JP4540060B2 - Method for producing tamsulosin - Google Patents
Method for producing tamsulosin Download PDFInfo
- Publication number
- JP4540060B2 JP4540060B2 JP2005198613A JP2005198613A JP4540060B2 JP 4540060 B2 JP4540060 B2 JP 4540060B2 JP 2005198613 A JP2005198613 A JP 2005198613A JP 2005198613 A JP2005198613 A JP 2005198613A JP 4540060 B2 JP4540060 B2 JP 4540060B2
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- Prior art keywords
- formula
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- compound
- ether
- acid
- Prior art date
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- Expired - Fee Related
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- 229960002613 tamsulosin Drugs 0.000 title claims description 32
- 238000004519 manufacturing process Methods 0.000 title claims description 30
- DRHKJLXJIQTDTD-OAHLLOKOSA-N Tamsulosine Chemical compound CCOC1=CC=CC=C1OCCN[C@H](C)CC1=CC=C(OC)C(S(N)(=O)=O)=C1 DRHKJLXJIQTDTD-OAHLLOKOSA-N 0.000 title claims description 24
- -1 acetamide compound Chemical class 0.000 claims description 122
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 50
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 32
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 28
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 28
- 150000001875 compounds Chemical class 0.000 claims description 25
- 239000002904 solvent Substances 0.000 claims description 25
- 125000000217 alkyl group Chemical group 0.000 claims description 24
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 21
- 239000002253 acid Substances 0.000 claims description 20
- 229940124530 sulfonamide Drugs 0.000 claims description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 17
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims description 15
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 14
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 14
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 12
- 150000001335 aliphatic alkanes Chemical group 0.000 claims description 12
- 239000004202 carbamide Substances 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 229960004441 tyrosine Drugs 0.000 claims description 10
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 9
- 150000002576 ketones Chemical class 0.000 claims description 9
- 150000002148 esters Chemical class 0.000 claims description 8
- 150000002170 ethers Chemical class 0.000 claims description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 8
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 claims description 7
- 229940100198 alkylating agent Drugs 0.000 claims description 6
- 239000002168 alkylating agent Substances 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 150000004820 halides Chemical group 0.000 claims description 6
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 5
- 239000003638 chemical reducing agent Substances 0.000 claims description 5
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 claims description 5
- 150000007524 organic acids Chemical class 0.000 claims description 5
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 claims description 4
- 229910010082 LiAlH Inorganic materials 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 229910052744 lithium Inorganic materials 0.000 claims description 4
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 235000006408 oxalic acid Nutrition 0.000 claims description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 3
- 150000004703 alkoxides Chemical class 0.000 claims description 3
- WPUJEWVVTKLMQI-UHFFFAOYSA-N benzene;ethoxyethane Chemical compound CCOCC.C1=CC=CC=C1 WPUJEWVVTKLMQI-UHFFFAOYSA-N 0.000 claims description 3
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 229910052793 cadmium Inorganic materials 0.000 claims description 3
- 229910052791 calcium Inorganic materials 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 229910052802 copper Inorganic materials 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 229910052742 iron Inorganic materials 0.000 claims description 3
- 229910052749 magnesium Inorganic materials 0.000 claims description 3
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 3
- 229910052759 nickel Inorganic materials 0.000 claims description 3
- 229910052763 palladium Inorganic materials 0.000 claims description 3
- 229910052697 platinum Inorganic materials 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 229910052725 zinc Inorganic materials 0.000 claims description 3
- MOEFFSWKSMRFRQ-UHFFFAOYSA-N 2-ethoxyphenol Chemical compound CCOC1=CC=CC=C1O MOEFFSWKSMRFRQ-UHFFFAOYSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- AWSBWONBTIKCHR-UHFFFAOYSA-K P(=O)([O-])([O-])[O-].[Cl+].[Cl+].[Cl+].[Cl+].[Cl+] Chemical compound P(=O)([O-])([O-])[O-].[Cl+].[Cl+].[Cl+].[Cl+].[Cl+] AWSBWONBTIKCHR-UHFFFAOYSA-K 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical group CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims 2
- 229920002614 Polyether block amide Polymers 0.000 claims 1
- 229910052748 manganese Inorganic materials 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- 239000000243 solution Substances 0.000 description 23
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 230000002829 reductive effect Effects 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- 239000000543 intermediate Substances 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 235000019441 ethanol Nutrition 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 9
- 235000019341 magnesium sulphate Nutrition 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 7
- 239000002994 raw material Substances 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 5
- 230000003287 optical effect Effects 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- HDECRAPHCDXMIJ-UHFFFAOYSA-N 2-methylbenzenesulfonyl chloride Chemical group CC1=CC=CC=C1S(Cl)(=O)=O HDECRAPHCDXMIJ-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 108700023418 Amidases Proteins 0.000 description 4
- 102000005922 amidase Human genes 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 229950005499 carbon tetrachloride Drugs 0.000 description 4
- 230000002194 synthesizing effect Effects 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 3
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical group ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 150000003456 sulfonamides Chemical class 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical group [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- VMWZRHGIAVCFNS-UHFFFAOYSA-J aluminum;lithium;tetrahydroxide Chemical group [Li+].[OH-].[OH-].[OH-].[OH-].[Al+3] VMWZRHGIAVCFNS-UHFFFAOYSA-J 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229910052811 halogen oxide Inorganic materials 0.000 description 2
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 2
- DLRJIFUOBPOJNS-UHFFFAOYSA-N phenetole Chemical compound CCOC1=CC=CC=C1 DLRJIFUOBPOJNS-UHFFFAOYSA-N 0.000 description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical class NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 description 2
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- ZZIZZTHXZRDOFM-UHFFFAOYSA-N 2-(2-ethoxyphenoxy)ethyl-[1-(4-methoxy-3-sulfamoylphenyl)propan-2-yl]azanium;chloride Chemical compound Cl.CCOC1=CC=CC=C1OCCNC(C)CC1=CC=C(OC)C(S(N)(=O)=O)=C1 ZZIZZTHXZRDOFM-UHFFFAOYSA-N 0.000 description 1
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 1
- POAOYUHQDCAZBD-UHFFFAOYSA-N 2-butoxyethanol Chemical compound CCCCOCCO POAOYUHQDCAZBD-UHFFFAOYSA-N 0.000 description 1
- LQIIEHBULBHJKX-UHFFFAOYSA-N 2-methylpropylalumane Chemical compound CC(C)C[AlH2] LQIIEHBULBHJKX-UHFFFAOYSA-N 0.000 description 1
- DNURLAUTFFPBFX-UHFFFAOYSA-N 4-methyl-2-phenylmethoxybenzenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C(OCC=2C=CC=CC=2)=C1 DNURLAUTFFPBFX-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical class NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical group [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 101150065749 Churc1 gene Proteins 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical group [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical group [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102100038239 Protein Churchill Human genes 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical group [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 150000003974 aralkylamines Chemical class 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- BDOSMKKIYDKNTQ-UHFFFAOYSA-N cadmium atom Chemical compound [Cd] BDOSMKKIYDKNTQ-UHFFFAOYSA-N 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Chemical group 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical group [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000006264 debenzylation reaction Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- PFBUKDPBVNJDEW-UHFFFAOYSA-N dichlorocarbene Chemical group Cl[C]Cl PFBUKDPBVNJDEW-UHFFFAOYSA-N 0.000 description 1
- DENRZWYUOJLTMF-UHFFFAOYSA-N diethyl sulfate Chemical group CCOS(=O)(=O)OCC DENRZWYUOJLTMF-UHFFFAOYSA-N 0.000 description 1
- 229940008406 diethyl sulfate Drugs 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229960003750 ethyl chloride Drugs 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 239000011630 iodine Chemical group 0.000 description 1
- 150000002497 iodine compounds Chemical class 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical group [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- FIHMZWNEKKQMFC-UHFFFAOYSA-N phenylmethanesulfonamide;hydrochloride Chemical compound Cl.NS(=O)(=O)CC1=CC=CC=C1 FIHMZWNEKKQMFC-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Chemical group 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 229960003198 tamsulosin hydrochloride Drugs 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
この発明は、タムスロシン化合物の新規な製造方法に関する。 The present invention relates to a novel process for the preparation of tamsulosin compound.
アメリカ合衆国特許第５，４４７，９５８号にはタムスロシン化合物が高血圧、心臓衰弱、心臓の痛み、前立腺肥大に対して極めて好ましい医療効果を有すると記載されている。また、該特許に開示するタムスロシン化合物は、以下の式２Ａのスルフォ化合物の塩基塩、及び以下の式３の臭化物を反応させて得る。
以下に掲げる式２Ｂのスルフォ塩（式２Ａのスルフォ化合物の塩基塩）は、以下の工程１の製法で合成する。該工程１は式４のベンゼン基アミノ化合物から生成し、式５Ａのスルフォ化合物を得てから式６Ａのスルフォンアミド化合物の中間生成物を得て、最終的に式２Ｂのスルフォ塩を得る。
式４Ａのフェニル基アミノ化合物の合成は、アメリカ合衆国特許第４，０００，１９７号、及びＪ．Ｍｅｄ．Ｃｈｅｍ．１９７２，１６，４８０−４８３に開示される。即ち、４−メトキシベンゼンアセトンと、（Ｒ）−α−メチルベンジルアミノとによって縮合し、次いでＮ＝Ｎの二重連結を水素化し、還元性の脱ベンジル反応を行う。式４Ａのフェニル基アミン化合物の総産出率は２５％であって、かつ対掌体の純度は９９％を超える。 Synthesis of phenyl group amino compounds of formula 4A is described in U.S. Pat. No. 4,000,197; Med. Chem. 1972, 16, 480-483. That is, condensation is performed with 4-methoxybenzeneacetone and (R) -α-methylbenzylamino, and then the N = N double linkage is hydrogenated to perform a reductive debenzylation reaction. The total yield of the phenyl group amine compound of formula 4A is 25% and the enantiomer purity is over 99%.
Ｓｙｎｔｈ，Ｃｏｍｍｕｎ．１９９８，２８，１９３５−１９４５においてＹａｍａｄａなどの人士が述べるところによれば、式４のフェニル基アミン化合物を合成する方法は、光学上純質のＬ―チロシン酸を初期材料とする。この反応の特徴は形成される産物が旋光純度を具える点にある。中間物である式４Ｂのフェニルアミド塩（式４のフェニルアミド化合物の塩基塩）の製造は８つのステップによってなり、中間物である式５Ａのアミド化合物に延伸させるとステップは９つになる。上述のＹａｍａｄａ氏の述べる製造方法を工程２に開示する。 Synth, Commun. 1998, 28, 1935-1945, as described by Yamada et al., The method for synthesizing the phenyl group amine compound of formula 4 uses optically pure L-tyrosine acid as the initial material. The characteristic of this reaction is that the product formed has optical rotation purity. Preparation of the intermediate phenylamide salt of formula 4B (base salt of the phenylamide compound of formula 4) consists of 8 steps, and stretching to the intermediate amide compound of formula 5A results in 9 steps. The manufacturing method described by Mr. Yamada is disclosed in Step 2.
工程２においては、式７のチロシン酸化合物から生成を開始し、式８のアミノエステル化合物、式９のフェノールアミターゼ化合物、式１０のエーテルアミターゼエステル化合物、式１１のアルコールエーテルアミターゼ化合物、式１２のベンゼンスルフォンアミターゼ化合物、式１３のヨウ素化合物、式１４のエーテルアミターゼ化合物の順に生成して、最終的に式４Ｂのフェニル基アミノ塩を得る。
この発明は、総収率が高く、反応のステップが少なく、効率のよい製造が得られるタムスロシンの製造を提供することを課題とする。 The present invention, the total yield is high, the step of the reaction is small, and an object thereof is to provide a preparation of Tamusuroshi emissions that efficient production can be obtained.
そこで本発明者は、従来の技術に鑑み鋭意研究を重ねた結果、スルフォンアミド化合物の塩酸塩とエーテル化合物とを反応させてタムスロシンを得る方法によって課題を解決できる点に着眼し、係る知見に基づき本発明を完成させた。
以下、この発明について具体的に説明する。
Therefore, as a result of intensive research in view of conventional techniques, the present inventor has focused on the point that the problem can be solved by a method of obtaining tamsulosin by reacting a hydrochloride of a sulfonamide compound and an ether compound, and based on such knowledge The present invention has been completed.
The present invention will be specifically described below.
請求項１に記載するタムスロシンの製造方法は、次に掲げる式１の分子式を含むタムスロシンの製造方法であって、
式１のタムスロシンを得るために、式２のスルフォンアミド化合物の塩酸塩を、式２１のエーテル化合物と反応させること；
Reacting the hydrochloride salt of a sulfonamide compound of formula 2 with an ether compound of formula 21 to obtain tamsulosin of formula 1;
請求項２に記載するタムスロシンの製造方法は、請求項１において、下記の中間物が、式５のアセトアミド化合物を準備するために使用される、
（５）
次の式を有する、式１５のフェノールアミド酸化物、ここに、Ｒはアルキル基またはアリル基を表す、
次の式を有する、式１６のフェノールアミドエステル、ここに、ＲおよびＲ′はアルキル基またはアリル基を表す、
次の式を有する、式１７のエーテルアミドエステル、ここに、Ｒ、Ｒ′およびＲ″はアルキル基またはアリル基を表す、および
次の式を有する、式１８の水酸化エーテルアミド酸化物、ここに、ＲおよびＲ′はアルキル基またはアリル基を表す、
(5)
A phenolamide oxide of formula 15 having the formula: wherein R represents an alkyl group or an allyl group,
A phenolamide ester of formula 16 having the formula: wherein R and R 'represent an alkyl group or an allyl group;
An ether amide ester of formula 17 having the formula: wherein R, R 'and R "represent an alkyl or allyl group, and
A hydroxylated etheramide oxide of formula 18 having the formula: wherein R and R ′ represent an alkyl group or an allyl group;
請求項３に記載するタムスロシンの製造方法は、請求項１において、式２１（Ｒ″はＭｅＣ ６ Ｈ ４ ＳＯ ２ またはＭｅＳｏ ２ ）のエーテルベンゼントシレイト化合物が、式１９の２−エトキシフェノールを式２０のエーテルベンゼンアルコールに、そして、式２１のエーテルベンゼントシレイトに転換することによって準備され、
請求項４に記載するタムスロシンの製造方法は、請求項１において、次に掲げる式１の分子式を含むタムスロシンの製造方法であって、
式１のタムスロシンを得るために、式２のスルフォンアミド化合物の塩酸塩を式２１のエーテル化合物と反応させること；
（ａ）クロロスルフォン酸、続く（ｂ）テトラヒドロフラン（ＴＨＦ）中のアンモニアと反応させ、続いて、塩酸水溶液のもとで、式２Ｂのスルフォンアミド化合物の塩酸塩を得ることにより行われる；
（５）
式１５のフェノールアミド酸は、次の式を有する：
（６）
式１６のフェノールアミドエステルは次式を有する。
（７）
式１７のエーテルアミドエステルは、次の式を有する、
該アルキル化剤は、Ｒ ２ ＳＯ ４ ，ＲＩ、ＲＢｒおよびそれらの結合物から成るグループから選択されり、該基は、アミン、炭酸エステル、炭酸水素塩、アミド、アルコキシドおよびそれらの結合物から成るグループから選択され、該溶剤は、Ｈ ２ Ｏ、ケトン、アルカン、エーテル、ＤＭＦ、ＤＭＳＯ、尿素およびそれらの結合物から成るグループから選択される：
（８）
式１８のヒドロキシエーテルアミドは、次の式を有する。
式１８のヒドロキシエーテルアミドは、酸ハロゲン化物、溶剤、有機酸、ＭＸｎおよびＭを使用して式５のアセトアミドを準備するために使用される、該酸ハロゲン化物は、ＴｓＣｌ、ＭｓＣｌ、ＳＯＣｌ ２ 、ＳＯ ２ Ｃｌ ２ 、ＰＣｌ ３ 、ＰＯＣｌ ５ 、塩化酸化物およびそれらの結合物から成るグループから選択され、該溶剤は、ＴＨＦ、ケトン、アルカン、エーテル、ＤＭＦ、ＤＭＳＯ、ＣＨ ２ Ｃｌ ２ 、ＣＨＣｌ ３ 、ＣＣｌ ４ 、尿素およびそれらの結合物から成るグループから選択され、該有機酸は、シュウ酸（ＣＯＯＨ） ２ 、ＲＣＯＯＨおよびそれらの結合物から成るグループから選択され、ここに、ＲはＨ、アルキル基あるいはアリル基であり、該Ｍは、Ｌｉ、Ｎａ、Ｋ、Ｍｇ、Ｃａ、Ｚｎ、Ｐｔ、Ｐｄ、Ｃｕ、Ｃｏ、Ｍｎ、Ｆｅ、ＮｉおよびＣｄであり、該Ｘは、Ｃｌ、Ｂｒ、ＩおよびＯＡｃから成るグループから選択され、ここに、ｎ値は、金属の原子価に基づく１−３である、ことを特徴とする。
The method for producing tamsulosin according to claim 4 is the method for producing tamsulosin according to claim 1, comprising the molecular formula of the following formula 1,
Reacting the hydrochloride salt of a sulfonamide compound of formula 2 with an ether compound of formula 21 to obtain tamsulosin of formula 1;
Carried out by reacting with (a) chlorosulfonic acid, followed by (b) ammonia in tetrahydrofuran (THF), followed by the hydrochloride of the sulfonamide compound of formula 2B under aqueous hydrochloric acid;
(5)
The phenolamic acid of formula 15 has the following formula:
(6)
The phenolamide ester of formula 16 has the following formula:
(7)
The ether amide ester of formula 17 has the following formula:
The alkylating agent is selected from the group consisting of R 2 SO 4 , RI, RBr and conjugates thereof, wherein the group consists of amines, carbonates, bicarbonates, amides, alkoxides and conjugates thereof. Selected from the group, the solvent is selected from the group consisting of H 2 O, ketones, alkanes, ethers, DMF, DMSO, urea, and combinations thereof:
(8)
The hydroxy ether amide of formula 18 has the following formula:
The hydroxy ether amide of formula 18 is used to prepare the acetamide of formula 5 using acid halide, solvent, organic acid, MXn and M. The acid halide is TsCl, MsCl, SOCl 2 , Selected from the group consisting of SO 2 Cl 2 , PCl 3 , POCl 5 , chloride oxide and combinations thereof, the solvent being THF, ketone, alkane, ether, DMF, DMSO, CH 2 Cl 2 , CHCl 3 , CCl 4 is selected from the group consisting of urea, and their conjugates, organic acid is selected from the group consisting of oxalic acid (COOH) 2, RCOOH and their conjugates, where, R represents H, an alkyl group Alternatively, it is an allyl group, and M is Li, Na, K, Mg, Ca, Zn, Pt, Pd, Cu, Co, M Fe, Ni and Cd, wherein X is selected from the group consisting of Cl, Br, I and OAc, wherein the n value is 1-3 based on the valence of the metal, To do.
本発明のタムスロシン、及び関連するアリル基派生物の製造は、総収率が高く、かつ反応のステップが少なく、効率のよい製造が得られるとともに、得られる薬物に含まれる不純物の含有率を規範内に押さえることができるという利点がある。さらに、光学的純度を具える初期原料を用いることによって、特定の規格の原料産物の化合物が得られ、医薬の要求に適合させることができるという利点がある。 The production of tamsulosin of the present invention and related allyl group derivatives has high overall yield, few reaction steps, efficient production, and the content of impurities contained in the resulting drug There is an advantage that it can be held in. Furthermore, by using an initial raw material having optical purity, there is an advantage that a compound of a raw material product of a specific standard can be obtained and can be adapted to the pharmaceutical requirements.
この発明は、アミノスルフォンアシルを合成して代替とするフェネチルアミノ派生物、及びタムスロシンの製造方法に関し、特に、次に掲げる式１の分子式を含むタムスロシン化合物（式１におけるＲ１及びＲ２がＣ１−Ｃ４アルキル基を表す）及びその塩酸塩、各種医薬上使用可能な塩類の製造方法を提供するものである。
該方法は、次に掲げる式２のスルフォンアミド化合物の塩酸塩と次に掲げる式２１のエーテル化合物とを反応させて式１のタムスロシンを得るものであって、
The method comprises reacting a hydrochloride salt of a sulfonamide compound of the following formula 2 with an ether compound of the following formula 21 to obtain a tamsulosin of the formula 1,
上述するように、式１のタムスロシン化合物（式１におけるＲ１及びＲ２がＣ１−Ｃ４アルキル基を表す）の合成は、キー中間物である次の式５Ａのアミド化合物に関連する。そこで、ホン発明においては、次に掲げる工程３に開示するように、中間物である式５Ａのアミド化合物を生成する新規な方法を開示する。該方法には次の式１５Ａのフェニルアミド酸化合物、式１６Ａのフェニルアミドエステル化合物、式１８のアルコールエーテルアミド化合物などの中間物を含み、かつこれら化合物は、いずれも新規に生成した新型の中間物である。
本発明のタムスロシン化合物は、従来の方法に比して総収率が高く、かつ反応のステップが少なく、効率のよい製造が得られるとともに、得られる薬物に含まれる不純物の含有率を規範の上限内に押さえることができる。さらに、光学的純度を具える初期原料を用いることによって、特定の規格の原料産物の化合物が得られ、医薬の要求に適合させることができる。 The tamsulosin compound of the present invention has an overall yield higher than that of the conventional method, and there are few reaction steps, and an efficient production can be obtained. Can be held in. Furthermore, by using an initial raw material with optical purity, a compound of a raw material product of a specific standard can be obtained and adapted to the requirements of medicine.
また、この発明では新規な、キー中間物である次の式２１のエーテルベンゼンスルフォン化合物を開示する。該エーテルベンゼンスルフォンを式３の臭化物の代替としてタムスロシン化合物を生成する。エトキシベンゼン（１９Ａ）を初期原料とし、クロルアセチルアルコールと式１９Ａのエーテルフェニル化合物とを反応させ。式２０Ａのエーテルフェニルアルコール化合物を得て、さらにトルエンスルフォンに作用させて、キー中間物である式２１Ａのエーテルベンゼンスルフォン化合物を得る。 The present invention also discloses a novel ether benzene sulphone compound of the following formula 21, which is a key intermediate. The ether benzene sulphone replaces the bromide of formula 3 to produce a tamsulosin compound. Using ethoxybenzene (19A) as an initial raw material, chloroacetyl alcohol is reacted with an ether phenyl compound of formula 19A. An ether phenyl alcohol compound of formula 20A is obtained and further reacted with toluene sulfone to obtain an ether benzene sulfone compound of formula 21A which is a key intermediate.
式２１Ａのエーテルベンゼンスルフォン化合物を式３の臭化物に変えて使用する利点は、反応の操作のステップが簡略化できるとともに、危険なハロゲン化廃棄物が招く汚染を防ぐことができるという点にある。式２１Ａのエーテルベンゼンスルフォン化合物の生成方法は下記の工程４に開示するように、式１９Ａのエーテルフェニル化合物を式２０Ａのエーテルフェニルアルコール化合物に転換した後、式２１Ａのエーテルベンゼンスルフォン化合物を生成する。
この発明の方法では、中間物の式５Ａのアミド化合物を式６Ａのスルフォンアミド化合物に転換し、酸性の条件の下において式２Ｂのスルフォンアミド塩を得る。式２Ｂのスルフォンアミド塩と式２１Ａのエーテルベンゼンスルフォン化合物とを反応させてタムスロシン（ｔａｍｓｕｌｏｓｉｎ、式１、Ｒ１＝乙基、Ｒ２＝甲基）を生成する。式１のタムスロシン化合物を部分的に合成するステップは工程５に開示する通りである。
この発明はアミノスルフォンアシルで代替とするフェネチルアミノ派生物、及びその酸化した後に生成するアミノ塩を製造する新規な方法に関し、初期原料である式７のチロシン酸（Ｌ−Tyrosine）から式１５のフェニルアミド酸化合物を生成する方法を次に掲げる工程６に開示する。
前記生成方法は、アシル剤及び溶剤を使用する。アシル化剤はＲＣＯＸ、（ＲＣＯＸ）２Ｏ、もしくはその組み合わせであって、該Ｒはアルキル基か、もしくはアリル基であり、Ｘはハロゲン素か、もしくはダ脱離基であって、溶剤はアルカンか、エーテルか、ジメチルホルムアミドか、ジメチルスルフォキシドか、ケトン類か、尿素か、もしくはその任意の組み合わせである。 The production method uses an acyl agent and a solvent. The acylating agent is RCOX, (RCOX) 2 O, or a combination thereof, wherein R is an alkyl group or an allyl group, X is a halogen or a da leaving group, and the solvent is an alkane. Or ether, dimethylformamide, dimethyl sulfoxide, ketones, urea, or any combination thereof.
式１５のフェニルアミド酸化合物から式１６のフェニルアミドエステル化合物を生成する方法は、次に掲げる工程７のとおりである。
この方法には酸塩化物及びＲ’ＯＨを使用する。酸塩化物は三塩化燐か、五塩化燐か、ＰＯＣＬ５か、塩化チオニルか、エチルチオニルか、もしくはその組み合わせであって、該Ｒ、Ｒ’はアルキル基かアリル基を代表する。 This method uses acid chloride and R′OH. The acid chloride is phosphorus trichloride, phosphorus pentachloride, POCL 5 , thionyl chloride, ethyl thionyl, or a combination thereof, and R and R ′ represent an alkyl group or an allyl group.
さらに、式１６のフェニルアミドエステルから式１７のエチルアミドエステル化合物を生成する方法は、次に掲げる工程８のとおりである。
前記方法にはアルキル化剤、アルカリと溶剤を使用する。該アルキル化剤は硫酸ジエチルか、ヨウ化メチルか、臭化アルカンか、もしくはその組み合わせであって、アルカリはアミド化物か、炭酸塩か、炭酸水素塩か、アミドか、アルコキシドか、もしくはその組み合わせであって、溶剤は水か、ケトン類か、アルカンか、エーテル類か、ジメチルホルムアミドか、ジメチルスルフォキシドか、尿素か、もしくはその組み合わせである。 The method uses an alkylating agent, an alkali and a solvent. The alkylating agent is diethyl sulfate, methyl iodide, alkane bromide, or a combination thereof, and the alkali is an amidated compound, carbonate, bicarbonate, amide, alkoxide, or a combination thereof The solvent is water, ketones, alkanes, ethers, dimethylformamide, dimethyl sulfoxide, urea, or a combination thereof.
式１７のエチルアミドエステル化合物から式１８のアルコールエーテルアミド化合物を生成する方法は、次に掲げる工程９のとおりである。
前記方法は還元剤と溶剤を使用する。該還元剤は水酸化アルミリチウム（ＬｉＡｌＨ４）か、水素化イソブチルアルミニウム（ＤＩＢＡＬ）か、Ｋ−セレクトレイド（Ｋ−ｓｅｌｅｃｔｒｉｄｅ）か、Ｌ−セレクトレイド（Ｌ−ｓｅｌｅｃｔｒｉｄｅ）か、水酸化ホウ素（ＢＨ３）か、四水素化ホウ素ナトリウム（ＮａＢＨ４）か、もしくはこれら組み合わせであって、溶剤はエーテル類か、アルコール類か、水か、アルカンか、ジメチルホルムアミドか、ジメチルスルフォキシドか、尿素か、もしくはこれらの組み合わせである。 The method uses a reducing agent and a solvent. The reducing agent is lithium aluminum hydroxide (LiAlH 4 ), isobutylaluminum hydride (DIBAL), K-selectride (K-selectride), L-selectride (L-selectride), boron hydroxide (BH). 3 ), sodium tetraborohydride (NaBH 4 ), or a combination thereof, and the solvent is ethers, alcohols, water, alkanes, dimethylformamide, dimethyl sulfoxide, urea Or a combination of these.
次に掲げる工程１０に開示する方法は、式１８のアルコールエーテルアミド化合物をアシル化する方法、即ち、式５のアミド化合物を生成する方法である。
前記方法は酸化ハロゲン、溶剤、有機酸化合物、ＭＸｎとＭを使用する。該酸化ハロゲンは塩化トルエンスルフォニル（ＴｓＣｌ）か、塩化メチルスルフォニル（ＭｓＣｌ）か、塩化スルフリル（ＳＯＣｌ２）か、塩化チオニル（ＳＯ２Ｃｌ２）か、三塩化燐（ＰＣｌ３）か、五塩化燐（ＰＣｌ５）か、ＰＯＣｌ５か、エチルチオニルか、もしくはこれらの組み合わせであって、溶剤はテトラヒドロフランか、ケトン類か、アルカンか、エーテル類か、ジメチルホルムアミドか、ジメチルスルフォキシドか、塩化メチレンか、クロロホルムか、四クロロメタンか、尿素か、もしくはこれらの組み合わせであり、該有機酸化合物はシュウ酸（（ＣＯＯＨ）２）か、ＲＣＯＯＨか、もしくはこれらの組み合わせであって、該Ｒは水素、アルキル基、もしくはアリル基であり、該Ｍはリチウムか、ナトリウムか、カリウムか、マグネシウムか、カルシウムか、亜鉛か、プラチナか、パラジウムか、銅か、コバルトか、マンガンか、鉄か、ニッケルか、もしくはカドミウムであって、該ｘは、塩素か、臭素か、ヨウ素か、もしくは酢酸根であって、かつｎの数値が金属の価数に基づき１〜３である。 The method uses halogen oxide, solvent, organic acid compound, MXn and M. The halogen oxide may be toluenesulfonyl chloride (TsCl), methylsulfonyl chloride (MsCl), sulfuryl chloride (SOCl 2 ), thionyl chloride (SO 2 Cl 2 ), phosphorus trichloride (PCl 3 ), phosphorus pentachloride (PCl 5 ), POCl 5 , ethyl thionyl, or a combination thereof, and the solvent is tetrahydrofuran, ketones, alkanes, ethers, dimethylformamide, dimethyl sulfoxide, methylene chloride , Chloroform, tetrachloromethane, urea, or a combination thereof, and the organic acid compound is oxalic acid ((COOH) 2 ), RCOOH, or a combination thereof, where R is hydrogen , An alkyl group, or an allyl group, and M is lithium, sodium, Potassium, magnesium, calcium, zinc, platinum, palladium, copper, cobalt, manganese, iron, nickel, or cadmium, where x is chlorine, bromine, iodine Or an acetic acid radical, and the value of n is 1 to 3 based on the valence of the metal.
上述の内容を受けて、式１のタムスロシン化合物の生成は、キーポイントの中間物である式５のホルムアミド化合物と相関関係がある。上述の生成方法によって得られた式５のホルムアミド化合物によって、式１のタムソロシン化合物が合成される。 In view of the above, the formation of the tamsulosin compound of formula 1 correlates with the formamide compound of formula 5 which is a key point intermediate. The tamsolocin compound of formula 1 is synthesized from the formamide compound of formula 5 obtained by the above-described production method.
この発明は、以下に記載する実例によって詳しく理解することができるが、但し、この発明は実例の範囲だけに限られるものではない。
式７のチロシン酸化合物（２０．０１ｇ、１１０．４ｍｍｏｌ）の水溶液（１２０ｍｌ）を無水酢酸（１３．５１ｇ、１３２．４ｍｍｏｌ）に加えた。４〜５時間加熱して回流後、蒸留法により該溶液を濃縮すると、淡い黄色の粘着性を具えた残留物が得られた。残留物はアセトン（８０ｍｌ）で溶解して、未反応の式７のチロシン化合物をろ過により取り除いた。減圧により、ろ過による抽出物を濃縮し、残留物を再び酢酸エチル（１００ｍｌ）で溶解し、水（５０ｍｌ）で洗浄した。硫酸マグネシウムを乾燥し、減圧により濃縮して７１％の収率のコロイド状の半固形の式１５Ａのフェニルアミドエステル化合物（１７．６２ｇ、７８．９３ｍｍｏｌ）を得た。 An aqueous solution (120 ml) of the tyrosine acid compound of formula 7 (20.01 g, 110.4 mmol) was added to acetic anhydride (13.51 g, 132.4 mmol). After heating for 4-5 hours and circulating, the solution was concentrated by distillation to obtain a light yellow sticky residue. The residue was dissolved with acetone (80 ml), and the unreacted tyrosine compound of formula 7 was removed by filtration. The extract by filtration was concentrated under reduced pressure, and the residue was dissolved again with ethyl acetate (100 ml) and washed with water (50 ml). Magnesium sulfate was dried and concentrated under reduced pressure to give a 71% yield of colloidal semi-solid phenylamide ester compound of formula 15A (17.62 g, 78.93 mmol).
ｍｐ（メチルアルコールから再結晶）１５２−１５３℃；施光率
＝＋50.9720°；１HNMR(D2O,400MHz)δ2.07（s.3H,COCH3）,
1.82-2.86(m,1H,ArCHH),2.96-3.01(m,1H,ArCHH),3.67-3.70(m,1H,CHCOO),6.70(d,j=8.0Hz,2H,ArH),7.01(d,j=8.0Hz,2H,ArH);IR(neat)3207(s),2961(m),1609(s),1591(s),1513(s),1455(s),1417(s),1363(s),1331(s),1267(m),1245(s),1214(m),1154(m),1112(m),1099(m),1042(m),984(w),939(w),897(w),877(m),841(s),794(m),740(m),713(w),640(m),575(s),529(s),493(m),433(m)cm-１．
mp (recrystallized from methyl alcohol) 152-153 ° C;
= + 50.9720 °; 1 HNMR (D 2 O, 400 MHz) δ 2.07 (s.3H, COCH3),
1.82-2.86 (m, 1H, ArCHH), 2.96-3.01 (m, 1H, ArCHH), 3.67-3.70 (m, 1H, CHCOO), 6.70 (d, j = 8.0Hz, 2H, ArH), 7.01 (d , j = 8.0Hz, 2H, ArH); IR (neat) 3207 (s), 2961 (m), 1609 (s), 1591 (s), 1513 (s), 1455 (s), 1417 (s), 1363 (s), 1331 (s), 1267 (m), 1245 (s), 1214 (m), 1154 (m), 1112 (m), 1099 (m), 1042 (m), 984 (w), 939 (w), 897 (w), 877 (m), 841 (s), 794 (m), 740 (m), 713 (w), 640 (m), 575 (s), 529 (s), 493 (m), 433 (m) cm −1 .
１６Ａ（８．２２５ｇ、３２．７３ｍｍｏｌ）：ｍｐ（５０％の酢酸エチルをヘキサンで再結晶した）１２６．０−１２８．０℃；施光率
＝−1.7632°;１HNMR(CDCl3,400MHz)δ1.24(t,J=6.8Hz,3H,CH2CH3),
1.97(s,3H,CHCH3)2.95-3.08(m,2H,ArCH2),4.16(q,J+8.0Hz,2H,ArH);IR(neat)3384(br).3020(m)2729(m),2851(m),1733(s)1652(s),1615(s),1542(m),1516(s),1446(m),1376(m),1219(s),1125(w),1026(w),828(w),769(s),668(m),518(m)cm-１．
16A (8.225 g, 32.73 mmol): mp (50% ethyl acetate recrystallized with hexane) 126.0-128.0 ° C .;
= −1.7632 °; 1 HNMR (CDCl 3 , 400 MHz) δ 1.24 (t, J = 6.8 Hz, 3H, CH 2 CH 3 ),
1.97 (s, 3H, CHCH 3 ) 2.95-3.08 (m, 2H, ArCH 2 ), 4.16 (q, J + 8.0Hz, 2H, ArH); IR (neat) 3384 (br) .3020 (m) 2729 ( m), 2851 (m), 1733 (s) 1652 (s), 1615 (s), 1542 (m), 1516 (s), 1446 (m), 1376 (m), 1219 (s), 1125 (w ), 1026 (w), 828 (w), 769 (s), 668 (m), 518 (m) cm −1 .
有機層は、１０％の水酸化ナトリウム水溶液（２５ml）と塩水（２５ml）で洗浄し、さらに硫酸マグネシウム内で乾燥させる。ろ過した後、減圧下において濃縮し、薄い褐色の半固態で粗収率８４％の式１７Ａに記載するエーテルアミドエステル化合物（７．１１３ｇ、２６．８１mmol）を得た。 The organic layer is washed with 10% aqueous sodium hydroxide (25 ml) and brine (25 ml) and further dried in magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain an ether amide ester compound described in Formula 17A (7.113 g, 26.81 mmol) in a light brown semisolid state with a crude yield of 84%.
ｍｐ（エチルアセテートの再結晶から）１４０−１４２℃、旋光率
＝−1.6950°;１HNMR(CDCl3,400MHz)δ1.21(t,J=6.8Hz,3H,CH2CH3),1.92(s,3H,COCH3),3.02-3.09(m,2H,ArCH2),
3.95(s,3H,OCH3),4.14(q,J=6.8Hz,2H,COCH2),4.76-4.81(m,1H,CHCOO),6.76(d,J=8.0Hz,2H,ArH),7.02(d,J=8.0Hz,2H,ArH);IR(neat),3282(m),3075(w),2968(m),2933(m),2837(w),1716(w),1651(s),1614(s),1557(s),1514(s),1456(s),1374(s),1300(m),1248(s),1178(m),1146(w),1114(w),1035(m),975(w),815(w),775(w),608(w),562(w),523(w),419(w)cm-１
mp (from recrystallization of ethyl acetate) 140-142 ° C, optical rotation
= −1.6950 °; 1 HNMR (CDCl 3 , 400 MHz) δ 1.21 (t, J = 6.8 Hz, 3H, CH 2 CH 3 ), 1.92 (s, 3H, COCH 3 ), 3.02-3.09 (m, 2H, ArCH 2 ),
3.95 (s, 3H, OCH 3 ), 4.14 (q, J = 6.8Hz, 2H, COCH 2 ), 4.76-4.81 (m, 1H, CHCOO), 6.76 (d, J = 8.0Hz, 2H, ArH), 7.02 (d, J = 8.0Hz, 2H, ArH); IR (neat), 3282 (m), 3075 (w), 2968 (m), 2933 (m), 2837 (w), 1716 (w), 1651 (s), 1614 (s), 1557 (s), 1514 (s), 1456 (s), 1374 (s), 1300 (m), 1248 (s), 1178 (m), 1146 (w), 1114 (w), 1035 (m), 975 (w), 815 (w), 775 (w), 608 (w), 562 (w), 523 (w), 419 (w) cm -1
mp（エチルアセテート及びヘキサンの再結晶から）１４０−１４２℃、旋光率
＝−10.9440°; １HNMR(CDCl3,400MHz)
δ1.95(s,3H, NCOCH3),2.40(br,1H,OH,),2.75-2.85(m,2H,ArCH2),
3.57-3.67(m,2H,CH2O),3.74(s,3H,OCH3),4.08-4.14(m,1H,CHN),6.84(d,J=8.4Hz,2H,ArH),7.12(d,J=8.4Hz,2H,ArH);IR(neat),3512(br),3002(w),2984(m),2834(m),1892(w),1645(s),1577(m),1551(m),1441(m),1377(m),1300(s),1245(s),1177(s),1083(m),1041(s),821(m),614(m)cm-１．
mp (from recrystallization of ethyl acetate and hexane) 140-142 ° C, optical rotation
= -10.9440 °; 1 HNMR (CDCl 3 , 400 MHz)
δ1.95 (s, 3H, NCOCH 3 ), 2.40 (br, 1H, OH,), 2.75-2.85 (m, 2H, ArCH 2 ),
3.57-3.67 (m, 2H, CH 2 O), 3.74 (s, 3H, OCH 3 ), 4.08-4.14 (m, 1H, CHN), 6.84 (d, J = 8.4Hz, 2H, ArH), 7.12 ( d, J = 8.4Hz, 2H, ArH); IR (neat), 3512 (br), 3002 (w), 2984 (m), 2834 (m), 1892 (w), 1645 (s), 1577 (m ), 1551 (m), 1441 (m), 1377 (m), 1300 (s), 1245 (s), 1177 (s), 1083 (m), 1041 (s), 821 (m), 614 (m ) cm -1 .
ｍｐ（酢酸エチルから再結晶）９０−９１℃；施光率
＝＋9.9083°;１HNMR(CDCl3,300MHz)
δ1.08(d,J,5.4Hz,3H,CCH3),1.92(s,3H,COCH3,),2.60-2.77(m,2H,ArCH2),3.76(s,3H,OCH3),4.10-4.25(m,1H,CHMe),6.81(d,J=7.8Hz,2H,ArH),7.06(d,J=7.8Hz,2H,ArH),IR(neat),3276(br),3077(m),2969(m),2933(m),2836(m),1716(m),1647(s),1615(s),1542(s),1513(s),1456(m),1374(m),1300(m),1247(s),1178(m),1035(m),814(m),755(w),518(w),420(w)
cm-１．
mp (recrystallized from ethyl acetate) 90-91 ° C;
= + 9.9083 °; 1 HNMR (CDCl 3 , 300 MHz)
δ1.08 (d, J, 5.4Hz, 3H, CCH 3 ), 1.92 (s, 3H, COCH 3 ), 2.60-2.77 (m, 2H, ArCH 2 ), 3.76 (s, 3H, OCH 3 ), 4.10-4.25 (m, 1H, CHMe), 6.81 (d, J = 7.8Hz, 2H, ArH), 7.06 (d, J = 7.8Hz, 2H, ArH), IR (neat), 3276 (br), 3077 (m), 2969 (m), 2933 (m), 2836 (m), 1716 (m), 1647 (s), 1615 (s), 1542 (s), 1513 (s), 1456 (m), 1374 (m), 1300 (m), 1247 (s), 1178 (m), 1035 (m), 814 (m), 755 (w), 518 (w), 420 (w)
cm -1 .
ｍｐ（メチルアルコールから再結晶）１９８−１９９℃；施光率
＝＋13.2634°;１HNMR(D2O,400MHz)
δ0.99(d,J,6.8Hz,3H,CCH3),1.68(s,3H,COCH3,),2.43-2.49(m,1H,ArCHH),2.69-2.74(m,1H,
ArCHH),3.72(s,3H,OCH3),3.80-3.86(m,1H,CHMe),7.01(d,J=8.8Hz,1H,ArH),7.33(d,J=8.8Hz,1H,ArH),7.48(s,1H,ArH);IR(neat),3132(br),1654(s),1609(m),1536(m),1496(m),1401(s),1320(m),1283(m),1253(m),1176(w),1148(s),1070(m),1024(m),977(w),927(w),860(w),838(w),828(w),761(m),701(w),669(w),614(m),599(m),572(m),535(m),505(m),450(m)cm-１;ESI-MSm/Z287.27(M+H+)．
mp (recrystallized from methyl alcohol) 198-199 ° C;
= + 13.2634 °; 1 HNMR (D 2 O, 400 MHz)
δ0.99 (d, J, 6.8Hz, 3H, CCH 3), 1.68 (s, 3H, COCH 3,), 2.43-2.49 (m, 1H, ArCHH), 2.69-2.74 (m, 1H,
ArCHH), 3.72 (s, 3H, OCH 3 ), 3.80-3.86 (m, 1H, CHMe), 7.01 (d, J = 8.8Hz, 1H, ArH), 7.33 (d, J = 8.8Hz, 1H, ArH ), 7.48 (s, 1H, ArH); IR (neat), 3132 (br), 1654 (s), 1609 (m), 1536 (m), 1496 (m), 1401 (s), 1320 (m) , 1283 (m), 1253 (m), 1176 (w), 1148 (s), 1070 (m), 1024 (m), 977 (w), 927 (w), 860 (w), 838 (w) , 828 (w), 761 (m), 701 (w), 669 (w), 614 (m), 599 (m), 572 (m), 535 (m), 505 (m), 450 (m) cm -1 ; ESI-MSm / Z287.27 (M + H + ).
ｍｐ（メチルアルコールから再結晶）２７２−２７３℃（分解）；施光率 mp (recrystallized from methyl alcohol) 272-273 ° C. (decomposition);
１HNMR(CDCl3,400MHz)δ1.44(t,J,7.2Hz,3H,O
CH2CH3),3.85(t,J=7.2Hz,2H,CH2,OH),4.05-4.12(m,4H,OCH2CH3+OCH2CH2OH),6.88-6.97(m,4H,ArH);IR(neat),3547(br),3066(m),2977(s),2931(s),2877(s),1739(m),1649(m),1593(s),1503(s),1455(s),1393(m),1324(m),1253(s),1219(s),1123(s),1041(s),922(s)cm-１．
1 HNMR (CDCl 3 , 400MHz) δ1.44 (t, J, 7.2Hz, 3H, O
CH 2 CH 3), 3.85 ( t, J = 7.2Hz, 2H, CH 2, OH), 4.05-4.12 (m, 4H, OCH 2 CH 3 + OCH 2 CH 2 OH), 6.88-6.97 (m, 4H , ArH); IR (neat), 3547 (br), 3066 (m), 2977 (s), 2931 (s), 2877 (s), 1739 (m), 1649 (m), 1593 (s), 1503 (s), 1455 (s), 1393 (m), 1324 (m), 1253 (s), 1219 (s), 1123 (s), 1041 (s), 922 (s) cm- 1 .
ｍｐ（ジクロメチレンと四クロロメタンから再結晶）８２−８３℃；１HNMR(CDCl3,300MHz)δ1.43(t,J=10.2Hz,3H,O
CH2CH3),2.51(s,3H,ArCH3,),4.04(q,J=10.2Hz,2H,OCH2CH3),4.36(t,J=6.9Hz,2H,OCH2CH2),4.59(t,J=6.9Hz,2H,OCH2CH2),6.86-6.97(m,4H,ArH),7.10-7.22(m,4H,ArH):IR(neat)3446(br),2982(m),2934(m),2884(m),1591(s),1558(w),1509(s),1478(s),1454(s),1407(s),1394(s),1371(s),1354(s),1279(m),1259(s),1247(s),1217(s),1178(s),1127(s),1066(s),1043(s),1031(s),977(s),929(s),905(s),809(s),776(s),749(s),776(m)cm-１．
mp (recrystallized from dichloromethylene and tetrachloromethane) 82-83 ° C .; 1 HNMR (CDCl 3 , 300 MHz) δ1.43 (t, J = 10.2 Hz, 3H, O
CH 2 CH 3), 2.51 ( s, 3H, ArCH 3,), 4.04 (q, J = 10.2Hz, 2H, OCH 2 CH 3), 4.36 (t, J = 6.9Hz, 2H, OCH 2 CH 2) , 4.59 (t, J = 6.9Hz, 2H, OCH 2 CH 2 ), 6.86-6.97 (m, 4H, ArH), 7.10-7.22 (m, 4H, ArH): IR (neat) 3446 (br), 2982 (m), 2934 (m), 2884 (m), 1591 (s), 1558 (w), 1509 (s), 1478 (s), 1454 (s), 1407 (s), 1394 (s), 1371 (s), 1354 (s), 1279 (m), 1259 (s), 1247 (s), 1217 (s), 1178 (s), 1127 (s), 1066 (s), 1043 (s), 1031 (s), 977 (s), 929 (s), 905 (s), 809 (s), 776 (s), 749 (s), 776 (m) cm −1 .
ｍｐ（塩化メチレンと酢酸エチルで再結晶）１２９−１３１℃；施光率
＝−14.7240°;１HNMR(CD3OD,400MHzδ0.99(d,J,6.4Hz,3H,NCHCH3),1.28(t,J=7.2Hz,3H,OCH2CH3),2.49-2.54(m,1H,ArCHH,),2.2.77-2.82(m,1H,ArCHH),2.89-2.98(m,3H,NCH2+NCH),3.88(s,3H,OCH3),3.93-4.57(m,4H,CH2CH2O+CH3CH2O),6.81-6.89(m,4H,ArH),7.03(d,J,8.4Hz,1H,ArH),7.36(d,J=804Hz,1H.ArH),7.63(s,1H,ArH);IR(neat)3284(m),2973(m),2939(m),1592(m),1504(s),1442(m),1324(s),1282(m),1249(s),1214(m),1154(s),1125(m),1073(m),1046(m),971(w),925(m),753(m)cm-１; ESI-MSm/Z409.40(M+H+)．
mp (recrystallized with methylene chloride and ethyl acetate) 129-131 ° C;
= -14.7240 °; 1 HNMR (CD 3 OD, 400 MHz δ 0.99 (d, J, 6.4 Hz, 3 H, NCHCH 3 ), 1.28 (t, J = 7.2 Hz, 3 H, OCH 2 CH 3 ), 2.49-2.54 ( m, 1H, ArCHH,), 2.2.77-2.82 (m, 1H, ArCHH), 2.89-2.98 (m, 3H, NCH 2 + NCH), 3.88 (s, 3H, OCH 3 ), 3.93-4.57 (m , 4H, CH 2 CH 2 O + CH 3 CH 2 O), 6.81-6.89 (m, 4H, ArH), 7.03 (d, J, 8.4Hz, 1H, ArH), 7.36 (d, J = 804Hz, 1H ArH), 7.63 (s, 1H, ArH); IR (neat) 3284 (m), 2973 (m), 2939 (m), 1592 (m), 1504 (s), 1442 (m), 1324 (s ), 1282 (m), 1249 (s), 1214 (m), 1154 (s), 1125 (m), 1073 (m), 1046 (m), 971 (w), 925 (m), 753 (m ) cm -1 ; ESI-MSm / Z409.40 (M + H + ).
ｍｐ（５０％のメチルアルコールをエチルアルコールで再結晶）２３０−２３１℃；施光率
＝-5.3843°；１HNMR(CD3OD,400MHz)δ1.44-1.17
(m,6H,NCHCH3+OCH2CH2),2.71-2.76(m,1H,ArCHH),3.36-3.43(m,2H,NCH2),3.53-3.55(m,1H,NCH),3.75(s,3H,OCH3),3.94-3.97(m,2H,MeCH2O),4.04-4.19(m,2H,OCH2CH),6.84-6.96(m,5H,ArH),7.35(d,J=8.8Hz,1H,ArH),7.54(s,1H,ArH):IR(neat)3304(m),3168(m),2981(m),1610(m),1589(m),1500(s)1458(m),1392(m),1339(s),1251(s),1215(s),1160(s),1128(s),1072(m),1046(m),1018(m),820(m),749(s),718(m)
cm-１．
mp (50% methyl alcohol recrystallized with ethyl alcohol) 230-231 ° C;
= -5.3843 °; 1 HNMR (CD 3 OD, 400 MHz) δ 1.44-1.17
(m, 6H, NCHCH 3 + OCH 2 CH 2 ), 2.71-2.76 (m, 1H, ArCHH), 3.36-3.43 (m, 2H, NCH 2 ), 3.53-3.55 (m, 1H, NCH), 3.75 ( s, 3H, OCH 3 ), 3.94-3.97 (m, 2H, MeCH 2 O), 4.04-4.19 (m, 2H, OCH 2 CH), 6.84-6.96 (m, 5H, ArH), 7.35 (d, J = 8.8Hz, 1H, ArH), 7.54 (s, 1H, ArH): IR (neat) 3304 (m), 3168 (m), 2981 (m), 1610 (m), 1589 (m), 1500 (s 1458 (m), 1392 (m), 1339 (s), 1251 (s), 1215 (s), 1160 (s), 1128 (s), 1072 (m), 1046 (m), 1018 (m) , 820 (m), 749 (s), 718 (m)
cm -1 .
この発明では、タムスロシン（ｔａｍｕｓｕｌｏｓｉｎ）と関連するアラキルアミン派生物の生成方法を開示した。タムスロシン化合物は、原料のＬ−チロシン酸を合成するステップは従来の方法に比べて簡単で短く、比較的高い収率が得られる。また、生成式１のタムスロシンを生成するために必要なキー中間物式１Ａから１８Ａは、この発明における代表的な中間物である。 In the present invention, a method for producing aralkylamine derivatives related to tammusulosin has been disclosed. The step of synthesizing the raw material L-tyrosine acid of the tamsulosin compound is simpler and shorter than the conventional method, and a relatively high yield can be obtained. Key intermediate formulas 1A to 18A necessary for producing tamsulosin of production formula 1 are representative intermediates in the present invention.
以上はこの発明の好ましい実施例であって、この発明の実施の範囲を限定するものではない。よって、当業者のなし得る修正、もしくは変更であって、この発明の精神の下においてなされ、この発明に対して均等の効果を有するものは、いずれも本発明の特許請求の範囲に属するものとする。 The above are preferred embodiments of the present invention, and do not limit the scope of the present invention. Therefore, any modifications or changes that can be made by those skilled in the art, which are made within the spirit of the present invention and have an equivalent effect on the present invention, shall belong to the scope of the claims of the present invention. To do.
Claims (4)
（１）
次の式を有する、式１５のフェノールアミド酸化物。（式中、Ｒはアルキル基またはアリル基を表す。）
次の式を有する、式１６のフェノールアミドエステル。（式中、ＲおよびＲ′はアルキル基またはアリル基を表す。）
次の式を有する、式１７のエーテルアミドエステル。（式中、Ｒ、Ｒ′およびＲ″はアルキル基またはアリル基を表す。）および
次の式を有する、式１８の水酸化エーテルアミド酸化物。（式中、ＲおよびＲ′はアルキル基またはアリル基を表す。）
The following compound (1), (2), (3) or (4) is used to prepare the acetamide compound:
(1)
Having the following formulas, phenolic amide oxide of formula 15. (In the formula, R represents an alkyl group or an allyl group .)
Having the following formulas, phenol amide ester of formula 16. (In the formula, R and R ′ represent an alkyl group or an allyl group .)
Having the following formulas, polyetheramide ester of formula 17. ( Wherein R, R ′ and R ″ represent an alkyl group or an allyl group ) and
Having the following formulas, hydroxide amide oxide of formula 18. (In the formula , R and R ′ represent an alkyl group or an allyl group .)
ことを特徴とする請求項１に記載のタムスロシンの製造方法。 Ether compound of formula 21A is Ru are prepared by converting a 2-ethoxy phenol of formula 19 in ether benzene alcohol of formula 20.
The method for producing tamsulosin according to claim 1.
式１５のフェノールアミド酸は、次の式を有する。
（２）
式１６のフェノールアミドエステルは、次式を有する。
（３）
式１７のエーテルアミドエステルは、次の式を有する。
該アルキル化剤は、Ｒ ２ ＳＯ ４ ，ＲＩ、ＲＢｒおよびそれらの結合物から成るグループから選択されり、該基は、アミン、炭酸エステル、炭酸水素塩、アミド、アルコキシドおよびそれらの結合物から成るグループから選択され、該溶剤は、Ｈ ２ Ｏ、ケトン、アルカン、エーテル、ＤＭＦ、ＤＭＳＯ、尿素およびそれらの結合物から成るグループから選択される。
（４）
式１８のヒドロキシエーテルアミドは、次の式を有する。
式１８のヒドロキシエーテルアミドは、酸ハロゲン化物、溶剤、有機酸、ＭＸｎおよびＭを使用して式５のアセトアミドを準備するために使用される、該酸ハロゲン化物は、ＴｓＣｌ、ＭｓＣｌ、ＳＯＣｌ ２ 、ＳＯ ２ Ｃｌ ２ 、ＰＣｌ ３ 、ＰＯＣｌ ５ 、塩化酸化物およびそれらの結合物から成るグループから選択され、該溶剤は、ＴＨＦ、ケトン、アルカン、エーテル、ＤＭＦ、ＤＭＳＯ、ＣＨ ２ Ｃｌ ２ 、ＣＨＣｌ ３ 、ＣＣｌ ４ 、尿素およびそれらの結合物から成るグループから選択され、該有機酸は、シュウ酸（ＣＯＯＨ） ２ 、ＲＣＯＯＨおよびそれらの結合物から成るグループから選択される。ここに、ＲはＨ、アルキル基あるいはアリル基であり、該Ｍは、Ｌｉ、Ｎａ、Ｋ、Ｍｇ、Ｃａ、Ｚｎ、Ｐｔ、Ｐｄ、Ｃｕ、Ｃｏ、Ｍｎ、Ｆｅ、ＮｉおよびＣｄであり、該Ｘは、Ｃｌ、Ｂｒ、ＩおよびＯＡｃから成るグループから選択され、ここに、ｎ値は、金属の原子価に基づく１−３である。
上記（１）、（２）、（３）または（４）の中間物質を使用して、下記式５Ａのアセトアミドを準備し、
The phenolamic acid of formula 15 has the following formula:
(2)
The phenolamide ester of formula 16 has the following formula:
(3)
The ether amide ester of formula 17 has the following formula:
The alkylating agent is selected from the group consisting of R 2 SO 4 , RI, RBr and conjugates thereof, wherein the group consists of amines, carbonates, bicarbonates, amides, alkoxides and conjugates thereof. Selected from the group, the solvent is selected from the group consisting of H 2 O, ketones, alkanes, ethers, DMF, DMSO, urea and combinations thereof.
(4)
The hydroxy ether amide of formula 18 has the following formula:
The hydroxy ether amide of formula 18 is used to prepare the acetamide of formula 5 using acid halide, solvent, organic acid, MXn and M. The acid halide is TsCl, MsCl, SOCl 2 , Selected from the group consisting of SO 2 Cl 2 , PCl 3 , POCl 5 , chloride oxide and combinations thereof, the solvent being THF, ketone, alkane, ether, DMF, DMSO, CH 2 Cl 2 , CHCl 3 , The organic acid is selected from the group consisting of CCl 4 , urea and combinations thereof, and the organic acid is selected from the group consisting of oxalic acid (COOH) 2 , RCOOH and combinations thereof. Here, R is H, an alkyl group, or an allyl group, and M is Li, Na, K, Mg, Ca, Zn, Pt, Pd, Cu, Co, Mn, Fe, Ni, and Cd, X is selected from the group consisting of Cl, Br, I and OAc, where the n value is 1-3 based on the valence of the metal.
Using the intermediate of (1), (2), (3) or (4) above, preparing an acetamide of the following formula 5A,
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| JP2000229901A (en) * | 1999-02-10 | 2000-08-22 | Yamanouchi Pharmaceut Co Ltd | New method for production of phenoxyalkylhalide derivative |
| WO2005058810A1 (en) * | 2003-12-17 | 2005-06-30 | Produits Chimiques Auxiliaires Et De Synthese | Novel intermediates for the synthesis of (r)-tamsulosin and of its pharmaceutically acceptable salts and process for their preparation |
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| JP2005523936A (en) * | 2002-04-30 | 2005-08-11 | ランバクシー ラボラトリーズ リミテッド | Tamsulosin derivative |
| WO2005058810A1 (en) * | 2003-12-17 | 2005-06-30 | Produits Chimiques Auxiliaires Et De Synthese | Novel intermediates for the synthesis of (r)-tamsulosin and of its pharmaceutically acceptable salts and process for their preparation |
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