CN102040649A - Synthesis process for preparing steride 6-fluorine with NFOBS (N-Fluoro-Ortho-Benzenedisulfonimide) or NBSI fluorinating agent - Google Patents

Synthesis process for preparing steride 6-fluorine with NFOBS (N-Fluoro-Ortho-Benzenedisulfonimide) or NBSI fluorinating agent Download PDF

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CN102040649A
CN102040649A CN2009100709021A CN200910070902A CN102040649A CN 102040649 A CN102040649 A CN 102040649A CN 2009100709021 A CN2009100709021 A CN 2009100709021A CN 200910070902 A CN200910070902 A CN 200910070902A CN 102040649 A CN102040649 A CN 102040649A
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孙亮
陈松
赵琳
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Tianjin Jinyao Group Co Ltd
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Abstract

The invention relates to a synthesis process for preparing steride 6-fluorine with NFOB (N-Fluoro-Ortho-Benzenedisulfonimide) or NBSI fluorinating agent. In the process, a compound in a formula (II) and a fluorinating agent react in an organic solvent to get a compound (I), wherein R1=H, halogen or OH; R2=H, alpha-OH, or acyloxy of alpha-C1-5; R3=H, OH, or alpha, beta C1-3 alkyl; R2, R3=alpha epoxy and double bonds; 15, 16 are 15-position C and 16-position C in a steroidring; M and Q are respectively H or alkyl of 1 to 6 C, such as methyl and cyclohexyl; the M and the Q can also be five-membered or six-membered heterocyclic rings with one O or N heteroatom, such as furan, pyridine, piperidine and the like; R4=H, or alpha and beta hydroxyl; R5=H or alpha halogen; R4 and R5=beta epoxy and double bonds; R6= H or alkyl of 1 to 4 C, and a serpentine curve in a molecular formula is represented as substituent alpha or beta; and a full line and a dotted line between position 1 and position 2 are single bond or double bonds.

Description

A kind of NFOBS of use or NBSI fluorizating agent prepare six fluorine-based synthesis techniques of steroidal
Technical field:
The present invention relates to a kind of steroidal six fluorine-based synthesis techniques, especially this technology of preparing requires less to the molecular structure of steroidal.
Background technology:
Introducing 6 α F in the structure of cortin can obviously increase antiphlogistic effect, and many cortins commonly used all have the structure of 6 α F, and as fluocinolone acetonide, Vecort, fluticasone etc., but owing to be optical isomer, it is synthetic to have bigger difficulty.
Many in history scientists have carried out multinomial research in this respect, have obtained certain achievement.Since the sixties in last century, scientist just obtains steroid 6 α F material by various synthetic methods.
At epicortisol is in the 6 α F synthesis techniques of initiator, Li Yuhua etc. (Li Yuhua, Liu Qiming, Lin Peining, etc. flaorination process improved during fluocinonide was synthetic. Chinese Journal of Pharmaceuticals, 1982; 13 (4): 19~20) factors such as temperature, pH value of solution, polarity of solvent of reaction are carried out condition optimizing, make the yield of compound 7 bring up to 92% by 85%.(Li Jinlu such as Li Jinlu, Wang Fujun, Fu Xizhen. the producing and manufacturing technique .CN1361110 of fluocinonide 6 α F, 2002) analyzed perchloryl fluoride by producing F+ carries out electrophilic addition to C6 reaction mechanism, as strong oxidizer, easily make the C6 oxidation generate 6 hydroxyls or keto compounds at perchloryl fluoride, and perchloryl fluoride chance water easily produce perchloric acid, make system pH reduce the shortcoming that the influence reaction is carried out, in system, add the Na of (40~70) % 2HPO 4Damping fluid stablized system pH, thereby the yield and the quality that have improved have reduced the content of impurity.Money is defended the country etc., and (money is defended the country, Hou Wei. the producing and manufacturing technique .CN1683388A of fluocinolone acetonide intermediate 6 α F, 2005) on the basis of Li Jinlu, further improve, the NaHCO3 damping fluid that adds (10~50) % in system comes the pH of maintenance system, reaction can be carried out under weakly alkaline, after reaction finishes, also added simultaneously 15% sodium sulfite aqueous solution and destroyed the strong oxidizer sodium perchlorate that generates.
Sun Changan etc. (Sun Changan, Wang Lianzheng, Duan Fenghui. the reform of fluocinonide intermediate " 9 α-fluorine thing " production technique, Chinese Journal of Pharmaceuticals, 1983; 14 (7): 5~7) proposing can first transposition, and the step of back bromine hydroxyl epoxy addition generation compound 10 is adjusted into transposition open loop behind the first bromine hydroxyl epoxy.Because the β epoxy that forms has increased the sterically hindered of steroid nucleus β-position earlier, the fluorine atom that helps 6 transfers alpha-position to by steroid nucleus β-position, thereby the transposition productive rate is improved.In addition, hydrogenchloride/haloform reaction system that transposition is used can be changed into hydrogen fluoride/dimethyl formamide, thereby makes transposition, hydrogen fluoride open loop two-step reaction become " one kettle way " and shorten reactions steps.
When the steroid 6 position produces β position F, can be converted to 6 α F by novel transposition reagent, early stage transposition is typically chosen in uses hydrochloric acid or potassium hydroxide to carry out in the appropriate organic solvent, and reaction conditions is violent, easily epoxy, ester group etc. in the system is impacted.
Da Col reports (Da Col M.A process for the preparation of 6 α-fluoro steroids.WO2003082896A2,2003) when initiator be pure 6 beta comfiguration things or at high proportion when 6 β and 6 αYi Gouti mixtures, in non-protonic solvent, use organic bases DBU or DBN as transposition reagent, mild condition, do not influence responsive functional group, 6 α of product/6 beta comfiguration ratios were greater than 90: 10.
The used fluorination reagent of fluoridation is a perchloryl fluoride, and it is a kind of explosivity and corrosive hazardous agents, and operational requirement is strict and need the long reaction times, has potential safety hazard.Novel and the safe fluorination reagent of one class such as Selectfluor etc. have appearred in the beginning of the nineties, their F that can dissociate +Ion carries out close electric attack to the negative electricity center in the system.Initial these fluorination reagents are widely used in the fluoridizing of nonsteroidal compound that aromatic nucleus, alkene, enol ether etc. have electrophilic center.
Yu Di tiger (Chinese patent 200310109243.0) report in 2003 use Selectfluor to contain 9 β, the steroid derivative of 11 beta epoxides is carried out 6 α-fluoridation, can save a direct step of translocation reaction to obtain content and be higher than 6 α-fluorine isomer of 90%.2008, Liu Caitian etc. (CN101250213A) are with 9 β, 11 beta epoxides-3 β, 17 α, 21-trihydroxy-pregnant steroid-3,5-diene-3,17,21-three esters are raw material, go up the reaction of 6-fluorine with Selectfluor, add buffered soln in reaction system, strict controlling reaction time and temperature of reaction obtain high-load 6 α-fluorochemical.This method makes reaction system be in the safe condition of stable and controllable all the time, has avoided making the explosive and corrosive perchloryl fluoride of apparatus.The step of transposition has been removed in the use of novel fluorination reagent from, and a direct step obtains 6 α configuration products, and impurity is few, productive rate is high.
But Selectfluor is because structure is special, and its manufacturing cost is higher, costs an arm and a leg, and is subjected to great restriction in course of industrialization.
Figure B2009100709021D0000021
a.X 1=X 2=OSO 2CF 3;b.X 1=X 2=HSO 4
c.X 1=HSO 4,X 2=F(HF) 2;d.X 1=X 2=BF 4
e.X 1=X 2=SbF 6;f.X 1=X 2=PF 6
N-fluoro-O-benzene disulfonyl imines (III-1, NFOBS, CAS:1344-80-5) and N-fluorine two benzenesulfonimide (III-2, NFSI, CAS:133745-75-2) be a class new fluorinating agent, be used for that compound is carried out close electricity and fluoridize, but also do not adopt fluorizating agent (III-1) at present, (III-2) carry out 6 α position fluorizated report to steroidal compounds.
Figure B2009100709021D0000022
(III-1) (III-2) Ph is a phenyl
Summary of the invention:
By test, the discovery that we are surprised, fluorizating agent (III-1), (III-2) and (II) compound reaction, can in structure, introduce 6 α F effectively, the synthetic difficulty of fluorizating agent (III-1), (III-2) is less simultaneously, and its cost is lower, is convenient to realize the industrialization use.
A kind of preparation method of steroid 6 α fluorine is to react in organic solvent with formula (II) compound and fluorizating agent (III-1), (III-2) to obtain compound (I):
Figure B2009100709021D0000031
Wherein, R 1=H, halogen, OH, or C 1-5Acyloxy.
R 2=H, α-OH, or α-C 1-5Acyloxy.
R 3=H, OH, or α, β C 1-3Alkyl.
R 2, R 3=α epoxy, or two key,
15,16 is the carbon of 15,16 of cyclopentanoperhydro-phenanthrenes
Wherein M, Q are respectively the alkyl of H or 1 to 6 carbon, for example methyl, cyclohexyl; M, Q can also be the heterocycle that contains an O or heteroatomic five-ring of N or six-ring such as furans, pyridine, piperidines etc.;
R 4=H, α, β hydroxyl,
R 5=H or α halogen,
R 4, R 5=α epoxy, two key,
R 6The alkyl of=H or 1 to 4 carbon,
Serpentine in the molecular formula is expressed as substituents alpha, β all can; Real between 1,2, dotted line is singly-bound or two key;
Above-claimed cpd (I) and each substituting group of compound (II) are preferred:
R 1=H, halogen or C 1-5Acyloxy,
R 2=α-OH or α-C 1-5Acyloxy,
R 3=H or α, β methyl.
R 2, R 3=α epoxy, two key,
R 4=H, α, β hydroxyl,
R 5=H or α halogen,
R 4, R 5=α epoxy, two key,
R 6The alkyl of=1 to 4 carbon.
Above-claimed cpd (I) and each substituting group of compound (II) be more preferably:
R 1=H or C 1-5Acyloxy,
R 2=α-OH,
R 3=H or α, β methyl.
R 2, R 3=α epoxy, two key,
R 4=α hydroxyl,
R 5=H,
R 4, R 5=α epoxy, two key,
R 6The alkyl of=1 to 4 carbon.
Above-claimed cpd (I) and each substituting group of compound (II) are further preferred:
R 1=H or C 1-5Acyloxy,
R 2=α-OH,
R 3=H or α, β methyl.
R 2, R 3=α epoxy, two key,
R 4=α hydroxyl,
R 5=H,
R 4, R 5=α epoxy,
R 6=methyl.
Above-claimed cpd (I) and each substituting group of compound (II) are further preferred:
R 1=H,
R 2=α-OH,
R 3=H or α, β methyl.
R 2, R 3=α epoxy, two key,
R 4=α hydroxyl,
R 5=H,
R 4, R 5=α epoxy,
R 6=methyl.
Especially R 1Be difficult for producing side reaction during the compound during=H (II) reaction, than R 1=halogen, OH or C 1-5Acyloxy the time preferably should the reaction.
Fluorizating agent can be selected from one or more among (III-1), (III-2).
Figure B2009100709021D0000041
Organic solvent in the above-mentioned reaction comprises one or more in the ether of methane amide, a 2-5 carbon of alcohol, a 1-4 carbon of nitrile, a 1-4 carbon of the ketone that contains enpara, a 3-6 carbon, a 1-3 carbon of 1-3 carbon of the liquid state under the temperature of reaction;
Preferably include chloroform, the methylene dichloride, 1 of the liquid state under the temperature of reaction, 2-ethylene dichloride, acetone, mibk, acetonitrile, methyl alcohol, ethanol, methane amide, N, dinethylformamide, ether, tetrahydrofuran (THF), 1, one or more in the 4-dioxane;
The chloroform, methylene dichloride, acetone, acetonitrile, methyl alcohol, ethanol, the N that more preferably comprise the liquid state under the temperature of reaction, dinethylformamide, ether, tetrahydrofuran (THF), 1, one or more in the 4-dioxane;
Further preferably include chloroform, methylene dichloride, acetone, acetonitrile, methyl alcohol, ethanol, the N of the liquid state under the temperature of reaction, dinethylformamide, ether, tetrahydrofuran (THF), 1, one or more in the 4-dioxane;
Further preferably include in the chloroform, methylene dichloride, acetone, acetonitrile, methyl alcohol, ethanol, tetrahydrofuran (THF) of the liquid state under the temperature of reaction one or more;
Further preferably include a kind of in the chloroform of the liquid state under the temperature of reaction or methylene dichloride and methyl alcohol or alcoholic acid mixture, the tetrahydrofuran (THF) again;
Most preferably comprise a kind of in the chloroform of the liquid state under the temperature of reaction or methylene dichloride and methanol mixture, the tetrahydrofuran (THF).
Add alkali in the last handling process of above-mentioned reaction, preferred organic bases, more preferably ammoniacal liquor, pyridine, triethylamine.
Feed nitrogen or argon gas in the process of reaction.
The reaction process temperature be-20 the degree to 60 the degree, be preferably-20 the degree to 40 the degree.
Its Chinese style (II) compound can obtain with corresponding ester reaction by through type (IV), this synthetic method be for the scientific research personnel known, for example Chinese patent 200310109243.0 is mentioned by isopropenyl acetate and is obtained the formula that R6 is a methyl (II) compound, and same EP1207166 has also carried out similarly synthetic.
Figure B2009100709021D0000051
Embodiment:
The raw material that is that belongs to formula (II) compound in following examples molecular formula, what belong to formula (I) compound is the 6F thing.
Embodiment 1
Figure B2009100709021D0000052
Add the 0.2mol raw material in reaction flask, add 400ml N, dinethylformamide stirs and feeds nitrogen down, cool to-10 degree, add NFOBS 0.24mol, react after 5 hours, utilize triethylamine to regulate PH and be neutrality, in frozen water, filtration drying gets the 0.187mol product with solution dilution.
Embodiment 2
Figure B2009100709021D0000061
In reaction flask, add the 0.2mol raw material, add 450ml chloroform, carbinol mixture (chloroform/methanol=2/8, v/v), stir down and feed nitrogen, cool to 10 degree, add NFSI 0.22mol, react after 2 hours, solution dilution in frozen water, is utilized ammoniacal liquor to regulate PH and is neutrality, stirred 10 minutes, use 200ml chloroform extraction twice again, combined chloroform layer concentrating under reduced pressure utilizes recrystallizing methanol, the freezing and filtering drying gets 0.179mol 6F thing.
Embodiment 3
Figure B2009100709021D0000062
In reaction flask, add the 0.2mol raw material, add the 250ml acetonitrile, stir and feed argon gas down, controlled temperature to 0 degree adds NFOBS 0.25mol, reacts after 2 hours, with solution dilution in frozen water, utilize ammoniacal liquor to regulate PH and be neutrality, stirred 10 minutes, use twice of 250ml chloroform extraction again, combined chloroform layer concentrating under reduced pressure, utilize recrystallizing methanol, the freezing and filtering drying gets 0.174mol 6F thing.
Embodiment 4
Figure B2009100709021D0000063
In reaction flask, add the 0.2mol raw material, add the 200ml acetonitrile, stir and feed argon gas down, controlled temperature to 10 degree adds NFOBS 0.28mol, reacts after 2 hours, with solution dilution in frozen water, utilize ammoniacal liquor to regulate PH and be neutrality, stirred 10 minutes, use twice of 300ml chloroform extraction again, combined chloroform layer concentrating under reduced pressure, utilize recrystallizing methanol, the freezing and filtering drying gets 0.180mol 6F thing.
Embodiment 5
Figure B2009100709021D0000071
In reaction flask, add the 0.2mol raw material, add the 200ml acetonitrile, stir and feed nitrogen down, controlled temperature to 10 degree adds NFSI0.26mol, reacts after 1.5 hours, with solution dilution in the frozen water that contains the 3g Sodium Pyrosulfite, utilize ammoniacal liquor to regulate PH and be neutrality, stirred 10 minutes, use twice of 400ml chloroform extraction again, combined chloroform layer concentrating under reduced pressure, utilize recrystallizing methanol, the freezing and filtering drying gets 0.180mol 6F thing.
Embodiment 6
Figure B2009100709021D0000072
In reaction flask, add the 0.2mol raw material, add N, dinethylformamide 400ml, stir and feed nitrogen down, controlled temperature to 10 degree adds NFOBS 0.28mol, react after 2 hours, solution dilution in the frozen water that contains the 3g Sodium Pyrosulfite, is utilized ammoniacal liquor to regulate PH and is neutrality, stirred 10 minutes, use 300ml chloroform extraction twice again, combined chloroform layer concentrating under reduced pressure utilizes recrystallizing methanol, the freezing and filtering drying gets 0.170mol 6F thing.
Embodiment 7
Figure B2009100709021D0000081
In reaction flask, add the 0.2mol raw material, add the 200ml acetonitrile, stir and feed nitrogen down, controlled temperature to 50 degree adds NFOBS 0.22mol, reacts after 1 hour, with solution dilution in the frozen water that contains the 3g Sodium Pyrosulfite, utilize ammoniacal liquor to regulate PH and be neutrality, stirred 10 minutes, use twice of 300ml chloroform extraction again, combined chloroform layer concentrating under reduced pressure, utilize recrystallizing methanol, the freezing and filtering drying gets 0.168mol 6F thing.
Embodiment 8
Figure B2009100709021D0000082
In reaction flask, add the 0.2mol raw material, add organic solvent, stir and feed nitrogen down, controlled temperature to 10 degree, bringing Selection In property fluorizating agent 0.22mol reacts after 3 hours, solution dilution in the frozen water that contains the 3g Sodium Pyrosulfite, is utilized triethylamine to regulate PH and is neutrality, stirred 10 minutes, use twice of 400ml chloroform extraction again, combined chloroform layer concentrating under reduced pressure utilizes recrystallizing methanol, the freezing and filtering drying, get the 6F thing, particular case sees the following form.
Group number Organic solvent Fluorizating agent The 6F thing
8-1 Acetone NFOBS 0.132mol
8-2 Chloroform/methanol (2/8, v/v) NFOBS 0.178mol
8-3 95% ethanol NFOBS 0.146mol
8-4 Tetrahydrofuran (THF) NFOBS 0.184mol
8-5 N, dinethylformamide NFOBS 0.182mol
8-6 Acetone NFSI 0.134mol
8-7 Chloroform/methanol (2/8, v/v) NFSI 0.177mol
8-8 95% ethanol NFSI 0.141mol
8-9 Tetrahydrofuran (THF) NFSI 0.188mol
8-10 N, dinethylformamide NFSI 0.183mol

Claims (10)

1. the preparation method of a steroid 6 α fluorine is to react in organic solvent with formula (II) compound and fluorizating agent (III-1), (III-2) to obtain compound (I):
Figure F2009100709021C0000011
Wherein, R 1=H, halogen, OH, or C 1-5Acyloxy,
R 2=H, α-OH, or α-C 1-5Acyloxy,
R 3=H, OH, or α, β C 1-3Alkyl,
R 2, R 3=α epoxy, two key,
Figure F2009100709021C0000012
15,16 is the carbon of 15,16 of cyclopentanoperhydro-phenanthrenes
Wherein M, Q are respectively the alkyl of H or 1 to 6 carbon, for example methyl, cyclohexyl; M, Q can also be the heterocycle that contains an O or heteroatomic five-ring of N or six-ring such as furans, pyridine, piperidines etc.;
R 4=H, or α, β hydroxyl,
R 5=H or α halogen,
R 4, R 5=β epoxy, two key,
R 6The alkyl of=H or 1 to 4 carbon,
Serpentine in the molecular formula is expressed as substituents alpha, β all can; Real between 1,2, dotted line is singly-bound or two key; Fluorizating agent can be selected from one or more among (III-1), (III-2).
Figure F2009100709021C0000013
2. preparation method as claimed in claim 1 is characterized in that formula (I) and each substituting group of formula (II) compound are preferred
R 1=H, halogen or C 1-5Acyloxy,
R 2=α-OH or α-C 1-5Acyloxy,
R 3=H or α, β methyl,
R 2, R 3=α epoxy, two key,
R 4=H, α, β hydroxyl,
R 5=H or α halogen,
R 4, R 5=α epoxy, two key,
R 6The alkyl of=1 to 4 carbon.
3. preparation method as claimed in claim 1 is characterized in that formula (I) and each substituting group of formula (II) compound more preferably
R 1=H or C 1-5Acyloxy,
R 2=α-OH,
R 3=H or α, β methyl,
R 2, R 3=α epoxy, two key,
R 4=α hydroxyl,
R 5=H,
R 4, R 5=α epoxy, two key,
R 6The alkyl of=1 to 4 carbon.
4. preparation method as claimed in claim 1 is characterized in that formula (I) and each substituting group of formula (II) compound are further preferred:
R 1=H,
R 2=α-OH,
R 3=H or α, β methyl.
R 2, R 3=α epoxy, two key,
R 4=α hydroxyl,
R 5=H,
R 4, R 5=α epoxy,
R 6=methyl.
5. as arbitrary described preparation method in the claim 1 to 4, it is characterized in that the organic solvent that reacts comprises one or more in the ether of methane amide, a 2-5 carbon of alcohol, a 1-4 carbon of nitrile, a 1-4 carbon of the ketone that contains enpara, a 3-6 carbon, a 1-3 carbon of 1-3 carbon of the liquid state under the temperature of reaction.
6. as described in the claim 5, it is characterized in that the organic solvent that reacts comprises a kind of in the chloroform of the liquid state under the temperature of reaction or methylene dichloride and methanol mixture, the tetrahydrofuran (THF).
7. as the arbitrary described preparation method of claim 1 to 6, add alkali in the last handling process that it is characterized in that reacting.
8. as the arbitrary described preparation method of claim 1 to 7, add ammoniacal liquor, pyridine, triethylamine in the last handling process that it is characterized in that reacting.
9. as the arbitrary described preparation method of claim 1 to 8, feed nitrogen or argon gas in the process that it is characterized in that reacting.
10. as the arbitrary described preparation method of claim 1 to 9, it is characterized in that the reaction process temperature is that-20 degree are to 60 degree.
CN2009100709021A 2009-10-22 2009-10-22 Synthesis process for preparing steride 6-fluorine with NFOBS (N-Fluoro-Ortho-Benzenedisulfonimide) or NBSI fluorinating agent Pending CN102040649A (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102516202A (en) * 2011-11-23 2012-06-27 天津大学 N-fluoro-1, 1'-binaphthyl-2, 2'-sulfimide and preparation method thereof
CN105669503A (en) * 2016-01-12 2016-06-15 中山大学 Trifluoromethylthiolation reagent and its preparation method and use in asymmetric trifluoromethylthiolation reaction
CN111217733A (en) * 2018-11-23 2020-06-02 上海交通大学 N-thiocyanobenzenesulfonylimide and preparation method and application thereof
CN113896759A (en) * 2021-12-10 2022-01-07 山东谷雨春生物科技有限公司 Synthesis method of fluocinonide

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102516202A (en) * 2011-11-23 2012-06-27 天津大学 N-fluoro-1, 1'-binaphthyl-2, 2'-sulfimide and preparation method thereof
CN102516202B (en) * 2011-11-23 2013-12-04 天津大学 N-fluoro-1, 1'-binaphthyl-2, 2'-sulfimide and preparation method thereof
CN105669503A (en) * 2016-01-12 2016-06-15 中山大学 Trifluoromethylthiolation reagent and its preparation method and use in asymmetric trifluoromethylthiolation reaction
CN105669503B (en) * 2016-01-12 2017-12-05 中山大学 Trifluoromethylthio reagent and preparation method thereof and the application in the reaction of asymmetric trifluoromethylthioization
CN111217733A (en) * 2018-11-23 2020-06-02 上海交通大学 N-thiocyanobenzenesulfonylimide and preparation method and application thereof
CN111217733B (en) * 2018-11-23 2021-12-31 上海交通大学 N-thiocyanobenzenesulfonylimide and preparation method and application thereof
CN113896759A (en) * 2021-12-10 2022-01-07 山东谷雨春生物科技有限公司 Synthesis method of fluocinonide

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Application publication date: 20110504