CN115873049A - Preparation method and application of adenosine - Google Patents
Preparation method and application of adenosine Download PDFInfo
- Publication number
- CN115873049A CN115873049A CN202310187276.4A CN202310187276A CN115873049A CN 115873049 A CN115873049 A CN 115873049A CN 202310187276 A CN202310187276 A CN 202310187276A CN 115873049 A CN115873049 A CN 115873049A
- Authority
- CN
- China
- Prior art keywords
- adenosine
- preparation
- reaction
- ammoniation
- chloropurine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 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 title claims abstract description 86
- 239000002126 C01EB10 - Adenosine Substances 0.000 title claims abstract description 43
- 229960005305 adenosine Drugs 0.000 title claims abstract description 43
- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 8
- 238000010438 heat treatment Methods 0.000 claims abstract description 8
- ZKBQDFAWXLTYKS-UHFFFAOYSA-N 6-Chloro-1H-purine Chemical compound ClC1=NC=NC2=C1NC=N2 ZKBQDFAWXLTYKS-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000003054 catalyst Substances 0.000 claims abstract description 6
- FVKFHMNJTHKMRX-UHFFFAOYSA-N 3,4,6,7,8,9-hexahydro-2H-pyrimido[1,2-a]pyrimidine Chemical compound C1CCN2CCCNC2=N1 FVKFHMNJTHKMRX-UHFFFAOYSA-N 0.000 claims abstract description 5
- 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 claims abstract description 5
- 239000003513 alkali Substances 0.000 claims abstract description 5
- 229930010555 Inosine Natural products 0.000 claims abstract description 3
- 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 claims abstract description 3
- 229960003786 inosine Drugs 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 13
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 8
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 7
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000001099 ammonium carbonate Substances 0.000 claims description 6
- 235000012501 ammonium carbonate Nutrition 0.000 claims description 6
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 5
- 239000005695 Ammonium acetate Substances 0.000 claims description 5
- 229940043376 ammonium acetate Drugs 0.000 claims description 5
- 235000019257 ammonium acetate Nutrition 0.000 claims description 5
- 235000019270 ammonium chloride Nutrition 0.000 claims description 5
- 150000001412 amines Chemical class 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 4
- 238000005809 transesterification reaction Methods 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 9
- -1 chloro triacetyl inosine Chemical compound 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000012535 impurity Substances 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 description 6
- 229940126214 compound 3 Drugs 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 239000012467 final product Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 description 3
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000007670 refining Methods 0.000 description 3
- 229940124602 FDA-approved drug Drugs 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 238000005915 ammonolysis reaction Methods 0.000 description 2
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 2
- QQVDYSUDFZZPSU-UHFFFAOYSA-M chloromethylidene(dimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)=CCl QQVDYSUDFZZPSU-UHFFFAOYSA-M 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 238000012790 confirmation Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 150000002191 fatty alcohols Chemical class 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 239000002777 nucleoside Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- 238000009662 stress testing Methods 0.000 description 2
- 230000000304 vasodilatating effect Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 1
- TYAGARVNQCFRBQ-ZJIFWQFVSA-N CC[C@@]([C@]1(CC)O)([C@](CC)(N2C(N=CN=C3O)=C3N=C2)O[C@@]1(CO)Cl)O Chemical compound CC[C@@]([C@]1(CC)O)([C@](CC)(N2C(N=CN=C3O)=C3N=C2)O[C@@]1(CO)Cl)O TYAGARVNQCFRBQ-ZJIFWQFVSA-N 0.000 description 1
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- 208000003734 Supraventricular Tachycardia Diseases 0.000 description 1
- 208000001871 Tachycardia Diseases 0.000 description 1
- OIRDTQYFTABQOQ-UHTZMRCNSA-N Vidarabine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O OIRDTQYFTABQOQ-UHTZMRCNSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000002371 cardiac agent Substances 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 230000003293 cardioprotective effect Effects 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 230000002530 ischemic preconditioning effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- MRWXACSTFXYYMV-FDDDBJFASA-N nebularine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC=C2N=C1 MRWXACSTFXYYMV-FDDDBJFASA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000002212 purine nucleoside Substances 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229960003636 vidarabine Drugs 0.000 description 1
Classifications
-
- 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
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/167—Purine radicals with ribosyl as the saccharide radical
-
- 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
Landscapes
- 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 provides a preparation method and application of adenosine; the preparation method comprises the following steps: (a) In the presence of a catalyst 1,5, 7-triazabicyclo (4.4.0) dec-5-ene, 6-chloropurine and tetraacetyl ribose are subjected to an amine ester exchange reaction to obtain an intermediate compound, namely chlorotriecyl inosine; (b) The obtained intermediate compound, namely chloro triacetyl inosine, is subjected to an ammoniation reaction with an ammoniation reagent in the presence of alkali under the condition of heating at normal pressure to obtain adenosine. The preparation method of the adenosine is environment-friendly, high in yield, high in product purity, free of special equipment and suitable for large-scale industrial production, and all the used reagents are bulk chemical reagents which are low in price and easy to obtain.
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a preparation method and application of adenosine.
Background
Adenosine is a naturally occurring, endogenous purine nucleoside found throughout the cells of the human body and is a degradation product of Adenosine Triphosphate (ATP). Adenosine is well known for its vasodilating action, and has cardioprotective effects such as triggering or mediating ischemic preconditioning, reducing reperfusion injury, etc., in addition to a broad cardiac effect and a rapid and significant coronary vasodilating action. In the united states, adenosine, a first-line FDA-approved drug for recurrent supraventricular tachycardia (PSVT), and one of two FDA-approved drugs for cardiac drug stress testing, has become a routine drug for emergency treatment of tachyarrhythmias and drug stress testing. In addition, adenosine is an important medicinal raw material, and adenosine can be used for preparing various medicines such as ATP, cyclic adenosine monophosphate, vidarabine and the like.
Chinese patent applications CN1408720A, CN100460416C, CN111808157B and the like all disclose adenosine preparation methods, however, vilsmeier reagent is used for chlorination in the adenosine preparation processes of the three patents, which is known to be unfriendly to the environment and corrosive to equipment, and the involved ammonolysis process needs to be performed in high-pressure equipment, which has high requirements on equipment, and has safety risks in the production process.
In addition, in the preparation method of adenosine of chinese patent applications CN1408720A and CN100460416C, the ammonolysis process is performed in the solution of ammonia-methanol or other fatty alcohol dissolved ammonia, and a large amount of impurities are generated under the conditions of high temperature and high pressure, which greatly affects the yield of the product.
For example, in the preparation method of adenosine of CN100460416C, the intermediate compound chlorotriecylinosine in methanol in ammonia solution can generate impurity I by the following reaction formula under high temperature and high pressure conditions:
The content of impurity I in the reaction solution is expected to be 10 to 15%.
For another example, in the preparation method of CN1408720A, methanol and ammonia gas may generate part of methylamine under high temperature and high pressure conditions, the intermediate compound (IV) is liable to generate 6-chloro nucleoside in ammonia solution of methanol, the generated methylamine and 6-chloro nucleoside may react to generate impurity II, and the reaction formula of the process is as follows:
the content of impurity II in the reaction solution is expected to be 5 to 10%.
Therefore, there is an urgent need for an adenosine preparation process that is environmentally friendly, has fewer impurities, and has a higher yield.
The information disclosed in this background section is only for enhancement of understanding of the general background of the invention and should not be taken as an acknowledgement or any form of suggestion that this information forms the prior art that is already known to a person skilled in the art.
Disclosure of Invention
Object of the Invention
In view of the above problems in the prior art, it is an object of the present invention to provide a method for preparing adenosine which is environmentally friendly and has greatly improved reaction yield and product purity, and uses thereof.
Solution scheme
In order to realize the purpose of the invention, the invention provides the following technical scheme:
a method for the preparation of adenosine comprising the steps of:
(a) In the presence of a catalyst 1,5, 7-triazabicyclo (4.4.0) dec-5-ene (TBD), 6-chloropurine and tetraacetyl ribose are subjected to an amine ester exchange reaction to obtain chlorotriethylinosine;
(b) In the presence of alkali, carrying out an ammoniation reaction on chlorotrieyl inosine and an ammoniation reagent under normal pressure and heating conditions to obtain adenosine;
the reaction formula of the preparation method is as follows:
for the above preparation method:
preferably, in step (a), the molar ratio of 6-chloropurine to tetraacetylribose is 1: (1-2), preferably 1: (1.2-1.4).
Preferably, in step (a), the molar ratio of 6-chloropurine to catalyst 1,5, 7-triazabicyclo (4.4.0) dec-5-ene is 1: (0.01-0.2), preferably 1:0.05.
preferably, in step (a), the amine transesterification reaction is carried out in a solvent which is: tetrahydrofuran and/or 1, 4-dioxane.
Preferably, in step (a), the amine transesterification reaction is carried out at 40-60 ℃, preferably 50-60 ℃.
Preferably, in step (b), the base is selected from: one or more of triethylamine, diethylamine and diisopropylethylamine.
Preferably, in the step (b), the molar ratio of the chlorotriecylinosine to the base is 1 (1-2), preferably 1 (1.2-1.4).
Preferably, in step (b), the ammoniating agent is selected from: one or more of ammonia, ammonium chloride, ammonium carbonate and ammonium acetate, preferably selected from: one or more of aqueous ammonia, aqueous ammonium chloride solution, aqueous ammonium carbonate solution and aqueous ammonium acetate solution, more preferably aqueous ammonia, aqueous ammonium chloride solution, aqueous ammonium carbonate solution or aqueous ammonium acetate solution.
Preferably, in step (b), the normal pressure is one atmosphere, namely about 0.1 MPa; the heating condition is heating to 40-60 deg.C, preferably 50-60 deg.C, i.e., the ammoniation reaction is carried out at 40-60 deg.C, preferably 50-60 deg.C.
Preferably, the step (b) further comprises a step of cooling and crystallizing the product for refining after the ammoniation reaction is completed; further preferably, the refining solvent is water.
In addition, the invention also provides the application of the preparation method of the adenosine in preparing the adenosine.
Advantageous effects
1) The Vilsmeier reagent is not used in the preparation method of the adenosine, so the preparation method is environment-friendly.
2) According to the adenosine preparation method, the amine ester exchange reaction in the first step adopts a specific catalyst TBD, so that the reaction yield and purity are greatly improved; the ammoniation reaction of the second step can be carried out under normal pressure because of introducing alkali reagents such as triethylamine, diethylamine, diisopropylethylamine and the like, and the ammoniation reaction does not use an ammonia solution of fatty alcohol including ammonia methanol as an ammoniation reagent and is carried out under normal pressure and at the temperature of below 100 ℃, so that the safety is high, a large amount of impurities cannot be generated, and the purity of the product is greatly improved.
3) The preparation method of adenosine also comprises a step of cooling crystallization for refining, and the purity of the adenosine raw material medicine is further improved.
In a word, the adenosine preparation method is environment-friendly, high in reaction yield (the total yield is about 82% or more), high in product purity (the final product adenosine purity is over 99.9%), free of special equipment, low in price and easy to obtain, and therefore suitable for large-scale industrial production.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are a part of the embodiments of the present invention, but not all of the embodiments. All other embodiments, which can be obtained by a person skilled in the art without inventive step based on the embodiments of the present invention, are within the scope of protection of the present invention.
Furthermore, in the following detailed description, numerous specific details are set forth in order to provide a better understanding of the invention. It will be understood by those skilled in the art that the present invention may be practiced without some of these specific details. In some embodiments, materials, elements, methods, means, and the like that are well known to those skilled in the art are not described in detail in order to not unnecessarily obscure the present invention.
Throughout the specification and claims, unless explicitly stated otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of stated elements but not the exclusion of any other elements.
Example 1: preparation of adenosine according to the method of the invention:
as a representative example of the production method of the present invention, adenosine was produced by the following steps in this example:
1. the synthesis of compound 3, the reaction scheme is as follows:
adding a compound 1 (5 kg, 32.35mol) into a 50L reaction kettle, adding 20L tetrahydrofuran, adding TBD (225g, 1.62mol) at the temperature of 20-30 ℃, stirring for 1h, then adding a compound 2 (13.39kg, 42.07mol) into a reaction system, heating to 55 ℃, stirring for 5h, cooling to room temperature, adding 10L saturated ammonium chloride solution into the reaction system, stirring for 30min, separating, reducing the temperature of an organic phase to 10L of solvent at 40-50 ℃, adding 20L n-heptane into the system, cooling to 0 ℃, stirring for crystallization for 2h, filtering, and drying at the temperature of 20-30 ℃ under reduced pressure to obtain 12.14kg of a solid product, namely the compound 3, wherein the purity is 99.5%, and the yield is 90.9%.
And (3) structure confirmation:
hydrogen spectrum solvent CDCl32.00-2.20 ppm (9H), 4.3-4.5 ppm (3H), 5.61ppm (1H), 5.92ppm (1H), 6.12ppm (1H), 8.31-8.73ppm (2H).
Carbon spectrum solvents CDCl320.66ppm,20.45ppm,20.30ppm,62.86ppm,70.43ppm,73.06ppm,80.50ppm,86.88ppm,132.29ppm,143.73ppm,151.24ppm,151.46ppm,152.22ppm,162.50ppm,169.49ppm,170.17ppm.
Mass spectrum: [ M + H ]] + ：413.32。
2. Compound (I) (i.e., adenosine) was prepared from compound 3, according to the reaction scheme shown below:
adding compound 3 (12kg, 29.07mol), triethylamine (3.82kg, 37.79mol) and 96L of 20% ammonia water into a 200L reaction kettle, heating to 55 ℃, stirring for reaction for 10h, cooling to 10 ℃, filtering to obtain an adenosine crude product, adding the adenosine crude product into 90L purified water, adding 300g of activated carbon, heating for reflux for 2h, carrying out heat filtration, cooling the filtrate to 20 ℃, crystallizing for 4h, filtering, and drying to obtain 7.11kg of a solid product, namely compound (I) (namely adenosine); purity: 99.96%, yield: 91.5 percent.
And (3) structure confirmation:
hydrogen spectrum solvent DMSO
3.50-3.70ppm（2H），3.90-4.00ppm（1H），4.10-4.20ppm（1H），4.60-4.65ppm（1H），5.20ppm（1H），5.42-5.47ppm（2H），5.89ppm（1H），7.36ppm（2H），8.15ppm（1H），8.36ppm（1H）。
Carbon spectrum solvent DMSO
62.15ppm，86.37ppm，71.14ppm，73.91ppm，88.39ppm，119.84ppm，140.42ppm，149.53，152.86ppm，156.64ppm。
Mass spectrum: m + H + =268.11.
In the preparation method of this example, the total yield of the final product, adenosine in two steps, was 83.2%.
Example 2: preparation of adenosine according to the method of the invention:
the difference from example 1 is that: in step 1, the molar ratio of compound 1 to compound 2 is modified from 1.3 to 1; the purity of the compound 3 obtained in the step 1 is 99.4%, and the yield is 90.2%; step 2 the yield of compound (I) was 91.2% with a purity of 99.95%.
In the preparation method of this example, the total yield of the final product, adenosine, in two steps was 82.3%.
Example 3: preparation of adenosine according to the method of the invention:
the difference from example 1 is that: in the step 1, changing the alkali from triethylamine to diethylamine, and keeping other conditions unchanged; the purity of the compound 3 obtained in the step 1 is 99.2%, and the yield is 90.0%; the compound (I) prepared in step 2 was obtained in 91.3% yield and 99.94% purity.
In the preparation method of this example, the total yield of the final product, adenosine in two steps, was 82.2%.
Example 4: preparation of adenosine according to the method of the invention:
the difference from example 1 is that: in the step 1, changing ammonia into ammonium carbonate in an ammoniation reagent, and keeping other conditions unchanged; the purity of the compound 3 obtained in the step 1 is 99.1%, and the yield is 89.8%; the compound (I) prepared in step 2 was obtained in 91.1% yield and 99.96% purity.
In the preparation method of this example, the total yield of the final product, adenosine in two steps, was 81.8%.
Finally, it should be noted that: the above examples are only intended to illustrate the technical solution of the present invention, and not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions.
Claims (10)
1. A method for producing adenosine, comprising the steps of:
(a) In the presence of a catalyst 1,5, 7-triazabicyclo (4.4.0) dec-5-ene, 6-chloropurine and tetraacetyl ribose are subjected to amine ester exchange reaction to obtain chlorotrietylinosine;
(b) In the presence of alkali, carrying out an ammoniation reaction on chlorotrieyl inosine and an ammoniation reagent under normal pressure and heating conditions to obtain adenosine;
the reaction formula of the preparation method is as follows:
2. the method according to claim 1, wherein in the step (a), the molar ratio of 6-chloropurine to tetraacetylribose is 1: (1-2).
3. The method according to claim 1, wherein in the step (a), the molar ratio of 6-chloropurine to 1,5, 7-triazabicyclo (4.4.0) dec-5-ene as a catalyst is 1: (0.01-0.2).
4. The process according to claim 1, wherein in step (a), the amine transesterification is carried out in a solvent which is: tetrahydrofuran and/or 1, 4-dioxane;
and/or the amine transesterification reaction is carried out at 40-60 ℃.
5. The method according to claim 1, wherein in the step (b), the base is selected from the group consisting of: one or more of triethylamine, diethylamine and diisopropylethylamine.
6. The method according to claim 1, wherein the molar ratio of chlorotriecylinosine to base in step (b) is 1: (1-2).
7. The method according to claim 1, wherein in step (b), the ammoniating agent is selected from the group consisting of: one or more of ammonia, ammonium chloride, ammonium carbonate and ammonium acetate.
8. The method according to claim 1, wherein in step (b), the ammoniating agent is selected from the group consisting of: one or more of aqueous ammonia, aqueous ammonium chloride, aqueous ammonium carbonate and aqueous ammonium acetate.
9. The method according to claim 1, wherein the step (b) is performed at 40 to 60 ℃.
10. Use of the preparation method according to any one of claims 1 to 9 for preparing adenosine.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310187276.4A CN115873049B (en) | 2023-02-13 | 2023-02-13 | Preparation method and application of adenosine |
| CN202310416368.5A CN116375772A (en) | 2023-02-13 | 2023-02-13 | Preparation method and application of adenosine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310187276.4A CN115873049B (en) | 2023-02-13 | 2023-02-13 | Preparation method and application of adenosine |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310416368.5A Division CN116375772A (en) | 2023-02-13 | 2023-02-13 | Preparation method and application of adenosine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115873049A true CN115873049A (en) | 2023-03-31 |
| CN115873049B CN115873049B (en) | 2023-05-02 |
Family
ID=85761729
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310187276.4A Active CN115873049B (en) | 2023-02-13 | 2023-02-13 | Preparation method and application of adenosine |
| CN202310416368.5A Pending CN116375772A (en) | 2023-02-13 | 2023-02-13 | Preparation method and application of adenosine |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310416368.5A Pending CN116375772A (en) | 2023-02-13 | 2023-02-13 | Preparation method and application of adenosine |
Country Status (1)
| Country | Link |
|---|---|
| CN (2) | CN115873049B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1408720A (en) * | 2001-09-30 | 2003-04-09 | 河南师范大学 | Process for producing adenosin by chemical synthesis |
| WO2019246403A1 (en) * | 2018-06-21 | 2019-12-26 | Calithera Biosciences, Inc. | Ectonucleotidase inhibitors and methods of use thereof |
| CN112159447A (en) * | 2020-10-10 | 2021-01-01 | 南京红杉生物科技有限公司 | Intermediate for synthesizing 2-chloroadenosine, synthesis process thereof and synthesis process of 2-chloroadenosine |
-
2023
- 2023-02-13 CN CN202310187276.4A patent/CN115873049B/en active Active
- 2023-02-13 CN CN202310416368.5A patent/CN116375772A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1408720A (en) * | 2001-09-30 | 2003-04-09 | 河南师范大学 | Process for producing adenosin by chemical synthesis |
| WO2019246403A1 (en) * | 2018-06-21 | 2019-12-26 | Calithera Biosciences, Inc. | Ectonucleotidase inhibitors and methods of use thereof |
| CN112159447A (en) * | 2020-10-10 | 2021-01-01 | 南京红杉生物科技有限公司 | Intermediate for synthesizing 2-chloroadenosine, synthesis process thereof and synthesis process of 2-chloroadenosine |
Non-Patent Citations (1)
| Title |
|---|
| SHANE M. DEVINE 等: "An efficient convergent synthesis of adenosine- 5′-N-alkyluronamides", TETRAHEDRON * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115873049B (en) | 2023-05-02 |
| CN116375772A (en) | 2023-07-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108948020B (en) | Refining method of tofacitinib citrate | |
| CN106397515A (en) | An improved sofosbuvir preparation method | |
| CN115873049A (en) | Preparation method and application of adenosine | |
| CN112724027B (en) | Preparation method of isoproterenol hydrochloride | |
| CN108623602B (en) | Method for preparing and purifying ibrutinib | |
| CN111499675B (en) | Synthetic method of fludarabine phosphate | |
| KR101462850B1 (en) | Process for the preparation of highly pure entecavir monohydrate | |
| CN110862382B (en) | Preparation method of ticagrelor intermediate | |
| CN112457353A (en) | Synthesis method of beta-nicotinamide riboside chloride | |
| CN112876524A (en) | Preparation method of Reidesciclovir intermediate | |
| CN112552283A (en) | Preparation method of novel tinib medicine | |
| CN111808157B (en) | Preparation method of adenosine bulk drug | |
| CN102153545B (en) | Preparation method for lamivudine | |
| CN113512079A (en) | Preparation method of beta-nicotinamide mononucleotide | |
| CN113527376A (en) | Preparation method of beta-nicotinamide mononucleotide | |
| JPS58190820A (en) | Manufacture of anhydrous lithium borofluoride | |
| CN111606929B (en) | Preparation method of Degatinib | |
| WO2023121566A1 (en) | Process for preparing cedazuridine | |
| CN114106043A (en) | Compound, preparation method thereof, method for preparing citicoline by compound and application | |
| CN110713502A (en) | Synthesis method of gemcitabine impurity | |
| CN116829534A (en) | Preparation method of 1, 4-butanedisulfonic acid | |
| CN107033133A (en) | A kind of preparation method of Iloperidone | |
| TW202329981A (en) | Process for preparing cedazuridine | |
| CN114644667A (en) | Separation method of decitabine and alpha-isomer | |
| CN105601688A (en) | Preparation methods for clofarabine intermediate and clofarabine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |