JP4603274B2 - Process for producing 2'-deoxy-5-trifluoromethyluridine - Google Patents
Process for producing 2'-deoxy-5-trifluoromethyluridine Download PDFInfo
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- JP4603274B2 JP4603274B2 JP2004047339A JP2004047339A JP4603274B2 JP 4603274 B2 JP4603274 B2 JP 4603274B2 JP 2004047339 A JP2004047339 A JP 2004047339A JP 2004047339 A JP2004047339 A JP 2004047339A JP 4603274 B2 JP4603274 B2 JP 4603274B2
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- deoxy
- trifluoromethyluridine
- organic solvent
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- VSQQQLOSPVPRAZ-RRKCRQDMSA-N trifluridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C(F)(F)F)=C1 VSQQQLOSPVPRAZ-RRKCRQDMSA-N 0.000 title claims description 40
- 238000000034 method Methods 0.000 title claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 239000007864 aqueous solution Substances 0.000 claims description 15
- 239000003960 organic solvent Substances 0.000 claims description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 8
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 229910017053 inorganic salt Inorganic materials 0.000 claims description 7
- 239000012046 mixed solvent Substances 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- 238000006911 enzymatic reaction Methods 0.000 claims description 6
- 150000008282 halocarbons Chemical class 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 238000001308 synthesis method Methods 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 claims description 3
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 3
- 150000002170 ethers Chemical class 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- LMNPKIOZMGYQIU-UHFFFAOYSA-N 5-(trifluoromethyl)-1h-pyrimidine-2,4-dione Chemical class FC(F)(F)C1=CNC(=O)NC1=O LMNPKIOZMGYQIU-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- VHFDCHXRWYAMBQ-VPCXQMTMSA-N FC[C@@]1([C@H](O)[C@H](O)[C@@H](CO)O1)N1C(=O)NC(=O)C=C1 Chemical compound FC[C@@]1([C@H](O)[C@H](O)[C@@H](CO)O1)N1C(=O)NC(=O)C=C1 VHFDCHXRWYAMBQ-VPCXQMTMSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000002198 insoluble material Substances 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- BLGKEJUTTUUIEN-IUYQGCFVSA-N (3s,4r)-3,4,5-trihydroxypentanoyl chloride Chemical compound OC[C@@H](O)[C@@H](O)CC(Cl)=O BLGKEJUTTUUIEN-IUYQGCFVSA-N 0.000 description 1
- GLXNCCKMEDEHOO-UHFFFAOYSA-N 1,1,1-trifluoro-n-nitroso-n-(trifluoromethyl)methanesulfonamide Chemical compound FC(F)(F)N(N=O)S(=O)(=O)C(F)(F)F GLXNCCKMEDEHOO-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- MXHRCPNRJAMMIM-SHYZEUOFSA-N 2'-deoxyuridine Chemical class C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 MXHRCPNRJAMMIM-SHYZEUOFSA-N 0.000 description 1
- KBDKAJNTYKVSEK-VPENINKCSA-N 2-deoxy-alpha-D-ribose 1-phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(O)=O)C[C@@H]1O KBDKAJNTYKVSEK-VPENINKCSA-N 0.000 description 1
- 125000000242 4-chlorobenzoyl group Chemical group ClC1=CC=C(C(=O)*)C=C1 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 101710132082 Pyrimidine/purine nucleoside phosphorylase Proteins 0.000 description 1
- 102000013537 Thymidine Phosphorylase Human genes 0.000 description 1
- 102000004357 Transferases Human genes 0.000 description 1
- 108090000992 Transferases Proteins 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229910001514 alkali metal chloride Inorganic materials 0.000 description 1
- 229910001963 alkali metal nitrate Inorganic materials 0.000 description 1
- 229910052936 alkali metal sulfate Inorganic materials 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- INHCSSUBVCNVSK-UHFFFAOYSA-L lithium sulfate Inorganic materials [Li+].[Li+].[O-]S([O-])(=O)=O INHCSSUBVCNVSK-UHFFFAOYSA-L 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229940097364 magnesium acetate tetrahydrate Drugs 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 235000011147 magnesium chloride Nutrition 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- XKPKPGCRSHFTKM-UHFFFAOYSA-L magnesium;diacetate;tetrahydrate Chemical compound O.O.O.O.[Mg+2].CC([O-])=O.CC([O-])=O XKPKPGCRSHFTKM-UHFFFAOYSA-L 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000004323 potassium nitrate Substances 0.000 description 1
- 235000010333 potassium nitrate Nutrition 0.000 description 1
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 description 1
- 229910052939 potassium sulfate Inorganic materials 0.000 description 1
- 235000011151 potassium sulphates Nutrition 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000004317 sodium nitrate Substances 0.000 description 1
- 235000010344 sodium nitrate Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- RBTVSNLYYIMMKS-UHFFFAOYSA-N tert-butyl 3-aminoazetidine-1-carboxylate;hydrochloride Chemical compound Cl.CC(C)(C)OC(=O)N1CC(N)C1 RBTVSNLYYIMMKS-UHFFFAOYSA-N 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- XHBKWMUWFRURGS-UHFFFAOYSA-N trimethyl-[5-(trifluoromethyl)-2-trimethylsilyloxypyrimidin-4-yl]oxysilane Chemical compound C[Si](C)(C)OC1=NC=C(C(F)(F)F)C(O[Si](C)(C)C)=N1 XHBKWMUWFRURGS-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Description
本発明は２’−デオキシ−５−トリフルオロメチルウリジンの製造法に関する。 The present invention relates to a process for producing 2'-deoxy-5-trifluoromethyluridine.
２’−デオキシ−５−トリフルオロメチルウリジンは、抗がん剤や抗ウイルス薬として有用な化合物である。 2'-deoxy-5-trifluoromethyluridine is a useful compound as an anticancer agent or antiviral agent.
２’−デオキシ−５−トリフルオロメチルウリジンは、それ自身制癌剤として有用であると同時に、他の医薬上有用な化合物の原料となるので、その需要は高まっている。 Since 2'-deoxy-5-trifluoromethyluridine itself is useful as an anticancer agent, it is also a raw material for other pharmaceutically useful compounds, so that its demand is increasing.
従来、２’−デオキシ−５−トリフルオロメチルウリジンの製造法としては、例えば、次の様な製造法が知られていた。
１）５−トリフルオロメチルウラシル誘導体をトリアルキルシリル化し、水酸基を保護した１−クロロ−２−デオキシリボースと触媒存在下、反応させ、次いで脱保護して目的物を得る方法。（特許文献１）
２）水酸基を保護した２’−デオキシウリジン誘導体にＮ−トリフルオロメチル−Ｎ−ニトロソトリフルオロメタンスルホンアミドを反応させトリフルオロメチル化後、脱保護して目的物を得る方法。（特許文献２）
３）ヌクレオシド−２’−デオキシリボース転移酵素を用いて、チミジンと５−トリフルオロメチルウラシルの核酸塩基交換反応を行い、目的物を得る方法。（特許文献３）
1) A method in which a 5-trifluoromethyluracil derivative is trialkylsilylated, reacted with 1-chloro-2-deoxyribose having a hydroxyl group protected in the presence of a catalyst, and then deprotected to obtain a target product. (Patent Document 1)
2) A method in which a 2′-deoxyuridine derivative having a hydroxyl group protected is reacted with N-trifluoromethyl-N-nitrosotrifluoromethanesulfonamide to trifluoromethylate and then deprotected to obtain the desired product. (Patent Document 2)
3) A method for obtaining a target product by performing nucleobase exchange reaction between thymidine and 5-trifluoromethyluracil using nucleoside-2′-deoxyribose transferase. (Patent Document 3)
しかしながら、前記の背景技術に記載した１）および２）の方法では目的物を得る為に多工程を要し、且つ、精製に多大な労力がかかる。 However, the methods 1) and 2) described in the background art require many steps in order to obtain the target product, and much effort is required for purification.
例えば、１）の方法を記載した特開平２-２８９５９５号公報には、得られた２’−デオキシ−５−トリフルオロメチルウリジンの水溶液を減圧濃縮後、カラムクロマトグラフィーを用いて単離精製を行なうことが記載されているが、この方法では濃縮による熱履歴がかからない少量合成には対応出来るが、工業的な規模での製造においては生成物が不安定な為、分解などを起こし、収率、品質低下が起こり好ましくない。 For example, in JP-A-2-289595 describing the method of 1), the obtained aqueous solution of 2′-deoxy-5-trifluoromethyluridine is concentrated under reduced pressure, followed by isolation and purification using column chromatography. Although it is described that this method can be used for small-scale synthesis that does not require heat history due to concentration, the product is unstable in production on an industrial scale, causing decomposition and yield. , Quality deterioration occurs and is not preferable.
３）の方法は酵素反応である為、１工程で目的物を得られるが、ここには反応で得られた目的物を単離する方法についての詳細は記載なされていない。 Since the method 3) is an enzymatic reaction, the target product can be obtained in one step. However, details of the method for isolating the target product obtained by the reaction are not described here.
一方、２’−デオキシ−５−トリフルオロメチルウリジンは、ｐＨ７．４、３０℃の水溶液中での半減期は１．５日であること、ｐＨ１〜４の水溶液中では比較的安定であることが記載されている（Ｊ．Ｐｈａｒｍ．Ｓｃｉ．，５７，１１１７（１９６８））。この為、２’−デオキシ−５−トリフルオロメチルウリジンが弱アルカリ水溶液中に存在する場合、その回収を効率よく行う必要がある。 On the other hand, 2′-deoxy-5-trifluoromethyluridine has a half-life of 1.5 days in an aqueous solution at pH 7.4 and 30 ° C., and is relatively stable in an aqueous solution at pH 1 to 4. (J. Pharm. Sci., 57, 1117 (1968)). For this reason, when 2'-deoxy-5-trifluoromethyluridine is present in a weak alkaline aqueous solution, it is necessary to efficiently recover it.
本発明は、上記の背景に鑑み、２’−デオキシ−５−トリフルオロメチルウリジンを簡便に、かつ効率的に製造する方法を提供することを目的とする。 In view of the above background, an object of the present invention is to provide a method for easily and efficiently producing 2'-deoxy-5-trifluoromethyluridine.
本発明者らは、上記課題について鋭意検討した結果、２’−デオキシ−５−トリフルオロメチルウリジンは無機塩を含む水に対しては溶解度が著しく低下すること、２’−デオキシ−５−トリフルオロメチルウリジンは水に対する溶解度が高いため単純な抽出方法では回収率が低いこと、更に、通常では溶解性が低い有機溶媒でも２’−デオキシ−５−トリフルオロメチルウリジンを高濃度で溶解する有機溶媒を併用することで、目的物を水中から効率良く抽出できることを見出し、本発明を完成するに至った。 As a result of intensive studies on the above problems, the present inventors have found that 2′-deoxy-5-trifluoromethyluridine has a markedly reduced solubility in water containing inorganic salts. Since fluoromethyluridine has a high solubility in water, the recovery rate is low by a simple extraction method. Furthermore, an organic solvent that normally dissolves 2'-deoxy-5-trifluoromethyluridine at a high concentration even in an organic solvent having low solubility. It has been found that the object can be efficiently extracted from water by using a solvent together, and the present invention has been completed.
即ち、本発明は、合成法又は酵素法により得られる、一般式（１）［化１］ That is, the present invention is a compound represented by the general formula (1) [chemical formula 1] obtained by a synthesis method or an enzymatic method.
で表される２’−デオキシ−５−トリフルオロメチルウリジンを含有するｐＨ１〜４の水溶液に、メタノール、エタノール、イソプロパノール、メチルセルソルブ、アセトン、テトラヒドロフラン、ジメトキシエタン、ジメチルホルムアミド、ジメチルイミダゾリジノン、及びジメチルスルホキシドからなる群より選択されるいずれか１つの有機溶媒と、ハロゲン化炭化水素類、エーテル類、及びメチルイソブチルケトンからなる群より選択されるいずれか１つの有機溶媒との混合溶媒の存在下、無機塩を溶解させ、該混合溶媒中に２’−デオキシ−５−トリフルオロメチルウリジンを抽出する工程を含むことを特徴とする２’−デオキシ−５−トリフルオロメチルウリジンの製造方法に関するものである。 In an aqueous solution of pH 1 to 4 containing 2′-deoxy-5-trifluoromethyluridine represented by: methanol, ethanol, isopropanol, methyl cellosolve, acetone, tetrahydrofuran, dimethoxyethane, dimethylformamide, dimethylimidazolidinone, And a mixed solvent of any one organic solvent selected from the group consisting of dimethyl sulfoxide and any one organic solvent selected from the group consisting of halogenated hydrocarbons, ethers, and methyl isobutyl ketone And a method for producing 2′-deoxy-5-trifluoromethyluridine, which comprises a step of dissolving an inorganic salt and extracting 2′-deoxy-5-trifluoromethyluridine into the mixed solvent. Is.
本発明により、従来困難であった水中からの２’−デオキシ−５−トリフルオロメチルウリジンの抽出を可能とし、酵素反応を用いた高選択的かつ高収率な２’−デオキシ−５−トリフルオロメチルウリジンの製造法を確立することができるようになった。 INDUSTRIAL APPLICABILITY According to the present invention, 2′-deoxy-5-trifluoromethyluridine can be extracted from water, which has heretofore been difficult, and highly selective and high yield 2′-deoxy-5-trimethyl using an enzymatic reaction. A process for producing fluoromethyluridine can be established.
本発明に用いられる２’−デオキシ−５−トリフルオロメチルウリジンを含有する水溶液に制限を設けるものではないが、例えば、特開平１４−２０５９９６号公報記載の酵素法または特開平２−２８９５９５号公報に記載の合成法に準じた方法を用いて得られる、２’−デオキシ−５−トリフルオロメチルウリジンを含有する水溶液を本発明に用いることができる。 The aqueous solution containing 2′-deoxy-5-trifluoromethyluridine used in the present invention is not limited. For example, the enzymatic method described in JP-A-14-205996 or JP-A-2-289595 is disclosed. An aqueous solution containing 2′-deoxy-5-trifluoromethyluridine obtained using a method according to the synthesis method described in 1) can be used in the present invention.
なお、２’−デオキシ−５−トリフルオロメチルウリジンの水溶液中に不溶物が存在する場合には、これを予め除去しておくことが、後記する後処理を容易にするため好ましい。 In addition, when an insoluble substance exists in the aqueous solution of 2'-deoxy-5-trifluoromethyluridine, it is preferable to remove this in advance in order to facilitate post-processing described later.
２’−デオキシ−５−トリフルオロメチルウリジンを含有する水溶液は、そのｐＨを酸性に調製して使用するのが安定性の点で好ましい。例えば、２’−デオキシ−５−トリフルオロメチルウリジンを含有する水溶液を、前記の文献Ｊ．Ｐｈａｒｍ．Ｓｃｉ．，５７，１１１７（１９６８）に記載されているように、ｐＨ１〜４に調製して使用することができる。 The aqueous solution containing 2'-deoxy-5-trifluoromethyluridine is preferably used after its pH is adjusted to be acidic. For example, an aqueous solution containing 2'-deoxy-5-trifluoromethyluridine is prepared according to the above-mentioned literature J.I. Pharm. Sci. 57, 1117 (1968), it can be used after adjusting to pH 1-4.
本発明に用いられる無機塩としては、２’−デオキシ−５−トリフルオロメチルウリジンの水に対する溶解度を低下させる効果があるものであれば特に制限されない。このような条件を満足する無機塩としては、例えば、塩化ナトリウム、塩化カリウム、塩化リチウム、塩化カルシウム、塩化マグネシウム等のアルカリ金属の塩化物、硫酸ナトリウム、硫酸カリウム、硫酸リチウム、硫酸カルシウム、硫酸マグネシウム等のアルカリ金属の硫酸塩、硝酸ナトリウム、硝酸カリウム等のアルカリ金属の硝酸塩等が挙げられる。 The inorganic salt used in the present invention is not particularly limited as long as it has an effect of reducing the solubility of 2'-deoxy-5-trifluoromethyluridine in water. Examples of inorganic salts that satisfy these conditions include alkali metal chlorides such as sodium chloride, potassium chloride, lithium chloride, calcium chloride, and magnesium chloride, sodium sulfate, potassium sulfate, lithium sulfate, calcium sulfate, and magnesium sulfate. Alkali metal sulfates such as alkali metal nitrates such as sodium nitrate and potassium nitrate.
本発明に用いられる、メタノール、エタノール、イソプロパノール、メチルセルソルブ、アセトン、テトラヒドロフラン、ジメトキシエタン、ジメチルホルムアミド、ジメチルイミダゾリジノン、ジメチルスルホキシドは、２５℃で２’−デオキシ−５−トリフルオロメチルウリジンを５重量％以上溶解する有機溶媒である。これらのなかでもメタノール、アセトン、テトラヒドロフランは好ましい。 Methanol, ethanol, isopropanol, methyl cellosolve, acetone, tetrahydrofuran, dimethoxyethane, dimethylformamide, dimethylimidazolidinone, dimethyl sulfoxide used in the present invention are prepared by converting 2′-deoxy-5-trifluoromethyluridine at 25 ° C. Ru organic solvent der dissolving 5% by weight or more. Methanol Among these, acetone, tetrahydrofuran preferred.
本発明に用いられる、ハロゲン化炭化水素類、エーテル類、及びメチルイソブチルケトンは、水と任意に交じり合わない有機溶媒であり、水と分液可能なものである。このような条件を満足する溶媒としては、例えば、ベンゼン、トルエン、キシレン等の芳香族炭化水素類、塩化メチレン、１，２−ジクロロエタン、クロロホルム等のハロゲン化炭化水素類、酢酸エチル、酢酸ブチル等のエステル類、ジエチルエーテル、ジイソプロピルエーテルなどのエーテル類、メチルイソブチルケトン等のケトン類等が挙げられる。 It used in the present invention, halogenated hydrocarbons, ethers, and methyl isobutyl ketone, an organic solvent that are not intermingle in water and optionally, Ru der water and separable ones. Examples of the solvent satisfying such conditions include aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane and chloroform, ethyl acetate, butyl acetate and the like. And esters such as diethyl ether and diisopropyl ether, and ketones such as methyl isobutyl ketone.
前記の合成法または酵素法により得られる２’−デオキシ−５−トリフルオロメチルウリジンを含有する水溶液に、２’−デオキシ−５−トリフルオロメチルウリジンを５重量％以上溶解する有機溶媒と、水と任意に交じり合わない有機溶媒との混合溶媒の存在下、無機塩を溶解させることにより、該混合溶媒中に２’−デオキシ−５−トリフルオロメチルウリジンを抽出することができる。 An organic solvent capable of dissolving 5% by weight or more of 2′-deoxy-5-trifluoromethyluridine in an aqueous solution containing 2′-deoxy-5-trifluoromethyluridine obtained by the synthesis method or enzymatic method, and water 2′-deoxy-5-trifluoromethyluridine can be extracted in the mixed solvent by dissolving the inorganic salt in the presence of a mixed solvent with an organic solvent that does not arbitrarily mix with the solvent.
この全操作を実施する際の温度、圧力に制限を設けるものではないが、例えば、操作温度は、０℃から８０℃、好ましくは１０℃から５０℃の範囲であり、操作圧力は、通常、常圧で実施される。 The temperature and pressure for carrying out all the operations are not limited. For example, the operation temperature is in the range of 0 ° C. to 80 ° C., preferably 10 ° C. to 50 ° C., and the operation pressure is usually It is carried out at normal pressure.
無機塩の使用量は無機塩の水に対する溶解度に対し３０重量％以上使用する事が望ましく、好適には５０重量％以上である。 The amount of the inorganic salt used is desirably 30% by weight or more, preferably 50% by weight or more, based on the solubility of the inorganic salt in water.
２’−デオキシ−５−トリフルオロメチルウリジンを５重量％以上溶解する良有機溶媒の使用量は特に限定は無いが、通常、２’−デオキシ−５−トリフルオロメチルウリジンに対し１から１０重量倍、好ましくは２から７重量倍使用すれば良い。 The amount of good organic solvent that dissolves 5% by weight or more of 2′-deoxy-5-trifluoromethyluridine is not particularly limited, but is usually 1 to 10% with respect to 2′-deoxy-5-trifluoromethyluridine. Double, preferably 2 to 7 times by weight may be used.
水と任意に交じり合わない有機溶媒の使用量は特に限定は無いが、通常、２’−デオキシ−５−トリフルオロメチルウリジンに対し２から２０重量倍、好ましくは２から１０重量倍使用すれば良い。 The amount of the organic solvent that is not arbitrarily mixed with water is not particularly limited, but it is usually 2 to 20 times by weight, preferably 2 to 10 times by weight with respect to 2′-deoxy-5-trifluoromethyluridine. good.
２’−デオキシ−５−トリフルオロメチルウリジンの前記混合溶媒への抽出方法に制限はないが、例えば、該水溶液に無機塩、２’−デオキシ−５−トリフルオロメチルウリジンを５重量％以上溶解する有機溶媒及び水と任意に交じり合わない有機溶媒を加えて撹拌して混合した後、有機層を水層と分離して回収する方法が挙げられる。 The extraction method of 2′-deoxy-5-trifluoromethyluridine into the mixed solvent is not limited. For example, an inorganic salt, 2′-deoxy-5-trifluoromethyluridine is dissolved in 5% by weight or more in the aqueous solution. The organic solvent which does not mix with the organic solvent and water which are arbitrarily mixed, and after stirring and mixing, the organic layer is isolate | separated from an aqueous layer, and the method of collect | recovering is mentioned.
２’−デオキシ−５−トリフルオロメチルウリジンの２’−デオキシ−５−トリフルオロメチルウリジンを含む有機層からの回収および精製は、濃縮、晶析、必要に応じてシリカゲルカラムクロマトグラフィーなどの公知の方法を組み合わせて行うことができる。 The recovery and purification of 2'-deoxy-5-trifluoromethyluridine from the organic layer containing 2'-deoxy-5-trifluoromethyluridine is well-known, such as concentration, crystallization, and, if necessary, silica gel column chromatography. These methods can be combined.
以下に実施例を挙げて本発明を具体的に説明するが、本発明はこれらによって限定されるものではない。 EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.
・実施例及び比較例のＨＰＬＣ条件
カラム：ＹＭＣ ＡＭ−３１３（２５０ｍｍ×直径６ｍｍ）
流速：１ｍＬ／ｍｉｎ．
カラム温度：４０℃
検出波長：２５４ｎｍ
移動相：２０ｍｍｏｌの酢酸アンモニウム水溶液（２．７Ｌ）に酢酸を加えｐＨを３．５に調整した後、ＭｅＯＨ（０．３Ｌ）を加え混和し、脱気する。
内標準物質：ニコチン酸
-HPLC condition column of Examples and Comparative Examples: YMC AM-313 (250 mm x diameter 6 mm)
Flow rate: 1 mL / min.
Column temperature: 40 ° C
Detection wavelength: 254 nm
Mobile phase: Acetic acid is added to 20 mmol aqueous ammonium acetate solution (2.7 L) to adjust the pH to 3.5, and then MeOH (0.3 L) is added and mixed to deaerate.
Internal standard substance: Nicotinic acid
実施例１
２’−デオキシ−５−トリフルオロメチルウリジンの製造
２−デオキシリボース−１−リン酸・２アンモニウム塩２０ｇ、水酸化マグネシウム１．８２ｇ、酢酸マグネシウム４水和物２０ｇ、５−トリフルオロメチルウラシル１３．２ｇを８８ｇの水に懸濁し、Ｓｉｇｍａ社より入手したチミジンホスフォリラーゼ２ｇを加え、３０℃で７時間反応する。反応終了後、ＨＰＬＣで目的物を分析した所、２’−デオキシ−５−トリフルオロメチルウリジンの収率は５−トリフルオロメチルウラシルに対し９５モル％であった。
Example 1
Production of 2′-deoxy-5-trifluoromethyluridine 20 g of 2-deoxyribose-1-phosphate / diammonium salt, 1.82 g of magnesium hydroxide, 20 g of magnesium acetate tetrahydrate, 5-trifluoromethyluracil 13 2 g is suspended in 88 g of water, 2 g of thymidine phosphorylase obtained from Sigma is added, and the mixture is reacted at 30 ° C. for 7 hours. After completion of the reaction, the target product was analyzed by HPLC. As a result, the yield of 2′-deoxy-5-trifluoromethyluridine was 95 mol% based on 5-trifluoromethyluracil.
この様にして得られた反応マスに、５０重量％硫酸２４．４ｇ、アセトン５７．１ｇ及び活性炭５．５ｇを加え３０℃で１時間処理した後、不溶物を濾別する。得られた水溶液に無水硫酸ナトリウム１７．７ｇ、メチルイソブチルケトン６６ｇを加え分液し、上層の有機層に無水硫酸マグネシウム１９．８ｇを加え、１時間脱水する。不溶物を濾別後、有機層を濃縮、更にメチルイソブチルケトンを加え濃縮し析出した目的物の結晶をろ取、洗浄する事で目的物である２’−デオキシ−５−トリフルオロメチルウリジン１６．３ｇを得る事が出来た。 To the reaction mass thus obtained, 24.4 g of 50% by weight sulfuric acid, 57.1 g of acetone and 5.5 g of activated carbon are added and treated at 30 ° C. for 1 hour, and then insoluble matter is filtered off. To the obtained aqueous solution, 17.7 g of anhydrous sodium sulfate and 66 g of methyl isobutyl ketone are added for liquid separation, and 19.8 g of anhydrous magnesium sulfate is added to the upper organic layer and dehydrated for 1 hour. The insoluble material was filtered off, the organic layer was concentrated, further added with methyl isobutyl ketone, concentrated and the precipitated crystals of the desired product were collected by filtration and washed to obtain the desired product, 2′-deoxy-5-trifluoromethyluridine 16 .3g was obtained.
実施例２
２’−デオキシ−５−トリフルオロメチルウリジンの製造
５−トリフルオロメチル−２,４−ビス（トリメチルシリルオキシ）ピリミジン４ｇの無水クロロホルム溶液２５ｍｌに塩化亜鉛６０ｍｇを加えた後、１−クロロ−２−デオキシ−３,５−ジ−Ｏ−ｐ−クロロベンゾイル−α−Ｄ−エリスロ−ペントフラノース１．３ｇを加え、室温で１５時間反応した。反応終了後、反応溶液を炭酸水素ナトリウム水溶液にあけ、クロロホルムで抽出、有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧濃縮した。得られた残留物をエタノールから結晶化して、Ｏ３’、Ｏ５’−ビス（ｐ−クロロベンゾイル）−２’−デオキシ−５−トリフルオロメチルウラシル１．４ｇを得た。
Example 2
Preparation of 2'-deoxy-5-trifluoromethyluridine 60 mg of zinc chloride was added to 25 ml of anhydrous chloroform solution of 4 g of 5-trifluoromethyl-2,4-bis (trimethylsilyloxy) pyrimidine, and then 1-chloro-2- 1.3 g of deoxy-3,5-di-Op-chlorobenzoyl-α-D-erythro-pentofuranose was added and reacted at room temperature for 15 hours. After completion of the reaction, the reaction solution was poured into an aqueous sodium hydrogen carbonate solution, extracted with chloroform, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The obtained residue was crystallized from ethanol to obtain 1.4 g of O3 ′, O5′-bis (p-chlorobenzoyl) -2′-deoxy-5-trifluoromethyluracil.
次いで上記化合物１．４ｇをメタノール溶液８０ｍｌに溶かし、ナトリウムメトキサイド０．２ｇを加え、室温で１時間反応した。反応終了後、陽イオン交換樹脂で中和後、樹脂を濾別し、溶媒を減圧留去した。得られた残留物に水２ｍｌ及びクロロホルム５ｍｌを加え、分液し、得られた水溶液に硫酸ナトリウム、アセトン、メチルイソブチルケトンを加え３０分間攪拌後、分液し、得られた有機層を無水硫酸マグネシウムで乾燥する。不溶物を濾別後、減圧濃縮し、メチルイソブチルケトンを加えて結晶化して、２’−デオキシ−５−トリフルオロメチルウリジン０．６ｇを得た。 Next, 1.4 g of the above compound was dissolved in 80 ml of methanol solution, 0.2 g of sodium methoxide was added, and the mixture was reacted at room temperature for 1 hour. After completion of the reaction, after neutralization with a cation exchange resin, the resin was filtered off and the solvent was distilled off under reduced pressure. To the obtained residue, 2 ml of water and 5 ml of chloroform were added for liquid separation, and sodium sulfate, acetone, and methyl isobutyl ketone were added to the obtained aqueous solution, and the mixture was stirred for 30 minutes, followed by liquid separation. Dry with magnesium. The insoluble material was filtered off, concentrated under reduced pressure, and crystallized by adding methyl isobutyl ketone to obtain 0.6 g of 2'-deoxy-5-trifluoromethyluridine.
Claims (1)
で表される２’−デオキシ−５−トリフルオロメチルウリジンを含有するｐＨ１〜４の水溶液に、メタノール、エタノール、イソプロパノール、メチルセルソルブ、アセトン、テトラヒドロフラン、ジメトキシエタン、ジメチルホルムアミド、ジメチルイミダゾリジノン、及びジメチルスルホキシドからなる群より選択されるいずれか１つの有機溶媒と、ハロゲン化炭化水素類、エーテル類、及びメチルイソブチルケトンからなる群より選択されるいずれか１つの有機溶媒との混合溶媒の存在下、無機塩を溶解させ、該混合溶媒中に２’−デオキシ−５−トリフルオロメチルウリジンを抽出する工程を含むことを特徴とする２’−デオキシ−５−トリフルオロメチルウリジンの製造方法。 General formula (1) [chemical formula 1] obtained by a synthesis method or an enzymatic method
In an aqueous solution of pH 1 to 4 containing 2′-deoxy-5-trifluoromethyluridine represented by: methanol, ethanol, isopropanol, methyl cellosolve, acetone, tetrahydrofuran, dimethoxyethane, dimethylformamide, dimethylimidazolidinone, And a mixed solvent of any one organic solvent selected from the group consisting of dimethyl sulfoxide and any one organic solvent selected from the group consisting of halogenated hydrocarbons, ethers, and methyl isobutyl ketone 2. A process for producing 2′-deoxy-5-trifluoromethyluridine, comprising the step of dissolving an inorganic salt and extracting 2′-deoxy-5-trifluoromethyluridine into the mixed solvent.
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| WO2019135405A1 (en) | 2018-01-05 | 2019-07-11 | 大鵬薬品工業株式会社 | Detection method for analog derived from trifluridine |
| US10809237B2 (en) | 2018-01-05 | 2020-10-20 | Taiho Pharmaceutical Co., Ltd. | Method for detecting trifluridine-related substance by high-performance liquid chromatography |
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| JPS63145296A (en) * | 1986-12-09 | 1988-06-17 | Taiho Yakuhin Kogyo Kk | Production of 5-trifluoromethyl-2'-deoxy-beta-uridines |
| JPH0217199A (en) * | 1988-07-05 | 1990-01-22 | Japan Tobacco Inc | Production of 2'-deoxy-beta-adenosine |
| JPH0231686A (en) * | 1988-07-22 | 1990-02-01 | Yuki Gosei Kogyo Co Ltd | Production of trifluorothymidine |
| JPH02289595A (en) * | 1989-02-22 | 1990-11-29 | Yuki Gosei Kogyo Co Ltd | Production of 2'-deoxy-5-trifluoromethyl-uridine |
| JPH04368382A (en) * | 1991-06-14 | 1992-12-21 | Japan Tobacco Inc | Production of 2',3'-dideoxy-beta-nucleoside |
| JPH05148261A (en) * | 1991-04-05 | 1993-06-15 | Bayer Ag | Substituted 2',3'-dideoxy-5-trifluoromethyl- uridines |
| JPH05178882A (en) * | 1991-06-07 | 1993-07-20 | Mitsui Toatsu Chem Inc | Trifluorothymidine derivative, its production and carcinostatic agent containing the same as active ingredient |
-
2004
- 2004-02-24 JP JP2004047339A patent/JP4603274B2/en not_active Expired - Lifetime
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63145296A (en) * | 1986-12-09 | 1988-06-17 | Taiho Yakuhin Kogyo Kk | Production of 5-trifluoromethyl-2'-deoxy-beta-uridines |
| JPH0217199A (en) * | 1988-07-05 | 1990-01-22 | Japan Tobacco Inc | Production of 2'-deoxy-beta-adenosine |
| JPH0231686A (en) * | 1988-07-22 | 1990-02-01 | Yuki Gosei Kogyo Co Ltd | Production of trifluorothymidine |
| JPH02289595A (en) * | 1989-02-22 | 1990-11-29 | Yuki Gosei Kogyo Co Ltd | Production of 2'-deoxy-5-trifluoromethyl-uridine |
| JPH05148261A (en) * | 1991-04-05 | 1993-06-15 | Bayer Ag | Substituted 2',3'-dideoxy-5-trifluoromethyl- uridines |
| JPH05178882A (en) * | 1991-06-07 | 1993-07-20 | Mitsui Toatsu Chem Inc | Trifluorothymidine derivative, its production and carcinostatic agent containing the same as active ingredient |
| JPH04368382A (en) * | 1991-06-14 | 1992-12-21 | Japan Tobacco Inc | Production of 2',3'-dideoxy-beta-nucleoside |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019124544A1 (en) | 2017-12-22 | 2019-06-27 | 大鵬薬品工業株式会社 | Method for detecting trifluridine- and/or tipiracil-derived analogs |
| US10866219B2 (en) | 2017-12-22 | 2020-12-15 | Taiho Pharmaceutical Co., Ltd. | Method for detecting trifluridine- and/or tipiracil-related substance |
| WO2019135405A1 (en) | 2018-01-05 | 2019-07-11 | 大鵬薬品工業株式会社 | Detection method for analog derived from trifluridine |
| US10809237B2 (en) | 2018-01-05 | 2020-10-20 | Taiho Pharmaceutical Co., Ltd. | Method for detecting trifluridine-related substance by high-performance liquid chromatography |
| US10816517B2 (en) | 2018-01-05 | 2020-10-27 | Taiho Pharmaceutical Co., Ltd. | Method for detecting trifluridine-related substance by high-performance liquid chromatography |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2005239552A (en) | 2005-09-08 |
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