JPH0269191A - Deacylation of nucleosides - Google Patents
Deacylation of nucleosidesInfo
- Publication number
- JPH0269191A JPH0269191A JP22205988A JP22205988A JPH0269191A JP H0269191 A JPH0269191 A JP H0269191A JP 22205988 A JP22205988 A JP 22205988A JP 22205988 A JP22205988 A JP 22205988A JP H0269191 A JPH0269191 A JP H0269191A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- lipase
- protease
- substituted
- compound
- 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.)
- Pending
Links
- 239000002777 nucleoside Substances 0.000 title claims abstract description 15
- 125000003835 nucleoside group Chemical group 0.000 title claims abstract description 9
- 238000005947 deacylation reaction Methods 0.000 title description 4
- 230000020176 deacylation Effects 0.000 title description 3
- 102000004882 Lipase Human genes 0.000 claims abstract description 17
- 108090001060 Lipase Proteins 0.000 claims abstract description 17
- 239000004367 Lipase Substances 0.000 claims abstract description 17
- 235000019421 lipase Nutrition 0.000 claims abstract description 17
- 239000004365 Protease Substances 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 13
- 108091005804 Peptidases Proteins 0.000 claims abstract description 12
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 abstract description 6
- 150000003833 nucleoside derivatives Chemical class 0.000 abstract description 6
- 239000002798 polar solvent Substances 0.000 abstract description 6
- 241000235527 Rhizopus Species 0.000 abstract description 5
- 102000004190 Enzymes Human genes 0.000 abstract description 4
- 108090000790 Enzymes Proteins 0.000 abstract description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 abstract description 4
- 241000589516 Pseudomonas Species 0.000 abstract description 3
- 230000000813 microbial effect Effects 0.000 abstract description 3
- 239000012046 mixed solvent Substances 0.000 abstract description 3
- 229940035893 uracil Drugs 0.000 abstract description 3
- 150000007523 nucleic acids Chemical class 0.000 abstract description 2
- 102000039446 nucleic acids Human genes 0.000 abstract description 2
- 108020004707 nucleic acids Proteins 0.000 abstract description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 abstract description 2
- 239000007795 chemical reaction product Substances 0.000 abstract 3
- 239000006172 buffering agent Substances 0.000 abstract 1
- 239000002904 solvent Substances 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
- 229910052739 hydrogen Inorganic materials 0.000 description 32
- 229940040461 lipase Drugs 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 7
- 235000019419 proteases Nutrition 0.000 description 6
- -1 0-fluorophenyl Chemical group 0.000 description 5
- 125000002252 acyl group Chemical group 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 108010043393 protease N Proteins 0.000 description 4
- 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
- 241000228212 Aspergillus Species 0.000 description 3
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 102000035195 Peptidases Human genes 0.000 description 3
- 101000968491 Pseudomonas sp. (strain 109) Triacylglycerol lipase Proteins 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 244000005700 microbiome Species 0.000 description 3
- 239000000243 solution Substances 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
- 241000186063 Arthrobacter Species 0.000 description 2
- 241000588881 Chromobacterium Species 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- 241000209094 Oryza Species 0.000 description 2
- 235000007164 Oryza sativa Nutrition 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000000872 buffer Substances 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
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
- 229940088598 enzyme Drugs 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
- 239000010410 layer Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000010446 mirabilite Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 235000009566 rice Nutrition 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 2
- RSIJVJUOQBWMIM-UHFFFAOYSA-L sodium sulfate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O RSIJVJUOQBWMIM-UHFFFAOYSA-L 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- LMNPKIOZMGYQIU-UHFFFAOYSA-N 5-(trifluoromethyl)-1h-pyrimidine-2,4-dione Chemical compound FC(F)(F)C1=CNC(=O)NC1=O LMNPKIOZMGYQIU-UHFFFAOYSA-N 0.000 description 1
- LQLQRFGHAALLLE-UHFFFAOYSA-N 5-bromouracil Chemical compound BrC1=CNC(=O)NC1=O LQLQRFGHAALLLE-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
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 241000590020 Achromobacter Species 0.000 description 1
- 241000908198 Actinomucor Species 0.000 description 1
- 240000006439 Aspergillus oryzae Species 0.000 description 1
- 235000002247 Aspergillus oryzae Nutrition 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241000186146 Brevibacterium Species 0.000 description 1
- 241000186216 Corynebacterium Species 0.000 description 1
- 241001337994 Cryptococcus <scale insect> Species 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- 241000588914 Enterobacter Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 101001091385 Homo sapiens Kallikrein-6 Proteins 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
- 241000155250 Iole Species 0.000 description 1
- 102100034866 Kallikrein-6 Human genes 0.000 description 1
- 241000186660 Lactobacillus Species 0.000 description 1
- 101710098554 Lipase B Proteins 0.000 description 1
- 241000235395 Mucor Species 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- 108050006759 Pancreatic lipases Proteins 0.000 description 1
- 102000019280 Pancreatic lipases Human genes 0.000 description 1
- 108090000526 Papain Proteins 0.000 description 1
- 241000228143 Penicillium Species 0.000 description 1
- 241000235648 Pichia Species 0.000 description 1
- 241000235545 Rhizopus niveus Species 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229960002949 fluorouracil Drugs 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
- 238000002513 implantation Methods 0.000 description 1
- 229910052738 indium Inorganic materials 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229940039696 lactobacillus Drugs 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 125000001421 myristyl 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])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([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
- 239000012044 organic layer Substances 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 229940116369 pancreatic lipase Drugs 0.000 description 1
- 229940055729 papain Drugs 0.000 description 1
- 235000019834 papain Nutrition 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 150000005374 primary esters Chemical class 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 150000008028 secondary esters Chemical class 0.000 description 1
- 125000004079 stearyl 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])C([H])([H])C([H])([H])C([H])([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
- 239000000758 substrate Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 229940075420 xanthine Drugs 0.000 description 1
Landscapes
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
Description
【発明の詳細な説明】
(産業上の利用分野)
本発明はリパーゼ及1プロテアーゼによるヌクレオシド
類の糖部アシル基の選択的脱アシル化方法に関し、本発
明により製造されるヌクレオシド類は医薬品又はその製
造中間体として有用である。Detailed Description of the Invention (Field of Industrial Application) The present invention relates to a method for selectively deacylating sugar acyl groups of nucleosides using lipase and protease. Useful as a manufacturing intermediate.
(従来の技術)
ヌクレオシド類の糖部水酸基の一般的保護基としてアシ
ル基が汎用されるが、それらの選択的保護、脱保護には
多段階の反応工程を必要とし、その際に、酸及びアルカ
リを泪いるなど製法上十分な解決をみていない。又、糖
水酸基の一級又は二級のエステルを位置選択的に認識し
、脱エステル化を行った例としてはヌクレオシドを基質
とした分野ではこれまで皆無である。(Prior art) Acyl groups are widely used as general protecting groups for the hydroxyl groups of sugar moieties of nucleosides, but their selective protection and deprotection require multi-step reaction steps, and at that time, acid and No satisfactory solutions have been found in terms of manufacturing methods, such as using alkali. Furthermore, there have been no examples in the field of nucleoside substrates in which primary or secondary esters of sugar hydroxyl groups are recognized regioselectively and deesterified.
(発明が解決しようとする課題)
本発明の目的は、酵素を用いた選択的な簡便でかつ容易
なヌクレオシド類の糖部アシル基の脱アシル化方法を提
供することにある。(Problems to be Solved by the Invention) An object of the present invention is to provide a method for selectively, simple and easy deacylation of sugar moiety acyl groups of nucleosides using an enzyme.
(課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、R,は水素原
子又は−0CORを、Rはフルキル基、又は置換又は非
rIl換のフェニル基を示す、)で表すされるヌクレオ
シド類をリパーゼ又はプロテアーゼと反応させ、一般式
(式中、R2は水素原子又は水酸基を、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又は一般式
(式中、B、R,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ヌクレオシド
類の脱アシル化方法に係る。(Means for Solving the Problems) The present invention relates to the general formula (wherein, B represents a substituted or unsubstituted nucleobase, R represents a hydrogen atom or -0COR, and R represents a fulkyl group or a substituted or unsubstituted nucleobase). A nucleoside represented by ) representing a phenyl group is reacted with lipase or protease to produce a compound represented by the general formula (wherein R2 represents a hydrogen atom or a hydroxyl group, and B and R have the same meanings as above). or a method for deacylating nucleosides, which is characterized by leading to a compound represented by the general formula (wherein B, R, and R have the same meanings as above).
更に詳細には、一般式(])で表わされる化合物に脱7
シル化Mとしてリパーゼを用いた場合には、糖部分の2
゛又は3゛位に置換されたアシル基−CORが選択的に
脱離し、一般式(2)で表わされる化合物が製造される
。一方、脱アシル化剤としてプロテアーゼを用いた場合
には、糖部分の5゛位に置換された7シル基−CORが
選択的に脱離し、一般式(3)で表わされる化合物が製
造される。このように、脱アシル化剤としてリパーゼ及
びプロテアーゼを使い分けることにより、糖アシル基の
脱離位置を制御することが可能である。More specifically, the compound represented by the general formula (]) is
When lipase is used as the sylation M, the sugar moiety 2
The acyl group -COR substituted at the `` or 3'' position is selectively eliminated, and a compound represented by general formula (2) is produced. On the other hand, when protease is used as a deacylating agent, the 7-syl group -COR substituted at the 5'-position of the sugar moiety is selectively eliminated, producing a compound represented by general formula (3). . In this way, by selectively using lipase and protease as deacylating agents, it is possible to control the position at which the sugar acyl group is eliminated.
一般式(1)、(2)及び(3)中、Bで表わされる置
換又は非fi12換核酸塩も(としてはウラシル、5−
フルオロウラシル、5−トリフルオロメチルウラシル、
5−クロロウラシル、5−ブロモウラシル等の5−r!
!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、ヒポキサンチン等
のプリン塩基を、Rで表わされるアルキル基としては、
メチル、エチル、プロピル、1−プロピル、ブチル、t
−ブチル、ヘキシル、オクチル、デシル、ドデシル、テ
トラデシル、オクタデシル等の炭素数1〜18のアルキ
ル基を、置換フェニル基としては塩素、弗素、アルキル
が置換したフェニル、具体的には0−クロロフェニル、
p−クロロフェニル、0−フルオロフェニル、p−フル
オロフェニル、0−メチルフェニル、鋤−メチルフェニ
ル、p−エチルフェニル、p−ブチルフェニルである。In general formulas (1), (2) and (3), substituted or non-fi12 substituted nucleic acid represented by B (such as uracil, 5-
Fluorouracil, 5-trifluoromethyluracil,
5-r! such as 5-chlorouracil, 5-bromouracil, etc.
! biriminone bases such as uracil, thymine, and cytosine,
Purine bases such as atenine, guanine, xanthine, hypoxanthine, etc. are represented by R as an alkyl group,
Methyl, ethyl, propyl, 1-propyl, butyl, t
- C1-C18 alkyl groups such as butyl, hexyl, octyl, decyl, dodecyl, tetradecyl, octadecyl, substituted phenyl groups include chlorine, fluorine, alkyl-substituted phenyl, specifically 0-chlorophenyl,
p-chlorophenyl, 0-fluorophenyl, p-fluorophenyl, 0-methylphenyl, methylphenyl, p-ethylphenyl, p-butylphenyl.
又、本反応のリパーゼとしては、微生物巾米、動物由来
及び植物由来のものが使用可能である。Furthermore, as the lipase for this reaction, lipases derived from microorganisms, animals, and plants can be used.
微生物の具体的なものとしてはエンテロバクタ−属、ア
ルスロバクタ−属、ブレビバクテリウム属、シュードモ
ナス属、アルカリ土類金属、ミクロフッカス属、クロモ
バクテリウム属、コリネバクテリウム属、バシルス属、
ラクトバシル金属、トリフデルマ属、キャンデイダ属、
サツカロミセス属、ロドトルグ属、クリプトコツカス属
、トルロブンス属、ビヒア属、ペニシリウム属、アスペ
ルギルス属、リゾプス属、ムコール属、オーレオバシデ
イフム属、アクチノムコール属、メカルディア属、スト
レプトミセス属、ハンゼヌラ属、アクロモバクタ−属に
属する微生物が例示できる。これらリパーゼは市販され
ており、代表的なものとしては、豚膵臓リパーゼ(半片
化学)、シュードモナス属のリパーゼP(大野製薬)、
アスペルギルス属のリパーゼAP(大野製薬)、リパー
ゼB(和光純薬)、キヤンヂイグ・ンリンドラツセのリ
パーゼMY(名糖産業)、アルカリ土類金属のリパーゼ
PL(名糖産業)、アクロモバクタ−属のリパーゼAL
(名糖産業)、アルスロバクタ−属のリパーゼ合同BS
L (合同酒製)、クロモバクテリウムのリパーゼ(東
洋醸造)、キャンデイグ(candida cylin
dracea)属のリパーゼ(半片化’F)、リゾプス
・デルマーのタリパーゼく田辺製薬)、リゾプス属のリ
パーゼサイケン(大阪at菌研究所)、植物白米のもの
としてはW l+eaL G rer+m(牛丼化学)
?Pが例示できる。取り分ケ、ンユードモナス フルオ
レッセンス由来のリパーゼP(大野製薬)が好適であっ
た。Specific microorganisms include Enterobacter, Arthrobacter, Brevibacterium, Pseudomonas, alkaline earth metals, Microfuccus, Chromobacterium, Corynebacterium, Bacillus,
Lactobacillus metal, Trifderma sp., Candida sp.
Satucharomyces, Rhodotorgue, Cryptococcus, Torlobus, Vichia, Penicillium, Aspergillus, Rhizopus, Mucor, Aureobasidihum, Actinomucor, Mecardia, Streptomyces, Hansenula Examples include microorganisms belonging to the genus Achromobacter. These lipases are commercially available, and representative examples include porcine pancreatic lipase (Hanka Kagaku), Pseudomonas lipase P (Ohno Pharmaceutical),
Aspergillus lipase AP (Ohno Pharmaceutical Co., Ltd.), lipase B (Wako Pure Chemical Industries), Kyanzig.
(Meito Sangyo), Arthrobacter lipase joint BS
L (Godo Shusei), Chromobacterium lipase (Toyo Jozo), Candida (candida cylin)
lipase of the genus Rhizopus (Tanabe Seiyaku), lipase of the genus Rhizopus (Osaka Atomic Bacteria Research Institute), and lipase of the genus Rhizopus (Osaka Atomic Research Institute); )
? An example is P. Particularly, lipase P derived from Neudomonas fluorescens (Ohno Pharmaceutical Co., Ltd.) was suitable.
又、本反応で使用されるプロテアーゼとしては微生物中
米、動物由来、植物白米のプロテアーゼが使用でさる6
市販されているプロテアーゼとしてはリゾプス・ニベウ
スのニューラーゼF(大野製薬)、アスペルギルス・オ
リザエのプロテアーゼM(大野製薬)、パシルス・サブ
チリスのプロテアーゼN(大野製薬)、アスペルギルス
・メルウスのプロテアーゼP、動物膵臓のバンクレアチ
ンF(大野製薬)、カリパ・パパインのパパインW−4
0(大野製薬)が例示でき、取り分はプロテアーゼNが
好適である。本反応は通常、極性溶媒−水の混合溶媒系
で行う。極性溶媒としては、ツメチルホルムアミド、ピ
リジン、アセトニトリル、ツメチルスルホキシド、アセ
トン等が使用できる。上記混合溶媒系には、通常、pH
を常に一定に保つため、緩衝剤を添加する。本反応の至
適pHは通常、6.5〜7.5、好ましくは6.8〜7
.2であり、緩衝剤としてはこれらpHの範囲内のもの
を使用すれば良い0本反応においては、pH7,0の場
合が最ら良好な結果を与えた。極性溶媒は単一又は、複
数混合して使用できる。水と極性溶媒の混合割合は脱ア
シル化反応に付する化合物の溶解性に応じ適宜選択され
、通常、10〜50%が好ましい。In addition, proteases used in this reaction include proteases from microbial Central Rice, animal origin, and plant white rice.
Commercially available proteases include Rhizopus niveus neurase F (Ohno Pharmaceutical), Aspergillus oryzae protease M (Ohno Pharmaceutical), Pacilus subtilis protease N (Ohno Pharmaceutical), Aspergillus meleus protease P, and animal pancreas. Vancreatin F (Ohno Pharmaceutical), Papain W-4 of Caripa Papain
An example is Protease N (manufactured by Ohno Pharmaceutical Co., Ltd.), and Protease N is preferred. This reaction is usually carried out in a mixed solvent system of polar solvent and water. As the polar solvent, trimethylformamide, pyridine, acetonitrile, trimethylsulfoxide, acetone, etc. can be used. The above mixed solvent system usually has a pH of
A buffer is added to keep it constant. The optimum pH for this reaction is usually 6.5 to 7.5, preferably 6.8 to 7.
.. 2, and in the reaction in which a buffer within these pH ranges could be used, a pH of 7.0 gave the best results. A single polar solvent or a mixture of a plurality of polar solvents can be used. The mixing ratio of water and polar solvent is appropriately selected depending on the solubility of the compound to be subjected to the deacylation reaction, and is usually preferably 10 to 50%.
反応温度は10〜60℃のIl!囲が適用でさ、酵素活
性化の最適温度は25〜35℃である。反応時間は0.
5時間−2日間を要し、好収率で目的物である親アシル
化されたヌクレオシドを得ることができる。リパーゼ及
びプロテアーゼの使用割合はヌクレオシド!(1)1モ
ルに対し20〜300g、好ましくは100〜200F
Kである。The reaction temperature was 10-60°C. The optimum temperature for enzyme activation is 25-35°C. The reaction time is 0.
It takes 5 hours to 2 days, and the desired parent acylated nucleoside can be obtained in good yield. The ratio of lipase and protease used is nucleoside! (1) 20 to 300g per mole, preferably 100 to 200F
It is K.
本反応で得られた化合物は、通常の分離手段、抽出、分
液、濃縮、再結品、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, separation, concentration, reconsolidation, 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
3’、5’−ノへキサメイル−2゛−デオキシウリジン
142u6(0,1m1Iole)を20%ツメチルホ
ルムアミド−0,IM ’J ンRH衝液(pH7,0
) 1 nlニFJ濁11t、次いで、リパーゼP(大
野製薬)40Bを加え、室温で撹拌した。・を時間後、
薄層クロマトグラフィーにより原料のスポットが消失し
たことを確認後、酢酸エチル20艶1を加え抽出した。Example 1 3',5'-Nohexamyl-2'-deoxyuridine 142u6 (0,1ml Iole) was mixed with 20% trimethylformamide-0,IM'J in RH buffer solution (pH 7,0
) 1 nl of FJ suspension 11t and then Lipase P (Ohno Pharmaceutical) 40B were added and stirred at room temperature.・After hours,
After confirming by thin layer chromatography that the spots of the raw material had disappeared, 20 ml of ethyl acetate was added for extraction.
有lfi層を飽和炭酸水素ナトリウム溶液(5k I
X 2 )、飽和食塩水(50+al X 2 )で洗
浄した後、芒硝で乾燥した。有機層を減圧濃縮した後、
シリカゾルカラムクロマトグラフィーにて単離精製する
と目的物である5゛−へキサメイル−2゛−デオキシウ
リジン30mg(収率94%)を得た。The lfi layer was diluted with saturated sodium bicarbonate solution (5k I
X 2 ) and saturated saline (50+al X 2 ), and then dried with Glauber's salt. After concentrating the organic layer under reduced pressure,
Isolation and purification by silica sol column chromatography gave 30 mg (yield 94%) of the target product, 5'-hexamyl-2'-deoxyuridine.
H’ NMR(DMSO−di)
0.95 (3H,3,−CH−)
1.00〜1.70 (6H2I11.(CH2)3
)2.00−2.50 (4H,m、 I
イ − 2 °、 −CH2CO−)3.80〜4
.40(4)(、繭、H−3’、H−4’H−5“)
5.35 (I H,d、 3 ’−0H)5.6
5 (I H,d、 H−5)6.15 (I
H,t、 H−1°)7.82 (I H,d、
H−6)11.40 (I H,s、 N 3
H)実施−例2〜7
実施例1と同様の繰作により下記化合物を得た。H' NMR (DMSO-di) 0.95 (3H,3,-CH-) 1.00-1.70 (6H2I11.(CH2)3
)2.00-2.50 (4H, m, I
i-2°, -CH2CO-)3.80~4
.. 40(4) (, cocoon, H-3', H-4'H-5") 5.35 (I H, d, 3'-0H) 5.6
5 (I H, d, H-5) 6.15 (I
H, t, H-1°) 7.82 (I H, d,
H-6) 11.40 (I H,s, N 3
H) Implementation-Examples 2 to 7 The following compounds were obtained in the same manner as in Example 1.
5°−ブチリル−2°−デオキシウリジン収率90%
)1’−NMR(DMSO−d、)
0.90 (3+4 、 s、 CH3)
1.05〜1.88 (2H、m 、 −CH2−
)2、OO〜2.40 (4H,II、 T−1−2°
、 −C82Co−)4、OO〜4.20 (3H、
論、)(−3’、t」−5’)4.30 (I +
(、lj、 H−4’)5.40<IH,d、3’−
0トI)
5.60 (I H、d、 T(−5)6.15
(I H,L、 H−1’)7.60 <1 1
4. d、 H−6)11.30 (I H,S
、 N 3−H)5′−オクタ/イル−2゛−デオキ
シツリノン収率8296
II”−NMR(DMSO−d6)
0.90 (3H,!i、 −C11,)1.03〜1
.95 (IOH,釦、−(CH2)5−)2.00−
2.60 (489m、H2’、 CH2C0−)3
.85〜4.35 (4H、噂、H−3’、H−4゜H
−5“)
5.40 (I H,d、 3°−0H)5.60 (
I H+ d、H−5)
6.20 (I H,L、 H−1’)7.60 (I
H,d、 H−(i )11.20 (L H,s、
N 3−H)5゛−へキサメイル−2°−デオキシウ
リノン収率84%
!1 ’−N M R(r) M S〇−dS)0.9
0 (3I(、s、 −CI−13)1.80 (3H
、d、 −CI())1.05〜1.60 (G H、
+s、(CI−12)) )2.00〜2.40 (
4H、Ifi、 H−2’、 C)−(□Co−13
,90(I HlL II 4 ’)4.05−4.
25 (3H,m、 ト1− 3 ’、
H−5’)5.39 (I H,d、 3 ’−0H
)6.12 (1f−i、 L、 H−1’)7.40
(l H,d、 H−6)
11.40 (I H,S、 N 3 H)5゛−ヘ
キサフィル−2゛−デオキシ−5−ブロムクリノン
収率67%
H’−NMR(DMSO−d、)
0.95 (3H、stC+−13)
1.10−1.70 (6H2m、(CH2)−)1.
95〜2.50 (4H、J l−(−2°、−C
1(、C0−)3.85〜4.25 (4H,ua、
H−3’、H4’H−5°)
5.45 (I II、 d、 3 ’−〇l−
()6.15 (I II、 L、 H−1’)
7.60 (1tl、 d、 H−6)11.4
5 (I H,st N 3−H)5゛−へキサメ
イル−2゛−デオキシ−5−フルオロウリジン
収率92%
H’−NMR(DMSO−d、)
0.92 (3H、m、CHd
l、00〜1.70 (G I(、J −(CH2)p
−)2.05〜2.40 (4H,1m、H−2’、
−C82CO)4.00〜4.20(3H,鎮、H
−3’、H−5°)3.90 (I H、論、H−61
)
5.40 (I H,b、 3 ’−OH)6.10
(I H,L、 H−1’)7.80 (I H、d、
HG )
11.70 (I H、bs+ N 3+()5°−へ
キサメイル−2°−デオキシアゾ7シン収率72%
H’−NMR(DMSO−d、)
0.98 (3H、s、 −CH))1.00〜1
.70 (G H,n−(CH2)) )2.05
〜2.45 (4H,+II、H2°、−CH2C0
−)3.90〜4,40 (41−1、In、H−3
°、)(−,1’H−5’)
5.28 (I H,d、 3 ’−〇H)6.1
0 (I H,t、 +−1−1’)7.30
(2H、s、N H2)
8.12 (I H,s、 c−8)8.31
(I H2St C2)実施例8
3°、5°−ノへキサ/イル−2゛−デオキシウリノン
142mg(0,1m+6ole)を20%ツメチルホ
ルムアミド−Oj、Mリン酸緩衝液(pH7,0) 1
mlに懸濁させ、次いで、プロテアーゼN(大野製薬
)40mgを加え、室温で撹拌した。・を時間後、薄層
クロマトグラフィーにより原料のスポットが消失したこ
とを確認後、酢酸エナル20+alを加え抽出した。有
8!層を飽和炭酸水素す) l)ラム溶液(5klX2
)、飽和食塩水(50【ΩI×2)で洗浄した後、芒硝
で乾燥した。a成層を減圧濃縮した後、シリカゾルカラ
ムクロマトグラフィーにて単離精製すると目的物である
3゛−へキサメイル−2゛−デオキンウリジン31+n
H(収率96%)を得た。5°-Butyryl-2°-deoxyuridine Yield 90%) 1'-NMR (DMSO-d,) 0.90 (3+4, s, CH3)
1.05-1.88 (2H, m, -CH2-
)2, OO~2.40 (4H, II, T-1-2°
, -C82Co-)4,OO~4.20 (3H,
theory, ) (-3', t''-5') 4.30 (I +
(,lj, H-4')5.40<IH,d,3'-
0 to I) 5.60 (I H, d, T(-5) 6.15
(I H, L, H-1') 7.60 <1 1
4. d, H-6) 11.30 (I H, S
, N3-H) 5'-octa/yl-2'-deoxyturinone Yield 8296 II''-NMR (DMSO-d6) 0.90 (3H,!i, -C11,) 1.03-1
.. 95 (IOH, button, -(CH2)5-)2.00-
2.60 (489m, H2', CH2C0-)3
.. 85~4.35 (4H, rumor, H-3', H-4゜H
-5") 5.40 (I H, d, 3°-0H) 5.60 (
I H+ d, H-5) 6.20 (I H, L, H-1') 7.60 (I
H,d, H-(i)11.20 (L H,s,
N3-H) 5'-hexamyl-2'-deoxyurinone yield 84%! 1'-NMR(r)MS〇-dS)0.9
0 (3I(,s, -CI-13)1.80 (3H
, d, -CI()) 1.05-1.60 (G H,
+s, (CI-12)) )2.00~2.40 (
4H, Ifi, H-2', C)-(□Co-13
, 90 (I HIL II 4') 4.05-4.
25 (3H, m, t1-3',
H-5') 5.39 (I H, d, 3'-0H
)6.12 (1f-i, L, H-1')7.40
(l H, d, H-6) 11.40 (I H, S, N 3 H) 5'-hexaphyll-2'-deoxy-5-bromocrinone Yield 67% H'-NMR (DMSO-d, ) 0.95 (3H, stC+-13) 1.10-1.70 (6H2m, (CH2)-)1.
95-2.50 (4H, J l-(-2°, -C
1(, C0-) 3.85-4.25 (4H, ua,
H-3', H4'H-5°) 5.45 (I II, d, 3'-〇l-
()6.15 (I II, L, H-1')
7.60 (1tl, d, H-6) 11.4
5 (I H, st N 3-H) 5'-hexamyl-2'-deoxy-5-fluorouridine Yield 92% H'-NMR (DMSO-d,) 0.92 (3H, m, CHd l ,00~1.70 (GI(,J-(CH2)p
-)2.05~2.40 (4H, 1m, H-2',
-C82CO) 4.00-4.20 (3H, Chin, H
-3', H-5°) 3.90 (I H, theory, H-61
) 5.40 (I H, b, 3'-OH) 6.10
(I H, L, H-1') 7.80 (I H, d,
HG) 11.70 (I H, bs+ N 3+ () 5°-hexamethyl-2°-deoxyazo7sine yield 72% H'-NMR (DMSO-d,) 0.98 (3H, s, -CH )) 1.00~1
.. 70 (GH, n-(CH2)) )2.05
~2.45 (4H, +II, H2°, -CH2C0
-) 3.90 to 4,40 (41-1, In, H-3
°, ) (-, 1'H-5') 5.28 (I H, d, 3'-〇H) 6.1
0 (I H, t, +-1-1')7.30
(2H, s, N H2) 8.12 (I H, s, c-8) 8.31
(I H2St C2) Example 8 142 mg (0,1m+6ole) of 3°, 5°-nohex/yl-2′-deoxyurinone was added to 20% trimethylformamide-Oj, M phosphate buffer (pH 7,0 ) 1
ml, and then 40 mg of Protease N (Ohno Pharmaceutical Co., Ltd.) was added and stirred at room temperature.・After confirming by thin layer chromatography that the spot of the raw material had disappeared, enal acetate 20+al was added for extraction. There are 8! 1) Rum solution (5 kl x 2
), washed with saturated saline (50 [ΩI x 2), and dried with Glauber's salt. After concentrating the a layer under reduced pressure, the target product 3'-hexamyl-2'-deokyneuridine 31+n was isolated and purified by silica sol column chromatography.
H (yield 96%) was obtained.
+1’−NMR(DMSO−d、)
0.92 (3H、III、CH、)
1.001,70 (G II、 m、
(CH2)3 )2.00〜28.iQ
(4I−1、噴、 )l−2’、 −C
H2CO−)3.50〜3.65 (3t(、IIl、
H4°、H−5°)5.35 (IH,bs、 H−
3’)5.20 (I H9bs、5 ’ Ol−1
)5.65(1トf、 d、 H−5)6.1
2 (I H,L、 Il −1’)7.85 (J
H,d、 H−6)
Il、30 (I H,S、 N 3−1−1)実施例
9〜12
以下、実施例8と同様の操作により下記の化会物を製造
した。+1'-NMR (DMSO-d,) 0.92 (3H, III, CH,) 1.001,70 (G II, m,
(CH2)3)2.00~28. iQ
(4I-1, jet, )l-2', -C
H2CO-)3.50-3.65 (3t(, IIl,
H4°, H-5°) 5.35 (IH, bs, H-
3') 5.20 (I H9bs, 5' Ol-1
) 5.65 (1t f, d, H-5) 6.1
2 (I H, L, Il -1') 7.85 (J
H, d, H-6) Il, 30 (I H, S, N 3-1-1) Examples 9 to 12 The following compounds were produced in the same manner as in Example 8.
3°−ヘキサフィル−2゛−デオキシチミノン収率86
%
H’−NMR(DMSO−c16)
0.90 (3H,s、CI+z)
1.00−1.68 (G H、In、 −(CH□)
3− )1.82 (3+(、d、 −CI−(、)2
.05〜2.60(4F(、w、H−2°、 −C
I−1、CO−)3.60〜3.70 (31−(、鋤
、H−4’、H−5’)5.30 (I H,bS、
H−3’)5.10 (I H,L、 5’−0H)6
.15 (1)(、t、 H−1’)7.60 (I
H,d、 H−6)
11.40 (1,Hls、 N 3 )()3゛−
ヘキサ/イル−2゛−デオキシ−5−フルオロウリノン
収率88%
H’−NMR(DMSO−d、)
0.85 (314、s、CH3)
1.00〜1.80 (6H、誦、−(CH,)、−)
2.052.60 (4H9m、H2’、 CH2
C0)3.80〜4.10 (3H,J H4’、
l−15’)5.10 (1)(、b、 H−
3°)5.15 (111,t、 5 ’−
0H)6.10 (I H,L、 H−1’)7
.77 (l H,d、 H−6)11.6
5 (I I−1,bs、 N 3−14)2’、
3’−ノへキサメイル−5−フルオロウリノン収率40
%
1(’−NMR(DMSOda)
0.82.0.85 (6t−1、S、 CI−(3
)1.00〜1.80 (12H1I11. (CH
2)、)2、OO〜 2.40 (41−1、鵠、!
(−2°、 −CH2CO−)3.60 (2H,
b、 H−5’)
4.05 (I H2b+ H4’)
5.20〜5.50 (3H,m、 H−2°、H−3
’5’O)+)
5.70 (I H,d、 H−5)
6.00 (I H,d、 H−1’)7.85 (I
H,d、 H−61
11,28(I H,s、 N 3 H)3°−ヘキ
サ/イル−2°−デオキシアゾ/シン収率82%
H’−NMR(DMSO−d6)
0.90 (3H、s、CHz)
1.03〜1.75 (6H,In、 (c+−12
)) )2.00〜2.45 (4H+ u+、H2
’、Cl−12co )3.70〜3.85(3H,
城、H−4”、H−5’)5.28 (I H,b、
H−3’)5.20 (5’−OH)
6.15 (I H,t、 H−1’)7.3]、 (
2H= s、N H2)8.14 (I H,s、 l
−[−8)8.32(IH,s、 H−2)
(以 上)
出 願 人 大鵬薬品工業株式会社
代 理 人 弁理士 1)村 巌
手
続
補
正置
平成元年10月 6 日
昭和63年特許願第222059号
発明の名称
ヌクレオシド類の脱アシル化方法
3、補正をする者
事件との関係 特許出願人
大鵬薬品工業株式会社
7、補正の内容
(1)明細書中温9頁第13行
「4時間後」を「24時間後」に訂正します。3°-hexaphyll-2′-deoxythyminone yield 86
% H'-NMR (DMSO-c16) 0.90 (3H, s, CI+z) 1.00-1.68 (GH, In, -(CH□)
3- )1.82 (3+(,d, -CI-(,)2
.. 05~2.60(4F(, w, H-2°, -C
I-1, CO-) 3.60-3.70 (31-(, plow, H-4', H-5') 5.30 (I H, bS,
H-3')5.10 (I H, L, 5'-0H)6
.. 15 (1)(,t, H-1')7.60 (I
H, d, H-6) 11.40 (1, Hls, N 3 ) ()3゛-
Hexa/yl-2'-deoxy-5-fluorourinone Yield 88% H'-NMR (DMSO-d,) 0.85 (314, s, CH3) 1.00-1.80 (6H, recited, -(CH,),-)
2.052.60 (4H9m, H2', CH2
C0) 3.80-4.10 (3H, J H4',
l-15')5.10 (1)(, b, H-
3°) 5.15 (111,t, 5'-
0H) 6.10 (I H, L, H-1') 7
.. 77 (l H, d, H-6) 11.6
5 (I I-1, bs, N 3-14) 2',
3'-Nohexamyl-5-fluorourinone yield 40
% 1('-NMR(DMSOda) 0.82.0.85 (6t-1, S, CI-(3
)1.00~1.80 (12H1I11. (CH
2),)2,OO~ 2.40 (41-1, Mouse,!
(-2°, -CH2CO-)3.60 (2H,
b, H-5') 4.05 (I H2b+ H4') 5.20-5.50 (3H, m, H-2°, H-3
'5'O)+) 5.70 (I H, d, H-5) 6.00 (I H, d, H-1') 7.85 (I
H, d, H-61 11,28 (I H, s, N 3 H) 3°-hexa/yl-2°-deoxyazo/syn Yield 82% H'-NMR (DMSO-d6) 0.90 ( 3H, s, CHz) 1.03 to 1.75 (6H, In, (c+-12
)) )2.00~2.45 (4H+ u+, H2
', Cl-12co) 3.70-3.85 (3H,
Castle, H-4", H-5') 5.28 (I H, b,
H-3') 5.20 (5'-OH) 6.15 (I H, t, H-1') 7.3], (
2H= s, N H2) 8.14 (I H, s, l
-[-8) 8.32 (IH, s, H-2) (and above) Applicant Taiho Pharmaceutical Co., Ltd. Agent Patent attorney 1) Iwao Mura procedural amendment dated October 6, 1989, 1988 Patent Application No. 222059 Name of the invention Method for deacylation of nucleosides 3 Relationship with the case by the person making the amendment Patent applicant Taiho Pharmaceutical Co., Ltd. 7 Contents of the amendment (1) Specification Nakaon page 9 line 13 Correct "4 hours later" to "24 hours later".
(2)明細書中温14真下から第3行 「4時間後」を「24時間後」に訂正します。(2) 3rd line from right below 14 on the statement Correct "4 hours later" to "24 hours later".
(3)明細書中温18頁第9行
[5,20(5°−0H)Jを
「5,20 (I H,L、 5 ’−0H)Jに訂
正します。(3) In the specification, page 18, line 9 [5, 20 (5°-0H) J is corrected to "5, 20 (I H, L, 5'-0H) J.
4、代 埋入 〒530大阪府大阪市北区曽根崎1丁目2番8号(以 上)4, generation implantation Address: 1-2-8 Sonezaki, Kita-ku, Osaka-shi, Osaka 530 (hereinafter referred to as Up)
Claims (1)
原子又は−OCORを、Rはアルキル基、又は置換又は
非置換のフエニル基を示す。)で表わされるヌクレオシ
ド類をリパーゼ又はプロテアーゼと反応させ、一般式 ▲数式、化学式、表等があります▼ (式中、R_2は水素原子又は水酸基を、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又は一般式 ▲数式、化学式、表等があります▼ (式中、B、R_1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ヌクレオシ
ド類の脱アシル化方法。(1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, B is a substituted or unsubstituted nucleobase, R_1 is a hydrogen atom or -OCOR, R is an alkyl group, or a substituted or unsubstituted phenyl The nucleosides represented by (representing a group) are reacted with lipase or protease, and the general formula ▲ has a mathematical formula, chemical formula, table, etc. ▼ (where R_2 is a hydrogen atom or a hydroxyl group, and B and R are the same as above). Compounds or general formulas (indicating meanings) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formulas, B, R_1 and R have the same meanings as above)
A method for deacylating nucleosides, which leads to a compound represented by:
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP22205988A JPH0269191A (en) | 1988-09-05 | 1988-09-05 | Deacylation of nucleosides |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP22205988A JPH0269191A (en) | 1988-09-05 | 1988-09-05 | Deacylation of nucleosides |
Publications (1)
Publication Number | Publication Date |
---|---|
JPH0269191A true JPH0269191A (en) | 1990-03-08 |
Family
ID=16776460
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP22205988A Pending JPH0269191A (en) | 1988-09-05 | 1988-09-05 | Deacylation of nucleosides |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH0269191A (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0894868A3 (en) * | 1997-07-31 | 1999-04-21 | Sumitomo Chemical Company, Limited | Process for producing nucleoside derivatives |
WO2005111056A1 (en) * | 2004-05-19 | 2005-11-24 | Fundacja Rozwoju Diagnostyki I Terapii | New esters of adenosine nucleosides and carboxylic acid |
-
1988
- 1988-09-05 JP JP22205988A patent/JPH0269191A/en active Pending
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0894868A3 (en) * | 1997-07-31 | 1999-04-21 | Sumitomo Chemical Company, Limited | Process for producing nucleoside derivatives |
WO2005111056A1 (en) * | 2004-05-19 | 2005-11-24 | Fundacja Rozwoju Diagnostyki I Terapii | New esters of adenosine nucleosides and carboxylic acid |
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