CN105085599A - Exemestane intermediate 17,17-ethyldioxy-6-methyleneandrost-1,4-diene-3-ketone and preparation method and application thereof - Google Patents
Exemestane intermediate 17,17-ethyldioxy-6-methyleneandrost-1,4-diene-3-ketone and preparation method and application thereof Download PDFInfo
- Publication number
- CN105085599A CN105085599A CN201410208236.4A CN201410208236A CN105085599A CN 105085599 A CN105085599 A CN 105085599A CN 201410208236 A CN201410208236 A CN 201410208236A CN 105085599 A CN105085599 A CN 105085599A
- Authority
- CN
- China
- Prior art keywords
- diene
- ketone
- exemestane
- methylenandrosta
- ethylenedioxy
- 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.)
- Pending
Links
- 0 CC(CC1)(C(CC2)[C@@](CC3)C1[C@@](C)(CC1)C3=CC1=O)C21OCC*1 Chemical compound CC(CC1)(C(CC2)[C@@](CC3)C1[C@@](C)(CC1)C3=CC1=O)C21OCC*1 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J21/005—Ketals
- C07J21/008—Ketals at position 17
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0003—Androstane derivatives
- C07J1/0011—Androstane derivatives substituted in position 17 by a keto group
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention discloses an exemestane intermediate 17,17-ethyldioxy-6-methyleneandrost-1,4-diene-3-ketone and its preparation method and application. Most existing methods have low overall yield and are not suitable for industrial production. The invention provides an exemestane intermediate 17,17-ethyldioxy-6-methyleneandrost-1,4-diene-3-ketone with a new structural formula. The preparation method comprises the following steps: firstly, dimethylamine hydrochloride and paraformaldehyde undergo reflux carrying water in isoamyl alcohol; and then, androstadienone ethylene glycol ketal is added to carry out an Mannich reaction so as to prepare 17,17-ethyldioxy-6-methyleneandrost-1,4-diene-3-ketone, and 17,17-ethyldioxy-6-methyleneandrost-1,4-diene-3-ketone is hydrolyzed to prepare exemestane. The method is simple and has industrial value.
Description
Technical field
The present invention relates to medicine intermediate field, specifically a kind of Exemestane intermediate 17,17-ethylenedioxy-6-methylenandrosta-Isosorbide-5-Nitrae-diene-3-ketone and its preparation method and application.
Background technology
Exemestane (exemestane), chemistry 6-methylene radical-androstane-Isosorbide-5-Nitrae-diene-3 by name, 17-diketone is s-generation aromatase inhibitor, and clinical application is in treatment metastatic breast cancer and the adjuvant therapy being used as breast carcinoma of early stage, determined curative effect, better tolerance, side effect is relatively less.Its synthetic method mainly contains two kinds:
1, with androstane-4-alkene-3,17-diketone (4) is raw material, first there is Mannich with dimethylamine hydrochloride and paraformaldehyde and react obtained 6-methylene compound (5), then obtain Exemestane (3) through the oxidizing Oxidative Dehydrogenation such as DDQ or tetrachlorobenzoquinone.Its synthetic route is as follows:
The method the first step yield is lower, and second step oxygenant large usage quantity, system are more complicated, and overall yield is lower, is not suitable for suitability for industrialized production.
2, with dehydrogenation Testosterone (6) for raw material, first there is Mannich with dimethylamine hydrochloride and paraformaldehyde and reacts and obtain 6-methylene radical dehydrogenation Testosterone (7), then obtain Exemestane (3) through Jones reagent oxidation.Its synthetic route is as follows:
The method raw material dehydrogenation Testosterone (6) costly, and Jones reagent price, is polluted large, and overall yield is lower, is not suitable for suitability for industrialized production.
Summary of the invention
Technical problem to be solved by this invention is the defect overcoming the existence of above-mentioned prior art, a kind of Exemestane intermediate 17 with new texture formula is provided, 17-ethylenedioxy-6-methylenandrosta-1,4-diene-3-ketone, its hydrolysis is utilized to prepare Exemestane, method is succinct, has industrial value.
The compound with new texture formula provided by the invention is Exemestane intermediate 17,17-ethylenedioxy-6-methylenandrosta-Isosorbide-5-Nitrae-diene-3-ketone (hereinafter referred to as the male dienone ethylene ketal of 6-methylene radical), and its structural formula is as follows:
The preparation method of the male dienone ethylene ketal of above-mentioned 6-methylene radical, its step is as follows:
First, reflux Dimethylammonium chloride and paraformaldehyde in primary isoamyl alcohol band water, then add male dienone ethylene ketal (2) and carry out male dienone ethylene ketal (1) of the obtained 6-methylene radical of Mannich reaction.Synthetic route is as follows:
In above-mentioned Mannich reaction, the molar weight of Dimethylammonium chloride is preferably 2 ~ 5 times of male dienone ethylene ketal molar weight; The molar weight that paraformaldehyde is scaled formaldehyde is 5 ~ 10 times of male dienone ethylene ketal molar weight, paraformaldehyde [HO (CH
2o)
nh, wherein n is the polymerization degree, n=10 ~ 100]; Mannich temperature of reaction preferably 130 ~ 150 DEG C.The male dienone ethylene ketal of raw material can by document (JournaloftheAmericanChemicalSociety; Vol.80; (1958); P3702) the method preparation in.
Present invention also offers the method that the male dienone ethylene ketal of application 6-methylene radical prepares Exemestane, its step is as follows:
By male for 6-methylene radical dienone ethylene ketal (1), acid catalyst, water and homogeneous solvent mixing, be hydrolyzed reaction, and obtain Exemestane (3), reaction scheme is as follows:
The acid catalyst that said hydrolyzed is reacted used is preferably sulfuric acid, tosic acid, trifluoroacetic acid, thionamic acid etc., and there is no particular restriction, and its consumption is preferably 5 ~ 10% of 6-methylene radical male dienone ethylene ketal quality; Described homogeneous solvent is preferably tetrahydrofuran (THF) or acetone, and its add-on is preferably 5 ~ 10 times of 6-methylene radical male dienone ethylene ketal quality; The consumption of water is preferably 1 ~ 3 times of 6-methylene radical male dienone ethylene ketal quality; Hydrolysising reacting temperature is preferably 10 ~ 35 DEG C.
The invention provides male dienone ethylene ketal of new compound 6-methylene radical and preparation method thereof, and can prepare Exemestane for raw material through an one-step hydrolysis with it, operational path is simple and direct, and raw material is easy to get, and cost is low, has industrial value.
Accompanying drawing explanation
Fig. 1 is the male dienone ethylene ketal of 6-methylene radical that the embodiment of the present invention 1 obtains
1hNMR spectrogram.
Fig. 2 is the male dienone ethylene ketal of 6-methylene radical that the embodiment of the present invention 1 obtains
13cNMR spectrogram.
Embodiment
Below in conjunction with embodiment, the invention will be further described.
The analytical instrument used in embodiment and equipment: gas chromatography mass spectrometry, MS5973N-GC6890N (Agilent company of the U.S.); Nuclear magnetic resonance analyser, AVANCEDMX II I 400M (marking in TMS, Bruker company); High performance liquid chromatograph: AgilentTechnologies1200Series; Infrared spectrometer, NICOLET360FT-IR (Buddhist nun's high-tensile strength instrument company of the U.S.).
Embodiment 1: the preparation of male dienone ethylene ketal (2)
Under nitrogen protection; successively by 28.4 gram 1; 4-AD (0.10mol), 14.4 grams of ethylene glycol (0.24mol), 0.4 gram of tosic acid (0.002mol) and 150 milliliters of toluene join in four mouthfuls of reaction flasks of 250 milliliters; reflux band water; high performance liquid chromatography tracing detection reacts, and reaction in about 12 hours terminates.Add 50 milliliters of aqueous solution containing 1 gram of sodium bicarbonate to neutralize, layering, reduce pressure after anhydrous magnesium sulfate drying decompression and solvent recovery, and ethyl alcohol recrystallization obtains light yellow crystal 30.2 grams, liquid content 99.1%, yield 91.2%.
Product structure is verified:
1HNMR(δ,ppm,400MHz,CDCl
3):7.062(d,J=10.0Hz,1H,CH=CH);6.315(d,J=10.0Hz,1H,CH=CH);6.070(s,1H,CH=C);3.817-3.925(m,4H,OCH
2CH
2O);2.457-2.470(m,1H);2.369-2.386(m,1H);1.975-1.992(m,2H);1.758-1.831(m,2H);1.570-1.697(m,4H);1.369-1.462(m,2H);1.282-1.327(m,1H);1.284(s,3H,CH
3);1.029-1.107(m,2H);0.918(s,3H,CH
3)。
13CNMR(δ,ppm,100MHz,CDCl
3):186.01;169.01;155.73;127.29;123.66;118.72;65.09;64.41;52.08;49.18;45.78;43.44;35.61;33.89;32.82;32.65;30.10;22.65;22.16;18.63;14.25。
The preparation of male dienone ethylene ketal (1) of embodiment 2:6-methylene radical
Under nitrogen protection; successively 3.0 grams of paraformaldehydes (0.10mol) (by formaldehyde conversion molar weight), 4.1 grams of dimethylamine hydrochlorides (0.05mol) and 150 milliliters of primary isoamyl alcohol are joined in four mouthfuls of reaction flasks of 250 milliliters, reflux band water 2 hours.Then 3.28 grams of male dienone ethylene ketals (0.01mol) are added, in 140 DEG C of insulated and stirred reactions, high performance liquid chromatography tracing detection reacts, and reaction in about 15 hours terminates, be cooled to room temperature, add 100 ml water washings, layering, decompression and solvent recovery after anhydrous magnesium sulfate drying, silica gel column chromatography (eluent: ethyl acetate: sherwood oil=4:6) obtains white solid 1.2 grams, liquid content 98.3%, yield 34.7%, fusing point 157 ~ 158 DEG C.
Product structure is verified:
1HNMR(δ,ppm,400MHz,CDCl
3):7.097(d,J=10.0Hz,1H,CH=CH);6.245(d,J=10.0Hz,1H,CH=CH);6.153(s,1H,CH=C);5.012,4.493(s,2H,C=CH
2);3.904-3.961(m,4H,OCH
2CH
2O);2.529(dd,J
1=13.2Hz,J
2=4.0Hz,1H);1.976-2.051(m,1H);1.794-1.888(m,3H);1.688-1.739(m,2H);1.587-1.677(m,2H);1.446-1.520(m,2H);1.244-1.389(m,2H);1.142(s,3H,CH
3);0.913(s,3H,CH
3)。
13CNMR(δ,ppm,100MHz,CDCl
3):186.62;167.98;154.66;145.91;127.58;122.49;118.87;111.93;65.27;64.57;49.66;45.88;43.82;39.83;35.96;34.01;30.12;22.64;22.18;19.69;14.36。
FT-IR(cm
-1):1656;1619;1311;1299;1273;1155。
Embodiment 3 ~ 8: male dienone ethylene ketal (1) of Mannich reaction preparation 6-methylene radical under different condition
Under nitrogen protection, successively paraformaldehyde, dimethylamine hydrochloride and 150ml primary isoamyl alcohol are joined in four mouthfuls of reaction flasks of 250 milliliters, reflux band water 2 hours.Then 3.28 grams of male dienone ethylene ketals (0.01mol) are added, stirring reaction under certain temperature, the reaction of high performance liquid chromatography tracing detection, to reacting end, is cooled to room temperature, add the washing of 100ml water, layering, decompression and solvent recovery after anhydrous magnesium sulfate drying, silica gel column chromatography (eluent: ethyl acetate: sherwood oil=4:6), weigh, survey liquid content, calculate productive rate, result is as following table.
Table 1: adopt different paraformaldehydes and dimethylamine hydrochloride consumption and differing temps to prepare, result is as follows:
The product nuclear magnetic data that embodiment 3 ~ 8 obtains is identical with embodiment 2.
Embodiment 9: the preparation of Exemestane (3)
Under nitrogen protection, successively by male for 3.4 grams of 6-methylene radical dienone ethylene ketal (1) (0.01mol), 0.1 gram of tosic acid and 20 grams of tetrahydrofuran (THF)s join in 100 milliliters of four-hole bottles, 10.0 grams of water are added dropwise to after stirring, in 20 ~ 25 DEG C of stirring reactions 10 hours, it is substantially complete that reaction followed the tracks of by high performance liquid chromatography, add 10 milliliters of aqueous solution containing 1 gram of sodium bicarbonate to neutralize, water pump decompression steams tetrahydrofuran (THF), then 20 milliliters of methylene dichloride are added, layering, organic layer is again with 10 milliliters of washings, decompression and solvent recovery after anhydrous magnesium sulfate drying, ethyl alcohol recrystallization obtains 2.80 grams, white Exemestane crystal, liquid-phase product content 99.3%, yield is 93.9%.
Product structure is verified:
1HNMR(δ,ppm,400MHz,CDCl
3):7.084(d,J=10.0Hz,1H,CH=CH);6.259(d,J=10.0Hz,1H,CH=CH);6.174(s,1H,CH=C);5.067,5.004(s,2H,C=CH
2);2.589-2.668(m,1H);2.465-2.535(m,1H);2.080-2.174(m,1H);1.890-2.302(m,5H);1.580-1.780(m,2H);1.294-1.398(m,3H);1.173(s,3H,CH
3);0.947(s,3H,CH
3)。
13CNMR(δ,ppm,100MHz,CDCl
3):219.56;186.21;167.24;154.08;145.23;127.69;122.63;112.40;50.66;49.80;47.56;43.60;39.15;35.56;35.20;31.06;21.95;21.75;19.66;13.76。
Embodiment 10 ~ 16: hydrolysis preparation Exemestane (3) under different condition
Under nitrogen protection; successively male for 1.7 grams of 6-methylene radical dienone ethylene ketal (1) (0.005mol), acid catalyst and solvent are joined in 100 milliliters of four-hole bottles; water is added dropwise to after stirring; stirring reaction under certain temperature; it is substantially complete that reaction followed the tracks of by high performance liquid chromatography; add 5 milliliters containing 0.1 gram of sodium bicarbonate aqueous solution neutralization; water pump decompression steams solvent; then 20 milliliters of methylene dichloride are added; layering; organic layer is again with 10 milliliters of washings, and after anhydrous magnesium sulfate drying, decompression and solvent recovery obtains Exemestane crude product.Weigh, survey liquid content, calculate productive rate, result is as following table.
Table 2: adopt different acid catalysts and different solvents, and regulate acid and water consumption, result is as follows:
The product nuclear magnetic spectrogram that embodiment 10 ~ 16 obtains is identical with embodiment 9.
Claims (12)
1. Exemestane intermediate 17,17-ethylenedioxy-6-methylenandrosta-Isosorbide-5-Nitrae-diene-3-ketone, its structural formula is as follows:
2. the preparation method of Exemestane intermediate 17,17-ethylenedioxy-6-methylenandrosta-Isosorbide-5-Nitrae-diene-3-ketone described in claim 1, its step is as follows:
First, reflux Dimethylammonium chloride and paraformaldehyde in primary isoamyl alcohol band water, then add male dienone ethylene ketal (2) and carry out obtained 17, the 17-ethylenedioxy-6-methylenandrosta-1 of Mannich reaction, 4-diene-3-ketone (1), synthetic route is as follows:
3. preparation method according to claim 2, is characterized in that, the molar weight of described Dimethylammonium chloride is 2 ~ 5 times of male dienone ethylene ketal molar weight.
4. preparation method according to claim 2, is characterized in that, the molar weight that described paraformaldehyde is scaled formaldehyde is 5 ~ 10 times of male dienone ethylene ketal molar weight.
5. preparation method according to claim 2, is characterized in that, described Mannich temperature of reaction is 130 ~ 150 DEG C.
6. described in claim 1, Exemestane intermediate 17,17-ethylenedioxy-6-methylenandrosta-Isosorbide-5-Nitrae-diene-3-ketone prepares the method for Exemestane, and its step is as follows:
By 17,17-ethylenedioxy-6-methylenandrosta-Isosorbide-5-Nitrae-diene-3-ketone (1), acid catalyst, water and homogeneous solvent mixing, be hydrolyzed reaction, and obtain Exemestane (3), reaction scheme is as follows:
。
7. method according to claim 6, is characterized in that, described acid catalyst is sulfuric acid, tosic acid, trifluoroacetic acid or thionamic acid.
8. method according to claim 6, is characterized in that, the consumption of described acid catalyst is 5 ~ 10% of 17,17-ethylenedioxy-6-methylenandrosta-Isosorbide-5-Nitrae-diene-3-ketone quality.
9. method according to claim 6, is characterized in that, described homogeneous solvent is tetrahydrofuran (THF) or acetone.
10. method according to claim 6, is characterized in that, the consumption of described homogeneous solvent is 5 ~ 10 times of 17,17-ethylenedioxy-6-methylenandrosta-Isosorbide-5-Nitrae-diene-3-ketone quality.
11. methods according to claim 6, is characterized in that, the consumption of described water is 1 ~ 3 times of 17,17-ethylenedioxy-6-methylenandrosta-Isosorbide-5-Nitrae-diene-3-ketone quality.
12. methods according to claim 6, is characterized in that, described hydrolysising reacting temperature is 10 ~ 35 DEG C.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201410208236.4A CN105085599A (en) | 2014-05-16 | 2014-05-16 | Exemestane intermediate 17,17-ethyldioxy-6-methyleneandrost-1,4-diene-3-ketone and preparation method and application thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201410208236.4A CN105085599A (en) | 2014-05-16 | 2014-05-16 | Exemestane intermediate 17,17-ethyldioxy-6-methyleneandrost-1,4-diene-3-ketone and preparation method and application thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
CN105085599A true CN105085599A (en) | 2015-11-25 |
Family
ID=54567001
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201410208236.4A Pending CN105085599A (en) | 2014-05-16 | 2014-05-16 | Exemestane intermediate 17,17-ethyldioxy-6-methyleneandrost-1,4-diene-3-ketone and preparation method and application thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN105085599A (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106243179A (en) * | 2016-07-31 | 2016-12-21 | 合肥远志医药科技开发有限公司 | A kind of exemestane industrialized preparing process |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4876045A (en) * | 1987-09-11 | 1989-10-24 | Farmitalia Carlo Erba S.R.L. | Process for the preparation of methylene derivatives of androsta-1,4-diene-3,17-dione |
US20080234505A1 (en) * | 2004-01-16 | 2008-09-25 | Cedarburg Pharmaceuticals, Inc | Exemestane and Its Intermediates and Methods of Making the Same |
WO2009093262A2 (en) * | 2008-01-21 | 2009-07-30 | Cadila Healthcare Limited | Process for preparing aromatase inhibitor exemestane |
US20110118488A1 (en) * | 2007-12-14 | 2011-05-19 | Crystal Pharma, S.A. | Process for obtaining 6-alkylidenandrost-1, 4-diene-3-one |
-
2014
- 2014-05-16 CN CN201410208236.4A patent/CN105085599A/en active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4876045A (en) * | 1987-09-11 | 1989-10-24 | Farmitalia Carlo Erba S.R.L. | Process for the preparation of methylene derivatives of androsta-1,4-diene-3,17-dione |
US20080234505A1 (en) * | 2004-01-16 | 2008-09-25 | Cedarburg Pharmaceuticals, Inc | Exemestane and Its Intermediates and Methods of Making the Same |
US20110118488A1 (en) * | 2007-12-14 | 2011-05-19 | Crystal Pharma, S.A. | Process for obtaining 6-alkylidenandrost-1, 4-diene-3-one |
WO2009093262A2 (en) * | 2008-01-21 | 2009-07-30 | Cadila Healthcare Limited | Process for preparing aromatase inhibitor exemestane |
Non-Patent Citations (1)
Title |
---|
L. KACZMAREK ET AL.: "Refined preparation of 1α,3-dipyrrolidino-androsta-3,5-diene-17-one, a key intermediate in the exemestane synthesis", 《PHARMAZIE》 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106243179A (en) * | 2016-07-31 | 2016-12-21 | 合肥远志医药科技开发有限公司 | A kind of exemestane industrialized preparing process |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN103641722A (en) | Production method for 2-nitrobenzyl bromide | |
CN114634482A (en) | Diazo difluoromethylation reagent and synthesis method and application thereof | |
CN104910104A (en) | Method for synthesizing dihydrofuran derivatives under catalytic action of copper | |
CN104326892A (en) | Synthetic method of indanone by gold-catalysis | |
CN105218540B (en) | A kind of preparation method of 3 thiocarbamoyl imidazoles of C simultaneously [1,2 a] pyridine compounds and their | |
CN105085599A (en) | Exemestane intermediate 17,17-ethyldioxy-6-methyleneandrost-1,4-diene-3-ketone and preparation method and application thereof | |
CN106892928A (en) | A kind of synthetic method of the carboxylate of 8 hydroxyl of the tert-butyl group, 5 oxa- 2 azaspiro [3.5] nonane 2 | |
Swift et al. | Tandem aza-Claisen rearrangement and ring-closing metathesis reactions: the stereoselective synthesis of functionalised carbocyclic amides | |
Yang et al. | Reaction of organozinc halides with aryl isocyanates | |
CN105294807A (en) | Exemestane intermediate oxime compound, and preparation method and application thereof | |
CN113173908B (en) | Preparation method of thiophene compound | |
CN105017370A (en) | Exemestane intermediate and preparation method therefor and application thereof | |
CN108383754B (en) | Preparation method and application of aryl oxime ester compound | |
CN102336763B (en) | Synthesis method for pyranocoumarin derivatives | |
CN106045827B (en) | A kind of preparation method of arylprop ketone compounds | |
CN103554074B (en) | Preparation method of 3-trifluoromethyl coumarin derivative | |
CN112724089B (en) | Synthesis process of 2-amino-3-bromo-6-chloropyrazine | |
CN106905098B (en) | A kind of synthetic method of neighbour's iodo alpha-acyloxy carbonyls | |
CN112125843B (en) | Preparation method of 3-hydroxymethyl-4-phenyl-3, 4-dihydroquinolinone compound | |
Luo et al. | A simple synthesis of octaphenylcyclotetra (siloxane) | |
CN110343047B (en) | Preparation method of aminopyrene compound | |
CN104829412B (en) | Method of preparing 1,3,5-triphenylbenzene with [beta]-methylchalcone as raw material | |
CN105801328A (en) | Preparation method of coronene | |
CN106967034A (en) | A kind of preparation method of 4H benzopyrans compounds | |
CN105712851B (en) | A kind of preparation method of the two arone compound containing betanaphthyl |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20151125 |
|
RJ01 | Rejection of invention patent application after publication |