CN113214149B - 苯基(喹啉-8-基)甲酮衍生物的合成方法 - Google Patents

苯基(喹啉-8-基)甲酮衍生物的合成方法 Download PDF

Info

Publication number
CN113214149B
CN113214149B CN202110342877.9A CN202110342877A CN113214149B CN 113214149 B CN113214149 B CN 113214149B CN 202110342877 A CN202110342877 A CN 202110342877A CN 113214149 B CN113214149 B CN 113214149B
Authority
CN
China
Prior art keywords
quinoline
methylquinoline
nmr
cdcl
phenyl
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.)
Active
Application number
CN202110342877.9A
Other languages
English (en)
Other versions
CN113214149A (zh
Inventor
王文蓉
李团结
成立
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.)
Jiangsu Normal University
Original Assignee
Jiangsu Normal University
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 Jiangsu Normal University filed Critical Jiangsu Normal University
Publication of CN113214149A publication Critical patent/CN113214149A/zh
Application granted granted Critical
Publication of CN113214149B publication Critical patent/CN113214149B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/18—Halogen atoms or nitro radicals

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

苯基(喹啉‑8‑基)甲酮衍生物的合成方法，是以8‑甲基喹啉或取代8‑甲基喹啉和芳基碘代物为原料，Ag2CO3为添加剂，KOAc为碱，Pd(OAc)2为催化剂，在六氟异丙醇和冰醋酸按体积比3:7混合的溶液中反应，130℃下封管反应24小时生成目标产物。合成工艺路线简捷，最高收率达到87％。

Description

苯基(喹啉-8-基)甲酮衍生物的合成方法
技术领域
本发明属于有机合成技术领域，涉及醋酸钯(Pd(OAc)2)催化8-甲基喹啉或取代8-甲基喹啉与芳基碘反应合成8-苯甲酰基喹啉衍生物的方法。
背景技术
8-苯甲酰基喹啉及其衍生物是一类重要的喹啉类有机分子，这些含有8-苯甲酰基喹啉结构单元的化合物不仅能够用于重要功能喹啉衍生物的合成(Wentzel,M.T.；Reddy,V.J.；Hyster, T.K.；Douglas,C.J.Chemoselectivity in Catalytic C-C and C-H BondActivation:Controlling Intermolecular Carboacylation and Hydroarylation ofAlkenes.Angew.Chem.Int.Ed.2009,48, 6121-6123；Dreis,A.M.；Douglas,C.J.CatalyticCarbon-Carbonσ-Bond Activation:An Intramolecular Carbo-Acylation Reactionwith Acylquinolines.J.Am.Chem.Soc.2009,131,412 -413.)，而且还有许多该类分子表现出重要的生物活性，如具可作为微管蛋白阻聚剂(Nien,C. -Y.；Chen,Y.-C.；Kuo,C.-C.；Hsieh,H.-P.；Chang,C.-Y.；Wu,J.-S.；Wu,S.-Y.；Liou,J.-P.； Chang,J.-Y.5-Amino-2-Aroylquinolines as Highly Potent Tubulin Polymerization Inhibitors.J.Med.Chem.2010,53,2309-2313.)，治疗骨代谢紊乱(Teruo,O.；Shigeki,S.；Takayuki,I.；Yasuji, U.；Tatsuya,Y.；Noriko,Y.Jpn.Kokai Tokkyo Koho JP H10291988A,1998.)，大麻素受体的配体 (Thomas,B.C.；James,C.A.；Karol,D.E.；Ulrich,S.WO Patent 02/42248A2,2002.)，治疗溃疡 (Yasuo,O.；Juji,N.；Haruki,T.；Naokatsu,S.；Hiroshi,K.；Shunei,Y.；Akio,I.Jpn.Kokai Tokkyo Koho JP H07173138A,1995.)和用作抗癌试剂(Diaz,P.；Horne,E.；Xu,C.；Hamel,E.； Wagenbach,M.；Petrov,R.R.；Uhlenbruck,B.；Haas,B.；Hothi,P.；Wordeman,L.；Gussio,R.； Stella,N.Modified carbazolesdestabilize microtubules and kill glioblastoma multiform cells. EuropeanJ.Med.Chem.2018,159,74-89.)等。由于该类有机分子独特的结构和重要的生物活性，寻找更为高效的合成8-苯甲酰基喹啉及其衍生物的方法称为有机化学和药物学家重要研究内容之一。目前主要的方法是在金属Rh或Ru等催化下以8-甲酰基喹啉如8-喹啉甲醛，8-喹啉甲酸酯，8-乙酰基喹啉等为原料合成8-苯甲酰基喹啉及其衍生物，但这些方法所用的金属催化剂和原料都相对价格较高，而且不易得。因此，发展催化剂和原料相对廉价的合成反应实现8-苯甲酰基喹啉及其衍生物的生成具有重要的工业应用前景。
发明内容
本发明的目的在于提供一种高效合成8-苯甲酰基喹啉及其衍生物的方法：以8-甲基喹啉或取代8-甲基喹啉和芳基碘代物为原料，Ag2CO3为添加剂，KOAc为碱，Pd(OAc)2为催化剂，在六氟异丙醇(Hexafluoroisopropanol,HFIP)和冰醋酸按体积比3:7混合的溶液中反应，130℃下封管反应24小时生成目标产物。
本发明通过下述方法实现的：在带有磁力搅拌子的10mL耐压管中加入0.1毫摩尔的8- 甲基喹啉或8-甲基喹啉衍生物、0.15毫摩尔的芳基碘，0.01毫摩尔的醋酸钯，0.15毫摩尔的碳酸银，0.12毫摩尔的醋酸钾，再加入1mL六氟异丙醇和冰醋酸的混合溶液(V/V＝3:7)，封管，在130℃下加热反应24小时，即得到相应的8-苯甲酰基喹啉衍生物。
所述的8-甲基喹啉或取代8-甲基喹啉和芳基碘代物为起始原料，催化体系为Pd(OAc)2和 Ag2CO3为组合催化剂，反应溶剂为六氟异丙醇(Hexafluoroisopropanol,HFIP)和冰醋酸的混合溶剂。
本发明具有以下优点：
本发明在合成8-苯甲酰基喹啉衍生物时采用价格相对低廉的醋酸钯为催化剂，8-甲基喹啉或取代8-甲基喹啉为起始原料，操作简便，产率高。
具体实施方式
Figure BDA0002999787120000021
实施例1
4-(喹啉-8-甲酰基)苯甲酸甲酯制备：在装有磁力搅拌子的10mL耐压管中加入8-甲基喹啉(0.1mmol)，4-碘苯甲酸甲酯(0.15mmol)，0.01毫摩尔的醋酸钯，0.15毫摩尔的碳酸银，0.12 毫摩尔的醋酸钾，再加入1mL六氟异丙醇和冰醋酸的混合溶液(V/V＝3:7)，封管，在130℃下加热反应24小时，将反应混合液加入30mL乙酸乙酯中稀释，然后用饱和碳酸钠溶液洗涤，分离出的有机层用无水硫酸镁干燥，过滤除去硫酸镁，得到粗产品的有机溶液通过减压旋蒸除去溶剂，残留物经柱层析纯化得到目标产物(淋洗剂V/V：石油醚:乙酸乙酯＝8:1).
实施例2
4-(5-溴喹啉-8-甲酰基)苯甲酸甲酯制备：在装有磁力搅拌子的10mL耐压管中加入5-溴 8-甲基喹啉(0.1mmol)，4-碘苯甲酸甲酯(0.15mmol)，0.01毫摩尔的醋酸钯，0.15毫摩尔的碳酸银，0.12毫摩尔的醋酸钾，再加入1mL六氟异丙醇和冰醋酸的混合溶液(V/V＝3:7)，封管，在130℃下加热反应24小时，将反应混合液加入30mL乙酸乙酯中稀释，然后用饱和碳酸钠溶液洗涤，分离出的有机层用无水硫酸镁干燥，过滤除去硫酸镁，得到粗产品的有机溶液通过减压旋蒸除去溶剂，残留物经柱层析纯化得到目标产物(淋洗剂V/V：石油醚:乙酸乙酯＝8:1).
实施例3-10
实施例3-0与实施例1、2类似，各实施例的反应原料，反应条件及产率见下表1。
表1实施例1-10的反应原料，反应条件及产率
Figure BDA0002999787120000031
由表1可知，本发明的方法原料易得，操作简单安全，收率高，后处理方便，因而具有极大的实施价值和潜在社会经济效益。
所得化合物的的表征数据如下。
4-(喹啉-8-甲酰基)苯甲酸甲酯(3a)
1H NMR(400MHz,CDCl3)δ8.83(dd,J＝4.4Hz,1.6Hz,1H),8.26(dd,J＝8.4Hz,1.6Hz, 1H),8.08-8.06(m,2H),8.01(dd,J＝8.2Hz,1.4Hz,1H),7.88-7.86(m,2H),7.80(dd,J＝7.0 Hz,1.4Hz,1H),7.67(dd,J＝8.0Hz,7.2Hz,1H),7.45(dd,J＝8.0,4.0Hz,1H),3.93(s,3H)；13C{1H}NMR(100MHz,CDCl3)δ197.3,166.3,150.8,145.7,141.1,138.4,136.4,133.7,130.3, 129.9,129.5,128.9,128.2,126.1,121.8,52.4；IR(KBr)(v,cm-1)1723,1673,1574,1495,1435, 1405,1318,1274,1210,1106,1017,930,817,797,781,761,728；HRMS(APCI-TOF)m/z:[M+ Na]+Calcd for C18H13NO3Na 314.0788；Found 314.0783.
(4-氯苯基)(喹啉-8-甲酰基)甲酮(3b)
1H NMR(400MHz,CDCl3)δ8.83(dd,J＝4.0Hz,1.6Hz,1H),8.23(dd,J＝8.4Hz,1.6Hz, 1H),7.98(dd,J＝8.0Hz,1.2Hz,1H),7.78-7.74(m,3H),7.64(dd,J＝8.0,7.2Hz,1H),7.43(dd, J＝8.4,4.0Hz,1H),7.39-7.36(m,2H)；13C{1H}NMR(100MHz,CDCl3)δ196.8,150.9,146.0, 139.7,138.8,136.2,136.1,131.5,130.0,128.6,128.5,128.3,126.0,121.7；IR(KBr)(v,cm-1)1655, 1585,1571,1495,1388,1319,1278,1177,928,854,839；HRMS(APCI-TOF)m/z:[M+H]+Calcd for C16H11ClNO 268.0524；Found 268.0529.
(4-硝基苯基)(喹啉-8-基)甲酮(3c).
1H NMR(400MHz,CDCl3)δ8.76(dd,J＝4.4,2.0Hz,1H),8.26-8.23(m,3H),8.04(dd,J＝ 8.4,1.6Hz,1H),7.95-7.92(m,2H),7.84(dd,J＝7.2,1.6Hz,1H),7.69(dd,J＝8.0,7.2Hz,1H), 7.45(dd,J＝8.4,4.4Hz,1H)；13C{1H}NMR(100MHz,CDCl3)δ196.5,150.8,150.1,146.0,142.8, 137.9,136.2,130.9,130.8,129.2,128.2,126.2,123.5,121.9；IR(KBr)(v,cm-1)1658,1510,1496, 1345,1319,1282,931,823,800,724,710,；HRMS(APCI-TOF)m/z:[M+Na]+Calcd for C16H10N2O3Na 301.0584；Found 301.0582.
喹啉-8-基(对甲基苯基)甲酮(3d)
1H NMR(400MHz,CDCl3)δ8.85(dd,J＝4.0,1.6Hz,1H),8.21(dd,J＝8.4,1.6Hz,1H), 7.95(dd,J＝8.4,1.2Hz,1H),7.75-7.71(m,3H),7.60(t,J＝7.6Hz,1H),7.41(dd,J＝8.4,4.4 Hz,1H),7.21(d,J＝8.0Hz,2H),2.40(s,3H)；13C{1H}NMR(100MHz,CDCl3)δ197.5,150.8, 146.1,144.2,139.6,136.0,135.3,130.4,129.5,129.1,128.2,128.1,125.8,121.6,21.7；IR(KBr)(v, cm-1)1662,1603,1574,1496,1319,1297,1218,1182,929,825,799,762,605；HRMS(APCI-TOF) m/z:[M+Na]+Calcd for C17H13NONa 270.0889；
苯基(喹啉-8-基)甲酮(3e)
1H NMR(400MHz,CDCl3)δ8.84(dd,J＝4.0,1.6Hz,1H),8.21(dd,J＝8.4,1.6Hz,1H), 7.96(dd,J＝8.0,1.2Hz,1H),7.85-7.83(m,2H),7.74(dd,J＝7.6,1.6Hz,1H),7.63(dd,J＝8.0, 3.2Hz,1H),7.55(t,J＝7.4Hz,1H),7.43-7.39(m,3H)；13C{1H}NMR(100MHz,CDCl3)δ197.9, 150.9,146.1,139.3,137.7,136.0,133.3,130.2,129.7,128.3,128.3,128.2,125.9,121.7；IR(KBr)(v, cm-1)1672,1593,1574,1448,1319,1278,1212,928,823,796,689,623；HRMS(APCI-TOF)m/z: [M+Na]+Calcd for C16H11NONa 256.0733；
3-(喹啉-8-甲酰基)苯甲醛(3f)
1H NMR(400MHz,CDCl3)δ9.99(s,1H),8.78(dd,J＝4.4,2.0Hz,1H),8.25-8.22(m,2H),8.10-8.06(m,2H),7.99(dd,J＝8.4,1.2Hz,1H),7.79(dd,J＝7.2,1.2Hz,1H),7.68-7.64 (m,1H),7.59(t,J＝7.6Hz,1H),7.42(dd,J＝8.4,4.4Hz,1H)；13C{1H}NMR(100MHz,CDCl3)δ 196.9,191.5,150.9,146.0,138.8,138.4,136.4,136.1,135.5,133.1,131.7,130.4,129.2,128.7,128.2, 126.0,121.8；IR(KBr)(v,cm-1)1700,1670,1494,1457,1377,1280,1177,1141,722；HRMS (APCI-TOF)m/z:[M+Na]+Calcd for C17H11NO2Na 284.0682；Found 284.0662.
(4-甲氧基-3-甲基苯基)(喹啉-8-基)甲酮(3g)
1H NMR(400MHz,CDCl3)δ8.86(dd,J＝4.0,1.6Hz,1H),8.20(dd,J＝8.4,1.6Hz,1H),7.93 (dd,J＝8.0,1.2Hz,1H),7.75(d,J＝1.6Hz,1H),7.70(dd,J＝6.8,1.6Hz,1H),7.63-7.59(m, 2H),7.40(dd,J＝8.4,4.4Hz,1H),6.77(d,J＝8.4Hz,1H),3.86(s,3H),2.19(s,3H)；13C{1H}NMR (100MHz,DMSO-d6)δ196.8,162.2,150.9,146.1,139.8,136.1,132.5,131.1,130.4,129.3,128.3, 128.0,126.8,125.9,121.6,109.1,77.4,77.1,76.8,55.6,16.3；IR(KBr)(v,cm-1)1654,1598,1573, 1494,1457,1440,1317,1289,1175,1026,966,828,790；HRMS(APCI-TOF)m/z:[M+Na]+ Calcd for C18H15NO2Na 300.0995；Found300.0981.
(3,4-二甲基苯基)(喹啉-8-基)甲酮(3h).
1H NMR(400MHz,CDCl3)δ8.85(dd,J＝4.4,2.0Hz,1H),8.20(dd,J＝8.0,1.6Hz,1H), 7.94(dd,J＝8.0,1.6Hz,1H),7.72-7.70(m,2H),7.61(dd,J＝8.0,7.2Hz,1H),7.48(dd,J＝8.0, 1.6Hz,1H),7.40(dd,J＝4.4,4.0Hz,1H),7.14(d,J＝8.0Hz,1H),2.30(s,3H),2.26(s,3H)；13C{1H}NMR(100MHz,CDCl3)δ197.7,150.8,146.1,143.0,139.6,136.7,136.0,135.6,130.9, 129.6,129.4,128.4,128.2,128.0,125.8,121.5,20.1,19.7；IR(KBr)(v,cm-1)1655,1602,1576, 1407,1316,1290,1272,1204,1177,1124,961,869,832,799,789,761；HRMS(APCI-TOF)m/z: [M+Na]+Calcd for C18H15NONa 284.1046；Found284.1041.
4-(5-溴喹啉-8-甲酰基)苯甲酸甲酯(3i).
1H NMR(400MHz,CDCl3)δ8.80(dd,J＝1.6Hz,J＝4.2Hz,1H),8.61(dd,J＝1.6Hz,J＝ 8.6Hz,1H),8.06(d,J＝8.5Hz,2H),7.96(d,J＝7.6Hz,1H),7.83(d,J＝8.5Hz,2H),7.65(d,J＝ 7.6Hz,1H),7.53(q,J＝4.4Hz,1H),3.93(s,3H)；13C{1H}NMR(100MHz,CDCl3)δ196.6,166.3, 151.4,146.7,141.1,138.6,135.6,133.9,129.9,129.9,129.6,128.8,127.7,124.5,122.9,52.5；IR (KBr)(v,cm-1)1723,1660,1562,1490,1281,1191,1037,935,872,795,688；HRMS(APCI-TOF) m/z:[M+Na]+Calcd for C18H12BrNO3Na 391.9893；Found391.9882.
4-(7-溴喹啉-8-甲酰基)苯甲酸甲酯(3j).
1H NMR(400MHz,CDCl3)δ8.81(d,J＝2.8Hz,1H),8.22(d,J＝8.0Hz,1H),8.09(d,J＝ 8.0Hz,2H),7.89(d,,J＝8.4Hz,2H),7.84(d,J＝8.8Hz,1H),7.77(d,J＝8.8Hz,2H),7.46(dd,J＝8.0,3.6Hz,1H),3.93(s,3H)；13C{1H}NMR(100MHz,CDCl3)δ195.3,166.2,151.5,146.6, 139.4,139.0,136.5,134,3,130.8,130.0,129.9,129.7,127.0,122.0,120.6,52.5；IR(KBr)(v,cm-1) 1722,1685,1272,1251,1222,1102,919,819,725；HRMS(APCI-TOF)m/z:[M+Na]+Calcd for C18H12BrNO3Na 391.9893；Found 391.9908。

Claims (2)

1.苯基(喹啉-8-基)甲酮衍生物的合成方法，其特征在于，包括：8-甲基喹啉或取代8-甲基喹啉和芳基碘代物在添加剂、碱、催化剂存在下于有机溶剂中反应得目标产物；
所述添加剂是Ag2CO3；
所述碱是KOAc；
4所述催化剂是Pd(OAc)2；
所述有机溶剂是六氟异丙醇和冰醋酸的混合物；
所述六氟异丙醇与冰醋酸的体积比是3:7。
2.根据权利要求1所述的方法，其特征在于，所述反应是在130℃中封管反应24小时。
CN202110342877.9A 2021-03-03 2021-03-30 苯基(喹啉-8-基)甲酮衍生物的合成方法 Active CN113214149B (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202110236244 2021-03-03
CN202110236244X 2021-03-03

Publications (2)

Publication Number Publication Date
CN113214149A CN113214149A (zh) 2021-08-06
CN113214149B true CN113214149B (zh) 2022-08-02

Family

ID=77086066

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202110342877.9A Active CN113214149B (zh) 2021-03-03 2021-03-30 苯基(喹啉-8-基)甲酮衍生物的合成方法

Country Status (1)

Country Link
CN (1) CN113214149B (zh)

Also Published As

Publication number Publication date
CN113214149A (zh) 2021-08-06

Similar Documents

Publication Publication Date Title
CN106892935B (zh) 一种壳聚糖固载铜催化制备有机硼化合物的方法及应用
CN108101733B (zh) 钌催化氟代芳酮与二苯乙炔反应制备多芳取代萘衍生物的方法
CN110483252B (zh) 一种不对称三芳基甲烷衍生物的合成方法
Sato et al. Synthesis of Biaryls via Palladium‐Catalyzed [2+ 2+ 2] Cocyclization of Arynes and Diynes: Application to the Synthesis of Arylnaphthalene Lignans
CN107522751A (zh) 一种高位阻手性二茂铁p,n,n配体及制备方法与应用
CN111808071A (zh) 一种铑催化吡啶与炔烃环化合成多取代氨基异喹啉化合物的方法
CN113666883B (zh) 一种合成4-乙烯基异噁唑衍生物的方法
CN102391154B (zh) 一种α-羟基-β-氨基酮衍生物及其合成方法和应用
CN113214149B (zh) 苯基(喹啉-8-基)甲酮衍生物的合成方法
CN105949118A (zh) 一种2-芳基喹啉衍生物的制备方法
CN109553633B (zh) 一种苯乙酸类型芳炔的制备方法
CN109776488B (zh) 一种邻位醛基的α-酮酰胺类化合物的合成方法
CN112500339A (zh) 一种8-酰基喹啉衍生物的合成方法
CN111718262B (zh) 一种9-羟基芴-9-羧酸酯类化合物的简易制备方法
CN106977545B (zh) 一种3-芳甲酰基二氟亚甲基烯丙基膦酸酯及其合成方法
CN115504946B (zh) 一种合成α-酮酰胺化合物的方法
CN115108979B (zh) 一种8-羟基喹啉衍生物的制备方法
CN115010649B (zh) 一种C-N轴手性苯并[c]咔唑类化合物及其合成方法
CN114195753B (zh) 一种钌催化一锅法制备3,4-二苯基异香豆素衍生物的制备方法
CN109776610A (zh) 基于苯乙胺骨架的手性p,n,n配体类化合物及制备方法与应用
CN111635437B (zh) 一种含邻位碳硼烷基苯并咪唑结构的钯配合物及其制备方法与应用
CN110746278B (zh) 一种非金属催化的基于炔酮制备1,3-二酮类化合物的方法
CN117229200A (zh) 一种钌催化合成酰氧基化2-苯甲酰吡啶类化合物的方法
CN118206512A (zh) 一种3-炔基苯并呋喃化合物的制备方法
CN105384708B (zh) 一种（s）‑（+）‑1‑（2‑哌啶苯基）‑3‑甲基正丁胺的制备方法

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