CN114644641B - 基于螺旋骨架的手性二酚及其制备方法和应用 - Google Patents
基于螺旋骨架的手性二酚及其制备方法和应用 Download PDFInfo
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- CN114644641B CN114644641B CN202011492969.7A CN202011492969A CN114644641B CN 114644641 B CN114644641 B CN 114644641B CN 202011492969 A CN202011492969 A CN 202011492969A CN 114644641 B CN114644641 B CN 114644641B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
- C07D493/14—Ortho-condensed systems
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
- B01J31/0255—Phosphorus containing compounds
- B01J31/0257—Phosphorus acids or phosphorus acid esters
- B01J31/0258—Phosphoric acid mono-, di- or triesters ((RO)(R'O)2P=O), i.e. R= C, R'= C, H
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
- C07F9/6574—Esters of oxyacids of phosphorus
- C07F9/65744—Esters of oxyacids of phosphorus condensed with carbocyclic or heterocyclic rings or ring systems
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
- B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
- B01J2231/4205—C-C cross-coupling, e.g. metal catalyzed or Friedel-Crafts type
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- 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
- Y02P20/52—Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
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Abstract
本发明提供一种基于螺旋骨架的手性二酚及其制备方法和应用,涉及手性化合物合成技术领域。本发明的手性二酚采用易得原料,经过简短的反应得到消旋的手性二酚,通过拆分可得到单一构型的螺旋手性二酚。将螺旋手性二酚衍生化后得到手性磷酸,手性磷酸可用于催化不对称傅克烷基化反应,具有良好的手性选择性。
Description
技术领域
本发明涉及手性化合物合成技术领域,特别是涉及一种基于螺旋骨架的手性二酚及其制备方法和应用。
背景技术
手性配体是手性催化剂产生不对称诱导和控制的源泉。在制药行业,手性药物的研发、生产和销售已成为全球医药工业发展的主流,不对称催化合成是当前有机合成化学研究领域中的热点。
手性二酚(如常用的BINOL和SPINOL)可以用于多种手性催化剂的合成。公开号为CN1342652A的中国专利申请中公开了一种螺环二酚单膦配体,公开号为CN1439643A的中国专利申请中公开了螺环双膦配体,螺环二酚手性磷酸等均衍生于SPINOL,可作为催化剂用于催化不对称氢化等多种反应,具有广泛的用途。BINOL和SPINOL的结构如下所示:
手性分为中心手性、轴手性、面手性及螺旋手性。中心手性和轴手性的手性分子比较容易合成,基于这两种手性模式的催化剂已广泛应用于各类不对称催化反应。而螺旋手性的催化剂具有独特的螺旋手性结构,由于合成难度较大,目前尚未得到广泛应用,仅有少量报道。因此,合成螺旋手性化合物并对其进行多样性修饰,筛选出效果更好的催化剂,具有重要意义。
发明内容
基于此,有必要针对上述问题,提供一种基于螺旋骨架的手性二酚,并通过易得的原料、简短的反应步骤得到该螺旋手性二酚,以该螺旋手性二酚为原料可衍生得到手性磷酸,手性磷酸可用于催化不对称傅克烷基化反应,提高产物的收率。
一种具有式Ⅰ所示结构特征的基于螺旋骨架的手性二酚:
本发明还提供一种上述手性二酚的合成方法,按照以下合成路线进行:
S1、将2-重氮-1,3-环己二酮与呋喃混合,在手性催化剂的催化下反应,得到化合物1;
S2、将化合物1与2-重氮-1,3-环己二酮混合,在手性催化剂的催化下反应,得到化合物2;
S3、将化合物2还原,得到消旋的手性二酚;
S4、将消旋的手性二酚与N-苄基奎宁氯混合,反应,经分离,得到式Ⅰ所示化合物。
上述合成方法,从简单物料呋喃和2-重氮-1,3-环己二酮出发,经过三步反应即可得到消旋的螺旋手性二酚(化合物3和化合物4的1:1的混合物),再通过拆分得到单一构型的螺旋手性二酚。
在其中一个实施例中,所述步骤S1中的2-重氮-1,3-环己二酮可采用现有的方法(如Organic Letters,2011,13,4124-4127)合成。2-重氮-1,3-环己二酮也可以按照以下方法合成:
将1,3-环己二酮与甲磺酰基叠氮(MsN3)混合,加入三乙胺(Et3N)和乙腈(ACN),反应得到2-重氮-1,3-环己二酮。
在其中一个实施例中,步骤S1和步骤S2中,所述手性催化剂选用醋酸铑二聚体;
步骤S3中,采用Pd/C脱氢法或DDQ(2,3-二氯-5,6-二氰对苯醌)氧化法将化合物2氧化芳构化;
步骤S4中,消旋的手性二酚与N-苄基奎宁氯反应后,分离固体,固体中加入有机溶剂和酸性溶液,混匀后萃取分液,有机相经干燥、浓缩,得到式Ⅰ所示化合物。
在其中一个实施例中,所述步骤S1具体为:将2-重氮-13-环己二酮和呋喃混合,在醋酸铑二聚体的催化下反应18~22h,经薄层色谱和柱层析,得到化合物1;
其中,2-重氮-13-环己二酮、呋喃、醋酸铑二聚体的用量比为(2.8~3.2)g:(28~32)mL:(190~194)mg。
在其中一个实施例中,所述步骤S2具体为:将化合物1和氟苯混合,加入醋酸铑二聚体和2-重氮-1,3-环己二酮,在48~52℃下反应2~20h,经薄层色谱和柱层析,得到化合物2;
其中,化合物1、氟苯、醋酸铑二聚体和2-重氮-1,3-环己二酮的用量比为(2.6~3.0)g:(28~32)mL:(137~141)mg:(2.0~2.4)g。
在其中一个实施例中,所述步骤S3具体为:将化合物2和三甘醇二甲醚混合,加入Pd/C催化剂,在210~220℃下反应,反应完成降温,过滤去除Pd/C催化剂,滤液经蒸馏去除溶剂,得到棕色油状物,经柱层析、薄层色谱、浓缩,得到消旋的手性二酚;其中,化合物2、三甘醇二甲醚、Pd/C催化剂的用量比为(4.8~5.2)g:(95~105)mL:(1.8~2.2)g。
在其中一个实施例中,所述步骤S3具体为:将化合物2、2,3-二氯-5,6-二氰对苯醌、二氧六环混合,在惰性气体氛围下,加入双(三甲基硅烷基)三氟乙酰胺,在15~35℃下反应4~5h,再升温至100~120℃下反应16~20h,降温后加入乙酸乙酯和亚硫酸氢钠水溶液,继续加入盐酸,进行萃取分液,有机相用盐酸洗涤,有机相经浓缩得到棕色固体,加入二氯甲烷溶解固体,经浓缩、柱分离,得到消旋的手性二酚;其中,化合物2、2,3-二氯-5,6-二氰对苯醌、二氧六环、双(三甲基硅烷基)三氟乙酰胺的用量比为(490~510)mg:(860~870)mg:(4.5~5.5)mL:(3.9~4.1)g。
在其中一个实施例中,所述步骤S4具体为:将消旋的手性二酚与乙酸乙酯混合,溶解澄清后加入N-苄基奎宁氯,75~85℃下回流反应4~6h,抽滤,将固体分散于乙酸乙酯中,加热至75~85℃搅拌25~35min,降温抽滤,固体用乙酸乙酯洗涤,再加入乙酸乙酯和3.5~4.5M的盐酸,搅拌后萃取分液,有机相用盐酸洗涤,合并有机相,用无水硫酸钠干燥,浓缩,得到式Ⅰ所示化合物;
其中,消旋的手性二酚、N-苄基奎宁氯的用量比为(3.6~4.0)g:(4.6~5.0)g。
在其中一个实施例中,所述步骤S4后还有步骤S5:将滤液与有机溶剂和酸性溶液混合,混合均匀后萃取分液,保留有机相,经干燥、浓缩,得固体,将固体溶于有机溶剂中,加入N-苄基奎宁氯,回流反应,反应后分离固体,洗涤固体,向固体中加入有机溶剂和酸性溶液,混合均匀后萃取分液,保留有机相,经干燥、浓缩,得化合物4。
本发明一方面还提供一种具有式Ⅱ所示结构特征的化合物:
其中,Ar选自:3,5-(CF3)2C6H3、4-联苯基、1-萘基、2-萘基、9-菲基、1-芘基。
上述化合物为手性磷酸,可用于催化不对称傅克烷基化反应,催化反应产物的收率高于BINOL或SPINOL衍生的手性磷酸,或与之相当,并具有良好手性选择性。
本发明还提供一种上述化合物的合成方法,按照以下合成路线进行:
S1、将权利要求1所述的手性二酚与N-碘代丁二酰亚胺混合,进行碘代反应,得到化合物5;
S2、将化合物5与芳基硼酸混合,进行取代反应,得到化合物6;
S3、将化合物6与三氯氧磷混合,反应,得到式Ⅱ所示化合物(即化合物7)。
在其中一个实施例中,所述芳基硼酸选自:3,5-双三氟甲基苯硼酸、4-联苯硼酸、1-萘硼酸、2-萘硼酸、9-菲硼酸、1-芘硼酸中的一种。
本发明一方面还提供一种上述式Ⅱ所示化合物在催化不对称傅克烷基化反应中的应用。
与现有技术相比,本发明具有以下有益效果:
本发明的手性二酚具有螺旋骨架,可通过易得的原料、简短的反应步骤得到该螺旋手性二酚,以该螺旋手性二酚为原料可衍生得到手性磷酸,手性磷酸可用于催化不对称傅克烷基化反应,提高产物的收率。
附图说明
图1为实施例中手性二酚的合成路线图;
图2为实施例中消旋手性二酚的拆分路线图;
图3为实施例中手性磷酸催化剂的合成路线图;
图4为消旋的手性二酚的HPLC图谱;
图5为化合物3的HPLC图谱;
图6为化合物4的HPLC图谱;
图7为Rac-10的HPLC图谱;
图8为以7a为催化剂、反应温度为0℃得到的化合物10的HPLC图谱;
图9为以7b为催化剂、反应温度为0℃得到的化合物10的HPLC图谱;
图10为以7c为催化剂、反应温度为0℃得到的化合物10的HPLC图谱;
图11为以7d为催化剂、反应温度为0℃得到的化合物10的HPLC图谱;
图12为以7d为催化剂、反应温度为-20℃得到的化合物10的HPLC图谱;
图13为以7e为催化剂、反应温度为0℃得到的化合物10的HPLC图谱;
图14为以7f为催化剂、反应温度为0℃得到的化合物10的HPLC图谱;
图15为以CPA-11为催化剂、反应温度为0℃得到的化合物10的HPLC图谱;
图16为以CPA-12为催化剂、反应温度为0℃得到的化合物10的HPLC图谱。
具体实施方式
为了便于理解本发明,以下将给出较佳实施例对本发明进行更全面的描述。但是,本发明可以以许多不同的形式来实现,并不限于本文所描述的实施例。相反地,提供这些实施例的目的是使对本发明的公开内容的理解更加透彻全面。
除非另有定义,本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施例的目的,不是旨在于限制本发明。
实施例1
基于螺旋骨架的手性二酚的合成。
手性二酚的合成路线如图1所示。具体步骤如下:
1、合成2-重氮-1,3-环己二酮
将1,3-环己二酮与甲磺酰基叠氮(MsN3)混合,加入三乙胺(Et3N)和乙腈(ACN),反应得到2-重氮-1,3-环己二酮。
2、合成化合物1
1)在100mL单口瓶中加入3g 2-重氮-1,3-环己二酮和192mg醋酸铑二聚体,再加入30mL呋喃搅拌溶解,得深绿色溶液;室温下搅拌,20h后,进行薄层色谱分离,PE(石油醚):EA(乙酸乙酯)=2:1,生成大量化合物1,反应至没有原料剩余,停止反应;
2)将反应液溶剂旋干,加入少量EA,析出固体(醋酸铑与化合物2),过滤,滤液旋干后,再加入少量EA,过滤,滤液加入硅胶拌样,柱层析,洗脱液用PE:EA=2:1,分离得到化合物1;
3)经过柱层析分离得到1.57g化合物1,收率为40.57%。
3、合成化合物2
1)向装有2.8g化合物1的100mL单口瓶中加入30mL氟苯,溶解后成黄色澄清透明溶液,再加入139mg Rh2(OAc)4和2.17g 2-重氮-1,3-环己二酮,升温至50℃下反应;
2)反应2h后,对反应物进行薄层色谱分析,先PE:EA=2:1,后PE:EA=1:2,分析发现有大量化合物1剩余,继续反应;
3)反应17h后,对反应物进行薄层色谱分析,先PE:EA=2:1,后PE:EA=1:2,分析发现有大量化合物1剩余,停止反应;
4)通过石油醚:乙酸乙酯=2:1柱层析纯化得化合物2为1.58g,实际参与反应化合物1为1.25g,收率为76.1%;柱层析回收得到化合物1为1.55g。
4、Pd/C脱氢法合成消旋的手性二酚
1)向装有5.0g化合物2的250mL单口瓶中加入100mL triglyme(三甘醇二甲醚),固体不能完全溶解,加入10%Pd/C 2.0g,升温至215℃下反应;
2)反应体系温度降至室温,过滤除去钯碳,并用20ml triglyme洗涤钯碳,滤液合并后减压(90℃左右)蒸馏除去溶剂,得棕色油状物。向上述残留物中加入硅胶,拌样,柱层析,用PE:EA=1:2洗脱,收集产物点,减压浓缩,得到2.75g消旋的手性二酚纯品,收率55%;
3)检测结果如下:1H NMR(400MHz,DMSO-d6)δ9.79(s,2H),7.02(t,J=8.0Hz,2H),6.47(d,J=8.1Hz,2H),6.34(d,J=7.9Hz,2H),6.18(d,J=4.9Hz,2H),4.41(d,J=4.9Hz,2H);13C NMR(100MHz,CDCl3)δ157.8,154.1,128.9,111.3,108.4,108.0,100.1,47.5;HRMS(ESI)calcd for C16H12O5([M-H]-):283.0612.Found:283.0605。
5、拆分消旋的手性二酚
拆分路线如图2所示。具体步骤如下:
1)在一250mL单口瓶中加入消旋的手性二酚(3.80g,13.40mmol)和70mL EA,溶解澄清后加入N-苄基奎宁氯(4.83g,10.72mmol),升温至80℃回流,5h后停止反应,降温至室温后抽滤,得母液一和固体一(滤饼);将滤饼分散于70mL EA中,再加热至80℃搅拌30min,降温抽滤,固体用20mL EA洗涤,将固体分散于250mL单口瓶中,加入70mL EA和70mL 4M HCl水溶液,室温搅拌澄清后萃取分液,EA相用4M HCl溶液洗涤两次,合并EA相无水硫酸钠干燥,浓缩得35.5%,1.35g棕色固体,棕色固体为化合物3,ee:100%。
2)向上述滤液(即母液一)中加入70mL EA和70mL 4M HCl水溶液,室温搅拌澄清后萃取分液,EA相用4M HCl溶液洗涤两次,合并EA相无水硫酸钠干燥,浓缩得2.09g浅黄色固体,ee:-26%。
3)将步骤2)中回收的固体(即enriched-化合物4)溶于50mL EA中,加入N-苄基奎尼丁氯(2.65g,5.88mmol)升温至80℃回流,反应5h,降温至室温后抽滤,得母液二和固体二(滤饼);将滤饼分散于70mL EA中,再加热至80℃搅拌30min,降温抽滤,固体用20mL EA洗涤,将固体分散于250mL单口瓶中,加入70mL EA和70mL 4M HCl水溶液,室温搅拌澄清后萃取分液,EA相用4M HCl溶液洗涤两次,合并EA相无水硫酸钠干燥,浓缩得拆分固体(34.2%,1.30g灰白色固体为化合物4,ee:-100%)。母液二经盐酸处理回收到少量消旋的手性二酚(0.6g浅棕色固体,ee:2%)。
实施例2
基于螺旋骨架的手性二酚的合成。
手性二酚的合成方法与实施例1基本相同,区别仅在于,步骤4采用DDQ氧化法合成消旋的手性二酚。
DDQ氧化法具体如下:
在反应瓶中加入化合物2(500mg,1.73mmol),DDQ(866.1mg,3.82mmol),5mLdioxane(二氧六环),氮气保护下加入BSTFA(双(三甲基硅烷基)三氟乙酰胺)(4.03g,15.64mmol),先在室温下反应4.5h,再升温至110℃反应18h,反应完降至室温,加EA(30mL),1%亚硫酸氢钠水溶液(10mL),无固体沉淀,再加入20mL 4M HCl水溶液萃取分液,EA相用4MHCl水溶液洗涤一次,合并有机相浓缩得棕色固体。粗品中加入10mL DCM(二氯甲烷)超声,有固体不溶解,过滤,DCM多次洗涤,合并DCM相,浓缩,柱分离得产物消旋的手性二酚(325.2mg淡黄色固体,yield:66%);产物的检测数据同实施例1。
实施例3
手性磷酸催化剂的合成。
手性磷酸催化剂的合成路线如图3所示。具体步骤如下:
1、合成化合物5
在反应瓶中将化合物3(0.60g,3.10mmol)溶于60mL DCM中,加入7滴TFA(三氟乙酸),0℃下分批缓慢加入NIS(N-碘代丁二酰亚胺)(0.95g,4.21mmol),加完转移至室温反应30min,TLC中控原料反应完全,加入50mL饱和硫代硫酸钠水溶液淬灭,DCM萃取三次,合并有机相,Brine(盐水)洗涤,浓缩柱分离得0.81g化合物5;淡黄色固体,yield:72%。
检测结果如下:Mp.134.5℃; 1H NMR(400MHz,DMSO-d6)δ9.77(s,2H),7.56(d,J=8.3Hz,2H),6.34(d,J=8.3Hz,2H),6.20(d,J=4.6Hz,2H),4.46(d,J=4.3Hz,2H);13C NMR(100MHz,CDCl3)δ159.6,153.5,139.7,114.1,110.2,105.4,77.8,49.2.HRMS(ESI)calcd for C16H9I2O5([M-H]-):534.8545.Found:534.8541。
2、合成化合物6a~6f
在反应瓶中加入化合物11(100mg,0.187mmol),3,5-双三氟甲基苯硼酸(183.6mg,0.746mmol),K2CO3(103.1mg,0.746mmol),3mL dioxane,3mL H2O,再加入10mg 10%Pd/C,N2置换三次,升温至80℃反应13h,TLC中控原料反应完全,停止反应,降至室温,加10mL 4MHCl溶液,30mL EA萃取,水相用EA洗涤两次,合并有机相,饱和食盐水洗涤,浓缩;柱分离得124.1mg淡黄色泡沫状固体,即为化合物6a。
化合物6b~6f的合成方法与合物6a的合成方法基本相同,区别在于,将3,5-双三氟甲基苯硼酸分别替换为等摩尔量的4-联苯硼酸、1-萘硼酸、2-萘硼酸、9-菲硼酸、1-芘硼酸。
化合物6a~6f的检测结果如下:
(6a).Rf=0.67(hexane:EA=5:1)淡黄色泡沫固体,124mg,94%. 1H NMR(400MHz,CDCl3)δ7.95(s,4H),7.86(s,2H),7.20(d,J=8.3Hz,2H),6.63(dd,J=10.5,6.9Hz,4H),4.21(d,J=5.3Hz,2H).13C{1H}NMR(100MHz,CDCl3)δ159.4,148.8,139.0,132.7,132.4,132.2,132.1,131.7,129.3,127.3,124.6,121.9,121.2,119.8,119.2,114.1,112.9,104.3,50.1.HRMS(ESI-TOF)m/z:[M-H]-calcd.for(C32H16F12O5)707.0733,found:707.0738.
(6b).Rf=0.48(hexane:EA=5:1)White solid,212.3mg,97%.Mp.281.3℃; 1H NMR(400MHz,CDCl3)δ7.68(dd,J=24.0,7.4Hz,8H),7.56(d,J=7.8Hz,4H),7.49(t,J=7.3Hz,4H),7.40(t,J=7.0Hz,2H),7.31-7.20(m,2H),6.71-6.31(m,6H),4.22(d,J=5.1Hz,2H).13C{1H}NMR(100MHz,CDCl3)δ158.4,149.0,140.5,140.3,135.7,131.7,129.5,128.9,127.7,127.5,127.1,122.1,113.6,112.7,103.4,50.2.HRMS(ESI-TOF)m/z:[M-H]-calcd.for(C40H28O5)587.1864,found:587.1862.
(6c).Rf=0.52(hexane:EA=5:1)白色固体,85.5mg,90%. 1H NMR(400MHz,CDCl3)δ7.86(t,J=8.2Hz,4H),7.78-7.68(m,1H),7.62(d,J=7.7Hz,1H),7.58-7.31(m,8H),7.16(d,J=8.1Hz,2H),6.69-6.48(m,4H),5.89(d,J=21.6Hz,2H),4.23(d,J=13.9Hz,2H).13C{1H}NMR(100MHz,CDCl3)δ158.64,158.62,158.60,149.72,149.66,134.2,134.1,134.0,133.9,133.85,133.80,132.7,132.6,132.3,132.1,132.0,128.5,128.4,128.3,128.1,126.5,126.2,125.7,125.6,125.5,120.8,120.7,120.6,120.5,113.33,113.29,113.24,113.20,112.63,112.56,103.1,103.0,102.9,50.4,50.3,50.20,50.17.HRMS(ESI-TOF)m/z:[M-H]-calcd.for(C36H24O5)535.1551,found:535.1557.
(6d).Rf=0.51(hexane:EA=5:1)白色固体,157.3mg,89%.Mp.159.3℃; 1H NMR(400MHz,CDCl3)δ7.95(s,4H),7.86(s,2H),7.20(d,J=8.3Hz,2H),6.63(dd,J=10.5,6.9Hz,4H),4.21(d,J=5.3Hz,2H).13C{1H}NMR(100MHz,CDCl3)δ158.4,149.1,134.2,133.6,132.5,132.0,128.8,128.0,127.7,127.6,127.3,126.5,126.2,122.5,113.5,112.7,103.5,50.1.HRMS(ESI-TOF)m/z:[M-H]-calcd.for(C36H24O5)535.1551,found:535.1559.
(6e).Rf=0.52(hexane:EA=5:1)白色固体,243.7mg,99%.Mp.202.9℃; 1H NMR(400MHz,CDCl3)δ8.87-8.55(m,4H),7.86(d,J=7.6Hz,1H),7.81-7.50(m,12H),7.46(t,J=7.5Hz,1H),7.21(t,J=8.4Hz,2H),6.71-6.48(m,4H),5.91(s,2H),4.51-4.08(m,2H).13C{1H}NMR(100MHz,CDCl3)δ158.72,158.68,158.63,158.60,150.0,149.9,149.8,132.7,132.8,132.6,131.5,131.4,131.3,131.2,131.0,130.9,130.7,130.3,129.2,129.0,128.7,127.6,127.0,126.9,126.8,126.6,126.5,126.4,113.3,113.25,113.20,113.18,112.6,112.5,112.4,103.1,103.0,102.9,50.35,50.25,50.21,50.19.HRMS(ESI-TOF)m/z:[M-H]-calcd.for(C44H28O5)635.1864,found:635.1855.
(6f).Rf=0.48(hexane:EA=5:1)白色固体,234.6mg,99%.Mp.297.9℃; 1H NMR(400MHz,CDCl3)δ8.37-7.74(m,18H),7.30(d,J=8.4Hz,2H),6.73-6.63(m,4H),5.94(br,2H),4.50-4.22(m,2H).13C{1H}NMR(100MHz,CDCl3)δ158.8,158.7,149.8,133.2,133.14,133.11,131.33,131.29,131.1,128.4,128.1,127.8,127.2,126.2,126.1,126.1,125.4,125.3,125.2,124.98,124.96,124.88,124.79,121.3,121.2,121.12,121.0,113.4,113.3,113.2,112.6,112.5,103.2,103.1,50.4,50.33,50.25.HRMS(ESI-TOF)m/z:[M-H]-calcd.for(C48H28O5)683.1864,found:683.1870.
3、合成催化剂7a~7f
在反应瓶中加入化合物6a(124.1mg,0.17mmol),吡啶(3mL),N2保护下滴加POCl3(52mg,3.4mmol),加完室温反应6h,然后缓慢滴加2mL H2O,搅拌30min,加入20mL EA,10mL4M HCl溶液萃取,EA相用4M HCl溶液洗涤一次,合并有机相浓缩,柱分离(hexane:EA(1:1))得产物7a,97.6mg白色固体,yield:72%。
化合物7b~7f的合成方法与化合物7a的合成方法基本相同,区别在于,将化合物6a分别替换为等摩尔量的化合物6b、6c、6d、6e、6f。
化合物7a~7f的检测结果如下:
(7a).Rf=0.5(hexane:EA=2:1)White solid,97.6mg,yield 72%.Mp.122.2℃; 1H NMR(400MHz,CDCl3)δ7.92(s,4H),7.70(s,2H),7.21(d,J=8.2Hz,2H),6.76(d,J=8.2Hz,2H),5.59(s,2H),4.41(s,2H).13C{1H}NMR(100MHz,CDCl3)δ158.9,145.7,145.6,141.3,139.6,131.9,131.6,131.4,131.2,131.1,130.9,129.4,128.9,126.4,126.0,124.2,122.4,120.6,120.5,120.3,114.3,107.1,51.5.HRMS(ESI-TOF)m/z:[M-H]-calcd.for(C32H15F12O7P)769.0291,found:769.0305.
(7b).Rf=0.28(hexane:EA=2:1)White solid,195.6mg,yield 83%.Mp.231.8℃; 1H NMR(400MHz,CDCl3)δ7.42-7.28(m,18H),7.12(d,J=5.7Hz,2H),6.68(s,2H),6.55(s,2H),4.30(s,2H),3.71(s,1H).13C{1H}NMR(100MHz,CDCl3)δ157.8,145.5,145.4,140.1,139.4,136.1,131.8,129.8,128.8,128.5,127.4,127.1,126.8,126.6,120.0,114.2,106.7,51.5.HRMS(ESI-TOF)m/z:[M-H]-calcd.for(C40H27O7P)649.1422,found:649.1410.
(7c).Rf=0.10(DCM:MeOH=20:1)White solid,129.2mg,yield 84%.Mp.234.6℃; 1H NMR(400MHz,CDCl3)δ7.65(s,1H),7.50-6.99(m,14H),6.88(d,J=4.6Hz,1H),6.84-6.69(m,4H),4.91-4.55(m,2H),4.27(s,1H).13C{1H}NMR(100MHz,CDCl3)δ158.1,158.0,157.8,146.5,140.1,135.2,135.0,133.5,133.3,133.12,133.0,132.9,132.3,132.1,132.0,128.3,128.1,128.0,127.5,126.2,126.0,125.9,125.6,125.5,120.8,120.0,119.6,119.0,114.4,114.3,114.2,106.5,106.2,106.0,105.7,52.2,52.0,51.8.HRMS(ESI-TOF)m/z:[M-H]-calcd.for(C36H23O7P)597.1109,found:597.1116.
(7d).Rf=0.12(hexane:EA=2:1)White solid,160.2mg,yield 91%.Mp.206.2℃; 1H NMR(400MHz,CDCl3)δ7.74-7.26(m,14H),7.19(d,J=6.9Hz,2H),6.73(d,J=6.9Hz,2H),6.60(s,2H),4.38(s,2H),3.14(br,1H).13C{1H}NMR(100MHz,CDCl3)δ157.9,145.6,134.8,133.1,132.2,132.0,128.0,127.82,127.77,127.5,127.4,127.2,126.0,125.9,124.5,120.2,114.3,106.7,51.6.HRMS(ESI-TOF)m/z:[M-H]-calcd.for(C36H23O7P)597.1109,found:597.1115.
(7e).Rf=0.11(hexane:EA=2:1)White solid,214.6mg,yield 98%.Mp.254.9℃; 1H NMR(400MHz,CDCl3)δ8.58-8.22(m,4H),7.83-7.00(m,15H),6.93-6.75(m,4H),6.39-6.02(m,1H),4.98-4.30(m,2H),3.27(br,1H).13C{1H}NMR(100MHz,CDCl3)δ158.2,158.1,158.0,146.7,146.6,141.7,139.1,134.1,133.7,133.1,133.0,132.8,131.5,131.3,131.2,130.1,130.0,129.9,129.8,129.0,128.6,126.8,126.7,126.6,126.5,126.4,126.3,126.2,124.1,122.5,122.3,122.1,121.9,120.5,120.0,119.7,119.4,114.44,114.36,114.3,106.5,106.4,106.0,105.9,52.2,52.1,52.0,51.9.HRMS(ESI-TOF)m/z:[M-H]-calcd.for(C44H27O7P)697.1422,found:697.1411.
(7f).Rf=0.16(hexane:EA=2:1)White solid,172.8mg,yield 97%.Mp.301.9℃; 1H NMR(400MHz,CDCl3)δ7.99-7.61(m,18H),7.09(d,J=8.8Hz,2H),6.93-6.69(m,4H),5.11-4.05(m,2H).13C{1H}NMR(100MHz,CDCl3)δ158.2,158.1,157.9,146.9,136.3,133.5,133.2,132.9,132.7,131.1,130.9,130.8,130.6,130.1,128.6,128.4,127.4,127.1,127.0,125.9,125.5,125.1,125.0,124.9,124.5,124.4,124.3,124.2,124.0,120.9,119.9,119.3,114.5,114.4,114.2,106.2,105.9,105.8,105.5,52.3,52.1,52.0.HRMS(ESI-TOF)m/z:[M-H]-calcd.for(C48H27O7P)745.1422,found:745.1412.
实施例4
手性磷酸催化剂的应用。
分别以实施例3中化合物7a~7f作为催化剂,催化以下不对称傅克烷基化反应,另外在相同反应条件下以CPA-11和CPA-12作为对比。
反应式如下:
以采用化合物7d作为催化剂为例,具体步骤为:
将磺酰亚胺(化合物8)(26mg,0.1mmol)、手性磷酸催化剂(CPA)(3mg,5mol)溶解于DCM(0.5mL),随后于0℃下一次性加入吲哚(化合物9)(35mg,0.3mmol),反应24h。反应结束后,将反应体系减压浓缩。粗品经柱层析纯化(hexane:EA=3:1),得到纯品(化合物10),白色固体,26.5mg,收率71%。
采用上述8种不同的催化剂,反应收率如下表所示:
表1不同催化剂的反应收率a
Entry | CPA | Yield(%)<sup>b</sup> | er<sup>c</sup> |
1 | 7a | 91 | 71:29 |
2 | 7b | 91 | 72:28 |
3 | 7c | 71 | 57:43 |
4 | 7d | 71 | 75:25 |
5<sup>d</sup> | 7d | 94 | 76:24 |
6 | 7e | 78 | 65:35 |
7 | 7f | 23 | 59:41 |
8 | CPA-11 | 82 | 6:94 |
9 | CPA-12 | 86 | 89:11 |
注:表中CPA为手性磷酸催化剂;er表示对映异构体的含量比值,在此处表示S:R的比值;a,上述反应1-9,底物8的用量为0.1mmol,底物9的用量为0.3mmol,催化剂的用量为5mol%,溶剂用量为0.5mL DCM中于0℃反应;b表示柱层析分离收率;c表示用手性柱正相色谱分离(手性柱型号为Phenomenex NX(2)column);d表示反应温度为零下20℃。
实施例5
对以上实施例中得到的消旋的手性二酚、化合物3、化合物4,以及采用不同手性磷酸催化剂反应得到的化合物10进行HPLC测试。
消旋的手性二酚的HPLC图谱如图4所示,化合物3的HPLC图谱如图5所示、化合物4的HPLC图谱如图6所示。
Rac-10(化合物10消旋体)的HPLC图谱如图7所示。
在实施例4中,以7a、7b、7c、7d、7e、7f、CPA-11、CPA-12为催化剂,反应温度为0℃,得到的单一对映异构体过量的化合物10的HPLC图谱分别如图8、9、10、11、13、14、15、16所示。以7d为催化剂,反应温度-20℃,得到的单一对映异构体过量的化合物10的HPLC图谱如图12所示。
以上所述实施例的各技术特征可以进行任意的组合,为使描述简洁,未对上述实施例中的各个技术特征所有可能的组合都进行描述,然而,只要这些技术特征的组合不存在矛盾,都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准。
Claims (5)
2.权利要求1所述的手性二酚的合成方法,其特征在于,按照以下合成路线进行:
S1、将2-重氮-1,3-环己二酮与呋喃混合,在醋酸铑二聚体的催化下反应18~22h,经薄层色谱和柱层析,得到化合物1;其中,2-重氮-13-环己二酮、呋喃、醋酸铑二聚体的用量比为(2.8~3.2)g:(28~32)mL:(190~194)mg;
S2、将化合物1和氟苯混合,加入醋酸铑二聚体和2-重氮-1,3-环己二酮,在48~52℃下反应2~20h,经薄层色谱和柱层析,得到化合物2;其中,化合物1、氟苯、醋酸铑二聚体和2-重氮-1,3-环己二酮的用量比为(2.6~3.0)g:(28~32)mL:(137~141)mg:(2.0~2.4)g;
S3、将化合物2和三甘醇二甲醚混合,加入Pd/C催化剂,在210~220℃下反应,反应完成降温,过滤去除Pd/C催化剂,滤液经蒸馏去除溶剂,得到棕色油状物,经柱层析、薄层色谱、浓缩,得到消旋的手性二酚;其中,化合物2、三甘醇二甲醚、Pd/C催化剂的用量比为(4.8~5.2)g:(95~105)mL:(1.8~2.2)g;或者,所述步骤S3具体为:将化合物2、2,3-二氯-5,6-二氰对苯醌、二氧六环混合,在惰性气体氛围下,加入双(三甲基硅烷基)三氟乙酰胺,在15~35℃下反应4~5h,再升温至100~120℃下反应16~20h,降温后加入乙酸乙酯和亚硫酸氢钠水溶液,继续加入盐酸,进行萃取分液,有机相用盐酸洗涤,有机相经浓缩得到棕色固体,加入二氯甲烷溶解固体,经浓缩、柱分离,得到消旋的手性二酚;其中,化合物2、2,3-二氯-5,6-二氰对苯醌、二氧六环、双(三甲基硅烷基)三氟乙酰胺的用量比为(490~510)mg:(860~870)mg:(4.5~5.5)mL:(3.9~4.1)g;
S4、将消旋的手性二酚与乙酸乙酯混合,溶解澄清后加入N-苄基奎宁氯,75~85℃下回流反应4~6h,抽滤,将固体分散于乙酸乙酯中,加热至75~85℃搅拌25~35min,降温抽滤,固体用乙酸乙酯洗涤,再加入乙酸乙酯和3.5~4.5M的盐酸,搅拌后萃取分液,有机相用盐酸洗涤,合并有机相,用无水硫酸钠干燥,浓缩,得到式Ⅰ所示化合物;其中,消旋的手性二酚、N-苄基奎宁氯的用量比为(3.6~4.0)g:(4.6~5.0)g。
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