CN103319555A - Preparation method of 2'-methoxy adenosine - Google Patents
Preparation method of 2'-methoxy adenosine Download PDFInfo
- Publication number
- CN103319555A CN103319555A CN2013102851723A CN201310285172A CN103319555A CN 103319555 A CN103319555 A CN 103319555A CN 2013102851723 A CN2013102851723 A CN 2013102851723A CN 201310285172 A CN201310285172 A CN 201310285172A CN 103319555 A CN103319555 A CN 103319555A
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- preparation
- described step
- adenosine
- 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
- MRELHLHKFPLDIX-UHFFFAOYSA-N CC(OCC(C(C1O)OC(C)=O)OC1[n]1c([n]cnc2N)c2nc1)=O Chemical compound CC(OCC(C(C1O)OC(C)=O)OC1[n]1c([n]cnc2N)c2nc1)=O MRELHLHKFPLDIX-UHFFFAOYSA-N 0.000 description 1
- 0 CC(OCC(C(C1OC)OC(C)=O)OC1*(C1CC1)(C=*1)C2=C1C(N)=*CN2C)=O Chemical compound CC(OCC(C(C1OC)OC(C)=O)OC1*(C1CC1)(C=*1)C2=C1C(N)=*CN2C)=O 0.000 description 1
- OIRDTQYFTABQOQ-UHFFFAOYSA-N Nc1c2nc[n](C(C3O)OC(CO)C3O)c2ncn1 Chemical compound Nc1c2nc[n](C(C3O)OC(CO)C3O)c2ncn1 OIRDTQYFTABQOQ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Saccharide Compounds (AREA)
Abstract
The invention discloses a preparation method of 2'-methoxy adenosine. The method comprises the following steps of: (1) enabling a compound in a formula (II) to react with acetic anhydride in a DMF (dimethyl formamide) solvent under the effect of a catalyst to prepare a compound in formula (III); (2) selectively removing a 2'-bit protecting group from the compound in the formula (III) under the effect of a stripping protecting agent in the DMF solvent to prepare a compound in a formula (IV); (3) enabling the compound in the formula (IV) to react with methyl iodide or dimethyl sulphate under an alkaline condition to prepare a compound in a formula (V); (4) removing an acetyl protecting group under the alkaline effect of the compound in the formula (V) in a mixed solvent, so as to obtain the 2'-methoxy adenosine. The preparation method of the 2'-methoxy adenosine provided by the invention is cheap and available in materials, mild in reaction condition, simple and convenient to operate, high in combining efficiency, friendly to the environment and applicable to industrial production.
Description
Technical field
The invention belongs to medicine and intermediate preparing technical field, be specifically related to a kind of 2 '-novel preparation method of methoxy adenosine.
Background technology
2 '-methoxy adenosine is present among the RNA widely, also is widely used in recent years synthetic new drug and pharmaceutical intermediate, as can be used for N6-benzoyl-2 '-methoxy adenosine, DMT-N6-benzoyl-2 '-methoxy adenosine synthetic etc.
Existing many pieces of bibliographical informations 2 '-synthetic method of methoxy adenosine, such as document Biochim.Biophys.Aata, 1980,629,178 reported a kind of synthetic 2 '-method of methoxy adenosine, the method is adenosine is directly methylated and to prepare.
The method can generate three kinds of products, and these three kinds of products are difficult the separation, therefore be not suitable for suitability for industrialized production.
Document Tetrahedron, also reported in 2004,199450,5361 a kind of synthetic 2 '-method of methoxy adenosine, the method is take ribose as starting raw material, through multistep prepared 2 '-methoxy adenosine.
The shortcoming of this method is that reaction preference is relatively poor, can produce multiple isomer in the reaction process, is difficult between these isomer separate; In addition, reactions steps is many, and yield is low.Also be not suitable for suitability for industrialized production.
Also disclose among the Chinese patent CN1765913A a kind of synthetic 2 '-method of methoxy adenosine; the method be take 3 ' adenosine that position and 5 ' position hydroxyl TIPDSi protects is as starting raw material; with methyl iodide or methyl-sulfate generation methylation reaction, then slough protecting group and prepare.
Methylation reaction needs just can occur in alkali system in the method, but blocking group TIPDSi is very easy to take off in alkaline medium in the starting raw material, will obtain multiple methylate like this.Therefore, reaction needs to carry out preventing coming off of blocking group TIPDSi in extremely low temperature under such as-35 ℃～-80 ℃; Because temperature requirement is lower, therefore methylation reaction is very slow, length consuming time, also very high to conversion unit and operational requirement, in addition, the adenosine price of starting raw material 3 ' position and 5 ' position hydroxyl TIPDSi protection is higher, and the method is unsuitable for equally industrialization and prepares in a large number.
Summary of the invention
The objective of the invention is to overcome that cost is high in the prior art, combined coefficient is low, separating-purifying is difficult, be unfavorable for the defective of commercial scale production, provide a kind of new preparation 2 '-synthetic method of methoxy adenosine.
Technical scheme of the present invention is summarized as follows:
Described 2 '-preparation method of methoxy adenosine, comprise the steps:
Step (1), reaction makes formula (III) compound under esterifying catalyst effect following formula (II) compound and aceticanhydride heat in the DMF solvent; Step (2) in the DMF solvent, is sloughed 2 ' position protecting group with formula (III) compound selectivity under the deprotection agent effect, makes formula (IV) compound; Step (3), formula (IV) compound are reacted with methyl iodide or methyl-sulfate under alkaline condition, make formula (V) compound; Step (4), in mixed solvent, formula (V) compound under the alkali effect, the deacetylate protecting group, products therefrom is formula (I) compound.
Wherein, the chemical name of formula (II) compound is adenosine; The chemical name of formula (III) compound is 2 ', 3 ', 5 '-three-O-ethanoyl adenosine; The chemical name of formula (IV) compound is 3 ', 5 '-two-O-ethanoyl adenosine; The chemical name of formula (V) compound is 2 '-methoxyl group-3 ', 5 '-two-O-ethanoyl adenosine; The chemical name of formula (I) compound is 2 '-methoxy adenosine.
The esterifying catalyst of described step (1) is the organic amine material, preferred pyridine, and with the mol ratio of formula (II) compound be 1.2～2: 1.
What the temperature of reaction in the described step (1) was better is 50～70 ℃.
Deprotection agent in the described step (2) is the acetic acid azanol, and the mol ratio of itself and formula (III) compound is 1.2～1.6: 1.
Alkali in the described step (3) refers to NaH, KH, the combination of any one or a few in alkali hydroxide metal or the alkaline-earth metal, wherein preferred sodium hydroxide.
Temperature of reaction in the described step (3) is room temperature.
Alkali in the described step (4) refers to any one the combination in any one and alkali hydroxide metal or the alkaline-earth metal in basic metal or alkaline earth metal carbonate or the supercarbonate, the mixture of preferred salt of wormwood and sodium hydroxide wherein, and the mol ratio of sodium hydroxide and salt of wormwood is 1: 1.5～2.5.
Mixed solvent in the described step (4) is the mixture of water and 2-methyltetrahydrofuran, and the volume ratio of water and 2-methyltetrahydrofuran is 1: 8～15.
Temperature of reaction in the described step (4) is 0～10 ℃.
Advantage of the present invention is: provided by the invention 2 '-preparation method's raw material of methoxy adenosine is cheap and easy to get, and reaction conditions is gentle, and easy and simple to handle, combined coefficient is high, and is environmentally friendly, is suitable for suitability for industrialized production.
Embodiment
Below in conjunction with implementing specific embodiment, further specify the present invention.Should be understood that these embodiment only to be used for explanation the present invention and be not used in and limit the scope of the invention.
Used raw material or reagent is except specifying among the embodiment, all commercially available getting.
Embodiment 1 formula (III) compound 2 ', 3 ', the preparation of 5 '-three-O-ethanoyl adenosine
With formula (II) compound adenosine 13.4g (50mmol), 5mL pyridine and 150mL DMF add in the reaction flask, after mixing diacetyl oxide 17.9g (175mmol) are added.System temperature is risen to 60 ℃, and stirring reaction 1h, stopped reaction, pressure reducing and steaming solvent, the thick solid that obtains is dissolved with a small amount of Virahol, filter insolubles, in filtrate, add ethyl acetate, have a large amount of solids to separate out, filter, vacuum-drying gets white solid 17.8g, yield 91%.
Embodiment 2 formulas (IV) compound 3 ', the preparation of 5 '-two-O-ethanoyl adenosine
Oxammonium hydrochloride 13.9g (200mmol), sodium-acetate 24.6g (200mmol) and 300mL pyridine add in the reaction flask, after stirring formula (III) compound 60g (150mmol) is added, slowly heating makes whole dissolvings, is cooled to room temperature and stirring reaction 12h.In system, add 400mL acetone and 100mL methyl alcohol afterwards, restir reaction 0.5h, concentrating under reduced pressure adds 100mL toluene continuation underpressure distillation and takes remaining pyridine out of in the residue, then add 300mL water product is separated out, dry solid 42g, the yield 79% of getting of suction filtration.
Embodiment 3 formulas (V) compound 2 '-methoxyl group-3 ', the preparation of 5 '-two-O-ethanoyl adenosine
Under nitrogen protection; formula (IV) compound 35g (100mmol) and 200mLDMF are added in the reaction flask; after the stirring and dissolving methyl iodide 21.3g (150mmol) is added, then add sodium hydroxide 8g (200mmol), stirring at room reaction 1h.Under vigorous stirring, reaction solution is poured in the 1000g trash ice, filter behind stirring 5～10min, get solid 33g, yield 90%.
Embodiment 4 formulas (I) compound 2 '-preparation of methoxy adenosine
Formula (V) compound 14g (38.6mmol), 150mL2-methyltetrahydrofuran and 15mL water are added in the reaction flask, after stirring, salt of wormwood 2.6g (19mmol) and sodium hydroxide 0.4g (10mmol) are added, reaction mixture is at 5～10 ℃ of lower stirring reaction 1h, and stopped reaction after the cooling adds 200mL water, with acetic acid adjust pH to 5～7, cooling is filtered, and gets thick solid.With thick solid 50% ethyl alcohol recrystallization, get solid 9.9g, yield 91%.
Claims (9)
- One kind suc as formula the compound 2 shown in (I) '-preparation method of methoxy adenosine, it is characterized in that comprising the following steps: step (1), react in the DMF solvent at esterifying catalyst effect following formula (II) compound and aceticanhydride, get formula (III) compound; Step (2), in the DMF solvent, (III) compound selectivity under the deprotection agent effect is sloughed 2 ' position protecting group, gets formula (IV) compound; Step (3), formula (IV) compound are reacted with methyl iodide or methyl-sulfate under alkaline condition, make formula (V) compound; Step (4), in mixed solvent, formula (V) compound under the alkali effect, the deacetylate protecting group, products therefrom is formula (I) compound.
- According to claim 12 '-the methoxy adenosine preparation method, it is characterized in that: the esterifying catalyst of described step (1) is the organic amine material, preferred pyridine, and with the mol ratio of formula (II) compound be 1.2～2: 1.
- 3. preparation method according to claim 1, it is characterized in that: what the temperature in the step (1) was better is 50～70 ℃.
- 4. preparation method according to claim 1, it is characterized in that: the deprotection agent in the step (2) is the acetic acid azanol, and the mol ratio of itself and formula (III) compound is 1.2～1.6: 1.
- 5. preparation method according to claim 1, it is characterized in that: the alkali in the described step (3) refers to NaH, KH, the combination of any one or a few in alkali hydroxide metal or the alkaline-earth metal, wherein preferred sodium hydroxide.
- 6. preparation method according to claim 1, it is characterized in that: the temperature of reaction in the described step (3) is room temperature.
- 7. preparation method according to claim 1, it is characterized in that: the alkali in the described step (4) refers to any one the combination in any one and alkali hydroxide metal or the alkaline-earth metal in basic metal or alkaline earth metal carbonate or the supercarbonate, the mixture of preferred salt of wormwood and sodium hydroxide wherein, and the mol ratio of sodium hydroxide and salt of wormwood is 1: 1.5～2.5.
- 8. preparation method according to claim 1, it is characterized in that: the mixed solvent in the described step (4) is the mixture of water and 2-methyltetrahydrofuran, and the volume ratio of water and 2-methyltetrahydrofuran is 1: 8～15.
- 9. preparation method according to claim 1, it is characterized in that: the temperature in the described step (4) is 0～10 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2013102851723A CN103319555A (en) | 2013-07-01 | 2013-07-01 | Preparation method of 2'-methoxy adenosine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2013102851723A CN103319555A (en) | 2013-07-01 | 2013-07-01 | Preparation method of 2'-methoxy adenosine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103319555A true CN103319555A (en) | 2013-09-25 |
Family
ID=49188640
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2013102851723A Pending CN103319555A (en) | 2013-07-01 | 2013-07-01 | Preparation method of 2'-methoxy adenosine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103319555A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115651047A (en) * | 2022-11-14 | 2023-01-31 | 天津奥瑞芙生物医药有限公司 | Process for preparing 2' -O-methyl nucleosides |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5852188A (en) * | 1990-01-11 | 1998-12-22 | Isis Pharmaceuticals, Inc. | Oligonucleotides having chiral phosphorus linkages |
| CN1765913A (en) * | 2005-11-16 | 2006-05-03 | 华东师范大学 | 2'-methoxy adenosine preparation method |
| CN102060899A (en) * | 2010-12-27 | 2011-05-18 | 江苏奥赛康药业有限公司 | Nelarabine N-9 site alpha isomer, and preparation method and application thereof |
| CN102485739A (en) * | 2010-12-06 | 2012-06-06 | 薛家禄 | Novel synthesis technology of 7-dehydrocholesterol |
-
2013
- 2013-07-01 CN CN2013102851723A patent/CN103319555A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5852188A (en) * | 1990-01-11 | 1998-12-22 | Isis Pharmaceuticals, Inc. | Oligonucleotides having chiral phosphorus linkages |
| CN1765913A (en) * | 2005-11-16 | 2006-05-03 | 华东师范大学 | 2'-methoxy adenosine preparation method |
| CN102485739A (en) * | 2010-12-06 | 2012-06-06 | 薛家禄 | Novel synthesis technology of 7-dehydrocholesterol |
| CN102060899A (en) * | 2010-12-27 | 2011-05-18 | 江苏奥赛康药业有限公司 | Nelarabine N-9 site alpha isomer, and preparation method and application thereof |
Non-Patent Citations (3)
| Title |
|---|
| B.S.ROSS等: "General preparative synthesis of 2-O-Methylpyrimidine Ribonucleosides", 《J.HETEROCYCLIC CHEM.》, vol. 31, 31 December 1994 (1994-12-31), pages 765 - 769 * |
| GILLES PARMENTIER等: "A Convergent Synthesis of 2’-O-Methyl Uridine", 《TETRAHEDRON》, vol. 50, no. 18, 31 December 1994 (1994-12-31), pages 5361 - 5368 * |
| MARY C. LONG等: "Structure–activity relationship for adenosine kinase from Mycobacterium tuberculosis II. Modifications to the ribofuranosyl moiety", 《BIOCHEMICAL PHARMACOLOGY》, vol. 75, 31 December 2008 (2008-12-31), pages 1588 - 1600 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115651047A (en) * | 2022-11-14 | 2023-01-31 | 天津奥瑞芙生物医药有限公司 | Process for preparing 2' -O-methyl nucleosides |
| CN115651047B (en) * | 2022-11-14 | 2023-03-17 | 天津奥瑞芙生物医药有限公司 | Process for preparing 2' -O-methyl nucleosides |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108129288B (en) | Synthesis method of trans-3-hydroxycyclobutylformic acid | |
| CN101735190B (en) | Method for preparing baicalein | |
| CN101781235B (en) | Method for preparing 2-cyanophenol | |
| CN104817505A (en) | Method of preparing N-[4-(4-fluorophenyl)-5-hydroxymethyl-6-isopropyl-pyrimidine-2-yl]-N-methylmethanesulfonamide | |
| CN102219817A (en) | Method for carrying out carbalkoxylation acylation on fluorouracil compound with active coupling agent | |
| CN103319555A (en) | Preparation method of 2'-methoxy adenosine | |
| CN102070430B (en) | Method for preparing xanthoxylin | |
| CN104672155B (en) | A kind of synthetic method for improving quinocetone | |
| CN101701027B (en) | Catalytic cracking method of nucleoside compound | |
| CN108484439B (en) | Preparation method of alpha-formyl-beta-formamido propionitrile alkali metal salt | |
| CN108727179B (en) | Synthetic method of alpha-allyl substituted alpha, beta-unsaturated ketone, ester or nitrile compound | |
| CN102786541A (en) | Preparation method and application of potassium (iso)quinoline thifluoroborate | |
| CN110938106B (en) | Method for preparing obeticholic acid intermediate and obeticholic acid thereof | |
| CN108610252A (en) | The new method of Acitretin acid isomerization | |
| CN102659579A (en) | preparation method of p-chlorine methyl cinnamate | |
| CN108727445B (en) | Synthesis method of azithromycin impurity F | |
| CN110172036B (en) | Preparation method of bromfenac sodium intermediate | |
| CN113045583A (en) | Preparation method of pinoxaden metabolite | |
| US20220235010A1 (en) | Synthesis method for 1-methyl-1h-indazole-6-carboxylic acid | |
| CN111574446A (en) | Triarylmethane compound and synthesis method thereof | |
| CN100355769C (en) | 2'-methoxy adenosine preparation method | |
| CN101348444B (en) | Preparation of 2-ethoxy-4-acetaminobenzoic acid methyl ester | |
| CN103193767B (en) | The preparation method of the two benzene pyrrone-2-C-β-D-glucopyranoside of 1,6,7-trihydroxy--3-methoxyl group | |
| CN102942602B (en) | The preparation method of o-nitrophenyl galactoside | |
| CN102875460A (en) | Method for preparing sorafenib |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| AD01 | Patent right deemed abandoned |
Effective date of abandoning: 20161102 |
|
| C20 | Patent right or utility model deemed to be abandoned or is abandoned |