JPS632278B2 - - Google Patents
Info
- Publication number
- JPS632278B2 JPS632278B2 JP12677580A JP12677580A JPS632278B2 JP S632278 B2 JPS632278 B2 JP S632278B2 JP 12677580 A JP12677580 A JP 12677580A JP 12677580 A JP12677580 A JP 12677580A JP S632278 B2 JPS632278 B2 JP S632278B2
- Authority
- JP
- Japan
- Prior art keywords
- silver
- deoxy
- benzyl
- fluorouridine
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- -1 benzyloxy deoxyfluorouridine Chemical compound 0.000 claims description 17
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 claims description 9
- 229910001958 silver carbonate Inorganic materials 0.000 claims description 9
- 229940100890 silver compound Drugs 0.000 claims description 9
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 claims description 8
- 150000003379 silver compounds Chemical class 0.000 claims description 8
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 229910001923 silver oxide Inorganic materials 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical compound [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 claims description 2
- 229940071536 silver acetate Drugs 0.000 claims description 2
- FHIDNBAQOFJWCA-UAKXSSHOSA-N 5-fluorouridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 FHIDNBAQOFJWCA-UAKXSSHOSA-N 0.000 claims 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 12
- 229910052739 hydrogen Inorganic materials 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical group O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 description 7
- 238000000921 elemental analysis Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 125000003118 aryl group Chemical group 0.000 description 4
- 239000012156 elution solvent Substances 0.000 description 4
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000012264 purified product Substances 0.000 description 3
- 150000003230 pyrimidines Chemical class 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- ATKVIWDGWAVUCC-GVDBMIGSSA-N [(2r,3s,5r)-5-(5-fluoro-2,4-dioxopyrimidin-1-yl)-3-hexanoyloxyoxolan-2-yl]methyl hexanoate Chemical compound C1[C@H](OC(=O)CCCCC)[C@@H](COC(=O)CCCCC)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ATKVIWDGWAVUCC-GVDBMIGSSA-N 0.000 description 2
- WKOCBSKQJVQFNA-RRFJBIMHSA-N [(2r,3s,5r)-5-(5-fluoro-2,4-dioxopyrimidin-1-yl)-3-pentanoyloxyoxolan-2-yl]methyl pentanoate Chemical compound C1[C@H](OC(=O)CCCC)[C@@H](COC(=O)CCCC)O[C@H]1N1C(=O)NC(=O)C(F)=C1 WKOCBSKQJVQFNA-RRFJBIMHSA-N 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 125000001033 ether group Chemical group 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- XJTQJERLRPWUGL-UHFFFAOYSA-N iodomethylbenzene Chemical compound ICC1=CC=CC=C1 XJTQJERLRPWUGL-UHFFFAOYSA-N 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 238000011403 purification operation Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 2
- LZIYAIRGDHSVED-UHFFFAOYSA-N 1-(bromomethyl)-3-chlorobenzene Chemical compound ClC1=CC=CC(CBr)=C1 LZIYAIRGDHSVED-UHFFFAOYSA-N 0.000 description 1
- QZNQSIHCDAGZIA-UHFFFAOYSA-N 1-(bromomethyl)-4-tert-butylbenzene Chemical compound CC(C)(C)C1=CC=C(CBr)C=C1 QZNQSIHCDAGZIA-UHFFFAOYSA-N 0.000 description 1
- IYRCFBNKBGBMIT-UHFFFAOYSA-N 1-(chloromethyl)-2-ethylbenzene Chemical compound CCC1=CC=CC=C1CCl IYRCFBNKBGBMIT-UHFFFAOYSA-N 0.000 description 1
- DUBCVXSYZVTCOC-UHFFFAOYSA-N 1-(chloromethyl)-4-ethylbenzene Chemical compound CCC1=CC=C(CCl)C=C1 DUBCVXSYZVTCOC-UHFFFAOYSA-N 0.000 description 1
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- OYKSQHMWDGUQSF-SDBHATRESA-N 5-fluoro-1-[(2S,3R,4S,5R)-2-hexanoyl-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dione Chemical compound C(CCCCC)(=O)[C@@]1([C@H](O)[C@H](O)[C@@H](CO)O1)N1C(=O)NC(=O)C(=C1)F OYKSQHMWDGUQSF-SDBHATRESA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- ZNSGWRKETCGQCL-VXXKDZQQSA-N [(2R,3R,4R,5R)-5-(5-fluoro-2,4-dioxopyrimidin-1-yl)-4-hexanoyloxy-2-(hydroxymethyl)oxolan-3-yl] hexanoate Chemical compound C(CCCCC)(=O)O[C@H]1[C@@H](O[C@@H]([C@H]1OC(CCCCC)=O)CO)N1C(=O)NC(=O)C(=C1)F ZNSGWRKETCGQCL-VXXKDZQQSA-N 0.000 description 1
- IMWAONMKDTZRAJ-HBNTYKKESA-N [(2r,3s,5r)-3-acetyloxy-5-(5-fluoro-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methyl acetate Chemical compound C1[C@H](OC(C)=O)[C@@H](COC(=O)C)O[C@H]1N1C(=O)NC(=O)C(F)=C1 IMWAONMKDTZRAJ-HBNTYKKESA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- YPNVIBVEFVRZPJ-UHFFFAOYSA-L silver sulfate Chemical compound [Ag+].[Ag+].[O-]S([O-])(=O)=O YPNVIBVEFVRZPJ-UHFFFAOYSA-L 0.000 description 1
- 229910000367 silver sulfate Inorganic materials 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は、次の一般式（）、
（式中、Ｒは水素原子、ハロゲン原子、直鎖状若
しくは分枝状の炭素数１ないし４のアルキル基を
示し、ｎは３又は４を示す）で表わされる新規な
デオキシフルオロウリジン４位ベンジルオキシ体
及びその製造方法に関する。
2′−デオキシ−５−フルオロウリジン（以下、
FUDRという）は、制癌剤として用いられてい
る化合物であり、その医薬品としての効果の改善
を計るべく、種々の誘導体が合成されている。例
えば2′−デオキシ−3′・5′−ジ−Ｏ−アセチル−
５−フルオロウリジン（以下、アセチルFUDR
という）（キヤンサー・リサーチ、23巻、49頁以
下、1963年）。また、FUDRやアセチルFUDRの
ピリミジン核上の３位をアロイル基で置換した化
合物も知られている（特開昭55−第35057号公報、
特開昭54−第163586号公報）。
しかしながら、ピリミジン核上の４位オキソを
エーテル体に導いた化合物は末だ知られていな
い。本発明者らは、先にアセチルFUDR誘導体
につき、その抗腫瘍活性の強化と毒性の低下を企
るべく鋭意研究を重ねたところ、驚くべきこと
に、アセチルFUDRのピリミジン核上の４位オ
キソを特定の基でエーテル体に導いた（）式の
新規化合物が優れた作用を有することを見い出
し、既に、出願した（特願昭55−第102956号）。
今回、本発明者らは、2′−デオキシ−3′・5′−
ジ−Ｏ−アルカノイル−５−フルオロウリジンの
４位を特定のベンジル基でエーテル化した化合物
を創製し本発明を完成した。本発明化合物は、医
薬、特に、抗腫瘍活性を有する医薬品として有用
である。
本発明を詳述すれば次の如くである。
（）式のＲの定義中、ハロゲン原子としては
塩素、臭素、弗素、沃素を、アルキル基として
は、メチル、エチル、ｎ−プロピル、イソプロピ
ル、ｎ−ブチル、イソブチル、sec−ブチル、
tert−ブチル等の基を挙げることができる。
本発明の（）式の化合物は例えば、一般式
（）、
（式中、ｎは前記と同義）で表わされる2′−デオ
キシ−3′・5′−ジ−Ｏ−アルカノイル−５−フル
オロウリジンに銀化合物及び一般式（）、
（式中、Ｒは前記と同義、halはハロゲン原子を
示す）で表わされるベンジル化合物を反応させて
製造することができる。
この方法において、原料として用いることので
きる銀化合物としては炭酸銀、酢酸銀、酸化銀、
硝酸銀、硫酸銀等を挙げることができる。また
（）式で表わされるベンジル化合物としては好
ましくは、ベンジルハライドを用いることができ
るが、特に好ましくはベンジル沃化物、ベンジル
臭化物、ベンジル塩化物が用いられる。
原料の使用比は、2′−デオキシ−3′・5′−ジ−
Ｏ−アルカノイル−５−フルオロウリジン１当量
に対し、銀化合物を１ないし７当量用いることが
でき、炭酸銀又は、酸化銀を１ないし４当量用い
るのが好ましく、また（）式で表わされるベン
ジル化合物は１ないし５当量の比率で用いること
ができ、特に、ベンジル沃化物及びベンジル臭化
物を１ないし３当量の比率で用いるのが好まし
い。
原料の仕込み順序は、2′−デオキシ−3′・5′−
ジ−Ｏ−アルカノイル−５−フルオロウリジン、
銀化合物及び（）式で表わされるベンジル化合
物の三つの原料をほぼ同時に仕込んでもよく、ま
た前二者を仕込んだ後、（）式で表わされるベ
ンジル化合物を仕込んでもよい。
三つの原料をほぼ同時に仕込む場合は、通常、
有機溶媒中で反応を行うのが好ましく、有機溶媒
としては、メタノール、エタノール、ｎ−プロパ
ノール、イソプロパノール、ｎ−ブタノール、イ
ソブタノール等のアルコール類、アセトン、メチ
ルエチルケトン、ジエチルケトン、等のケトン
類、エーテル、イソプロピルエーテル、テトラヒ
ドロフラン、ジオキサン等のエーテル類、ベンゼ
ン、トルエン等の芳香族炭化水素類又はこれらの
混合溶媒を用いることができ、特にアセトン、メ
チルエチルケトン又はトルエンの溶媒を用いるの
が好ましい。反応は室温ないし溶媒の還流温度で
10分ないし３日の条件下で充分進行する。要すれ
ば、加熱することにより反応時間を数分ないし数
時間に短縮することもできる。また反応は遮光下
に行うのが好ましい。
2′−デオキシ−3′・5′−ジ−Ｏ−アルカノイル
−５−フルオロウリジン及び銀化合物を先に仕込
む場合は、先ず、両者を反応させるに当り、通常
有機溶媒中で反応させるのが好ましく、有機溶媒
としては、前掲の如き溶媒を用いることができ、
反応は室温ないし溶媒の還流温度で30分ないし３
日行えば充分であり、特に室温で１日ないし２日
行うのが好ましい。
このようにして得られた反応混合物を濃縮乾固
するか又はすることなく（）式で表わされる原
料ベンジル化合物を反応系中に加える。濃縮乾固
した場合は、新たに前掲の如き溶媒を加えて用い
ることができる。反応は室温ないし溶媒の還流温
度で30分ないし３日間で行うことができ、要すれ
ば溶媒の還流温度で1.5時間ないし４時間で行う
ことができる。また反応は遮光下に行うのが好ま
しい。
2′−デオキシ−3′・5′−ジ−Ｏ−アルカノイル
−５−フルオロウリジン、銀化合物及び（）式
で表わされるベンジル化合物をほぼ同時に仕込む
場合も、前二者を仕込んだ後にベンジル化合物を
仕込む場合も、2′−デオキシ−3′・5′−ジ−Ｏ−
アルカノイル−５−フルオロウリジンと銀化合物
との反応により中間体として式（）
（式中、ｎは前記に同義）
で表わされる2′−デオキシ−3′・5′−ジ−Ｏ−ア
ルカノイル−５−フルオロウリジンの銀塩が生成
すると考えられ、これと（）式で表わされるベ
ンジル化合物との反応により一般式（）で表わ
されるデオキシフルオロウリジン４位ベンジルオ
キシ体が生成すると考えられる。
生成した目的物の単離、取得は、通常の処理操
作により行うことができ、例えば、反応混合物を
過して不溶物を去し、液を減圧下で濃縮
し、残渣を再結晶させることによつて、又はクロ
マトグラフイーによつて単離精製し、本発明化合
物を取得することができる。
次に実施例を挙げて説明する。
実施例 １
2′−デオキシ−3′・5′−ジ−Ｏ−ｎ−ヘキサノ
イル−５−フルオロウリジン6.6ｇ（15ミリモル）
およびベンジルブロミド6.2ｇ（36ミリモル）の
乾燥アセトン50ml溶液に炭酸銀5.0ｇ（18ミリモ
ル）を加え２時間還流した。不溶物を去し、
液を減圧濃縮した。油状残渣をシリカゲルカラム
クロマトグラフイー（溶出溶媒：クロロホルム）
で精製し、得られた油状残渣を再びシリカゲルカ
ラムクロマトグラフイー（溶出溶媒：エーテル−
ｎ−ヘキサン＝１：３）で精製した。得られた油
状精製物を室温で減圧乾燥し、４−Ｏ−ベンジル
−2′−デオキシ−3′・5′−ジ−Ｏ−ｎ−ヘキサノ
イル−５−フルオロウリジン3.4ｇ（43％）を油
状物として得た。
UV λEtOH naxnm：288
NMR δ（ppm、CDCl3）：ウリジン部分7.88（ｄ、
H6）、6.26（broad−ｔ、H1′）、5.14−5.31（ｍ、
H3′）、4.22−4.32（ｍ、H4′、H5′）、1.90−2.90
（ｍ、H2′）、2.34（ｔ、２×CH2CO）、1.12−
1.81（ｍ、６×CH2）、0.76−1.04（ｍ、２×
CH3）、ベンジル部分7.26−7.56（ｍ、aromatic
Ｈ）、5.51（ｓ、CH2）
元素分析値：C28H37FN2O7として
計算値(%)：Ｃ、63.14；Ｈ、7.00；Ｎ、5.26
実測値(%)：Ｃ、63.36；Ｈ、7.17；Ｎ、5.23
実施例 ２〜14
実施例１と同様または反応時間のみは違えてそ
の他の処理操作は同様に行い、次のデオキシフル
オロウリジン４位ベンジルオキシ体を製造した。
得られた目的物の構造、収率およびその物性値並
びに反応時間を表１に掲げる。
The present invention is based on the following general formula (), (wherein, R represents a hydrogen atom, a halogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, and n represents 3 or 4). This invention relates to an oxyform and a method for producing the same. 2'-deoxy-5-fluorouridine (hereinafter referred to as
FUDR) is a compound used as an anticancer drug, and various derivatives have been synthesized to improve its effectiveness as a drug. For example, 2'-deoxy-3', 5'-di-O-acetyl-
5-fluorouridine (hereinafter acetyl FUDR)
) (Cancer Research, Vol. 23, pp. 49 et seq., 1963). In addition, compounds in which the 3-position on the pyrimidine nucleus of FUDR and acetyl FUDR is substituted with an aroyl group are also known (Japanese Patent Application Laid-open No. 35057-1989,
(Japanese Unexamined Patent Publication No. 163586/1983). However, no compound is known in which the oxo at the 4-position on the pyrimidine nucleus is converted into an ether form. The present inventors have previously conducted intensive research on acetyl FUDR derivatives with the aim of enhancing their antitumor activity and reducing their toxicity, and surprisingly found that the 4-oxo on the pyrimidine nucleus of acetyl FUDR It was discovered that a new compound of the formula (), which is converted into an ether form with a specific group, has excellent effects, and an application has already been filed (Japanese Patent Application No. 102956-1982). This time, the present inventors have discovered that 2′-deoxy-3′・5′-
The present invention was completed by creating a compound in which the 4-position of di-O-alkanoyl-5-fluorouridine was etherified with a specific benzyl group. The compounds of the present invention are useful as medicines, particularly as medicines having antitumor activity. The present invention will be described in detail as follows. In the definition of R in formula (), halogen atoms include chlorine, bromine, fluorine, and iodine, and alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,
Mention may be made of groups such as tert-butyl. The compound of formula () of the present invention is, for example, general formula (), 2'-deoxy-3',5'-di-O-alkanoyl-5-fluorouridine represented by (where n has the same meaning as above), a silver compound, It can be produced by reacting a benzyl compound represented by the formula (wherein R has the same meaning as above and hal represents a halogen atom). In this method, silver compounds that can be used as raw materials include silver carbonate, silver acetate, silver oxide,
Examples include silver nitrate and silver sulfate. As the benzyl compound represented by the formula (), benzyl halide can be preferably used, and benzyl iodide, benzyl bromide, and benzyl chloride are particularly preferably used. The ratio of raw materials used is 2′-deoxy-3′・5′-di-
For 1 equivalent of O-alkanoyl-5-fluoroururidine, 1 to 7 equivalents of the silver compound can be used, preferably 1 to 4 equivalents of silver carbonate or silver oxide, and a benzyl compound represented by the formula () can be used in a ratio of 1 to 5 equivalents, and it is particularly preferred to use benzyl iodide and benzyl bromide in a ratio of 1 to 3 equivalents. The order of preparing raw materials is 2′-deoxy-3′・5′-
di-O-alkanoyl-5-fluorouridine,
The three raw materials, the silver compound and the benzyl compound represented by the formula (), may be charged almost simultaneously, or the benzyl compound represented by the formula () may be charged after the former two are charged. When preparing three raw materials almost simultaneously,
It is preferable to carry out the reaction in an organic solvent, and examples of the organic solvent include alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, and isobutanol, ketones such as acetone, methyl ethyl ketone, diethyl ketone, and ether. , ethers such as isopropyl ether, tetrahydrofuran, and dioxane, aromatic hydrocarbons such as benzene and toluene, or mixed solvents thereof, and it is particularly preferable to use acetone, methyl ethyl ketone, or toluene as a solvent. The reaction takes place at room temperature or the reflux temperature of the solvent.
It progresses satisfactorily under conditions of 10 minutes to 3 days. If necessary, the reaction time can be shortened to several minutes to several hours by heating. Moreover, it is preferable to carry out the reaction under light shielding. When 2'-deoxy-3',5'-di-O-alkanoyl-5-fluorouridine and the silver compound are charged first, it is preferable to react them first in an organic solvent. , As the organic solvent, the solvents listed above can be used,
The reaction is carried out at room temperature to the reflux temperature of the solvent for 30 minutes to 30 minutes.
It is sufficient to conduct the treatment for one day, and it is particularly preferable to conduct the treatment for one to two days at room temperature. The reaction mixture thus obtained is concentrated to dryness, or a raw material benzyl compound represented by the formula () is added to the reaction system. When it is concentrated to dryness, it can be used by adding a new solvent as mentioned above. The reaction can be carried out for 30 minutes to 3 days at room temperature to the reflux temperature of the solvent, and if necessary, for 1.5 hours to 4 hours at the reflux temperature of the solvent. Moreover, it is preferable to carry out the reaction under light shielding. Even when 2'-deoxy-3', 5'-di-O-alkanoyl-5-fluorouridine, the silver compound, and the benzyl compound represented by the formula () are charged almost simultaneously, the benzyl compound is added after the former two are charged. When preparing, 2′-deoxy-3′・5′-di-O-
By the reaction of alkanoyl-5-fluorouridine with a silver compound, the formula () is formed as an intermediate. It is thought that a silver salt of 2'-deoxy-3',5'-di-O-alkanoyl-5-fluorouridine represented by the formula (in the formula, n has the same meaning as above) is produced, and this and the silver salt represented by the formula () are produced. It is thought that a benzyloxy derivative at the 4-position of deoxyfluorouridine represented by the general formula () is produced by the reaction with a benzyl compound. Isolation and acquisition of the generated target product can be performed by normal processing operations, for example, by filtering the reaction mixture to remove insoluble matter, concentrating the liquid under reduced pressure, and recrystallizing the residue. Thus, the compound of the present invention can be obtained by isolation and purification by chromatography. Next, an example will be given and explained. Example 1 2'-deoxy-3',5'-di-O-n-hexanoyl-5-fluorouridine 6.6 g (15 mmol)
5.0 g (18 mmol) of silver carbonate was added to a solution of 6.2 g (36 mmol) of benzyl bromide in 50 ml of dry acetone and refluxed for 2 hours. remove insoluble matter,
The liquid was concentrated under reduced pressure. Silica gel column chromatography of the oily residue (elution solvent: chloroform)
The oily residue obtained was purified again by silica gel column chromatography (elution solvent: ether-
(n-hexane = 1:3). The obtained oily purified product was dried under reduced pressure at room temperature, and 3.4g (43%) of 4-O-benzyl-2'-deoxy-3',5'-di-O-n-hexanoyl-5-fluorouridine was extracted as an oily product. I got it as a thing. UV λ EtOH nax nm: 288 NMR δ (ppm, CDCl 3 ): uridine moiety 7.88 (d,
H 6 ), 6.26 (broad-t, H 1 '), 5.14-5.31 (m,
H 3 ′), 4.22−4.32 (m, H 4 ′, H 5 ′), 1.90−2.90
(m, H 2 ′), 2.34 (t, 2×CH 2 CO), 1.12−
1.81 (m, 6 x CH 2 ), 0.76−1.04 (m, 2 x
CH 3 ), benzyl part 7.26−7.56 (m, aromatic
H), 5.51 (s, CH 2 ) Elemental analysis value: C 28 H 37 FN 2 O 7 Calculated value (%): C, 63.14; H, 7.00; N, 5.26 Actual value (%): C, 63.36; H, 7.17; N, 5.23 Examples 2 to 14 The following 4-position benzyloxy derivatives of deoxyfluorouridine were produced in the same manner as in Example 1, except for the reaction time.
Table 1 lists the structure, yield, physical property values, and reaction time of the obtained target product.
【表】【table】
【表】【table】
【表】
実施例 15
2′−デオキシ−3′・5′−ジ−Ｏ−ｎ−ヘキサノ
イル−５−フルオロウリジン5.0ｇ（11ミリモル）
および約30％の２−エチルベンジルクロリドを含
有する４−エチルベンジルクロリド4.2ｇ（27ミ
リモル）の乾燥アセトン50ml溶液に炭酸銀3.7ｇ
（13ミリモル）を加え30時間還流した。反応後実
施例１と同様に後処理および精製し、約30％の２
−エチルベンジル体を含有する４−Ｏ−（４−エ
チルベンジル）−2′−デオキシ−3′・5′−ジ−Ｏ−
ｎ−ヘキサノイル−５−フルオロウリジン2.23ｇ
（35.2％）を油状物として得た。
UV λEtOH naxnm：289
NMR δ（ppm、CDCl3）：ウリジン部分7.40（ｄ、
H6）、6.22（broad−ｔ、H1′）、5.12−5.24（ｍ、
H3′）、4.24−4.40（ｍ、H4′、H5′）、1.94−2.7付
近（ｍ、H2′）、2.32（ｔ、２×CH2CO）、1.14−
1.76（ｍ、６×CH2）、0.80−1.00（ｍ、２×
CH3）、ベンジル部分7.08−7.40（ｍ、aromatic
Ｈ）、5.44と5.50（各々ｓ、２位および４位体の
ＣH2 −C6H5）、2.50−2.82（ｍ、ＣH2 CH3）、
1.3付近（ｍ、CH3）
元素分析値：C30H41FN2O7として
計算値(%)：Ｃ、64.27；Ｈ、7.37；Ｎ、5.00
実測値(%)：Ｃ、64.13；Ｈ、7.48；Ｎ、4.75
実施例 16
2′−デオキシ−3′・5′−ジ−Ｏ−ｎ−ペンタノ
イル−５−フルオロウリジン3.1ｇ（7.5ミリモ
ル）およびベンジルブロミド3.2ｇ（19ミリモル）
のトルエン50ml溶液に炭酸銀2.5ｇ（9.1ミリモ
ル）を加え、30分間、加熱還流下撹拌した。熱
時、不溶物を去し、不溶物は熱トルエン50mlで
洗浄した。液および洗浄液は一緒に合わせて減
圧下濃縮した。油状残渣をシリカゲルカラムクロ
マトグラフイー（溶出溶媒：クロロホルム）で精
製し、得られた油状残渣をシリカゲル分取用薄層
クロマトグラフイー（展開溶媒：エーテル−ｎ−
ヘキサン＝１：１）で再び精製した。得られた油
状精製物を室温で減圧乾燥し、４−Ｏ−ベンジル
−2′−デオキシ−3′・5′−ジ−Ｏ−ｎ−ペンタノ
イル−５−フルオロウリジン1.4ｇ（37％）を油
状物として得た。
UV λEtOH naxnm：289.5
NMR δ（ppm、CDCl3）：ウリジン部分7.88（ｄ、
H6）、6.24（broad−ｔ、H1′）、5.08−5.29（ｍ、
H3′）、4.10−4.50（ｍ、H4′、H5′）、1.96（2.87
（ｍ、H2′）、2.33（ｔ、２×CH2CO）、1.13−
1.78（ｍ、４×CH2）、0.68−1.04（ｍ、２×
CH3）、ベンジル部分7.12−7.54（ｍ、aromatic
Ｈ）、5.41（ｓ、CH2）
元素分析値：C26H33FN2O7として
計算値(%)：Ｃ、61.89；Ｈ、6.59；Ｎ、5.55
実測値(%)：Ｃ、61.41；Ｈ、6.73；Ｎ、5.59
実施例 17
2′−デオキシ−3′・5′−ジ−Ｏ−ｎ−ペンタノ
イル−５−フルオロウリジン2.5ｇ（6.0ミリモ
ル）および４−tert−ブチルベンジルブロミド4.5
ｇ（20ミリモル）のトルエン50ml溶液に炭酸銀
3.0ｇ（11ミリモル）を加え、30分間加熱還流下
撹拌した。以下実施例16と同様の後処理および精
製操作を行い、４−Ｏ−（４−tert−ブチルベン
ジル）−2′−デオキシ−3′・5′−ジ−Ｏ−ｎ−ペン
タノイル−５−フルオロウリジン1.2ｇ（35％）
を油状物として得た。
UV λEtOH naxnm：217、289
NMR δ（ppm、CDCl3）：ウリジン部分7.86（ｄ、
H6）、6.26（broad−ｔ、H1′）、5.12−5.30（ｍ、
H3′）、4.20−4.44（ｍ、H4′、H5′）、1.92−2.88
（ｍ、H2′）、2.34（ｔ、２×CH2CO）、1.12−
1.80（ｍ、４×CH2）、0.78−1.04（ｍ、２×
CH3）、ベンジル部分7.40（ｓ、aromatic Ｈ）、
5.47（ｓ、CH2）、1.32（ｓ、３×CH3）
元素分析値：C30H41FN2O7として
計算値(%)：Ｃ、64.27；Ｈ、7.37；Ｎ、5.00
実測値(%)：Ｃ、64.14；Ｈ、7.46；Ｎ、5.17
実施例 18
2′−デオキシ−3′・5′−ジ−Ｏ−ｎ−ペンタノ
イル−５−フルオロウリジン3.1ｇ（7.5ミリモ
ル）および４−フルオロベンジルブロミド3.6ｇ
（19ミリモル）のメチルエチルケトン50ml溶液に
炭酸銀2.7ｇ（9.8ミリモル）を加え、1.5時間、加
熱還流下撹拌した。不溶物を去し、液を減圧
下濃縮した。油状残渣は実施例16と同様の精製操
作を行い、４−Ｏ−（４−フルオロベンジル）−
2′−デオキシ−3′・5′−ジ−Ｏ−ｎ−ペンタノイ
ル−５−フルオロウリジン1.6ｇ（41％）を油状
物として得た。
UVEtOH naxnm：290
NMR δ（ppm、CDCl3）：ウリジン部分7.90（ｄ、
H6）、6.24（broad−ｔ、H1′）、5.14−5.30（ｍ、
H3′）、4.22−4.50（ｍ、H4′、H5′）、1.96−2.88
（ｍ、H2′）、2.34（ｔ、２×CH2CO）、1.14−
1.80（ｍ、４×CH2）、0.78−1.06（ｍ、２×
CH3）、ベンジル部分7.44（dd、H3、H5）、7.04
（ｔ、H2、H6）、5.46（ｓ、CH2）
元素分析値：C26H32F2N2O7として
計算値(%)：Ｃ、59.76；Ｈ、6.17；Ｎ、5.36
実測値(%)：Ｃ、59.59；Ｈ、6.41；Ｎ、5.16
実施例 19
2′−デオキシ−3′・5′−Ｏ−ｎ−ペンタノイル
−５−フルオロウリジン2.0ｇ（4.8ミリモル）お
よび３−クロロベンジルブロミド2.5ｇ（12ミリ
モル）のメチルエチルケトン50ml溶液に炭酸銀
1.7ｇ（6.2ミリモル）を加え、２時間加熱還流下
撹拌した。以下、実施例18と同様の後処理および
精製操作を行い、４−Ｏ−（３−クロロベンジル）
−2′−デオキシ−3′・5′−ジ−Ｏ−ｎ−ペンタノ
イル−５−フルオロウリジン0.89ｇ（34％）を油
状物として得た。
UV λEtOH naxnm：289
NMR δ（ppm、CDCl3）：ウリジン部分7.90（ｄ、
H6）、6.26（broad−ｔ、H1′）、5.14−5.30（ｍ、
H3′）、4.23−4.53（ｍ、H4′、H5′）、1.95−2.88
（ｍ、H2′）、2.35（ｔ、２×CH2CO）、1.16−
1.80（ｍ、４×CH2）、0.80−1.06（ｍ、２×
CH3）、ベンジル部分7.44（broad−ｓ、H2）、
7.32（ｓ、H4、H5、H6）、5.48（ｓ、CH2）
元素分析値：C26H32ClFN2O7として
計算値(%)：Ｃ、57.94；Ｈ、5.99；Ｎ、5.20
実測値(%)：Ｃ、57.71；Ｈ、6.16；Ｎ、4.92
実施例 20
2′−デオキシ−3′・5′−ジ−Ｏ−ｎ−ヘキサノ
イル−５−フルオロウリジン5.0ｇ（11ミリモ
ル）、ジオキサン45mlおよびメタノール５mlの溶
液に酸化銀3.9ｇ（17ミリモル）を加え、遮光下、
室温で３日間撹拌した。減圧下濃縮乾固し、残渣
に乾燥トルエン30mlを加え、再び減圧下濃縮乾固
した。残渣に３−クロロベンジルブロミド3.2ｇ
（16ミリモル）および乾燥トルエン50mlを加え、
１時間加熱還流した。不溶物を去し、液を減
圧下濃縮した。油状残渣をシリカゲルカラムクロ
マトグラフイー（溶出溶媒：クロロホルム）で精
製し、得られた油状残渣を再びシリカゲルカラム
クロマトグラフイー（溶出溶媒：エーテル−ｎ−
ヘキサン＝１：１）で精製した。得られた油状精
製物を室温で減圧乾燥し、４−Ｏ−（３−クロロ
ベンジル）−2′−デオキシ−3′・5′、ジ−Ｏ−ｎ−
ヘキサノイル−５−フルオロウリジン2.5ｇ（39
％）を油状物として得た。
UV λEtOH naxnm：290
NMR δ（ppm、CDCl3）：ウリジン部分7.92（ｄ、
H6）、6.25（broad−ｔ、H1′）、5.12−5.32（ｍ、
H3′）、4.20−4.52（ｍ、H4′、H5′）、1.98−2.90
（ｍ、H2′）、2.35（ｔ、２×CH2CO）、1.12−
1.82（ｍ、６×CH2）、0.74−1.04（ｍ、２×
CH3）、ベンジル部分7.44（broad−ｓ、H2）、
7.32（ｓ、H4、H5、H6）、5.48（ｓ、CH2）
元素分析値：C28H36ClFN2O7として
計算値(%)：Ｃ、59.31；Ｈ、6.40；Ｎ、4.94
実測値(%)：Ｃ、59.57；Ｈ、6.64；Ｎ、4.74[Table] Example 15 2'-deoxy-3', 5'-di-O-n-hexanoyl-5-fluorouridine 5.0 g (11 mmol)
and 3.7 g of silver carbonate in 50 ml of dry acetone solution of 4.2 g (27 mmol) of 4-ethylbenzyl chloride containing about 30% of 2-ethylbenzyl chloride.
(13 mmol) was added and refluxed for 30 hours. After the reaction, post-treatment and purification were carried out in the same manner as in Example 1, and about 30% of 2
-4-O-(4-ethylbenzyl)-2'-deoxy-3',5'-di-O- containing -ethylbenzyl compound
n-hexanoyl-5-fluorouridine 2.23g
(35.2%) was obtained as an oil. UV λ EtOH nax nm: 289 NMR δ (ppm, CDCl 3 ): uridine moiety 7.40 (d,
H 6 ), 6.22 (broad-t, H 1 '), 5.12-5.24 (m,
H 3 ′), 4.24−4.40 (m, H 4 ′, H 5 ′), around 1.94−2.7 (m, H 2 ′), 2.32 (t, 2×CH 2 CO), 1.14−
1.76 (m, 6 x CH 2 ), 0.80−1.00 (m, 2 x
CH 3 ), benzyl part 7.08−7.40 (m, aromatic
H), 5.44 and 5.50 (s, CH2 - C6H5 in the 2- and 4-positions , respectively), 2.50-2.82 (m, CH2CH3 ),
Around 1.3 (m, CH 3 ) Elemental analysis value: C 30 H 41 FN 2 O 7 Calculated value (%): C, 64.27; H, 7.37; N, 5.00 Actual value (%): C, 64.13; H, 7.48; N, 4.75 Example 16 2'-deoxy-3',5'-di-O-n-pentanoyl-5-fluorouridine 3.1 g (7.5 mmol) and benzyl bromide 3.2 g (19 mmol)
2.5 g (9.1 mmol) of silver carbonate was added to a 50 ml solution of toluene, and the mixture was stirred under heating under reflux for 30 minutes. While hot, the insoluble matter was removed, and the insoluble matter was washed with 50 ml of hot toluene. The liquid and washings were combined and concentrated under reduced pressure. The oily residue was purified by silica gel column chromatography (eluent: chloroform), and the obtained oily residue was purified by silica gel preparative thin layer chromatography (developing solvent: ether-n-
It was purified again using hexane (1:1). The obtained oily purified product was dried under reduced pressure at room temperature, and 1.4g (37%) of 4-O-benzyl-2'-deoxy-3',5'-di-O-n-pentanoyl-5-fluorouridine was extracted as an oily product. I got it as a thing. UV λ EtOH nax nm: 289.5 NMR δ (ppm, CDCl 3 ): uridine moiety 7.88 (d,
H 6 ), 6.24 (broad-t, H 1 '), 5.08-5.29 (m,
H 3 ′), 4.10−4.50 (m, H 4 ′, H 5 ′), 1.96 (2.87
(m, H 2 ′), 2.33 (t, 2×CH 2 CO), 1.13−
1.78 (m, 4 x CH 2 ), 0.68−1.04 (m, 2 x
CH 3 ), benzyl part 7.12−7.54 (m, aromatic
H), 5.41 (s, CH 2 ) Elemental analysis value: C 26 H 33 FN 2 O 7 Calculated value (%): C, 61.89; H, 6.59; N, 5.55 Actual value (%): C, 61.41; H, 6.73; N, 5.59 Example 17 2'-deoxy-3',5'-di-O-n-pentanoyl-5-fluorouridine 2.5 g (6.0 mmol) and 4-tert-butylbenzyl bromide 4.5 g
g (20 mmol) of silver carbonate in 50 ml of toluene solution.
3.0 g (11 mmol) was added, and the mixture was stirred under heating and reflux for 30 minutes. Thereafter, the same post-treatment and purification operations as in Example 16 were carried out, and 4-O-(4-tert-butylbenzyl)-2'-deoxy-3',5'-di-O-n-pentanoyl-5-fluoro Uridine 1.2g (35%)
was obtained as an oil. UV λ EtOH nax nm: 217, 289 NMR δ (ppm, CDCl3 ): uridine moiety 7.86 (d,
H 6 ), 6.26 (broad-t, H 1 '), 5.12-5.30 (m,
H 3 ′), 4.20−4.44 (m, H 4 ′, H 5 ′), 1.92−2.88
(m, H 2 ′), 2.34 (t, 2×CH 2 CO), 1.12−
1.80 (m, 4 x CH 2 ), 0.78−1.04 (m, 2 x
CH 3 ), benzyl moiety 7.40 (s, aromatic H),
5.47 (s, CH 2 ), 1.32 (s, 3×CH 3 ) Elemental analysis value: C 30 H 41 FN 2 O 7 Calculated value (%): C, 64.27; H, 7.37; N, 5.00 Actual value ( %):C, 64.14; Benzyl bromide 3.6g
2.7 g (9.8 mmol) of silver carbonate was added to a 50 ml solution of (19 mmol) in methyl ethyl ketone, and the mixture was stirred under heating under reflux for 1.5 hours. Insoluble matter was removed, and the liquid was concentrated under reduced pressure. The oily residue was purified in the same manner as in Example 16 to obtain 4-O-(4-fluorobenzyl)-
1.6 g (41%) of 2'-deoxy-3'.5'-di-O-n-pentanoyl-5-fluorouridine was obtained as an oil. UV EtOH nax nm: 290 NMR δ (ppm, CDCl3 ): uridine moiety 7.90 (d,
H 6 ), 6.24 (broad-t, H 1 '), 5.14-5.30 (m,
H 3 ′), 4.22−4.50 (m, H 4 ′, H 5 ′), 1.96−2.88
(m, H 2 ′), 2.34 (t, 2×CH 2 CO), 1.14−
1.80 (m, 4 x CH 2 ), 0.78−1.06 (m, 2 x
CH3 ), benzyl moiety 7.44 (dd, H3 , H5 ), 7.04
(t, H 2 , H 6 ), 5.46 (s, CH 2 ) Elemental analysis value: C 26 H 32 F 2 N 2 O 7 Calculated value (%): C, 59.76; H, 6.17; N, 5.36 Actual measurement Value (%): C, 59.59; H, 6.41; N, 5.16 Example 19 2'-deoxy-3', 5'-O-n-pentanoyl-5-fluorouridine 2.0 g (4.8 mmol) and 3-chloro Silver carbonate in a solution of 2.5 g (12 mmol) of benzyl bromide in 50 ml of methyl ethyl ketone.
1.7 g (6.2 mmol) was added, and the mixture was stirred under heating and reflux for 2 hours. Hereinafter, the same post-treatment and purification operations as in Example 18 were performed, and 4-O-(3-chlorobenzyl)
0.89 g (34%) of -2'-deoxy-3'.5'-di-O-n-pentanoyl-5-fluorouridine was obtained as an oil. UV λ EtOH nax nm: 289 NMR δ (ppm, CDCl3 ): uridine moiety 7.90 (d,
H 6 ), 6.26 (broad-t, H 1 '), 5.14-5.30 (m,
H 3 ′), 4.23−4.53 (m, H 4 ′, H 5 ′), 1.95−2.88
(m, H 2 ′), 2.35 (t, 2×CH 2 CO), 1.16−
1.80 (m, 4 x CH 2 ), 0.80−1.06 (m, 2 x
CH 3 ), benzyl moiety 7.44 (broad-s, H 2 ),
7.32 (s, H 4 , H 5 , H 6 ), 5.48 (s, CH 2 ) Elemental analysis value: C 26 H 32 ClFN 2 O 7 Calculated value (%): C, 57.94; H, 5.99; N, 5.20 Actual value (%): C, 57.71; H, 6.16; N, 4.92 Example 20 2'-deoxy-3', 5'-di-O-n-hexanoyl-5-fluorouridine 5.0 g (11 mmol) , 3.9 g (17 mmol) of silver oxide was added to a solution of 45 ml of dioxane and 5 ml of methanol, and
Stirred at room temperature for 3 days. The mixture was concentrated to dryness under reduced pressure, 30 ml of dry toluene was added to the residue, and the mixture was concentrated to dryness under reduced pressure again. 3.2g of 3-chlorobenzyl bromide in the residue
(16 mmol) and 50 ml of dry toluene,
The mixture was heated under reflux for 1 hour. Insoluble matter was removed, and the liquid was concentrated under reduced pressure. The oily residue was purified by silica gel column chromatography (elution solvent: chloroform), and the obtained oily residue was purified again by silica gel column chromatography (elution solvent: ether-n-
Purification was performed using hexane (1:1). The obtained oily purified product was dried under reduced pressure at room temperature to give 4-O-(3-chlorobenzyl)-2'-deoxy-3'·5', di-O-n-
Hexanoyl-5-fluorouridine 2.5g (39
%) was obtained as an oil. UV λ EtOH nax nm: 290 NMR δ (ppm, CDCl 3 ): uridine moiety 7.92 (d,
H 6 ), 6.25 (broad-t, H 1 '), 5.12-5.32 (m,
H 3 ′), 4.20−4.52 (m, H 4 ′, H 5 ′), 1.98−2.90
(m, H 2 ′), 2.35 (t, 2×CH 2 CO), 1.12−
1.82 (m, 6 x CH 2 ), 0.74−1.04 (m, 2 x
CH 3 ), benzyl moiety 7.44 (broad-s, H 2 ),
7.32 (s, H 4 , H 5 , H 6 ), 5.48 (s, CH 2 ) Elemental analysis value: C 28 H 36 ClFN 2 O 7 Calculated value (%): C, 59.31; H, 6.40; N, 4.94 Actual value (%): C, 59.57; H, 6.64; N, 4.74
Claims (1)
しくは分枝状の炭素数１ないし４のアルキル基を
示し、ｎは３又は４を示す）で表わされるデオキ
シフルオロウリジン４位ベンジルオキシ体。 ２ 一般式（）、 （式中、ｎは３又は４を示す）で表わされる2′−
デオキシ−3′・5′−ジ−Ｏ−アルカノイル−５−
フルオロウリジンに銀化合物及び一般式（）、 （式中、Ｒは水素原子、ハロゲン原子、直鎖状若
しくは分枝状の炭素数１ないし４のアルキル基
を、halはハロゲン原子を示す）で表わされるベ
ンジル化合物を反応させることを特徴とする一般
式（）、 （式中、Ｒ及びｎは前記に同義）で表わされるデ
オキシフルオロウリジン４位ベンジルオキシ体の
製造方法。 ３ 銀化合物が炭酸銀又は酢酸銀又は酸化銀であ
る特許請求の範囲第２項記載のデオキシフルオロ
ウリジン４位ベンジルオキシ体の製造方法。[Claims] 1 General formula (), (wherein, R represents a hydrogen atom, a halogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, and n represents 3 or 4). . 2 General formula (), 2'- (wherein n represents 3 or 4)
Deoxy-3'・5'-di-O-alkanoyl-5-
Silver compound and general formula () to fluorouridine, (In the formula, R represents a hydrogen atom, a halogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, and hal represents a halogen atom). General formula (), A method for producing a benzyloxy deoxyfluorouridine at the 4-position represented by the formula (wherein R and n are the same as defined above). 3. The method for producing a 4-position benzyloxy deoxyfluorouridine compound according to claim 2, wherein the silver compound is silver carbonate, silver acetate, or silver oxide.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP12677580A JPS5750999A (en) | 1980-09-11 | 1980-09-11 | Benzyloxy derivative at 4-position of deoxyfluorouridine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP12677580A JPS5750999A (en) | 1980-09-11 | 1980-09-11 | Benzyloxy derivative at 4-position of deoxyfluorouridine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5750999A JPS5750999A (en) | 1982-03-25 |
| JPS632278B2 true JPS632278B2 (en) | 1988-01-18 |
Family
ID=14943617
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP12677580A Granted JPS5750999A (en) | 1980-09-11 | 1980-09-11 | Benzyloxy derivative at 4-position of deoxyfluorouridine |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5750999A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP3074341B2 (en) * | 1993-12-24 | 2000-08-07 | 大鵬薬品工業株式会社 | 2'-deoxy-5-fluorouridine derivative |
-
1980
- 1980-09-11 JP JP12677580A patent/JPS5750999A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5750999A (en) | 1982-03-25 |
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