CN1164571C - 制备2-甲氧基-4-(n-叔丁基氨基羰基)苯磺酰氯的方法 - Google Patents
制备2-甲氧基-4-(n-叔丁基氨基羰基)苯磺酰氯的方法 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 33
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 title claims description 7
- 238000002360 preparation method Methods 0.000 title abstract description 5
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- WIYRJJJJASYEKE-UHFFFAOYSA-N 2,3-dihydroxy-4-sulfobenzoic acid Chemical compound OC(=O)C1=CC=C(S(O)(=O)=O)C(O)=C1O WIYRJJJJASYEKE-UHFFFAOYSA-N 0.000 claims description 2
- 150000003973 alkyl amines Chemical class 0.000 claims description 2
- 229910052728 basic metal Inorganic materials 0.000 claims description 2
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- NDKBVBUGCNGSJJ-UHFFFAOYSA-M benzyltrimethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)CC1=CC=CC=C1 NDKBVBUGCNGSJJ-UHFFFAOYSA-M 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
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- 125000005270 trialkylamine group Chemical group 0.000 claims description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical group [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims 1
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- DNUYOWCKBJFOGS-UHFFFAOYSA-N 2-[[10-(2,2-dicarboxyethyl)anthracen-9-yl]methyl]propanedioic acid Chemical compound C1=CC=C2C(CC(C(=O)O)C(O)=O)=C(C=CC=C3)C3=C(CC(C(O)=O)C(O)=O)C2=C1 DNUYOWCKBJFOGS-UHFFFAOYSA-N 0.000 abstract 1
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
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- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
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- 238000005891 transamination reaction Methods 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- SEKLSGHFCVUDDM-UHFFFAOYSA-M O.[K+].OC1=C(C(C(=O)O)=CC=C1S(=O)(=O)[O-])O Chemical compound O.[K+].OC1=C(C(C(=O)O)=CC=C1S(=O)(=O)[O-])O SEKLSGHFCVUDDM-UHFFFAOYSA-M 0.000 description 1
- JKAFEYLQBNLQGD-UHFFFAOYSA-N O.[K].OC1=C(C(C(=O)O)=CC=C1S(=O)(=O)O)O Chemical compound O.[K].OC1=C(C(C(=O)O)=CC=C1S(=O)(=O)O)O JKAFEYLQBNLQGD-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
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- LTUDISCZKZHRMJ-UHFFFAOYSA-N potassium;hydrate Chemical compound O.[K] LTUDISCZKZHRMJ-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
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- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/02—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof
- C07C303/04—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof by substitution of hydrogen atoms by sulfo or halosulfonyl groups
- C07C303/06—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof by substitution of hydrogen atoms by sulfo or halosulfonyl groups by reaction with sulfuric acid or sulfur trioxide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/02—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof
- C07C303/22—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof from sulfonic acids, by reactions not involving the formation of sulfo or halosulfonyl groups; from sulfonic halides by reactions not involving the formation of halosulfonyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/57—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing carboxyl groups bound to the carbon skeleton
- C07C309/60—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing carboxyl groups bound to the carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及通过磺化间羟基苯甲酸，使所得的磺酸或其盐的羟基甲基化，把羧基和磺酸基转变为酰氯基，以及使4-氯磺酰基-3-甲氧基-苯甲酰氯与叔丁基胺反应来制备2-甲氧基-4-(N-叔丁基氨基羰基)苯磺酰氯的方法，该方法包括用96%的硫酸把通式(II)的3-甲氧基苯甲酸磺化，把所得的通式(III)的3-羟基-4-磺基苯甲酸以其通式(IV)的盐形式分离出来，其中Z代表碱金属或铵根，在相转移催化剂存在下，在大约11.5的pH值下进行通式(IV)化合物的甲基化，把其中Z具有如上定义的通式(V)的3-甲氧基-4-磺基苯甲酸单盐转变为通式(VI)的酰氯，并且在酸结合剂存在下，在一种非质子性溶剂中并在低温下使通式(VI)化合物与等摩尔量或少量过量的叔丁基胺反应。
Description
2-甲氧基-4-(N-叔丁基氨基羰基)苯磺酰氯对于血管加压素拮抗化合物SR 121463来说是一种重要的构件单元，在专利申请WO9715556中描述了它的制备方法。由于所用的原料和反应，上述专利申请中描述的方法只适用于以实验室规模和低产率制备产物，而且涉及几步纯化步骤。该方法是这样的：以3-甲氧基-4-硝基苯甲酸为原料，经过酰氯把它转变为酰胺，然后还原硝基并在乙酸介质中使用大量过量的二氧化硫通过Sandmeyer型反应进行氨基交换。该合成的最薄弱的部分是氨基交换为氯磺酰基，反应难以控制，主反应伴随着一系列副反应，因而只以大约50％的产率制得了带有大量杂质的产物。
从文献中，从SHAN的工作(J.Chem.Soc.1930，1293)中已知2-甲氧基-(4-氨基羰基)苯磺酰胺和4-氯磺酰基-3-甲氧基苯甲酰氯的制备方法。
我们的新方法利用上述1930的研究工作的基本要素，但是把它改进为一种在技术上可以实现并且能广泛满足二十世纪后期对环境、经济和技术要求的方法。
与SHAN的方法相比，我们的方法包含下列发现：间-羟基苯甲酸的磺化不是采用危险并且难于处理的发烟硫酸而是采用96％的硫酸进行，它也作为反应的溶剂。把反应混合物倾倒在冰上后，得到产物的沉淀，可以把不含异构体的产物纯品过滤出来。反应的产率在90％左右，可以其钾盐的形式把磺酸分离出来。
在文献描述的方法中，使用过量18-倍的硫酸二甲酯进行甲基化步骤，随后分小批加入大量的25％的氢氧化钾。然而，我们也发现，如果使用较高的温度，将pH值维持在11.5以上，并且在水性介质或两相混合物中使用相转移催化剂(PTC)，只要少量过量的硫酸二甲酯就足够了。把产物以其盐形式分离出来后，不需要进一步纯化就可以得到分析纯(96-99％)的产物，产率达到90％。
使3-甲氧基-4-磺基苯甲酸单钾盐与一种无机酸卤化物反应，可以得到4-氯磺酰基-3-甲氧基苯甲酰氯。
我们意外地发现，在低温下并且合适的溶剂中，叔丁基胺选择性地与芳族酰氯反应，得到所要的2-甲氧基-4-(N-叔丁基氨基羰基)苯磺酰氯，产率为92％，纯度为96％，因此，其不需要进一步纯化就可用于合成药物物质。
根据上面的描述，本发明的主题是一种通过磺化间羟基苯甲酸，使所得的磺酸或其盐的羟基甲基化，把羧基和磺酸基转变为酰氯基，并且使4-氯磺酰基-3-甲氧基苯甲酰氯与叔丁基胺反应来制备2-甲氧基-4-(N-叔丁基氨基羰基)苯磺酰氯的方法，该方法包括用96％的硫酸磺化式II 3-羟基苯甲酸，
把所得的式III 3-羟基-4-磺基苯甲酸
以其通式IV的盐形式
分离出来，-其中Z代表碱金属或铵根-，在相转移催化剂存在下、在大于11.5的pH值下进行通式IV化合物的甲基化，
把其中Z具有如上定义的通式V 3-甲氧基-4-磺基苯甲酸单盐
转变为式VI酰氯，
并且在酸结合剂存在下，在非质子性溶剂中并且低温下，使所得式VI化合物与等摩尔量或少量过量的叔丁基胺反应。
按照本发明的优选实施方案，用过量的96％的硫酸进行磺化，硫酸也用作反应的溶剂。反应在60-120℃、优选90℃的温度下进行。把式IV的化合物
以其钠盐、钾盐或铵盐、优选钾盐的形式分离出来。至于相转移催化剂，可使用四丁基氢氧化铵(TEBA)或三甲基苄基氢氧化铵或它们的盐，优选使用四丁基氯化铵或三甲基苄基氯化铵。在水中或在水和一种不与水混溶的溶剂的混合物中进行通式IV化合物的甲基化，
其中Z如上所定义。至于不与水混溶的溶剂可以使用甲苯、二甲苯或二氯甲烷。将通式V化合物
以其钠盐、钾盐或铵盐、优选以其钾盐的形式分离出来。
至于酸结合剂，可使用三烷基胺、二烷基苯胺、叔烷基胺，优选叔丁基胺。至于非质子性溶剂，可使用氯化烃，例如二氯甲烷、二氯乙烷、氯仿；或乙腈或丙酮，优选二氯甲烷或丙酮。3-甲氧基-4-氯磺酰基苯甲酰氯与叔丁基胺的反应在-40℃至室温、优选-5℃至-10℃的温度下进行。
下列实施例进一步详细说明本发明，但权利要求不受实施例的限定。
实施例
实施例1
在室温和搅拌下，向550g(300cm3)96％的硫酸中加入80g(0.58mol)3-羟基苯甲酸，把所得的棕色溶液加热到90℃并保持该温度。将粘稠的可处理物质倾倒在碎冰上，过滤沉淀，用冰冷的水洗涤。把湿产物溶于热水中，用活性炭澄清，将pH调节到3-3.5，冷却后，过滤出沉淀出来的白色结晶，接着用水和丙酮洗涤，干燥，得到140g 3-羟基-4-磺基苯甲酸单钾盐一水合物。该产物不需要纯化就可用于下一步。熔点：＞300℃；产率：87.9％。
实施例2
向11.2g(0.2mol)氢氧化钾在50cm3蒸馏水中的溶液中加入27.5g(0.1mol)3-羟基-4-磺基苯甲酸钾一水合物，把0.5g TEBA溶于该溶液中。把溶液加热到50℃，在剧烈搅拌下滴加由25cm3(33.25g，0.26mol)硫酸二甲酯、17.4g(0.31mol)氢氧化钾和60cm3水组成的溶液，同时把pH维持在11.5-12.5之间。把反应混合物的温度保持在50℃，经常核查pH值。用活性炭澄清溶液，过滤，用盐酸把pH调节到2，然后在冰箱中冷却过夜。
过滤出沉淀出来的结晶，用蒸馏水洗涤，干燥至恒重：26.7g(92.7％)。
实施例3a
在搅拌下，向105cm3(172.7g，1.128mol)磷酰氯中加入57.6g(0.2mol)3-甲氧基-4-磺基苯甲酸钾一水合物。在油浴中把反应混合物加热到110-120℃。3小时之内停止产生氯化氢气体，在该温度下再保温反应混合物1小时，然后加入500g碎冰。过滤出沉淀出来的白色结晶，用冰冷的水洗涤，在真空下干燥，得到45-49g 3-甲氧基-4-氯磺酰基苯甲酰氯。
熔点：86-88℃；产率：84-91％。
实施例3b
在搅拌下，向105cm3(172.7g，1.128mol)磷酰氯中加入57.6g(0.2mol)3-甲氧基-4-磺基苯甲酸钾盐一水合物。在油浴中把反应混合物加热到110-120℃。3小时之内停止产生氯化氢气体，在该温度下再保温反应混合物1小时，然后加入500g碎冰。用二氯甲烷萃取反应混合物几次。干燥合并后的有机相。经过分析测定，溶液可直接用于下一步。
实施例3c
把137g二甲基甲酰胺冷却到-5℃，加入235g磷酰氯。在搅拌下温热混合物，分批加入125g 3-甲氧基-4-磺基苯甲酸，然后加热到40-45℃，在该温度下保温1小时，然后倾倒在550g碎冰上。过滤沉淀，用水充分洗涤，干燥，得到110g产物，产物的品质与实施例3a中得到的产物类似。
实施例4
把49g(0.182mol)按照实施例3b中所述方法制得的3-甲氧基-4-氯磺酰基苯甲酰氯的二氯甲烷溶液冷却到-10℃，在剧烈搅拌下用50-60分钟的时间向其中滴加-10℃的26.7g(0.364mol)叔丁基胺在260cm3二氯甲烷中的溶液。然后把混合物倾倒在含有40cm3 1M盐酸的1000cm3冰水中。分离出二氯甲烷相，用2×1000cm3冰水洗涤，通过硫酸钠干燥，用活性炭澄清，过滤并且蒸发，得到51.0g 2-甲氧基-4-(N-叔丁基氨基羰基)苯磺酰氯。产率：92％；熔点：145-149℃。纯度：95-96％(通过HPLC、NMR测定)；杂质：1-3％的二叔丁基酰胺衍生物。
Claims (19)
1.通过磺化间羟基苯甲酸，使所得的磺酸或其盐的羟基甲基化，把羧基和磺酸基转变为酰氯基，以及使4-氯磺酰基-3-甲氧基-苯甲酰氯与叔丁基胺反应来制备2-甲氧基-4-(N-叔丁基氨基羰基)苯磺酰氯的方法，该方法包括用96％的硫酸磺化式II3-羟基苯甲酸，
把所得的式III 3-羟基-4-磺基苯甲酸
以其通式IV的盐形式
分离出来，-其中Z代表碱金属或铵根-，在相转移催化剂存在下，在11.5的pH值下进行通式IV化合物的甲基化，把其中Z具有如上定义的通式V3-甲氧基-4-磺基苯甲酸单盐
转变为式VI的酰氯，
并且在酸结合剂存在下，在非质子性溶剂中并在低温下，使式VI化合物
与等摩尔量或少量过量的叔丁基胺反应。
2.权利要求1中所述的方法，其包含使用过量的96％的硫酸进行磺化反应，硫酸也用作反应的溶剂。
3.权利要求2中所述的方法，其包含在60-120℃的温度下进行反应。
4.权利要求3中所述的方法，其包含在90℃的温度下进行反应。
5.权利要求1中所述的方法，其包含将式IV的化合物
以其钠盐、钾盐或铵盐的形式分离出来。
6.权利要求5中所述的方法，其包含将IV的化合物以钾盐的形式分离出来。
7.权利要求1中所述的方法，其包含使用四丁基氢氧化铵或三甲基苄基氢氧化铵或其盐、四丁基氯化铵或三甲基苄基氯化铵作为相转移催化剂。
8.权利要求7中所述的方法，其包括使用四丁基氯化铵或三甲基苄基氯化铵作为相转移催化剂。
9.权利要求1中所述的方法，其包含在水中或在水和一种不与水混溶的溶剂的混合物中进行通式IV化合物
的甲基化，其中Z如权利要求1所定义。
10.权利要求9中所述的方法，其包含使用甲苯、二甲苯或二氯甲烷作为不与水混溶的溶剂。
11.权利要求1中所述的方法，其包含将通式V化合物
以其钠盐、钾盐或铵盐的形式分离出来。
12.权利要求11中所述的方法，其包含将通式V化合物以钾盐形式分离出来。
13.权利要求1中所述的方法，其包含使用三烷基胺、二烷基苯胺、叔烷基胺作为酸结合剂。
14.权利要求13中所述的方法，其包括使用叔丁基胺作为酸结合剂。
15.权利要求1中所述的方法，其包含使用氯化烃、乙腈或丙酮作为非质子性溶剂。
16.权利要求15中所述的方法，其中的氯化烃为二氯甲烷、二氯乙烷、氯仿。
17.权利要求15中所述的方法，其中包含使用二氯甲烷或丙酮作为非质子性溶剂。
18.权利要求1中所述的方法，其包含在-40℃至室温的温度下进行3-甲氧基-4-氯磺酰基苯甲酰氯与叔丁基胺的反应。
19.权利要求18中所述的方法，其包含在-5℃至-10℃温度下进行3-甲氧基-4-氯磺酰基苯甲酰氯与叔丁基胺的反应。
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| HUP9902375 | 1999-07-15 | ||
| HU9902375A HU225150B1 (en) | 1999-07-15 | 1999-07-15 | Novel process for producing 2-methoxy-4-(t-butylaminocarbonyl)-benzenesulfonyl chloride |
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| AU (1) | AU6308300A (zh) |
| BR (1) | BR0012430B1 (zh) |
| CA (1) | CA2378337C (zh) |
| CZ (1) | CZ2002146A3 (zh) |
| DE (1) | DE60008884T2 (zh) |
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| HR (1) | HRP20020141B1 (zh) |
| HU (1) | HU225150B1 (zh) |
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| CN105621518A (zh) * | 2015-12-29 | 2016-06-01 | 浙江奇彩环境科技股份有限公司 | 一种3,4-二氯苯磺酸废水的资源化处理方法 |
| CN110372548A (zh) * | 2018-04-12 | 2019-10-25 | 南京化学试剂股份有限公司 | 一种5-磺基水杨酸的精制方法 |
| CN113402437B (zh) * | 2021-06-29 | 2023-07-14 | 河北维达康生物科技有限公司 | 一种合成膳食补充剂褪黑素的新方法 |
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| US3953507A (en) | 1973-08-31 | 1976-04-27 | Stauffer Chemical Company | N-t-butyl-α-(3,5-substituted phenoxy) alkyl amides and their use as herbicides |
| FR2740136B1 (fr) | 1995-10-24 | 1998-01-09 | Sanofi Sa | Derives d'indolin-2-one, procede pour leur preparation et les compositions pharmaceutiques les contenant |
| FR2757157B1 (fr) * | 1996-12-13 | 1999-12-31 | Sanofi Sa | Derives d'indolin-2-one, procede pour leur preparation et compositions pharmaceutiques les contenant |
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Also Published As
| Publication number | Publication date |
|---|---|
| HUP9902375A3 (en) | 2002-11-28 |
| CN1360569A (zh) | 2002-07-24 |
| HRP20020141A2 (en) | 2003-10-31 |
| JP4636761B2 (ja) | 2011-02-23 |
| CZ2002146A3 (cs) | 2002-11-13 |
| HUP9902375A2 (hu) | 2001-05-28 |
| US6548702B1 (en) | 2003-04-15 |
| BR0012430A (pt) | 2002-03-26 |
| CA2378337A1 (en) | 2001-01-25 |
| JP2003505366A (ja) | 2003-02-12 |
| EP1202960A1 (en) | 2002-05-08 |
| AU6308300A (en) | 2001-02-05 |
| SK286031B6 (sk) | 2008-01-07 |
| DE60008884T2 (de) | 2005-02-03 |
| EP1202960B1 (en) | 2004-03-10 |
| HRP20020141B1 (en) | 2010-09-30 |
| HU225150B1 (en) | 2006-07-28 |
| WO2001005754A1 (en) | 2001-01-25 |
| MXPA01013342A (es) | 2002-08-20 |
| PL199425B1 (pl) | 2008-09-30 |
| BR0012430B1 (pt) | 2011-05-17 |
| CA2378337C (en) | 2008-05-20 |
| ES2215699T3 (es) | 2004-10-16 |
| ATE261430T1 (de) | 2004-03-15 |
| HU9902375D0 (en) | 1999-10-28 |
| PL352466A1 (en) | 2003-08-25 |
| DE60008884D1 (de) | 2004-04-15 |
| SK472002A3 (en) | 2003-02-04 |
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