WO2005037777A1 - ビカルタミドの製造方法及びその中間体の精製方法 - Google Patents
ビカルタミドの製造方法及びその中間体の精製方法 Download PDFInfo
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- WO2005037777A1 WO2005037777A1 PCT/JP2004/015669 JP2004015669W WO2005037777A1 WO 2005037777 A1 WO2005037777 A1 WO 2005037777A1 JP 2004015669 W JP2004015669 W JP 2004015669W WO 2005037777 A1 WO2005037777 A1 WO 2005037777A1
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- Prior art keywords
- compound
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- formula
- crystallization
- crystals
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 54
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 title claims abstract description 9
- 229960000997 bicalutamide Drugs 0.000 title claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 138
- 239000013078 crystal Substances 0.000 claims abstract description 69
- 239000002904 solvent Substances 0.000 claims abstract description 45
- SCKXCAADGDQQCS-UHFFFAOYSA-N Performic acid Chemical compound OOC=O SCKXCAADGDQQCS-UHFFFAOYSA-N 0.000 claims abstract description 31
- OKIHXNKYYGUVTE-UHFFFAOYSA-N 4-Fluorothiophenol Chemical compound FC1=CC=C(S)C=C1 OKIHXNKYYGUVTE-UHFFFAOYSA-N 0.000 claims abstract description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 75
- 238000002425 crystallisation Methods 0.000 claims description 31
- 230000008025 crystallization Effects 0.000 claims description 31
- 238000001816 cooling Methods 0.000 claims description 27
- 230000032683 aging Effects 0.000 claims description 16
- -1 4-fluorophenylthio Chemical group 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 69
- 239000000243 solution Substances 0.000 description 46
- AWYDPLFHUNXJRH-UHFFFAOYSA-N 3,3,3-trifluoro-2-methyl-n-phenylpropanamide Chemical compound FC(F)(F)C(C)C(=O)NC1=CC=CC=C1 AWYDPLFHUNXJRH-UHFFFAOYSA-N 0.000 description 38
- 239000000203 mixture Substances 0.000 description 25
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 21
- 238000004811 liquid chromatography Methods 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- LGRFSURHDFAFJT-UHFFFAOYSA-N Phthalic anhydride Natural products C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 description 11
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 description 11
- 239000012044 organic layer Substances 0.000 description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- 239000002585 base Substances 0.000 description 10
- 238000005406 washing Methods 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000007810 chemical reaction solvent Substances 0.000 description 9
- 238000001914 filtration Methods 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 8
- 239000012535 impurity Substances 0.000 description 7
- 235000011121 sodium hydroxide Nutrition 0.000 description 7
- GLVYLTSKTCWWJR-UHFFFAOYSA-N 2-carbonoperoxoylbenzoic acid Chemical compound OOC(=O)C1=CC=CC=C1C(O)=O GLVYLTSKTCWWJR-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- 235000017550 sodium carbonate Nutrition 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 235000012970 cakes Nutrition 0.000 description 4
- 239000008367 deionised water Substances 0.000 description 4
- 229910021641 deionized water Inorganic materials 0.000 description 4
- 235000021463 dry cake Nutrition 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- ZTHRQJQJODGZHV-UHFFFAOYSA-N n-phenylpropanamide Chemical compound CCC(=O)NC1=CC=CC=C1 ZTHRQJQJODGZHV-UHFFFAOYSA-N 0.000 description 4
- 150000004965 peroxy acids Chemical class 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- RQXGETUNXUENJX-UHFFFAOYSA-N n-[3-(trifluoromethyl)phenyl]propanamide Chemical compound CCC(=O)NC1=CC=CC(C(F)(F)F)=C1 RQXGETUNXUENJX-UHFFFAOYSA-N 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 230000005070 ripening Effects 0.000 description 3
- 235000010265 sodium sulphite Nutrition 0.000 description 3
- RRHGJUQNOFWUDK-UHFFFAOYSA-N Isoprene Chemical compound CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- XDLDASNSMGOEMX-UHFFFAOYSA-N benzene benzene Chemical compound C1=CC=CC=C1.C1=CC=CC=C1 XDLDASNSMGOEMX-UHFFFAOYSA-N 0.000 description 2
- 239000003518 caustics Substances 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- HRKQOINLCJTGBK-UHFFFAOYSA-N dihydroxidosulfur Chemical group OSO HRKQOINLCJTGBK-UHFFFAOYSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- LKCHSNFSFPARNH-UHFFFAOYSA-N 2,3-dihydrothiophen-5-ol Chemical compound OC1=CCCS1 LKCHSNFSFPARNH-UHFFFAOYSA-N 0.000 description 1
- WDRCPKDLZOQCFU-UHFFFAOYSA-N 2-methyl-n-phenylpropanamide Chemical compound CC(C)C(=O)NC1=CC=CC=C1 WDRCPKDLZOQCFU-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 108091006629 SLC13A2 Proteins 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- MMCOUVMKNAHQOY-UHFFFAOYSA-N carbonoperoxoic acid Chemical compound OOC(O)=O MMCOUVMKNAHQOY-UHFFFAOYSA-N 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000002781 deodorant agent Substances 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- MQRJBSHKWOFOGF-UHFFFAOYSA-L disodium;carbonate;hydrate Chemical compound O.[Na+].[Na+].[O-]C([O-])=O MQRJBSHKWOFOGF-UHFFFAOYSA-L 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- KIWBPDUYBMNFTB-UHFFFAOYSA-M ethyl sulfate Chemical compound CCOS([O-])(=O)=O KIWBPDUYBMNFTB-UHFFFAOYSA-M 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- YXVFYQXJAXKLAK-UHFFFAOYSA-N p-hydroxybiphenyl Natural products C1=CC(O)=CC=C1C1=CC=CC=C1 YXVFYQXJAXKLAK-UHFFFAOYSA-N 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/02—Preparation of sulfones; Preparation of sulfoxides by formation of sulfone or sulfoxide groups by oxidation of sulfides, or by formation of sulfone groups by oxidation of sulfoxides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/06—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
- C07C317/46—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
Definitions
- the present invention relates to a method for producing bicalutamide and a method for purifying an intermediate thereof.
- pharmaceuticals are often administered to the human body, and the amount of impurities in them is generally tightly controlled.
- the administered drug contains 0.10% or more impurities, the structure of the impurity is usually examined, and if 0.15% or more, its toxicity is checked, and there is no safety problem. Need to be reviewed and confirmed.
- compound (3) Obtained through 4'-cyano 3 — (4—fluo Mouth phenylthio) 1-2—hydroxy-2—methinolee 3′—triphenylphenolmethylpropionaylide (hereinafter, referred to as compound (3)) is generally produced and oxidized to compound (3).
- compound (3) Obtained through 4'-cyano 3 — (4—fluo Mouth phenylthio) 1-2—hydroxy-2—methinolee 3′—triphenylphenolmethylpropionaylide (hereinafter, referred to as compound (3)) is generally produced and oxidized to compound (3).
- An object of the present invention is to provide a method which is industrially superior in the production of compound (4), in which the production of irremovable impurities contained in the final product is suppressed.
- the deoxysulfide compound is contained in (3) in excess of 0.06% (LC area percentage) relative to compound (3), compound (3) crystals are purified by crystallization. And subjecting the resulting purified crystals to an oxidation reaction. As a result, it has been found that the content of the deoxysulfonyl compound in the crystal of the compound (4) can be reduced to less than 0.10% (LC area percentage) relative to the compound (4).
- the present invention has been completed. That is, the present invention is as described below.
- a step A comprising obtaining a compound (2) represented by
- the compound (2) is reacted with 4-fluorothiophenol to obtain a compound of the formula A step B comprising obtaining a crude crystal of the compound (3) represented by the formula (I), dissolving the crude crystal in a solvent, and then crystallization to obtain a purified crystal of the compound (3);
- a formula (4) comprising a step C comprising reacting a purified crystal of the compound (3) with a percarboxylic acid to obtain bicalutamide;
- ⁇ 4> The method according to any one of ⁇ 1> to ⁇ 3>, wherein a seed crystal of the purified compound (3) is added before the start of crystallization.
- ⁇ 5> The method according to any one of ⁇ 1> to ⁇ 4>, wherein the crystallization includes aging and cooling.
- ⁇ 6> The method according to ⁇ 5>, wherein the aging is performed at around 55 ° C.
- ⁇ 7> The method according to ⁇ 5> or ⁇ 6>, wherein the aging time is 1 to 2 hours.
- a method for purifying a compound (3) crystal comprising dissolving a crude crystal of the compound (3) represented by
- the crude crystal of the compound (3) is represented by the formula (2)
- the compound (2) has the formula (1)
- a method obtained by reacting a compound represented by the formula with a percarboxylic acid is a method obtained by reacting a compound represented by the formula with a percarboxylic acid.
- ⁇ 1 2> The crystal of the compound (3) is 4′-Icyan-13- (4-fluorophenythio) _2-Methyl_3,1-Trifluoromethylpropionanilide 0.06 The method according to ⁇ 1>, wherein the content is 0.1 to 0.3%.
- ⁇ 15> The method according to any one of ⁇ 10> to ⁇ 14>, wherein a seed crystal of the purified compound (3) is added before the start of crystallization.
- ⁇ 16> The method according to any one of ⁇ 10> to ⁇ 15>, wherein the crystallization includes aging and cooling.
- ⁇ 17> The method according to ⁇ 16>, wherein the aging is performed at around 55 ° C. ⁇ 18> The method according to ⁇ 16> or ⁇ 17>, wherein the aging time is 1-2 hours.
- ⁇ 20> The method according to any one of ⁇ 16> to ⁇ 19>, wherein the cooling rate is 5 to 15 ° C / hour.
- compound (1) a commercially available product may be used, or a compound synthesized according to a method known in the art (for example, International Patent Publication WO 03/053920 pan fret) or a method analogous thereto. May be.
- 4-fluorothiophenol hereinafter, referred to as compound (5) is commercially available and can be used.
- the compound (2) can be obtained by oxidizing the compound (1) (hereinafter, this step is referred to as step A).
- step A an oxidizing agent, percarboxylic acid, is added to compound (1) in a suitable reaction solvent.
- percarboxylic acid examples include m-chloroperbenzoic acid, monoperphthalic acid and the like.
- Monoperphthalic acid is preferred from the viewpoint of safety and reactivity.
- Monoperphthalic acid can be easily prepared, for example, by reacting phthalic anhydride with hydrogen peroxide.
- monoperphthalic acid is prepared by mixing phthalic anhydride and hydrogen peroxide in approximately equimolar amounts in a suitable solvent in the presence of a base.
- hydrogen peroxide is used in a small excess relative to phthalic anhydride.
- hydrogen peroxide is used in an amount of usually 1 to 1.5 mol, preferably 1 to 1.3 mol, per 1 mol of phthalic anhydride.
- phthalic anhydride Since phthalic anhydride is inexpensive, has no hygroscopicity, and is easy to handle, it is preferred as a raw material for synthesizing mono-perphthalic acid.
- Hydrogen peroxide solution is usually 20
- a solution having a concentration of 550%, preferably 30-35% is used. 30 ⁇
- Hydrogen peroxide at a concentration of 35% is preferred because it has a low risk of explosion, is commercially available, and is inexpensive.
- Examples of the base include sodium carbonate, sodium hydrogencarbonate, potassium carbonate, sodium hydroxide and the like. From the viewpoint of economy, sodium carbonate is preferred.
- the amount of the base to be used is generally 1 to 1.3 mol, preferably 1 to 1.2 mol, per 1 mol of phthalic anhydride.
- Solvents to be used include solvents such as water.Among them, there are no metals that may exhibit catalytic activity for decomposition of hydrogen peroxide.Solubility and economy of hydrogen peroxide In view of this, deionized water is preferred.
- the amount of the solvent to be used is generally 2 to 5 ml, preferably 3 to 4 ml, per 1 g of phthalic anhydride.
- the reaction temperature is usually ⁇ 5 to + 5 ° C., preferably 15 to 0 ° C.
- the reaction time varies depending on the reaction temperature and the like, but is usually 0.5 to 2 hours, preferably 0.5 to 0.8 hours.
- the reaction system is neutralized with an acid such as sulfuric acid (preferably, 98% sulfuric acid), and is isolated by a usual post-treatment. It can be used for the subsequent oxidation reaction (that is, the above step A and step C) without purification.
- an acid such as sulfuric acid (preferably, 98% sulfuric acid)
- Suitable solvents for the reaction in step A include, for example, toluene, benzene benzene, ethyl acetate and the like, among which ethyl acetate is preferred from the viewpoint of solubility in the compound (1).
- the amount of the solvent to be used is usually 2 to 5 ml, preferably 2.5 to 4 ml, per 1 g of compound (1).
- the amount of percarboxylic acid to be used is generally 1.5 to 3 moles, preferably 1.8 to 2.5 moles, per 1 mole of compound (1).
- a percarboxylic acid solution dropwise from the viewpoint of ease of addition, safety and operability.
- the solution may be added in two or more portions.
- Suitable solvents for preparing the percarboxylic acid solution include, for example, ethyl acetate, ethers (eg, getyl ether, etc.), and among them, ethyl acetate is preferred from the viewpoint of safety. It is desirable to use the same solvent as the above reaction solvent.
- the amount of the solvent used for preparing the percarboxylic acid solution is usually 3 to 10 ml, preferably 3.5 to 7 ml, per 1 g of the percarboxylic acid.
- the dropping speed depends on the concentration of the dropping solution and the temperature of the dropping solution and the solution to be dropped. It is usually 1-4 ml / min, preferably 1.5-3 m1 / min per gram.
- the temperature of the dropping solution is usually 0 to 35 ° C, preferably 10 to 30 ° C, and the temperature of the solution to be dropped is usually 20 to 60, preferably Is between 40 and 55 ° C.
- the reaction temperature is generally from 20 to 60 ° (preferably, from 45 to 55 ° C.
- the reaction time varies depending on the reaction temperature and other reaction conditions, but is usually from 5 to 15 hours, preferably from 5 to 15 hours. Is 6-9 hours.
- the compound (3) can be obtained by reacting the compound (2) obtained in the above step A with the compound (5) (hereinafter, this step is referred to as step B).
- the reaction in step B is usually performed in the presence of a base.
- examples of the base include sodium hydride, sodium hydroxide, sodium carbonate, potassium hydroxide and the like. From the viewpoint of economy, sodium hydroxide is preferred.
- sodium hydroxide is preferred.
- an aqueous sodium hydroxide solution is preferred due to its ease of handling, and a commercially available sodium hydroxide aqueous solution can be used as it is or by diluting the commercially available product. it can.
- the concentration of the aqueous sodium hydroxide solution used is usually 5 to 20% by weight, preferably 15 to 20% by weight.
- a base is added in advance to a solution of compound (5) in an appropriate reaction solvent (preferably by adding a base-containing solution dropwise), and the mixture is added to compound (2). ) (Preferably (Addition by dropping a solution containing the compound (2)) is preferred from the viewpoint of operability.
- Suitable reaction solvents include polar solvents such as THF and t-butanol. Among them, THF is preferable from the viewpoint of solubility in compound (2).
- the amount of the reaction solvent to be used is generally 1 to 40 ml, preferably 2 to 20 ml, per 1 g of compound (2).
- the amount of the base to be used is generally 1 to 1.3 mol, preferably 1 to 1.2 mol, per 1 mol of fluorithiophenol.
- the addition temperature of the base is generally 0 to 30 ° C, preferably 0 to 20 ° C.
- the temperature at which the compound (2) is added is generally 0 to 15 ° C, preferably 0 to 10 ° C.
- examples of the solvent include non-protonic solvents such as THF. Among them, THF is preferred from the viewpoint of solubility in compound (2). preferable.
- the same solvent as the above reaction solvent is desirable.
- the amount of the solvent to be used is generally 1-10 ml, preferably 2-6 ml, per 1 g of compound (2).
- the reaction temperature is usually 0 to 30 ° C, preferably 0 to 20 ° C.
- the reaction time varies depending on the reaction temperature and other reaction conditions, but is usually 1 to 20 hours, preferably 2 to 15 hours.
- crude crystals of compound (3) can be obtained by performing a normal isolation treatment such as washing with alkali, acid, and concentrating the solvent.
- step B it was found that a reaction with the unreacted compound (1) and the compound (5) produced a by-product of a dioxysulfide. This is what the present inventors have clarified for the first time. In addition, it was also found that a deoxysulfonyl compound can be derived from compound (3).
- the compound (3) is synthesized from the compound (1) by the steps A and B, and even if the obtained compound (3) does not contain a deoxysulfide compound, (4)
- the deoxysulfol compound may be contained as an impurity.
- the deoxysulfonyl form is very similar to those of the compound (4), it is difficult to isolate the compound (4) by a conventional method and remove the deoxysulfonyl form. . Therefore, in the present invention, the crude crystals of the compound (3) obtained after the synthesis of the compound (3) are purified (that is, the deoxysulfide form is removed).
- crystallization solvent examples include crystallization solvents containing tonolen and benzene benzene. Among them, crystallization containing toluene from the viewpoint of economic efficiency. Solvents are preferred, crystallization solvents containing 50% by weight or more of toluene are more preferred, and crystallization solvents consisting essentially of toluene are particularly preferred.
- the amount of the crystallization solvent to be used is generally 4 to 7 ml, preferably 5 to 6 ml, per 1 g of compound (3).
- -Dissolve compound (3) by heating in the above crystallization solvent.
- the heating dissolution temperature is usually 65 to 80 ° C, preferably 65 to 75 ° C.
- seed crystals (purified crystals of compound (3)) are added in the crystallization step. After the heating and dissolution, it is usually added before crystals start to precipitate.
- seed crystals makes it possible to prevent the crystals from adhering to the vessel wall due to rapid crystallization and to prevent a non-uniform crystal morphology, thereby facilitating subsequent filtration, washing and drying. Prone and preferred.
- the amount of the seed crystal to be added is usually from 0.01 to 0% based on the compound (3). 0.2% by weight, preferably from 0.01 to 0.015% by weight.
- the temperature of the solution when the seed crystals are added is usually 50 to 60 ° C, preferably 53 to 57 ° C.
- ripening refers to a compound in a temperature range defined below.
- stirring at a temperature around 55 ° C has advantages such as stabilization of quality.
- the ripening time (the duration of stirring at a temperature around 55 ° C) is usually 1 to 3 hours, preferably 1 to 3, because uniform crystals are precipitated and filtration, washing and drying are facilitated. It is 2 hours, more preferably about 1 hour.
- the solution Upon cooling in crystallization, the solution is allowed to reach the aging temperature (around 55 ° C), usually 55 ⁇ 5. Cool from C, preferably 55 ⁇ 2 ° C., to around 10 ° C., usually to 10 ° C., preferably 10 ⁇ 2 ° C.
- the cooling rate is usually 5 to 15 ° C / hour, preferably 10 to 15 ° CZ hour, more preferably 10 to 15 ° C / hour, because of the advantage that the compound (3) can be obtained in a stable yield. Is about 10 ° C hours.
- the crystals When the obtained crystals are filtered, the crystals may be washed with the same crystallization solvent (preferably toluene) at 5 to 12 ° C, preferably 8 to 12 ° C. desirable.
- the same crystallization solvent preferably toluene
- the amount of the solvent to be used for washing is usually 1.5 to 3.5 ml, preferably 2 to 3 ml, per 1 g of compound (3).
- the purification of the above compound (3) is particularly effective when the dexulsulfide is contained in an amount exceeding 0.06% (LC plane percentage) with respect to the crude crystal of the compound (3).
- Compound (3) is the target compound by controlling the amount of the deoxysulfide compound contained in the purified crystal to 0.06% (LC area percentage) or less of compound (3).
- the content of the deoxysulfonyl compound in the crystal of the compound (4) can be less than 0.10% (LG area percentage) based on the compound (4).
- Purification of the crude crystals of the compound (3) by this crystallization is particularly effective even when the crude crystals of the compound (3) obtained through the above-mentioned steps A and B are not crude crystals.
- Compound (4) can be obtained by reacting compound (3) with percarboxylic acid using the purified crystals of compound (3) obtained by the above purification (hereinafter, this step). Is referred to as process C).
- percarboxylic acid those exemplified in the step A can be used similarly, and preferably, monoperphthalic acid can be mentioned.
- Step C a percarboxylic acid is added to the compound (3) in a suitable reaction solvent in an amount of zero.
- ethyl acetate is preferred from the viewpoint of operability.
- the amount of the solvent to be used is usually 1 to 3 ml, preferably 1.5 to 2.5 ml, per 1 g of the compound (3).
- the amount of the percarboxylic acid to be used is 1 mol of compound (3), usually 3 to 5 mol, preferably 3.5 to 4.5 mol.
- dropping of a percarboxylic acid solution is preferable from the viewpoint of easy addition, safety and operability.
- the solution may be dropped in two or more portions.
- Suitable solvents for preparing the percarboxylic acid solution include, for example, ethyl acetate, ethers (eg, getyl ether, etc.), among which ethyl acetate is preferred from the viewpoint of safety. It is desirable to use the same solvent as the above reaction solvent.
- the amount of the solvent used for preparing the percarboxylic acid solution is usually 3 to 10 ml, preferably 3.5 to 7 ml per 1 g of percarboxylic acid.
- the rate of drop depends on the concentration of the dropping solution and the temperature of the dropping solution and the solution to be dropped.
- the temperature of the solution is usually 0 to 30 ° C, preferably 10 to 25 ° C.
- the temperature of the solution to be added is usually 0 to 20 ° C, preferably 0 to 10 ° C.
- the reaction temperature is usually 0 to 20 ° C, preferably 0 to 10 ° C.
- the reaction time varies depending on the reaction temperature and other reaction conditions, but is usually 0.5 to 5 hours, preferably 1 to 3 hours.
- an extraction solvent for example, an organic solvent such as ethyl acetate
- the compound (4) can be isolated by washing and concentrating the extract (organic layer) obtained by separation after standing.
- the compound (4) obtained as necessary may be purified by a known method (for example, the method described in W003 / 053920) or a method analogous thereto.
- the LC area percentage (%) refers to the LC (liquid chromatography), preferably the HPLC (high performance liquid chromatography), chromatogram obtained from the analysis. It means the peak area value of the deoxysulfide compound for (3) or the deoxysulfonyl compound for compound (4), expressed as a percentage, respectively.
- a seed crystal (10 mg) of 3'-trifluoromethylpropionanilide was added, and the mixture was cooled to 50 ° C over 1 hour. Then, it was cooled at a rate of 10 ° C / hour to 10 ° C over 4 hours. The mixture was stirred at 10 ° C for 2 hours, filtered, and washed with toluene (226 ml) cooled to 10 ° C.
- N-Methacryloyl-l 4-cyano 3_ trifluoromethylylaniline (57.3 g, 0.225 mol), ethyl acetate (3'40 ml) and phthalic anhydride (116.9 g, 0.789 mol / l) Charge and heat to 50-55 ° C.
- a 35% aqueous hydrogen peroxide solution (43.8 g, 0.451 mol) was added dropwise over 8 hours, and the mixture was aged for 20 hours. After adding ethyl acetate (114 ml) and cooling to 15 ° C., a solution of sodium sulfite (25.6 g) in water (145 ml) was added dropwise. After confirming that no peracid is present, add 15% aqueous caustic solution dropwise, adjust the pH to 7.3, separate, and separate with water (230 ml), salt (40.5 g), and 35% hydrochloric acid. (0.23 g).
- N-Methacryloyl-1-4-Cano-3 Trifluoromethylanilinine (1 part by weight), ethyl acetate (5.4 parts by weight) and phthalic anhydride (2 parts by weight) are charged at 50-55 ° Heated to C.
- aqueous hydrogen peroxide (0.57 parts by weight) was added dropwise over 9.7 hours, and the mixture was aged for 22.3 hours.
- Ethyl acetate (1.8 parts by weight) was added, and after cooling to 15 ° C., a solution of sodium sulfite (0.17 parts by weight) in water (1 part by weight) was added dropwise. After confirming that no peracid is present, drop a 15% aqueous solution of caustic solution to adjust the pH to 7.0. After partitioning, add water (4 parts by weight), salt (0.7 parts by weight), It was washed with a solution prepared from aqueous hydrochloric acid (0.004 parts by weight).
- the solution was washed with a solution prepared from water (2 parts by weight), salt (0.14 parts by weight), and sodium carbonate (0.35 parts by weight). At this time, the content of the deoxysulfide compound was 0.22% (LC area percentage). After liquid separation, the organic layer was concentrated, toluene (8.8 parts by weight) was added, and the mixture was further concentrated under reduced pressure.
- the content of the deoxysulfide compound was 0.035% (LC surface percentage).
- aqueous hydrogen peroxide (0.54 parts by weight) was added dropwise over 9.6 hours, and the mixture was aged for 2 hours. After adding ethyl acetate (8.1 parts by weight) and cooling to 5 ° C, 10% aqueous sodium sulfite (0.8 parts by weight) was added dropwise.
- the compound (4) power which is a pharmaceutical agent useful as an anticancer agent can be provided with the high quality (impurity less than 0.10%) and industrially advantageous method.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Description
Claims
Priority Applications (11)
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AU2004282077A AU2004282077A1 (en) | 2003-10-16 | 2004-10-15 | Process for producing bicalutamide and method of purifying intermediate therefor |
KR1020067009306A KR101126948B1 (ko) | 2003-10-16 | 2004-10-15 | 비칼루타미드의 제조 방법 및 그 중간체의 정제 방법 |
CA2542788A CA2542788C (en) | 2003-10-16 | 2004-10-15 | Process for producing bicalutamide and method of purifying intermediate thereof |
EP04792811A EP1679306B1 (en) | 2003-10-16 | 2004-10-15 | Process for producing bicalutamide and method of purifying intermediate therefor |
AT04792811T ATE461170T1 (de) | 2003-10-16 | 2004-10-15 | Verfahren zur herstellung von bicalutamid und verfahren zur aufreinigung von zwischenprodukten dafür |
NZ546466A NZ546466A (en) | 2003-10-16 | 2004-10-15 | Process for producing bicalutamide and method of purifying intermediate crystals therefor |
BRPI0415347-2A BRPI0415347A (pt) | 2003-10-16 | 2004-10-15 | processo para a produção de bicalutamida e método para a purificação de intermediário da mesma |
DE602004026088T DE602004026088D1 (de) | 2003-10-16 | 2004-10-15 | Verfahren zur herstellung von bicalutamid und verfahren zur aufreinigung von zwischenprodukten dafür |
IL174781A IL174781A (en) | 2003-10-16 | 2006-04-04 | Process for producing bicalutamide and method of purifying intermediate therefor |
US11/401,262 US20060183934A1 (en) | 2003-10-16 | 2006-04-11 | Process for producing bicalutamide and method of purifying intermediate thereof |
IS8459A IS2757B (is) | 2003-10-16 | 2006-05-11 | Aðferð til að framleiða bíkalútamíð og aðferð til að hreinsa milliefni fyrir það |
Applications Claiming Priority (2)
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JP2003-357038 | 2003-10-16 | ||
JP2003357038A JP4322621B2 (ja) | 2003-10-16 | 2003-10-16 | 4’−シアノ−3−[(4−フルオロフェニル)スルホニル]−2−ヒドロキシ−2−メチル−3’−トリフルオロメチルプロピオンアニリドの製造方法 |
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US11/401,262 Continuation-In-Part US20060183934A1 (en) | 2003-10-16 | 2006-04-11 | Process for producing bicalutamide and method of purifying intermediate thereof |
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WO2005037777A1 true WO2005037777A1 (ja) | 2005-04-28 |
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PCT/JP2004/015669 WO2005037777A1 (ja) | 2003-10-16 | 2004-10-15 | ビカルタミドの製造方法及びその中間体の精製方法 |
Country Status (15)
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US (1) | US20060183934A1 (ja) |
EP (1) | EP1679306B1 (ja) |
JP (1) | JP4322621B2 (ja) |
KR (1) | KR101126948B1 (ja) |
AT (1) | ATE461170T1 (ja) |
AU (1) | AU2004282077A1 (ja) |
BR (1) | BRPI0415347A (ja) |
CA (1) | CA2542788C (ja) |
DE (1) | DE602004026088D1 (ja) |
ES (1) | ES2341008T3 (ja) |
IL (1) | IL174781A (ja) |
IS (1) | IS2757B (ja) |
NZ (1) | NZ546466A (ja) |
WO (1) | WO2005037777A1 (ja) |
ZA (1) | ZA200603289B (ja) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7544828B2 (en) | 2005-12-27 | 2009-06-09 | Dabur Pharma Limited | Process for preparation of Bicalutamide |
Families Citing this family (9)
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KR101185662B1 (ko) * | 2004-07-14 | 2012-09-24 | 스미또모 가가꾸 가부시키가이샤 | 비칼루타미드의 결정 석출 방법 |
AU2005329762A1 (en) * | 2005-03-29 | 2006-10-05 | Usv Limited | Process for preparation of bicalutamide |
CA2513356A1 (en) * | 2005-07-26 | 2007-01-26 | Apotex Pharmachem Inc. | Process for production of bicalutamide |
CZ299577B6 (cs) * | 2005-12-20 | 2008-09-03 | Interpharma Praha, A. S. | Zpusob výroby vysoce cistého 4-kyano-3-trifluoromethyl-N-(3-p-fluorfenylsulfonyl-2-hydroxy-2-methylpropionyl) anilinu |
CN105541680B (zh) * | 2016-02-16 | 2017-12-22 | 重庆硕奥科技有限公司 | 一种比卡鲁胺的合成方法 |
CN106748884B (zh) * | 2016-12-13 | 2021-08-20 | 山西振东制药股份有限公司 | 一种比卡鲁胺中间体的制备方法 |
CN106831509B (zh) * | 2017-02-07 | 2018-05-18 | 西北师范大学 | 一种比卡鲁胺的合成方法 |
CN106905265A (zh) * | 2017-03-09 | 2017-06-30 | 常州沃腾化工科技有限公司 | N‑[4‑氰基‑3‑(三氟甲基)苯基]‑2,3‑环氧‑2‑甲基丙酰胺的制备方法 |
CN109456227B (zh) * | 2018-11-19 | 2021-11-16 | 常州新星联生物科技有限公司 | 一种比卡鲁胺环氧中间体的制备方法 |
Citations (4)
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WO2001000608A1 (en) | 1999-06-10 | 2001-01-04 | Richter Gedeon Vegyészeti Gyár Rt. | Process for the synthesis of n-(4-cyano-3-trifluoromethylphenyl)-3-(4-fluorophenylsulfonyl)-2-hydroxy-2-methylpropionamide |
WO2001028990A2 (en) | 1999-10-19 | 2001-04-26 | Nobex Corporation | Methods of asymmetrically synthesizing enantiomers of casodex, its derivatives and intermediates thereof |
WO2002024638A1 (en) | 2000-09-21 | 2002-03-28 | Bristol-Myers Squibb Company | Process for the preparation of n-(substituted phenyl)-3-alkyl-, aryl- and heteroarylsulfonyl-2-hydroxy-2-alkyl- and haloalkylpropanamide compounds |
WO2003053920A1 (fr) | 2001-12-13 | 2003-07-03 | Sumika Fine Chemicals Co., Ltd. | Cristaux de bicalutamide et leur procede de production |
-
2003
- 2003-10-16 JP JP2003357038A patent/JP4322621B2/ja not_active Expired - Fee Related
-
2004
- 2004-10-15 EP EP04792811A patent/EP1679306B1/en not_active Not-in-force
- 2004-10-15 ES ES04792811T patent/ES2341008T3/es active Active
- 2004-10-15 WO PCT/JP2004/015669 patent/WO2005037777A1/ja active Application Filing
- 2004-10-15 AU AU2004282077A patent/AU2004282077A1/en not_active Abandoned
- 2004-10-15 NZ NZ546466A patent/NZ546466A/en not_active IP Right Cessation
- 2004-10-15 ZA ZA200603289A patent/ZA200603289B/en unknown
- 2004-10-15 AT AT04792811T patent/ATE461170T1/de not_active IP Right Cessation
- 2004-10-15 BR BRPI0415347-2A patent/BRPI0415347A/pt not_active IP Right Cessation
- 2004-10-15 DE DE602004026088T patent/DE602004026088D1/de active Active
- 2004-10-15 CA CA2542788A patent/CA2542788C/en not_active Expired - Fee Related
- 2004-10-15 KR KR1020067009306A patent/KR101126948B1/ko not_active IP Right Cessation
-
2006
- 2006-04-04 IL IL174781A patent/IL174781A/en not_active IP Right Cessation
- 2006-04-11 US US11/401,262 patent/US20060183934A1/en not_active Abandoned
- 2006-05-11 IS IS8459A patent/IS2757B/is unknown
Patent Citations (4)
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WO2001000608A1 (en) | 1999-06-10 | 2001-01-04 | Richter Gedeon Vegyészeti Gyár Rt. | Process for the synthesis of n-(4-cyano-3-trifluoromethylphenyl)-3-(4-fluorophenylsulfonyl)-2-hydroxy-2-methylpropionamide |
WO2001028990A2 (en) | 1999-10-19 | 2001-04-26 | Nobex Corporation | Methods of asymmetrically synthesizing enantiomers of casodex, its derivatives and intermediates thereof |
WO2002024638A1 (en) | 2000-09-21 | 2002-03-28 | Bristol-Myers Squibb Company | Process for the preparation of n-(substituted phenyl)-3-alkyl-, aryl- and heteroarylsulfonyl-2-hydroxy-2-alkyl- and haloalkylpropanamide compounds |
WO2003053920A1 (fr) | 2001-12-13 | 2003-07-03 | Sumika Fine Chemicals Co., Ltd. | Cristaux de bicalutamide et leur procede de production |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7544828B2 (en) | 2005-12-27 | 2009-06-09 | Dabur Pharma Limited | Process for preparation of Bicalutamide |
Also Published As
Publication number | Publication date |
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IL174781A (en) | 2011-05-31 |
IS2757B (is) | 2011-10-15 |
KR20060117948A (ko) | 2006-11-17 |
EP1679306A1 (en) | 2006-07-12 |
KR101126948B1 (ko) | 2012-03-20 |
AU2004282077A1 (en) | 2005-04-28 |
IS8459A (is) | 2006-05-11 |
AU2004282077A2 (en) | 2005-04-28 |
BRPI0415347A (pt) | 2006-12-05 |
EP1679306A4 (en) | 2006-10-11 |
US20060183934A1 (en) | 2006-08-17 |
NZ546466A (en) | 2009-08-28 |
CA2542788C (en) | 2012-01-03 |
CA2542788A1 (en) | 2005-04-28 |
DE602004026088D1 (de) | 2010-04-29 |
ATE461170T1 (de) | 2010-04-15 |
ES2341008T3 (es) | 2010-06-14 |
IL174781A0 (en) | 2006-08-20 |
JP4322621B2 (ja) | 2009-09-02 |
JP2005120024A (ja) | 2005-05-12 |
ZA200603289B (en) | 2007-07-25 |
EP1679306B1 (en) | 2010-03-17 |
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