CN114835765B - Synthesis process of 2' -O- (2-methoxyethyl) guanosine - Google Patents
Synthesis process of 2' -O- (2-methoxyethyl) guanosine Download PDFInfo
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- CN114835765B CN114835765B CN202210789007.0A CN202210789007A CN114835765B CN 114835765 B CN114835765 B CN 114835765B CN 202210789007 A CN202210789007 A CN 202210789007A CN 114835765 B CN114835765 B CN 114835765B
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- DLLBJSLIKOKFHE-WOUKDFQISA-N 2-amino-9-[(2r,3r,4r,5r)-4-hydroxy-5-(hydroxymethyl)-3-(2-methoxyethoxy)oxolan-2-yl]-3h-purin-6-one Chemical compound COCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=C(N)NC2=O)=C2N=C1 DLLBJSLIKOKFHE-WOUKDFQISA-N 0.000 title claims abstract description 61
- 238000000034 method Methods 0.000 title claims abstract description 42
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 16
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 15
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 claims abstract description 94
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 claims abstract description 47
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 claims abstract description 47
- 229940029575 guanosine Drugs 0.000 claims abstract description 47
- 239000002168 alkylating agent Substances 0.000 claims abstract description 22
- 229940100198 alkylating agent Drugs 0.000 claims abstract description 22
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 60
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 39
- 238000006243 chemical reaction Methods 0.000 claims description 36
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 30
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 21
- 239000002585 base Substances 0.000 claims description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 17
- YZUPZGFPHUVJKC-UHFFFAOYSA-N 1-bromo-2-methoxyethane Chemical compound COCCBr YZUPZGFPHUVJKC-UHFFFAOYSA-N 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 15
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 11
- 239000003054 catalyst Substances 0.000 claims description 11
- 229910052740 iodine Inorganic materials 0.000 claims description 11
- 239000011630 iodine Substances 0.000 claims description 11
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 11
- XTIGGAHUZJWQMD-UHFFFAOYSA-N 1-chloro-2-methoxyethane Chemical group COCCCl XTIGGAHUZJWQMD-UHFFFAOYSA-N 0.000 claims description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- SZCAORBAQHOJQI-UHFFFAOYSA-N 1-iodo-2-methoxyethane Chemical compound COCCI SZCAORBAQHOJQI-UHFFFAOYSA-N 0.000 claims description 7
- TZXJJSAQSRHKCZ-UHFFFAOYSA-N 2-methoxyethyl 4-methylbenzenesulfonate Chemical compound COCCOS(=O)(=O)C1=CC=C(C)C=C1 TZXJJSAQSRHKCZ-UHFFFAOYSA-N 0.000 claims description 7
- BCKAHDGFNHDQST-UHFFFAOYSA-N 2-methoxyethyl methanesulfonate Chemical compound COCCOS(C)(=O)=O BCKAHDGFNHDQST-UHFFFAOYSA-N 0.000 claims description 7
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 7
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 6
- 230000002152 alkylating effect Effects 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 239000012043 crude product Substances 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- DKGAYXWJBJGWDS-UHFFFAOYSA-N COCCOS(=O)(=O)C1=CC=C(C=C1)Cl Chemical compound COCCOS(=O)(=O)C1=CC=C(C=C1)Cl DKGAYXWJBJGWDS-UHFFFAOYSA-N 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 claims description 3
- 239000012295 chemical reaction liquid Substances 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- 235000009518 sodium iodide Nutrition 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 abstract description 12
- 239000002994 raw material Substances 0.000 abstract description 12
- 230000029936 alkylation Effects 0.000 abstract description 7
- 238000005804 alkylation reaction Methods 0.000 abstract description 7
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000010189 synthetic method Methods 0.000 abstract 1
- 239000000047 product Substances 0.000 description 22
- 238000004128 high performance liquid chromatography Methods 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 239000003814 drug Substances 0.000 description 8
- 108020004707 nucleic acids Proteins 0.000 description 7
- 150000007523 nucleic acids Chemical class 0.000 description 7
- 102000039446 nucleic acids Human genes 0.000 description 7
- 239000012065 filter cake Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 230000002194 synthesizing effect Effects 0.000 description 6
- 238000001035 drying Methods 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000002773 nucleotide Substances 0.000 description 5
- 125000003729 nucleotide group Chemical group 0.000 description 5
- 108091034117 Oligonucleotide Proteins 0.000 description 4
- 239000000074 antisense oligonucleotide Substances 0.000 description 4
- 238000012230 antisense oligonucleotides Methods 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- 229940079593 drug Drugs 0.000 description 3
- 239000002777 nucleoside Substances 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- 108020000948 Antisense Oligonucleotides Proteins 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
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- 125000003835 nucleoside group Chemical group 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- ZDTFMPXQUSBYRL-UUOKFMHZSA-N 2-Aminoadenosine Chemical compound C12=NC(N)=NC(N)=C2N=CN1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O ZDTFMPXQUSBYRL-UUOKFMHZSA-N 0.000 description 1
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 101710169336 5'-deoxyadenosine deaminase Proteins 0.000 description 1
- 102000055025 Adenosine deaminases Human genes 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 102000004533 Endonucleases Human genes 0.000 description 1
- 108010042407 Endonucleases Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 108060002716 Exonuclease Proteins 0.000 description 1
- 238000010268 HPLC based assay Methods 0.000 description 1
- 208000026350 Inborn Genetic disease Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006477 desulfuration reaction Methods 0.000 description 1
- 230000023556 desulfurization Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 102000013165 exonuclease Human genes 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 208000016361 genetic disease Diseases 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000002515 oligonucleotide synthesis Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- DMHSCCFHYJAXNG-UHFFFAOYSA-N sodium;bis(trimethylsilyl)azanide;oxolane Chemical compound [Na+].C1CCOC1.C[Si](C)(C)[N-][Si](C)(C)C DMHSCCFHYJAXNG-UHFFFAOYSA-N 0.000 description 1
- IYGPXXORQKFXCZ-UHFFFAOYSA-N tris(2-methoxyethyl) borate Chemical compound COCCOB(OCCOC)OCCOC IYGPXXORQKFXCZ-UHFFFAOYSA-N 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/167—Purine radicals with ribosyl as the saccharide radical
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- 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
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Abstract
The invention discloses a synthesis process of 2' -O- (2-methoxyethyl) guanosine, which comprises the following steps: guanosine is reacted with an alkylating agent in a reaction solvent in the presence of a base to produce 2' -O- (2-methoxyethyl) guanosine. The synthetic method of the invention avoids O on the basic group 6 Alkylation improves the product yield, has short preparation steps, high synthesis efficiency, simple and convenient operation, easily obtained raw materials and low requirement on equipment, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of chemical synthesis, and particularly relates to a synthesis process of 2' -O- (2-methoxyethyl) guanosine.
Background
Gene therapy is one of the leading technologies at present, and has continuously made breakthrough progress in the treatment of tumors, genetic diseases, metabolic diseases, prevention of infectious diseases, and the like. Among them, the small nucleic acid drug is one of the most rapidly developed gene therapies at present, and is outstanding in the third wave of new drug development. In the future, with continuous breakthrough and innovation in the application field and the technical field of small nucleic acid drugs, the technology updating will contribute to the development of small nucleic acid drugs, and the market demand and the market scale will be continuously expanded.
Antisense oligonucleotides (ASOs) are an emerging class of small nucleic acid drugs with high selectivity and affinity properties. Recently, with the development of the gene group medicine, the antisense oligonucleotide medicine is developed rapidly, with the second generation antisense oligonucleotide medicine deep research, people find in nucleotide introduction 2 '-O-alkyl nucleoside, can enhance with RNA affinity, enhance oligonucleotide to endonuclease and exonuclease resistance, this again with 2' -O-methoxyethyl effect is superior. Therefore, 2' -O- (2-methoxyethyl) guanosine has important market prospect in the field of medicine.
Heretofore, there have been mainly used the following methods for producing 2' -O- (2-methoxyethyl) guanosine.
The preparation method of 2' -O- (2-methoxyethyl) guanosine disclosed in US20080234475 A1 comprises the following reaction equation:
the first step in the process uses tris (2-methoxyethyl) borate as the alkylating agent, the reaction is very water demanding and is a high temperature reaction. The second step of desulfurization by using Raney nickel has higher requirements on production equipment and has great problems on production safety and environmental protection. In addition, the method has the advantages of fewer raw material suppliers, high price and no contribution to industrial production.
2. The preparation method of 2' -O- (2-methoxyethyl) guanosine disclosed in WO 2003087053A 2 has the following reaction equation:
the first step in the process was the use of MDPSCl 2 As protecting group, protecting hydroxyl group at 3 'and 5', reacting in the presence of NaHMDS and TBAI by using 2-bromoethyl methyl ether as alkylating reagent, and deprotecting with tetrabutylammonium fluoride in the third step. The disadvantages of this method are: MDPSCl 2 The protecting group is not yet industrialized and is expensive, so that it cannot be commercially used. And tetrabutylammonium fluoride is difficult to completely remove when purifying the final product.
3. “PROCESS RESEARCH ON THE PREPARATION OF DMT PROTECTED 2'-O-METHOXYETHYLGUANOSINE FOR OLIGONUCLEOTIDE SYNTHESIS IN THERAPEUTIC APPLICATIONS”, Shabbir Ali S. Taj, et al.,Nucleosides, nucleotides and Nucleic Acids, 27 (9): 1024-1033, 2008 discloses a method for preparing 2' -O- (2-methoxyethyl) guanosine, which has the following reaction equation:
in the method, 2-aminoadenosine is used as a starting material to react with 2-bromoethyl methyl ether in the presence of KOH to generate an intermediate product in the first step, and adenosine deaminase is used as the intermediate product to react in a sodium phosphate buffer solution to generate 2' -O- (2-methoxyethyl) guanosine in the second step. The disadvantages of this method are: the conditions of the second step are harsh, and the raw materials are expensive, so that the method is not beneficial to industrial large-scale production.
IN addition, THE above-mentioned prior art "PROCESSS RESONARCH ON THE PREPARTATION OF DMT PROCESSED 2' -O-METHOXYTHYLGLUTANONE FOR OLIGONUCLEOTIDE SYNTHESISS IN THERAPEUTIC APPLICATIONS", shabbir Ali S. Taj,et al.,it is also mentioned in Nucleosides, nucleotides and Nucleic Acids, 27 (9): 1024-1033, 2008 that direct alkylation of guanosine is undesirable because direct alkylation results in partial alkylation of the majority of the product as bases (O) 6 Alkylated) product, which is a by-product, so the document abandons the synthesis of 2'-O- (2-methoxyethyl) guanosine by direct alkylation of 2' -O thereon using guanosine as starting material.
Therefore, the preparation method which is suitable for industrial production, has low requirements on equipment, is easy to obtain raw materials and can obtain high-purity 2' -O- (2-methoxyethyl) guanosine is urgently needed in the field.
Disclosure of Invention
In order to solve the problems in the prior art, the invention aims to provide a synthesis process of 2'-O- (2-methoxyethyl) guanosine, guanosine is used as a raw material to prepare the 2' -O- (2-methoxyethyl) guanosine through one-step reaction, and the synthesis process has the advantages of cheap and easily available raw material, high production efficiency, simple process, easy amplification production and low requirement on equipment. In order to realize the purpose of the invention, the invention adopts the following technical scheme:
a synthesis process of 2' -O- (2-methoxyethyl) guanosine shown in a formula II comprises the following steps: guanosine shown in the formula I and an alkylating reagent react in a reaction solvent in the presence of alkali to generate 2' -O- (2-methoxyethyl) guanosine shown in the formula II, and the reaction equation is as follows:
preferably, in step (I), the molar ratio of guanosine represented by formula I to the alkylating agent is 1:1 to 1:10, more preferably 1:1 to 1:2, most preferably 1 to 1:1.5.
preferably, in step (I), the molar ratio of guanosine represented by formula I to the base is 1:1 to 1:10, more preferably 1:1 to 1:4, most preferably 1 to 1:3.
preferably, the volume molar ratio of the reaction solvent to the guanosine represented by the formula I in the step (I) is 5 to 50L/mol, more preferably 15 to 25L/mol.
Preferably, the reaction temperature in step (i) is from 10 to 100 ℃.
Preferably, the alkylating agent is selected from 2-chloroethyl methyl ether, 2-bromoethyl methyl ether, 2-iodoethyl methyl ether, 2-methoxyethyl methanesulfonate, 2-methoxyethyl p-toluenesulfonate or 2-methoxyethyl p-chlorobenzenesulfonate.
Preferably, when the alkylating agent is selected from 2-chloroethyl methyl ether or 2-bromoethyl methyl ether, the reaction system further comprises an iodine catalyst.
Preferably, the iodine catalyst is selected from one or more of potassium iodide, sodium iodide and tetrabutylammonium iodide.
Preferably, the base is selected from one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, butyllithium, sodium tert-butoxide, potassium tert-butoxide and sodium bis (trimethylsilyl) amide.
Preferably, the reaction solvent is selected from one or more of dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone, and more preferably is dimethyl sulfoxide.
Preferably, step (i) further comprises, after the reaction is completed, treating the reaction solution, wherein treating the reaction solution comprises: and cooling the reaction liquid to 5-40 ℃, adding a poor solvent, stirring for 0.5-2 hours, and filtering or centrifuging to obtain a 2' -O- (2-methoxyethyl) guanosine crude product.
Preferably, the above poor solvent is selected from one or more of acetonitrile, propionitrile, butyronitrile, dichloromethane, tetrahydrofuran, methyl tert-butyl ether, acetone and ethyl acetate, more preferably acetonitrile.
Preferably, the volume molar ratio of the poor solvent to the guanosine represented by the formula I is from 30 to 300L/mol, more preferably from 50 to 150L/mol.
Drawings
FIG. 1 is an HPLC chromatogram of 2' -O- (2-methoxyethyl) guanosine obtained in example 1.
FIG. 2 is a HNMR map of 2' -O- (2-methoxyethyl) guanosine obtained in example 1.
FIG. 3 is an HPLC chromatogram of 2' -O- (2-methoxyethyl) guanosine obtained in example 2.
FIG. 4 is an HPLC chromatogram of 2' -O- (2-methoxyethyl) guanosine obtained in example 3.
FIG. 5 is an HPLC chromatogram of 2' -O- (2-methoxyethyl) guanosine obtained in example 4.
FIG. 6 is an HPLC chromatogram of 2' -O- (2-methoxyethyl) guanosine obtained in example 5.
FIG. 7 is an HPLC chromatogram of 2' -O- (2-methoxyethyl) guanosine obtained in example 6.
Detailed Description
Aiming at the defects of the preparation method of 2'-O- (2-methoxyethyl) guanosine in the prior art, the inventor of the application finds that the target product can be prepared by directly carrying out alkylation on 2' -O by taking guanosine as a raw material through deep research, and the method has the advantages of easily available raw materials and simple process, and is suitable for industrial large-scale production. The present invention has been completed on the basis of this finding.
In the invention, the synthesis process of 2' -O- (2-methoxyethyl) guanosine comprises the following steps: guanosine is reacted with an alkylating reagent in a reaction solvent in the presence of a base to form 2' -O- (2-methoxyethyl) guanosine according to the following reaction equation:
in the synthesis method of the present invention, the amount of the alkylating agent may be the amount conventionally used in the art for carrying out such reactions, and preferably, the molar ratio of guanosine represented by the formula I to the alkylating agent is 1:1 to 1:10, more preferably 1:1 to 1:2. the amount of base may be that conventionally used in the art for such reactions, and preferably the molar ratio of guanosine to base represented by formula I is 1:1 to 1:10, more preferably 1:1 to 1:3. the amount of the reaction solvent used is such that the reaction raw material can be completely dissolved at the reaction temperature, and the volume molar ratio of the reaction solvent to the guanosine represented by the formula I is preferably 5 to 50L/mol.
In the synthesis process of the present invention, the alkylating reagent includes, but is not limited to, 2-chloroethyl methyl ether, 2-bromoethyl methyl ether, 2-iodoethyl methyl ether, 2-methoxyethyl methanesulfonate, 2-methoxyethyl p-toluenesulfonate or 2-methoxyethyl p-chlorobenzenesulfonate. Bases include, but are not limited to, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, butyllithium, sodium tert-butoxide, potassium tert-butoxide, or sodium bis (trimethylsilyl) amide. The reaction solvent includes, but is not limited to, dimethylsulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, or N-methylpyrrolidone.
In one embodiment of the present invention, the reaction system of step (i) comprises: guanosine, an alkylating agent selected from 2-bromoethyl methyl ether, a base selected from sodium bis (trimethylsilyl) amide, an iodine catalyst selected from tetrabutylammonium iodide, and a solvent selected from DMF. In one embodiment of the present invention, the process for synthesizing 2' -O- (2-methoxyethyl) guanosine comprises the following steps: guanosine is reacted with 2-bromoethyl methyl ether in a reaction solvent in the presence of sodium bis (trimethylsilyl) amide and tetrabutylammonium iodide at 10 to 40 ℃, more preferably 15 to 35 ℃ for 5 to 7 hours to produce 2' -O- (2-methoxyethyl) guanosine.
In one embodiment of the present invention, the reaction system of step (i) comprises: guanosine, an alkylating agent selected from 2-bromoethyl methyl ether, a base selected from potassium hydroxide, an iodine catalyst selected from potassium iodide, and a solvent selected from DMSO. In one embodiment of the present invention, the process for synthesizing 2' -O- (2-methoxyethyl) guanosine comprises the following steps: guanosine is reacted with 2-bromoethyl methyl ether in a reaction solvent in the presence of potassium hydroxide and potassium iodide at 40 to 80 ℃, preferably 50 to 70 ℃ for 2 to 4 hours to produce 2' -O- (2-methoxyethyl) guanosine.
In one embodiment of the present invention, the reaction system of step (i) comprises: guanosine, an alkylating agent selected from 2-chloroethyl methyl ether, a base selected from potassium hydroxide, an iodine catalyst selected from potassium iodide, and a solvent selected from DMSO. In one embodiment of the present invention, the process for synthesizing 2' -O- (2-methoxyethyl) guanosine comprises the following steps: guanosine is reacted with 2-chloroethyl methyl ether in a reaction solvent in the presence of potassium hydroxide and potassium iodide at 50 to 80 ℃, preferably 60 to 70 ℃ for 15 to 24 hours to produce 2' -O- (2-methoxyethyl) guanosine.
In one embodiment of the present invention, the reaction system of step (i) comprises: guanosine, an alkylating agent selected from 2-iodoethyl methyl ether, a base selected from sodium hydroxide, and a solvent selected from DMSO. In one embodiment of the present invention, the process for synthesizing 2' -O- (2-methoxyethyl) guanosine comprises the following steps: guanosine is reacted with 2-iodoethyl methyl ether in a reaction solvent in the presence of potassium hydroxide and sodium iodide at 10 to 40 ℃, preferably 15 to 25 ℃, for 15 to 24 hours, thereby producing 2' -O- (2-methoxyethyl) guanosine.
In one embodiment of the present invention, the reaction system of step (i) comprises: guanosine, an alkylating agent selected from 2-methoxyethyl methanesulfonate, a base selected from sodium tert-butoxide, and a solvent selected from DMSO. In one embodiment of the present invention, the process for synthesizing 2' -O- (2-methoxyethyl) guanosine comprises the following steps: guanosine is reacted with 2-methoxyethyl methanesulfonate in a reaction solvent in the presence of sodium tert-butoxide at 10 to 40 ℃, more preferably at 15 to 25 ℃ for 15 to 24 hours to produce 2' -O- (2-methoxyethyl) guanosine.
In one embodiment of the present invention, the reaction system of step (i) comprises: guanosine, an alkylating agent selected from 2-methoxyethyl tosylate, a base selected from sodium bis (trimethylsilyl) amide, and a solvent selected from DMF. In one embodiment of the present invention, the process for synthesizing 2' -O- (2-methoxyethyl) guanosine comprises the following steps: guanosine is reacted with 2-methoxyethyl tosylate in a reaction solvent in the presence of sodium bis (trimethylsilyl) amide at 10 to 40 ℃, more preferably 15 to 25 ℃ for 15 to 24 hours to produce 2' -O- (2-methoxyethyl) guanosine.
In the synthesis method of the present invention, whether the reaction is completed or not can be monitored by a method commonly used in the art, for example, TLC, HPLC, or NMR. The time when the raw material guanosine disappears is taken as the reaction end point.
In the synthesis process of the present invention, the reaction temperature depends on the nature of the reagents used to carry out the alkylation. The reaction temperature is 10 to 100 ℃.
In the synthesis method of the present invention, the step (i) further comprises treating the reaction solution after the reaction is completed, wherein the treating the reaction solution comprises: cooling the reaction liquid to 5 to 40 ℃, preferably 15 to 35 ℃, adding a poor solvent, stirring for 0.5 to 2 hours, and filtering or centrifuging to obtain a 2' -O- (2-methoxyethyl) guanosine crude product. The poor solvent includes, but is not limited to, acetonitrile, propionitrile, butyronitrile, dichloromethane, tetrahydrofuran, methyl tert-butyl ether, acetone or ethyl acetate, more preferably acetonitrile. The amount of the poor solvent is such that the product can be sufficiently precipitated from the reaction solvent, and the volume molar ratio of the poor solvent to the guanosine represented by the formula I is preferably from 30 to 300L/mol, and more preferably from 50 to 150L/mol.
In the present invention, the crude 2' -O- (2-methoxyethyl) guanosine can be purified by a method commonly used in the art, such as column chromatography, preferably by a reverse phase column, under the following elution conditions: the mobile phase is acetonitrile and water, wherein the acetonitrile accounts for 5 percent and the water accounts for 95 percent for 30 minutes by volume, so as to obtain the product.
In the synthesis process, the whole system reaction process is a heterogeneous system.
In the description of the present invention, "plural" means two or more.
In the present invention, the reagents used, for example, guanosine, an alkylating agent, a base, an iodine catalyst and the like are commercially available unless otherwise specified.
The synthesis process of 2'-O- (2-methoxyethyl) guanosine takes guanosine as a raw material to synthesize the 2' -O- (2-methoxyethyl) guanosine by one-step reaction, the whole process is simple and convenient, the efficiency is high, the amplification production is easy, the requirement on equipment is not high, the raw material is cheap and easy to obtain, and the use of expensive protecting groups, enzymes and heavy metals is avoided.
The final product yield of the synthetic process of 2'-O- (2-methoxyethyl) guanosine reaches 35 percent, which is close to that of the prior art (the yield of guanosine reported by Nucleotides, nucleotides and Nucleic Acids (2003), 22 (5-8), 1327-1330 is 40 percent when the yield of 2' -O- (2-methoxyethyl) is reported).
The invention will be further illustrated with reference to the following specific examples. The specific embodiment is implemented on the premise of the technical scheme of the invention, and a detailed implementation mode and an operation process are given. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental methods in the following examples, which are not specified under specific conditions, are generally carried out under conventional conditions. Unless otherwise indicated, ratios and percentages are by weight.
The apparatus used in the HPLC assays carried out in the following examples was made by Waters, model UPLC Hclass. The instrument used for the HNMR detection was manufactured as bruker, model avancell 300. The medium pressure chromatography manufacturer performing the purification was orange da, model 1802.
Example 1
Preparation of 2' -O- (2-methoxyethyl) guanosine
Under the protection of nitrogen, 20.0 g of guanosine is taken to be dissolved in 200 mL of DMF at the temperature of between 15 and 30 ℃, 3.8 g of tetrabutylammonium iodide and 17.0 g of 2-bromoethyl methyl ether are added, the temperature is reduced to between 0 and 10 ℃, 106mL of 1.0M sodium bis (trimethylsilyl) amide is dropwise added, after dropwise addition is completed, the temperature is returned to between 15 and 30 ℃, the temperature is kept (between 15 and 30 ℃) for stirring for 6 hours, 2000 mL of ethyl acetate is added, the temperature is kept (between 15 and 30 ℃) for stirring for 1 hour, filtration is carried out, a filter cake is dried in vacuum at the temperature of 50 ℃ to obtain 14.3 g of crude 2' -O-methoxyethyl guanosine, and reverse phase column purification is carried out (the mobile phase comprises acetonitrile and water, wherein the acetonitrile accounts for 5 percent, the water accounts for 95 percent and is kept for 30 ℃ according to volumeMin elution of product) gave 6.8 g of 2' -O- (2-methoxyethyl) guanosine in 28.1% yield and 98.6% HPLC purity. The HPLC profile of the product is shown in FIG. 1, with 0.8 min as the product peak. The HNMR map of the product is shown in figure 2, 1 the H NMR spectrum was assigned in Table 1.
The product has the structural formula shown in formula II:
example 2
Preparation of 2' -O- (2-methoxyethyl) guanosine
Dissolving 10.0 g of guanosine in 200 mL of DMSO (dimethylsulfoxide) at 15 to 30 ℃, adding 10.0 g of potassium hydroxide and 6.0 g of potassium iodide, heating to 50 to 70 ℃, adding 15.0 g of 2-bromoethyl methyl ether, keeping the temperature (50 to 70 ℃) for stirring for 3 hours, cooling to 15 to 30 ℃, adding 1000 mL of dichloromethane, keeping the temperature (15 to 30 ℃) for stirring for 1 hour, filtering, and drying a filter cake in vacuum at 50 ℃ to obtain 8.1 g of a 2'-O-methoxyethyl guanosine crude product, wherein the mobile phase comprises acetonitrile and water, wherein acetonitrile 5% by volume and water 95% by volume are kept for 30 minutes to elute the product), so that 3.8 g of 2' -O- (2-methoxyethyl) guanosine is obtained, the yield is 31.6%, and the purity of HPLC is 98.3%. The HPLC profile of the product is shown in FIG. 3, where 0.8 min is the product peak.
Example 3
Preparation of 2' -O- (2-methoxyethyl) guanosine
Dissolving 100.0 g of guanosine in 1000 mL of DMSO at 15-30 ℃, adding 79.0 g of potassium hydroxide and 58.0 g of potassium iodide, heating to 60-70 ℃, adding 67.1 g of 2-chloroethyl methyl ether, keeping the temperature (60-70 ℃) for stirring for 19 hours, cooling to 15-30 ℃, adding 15000 mL of acetonitrile, keeping the temperature (15-30 ℃) for stirring for 1 hour, filtering, and drying a filter cake at 50 ℃ in vacuum to obtain 93.0 g of a 2'-O-methoxyethyl guanosine crude product, and performing reverse phase column purification (the mobile phase comprises acetonitrile and water, wherein acetonitrile is 5% by volume, water is 95% by volume, and the product is eluted after the vacuum drying is kept for 30 minutes) to obtain 42.4 g of 2' -O- (2-methoxyethyl) guanosine, the yield is 35.2%, and the HPLC purity is 98.3%. The HPLC profile of the product is shown in FIG. 4, where 0.8 min is the product peak.
Example 4
Preparation of 2' -O- (2-methoxyethyl) guanosine
Dissolving 20.0 g of guanosine in 200 mL of DMSO (dimethylsulfoxide) at 15 to 30 ℃, adding 11.3 g of sodium hydroxide, controlling the temperature to 15 to 25 ℃, adding 26.4 g of 2-iodoethyl methyl ether, stirring for 19 hours under the condition of heat preservation (15 to 25 ℃), adding 3000 mL of tetrahydrofuran, stirring for 1 hour under the condition of heat preservation (15 to 25 ℃), filtering, and drying a filter cake under vacuum at 50 ℃ to obtain 19.0 g of crude 2'-O-methoxyethyl guanosine, and performing reverse phase column purification (the mobile phase comprises acetonitrile and water, wherein the acetonitrile is 5% by volume, the water is 95% by volume, and the water is kept for 30 minutes) to obtain 7.4 g of 2' -O- (2-methoxyethyl) guanosine, the yield is 30.6%, and the HPLC purity is 97.2%. The HPLC profile of the product is shown in FIG. 5, with the product peak at 0.8 min.
Example 5
Preparation of 2' -O- (2-methoxyethyl) guanosine
Dissolving 10.0 g of guanosine in 200 mL of DMSO at 15-30 ℃, adding 9.7 g of sodium tert-butoxide, controlling the temperature at 15-25 ℃, adding 12.0 g of methanesulfonic acid-2-methoxyethyl ester, stirring for 19 hours at the temperature of 15-25 ℃, adding 1000 mL of methyl tert-butyl ether, stirring for 1 hour at the temperature of 15-25 ℃, filtering, and drying a filter cake at 50 ℃ in vacuum to obtain 10.5 g of crude 2'-O-methoxyethyl guanosine, and purifying by using an inverse phase column (wherein the mobile phase comprises acetonitrile and water, the volume of the acetonitrile is 5%, the volume of the water is 95%, the content of the water is kept for 30 minutes) to obtain 3.6 g of 2' -O- (2-methoxyethyl) guanosine, the yield is 30.1%, and the HPLC purity is 97.6%. The HPLC profile of the product is shown in FIG. 6, where 0.8 min is the product peak.
Example 6
Preparation of 2' -O- (2-methoxyethyl) guanosine
Dissolving 50.0 g of guanosine in 1000 mL of DMF at 15-30 ℃, cooling to 0-10 ℃, dropwise adding 264mL of 1M sodium bis (trimethylsilyl) amide tetrahydrofuran solution, adding 81.7 g of 2-methoxyethyl p-toluenesulfonate, returning to 15-30 ℃, keeping the temperature (15-30 ℃) for 19 hours while stirring, adding 8000 mL of acetone, keeping the temperature (15-30 ℃) for 1 hour while stirring, filtering, and drying a filter cake at 50 ℃ in vacuum to obtain 51.0 g of crude 2'-O-methoxyethyl guanosine, and purifying by using an inverse phase column (the mobile phase comprises acetonitrile and water, wherein the volume of the acetonitrile is 5 percent, the volume of the water is 95 percent, the content of the water is kept for 30 minutes) to obtain 19.6 g of 2' -O- (2-methoxyethyl) guanosine, the yield is 32.6 percent, and the HPLC purity is 98.2 percent. The HPLC profile of the product is shown in FIG. 7, where 0.8 min is the product peak.
The above embodiments are merely preferred embodiments of the present invention, which are not intended to limit the scope of the present invention, and various changes may be made in the above embodiments of the present invention. All simple and equivalent changes and modifications made according to the claims and the content of the specification of the present application fall within the scope of the claims of the present patent application. The invention has not been described in detail in order to avoid obscuring the invention.
Claims (6)
1. A synthesis process of 2' -O- (2-methoxyethyl) guanosine represented by a formula II, which is characterized by comprising the following steps: guanosine shown in the formula I and an alkylating reagent react in a reaction solvent in the presence of alkali to generate 2' -O- (2-methoxyethyl) guanosine shown in the formula II, wherein the reaction equation is as follows:
the alkylating reagent is selected from 2-chloroethyl methyl ether, 2-bromoethyl methyl ether, 2-iodoethyl methyl ether, methanesulfonic acid-2-methoxyethyl ester, p-toluenesulfonic acid-2-methoxyethyl ester or p-chlorobenzenesulfonic acid-2-methoxyethyl ester,
the alkali is selected from one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, butyl lithium, sodium tert-butoxide, potassium tert-butoxide and sodium bis (trimethylsilyl) amide,
when the alkylating agent is selected from 2-chloroethylmethyl ether or 2-bromoethyl methyl ether, the reaction system of step (i) further comprises an iodine catalyst,
the iodine catalyst is selected from one or more of potassium iodide, sodium iodide and tetrabutylammonium iodide.
2. The process of claim 1, wherein step (i) has one or more characteristics selected from the group consisting of:
the molar ratio of guanosine represented by the formula I to the alkylating agent is 1:1 to 1:10, and/or
The molar ratio of guanosine represented by the formula I to the base is 1:1 to 1:10, and/or
The volume molar ratio of the reaction solvent to the guanosine shown in the formula I is 5-50L/mol.
3. The process of claim 1, wherein the reaction solvent is selected from the group consisting of one or more of dimethylsulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, and N-methylpyrrolidone.
4. The process of claim 1, wherein the reaction system of step (i) comprises:
the alkylating agent selected from 2-bromoethyl methyl ether, the base selected from sodium bis (trimethylsilyl) amide, and an iodine catalyst selected from tetrabutylammonium iodide, or
The alkylating agent is selected from 2-bromoethyl methyl ether, the base is selected from potassium hydroxide, and the iodine catalyst is selected from potassium iodide, or
The alkylating agent is selected from 2-chloroethyl methyl ether, the base is selected from potassium hydroxide, and the iodine catalyst is selected from potassium iodide, or
Said alkylating agent selected from 2-iodoethyl methyl ether, and said base selected from sodium hydroxide, or
The alkylating agent is selected from methanesulfonic acid-2-methoxyethyl ester, and the base is selected from sodium tert-butoxide, or
The alkylating agent selected from 2-methoxyethyl p-toluenesulfonate and the base selected from sodium bis (trimethylsilyl) amide.
5. The process of claim 1, wherein step (i) further comprises treating the reaction solution after the reaction is completed, the treating the reaction solution comprising: and cooling the reaction liquid to 5-40 ℃, adding a poor solvent, stirring for 0.5-2 hours, and filtering or centrifuging to obtain a 2' -O- (2-methoxyethyl) guanosine crude product.
6. The process of claim 5, wherein the poor solvent is selected from one or more of acetonitrile, propionitrile, butyronitrile, dichloromethane, tetrahydrofuran, methyl tert-butyl ether, acetone, and ethyl acetate.
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| WO2003087053A2 (en) * | 2002-04-11 | 2003-10-23 | Isis Pharmaceuticals, Inc. | Reagent and process for protecting nucleoside active groups |
| CN102532228A (en) * | 2010-12-31 | 2012-07-04 | 上海兆维科技发展有限公司 | 2'-O-(2-methoxyethyl)adenosine and 2'-O-(2-methoxyethyl)guanosine, preparation of derivatives thereof and purifying methods thereof |
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| WO2003087053A2 (en) * | 2002-04-11 | 2003-10-23 | Isis Pharmaceuticals, Inc. | Reagent and process for protecting nucleoside active groups |
| CN102532228A (en) * | 2010-12-31 | 2012-07-04 | 上海兆维科技发展有限公司 | 2'-O-(2-methoxyethyl)adenosine and 2'-O-(2-methoxyethyl)guanosine, preparation of derivatives thereof and purifying methods thereof |
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| Title |
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| PROCESS RESEARCH ON THE PREPARATION OF DMT PROTECTED 2-O-METHOXYETHYLGUANOSINE FOR OLIGONUCLEOTIDE SYNTHESIS IN THERAPEUTIC APPLICATIONS;Shabbir Ali S. Taj;《Nucleosides, Nucleotides and Nucleic Acids》;20081231;第27卷;1024-1033页 * |
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