CN114891048B - Method for preparing 4-fluoro-2, 3, 5-tri-oxo-benzoyl-beta-L-ribofuranose - Google Patents
Method for preparing 4-fluoro-2, 3, 5-tri-oxo-benzoyl-beta-L-ribofuranose Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 18
- 239000011973 solid acid Substances 0.000 claims abstract description 53
- 241000404883 Pisa Species 0.000 claims abstract description 50
- 239000003054 catalyst Substances 0.000 claims abstract description 39
- 238000006640 acetylation reaction Methods 0.000 claims abstract description 12
- 238000006480 benzoylation reaction Methods 0.000 claims abstract description 4
- 230000006196 deacetylation Effects 0.000 claims abstract description 4
- 238000003381 deacetylation reaction Methods 0.000 claims abstract description 4
- 238000007069 methylation reaction Methods 0.000 claims abstract description 4
- 239000002994 raw material Substances 0.000 claims abstract description 4
- 230000021736 acetylation Effects 0.000 claims abstract description 3
- 238000003682 fluorination reaction Methods 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 50
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic acid anhydride Natural products CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 49
- 238000003756 stirring Methods 0.000 claims description 40
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 35
- 229910021389 graphene Inorganic materials 0.000 claims description 35
- 239000002243 precursor Substances 0.000 claims description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 20
- 238000001914 filtration Methods 0.000 claims description 20
- 238000001035 drying Methods 0.000 claims description 17
- 238000004321 preservation Methods 0.000 claims description 17
- 239000002904 solvent Substances 0.000 claims description 16
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 claims description 15
- 239000007787 solid Substances 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 238000001354 calcination Methods 0.000 claims description 14
- 239000000047 product Substances 0.000 claims description 14
- 239000000725 suspension Substances 0.000 claims description 14
- 238000005406 washing Methods 0.000 claims description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- JJLJMEJHUUYSSY-UHFFFAOYSA-L Copper hydroxide Chemical compound [OH-].[OH-].[Cu+2] JJLJMEJHUUYSSY-UHFFFAOYSA-L 0.000 claims description 10
- 239000005750 Copper hydroxide Substances 0.000 claims description 10
- 229910001956 copper hydroxide Inorganic materials 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 10
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 7
- 229910052751 metal Inorganic materials 0.000 claims description 6
- 239000002184 metal Substances 0.000 claims description 6
- 239000002244 precipitate Substances 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 238000001132 ultrasonic dispersion Methods 0.000 claims description 6
- 238000000643 oven drying Methods 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- NTJBWZHVSJNKAD-UHFFFAOYSA-N triethylazanium;fluoride Chemical compound [F-].CC[NH+](CC)CC NTJBWZHVSJNKAD-UHFFFAOYSA-N 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- HMFHBZSHGGEWLO-OWMBCFKOSA-N L-ribofuranose Chemical compound OC[C@@H]1OC(O)[C@@H](O)[C@H]1O HMFHBZSHGGEWLO-OWMBCFKOSA-N 0.000 claims 1
- 230000003197 catalytic effect Effects 0.000 abstract description 20
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 abstract description 9
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 abstract description 8
- PYMYPHUHKUWMLA-MROZADKFSA-N aldehydo-L-ribose Chemical compound OC[C@H](O)[C@H](O)[C@H](O)C=O PYMYPHUHKUWMLA-MROZADKFSA-N 0.000 abstract description 7
- 239000007788 liquid Substances 0.000 abstract description 3
- 239000003377 acid catalyst Substances 0.000 abstract description 2
- 230000011987 methylation Effects 0.000 abstract description 2
- 230000000052 comparative effect Effects 0.000 description 20
- 239000000243 solution Substances 0.000 description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 7
- 239000010949 copper Substances 0.000 description 7
- 229910052802 copper Inorganic materials 0.000 description 7
- 238000001704 evaporation Methods 0.000 description 7
- 238000002156 mixing Methods 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 239000013067 intermediate product Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- HYBBIBNJHNGZAN-UHFFFAOYSA-N furfural Chemical compound O=CC1=CC=CO1 HYBBIBNJHNGZAN-UHFFFAOYSA-N 0.000 description 2
- 239000002342 ribonucleoside Substances 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- IVORCBKUUYGUOL-UHFFFAOYSA-N 1-ethynyl-2,4-dimethoxybenzene Chemical compound COC1=CC=C(C#C)C(OC)=C1 IVORCBKUUYGUOL-UHFFFAOYSA-N 0.000 description 1
- ASJSAQIRZKANQN-CRCLSJGQSA-N 2-deoxy-D-ribose Chemical compound OC[C@@H](O)[C@@H](O)CC=O ASJSAQIRZKANQN-CRCLSJGQSA-N 0.000 description 1
- 229910018072 Al 2 O 3 Inorganic materials 0.000 description 1
- 229910004298 SiO 2 Inorganic materials 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000919 ceramic Substances 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000005549 deoxyribonucleoside Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000013335 mesoporous material Substances 0.000 description 1
- 239000007769 metal material Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229910052814 silicon oxide Inorganic materials 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229920001221 xylan Polymers 0.000 description 1
- 150000004823 xylans Chemical class 0.000 description 1
Classifications
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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
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J27/00—Catalysts comprising the elements or compounds of halogens, sulfur, selenium, tellurium, phosphorus or nitrogen; Catalysts comprising carbon compounds
- B01J27/02—Sulfur, selenium or tellurium; Compounds thereof
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J35/00—Catalysts, in general, characterised by their form or physical properties
- B01J35/60—Catalysts, in general, characterised by their form or physical properties characterised by their surface properties or porosity
- B01J35/61—Surface area
- B01J35/617—500-1000 m2/g
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/08—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals directly attached to carbocyclic rings
-
- 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
- Y02P20/584—Recycling of catalysts
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- Materials Engineering (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Saccharide Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a method for preparing 4-fluoro-2, 3, 5-tri-oxo-benzoyl-beta-L-ribofuranose, which comprises the following steps: s1: preparing a solid acid catalyst PISA/Gu-O-GN; s2: taking L-ribose as a raw material; 1-oxo-methyl-L-ribofuranose is obtained by methylation; then carrying out benzoylation reaction on the 1-oxo-methyl-L-ribofuranose to obtain 1-oxo-methyl-2, 3, 5-trioxybenzoyl-L-ribofuranose; s3: 1-oxo-acetyl-2, 3, 5-trioxybenzoyl-beta-L-ribofuranose is prepared by acetylation reaction in the presence of solid acid PISA/Gu-O-GN; then preparing 1-oxo-2, 3, 5-trioxybenzoyl-beta-L-ribofuranose through deacetylation; s4: preparing 1-oxo-4-fluoro-2, 3, 5-trioxybenzoyl-L-ribofuranose by a fluorination reaction; in the process of acetylation, the solid acid catalyst PISA/Gu-O-GN is added, the catalytic rate is improved to 95.8%, and the catalytic rate is improved by 20% -50% compared with the existing liquid acid catalyst, solid acid catalyst and the like.
Description
Technical Field
The invention belongs to the technical field of biological sugar, and particularly relates to a method for preparing 4-fluoro-2, 3, 5-tri-oxo-benzoyl-beta-L-ribofuranose.
Background
Ribose and its derivative deoxyribose are important components of nucleic acids, as well as components of certain vitamins and coenzymes. D-ribose and derivatives thereof are widely present in natural compounds in the form of furans, while the enantiomer of D-ribose, L-ribose, does not exist in nature and is generally obtainable only by synthetic methods; in recent years, the application of L-ribose and derivatives in medicines has been reported to be increasing. The reason for this is that L-ribonucleosides have significant antiviral activity, but are less toxic than D-ribonucleosides, wherein 1-oxo-fluoro-2, 3, 5-trioxybenzoyl-L-ribose is an important intermediate for the synthesis of deoxyribonucleosides; however, in the existing process, the product yield of each process is lower, such as the production process of preparing 1-oxo-acetyl-2, 3, 5-trioxybenzoyl-beta-L-ribofuranose by a patent, the application number is 200810060210.4, the existing process is prepared by adopting methylation-benzoylation-acetylation reaction, and the total yield of three steps is only about 60%; the catalyst is an important additive for improving the yield of biological sugar, and is sulfurAcid radical composite oxide solid acid catalyst, its preparation process and method of catalyzing xylan to furfural, application number 201410167436.X, discloses a catalyst-SO using solid acid 4 2- /SiO 2 -Al 2 O 3 /La 3+ However, such solid acid catalysts have problems in that the specific surface area is small, and the catalytic activity is lowered; or the sulfur-containing groups are easy to lose, the activity is fast to lose, and the repeatability is poor.
Disclosure of Invention
The invention aims to provide a method for preparing 1-oxo-fluoro-2, 3, 5-trioxybenzoyl-L-ribose, which utilizes a solid acid PISA/Gu-O-GN catalyst with high specific surface area in the reaction process to improve the product yield.
In order to solve the technical problem, the technical scheme of the invention is as follows: a process for preparing 1-oxo-fluoro-2, 3, 5-trioxybenzoyl-L-ribose, comprising the steps of:
s1: preparing a solid acid catalyst PISA/Gu-O-GN;
s2: taking L-ribose as a raw material;
1-oxo-methyl-L-ribofuranose is obtained by methylation;
then the 1-oxygen-methyl-L-ribofuranose is subjected to benzoylation reaction to obtain 1-oxygen-methyl-2, 3,5-
trioxybenzoyl-L-ribofuranose;
s3: the product obtained in the step S2 is reacted by acetylation in the presence of solid acid PISA/Gu-O-GN
1-oxo-acetyl-2, 3, 5-trioxybenzoyl-beta-L-ribofuranose should be produced; in the reaction process, intermittently oscillating the reaction solution by ultrasonic waves;
then preparing 1-oxo-2, 3, 5-trioxybenzoyl-beta-L-ribofuranose through deacetylation;
s4: preparation of 1-oxo-4-fluoro-2, 3, 5-tri-form the product obtained in step S3 by a fluorination reaction
oxybenzoyl-L-ribofuranose.
Preferably, the solid acid PISA/Gu-O-GN is used in an amount of 15% by mass of 1-oxo-methyl-2, 3, 5-trioxybenzoyl-L-ribofuranose.
Preferably, in step S3, the acetylation reaction time is 5h to 6h.
Preferably, the preparation method of the solid acid PISA/Gu-O-GN in S1 comprises the following steps:
s11: preparing graphene suspension; adding graphene oxide and hydrazine into a reaction kettle, performing ultrasonic dispersion, and heating to a reaction temperature for reaction to obtain a graphene precipitate; washing the precipitate, adding water again, and performing ultrasonic dispersion to obtain graphene suspension;
s12: adding a copper hydroxide solution into the graphene suspension under the stirring condition at the temperature of 40-80 ℃, wherein copper hydroxide is embedded into graphene through a metal bond; filtering, washing and drying to obtain a precursor Gu-O-GN;
s13: adding the precursor into toluene sulfonic acid, filtering and drying;
s14: calcining to obtain the PISA/Gu-O-GN solid acid.
The solid acid catalyst PISA/Gu-O-GN adopts the graphene suspension to mix the strong copper hydroxide solution, so that the copper-based material and the graphene suspension are fused better; according to the invention, active sites exist on the surface of graphene, so that metal materials can be adsorbed and grown, and after co-calcination, graphene and copper elements are better adsorbed, so that the effective acid center number of the catalyst is increased, and the catalytic performance of a product is improved.
Preferably, the molar ratio of graphene oxide to hydrazine in S11 is 1: (1.3-1.8).
Preferably 1 gram of precursor is mixed per 12ml to 18ml of toluene sulfonic acid in S13.
Preferably the calcination temperature in S14 is 300-450 degrees celsius.
In the S2 of the invention, the specific method for obtaining the 1-oxygen-methyl-L-ribofuranose through methylation reaction comprises the following steps: mixing L-ribose, pyridine and methanol with each other, adding thionyl chloride, performing heat preservation, airtight stirring and reaction for 10 hours at the water bath of 0 ℃, and evaporating under reduced pressure to obtain 1-oxygen-methyl-L-ribofuranose; the specific method for preparing the 1-oxo-methyl-2, 3, 5-trioxybenzoyl-L-ribofuranose by the benzoylation reaction comprises the following steps: and (3) dissolving the product obtained in the step (S1) in dichloromethane and pyridine, cooling in an ice water bath, dropwise adding benzoyl chloride under stirring, performing airtight stirring reaction for 2-5 h, washing the reaction solution by a sodium chloride solution, taking a solvent layer, drying by anhydrous magnesium sulfate, filtering, and evaporating the solvent under reduced pressure to obtain syrup.
Preferably, the acetylation reaction in S3 yields 1-oxo-acetyl-2, 3, 5-trioxybenzoyl-beta-L-
The method for ribofuranose comprises the following steps:
taking 1-oxygen-methyl-2, 3, 5-trioxybenzoyl-L-ribofuranose, adding solid acid PISA/Gu-O-GN, acetic acid and acetic anhydride, and carrying out heat preservation, airtight stirring and reaction for 3-5 h at the water bath of 0 ℃;
concentrating, crystallizing, washing and filtering to obtain solid 1-oxo-acetyl-2, 3, 5-trioxybenzoyl-beta-L-ribofuranose.
Preferably, the method for preparing the 1-oxo-2, 3, 5-trioxybenzoyl-beta-L-ribofuranose by deacetylation in S3 comprises the following steps: dissolving 1-oxo-acetyl-2, 3, 5-trioxybenzoyl-beta-L-ribofuranose in dichloromethane, adding acetic anhydride, introducing HCL gas, performing heat preservation and airtight stirring reaction for 4-6 hours at-5 ℃, adding saturated sodium bicarbonate solution after the reaction is finished, stirring, standing, taking an extraction layer, adding imidazole and sulfuryl chloride into the extraction solution, performing heat preservation and airtight stirring reaction for 16-24 hours at 25 ℃, and stirring and taking a solvent layer after the reaction is finished;
drying the solvent layer, filtering, concentrating, crystallizing and drying to obtain solid 1-oxo-2, 3, 5-trioxybenzoyl-beta-L-ribofuranose.
Preferably, in the step S4, dissolving solid 1-oxo-2, 3, 5-trioxybenzoyl-beta-L-ribofuranose with ethyl acetate, adding triethylamine hydrofluoric acid, keeping reflux and stirring for reaction for 18-25 h at 80 ℃, adding saturated sodium bicarbonate solution after the reaction is finished, and taking a solvent layer;
concentrating under reduced pressure, crystallizing, filtering, oven drying to obtain solid 1-oxo-4-fluoro-2, 3, 5-trioxybenzoyl
-L-ribofuranose.
The technical scheme has the beneficial effects that: in the process of preparing the intermediate product 1-oxo-acetyl-2, 3, 5-trioxybenzoyl-beta-L-ribofuranose through the acetylation reaction, the solid acid catalyst PISA/Gu-O-GN is added, the catalytic rate is improved to 95.8 percent, and the catalytic rate is improved by 20 to 50 percent compared with the existing liquid acid catalyst, solid acid catalyst and the like; in addition, compared with the traditional solid acid, the graphene suspension is adopted as a carrier, the dispersibility is good, the specific surface area of the obtained catalyst is larger than that of the product obtained by the traditional mesoporous materials such as silicon oxide, and the like, and the catalysis is good; in addition, as all p orbits of the graphene are mutually perpendicular, electrons in the p orbits can move in the whole carbon atom plane, so that metal bonds exist, the metal bonds of the graphene can be mutually bonded with copper hydroxide, the copper hydroxide is embedded into the graphene to form a precursor, copper is connected with PISA while being connected with the graphene to form a stable space three-dimensional connection structure, copper-based solid acid with a space three-dimensional distribution structure has larger specific surface area, the number of effective acid centers of the catalyst is increased, active sites are increased, and the catalytic activity is obviously improved.
Detailed Description
In order to further explain the technical scheme of the invention, the invention is explained in detail by specific examples.
Example 1
This example discloses a process for preparing 1-oxo-fluoro-2, 3, 5-trioxybenzoyl-L-ribose comprising the steps of: mixing L-ribose, pyridine and methanol with each other, adding thionyl chloride, performing heat preservation, airtight stirring and reaction for 10 hours at the water bath of 0 ℃, and evaporating under reduced pressure to obtain 1-oxygen-methyl-L-ribofuranose; dissolving 1-oxygen-methyl-L-ribofuranose in dichloromethane and pyridine, cooling in ice water bath, dropwise adding benzoyl chloride under stirring, sealing, stirring for reacting for 4h, washing the reaction solution with sodium chloride solution, taking a solvent layer, drying with anhydrous magnesium sulfate, filtering, and evaporating the solvent under reduced pressure to obtain syrup 1-oxygen-methyl-2, 3, 5-trioxybenzoyl-L-ribofuranose;
taking 1-oxygen-methyl-2, 3, 5-trioxybenzoyl-L-ribofuranose, adding solid acid PISA/Gu-O-GN, acetic acid and acetic anhydride, wherein the dosage of the solid acid PISA/Gu-O-GN is 10 percent of the total amount of the 1-oxygen-methyl-2, 3, 5-trioxybenzoyl-L-ribofuranose, and carrying out heat preservation, airtight stirring and reaction for 5 hours at the temperature of 0 ℃; intermittently oscillating the reaction solution by ultrasonic waves under the power of 40W; concentrating, crystallizing, washing and filtering to obtain solid 1-oxo-acetyl-2, 3, 5-trioxybenzoyl-beta-L-ribofuranose;
dissolving 1-oxo-acetyl-2, 3, 5-trioxybenzoyl-beta-L-ribofuranose in dichloromethane, adding acetic anhydride, introducing HCL gas, performing heat preservation and airtight stirring reaction for 4-6 hours at-5 ℃, adding saturated sodium bicarbonate solution after the reaction is finished, stirring, standing, taking an extraction layer, adding imidazole and sulfuryl chloride into the extraction solution, performing heat preservation and airtight stirring reaction for 16-24 hours at 25 ℃, and stirring and taking a solvent layer after the reaction is finished; drying the solvent layer, filtering, concentrating, crystallizing and drying to obtain solid 1-oxo-2, 3, 5-trioxybenzoyl-beta-L-ribofuranose; dissolving solid 1-oxo-2, 3, 5-trioxybenzoyl-beta-L-ribofuranose with ethyl acetate, adding triethylamine hydrofluoric acid, stirring at 80deg.C under reflux for 18-25 h, adding saturated sodium bicarbonate solution after the reaction, and collecting solvent layer; concentrating under reduced pressure, crystallizing, filtering, and oven drying to obtain solid 1-oxo-4-fluoro-2, 3, 5-trioxybenzoyl-L-ribofuranose.
Wherein, preparing solid acid PISA/Gu-O-GN; the specific method comprises the following steps: graphene oxide and hydrazine according to 1:1.5, adding the mixture into a reaction kettle, performing ultrasonic dispersion for 2 hours, then heating to 100 ℃, reacting for 4 hours to obtain graphene precipitate, washing the precipitate with absolute ethyl alcohol for three times, adding 3 times of water again, and performing ultrasonic dispersion to obtain graphene suspension; the concentration of the graphene suspension is 0.35mg/mL, and a copper hydroxide solution is added into the graphene suspension at the temperature of 40 ℃ to ensure that the molar ratio of graphene to copper element is 1:1.6, stirring for 24 hours at room temperature, precipitating, filtering, washing with absolute ethyl alcohol, and drying at 120 ℃ to obtain a precursor Gu-O-GN; adding the precursor into toluene sulfonic acid, adding 12ml toluene sulfonic acid into each gram of precursor, vibrating intermittently at room temperature under 30W power for 24 hours, drying at 150 ℃ each time at 25 minutes, transferring into a ceramic container, placing into a muffle furnace, and calcining at 300 ℃ for 6 hours to obtain PISA/Gu-O-GN solid acid.
Example 2
The difference from example 1 is that: the dosage of the solid acid PISA/Gu-O-GN is 13% of the total amount of 1-oxo-methyl-2, 3, 5-trioxybenzoyl-L-ribofuranose;
example 3
The difference from example 1 is that: the usage amount of the solid acid PISA/Gu-O-GN is 15% of the total amount of 1-oxo-methyl-2, 3, 5-trioxybenzoyl-L-ribofuranose;
example 4
The difference from example 1 is that: the dosage of the solid acid PISA/Gu-O-GN is 18% of the total amount of 1-oxo-methyl-2, 3, 5-trioxybenzoyl-L-ribofuranose;
example 5
The difference from example 1 is that: the dosage of the solid acid PISA/Gu-O-GN is 20 percent of the total amount of 1-oxo-methyl-2, 3, 5-trioxybenzoyl-L-ribofuranose;
example 6
The difference from example 3 is that: mixing solid acid PISA/Gu-O-GN, acetic acid and acetic anhydride in 1-oxygen-methyl-2, 3, 5-trioxybenzoyl-L-ribofuranose, and performing heat preservation, airtight stirring and reaction for 3h in a water bath at 0 ℃;
example 7
The difference from example 3 is that: mixing solid acid PISA/Gu-O-GN, acetic acid and acetic anhydride in 1-oxygen-methyl-2, 3, 5-trioxybenzoyl-L-ribofuranose, and performing heat preservation, airtight stirring and reaction for 4 hours in a water bath at 0 ℃;
example 8
The difference from example 3 is that: mixing solid acid PISA/Gu-O-GN, acetic acid and acetic anhydride in 1-oxygen-methyl-2, 3, 5-trioxybenzoyl-L-ribofuranose, and performing heat preservation, airtight stirring and reaction for 6h in a water bath at 0 ℃;
example 9
The difference from example 3 is that: mixing solid acid PISA/Gu-O-GN, acetic acid and acetic anhydride in 1-oxygen-methyl-2, 3, 5-trioxybenzoyl-L-ribofuranose, and performing heat preservation, airtight stirring and reaction for 8 hours in a water bath at 0 ℃;
example 10
The difference from example 8 is that: the calcination temperature of the solid acid catalyst PISA/Gu-O-GN is 350 ℃;
example 11
The difference from example 8 is that: the calcination temperature of the solid acid catalyst PISA/Gu-O-GN is 400 ℃;
example 12
The difference from example 8 is that: the calcination temperature of the solid acid catalyst PISA/Gu-O-GN is 450 ℃;
example 13
The difference from example 11 is that: 14ml of toluene sulfonic acid is prepared for each gram of precursor in the process of preparing the solid acid catalyst PISA/Gu-O-GN;
example 14
The difference from example 11 is that: in the process of preparing the solid acid catalyst PISA/Gu-O-GN, 16ml of toluene sulfonic acid is prepared per gram of precursor;
comparative example 1
This example discloses a process for preparing 1-oxo-fluoro-2, 3, 5-trioxybenzoyl-L-ribose comprising the steps of: mixing L-ribose, pyridine and methanol with each other, adding thionyl chloride, performing heat preservation, airtight stirring and reaction for 10 hours at the water bath of 0 ℃, and evaporating under reduced pressure to obtain 1-oxygen-methyl-L-ribofuranose; dissolving 1-oxygen-methyl-L-ribofuranose in dichloromethane and pyridine, cooling in ice water bath, dropwise adding benzoyl chloride under stirring, sealing, stirring for reacting for 4h, washing the reaction solution with sodium chloride solution, taking a solvent layer, drying with anhydrous magnesium sulfate, filtering, and evaporating the solvent under reduced pressure to obtain syrup 1-oxygen-methyl-2, 3, 5-trioxybenzoyl-L-ribofuranose;
taking 1-oxygen-methyl-2, 3, 5-trioxybenzoyl-L-ribofuranose, adding acetic acid and acetic anhydride, and reacting for 5h in a water bath at 0 ℃ under heat preservation and airtight stirring; concentrating, crystallizing, washing and filtering to obtain solid 1-oxo-acetyl-2, 3, 5-trioxybenzoyl-beta-L-ribofuranose;
dissolving 1-oxo-acetyl-2, 3, 5-trioxybenzoyl-beta-L-ribofuranose in dichloromethane, adding acetic anhydride, introducing HCL gas, performing heat preservation and airtight stirring reaction for 4-6 hours at-5 ℃, adding saturated sodium bicarbonate solution after the reaction is finished, stirring, standing, taking an extraction layer, adding imidazole and sulfuryl chloride into the extraction solution, performing heat preservation and airtight stirring reaction for 16-24 hours at 25 ℃, and stirring and taking a solvent layer after the reaction is finished; drying the solvent layer, filtering, concentrating, crystallizing and drying to obtain solid 1-oxo-2, 3, 5-trioxybenzoyl-beta-L-ribofuranose; dissolving solid 1-oxo-2, 3, 5-trioxybenzoyl-beta-L-ribofuranose with ethyl acetate, adding triethylamine hydrofluoric acid, stirring at 80deg.C under reflux for 18-25 h, adding saturated sodium bicarbonate solution after the reaction, and collecting solvent layer; concentrating under reduced pressure, crystallizing, filtering, and oven drying to obtain solid 1-oxo-4-fluoro-2, 3, 5-trioxybenzoyl-L-ribofuranose.
Comparative example 2
The difference from comparative example 1 is that: during the acetylation reaction, 1-oxygen-methyl-2, 3, 5-trioxybenzoyl-L-ribofuranose is taken, acetic acid and acetic anhydride are added, and concentrated H2SO4 is dropwise added as a catalyst for reaction under the conditions of ice water bath cooling and intense stirring;
in the embodiment, the concentrated sulfuric acid is 98.3% of the concentrated sulfuric acid by mass fraction;
comparative example 3
The difference from comparative example 2 is that: during the acetylation reaction, PISA/ZrO is added into the mixed solution of 1-oxo-methyl-2, 3, 5-trioxybenzoyl-L-ribofuranose, acetic acid and acetic anhydride 2 As a catalyst;
wherein PISA/ZrO 2 The preparation method comprises the following steps:
taking ZrOCl with certain mass 2 ·8H 2 0, dissolving in water, dropwise adding ammonia water in a stirring state, regulating the pH value to about 9, stopping ammonia water dropwise adding until the reaction is completed, continuously stirring the reaction liquid, putting into a drying box, ageing for 4 hours, filtering, washing, drying, grinding to obtain zirconium hydroxide powder, putting into a muffle furnace, and calcining at 360 ℃ for 5 hours to obtain a precursor ZrO 2 ，
Adding the precursor into toluene sulfonic acid, soaking for 4h, continuously stirring with a magnetic stirrer, evaporating excessive water, and calcining in a muffle furnace at 300deg.C for 4h to obtain PISA/ZrO 2 A solid acid.
The catalysts obtained in example 1 and comparative example 3 were subjected to specific surface area test using a specific surface area tester, and specific data are shown in table 1.
TABLE 1 specific surface area of the catalysts obtained in example 1 and comparative example 3
| Group of | Specific surface area (m) 2 /g） |
| Comparative example 3 | 168 |
| Example 1 | 805 |
From Table 1, the specific surface area of the prepared solid acid catalyst is increased by 4-5 times by taking the graphene suspension as a precursor raw material, which proves that the graphene can effectively increase the specific surface area of the catalyst;
according to the formula: catalytic rate = { (amount of 1-oxo-methyl-2, 3, 5-trioxybenzoyl-L-ribofuranose before reaction-amount of 1-oxo-acetyl-2, 3, 5-trioxybenzoyl- β -L-ribofuranose after reaction)/amount of 1-oxo-methyl-2, 3, 5-trioxybenzoyl-L-ribofuranose before reaction } x100%; comparative examples 1-3 and intermediate product catalytic rates of examples 1 to 14 were calculated; specific catalytic ratios are shown in Table 2;
TABLE 2 catalytic Rate of intermediate products obtained in comparative examples 1-3 and examples 1 to 14
| Group of | Catalytic rate |
| Comparative example 1 | 60.3 |
| Comparative example 2 | 68.8 |
| Comparative example 3 | 76.5 |
| Example 1 | 91.4 |
| Example 2 | 92.2 |
| Example 3 | 93.1 |
| Example 4 | 93.2 |
| Example 5 | 93.4 |
| Example 6 | 89.2 |
| Example 7 | 90.8 |
| Example 8 | 93.8 |
| Example 9 | 93.9 |
| Example 10 | 92.3 |
| Example 11 | 94.8 |
| Example 12 | 92.6 |
| Example 13 | 95.8 |
| Example 14 | 95.3 |
From the data in Table 2, it can be seen that the catalytic rate of the solid acid of PISA/Gu-O-GN was increased by more than 50% as compared with that of comparative example 1 in which the catalyst was not increased, by more than 30% as compared with comparative example 2 in which the ordinary liquid acid catalyst-concentrated sulfuric acid was increased, and by more than 20% as compared with comparative example 3 in which the ordinary solid acid catalyst was increased; the PISA/Gu-O-GN solid acid greatly improves the catalytic activity; on the one hand, the precursor prepared from the graphene suspension has large specific surface area, in addition, the precursor and the active substance PISA form more active sites after being combined, particularly all p orbits of the graphene are mutually perpendicular, electrons in the p orbits can move in the whole carbon atom plane, so metal bonds exist, the metal bonds of the graphene can be mutually bonded with copper hydroxide, the copper hydroxide is embedded into the graphene to form the precursor, and when the precursor is connected, copper is connected with the PISA, and is connected with the graphene to form a stable space three-dimensional connection structure, copper-based solid acid with a space three-dimensional distribution structure has larger specific surface area, the number of effective acid centers of the catalyst is increased, and the active sites are more; thus, the catalytic activity is high.
As is clear from comparative examples 3 and 6 to 9, the reaction time is prolonged from 3h to 8h, the catalytic rate of 1-oxo-methyl-2, 3, 5-trioxybenzoyl-L-ribofuranose is continuously increased, the catalytic rate is linearly increased within 3h to 5h, and then the catalytic rate is slowly increased, which indicates that the optimal time for the reaction is 5h to 6h;
comparative examples 1 to 5 show that with the increase of the solid acid PISA/Gu-O-GN usage and the total 1-oxo-methyl-2, 3, 5-trioxybenzoyl-L-ribofuranose, the product catalytic rate increases and then stabilizes; the solid acid PISA/Gu-O-GN is proved to be no longer a factor limiting the catalysis rate of the product when the dosage of the solid acid PISA/Gu-O-GN exceeds 15 percent of the total amount of the 1-oxo-methyl-2, 3, 5-trioxybenzoyl-L-ribofuranose, so that the catalysis rate of the product is high and the economic benefit is maximum under the condition when the dosage of the solid acid PISA/Gu-O-GN is 15 percent of the total amount of the 1-oxo-methyl-2, 3, 5-trioxybenzoyl-L-ribofuranose;
in comparative example 8, example 10-example 12, it is known that when the calcination temperature of the catalyst is low, the catalyst has low catalytic activity because the PISA binding ability is weak and the catalyst is able to form less active sites, and when the calcination temperature of the catalyst is too high, this will cause decomposition of active ingredients in the catalyst, resulting in a decrease in the amount of active ingredients effective in the catalyst, and thus, the optimum calcination temperature of the present invention is about 400 ℃.
As is clear from comparative examples 11, 13 to 14, the catalyst productivity of the product gradually increased with increasing amount of toluene sulfonic acid per gram of precursor, i.e., increasing amount of PISA, but the catalyst productivity of the product did not significantly increase when 14ml of toluene sulfonic acid per gram of precursor was added, and the reason why the catalyst productivity of 1-oxo-methyl-2, 3, 5-trioxybenzoyl-L-ribofuranose increased gradually became gentle was that, with increasing amount of toluene sulfonic acid, excessive toluene sulfonic acid was not sufficiently adhered to the precursor, and the catalyst activity of solid acid PISA/Gu-O-GN was not increased any more, so that 14ml of toluene sulfonic acid per gram of precursor was the optimum ratio of precursor to toluene sulfonic acid.
Claims (7)
1. A process for preparing 4-fluoro-2, 3, 5-tri-oxo-benzoyl-beta-L-ribofuranose, characterized by comprising the steps of:
s1: preparing a solid acid catalyst PISA/Gu-O-GN;
s2: taking L-ribofuranose as a raw material;
1-oxygen-methyl-beta-L-ribofuranose is obtained through methylation reaction;
→/>；
then carrying out benzoylation reaction on the 1-oxo-methyl-beta-L-ribofuranose to obtain 1-oxo-methyl-2, 3, 5-tri-oxo-benzoyl-beta-L-ribofuranose;
→/>；
s3: the product obtained in the step S2 is reacted by acetylation in the presence of solid acid PISA/Gu-O-GN
1-oxo-acetyl-2, 3, 5-tri-oxo-benzoyl-beta-L-ribofuranose should be produced; in the reaction process, intermittently oscillating the reaction solution by ultrasonic waves;
→/>；
then preparing 2,3, 5-tri-oxo-benzoyl-beta-L-ribofuranose by deacetylation;
→/>；
s4: preparing 4-fluoro-2, 3, 5-tri-oxo-benzoyl-beta-L-ribofuranose from the product obtained in step S3 by a fluorination reaction;
→/>；
the preparation method of the solid acid PISA/Gu-O-GN in S1 comprises the following steps:
s11: preparing graphene suspension; adding graphene oxide and hydrazine into a reaction kettle, performing ultrasonic dispersion, and heating to a reaction temperature for reaction to obtain a graphene precipitate; washing the precipitate, adding water again, and performing ultrasonic dispersion to obtain graphene suspension;
s12: adding a copper hydroxide solution into the graphene suspension under the stirring condition at the temperature of 40-80 ℃, wherein copper hydroxide is embedded into graphene through a metal bond; filtering, washing and drying to obtain a precursor Gu-O-GN;
s13: adding the precursor into toluene sulfonic acid, filtering and drying;
s14: calcining to obtain the PISA/Gu-O-GN solid acid.
2. A process for preparing 4-fluoro-2, 3, 5-tri-oxo-benzoyl-beta-L-ribofuranose according to claim 1, wherein the solid acid PISA/Gu-O-GN is used in an amount of 15% by mass of 1-oxo-methyl-2, 3, 5-tri-oxo-benzoyl-beta-L-ribofuranose.
3. A process for preparing 4-fluoro-2, 3, 5-tri-oxo-benzoyl- β -L-ribofuranose according to claim 1, wherein the acetylation reaction time is 5h to 6h in step S3.
4. A process for preparing 4-fluoro-2, 3, 5-tri-oxo-benzoyl- β -L-ribofuranose according to claim 1, wherein the calcination temperature in S14 is 400 ℃.
5. A process for preparing 4-fluoro-2, 3, 5-tri-oxo-benzoyl-beta-L-ribofuranose according to claim 1, wherein 1 g of precursor is mixed per 14ml of toluene sulfonic acid in S13.
6. A process for preparing 4-fluoro-2, 3, 5-tri-oxo-benzoyl-beta-L-ribofuranose according to claim 1, wherein the acetylation reaction in S3 is carried out to obtain 1-oxo-acetyl-2, 3, 5-tri-oxo-benzoyl-beta-L-ribofuranose:
taking 1-oxygen-methyl-2, 3, 5-tri-oxygen-benzoyl-beta-L-ribofuranose, adding solid acid PISA/Gu-O-GN, acetic acid and acetic anhydride, and carrying out heat preservation, airtight stirring and reaction for 3-5 h at the water bath of 0 ℃;
concentrating, crystallizing, washing and filtering to obtain solid 1-oxo-acetyl-2, 3, 5-tri-oxo-benzoyl-beta-L-ribofuranose.
7. The method for preparing 4-fluoro-2, 3, 5-tri-oxo-benzoyl-beta-L-ribofuranose according to claim 1, wherein in step S4, solid 2,3, 5-tri-oxo-benzoyl-beta-L-ribofuranose is dissolved by ethyl acetate, triethylamine hydrofluoric acid is added, reflux stirring reaction is carried out at 80 ℃ for 18h-25h, saturated sodium bicarbonate solution is added after the reaction is finished, and a solvent layer is taken;
concentrating under reduced pressure, crystallizing, filtering, and oven drying to obtain solid 4-fluoro-2, 3, 5-tri-oxo-benzoyl-beta
-L-ribofuranose.
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| WO2009058800A2 (en) * | 2007-10-29 | 2009-05-07 | President And Fellows Of Harvard College | Synthesis of nucleosides |
| CN108440286A (en) * | 2018-04-18 | 2018-08-24 | 肖锦 | A kind of method for preparing acetylsalicylic acid |
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| CN101274950A (en) * | 2008-03-31 | 2008-10-01 | 葛建利 | Production process for preparing 1-oxy-acetyl-2,3,5-3-benzoyl-beta-Lribofuranose |
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