JP4067226B2 - Method for producing 1-halogeno-2-deoxyribofuranose derivative - Google Patents
Method for producing 1-halogeno-2-deoxyribofuranose derivative Download PDFInfo
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- JP4067226B2 JP4067226B2 JP09455199A JP9455199A JP4067226B2 JP 4067226 B2 JP4067226 B2 JP 4067226B2 JP 09455199 A JP09455199 A JP 09455199A JP 9455199 A JP9455199 A JP 9455199A JP 4067226 B2 JP4067226 B2 JP 4067226B2
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- deoxyribofuranose
- carbon atoms
- halide
- derivative
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- 238000004519 manufacturing process Methods 0.000 title claims description 8
- -1 halogen atom 2-deoxyribofuranose derivative Chemical class 0.000 claims description 58
- 239000007789 gas Substances 0.000 claims description 19
- 125000004432 carbon atom Chemical group C* 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 229910000039 hydrogen halide Inorganic materials 0.000 claims description 11
- 239000012433 hydrogen halide Substances 0.000 claims description 11
- 125000005843 halogen group Chemical group 0.000 claims description 10
- 125000002252 acyl group Chemical group 0.000 claims description 9
- 150000001266 acyl halides Chemical class 0.000 claims description 9
- 239000000010 aprotic solvent Substances 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000001931 aliphatic group Chemical group 0.000 claims description 3
- 125000000547 substituted alkyl group Chemical group 0.000 claims 1
- 238000000034 method Methods 0.000 description 18
- 239000000047 product Substances 0.000 description 17
- 239000002994 raw material Substances 0.000 description 17
- 239000006227 byproduct Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 6
- PDWIQYODPROSQH-PYHARJCCSA-N 2-deoxy-D-ribofuranose Chemical class OC[C@H]1OC(O)C[C@@H]1O PDWIQYODPROSQH-PYHARJCCSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 238000007796 conventional method Methods 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- XRHGYUZYPHTUJZ-UHFFFAOYSA-N 4-chlorobenzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C=C1 XRHGYUZYPHTUJZ-UHFFFAOYSA-N 0.000 description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- 238000002955 isolation Methods 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- RVWBDHDMEWROTH-KNCVXQGMSA-N 2-[(2r,3s)-5-chloro-3-(4-chlorobenzoyl)-3,5-dihydroxyoxolan-2-yl]-1-(4-chlorophenyl)-2-hydroxyethanone Chemical compound O=C([C@]1(O)CC(O)(Cl)O[C@@H]1C(O)C(=O)C=1C=CC(Cl)=CC=1)C1=CC=C(Cl)C=C1 RVWBDHDMEWROTH-KNCVXQGMSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical class CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 3
- 239000012346 acetyl chloride Substances 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 150000004820 halides Chemical class 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- UIPFRITZTFQFHX-RDVQEIBISA-N 2-[(2r,3s)-3-(4-chlorobenzoyl)-3,5-dihydroxy-5-methyloxolan-2-yl]-1-(4-chlorophenyl)-2-hydroxyethanone Chemical compound OC([C@@H]1[C@@](O)(CC(O1)(O)C)C(=O)C=1C=CC(Cl)=CC=1)C(=O)C1=CC=C(Cl)C=C1 UIPFRITZTFQFHX-RDVQEIBISA-N 0.000 description 2
- 125000003541 2-chlorobenzoyl group Chemical group ClC1=C(C(=O)*)C=CC=C1 0.000 description 2
- 125000000242 4-chlorobenzoyl group Chemical group ClC1=CC=C(C(=O)*)C=C1 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 230000032683 aging Effects 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
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 229910000043 hydrogen iodide Inorganic materials 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- KZVAAIRBJJYZOW-LMVFSUKVSA-N (2r,3s,4s)-2-(hydroxymethyl)oxolane-3,4-diol Chemical class OC[C@H]1OC[C@H](O)[C@@H]1O KZVAAIRBJJYZOW-LMVFSUKVSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 125000006083 1-bromoethyl group Chemical group 0.000 description 1
- VFWCMGCRMGJXDK-UHFFFAOYSA-N 1-chlorobutane Chemical compound CCCCCl VFWCMGCRMGJXDK-UHFFFAOYSA-N 0.000 description 1
- 125000001478 1-chloroethyl group Chemical group [H]C([H])([H])C([H])(Cl)* 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 125000006280 2-bromobenzyl group Chemical group [H]C1=C([H])C(Br)=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- NAMYKGVDVNBCFQ-UHFFFAOYSA-N 2-bromopropane Chemical compound CC(C)Br NAMYKGVDVNBCFQ-UHFFFAOYSA-N 0.000 description 1
- 125000006282 2-chlorobenzyl group Chemical group [H]C1=C([H])C(Cl)=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000006179 2-methyl benzyl group Chemical group [H]C1=C([H])C(=C(C([H])=C1[H])C([H])([H])*)C([H])([H])[H] 0.000 description 1
- 125000006279 3-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(Br)=C1[H])C([H])([H])* 0.000 description 1
- 125000003852 3-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(Cl)=C1[H])C([H])([H])* 0.000 description 1
- 125000006180 3-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1[H])C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000002672 4-bromobenzoyl group Chemical group BrC1=CC=C(C(=O)*)C=C1 0.000 description 1
- 125000006281 4-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Br)C([H])([H])* 0.000 description 1
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 1
- 125000006181 4-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])C([H])([H])* 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- FXXACINHVKSMDR-UHFFFAOYSA-N acetyl bromide Chemical compound CC(Br)=O FXXACINHVKSMDR-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- LEKJTGQWLAUGQA-UHFFFAOYSA-N acetyl iodide Chemical compound CC(I)=O LEKJTGQWLAUGQA-UHFFFAOYSA-N 0.000 description 1
- 150000003855 acyl compounds Chemical class 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000005997 bromomethyl group Chemical group 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-M hexanoate Chemical compound CCCCCC([O-])=O FUZZWVXGSFPDMH-UHFFFAOYSA-M 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- RIBFXMJCUYXJDZ-UHFFFAOYSA-N propanoyl bromide Chemical compound CCC(Br)=O RIBFXMJCUYXJDZ-UHFFFAOYSA-N 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- GLCSNYFRXVGJJF-UHFFFAOYSA-N propanoyl iodide Chemical compound CCC(I)=O GLCSNYFRXVGJJF-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 125000000548 ribosyl group Chemical group C1([C@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 125000006488 t-butyl benzyl group Chemical group 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 description 1
- RKIDPTUGNXTOMU-UHFFFAOYSA-N thionyl iodide Chemical compound IS(I)=O RKIDPTUGNXTOMU-UHFFFAOYSA-N 0.000 description 1
- 125000005425 toluyl group Chemical group 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
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- Saccharide Compounds (AREA)
Description
【０００１】
【発明の属する技術分野】
本発明は、２’−デオキシヌクレオシド誘導体の原料として有用である１―ハロゲノ−２−デオキシリボフラノース誘導体の製造方法に関するものである。
【０００２】
【従来の技術】
１―ハロゲノ−２−デオキシリボフラノース誘導体の製造法として、以下の方法が知られている。
（１）３，５−ジアシル−２−デオキシ−１−メチルリボフラノース誘導体を、アルコールの存在下において、ハロゲン化アセチルと反応させる方法（特開平７−２２４０８１号公報）。
（２）３，５−ビス（４−クロロベンゾイル）−２−デオキシ−１−メチルリボフラノースを塩化水素ガスと反応させる方法（Journal of Organic Chemistry,３４, ３８０６（１９６９））。
（３）３，５−ジアシル−２−デオキシ−１−メチルリボフラノース誘導体を、酢酸溶媒中において、ハロゲン化アセチルと反応させる方法（特開昭６２−１２７９０号公報）。
【０００３】
上記の１―ハロゲノ−２−デオキシリボフラノース誘導体の製造法のうち、（１）のアルコール存在下においてハロゲン化アセチルと反応させる方法は、リボースの保護基が脱離して副生物が生成する。この副生物を目的物から分離し除去することは困難であり、目的物の単離収率の低下と工数の増加を必要とし、工業的製法として適さない。また（２）の塩化水素ガスを作用させる方法は、原料を全て反応させることが困難である。このため反応収率が低く、さらに原料を目的物から分離することが困難であり、その精製によって目的物の単離収率のさらなる低下と工数の増加を伴い、効率的な工業的製法ではない。さらに（３）の酢酸溶媒中においてハロゲン化アセチルと反応させる方法は、多量の酸ハロゲン化物を使用するため作業環境中に好ましくない酸ハロゲン化物のミストが散乱する問題がある。
【０００４】
【発明が解決しようとする課題】
本発明の課題は、分離が困難な副生物が生成すること、反応が未完結で分離困難な原料が残存すること、作業環境上好ましくない多量の酸ハロゲン化物を使用することなどの従来の問題点を解消した１―ハロゲノ−２−デオキシリボフラノース誘導体の製造法を提供するものである。
【０００５】
【課題を解決するための手段】
本発明者らは前記課題を解決すべく、１―ハロゲノ−２−デオキシリボフラノース誘導体を高収率かつ高純度で工業的に容易に製造できる方法について検討を重ねた。
【０００６】
この結果、２−デオキシリボフラノース誘導体を、非プロトン性溶媒中においてハロゲン化水素ガスと反応させたのち、アシルハライドもしくはチオニルハライドと反応させることにより、驚くべきことに、反応が定量的に進行するため、原料が残存することもなく、原料由来の副生物の生成もなく、従って単離収率も従来法に比較して格段に良く、高純度で安全かつ効率的に、１―ハロゲノ−２−デオキシリボフラノース誘導体を製造できることを見出し、当該知見に基づき本発明を完成したものである。
【０００７】
すなわち本発明は、一般式（１）（化３）
【０００８】
【化３】
（式中、Ｒ1はハロゲン原子で置換されていてもよい炭素数１から４のアルキル基を表し、Ｒ2およびＲ3はそれぞれ独立に、炭素数１から４のアルキル基、炭素数１から４のアルキル基又はハロゲン原子で置換されていてもよいベンジル基、炭素数２から４の脂肪族アシル基、炭素数１から４のアルキル基又はハロゲン原子で置換されていてもよい芳香族アシル基を表す。）で示される２−デオキシリボフラノース誘導体を、非プロトン性溶媒中においてハロゲン化水素ガスと反応させたのち、アシルハライドもしくはチオニルハライドと反応させることを特徴とする下記一般式（２）（化４）
【００１０】
【化４】
（式中、Ｒ2およびＲ3は一般式（１）の場合と同義であり、Ｘはハロゲン原子を表す。）で示される１―ハロゲノ−２−デオキシリボフラノース誘導体の製造方法を提供するものである。
【００１２】
【発明の実施の形態】
以下、本発明を詳細に説明する。
一般式（１）においてＲ１の表す炭素数１から４のアルキル基として、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｔ−ブチル基礎を例示することができ、好ましくはメチル基、エチル基、イソプロピル基である。ハロゲン原子で置換された炭素数１から４のアルキル基として、クロロメチル基、ジクロロメチル基、トリクロロメチル基、ブロモメチル基、ジブロモメチル基、トリブロモメチル基、１−クロロエチル基、１，２−ジクロロエチル基、１−ブロモエチル基、１，２−ジブロモエチル基、クロロイソプロピル基、クロロブチル基、クロロイソブチル基、ブロモイソプロピル基、ブロモブチル基、ブロモイソブチル基を例示することができる。
また、Ｒ２およびＲ３の示す炭素数１から４のアルキル基として、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｔ−ブチル基礎を例示することができ、好ましくはメチル基、エチル基、イソプロピル基である。
【００１３】
炭素数１から４のアルキル基で置換されたベンジル基として、２−メチルベンジル基、３−メチルベンジル基、４−メチルベンジル基、２−エチルベンジル基、３−エチルベンジル基、４−エチルベンジル基、プロピルベンジル基、イソプロピルベンジル基、イソブチルベンジル基、ｔ−ブチルベンジル基を例示することができる。
ハロゲン原子で置換されたベンジル基として、２−クロロベンジル基、３−クロロベンジル基、４−クロロベンジル基、２，３−ジクロロベンジル基、２，４−ジクロロベンジル基、２−ブロモベンジル基、３−ブロモベンジル基、４−ブロモベンジル基、２，３−ジブロモベンジル基、２，４−ジブロモベンジル基を例示することができる。
【００１４】
炭素数２から４の脂肪族アシル基としてはアセチル基、プロピオニル基を例示することができる。
芳香族アシル基としてはベンゾイル基、トルオイル基、４−クロロベンゾイル基、３−クロロベンゾイル基、２−クロロベンゾイル基、メトキシベンゾイル基、ブロモベンゾイル基を例示することができる。
炭素数１から４のアルキル基で置換された芳香族アシル基として、２−メチルベンゾイル基、３−メチルベンゾイル基、２−エチルベンゾイル基、２−エチルベンゾイル基、４−エチルベンゾイル基、プロピルベンゾイル基、イソプロピルベンゾイル基、ブチルベンゾイル基、ｔ−ブチルベンゾイル基を例示することができる。
ハロゲン原子で置換された芳香族アシル基として、２−クロルベンゾイル基、３−クロロベンゾイル基、４−クロロベンゾイル基、２，３−ジクロロベンゾイル基、２，４−ジクロロベンゾイル基、２−ブロモベンゾイル基、３−ブロモベンゾイル基、４−ブロモベンゾイル基、２，３−ジブロモベンゾイル基、２，４−ジブロモベンゾイル基を例示することができる。
【００１５】
本発明で使用するハロゲン化水素ガスとしては、塩化水素ガス、臭化水素ガス、ヨウ化水素ガスなどが使用可能であり、水分含有量が少ないものほど好ましい。
ハロゲン化水素の使用量は、出発物質である２−デオキシリボフラノース誘導体１モルに対して１モルから１０モルを用いることが好ましい。
【００１６】
アシルハライドもしくはチオニルハライドとしては、上記で使用したハロゲン化水素ガスと同じ種類のハロゲンを含むものを使用する。この条件を満たすものであれば、脂肪族アシルハライド、芳香族アシルハライド、チオニルハライドともに使用可能であるが、反応後の除去のしやすさから脂肪族アシルハライドが好ましい。より具体的には、ハロゲン化水素として塩化水素ガスを用いた場合には塩化アセチル、塩化プロピオニル、塩化チオニルなどが好ましい。また臭化水素ガスを用いた場合には、臭化アセチル、臭化プロピオニル、臭化チオニルが好ましい。またヨウ化水素ガスを用いた場合には、ヨウ化アセチル、ヨウ化プロピオニル、ヨウ化チオニルが好ましい。
アシルハライドもしくはチオニルハライドの使用量は、出発物質である２−デオキシリボフラノース誘導体１モルに対して０．５モルから１モルが好ましく、さらには０．８モルから０．９９モル用いることが好ましい。
【００１７】
本反応に使用する非プロトン性溶媒は、本反応に不活性な溶媒ならばいずれも使用することができる。具体的には、ヘキサン、シクロヘキサン、およびトルエンなどの炭化水素類、ジクロロメタン、クロロホルム、１，２−ジクロロエタン、臭化イソプロピル、ｎ−ブチルクロライド、およびクロロベンゼンなどのハロゲン化炭化水素類、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、および１，４−ジオキサンなどのエーテル類、アセトン、メチルエチルケトン、およびメチルイソブチルケトンなどのケトン類、酢酸エチル、酢酸ブチルなどのエステル類を、使用することができる。これらの溶媒は、単独で使用することができると共に、適当な比率で混合して用いることもできる。
非プロトン性溶媒の使用量は、出発物質である２−デオキシリボフラノース誘導体の反応前の濃度が１０重量％から２０重量％となるようにすることが好ましい。
【００１８】
反応はハロゲン化水素ガスの装入工程とアシルハライドもしくはチオニルハライドによる反応の連続した工程からなる。
ハロゲン化水素ガスの装入工程では、反応温度は０℃から３０℃が好ましい。装入に要する時間は０．５時間から１０時間が好ましく、更には０．５時間から３時間が好ましい。
ハロゲン化水素ガス装入後の熟成反応は、反応温度は０℃から３０℃が好ましく、反応時間は０．１時間から１８時間が好ましく、更には０．５時間から２時間が好ましい。
【００１９】
続く第二段階のアシルハライドもしくはチオニルハライドによる反応は、反応温度は０℃から３０℃が好ましい。装入に要する時間は通常０．１時間から５時間であり、更には０．５時間から３時間が好ましい。アシルハライドもしくはチオニルハライド装入後の熟成反応は、反応温度は０℃から３０℃が好ましく、反応時間は０．５時間から５時間が好ましく、更には０．５時間から２時間が好ましい。
【００２０】
上記反応によって目的物の１―ハロゲノ−２−デオキシリボフラノース誘導体が生成し、結晶として析出する。この結晶を濾過により分離し、乾燥することにより単離することができる。また溶媒を減圧下除去して単離することもできるが、これらの方法に限定されるものではない。
以上の操作によって得られた１―ハロゲノ−２−デオキシリボフラノース誘導体はそのまま次反応に使用することも可能であるが、再結晶などにより生成することもできる。
【００２１】
【実施例】
以下において、実施例と比較例を挙げて本発明を説明する。
【００２２】
実施例１
窒素置換した３００ｍＬのガラス製反応器に、２０重量％３，５−ビス（４−クロロベンゾイル）−２−デオキシ−１−メチルリボフラノースのジイソプロピルエーテル溶液１００ｇ（４８．６ミリモル）を仕込み、氷冷下で攪拌しながら、乾燥塩化水素ガス１８ｇを１時間かけて３℃から１３℃にて吹き込み、さらに室温（２０℃）にて０．５時間攪拌した。
この溶液を、室温（２０℃）にて攪拌しながら、塩化アセチル３．３ｍＬ（４６ミリモル、０．９５等量）を５分間で滴下装入し、さらに室温にて反応液を１時間攪拌した。
この段階で原料はすべて消費され反応は定量的であった。
析出した結晶を濾過し、少量のジイソプロピルエーテルで洗浄した。生成物を減圧下４０℃にて４時間乾燥して、１−クロロ−３，５−ビス（４−クロロベンゾイル）−２−デオキシリボフラノース１７．７ｇを得た（単離収率８５％）。
生成物を高速液体クロマトグラフ法（逆相カラム、溶離液：水／アセトニトリル、検出波長：２５４ｎｍ）で分析した結果、目的物は９６面積％であり、未反応の原料は見出されなかった。
また、高速液体クロマトグラフ法から求めた４−クロロ安息香酸の含量は０重量％であり、保護基由来の副生物が含まれていなかった。
融点１２２℃
１Ｈ−ＮＭＲ（９０ＭＨｚ、ＣＤＣｌ３、σ（ｐｐｍ））２．７〜２．９（２Ｈ，ｍ）、４．５〜４．７（２Ｈ，ｍ）、４．７〜４．９（１Ｈ，ｍ）、 ５．５〜５．６（１Ｈ，ｍ）、６．５（１Ｈ，ｄ）、７．４〜７．５（４Ｈ，ｍ）、７．９〜８．０（４Ｈ，ｍ）。
【００２３】
比較例１
従来法（１）の方法を追試した。結果を以下に示す。
窒素置換した３００ｍＬのガラス製反応器に、３，５−ビス（４−クロロベンゾイル）−２−デオキシ−１−メチルリボフラノース１０ｇ（２５ミリモル）と乾燥シクロヘキサン１０ｍＬを装入し、窒素微加圧下に攪拌しながら室温にて塩化アセチル６．４ｇ（８１ミリモル）を約５分間で滴下装入後、続いて無水メタノール０．９６ｍＬを加えた。得られた溶液を２０℃にて４時間攪拌し反応した。反応混合物から減圧下低沸点物質を溜去し、この中に室温にて乾燥シクロヘキサン１１ｍＬを加え溶解したのち、氷冷下で２時間攪拌した。析出した結晶を濾過し、少量のシクロヘキサンで洗浄した。次に生成物を減圧下４０℃にて４時間乾燥して、１−クロロ−３，５−ビス（４−クロロベンゾイル）−２−デオキシリボフラノース８．５ｇを得た。
生成物を高速液体クロマトグラフ法（実施例と同一条件）で分析した結果９０面積％であり、未反応の原料は見出されなった。
また高速液体クロマトグラフ法にて副生物を定量した結果、４−クロロ安息香酸の含量は１２重量％含まれており、目的物の収率は７３％であった。
以上示したように、従来法（１）の方法では、原料の保護基に由来する４−クロロ安息香酸が副生し、副生物と目的物の分離が困難であった。
【００２４】
比較例２
従来法（２）の方法を追試した結果を、以下に示す。
窒素置換した３００ｍＬのガラス反応器に、２０重量％３，５−ビス（４−クロロベンゾイル）−２−デオキシ−１−メチルリボフラノースのジイソプロピルエーテル溶液１００ｇ（４８．６ミリモル）を仕込み、氷冷下で攪拌しながら乾燥塩化水素ガス３６ｇを３時間かけて３℃から１３℃にて吹き込み、さらに室温（２０℃）にて３時間攪拌した。
析出した結晶を濾取し、少量のジイソプロピルエーテルで洗浄した。生成物を４０℃にて４時間減圧乾燥して、１−クロロ−３，５−ビス（４−クロロベンゾイル）−２−デオキシリボフラノース１６．２ｇを得た。
得られた生成物を、高速液体クロマトグラフ法（実施例と同一条件）で分析した結果８６面積％であり、未反応の原料が１２面積％であった。
また高速液体クロマトグラフ法にて副生物を定量した結果、４−クロロ安息香酸の含量は０重量％であった。
以上から目的物の収率は７４％であり、生成物には原料が残存していることが判った。
以上示したように、従来法（２）による方法では、原料が残存し、このため反応収率が低く、生成物からの原料の分離は困難であった。
【００２５】
【発明の効果】
以上述べたよう、従来知られている１―ハロゲノ−２−デオキシリボフラノース誘導体の製造方法では、分離困難な原料由来のアシル化合物が副生したり、反応が完結しないため収率が低く、さらに残存する原料は目的物から分離が困難であるという、問題が存在していた。しかしながら本発明によれば、２−デオキシリボフラノース誘導体を、非プロトン性溶媒中でハロゲン化水素ガスと反応させたのち、アシルハライドと反応する方法によって、驚くべきことに反応は定量的になり、分離困難な副生物も生じずに１―ハロゲノ−２−デオキシリボフラノース誘導体を高純度、安全かつ工業的に製造することができる。さらに本方法では、製造に際し高価な触媒や取り扱いに危険の伴う原料を必要としない。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for producing a 1-halogeno-2-deoxyribofuranose derivative which is useful as a raw material for a 2′-deoxynucleoside derivative.
[0002]
[Prior art]
The following methods are known as methods for producing 1-halogeno-2-deoxyribofuranose derivatives.
(1) A method in which a 3,5-diacyl-2-deoxy-1-methylribofuranose derivative is reacted with an acetyl halide in the presence of an alcohol (Japanese Patent Laid-Open No. 7-224081).
(2) A method of reacting 3,5-bis (4-chlorobenzoyl) -2-deoxy-1-methylribofuranose with hydrogen chloride gas (Journal of Organic Chemistry, 34, 3806 (1969)).
(3) A method of reacting a 3,5-diacyl-2-deoxy-1-methylribofuranose derivative with an acetyl halide in an acetic acid solvent (Japanese Patent Laid-Open No. 62-12790).
[0003]
Among the methods for producing the 1-halogeno-2-deoxyribofuranose derivative described above, in the method of reacting with acetyl halide in the presence of alcohol in (1), the ribose protecting group is eliminated and a by-product is produced. It is difficult to separate and remove this by-product from the target product, which requires a decrease in the isolation yield of the target product and an increase in the number of man-hours, and is not suitable as an industrial production method. Moreover, it is difficult for the method of (2) using hydrogen chloride gas to react all the raw materials. For this reason, the reaction yield is low, and it is difficult to separate the raw material from the target product. This purification is accompanied by a further decrease in the isolation yield of the target product and an increase in the number of steps, and is not an efficient industrial process. . Further, the method (3) of reacting with acetyl halide in an acetic acid solvent has a problem that mists of undesirable acid halides are scattered in the working environment because a large amount of acid halide is used.
[0004]
[Problems to be solved by the invention]
The problems of the present invention include conventional problems such as formation of by-products that are difficult to separate, raw materials that are difficult to separate due to incomplete reaction, and the use of a large amount of acid halide that is undesirable in the working environment. The present invention provides a method for producing a 1-halogeno-2-deoxyribofuranose derivative in which the points are eliminated.
[0005]
[Means for Solving the Problems]
In order to solve the above-mentioned problems, the present inventors have repeatedly studied a method for easily producing a 1-halogeno-2-deoxyribofuranose derivative industrially in a high yield and high purity.
[0006]
As a result, since the 2-deoxyribofuranose derivative is reacted with hydrogen halide gas in an aprotic solvent and then reacted with acyl halide or thionyl halide, the reaction proceeds surprisingly quantitatively. The raw material does not remain and the production of by-products derived from the raw material is not generated. Therefore, the isolation yield is much better than that of the conventional method, and it is highly pure, safe and efficient. It has been found that a deoxyribofuranose derivative can be produced, and the present invention has been completed based on this finding.
[0007]
That is, the present invention relates to the general formula (1)
[0008]
[Chemical 3]
(In the formula, R 1 represents an alkyl group having 1 to 4 carbon atoms which may be substituted with a halogen atom, and R 2 and R 3 are each independently an alkyl group having 1 to 4 carbon atoms, A benzyl group optionally substituted with 4 alkyl groups or a halogen atom, an aliphatic acyl group having 2 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms or an aromatic acyl group optionally substituted with a halogen atom 2-deoxyribofuranose derivative represented by formula (2) is reacted with hydrogen halide gas in an aprotic solvent, and then reacted with acyl halide or thionyl halide. 4)
[0010]
[Formula 4]
(Wherein R 2 and R 3 have the same meanings as in the general formula (1), and X represents a halogen atom), and provides a method for producing a 1-halogeno-2-deoxyribofuranose derivative represented by is there.
[0012]
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, the present invention will be described in detail.
Examples of the alkyl group having 1 to 4 carbon atoms represented by R1 in the general formula (1) include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, and a t-butyl basis. A methyl group, an ethyl group, and an isopropyl group; Examples of the alkyl group having 1 to 4 carbon atoms substituted with a halogen atom include chloromethyl group, dichloromethyl group, trichloromethyl group, bromomethyl group, dibromomethyl group, tribromomethyl group, 1-chloroethyl group, 1,2-dichloro Examples thereof include an ethyl group, 1-bromoethyl group, 1,2-dibromoethyl group, chloroisopropyl group, chlorobutyl group, chloroisobutyl group, bromoisopropyl group, bromobutyl group, and bromoisobutyl group.
Examples of the alkyl group having 1 to 4 carbon atoms represented by R2 and R3 include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, and a t-butyl base, preferably a methyl group. , Ethyl group and isopropyl group.
[0013]
As a benzyl group substituted with an alkyl group having 1 to 4 carbon atoms, 2-methylbenzyl group, 3-methylbenzyl group, 4-methylbenzyl group, 2-ethylbenzyl group, 3-ethylbenzyl group, 4-ethylbenzyl Group, propylbenzyl group, isopropylbenzyl group, isobutylbenzyl group and t-butylbenzyl group.
As a benzyl group substituted with a halogen atom, 2-chlorobenzyl group, 3-chlorobenzyl group, 4-chlorobenzyl group, 2,3-dichlorobenzyl group, 2,4-dichlorobenzyl group, 2-bromobenzyl group, Examples include 3-bromobenzyl group, 4-bromobenzyl group, 2,3-dibromobenzyl group, and 2,4-dibromobenzyl group.
[0014]
Examples of the aliphatic acyl group having 2 to 4 carbon atoms include an acetyl group and a propionyl group.
Examples of the aromatic acyl group include benzoyl group, toluoyl group, 4-chlorobenzoyl group, 3-chlorobenzoyl group, 2-chlorobenzoyl group, methoxybenzoyl group, and bromobenzoyl group.
As an aromatic acyl group substituted with an alkyl group having 1 to 4 carbon atoms, 2-methylbenzoyl group, 3-methylbenzoyl group, 2-ethylbenzoyl group, 2-ethylbenzoyl group, 4-ethylbenzoyl group, propylbenzoyl Group, isopropyl benzoyl group, butyl benzoyl group, t-butyl benzoyl group.
Examples of the aromatic acyl group substituted with a halogen atom include 2-chlorobenzoyl group, 3-chlorobenzoyl group, 4-chlorobenzoyl group, 2,3-dichlorobenzoyl group, 2,4-dichlorobenzoyl group, 2-bromobenzoyl group Examples thereof include a group, 3-bromobenzoyl group, 4-bromobenzoyl group, 2,3-dibromobenzoyl group, and 2,4-dibromobenzoyl group.
[0015]
As the hydrogen halide gas used in the present invention, hydrogen chloride gas, hydrogen bromide gas, hydrogen iodide gas and the like can be used, and those having a lower water content are preferred.
The amount of hydrogen halide used is preferably 1 to 10 mol per 1 mol of the starting material 2-deoxyribofuranose derivative.
[0016]
As the acyl halide or thionyl halide, those containing the same type of halogen as the hydrogen halide gas used above are used. Any aliphatic acyl halide, aromatic acyl halide, and thionyl halide can be used as long as these conditions are satisfied. However, aliphatic acyl halides are preferred because of their ease of removal after the reaction. More specifically, when hydrogen chloride gas is used as the hydrogen halide, acetyl chloride, propionyl chloride, thionyl chloride and the like are preferable. When hydrogen bromide gas is used, acetyl bromide, propionyl bromide, and thionyl bromide are preferable. When hydrogen iodide gas is used, acetyl iodide, propionyl iodide, and thionyl iodide are preferred.
The amount of acyl halide or thionyl halide to be used is preferably 0.5 mol to 1 mol, more preferably 0.8 mol to 0.99 mol, per 1 mol of 2-deoxyribofuranose derivative which is a starting material.
[0017]
Any aprotic solvent used in this reaction can be used as long as it is an inert solvent for this reaction. Specifically, hydrocarbons such as hexane, cyclohexane, and toluene, halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, isopropyl bromide, n-butyl chloride, and chlorobenzene, diethyl ether, diisopropyl Ethers such as ether, tetrahydrofuran, and 1,4-dioxane, ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone, and esters such as ethyl acetate, butyl acetate can be used. These solvents can be used alone or in a mixture at an appropriate ratio.
The amount of the aprotic solvent used is preferably such that the concentration of the 2-deoxyribofuranose derivative, which is a starting material, before the reaction is 10% by weight to 20% by weight.
[0018]
The reaction comprises a hydrogen halide gas charging step and a continuous step of reaction with acyl halide or thionyl halide.
In the hydrogen halide gas charging step, the reaction temperature is preferably 0 ° C to 30 ° C. The time required for charging is preferably 0.5 to 10 hours, more preferably 0.5 to 3 hours.
In the aging reaction after charging the hydrogen halide gas, the reaction temperature is preferably 0 ° C. to 30 ° C., the reaction time is preferably 0.1 hours to 18 hours, and more preferably 0.5 hours to 2 hours.
[0019]
In the subsequent reaction with the acyl halide or thionyl halide in the second stage, the reaction temperature is preferably from 0 ° C to 30 ° C. The time required for charging is usually 0.1 to 5 hours, and more preferably 0.5 to 3 hours. In the aging reaction after the acyl halide or thionyl halide is charged, the reaction temperature is preferably 0 ° C. to 30 ° C., the reaction time is preferably 0.5 hours to 5 hours, and more preferably 0.5 hours to 2 hours.
[0020]
By the above reaction, the target 1-halogeno-2-deoxyribofuranose derivative is produced and precipitated as crystals. The crystals can be isolated by filtration and isolated by drying. Although the solvent can be isolated by removing under reduced pressure, it is not limited to these methods.
The 1-halogeno-2-deoxyribofuranose derivative obtained by the above operation can be used in the next reaction as it is, but can also be produced by recrystallization or the like.
[0021]
【Example】
Hereinafter, the present invention will be described with reference to examples and comparative examples.
[0022]
Example 1
A 300-mL glass reactor purged with nitrogen was charged with 100 g (48.6 mmol) of a 20 wt% 3,5-bis (4-chlorobenzoyl) -2-deoxy-1-methylribofuranose diisopropyl ether solution and iced. While stirring under cooling, 18 g of dry hydrogen chloride gas was blown at 3 to 13 ° C. over 1 hour, and further stirred at room temperature (20 ° C.) for 0.5 hour.
While stirring this solution at room temperature (20 ° C.), 3.3 mL of acetyl chloride (46 mmol, 0.95 equivalent) was added dropwise over 5 minutes, and the reaction solution was further stirred at room temperature for 1 hour. .
At this stage, all raw materials were consumed and the reaction was quantitative.
The precipitated crystals were filtered and washed with a small amount of diisopropyl ether. The product was dried at 40 ° C. under reduced pressure for 4 hours to obtain 17.7 g of 1-chloro-3,5-bis (4-chlorobenzoyl) -2-deoxyribofuranose (isolation yield 85%).
As a result of analyzing the product by high performance liquid chromatography (reverse phase column, eluent: water / acetonitrile, detection wavelength: 254 nm), the target product was 96 area%, and no unreacted raw material was found.
Further, the content of 4-chlorobenzoic acid determined by high performance liquid chromatography was 0% by weight, and no by-products derived from protecting groups were contained.
Melting point 122 ° C
1H-NMR (90 MHz, CDCl3, σ (ppm)) 2.7 to 2.9 (2H, m), 4.5 to 4.7 (2H, m), 4.7 to 4.9 (1H, m ), 5.5-5.6 (1H, m), 6.5 (1H, d), 7.4-7.5 (4H, m), 7.9-8.0 (4H, m).
[0023]
Comparative Example 1
The method of the conventional method (1) was additionally tested. The results are shown below.
A 300 mL glass reactor purged with nitrogen was charged with 10 g (25 mmol) of 3,5-bis (4-chlorobenzoyl) -2-deoxy-1-methylribofuranose and 10 mL of dry cyclohexane, and under slightly pressurized nitrogen. Then, 6.4 g (81 mmol) of acetyl chloride was added dropwise at room temperature with stirring for about 5 minutes, and then 0.96 mL of anhydrous methanol was added. The resulting solution was stirred and reacted at 20 ° C. for 4 hours. The low boiling point substance was distilled off from the reaction mixture under reduced pressure, and 11 mL of dry cyclohexane was dissolved therein at room temperature, followed by stirring for 2 hours under ice cooling. The precipitated crystals were filtered and washed with a small amount of cyclohexane. Next, the product was dried under reduced pressure at 40 ° C. for 4 hours to obtain 8.5 g of 1-chloro-3,5-bis (4-chlorobenzoyl) -2-deoxyribofuranose.
As a result of analyzing the product by high performance liquid chromatography (same conditions as in Examples), it was 90 area%, and no unreacted raw material was found.
As a result of quantifying by-products by high performance liquid chromatography, the content of 4-chlorobenzoic acid was 12% by weight, and the yield of the desired product was 73%.
As described above, in the method of the conventional method (1), 4-chlorobenzoic acid derived from the protective group of the raw material was by-produced, and it was difficult to separate the by-product from the target product.
[0024]
Comparative Example 2
The results of additional trial of the method of the conventional method (2) are shown below.
A 300-mL glass reactor purged with nitrogen was charged with 100 g (48.6 mmol) of a 20 wt% 3,5-bis (4-chlorobenzoyl) -2-deoxy-1-methylribofuranose diisopropyl ether solution, and cooled on ice. Under stirring, 36 g of dry hydrogen chloride gas was blown in at 3 to 13 ° C. over 3 hours, and further stirred at room temperature (20 ° C.) for 3 hours.
The precipitated crystals were collected by filtration and washed with a small amount of diisopropyl ether. The product was dried under reduced pressure at 40 ° C. for 4 hours to obtain 16.2 g of 1-chloro-3,5-bis (4-chlorobenzoyl) -2-deoxyribofuranose.
The obtained product was analyzed by high performance liquid chromatography (same conditions as in Examples) and found to be 86 area% and unreacted raw material was 12 area%.
As a result of quantifying by-products by high performance liquid chromatography, the content of 4-chlorobenzoic acid was 0% by weight.
From the above, the yield of the target product was 74%, and it was found that the raw material remained in the product.
As described above, in the method according to the conventional method (2), the raw material remains, so that the reaction yield is low and it is difficult to separate the raw material from the product.
[0025]
【The invention's effect】
As described above, in the conventionally known methods for producing 1-halogeno-2-deoxyribofuranose derivatives, acyl compounds derived from raw materials that are difficult to separate are by-produced or the reaction is not completed, so the yield is low, and the remaining However, there is a problem that the raw material to be separated from the target product is difficult. However, according to the present invention, by reacting 2-deoxyribofuranose derivative with hydrogen halide gas in an aprotic solvent and then reacting with acyl halide, the reaction is surprisingly quantitative and separated. The 1-halogeno-2-deoxyribofuranose derivative can be produced with high purity, safety and industrial production without causing any difficult by-products. Furthermore, this method does not require expensive catalysts or raw materials that are dangerous to handle.
Claims (2)
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