JPS5862188A - 6-acyluridine and its preparation - Google Patents
6-acyluridine and its preparationInfo
- Publication number
- JPS5862188A JPS5862188A JP56160777A JP16077781A JPS5862188A JP S5862188 A JPS5862188 A JP S5862188A JP 56160777 A JP56160777 A JP 56160777A JP 16077781 A JP16077781 A JP 16077781A JP S5862188 A JPS5862188 A JP S5862188A
- Authority
- JP
- Japan
- Prior art keywords
- general formula
- formula
- protecting group
- compound
- reaction
- 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.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title abstract description 3
- 125000006239 protecting group Chemical group 0.000 claims abstract description 8
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 5
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 239000007800 oxidant agent Substances 0.000 claims description 2
- ODDDVFDZBGTKDX-VPCXQMTMSA-N 1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)-2-methyloxolan-2-yl]pyrimidine-2,4-dione Chemical compound C1=CC(=O)NC(=O)N1[C@]1(C)O[C@H](CO)[C@@H](O)[C@H]1O ODDDVFDZBGTKDX-VPCXQMTMSA-N 0.000 claims 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 abstract description 14
- 150000001875 compounds Chemical class 0.000 abstract description 11
- 238000006243 chemical reaction Methods 0.000 abstract description 10
- -1 e.g. Proteins 0.000 abstract description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 abstract description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 abstract description 7
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 abstract description 4
- 239000002253 acid Substances 0.000 abstract description 3
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- 239000002904 solvent Substances 0.000 abstract description 3
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 abstract description 2
- 102000004190 Enzymes Human genes 0.000 abstract description 2
- 108090000790 Enzymes Proteins 0.000 abstract description 2
- 102000006601 Thymidine Kinase Human genes 0.000 abstract description 2
- 108020004440 Thymidine kinase Proteins 0.000 abstract description 2
- 230000000340 anti-metabolite Effects 0.000 abstract description 2
- 229940100197 antimetabolite Drugs 0.000 abstract description 2
- 239000002256 antimetabolite Substances 0.000 abstract description 2
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 abstract description 2
- 239000000758 substrate Substances 0.000 abstract description 2
- 229940104230 thymidine Drugs 0.000 abstract description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 230000001590 oxidative effect Effects 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- UXTMROKLAAOEQO-UHFFFAOYSA-N chloroform;ethanol Chemical compound CCO.ClC(Cl)Cl UXTMROKLAAOEQO-UHFFFAOYSA-N 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 description 3
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 3
- 229940045145 uridine Drugs 0.000 description 3
- TVZRAEYQIKYCPH-UHFFFAOYSA-N 3-(trimethylsilyl)propane-1-sulfonic acid Chemical compound C[Si](C)(C)CCCS(O)(=O)=O TVZRAEYQIKYCPH-UHFFFAOYSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical compound OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000002719 pyrimidine nucleotide Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- SGKGZYGMLGVQHP-ZOQUXTDFSA-N 1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-methylpyrimidine-2,4-dione Chemical class CC1=CC(=O)NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 SGKGZYGMLGVQHP-ZOQUXTDFSA-N 0.000 description 1
- RFEIWLOZHAFVIE-PEBGCTIMSA-N 6-acetyl-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dione Chemical compound CC(=O)C1=CC(=O)NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 RFEIWLOZHAFVIE-PEBGCTIMSA-N 0.000 description 1
- YKQQSVFYLFELCK-UHFFFAOYSA-N CCOC=C=COC Chemical group CCOC=C=COC YKQQSVFYLFELCK-UHFFFAOYSA-N 0.000 description 1
- 101150041968 CDC13 gene Proteins 0.000 description 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 101100327316 Schizosaccharomyces pombe (strain 972 / ATCC 24843) cdc18 gene Proteins 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 238000005377 adsorption chromatography Methods 0.000 description 1
- 125000001118 alkylidene group Chemical group 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N butyric aldehyde Natural products CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 239000011651 chromium Substances 0.000 description 1
- 229940090961 chromium dioxide Drugs 0.000 description 1
- IAQWMWUKBQPOIY-UHFFFAOYSA-N chromium(4+);oxygen(2-) Chemical compound [O-2].[O-2].[Cr+4] IAQWMWUKBQPOIY-UHFFFAOYSA-N 0.000 description 1
- VTHIKKVKIVQWHV-UHFFFAOYSA-N chromium(6+) oxygen(2-) pyridine Chemical group [O-2].[O-2].[O-2].[Cr+6].C1=CC=NC=C1 VTHIKKVKIVQWHV-UHFFFAOYSA-N 0.000 description 1
- AYTAKQFHWFYBMA-UHFFFAOYSA-N chromium(IV) oxide Inorganic materials O=[Cr]=O AYTAKQFHWFYBMA-UHFFFAOYSA-N 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- FJKIXWOMBXYWOQ-UHFFFAOYSA-N ethenoxyethane Chemical group CCOC=C FJKIXWOMBXYWOQ-UHFFFAOYSA-N 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000002955 isolation Methods 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
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 229960005010 orotic acid Drugs 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002718 pyrimidine nucleoside 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
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
本発明は、新規化合物の６−アシルウリジンおよびその
製造法に関するものである。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel compound, 6-acyluridine, and a method for producing the same.
本発明の６−アシルウリジンは次の一般式〔１〕で表わ
されるものである。The 6-acyl uridine of the present invention is represented by the following general formula [1].
該式中、′Ｒ１は、メチル、エチル、プロピル、ブチル
なとの低級アルキル基を示す。Ｒ２、Ｒ８、Ｒ４は水素
または一保護基を示す。Ｒ２、Ｒ３、Ｒ４の保護基の種
類には特に限定はないが、その合成反応においては酸処
理により脱離することができるリボース残基の水酸基に
エーテル結合により結合するものが好ましく、具体的に
はＲ２およびＲ３の場合にはインプロピリデン、エチリ
デンなどのアルキリデン基、メトキシメチレン、エトキ
シエチレン、エトキシエチレンなどのアルコキンアルキ
−リデン基 Ｒ４のきる。In the formula, 'R1 represents a lower alkyl group such as methyl, ethyl, propyl, butyl. R2, R8 and R4 represent hydrogen or a monoprotective group. There are no particular limitations on the types of protecting groups for R2, R3, and R4, but in the synthesis reaction, those that bond to the hydroxyl group of the ribose residue that can be removed by acid treatment are preferable, and specifically, In the case of R2 and R3, R4 is an alkylidene group such as impropylidene or ethylidene, or an alkoxyalkylidene group such as methoxymethylene, ethoxyethylene or ethoxyethylene.
６〜置換ピリミジンヌクレオンドは、その合成が困難で
ある理由もあって、５−置顎ピリミノンヌクレオンドに
比へて合成例が少ないが、６−メチルウリジンおよび６
−メチルシチジンには抗ウィルス活性があることが知ら
れており、チミジンまたはオロチン酸代謝における代謝
拮抗物質として種々の生理活性が期待されるものである
。本発明化合物の６−アンルウリジンは同様に生理活性
物質としての種々の有用性が期待されるものである。ま
た前記ピリミジン系核酸関連物質代謝に関与しているた
とえばチミジンキナーゼなどの種々の酵素についてその
酵素的性質を研究する王での基質としてなど生化学研究
用試薬としても有用である。There are fewer examples of synthesis of 6-substituted pyrimidine nucleotides compared to 5-substituted pyriminone nucleotides, partly because their synthesis is difficult, but 6-methyluridine and 6-substituted pyrimidine nucleotides
- Methylcytidine is known to have antiviral activity, and is expected to have various physiological activities as an antimetabolite in thymidine or orotic acid metabolism. 6-Anluuridine, a compound of the present invention, is also expected to have various usefulness as a physiologically active substance. It is also useful as a reagent for biochemical research, such as as a substrate for studying the enzymatic properties of various enzymes, such as thymidine kinase, which are involved in the metabolism of pyrimidine-based nucleic acid-related substances.
本発明化合物は、一般式〔１） 〔式中、Ｒ２’、Ｒ８′およびＲ４′は保護基を示す。The compound of the present invention has the general formula [1] [In the formula, R2', R8' and R4' represent a protecting group.
〕で表わされるＮ１，６−ジ−リチオウリジンに一般式
〔団〕
ＲＩＣＨＯ［１１
〔式中、Ｒ１は低級アルキル基を示す。〕で表わされる
脂肪族アルデヒドを反応させて一般式〔■〕〔式中、Ｒ
１，Ｒ２’、Ｒ８’オ、Ｊ： ＩＪ Ｒ４’ｌ；Ｌ Ｍ
記ト同意義。〕て表わされる６−アルキルヒドロキシ
メチルウリノンを合成し、次いでこれに酸化剤を′作用
させ、必要に応してその後脱保護反応に、付す方法によ
り調製することかできる。] to N1,6-di-lithiouridine represented by the general formula [group] RICHO[11 [wherein R1 represents a lower alkyl group]. ] is reacted with an aliphatic aldehyde represented by the general formula [■] [where R
1, R2', R8'o, J: IJ R4'l; L M
Same meaning as above. It can be prepared by a method in which 6-alkylhydroxymethylurinone represented by the following formula is synthesized, then treated with an oxidizing agent, and then subjected to a deprotection reaction if necessary.
一般式〔Ｉ〕の原料化合物は公知方法により調製するこ
とができる（昭和５６年３月ｌＯ日、社団法人口本薬学
会発行、日本薬学会第１０１年会講演要旨集、第３９４
頁参照）。原料化合物のジリチオ体の保護基の種類は、
Ｒ２′およびＲ８’は前記一般式〔肩〕のＲ２およびＲ
８の保護基に、Ｒ４’はＲ４のものにそれぞれ対応する
ものである。The raw material compound of general formula [I] can be prepared by a known method (March 1980, Published by the Pharmaceutical Society of Japan, Abstracts of the 101st Annual Meeting of the Pharmaceutical Society of Japan, No. 394.
(see page). The type of protecting group for the dilithio form of the raw material compound is
R2' and R8' are R2 and R of the above general formula [shoulder]
8, R4' corresponds to that of R4, respectively.
脂肪族アルデヒ・ドの種類は、目的化合物の一般式〔１
〕中のＲ１に、対応するＲ１を有する一般式〔曽〕化合
物を選択すればよい。反応は、通常、無水条件および低
温（好ましくは一７８〜０°Ｃ）条件下、溶媒中で行う
。溶媒としては、ジエチルエーテル、テトラヒドロフラ
ン、ジオキサン、ジフト４ノ
キンタン、ジエチレングリコールジメチルエーテルなと
のエーテル系溶媒が適用できる。The type of aliphatic aldehyde is determined by the general formula of the target compound [1
], a compound of the general formula [Zeng] having a corresponding R1 may be selected for R1. The reaction is usually carried out in a solvent under anhydrous conditions and low temperature (preferably -78 to 0°C) conditions. As the solvent, ether solvents such as diethyl ether, tetrahydrofuran, dioxane, diphthoquintan, and diethylene glycol dimethyl ether can be used.
６−アルキルヒドロキシメチルウリジン（一般式ｒ ■
Ｈ」）の酸化反応は、α、β位に不飽和結合を有する第
二アルコールのケトンへの酸化反応に応用でき、しかも
、グルコノド結合を分解しないような弱酸性条件下にお
ける方法を適用すればよく、たとえば三酸化クロム−ピ
リジン鎖体による酸化反応（５ａｒｅ ｔｔ酸化 ）な
とにより実施することができる。反応条件は常法に準す
る。6-alkylhydroxymethyluridine (general formula r
The oxidation reaction of ``H'') can be applied to the oxidation reaction of secondary alcohols having unsaturated bonds at the α and β positions to ketones, and if the method is applied under weakly acidic conditions that do not break down the gluconodo bond. This can often be carried out, for example, by an oxidation reaction with a chromium trioxide-pyridine chain (5aret oxidation). The reaction conditions are according to conventional methods.
脱保護反応は、トリフルオロ酢酸、過塩素酸、希硫酸、
希塩酸なとの酸を用いる通常の方法によればよいっ
かくして合成される１］的化合物の単離精製は通常のピ
リミジンヌクレオシド化学に応用される方法を適宜に採
用して行い、たとえば吸着クロマトグラフィー、再結晶
などの方法を応用することができる。The deprotection reaction is performed using trifluoroacetic acid, perchloric acid, dilute sulfuric acid,
Isolation and purification of the compound (1) synthesized in this way can be carried out by a conventional method using an acid such as dilute hydrochloric acid, by appropriately adopting a method applied to conventional pyrimidine nucleoside chemistry, such as adsorption chromatography. , recrystallization, and other methods can be applied.
以下、本発鱈ヒ合物およびその製造法を例示する実施例
を挙げて、本発明のより具体的な説明とする。EXAMPLES Hereinafter, the present invention will be more specifically explained with reference to examples illustrating the present cod fish compound and its manufacturing method.
実施例 １
２’、８’−０−インプロピリデン−５′−Ｏ−メトキ
ンメチルウリジン５８９ ｍｙをテトラヒドロフラン１
０ｇ／に溶解させ、これを窒素ガス陽圧下リチウムジイ
ソプロピルアミド４．１ 、、ｍｍｏ Ｉｅのテトラヒ
ドロフラン１０ｔｘｔ溶液に一７０℃以下に保ちながら
滴Ｆし、１時間撹拌した（Ｎ］、６−ノリチオ体の調製
）。Example 1 589 my of 2',8'-0-impropylidene-5'-O-methquinemethyluridine was added to 1 of tetrahydrofuran.
This was added dropwise to a solution of 4.1 mmol of lithium diisopropylamide in 10 txt of tetrahydrofuran under a positive pressure of nitrogen gas while keeping the temperature below 70°C, and the mixture was stirred for 1 hour. preparation).
この反応液にアセトアルデヒド０．１８ ｍｌを含むテ
トラヒドロフラン溶液を滴下し、３時間反応させた。反
応液に酢酸を加えて室温に戻し、減圧Ｆ濃縮乾固し、残
渣をエタノールに溶解させて適量のシリカゲルを加えて
減圧乾固し、こｔｌをンリカゲルのカラムに負荷し、２
．５９６エタノールークロロホルムで溶出し、溶出液を
減圧乾固して２’、８’−〇−インプロピリデンー５′
−〇−メトキノメチル−６−メチルヒトロキシメチルウ
リンン８１０ｍｇを得た（収率５０．８％）。A tetrahydrofuran solution containing 0.18 ml of acetaldehyde was added dropwise to this reaction solution, and the mixture was reacted for 3 hours. Add acetic acid to the reaction solution, return to room temperature, concentrate to dryness with F under reduced pressure, dissolve the residue in ethanol, add an appropriate amount of silica gel and dry under reduced pressure, load this TL onto a column of silica gel,
．． Elute with 596 ethanol-chloroform, and dry the eluate under reduced pressure to obtain 2',8'-〇-impropylidene-5'
-0-Methoquinomethyl-6-methylhydroxymethylurin (810 mg) was obtained (yield 50.8%).
質量分析スペクトル（ｍｌｚ）
８７８（Ｍ−４−１）、８５７（Ｍ−１５１，１５６（
Ｂ＋−１３核磁気共鳴スペクトル（ＣＤＣ１３、Ｄ２０
添加）δｐｐｍ１．５６ （６Ｈ，ｓ、 イソプロ
ピリデン−メチル、−ＣＨ０ＨＣＨ３）３．７４−３．
８４ （２Ｉｆ ｍ、 Ｃｌ４２−５’ ）４．２
１−４．８４ （１１（、ｍ、 Ｈ−４’ １４．７
６−４．８９ （２Ｈ，ｍ、 Ｈ−３’、ＣｊｊＯＨ
ＣＨ３１５，１９（１）（、ｄ、 、１−−６．３Ｈ
ｚ、 Ｈ−２’）５８１．６．１５ （Ｉ Ｔ−１各
ｓ、Ｈ−１’１５７７．５．９０ Ｉ ］ １−Ｌ各Ｓ
、Ｉ（−５）２’、３’−０−イノプロピリデン−５′
−０−メトキ／メチル−６−メチルヒドロキツメチルウ
リジン８０４ ｍｙをピリジン６ ｒｘｌに溶解させ、
これを三路
酸クロム８１６ ｍｆ！のピリジン８．２ ｒｘｌ 漬
液１こ滴下し、室温下１晩反応させた。反応液を氷水に
あけ、クロロホルム３００ ｍｌで抽出し、飽和炭酸水
素ナトリウム水溶液（，２００肩／ｘ８）で洗滌後、硫
酸ナトリウムで乾燥し、硫酸ナトリウムを濾去し、ノリ
力ゲル力ラムクロマトグラフイ＝（３％エタノール−ク
ロロホルム）で精製して６−アセチル−２’、８’−０
−インプロピリデン−５′−０−メトキノメチルウリジ
ン２５８１ＭＩを得た（収率８５４％晃質量分析スペク
トル（ｍｌｚ）
８７０（Ｍ＋、）、８５５（Ｍ−１５１，１５５（Ｂ＋
２）核磁気共鳴スペクトル（ＣＤＣ１８）６９９ｍ２．
５２ （８Ｈ，Ｓ、 ｃｏｃＰＬ８１３６５−８．７８
（２Ｈ，ｍ、 ＣＨ２−５’１４、ｏ４〜４．２１
（ｌＨ，ｍ、 Ｈ−４’ ３４．６５ （ＩＨ，ｔ、Ｈ
−８’）
５．１２ （Ｉ Ｈ，ｄｄ、 Ｊ＝２．５Ｈｚ、 ６．
８Ｈｚ、、Ｈ−２’ １５．９２ ＭＨ，ｄ、 Ｊ＝２
．５Ｈｚ、 Ｈ−１’）５．８４ （ＩＨ，ｄ、 Ｊ＝
２．ＯＨ２，Ｈ−５）、８．６４ （Ｉ Ｈ，ｂｒ 、
ＮＨ１６−アセチル−２’、８’−０−イソプロピリ
デン−５’ −０−メトキンメチルウリジ・ン７９■を
５０％トリフルオロ酢酸水溶液２ ｗ／に溶解させ、２
４時間撹拌した。反応液を減圧上乾固し、残渣′をエタ
ノールに溶解させ１．少量のシリカケルを加えて減圧乾
固し、シリカゲルカラムに負萄し、７％エタノール−ク
ロロホルムで溶出し、６−アセチルウリジン６ａｓｙを
得た゛（収率９８．６％１゜核磁気共鳴スペクトル（Ｄ
２０ 、 ＤＳＳ ）δｐｐｍ２．６０ （８Ｈ，！ｉ
、 ＣＯＣＨ３）３．５１〜４．０１ （８Ｈ，ｍ、
Ｈ−４’、ＣＨ２−５’ ）４．１４ （ＩＨ，ｔ、
Ｈ−３’）４．６０ （ＩＨ，ｄｄ、Ｊ＝８．９Ｈ
ｚ、６．６ＴＩＺ、 Ｈ−２’）５．５９ （ＩＨ，
ｄ、Ｊ ＝１９Ｈｚ、Ｈ−１’）６．１２（ＩＨ，ｓ、
Ｈ−５）
実施例 ２
２’、８’−０−イソプロピリデン−５′−〇−メトキ
シメチルウリジン１．５ｇをテトラヒドロフラン・２５
ｍｌに溶解させ、これを窒素ガス陽圧下リチウムジイ
ソプロピルアミド２２．８ ｍｒｒｌｏｌｅのテトラヒ
ドロフラント５ ｍｌ溶液に一７０℃以１”ｌこ保ちｌ
、１′から滴下し、１時間撹拌した。Mass spectrometry spectrum (mlz) 878 (M-4-1), 857 (M-151, 156 (
B+-13 nuclear magnetic resonance spectrum (CDC13, D20
addition) δppm 1.56 (6H, s, isopropylidene-methyl, -CH0HCH3) 3.74-3.
84 (2If m, Cl42-5')4.2
1-4.84 (11(, m, H-4' 14.7
6-4.89 (2H, m, H-3', CjjOH
CH315,19(1)(,d, ,1--6.3H
z, H-2') 581.6.15 (IT-1 each s, H-1' 1577.5.90 I] 1-L each S
, I(-5)2',3'-0-inopropylidene-5'
-0-methoxy/methyl-6-methylhydroxymethyluridine 804 my was dissolved in pyridine 6 rxl,
This is Sanro acid chromium 816 mf! One 8.2 rxl solution of pyridine was added dropwise, and the mixture was allowed to react overnight at room temperature. The reaction solution was poured into ice water, extracted with 300 ml of chloroform, washed with a saturated aqueous sodium bicarbonate solution (200ml/x8), dried over sodium sulfate, filtered off the sodium sulfate, and subjected to gel-pressure column chromatography. 6-acetyl-2',8'-0
-Impropylidene-5'-0-methoquinomethyluridine 2581 MI was obtained (yield 854%.
2) Nuclear magnetic resonance spectrum (CDC18) 699m2.
52 (8H, S, cocPL81365-8.78
(2H, m, CH2-5'14, o4~4.21
(IH, m, H-4' 34.65 (IH, t, H
-8') 5.12 (I H, dd, J=2.5Hz, 6.
8Hz, H-2' 15.92 MH, d, J=2
．． 5Hz, H-1') 5.84 (IH, d, J=
2. OH2, H-5), 8.64 (I H, br,
NH16-acetyl-2',8'-0-isopropylidene-5'-0-methquinemethyluridine was dissolved in 2 w/50% trifluoroacetic acid aqueous solution, and 2
Stirred for 4 hours. The reaction solution was dried under reduced pressure, and the residue was dissolved in ethanol.1. A small amount of silica gel was added and the mixture was dried under reduced pressure, loaded onto a silica gel column, and eluted with 7% ethanol-chloroform to obtain 6-acetyluridine 6asy (yield 98.6%, 1° nuclear magnetic resonance spectrum (D
20, DSS) δppm2.60 (8H,!i
, COCH3) 3.51-4.01 (8H, m,
H-4', CH2-5')4.14 (IH,t,
H-3') 4.60 (IH, dd, J=8.9H
z, 6.6TIZ, H-2') 5.59 (IH,
d, J = 19Hz, H-1') 6.12 (IH, s,
H-5) Example 2 1.5 g of 2',8'-0-isopropylidene-5'-〇-methoxymethyluridine was dissolved in tetrahydrofuran.25
ml of lithium diisopropylamide and 5 ml of tetrahydrofuran solution under positive pressure of nitrogen gas.
, 1' and stirred for 1 hour.
この反応、液にプロピオンアルデヒド４６ ｍｍｏｌｅ
ま巨
様にしてシリカゲルクロマトグラフィーに付し、１９６
エタノールークロロホルムで溶出して２’、８’−〇−
インプロピリデンー５′−〇−メトキンメチル−６−ニ
チルヒドロキシメチルウリジン１．３４りを得た（収率
７５．７％）。In this reaction, 46 mmole of propionaldehyde was added to the solution.
Then, it was subjected to silica gel chromatography in a large size, and 196
Elute with ethanol-chloroform to obtain 2', 8'-〇-
1.34 pieces of impropylidene-5'-0-methquinmethyl-6-nitylhydroxymethyluridine were obtained (yield 75.7%).
高分解能質量分析スペクトルｔｍ７ｚ）Ｃ１７Ｈ２６Ｎ
２０ｇとして計算値 ３８６，１６８２実験値 ３８６
．１６４４ ＩＭ”＋）核磁気共鳴スペクトル（ＣＤＣ
ｌ２）δｐｐｍ０．８８−１．１８ （８Ｈ、ｍ、 Ｃ
Ｈ２ＣＨ２）１．６８〜１．９２ （２Ｈ，ｍ、 ＣＨ
２ＣＨ２）８．７８〜８．８４ （２Ｈ，ｍ、 ＣＨ２
−５’ １４．２２ 〜４．６１ （２Ｈ，ｍ、
Ｈ−４’、 （４０ＨＣＨ２ＣＨａ 、）４．８８〜４
．８９ （Ｉ Ｈ，ｍ、 Ｈ−３’ ）５．２１ （Ｉ
Ｈ，ｄ、 Ｊ＝２．９Ｈ２，Ｈ−２′）５７２．５．ｓ
８＜ Ｉ Ｈ，各ｓ、）（−５１５７９，６，１７（Ｉ
Ｈ，各ｉ、Ｈ−１’）９．６１−（ＩＨ，ｂｒ、 ＮＨ
）
２’、８’−０−イ゛ソブロピリデンー５′−〇−メト
キンメチル−６−エチールヒドロキシメチルウリジン７
１８ｊＩ９をピリジン１４ｇ／に溶解させ、これを二酸
化クロム１．８６ｇのピリ層ジン１８．６ ｍｌ溶液に
゛滴ドし、室温下３０時間反応させた。反応液を氷水に
あけ、クロロホルム５００ ｗ／て抽出し、飽和炭酸水
素す） ＩＪウム水溶液（８００ｇ／Ｘ５）て洗滌後、
硫酸ナトリウムで乾燥し、硫酸ナトリウムを濾去し、シ
リカゲルカラムクロマトグラフィー （溶出＋＆ ：
１９ｂエタノール−クロロホルム）で精製後、２’、８
’−０〜インプロピリデン−５′−０−メトキ／メチル
−６−プロピオニルウリジン４６３ｍｇを得た（収率６
３５％）。エーテルから再結晶した。High resolution mass spectrometry spectrum tm7z) C17H26N
Calculated value as 20g: 386,1682 Experimental value: 386
．． 1644 IM”+) Nuclear Magnetic Resonance Spectrum (CDC
l2) δppm0.88-1.18 (8H, m, C
H2CH2) 1.68-1.92 (2H, m, CH
2CH2) 8.78-8.84 (2H, m, CH2
-5' 14.22 ~ 4.61 (2H, m,
H-4', (40HCH2CHa,)4.88~4
．． 89 (I H, m, H-3')5.21 (I
H, d, J=2.9H2,H-2') 572.5. s
8< I H, each s, ) (-51579, 6, 17 (I
H, each i, H-1')9.61-(IH, br, NH
) 2',8'-0-isopropylidene-5'-〇-methquinmethyl-6-ethylhydroxymethyluridine 7
18jI9 was dissolved in 14 g of pyridine, and this was added dropwise to a solution of 1.86 g of chromium dioxide in 18.6 ml of pyridine, and reacted at room temperature for 30 hours. The reaction solution was poured into ice water, extracted with 500 w/chloroform, washed with saturated hydrogen carbonate, and washed with an aqueous IJ solution (800 g/X5).
Dry with sodium sulfate, remove sodium sulfate by filtration, and perform silica gel column chromatography (elution+&:
After purification with 19b ethanol-chloroform), 2', 8
463 mg of '-0-inpropylidene-5'-0-methoxy/methyl-6-propionyl uridine was obtained (yield 6
35%). Recrystallized from ether.
融点１ １１７〜１１８℃
元素分析 ＣＩ７８２４Ｎ ２０８として計算値（イ
）： Ｃ，５８，１２Ｈ，６，２９Ｎ、 ７．２９実験
値（剣： Ｃ，５３，８５Ｈ，６，４８Ｎ、 ７．１８
紫外線・吸収スペクトル
λ’ｍ−ＯＨ２７２ｎｍ （Ｅ ７３００ ）増’ｉ’
ｇＨ２３７ｎｍ （ε２２００）２’、８’−０−イン
プロピリデン−５′−Ｏ〜メトキシメチル〜６−プロピ
オニルウリジン１００ ｍｙを５０９６トリフルオロ酢
酸水溶液５ ｗ／に溶解させ、２４時間撹拌した。反応
液を実施例１と同様にしてシリカゾルカラムクロマトグ
ラフィー（溶出液＝７％エタノール−クロロホルム）で
精製して６−プロピオニルウリジン？ ２ ＩＩｇ（収
率９２．８％）を得た。Melting point 1 117-118℃ Elemental analysis Calculated value as CI7824N 208 (A): C, 58, 12H, 6, 29N, 7.29 Experimental value (Sword: C, 53, 85H, 6, 48N, 7.18
Ultraviolet absorption spectrum λ'm-OH272nm (E 7300) increase 'i'
gH237nm (ε2200) 2',8'-0-Impropylidene-5'-O-methoxymethyl-6-propionyl uridine 100 my was dissolved in 5 w/5096 trifluoroacetic acid aqueous solution and stirred for 24 hours. The reaction solution was purified by silica sol column chromatography (eluent = 7% ethanol-chloroform) in the same manner as in Example 1 to obtain 6-propionyluridine? 2IIg (yield 92.8%) was obtained.
質量分析スペクトル（ｍ／ｚ）
３’ＯＯｆＭ＋）、１６８（Ｂ＋１）
核磁気共鳴スペクトル（Ｄ２０． ＤＳＳ）δｐｐｍ１
．１８ （８Ｈ，ｌ 、 Ｃ０ＣＨ２ＣＨＢ ）２．８
８−８．０１ （２Ｈ，ｍ、 Ｃ０ＣＨ２ＣＨＢＡ８．
５４〜８．９９ （８Ｈ，ｍ、 Ｈ−４’、ＣＨ２−５
’ １４．１４ （ＩＨ，ｔ、 Ｈ−ｓ’１
４．６８ （ＩＨ，ｄｄ、 Ｊ＝３．９Ｈ２，６，８Ｈ
２，Ｈ−２’）５．４８ （ＩＨ，ｄ、 Ｊ−８，９Ｈ
ｚ、 Ｈ−ｔ′）６、．０６ （ＩＨ，ｓ、 Ｈ−５）Mass spectrometry spectrum (m/z) 3'OOfM+), 168 (B+1) Nuclear magnetic resonance spectrum (D20. DSS) δppm1
．． 18 (8H,l, C0CH2CHB)2.8
8-8.01 (2H, m, C0CH2CHBA8.
54-8.99 (8H, m, H-4', CH2-5
' 14.14 (IH, t, H-s'1 4.68 (IH, dd, J=3.9H2,6,8H
2,H-2')5.48 (IH,d, J-8,9H
z, H-t')6, . 06 (IH,s, H-5)
Claims (1)
は水素または保護基を示す。〕で表わされる６−アンル
ウリジン。 ２）一般式〔ｌ） 〔式中、Ｒ２： Ｒ８’およびＲ４’は保護基を示す。 〕で表わされるＮ１． ６−ジ−リチオウリジンに一般
式〔■〕 ＲＩＣＨＯ〔１） １式中、Ｒ１は低級アルキル基を示す。〕で表わされる
脂肪族アルデヒドを反応させて一般式〔ｎ′〕 「式中、Ｒ１，Ｒ２およびＲ８’およびＲ４’は前記と
同意義。〕で表わされる６−アルキルヒドロキンメチル
ウリジンを合成し、次いてこれに酸化剤を作用させ、必
要に応してその後脱保護反応に付して一般式〔１〕。 Ｌ′式中、Ｒ１およびＲ４は前記と同意義、Ｒ２および
Ｒ８ｆｉ水゛素または保護基を示す。〕て表わきれる６
−アンルウリジンを得ることを特徴とする＆[Claims] 1) General formula [1] O [In the formula, R1 is a lower alkyl group, R2, R8 and R4
represents hydrogen or a protecting group. ] 6-Anluuridine. 2) General formula [l] [In the formula, R2: R8' and R4' represent a protecting group. ] N1. 6-di-lithiouridine has the general formula [■] RICHO [1] In formula 1, R1 represents a lower alkyl group. ] to synthesize 6-alkylhydrokine methyluridine represented by the general formula [n'] "wherein R1, R2, R8' and R4' have the same meanings as above." , and then treated with an oxidizing agent and, if necessary, subjected to a deprotection reaction to obtain the general formula [1]. In the L' formula, R1 and R4 have the same meanings as above, and R2 and R8fi hydrogen. or indicates a protecting group.]6 can be expressed as
- characterized by obtaining anluuridine &
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP56160777A JPS5862188A (en) | 1981-10-07 | 1981-10-07 | 6-acyluridine and its preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP56160777A JPS5862188A (en) | 1981-10-07 | 1981-10-07 | 6-acyluridine and its preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5862188A true JPS5862188A (en) | 1983-04-13 |
| JPH0134233B2 JPH0134233B2 (en) | 1989-07-18 |
Family
ID=15722221
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP56160777A Granted JPS5862188A (en) | 1981-10-07 | 1981-10-07 | 6-acyluridine and its preparation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5862188A (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5118432A (en) * | 1974-08-06 | 1976-02-14 | Matsushita Electric Ind Co Ltd | KARAATEREBIJONJUZOKI |
-
1981
- 1981-10-07 JP JP56160777A patent/JPS5862188A/en active Granted
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5118432A (en) * | 1974-08-06 | 1976-02-14 | Matsushita Electric Ind Co Ltd | KARAATEREBIJONJUZOKI |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0134233B2 (en) | 1989-07-18 |
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