CN101993383A - New method for synthesizing dronedarone key intermediate 4-(3-(dibutylamino) propoxy] methyl benzoates - Google Patents
New method for synthesizing dronedarone key intermediate 4-(3-(dibutylamino) propoxy] methyl benzoates Download PDFInfo
- Publication number
- CN101993383A CN101993383A CN2009101642673A CN200910164267A CN101993383A CN 101993383 A CN101993383 A CN 101993383A CN 2009101642673 A CN2009101642673 A CN 2009101642673A CN 200910164267 A CN200910164267 A CN 200910164267A CN 101993383 A CN101993383 A CN 101993383A
- Authority
- CN
- China
- Prior art keywords
- methyl
- propoxy
- reaction
- preferred
- equivalent
- 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
- LXCFILQKKLGQFO-UHFFFAOYSA-N COC(c(cc1)ccc1O)=O Chemical compound COC(c(cc1)ccc1O)=O LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 0 COC(c(cc1)ccc1OCCC*)=O Chemical compound COC(c(cc1)ccc1OCCC*)=O 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a new method for synthesizing a dronedarone key intermediate 4-(3-(dibutylamino) propoxy] methyl benzoates. The method comprises the following steps: 1, weighting methyl parahydroxybenzoats and 3-bromopropanol, weighting 1 to 2 moles of base catalyst, dissolving the methyl parahydroxybenzoats, the 3-bromopropanol and the base catalyst into organic solvent, and carrying out heating and backflow on the obtained mixture until the reaction is completed, wherein the molar ratio of the methyl parahydroxybenzoats to the 3-bromopropanol is 1: 1-2.5; 2, in the presence of an organic base as a catalyst, reacting the product obtained in step 1 with 1 to moles of mesyl chloride so as to obtain a product by the esterification of hydroxies by methanesulfonic acids; and 3, mixing the product obtained in step 2 with 2-4 moles of butyl amines in appropriate organic solvent, stirring the obtained mixture to react so as to obtain the target molecule 4-(3-(dibutylamino) propoxy] methyl benzoate. The invention has the advantages of reasonable route, simple process, low cost, easily-recycled solvent, and little environmental pollution.
Description
Technical field
The invention belongs to pharmacy synthesis technology field, specifically relate to a kind of synthetic 4-[3-(dibutylamino) propoxy-] method of methyl benzoate, this compound is the key intermediate of preparation Dronedarone.
Background information
Formula I, chemical name 4-[3-(dibutylamino) propoxy-] methyl benzoate is the key intermediate of preparation Dronedarone (Dronedarone).The chemistry of Dronedarone is called 2-butyl-3-(4-[3-(dibutylamino) propoxy-] benzoyl)-5-methylsulfonyl amido-cumarone (formula II), is released by the exploitation of Sanofi-Aventis company.Dronedarone is an antiarrhythmic drug of new generation, and molecular structure and amiodarone are similar, but does not contain iodine element, can avoid taking place the toxicity untoward reaction that produces because of the prolonged application amiodarone, is considered to safer than amiodarone, therefore promptly receives much concern beginning from research and development.
On July 2nd, 2009, FDA (U.S. food Drug Administration) approved Dronedarone (Dronedarone, trade(brand)name
) listing of 400mg tablet, be used for the treatment that the patient is pounced in atrial fibrillation and room,
Be first in U.S.'s approval listing, can effectively reduce the be in hospital medicine of risk of atrial fibrillation or auricular flutter patient cardiovascular event.Atrial fibrillation is kind of a disease that has potential life to threaten, and patient, medical and health organization and payer mechanism have been brought great burden.Because aging population, global atrial fibrillation sickness rate is constantly high, and becomes a new public health difficult problem.Atrial fibrillation patient's number of the U.S. reaches 2,500,000 people, and patient's number of European Union is especially up to 4,500,000 people.
Up till now, synthetic dronedarone key intermediate 4-[3-(dibutylamino) propoxy-that can look into] route of methyl benzoate has two.
Patent WO0248078 reported with methyl p-hydroxybenzoate in the presence of salt of wormwood with 3-(dibutylamino)-this key intermediate of chloropropane prepared in reaction, as shown below.
The weak point of this method is this reaction with N, and dinethylformamide (DMF) is a reaction medium, N, the dinethylformamide boiling point is higher, and the reaction back is difficult to distillation and removes, if do not remove N, dinethylformamide then produces considerable waste water, causes environmental pollution.
WO03040120 and Chinese patent CN101153012A have reported the route of other synthetic this key intermediate, and be as shown below.
WO03040120 is with 1, and the 3-dibromopropane is as alkylating reagent, and Chinese patent CN101153012A then uses 1-bromo-3-chloropropane as alkylating reagent.Although their used alkylating reagent is slightly different, but all inevitably a kind of reaction can take place in reaction process, that is exactly the alkylating reagent (1 of a part, 3-dibromopropane or 1-bromo-3-chloropropane) react with bimolecular methyl p-hydroxybenzoate, generate two substitution products, as shown below:
The generation of two substitution reactions has not only reduced reaction yield, wastes raw material, and the more important thing is to follow-up separation and purifying and has brought very big difficulty.The WO03040120 report, synthetic final product Dronedarone must be by the method separation and purification of column chromatography in this way.The dosage of Dronedarone is 400 milligrams, and this has just determined that the demand to the Dronedarone bulk drug is very large, and therefore, the method separation and purification Dronedarone by column chromatography is can not satisfy market far away to the demand of Dronedarone.
4-[3-(dibutylamino) propoxy-] methyl benzoate is the key intermediate of synthetic Dronedarone, solved preparation of industrialization 4-[3-(dibutylamino) propoxy-] problem of methyl benzoate, also just solved the bottleneck problem in a large amount of preparation Dronedarone technologies.Therefore, seek a kind of highly selective, easily handle synthetic 4-[3-(dibutylamino) propoxy-that cost is low] methyl benzoate is still very necessary.
Summary of the invention
The objective of the invention is to invent that a technology is simple, the route of strong operability, selectivity height, yield height, synthetic dronedarone key intermediate that cost is low.
Specifically, the present invention has provided a synthetic 4-[3-(dibutylamino) propoxy-] route of methyl benzoate.
Synthetic route of the present invention is as follows
The present invention has comprised following synthesis step:
A) methyl p-hydroxybenzoate with 3-bromo-1-propyl alcohol generation alkylated reaction, generates 4-(3-hydroxyl propoxy-) methyl benzoate under the mineral alkali effect;
B) reaction of hydroxyl on 4-(the 3-hydroxyl propoxy-) methyl benzoate and methylsulfonyl chloride generates methanesulfonates;
C) methanesulfonates is replaced back generation target compound 4-[3-(dibutylamino) propoxy-by Di-n-Butyl Amine] methyl benzoate.
In the alkylated reaction step, WO03040120 and Chinese patent CN101153012A adopt 1 respectively, 3-dibromopropane and 1-bromo-3-chloropropane are as alkylating reagent, these two kinds of alkylating reagents all inevitably can produce two substitution products, after reason just is carbon atom that is connected with bromine and the phenolic hydroxyl group generation alkylation in the methyl p-hydroxybenzoate in these two alkylating reagents, the carbon atom that another one is connected with bromine or chlorine also can with the phenolic hydroxyl group generation alkylation in the methyl p-hydroxybenzoate, and this reaction is bound to take place.
The present invention replaces 1 with hydroxyl, a halogen atom in 3-dibromopropane and the 1-bromo-3-chloropropane, thus can suppress the generation of two substitution reactions fully.On the other hand, replace 1 with 3-bromo-1-propyl alcohol, the consumption behind 3-dibromopropane and the 1-bromo-3-chloropropane also reduces greatly, is generally 1 to 2.5 equivalent and gets final product.
Mineral alkali that some are conventional such as yellow soda ash, salt of wormwood, sodium hydroxide, potassium hydroxide is this alkylated reaction of catalysis all, and the present invention selects salt of wormwood as this catalyst for reaction especially.Aspect catalyst consumption, the normal catalyst levels of 1-5 all can be good at this reaction of catalysis, and the present invention selects 1-2 equivalent catalyzer especially, preferred especially 1.1 equivalent catalyst levelss.
The solvent that is fit to the reaction of this step has N, dinethylformamide (DMF), methyl-sulphoxide, acetone, butanone, tetrahydrofuran (THF), toluene etc.
The reaction of this step can be carried out between the solvent refluxing temperature smoothly in room temperature, considers that from the angle of reaction efficiency preferred solvent reflux temperature of the present invention is as temperature of reaction.
In the reaction that generates methanesulfonates, the solvent that is fit to has methylene dichloride, chloroform, and toluene, tetrahydrofuran (THF), butanone etc., the preferred methylene dichloride of the present invention is as reaction solvent; The organic bases that can react in this step of catalysis has triethylamine, pyridine, and DMAP, N, the N-diisopropylethylamine, N-methylmorpholine, these organic basess both can use separately, also can mix use mutually.Aspect catalyst consumption, the normal catalyst levels of 1-3 all can be good at this reaction of catalysis, and the present invention selects 1-2 equivalent catalyzer especially, preferred especially 1.3 equivalent catalyst levelss.The temperature of reaction of this step all can fine carrying out between 0 ℃ to 40 ℃, the present invention preferred 20 ℃ to 25 ℃ as temperature of reaction.
In the substitution reaction of methanesulfonates, the solvent that is fit to has N, dinethylformamide (DMF), and methyl-sulphoxide, methylene dichloride, chloroform, toluene, tetrahydrofuran (THF), butanone etc., the preferred toluene of the present invention is as reaction solvent; In this substitution reaction, the consumption of Di-n-Butyl Amine all can well take place at the 1-10 equivalent, selects the 2-4 equivalent especially, preferred 3 normal Di-n-Butyl Amine substrates.Originally be reflected at room temperature and all can finely take place to reflux temperature, under the backflow situation, reaction is carried out fast, and by product is few, the yield height.
Specific embodiment
Embodiments of the invention given below are to explanation of the present invention rather than restriction.
Embodiment 1
4-(3-hydroxyl propoxy-) methyl benzoate
With methyl p-hydroxybenzoate 10 gram, 18.2 gram salt of wormwood, 200 milliliters of butanone and 27.4 gram bromopropyl alcohols join in 500 milliliters the single port bottle, and room temperature reaction spends the night.Reacting liquid filtering, filtrate decompression distillation concentrates, and adds 100 milliliters of ethyl acetate and 100 ml waters in the resistates, use anhydrous sodium sulfate drying after 100 milliliters of washings of organic layer water three times, concentrates to such an extent that solid phase prod 10.5 restrains yield: 76%.
Embodiment 2
4-(3-hydroxyl propoxy-) methyl benzoate
With methyl p-hydroxybenzoate 10 gram, 10 gram salt of wormwood, 200 milliliters of butanone and 27.4 gram bromopropyl alcohols join in 500 milliliters the single port bottle, and room temperature reaction spends the night.Reacting liquid filtering, filtrate decompression distillation concentrates, and adds 100 milliliters of ethyl acetate and 100 ml waters in the resistates, use anhydrous sodium sulfate drying after 100 milliliters of washings of organic layer water three times, concentrates to such an extent that solid phase prod 10.7 restrains yield: 77.8%.
Embodiment 3
4-(3-hydroxyl propoxy-) methyl benzoate
With methyl p-hydroxybenzoate 10 gram, 10 gram salt of wormwood, 200 milliliters of butanone and 27.4 gram bromopropyl alcohols join in 500 milliliters the single port bottle, and reaction solution refluxes 3 hours postcooling to room temperature.Reacting liquid filtering, filtrate decompression distillation concentrates, and adds 100 milliliters of ethyl acetate and 100 ml waters in the resistates, use anhydrous sodium sulfate drying after 100 milliliters of washings of organic layer water three times, concentrates to such an extent that solid phase prod 12.1 restrains yield: 87.6%.
Embodiment 4
4-(3-hydroxyl propoxy-) methyl benzoate
With methyl p-hydroxybenzoate 10 gram, 10 gram salt of wormwood, 200 milliliters of tetrahydrofuran (THF)s and 27.4 gram bromopropyl alcohols join in 500 milliliters the single port bottle, and reaction solution refluxes 5 hours postcooling to room temperature.Reacting liquid filtering, filtrate decompression distill and concentrate, and add 100 milliliters of ethyl acetate and 100 ml waters in the resistates, and three after drying of 100 milliliters of washings of organic layer water concentrate to such an extent that solid phase prod 12.4 restrains yield: 89.8%.
Embodiment 5
4-(3-methanesulfonyloxy group propoxy-) methyl benzoate
4-(3-hydroxyl propoxy-) methyl benzoate 14 is restrained in the there-necked flask that joins 200 milliliters, add 120 milliliters of methylene dichloride and 7.4 gram N-methylmorpholines.Under ice bath, drip 15.3 gram methylsulfonyl chlorides, drip off back 20 ℃ of reactions 1 hour.The underpressure distillation concentrated solvent, resistates obtains solid 14.4 grams, yield 75.7% with 20ml Virahol recrystallization.
Embodiment 6
4-(3-methanesulfonyloxy group propoxy-) methyl benzoate
To restrain in the there-necked flask that joins 200 milliliters (3-hydroxyl propoxy-) methyl benzoate 14, add 120 milliliters of methylene dichloride, and add N-methylmorpholine 14.5 grams.Under ice bath, drip methylsulfonyl chloride 15.3 grams, drip off back 20 ℃ of reactions 1 hour.The underpressure distillation concentrated solvent, resistates obtains solid 14.5 grams, yield 76% with 20ml Virahol recrystallization.
Embodiment 7
4-(3-methanesulfonyloxy group propoxy-) methyl benzoate
To restrain in the there-necked flask that joins 200 milliliters (3-hydroxyl propoxy-) methyl benzoate 14, add 120 milliliters of methylene dichloride, and add triethylamine 7.4 grams.Under ice bath, drip methylsulfonyl chloride 15.3 grams, drip off back 20 ℃ of reactions 1 hour.The underpressure distillation concentrated solvent, resistates obtains solid 14 grams, yield 74% with 20ml Virahol recrystallization.
Embodiment 8
To (3-methanesulfonyloxy group propoxy-) methyl benzoate
To restrain in the there-necked flask that joins 200 milliliters (3-hydroxyl propoxy-) methyl benzoate 14, add 120 milliliters of methylene dichloride, and add N-methylmorpholine 7.4 grams.Drip methylsulfonyl chloride 23 grams under ice bath, ice bath continued stirring reaction 6 hours down.The underpressure distillation concentrated solvent, resistates obtains solid 14.1 grams, yield 74% with 20ml Virahol recrystallization.
Embodiment 9
4-[3-(dibutylamino) propoxy-] methyl benzoate
To restrain in the there-necked flask that joins 500 milliliters (3-methanesulfonyloxy group propoxy-) methyl benzoate 10, add 200 milliliters of toluene, add Di-n-Butyl Amine 13.5 grams again, reaction mixture reflux 5 hours.Add 100 ml waters to reaction mixture, separatory, water layer are with 50 milliliters of ethyl acetate extractions, and separatory merges organic phase, and organic phase use dried over sodium sulfate with after the 100 ml waters washing three times, and the concentrated product 9 that obtains restrains yield 81%.
Embodiment 10
4-[3-(dibutylamino) propoxy-] methyl benzoate
To restrain in the there-necked flask that joins 500 milliliters (3-methanesulfonyloxy group propoxy-) methyl benzoate 10, add 200 milliliters of toluene, add Di-n-Butyl Amine 45 grams again, reaction mixture reflux 5 hours.Add 100 ml waters to reaction mixture, separatory, water layer are with 50 milliliters of ethyl acetate extractions, and separatory merges organic phase, and organic phase use dried over sodium sulfate with after the 100 ml waters washing three times, and the concentrated product 9.2 that obtains restrains yield 84%.
Claims (9)
1. a 4-[3-(dibutylamino) propoxy-] synthetic method of methyl benzoate.
Wherein comprise following reactions steps:
1) methyl p-hydroxybenzoate with 3-bromo-1-propyl alcohol generation alkylated reaction, generates 4-(3-hydroxyl propoxy-) methyl benzoate under the mineral alkali effect;
2) reaction of hydroxyl on 4-(the 3-hydroxyl propoxy-) methyl benzoate and methylsulfonyl chloride generates methanesulfonates;
3) methanesulfonates is replaced back generation target compound 4-[3-(dibutylamino) propoxy-by Di-n-Butyl Amine] methyl benzoate.
2. according to the method for claim 1,1) used mineral alkali is a yellow soda ash in the step, salt of wormwood, sodium hydroxide, potassium hydroxide, wherein preferred salt of wormwood.Catalyst consumption is the 1-5 equivalent, selects 1-2 equivalent catalyzer especially, preferred especially 1.1 equivalent catalyst levelss.
3. according to the method for claim 1,1) used solvent has N, dinethylformamide (DMF), methyl-sulphoxide, acetone, butanone, tetrahydrofuran (THF), toluene, wherein preferred butanone in the step.
4. according to the method for claim 1,1) selected temperature is that room temperature arrives reflux temperature in the step, wherein preferred reflux temperature.
5. according to the method for claim 1,2) in the step, selected solvent has methylene dichloride, chloroform, toluene, tetrahydrofuran (THF), butanone etc., the preferred methylene dichloride of the present invention is as reaction solvent.
6. according to the method for claim 1,2) in the step, need this reaction of organic base catalytic, selected organic bases has triethylamine, pyridine, DMAP, N, N-diisopropylethylamine, N-methylmorpholine.
7. according to the method for claim 6, these alkali promptly can use separately, and use also can cooperatively interact; Aspect catalyst consumption, the normal catalyst levels of 1-3 all can be good at this reaction of catalysis, and the present invention selects 1-2 equivalent catalyzer especially, preferred especially 1.3 equivalent catalyst levelss.
8. according to the method for claim 1,3) in the step, selected solvent has N, dinethylformamide (DMF), methyl-sulphoxide, methylene dichloride, chloroform, toluene, tetrahydrofuran (THF), butanone etc., the preferred toluene of the present invention is as reaction solvent.
9. according to the method for claim 1,3) in the step, the amount of selecting Di-n-Butyl Amine is selected the 2-4 equivalent, preferred 3 equivalents especially at the 1-10 equivalent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009101642673A CN101993383A (en) | 2009-08-26 | 2009-08-26 | New method for synthesizing dronedarone key intermediate 4-(3-(dibutylamino) propoxy] methyl benzoates |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009101642673A CN101993383A (en) | 2009-08-26 | 2009-08-26 | New method for synthesizing dronedarone key intermediate 4-(3-(dibutylamino) propoxy] methyl benzoates |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101993383A true CN101993383A (en) | 2011-03-30 |
Family
ID=43784204
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2009101642673A Pending CN101993383A (en) | 2009-08-26 | 2009-08-26 | New method for synthesizing dronedarone key intermediate 4-(3-(dibutylamino) propoxy] methyl benzoates |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101993383A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102349501A (en) * | 2011-08-19 | 2012-02-15 | 烟台爱德泰克光电材料有限公司 | Preparation method of 1-methylcyclopropene clathrate compound |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1925878A (en) * | 2004-02-13 | 2007-03-07 | 布里斯托尔-迈尔斯·斯奎布制药公司 | Contrast agents for myocardial perfusion imaging |
| CN101153012A (en) * | 2006-09-29 | 2008-04-02 | 北京德众万全药物技术开发有限公司 | Novel method of producing dronedarone key intermediate |
-
2009
- 2009-08-26 CN CN2009101642673A patent/CN101993383A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1925878A (en) * | 2004-02-13 | 2007-03-07 | 布里斯托尔-迈尔斯·斯奎布制药公司 | Contrast agents for myocardial perfusion imaging |
| CN101153012A (en) * | 2006-09-29 | 2008-04-02 | 北京德众万全药物技术开发有限公司 | Novel method of producing dronedarone key intermediate |
Non-Patent Citations (1)
| Title |
|---|
| VERN G.DEVRIES ET AL.: "Hypolipidemic Alkoxybenzoic Acids", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102349501A (en) * | 2011-08-19 | 2012-02-15 | 烟台爱德泰克光电材料有限公司 | Preparation method of 1-methylcyclopropene clathrate compound |
| CN102349501B (en) * | 2011-08-19 | 2013-11-20 | 烟台爱德泰克光电材料有限公司 | Preparation method of 1-methylcyclopropene clathrate compound |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101993427B (en) | New method for preparing Dronedarone | |
| CN102267985B (en) | The preparation method of vilazodone or its hydrochloride | |
| CN101153012B (en) | Novel method of producing dronedarone key intermediate | |
| CN102725258A (en) | Cyclohexane-1,4-dicarboxylates | |
| CN104974073B (en) | A kind of method for preparing Silodosin intermediate | |
| WO2019128983A1 (en) | Method for preparing elagolix intermediate and composition thereof | |
| CN105461704A (en) | Preparing method for brexpiprazole | |
| CN102471302A (en) | Preparation process of dronedarone and its salts | |
| CN101671242B (en) | Method for synthesizing trans-4-(trans-4'-alkyl cyclohexyl) cyclohexanal | |
| CN113214134B (en) | Synthesis method of quaternary carbon oxoindole skeleton | |
| CN101768148B (en) | New preparation method of hydrochloride landiolol | |
| CN101993383A (en) | New method for synthesizing dronedarone key intermediate 4-(3-(dibutylamino) propoxy] methyl benzoates | |
| CN103467445B (en) | Preparation method of alogliptin benzoate | |
| CN102863371B (en) | Fluoro pyrrolin or fluoro pyrroles | |
| CN101948455B (en) | Preparation method of 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran | |
| CN117510506A (en) | New preparation method of fezobactam | |
| CN104987325B (en) | A kind of preparation method of voriconazole | |
| CN102336676A (en) | New preparation method of dopexamine hydrochloride by ArCHR protection strategy | |
| CN111116493B (en) | Method for preparing Apabetalone, intermediate and preparation method of intermediate | |
| CN103896938B (en) | A kind of preparation method of succsinic acid YM-905 | |
| CN103709030A (en) | Environmentally-friendly preparation method of ciprofibrate | |
| CN113816914A (en) | Preparation method of lorazepam intermediate | |
| CN103275052A (en) | Method for synthesizing isoflavone by nickel-catalyzed Negishi cross coupling reaction at room temperature | |
| CN109232544B (en) | Preparation method of prucalopride | |
| CN101759666A (en) | Preparation method of pinaverium bromide |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C53 | Correction of patent of invention or patent application | ||
| CB02 | Change of applicant information |
Address after: 610041 Tianfu Life Science Park, No. 88 South Garden Road, Chengdu hi tech Zone, Sichuan, B6-1001 Applicant after: Chengdu Yinuo Dabo Pharmaceutical Technology Co., Ltd. Address before: No. 5 high tech Zone Gaopeng road in Chengdu city of Sichuan Province in 610064 Applicant before: Chengdu Yinuo Dabo Pharmaceutical Technology Co., Ltd. |
|
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20110330 |