CN1918150B - Process for preparing substituted benzopyran compounds - Google Patents
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- CN1918150B CN1918150B CN2005800047261A CN200580004726A CN1918150B CN 1918150 B CN1918150 B CN 1918150B CN 2005800047261 A CN2005800047261 A CN 2005800047261A CN 200580004726 A CN200580004726 A CN 200580004726A CN 1918150 B CN1918150 B CN 1918150B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The present invention relates to a novel method of synthesizing substituted benzopyran compounds, their novel intermediates and a method of their preparation thereof.
Description
Invention field
The present invention relates to a kind of novel method of benzopyran compounds of the replacement for preparing following formula 1, their corresponding new intermediate and described intermediates preparation.
In following formula 1, R
1, R
2, R
3, R
4, A is identical with the definition in the detailed Description Of The Invention with Y.
Background of invention
As disclosed in EP0173516 and other documents, benzopyran compounds is a kind of LTRA, also known it be the medicine of a kind of treatment by leukotriene and 5-5 alpha-reductases inductive disease.For example, JP Hei 3-95144 discloses a kind of method that is prepared 3-amino-2-parahydroxyacet-ophenone by the oxybenzene compound of following formula (A) through four steps.Yet this method thinks that owing to step is long benefit is not high, and owing to use Pd/C to carry out hydrogenation in the reduction step (a) of introducing amine groups, has the danger of blast, therefore lacks industrial applicibility.
In above reaction, X represents halogen atom.
Simultaneously, at USP5,675,036,5,597,929 and WO94/124923 in, consider that from safety and environment aspect their synthetic method is inappropriate, not only because they have used the acetophenone compound (D) of synthetic quite difficulty as intermediate, and because they have used the reactant SOCl of very easily blast and high corrosion
2Prepare acyl chlorides (E), it is required that this introduces amide group by amine moiety.Further, the chloride of acid that obtains thus is not very stable usually, is very difficult to adjust in commercial production.
Summary of the invention
The present invention relates to a kind of method of synthesizing discloseder novel benzopyran compounds in EP0173516.Method of the present invention is industrial more suitable, because compare with ordinary method, it has still less processing step and more safe and effective.Especially, method of the present invention has been followed the convergency approach, and is more more effective than the linear method of routine.Further, method of the present invention does not adopt for example hydrogenation of dangerous technology, to such an extent as to enough stable their separation and purification of the intermediate materials that generates in the reaction process is quite easy.
Detailed Description Of The Invention
The present invention relates to the method for benzopyran compounds that a kind of preparation has the replacement of following formula 1 chemical structure, be used for the new intermediate compound of this method, prepare the method for this midbody compound.
In following formula 1,
R
1Be selected from following group: C
1-20Alkyl, C
2-20Alkenyl, C
2-20Alkynyl group, phenyl, naphthyl and indanyl, wherein these groups can be replaced by 1 or 2 substituting group independently, and these substituting groups are selected from C
1-20Alkyl, C
2-20Alkenyl, C
2-20Alkynyl group, wherein in these substituting groups at the most 5 carbon atom alternatives by following replacement: O, S, N, halogen atom, phenyl ring, thiphene ring, naphthalene nucleus, C
4-7Carbocyclic ring, carbonyl, the ketonic oxygen base, hydroxyl, carboxyl, azido-or nitro,
R
2And R
4Independently be H, C
1-6Alkyl, C
2-6Alkenyl is by the C of 1-3 aryl replacement
1-6Alkyl, C
1-6Carbalkoxy, the C that is replaced by aryl
1-6Carbalkoxy, aryloxy carbonyl, C
1-6Alkoxy C
1-6Alkyl, C
3-9Three alkane tinbases, three fragrant tinbases, or C
3-9Trialkylsilkl, wherein aryl or described aryl are by the phenyl of 1-3 substituting group replacement, and these substituting groups are selected from following group: phenyl, halogen atom, C
1-6Alkyl and C
1-6Alkoxyl group;
R
3Be H, halogen atom, hydroxyl, nitro, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio or-COOR
5(R wherein
5Be H or C
1-6Alkyl);
A is a singly-bound; Or C
1-10Alkylidene group, C
2-10Alkenylene, or C
2-10Alkynylene is selected from C by 1-3
1-10The substituting group of alkyl and phenyl replaces or does not replace;
X is a halogen atom; And
Y is O or S.
In the benzopyran compounds of the replacement for preparing following formula 1, R
1Be phenyl or substituted-phenyl, wherein above-mentioned substituted-phenyl can be replaced by 1 or 2 substituting group, and described substituting group is selected from C
1-20Alkyl, C
2-20Alkenyl, C
2-20Alkynyl group, wherein in the substituting group at the most 5 carbon atoms can selectivity by following replacement: O, S, N, halogen atom, phenyl ring, thiphene ring, naphthalene nucleus, C4-7 carbocyclic ring, carbonyl, carbonyl oxygen base, hydroxyl, carboxyl, azido-, or nitro.Preferably, R
1Be the phenyl that is replaced by top illustrative substituting group in contraposition, and more preferably
In the benzopyran compounds of the replacement for preparing following formula 1, R
2And R
4Independently be H, C
1-6Alkyl, C
2-6Alkenyl is by the C of 1-3 aryl replacement
1-6Alkyl, or C
1-6Alkoxy carbonyl.More preferably, R
2And R
4Be H independently.
In the benzopyran compounds of the replacement for preparing following formula 1, R
3Be H.
In the benzopyran compounds of the replacement for preparing following formula 1, A is a singly-bound; Or methylene radical, vinyl, trimethylene, tetramethylene, vinylene, propenylene, crotonylidene, Aden's dialkylene (butadienylene) or ethynylene are selected from C by 1-3
1-10The substituting group of alkyl and phenyl replaces or is unsubstituted.More preferably, A is a singly-bound.
Shown in following reaction process 1, can prepare the benzopyran compounds of the replacement of following formula 1 of the present invention by the compound of following formula 2 and the compound reaction of following formula 3.
[reaction process 1]
In above reaction process 1, R
1, R
2, R
3, R
4, definition is identical among the A, X and Y and following formula 1.
Under reflux temperature, with an organic solvent, in the presence of Pd or Cu catalyzer, part and alkali, carry out the preparation method of above-mentioned reaction process 1.
More than the solvent that uses in the reaction can be selected from and have high polar solvent, N for example, N '-dimethyl formamide, N-Methyl pyrrolidone, pyridine, 1,4-dioxane, C
1-6Alkyl alcohol (methyl alcohol, ethanol, propyl carbinol) or their mixture, preferred N, N '-dimethyl formamide.
More than the catalyzer that uses in the reaction is the compound that comprises Pd or Cu, and its consumption is the about 0.1-100mol% based on reaction volume.Preferably, catalyzer is selected from CuI, CuCl and Cu
2O, more preferably CuI.
More than the part consumption that uses in the reaction is the 0.5-3 equivalent based on the amount of catalyst system therefor.The part that uses is diamines or phosphine, preferred N, and N '-dimethyl-ethylenediamine, trans-N, N '-1,2-cyclohexanediamine and trans-N, N '-dimethyl-1, one of 2-cyclohexanediamine, more preferably N, N '-dimethyl-ethylenediamine.
In above-mentioned reaction, the consumption of alkali is the about 1-10 equivalent based on substrate.Alkali can be selected from alkali metal alkoxide, potassium tert.-butoxide for example, potassium methylate and sodium methylate; Hydride is sodium hydride and potassium hydride KH for example; Alkaline carbonate is salt of wormwood, cesium carbonate and yellow soda ash for example; Or alkali metal phosphate for example potassiumphosphate and sodium phosphate; And preferred as alkali phosphoric acid salt.
In a preferred embodiment according to the preparation method of reaction process 1, shown in following reaction process 1a, the benzopyran compounds of the replacement of following formula 1a, its salt or its solvate (as hydrate) by following formula 2a compound and following formula 3a compound, its salt or or its solvate (as hydrate) reaction synthesize.
[reaction process 1a]
In above-mentioned reaction process 1a, followingly carry out this reaction: as the CuI of catalyzer, as the N of part, N '-dimethyl-ethylenediamine and exist down as the potassiumphosphate of alkali uses N, N '-dimethyl formamide as solvent in the about 100 ℃ of stirrings of about 70-above one day.
Therebetween, in carrying out above-mentioned reaction process 1 synthetic, reactant, promptly the compound (the especially compound of following formula 3a) of compound of following formula 2 (the especially compound of following formula 2a) and following formula 3 is the new intermediate compounds that are used for the compound of synthetic following formula 1.Therefore, following formula 2 and 3 compound also belong to scope of the present invention.
The compound of following formula 2, it is a new intermediate compound of the present invention, can be synthetic by the compound of hydrolysis following formula 4, as shown in following reaction process 2.
[reaction process 2]
In above-mentioned reaction process 2, R
1, R
2, A and Y be as following formula 1 definition.
In above-mentioned reaction process 2, in the presence of water, organic solvent or its mixture, use alkali to introduce amide group through hydrolysis.Those skilled in the art obviously will appreciate that the alkali/solvent condition that is used for said hydrolyzed.For example, use single C
1-6For example methyl alcohol, ethanol, the trimethyl carbinol or their mixture are as solvent for the alkanol solvent, and for example sodium hydroxide or potassium hydroxide carry out this reaction as alkali to use alkali metal hydroxide simultaneously.
In the preferred embodiment of reaction process 2 via the preparation method of hydrolysis, shown in following reaction process 2a, following formula 2a compound, its salt or its solvate (as hydrate) synthesize by the compound of reaction following formula 4a in the presence of the NaOH/ trimethyl carbinol.
[reaction process 2a]
In addition, the compound of following formula 3, it is a new intermediate compound of the present invention, can be prepared as follows: (a) react the compound that synthesizes following formula 7 by the compound of following formula 5 and the compound of following formula 6, (b) carries out cyclization to the compound of the following formula 7 that obtains thus then, shown in following reaction process 3.
[reaction process 3]
In above-mentioned reaction process 2, R
3, R
4Represent the activatory leavings group with X as following formula 1 definition and Z.
The example of the activatory leavings group (Z) of above-mentioned reaction process 3 for example is a halogen atom, by-N (R
6) (OR
6) (R wherein
6Be C
1-6Alkyl) Biao Shi activatory amide group, R
7O-, R
7S-or R
7SO
2O-(R wherein
7Be C
1-6Alkyl, the phenyl that replaces or the phenyl C of replacement arbitrarily arbitrarily
1-6Alkyl), or
(R wherein
8Be C
1-6Alkyl, the phenyl that replaces or the phenyl C of replacement arbitrarily arbitrarily
1-6Alkyl, Y ' are O or S independently).
Preferably, the activatory leavings group is R
7O-, wherein R
7Be C
1-6Alkyl, the phenyl that replaces or the phenyl C of replacement arbitrarily arbitrarily
1-6Alkyl, more preferably, R
7Be C
1-6Alkyl, methyl for example, ethyl, the isobutyl-or the tertiary butyl, most preferably R
7It is ethyl.
Synthetic step (a) according to above-mentioned reaction process 3 is to have N, N '-dimethyl formamide, and ether solvents is tetrahydrofuran (THF) for example; Organic solvent is toluene for example, benzene, hexane or C
1-6Alkanol (as, methyl alcohol, the ethanol trimethyl carbinol); And alkali, wherein alkali is selected from alkali metal alkoxide for example potassium tert.-butoxide, potassium methylate and sodium methylate; Hydride is sodium hydride for example; For example carry out under the condition of acid amides potassium and acid amides sodium with acid amides.
Under the condition that has acid, carry out the cyclisation of the step (b) of above-mentioned reaction process 3 synthesis methods.For example, can in the presence of sulfuric acid, use for example C of solvent
1-6Alkanol or acetate carry out cyclisation.In addition, can be at C in the presence of spirit of salt
1-6Carry out cyclisation in alkanol/tetrahydrofuran (THF) mixed solvent.
Those skilled in the art obviously will appreciate that alternative acid/solvent condition.Can be at The suitable solvent for example water or C
1-6Alkanol, unsaturated carbon cyclic hydrocarbon be for example in benzene or the toluene, use acid for example Hydrogen bromide, hydroiodic acid HI, cross chloric acid or tosic acid; For example aluminum chloride or titanium tetrachloride carry out this reaction with lewis' acid.Preferably, in methanol solvate, in the presence of sulfuric acid, carry out above-mentioned reaction.
In the preparation method's of reaction process 3 preferred embodiment, shown in following reaction process 3a, the compound of following formula 3a, its salt or its solvate (as hydrate) are prepared as follows: (a) compound, its salt or its solvate (as hydrate) of the compound of compound by making following formula 5a and following formula 6a, its salt or the synthetic following formula 7a of its solvate (as hydrate) reaction, (b) carries out the cyclization of compound, its salt or its solvate of following formula 7a then.
[reaction process 3a]
Simultaneously, in carrying out above-mentioned reaction process 3 synthetic, the compound of following formula 7 (the especially compound of following formula 7a) is a reaction process institute synthetic new intermediate.Therefore, the compound of following formula 7 also belongs to scope of the present invention.
For convenience, the compound with following formula 7 is called diketone type compound in the present invention, and it also can exist with keto-enol and cyclic hydroxyl benzofuran 4-ketone form.Thus, following formula 7 all tautomeric forms all belong to the scope of the invention.
Cyclic hydroxyl benzofuran 4-ketone
Specific embodiments
Embodiment
Can understand the present invention better according to the following examples, these embodiment are for the purpose of explaining, and are not intended to limit the present invention.
The preparation of embodiment 1:4-(4-phenyl butoxy) benzamide
To 4-(4-phenyl butoxy) phenyl cyanide (1.9g, 7.5mmol) and add in the mixture of the trimethyl carbinol (37mL) NaOH (2.1g, 38mmol) and refluxed 4 hours.With this mixture be chilled to the mixing solutions that adds entry and methyl alcohol after the room temperature (4: 1,100mL).Filtration gained precipitation, through water washing, vacuum-drying generates target compound, is white solid (1.9g, 94%).
1H?NMR(300MHz，DMSO-d6)δ7.81-7.83(m，3H)，7.15-7.30(m，6H)，6.95(d，J＝9.0Hz，2H)，4.04(t，J＝5.9Hz，2H)，2.65(t，J＝6.9Hz，2H)，1.73(t，J＝3.2Hz，4H)
Embodiment 2:2-iodo-6-[1,3-dioxo-3-(tetrazolium-5-yl) propyl group] phenol
In the nitrogen atmosphere, with anhydrous dimethyl formamide (30mL) join 2-hydroxyl-3-iodobenzene ethyl ketone (1.5g, 5.7mmol), 1H-tetrazolium-5-carboxylic acid, ethyl ester (1.1g, 7.5mmol) and potassium tert.-butoxide (3.2g, 28.7mmol) mixture in, stirred 3 hours in 50 ℃ then.This mixture is chilled to room temperature slowly to be added among the cold 1N HCl (120mL) then.Filter gained orange precipitation, through water washing, vacuum-drying is to obtain target compound.By heating, add hexane, place at 0 ℃ then and dissolved the gained target compound in 2 hours.Filter products obtained therefrom, use hexane wash, vacuum-drying obtains pure product then, is yellow solid (1.7g, 83%).
1H?NMR(300MHz，DMSO-d6)δ8.99(br?s，1H)，8.10(dd，J＝7.7，1.8Hz，1H)，7.80(dd，J＝8.0，1.7Hz，1H)，6.95(t，J＝7.8Hz，1H)，3.57(d，J＝16.5Hz，1H)，3.20(d，J＝16.5Hz，1H)
The preparation of embodiment 3:8-iodo-4-oxo-2-tetrazolium-5-base-1H-1-chromene
(1.5g 4.2mmol) mixes in methyl alcohol (20mL) and stirs to form slurry with the pure product of embodiment 2 gained.In this slurry, add then the vitriol oil (265 μ L, 5.0mmol) and refluxed 7 hours.With mixture be chilled to room temperature keep then 0 ℃ one hour.Filter products obtained therefrom, through cold methanol, water and cold methanol washing.Products obtained therefrom obtains title compound through vacuum-drying, is light yellow solid (1.3g, 93%).
1H?NMR(300MHz，DMSO-d6)δ8.35(dd，J＝7.7，1.7Hz，1H)，8.07(dd?J＝7.8，1.5Hz，1H)，7.33(t，J＝8.0，1H)，7.11(s，1H)
Embodiment 4:4-oxo-8-[4-(4-phenyl butoxy) benzamide]-preparation of 2-tetrazolium-5-base-4H-1-chromene
In the nitrogen atmosphere, pure product (108mg with embodiment 1 gained, 0.40mmol), the pure product (68mg of embodiment 3 gained, 0.20mmol), CuI (11.4mg, 0.04mmol), potassiumphosphate (255mg, 0.80mmol) and N, (13 μ L 0.08mmol) are mixed together N '-dimethyl-ethylenediamine.In this mixture, add anhydrous dimethyl formamide (1mL) then and stirred two days in 100 ℃.Reaction soln is chilled to room temperature and adds entry (15mL).Add saturated HCl solution acidifying gained solution to pH 1-2.The solid of filtering-depositing and in methyl alcohol (10mL) suspension gained solid, remove by filter the pure product of gained among the residual embodiment 1 then.(32mg 0.40mmol) is dissolved in the methyl alcohol (7mL) the gained solid and filters then to add sodium acetate.In filtrate, add saturated HCl solution.The solid of filtering-depositing washs vacuum-drying then to obtain target compound through cold methanol, is light yellow solid (77mg, 81%).
Industrial applicibility
As mentioned above, the present invention relates to be suitable for the production method of industrial application, it provides remarkable improvement and high-efficiency method more, and safer than ordinary method.Especially, the compound of following formula 2,3 and 7 representatives is the new intermediate compounds that produce in the benzopyran compounds process of the replacement of synthesis type 1, because they are highly stable, therefore also is suitable for very much industrial application.
The present invention describes in detail with reference to its embodiment preferred.What however, it should be understood that is that those skilled in the art according to this paper, can make amendment within scope and spirit of the present invention and improve.
Claims (10)
1. the preparation method of following formula (1) compound or its salt comprises: make the reaction of following formula (2) compound and following formula (3) compound
R wherein
1Be selected from following group: phenyl, naphthyl or indanyl, wherein these groups are not substituted or are replaced by 1 or 2 substituting group independently, and described substituting group is selected from C
1-20Alkyl, wherein in these substituting groups at the most 5 carbon atoms be not substituted or by following optional replacement: O, phenyl ring, thiphene ring or naphthalene nucleus,
R
2And R
4Independently be H or C
1-6Alkyl;
R
3Be H or C
1-6Alkyl;
A is a singly-bound;
X is a halogen atom; And
Y is O or S.
2. according to the process of claim 1 wherein that described R1 is
R
2, R
3And R
4Independently be H, A is a singly-bound, and X is I, Br or Cl; Y is O.
3. according to the process of claim 1 wherein that described being reflected under the compound that comprises palladium or copper as catalyzer, the existence as the diamines of part and alkali carry out.
4. according to the method for claim 3, wherein said being reflected at is selected from CuI, CuCl and Cu
2The catalyzer of O, be selected from N, N '-dimethyl-ethylenediamine, trans-N, N '-1,2-cyclohexanediamine or trans-N, N '-dimethyl-1, the part of 2-cyclohexanediamine and be selected from cesium carbonate or the existence of the alkali of potassiumphosphate under carry out.
5. according to the method for claim 4, wherein saidly be reflected at CuI, as the N of part as catalyzer, carry out under N '-dimethyl-ethylenediamine and the existence as the potassiumphosphate of alkali.
6. according to each method of claim 3-5, N is used in wherein said reaction, and N '-dimethyl formamide carries out as solvent.
7. prepare according to the formula of the process of claim 1 wherein (1a) compound or its salt through type (2a) compound and the reaction of following formula (3a) compound or its salt
8. according to the method for claim 7, wherein at the N as solvent, N '-dimethyl formamide, as the CuI of catalyzer, as the N of part carries out described reaction in 70-100 ℃ under N '-dimethyl-ethylenediamine and the existence as the potassiumphosphate of alkali.
9. midbody compound or its salt of following formula (2) expression
R wherein
1Be phenyl, it is not substituted or is replaced by 1 or 2 substituting group independently, and described substituting group is selected from C
1-20Alkyl, in the wherein said substituting group at the most 5 carbon atoms be not substituted or replaced by following groups is optional: O or phenyl ring,
R
2Be C
1-6Alkyl,
A is a singly-bound; With
Y is O.
10. midbody compound 4-(4-phenyl butoxy) benzamide.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2004-0009280 | 2004-02-12 | ||
| KR1020040009280A KR100683274B1 (en) | 2004-02-12 | 2004-02-12 | Process for preparing substituted benzopyran compound |
| KR1020040009280 | 2004-02-12 | ||
| PCT/KR2005/000365 WO2005077942A1 (en) | 2004-02-12 | 2005-02-07 | Process for preparing substituted benzopyran compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1918150A CN1918150A (en) | 2007-02-21 |
| CN1918150B true CN1918150B (en) | 2010-05-05 |
Family
ID=34858705
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2005800047261A Expired - Fee Related CN1918150B (en) | 2004-02-12 | 2005-02-07 | Process for preparing substituted benzopyran compounds |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP1713796A4 (en) |
| JP (1) | JP4512100B2 (en) |
| KR (1) | KR100683274B1 (en) |
| CN (1) | CN1918150B (en) |
| WO (1) | WO2005077942A1 (en) |
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| ES2537529T3 (en) | 2008-06-05 | 2015-06-09 | Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. | Novel modulators of protein kinase signaling |
| US9770454B2 (en) | 2013-07-14 | 2017-09-26 | Yissum Research Development Company Of The Hebrew University Of Jerusalem, Ltd. | IGF-1R signaling pathway inhibitors useful in the treatment of neurodegenerative diseases |
| WO2016125169A1 (en) | 2015-02-05 | 2016-08-11 | Tyrnovo Ltd. | Combinations of irs/stat3 dual modulators and anti-cancer agents for treating cancer |
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| US5675036A (en) * | 1995-06-29 | 1997-10-07 | Sumitomo Chemical Company, Limited | Process for preparing aromatic amide compound |
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| AR004029A1 (en) * | 1995-10-20 | 1998-09-30 | Smithkline Beecham Plc | NEW PHARMACEUTICAL FORMULATIONS |
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- 2004-02-12 KR KR1020040009280A patent/KR100683274B1/en not_active IP Right Cessation
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- 2005-02-07 EP EP05726439A patent/EP1713796A4/en not_active Withdrawn
- 2005-02-07 CN CN2005800047261A patent/CN1918150B/en not_active Expired - Fee Related
- 2005-02-07 JP JP2006553050A patent/JP4512100B2/en not_active Expired - Fee Related
- 2005-02-07 WO PCT/KR2005/000365 patent/WO2005077942A1/en active Application Filing
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| US3839339A (en) * | 1970-02-05 | 1974-10-01 | Allen & Hanburys Ltd | Tetrazolyl chromones |
| US5675036A (en) * | 1995-06-29 | 1997-10-07 | Sumitomo Chemical Company, Limited | Process for preparing aromatic amide compound |
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Also Published As
| Publication number | Publication date |
|---|---|
| EP1713796A1 (en) | 2006-10-25 |
| KR100683274B1 (en) | 2007-02-15 |
| CN1918150A (en) | 2007-02-21 |
| JP2007522206A (en) | 2007-08-09 |
| EP1713796A4 (en) | 2009-11-25 |
| KR20050081042A (en) | 2005-08-18 |
| WO2005077942A1 (en) | 2005-08-25 |
| JP4512100B2 (en) | 2010-07-28 |
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