嗪酮环的制备方法。
背景技术
1,3-恶嗪-2-酮作为六元环的氮杂骨架,是药物合成中的重要结构单元,现已被发现具有多种药物活性,比如抗逆转录病毒活性,抗细菌作用等。1998年杜邦公司开发的依法韦仑(英文:Efavirenz)被FDA批准用于治疗艾滋病,这是一种抵抗艾滋病毒的特效药物,该药的核心结构就是1,3-恶嗪-2-酮。该核心结构也广泛作为农用化学品,杀虫剂,除草剂和手性助剂制备中的重要中间体。
四氢吡咯作为五元环的氮杂骨架,也是熟知的具有多种药理活性的结构单元,被广泛应用在抗肿瘤、抗菌、抗糖尿病、抗病毒等药物中,迄今已有上百种上市药物和临床候选化合物含有四氢吡咯结构。比如盐酸丁咯地尔(治疗脑血管病)、吡咯米酸(抗生素、苄普地尔(钙拮抗药)、吡咯卡因(局部麻醉药)、艾多昔芬(防治骨质疏松症和乳房癌)等。
在小分子药物领域,研究人员发现多元含氮杂环往往具有更好的生物活性,目前临床已经证明,核心骨架为四氢吡咯并恶嗪酮环的化合物具有杀菌、消炎、抑制非核苷逆转录酶性、抑制磷酸二酯酶性、抗血栓性、镇痛等生物活性,同时,也是制备具有抗疟、抗癌、除草和杀虫等活性。因此,引入四氢吡咯环和恶嗪酮环的方法受到越来越多的关注,四氢吡咯并恶嗪酮环结构是重要的五元并六元双杂环骨架单元,包含该结构的药物活性分子显现出了明显的抗病毒活性,以及对MEK酶的抑制作用。已经上市的抗HIV药物依法韦仑(英文:Efavirenz),核心结构就包含恶嗪酮环;比利时UCB Pharma S.A.公司在2009年发布的关于MEK酶抑制剂专利,活性药物分子的核心结构也包含四氢吡咯并恶嗪酮环。目前已有多种方法报道合成恶嗪酮环:用光气或者三光气作为缩合剂,使β-氨基醇类结构光气化合环;氨基醇或者氨基卤代烃在加压二氧化碳条件下合环;醇和羰基肼在在亚硝酸条件下合环;CDI作为缩合剂合环,但是需要先做成裸漏的氨基和羟基。这些方法或者需要剧毒的试剂,或者需要苛刻的高压环境,或者需要高能的危险试剂。中国专利CN202310292351.3公开了一种4H-苯并[d][1,3]恶嗪-4-酮化合物的制备方法,其中的反应条件为在一氧化碳气体氛围下于50-120℃反应12-30h,可见安全性较低。而且目前公开的现有技术仅限于单独合成恶嗪酮环结构,还没有报道通过一条路线同时合成四氢吡咯和恶嗪酮环的方法。
发明内容
有鉴于此,本发明创造旨在克服现有技术中的缺陷,提出一种四氢吡咯并恶嗪酮环的制备方法。
为达到上述目的,本发明创造的技术方案是这样实现的:
一种四氢吡咯并恶嗪酮环的制备方法,所述四氢吡咯并恶嗪酮环为顺式构型,其结构如式Ⅰ所示
其制备方法包括以下合成路线1或合成路线2:合成路线1:
合成路线2:
优选地,所述步骤1的具体步骤为:
以马来酸酐、N-甲氧基甲基-N-(三甲基硅烷)苄基胺和三氟乙酸为原料,溶于有机溶剂A中反应得到化合物1。
进一步的,所述马来酸酐、N-甲氧基甲基-N-(三甲基硅烷)苄基胺和三氟乙酸的摩尔比为(0.8~1.5):(1.0~2.0):(0.1~1.0),反应温度为0~10℃,所述有机溶剂A选自二氯甲烷、1,2-二氯乙烷或四氢呋喃。
优选地,所述步骤2的具体步骤为:
将化合物1溶于有机溶剂B中后加入三乙胺、叔丁醇、叠氮化物混合发生curtius重排反应得到化合物2。
进一步的,所述化合物1、三乙胺、叔丁醇、叠氮化试剂的摩尔比为(0.8~1.5):(1.0~3.0):(3.0~10.0):(1.0~3.0);反应温度为自10~40℃阶梯升温至90~120℃;所述叠氮化试剂选自叠氮磷酸二苯酯、叠氮化钠或叠氮基三甲基硅烷;有机溶剂B选自甲苯、叔丁醇或二甲苯。
优选地,所述步骤3的具体步骤为:
将化合物2、甲醇、还原剂溶于有机溶剂C发生还原反应得到化合物3。
进一步的,所述化合物2、甲醇、还原剂的摩尔比为(0.8~1.5):(0.5~3.0):(1.0~3.0),所述有机溶剂C选自四氢呋喃、2-甲基四氢呋喃或甲醇,还原剂选自LiBH4、氢化铝锂或仲丁基硼氢化锂。
优选地,所述步骤4的具体步骤为:
化合物3溶于有机溶剂D中加入钯碳催化剂在氢气环境下脱除苄基保护得到化合物4。
进一步的,所述化合物3、钯碳催化剂的摩尔比为(0.5~1.5):(0.01~1.0);所述钯碳催化剂选自Pd(OH)2/C、Pd/C;所述有机溶剂D选自甲醇、乙醇或四氢呋喃。
优选地,所述步骤5的具体步骤为:
将化合物4在有机溶剂E中在碱性条件下与氨基保护试剂反应得到化合物5。
进一步的,进一步的,所述化合物4与氨基保护试剂、碱的摩尔比为(0.1~1.5):(1.0~2.0):(1.0~4.0);所述氨基保护试剂选自氯甲酸苄酯、碳酸二叔丁基酯、(9H-芴-9-基)甲基氯甲酸酯;所述碱试剂选自碳酸钠、三乙胺或磷酸钾;所述有机溶剂E选自四氢呋喃、二氧六环或二氯甲烷。
优选地,所述步骤6-1的具体步骤为:
将化合物5溶于有机溶剂F中与有机碱、甲烷磺酰氯发生亲核取代反应得到化合物6。
进一步的,所述化合物5、有机碱、甲烷磺酰氯的摩尔比为(0.8~1.5):(1.0~4.0):(1.0~4.0);所述有机碱选自三乙胺、N,N-二异丙基乙胺或二甲氨基吡啶;所述有机溶剂F选自二氯甲烷、四氢呋喃或二氧六环。
优选地,所述步骤6-2的具体步骤为:
将化合物5在有机溶剂G中加入叔丁醇钾发生反应生成得到化合物Ⅰ。
进一步的,所述化合物5与叔丁醇钾的摩尔比为(0.8~1.5):(1.0~4.0);所述有机溶剂G选自四氢呋喃、2-甲基四氢呋喃或DMF;反应温度为0~10℃。
优选地,所述步骤7的具体步骤为:
将化合物6在有机溶剂H中加入60%NaH反应得到化合物Ⅰ。
进一步的,所述化合物6与NaH的摩尔比为(0.8~1.5):(1.0~3.0);所述有机溶剂H选自二甲基甲酰胺、四氢呋喃或二甲基乙酰胺;反应温度为0~10℃。
相对于现有技术,本发明具有以下优势:
(1)本发明首先通过叶立德[3+2]合环构建多官能团化的四氢吡咯结构,此时保证环上官能团处于cis构型,再对环上官能团进行curtius重排反应、酯的还原反应、醇酯交换合环构建恶嗪酮环,最终合成四氢吡咯并恶嗪酮环双环结构。还可以在-OMs基团存在时,通过叔丁氧羰基(Boc)的丢失构建恶嗪酮环,最终合成顺势构型的四氢吡咯并恶嗪酮环结构。
(2)本发明采用的合成方法高效,所用试剂温和友好,能够同时合成四氢吡咯和恶嗪酮环双杂环的方法,为药物合成中构建并双杂环的重要骨架提供了新的思路和方法。
具体实施方式
除有定义外,以下实施例中所用的技术术语具有与本发明创造所属领域技术人员普遍理解的相同含义。以下实施例中所用的试验试剂,如无特殊说明,均为常规生化试剂;所述实验方法,如无特殊说明,均为常规方法。
下面结合实施例来详细说明本发明创造。
实施例1:
将500mL反应瓶氮气置换三次,加入SM2(18.83g,1.0eq)和DCM(151mL,8.0vol),体系降温至0~10℃,控温,将SM1(50g,1.01eq)的DCM(15mL,0.8vol)溶液滴加入体系中,滴加过程无明显升温。滴毕,体系变为黄绿色。保持体系0~10℃,滴加三氟乙酸(2.189g,0.1eq)的DCM(30mL,1.6vol)溶液。滴毕,撤去冰水浴,缓慢升温至室温反应24h。加入水(18.83g,1.0eq),析出固体,将EA(35mL,1.86vol)加入体系中,搅拌30min。抽滤,滤饼用EA(30mL,1.6vol)淋洗,滤液舍弃,滤饼50℃鼓风干燥3h至恒重,得到白色固体产品34.6g,收率70%。1HNMR(DMSO-d6,400MHz)δ7.32~7.20(m,5H),3.59(s,2H),3.52(s,3H),3.27~3.17(m,2H),2.96~2.89(m,2H),2.65~2.58(m,2H)。LCMS[M+1]=264.16。
实施例2:
将一个洁净干燥的500mL三口瓶,氮气置换三次,在30℃外浴下依次加入SM(15.1g,1.0eq),甲苯(151mL,10vol),三乙胺(7.5g,1.3eq),叔丁醇(21.25g,5.0eq),DPPA(18.94g,1.2eq)后,阶梯升温至110℃,在外浴110℃反应过夜。反应完毕后降温至室温,将体系在40℃下减压浓缩至无馏分流出,加入饱和碳酸氢钠水溶液(225mL,15vol),搅拌20min。用DCM(150mL,10vol)萃取三次,合并有机相,无水硫酸钠干燥有机相。有机相用DCM/MeOH柱层析纯化(DCM:MeOH=100:1至DCM:MeOH=20:1),得到淡黄色固体(12.9g,产率67.4%)。1H NMR(CDCl3,400MHz)δ7.34~7.23(m,5H),5.10~4.97(m,1H),4.58~4.40(m,1H),3.67(s,3H),3.63(s,2H),3.33~3.27(m,1H),3.03~2.99(m,1H),2.87~2.80(m,1H),2.73~2.68(m,1H),2.50~2.45(m,1H),1.42(s,9H)。LCMS[M+1]=335.89。
实施例3:
将一个洁净干燥的500mL三口瓶,氮气置换三次,依次加入SM(7g,1.0eq),THF(49mL,7vol),甲醇(1.174g,1.75eq),LiBH4(684mg,1.5eq),在30℃下反应过夜。反应完毕后,将体系用冰水浴降温至5℃左右,滴加甲醇(25mL,3.57vol)淬灭反应。将反应体系在40℃下减压浓缩。通过hex/EA柱层析纯化(hex:EA=3;1至EA),得到淡黄色固体(5.3g,产率82.64%)。1H NMR(CDCl3,400MHz)δ7.34~7.24(m,5H),5.02(d,1H),3.88~3.83(m,1H),3.60~3.49(m,4H),2.94~2.89(m,1H),2.74~2.67(m,1H),2.51~2.47(m,1H),2.23~2.15(m,1H),2.07~2.03(m,1H),1.43(s,9H)。LCMS[M+1]=307.47。
实施例4:
向反应瓶中加入SM(1.84g,1.0eq),加入MeOH(18.4mL,10vol),加毕,体系淡黄色清液,氮气置换三次。向体系中加入Pd(OH)2/C(0.92g,0.5g/g),体系变为灰黑色浊液,氢气置换三次后持续通入氢气。1h后取反应体系DCM稀释五倍TLC点板,展开剂EA,茚三酮显色原料(Rf=0.4)消失。垫硅藻土(18.4g,10g/g)抽滤,滤饼用甲醇(55.2mL,30vol)淋洗。40℃减压浓缩至无馏分得到1.33g黄色油状物产品,收率100%。LCMS[M+1]=217.48。
实施例5:
向反应瓶中加入SM(1.33g,1.0eq),加入THF(6.65mL,5vol),加入水(6.65mL,5vol)加毕,体系淡黄色清液,氮气置换三次。向体系中加入Na2CO3(1.30g,2eq),无明显升温,体系轻微浑浊,冰盐水降温至0~10℃。控温0~10℃向体系中加入CbzCl(1.57g,1.5eq),放热较明显(约3min加毕,升温3℃)。撤去冰盐水浴,回至15~25℃。在15~25℃条件下搅拌16h。体系中有白色固体析出,取反应体系DCM稀释五倍TLC点板,展开剂DCM:MeOH=7:1,茚三酮显色,原料(Rf=0)消失。向体系中加入水(26.6mL,20vol),加入EA(26.6mL,20vol)萃取一次,有机相在40℃减压浓缩至无馏分得到粗品。湿法上样,加入硅胶(19.95g,15g/g)柱层析纯化,Hex:EA=10:1~2:1洗脱除杂质,Hex:EA=1:1洗脱产品。减压浓缩得到1.66g黄色油状物,收率77.08%。1H NMR(CDCl3,400MHz)δ7.36~7.29(m,5H),5.12(s,2H),4.82(t,1H),4.13~4.05(m,1H),3.88~3.84(m,1H),3.68~3.60(m,2H),3.30~3.12(m,2H),2.15~2.09(m,1H),1.44(s,9H)。LCMS[M+1]=351.34。
实施例6:
向50mL三口瓶中加入SM(0.3g,1.0eq),加入DCM(4.11mL,13.7vol)无色清液,向体系中加入TEA(0.173g,2,0eq),加毕冰盐水降温至-10~0℃。控温-10~0℃向体系中加入MsCl(0.13g,1.304eq)的DCM(0.34mL,1.14vol)溶液,无明显放热,体系无色透明清液,撤去冰盐水浴回至15~25℃。在15~25℃条件下反应30分钟,取样DCM稀释进行TLC点板检测,展开剂Hex:EA=1:1,茚三酮显色原料(Rf=0)消失。降温至0~15℃,向体系中加入1N HCl(20mL,66.67vol),放热较明显,分液水相用DCM(10mL,33.33vol)萃取一次,合并有机相。有机相用饱和食盐水(10mL,33.33vol)洗涤一次,无水硫酸钠(0.3g,1g/g)干燥。在40℃减压浓缩至无馏分得到337mg无色透明油状物,收率91.74%。1H NMR(CDCl3,400MHz)δ7.37~7.30(m,5H),5.13(s,2H),4.66(d,1H),4.35~4.31(m,1H),4.23~4.07(m,2H),3.88~3.84(m,1H),3.79~3.72(m,1H),3.34~3.29(m,1H),3.23~3.17(m,1H),3.04(s,3H),2.52~2.46(m,1H),1.44(s,9H)。LCMS[M+1]=429.33。
实施例7:
向25mL三口瓶中加入SM(0.3g,1.0eq),加入DMF(3mL,10vol)无色透明清液,氮气置换三次,冰水降温至0~10℃。控温0~10℃向体系中加入60% NaH(42.1mg,1.5eq)无明显放热,有明显放气。体系变为浅黄色浊液。撤去冰水浴回至15~25℃。向反应体系中加入水(10mL,33.33vol),加EA(10mL,33.33vol)*2萃取两次,合并有机相。有机相无水硫酸钠(0.3g,1g/g)干燥。在40℃减压浓缩至无馏分得到黄色油状物粗品。湿法上样,加入硅胶(15g,50g/g),Hex:EA=10:1~1:1除杂,EA洗脱产品。40℃减压浓缩至无馏分,得到164mg浅黄色油状物产品,收率85%。1H NMR(DMSO-d6,400MHz)δ7.77(d,1H),7.38~7.31(m,5H),5.07(s,2H),4.41~4.34(m,1H),4.26~4.18(m,1H),3.70~3.47(m,3H),3.10~2.88(m,2H),2.32~2.23(m,1H)。LCMS[M+1]=277.75。
实施例8:
向25mL三口瓶中加入SM(0.2g,1.0eq),加入THF(2.76mL,13.8vol)体系无色清液,氮气置换三次,冰水降温至0~10℃。控温0~10℃向体系中加入叔丁醇钾(128mg,2.0eq)无明显放热,体系呈黄色浊液,撤去外浴回温至15~25℃,反应16h。向反应体系中加入水(33mL,165vol),加DCM(33mL,165vol)*2萃取两次,合并有机相。有机相用无水硫酸钠(0.2g,1g/g)干燥。在40℃减压浓缩至无馏分得到黄色油状物粗品。柱层析纯化。40℃减压浓缩至无馏分,得到110mg浅黄色油状物产品,收率70%。
本文描述和要求保护的发明具有许多属性和实施例,包括但不限于本发明详细阐述或描述或引用的那些。但这并不意味着是包括一切的,并且在此描述和要求保护的发明并不限于本文详细公开的确定的特征或实施例,或者不受其限制,本文详细公开仅是为了说明而不是限制的目的而被包括。本领域普通技术人员将容易认识到,在不偏离本发明的范围的情况下,许多部件和参数可以在一定程度上改变或修改,或者可以用已知的等效物代替。应当理解,这些修改和等效物被包括在内,如同单独阐述一样。本发明还包括本说明书中单独或共同提及或指出的所有步骤、特征、组合物和化合物,以及任何两个或更多个所述步骤或特征的任何和所有组合。
本文引用或提及的所有专利、出版物、科学文章、网站和其它文献和材料均表明本发明所属领域的技术人员的技术水平,且每个在此引用的文献和材料均以引用方式并入本文,其程度与通过单独引用的方式整体并入或在此整体阐述的程度相同。申请人保留将任何和所有来自任何此类专利、出版物、科学文章和其它参考材料或文献的材料和信息物理地并入本说明书的权利。本说明书中对任何申请、专利和出版物的引用不是也不应被视为承认或任何形式的暗示它们构成有效的现有技术或构成世界上任何国家的公知常识的一部分。
Claims (10)
1.一种四氢吡咯并恶嗪酮环的制备方法,其特征在于:所述四氢吡咯并恶嗪酮环为顺式构型,其结构如式Ⅰ所示:
其制备方法包括以下合成路线1或合成路线2:
合成路线1:
合成路线2:
2.根据权利要求1所述的制备方法,其特征在于:所述步骤1的具体步骤为:
以马来酸酐、N-甲氧基甲基-N-(三甲基硅烷)苄基胺和三氟乙酸为原料,溶于有机溶剂A中反应得到化合物1;
进一步的,所述马来酸酐、N-甲氧基甲基-N-(三甲基硅烷)苄基胺和三氟乙酸的摩尔比为(0.8~1.5):(1.0~2.0):(0.1~1.0),反应温度为0~10℃,所述有机溶剂A选自二氯甲烷、1,2-二氯乙烷或四氢呋喃。
3.根据权利要求1所述的制备方法,其特征在于:所述步骤2的具体步骤为:
将化合物1溶于有机溶剂B中后加入三乙胺、叔丁醇、叠氮化物混合发生curtius重排反应得到化合物2;
进一步的,所述化合物1、三乙胺、叔丁醇、叠氮化试剂的摩尔比为(0.8~1.5):(1.0~3.0):(3.0~10.0):(1.0~3.0);反应温度为自10~40℃阶梯升温至90~120℃;所述叠氮化试剂选自叠氮磷酸二苯酯、叠氮化钠或叠氮基三甲基硅烷;有机溶剂B选自甲苯、叔丁醇或二甲苯。
4.根据权利要求1所述的制备方法,其特征在于:所述步骤3的具体步骤为:
将化合物2、甲醇、还原剂溶于有机溶剂C发生还原反应得到化合物3;
进一步的,所述化合物2、甲醇、还原剂的摩尔比为(0.8~1.5):(0.5~3.0):(1.0~3.0),所述有机溶剂C选自四氢呋喃、2-甲基四氢呋喃或甲醇,还原剂选自LiBH4、氢化铝锂或仲丁基硼氢化锂。
5.根据权利要求1所述的制备方法,其特征在于:所述步骤4的具体步骤为:
化合物3溶于有机溶剂D中加入钯碳催化剂在氢气环境下脱除苄基保护得到化合物4;
进一步的,所述化合物3、钯碳催化剂的摩尔比为(0.5~1.5):(0.01~1.0);所述钯碳催化剂选自Pd(OH)2/C、Pd/C;所述有机溶剂D选自甲醇、乙醇或四氢呋喃。
6.根据权利要求1所述的制备方法,其特征在于:所述步骤5的具体步骤为:
将化合物4在有机溶剂E中在碱性条件下与氨基保护试剂反应得到化合物5;
进一步的,所述化合物4与氨基保护试剂、碱的摩尔比为(0.1~1.5):(1.0~2.0):(1.0~4.0);所述氨基保护试剂选自氯甲酸苄酯、碳酸二叔丁基酯、(9H-芴-9-基)甲基氯甲酸酯;所述碱试剂选自碳酸钠、三乙胺或磷酸钾;所述有机溶剂E选自四氢呋喃、二氧六环或二氯甲烷。
7.根据权利要求1所述的制备方法,其特征在于:所述步骤6-1的具体步骤为:
将化合物5溶于有机溶剂F中与有机碱、甲烷磺酰氯发生亲核取代反应得到化合物6;
进一步的,所述化合物5、有机碱、甲烷磺酰氯的摩尔比为(0.8~1.5):(1.0~4.0):(1.0~4.0);所述有机碱选自三乙胺、N,N-二异丙基乙胺或二甲氨基吡啶;所述有机溶剂F选自二氯甲烷、四氢呋喃或二氧六环。
8.根据权利要求1所述的制备方法,其特征在于:所述步骤6-2的具体步骤为:
将化合物5在有机溶剂G中加入叔丁醇钾发生反应生成得到化合物Ⅰ;
进一步的,所述化合物5与叔丁醇钾的摩尔比为(0.8~1.5):(1.0~4.0);所述有机溶剂G选自四氢呋喃、2-甲基四氢呋喃或DMF;反应温度为0~10℃。
9.根据权利要求1所述的制备方法,其特征在于:所述步骤7的具体步骤为:
将化合物6在有机溶剂H中加入60%NaH反应得到化合物Ⅰ。
10.根据权利要求9所述的制备方法,其特征在于:所述化合物6与NaH的摩尔比为(0.8~1.5):(1.0~3.0);所述有机溶剂H选自二甲基甲酰胺、四氢呋喃或二甲基乙酰胺;反应温度为0~10℃。
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