EP1636164A2 - Verfahren zur herstellung von 3-aryl-2-hydroxypropansäurederivaten ohne racematspaltung - Google Patents

Verfahren zur herstellung von 3-aryl-2-hydroxypropansäurederivaten ohne racematspaltung

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Publication number
EP1636164A2
EP1636164A2 EP04785914A EP04785914A EP1636164A2 EP 1636164 A2 EP1636164 A2 EP 1636164A2 EP 04785914 A EP04785914 A EP 04785914A EP 04785914 A EP04785914 A EP 04785914A EP 1636164 A2 EP1636164 A2 EP 1636164A2
Authority
EP
European Patent Office
Prior art keywords
formula
compound
alkyl
agent
base
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04785914A
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English (en)
French (fr)
Inventor
Vijay Kumar Gajubhai Barot
Himanshu Madhusudanbhai Kothari
Braj Bhushan Lohray
Vidya Bhushan Lohray
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zydus Lifesciences Ltd
Original Assignee
Cadila Healthcare Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cadila Healthcare Ltd filed Critical Cadila Healthcare Ltd
Publication of EP1636164A2 publication Critical patent/EP1636164A2/de
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/297—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/10—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with ester groups or with a carbon-halogen bond
    • C07C67/11—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with ester groups or with a carbon-halogen bond being mineral ester groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/377—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to a process for the preparation of S (-) & R (+) isomers of 3- aryl-2-alkoxy propanoic acid derivatives of the structural formula (la) & (lb) respectively,
  • S (-)-3-aryl-2-alkoxy propanoic acid derivatives are essential intermediates for the preparation of a number of promising drugs. These compounds also have been considered useful for the treatment of eating disorders. They are also used as sweetening agents, in photosensitive materials and also in liquid crystals.
  • WO 0026200 Such processes are described in WO 0026200, WO 0140159, WO 0224625, WO 9962871 and WO 0063189.
  • the processes described in WO 0026200 (Rao et. al.) uses benzyl bromide for benzylation, which is highly lachrymatory. Again, in the processes described, the debenzylation of the final intermediate was done by using Pd/C under pressure. Such a process is costly and not very efficient at a large scale.
  • WO 0224625 describes a process for preparing chirally pure S (-) alkyl-2-alkoxy-3-(4-benzyloxyphenyl) propanoate. However, the process for obtaining the chirally pure product involves the following steps:
  • R 3 H .
  • the present invention relates to a process for . the preparation of S (-) & R (+) 3-aryl ⁇ 2-alkoxy propanoic acid derivatives of the structural formula (la) & (lb) respectively, which not only overcomes the draw backs of prior art, but also provides an improved process which possess several advantages like operational simplicity, cost effectiveness and easily implementable on a large scale.
  • the present invention relates to an improved process of preparation of S (-) & R (+) 3-aryl-2- alkoxy propanoic acid derivatives of the structural formula (la) & (lb) respectively, of high chemical and chiral purity.
  • the main objective of the present invention is to provide an improved process for the preparation of S (-) & R (+) 3-aryl-2-alkoxy propanoic acid derivatives of formula (la) &
  • Another objective of is to provide a cost-effective, safe and efficient process for obtaining chirally pure compounds of formula (la) & (lb) respectively.
  • a further objective of the present invention is to provide a process for the large scale production of compound of formula (la) & (lb) in a chirally pure form.
  • the present invention describes an improved process for the preparation of compound of the general formula (la) and (lb).
  • R 1 represent H or (Ci-C ⁇ ) alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl and the like.
  • R 2 represents (C C ⁇ ) alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl and the like.
  • R 3 represents H, protecting groups such as benzyl, substituted benzyl, (C ⁇ -C- alkyl and like.
  • Step 1 Selective O-alkylation or O-aralkylation of L-Tyrosine of formula (2a) using a base, a chelating agent, an alkyl or aralkyl halide in the presence of solvents to obtain the compound of formula (3a) (according to the general method described in "The practice of peptide synthesis", Bodanszky et. al., pp 50)
  • the selective O-alkylation or O-aralkylation of compound of formula (2a) can be carried out by reacting a base such as NaOH, KOH, K 2 CO 3 and the like, a chelating agent such as CuSO 4 , Cu (OAc) 2 and the like, and an alkyl or aralkyl halide in the presence of solvents such as aq. methanol, ethanol, DMF and the like or their combination thereof, at 25 °C-65 °C.
  • the bases may be present in 2-2.5 equivalents, the chelating agent in 0.5-0.7 equivalents, alkyl or aralkyl halide in 1-1.5 eq. and the solvent may be present in 4-20 times to the weight of L- tyrosine.
  • the base used is KOH (2 to 2.2 eq.)
  • the chelating agent is CuSO 4 (0.5 to 0.65 eq.)
  • Benzyl chloride is the aralkylating agent and the solvent used is aq. DMF at 50 °C-60 °C, to afford the copper complex of O-benzyl-L-tyrosine.
  • aqueous methanol WO 0026200 & WO 0224625
  • the rate of reaction is enhanced resulting in higher yield and better purity.
  • the volume of solvent required is reduced substantially (from ⁇ 20 times of the starting compound in case of MeOH to 4 times the starting compound in case of DMF).
  • Step 2 Diazotisation of the compound of the formula (3a) using a diazotising agent, in suitable solvents in acidic media to obtain the compound of formula (4a).
  • Diazotisation of the compound of formula (3a) is carried out with sodium nitrite in 2-5 equivalents, preferably 3-4 equivalents and strong acids such as sulfuric acid, orthophosphoric acid, cone. HC1 in 2-8 equivalents, KHSO 4 , preferably sulfuric acid in 3-5 equivalents at 0 °C to 25 °C. Solvents such as dioxane, acetone, methyl ethyl ketone and the like or their mixtures, preferably dioxane, may be used. [Tetrahedron Lett., 25, 2287- 2290(1971) & US 5,747,448 which are incorporated herein as reference]. The hydroxy acid (4a) was obtained in high chemical & chiral purity (e.e. > 98 %) with retention of configuration. Step 3: Dialkylation of the compound of formula (4a) using an excess of alkylating agent and excess base, in presence of suitable solvent to obtain optically pure compound of formula
  • compound of formula (4a) may be selectively esterif ⁇ ed to obtain compound of formula (5a), which is subsequently O-alkylated to obtain compound of formula (la) (Scheme 2)
  • Dialkylation of the compound of formula (4a) to get the dialkylated compound of formula (la) with high chemical and chiral purity was carried out by suitably modifying the process reported by Robert A.W. Johnstone et.al. (Tetrahedron, 35, 2169-2173, (1979)), which describes the alkylation of aliphatic alcohols and acids with alkylating agents at ambient temperature i.e.18-20 °C using an excess of potassium hydroxide as a base and DMSO as a solvent.
  • dialkylation of the compound of formula (4a) was carried out using an excess of base w.r.to the starting compound, with a suitable alkylating agent in presence of a solvent to obtain the compound of formula (la).
  • Suitable alkylating agents may be alkyl sulfates such as diethyl sulfate, dimethyl sulfate and the like; alkyl halides may be methyl iodide, ethyl iodide, ethyl bromide, propyl bromide, isopropyl bromide and the like.
  • the solvent used is DMSO.
  • the base may be present in 2 to 7 equivalents, preferably in 5 to 7 equivalents, the alkylating agent is present in equal moles w.r.to the base, and the solvent volume may be 4-10 times w.r.to the weight of the intermediate of formula (4a).
  • Suitable base may be selected from NaH, KOH, t-BuOK and the like.
  • the compound (4a) is obtained with high chemical (> 98 %) and chiral (e. e > 97 %) purity.
  • Prior art for this conversion reports the formation of ⁇ 20 % byproduct and upto 4 % racemization. (Deussen et. al.
  • the esterification may be carried out in the presence of a suitable base selected from Na 2 CO 3 , K 2 CO 3 , KOH, NaOMe, NaOEt and the like or mixture thereof in the presence of corresponding alkylating agents such as methyl iodide, ethyl iodide, dimethyl sulfate, diethyl sulfate and the like in solvents selected from DMF, DMSO and the like or mixtures thereof.
  • the alkylation of compound of formula (5a) to obtain compound of formula (la) may be carried out using an excess of base w.r.to the starting compound, with a suitable alkylating agent in the presence of a solvent to obtain compound of formula (la).
  • Suitable alkylating agents may be alkyl sulfates such as diethyl sulfate, dimethyl sulfate and the like; alkyl halides selected from methyl iodide, ethyl iodide, ethyl bromide, propyl bromide, isopropyl bromide and the like.
  • the solvent used is DMSO.
  • the base may be present in 2 to 7 equivalents, preferably in 5 to 7 equivalents, the alkylating agent is present in equal moles w.r.to the base, and the solvent volume may be 4-10 times w.r.to the weight of the intermediate of formula (5a).
  • Suitable base may be selected from NaH, KOH, t-BuOK and the like.
  • the crude product of formula (la) was purified by removal of excess alkyl halide or alkyl sulfate to obtain chemically pure and high chirally pure (e.e > 97%) compound of formula (la) without resolution. Removal of excess alkyl halide from the product can be done by vacuum distillation or by reacting with trialkyl amines like triethyl amine.
  • alkyl sulfate the excess alkyl sulfate, may be removed by treating with an organic base such as, trialkyl amines preferably with triethylamine and diisopropyl ethylamine (1-2 equivalents to alkyl sulfate) in suitable alcohol at a temp, ranging from 25-30 °C to reflux temperature of the solvent.
  • an organic base such as, trialkyl amines preferably with triethylamine and diisopropyl ethylamine (1-2 equivalents to alkyl sulfate) in suitable alcohol at a temp, ranging from 25-30 °C to reflux temperature of the solvent.
  • the deprotection may be carried out in the presence of an ester group.
  • Suitable acids for carrying out such deprotection may be Lewis acids such as AICI3, BF 3 etherate, BF 3 acetate and the like, preferably BF 3 etherate in 1.5 to 6 equivalents.
  • Suitable nucleophiles may be alkylthiols like ethanethiol, propanethiol, ethanedithiol, and the like, or -suitable alkyl aryl sulphides or dialkyl sulfides, preferably alkyl aryl sulfides more preferably thioanisole, in 1.5-7 equivalents. Solvents, if required may be selected from CH 2 C1 2 , CHC1 3 and like or mixtures thereof. The product contains less than or equal to 0.3 % of the rearranged product S (-) alkyl-2-alkoxy-3-(3-benzyl-4-hydroxyphenyl) propanoate. Suitable proportion of the Lewis acid and nucleophile may be used to minimize or remove the re- arranged side product.
  • suitable solvents include ethyl acetate, THF, dioxane, glacial acetic acid, aqueous or non aqueous alcohols such as methanol, ethanol, isopropanol and the like or their mixtures.
  • ethyl acetate in 5-10 volumes is used.
  • Suitable hydrogen donor reagent may be ammonium formate, cyclohexene, 1,4-cyclohexadiene and the like, preferably, ammonium formate in 3-6 equivalent.
  • the product often contains less than or equal to 0.3 % of the rearranged product S (-) alkyl-2-alkoxy-3-(3-benzyl-4-hydroxyphenyl) propanoate.
  • One skilled in the art may appreciate that minor differences in the temperature and reaction times may produce the same result and the other temperatures and time may produce the same result under other condition.
  • the present invention provides a novel process for the preparation of chemically & chirally pure S (-) 3-aryl-2-alkoxy propanoic acid derivatives of formula (la). 2.
  • the present invention provides a manufacturing process for the preparation of chemically and optically pure compounds of formula (la), without using resolution at any stage.
  • the invention also describes a process of converting compound of formula (2a) to compound of formula (3a) using DMF as the solvent. This has the benefit of enhancing the reactivity; thereby the reaction goes to completion and the product is obtained in high yield (55 %) with high chemical and chiral purity.
  • Another advantage is the reduction of reaction time (4-6 hours) during conversion of compound of formula (4a) to (la) compared to that reported in some of the literature ( 24 - 36 hours, WO 0224625).
  • This invention provides a method to obtain compound of formula (3a) in high assay and purity.
  • This invention provides a method to remove excess dialkyl sulfate in the presence of sensitive ester functional group during the conversion of compound of formula (4a) to (la) (R 3 ⁇ H).
  • the present invention provides an industrial process for the manufacture of compound of formula (la) which is practical, safe and cost effective.
  • Scheme 3 (i) Selective O-alkylation or O-aralkylation of D-tyrosine of formula (2b) by reacting a) a base and a chelating agent to obtain the copper complex; b) reacting the chelated product with an alkylating agent in the presence of solvents to obtain the compound of formula (3b), where R 3 represents suitable protective groups, by a process similar to that disclosed for the preparation of compound of formula (3a), scheme 1;
  • the compound of formula (lb), where all symbols are as defined earlier is obtained by the process comprising (i) converting the compound of formula (4b) to compound of formula (5b), by a process similar to that disclosed for the preparation of compound of formula (5 a), scheme 2;
  • the wet cake of O-benzyl-L-tyrosine copper complex (18.2 kg) was stirred with methanol in a 50 L glass assembly at reflux temperature. The solids were filtered hot through filter cloth using nutch filter, drained well and washed with methanol. It was dried in an oven at 65 °C- 70 °C.
  • the copper complex of O-benzyl-L-tyrosine weighed about 4.6 kg.
  • the Cu complex of O-benzyl-L-tyrosine was added into water in a 30 lit S.S. tank. It was stirred at ca.26-28 °C. To this slurry 35 % cone. HC1 (3.32 L) was added with stirring, and the solids obtained were filtered and drained well followed by washing with water and 10 % ammonia solution. The wet cake was centrifuged and again washed with water. The solids were dried in an oven at 65 °C-70 °C. The off white O-benzyl-L-tyrosine was obtained in 56 % yield (2.63 kg) with 95.8 % assay by HPLC and 100 % e.e.
  • the mixture was cooled to ca 26-28 °C, stirred, and resulting solids were collected by filtration, washed with water and drained well under vacuum.
  • the wet cake of O-benzyl-L-tyrosine copper complex (25.6 kg) was stirred with methanol in a 100 L glass assembly at reflux temperature. The solids were filtered hot through filter cloth using nutch filter, drained well and washed with methanol. It was dried in an oven at 65 °C- 70 °C.
  • the copper complex of O-benzyl-L-tyrosine weighed about 8.2 kg.
  • the Cu complex of O-benzyl-L-tyrosine was added into water in a 50 lit S. S.
  • Example 8 S (-) 2-hydroxy-3- (4-benzyloxyphenyl) propanoic acid To a 20 L round bottom three necked flask, 1,4 dioxane (6.25 L) was added followed by O- benzyl-L-tyrosine (500g, 1.84 mol). To this suspension dilute aqueous sulfuric acid solution (540 g, 5.53 mol, in 2.5 L water) was added at RT. It was cooled to 0 °C-2 °C in an ice salt bath. At 0 °C, aqueous sodium nitrite solution (636 g, 9.22 mol) was added. After the addition, it was stirred for extended period of time ( ⁇ upto 24 hours) below 30 °C.
  • the layers were separated, the organic layer was collected and aqueous layer again extracted with toluene. The combined organic layers were washed with water and brine. The organic layer after drying over anhydrous sodium sulfate and distilling under reduced pressure gave reddish brown liquid product.
  • the liquid product weighs 1 kg which contains 38.39 % diethyl sulfate (GC). The chemical purity of the product was 98.0 % by HPLC.
  • the crude liquid product was taken in a three-necked round bottom flask. To the product ethanol (2.2 L) and triethylamine (440 ml) were added. It was heated to reflux temperature and stirred. The excess ethanol was distilled out at reduced pressure.
  • the layers were separated, the organic layer was collected and aqueous layer again extracted with toluene. The combined organic layers were washed with water and brine. The organic layer after drying over anhydrous sodium sulfate and distilling under reduced pressure gave reddish brown liquid product.
  • the liquid product weighs 2.628 kg which contains 48.3 % diethyl sulfate by GC. The chemical purity of the product was 97.9 % by HPLC.
  • the crude liquid product was taken in a three necked round bottom flask. To the product ethanol (10 L) and triethylamine (1.4 1) were added. It was heated to reflux temperature and stirred. The excess ethanol was distilled out at reduced pressure.
  • the organic layer after drying over anhydrous sodium sulfate was distilled out at reduced pressure to obtain title compound in a liquid form.
  • the liquid product weighs 33.2 g which contains 68 % diethyl sulfate by GC.
  • the chemical purity of the product is 93.0 % by HPLC.
  • the crude liquid product was taken in a three necked round bottom flask. To the product ethanol (150 mL) and triethylamine (23.0 ml) were added. It was heated to reflux temperature with stirring. The excess ethanol was distilled out at reduced pressure. The liquid residue was dumped into ice-cold water and extracted with ethyl acetate. The organic layer was washed with brine.
  • the crude liquid product was stirred with diisopropyl ether at ca. 25-30 °C to extract the desired product.
  • the d ⁇ soisopropyl ether was removed to obtain the crude liquid product, which was stirred with n-heptane at ca. 25-30 °C to obtain the solid product in 70 % yield
  • the mixture was cooled to ca. 26-28 °C, stirred and resulting solids were collected by filtration, washed with water and drained well under vacuum.
  • the wet cake of O-benzyl-D-tyrosine copper complex (200 g) was stirred with methanol at reflux temperature. The solids were filtered and washed with methanol. It was dried in an oven at 65 °C-70 °C. The copper complex of O-benzyl-D-tyrosine weighed about 150 g.
  • Example 23 (+)-ethyl-2-ethoxy-3 -(4-benzyloxyphenyl) propanoate In a dry, three necked round bottom flask dimethyl sulfoxide (DMSO, 96 mL) was added followed by potassium hydroxide pellets (39 g, 0.59 mol).
  • DMSO dimethyl sulfoxide

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
EP04785914A 2003-06-06 2004-06-04 Verfahren zur herstellung von 3-aryl-2-hydroxypropansäurederivaten ohne racematspaltung Withdrawn EP1636164A2 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN586MU2003 2003-06-06
PCT/IN2004/000156 WO2005019152A2 (en) 2003-06-06 2004-06-04 Process for preparing 3-aryl-2-hydroxy propanoic acid derivatives without resolution

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EP1636164A2 true EP1636164A2 (de) 2006-03-22

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Country Link
EP (1) EP1636164A2 (de)
JP (1) JP2006527186A (de)
KR (1) KR20060015640A (de)
AP (1) AP2005003462A0 (de)
AU (1) AU2004266204A1 (de)
BR (1) BRPI0411409A (de)
CA (1) CA2527953A1 (de)
GB (1) GB0526499D0 (de)
IL (1) IL172260A0 (de)
MX (1) MXPA05013216A (de)
WO (1) WO2005019152A2 (de)

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Publication number Priority date Publication date Assignee Title
WO2006016517A1 (ja) * 2004-08-13 2006-02-16 Kaneka Corporation 光学活性２－置換オキシ－３－（４－置換オキシフェニル）プロピオン酸誘導体の製造方法
WO2014181362A1 (en) 2013-05-09 2014-11-13 Council Of Scientific & Industrial Research A process for the preparation of 3-aryl-2-hydroxy propanoic acid compounds

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE9801992D0 (sv) * 1998-06-04 1998-06-04 Astra Ab New 3-aryl-2-hydroxypropionic acid derivative I
WO2002024625A2 (en) * 2000-09-22 2002-03-28 Dr. Reddy's Research Foundation Process for the preparation of 3-aryl-2-hydroxy propanoic acid derivatives
WO2003027084A1 (en) * 2001-09-25 2003-04-03 Dr. Reddy's Laboratories Ltd. Improved process for the preparation of optically active phenoxazine derivatives as antidiabetic agents

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Title
See references of WO2005019152A2 *

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GB0526499D0 (en) 2006-02-08
AU2004266204A1 (en) 2005-03-03
AP2005003462A0 (en) 2005-12-31
JP2006527186A (ja) 2006-11-30
WO2005019152A3 (en) 2005-08-11
CA2527953A1 (en) 2005-03-03
KR20060015640A (ko) 2006-02-17
WO2005019152A2 (en) 2005-03-03
MXPA05013216A (es) 2006-03-09
IL172260A0 (en) 2009-02-11
BRPI0411409A (pt) 2006-07-25

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