CN104276935A - 4-(3-羟基丙氧基)-8-羟基-1-四氢萘酮及合成方法 - Google Patents
4-(3-羟基丙氧基)-8-羟基-1-四氢萘酮及合成方法 Download PDFInfo
- Publication number
- CN104276935A CN104276935A CN201410502170.XA CN201410502170A CN104276935A CN 104276935 A CN104276935 A CN 104276935A CN 201410502170 A CN201410502170 A CN 201410502170A CN 104276935 A CN104276935 A CN 104276935A
- Authority
- CN
- China
- Prior art keywords
- tetralone
- add
- alpha
- hydroxyl
- ethyl acetate
- 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
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/65—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/64—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of functional groups containing oxygen only in singly bound form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
- C07C67/29—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by introduction of oxygen-containing functional groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Abstract
本发明公开了4-(3-羟基丙氧基)-8-羟基-1-四氢萘酮及合成方法,4-(3-羟基丙氧基)-8-羟基-1-四氢萘酮是4,8-二羟基-1-四氢萘酮的衍生物,熔点413-415K,溶于水、乙醇、丙酮及氯仿,为外消旋体,具有显著抑制植物种子萌发和幼苗生长的作用。其合成方法工艺简单,产物纯度高,达到99.08%,反应总收率为19-24%。
Description
技术领域
本发明涉及4,8-二羟基-1-四氢萘酮的衍生物,具体涉及4-(3-羟基丙氧基)-8-羟基-1-四氢萘酮及合成方法。
背景技术
4,8-二羟基-1-四氢萘酮(4,8-DHT),化学名4,8-dihydroxy-1-tetralone,无色细簇针状结晶,其中4位与羟基相连的碳为一个手性碳,具有抗肿瘤、抗真菌、降血糖及免疫调节等作用。4,8-DHT的左旋对映体(–)被称为regiolone,右旋对映体(+)被称为isosclerone,4,8-DHT还有外消旋体。Regiolone最早是从青核桃中鉴定出的,可用于治疗皮肤瘙痒及痛等病症。Isosclerone最早是从Sclerotinia sclerotium中分离鉴定出,后来从一些真菌中也分离出了该化合物,它能引起葡萄灰色斑点病。山核桃中就发现外消旋体的4,8-DHT。
发明内容
本发明所要解决的技术问题是提供一种4-(3-羟基丙氧基)-8-羟基-1-四氢萘酮及合成方法,4-(3-羟基丙氧基)-8-羟基-1-四氢萘酮具有显著抑制植物种子萌发和幼苗生长的作用。
本发明解决上述技术问题所采用的技术方案为:4-(3-羟基丙氧基)-8-羟基-1-四氢萘酮,其分子式为C13H16O4,结构式为:熔点413-415K,溶于水、乙醇、丙酮及氯仿,为外消旋体,[α]20 D=±0°(c1.3,CH2Cl2)。
4-(3-羟基丙氧基)-8-羟基-1-四氢萘酮的合成方法,步骤如下:
(1)将0.54g4-苯甲酰酯基-8-羟基-1-四氢萘酮溶于15-18ml无水四氢呋喃,加入1.2当量的氢化钠,反应30min,再加入2.5当量的苄溴,升温至50℃反应5h,氯化铵 淬灭反应,减压浓缩至干,体积比1:1的乙酸乙酯和水混合液45-60ml萃取,有机相用50-75ml饱和食盐水除盐,50g无水硫酸钠除水后,减压浓缩至干,与300-400目硅胶(重量比)1:1混匀,过200-300目硅胶柱,1:6-8的乙酸乙酯:石油醚洗脱,得到:4-苯甲酰基-8-苯甲氧基-1-四氢萘酮,其分子式为C24H20O4;
(2)将上述C24H20O4溶于10-12ml甲醇,加入1当量的碳酸铯,室温下反应2h,除去甲醇,每次用15-20ml乙酸乙酯萃取,共萃取三次,合并萃取液,加35ml饱和食盐水除盐,减压浓缩至干,与300-400目硅胶(重量比)1:1混匀,过200-300目硅胶柱,1:5的乙酸乙酯:石油醚洗脱,得到:4-羟基-8-苯甲氧基-1-四氢萘酮,其分子式为C17H16O3;
(3)将上述C17H16O3溶于12-15ml无水四氢呋喃,加入1当量的氢化钠,室温下反应30min,加入三溴丙醇,升温至50℃反应5h,氯化铵淬灭反应,减压浓缩至干,体积比1:1的乙酸乙酯和水混合液25ml萃取,有机相用30-45ml饱和食盐水除盐,45-60g无水硫酸钠除水后,减压浓缩至干,得到:4-(3-羟基苯氧基)-8-苯甲氧基-1-四氢萘酮,其分子式为C20H22O4;
(4)将上述C20H22O4溶于12-15ml甲醇,加入0.1当量的钯碳,反应4h,除去甲醇,每次用20-25ml乙酸乙酯萃取,共萃取三次,合并萃取液,加35-50ml饱和食盐水除盐,减压浓缩至干,与300-400目硅胶(重量比)1:1混匀,过200-300目硅胶柱,乙酸乙酯洗脱,得到4-(3-羟基丙氧基)-8-羟基-1-四氢萘酮无色针状晶体。采用高效液相色谱法测定该无色针状晶体,其纯度达到99.08%。反应总收率为19-24%。
与现有技术相比,本发明的优点在于4-(3-羟基丙氧基)-8-羟基-1-四氢萘酮及合成方法,4-(3-羟基丙氧基)-8-羟基-1-四氢萘酮是4,8-二羟基-1-四氢萘酮的衍生物,熔点413-415K,溶于水、乙醇、丙酮及氯仿,为外消旋体,具有显著抑制植物种子萌发和幼苗生长的作用。其合成方法工艺简单,产物纯度高,达到99.08%,反应总收率为19-24%。
附图说明
图1为本发明的合成示意图。
具体实施方式
以下结合附图实施例对本发明作进一步详细描述。
实施例1
一种以4,8-二苯甲酰酯基-1-四氢萘酮为原料合成外消旋4-(3-羟基丙氧基)-8-羟基 -1-四氢萘酮的方法:(1)将0.54g4-苯甲酰酯基-8-羟基-1-四氢萘酮溶于15-18ml无水四氢呋喃,加入1.2当量的氢化钠,反应30min,再加入2.5当量的苄溴,升温至50℃反应5h,氯化铵淬灭反应,减压浓缩至干,体积比1:1的乙酸乙酯和水混合液45-60ml萃取,有机相用50-75ml饱和食盐水除盐,50g无水硫酸钠除水后,减压浓缩至干,与300-400目硅胶(重量比)1:1混匀,过200-300目硅胶柱,1:6-8的乙酸乙酯:石油醚洗脱,得到:4-苯甲酰基-8-苯甲氧基-1-四氢萘酮,其分子式为C24H20O4;
(2)将上述C24H20O4溶于10-12ml甲醇,加入1当量的碳酸铯,室温下反应2h,除去甲醇,每次用15-20ml乙酸乙酯萃取,共萃取三次,合并萃取液,加35ml饱和食盐水除盐,减压浓缩至干,与300-400目硅胶(重量比)1:1混匀,过200-300目硅胶柱,1:5的乙酸乙酯:石油醚洗脱,得到:4-羟基-8-苯甲氧基-1-四氢萘酮,其分子式为C17H16O3;
(3)将上述C17H16O3溶于12-15ml无水四氢呋喃,加入1当量的氢化钠,室温下反应30min,加入三溴丙醇,升温至50℃反应5h,氯化铵淬灭反应,减压浓缩至干,体积比1:1的乙酸乙酯和水混合液25ml萃取,有机相用30-45ml饱和食盐水除盐,45-60g无水硫酸钠除水后,减压浓缩至干,得到:4-(3-羟基苯氧基)-8-苯甲氧基-1-四氢萘酮,其分子式为C20H22O4;
(4)将上述C20H22O4溶于12-15ml甲醇,加入0.1当量的钯碳,反应4h,除去甲醇,每次用20-25ml乙酸乙酯萃取,共萃取三次,合并萃取液,加35-50ml饱和食盐水除盐,减压浓缩至干,与300-400目硅胶(重量比)1:1混匀,过200-300目硅胶柱,乙酸乙酯洗脱,得到4-(3-羟基丙氧基)-8-羟基-1-四氢萘酮无色针状晶体。采用高效液相色谱法测定该无色针状晶体,其纯度达到99.08%。其熔点413-415K,溶于水、乙醇、丙酮及氯仿,为外消旋体,[α]20 D=±0°(c1.3,CH2Cl2)。
实施例2
将获得的4-(3-羟基丙氧基)-8-羟基-1-四氢萘酮配置成0.01mM、0.05mM、0.1mM和0.5mM的处理液作对莴苣种子萌发抑制实验,取100粒测试物种种子均匀摆放在铺有两层滤纸、大小15×20cm发芽盒,加10ml不同浓度处理液(对照组为去离子水),每个处理设置3个重复。培养条件为光周期25℃,12h;暗周期15℃,12h。种子萌发以胚根突破种皮为标准,第四天和第七天记录莴苣种子发芽数。0.01m处理液可以使莴苣种子发芽势降低80%,发芽率降低85%;0.05mM、0.1mM和0.5mM处理液种子不 发芽。用0.01mM、0.05mM、0.1mM和0.5mM的处理液作对莴苣实生苗生长抑制实验,取胚根突破种皮种子100粒均匀摆放在铺有两层滤纸、大小15×20cm发芽盒,加入10ml不同浓度处理液(对照组为去离子水),每个处理设置3个重复。培养条件为光周期25℃,12h;暗周期15℃,12h。每隔一天从发芽盒中随机取5粒种子测其胚根、胚芽长度及鲜重,共测6次。0.01m处理液可以使莴苣实生苗胚根长度降低81%、胚芽长度降低65%、鲜重降低75%,0.05mM、0.1mM和0.5mM处理液实生苗无生长迹象。
实施例3
将获得的4-(3-羟基丙氧基)-8-羟基-1-四氢萘酮配置成0.01mM、0.05mM、0.1mM和0.5mM的处理液作对萝卜种子萌发抑制实验,取100粒测试物种种子均匀摆放在铺有两层滤纸、大小15×20cm发芽盒,加10ml不同浓度处理液(对照组为去离子水),每个处理设置3个重复。培养条件为光周期25℃,12h;暗周期15℃,12h。种子萌发以胚根突破种皮为标准,第四天和第十天记录萝卜种子发芽数。0.01m处理液可以使萝卜种子发芽势降低69%,发芽率降低70%;0.1mM、0.5mM处理种子不发芽。用0.01mM、0.05mM、0.1mM和0.5mM的处理液作对萝卜实生苗生长抑制实验,取胚根突破种皮种子100粒均匀摆放在铺有两层滤纸、大小15×20cm发芽盒,加入10ml不同浓度处理液(对照组为去离子水),每个处理设置3个重复。培养条件为光周期25℃,12h;暗周期15℃,12h。每隔一天从发芽盒中随机取5粒种子测其胚根、胚芽长度及鲜重,共测6次。0.01m处理液可以使萝卜实生苗胚根长度降低71%、胚芽长度降低56%、鲜重降低66%;0.1mM、0.5mM处理实生苗无生长迹象。
实施例4
将获得的4-(3-羟基丙氧基)-8-羟基-1-四氢萘酮配置成0.01mM、0.05mM、0.1mM和0.5mM的处理液作对黄瓜种子萌发抑制实验,取100粒测试物种种子均匀摆放在铺有两层滤纸、大小15×20cm发芽盒,加10ml不同浓度处理液(对照组为去离子水),每个处理设置3个重复。培养条件为光周期25℃,12h;暗周期15℃,12h。种子萌发以胚根突破种皮为标准,第四天和第八天记录黄瓜种子发芽数。0.01m处理液种子发芽势降低40%,种子发芽率降低36%;0.5mM处理种子不发芽。用0.01mM、0.05mM、0.1mM和0.5mM的处理液作对黄瓜实生苗生长抑制实验,取胚根突破种皮种子100粒均匀摆放在铺有两层滤纸、大小15×20cm发芽盒,加入10ml不同浓度处理液(对照组为去离子水),每个处理设置3个重复。培养条件为光周期25℃,12h;暗周期15℃, 12h。每隔一天从发芽盒中随机取5粒种子测其胚根、胚芽长度及鲜重,共测6次。0.01m处理液胚根长度降低47%、胚芽长度降低36%、鲜重降低49%,0.5mM处理实生苗无生长迹象。
Claims (2)
1.4-(3-羟基丙氧基)-8-羟基-1-四氢萘酮,其特征在于分子式为C13H16O4,结构式为:熔点413-415K,溶于水、乙醇、丙酮及氯仿,为外消旋体。
2.权利要求1所述的4-(3-羟基丙氧基)-8-羟基-1-四氢萘酮的合成方法,其特征在于步骤如下:
(1)将0.54 g4-苯甲酰酯基-8-羟基-1-四氢萘酮溶于15-18ml无水四氢呋喃,加入1.2当量的氢化钠,反应30min,再加入2.5当量的苄溴,升温至50℃反应5h,氯化铵淬灭反应,减压浓缩至干,体积比1:1的乙酸乙酯和水混合液45-60ml萃取,有机相用50-75ml饱和食盐水除盐,50g无水硫酸钠除水后,减压浓缩至干,与300-400目硅胶(重量比)1:1混匀,过200-300目硅胶柱,1:6-8的乙酸乙酯:石油醚洗脱,得到:4-苯甲酰基-8-苯甲氧基-1-四氢萘酮,其分子式为C24H20O4;
(2)将上述C24H20O4溶于10-12ml甲醇,加入1当量的碳酸铯,室温下反应2h,除去甲醇,每次用15-20ml乙酸乙酯萃取,共萃取三次,合并萃取液,加35ml饱和食盐水除盐,减压浓缩至干,与300-400目硅胶(重量比)1:1混匀,过200-300目硅胶柱,1:5的乙酸乙酯:石油醚洗脱,得到:4-羟基-8-苯甲氧基-1-四氢萘酮,其分子式为C17H16O3;
(3)将上述C17H16O3溶于12-15ml无水四氢呋喃,加入1当量的氢化钠,室温下反应30min,加入三溴丙醇,升温至50℃反应5h,氯化铵淬灭反应,减压浓缩至干,体积比1:1的乙酸乙酯和水混合液25ml萃取,有机相用30-45ml饱和食盐水除盐,45-60g无水硫酸钠除水后,减压浓缩至干,得到:4-(3-羟基苯氧基)-8-苯甲氧基-1-四氢萘酮,其分子式为C20H22O4;
(4)将上述C20H22O4溶于12-15ml甲醇,加入0.1当量的钯碳,反应4h,除去甲醇,每次用20-25ml乙酸乙酯萃取,共萃取三次,合并萃取液,加35-50ml饱和食盐水除盐,减压浓缩至干,与300-400目硅胶(重量比)1:1混匀,过200-300目硅胶柱,乙酸乙酯洗脱,得到4-(3-羟基丙氧基)-8-羟基-1-四氢萘酮无色针状晶体。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201410502170.XA CN104276935B (zh) | 2014-09-26 | 2014-09-26 | 4-(3-羟基丙氧基)-8-羟基-1-四氢萘酮及合成方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201410502170.XA CN104276935B (zh) | 2014-09-26 | 2014-09-26 | 4-(3-羟基丙氧基)-8-羟基-1-四氢萘酮及合成方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN104276935A true CN104276935A (zh) | 2015-01-14 |
CN104276935B CN104276935B (zh) | 2016-05-04 |
Family
ID=52252343
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201410502170.XA Active CN104276935B (zh) | 2014-09-26 | 2014-09-26 | 4-(3-羟基丙氧基)-8-羟基-1-四氢萘酮及合成方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN104276935B (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104649879A (zh) * | 2015-02-06 | 2015-05-27 | 中国人民解放军第二军医大学 | 取代苯亚甲基四氢萘酮类衍生物及制备方法、应用 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB949295A (en) * | 1961-12-27 | 1964-02-12 | Roussel Uclaf | Improvements in or relating to the preparation of certain substituted tetralones, and the compounds thus produced |
CN1108248A (zh) * | 1993-07-22 | 1995-09-13 | 伊莱利利公司 | 糖蛋白IIb/IIIa拮抗剂 |
WO2004089300A2 (en) * | 2003-04-04 | 2004-10-21 | Pharmacyclics, Inc. | Sapphyrins and uses thereof |
WO2005108345A1 (en) * | 2004-05-10 | 2005-11-17 | National Research Council Of Canada | Synthesis and biological activity or novel bicyclic aba analogs |
CN103435472A (zh) * | 2013-08-30 | 2013-12-11 | 中国农业大学 | 一类高活性苯并异脱落酸类似物及其制备方法 |
-
2014
- 2014-09-26 CN CN201410502170.XA patent/CN104276935B/zh active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB949295A (en) * | 1961-12-27 | 1964-02-12 | Roussel Uclaf | Improvements in or relating to the preparation of certain substituted tetralones, and the compounds thus produced |
CN1108248A (zh) * | 1993-07-22 | 1995-09-13 | 伊莱利利公司 | 糖蛋白IIb/IIIa拮抗剂 |
WO2004089300A2 (en) * | 2003-04-04 | 2004-10-21 | Pharmacyclics, Inc. | Sapphyrins and uses thereof |
WO2005108345A1 (en) * | 2004-05-10 | 2005-11-17 | National Research Council Of Canada | Synthesis and biological activity or novel bicyclic aba analogs |
CN103435472A (zh) * | 2013-08-30 | 2013-12-11 | 中国农业大学 | 一类高活性苯并异脱落酸类似物及其制备方法 |
Non-Patent Citations (1)
Title |
---|
ALEXANDER A. BREDIKHIN ET AL: "Systematic search for conglomerates among glycerol aromatic monoethers: guaifenesin and mephenesin are the cases", 《MENDELEEV COMMUNICATIONS》, vol. 13, no. 3, 31 December 2003 (2003-12-31), pages 104 - 105, XP 022541381, DOI: doi:10.1070/MC2003v013n03ABEH001752 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104649879A (zh) * | 2015-02-06 | 2015-05-27 | 中国人民解放军第二军医大学 | 取代苯亚甲基四氢萘酮类衍生物及制备方法、应用 |
Also Published As
Publication number | Publication date |
---|---|
CN104276935B (zh) | 2016-05-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN105541643B (zh) | 一种可聚合有机胺阳离子水化页岩抑制剂的制备方法 | |
RU2010133160A (ru) | Способ синтеза тетрагидробиоптерина | |
CN105168649A (zh) | 一种从大叶藻中提取黄酮类化合物的方法 | |
Satishkumar et al. | A convenient method for the synthesis and resolution of Tröger base | |
CN104276935A (zh) | 4-(3-羟基丙氧基)-8-羟基-1-四氢萘酮及合成方法 | |
CN104311597A (zh) | 一种磷酸左奥硝唑酯二钠的工业化生产方法 | |
CN103804386A (zh) | 4,5-二羟基-3-h-螺[呋喃-2,3’-吲哚]-2’-酮衍生物及其合成方法和应用 | |
CN104370713B (zh) | 4-(2,3-二羟基丙氧基)-8-羟基-1-四氢萘酮及合成方法 | |
CN104355980B (zh) | 4-羟基-8-(3-羟基丙氧基)-1-四氢萘酮及合成方法 | |
CN106132207A (zh) | (s)‑3’‑甲基‑脱落酸及其酯 | |
CN104355979A (zh) | 4-羟基-8-(2,3-二羟基丙氧基)-1-四氢萘酮及合成方法 | |
CN104326889A (zh) | 乙二醇二-8-(4-羟基-1-四氢萘酮)醚及合成方法 | |
CN107383006A (zh) | 独龙乌头中分离的新型c19‑二萜生物碱制备方法及其用途 | |
CN104478974B (zh) | 一种20,23-二哌啶基-5-o-碳霉胺糖基-泰乐内酯的合成方法 | |
CN103664782A (zh) | 异紫堇碱衍生物及其制备方法和应用 | |
CN115974797A (zh) | 1,5-双取代(4-f)苄基-3-脱氢枞基-1,2,4-***、其制备方法及其应用 | |
CN107162907B (zh) | 调环酸钙和抗倒酯的合成方法 | |
CN102746347B (zh) | 一种阳离子烷基糖苷的提纯方法 | |
CN103497155A (zh) | (+)-4-(2,3-二羟基丙基)-甲酰胺-6-氮杂苯并蒽酮及其合成方法和应用 | |
CN105693660B (zh) | Jaspine B、3‑epi Jaspine B氧代类似物、其制备方法及应用 | |
CN103467373B (zh) | 一种喹啉类化合物的合成方法 | |
CN103450314B (zh) | 具有抗肿瘤活性的植物提取物及其活性成分 | |
CN105085321B (zh) | 一种n‑甲氧羰基‑l‑叔亮氨酸的制备方法 | |
CN115353500B (zh) | 具有独脚金内酯活性的肉桂酰胺内酯类化合物及其制备与应用 | |
CN103875327B (zh) | 一种喜树种子发芽方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant |