CN112341509A - Preparation method of N6-benzoyl adenosine - Google Patents
Preparation method of N6-benzoyl adenosine Download PDFInfo
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- CN112341509A CN112341509A CN201910732061.XA CN201910732061A CN112341509A CN 112341509 A CN112341509 A CN 112341509A CN 201910732061 A CN201910732061 A CN 201910732061A CN 112341509 A CN112341509 A CN 112341509A
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- NZDWTKFDAUOODA-CNEMSGBDSA-N n-[9-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]purin-6-yl]benzamide Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(NC(=O)C=3C=CC=CC=3)=C2N=C1 NZDWTKFDAUOODA-CNEMSGBDSA-N 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims abstract description 46
- 238000003756 stirring Methods 0.000 claims abstract description 30
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 claims abstract description 28
- 239000012065 filter cake Substances 0.000 claims abstract description 28
- 239000005711 Benzoic acid Substances 0.000 claims abstract description 23
- 235000010233 benzoic acid Nutrition 0.000 claims abstract description 23
- 239000003223 protective agent Substances 0.000 claims abstract description 22
- 239000002904 solvent Substances 0.000 claims abstract description 20
- 238000001914 filtration Methods 0.000 claims abstract description 18
- 239000002126 C01EB10 - Adenosine Substances 0.000 claims abstract description 14
- 229960005305 adenosine Drugs 0.000 claims abstract description 14
- 238000001816 cooling Methods 0.000 claims abstract description 10
- 150000002191 fatty alcohols Chemical class 0.000 claims abstract description 10
- 238000010992 reflux Methods 0.000 claims abstract description 10
- 238000001035 drying Methods 0.000 claims abstract description 8
- 238000001704 evaporation Methods 0.000 claims abstract description 8
- 238000010438 heat treatment Methods 0.000 claims abstract description 8
- 239000000203 mixture Substances 0.000 claims abstract description 8
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- 239000012670 alkaline solution Substances 0.000 claims abstract description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 4
- 238000004321 preservation Methods 0.000 claims abstract description 3
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 claims description 26
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 15
- 239000000706 filtrate Substances 0.000 claims description 14
- 238000002386 leaching Methods 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 14
- 229940095102 methyl benzoate Drugs 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 239000008367 deionised water Substances 0.000 claims description 12
- 229910021641 deionized water Inorganic materials 0.000 claims description 12
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 claims description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical group OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 10
- KYZHGEFMXZOSJN-UHFFFAOYSA-N isobutyl benzoate Chemical compound CC(C)COC(=O)C1=CC=CC=C1 KYZHGEFMXZOSJN-UHFFFAOYSA-N 0.000 claims description 10
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 claims description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- XSIFPSYPOVKYCO-UHFFFAOYSA-N butyl benzoate Chemical compound CCCCOC(=O)C1=CC=CC=C1 XSIFPSYPOVKYCO-UHFFFAOYSA-N 0.000 claims description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 6
- DUAYDERMVQWIJD-UHFFFAOYSA-N 2-n,2-n,6-trimethyl-1,3,5-triazine-2,4-diamine Chemical compound CN(C)C1=NC(C)=NC(N)=N1 DUAYDERMVQWIJD-UHFFFAOYSA-N 0.000 claims description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 150000002148 esters Chemical group 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- FEXQDZTYJVXMOS-UHFFFAOYSA-N Isopropyl benzoate Chemical compound CC(C)OC(=O)C1=CC=CC=C1 FEXQDZTYJVXMOS-UHFFFAOYSA-N 0.000 claims description 2
- UDEWPOVQBGFNGE-UHFFFAOYSA-N benzoic acid n-propyl ester Natural products CCCOC(=O)C1=CC=CC=C1 UDEWPOVQBGFNGE-UHFFFAOYSA-N 0.000 claims description 2
- 238000009835 boiling Methods 0.000 claims description 2
- OLXYLDUSSBULGU-UHFFFAOYSA-N methyl pyridine-4-carboxylate Chemical compound COC(=O)C1=CC=NC=C1 OLXYLDUSSBULGU-UHFFFAOYSA-N 0.000 claims description 2
- -1 protectant Substances 0.000 claims description 2
- 239000006227 byproduct Substances 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 3
- 125000004429 atom Chemical group 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 231100000331 toxic Toxicity 0.000 abstract description 2
- 230000002588 toxic effect Effects 0.000 abstract description 2
- 125000004122 cyclic group Chemical group 0.000 abstract 1
- 125000004185 ester group Chemical group 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 10
- VTAPXODOLMOLNK-PCYKNENESA-N [(2s,3r,4s,5r)-2-(6-aminopurin-9-yl)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-phenylmethanone Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@]1(C(=O)C=2C=CC=CC=2)O[C@H](CO)[C@@H](O)[C@H]1O VTAPXODOLMOLNK-PCYKNENESA-N 0.000 description 10
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 8
- 238000005886 esterification reaction Methods 0.000 description 7
- 230000032050 esterification Effects 0.000 description 6
- 238000006555 catalytic reaction Methods 0.000 description 5
- 238000005303 weighing Methods 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- 238000006136 alcoholysis reaction Methods 0.000 description 2
- 238000007098 aminolysis reaction Methods 0.000 description 2
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000005051 trimethylchlorosilane Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000006480 benzoylation reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 239000010815 organic waste Substances 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/19—Purine radicals with arabinosyl as the saccharide radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Saccharide Compounds (AREA)
Abstract
The invention discloses a preparation method of N6-benzoyl adenosine, which comprises the following steps: (1) putting adenosine and a protective agent into a flask, adding a solvent and a catalyst, stirring and refluxing for a period of time, evaporating part of the solvent, and continuing heat preservation treatment, wherein the protective agent is ester formed by benzoic acid and fatty alcohol with less than or equal to five carbon atoms; (2) cooling the mixture obtained in the step (1), continuously stirring, and filtering to obtain a filter cake; (3) and (3) heating the weak alkaline solution in the filter cake obtained in the step (2), stirring for a period of time, filtering, and drying the filter cake to obtain the N6-benzoyl adenosine. The preparation method of the N6-benzoyl adenosine provided by the invention fully utilizes the byproducts in the preparation process, has an atom utilization rate close to 100%, realizes the cyclic utilization of the protective agent raw material, does not generate toxic and harmful substances, is environment-friendly, reduces the cost, and improves the production efficiency of enterprises.
Description
Technical Field
The invention relates to the field of compound synthesis, in particular to a preparation method of N6-benzoyl adenosine.
Background
N6-benzoyladenosine, a nucleoside compound, having the formula:
in the prior art, the method for preparing N6-benzoyl adenosine generally adopts trimethylchlorosilane protection to obtain trimethyl protected adenosine, then benzoyl chloride is added for benzoylation, finally the protection is removed under the protection of ammonia water, then the benzoyl chloride is concentrated, the solvent is evaporated to dryness, and water is added for crystallization. During the synthesis process, trimethylchlorosilane is used for protection, about 0.3 ton of hydrogen chloride gas is generated in each ton of products, a large amount of hexamethyldisilazane waste liquid is generated during deprotection, about 0.6 ton of organic waste liquid is generated in each ton of products, the environmental pollution is serious, and the current environmental protection requirements cannot be met.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide the preparation method of the N6-benzoyl adenosine, which has the characteristics of simple reaction steps, low cost and environmental friendliness.
The purpose of the invention is realized by adopting the following technical scheme:
a preparation method of N6-benzoyl adenosine comprises the following steps:
(1) adding adenosine and a protective agent into a flask, adding a solvent and a catalyst, stirring and refluxing for a period of time, evaporating part of the solvent, and continuing to perform heat preservation treatment at the reaction temperature, wherein the protective agent is ester formed by benzoic acid and fatty alcohol with less than or equal to five carbon atoms;
(2) cooling the mixture obtained in the step (1), continuously stirring, and filtering to obtain a filter cake;
(3) and (3) heating the weak alkaline solution in the filter cake obtained in the step (2), stirring for a period of time, filtering, and drying the filter cake to obtain the N6-benzoyl adenosine.
Further, the protective agent in the step (1) is one of methyl benzoate, ethyl benzoate, propyl benzoate, isopropyl benzoate, butyl benzoate, 2-methylpropyl benzoate, 3-methylpropyl benzoate and isobutyl benzoate.
Further, the protective agent in the step (1) is methyl benzoate or ethyl benzoate.
Further, the mass ratio of the adenosine, the protective agent, the catalyst and the solvent in the step (1) is 1: 2.1-2.5: 0.01-0.05: 5-10.
Further, the boiling point of the solvent in the step (1) is 100-140 ℃.
Further, the solvent is one of toluene, benzene, ethylbenzene and pyridine.
Further, the catalyst is trifluoroacetic acid or p-toluenesulfonic acid.
Further, the weak alkaline solution in the step (3) is an aqueous solution of sodium bicarbonate or sodium carbonate.
Further, the method also comprises the following steps: and (3) rectifying the filtrate obtained in the step (2) to separate out fatty alcohol, rectifying the filtrate obtained in the step (3) to separate out benzoic acid, esterifying the fatty alcohol and the benzoic acid to regenerate a protective agent, wherein the protective agent can be used for the reaction in the step (1) again.
Further, stirring and refluxing for 2-6h in the step (1), and preserving heat for 2-4 h; cooling to 0-10 ℃, preferably 5 ℃, stirring for 0.5h in the step (2), filtering, and leaching the filter cake with a solvent for one time; and (4) in the step (3), heating to 30-50 ℃, stirring for 0.5h, preferably 40 ℃, and leaching the filter cake with deionized water for three times.
Compared with the prior art, the invention has the beneficial effects that: the preparation method of the N6-benzoyl adenosine takes adenosine as a substrate, ester formed by benzoic acid and fatty alcohol with less than or equal to five carbon atoms is subjected to aminolysis and alcoholysis to obtain esterified benzoyl adenosine and fatty alcohol, the esterified benzoyl adenosine is hydrolyzed to obtain N6-benzoyl adenosine and benzoic acid, the benzoic acid and the fatty alcohol are separated and recovered, and the esterified benzoyl adenosine is used as a protective agent to participate in the reaction again after esterification. The method provided by the invention fully utilizes the byproducts in the preparation process, has the atom utilization rate close to 100 percent, realizes the recycling of the raw materials of the protective agent, does not generate toxic and harmful substances, is environment-friendly, reduces the cost and improves the production efficiency of enterprises.
Drawings
FIG. 1 is a reaction scheme of the process for preparing N6-benzoyladenosine according to the present invention, wherein methyl benzoate is used as the protecting agent;
FIG. 2 is a schematic diagram of the esterification reaction between benzoic acid and methanol as by-products when methyl benzoate is used as a protective agent in the method for preparing N6-benzoyladenosine according to the present invention.
Detailed Description
The present invention will be further described with reference to the accompanying drawings and the detailed description, and it should be noted that any combination of the embodiments or technical features described below can be used to form a new embodiment without conflict.
As shown in fig. 1 to 2: the reaction principle of the present invention is further illustrated by taking methyl benzoate as an example of the protective agent. In the figure 1, adenosine and methyl benzoate are subjected to aminolysis and alcoholysis to obtain esterified benzoyladenosine and methanol, the esterified benzoyladenosine is hydrolyzed under the alkalescent condition to obtain N6-benzoyladenosine and benzoic acid, and the generated benzoic acid and the methanol are esterified under the acidic condition to generate methyl benzoate which can be recycled as a protective agent.
The adenosine used in the examples described below was purchased from Xinxiang Tuo Chemicals GmbH, with a liquid phase purity of 99%, a moisture content of less than 0.03%, and other reagents of reagent grade.
Example 1
(1) Weighing 100.0g of adenosine and 240.0g of methyl benzoate, adding into a dry four-neck flask, adding 800.0g of toluene and 4.0g of p-trifluoroacetic acid, stirring, refluxing for 2h, evaporating 100ml of solvent, and keeping the temperature for 2 h;
(2) cooling the mixture obtained in the step (1) to 5 ℃, stirring for 0.5h, filtering, leaching with 200ml of toluene once, wherein the filter cake is esterified benzoyladenosine;
(3) adding the filter cake obtained in the step (2) into a four-mouth bottle, and adding 600g of deionized water and 100g of carbonHeating sodium hydrogen carbonate to 40 ℃, stirring for 0.5h, filtering, leaching a filter cake with deionized water for three times (200ml multiplied by 3), and drying to obtain 93.3g of N6-benzoyladenosine with the purity of 99.5 percent and the yield of 93.3 percent; the nuclear magnetic spectrum data of the product N6-benzoyladenosine are as follows:1H NMR(600MHz，DMSO-d6)δ11.21(s，1H)，8.74 (d，J＝23.9Hz，2H)，8.05(d，J＝7.6Hz，2H)，7.65(t，J＝7.4Hz，1H)，7.56 (t，J＝7.6Hz，2H)，6.04(d，J＝5.7Hz，1H)，5.25(d，J＝4.9Hz，1H)，5.13 (t，J＝5.6Hz，1H)，4.19(q，J＝4.5Hz，1H)，3.99(q，J＝3.9Hz，1H)，3.70 (dt，J＝12.0，4.8Hz，1H)，3.58(ddd，J＝11.9，6.0，4.1Hz，1H)。
(4) rectifying the filtrate obtained in the step (2) to separate 30.1g of methanol, distilling the filtrate obtained in the step (3) to separate 114.0g of benzoic acid, esterifying the methanol and the benzoic acid under the catalysis of sulfuric acid, and rectifying to obtain 120.0g of methyl benzoate, wherein the content is not lower than 99 percent, and the esterification yield is 93.8 percent.
Example 2
(1) Weighing 100.0g of adenosine and 250.0g of methyl benzoate, adding into a dry four-neck flask, adding 1000.0g of toluene and 4.0g of p-trifluoroacetic acid, stirring, refluxing for 4h, evaporating 200ml of solvent, and keeping the temperature for 3 h;
(2) cooling the mixture obtained in the step (1) to 0 ℃, stirring for 0.5h, filtering, leaching with 200ml of toluene once, wherein the filter cake is esterified benzoyladenosine;
(3) adding the filter cake obtained in the step (2) into a four-mouth bottle, adding 600g of deionized water and 100g of sodium bicarbonate, heating to 30 ℃, stirring for 0.5h, filtering, leaching the filter cake with deionized water for three times (200ml multiplied by 3), and drying to obtain 94.0g of N6-benzoyladenosine, wherein the purity is 99.7%, and the yield is 94.0%;
(4) rectifying the filtrate obtained in the step (2) to separate 29.8g of methanol, distilling the filtrate obtained in the step (3) to separate 114.0g of benzoic acid, esterifying the methanol and the benzoic acid under the catalysis of sulfuric acid, and rectifying to obtain 121.0g of methyl benzoate, wherein the content is not lower than 99 percent, and the esterification yield is 94.5 percent.
Example 3
(1) Weighing 20.0g of adenosine and 46.0g of ethyl benzoate, adding into a dry four-neck flask, adding 140.0g of benzene and 0.6g of p-toluenesulfonic acid, stirring, refluxing for 6h, evaporating 20ml of solvent, and keeping the temperature for 4 h;
(2) cooling the mixture obtained in the step (1) to 10 ℃, stirring for 0.5h, filtering, leaching with 40ml of benzene for one time, wherein the filter cake is esterified benzoyladenosine;
(3) adding the filter cake obtained in the step (2) into a four-mouth bottle, adding 120.0g of deionized water and 13g of sodium carbonate, heating to 50 ℃, stirring for 0.5h, filtering, leaching the filter cake with deionized water for three times (20ml multiplied by 3), and drying to obtain 18.4g of N6-benzoyladenosine, wherein the purity is 99.6% and the yield is 92.0%;
(4) and (3) rectifying the filtrate obtained in the step (2) to separate 13g of ethanol, distilling the filtrate obtained in the step (3) to separate 34g of benzoic acid, esterifying the ethanol and the benzoic acid under the catalysis of sulfuric acid, and rectifying to obtain 39.5g of ethyl benzoate, wherein the content is not lower than 99%, and the esterification yield is 94.5%.
Example 4
(1) Weighing 10.0g of adenosine and 22.0g of benzoic acid-2-methylpropyl ester, adding into a dry four-neck flask, adding 60.0g of pyridine and 0.2g of trifluoroacetic acid, stirring, refluxing for 2h, evaporating 10ml of solvent, and keeping the temperature for 2 h;
(2) cooling the mixture obtained in the step (1) to 5 ℃, stirring for 0.5h, filtering, leaching with 40ml of benzene for one time, wherein the filter cake is esterified benzoyladenosine;
(3) adding the filter cake obtained in the step (2) into a four-mouth bottle, adding 60.0g of deionized water and 7g of sodium carbonate, heating to 40 ℃, stirring for 0.5h, filtering, leaching the filter cake with deionized water for three times (10ml multiplied by 3), and drying to obtain 9.2g of N6-benzoyladenosine, wherein the purity is 99.8% and the yield is 92.0%;
(4) rectifying the filtrate obtained in the step (2) to separate 11g of 2-methylpropanol, distilling the filtrate obtained in the step (3) to separate 13.1g of benzoic acid, esterifying the 2-methylpropanol and the benzoic acid under the catalysis of sulfuric acid, and rectifying to obtain 13.8g of benzoic acid-2-methylpropyl ester, wherein the content is not lower than 99 percent, and the esterification yield is 94.5 percent.
Example 5
(1) Weighing 10.0g of adenosine and 21.0g of isobutyl benzoate, adding into a dry four-neck flask, adding 50.0g of ethylbenzene and 0.1g of trifluoroacetic acid, stirring, refluxing for 5h, evaporating 10ml of solvent, and keeping the temperature for 4 h;
(2) cooling the mixture obtained in the step (1) to 5 ℃, stirring for 0.5h, filtering, leaching with 20ml of ethylbenzene once, wherein the filter cake is esterified benzoyladenosine;
(3) adding the filter cake obtained in the step (2) into a four-mouth bottle, adding a sodium bicarbonate aqueous solution consisting of 60.0g of deionized water and 10.0g of sodium bicarbonate, heating to 50 ℃, stirring for 0.5h, filtering, leaching the filter cake with deionized water for three times (10ml multiplied by 3), and drying to obtain 9.2g of N6-benzoyladenosine with the purity of 99.6 percent and the yield of 92.0 percent;
(4) and (3) rectifying the filtrate obtained in the step (2) to separate 10.8g of isobutanol, distilling the filtrate obtained in the step (3) to separate 13.3g of benzoic acid, esterifying the isobutanol and the benzoic acid under the catalysis of sulfuric acid, and rectifying to obtain 13.7g of isobutyl benzoate, wherein the content is not lower than 99%, and the esterification yield is 94.1%.
The above embodiments are only preferred embodiments of the present invention, and the protection scope of the present invention is not limited thereby, and any insubstantial changes and substitutions made by those skilled in the art based on the present invention are within the protection scope of the present invention.
Claims (10)
1. A preparation method of N6-benzoyl adenosine is characterized by comprising the following steps:
(1) adding adenosine and a protective agent into a flask, adding a solvent and a catalyst, stirring and refluxing for a period of time, evaporating part of the solvent, and continuing to perform heat preservation treatment at the reaction temperature, wherein the protective agent is ester formed by benzoic acid and fatty alcohol with less than or equal to five carbon atoms;
(2) cooling the mixture obtained in the step (1), continuously stirring, and filtering to obtain a filter cake;
(3) and (3) heating the weak alkaline solution in the filter cake obtained in the step (2), stirring for a period of time, filtering, and drying the filter cake to obtain the N6-benzoyl adenosine.
2. The method for preparing N6-benzoyladenosine according to claim 1, wherein the protecting agent in step (1) is one of methyl benzoate, ethyl benzoate, propyl benzoate, isopropyl benzoate, butyl benzoate, 2-methylpropyl benzoate, 3-methylpropyl benzoate, and isobutyl benzoate.
3. The method for preparing N6-benzoyladenosine according to claim 1, wherein the protecting agent in step (1) is methyl benzoate or ethyl benzoate.
4. The method for preparing N6-benzoyladenosine according to claim 1, wherein the weight ratio of adenosine, protectant, catalyst and solvent in step (1) is 1: 2.1-2.5: 0.01-0.05: 5-10.
5. The method for preparing N6-benzoyladenosine according to claim 1, wherein the boiling point of the solvent in step (1) is 100-140 ℃.
6. The method for preparing N6-benzoyladenosine according to claim 5, wherein the solvent is one of toluene, benzene, ethylbenzene, and pyridine.
7. The method for preparing N6-benzoyl adenosine according to claim 1, wherein the catalyst is trifluoroacetic acid or p-toluenesulfonic acid.
8. The method for preparing N6-benzoyladenosine according to claim 1, wherein the weak alkaline solution in step (3) is aqueous solution of sodium bicarbonate or sodium carbonate.
9. The method for preparing N6-benzoyl adenosine according to claim 1, further comprising the steps of: and (3) rectifying the filtrate obtained in the step (2) to separate out fatty alcohol, rectifying the filtrate obtained in the step (3) to separate out benzoic acid, esterifying the fatty alcohol and the benzoic acid to regenerate a protective agent, wherein the protective agent can be used for the reaction in the step (1) again.
10. The method for preparing N6-benzoyladenosine according to claim 1, wherein the step (1) is performed by stirring and refluxing for 2-6h, and maintaining the temperature for 2-4 h; cooling to 0-10 ℃ in the step (2), stirring for 0.5h, filtering, and leaching a filter cake once by using a solvent; and (4) after the temperature is raised to 30-50 ℃ in the step (3), stirring for 0.5h, and leaching the filter cake with deionized water for three times.
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| JP2002193993A (en) * | 2000-12-27 | 2002-07-10 | Mitsui Chemicals Inc | Method of producing perbenzoylated 2'-deoxyadenosine |
| WO2002083702A1 (en) * | 2001-04-17 | 2002-10-24 | Isis Pharmaceuticals, Inc. | Process for selective n-acylation of purine nucleosides |
| CN1900103A (en) * | 2005-07-18 | 2007-01-24 | 张必良 | Nucleoside phosphoramidite used in RNA oligo-nucleotide synthesis and its synthesizing method |
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| JP2002193993A (en) * | 2000-12-27 | 2002-07-10 | Mitsui Chemicals Inc | Method of producing perbenzoylated 2'-deoxyadenosine |
| WO2002083702A1 (en) * | 2001-04-17 | 2002-10-24 | Isis Pharmaceuticals, Inc. | Process for selective n-acylation of purine nucleosides |
| CN1900103A (en) * | 2005-07-18 | 2007-01-24 | 张必良 | Nucleoside phosphoramidite used in RNA oligo-nucleotide synthesis and its synthesizing method |
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