CN115073395A - 一种拆分外消旋面手性环芳烷磺酰亚胺类化合物的方法 - Google Patents

一种拆分外消旋面手性环芳烷磺酰亚胺类化合物的方法 Download PDF

Info

Publication number
CN115073395A
CN115073395A CN202110269183.7A CN202110269183A CN115073395A CN 115073395 A CN115073395 A CN 115073395A CN 202110269183 A CN202110269183 A CN 202110269183A CN 115073395 A CN115073395 A CN 115073395A
Authority
CN
China
Prior art keywords
chiral
formula
cyclophane
nickel
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN202110269183.7A
Other languages
English (en)
Other versions
CN115073395B (zh
Inventor
周永贵
赵洋
孙蕾
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dalian Institute of Chemical Physics of CAS
Original Assignee
Dalian Institute of Chemical Physics of CAS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dalian Institute of Chemical Physics of CAS filed Critical Dalian Institute of Chemical Physics of CAS
Priority to CN202110269183.7A priority Critical patent/CN115073395B/zh
Publication of CN115073395A publication Critical patent/CN115073395A/zh
Application granted granted Critical
Publication of CN115073395B publication Critical patent/CN115073395B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D291/00—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms
    • C07D291/08—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms condensed with carbocyclic 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
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
    • B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
    • B01J31/2419—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising P as ring member
    • B01J31/2423—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising P as ring member comprising aliphatic or saturated rings
    • 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
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
    • B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
    • B01J31/2419—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising P as ring member
    • B01J31/2428—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising P as ring member with more than one complexing phosphine-P atom
    • B01J31/2433—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising P as ring member with more than one complexing phosphine-P atom comprising aliphatic or saturated rings
    • 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
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
    • B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
    • B01J31/2442—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems
    • B01J31/2447—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as substituents on a ring of the condensed system or on a further attached ring
    • B01J31/2452—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as substituents on a ring of the condensed system or on a further attached ring with more than one complexing phosphine-P atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds
    • 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
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
    • B01J2531/84—Metals of the iron group
    • B01J2531/847—Nickel
    • 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
    • Y02P20/584—Recycling of catalysts

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

本发明提供一种拆分外消旋面手性环芳烷磺酰亚胺类化合物的方法，所述方法以式I所示的环芳烷磺酰亚胺类化合物为底物，进行催化还原反应，得到面手性环芳烷磺酰亚胺类化合物(对映体过量可达92.1％)和面手性环芳烷磺酰胺类化合物(对映体过量可达93.0％，非对映体比例可达>20:1)，拆分系数可达到s＝80.2；催化还原反应的催化剂是镍的手性双膦配合物，由镍盐与手性双膦配体原位络合而成；本发明可以实现催化拆分，操作简单易行，催化剂商业可得，条件温和，能耗低，环境友好且拆分系数高，产率好。

Description

一种拆分外消旋面手性环芳烷磺酰亚胺类化合物的方法
技术领域
本发明属于不对称催化合成领域，涉及一种拆分外消旋面手性环芳烷磺酰亚胺类化合物的方法，具体地通过镍均相体系催化的氢化反应实现消旋环芳烷磺酰亚胺类化合物的拆分。
背景技术
面手性[2.2]环芳烷化合物广泛应用于各种手性材料中，同时也可以作为配体或辅基在不对称合成中起着不可或缺的作用。(参考文献一：(a)Morisaki,Y.；Inoshita,K.；Chujo,Y.Chem.Eur.J.2014,20,8386.(b)Gibson,S.E.；Knight,J.D.Org.Biomol.Chem.2003,1,1256.(c)Fringuelli,F.；Piermatti,O.；Pizzo,F.；Ruzziconi,R.Chem.Lett.2000,38.)。目前，获得面手性[2.2]环芳烷化合物的方法主要有传统的化学拆分，手性色谱分离等方法。(参考文献二：(a)Braddock,D.C.；MacGilp,I.D.；Perry,B.G.J.Org.Chem.2002,67,8679.(b)Wang,Y.；Yuan,H.；Lu,H.；Zheng,W.-H.Org.Lett.2018,20,2555.)。近年来，通过催化动力学拆分制备面手性环芳烷引起了人们的注意，相比其他方法，它的优势在于可以显著降低手性试剂的用量。但目前发展的方法底物范围受限。(参考文献三：(a)Dorizon,P.；Martin,C.；Daran,J.-C.；Fiauda,J.-C.；Kagana,H.B.Tetrahedron:Asymmetry 2001,12,2625.(b)Akagawa,K.；Nishi,N.；Yoshikawa,I.；Kudo,K.Eur.J.Org.Chem.2015,5055.)。近年来廉价金属镍催化磺酰亚胺的氢化反应是一种构建手性化合物的有效手段。(参考文献四：Liu,Y.；Dong,X.-Q.；Zhang,X.；Chin.J.Org.Chem.2020,40,1096-1104.)。但是此前镍催化面手性化合物的动力学拆分没有文献报道。
发明内容
本发明的目的是提供一种通过对磺酰亚胺的氢化反应实现环芳烷类外消旋面手性化合物拆分的方法，以镍的手性双膦配合物为催化剂，以环芳烷磺酰亚胺为底物，通过对磺酰亚胺的氢化反应实现环芳烷类外消旋面手性化合物的拆分。本发明操作简便实用，原料易得，拆分系数高，产率好，能耗低且反应具有环境友好等优点。
本发明的技术方案如下：
一种拆分外消旋面手性环芳烷磺酰亚胺类化合物的方法，所述方法以式I所示的外消旋面手性环芳烷磺酰亚胺类化合物为底物，进行催化还原反应，得到式II所示的面手性环芳烷磺酰亚胺类化合物和式III所示的面手性环芳烷磺酰胺类化合物；所述催化还原反应的催化剂是镍的手性双膦配合物；
Figure BDA0002973554660000021
所述式I、式II、式III中：
R1选自H、C1-C5烷基、苯基、萘基或含有取代基N1的苯基中的一种；
R2选自H、C1-C5烷基中的一种；
所述的取代基N1选自卤素，C1-C5烷氧基、C1-C5烷基中的一种。
优选地，所述方法是在还原气氛中将含有底物的原料与催化剂混合，40～80℃温度下，优选60℃～80℃；下限选自40℃、上限选自60℃、80℃反应12h～176h，优选12h～72h，优选30～120h，上限选自72h、120h、下限选自12h、30h。
优选地，所述催化剂与环芳烷磺酰亚胺类化合物的摩尔比为0.02:1～0.25:1，优选0.02:1～0.05:1，上限选自0.25:1、0.05:1，下限选自0.02：1。
优选地，所述镍的手性双膦配合物是由镍盐与手性双膦配体原位络合而成；所述镍盐优选为四水合醋酸镍。
优选地，所述镍盐与手性双膦配体的摩尔比例为1:1～5:1。
优选地，所述手性双膦配体选自式L1、式L2、式L3、式L4、式L5中的任一种：
Figure BDA0002973554660000031
可选地，所述原料中还含有机溶剂，所述环芳烷磺酰亚胺类化合物与有机溶剂的用量比为0.02:1～0.08:1mol/L，优选1:30～1:15mol/L，下限选自0.02:1mol/L、1:30mol/L；上限选自0.08:1mol/L、1:15mol/L。
可选地，所述方法包括以下步骤：
(1)在还原气氛中将催化剂、环芳烷磺酰亚胺类化合物和有机溶剂混合，反应；
(2)旋干有机溶剂，柱层析分离，得到式II所示的面手性环芳烷磺酰亚胺类化合物和式III所示的面手性环芳烷磺酰胺类化合物。
可选地，所述有机溶剂为三氟乙醇、六氟异丙醇中的至少一种。
可选地，所述还原气氛为氢气，氢气压力为500～1000psi。
基于以上技术方案，优选的，所述方法的具体反应步骤为：
作为可实施的方案，在氮气保护下，在反应瓶中投入四水合醋酸镍(环芳烷磺酰亚胺用量的5mol％)和手性双膦配体(环芳烷磺酰亚胺用量的5mol％)，环芳烷磺酰亚胺，有机溶剂装入高压釜，经3次氢气置换后，使初始氢气压力为600psi，60℃温度下搅拌反应120小时。冷却，小心放出气体，打开高压釜，取出小瓶。除去溶剂后直接柱层析分离得到纯的面手性环芳烷磺酰亚胺和面手性环芳烷磺酰胺。
基于以上技术方案，优选的，所述的反应为镍催化环芳烷磺酰亚胺的不对称氢化反应反应实现环芳烷亚胺的拆分，R1为苯基，R2为H，所述的催化剂为镍的手性双膦配体L1的配合物，有机溶剂为六氟异丙醇，温度为60℃，反应时间为120h，拆分后得到的面手性环芳烷磺酰亚胺1a对映体过量92.1％，面手性环芳烷磺酰胺对映体过量93.0％，拆分系数s值为80.2。
本发明具有以下优点：
1.反应活性和对映选择性高，且拆分系数高。
2.能得到面手性环芳烷磺酰亚胺化合物以及面手性环芳烷磺酰胺化合物。
3.催化剂商业可得，反应操作简便。
4.反应条件温和，能耗低。
具体实施方式
下面通过实施例详述本发明，但本发明并不限于下述的实施例。
本发明的底物环芳烷磺酰亚胺分两个步骤合成：步骤(1)氮气保护下，向反应瓶中加入4-羟基环芳烷、二氯甲烷，0℃下向该体系中加入酰氯、四氯化钛，搅拌3小时，可以得到邻位酰基取代的4-羟基环芳烷；步骤(2)将步骤(1)得到的邻位酰基取代的4-羟基环芳烷投入反应瓶中，将其溶于甲苯中，随后加入氯磺酰胺回流搅拌过夜，可以得到环芳烷磺酰亚胺。
作为一种实施方式，本发明的一种拆分环芳烷磺酰亚胺的方法，以镍的手性双膦配合物为催化剂，以环芳烷磺酰亚胺为底物，通过对磺酰亚胺的氢化反应实现环芳烷类外消旋面手性化合物的拆分，拆分得到面手性环芳烷磺酰亚胺1和面手性环芳烷磺酰胺2。所述方法的反应式如下：
具体反应式如下：
Figure BDA0002973554660000041
本发明实施例20-21进行底物拓展使用的环芳烷磺酰亚胺为rac-1m(消旋-1m)和rac-1n(消旋-1n)是由4-甲基环芳烷为原料合成的，环芳烷磺酰亚胺rac-1m(消旋-1m)和rac-1n(消旋-1n)具体合成步骤参照上文。4-甲基环芳烷的合成参考文献(a)Gready,J.E.；Hambley,T.W.；Kakiuchi,K.；Kobiro,K.；Sternhell,S.；Tansey,C.W.；Tobe,Y.J.Am.Chem.Soc.1990,112,7537.其余原料均商业可得。
Figure BDA0002973554660000051
本发明得到的产物面手性环芳烷磺酰亚胺可以进行一系列衍生化生成手性转氧试剂应用于不对称合成中。面手性环芳烷磺酰胺可以进行一系列的转化合成带有面手性的胺基化合物，可以作为手性辅基应用于手性合成中。
实施例1-7条件的优化
改变手性双膦配体、有机溶剂的种类以及溶剂用量。
在反应瓶中投入四水合醋酸镍(1a用量的5mol％)和手性双膦配体L1-L5(1a用量的5mol％)，环芳烷磺酰亚胺1a(0.1毫摩尔)，3毫升六氟异丙醇(实施例1-6中溶剂用量为3毫升，实施例7为溶剂用量为1.5毫升)，60℃反应30h。除去溶剂后直接柱层析分离得到纯的面手性环芳烷磺酰亚胺1a和面手性环芳烷磺酰胺2a。回收环芳烷亚胺1a的转化率用核磁测定，回收环芳烷亚胺1a和产物2a的对映体过量用手性液相色谱测定，产物2a的非对映体比例用核磁测定，拆分系数s值用这一算式算得s＝ln[(1-C)(1-ee of 1a)]/ln[(1-C)(1+eeof 1a)](其中C为环芳烷磺酰亚胺1a的转化率，由核磁确定；ee of 1a为环芳烷磺酰亚胺1a的对映体过量值)，改变配体、有机溶剂的种类，具体结果如表1；dr为非对映体比例。
Figure BDA0002973554660000061
表1.环芳烷磺酰亚胺类面手性化合物动力学拆分条件的优化
Figure BDA0002973554660000062
实施例8-21
一系列环芳烷磺酰亚胺化合物的氢化拆分反应。
在反应瓶中投入四水合醋酸镍(实施例8-18中用量为1用量的5mol％，实施例19-21中用量为1用量的25mol％)和手性双膦配体(S,S)-Ph-BPE(1用量的5mol％)，环芳烷磺酰亚胺1(0.2毫摩尔)，3毫升六氟异丙醇。除去溶剂后直接柱层析分离得到纯的面手性环芳烷磺酰亚胺1和面手性环芳烷磺酰胺2，实施例8为60℃反应120h，实施例19为60℃反应72h，实施例20-21为40℃反应176h。除去溶剂后直接柱层析分离得到纯的面手性环芳烷磺酰亚胺1和面手性环芳烷磺酰胺2。回收环芳烷亚胺1的转化率用核磁测定，回收环芳烷亚胺1和产物2的对映体过量用手性液相色谱测定，产物2的非对映体比例用核磁测定，s值用这一算式算得s＝ln[(1-C)(1-ee of 1)]/ln[(1-C)(1+ee of 1)](其中C为环芳烷磺酰亚胺1的转化率，由核磁确定；ee of 1为环芳烷磺酰亚胺1的对映体过量值)，具体见表2。
其中，实施例8中R1为苯基，R2为H，所述的催化剂为四水合醋酸镍和手性双膦配体的配合物，有机溶剂为六氟异丙醇，温度为60℃，反应时间120h，拆分后得到的面手性环芳烷磺酰亚胺对映体过量92.1％，面手性环芳烷磺酰胺对映体过量93.0％，拆分系数s值为80.2。
Figure BDA0002973554660000071
表2.一系列环芳烷磺酰亚胺的氢化拆分反应
Figure BDA0002973554660000072
Figure BDA0002973554660000081
(+)-4-Phenyl-3,4-dihydro-[2.2]paracyclophano[5,6-d]-1,2,3-benzoxathiazine 2,2-Dioxide(2a):39.0
Figure BDA0002973554660000082
NMR(100MHz,CDCl3)δ149.3,139.9,139.2,138.6,137.1,136.2,133.2,133.0,132.9,131.2,130.0,129.5,129.4,128.9,124.5,61.2,35.2,34.6,32.1,28.7.HPLC:Chiracel IAcolumn,254nm,30℃,n-Hexane/i-PrOH＝60/40,flow＝0.6mL/min,retention time18.8min(major)and 24.4min.
4-Phenyl-3,4-dihydro-[2.2]paracyclophano[5,6-d]-1,2,3-benzoxathiazine2,2-Dioxide(2a’):白色固体,已知化合物,Rf＝0.45(hexanes/acetone 5/1).1H NMR(400MHz,CDCl3)δ7.40-7.30(m,3H),
Figure BDA0002973554660000083
(+)-4-Phenyl-[2.2]paracyclophano[5,6-d]-1,2,3-benzoxathiazine 2,2-Dioxide(1a):38.0mg,49％yield,92.1％ee,[α]20 D＝+389.97(c 0.62,CHCl3).HPLC:Chiralcel IA column,254nm,30℃,n-Hexane/i-PrOH＝60/40,flow＝0.6mL/min,retention time 9.1min and 10.5min(major).
(+)-4-(m-Tolyl)-3,4-dihydro-[2.2]paracyclophano[5,6-d]-1,2,3-benzoxathiazine 2,2-Dioxide(2b):41.0mg,51％yield,>20:1dr,白色固体,mp＝167-169℃,未知化合物,Rf＝0.30(hexanes/
Figure BDA0002973554660000084
137.0,136.2,133.2,133.0,132.9,131.3,130.1,129.9,129.6,129.4,129.3,125.9,124.3,61.1,35.2,34.6,32.1,28.7,21.7.HPLC:Chiracel IA column,254nm,30℃,n-Hexane/i-PrOH＝60/40,flow＝0.6mL/min,retention time 14.7min(major)and22.0min.HRMS:Calculated for C24H27N2O3S[M+NH4]+423.1737,found:423.1735.
(+)-4-(m-Tolyl)-[2.2]paracyclophano[5,6-d]-1,2,3-benzoxathiazine 2,2-Dioxide(1b):37.0mg,46％yield,98.8％ee,[α]20 D＝+296.77(c 0.78,CHCl3).HPLC:Chiralcel IA column,254nm,30℃,n-Hexane/i-PrOH＝60/40,flow＝0.6mL/min,retention time 8.5min and 9.6min(major).
4-(p-Tolyl)-3,4-dihydro-[2.2]paracyclophano[5,6-d]-1,2,3-benzoxathiazine 2,2-Dioxide(2c):40.0mg,49％yield,9.2:1dr,白色固体,mp＝174-176℃,未知化合物,Rf＝0.35(hexanes/
Figure BDA0002973554660000091
60/40,flow＝0.6mL/min,retention time 18.6min(major)and 25.4min.HRMS:Calculated for C24H24NO3S[M+H]+406.1471,found:406.1470.
(+)-4-(p-Tolyl)-[2.2]paracyclophano[5,6-d]-1,2,3-benzoxathiazine 2,2-Dioxide(1c):39.0mg,48％yield,93.5％ee,[α]20 D＝+279.70(c 0.72,CHCl3).HPLC:Chiralcel IA column,254nm,30℃,n-Hexane/i-PrOH＝60/40,flow＝0.6mL/min,retention time 9.1min and 11.5min(major).
(+)-4-(4-Methoxyphenyl)-3,4-dihydro-[2.2]paracyclophano[5,6-d]-1,2,3-benzoxathiazine 2,2-Dioxide(2d):23.0mg,46％yield,1.5:1dr,白色固体,mp＝84-86℃,未知化合物,Rf＝0.25
Figure BDA0002973554660000092
n-Hexane/i-PrOH＝60/40,flow＝0.6mL/min,retention time 22.6min(major)and30.8min.HRMS:Calculated for C24H24NO4S[M+H]+422.1421,found:422.1420.
(+)-4-(4-Methoxyphenyl)-3,4-dihydro-[2.2]paracyclophano[5,6-d]-1,2,3-benzoxathiazine 2,2-Dioxide(2d’):15.0mg,1.5:1dr,白色固体,已知化合物,Rf＝0.30(hexanes/dichloro-methane 1/1),
Figure BDA0002973554660000093
30℃,n-Hexane/i-PrOH＝60/40,flow＝0.6mL/min,retention time 16.3min(major)and20.1min.
(+)-4-(4-Methoxyphenyl)-[2.2]paracyclophano[5,6-d]-1,2,3-benzoxathiazine 2,2-Dioxide(1d):42.0mg,50％yield,87.9％ee,[α]20 D＝+276.17(c0.84,CHCl3).HPLC:Chiralcel IA column,254nm,30℃,n-Hexane/i-PrOH＝60/40,flow＝0.6mL/min,retention time 11.4min and 15.7min(major).
(+)-4-(4-Fluorophenyl)-3,4-dihydro-[2.2]paracyclophano[5,6-d]-1,2,3-benzoxathiazine 2,2-Dioxide(2e):41.0mg,50％yield,15.0:1dr,白色固体,mp＝84-86℃,未知化合物,Rf＝0.35
Figure BDA0002973554660000101
35.1,34.6,31.9,28.7.19F NMR(376MHz,CDCl3)δ-111.6.HPLC:Chiracel IA column,254nm,30℃,n-Hexane/i-PrOH＝60/40,flow＝0.6mL/min,retention time 21.7min(major)and 23.8min.HRMS:Calculated for C23H20FNaNO3S[M+Na]+432.1040,found:432.1047.
(+)-4-(4-Fluorophenyl)-[2.2]paracyclophano[5,6-d]-1,2,3-benzoxathiazine 2,2-Dioxide(1e):38.0mg,47％yield,97.2％ee,[α]20 D＝+329.83(c0.68,CHCl3).HPLC:Chiralcel IA column,254nm,30℃,n-Hexane/i-PrOH＝60/40,flow＝0.6mL/min,retention time 9.4min and 11.1min(major).
Figure BDA0002973554660000102
NMR(100MHz,CDCl3)δ149.1,139.9,139.2,138.4,136.4,135.4,133.1,133.0,133.0,131.1,130.5,129.8,129.5,129.5,124.8,60.4,35.1,34.6,32.0,28.7.HPLC:Chiracel IAcolumn,254nm,30℃,n-Hexane/i-PrOH＝60/40,flow＝0.6mL/min,retention time24.2min and 27.9min(major).HRMS:Calculated for C23H21ClNO3S[M+H]+426.0925,found:426.0929(35Cl)and 428.0904(37Cl).
(+)-4-(4-Chlorophenyl)-[2.2]paracyclophano[5,6-d]-1,2,3-benzoxathiazine 2,2-Dioxide(1f):
40.0mg,47％yield,96.4％ee,[α]20 D＝+331.13(c 0.78,CHCl3).HPLC:ChiralcelIA column,254nm,30℃,n-Hexane/i-PrOH＝60/40,flow＝0.6mL/min,retention time10.1min and 12.1min(major).
(+)-4-(4-Bromophenyl)-3,4-dihydro-[2.2]paracyclophano[5,6-d]-1,2,3-benzoxathiazine 2,2-Dioxide(2g):48.0mg,51％yield,14.0:1dr,白色固体,mp＝108-110℃,未知化合物,Rf＝0.33
Figure BDA0002973554660000103
34.6,32.0,28.7.HPLC:Chiracel IA column,254nm,30℃,n-Hexane/i-PrOH＝60/40,flow＝0.6mL/min,retention time 25.1min and 29.9min(major).HRMS:Calculated forC23H24BrN2O3S[M+NH4]+487.0686,found:487.0687(79Br)and 489.0668(81Br).
(+)-4-(4-Bromophenyl)-[2.2]paracyclophano[5,6-d]-1,2,3-benzoxathiazine 2,2-Dioxide(1g):48.0mg,47％yield,97.1％ee,[α]20 D＝+313.40(c0.76,CHCl3).HPLC:Chiralcel IA column,254nm,30℃,n-Hexane/i-PrOH＝60/40,flow＝0.6mL/min,retention time 10.6min and 12.7min(major).
(+)-4-(4-Iodophenyl)-3,4-dihydro-[2.2]paracyclophano[5,6-d]-1,2,3-benzoxathiazine 2,2-Dioxide(2h):46.0mg,44％yield,>20:1dr,白色固体,mp＝213-215℃,未知化合物,Rf＝0.36
Figure BDA0002973554660000111
32.0,28.7.HPLC:Chiracel IA column,254nm,30℃,n-Hexane/i-PrOH＝60/40,flow＝0.6mL/min,retention time 25.4min(major)and 27.4min.HRMS:Calculated forC23H24IN2O3S[M+NH4]+535.0547,found:535.0546.
(+)-4-(4-Iodophenyl)-[2.2]paracyclophano[5,6-d]-1,2,3-benzoxathiazine2,2-Dioxide(1h):56.0mg,54％yield,77.6％ee,[α]20 D＝+228.11(c 0.96,CHCl3).HPLC:Chiralcel IA column,254nm,30℃,n-Hexane/i-PrOH＝60/40,flow＝0.6mL/min,retention time 11.3min and 13.5min(major).
(+)-4-(3-Fluorophenyl)-3,4-dihydro-[2.2]paracyclophano[5,6-d]-1,2,3-benzoxathiazine 2,2-
Figure BDA0002973554660000112
3.12-2.97(m,1H),2.94-2.79(m,3H),2.79-2.64(m,1H),2.62-2.46(m,1H).13C NMR(100MHz,CDCl3)δ163.1(JC-F＝248.0Hz),149.2,139.9,139.3(JC-F＝6.9Hz),139.2,138.5,136.4,133.2,133.0,133.0,131.0,131.0(JC-F＝8.1Hz),129.9,129.5,124.7(JC-F＝2.9Hz),124.5,116.4(JC-F＝20.8Hz),116.3(JC-F＝22.6Hz),60.4,35.1,34.6,32.0,28.7.19F NMR(376MHz,CDCl3)δ-110.7.HPLC:Chiracel IB column,254nm,30℃,n-Hexane/i-PrOH＝70/30,flow＝0.8mL/min,retention time 8.7min(major)and 17.7min.HRMS:Calculated for C23H21FNO3S[M+H]+410.1221,found:410.1224.
(+)-4-(3-Fluorophenyl)-[2.2]paracyclophano[5,6-d]-1,2,3-benzoxathiazine 2,2-Dioxide(1i):39.0mg,48％yield,91.4％ee,[α]20 D＝+357.27(c0.74,CHCl3).HPLC:Chiralcel IA column,254nm,30℃,n-Hexane/i-PrOH＝90/10,flow＝1.0mL/min,retention time 10.9min and 12.2min(major).
(+)-4-(3-Chlorophenyl)-3,4-dihydro-[2.2]paracyclophano[5,6-d]-1,2,3-benzoxathiazine 2,2-Dioxi de(2j):46.0mg,54％yield,17.0:1dr,白色固体,mp＝212-214℃,未知化合物,Rf ＝0.25
Figure BDA0002973554660000113
133.0,133.0,131.0,130.6,129.8,129.6,129.3,127.2,124.4,60.4,35.1,34.6,32.0,28.7.HPLC:Chiracel IB column,254nm,30℃,n-Hexane/i-PrOH＝60/40,flow＝0.6mL/min,retention time 9.8min(major)and 16.5min.HRMS:Calculated for C23H20ClNNaO3S[M+Na]+448.0745,found:448.0740(35Cl)and 450.0711(37Cl).
(+)-4-(3-Chlorophenyl)-[2.2]paracyclophano[5,6-d]-1,2,3-benzoxathiazine 2,2-Dioxide(1j):37.0mg,44％yield,98.8％ee,[α]20 D＝+317.48(c0.72,CHCl3).HPLC:Chiralcel AD-H column,254nm,30℃,n-Hexane/i-PrOH＝60/40,flow＝0.6mL/min,retention time 11.2min(major)and 15.0min.
(+)-4-(2-Naphthyl)-3,4-dihydro-[2.2]paracyclophano[5,6-d]-1,2,3-benzoxathiazine 2,2-Dioxide(2k):45.0mg,51％yield,16.0:1dr,白色固体,mp＝103-105℃,未知化合物,Rf＝0.30
Figure BDA0002973554660000121
131.3,129.8,129.4,129.2,128.3,128.0,128.0,127.2,127.1,126.3,124.3,61.2,35.1,34.6,32.2,28.7.HPLC:Chiracel IA column,254nm,30℃,n-Hexane/i-PrOH＝60/40,flow＝0.6mL/min,retention time19.0min(major)and 30.5min.HRMS:Calculated forC27H24NO3S[M+H]+442.1471,found:442.1477.
(+)-4-(2-Naphthyl)-[2.2]paracyclophano[5,6-d]-1,2,3-benzoxathiazine2,2-Dioxide(1k):40.0mg,46％yield,96.9％ee,[α]20 D＝+326.19(c 0.74,CHCl3).HPLC:Chiralcel IA column,254nm,30℃,n-Hexane/i-PrOH＝60/40,flow＝0.6mL/min,retention time 10.8min and 15.5min(major).
(+)-4-Methyl-3,4-dihydro-[2.2]paracyclophano[5,6-d]-1,2,3-benzoxathiazine 2,2-Dioxide(2l):The reaction was conducted for 12h.19.0mg,56％yield,1.1:1dr,白色固体,mp＝153-155℃,未知化
Figure BDA0002973554660000122
CDCl3)δ150.0,140.4,138.9,138.1,135.7,133.4,133.0,131.7,131.1,129.4,129.2,127.8,52.0,35.3,34.5,31.4,28.8,18.7.HPLC:Chiracel AD-H column,254nm,30℃,n-Hexane/i-PrOH＝60/40,flow＝0.6mL/min,retention time 14.6min(major)and24.3min.HRMS:Calculated for C18H20NO3S[M+H]+330.1158,found:330.1154.
(-)-4-Methyl-3,4-dihydro-[2.2]paracyclophano[5,6-d]-1,2,3-benzoxathiazine 2,2-Dioxide(2l’):18.0mg,1.1:1dr,白色固体,已知化合物,Rf＝0.50(hexanes/dichloromethane/ethyl acetate 10/10/1),
Figure BDA0002973554660000123
13C NMR(100MHz,CDCl3)δ149.6,140.1,138.3,138.1,134.7,134.1,133.3,131.1,129.6,128.8,128.1,122.5,53.8,33.9,33.8,32.7,29.7,22.5.HPLC:Chiracel OD-H column,254nm,30℃,n-Hexane/i-PrOH＝60/40,flow＝0.6mL/min,retention time 9.4min and10.7min(major).
(-)-4-Methyl-[2.2]paracyclophano[5,6-d]-1,2,3-benzoxathiazine 2,2-Dioxide(1l):27.0mg,41％yield,1.9％ee,[α]20 D＝-7.18(c 0.78,CHCl3).HPLC:Chiralcel OD-H column,254nm,30℃,n-Hexane/i-PrOH＝60/40,flow＝0.6mL/min,retention time 13.3min(major)and 15.2min.
4-tert-Butyl-3,4-dihydro-[2.2]paracyclophano[5,6-d]-1,2,3-benzoxathiazine 2,2-Dioxide(2m):Nickel acetate tetrahydrate(12.4mg,25mol％),(S,S)-Ph-BPE(5.1mg,5mol％)were used in this
Figure BDA0002973554660000131
2.89-2.75(m,1H),0.95(s,9H).13C NMR(100 MHz,CDCl3)δ151.9,140.4,138.6,138.4,135.8,133.3,132.7,132.3,131.4,130.7,129.1,120.5,65.7,37.6,35.0,34.8,33.1,29.1,26.7.HPLC:Chiracel IC column,254nm,30℃,n-Hexane/i-PrOH＝60/40,flow＝0.6mL/min,retention time 7.7min and 8.8min(major).HRMS:Calculated forC21H26NO3S[M+H]+372.1628,found:372.1630.
(-)-4-tert-Butyl-[2.2]paracyclophano[5,6-d]-1,2,3-benzoxathiazine 2,2-Dioxide(1m):36.0mg,49％yield,69.4％ee,[α]20 D＝-318.49(c 0.74,CHCl3).HPLC:Chiralcel IA column,254nm,30℃,n-Hexane/i-PrOH＝60/40,flow＝0.6mL/min,retention time 7.2min(major)and 7.8min.
(+)-4-(4-Phenyl)-3,4-dihydro-(8-methyl[2.2]paracyclophano)[5,6-d]-1,2,3-benzoxathiazine2,2-Dioxide(2n):Nickel acetate tetrahydrate(12.4mg,25mol％),(S,S)-Ph-BPE(5.1mg,5mol％)were
Figure BDA0002973554660000132
3.26-3.13(m,1H),3.12-2.94(m,2H),2.90-2.79(m,2H),2.78-2.68(m,1H),2.67-2.54(m,1H),2.06(s,3H).13C NMR(100MHz,CDCl3)δ147.1,139.3,138.7,137.9,137.8,137.3,136.0,131.5,131.4,130.0,129.5,129.3,129.3,128.1,128.0,126.4,61.9,34.3,32.7,28.1,27.9,20.6.HPLC:Chiracel IB column,254nm,30℃,n-Hexane/i-PrOH＝60/40,flow＝0.6mL/min,retention time 13.0min(major)and 15.2min.HRMS:Calculated forC24H27N2O3S[M+NH4]+423.1737,found:423.1747.
(+)-4-(4-Phenyl)-(8-methyl[2.2]paracyclophano)[5,6-d]-1,2,3-benzoxathiazine 2,2-Dioxide(1n):49.0mg,61％yield,55.6％ee,[α]20 D＝+146.76(c0.96,CHCl3).HPLC:Chiralcel AD-H column,254nm,30℃,n-Hexane/i-PrOH＝60/40,flow＝0.6mL/min,retention time 8.8min and 10.1min(major).
(+)-4-(4-Chlorophenyl)-3,4-dihydro-(8-methyl[2.2]paracyclophano)[5,6-d]-1,2,3-benzoxathiazine2,2-Dioxide(2o):Nickel acetate tetrahydrate(12.4mg,25mol％),(S,S)-Ph-BPE(5.1mg,5mol％)were
Figure BDA0002973554660000133
139.4,138.6,138.0,137.8,136.2,135.5,135.4,131.7,131.3,131.0,129.8,129.5,128.3,128.2,126.6,61.2,34.3,32.8,28.4,27.9,20.6.HPLC:Chiracel IB column,254nm,30℃,n-Hexane/i-PrOH＝80/20,flow＝0.8mL/min,retention time 11.1min(major)and 15.3min.HRMS:Calculated for C24H23ClNO3S[M+H]+440.1082,found:440.1098(35Cl)and 442.1079(37Cl).
(+)-4-(4-Chlorophenyl)-(8-methyl[2.2]paracyclophano)[5,6-d]-1,2,3-benzoxathiazine 2,2-Di-oxide(1o):67.0mg,77％yield,26.3％ee,[α]20 D＝+102.45(c1.22,CHCl3).HPLC:Chiralcel IA column,254nm,30℃,n-Hexane/i-PrOH＝90/10,flow＝1.0mL/min,retention time 12.3min and 13.5min(major).

Claims (10)

1.一种拆分外消旋面手性环芳烷磺酰亚胺类化合物的方法，其特征在于，所述方法将含有底物的原料，进行催化还原反应，得到式II所示的面手性环芳烷磺酰亚胺类化合物和式III所示的面手性环芳烷磺酰胺类化合物；所述底物为式I所示的外消旋面手性环芳烷磺酰亚胺类化合物；所述催化还原反应的催化剂是镍的手性双膦配合物；
Figure FDA0002973554650000011
所述式I、式II、式III中：
R1选自H、C1-C5烷基、苯基、萘基或含有取代基N1的苯基中的一种；
R2选自H、C1-C5烷基中的一种；
所述的取代基N1选自卤素，C1-C5烷氧基、C1-C5烷基中的一种。
2.根据权利要求1所述的方法，其特征在于，所述方法是在还原气氛中将含有底物的原料与催化剂混合，40℃～80℃温度下，优选60℃～80℃；反应12h～176h，优选12h～72h，优选30h～120h。
3.根据权利要求1所述的方法，其特征在于，所述催化剂与环芳烷磺酰亚胺类化合物的摩尔比为0.02:1～0.25:1，优选0.02:1～0.05:1。
4.根据权利要求1所述的方法，其特征在于，所述镍的手性双膦配合物是由镍盐与手性双膦配体原位络合而成；所述镍盐优选为四水合醋酸镍。
5.根据权利要求4所述的方法，其特征在于，所述镍盐与手性双膦配体的摩尔比例为1:1～5:1。
6.根据权利要求4所述的方法，其特征在于，所述手性双膦配体选自式L1、式L2、式L3、式L4、式L5中的任一种：
Figure FDA0002973554650000021
7.根据权利要求1所述的方法，其特征在于，所述原料中还含有机溶剂，所述环芳烷磺酰亚胺类化合物与有机溶剂的用量比为0.02:1～0.08:1mol/L，优选1:30～1:15mol/L。
8.根据权利要求7所述的方法，其特征在于，所述方法包括以下步骤：
(1)在还原气氛中将催化剂、环芳烷磺酰亚胺类化合物和有机溶剂混合，反应；
(2)旋干有机溶剂，柱层析分离，得到式II所示的面手性环芳烷磺酰亚胺类化合物和式III所示的面手性环芳烷磺酰胺类化合物。
9.根据权利要求7或8所述的方法，其特征在于，所述有机溶剂为三氟乙醇、六氟异丙醇中的至少一种。
10.根据权利要求1-9任一项所述的方法，其特征在于，所述还原气氛为氢气，氢气压力为500～1000psi。
CN202110269183.7A 2021-03-12 2021-03-12 一种拆分外消旋面手性环芳烷磺酰亚胺类化合物的方法 Active CN115073395B (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202110269183.7A CN115073395B (zh) 2021-03-12 2021-03-12 一种拆分外消旋面手性环芳烷磺酰亚胺类化合物的方法

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202110269183.7A CN115073395B (zh) 2021-03-12 2021-03-12 一种拆分外消旋面手性环芳烷磺酰亚胺类化合物的方法

Publications (2)

Publication Number Publication Date
CN115073395A true CN115073395A (zh) 2022-09-20
CN115073395B CN115073395B (zh) 2023-11-10

Family

ID=83240454

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202110269183.7A Active CN115073395B (zh) 2021-03-12 2021-03-12 一种拆分外消旋面手性环芳烷磺酰亚胺类化合物的方法

Country Status (1)

Country Link
CN (1) CN115073395B (zh)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101423504A (zh) * 2007-10-31 2009-05-06 中国科学院大连化学物理研究所 一种钯催化不对称氢化合成手性含杂原子磺内酰胺的方法
CN101475548A (zh) * 2009-02-03 2009-07-08 中国科学院上海有机化学研究所 一种制备手性3-取代苯酞类化合物的方法
CN102030721A (zh) * 2009-09-29 2011-04-27 中国科学院大连化学物理研究所 一种钯催化不对称氢化合成手性苯并磺内酰胺的方法
CN106554325A (zh) * 2015-09-29 2017-04-05 上海交通大学 一种手性苯并磺酰胺类化合物的制备方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101423504A (zh) * 2007-10-31 2009-05-06 中国科学院大连化学物理研究所 一种钯催化不对称氢化合成手性含杂原子磺内酰胺的方法
CN101475548A (zh) * 2009-02-03 2009-07-08 中国科学院上海有机化学研究所 一种制备手性3-取代苯酞类化合物的方法
CN102030721A (zh) * 2009-09-29 2011-04-27 中国科学院大连化学物理研究所 一种钯催化不对称氢化合成手性苯并磺内酰胺的方法
CN106554325A (zh) * 2015-09-29 2017-04-05 上海交通大学 一种手性苯并磺酰胺类化合物的制备方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YANG ZHAO,等人: "Kinetic Resolution of [2.2]Paracyclophane-Derived Cyclic N‐Sulfonylimines via Palladium-Catalyzed Addition of Arylboronic Acids", THE JOURNAL OF ORGANIC CHEMISTRY, vol. 2021, no. 87, pages 1162 - 1272 *

Also Published As

Publication number Publication date
CN115073395B (zh) 2023-11-10

Similar Documents

Publication Publication Date Title
Verdaguer et al. Amine additives greatly expand the scope of asymmetric hydrosilylation of imines
Wang et al. Dinuclear zinc catalyzed asymmetric Friedel–Crafts amidoalkylation of indoles with aryl aldimines
Reznikov et al. Recent developments in asymmetric Heck type cyclization reactions for constructions of complex molecules
Wang et al. Synthesis of 3-indolylglycine derivatives via dinuclear zinc catalytic asymmetric Friedel–Crafts alkylation reaction
Yu et al. The effects of solvent on switchable stereoselectivity: copper-catalyzed asymmetric conjugate additions using D 2-symmetric biphenyl phosphoramidite ligands
Zhou et al. Catalytic effect and recyclability of imidazolium-tagged bis (oxazoline) based catalysts in asymmetric Henry reactions
Infante et al. Asymmetric additive-free aryl addition to aldehydes using perhydrobenzoxazines as ligands and boroxins as aryl source
AU674067B2 (en) Enantioselective oxazaborolidine catalysts
Chen et al. [2.2] Paracyclophane-based N-heterocyclic carbene as efficient catalyst or as ligand for copper catalyst for asymmetric α-silylation of N-tosylaldimines
CN114262295A (zh) 螺二氢茚骨架手性季铵盐及制备方法和应用
Wang et al. Chiral Spiro Dienes Derived Boranes for Asymmetric Hydrosilylation of Ketones
Alimohammadi et al. Λ-[Co ((S, S)-dpen) 3] 3+ 2I–B (C6F5) 4–: A Second Generation Air-and Water-Stable Chiral Solvating Agent for Chirality Sensing (dpen= NH2CHPhCHPhNH2)
Aydemir et al. New active ruthenium (II) complexes based N3, N3′-bis (diphenylphosphino)-2, 2′-bipyridine-3, 3′-diamine and P, P′-diphenylphosphinous acid-P, P′-[2, 2′-bipyridine]-3, 3′-diyl ester ligands for transfer hydrogenation of aromatic ketones by propan-2-ol
JP2003520261A (ja) 非金属有機触媒組成物を使用する基質の化学変換
Özdemir et al. Asymmetric Friedel–Crafts alkylation of pyrrole with nitroalkenes catalyzed by a copper complex of a bisphenol A-derived Schiff base
CN109692709A (zh) 一种烯烃复分解反应的催化剂及其制备和应用方法
CN115073395A (zh) 一种拆分外消旋面手性环芳烷磺酰亚胺类化合物的方法
Zhang et al. A general nickel-catalyzed highly regioselective hydroarylation of unactivated alkenes enabled by the picolinamide auxiliary
Zheng et al. A Chiral Secondary Amine–Amidophosphane Precatalyst for Silver-Catalyzed Asymmetric 1, 3-Dipolar Cycloaddition Reactions
Zhao et al. Ru-catalyzed asymmetric hydrogenation of δ-keto Weinreb amides: enantioselective synthesis of (+)-Centrolobine
Kündig et al. Asymmetric Syntheses of 2‐(1‐Aminoethyl) phenols
CN112538033B (zh) 一种环芳烷类面手性化合物的拆分方法
JP6065259B2 (ja) 光学活性アミン類の製造方法
Zou et al. New bis (1-ferrocenylethyl) amine-derived monodentate phosphoramidite ligands for highly enantioselective copper-catalyzed 1, 4-conjugate addition
Shi et al. Axially dissymmetric (R)‐(+)‐5, 5′, 6, 6′, 7, 7′, 8, 8′ octahydro‐[1, 1′] binaphthyldiimine chiral salen type‐ligands for copper‐catalyzed asymmetric aziridination

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant