WO2008087656A2 - Process for the preparation of unsymmetrically substituted biphenyl compounds - Google Patents
Process for the preparation of unsymmetrically substituted biphenyl compounds Download PDFInfo
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- WO2008087656A2 WO2008087656A2 PCT/IN2008/000018 IN2008000018W WO2008087656A2 WO 2008087656 A2 WO2008087656 A2 WO 2008087656A2 IN 2008000018 W IN2008000018 W IN 2008000018W WO 2008087656 A2 WO2008087656 A2 WO 2008087656A2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
Definitions
- the present invention relates to a process for the preparation of unsymmetrical biaryl compounds of formula I
- R is alkyl.
- R " is alkyl. aryl.'aralkyl or alkoxy.
- the present invention relates to a process for the preparation of unsymmetrical biphenyl compounds of Formula I in which R is methyl and R' is a cyano group.
- Biphenyls are valuable as fine chemicals for liquid crystals and related applications and as precursors for pharmaceutically active compounds.
- 2-(4'-methylphenyl) benzonitrile also known as 4-methyl-2'-cyanobiphenyl
- OTBN o-tolylbenzonitrile
- 2-(tetrazolyl)-4' -methyl biphenyl can be used as an intermediate in the preparation of various angiotensin II antagonists.
- the unsymmetrical biaryl coupling reactions require a metal catalyst.
- these catalysts are selected from palladium, nickel or manganese.
- the palladium catalyzed coupling of an aryl Grignard compound with an iodo-substituted benzonitrile has been described in the art.
- US 5288895 discloses a method in which a halobenzonitrile is treated with aryl magnesium halide in the presence of a manganese salt as catalyst.
- the patent reports very low yields of biaryl compounds.
- US 6121480 describes a method for the synthesis of unsymmetrically substituted biphenyls comprising the palladium catalyzed coupling of an aryl magnesium halide with bromobenzonitrile.
- US 6407253 discloses a method for preparing the biphenyl compounds by reacting an aryl halide with a Grignard reagent using a palladium complex - PdCl 2 /dppp in the presence of a linear or branched polyether as solvent.
- a cyclic diether discloses a process for the preparation biphenyl compounds by reacting o- halobenzonitrile with a p-tolylmagnesium halide in the presence of MnCl 2 / a mixture of 1 mole of MnCb and 2 moles of LiCl and PdCb/dppp complex.
- US 6194599 describes a process for preparing the biaryl compounds by reacting an aryl group bonded to zinc with an aryl chloride in the presence of palladium or nickel catalyst.
- US 5922898 discloses reaction of aryl magnesium reagents and aryllithium reagents with an aryl halide in the presence of catalysts such as palladium catalysts and nickel catalysts and a cocatalyst is selected from zinc cocatalysts and cadmium cocatalysts.
- unsymmetrical biaryl compounds can be prepared by reacting a Grignard reagent with an aryl halide in the presence of transition metal catalysts like palladium catalysts or nickel catalysts in the form of salts or in the form of complexes with ligands with/without any cocatalysts.
- transition metal catalysts like palladium catalysts or nickel catalysts in the form of salts or in the form of complexes with ligands with/without any cocatalysts. The reaction is shown schematically below.
- the present inventors have observed that, when p-tolylmagnesium bromide was reacted with o-bromobenzonitrile using palladium chloride/triphenyl phosphine as catalyst, only 47% conversion to the product (OTBN) was obtained wherein palladium chloride was used in the concentration of 6 mole% with reference to o-bromobenzonitrile.
- OTBN palladium chloride/triphenyl phosphine catalyst system
- the conversion to the product was upto 75% wherein palladium acetate used was in the concentration of 6 mole% with reference to o-bromobenzonitrile.
- the compounds of Formula I can be prepared in good yield and better purity by a novel process comprising reaction of a Grignard reagent with an aryl halide in a suitable solvent in the presence of a palladium catalyst and a ligand and a co catalyst selected from Lewis acid like boron trifluoride etherate, perchloric acid or salt of perchloric acid that is inexpensive, safe and easy to handle.
- a novel process comprising reaction of a Grignard reagent with an aryl halide in a suitable solvent in the presence of a palladium catalyst and a ligand and a co catalyst selected from Lewis acid like boron trifluoride etherate, perchloric acid or salt of perchloric acid that is inexpensive, safe and easy to handle.
- R is alkyl
- R" is alkyl, aryl, aralkyl or alkoxy; said process comprising, reacting the Grignard reagent of Formula II
- R is alkyl
- X is halogen with an aryl halide of Formula III
- R is alkyl
- X is halogen with an aryl halide of Formula III
- Lewis acid is simple, safe, inexpensive and easy to handle and can be used in catalytic amounts with palladium catalyst to prepare unsymmetrical biphenyl compounds. It is observed that when Lewis acid is added as cocatalyst in the reaction, the amount of palladium catalyst required for the reaction reduces considerably, thus making the process economically viable.
- R. X and R' are same as defined above.
- the palladium catalyst is selected from palladium salts such as palladium chloride or palladium acetate.
- the cocatalyst is selected from Lewis acid like boron trifluoride etherate, perchloric acid or salt of perchloric acid.
- the Grignard reagent is added during 0.5 to 10 hours, preferably during 1 to 8 hours, more preferably during 2 to 6 hours, most preferably during 3 to 6 hours.
- the Grignard reagent is added at temperature 10 0 C to 100 0 C. preferably at 20 0 C to 85°C. more preferably at 65°C to 75°C.
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- Chemical & Material Sciences (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
A process for the preparation of unsymmetrical biaryl compounds of Formula (I) wherein, R is alkyl, R' is cyano, protected or unprotected tetrazole, or Formula (a) wherein, R" is alkyl, aryl, aralkyl or alkoxy, said process comprising, reacting Grignard reagent of Formula (II) wherein, R is alkyl; X is halogen with an aryl halide of Formula (III) wherein, X is halogen; R' is a cyano, protected or unprotected tetrazole, or Formula (a) wherein, R" is alkyl, aryl, aralkyl or alkoxy in a suitable solvent in the presence of a palladium catalyst and a ligand and Lewis acid as a co catalyst.
Description
PROCESS FOR THE PREPARATION OF UNSYMMETRICALLY SUBSTITUTED BIPHENYL COMPOUNDS
FIELD OF INVENTION
The present invention relates to a process for the preparation of unsymmetrical biaryl compounds of formula I
Formula I
wherein. R is alkyl. R" is a cyano. protected or unprotected tetrazole, or C:^=NR" wherein,
R" is alkyl. aryl.'aralkyl or alkoxy.
In particular the present invention relates to a process for the preparation of unsymmetrical biphenyl compounds of Formula I in which R is methyl and R' is a cyano group.
BACKGROUND OF THE INVENTION Biphenyls are valuable as fine chemicals for liquid crystals and related applications and as precursors for pharmaceutically active compounds. In particular, 2-(4'-methylphenyl) benzonitrile (also known as 4-methyl-2'-cyanobiphenyl) or o-tolylbenzonitrile (referred to herein below as OTBN) which is a precursor of 2-(tetrazolyl)-4' -methyl biphenyl, can be used as an intermediate in the preparation of various angiotensin II antagonists.
A number of coupling approaches have been developed for the construction of the unsymmetrical biphenyl systems. As OTBN and related compounds are very important intermediates, various methods have been reported for the preparation of OTBN. Reported methods include the reaction of organo-boron (Suzuki reaction), zinc (Negishi reaction) or tin (Stille coupling) compounds with bromobenzonitriles. Suzuki coupling involves reaction of aryl-boron compounds with aryl halides in the presence of palladium catalysts.
A Grignard reagent can be reacted with an aryl halide in a suitable solvent in the presence of transition metal catalysts like palladium, nickel and manganese.
Tamao et al., in Bull. Chem. Soc. Japan, vol. 49 (1976), pp. 1958-1969, discloses that aryl bromides can be reacted with aryl magnesium halides (aryl Grignard reagents) in the presence of dihalodiphosphinenickel complexes to give biaryl compounds. The most serious limitation mentioned is the said reaction is not suitable for all the substituents, thus excluding those which will react with Grignard reagents.
The unsymmetrical biaryl coupling reactions require a metal catalyst. Generally these catalysts are selected from palladium, nickel or manganese. The palladium catalyzed coupling of an aryl Grignard compound with an iodo-substituted benzonitrile has been described in the art.
US 5288895 discloses a method in which a halobenzonitrile is treated with aryl magnesium halide in the presence of a manganese salt as catalyst. The patent reports very low yields of biaryl compounds.
US 6121480 describes a method for the synthesis of unsymmetrically substituted biphenyls comprising the palladium catalyzed coupling of an aryl magnesium halide with bromobenzonitrile.
US 6407253 discloses a method for preparing the biphenyl compounds by reacting an aryl halide with a Grignard reagent using a palladium complex - PdCl2/dppp in the presence of a linear or branched polyether as solvent. However, the said patent also states that such results could not be obtained when the solvent was replaced by a cyclic diether.
US 6392080 discloses a process for the preparation biphenyl compounds by reacting o- halobenzonitrile with a p-tolylmagnesium halide in the presence of MnCl2 / a mixture of 1 mole of MnCb and 2 moles of LiCl and PdCb/dppp complex.
US 6194599 describes a process for preparing the biaryl compounds by reacting an aryl group bonded to zinc with an aryl chloride in the presence of palladium or nickel catalyst.
US 5922898 discloses reaction of aryl magnesium reagents and aryllithium reagents with an aryl halide in the presence of catalysts such as palladium catalysts and nickel catalysts and a cocatalyst is selected from zinc cocatalysts and cadmium cocatalysts.
Tetrahedron Letters, 39(1998), 7275-7278 reports the lower yield (20%) of OTBN when the coupling of p-tolylmagnesium chloride with o-bromobenzonitrile was carried out using dichloro-bis (triphenyl) phosphine palladium without any cocatalyst.
Thus, unsymmetrical biaryl compounds can be prepared by reacting a Grignard reagent with an aryl halide in the presence of transition metal catalysts like palladium catalysts or nickel catalysts in the form of salts or in the form of complexes with ligands with/without any cocatalysts. The reaction is shown schematically below.
catahsl
The present inventors have observed that, when p-tolylmagnesium bromide was reacted with o-bromobenzonitrile using palladium chloride/triphenyl phosphine as catalyst, only 47%
conversion to the product (OTBN) was obtained wherein palladium chloride was used in the concentration of 6 mole% with reference to o-bromobenzonitrile. When palladium acetate/triphenyl phosphine catalyst system was used, the conversion to the product was upto 75% wherein palladium acetate used was in the concentration of 6 mole% with reference to o-bromobenzonitrile.
Thus, the processes for the synthesis of unsymmetrical biaryl compounds using palladium catalysts require higher concentration of the catalyst or require special kind of solvent like polyether when used without any cocatalyst. Cocatalyst like manganous chloride is difficult to handle on commercial scale due to its hygroscopic nature.
Hence, there is a need to develop a more economical, a highly selective and simple method for the synthesis of unsymmetrical biphenyls.
The present inventors have surprisingly found that the compounds of Formula I can be prepared in good yield and better purity by a novel process comprising reaction of a Grignard reagent with an aryl halide in a suitable solvent in the presence of a palladium catalyst and a ligand and a co catalyst selected from Lewis acid like boron trifluoride etherate, perchloric acid or salt of perchloric acid that is inexpensive, safe and easy to handle.
OBJECT QF THE INVENTION
It is an object of the invention to provide a simple process for the preparation of unsymmetrical biaryl comopounds
It is another object of the invention to provide an economically viable process for the preparation of unsymmetrical biaryl comopounds..
It is yet another object of the invention to provide a better yielding process for the preparation of unsymmetrical biaryl compounds.
It is a further object of the invention to provide a process for the preparation of unsymmetrical biaryl compounds with a high purity.
It is yet another object of the invention to provide environmentally safe process for the preparation of unsymmetrical biaryl compounds..
SUMMARY OF THE INVENTION
According to an aspect of the invention there is provided a novel process for the preparation of unsymmetrical biaryl compounds of Formula I
Formula I
wherein, R is alkyl, R' is cyano, protected or unprotected tetrazole, or C=NFΓ wherein,
R" is alkyl, aryl, aralkyl or alkoxy; said process comprising, reacting the Grignard reagent of Formula II
Formula II
wherein, R is alkyl; X is halogen with an aryl halide of Formula III
wherein. X is halogen: R" is a cyano. protected or unprotected tetrazole, or C=NR" wherein, R" is alkyl. aryl. aralkyl or alkoxy in a suitable solvent in the presence of a palladium catalyst and a ligand and a co catalyst selected from Lewis acid like boron trifluoride etherate, perchloric acid or salt of perchloric acid.
DETAILED DESCRIPTION OF THE PRESENT INVENTION Biphenyls are valuable as fine chemicals for liquid crystals and related applications and as precursors for pharmaceutically active compounds. In particular, 2-(4'-methylphenyl) benzonitrile (also known as 4-methyl-2'-cyanobiphenyl) or o-tolylbenzonitrile (referred to herein below as OTBN) can be used as an intermediate in the preparation of various angiotensin II antagonists.
According to an aspect of the invention there is provided a novel process for the preparation of unsymmetrical biaryl compounds of Formula I
wherein R is alkyl. R' is cyano. protected or unprotected tetrazole, or C=NFΓ wherein,
R" is alkyl. aryl, aralkyl or alkoxy. said process comprising, reacting the Grignard reagent of Formula II
Formula II
wherein, R is alkyl; X is halogen with an aryl halide of Formula III
In particular the present invention relates to a novel process for the preparation of unsymmetrically substituted biphenyl compounds of Formula I, as shown above, in which R is methyl and R' is a cyano group.
The present inventors have found that Lewis acid is simple, safe, inexpensive and easy to handle and can be used in catalytic amounts with palladium catalyst to prepare unsymmetrical biphenyl compounds. It is observed that when Lewis acid is added as cocatalyst in the reaction, the amount of palladium catalyst required for the reaction reduces considerably, thus making the process economically viable.
According to the present invention, the Grignard reagent is prepared in a suitable solvent and slowly added to the mixture of the aryl halide. palladium complex which is prepared in situ from palladium salts and a ligand and a cocatalyst selected from a Lewis acid.
The reaction is shown in the scheme below:
Palladium catalyst
wherein, R. X and R' are same as defined above.
The molar ratio of the aryl halide to Grignard reagent is 2:1 to 1 :2, preferably between 1:1 and 1 :1.5, more preferably between 1:1 and 1 :1.3.
The palladium catalyst is selected from palladium salts such as palladium chloride or palladium acetate.
The palladium catalyst is used in the form of a complex which is prepared in situ by reacting palladium salts like palladium chloride or palladium acetate with a ligand
The ligand is selected from bis(tripenylphosphine)dichloro-, bis(tributylphosphine)dichloro-, bis(tri-cyclohexylphosphine)dichloro-, diallyltriphenyl-phosphine dichloro-, triphenylphosphinepiperdine dichloro-, bis(cyclohexyloxime)dicarbonyl, 1,5,9- cyclododecatrienedichloro-, bis(tripenylphosphine)dicarbonyl, bis(tripenylphosphine)diacetate-, bis(tripenylphosphine)sulphate-,(2,4-pentanedione)- tetrakis(triphenylphosphine) or bis(diphenylphosphino)propane.
The palladium catalyst is present in the reaction mixture in a concentration of 0.1 mole% to 2.5 mole% with reference to the aryl halide.
The ligand is used in the concentration of 0.2 mole% to 5 mole% with reference to the aryl halide.
The cocatalyst is selected from Lewis acid like boron trifluoride etherate, perchloric acid or salt of perchloric acid.
The Lewis acid catalyst is used in the concentration of 0.01 to 10 mole% with reference to the aryl halide.
The organic solvent is selected from cyclic ethers, linear or branched chain acyclic ethers, mono- or diether types, N-methylpyrrolidone, alone or in combination, preferably the cyclic ethers such as THF.
According to the present invention the Grignard reagent is added during 0.5 to 10 hours, preferably during 1 to 8 hours, more preferably during 2 to 6 hours, most preferably during 3 to 6 hours.
According to the present invention the Grignard reagent is added at temperature 100C to 1000C. preferably at 200C to 85°C. more preferably at 65°C to 75°C.
The reaction conditions are to a large extent interchangeable depending upon the reactants.
The invention is demonstrated below by non-limiting examples.
EXAMPLES Example 1:
A solution of o-bromobenzonitrile (100 g, 0.55 mol) and dichloro-bis (triphenyl) phosphine palladium (3.849g, 0.0055 mol, 1 mole %) [prepared in situ from palladium chloride (0.972 g, 0.0055 mol) and triphenylphosphine (2.877 g. 0.01 1 mole)] and lithium perchlorate (1.46
g, 0.014 mol, 2.5 mol%) in tetrahydrofuran (550 ml) was placed in a three-necked round- bottomed flask and heated to reflux under inert atmosphere. p-Tolylmagnesium bromide (139 g, 0.715 mol, 1.3 mole eq.) hi tetrahydrofuran (820 ml) was added slowly over 4 hours while maintaining the temperature 67°C to 690C. The reaction mixture was stirred at the same temperature for another 30 minutes. The reaction was monitored by GC. GC analysis of the reaction mixture showed OTBN 91% and 4, 4'-dimethydiphenyl 2.7%. Water (100 ml) was added and THF was distilled off under vacuum. Dichloromethane (300 ml) was added and the organic layer was extracted with 15% HCl (100 ml). Dichloromethane was distilled off and heptane (300 ml) was added, refluxed for 30 minutes, and cooled to 0°C-5°C. The product was filtered.
Yield: 85 g.; GC purity: 98%.
Example 2:
A solution of o-bromobenzonitrile (100 g, 0.55 mol) and diacetate-bis (triphenyl) phosphine palladium (8.23g, 0.011 mol, 2 mole %) [prepared in situ from palladium acetate (2.46 g, 0.011 mol) and triphenylphosphine (5.77 g, 0.022 mole)] and boron trifluoride etherate (1.95 g, 0.0138 mol, 2.5 mol%) in tetrahydrofuran (550 ml) was placed in a three-necked round- bottomed flask and heated to reflux under inert atmosphere. p-Tolylmagnesium bromide (139 g, 0.715 mol, 1.3 mole eq.) in tetrahydrofuran (820 ml) was added slowly over 4 hours while maintaining the temperature at 67°C to 69°C. The reaction mixture was stirred at the same temperature for another 30 minutes. The reaction was monitored by GC and the product was isolated as mentioned in example 1. Yield: 55 g;
Example 3:
A solution of o-bromobenzonitrile (100 g, 0.55 mol) and dichloro-bis (triphenyl) phosphine palladium (3.849g, 0.0055 mol, 1 mole %) [prepared in situ from palladium chloride (0.972 g, 0.0055 mol) and triphenylphosphine (2.877 g, 0.011 mole)] and lithium perchlorate (1.46 g, 0.014 mol, 2.5 mol%) in tetrahydrofuran (550 ml) was placed in a three-necked round-
bottomed flask and heated to reflux under inert atmosphere. p-Tolylmagnesium chloride (107 g, 0.715 mol, 1.3 mole eq.) in tetrahydrofuran (800 ml) was added slowly over 6 hours while maintaining the temperature 67°C to 69°C. The reaction mixture was stirred at the same temperature for another 30 minutes. The reaction was monitored by GC. GC analysis of the reaction mixture showed OTBN 91% and 4, 4'-dimethydiphenyl 2.7%. Water (100 ml) was added and THF was distilled off under vacuum. Dichloromethane (300 ml) was added and the organic layer was extracted with 15% HCl (100 ml). Dichloromethane was distilled off and heptane (300 ml) was added, refluxed for 30 minutes, and cooled to 0°C-5°C. The product was filtered. Yield: 85 g.; GC purity: 98%.
Claims
1. A process for preparation of unsymmetrical biaryl compounds of Formula I
Formula I wherein, R is alkyl, R' is cyano, protected or unprotected tetrazole, or -C=NR- wherein,
R" is alkyl, aryl, aralkyl or alkoxy, said process comprising, reacting Grignard reagent of Formula II
Formula II wherein, R is alkyl; X is halogen with an aryl halide of Formula III
Formula III
H wherein, X is halogen; R' is a cyano, protected or unprotected tetrazole, or C=NR" wherein, R"° is alkyl, aryl, aralkyl or alkoxy in a suitable solvent in the presence of a palladium catalyst and a ligand and Lewis acid as a co catalyst.
2. The process as claimed in claim 1, wherein Lewis acid co catalyst is selected from boron trifluoride etherate, perchloric acid or salt of perchloric acid.
3. The process as claimed in claim 1. wherein palladium catalyst is selected from palladium salt such as palladium chloride or palladium acetate.
4. The process as claimed in claim 1, wherein ligand is selected from bis(tripenylphosphine)dichloro-, bis(tributylphosphine)dichloro-, bis(tri- cyclohexylphosphine)dichloro-, diallyltriphenyl-phosphine dichloro-, triphenylphosphinepiperdine dichloro-, bis(cyclohexyloxime)dicarbonyl, 1,5,9- cyclododecatrienedichloro-, bis(tripenylphosphine)dicarbonyl. bis(tripenylphosphine)diacetate-, bis(tripenylphosphine)sulphate-, (2,4-pentanedione)- tetrakis(triphenylphosphine) or bis(diphenylphosphino)propane.
5. The process as claimed in claim 1. wherein the molar ratio of aryl halide of formula III to Grignard reagent of formula II is 2: 1 to 1 :2. preferably between 1 :1 and 1 : 1.5, more preferably between 1 : 1 and 1 : 1.3.
6. The process as claimed in claim 1 or claim 2, wherein the Lewis acid catalyst used in the reaction mixture is in the concentration of 0.01 to 10 mole%- with reference to the aryl halide of formula III.
7. The process as claimed in claim 1 or claim 3, wherein the palladium catalyst used in the reaction mixture is in the concentration of 0.1 mole% to 2.5 mole% with reference to the aryl halide of formula III.
8. The process as claimed in claim 1 or claim 4, wherein the ligand used in the reaction mixture is in the concentration of 0.2 mole% to 5 mole% with reference to the aryl halide of formula III.
9. The process as claimed in claim 1, wherein the Grignard reagent of formula II is added at temperature 10°C to 100°C, preferably at 20°C to 85°C, more preferably at 65°C to 750C.
10. The process as claimed in claim 1 , wherein the Grignard reagent is added during 0.5 to 10 hours, preferably during 1 to 8 hours, more preferably during 2 to 6 hours, most preferably during 3 to 6 hours.
11. The process as claimed in claim 1, wherein the suitable solvent used alone or in combination is selected from cyclic ethers, linear or branched chain acyclic ethers, mono- or diether types, N-methylpyrrolidone, preferably the cyclic ethers such as THF.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN76/MUM/2007 | 2007-01-15 | ||
| IN76MU2007 | 2007-01-15 |
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| Publication Number | Publication Date |
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| WO2008087656A2 true WO2008087656A2 (en) | 2008-07-24 |
| WO2008087656A3 WO2008087656A3 (en) | 2008-09-18 |
| WO2008087656B1 WO2008087656B1 (en) | 2008-11-06 |
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| PCT/IN2008/000018 Ceased WO2008087656A2 (en) | 2007-01-15 | 2008-01-14 | Process for the preparation of unsymmetrically substituted biphenyl compounds |
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Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5922898A (en) * | 1997-04-08 | 1999-07-13 | Catalytica Pharmaceuticals, Inc. | Process for preparing biaryl compounds |
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- 2008-01-14 WO PCT/IN2008/000018 patent/WO2008087656A2/en not_active Ceased
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| WO2008087656A3 (en) | 2008-09-18 |
| WO2008087656B1 (en) | 2008-11-06 |
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