JPH027591B2 - - Google Patents
Info
- Publication number
- JPH027591B2 JPH027591B2 JP3795483A JP3795483A JPH027591B2 JP H027591 B2 JPH027591 B2 JP H027591B2 JP 3795483 A JP3795483 A JP 3795483A JP 3795483 A JP3795483 A JP 3795483A JP H027591 B2 JPH027591 B2 JP H027591B2
- Authority
- JP
- Japan
- Prior art keywords
- formula
- nucleoside
- general formula
- uracil
- represented
- 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 5-formyluracil nucleoside Chemical class 0.000 claims description 13
- 239000002777 nucleoside Substances 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 229910052736 halogen Chemical group 0.000 claims description 6
- 150000002367 halogens Chemical group 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 230000002194 synthesizing effect Effects 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 17
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000002904 solvent Substances 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 229940035893 uracil Drugs 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 5
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 5
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 238000000921 elemental analysis Methods 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- VRIUYSDAKYHMAA-UHFFFAOYSA-N ethyl 2-[(2-bromophenyl)-diphenyl-lambda5-phosphanylidene]acetate Chemical compound BrC1=C(C=CC=C1)P(C1=CC=CC=C1)(C1=CC=CC=C1)=CC(=O)OCC VRIUYSDAKYHMAA-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 238000012746 preparative thin layer chromatography Methods 0.000 description 3
- 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 2
- MZBPLEJIMYNQQI-JAGXHNFQSA-N 1-[(2r,3s,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-2,4-dioxopyrimidine-5-carbaldehyde Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C=O)=C1 MZBPLEJIMYNQQI-JAGXHNFQSA-N 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-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
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000003729 cation exchange resin Substances 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 125000003944 tolyl group Chemical group 0.000 description 2
- IIHPVYJPDKJYOU-UHFFFAOYSA-N triphenylcarbethoxymethylenephosphorane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=CC(=O)OCC)C1=CC=CC=C1 IIHPVYJPDKJYOU-UHFFFAOYSA-N 0.000 description 2
- RNHDAKUGFHSZEV-UHFFFAOYSA-N 1,4-dioxane;hydrate Chemical compound O.C1COCCO1 RNHDAKUGFHSZEV-UHFFFAOYSA-N 0.000 description 1
- RHNKTNRPTOLWJS-BDNRQGISSA-N 1-[(2r,3s,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-ethenylpyrimidine-2,4-dione Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C=C)=C1 RHNKTNRPTOLWJS-BDNRQGISSA-N 0.000 description 1
- HXDYHJGZXSPLJE-UHFFFAOYSA-N 2,4-dioxopyrimidine-1-carbaldehyde Chemical compound O=CN1C=CC(=O)NC1=O HXDYHJGZXSPLJE-UHFFFAOYSA-N 0.000 description 1
- GCQYYIHYQMVWLT-BDNRQGISSA-N 5-(2-bromoethenyl)-1-[(2r,3s,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dione Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C=CBr)=C1 GCQYYIHYQMVWLT-BDNRQGISSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- ATSFSUUXRHMGQU-VFGKCITPSA-N ethyl (e)-3-[1-[(2r,3s,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-2,4-dioxopyrimidin-5-yl]prop-2-enoate Chemical compound O=C1NC(=O)C(/C=C/C(=O)OCC)=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 ATSFSUUXRHMGQU-VFGKCITPSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 150000002941 palladium compounds Chemical class 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Saccharide Compounds (AREA)
Description
【発明の詳細な説明】
本発明は、５−カルボキシビニルウラシルヌク
レオシドの新規な製造法に関するものである。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing 5-carboxyvinyluracil nucleosides.
本発明方法の目的化合物である５−カルボキシ
ビニルウラシルヌクレオシドは次の一般式〔〕
で示される化合物を総称する。 5-carboxyvinyluracil nucleoside, which is the target compound of the method of the present invention, has the following general formula []
The compounds represented by are collectively referred to as
該式中、R1は水素または水酸基を示し、Ｘは
水素またはハロゲンを示す。Ｘのハロゲンの具体
例は臭素、塩素、またはヨウ素である。以下、本
発明方法の目的化合物を５−カルボキシビニル
Usと総称する。 In this formula, R 1 represents hydrogen or a hydroxyl group, and X represents hydrogen or halogen. Specific examples of halogen for X are bromine, chlorine, or iodine. Hereinafter, the target compound of the method of the present invention is 5-carboxyvinyl
Collectively referred to as Us.
５−カルボキシビニルUsは、たとえばそれら
を脱炭酸反応に供することにより、強力な抗ウイ
ルス活性を有する化合物として公知の１−β−Ｄ
−2′−デオキシリボフラノシル−５−ビニルウラ
シル（VDU）、１−β−Ｄ−アラビノフラノシル
−５−ビニルウラシル（VAU）、５−ブロモビニ
ル−１−β−Ｄ−2′−デオキシリボフラノシルウ
ラシル（BVDU）、１−β−Ｄ−アラビノフラノ
シル−５−ブロモビニルウラシル（BVAU）な
どに導くことができ、それら有用化合物の合成中
間体として重要なものである。 5-carboxyvinyl Us can be converted into 1-β-D, which is known as a compound with strong antiviral activity, by subjecting them to decarboxylation, for example.
-2'-deoxyribofuranosyl-5-vinyluracil (VDU), 1-β-D-arabinofuranosyl-5-vinyluracil (VAU), 5-bromovinyl-1-β-D-2'-deoxyribofurano It can lead to siluracil (BVDU), 1-β-D-arabinofuranosyl-5-bromovinyluracil (BVAU), etc., and is important as a synthetic intermediate for these useful compounds.
従来、５−カルボキシビニルUsの製造法とし
ては、５−ハロゲノウラシルヌクレオシドとア
クリル酸アルキルエステルとを極性溶媒中、三級
有機アミン、ホスフイン化合物およびパラジウム
化合物の存在下で反応させることにより５−アル
コキシカルボニル体に導びき、これを加水分解し
て目的化合物を得る方法（特開昭58−62194号公
報（特願昭56−161152））、５−ハロゲノマーキ
ユリウラシルとアクリル酸アルキルエステルとを
ハロゲン化リチウム、パラジウム触媒の存在下で
反応させて５−アルコキシカルボニル体を導び
き、これを加水分解して目的化合物を得る方法
（特開昭58−62194号公報（特願昭56−161152）テ
トラヘドロン・レターズ（Tetrahedron
Letters）No.45、pp4415−4418（1979））がある。
なお、前記一般式〔〕においてＸがハロゲンで
あるものは新規化合物であり、そのもの自体およ
びその製造法を記載した文献は知られていない。 Conventionally, 5-carboxyvinyl Us is produced by reacting 5-halogenouracil nucleoside with an acrylic acid alkyl ester in a polar solvent in the presence of a tertiary organic amine, a phosphine compound, and a palladium compound. A method in which a 5-halogenomer kyuriuracil and an acrylic acid alkyl ester are converted into a carbonyl form and then hydrolyzed to obtain the target compound (Japanese Patent Application Laid-Open No. 1983-62194 (Japanese Patent Application No. 161152-1982)) A method of reacting in the presence of lithium chloride and a palladium catalyst to derive a 5-alkoxycarbonyl compound, which is then hydrolyzed to obtain the target compound (Japanese Unexamined Patent Publication No. 58-62194 (Japanese Patent Application No. 161152-1982)) Tetrahedron Letters
Letters) No.45, pp4415-4418 (1979)).
In addition, in the above general formula [], a compound in which X is a halogen is a new compound, and no literature describing itself or its production method is known.
本発明者らは、高収率で目的化合物を製造しう
る新規な製造法を確立するため、種々研究を重ね
た結果、本発明を完成するに至つた。すなわち、
本発明は、一般式〔〕
〔式中、R1は水素または水酸基を示す。〕で表わ
される５−ホルミルウラシルヌクレオシドに一般
式〔〕
（R2）3P＝CXCOOR3 〔〕
〔式中、R2はアルキル基および／またはアリー
ル基を示し、R3はアルキル基またはアリール基
を示し、Ｘは水素またはハロゲンを示す。〕で表
わされるホスホランを反応させて一般式〔〕
〔式中、R1、R3およびＸは前記と同意義であ
る。〕で表わされる５−アルコキシもしくはアロ
キシカルボニルビニルウラシルヌクレオシドを
得、次いでこれを加水分解することによつて５−
カルボキシビニルUsを得る方法である。 The present inventors have completed the present invention as a result of various studies in order to establish a new production method that can produce the target compound in high yield. That is,
The present invention is based on the general formula [] [In the formula, R 1 represents hydrogen or a hydroxyl group. 5-formyluracil nucleoside represented by the general formula [] (R 2 ) 3 P=CXCOOR 3 [] [In the formula, R 2 represents an alkyl group and/or an aryl group, and R 3 represents an alkyl group or an aryl group. and X represents hydrogen or halogen. ] by reacting the phosphorane represented by the general formula [ ] [In the formula, R 1 , R 3 and X have the same meanings as above. 5-alkoxy or aryloxycarbonyl vinyl uracil nucleoside represented by is obtained and then hydrolyzed to obtain 5-
This is a method to obtain carboxyvinyl Us.
本発明方法における一般式〔〕化合物、すな
わち５−ホルミルウラシルヌクレオシドは公知化
合物であり、特にその調製法に制約はない。 The compound of general formula [] in the method of the present invention, that is, 5-formyluracil nucleoside, is a known compound, and there are no particular restrictions on its preparation method.
また、第一の工程における反応試薬であるホス
ホランは前記一般式〔〕で表わされる。一般式
〔〕のR2のアルキル基および／またはアリール
基の具体例としては、メチル、エチル、プロピ
ル、ブチル、ベンジル、フエニル、トリルなどが
挙げられる。三つのR2は互いに同一である必要
はなく、たとえば一つがメチルで他の二つがフエ
ニル、もしくは二つがエチルで一つがトリルなど
の場合を含む。R3のアルキル基またはアリール
基の具体例としてはメチル、エチル、プロピル、
ブチル、フエニルなどが挙げられる。Ｘのハロゲ
ンは、臭素、塩素もしくはヨウ素である。 Further, phosphorane, which is a reaction reagent in the first step, is represented by the above general formula []. Specific examples of the alkyl group and/or aryl group for R 2 in the general formula [] include methyl, ethyl, propyl, butyl, benzyl, phenyl, and tolyl. The three R2s do not have to be the same, and include cases where one is methyl and the other two are phenyl, or two are ethyl and one is tolyl. Specific examples of the alkyl group or aryl group for R3 include methyl, ethyl, propyl,
Examples include butyl and phenyl. The halogen of X is bromine, chlorine or iodine.
第一工程の反応は反応溶媒中で行なわれる。使
用しうる反応溶媒としてはジオキサン、テトラヒ
ドロフラン、エチレングリコールジメチルエーテ
ルなどのエーテル類、ジメチルホルムアミドなど
のアミド系溶媒、ジメチルスルホキシドなどが例
示できる。反応条件にも特に制約なく、室温で十
分反応は進行する。 The first step reaction is carried out in a reaction solvent. Examples of usable reaction solvents include ethers such as dioxane, tetrahydrofuran, and ethylene glycol dimethyl ether, amide solvents such as dimethylformamide, and dimethyl sulfoxide. There are no particular restrictions on the reaction conditions, and the reaction proceeds satisfactorily at room temperature.
かくして得られる一般式〔〕化合物、５−ア
ルコキシもしくはアロキシカルボニルビニル体を
加水分解反応に供することにより目的化合物に導
くことができる。 The compound of the general formula [], 5-alkoxy or aroxycarbonylvinyl compound thus obtained can be led to the target compound by subjecting it to a hydrolysis reaction.
加水分解反応は、水酸化ナトリウム、水酸化カ
リウム、水酸化アンモニウム、炭酸ナトリウム、
炭酸水素ナトリウム、トリエチルアミンなどのア
ルカリを用いて水または含水溶媒（たとえば、ジ
オキサン−水、メタノール−水、エタノール−水
など）中で行う。反応は０℃〜室温で数時間の条
件下で実施することができる。 The hydrolysis reaction involves sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium carbonate,
The reaction is carried out in water or a water-containing solvent (eg, dioxane-water, methanol-water, ethanol-water, etc.) using an alkali such as sodium hydrogen carbonate or triethylamine. The reaction can be carried out at 0°C to room temperature for several hours.
目的化合物の分離精製は常法によればよく、吸
着カラムクロマトグラフイー、イオン交換カラム
クロマトグラフイー、再結晶などの方法を適宜に
応用することができる。 The target compound may be separated and purified by conventional methods, and methods such as adsorption column chromatography, ion exchange column chromatography, and recrystallization can be applied as appropriate.
本発明方法は、目的化合物の合成収率が高い、
反応操作が容易で単離も簡単である、合成コスト
が低いなどの利点を有する。 The method of the present invention has a high synthesis yield of the target compound.
It has advantages such as easy reaction operation, simple isolation, and low synthesis cost.
以下、本発明の実施例を示し、本発明の構成お
よび効果をより具体的に説明する。 EXAMPLES Hereinafter, examples of the present invention will be shown, and the structure and effects of the present invention will be explained more specifically.
実施例 １
１−β−Ｄ−アラビノフラノシル−５−ホルミ
ルウラシル81.6mg、ブロモ（エトキシカルボニ
ル）メチレントリフエニルホスホラン141mgをジ
オキサン３mlに懸濁させ、室温にて４時間攪拌反
応させた。溶媒を留去した後、残渣をプレパラテ
イヴ薄層クロマトグラフイー（PLC）にて分離
し（溶媒、クロロホルム−メタノール＝10：１）、
目的の部分をクロロホルム−メタノール＝10：１
で抽出し、溶媒を留去し、残渣をエタノールから
再結晶して１−β−Ｄ−アラビノフラノシル−５
−（２−ブロモ−２−エトキシカルボニルビニル）
ウラシル112mgを得た（収率89％）。Example 1 81.6 mg of 1-β-D-arabinofuranosyl-5-formyluracil and 141 mg of bromo(ethoxycarbonyl)methylenetriphenylphosphorane were suspended in 3 ml of dioxane and reacted with stirring at room temperature for 4 hours. After distilling off the solvent, the residue was separated using preparative thin layer chromatography (PLC) (solvent: chloroform-methanol = 10:1),
Add the desired part to chloroform-methanol = 10:1
The solvent was distilled off, and the residue was recrystallized from ethanol to give 1-β-D-arabinofuranosyl-5.
-(2-bromo-2-ethoxycarbonylvinyl)
112 mg of uracil was obtained (yield 89%).
融点 219〜220℃
紫外部吸収スペクトル
λEtOH nax 263nｍ、23nｍ
核磁気共鳴スペクトル（DMSO−d6）
ビニル基プロトン 8.17ppm
元素分析 C14H17N2O8Brとして
理論値 Ｃ、39.92；Ｈ、4.07；Ｎ、6.65；
Br、18.97
実測値 Ｃ、39.99；Ｈ、4.07；Ｎ、6.54；
Br、19.01
１−β−Ｄ−アラビノフラノシル−５−（２−
ブロモ−２−エトキシカルボニルビニル）ウラシ
ル121.4mgをジオキサン３mlに懸濁させ、0.5N水
酸化ナトリウム２mlを加えて室温で１時間攪拌し
ながら反応させた。強酸性カチオン交換樹脂ダウ
エツクス50W−X8（H+型）にてPH３〜４にし、
濾過後、溶媒を留去し、残渣を水より再結晶して
１−β−Ｄ−アラビノフラノシル−５−（２−ブ
ロモ−２−カルボキシビニル）ウラシル101mgを
得た（収率88％）。Melting point 219-220℃ Ultraviolet absorption spectrum λ EtOH nax 263 nm, 23 nm Nuclear magnetic resonance spectrum (DMSO-d 6 ) Vinyl group proton 8.17 ppm Elemental analysis C 14 H 17 N 2 O 8 As Br Theoretical value C, 39.92; H, 4.07; N, 6.65; Br, 18.97 Actual value C, 39.99; H, 4.07; N, 6.54; Br, 19.01 1-β-D-arabinofuranosyl-5-(2-
121.4 mg of bromo-2-ethoxycarbonylvinyl) uracil was suspended in 3 ml of dioxane, 2 ml of 0.5N sodium hydroxide was added, and the mixture was reacted with stirring at room temperature for 1 hour. Adjust the pH to 3 to 4 using the strongly acidic cation exchange resin Dowex 50W-X8 (H + type).
After filtration, the solvent was distilled off, and the residue was recrystallized from water to obtain 101 mg of 1-β-D-arabinofuranosyl-5-(2-bromo-2-carboxyvinyl)uracil (yield 88%). ).
融点 187℃（分解）
紫外部吸収スペクトル
λpH7 nax 261nｍ、308nｍ
元素分析 C12H13N2O8Brとして
理論値 Ｃ、36.66；Ｈ、3.33；Ｎ、7.13；
Br、20.32
実測値 Ｃ、36.48；Ｈ、3.32；Ｎ、7.02；
Br、20.16
実施例 ２
１−β−Ｄ−アラビノフラノシル−５−ホルミ
ルウラシル136mgをジメチルホルムアミド５mlに
溶解し、エトキシカルボニルメチレントリフエニ
ルホスホラン192mgを加えて室温で10時間攪拌し
ながら反応させた。溶媒を留去した後、残渣をメ
タノールに溶解させ、シリカゲルクロマトグラフ
イーにて分離し（溶離後、クロロホルム−メタノ
ール＝７：１）、１−β−Ｄ−アラビノフラノシ
ル−５−（２−エトキシカルボニルビニル）ウラ
シルの(E)体および（Ｚ）体の混合物を得た。これ
をエタノールより再結晶して(E)体を得た。（収率
75％）
融点 171〜176℃
元素分析 C14H18N2O8として
理論値 Ｃ、49.12；Ｈ、5.30；Ｎ、8.19
実測値 Ｃ、48.98；Ｈ、5.28；Ｎ、8.07
１−β−Ｄ−アラビノフラノシル−(E)−５−
（２−エトキシカルボニルビニル）ウラシル172mg
をジオキサン６mlに溶解させ、1.25M水酸化ナト
リウム４mlを加え、室温にて１時間攪拌しながら
反応させ、強酸性カチオン交換樹脂ダウエツクス
50W−X8（H+型）でPH３〜４にした後、樹脂を
濾去し、濾液を濃縮し、水より再結晶して１−β
−Ｄ−アラビノフラノシル−５−（２−カルボキ
シビニル）ウラシル146mgを得た。（収率93％）
融点 243〜248℃
元素分析 C12H14N2O8として
理論値 Ｃ、45.86；Ｈ、4.49；Ｎ、8.92
実測値 Ｃ、45.92；Ｈ、4.45；Ｎ、8.82
実施例 ３
１−β−Ｄ−2′−デオキシリボフラノシル−５
−ホルミルウラシル512mgをジメチルスルホキシ
ド５mlにブロモ（エトキシカルボニル）メチレン
トリフエニルホスホラン970mgを加え、攪拌下一
夜室温にて反応させた。溶媒を減圧下留去し、残
渣をプレパラテイブ薄層クロマトグラフイーにて
分離し（溶媒、クロロホルム−メタノール＝20：
１）、目的の部分をクロロホルム−メタノール＝
10：１で抽出し、抽出液を濃縮乾固して１−β−
Ｄ−2′−デオキシリボフラノシル−５−（２−ブ
ロモ−２−エトキシカルボニルビニル）ウラシル
1.01ｇを得た。Melting point 187℃ (decomposition) Ultraviolet absorption spectrum λ pH7 nax 261nm, 308nm Elemental analysis C 12 H 13 N 2 O 8 As Br Theoretical value C, 36.66; H, 3.33; N, 7.13; Br, 20.32 Actual value C, 36.48 ; H, 3.32; N, 7.02; Br, 20.16 Example 2 136 mg of 1-β-D-arabinofuranosyl-5-formyluracil was dissolved in 5 ml of dimethylformamide, and 192 mg of ethoxycarbonylmethylenetriphenylphosphorane was added. The reaction was allowed to proceed at room temperature for 10 hours with stirring. After evaporating the solvent, the residue was dissolved in methanol and separated by silica gel chromatography (chloroform-methanol = 7:1 after elution) to give 1-β-D-arabinofuranosyl-5-(2 A mixture of the (E) and (Z) forms of -ethoxycarbonylvinyl) uracil was obtained. This was recrystallized from ethanol to obtain the (E) form. (yield
75%) Melting point 171-176℃ Elemental analysis C 14 H 18 N 2 O 8 Theoretical value C, 49.12; H, 5.30; N, 8.19 Actual value C, 48.98; H, 5.28; N, 8.07 1-β-D -Arabinofuranosyl-(E)-5-
(2-ethoxycarbonylvinyl)uracil 172mg
was dissolved in 6 ml of dioxane, 4 ml of 1.25M sodium hydroxide was added, and the mixture was reacted at room temperature with stirring for 1 hour.
After adjusting the pH to 3 to 4 with 50W-X8 (H + type), the resin was filtered off, the filtrate was concentrated, and recrystallized from water to obtain 1-β.
146 mg of -D-arabinofuranosyl-5-(2-carboxyvinyl)uracil was obtained. (Yield 93%) Melting point 243-248℃ Elemental analysis C 12 H 14 N 2 O 8 Theoretical value C, 45.86; H, 4.49; N, 8.92 Actual value C, 45.92; H, 4.45; N, 8.82 Example 3 1-β-D-2'-deoxyribofuranosyl-5
- 512 mg of formyluracil and 970 mg of bromo(ethoxycarbonyl)methylenetriphenylphosphorane were added to 5 ml of dimethyl sulfoxide, and the mixture was reacted with stirring overnight at room temperature. The solvent was distilled off under reduced pressure, and the residue was separated by preparative thin layer chromatography (solvent: chloroform-methanol = 20:
1), convert the target part into chloroform-methanol=
Extract at a ratio of 10:1 and concentrate the extract to dryness to obtain 1-β-
D-2'-deoxyribofuranosyl-5-(2-bromo-2-ethoxycarbonylvinyl)uracil
1.01g was obtained.
核磁気共鳴スペクトル（DMSO−d6）δppm
9.00（Ｈ−６）、8.14（ビニル基プロトン）
１−β−Ｄ−2′−デオキシリボフラノシル−５
−（２−ブロモ−２−エトキシカルボニルビニル）
ウラシル634mgをジオキサン10mlに懸濁させ、
1.25M水酸化ナトリウム４mlを加え、室温にて攪
拌し、１〜２時間後、強酸性カチオン交換樹脂ダ
ウエツクス50W（H+型）でPH３とした後、樹脂を
濾去し、濾液を濃縮乾固して１−β−Ｄ−2′−デ
オキシリボフラノシル−５−（２−ブロモ−２−
カルボキシビニル）ウラシルを得た。Nuclear magnetic resonance spectrum (DMSO- d6 ) δppm 9.00 (H-6), 8.14 (vinyl group proton) 1-β-D-2'-deoxyribofuranosyl-5
-(2-bromo-2-ethoxycarbonylvinyl)
Suspend 634 mg of uracil in 10 ml of dioxane,
Add 4 ml of 1.25M sodium hydroxide, stir at room temperature, and after 1 to 2 hours, adjust the pH to 3 using a strongly acidic cation exchange resin Dowex 50W (H + type), remove the resin by filtration, and concentrate the filtrate to dryness. 1-β-D-2'-deoxyribofuranosyl-5-(2-bromo-2-
(carboxyvinyl) uracil was obtained.
核磁気共鳴スペクトル（DMSO−d6）δppm
8.68（Ｈ−６） 7.80（ビニル基プロトン）
6.24（Ｈ−1′）
実施例 ４
ブロモ（エトキシカルボニル）メチレントリフ
エニルホスホランの代りにエトキシカルボニルメ
チレントリフエニルホスホラン800mgを用いた以
外は実施例３と同様にして１−β−Ｄ−2′−デオ
キシリボフラノシル−５−（２−エトキシカルボ
ニルビニル）ウラシル512mgを得た。Nuclear magnetic resonance spectrum (DMSO- d6 ) δppm 8.68 (H-6) 7.80 (vinyl group proton)
6.24(H-1') Example 4 1-β-D-2 was prepared in the same manner as in Example 3 except that 800 mg of ethoxycarbonylmethylenetriphenylphosphorane was used instead of bromo(ethoxycarbonyl)methylenetriphenylphosphorane. 512 mg of '-deoxyribofuranosyl-5-(2-ethoxycarbonylvinyl)uracil was obtained.
核磁気共鳴スペクトル（DMSO−d6）δppm
8.42（Ｈ−６） 7.38、6.85（ｄ、−CH＝CH−）
１−β−Ｄ−2′−デオキシリボフラノシル−５
−（２−エトキシカルボニルビニル）ウラシル326
mgを用いて以下実施例３と同様にして１−β−Ｄ
−2′−デオキシリボフラノシル−５−（２−カル
ボキシビニル）ウラシルを得た。Nuclear magnetic resonance spectrum (DMSO- d6 ) δppm 8.42 (H-6) 7.38, 6.85 (d, -CH=CH-) 1-β-D-2'-deoxyribofuranosyl-5
-(2-ethoxycarbonylvinyl)uracil 326
1-β-D in the same manner as in Example 3 using mg.
-2'-deoxyribofuranosyl-5-(2-carboxyvinyl)uracil was obtained.
核磁気共鳴スペクトル（DMSO−d6）δppm
8.29（Ｈ−６） 7.11（ｄ、Ｊ＝16Hz、ビニル基
プロトン） 6.65（ｄ、Ｊ＝16Hz、ビニル基プ
ロトン） 6.06（Ｈ−1′）Nuclear magnetic resonance spectrum (DMSO- d6 ) δppm 8.29 (H-6) 7.11 (d, J = 16Hz, vinyl group proton) 6.65 (d, J = 16Hz, vinyl group proton) 6.06 (H-1')
Claims (1)
される５−ホルミルウラシルヌクレオシドに一般
式〔〕 （R2）3P＝CXCOOR3 〔〕 〔式中、R2はアルキル基および／またはアリー
ル基を示し、R3はアルキル基またはアリール基
を示し、Ｘは水素またはハロゲンを示す。〕で表
わされるホスホランを反応させて一般式〔〕 〔式中、R1、R3およびＸは前記と同意義であ
る。〕で表わされる５−アルコキシもしくはアロ
キシカルボニルビニルウラシルヌクレオシドを
得、次いでこれを加水分解して式〔〕 〔式中、R1およびＸは前記と同意義である。〕で
表わされる５−カルボキシビニルウラシルヌクレ
オシドを合成することを特徴とする５−カルボキ
シビニルウラシルヌクレオシドの製造法。[Claims] 1. General formula [] [In the formula, R 1 represents hydrogen or a hydroxyl group. 5-formyluracil nucleoside represented by the general formula [] (R 2 ) 3 P=CXCOOR 3 [] [In the formula, R 2 represents an alkyl group and/or an aryl group, and R 3 represents an alkyl group or an aryl group. and X represents hydrogen or halogen. ] by reacting the phosphorane represented by the general formula [ ] [In the formula, R 1 , R 3 and X have the same meanings as above. 5-alkoxy or aryloxycarbonyl vinyl uracil nucleoside represented by the following formula is obtained, and this is then hydrolyzed to obtain a 5-alkoxy or aryloxycarbonyl vinyl uracil nucleoside of the formula [] [In the formula, R 1 and X have the same meanings as above. A method for producing 5-carboxyvinyluracil nucleoside, which comprises synthesizing 5-carboxyvinyluracil nucleoside represented by the following.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3795483A JPS59163394A (en) | 1983-03-08 | 1983-03-08 | Preparation of 5-carboxyvinyluracil nucleoside |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3795483A JPS59163394A (en) | 1983-03-08 | 1983-03-08 | Preparation of 5-carboxyvinyluracil nucleoside |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS59163394A JPS59163394A (en) | 1984-09-14 |
| JPH027591B2 true JPH027591B2 (en) | 1990-02-19 |
Family
ID=12511939
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP3795483A Granted JPS59163394A (en) | 1983-03-08 | 1983-03-08 | Preparation of 5-carboxyvinyluracil nucleoside |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS59163394A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104497083B (en) * | 2014-05-12 | 2017-07-07 | 河南师范大学 | Nucleosides phenylpropen ketone hybrid with Antiparasitic Activity and its preparation method and application |
-
1983
- 1983-03-08 JP JP3795483A patent/JPS59163394A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS59163394A (en) | 1984-09-14 |
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