CN101550080A - Industrial preparation method of 2,3-difluorophenyl acetic acid - Google Patents
Industrial preparation method of 2,3-difluorophenyl acetic acid Download PDFInfo
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- CN101550080A CN101550080A CNA2009100308219A CN200910030821A CN101550080A CN 101550080 A CN101550080 A CN 101550080A CN A2009100308219 A CNA2009100308219 A CN A2009100308219A CN 200910030821 A CN200910030821 A CN 200910030821A CN 101550080 A CN101550080 A CN 101550080A
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Abstract
The invention provides an industrial preparation method of 2,3-difluorophenylacetic acid. The method comprises the following steps: (1) at low temperature, o-difluorobenzene acts with organolithium to generate o-difluorobenzene lithium which reacts with oxalic acid ester or oxalic acid ester chloride to generate 2,3-difluorophenylglyoxylic acid ester; and (2) the 2,3-difluorophenylglyoxylic acid ester is reduced in alkali condition, the 2,3-difluorophenyl acetic acid is obtained by acidification and precipitation and then the 2,3-difluorophenyl acetic acid is crystallized and purified. The industrial preparation method overcomes the defects in the existing synthesis technique and provides a preparation method which has simple technique process, mild reaction condition, clean and convenient for post processing, high purity of product and low cost and is applicable to industrial production.
Description
Technical field
The invention belongs to medicine intermediate and liquid crystal field of new, be specifically related to 2, the preparation method of 3-difluorophenyl acetic acid.
Background technology
2, the 3-difluorophenyl acetic acid is the medicine intermediate that a kind of wide spectrum uses, and also is the important raw and processed materials of preparation novel liquid crystal, and the market requirement is big, has a extensive future.2, in the synthesis strategy of 3-difluorophenyl acetic acid, because the singularity of its structure, on the carbon of next-door neighbour's fluorine atom, connect a group as intending, with traditional richness gram reaction method, the positional isomers of products therefrom is many, and not only being difficult to separation but also target compound is not principal product; Adopt general nucleophilic substitution reaction, as with 1,2,3 ,-trifluoro-benzene is reactive agent (Fig. 1), one expensive raw material price, moreover the isomer that side reaction produced is difficult for removing (must crystallization repeatedly can get pure product), causes yield (＜30%) on the low side, is not inconsistent industrial requirement (B.A.Kowalczyk, Synthesis, 1411 (1997)).German Patent WO2008078350 (Fig. 2) report with 2,3-difluoro-mandelic aid is that initiator is through esterification, chlorination, reduction prepares 2 after alkaline hydrolysis and the acidifying, the 3-difluorophenyl acetic acid again, because step is various, cause yield (44.2%) on the low side, and initiator costs an arm and a leg, also be not suitable for suitability for industrialized production.In addition, (also apply for Chinese patent: CN100378062C) (Fig. 3) proposition is an initiator with the 1,2-Difluorobenzene to Japanese Patent: JP2004352724, in the presence of two kinds of catalyzer, produce 2 with n-Butyl Lithium and the effect of 2-ethyl bromoacetate, 3-difluorophenyl acetic acid ethyl ester, yield is up to 77%, again carry out saponification reaction and recrystallization thereafter, then the total recovery of products therefrom reduces to 51.92%, moreover its employed catalyzer influences very big (total recovery 8%～77%) to its reaction result, but this catalyzer [two (methyl ethyl diketones-2,2 '-dipyridyl nickel (II)] because structure special being difficult for bought, do not know whether can repeat cover in order to reduce cost yet.As preparing the cost of this type of effective catalyzer possibility palpus consumes expensive voluntarily, so neither be put to the approach of industrialization the best.Other synthesis strategies, with 2, the 3-difluoro bromobenzene is that grignard reaction is carried out on the basis such as method (1), because of initiator costs an arm and a leg, reaction conditions is wayward, is unworthy attempting suitability for industrialized production; Method (2) is with 2; monochloroization is carried out cyanogenation to the 3-difluoro toluene again and last hydrolysis obtains 2 for carry out on the basis, the 3-difluorophenyl acetic acid, and method (3) is matrix with the 1,2-Difluorobenzene; carry out acidylate earlier; reduction, cyaniding is carried out in then chlorination again; last hydrolysis obtains difluorophenyl acetic acid; both also all because of or the initiator costliness, or step is many and use the sodium cyanide of severe toxicity, causes the industrialized production (Fig. 4) of dangerous also not environmental protection.
Summary of the invention
The objective of the invention is to overcome deficiency and defective that existing synthetic technology exists, provide a kind of technical process simple, the reaction conditions gentleness, the aftertreatment cleaning is easy and product purity is high, the preparation method of with low cost and suitable suitability for industrialized production.
The invention provides 2, the industrial production process of 3-difluorophenyl acetic acid, its concrete steps are:
(1) at low temperatures, 1,2-Difluorobenzene and organolithium effect generate 1,2-Difluorobenzene base lithium, and this 1,2-Difluorobenzene base lithium reacts with oxalic acid fat or chlorine barkite again, generates 2,3-difluoro acetophenone acid esters;
(2) with described 2,3-difluoro acetophenone acid esters reduces under alkaline condition, separates out through acidifying and obtains 2,3-difluorophenyl acetic acid, crystallization purifying then.
Organolithium described in the step (1) is n-Butyl Lithium, tert-butyl lithium, two Iso propyl group ammonia lithiums or two (trimethyl silicon based) ammonia lithium, preferred n-Butyl Lithium.The described low temperature of step (1) is-40～-78 ℃, preferred-65～-78 ℃.Described barkite is dimethyl oxalate or oxalic acid diethyl ester, and described chlorine barkite is Dikalii Clorazepas ester or chlorine ethyl oxalate.The mol ratio of described 1,2-Difluorobenzene and n-Butyl Lithium and barkite is 1: 1.0-2.5: 1.0-3.0, being preferably mol ratio is 1: 1.05: 1.05.The solvent that the described reaction of step (1) is used is one of ether, dimethyl ether ethane (DME), tetrahydrofuran (THF), methyl tertiary butyl ether, dioxane or any the two mixture, preferred tetrahydrofuran (THF) or methyl tertiary butyl ether.
The described alkaline reagents of step of the present invention (2) is a sodium hydroxide, potassium hydroxide, and yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus is preferably sodium hydroxide and potassium hydroxide, and the best is a potassium hydroxide; Reductive agent in the described reduction reaction is preferably 80% hydrazine hydrate for the hydrazine hydrate (100 grams contain 60～80 gram hydrazine hydrates) of connection thioic acid sulfoacid sodium or 60%～80%.The reductive temperature is 60 ℃～120 ℃ under the described alkaline condition, and preferred temperature is 85～95 ℃.Described 2, the mol ratio of 3-difluoro acetophenone acid esters and hydrazine hydrate is 1: 1.5～3.0, and preferred molar ratio is 1: 1.5.Described 2, the employed solvent of the crystallization purifying of 3-difluorophenyl acetic acid is the mixture of methyl alcohol, ethanol, methyl alcohol and water or the mixture of ethanol and water, it perhaps is the mixture of one of normal hexane, hexanaphthene, sherwood oil, toluene, ethyl acetate, ethyl acetate and normal hexane, hexanaphthene, toluene or sherwood oil, preferred solvent is the mixture of methyl alcohol and water, its mixed volume ratio is 1: 2～10, and preferred volume ratio is 1: 3.In order to obtain purer reduzate, intermediate 2, behind the 3-difluoro acetophenone acid esters alkaline hydrolysis, with appropriate amount of organic extraction and the relevant impurity of removal, this organic solvent is nonpolar normal hexane, hexanaphthene, normal heptane, octane, benzene,toluene,xylene or sherwood oil etc., is preferably normal hexane.
Of the present invention 2; the preparation method of 3-difluorophenyl acetic acid is that raw material and n-Butyl Lithium are 1,2-Difluorobenzene base lithium through the low-temperature deep reaction with the 1,2-Difluorobenzene; under the temperature control condition, carry out the acidylate substitution reaction and make intermediate 1,2-Difluorobenzene ethyl ketone acid esters with barkite or its analogue; with after after alkalizing into salt and removing relevant organic impurity; again through reduction reaction; last acidifying separate out wished to get 2; 3-difluorophenyl acetic acid crude product; behind recrystallization purifying; total recovery is up to 77.6%, content 99.6% (HPLC).
Of the present invention 2, the preparation method of 3-difluorophenyl acetic acid has overcome deficiency and defective that prior art exists, and raw material is cheap and easy to get, step is few, aftertreatment simply is easy to realize industrialization, and constant product quality, and purity is good, total recovery is also high, make manufacturing cost significantly reduce, meet very much service requirements, be suitable for big standard industrialization to be produced as medicine intermediate and preparation liquid crystal.
Description of drawings
Fig. 1 represents that with 1,2,3-trifluoro-benzene is 2 of a reactive agent, the preparation method of 3-difluorophenyl acetic acid;
Fig. 2 represents 2 of German Patent WO2008078350 record, the preparation method of 3-difluorophenyl acetic acid;
Fig. 3 represents 2 of Japanese Patent JP2004352724 record, the preparation method of 3-difluorophenyl acetic acid;
Fig. 4 represents the reactions steps of method described in the background technology (1), (2) and (3);
Fig. 5 represents the present invention 2,3-difluorophenyl acetic acid preparation method's key step.
Embodiment
The present invention is elaborated with embodiment below in conjunction with accompanying drawing 5, embodiment 1-8 is in order to illustrating 2, the preparation of 3-difluoro acetophenone acid esters, and embodiment 9-14 is used for explanation with 2,3-difluoro acetophenone acid esters preparation 2, the process of 3-difluorophenyl acetic acid.This preparation method's key step as shown in Figure 5.Within the technical scheme scope that those skilled in that art all belong to the present invention and protected simple modifications that the present invention does or replacement etc.
Embodiment 1: illustrate 2, the preparation of 3-difluoro acetophenone acetoacetic ester
In the there-necked flask (A) of a 2L, add the 1,2-Difluorobenzene of 50g (0.438mol) and the anhydrous THF of 400ml, the airtight then N that fills
2, be cooled to-70 ℃ and begin to drip 2.5M n-Butyl Lithium when shared (2h) of 176ml (0.440mol) subsequently, drip Bi Houyu-65～-75 a ℃ insulation and continue to stir 2h; At the same time, in the there-necked flask (B) of another 2L, insert the oxalic acid diethyl ester of 67.2g (0.46mol) and the anhydrous THF of 100ml, the airtight then N that fills
2And be cooled to-70 ℃ thereupon.
Utilize N
2The material of bottle (A) slowly is pressed in the bottle (B) (time spent 1h and temperature control are in-65～-70 ℃ of intervals), in this temperature range, continue reaction 1h afterwards and open temperature naturally to 0 ℃ (time spent 1h), drip 60ml subsequently, 6N HCl is (time spent 30min in the previous reaction mixture, temperature is opened to 15 ℃, PH 3～4), after dripping HCl, this mixture is continued to stir 30min and standing demix, with the ethyl acetate extraction secondary of lower floor's milk sap water layer with 80ml, direct precipitation and distillation purifying behind the merging organic layer, get 2,3-difluoro acetophenone acetoacetic ester (weak yellow liquid): 85.1g, content: 96% (HPLC), yield: 90.8%.
IR(CHCl
3)V
max?1743.3(＞＝0)，1695.4(EtCO
2-)，1621.6(C
6H
5-)cm
-1；
1H-NMR(500MHz，CDCI
3)δ(ppm)1.41(t，J＝7Hz，3H)，4.45(q，J＝7Hz，2H)，7.25～7.69(m，3H)
MS?m/e：214(M
+)，141，113，63，29。
Embodiment 2: illustrate 2, the preparation of 3-difluoro acetophenone acid methyl esters
Press embodiment 1, replace oxalic acid diethyl ester and 1,2-Difluorobenzene effect, generate 2 by dimethyl oxalate, 3-difluoro acetophenone acid methyl esters, yield is 90.2%.
Embodiment 3: illustrate 2, the preparation of 3-difluoro acetophenone acetoacetic ester
Press embodiment 1, generate 2 by 1,2-Difluorobenzene and oxalic acid diethyl ester effect, 3-difluoro acetophenone acetoacetic ester, what be different from embodiment 1 is, and the molar ratio of 1,2-Difluorobenzene and ester is 1: 1.5, and yield is 90.5%.
Embodiment 4: illustrate 2, the preparation of 3-difluoro acetophenone acid methyl esters
Press embodiment 2, generate 2 by 1,2-Difluorobenzene and dimethyl oxalate effect, 3-difluoro acetophenone acid methyl esters, what be different from embodiment 2 is, and the molar ratio of 1,2-Difluorobenzene and ester is 1: 1.5, and yield is 89.6%.
Embodiment 5: illustrate 2, the preparation of 3-difluoro acetophenone acetoacetic ester
Press embodiment 1, replace the oxalic acid diethyl ester reaction, generate 2 by 1,2-Difluorobenzene and chlorine ethyl oxalate, the acid of 3-difluoro acetophenone, yield is 90.6%.
Embodiment 6: illustrate 2, the preparation of 3-difluoro acetophenone acetoacetic ester
Press embodiment 1,, generate 2 by 1,2-Difluorobenzene and oxalic acid diethyl ester effect, 3-difluoro acetophenone acetoacetic ester, what be different from embodiment 1 is that the organolithium of use makes tert-butyl lithium into by n-Butyl Lithium, yield 90.6%.
Embodiment 7: illustrate 2, the preparation of 3-difluoro acetophenone acetoacetic ester
Press embodiment 1,, generate 2 by 1,2-Difluorobenzene and oxalic acid diethyl ester effect, 3-difluoro acetophenone acetoacetic ester, what be different from embodiment 1 is that the reductive agent of use changes connection thioic acid sulfoacid sodium, yield 42.6% into.
Embodiment 8: illustrate 2, the preparation of 3-difluoro acetophenone acetoacetic ester
Press embodiment 1, by 1,2-two fluorobenzene and oxalic acid diethyl ester effect generate 2,3-difluoro acetophenone acetoacetic ester, and what be different from embodiment 1 is that temperature of reaction changes-45～-55 ℃ into, yield 35.8% by-65～-75 ℃.
Embodiment 9: illustrate 2, the preparation of 3-difluorophenyl acetic acid
Insert 2 of 91g (0.425mol) in a 1L single port bottle, 3-difluoro acetophenone acetoacetic ester also adds 270mlH
2The O dilution, 1h (the TLC demonstration is converted into the Jia salt fully) is stirred in the 50%KOH of Dropwise 5 7.3g (0.51mol) and continuation then; Add the 90ml normal hexane subsequently and stir 30min to remove organic layer impurity, the water layer that will tell moves in the there-necked flask of another clean 1L, adds 180mlH down in room temperature (20～25 ℃)
2The O dilution, 80% hydrazine hydrate (each time spent 30min of the 50%KOH of Dropwise 5 7.3g (0.51mol) and 39.9g (0.638mol) then, temperature～28 ℃), continue stirring reaction 1h again, in 30min, temperature of reaction risen to 85～95 ℃ and continue back flow reaction 16h thereafter.
Subsequently the reactive system temperature is reduced to room temperature (time spent 1h) and drip the 6NHCL of 230ml and regulate PH to 1 (time spent 30min, temperature～30 ℃) and continue again to stir 30min, separate out a large amount of white solids simultaneously, after filtration and with 100mlH in this
2 O washes 2～3 times until the water liquid PH 3～4 that leaches, then white solid is taken out in and place baking oven (～85 ℃) and dry by the fire in 4h, 69.5g 2,3-difluorophenyl acetic acid crude product, content (HPLC)＞96%.Aforementioned crude product is with methyl alcohol and H
2O=1: 3 crystallizations, get off-white color 2, the pure product 62.53g of 3-difluorophenyl acetic acid, content (HPLC): 99.6%, yield 85.5%.
IR(CH
3Cl
3)v
max?1690(＞＝O)，1631(C
6H
5-)cm
-1；
1H-NMR(500MHz，CDCl
3)δ(ppm)3.74(d，J＝1.14Hz，2H)，7.0～7.25(m，3H)MS?m/e：172(M
+)，142，141，127。
Embodiment 10: illustrate 2, the preparation of 3-difluorophenyl acetic acid
Press embodiment 9, by 2,3-difluoro acetophenone acetoacetic ester alkalization back and hydrazine hydrate reaction also make 2 after the acidifying, the 3-difluorophenyl acetic acid, and what be different from embodiment 9 is, used 2, and 3-difluoro acetophenone acetoacetic ester does not pass through distillation purifying, and yield is 82.1%.
Embodiment 11: illustrate 2, the preparation of 3-difluorophenyl acetic acid
Press embodiment 10, by 2,3-difluoro acetophenone acid methyl esters replaces 2, makes 2 after 3-difluoro acetophenone acetoacetic ester and hydrazine hydrate reduction and the acidifying, and 3-difluorophenyl acetic acid, yield are 83.5%.
Embodiment 12: illustrate 2, the preparation of 3-difluorophenyl acetic acid
Press embodiment 9, by 2,3-difluoro acetophenone acetoacetic ester and hydrazine hydrate carry out generating 2 after reduction reaction and the acidifying, the 3-difluorophenyl acetic acid, what be different from embodiment 9 is 2, handle without normal hexane 3-difluoro acetophenone acetoacetic ester alkalization back, directly with hydrazine hydrate reduce and acidifying become 2,3-difluorophenyl acetic acid, yield are 70.2%.
Embodiment 13: illustrate 2, the preparation of 3-difluorophenyl acetic acid
Press embodiment 9, with hydrazine hydrate reduction 2,3-difluoro acetophenone acetoacetic ester generates 2 through acidifying, the 3-difluorophenyl acetic acid, and what be different from embodiment 9 is that the temperature of reduction reaction changes 65～75 ℃ into, yield 60.6% by 85～95 ℃.
Embodiment 14: illustrate 2, the preparation of 3-difluorophenyl acetic acid
Press embodiment 9, with hydrazine hydrate reduction 2,3-difluoro acetophenone acetoacetic ester generates 2 through acidifying, the 3-difluorophenyl acetic acid, and what be different from embodiment 9 is that the amount of employed KOH and hydrazine hydrate respectively increases by 20%, yield 84.5%.
Embodiment 15: illustrate 2, the preparation of 3-difluorophenyl acetic acid
Press embodiment 9, the crude product recrystallization is with the mixture of ethyl acetate and normal hexane mixture replacement first alcohol and water, yield 75.6%.
Claims (20)
1. one kind 2, the industrial production process of 3-difluorophenyl acetic acid, its concrete steps are:
(1) at low temperatures, 1,2-Difluorobenzene and organolithium effect generate 1,2-Difluorobenzene base lithium, and this 1,2-Difluorobenzene base lithium reacts with oxalic acid fat or chlorine barkite again, generates 2,3-difluoro acetophenone acid esters;
(2) with described 2,3-difluoro acetophenone acid esters reduces under alkaline condition, separates out 2 through acidifying again, 3-difluorophenyl acetic acid, crystallization purifying then.
2. described 2 according to claim 1, the preparation method of 3-difluorophenyl acetic acid is characterized in that, organolithium described in the step (1) is n-Butyl Lithium, tert-butyl lithium, two tool propyl group ammonia lithiums or two (trimethyl silicon based) ammonia lithium.
3. described 2 according to claim 2, the preparation method of 3-difluorophenyl acetic acid is characterized in that the described organolithium of step (1) is a n-Butyl Lithium.
4. described 2 according to claim 1, the preparation method of 3-difluorophenyl acetic acid is characterized in that, the described low temperature of step (1) is-40～-78 ℃.
5. described 2 according to claim 4, the preparation method of 3-difluorophenyl acetic acid is characterized in that, the described low temperature of step (1) is-65～-78 ℃.
6. described 2 according to claim 1, the preparation method of 3-difluorophenyl acetic acid is characterized in that, the described barkite of step (1) is a dimethyl oxalate, oxalic acid diethyl ester, and described chlorine barkite is the Dikalii Clorazepas ester, the chlorine ethyl oxalate.
7. according to claim 2 or 3 described 2, the preparation method of 3-difluorophenyl acetic acid is characterized in that, the mol ratio of 1,2-Difluorobenzene and n-Butyl Lithium and barkite is 1: 1.0～2.5: 1.0～3.0 described in the step (1).
8. described 2 according to claim 7, the preparation method of 3-difluorophenyl acetic acid is characterized in that rubbing than being 1: 1.05: 1.05 of 1,2-Difluorobenzene described in the step (1) and n-Butyl Lithium and barkite.
9. described 2 according to claim 1, the preparation method of 3-difluorophenyl acetic acid is characterized in that the reductive agent in the described reduction reaction of step (2) is the hydrazine hydrate of connection thioic acid sulfoacid sodium or 60%～80%.
10. described 2 according to claim 9, the preparation method of 3-difluorophenyl acetic acid is characterized in that the used reductive agent of step (2) is 80% hydrazine hydrate.
11. described 2 according to claim 1, the preparation method of 3-difluorophenyl acetic acid is characterized in that the reductive temperature is 60～120 ℃ under the described alkaline condition of step (2).
12. described 2 according to claim 11, the preparation method of 3-difluorophenyl acetic acid is characterized in that the reductive temperature is 85～95 ℃ under the described alkaline condition of step (2).
13. according to claim 9 or 10 described 2, the preparation method of 3-difluorophenyl acetic acid is characterized in that step (2) is described 2, the mol ratio of 3-difluoro acetophenone acid esters and hydrazine hydrate is 1: 1.5～3.0.
14. described 2 according to claim 13, the preparation method of 3-difluorophenyl acetic acid is characterized in that step (2) is described 2, the rubbing than being 1: 1.5 of 3-difluoro acetophenone acid esters and hydrazine hydrate.
15. according to claim 1 described 2, the preparation method of 3-difluorophenyl acetic acid is characterized in that solvent that the described reaction of step (1) uses is one of ether, dimethyl ether ethane (DME), tetrahydrofuran (THF), methyl tertiary butyl ether, dioxane or any the two mixture.
16. according to claim 15 2, the preparation method of 3-difluorophenyl acetic acid is characterized in that the employed solvent of step (1) is tetrahydrofuran (THF) or methyl tertiary butyl ether.
17. according to claim 2 described 2, the preparation method of 3-difluorophenyl acetic acid, it is characterized in that step (2) described 2, the employed solvent of the crystallization purifying of 3-difluorophenyl acetic acid is the mixture of methyl alcohol, ethanol, methyl alcohol and water or the mixture of ethanol and water, perhaps is normal hexane, hexanaphthene, sherwood oil, toluene, ethyl acetate or is the mixture of ethyl acetate and one of normal hexane, hexanaphthene, toluene or sherwood oil.
18. according to claim 17 2, the preparation method of 3-difluorophenyl acetic acid is characterized in that step (2) is described 2, the solvent that uses in the 3-difluorophenyl acetic acid crystallization purifying is the mixture of ethanol and water.
19. described 2 according to claim 18, the preparation method of 3-difluorophenyl acetic acid is characterized in that the mixture of described methyl alcohol of step (2) and water, its mixed volume ratio is 1: 2～10.
20. described 2 according to claim 19, the preparation method of 3-difluorophenyl acetic acid is characterized in that the described mixed volume ratio of step (2) is 1: 3.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104892393A (en) * | 2015-04-29 | 2015-09-09 | 浙江普洛医药科技有限公司 | Preparation method of substituted phenylacetic acid derivative |
| CN107011134A (en) * | 2017-04-28 | 2017-08-04 | 浙江中欣氟材股份有限公司 | A kind of synthetic method of the bromoacetophenone of 2 fluorine 5 |
| CN108658759A (en) * | 2018-07-12 | 2018-10-16 | 河北凡克新材料有限公司 | A kind of preparation method of 2,3- difluoro-benzoic acids |
-
2009
- 2009-04-16 CN CNA2009100308219A patent/CN101550080A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104892393A (en) * | 2015-04-29 | 2015-09-09 | 浙江普洛医药科技有限公司 | Preparation method of substituted phenylacetic acid derivative |
| CN104892393B (en) * | 2015-04-29 | 2016-08-24 | 浙江普洛医药科技有限公司 | A kind of preparation method of substituted phenylacetic acid derivant |
| CN107011134A (en) * | 2017-04-28 | 2017-08-04 | 浙江中欣氟材股份有限公司 | A kind of synthetic method of the bromoacetophenone of 2 fluorine 5 |
| CN108658759A (en) * | 2018-07-12 | 2018-10-16 | 河北凡克新材料有限公司 | A kind of preparation method of 2,3- difluoro-benzoic acids |
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Application publication date: 20091007 |