CN111961056A - Method for simultaneously synthesizing hypoxanthine and tetraacetyl ribose by utilizing inosine - Google Patents
Method for simultaneously synthesizing hypoxanthine and tetraacetyl ribose by utilizing inosine Download PDFInfo
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- CN111961056A CN111961056A CN202010872784.2A CN202010872784A CN111961056A CN 111961056 A CN111961056 A CN 111961056A CN 202010872784 A CN202010872784 A CN 202010872784A CN 111961056 A CN111961056 A CN 111961056A
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- hypoxanthine
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- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical compound O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 title claims abstract description 154
- UGQMRVRMYYASKQ-UHFFFAOYSA-N Hypoxanthine nucleoside Natural products OC1C(O)C(CO)OC1N1C(NC=NC2=O)=C2N=C1 UGQMRVRMYYASKQ-UHFFFAOYSA-N 0.000 title claims abstract description 76
- IHNHAHWGVLXCCI-FDYHWXHSSA-N [(2r,3r,4r,5s)-3,4,5-triacetyloxyoxolan-2-yl]methyl acetate Chemical compound CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O IHNHAHWGVLXCCI-FDYHWXHSSA-N 0.000 title claims abstract description 69
- UGQMRVRMYYASKQ-KQYNXXCUSA-N Inosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(O)=C2N=C1 UGQMRVRMYYASKQ-KQYNXXCUSA-N 0.000 title claims abstract description 35
- 229930010555 Inosine Natural products 0.000 title claims abstract description 35
- 229960003786 inosine Drugs 0.000 title claims abstract description 35
- 238000000034 method Methods 0.000 title claims abstract description 33
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 23
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims abstract description 120
- 238000002156 mixing Methods 0.000 claims abstract description 45
- 238000006243 chemical reaction Methods 0.000 claims abstract description 37
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 36
- 238000001816 cooling Methods 0.000 claims abstract description 34
- 238000001035 drying Methods 0.000 claims abstract description 27
- 238000005406 washing Methods 0.000 claims abstract description 21
- 239000012065 filter cake Substances 0.000 claims abstract description 19
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000000706 filtrate Substances 0.000 claims abstract description 18
- 238000004321 preservation Methods 0.000 claims abstract description 16
- 239000012043 crude product Substances 0.000 claims abstract description 15
- 239000007788 liquid Substances 0.000 claims abstract description 13
- 238000000926 separation method Methods 0.000 claims abstract description 13
- 239000003960 organic solvent Substances 0.000 claims abstract description 7
- 239000000047 product Substances 0.000 claims abstract description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 51
- 239000011259 mixed solution Substances 0.000 claims description 50
- 238000010438 heat treatment Methods 0.000 claims description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 239000012141 concentrate Substances 0.000 claims description 16
- 238000001914 filtration Methods 0.000 claims description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 10
- 239000004327 boric acid Substances 0.000 claims description 10
- 238000004821 distillation Methods 0.000 claims description 8
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 14
- 238000005119 centrifugation Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 6
- 238000000967 suction filtration Methods 0.000 description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000012668 chain scission Methods 0.000 description 2
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 2
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- 230000004048 modification Effects 0.000 description 2
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- 238000006467 substitution reaction Methods 0.000 description 2
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- 201000005569 Gout Diseases 0.000 description 1
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 1
- ULGWSQDVFZIBKN-FDYHWXHSSA-N [(2R,3R,4S,5S)-3,4,5-triacetyl-3,4,5-trihydroxyoxolan-2-yl]methyl acetate Chemical compound C(C)(=O)[C@]1(O)[C@](O)([C@](O)([C@H](O1)COC(C)=O)C(C)=O)C(C)=O ULGWSQDVFZIBKN-FDYHWXHSSA-N 0.000 description 1
- IHNHAHWGVLXCCI-PFGBXZAXSA-N [(2r,3r,4r)-3,4,5-triacetyloxyoxolan-2-yl]methyl acetate Chemical compound CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O IHNHAHWGVLXCCI-PFGBXZAXSA-N 0.000 description 1
- 238000007171 acid catalysis Methods 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 238000012271 agricultural production Methods 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 230000009876 antimalignant effect Effects 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 1
- 229960002170 azathioprine Drugs 0.000 description 1
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- 230000036772 blood pressure Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
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- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 201000002364 leukopenia Diseases 0.000 description 1
- 231100001022 leukopenia Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
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- 229960000329 ribavirin Drugs 0.000 description 1
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/28—Oxygen atom
- C07D473/30—Oxygen atom attached in position 6, e.g. hypoxanthine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- 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
-
- 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
- C07H13/04—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 attached to acyclic carbon atoms
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- Chemical & Material Sciences (AREA)
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
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- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
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Abstract
The invention discloses a method for simultaneously synthesizing hypoxanthine and tetraacetyl ribose by utilizing inosine, which comprises the steps of taking inosine and acetic anhydride as raw materials, carrying out heat preservation reaction at 105-110 ℃, cooling to 0-5 ℃ after the reaction is finished, carrying out solid-liquid separation, and collecting filter cakes and filtrate; washing and drying a filter cake to obtain a crude product hypoxanthine, mixing the crude product hypoxanthine with a certain amount of water, adjusting the pH value of a system to 7-7.5, carrying out heat preservation reaction at the temperature of 60-65 ℃, cooling to room temperature, carrying out solid-liquid separation, and obtaining a finished product hypoxanthine; and (3) concentrating the filtrate, recrystallizing with water, carrying out solid-liquid separation and washing with water to obtain a crude product of tetraacetyl ribose, dissolving in an organic solvent, decolorizing with activated carbon, recrystallizing, carrying out solid-liquid separation, and drying to obtain a finished product of tetraacetyl ribose. The inosine is utilized to simultaneously synthesize hypoxanthine and tetraacetyl ribose, wherein the yield of the hypoxanthine is more than 95%, the purity of the hypoxanthine is more than 99.5%, the yield of the tetraacetyl ribose is more than 95%, the purity of the tetraacetyl ribose is more than 99.5%, and the method is suitable for industrial production and high in economic benefit.
Description
Technical Field
The invention relates to the field of chemical synthesis, in particular to a method for simultaneously synthesizing hypoxanthine and tetraacetyl ribose by utilizing inosine.
Background
Hypoxanthine (Hypoxanthine), also known as 6-hydroxypurine, has the molecular formula C5H4N4And O. Hypoxanthine is an unimportant alkaloid, is widely distributed in a human body, can participate in regulating some important physiological functions in the human body, has pharmacological activities of reducing blood pressure, relieving asthma, treating gout and the like, and can be used for treating diseases such as leukopenia, thrombocytopenia and the like caused by various reasons; meanwhile, hypoxanthine is also an important intermediate for synthesizing 6-mercaptopurine and azathioprine which are anti-malignant tumor drugs. In addition, hypoxanthine is a biological pigment with pearlescent characteristic, is safe and nontoxic, and can be used as food pigment, cosmetic pigment and accessory additive, and also has fresh-keeping effect. In agricultural production, hypoxanthine has a bactericidal effect and can be used as an intermediate of pesticides.
Tetraacetyl ribose (1,2,3,5-tetra-O-acetyl-D-ribofuranose), also known as 1,2,3, 5-O-tetraacetyl-beta-D-ribofuranose, having the molecular formula C13H18O9It is prepared by degrading and acylating nucleotide, and is an important intermediate for producing ribavirin as antiviral medicine in medicine industry.
Chinese patent application CN111333650A discloses a method for preparing hypoxanthine by inosine hydrolysis, which uses inosine as raw material and water as reaction solvent to obtain hypoxanthine under acidic hydrolysis condition. Meanwhile, the synthesis of tetraacetyl ribose by acid catalysis using inosine as raw material has also been widely used in industry.
Disclosure of Invention
The invention aims to provide a method for simultaneously synthesizing hypoxanthine and tetraacetyl ribose by utilizing inosine.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows: a method for simultaneously synthesizing hypoxanthine and tetraacetyl ribose by utilizing inosine comprises the following steps:
(1) uniformly mixing acetic anhydride and inosine according to a certain proportion to obtain a mixed solution 1; uniformly mixing acetic anhydride and boric acid according to a certain proportion, and heating to 105-110 ℃ to obtain a mixed solution 2; slowly adding the mixed solution 1 into the mixed solution 2, and after all the mixed solution is added, carrying out heat preservation reaction at 105-110 ℃ for 6-6.5 h; then distilling off part of acetic acid under the condition of micro negative pressure below 0.04MPa, and continuing to perform heat preservation reaction at 105-110 ℃ for 6-6.5 h after the distillation is finished; after the reaction is finished, cooling to 0-5 ℃, carrying out solid-liquid separation, and collecting a filter cake and filtrate; further washing and drying the filter cake to obtain a crude product of hypoxanthine;
(2) heating and concentrating the filtrate prepared in the step (1) to obtain a concentrate; mixing the concentrate with a certain amount of water, heating, cooling to 0-5 ℃, crystallizing, performing solid-liquid separation, and washing with water to obtain a crude product of tetraacetyl ribose;
(3) dissolving the crude product tetraacetyl ribose prepared in the step (2) in an organic solvent, adding activated carbon, decoloring at 60-65 ℃, filtering after decoloring, cooling to 0-5 ℃ for crystallization, performing solid-liquid separation, and drying to obtain a finished product tetraacetyl ribose;
(4) mixing the crude hypoxanthine prepared in the step (1) with a certain amount of water, adjusting the pH value of a system to 7-7.5, carrying out heat preservation reaction at 60-65 ℃ for 30min, then cooling to 20-30 ℃, carrying out solid-liquid separation, and drying to obtain the finished hypoxanthine.
Preferably, the mass ratio of the total amount of acetic anhydride to boric acid in inosine, the mixed solution 1 and the mixed solution 2 in the step (1) is 1: 4.4: 0.005.
preferably, the mass ratio of the acetic anhydride in the mixed solution 1 to the acetic anhydride in the mixed solution 2 in the step (1) is 1: 1.
preferably, the amount of the distilled acetic acid in the step (1) is 20-30% of the total amount of the theoretically generated acetic acid.
Preferably, the feeding speed of the mixed solution 1 in the step (1) is 4-6 cubic meters per hour.
Preferably, the filter cake washing in the step (1) adopts acetic anhydride for washing for 2-4 times.
Preferably, the drying manner in the step (1) is vacuum drying.
Preferably, the heating temperature in the step (2) is 80-85 ℃.
Preferably, the solid-liquid separation method in step (3) and step (4) is centrifugation.
Preferably, the mass ratio of the crude tetraacetyl ribose and the organic solvent in the step (3) is 1: 3.
More preferably, the organic solvent in step (3) is selected from one or more of methanol, ethanol and ethyl acetate.
Preferably, the mass ratio of the crude hypoxanthine and water in the step (4) is 1: 5.
The reaction principle of the invention is as follows:
compared with the prior art, the invention has the following beneficial effects:
(1) during the preparation of hypoxanthine, inosine needs to absorb heat during chain scission, the chain scission instant releases heat, the scheme neutralizes the heat release, improves the safety, distills acetic acid in the middle period, promotes the positive reaction, improves the yield, and distills solvent to reduce the solubility.
(2) The method utilizes inosine and acetic anhydride as raw materials and phosphoric acid as a catalyst to simultaneously synthesize hypoxanthine and tetraacetyl ribose, wherein the yield of the hypoxanthine is more than 95%, the purity of the hypoxanthine is more than 99.5%, the yield of the tetraacetyl ribose is more than 95%, and the purity of the tetraacetyl ribose is more than 99.5%.
(3) The method has simple process, is very beneficial to the large-scale production of hypoxanthine and tetraacetyl ribose, can greatly reduce the processing cost of the hypoxanthine and the tetraacetyl ribose, and improves the production efficiency of the hypoxanthine and the tetraacetyl ribose.
Drawings
FIG. 1 is an HPLC chromatogram of hypoxanthine prepared in example 1 of the present invention;
FIG. 2 is an HPLC chromatogram of tetraacetylribose prepared in example 1 of the present invention.
Detailed Description
The invention is described in further detail below with reference to the figures and specific examples.
Example 1
A method for simultaneously synthesizing hypoxanthine and tetraacetyl ribose by utilizing inosine comprises the following steps:
(1) mixing acetic anhydride and inosine according to a mass ratio of 2.2: 1, uniformly mixing to obtain a mixed solution 1; mixing acetic anhydride and boric acid according to a mass ratio of 2.2: 0.005, uniformly mixing, and heating to 105 ℃ to obtain a mixed solution 2; adding the mixed solution 1 into the mixed solution 2 at a speed of 5 cubic meters per hour, and after all the mixed solution is added, keeping the temperature at 105 ℃ for reaction for 6.5 hours; then distilling off acetic acid with the theoretical yield of 20% under the condition of micro negative pressure below 0.04MPa, and keeping the temperature at 105 ℃ after the distillation is finished to continue the reaction for 6.5 hours; after the reaction is finished, cooling to 0 ℃, performing suction filtration, and collecting a filter cake and filtrate; washing the filter cake for 2 times by using acetic anhydride, and drying in vacuum to obtain a crude product hypoxanthine;
(2) concentrating the filtrate obtained in the step (1) under reduced pressure to obtain a concentrate, and recovering a mixture of acetic acid and acetic anhydride in the process of concentrating under reduced pressure; mixing the concentrate with a certain amount of water, heating to dissolve, cooling to 0 ℃, crystallizing, filtering, and washing with water to obtain crude tetraacetyl ribose;
(3) dissolving the crude tetraacetyl ribose prepared in the step (2) in ethanol, wherein the mass ratio of the ethanol to the crude tetraacetyl ribose is 3:1, adding activated carbon, decoloring at 60 ℃, filtering after decoloring, cooling to 0 ℃, crystallizing, centrifuging, and drying in a double-cone dryer at 70 ℃ to obtain a finished product of tetraacetyl ribose, wherein the yield is 95.6%; according to the HPLC analysis result, as shown in FIG. 2, the purity of tetraacetyl ribose was 99.91%;
(4) mixing the crude hypoxanthine prepared in the step (1) with water, wherein the mass ratio of the crude hypoxanthine to the water is 1:5, heating to 60 ℃ after feeding is finished, adjusting the pH of a system to be 7.1 by using ammonia water, carrying out heat preservation reaction at 60 ℃ for 30min, then cooling to 20 ℃, carrying out centrifugation, and drying at 70 ℃ in a double-cone dryer to obtain a finished product hypoxanthine, wherein the yield is 95.5%; according to the HPLC analysis, the purity was 99.88% as shown in FIG. 1.
Example 2
A method for simultaneously synthesizing hypoxanthine and tetraacetyl ribose by utilizing inosine comprises the following steps:
(1) mixing acetic anhydride and inosine according to a mass ratio of 2.2: 1, uniformly mixing to obtain a mixed solution 1; mixing acetic anhydride and boric acid according to a mass ratio of 2.2: 0.005, uniformly mixing, and heating to 106 ℃ to obtain a mixed solution 2; adding the mixed solution 1 into the mixed solution 2 at a speed of 4 cubic meters per hour, and after all the mixed solution is added, keeping the temperature at 106 ℃ for reaction for 6.5 hours; then distilling off acetic acid with the theoretical yield of 25% under the condition of micro negative pressure below 0.04MPa, and keeping the temperature at 106 ℃ after the distillation is finished to continue the reaction for 6.5 hours; after the reaction is finished, cooling to 5 ℃, carrying out suction filtration, and collecting a filter cake and filtrate; washing the filter cake for 3 times by using acetic anhydride, and drying in vacuum to obtain a crude product hypoxanthine;
(2) concentrating the filtrate obtained in the step (1) under reduced pressure to obtain a concentrate, and recovering a mixture of acetic acid and acetic anhydride in the process of concentrating under reduced pressure; mixing the concentrate with a certain amount of water, heating to dissolve, cooling to 5 ℃, crystallizing, filtering, and washing with water to obtain crude tetraacetyl ribose;
(3) dissolving the crude tetraacetyl ribose prepared in the step (2) in methanol, wherein the mass ratio of the methanol to the crude tetraacetyl ribose is 3:1, adding activated carbon, decoloring at 60 ℃, filtering after decoloring, cooling to 0 ℃, crystallizing, centrifuging, and drying in a double-cone dryer at 70 ℃ to obtain the finished tetraacetyl ribose, wherein the yield is 95.3%, and the HPLC purity is 99.82%;
(4) mixing the crude hypoxanthine prepared in the step (1) with water, wherein the mass ratio of the crude hypoxanthine to the water is 1:5, heating to 65 ℃ after feeding is finished, adjusting the pH of a system to be 7.2 by using sodium hydroxide, carrying out heat preservation reaction at 65 ℃ for 30min, then cooling to 25 ℃, carrying out centrifugation, and drying at 70 ℃ in a double-cone dryer to obtain the finished hypoxanthine, wherein the yield is 96.5%, and the HPLC purity is 99.55%.
Example 3
A method for simultaneously synthesizing hypoxanthine and tetraacetyl ribose by utilizing inosine comprises the following steps:
(1) mixing acetic anhydride and inosine according to a mass ratio of 2.2: 1, uniformly mixing to obtain a mixed solution 1; mixing acetic anhydride and boric acid according to a mass ratio of 2.2: 0.005 uniformly mixing, and heating to 107 ℃ to obtain a mixed solution 2; adding the mixed solution 1 into the mixed solution 2 at a speed of 5 cubic meters per hour, and after all the mixed solution is added, keeping the temperature at 107 ℃ for reaction for 6 hours; then distilling off acetic acid with the theoretical yield of 20% under the condition of micro negative pressure below 0.04MPa, and keeping the temperature at 107 ℃ after the distillation is finished to continue the reaction for 6 hours; after the reaction is finished, cooling to 0 ℃, performing suction filtration, and collecting a filter cake and filtrate; washing the filter cake for 2 times by using acetic anhydride, and drying in vacuum to obtain a crude product hypoxanthine;
(2) concentrating the filtrate obtained in the step (1) under reduced pressure to obtain a concentrate, and recovering a mixture of acetic acid and acetic anhydride in the process of concentrating under reduced pressure; mixing the concentrate with a certain amount of water, heating to dissolve, cooling to 0 ℃, crystallizing, filtering, and washing with water to obtain crude tetraacetyl ribose;
(3) dissolving the crude tetraacetyl ribose prepared in the step (2) in ethanol, wherein the mass ratio of the ethanol to the crude tetraacetyl ribose is 3:1, adding activated carbon, decoloring at 60 ℃, filtering after decoloring, cooling to 0 ℃, crystallizing, centrifuging, and drying in a double-cone dryer at 70 ℃ to obtain the finished tetraacetyl ribose, wherein the yield is 96.2%, and the HPLC purity is 99.70%;
(4) mixing the crude hypoxanthine prepared in the step (1) with water, wherein the mass ratio of the crude hypoxanthine to the water is 1:5, heating to 60 ℃ after feeding is finished, adjusting the pH of a system to 7 by using ammonia water, carrying out heat preservation reaction at 60 ℃ for 30min, then cooling to 30 ℃, carrying out centrifugation, and drying at 70 ℃ in a double-cone dryer to obtain the finished hypoxanthine, wherein the yield is 96.0%, and the HPLC purity is 99.73%.
Example 4
A method for simultaneously synthesizing hypoxanthine and tetraacetyl ribose by utilizing inosine comprises the following steps:
(1) mixing acetic anhydride and inosine according to a mass ratio of 2.2: 1, uniformly mixing to obtain a mixed solution 1; mixing acetic anhydride and boric acid according to a mass ratio of 2.2: 0.005, uniformly mixing, and heating to 108 ℃ to obtain a mixed solution 2; adding the mixed solution 1 into the mixed solution 2 at a speed of 4.5 cubic meters per hour, and after all the mixed solution is added, carrying out heat preservation reaction at 108 ℃ for 6 hours; then distilling off acetic acid with the theoretical yield of 20% under the condition of micro negative pressure below 0.04MPa, and keeping the temperature at 108 ℃ after the distillation is finished to continue the reaction for 6.5 hours; after the reaction is finished, cooling to 0 ℃, performing suction filtration, and collecting a filter cake and filtrate; washing the filter cake for 2 times by using acetic anhydride, and drying in vacuum to obtain a crude product hypoxanthine;
(2) concentrating the filtrate obtained in the step (1) under reduced pressure to obtain a concentrate, and recovering a mixture of acetic acid and acetic anhydride in the process of concentrating under reduced pressure; mixing the concentrate with a certain amount of water, heating to dissolve, cooling to 0 ℃, crystallizing, filtering, and washing with water to obtain crude tetraacetyl ribose;
(3) dissolving the crude tetraacetyl ribose prepared in the step (2) in ethanol, wherein the mass ratio of the ethanol to the crude tetraacetyl ribose is 3:1, adding activated carbon, decoloring at 60 ℃, filtering after decoloring, cooling to 0 ℃, crystallizing, centrifuging, and drying in a double-cone dryer at 70 ℃ to obtain the finished tetraacetyl ribose, wherein the yield is 95.8%, and the HPLC purity is 99.83%;
(4) mixing the crude hypoxanthine prepared in the step (1) with water, wherein the mass ratio of the crude hypoxanthine to the water is 1:5, heating to 60 ℃ after feeding is finished, adjusting the pH value of a system to 7.3 by using ammonia water, carrying out heat preservation reaction at 60 ℃ for 30min, then cooling to 20 ℃, carrying out centrifugation, and drying at 70 ℃ in a double-cone dryer to obtain the finished hypoxanthine, wherein the yield is 96.2%, and the HPLC purity is 99.68%.
Example 5
A method for simultaneously synthesizing hypoxanthine and tetraacetyl ribose by utilizing inosine comprises the following steps:
(1) mixing acetic anhydride and inosine according to a mass ratio of 2.2: 1, uniformly mixing to obtain a mixed solution 1; mixing acetic anhydride and boric acid according to a mass ratio of 2.2: 0.005, uniformly mixing, and heating to 109 ℃ to obtain a mixed solution 2; adding the mixed solution 1 into the mixed solution 2 at a speed of 5.5 cubic meters per hour, and after all the mixed solution is added, carrying out heat preservation reaction at 109 ℃ for 6 hours; then distilling to remove acetic acid with the theoretical yield of 30% under the condition of micro negative pressure below 0.04MPa, and keeping the temperature at 109 ℃ after the distillation is finished to continue the reaction for 6.5 hours; after the reaction is finished, cooling to 5 ℃, carrying out suction filtration, and collecting a filter cake and filtrate; washing the filter cake for 4 times by using acetic anhydride, and drying in vacuum to obtain a crude product hypoxanthine;
(2) concentrating the filtrate obtained in the step (1) under reduced pressure to obtain a concentrate, and recovering a mixture of acetic acid and acetic anhydride in the process of concentrating under reduced pressure; mixing the concentrate with a certain amount of water, heating to dissolve, cooling to 5 ℃, crystallizing, filtering, and washing with water to obtain crude tetraacetyl ribose;
(3) dissolving the crude tetraacetyl ribose prepared in the step (2) in ethyl acetate, wherein the mass ratio of the ethyl acetate to the crude tetraacetyl ribose is 3:1, adding activated carbon, decoloring at 65 ℃, filtering after decoloring, cooling to 5 ℃, crystallizing, centrifuging, and drying in a double-cone dryer at 75 ℃ to obtain the finished tetraacetyl ribose, wherein the yield is 96.5%, and the HPLC purity is 99.64%;
(4) mixing the crude hypoxanthine prepared in the step (1) with water, wherein the mass ratio of the crude hypoxanthine to the water is 1:5, heating to 65 ℃ after feeding is finished, adjusting the pH value of a system to 7.5 by using ammonia water, carrying out heat preservation reaction at 65 ℃ for 30min, then cooling to 25 ℃, carrying out centrifugation, and drying at 75 ℃ in a double-cone dryer to obtain the finished hypoxanthine, wherein the yield is 95.6%, and the HPLC purity is 99.69%.
Example 6
A method for simultaneously synthesizing hypoxanthine and tetraacetyl ribose by utilizing inosine comprises the following steps:
(1) mixing acetic anhydride and inosine according to a mass ratio of 2.2: 1, uniformly mixing to obtain a mixed solution 1; mixing acetic anhydride and boric acid according to a mass ratio of 2.2: 0.005, uniformly mixing, and heating to 110 ℃ to obtain a mixed solution 2; adding the mixed solution 1 into the mixed solution 2 at the speed of 6 cubic meters per hour, and after all the mixed solution is added, keeping the temperature at 110 ℃ for reaction for 6 hours; then distilling to remove acetic acid with the theoretical yield of 30% under the condition of micro negative pressure below 0.04MPa, and keeping the temperature at 110 ℃ after the distillation is finished to continue the reaction for 6 hours; after the reaction is finished, cooling to 5 ℃, carrying out suction filtration, and collecting a filter cake and filtrate; washing the filter cake for 4 times by using acetic anhydride, and drying in vacuum to obtain a crude product hypoxanthine;
(2) concentrating the filtrate obtained in the step (1) under reduced pressure to obtain a concentrate, and recovering a mixture of acetic acid and acetic anhydride in the process of concentrating under reduced pressure; mixing the concentrate with a certain amount of water, heating to dissolve, cooling to 5 ℃, crystallizing, filtering, and washing with water to obtain crude tetraacetyl ribose;
(3) dissolving the crude tetraacetyl ribose prepared in the step (2) in ethyl acetate, wherein the mass ratio of the ethyl acetate to the crude tetraacetyl ribose is 3:1, adding activated carbon, decoloring at 65 ℃, filtering after decoloring, cooling to 5 ℃, crystallizing, centrifuging, and drying at 75 ℃ in a double-cone dryer to obtain the finished tetraacetyl ribose, wherein the yield is 96.6%, and the HPLC purity is 99.58%;
(4) mixing the crude hypoxanthine prepared in the step (1) with water, wherein the mass ratio of the crude hypoxanthine to the water is 1:5, heating to 65 ℃ after feeding is finished, adjusting the pH value of a system to 7.4 by using ammonia water, carrying out heat preservation reaction at 65 ℃ for 30min, then cooling to 30 ℃, carrying out centrifugation, and drying at 75 ℃ in a double-cone dryer to obtain the finished hypoxanthine, wherein the yield is 96.8%, and the HPLC purity is 99.51%.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (10)
1. A method for simultaneously synthesizing hypoxanthine and tetraacetyl ribose by utilizing inosine is characterized by comprising the following steps:
(1) uniformly mixing acetic anhydride and inosine according to a certain proportion to obtain a mixed solution 1; uniformly mixing acetic anhydride and boric acid according to a certain proportion, and heating to 105-110 ℃ to obtain a mixed solution 2; slowly adding the mixed solution 1 into the mixed solution 2, and after all the mixed solution is added, carrying out heat preservation reaction at 105-110 ℃ for 6-6.5 h; then distilling off part of acetic acid under the condition of micro negative pressure below 0.04MPa, and continuing to perform heat preservation reaction at 105-110 ℃ for 6-6.5 h after the distillation is finished; after the reaction is finished, cooling to 0-5 ℃, carrying out solid-liquid separation, and collecting a filter cake and filtrate; further washing and drying the filter cake to obtain a crude product of hypoxanthine;
(2) heating and concentrating the filtrate prepared in the step (1) to obtain a concentrate; mixing the concentrate with a certain amount of water, heating to dissolve, cooling to 0-5 ℃, crystallizing, performing solid-liquid separation, and washing with water to obtain a crude product of tetraacetyl ribose;
(3) dissolving the crude product tetraacetyl ribose prepared in the step (2) in an organic solvent, adding activated carbon, decoloring at 60-65 ℃, filtering after decoloring, cooling to 0-5 ℃ for crystallization, performing solid-liquid separation, and drying to obtain a finished product tetraacetyl ribose;
(4) mixing the crude hypoxanthine prepared in the step (1) with a certain amount of water, adjusting the pH value of a system to 7-7.5, carrying out heat preservation reaction at 60-65 ℃ for 30min, then cooling to 20-30 ℃, carrying out solid-liquid separation, and drying to obtain the finished hypoxanthine.
2. The method for simultaneously synthesizing hypoxanthine and tetraacetylribose according to claim 1, wherein the weight ratio of the total amount of acetic anhydride in inosine, mixed solution 1 and mixed solution 2 to boric acid in step (1) is 1: 4.4: 0.005.
3. the method for simultaneously synthesizing hypoxanthine and tetraacetyl ribose according to claim 1, wherein the ratio of the mass of acetic anhydride in the mixed solution 1 to the mass of acetic anhydride in the mixed solution 2 in step (1) is 1: 1.
4. the method for simultaneously synthesizing hypoxanthine and tetraacetyl ribose using inosine according to claim 1, wherein the amount of acetic acid distilled off in step (1) is 20 to 30% of the total amount of theoretically generated acetic acid.
5. The method for simultaneously synthesizing hypoxanthine and tetraacetyl ribose using inosine according to claim 1, wherein the feeding speed of the mixed solution 1 in the step (1) is 4 to 6 cubic meters per hour.
6. The method for simultaneously synthesizing hypoxanthine and tetraacetyl ribose according to claim 1, wherein the cake washing in step (1) is performed 2-4 times using acetic anhydride.
7. The method for simultaneously synthesizing hypoxanthine and tetraacetyl ribose using inosine according to claim 1, wherein the heating temperature in the step (2) is 80 to 85 ℃.
8. The method for simultaneously synthesizing hypoxanthine and tetraacetyl ribose using inosine as claimed in claim 1, wherein the ratio of the crude tetraacetyl ribose in step (3) to the organic solvent is 1:3 by mass.
9. The method for simultaneously synthesizing hypoxanthine and tetraacetyl ribose according to claim 8, wherein the organic solvent in step (3) is one or more selected from methanol, ethanol, and ethyl acetate.
10. The method for simultaneously synthesizing hypoxanthine and tetraacetylribose using inosine according to claim 1, wherein the mass ratio of the crude hypoxanthine and water in step (4) is 1: 5.
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