JPH04104796A - Method for selectively acylating 2'-deoxynucleosides - Google Patents
Method for selectively acylating 2'-deoxynucleosidesInfo
- Publication number
- JPH04104796A JPH04104796A JP22306390A JP22306390A JPH04104796A JP H04104796 A JPH04104796 A JP H04104796A JP 22306390 A JP22306390 A JP 22306390A JP 22306390 A JP22306390 A JP 22306390A JP H04104796 A JPH04104796 A JP H04104796A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- deoxynucleosides
- lipase
- compound
- aprotic polar
- 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
- 238000000034 method Methods 0.000 title claims description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 4
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims abstract description 3
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims abstract 2
- 239000004367 Lipase Substances 0.000 claims description 10
- 102000004882 Lipase Human genes 0.000 claims description 10
- 108090001060 Lipase Proteins 0.000 claims description 10
- 235000019421 lipase Nutrition 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 230000010933 acylation Effects 0.000 claims description 6
- 238000005917 acylation reaction Methods 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- 239000003814 drug Substances 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract 1
- 150000007523 nucleic acids Chemical class 0.000 abstract 1
- 102000039446 nucleic acids Human genes 0.000 abstract 1
- 108020004707 nucleic acids Proteins 0.000 abstract 1
- 239000002773 nucleotide Substances 0.000 abstract 1
- 125000003729 nucleotide group Chemical group 0.000 abstract 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract 1
- 229920002554 vinyl polymer Polymers 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 8
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000002777 nucleoside Substances 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 4
- -1 5-bromo 5-substituted uracil Chemical class 0.000 description 3
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 150000003833 nucleoside derivatives Chemical class 0.000 description 3
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- 239000004365 Protease Substances 0.000 description 2
- 241000589540 Pseudomonas fluorescens Species 0.000 description 2
- 101000968491 Pseudomonas sp. (strain 109) Triacylglycerol lipase Proteins 0.000 description 2
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 2
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical compound O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 125000003835 nucleoside group Chemical group 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 210000001747 pupil Anatomy 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 2
- 229940035893 uracil Drugs 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- MKXBOPXRKXGSTI-PJKMHFRUSA-N 1-[(2s,4s,5r)-2-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(C)=CN1[C@]1(F)O[C@H](CO)[C@@H](O)C1 MKXBOPXRKXGSTI-PJKMHFRUSA-N 0.000 description 1
- LDXJRKWFNNFDSA-UHFFFAOYSA-N 2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound C1CN(CC2=NNN=C21)CC(=O)N3CCN(CC3)C4=CN=C(N=C4)NCC5=CC(=CC=C5)OC(F)(F)F LDXJRKWFNNFDSA-UHFFFAOYSA-N 0.000 description 1
- JQMFQLVAJGZSQS-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-N-(2-oxo-3H-1,3-benzoxazol-6-yl)acetamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)NC1=CC2=C(NC(O2)=O)C=C1 JQMFQLVAJGZSQS-UHFFFAOYSA-N 0.000 description 1
- IHCCLXNEEPMSIO-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperidin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 IHCCLXNEEPMSIO-UHFFFAOYSA-N 0.000 description 1
- ZFTBZKVVGZNMJR-UHFFFAOYSA-N 5-chlorouracil Chemical compound ClC1=CNC(=O)NC1=O ZFTBZKVVGZNMJR-UHFFFAOYSA-N 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- UGQMRVRMYYASKQ-UHFFFAOYSA-N Hypoxanthine nucleoside Natural products OC1C(O)C(CO)OC1N1C(NC=NC2=O)=C2N=C1 UGQMRVRMYYASKQ-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- PKHMTIRCAFTBDS-UHFFFAOYSA-N hexanoyl hexanoate Chemical compound CCCCCC(=O)OC(=O)CCCCC PKHMTIRCAFTBDS-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- 229920001567 vinyl ester resin Polymers 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 229940075420 xanthine Drugs 0.000 description 1
Landscapes
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Saccharide Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明はリパーゼによる２′−デオキシヌクレオシド類
の糖部２級水酸基の選択的アンル化方法に関し、本発明
により製造される２゛−デオキシヌクレオシド類は医薬
品の製造中間体として有用である。Detailed Description of the Invention (Industrial Application Field) The present invention relates to a method for selectively unlying the secondary hydroxyl group of the sugar moiety of 2'-deoxynucleosides using lipase, and relates to a method for selectively unlying the secondary hydroxyl group of the sugar moiety of 2'-deoxynucleosides using lipase. These compounds are useful as intermediates in the production of pharmaceuticals.
（従来の１支術）
ヌク−オシ１′類の糖部水酸基の一般的保護基としてア
シル基が汎用される。ヌクレオノド類の糖部水酸基のア
ンル化に酵素が使用された例としてはツメチルホルムア
ミド
リス（Ｂａｃｉｌｌｕｓ ５ｕｂｔｉｌｌｉｓ）由来
のプロテアーゼをウリノン、アゾ／シンのアシル化に用
いた報告（ツヤ−ナル オブ アメリカン ケミカル
ソサエティー 第１１０巻 １９８８年 第５８４頁）
、ジメチルホルムアミド中、シュードモナス フルオレ
ッセンス由来のリパーゼを用いて２゛−デオキシービリ
ミノンヌクレオシドのアシル化を行った報告（テトラヘ
ドロン レターズ 第３０巻 １９８９年第３８１７頁
）及び改変型プロテアーゼを用い、ジメチルホルムアミ
ド中、ヌクレオシド類のアシル化を行った報告（ツヤ−
ナル オブ アメリカンケミカル ソサエティー 第１
１２巻 １９９０年第９４５頁）等があるが、それらは
いずれも糖部１級水酸基に選択的に、もしくは１級、２
級両水酸基に効率的にアシル基が導入される報告であり
、糖部２級水酸基の選択的アシル化についての記載はな
い。(One Conventional Technique) An acyl group is commonly used as a general protecting group for the hydroxyl group of the sugar moiety of Nuku-Osi 1's. An example of the use of an enzyme to unnucleate the hydroxyl group of the sugar moiety of nucleonoids is the report of the use of protease derived from Bacillus 5ubtillis for the acylation of urinone and azo/syn (Tsuary of American Chemical).
Society Vol. 110, 1988, p. 584)
, a report on the acylation of 2'-deoxybiriminone nucleoside using lipase derived from Pseudomonas fluorescens in dimethylformamide (Tetrahedron Letters Vol. 30, 1989, p. 3817) and the acylation of 2'-deoxybiliminone nucleoside in dimethylformamide using a modified protease. In the middle, a report on acylation of nucleosides (glossy)
Null of American Chemical Society 1
12, 1990, p. 945), but all of them selectively target the primary hydroxyl group of the sugar moiety, or
This is a report on the efficient introduction of acyl groups into both primary and secondary hydroxyl groups, and there is no description of selective acylation of secondary hydroxyl groups in sugar moieties.
（発明が解決しようとする課題）
本発明の目的は、酵素を用いた簡便でかつ容易な２゛−
デオキシヌクレオシド類の糖部２級水酸基の選択的アシ
ル化方法を提供することにある。(Problems to be Solved by the Invention) The object of the present invention is to provide a simple and easy two-dimensional method using enzymes.
The object of the present invention is to provide a method for selectively acylating secondary hydroxyl groups in sugar moieties of deoxynucleosides.
（！Ｉ題を解決するための手段）
本発明は一般式
（式中、Ｂは置換又は非置換核酸塩基を示す）で表わさ
れる２゛−デオキシヌクレオシド類に一般式％式％（２
）
（式中、Ｒ’は炭素数１〜１０のアルキル基、Ｒ２は炭
素数１〜１０のフルキルカルボニル基又はビニル基を示
す）で表わされるアシル供与体を非プロトン性極性エー
テル溶媒中、リパーゼの存在下反応させ、−船人
（式中、Ｂ及びＲ’は前記と同一の意味を示す）で表わ
される化合物に導くことを特徴とする２゛ヂオキシスク
レオンド類の選択的アンル化方法に係る。(Means for Solving Problem !I) The present invention provides 2'-deoxynucleosides represented by the general formula (wherein B represents a substituted or unsubstituted nucleobase).
) (wherein, R' is an alkyl group having 1 to 10 carbon atoms, R2 is a furkylcarbonyl group or vinyl group having 1 to 10 carbon atoms) in an aprotic polar ether solvent, Selective unbinding of 2゛dioxyscreondos, characterized by reacting in the presence of lipase to lead to a compound represented by -Funenin (in the formula, B and R' have the same meanings as above) Regarding the method.
船人（１）、（２）及Ｖ（３）中、Ｂで表わされる置換
又は非置換核酸塩基としてはウラシル、５−フルオロウ
ラシル、５−トリプルオロメチルウランル、５−クロロ
ウラシル、５−ブロモウラシル等の５−置換ウラシル、
チミン、シトシン等のビリミノン塩基、アテ°ニン、グ
アニン、キサンチン、ヒボキサンチン等のプリン塩基を
、Ｒ１で表わされるアルキル基としては、炭素数１〜１
０の直鎖又は分枝状のフルキル基であり、例えばメチル
、エチル、７０ビル、］−７０ビル、フチル、ｔ−ブチ
ル、ヘキシル、オクチル、アシル等が挙げられる。In Saijin (1), (2) and V (3), substituted or unsubstituted nucleobases represented by B include uracil, 5-fluorouracil, 5-triple olomethyluranyl, 5-chlorouracil, 5-bromo 5-substituted uracil such as uracil,
Biliminone bases such as thymine and cytosine, purine bases such as atenine, guanine, xanthine, and hypoxanthine, and the alkyl group represented by R1 have 1 to 1 carbon atoms.
0 straight-chain or branched furkyl group, such as methyl, ethyl, 70-biru, ]-70-biru, phthyl, t-butyl, hexyl, octyl, acyl, and the like.
又、本反応に用いられるリパーゼとしては、般に市販さ
れているものを用いることができ、例えばシュードモナ
ス フルオレッセンス由来のリパーゼＰ Ｓ （大野製
薬）、リパーゼＰ（大野製薬）等が好適である。Furthermore, as the lipase used in this reaction, generally commercially available lipases can be used, and for example, lipase PS derived from Pseudomonas fluorescens (Ohno Pharmaceutical Co., Ltd.), lipase P (Ohno Pharmaceutical Co., Ltd.), etc. are suitable.
本反応溶媒の非プロトン性極性エーテルとしては、例え
ばノオキサン、テトラヒドロフラン等が挙げられる。Examples of the aprotic polar ether used as the reaction solvent include nooxane and tetrahydrofuran.
反応温度は１０〜３０°Ｃの範囲が適用でき、２５°Ｃ
付近が好適である。反応時間は１８〜４８時間で終了し
、好収率で目的物を得ることができる。−船人（２）で
表わされるカルボン酸無水物又はカルボン酸ビニルエス
テルの使用割合は一般式（＋）で表わされるヌクレオシ
ド類１当量に対し、２〜５当量、好ましくは２〜３当量
使用する。リパーゼの使用割合は一般式（１）で表わさ
れるヌクレオシド類の重量に対し０．５〜３倍重量、好
ましくは等重量使用する。The reaction temperature can be in the range of 10 to 30°C, and 25°C
Preferably nearby. The reaction time is completed in 18 to 48 hours, and the desired product can be obtained in good yield. - The usage ratio of the carboxylic acid anhydride or carboxylic acid vinyl ester represented by Shipman (2) is 2 to 5 equivalents, preferably 2 to 3 equivalents, per 1 equivalent of the nucleoside represented by the general formula (+). . The ratio of lipase used is 0.5 to 3 times the weight of the nucleosides represented by general formula (1), preferably the same weight.
本反応で得られた化合物は、通常の分離手段、抽出、分
液、ｓｒｓ、再結晶、カラムクロマトグラフィー等によ
り単離精製することができる。The compound obtained in this reaction can be isolated and purified by conventional separation means, extraction, liquid separation, SRS, recrystallization, column chromatography, etc.
（実 施 例） 以下に本発明の実施例を示す。(Example) Examples of the present invention are shown below.
実施例１
２゛−デオキシ−５−フルオロウリノン２５０鵠ｇ（１
−−ｏｌｅ）及び酢酸ビニル３００ｍｇ（３ｍｍｏｌｅ
）をジオ斗サン１０論ｌに溶解し、次いで、リパーゼＰ
Ｓ（天野製薬） ２５０１１１１＋を加え、室温で一夜
撹拌放置した。Example 1 250 g of 2'-deoxy-5-fluorourinone (1
--ole) and 300 mg vinyl acetate (3 mmole)
) was dissolved in 10 liters of Geotosan, and then lipase P
S (Amano Pharmaceutical Co., Ltd.) 2501111+ was added, and the mixture was left stirring at room temperature overnight.
反応が終了したことを液体クロマトグラフィーで確認し
た後、酵素を減圧下、枦取し、炉液を酢酸エチル２０Ｉ
１１、水３０−１で水洗抽出した。有機層を無水硫酸ナ
トリウムで乾燥した後、減圧留去し、カラムクロマトグ
ラフィーにより単離精製（溶出液 ヘキサン ：酢酸エ
チル＝ １ ：１ ）することにより目的物である３゛
−７セチルー２゛−デオキシ−５−フルオロウリノン
１８０１１Ｅ（収率８０％）を得た。After confirming the completion of the reaction by liquid chromatography, the enzyme was removed under reduced pressure and the reaction solution was diluted with 20I ethyl acetate.
11.Washing and extraction with water 30-1. The organic layer was dried over anhydrous sodium sulfate, evaporated under reduced pressure, and isolated and purified by column chromatography (eluent: hexane:ethyl acetate = 1:1) to obtain the desired product, 3'-7cetyl-2'- Deoxy-5-fluorourinone
18011E (yield 80%) was obtained.
Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６） δｐｐ瞳２．０６
（３Ｈ，Ｓ、 −ＣＯＣＨ，）２．２０〜２．４０（
２Ｈ，曽、Ｈ−２’）３．５０〜３．７０（２Ｈ，髄、
Ｈ−５’）３．９０−４．１０（Ｉ Ｈ，ｂｒ、）（４
’）５．１０−５．３１（２Ｈ，ｂｒ、 Ｈ−３’、
５°−０Ｈ）６．１６ ＜Ｉ Ｈ，ｔ、 ）Ｉ −１
’）８．２１ （Ｉ Ｈ，ｄ、 Ｈ−６）
実施例２
出発原料として５，５．５− ）リフルオロチミノン及
び酢酸ビニルを用いた以外は実施例１と同様の操作によ
り３゛−７セチルー５＋５＋５ ） ’） フルオロ
チミジンを収率８０％で得た。H-NMR (DMSO-d6) δpp pupil 2.06
(3H,S, -COCH,)2.20~2.40(
2H, Zeng, H-2') 3.50-3.70 (2H, Pith,
H-5') 3.90-4.10 (I H, br, ) (4
') 5.10-5.31 (2H, br, H-3',
5°-0H)6.16 <I H,t, )I -1
') 8.21 (I H, d, H-6) Example 2 3'- 7 Cetyl-5+5+5)') Fluorothymidine was obtained in a yield of 80%.
Ｈ−ＮＭＲ（ＤＭＳＯ−、（、） δｐｐｍ２．０
６ （３Ｈ９ｓ、Ｃ０ＣＨ５）
２．２０〜２．５０ （２Ｈ，１１１１Ｈ２’）３．５
２〜３．７５ （２Ｈ，Ｉｍ、 ）ｌ −５’）４
．００−４．１９ （Ｉ Ｈｌｂｒ、 Ｈ−４’）５．
０８”−５，４０（２Ｈ２ｂｒ、Ｈ３Ｚ ５ ’
ＯＨ）６、Ｏ８（Ｉ Ｈ，ｔ、 Ｈ−１°）
８．６２ （Ｉ Ｈ，ｄ、 Ｈ−６）
１１．８０ （ｌ Ｈ，ｂｒｓ、 Ｎ ３ Ｈ）実施
例３
出発原料として２゛−チオキン−５−ブロモウリノン及
び酢酸ビニルを用いた以外は実施例１と同様の操作によ
り３゛−アセチル−２゛−デオキシ−５−ブロモウリノ
ンを収率４０％で得た。H-NMR (DMSO-, (,) δppm2.0
6 (3H9s, C0CH5) 2.20-2.50 (2H, 1111H2') 3.5
2-3.75 (2H, Im, )l -5')4
．． 00-4.19 (I Hlbr, H-4')5.
08"-5,40 (2H2br, H3Z 5'
OH) 6, O8 (I H, t, H-1°) 8.62 (I H, d, H-6) 11.80 (l H, brs, N 3 H) Example 3 2゛ as a starting material 3'-acetyl-2'-deoxy-5-bromoulinone was obtained in a yield of 40% by the same procedure as in Example 1 except that -thioquine-5-bromoulinone and vinyl acetate were used.
Ｈ−ＮＭＲ（ＤＭＳＯ−ｃ１６） δｐｐ曽２．０
５ （３Ｈ、ｓ、ＣＨｓ）
２．１５〜２．４０（２Ｆ（、ｍ、Ｈ２’）３．５５〜
３．７５ （２８９ｍ、 ）Ｉ −５’）３．９０
〜４．０８ （ｌ Ｈ，ｍ、 Ｈ−４”）５．０
５−５．４０ （２Ｈ，ｂｒ、Ｈ−３”、 ５’−
０Ｈ）６．１２ （Ｉ Ｈ，ｔ、 Ｈ−１°）８
．３３ （Ｉ Ｈ，ｓ、 Ｈ−６）実施例４
出発原料として２゛−デオキシアゾ７シン及び酢酸ビニ
ルを用いた以外は実施例１と同様の操作により３゛−７
セチルー２゛−デオキシアデノシンを収率６０％で得た
。H-NMR (DMSO-c16) δpp so 2.0
5 (3H, s, CHs) 2.15~2.40 (2F(, m, H2') 3.55~
3.75 (289m, )I-5')3.90
~4.08 (l H, m, H-4") 5.0
5-5.40 (2H, br, H-3", 5'-
0H) 6.12 (I H, t, H-1°) 8
．． 33 (I H, s, H-6) Example 4 3゛-7 was prepared in the same manner as in Example 1 except that 2゛-deoxyazo7cine and vinyl acetate were used as starting materials.
Cetyl-2'-deoxyadenosine was obtained in a yield of 60%.
Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６） δｐｐ瞳２．１０
（３Ｈ，ｓ、Ｃ）（３）
２．３０〜２．６０（２Ｈ，閣、Ｈ−２’）３．４８〜
３．７２（２８，輪、Ｈ−５’）３．９２−４．２０
（Ｉ Ｈ，ｂｒ＋ ８ ４ ’）５．２０−５．５５（
２Ｈ，ｂｒ、Ｈ３’、５”ＯＨ＞６．３５ （ｌ Ｈ，
Ｌ、 Ｈ−１’）７．３２ （２Ｈ，Ｓ、 −ＮＨ２）
８．１２ （］ Ｈ，Ｓ、 Ｈ−８＞
８．３２ （Ｉ Ｈ，Ｓ、 Ｈ−２）
実施例５
２゛−デオキンウリノン２２！ｈｇ（１＋ｍ５ｏｌｅ）
及び無水カプロン酸２６０ｍ＠（３ｍ＋ｆｉｏｌｅ）を
ノオキサン１０１Ｉｌｅに溶解し、次いでリパーゼＰＳ
（天野製薬）２２８町を加え、室温で一夜撹拌放置した
。酵素を減圧下、枦取し、炉液を酢酸エチル２０ＩＩｌ
、水３０＋ｎｌで水洗抽出した。有機層を無水硫酸ナト
リウムで乾燥した後、減圧留去し、カラムクロマトグラ
フィーにより単離精製（溶出液 ヘキサン ：酢酸エチ
ル＝１：２）することにより目的物である３°−ヘキサ
フィル−２゛−テ゛オキシウリノン １３０−ｇ（収率
４ｏ％）を得た。H-NMR (DMSO-d6) δpp pupil 2.10
(3H, s, C) (3) 2.30~2.60 (2H, Kaku, H-2') 3.48~
3.72 (28, ring, H-5') 3.92-4.20
(I H,br+8 4')5.20-5.55(
2H, br, H3', 5"OH>6.35 (l H,
L, H-1') 7.32 (2H, S, -NH2) 8.12 (] H, S, H-8> 8.32 (I H, S, H-2) Example 5 2゛- Deoquinurinone 22!hg (1+m5ole)
and caproic anhydride 260m@(3m+fiole) were dissolved in Nooxane 101Ile, then lipase PS
(Amano Pharmaceutical Co., Ltd.) 228 Town was added thereto, and the mixture was left stirring at room temperature overnight. The enzyme was taken out under reduced pressure, and the furnace solution was diluted with 20 liters of ethyl acetate.
, washed and extracted with 30+nl of water. The organic layer was dried over anhydrous sodium sulfate, evaporated under reduced pressure, and isolated and purified by column chromatography (eluent: hexane:ethyl acetate = 1:2). 130-g (yield: 4o%) of -dioxyurinone was obtained.
）１−ＮＭＲ（ＤＭＳＯ−ｄ ６１ δ１ｌｐＨ０，
８４（３Ｈ、ｓ、ＣＨ］）
１．１０〜１．７５ （６Ｈ，１１，（Ｃ）（：）、
）２．１（１−２，４０（４Ｈ，ＩＩ、 Ｈ
−２° ｒ −ＣＩＩ 、ＣＯ−）３．５０〜３．
７０ （２＋（、ｗ、 ）（−５’）３．８５−４．０
５ ＩＩ Ｈ，ｂｒ、 Ｈ−４°）５．１０−５．３０
（２Ｈ，ｂｒ、 Ｈ−３’、 ５ ’−
０Ｈ）５．６５ （Ｉ Ｈ，ｄ、 Ｈ−５）６
．１４ （Ｉ Ｈ，Ｌ、 Ｈ−１’）７．８４
（Ｉ Ｈ，’ｄ、 Ｈ−６）１１．２０ （Ｉ Ｈ
９ｂｒｓ、 Ｎ ３−Ｈ）実施例６
出発原料として５，５．５− ）リフルオロチミノン及
び無水カプロン酸を用いた以外は実施例５と同様の操作
により３′−ヘキサフィル−５，５，５−）リフルオロ
チミノンを収率９４％で得た。) 1-NMR (DMSO-d 61 δ1lpH0,
84 (3H, s, CH]) 1.10-1.75 (6H, 11, (C) (:),
)2.1(1-2,40(4H,II,H
-2° r -CII, CO-)3.50~3.
70 (2+(,w, )(-5')3.85-4.0
5 II H, br, H-4°) 5.10-5.30
(2H, br, H-3', 5'-
0H) 5.65 (I H, d, H-5) 6
．． 14 (I H, L, H-1') 7.84
(I H,'d, H-6) 11.20 (I H
9brs, N3-H) Example 6 3'-hexaphyll-5,5, 5-) Lifluorothyminone was obtained in a yield of 94%.
Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６） ＃ｐｐｍ０，８６
（３Ｈ，ｓ、ＣＨ））
１．００〜１．８５ （６Ｈ，ｍ−（ＣＨ２）３
）２．０５−２．６０ （４１（、ａ＋、Ｈ２’、Ｃ
Ｈ２Ｃ０）３．５５〜３．７０ （２Ｈ，Ｍ、 Ｈ５’
）３．８０４．０３ （Ｉ Ｈ，ｂｒ、 Ｈ４’）５．
１０−５．３０ （２Ｈ，ｂｒ、 Ｈ−３’、 ５
’−ＯＨ）６、Ｏ１’ｌ （Ｉ Ｈ，ｔ、 Ｈ−１’）
８．７０ （ｌ Ｈ，ｄ、 Ｈ−６）
ＩＩ、８０ （Ｉ Ｈ，ｂｒ、 Ｎ ３−Ｈ）実施例７
溶媒としてテトラヒドロ７ランを用いた以外は実施例１
と同様の操作により３゛−７セチルー２゛−デオキシ−
５−フルオロウリジンを収率７２％で得た。尚、’Ｈ−
ＮＭＲの値は実施例１の化合物と同じである。H-NMR (DMSO-d6) #ppm0,86
(3H,s,CH)) 1.00~1.85 (6H,m-(CH2)3
)2.05-2.60 (41(,a+,H2',C
H2C0) 3.55-3.70 (2H, M, H5'
)3.804.03 (I H, br, H4')5.
10-5.30 (2H,br, H-3', 5
'-OH)6, O1'l (I H,t, H-1')
8.70 (I H, d, H-6) II, 80 (I H, br, N 3-H) Example 7 Example 1 except that tetrahydro7ran was used as the solvent
3゛-7cetyl-2゛-deoxy-
5-fluorouridine was obtained with a yield of 72%. Furthermore, 'H-
The NMR values are the same as for the compound of Example 1.
（以 上） 呂 願 人 大鵬薬品工業株式会社 代 理 人 弁理士 １）村 巖(that's all) Taiho Pharmaceutical Co., Ltd. Representative Patent Attorney 1) Iwao Mura
Claims (1)
れる２’−デオキシヌクレオシド類に一般式▲数式、化
学式、表等があります▼（２） （式中、Ｒ＾１は炭素数１〜１０のアルキル基、Ｒ＾２
は炭素数１〜１０のアルキルカルボニル基又はビニル基
を示す）で表わされるアシル供与体を非プロトン性極性
エーテル溶媒中、リパーゼの存在下反応させ、一般式 ▲数式、化学式、表等があります▼（３） （式中、Ｂ及びＲ＾１は前記と同一の意味を示す）で表
わされる化合物に導くことを特徴とする２’−デオキシ
ヌクレオシド類の選択的アシル化方法。(1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (1) 2'-deoxynucleosides represented by (in the formula, B represents a substituted or unsubstituted nucleobase) have the general formula ▲ mathematical formula, chemical formula, There are tables etc.▼(2) (In the formula, R^1 is an alkyl group having 1 to 10 carbon atoms, R^2
represents an alkyl carbonyl group or a vinyl group having 1 to 10 carbon atoms) is reacted in an aprotic polar ether solvent in the presence of lipase to form the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (3) A method for selective acylation of 2'-deoxynucleosides, which leads to a compound represented by the formula (wherein B and R^1 have the same meanings as above).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP22306390A JP2747849B2 (en) | 1990-08-24 | 1990-08-24 | Method for selective acylation of 2'-deoxynucleosides |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP22306390A JP2747849B2 (en) | 1990-08-24 | 1990-08-24 | Method for selective acylation of 2'-deoxynucleosides |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH04104796A true JPH04104796A (en) | 1992-04-07 |
| JP2747849B2 JP2747849B2 (en) | 1998-05-06 |
Family
ID=16792251
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP22306390A Expired - Lifetime JP2747849B2 (en) | 1990-08-24 | 1990-08-24 | Method for selective acylation of 2'-deoxynucleosides |
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| Country | Link |
|---|---|
| JP (1) | JP2747849B2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002006268A1 (en) * | 2000-07-13 | 2002-01-24 | Sankyo Company, Limited | Amino alcohol derivatives |
-
1990
- 1990-08-24 JP JP22306390A patent/JP2747849B2/en not_active Expired - Lifetime
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002006268A1 (en) * | 2000-07-13 | 2002-01-24 | Sankyo Company, Limited | Amino alcohol derivatives |
| US6723745B2 (en) | 2000-07-13 | 2004-04-20 | Sankyo Company, Limited | Amino alcohol derivatives |
| US6964976B2 (en) | 2000-07-13 | 2005-11-15 | Sankyo Company, Limited | Amino alcohol derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2747849B2 (en) | 1998-05-06 |
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