JPH027593B2 - - Google Patents
Info
- Publication number
- JPH027593B2 JPH027593B2 JP3795683A JP3795683A JPH027593B2 JP H027593 B2 JPH027593 B2 JP H027593B2 JP 3795683 A JP3795683 A JP 3795683A JP 3795683 A JP3795683 A JP 3795683A JP H027593 B2 JPH027593 B2 JP H027593B2
- Authority
- JP
- Japan
- Prior art keywords
- uracil
- reaction
- solvent
- halogenovinyl
- 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
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Natural products O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims description 23
- -1 uracil nucleoside Chemical class 0.000 claims description 17
- 229940035893 uracil Drugs 0.000 claims description 16
- 239000002777 nucleoside Substances 0.000 claims description 13
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 238000006114 decarboxylation reaction Methods 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 19
- 238000000034 method Methods 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 13
- 239000002904 solvent Substances 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 150000002367 halogens Chemical group 0.000 description 8
- 239000002994 raw material Substances 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 6
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 238000000862 absorption spectrum Methods 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 4
- 238000012746 preparative thin layer chromatography Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000007810 chemical reaction solvent Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000000921 elemental analysis Methods 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 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
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-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
- GCQYYIHYQMVWLT-HQNLTJAPSA-N Sorivudine Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(\C=C\Br)=C1 GCQYYIHYQMVWLT-HQNLTJAPSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 125000001246 bromo group Chemical group Br* 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
- 239000003054 catalyst Substances 0.000 description 2
- 239000003729 cation exchange resin Substances 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 2
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 125000003944 tolyl group Chemical group 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- RNHDAKUGFHSZEV-UHFFFAOYSA-N 1,4-dioxane;hydrate Chemical compound O.C1COCCO1 RNHDAKUGFHSZEV-UHFFFAOYSA-N 0.000 description 1
- 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 1
- HXDYHJGZXSPLJE-UHFFFAOYSA-N 2,4-dioxopyrimidine-1-carbaldehyde Chemical compound O=CN1C=CC(=O)NC1=O HXDYHJGZXSPLJE-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- ODZBBRURCPAEIQ-DJLDLDEBSA-N Brivudine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C=CBr)=C1 ODZBBRURCPAEIQ-DJLDLDEBSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 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
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 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
- 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 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
Landscapes
- Saccharide Compounds (AREA)
Description
【発明の詳細な説明】
本発明は、５−（２−ハロゲノビニル）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-(2-halogenovinyl)uracil nucleoside.
本発明の目的化合物は、次の一般式〔〕で表
わされる。 The target compound of the present invention is represented by the following general formula [].
該式中、Ｒは水素または水酸基を示し、Ｘはハ
ロゲンである。Ｘのハロゲンの具体例は、臭素、
塩素、またはヨウ素である。これらの代表的化合
物である５−（２−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−（２−ブ
ロモビニル）ウラシル（BVAU）、１−β−Ｄ−
アラビノフラノシル−５−（２−クロロビニル）
ウラシル（CVAU）などは強力な抗ウイルス活
性を有し、現在抗ウイルス剤としての開発が進め
られているものである。 In this formula, R represents hydrogen or a hydroxyl group, and X is a halogen. Specific examples of halogen for X are bromine,
Chlorine or iodine. A representative compound of these, 5-(2-bromovinyl)-1-β-D-
2′-deoxyribofuranosyluracil (BVDU),
1-β-D-arabinofuranosyl-5-(2-bromovinyl)uracil (BVAU), 1-β-D-
Arabinofuranosyl-5-(2-chlorovinyl)
Uracil (CVAU) has strong antiviral activity and is currently being developed as an antiviral agent.
従来、これら５−（２−ハロゲノビニル）ウラ
シルヌクレオシドの製造法としては、５−ビニ
ルウラシルヌクレオシドにハロゲンを付加させ、
次いで脱ハロゲン化水素化して目的化合物を得る
方法、５−（２−カルボキシビニル）ウラシル
ヌクレオシドをＮ−ハロゲノコハク酸イミドと反
応させて目的化合物を含成する方法が知られてい
る。 Conventionally, methods for producing these 5-(2-halogenovinyl)uracil nucleosides include adding halogen to 5-vinyluracil nucleoside,
A method of subsequently dehydrohalogenating to obtain the target compound, and a method of reacting 5-(2-carboxyvinyl)uracil nucleoside with N-halogenosuccinimide to contain the target compound are known.
本発明者らは、新規で、高収率で目的化合物を
合成する方法を開発する目的で研究を重ねた結
果、新規な原料化合物からの合成法を確立するこ
とに成功し、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、Ｒは水素または水酸基を示し、Ｘはハロ
ゲンを示す。〕で表わされる５−（２−カルボキシ
−２−ハロゲノビニル）ウラシルヌクレオシドを
脱炭酸反応に付すことにより目的化合物を合成す
る方法である。 As a result of repeated research aimed at developing a novel method for synthesizing the target compound with high yield, the present inventors succeeded in establishing a synthesis method from a new raw material compound, and completed the present invention. I came to the conclusion. That is, the present invention provides general formula [] [In the formula, R represents hydrogen or a hydroxyl group, and X represents a halogen. This is a method for synthesizing a target compound by subjecting 5-(2-carboxy-2-halogenovinyl)uracil nucleoside represented by the following formula to a decarboxylation reaction.
本発明方法において原料化合物として使用され
る５−（２−カルボキシ−２−ハロゲノビニル）
ウラシルヌクレオシドは新規化合物である。前記
一般式〔〕によつて表わされるが、該式中のＲ
は水素または水酸基であり、Ｘはハロゲンであ
る。Ｘのハロゲンはより具体的には、臭素、塩素
またはヨウ素である。 5-(2-carboxy-2-halogenovinyl) used as a raw material compound in the method of the present invention
Uracil nucleoside is a new compound. It is represented by the general formula [], in which R
is hydrogen or a hydroxyl group, and X is a halogen. The halogen of X is more specifically bromine, chlorine or iodine.
原料化合物の調製にあたつては、特にその製造
ルートに制約されるものではなく、原料化合物の
合成にあたつてデザインされうるあらゆる化学合
成的手法が採用できる。製造法を具体的に提示す
れば次のような方法が挙げられる。 The preparation of the raw material compound is not particularly limited by its production route, and any chemical synthesis method that can be designed for the synthesis of the raw material compound can be employed. Specific manufacturing methods include the following methods.
すなわち、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−（２−アルコキシもしくは
アロキシカルボニル−２−ハロゲノビニル）ウラ
シルヌクレオシドを得、次いでこれを加水分解す
る方法によつて、本発明方法における原料化合物
を合成することができる。 In other words, 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 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. The raw material compound in the method of the present invention can be synthesized by a method of obtaining 5-(2-alkoxy or aroxycarbonyl-2-halogenovinyl) uracil nucleoside represented by and then hydrolyzing it.
本法において、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がない。 In this method, the compound of general formula [], that is, 5-formyluracil nucleoside, is a known compound, and there are no particular restrictions on its preparation method.
また、第一の反応工程において反応試薬として
用いられるホスホランは前記一般式〔〕で表わ
されるが、その式中の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。 In addition, the phosphorane used as a reaction reagent in the first reaction step is represented by the above general formula [], and in the formula, R 2 is an alkyl group and /
Specific examples of the aryl group 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,
Examples include propyl, butyl, phenyl, etc.
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。反
応溶媒としては、たとえばジオキサン、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を使
用しうる。反応条件にも特に制約はなく、室温条
件下で実施することができる。 The first step reaction is carried out in a reaction solvent. As the reaction solvent, for example, ethers such as dioxane, tetrahydrofuran, and ethylene glycol dimethyl ether, amide solvents such as dimethylformamide, dimethyl sulfoxide, and the like can be used. There are no particular restrictions on the reaction conditions, and the reaction can be carried out at room temperature.
かくして得られる５−（２−アルコキシもしく
はアロキシカルボニル−２−ハロゲノビニル）体
の加水分解反応は、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
ルカリを用いて水素または含水溶媒（たとえば、
ジオキサン−水、メタノール水、エタノール−水
など）中で行なう。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 of the 5-(2-alkoxy or aryloxycarbonyl-2-halogenovinyl) body obtained in this way is carried out using sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium carbonate,
Hydrogen or aqueous solvents (e.g.
dioxane-water, methanol-water, ethanol-water, etc.). The reaction can be carried out at 0°C to room temperature for several hours.
反応液からの原料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。 Separation and purification of the raw material compound from the reaction solution may be carried out by conventional methods, and methods such as adsorption column chromatography, ion exchange column chromatography, recrystallization, etc. can be applied as appropriate.
本発明方法は、このようにして合成されうる新
規原料化合物、すなわち５−（２−カルボキシ−
２−ハロゲノビニル）ウラシルヌクレオシドを脱
炭酸反応工程に付して目的化合物を合成するもの
である。 The method of the present invention provides a novel starting material compound that can be synthesized in this way, namely 5-(2-carboxy-
The target compound is synthesized by subjecting 2-halogenovinyl) uracil nucleoside to a decarboxylation reaction step.
脱炭酸反応は、塩基触媒の存在下で加熱反応さ
せることにより実施できる。このような塩基触媒
としては反応溶媒を兼ねてピリジン、ピペリジ
ン、ピロリジンなどの複素環塩基、二級アミンを
用いることができる。また、反応を促進するため
に反応系にフツ素アニオンを存在させることも有
効である。加熱反応における温度条件は、通常80
℃〜溶媒還流温度の条件を設定すればよい。この
ような条件下で反応は15〜24時間で終了する。 The decarboxylation reaction can be carried out by heating the reaction in the presence of a base catalyst. As such a base catalyst, a heterocyclic base such as pyridine, piperidine, or pyrrolidine, or a secondary amine, which also serves as a reaction solvent, can be used. Furthermore, it is also effective to have a fluorine anion present in the reaction system in order to promote the reaction. The temperature conditions for heating reactions are usually 80°C.
The conditions may be set from °C to solvent reflux temperature. Under these conditions the reaction is complete in 15-24 hours.
反応液からの目的化合物の分離精製も常法によ
つて行なうことができ、吸着カラムクロマトグラ
フイー、イオン交換クロマトグラフイー、再結晶
などの方法を適宜に応用して行なう。 Separation and purification of the target compound from the reaction solution can also be carried out by conventional methods, such as adsorption column chromatography, ion exchange chromatography, recrystallization, etc., as appropriate.
以下、本発明方法の原料化合物の製造例を示す
参考例、および実施の態様を示す実施例を挙げて
より具体的に説明する。 Hereinafter, a more specific explanation will be given with reference examples showing production examples of raw material compounds of the method of the present invention and examples showing embodiments.
参考例 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時間撹拌し
ながら反応させた。溶媒を留去した後、残渣をプ
レパラテイブ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％）。Reference 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. Ta. After distilling off the solvent, the residue was subjected to preparative thin layer chromatography (PLC).
(solvent, chloroform-methanol =
10:1), the target portion was extracted with chloroform-methanol = 10:1, the solvent was distilled off, and the residue was recrystallized from ethanol to obtain 1-β-D-arabinofuranosyl-5-(2- 112 mg of bromo-2-ethoxycarbonylvinyl)uracil was obtained. (yield 89%).
融点 219〜220℃
紫外部吸収スペクトル
λEtOH nax 263nｍ、323nｍ
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時間撹拌し
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−カルボニルビニル）ウラシル101mgを
得た（収率88％）。Melting point 219-220℃ Ultraviolet absorption spectrum λ EtOH nax 263 nm, 323 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-carbonylvinyl)uracil (yield 88%). ).
融点 187℃（分解）
紫外部吸収スペクトル
λpH7 nax 216nｍ、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 １
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40mgを
ピリジン２mlに溶解させ、80℃で18時間加熱反応
させ、さらに２時間100℃で加熱反応させた。溶
媒を留去した後、メタノールに溶解させ、PLC
（溶媒、クロロホルム：メタノール＝７：１）で
分離し、目的の部分をクロロホルム：メタノール
＝７：１で抽出し、溶媒を留去した後、水より再
結晶して１−β−Ｄ−アラビノフラノシル−５−
（２−ブロモビニル）ウラシルを得た。Melting point 187℃ (decomposition) Ultraviolet absorption spectrum λ pH7 nax 216nm, 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 1 1-β-D-arabinofuranosyl-5-(2-
40 mg of bromo-2-carboxyvinyl (bromo-2-carboxyvinyl) uracil was dissolved in 2 ml of pyridine, heated and reacted at 80°C for 18 hours, and further heated at 100°C for 2 hours. After distilling off the solvent, dissolve in methanol and perform PLC
(solvent, chloroform:methanol = 7:1), extract the target portion with chloroform:methanol = 7:1, distill off the solvent, recrystallize from water and 1-β-D-arabi. Nofuranosyl-5-
(2-bromovinyl)uracil was obtained.
融点 189℃（分解）
紫外部吸収スペクトル
λEtOH nax 253nｍ、295nｍ
核磁気共鳴スペクトル（DMSO−d6）δppm
7.16（ビニル基プロトン、Ｊ＝13Hz）
6.86（ビニル基プロトン、Ｊ＝13Hz）
7.89（Ｈ−６）
5.98（Ｈ−1′）
元素分析 C11H13N2O6Brとして
理論値 Ｃ、37.84；Ｈ、3.75；Ｎ、8.03；
Br、22.89
実測値 Ｃ、37.87；Ｈ、3.75；Ｎ、7.94；
Br、22.90
参考例 ２
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
トリフエニルスルホラン970mgを加え、撹拌下一
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 189℃ (decomposition) Ultraviolet absorption spectrum λ EtOH nax 253nm, 295nm Nuclear magnetic resonance spectrum (DMSO-d 6 ) δppm 7.16 (vinyl group proton, J = 13Hz) 6.86 (vinyl group proton, J = 13Hz) 7.89 (H -6) 5.98 (H-1') Elemental analysis C 11 H 13 N 2 O 6 As Br Theoretical value C, 37.84; H, 3.75; N, 8.03; Br, 22.89 Actual value C, 37.87; H, 3.75; N , 7.94; Br, 22.90 Reference example 2 1-β-D-2'-deoxyribofuranosyl-5
- 512 mg of formyluracil and 970 mg of bromo(ethoxycarbonyl)methylenetriphenyl sulfolane 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、室温にて撹
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−
カルボニルビニル）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-
Carbonyl vinyl) 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 ２
参考例２で得られた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）ウラシルをピリジン10mlに溶解さ
せ、フツ化カリウム５mgを加え、20時間加熱還流
した。溶媒を留去し、残渣を薄層クロマトグラフ
イーにより分離して１−β−Ｄ−2′−デオキシリ
ボフラノシル−５−（２−ブロモビニル）ウラシ
ルを得た。Nuclear magnetic resonance spectrum (DMSO- d6 ) δppm 8.68 (H-6) 7.80 (vinyl group proton) 6.24 (H-1') Example 2 1-β-D-2'-deoxyribo obtained in Reference Example 2 Furanosyl-5-(2-bromo-2-carboxyvinyl)uracil was dissolved in 10 ml of pyridine, 5 mg of potassium fluoride was added, and the mixture was heated under reflux for 20 hours. The solvent was distilled off and the residue was separated by thin layer chromatography to obtain 1-β-D-2'-deoxyribofuranosyl-5-(2-bromovinyl)uracil.
紫外線吸収スペクトル λnax 252nｍ、296nｍ 核磁気共鳴スペクトル（DMSO−d6）δppm 8.07（Ｈ−６） 7.25、6.81（Ｊ＝13Hz、ビニル基プロトン） 6.12（Ｈ−1′）Ultraviolet absorption spectrum λ nax 252 nm, 296 nm Nuclear magnetic resonance spectrum (DMSO-d 6 ) δppm 8.07 (H-6) 7.25, 6.81 (J = 13 Hz, vinyl group proton) 6.12 (H-1')
Claims (1)
ゲンを示す。〕で表わされる５−（２−カルボキシ
−２−ハロゲノビニル）ウラシルヌクレオシドを
脱炭酸反応に付し、一般式〔〕 〔式中、ＲおよびＸは前記と同意義である。〕で
表わされる５−（２−ハロゲノビニル）ウラシル
ヌクレオシドを合成することを特徴とする５−
（２−ハロゲノビニル）ウラシルヌクレオシドの
製造法。[Claims] 1. General formula [] [In the formula, R represents hydrogen or a hydroxyl group, and X represents a halogen. 5-(2-carboxy-2-halogenovinyl)uracil nucleoside represented by ] is subjected to decarboxylation reaction to form the general formula [] [In the formula, R and X have the same meanings as above. 5-(2-halogenovinyl)uracil nucleoside represented by
A method for producing (2-halogenovinyl)uracil nucleoside.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3795683A JPS59163396A (en) | 1983-03-08 | 1983-03-08 | Preparation of 5-(2-halogenovinyl)uracil nucleoside |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3795683A JPS59163396A (en) | 1983-03-08 | 1983-03-08 | Preparation of 5-(2-halogenovinyl)uracil nucleoside |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS59163396A JPS59163396A (en) | 1984-09-14 |
| JPH027593B2 true JPH027593B2 (en) | 1990-02-19 |
Family
ID=12512001
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP3795683A Granted JPS59163396A (en) | 1983-03-08 | 1983-03-08 | Preparation of 5-(2-halogenovinyl)uracil nucleoside |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS59163396A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5446031A (en) * | 1991-04-24 | 1995-08-29 | Yamasa Shuyu Kabushiki Kaisha | 1-β-D-arabinofuranosyl-(E)-5-(2-halogenovinyl)uracil derivatives |
-
1983
- 1983-03-08 JP JP3795683A patent/JPS59163396A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS59163396A (en) | 1984-09-14 |
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