CN1727356A - Technique of chemical synthesis of producing adenosine - Google Patents
Technique of chemical synthesis of producing adenosine Download PDFInfo
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- CN1727356A CN1727356A CN 200510044192 CN200510044192A CN1727356A CN 1727356 A CN1727356 A CN 1727356A CN 200510044192 CN200510044192 CN 200510044192 CN 200510044192 A CN200510044192 A CN 200510044192A CN 1727356 A CN1727356 A CN 1727356A
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- inosine
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Abstract
A process for preparing adenosine from inosine by chemical synthesis method includes such steps as acetylating by excessive acetic anhydride under existence of anhydrous sodium acetate to obtain acetylinosine, chlorinating it by trichloroxyphosphate in pyridine to obtain chloro-acetylinosine, ammonolyzing in ammonia-methanol solution to obtain coarse adenosine, and refining. Its advantage is high output rate.
Description
Technical field
The present invention relates to the new process of production method of adenosine, be specially a kind of technology of chemical synthesis of producing adenosine.
Background technology
According to bibliographical information, the chemical synthesis of adenosine has multiple synthetic route.Wherein with adenylic acid (AMP), 2-methyl sulfo-adenosine, 8-sulfydryl-9-methyladenine and 5-amino-4-cyano group-1-imidazoles-ribofuranose and 2, the 8-dichloropurine is the synthetic route of starting raw material, or because of raw materials used (particularly starting raw material) price height; Or because of synthetic route is longer, processing condition require high, all are difficult to be applied in extensive synthesizing.
Relatively be suitable for industrial synthetic route and have following three kinds:
1, with 2 ', 3 ', 5 '-triacetyl Trophicardyl is a starting raw material; it is dissolved in the anhydrous pyridine, makes condensing agent with 4-chlorobenzene phosphinylidyne dichloro, with 1; 2; 4 ,-triazole room temperature reaction get N-6-pyridinium salt-9-(β-D-2 ', 3 '; 5 '-triacetyl ribofuranose) purine; again above-mentioned product is dissolved in the saturated ammonia methanol solution ammonia and separates, adenosine, overall yield is 62%.
2, with the xanthoglobulin be starting raw material; through making 6-chloropurine with phosphorus oxychloride reaction; again with tetrem acyl ribose under the effect of special catalyzer, obtain 6-chloro-9 (β-D-2 '; 3 '; 5 '-triacetyl ribofuranose) purine; obtain adenosine at last in the saturated ammonia methanol solution, overall yield is 45%.
3, with the inosine be starting raw material; with excessive aceticanhydride with the inosine acetylize; the triacetyl inosine that obtains Vilsmeier reagent chlorination; obtain the chloroacetylation inosine; the chloroacetylation inosine is through deacetylation; obtain the chlorination inosine, carry out amination by liquefied ammonia again, thereby inosine is converted into adenosine.Total weight yield 52.2%.
More than three synthetic routes all to have synthetic route shorter, the characteristics of better economic benefit, but comparatively speaking, the 3rd route better, this be because:
(1) starting raw material inosine price is lower, and productive rate is higher.
(2) triacetyl Trophicardyl and xanthoglobulin are the derived products of inosine, have directly shortened synthetic route with the inosine synthesizing adenosine.Help reducing production costs.
(3) used starting raw material inosine can guarantee supply of raw material and quality, and has reduced the expense of aspects such as outsourcing transportation, helps reducing production costs.Simultaneously, also help enlarging the production of inosine.
Though the 3rd synthetic route is better than first and second route, also has following subject matter:
(1) chlorination reaction temperature is 110 ℃, and tank pressure maintains 74～79 kilograms, must carry out in high voltage bearing retort, and this has brought very big difficulty to industrial production.And long reaction time (chlorination reaction requires more than 30 hours), thereby reduced throughput.
(2) deacetylation of chloroacetylation inosine reaction required under less than 0 ℃ temperature placing response 5～30 hours, because temperature of reaction is low, had also brought certain difficulty for industrial production.
(3) acetylization reaction of inosine requires to make acylating agent with excessive aceticanhydride in the presence of alkali, and the preferred pyridine of described alkali.Because a large amount of pyridines is used in acetylize, not only increased production cost but also caused certain difficulty for the recycling of pyridine and aceticanhydride.
Summary of the invention
A kind of synthetic route is short in order to explore, processing condition are easy to reach, the synthetic method of the adenosine of better economic benefit, we are in above three synthetic routes of study, particularly on the basis of the 3rd synthetic route, explore, test repeatedly through research, proposed a kind of novel process of chemical synthesis of producing adenosine.
Technical scheme of the present invention is:
The technology of chemical synthesis of producing adenosine, with the inosine is starting raw material, it is characterized in that: with inosine at the sodium acetate, anhydrous existence condition, with excessive aceticanhydride acetylize, obtain the acetylize inosine, the acetylize inosine through the phosphorus oxychloride chlorination, obtains chloro-acetylize inosine in the solvent pyridine, chloro-acetylize inosine ammonia in the ammonia/methanol solution that keeps certain ammonia to press is separated reflection, obtains product adenosine crude product; Through refining get final product the qualified product of adenosine; Its synthetic route is:
Its synthesis step is:
(1) acylation reaction adds aceticanhydride and sodium acetate, anhydrous in the exsiccant reactor, when being heated to 80～85 ℃, adds inosine in batches; Feed in raw material and finish insulation reaction 0.5～1 hour; When underpressure distillation steams to dripless, add 1.5 times to the pure water of inosine, stir cooling, centrifugal when reducing to 5-10 ℃, the crystallization oven dry promptly gets white triacetyl inosine;
(2) chlorination reaction
A, in the exsiccant reactor, add triacetyl inosine and pyridine and under agitation be cooled to 5-10 ℃, slowly add phosphorus oxychloride, insulation reaction 10～20 hours is cooled to 10-15 ℃ thereafter;
B, above-mentioned reaction solution is slowly joined in the methyl alcohol that is cooled to 5 ℃, stream adds that control reaction temperature after stream adds end, adds an amount of morpholine at 15-20 ℃ again in the process;
(3) ammonolysis reaction
A, add methyl alcohol in exsiccant ammonolysis reaction still, logical ammonia adds thereafter and goes up the chlorination reaction liquid that the step obtains to saturated and cool to 5-10 ℃, and control ammonolysis reaction temperature in the kettle is at 10-15 ℃; With chlorination reaction liquid shift finish after, the logical ammonia of pressurization, heat-insulation pressure keeping reaction 10～20 hours;
After b, heat-insulation pressure keeping reaction finish, get rid of ammonia in the still, feed liquid is transferred in the still kettle; Solvent is reclaimed in air distillation; When temperature in the kettle reaches 90～95 ℃, stop the distillation, in still kettle, add 1～1.2 times of methyl alcohol to the acetylize inosine, after the stirring and dissolving, be cooled to 0-5 ℃ centrifugal, promptly get the adenosine crude product; Adenosine crude product pure water recrystallization, and, promptly get the adenosine after making with extra care with behind the activated carbon decolorizing.
The further technical scheme of the present invention is:
The consumption of the middle aceticanhydride of synthesis step (1) is 1.5～2 times of inosine, and the consumption of sodium acetate, anhydrous is 8～9% of an inosine, and the insulation reaction temperature is 115 ℃～125 ℃.Be preferably 120 ℃.
The consumption of the middle pyridine of synthesis step (2) is 1.5～2 times of triacetyl inosine, and the consumption of methyl alcohol is 1～1.2 times of triacetyl inosine, and the consumption of morpholine is 6.5～7% of a triacetyl inosine, and the insulation reaction temperature is 30～60 ℃.Be preferably 45 ℃～50 ℃.
Heat-insulation pressure keeping ammonolysis reaction described in the synthesis step (3), 10～30 ℃ of its temperature, pressure is 0.15～0.35Mpa; The consumption of described methyl alcohol is 3～5 times of triacetyl inosine.
The amount of used pure water was 5～7 times of adenosine crude product when crude product adenosine described in the synthesis step (3) was refining, and is centrifugal below 5 ℃, and with 50% washing with alcohol.
The invention has the beneficial effects as follows: this production technique, preferably resolve the 3rd problem that synthetic route exists in the prior art, established the synthetic route of oneself, make it to be more suitable for industrial production, obtained effect preferably.Adenosine meets the quality standard of " American Pharmacopeia 24 editions ", and the total recovery of adenosine is 53%.
The subject matter that solves:
(1) carry out aminating reaction under normal temperature and low pressure, solved former technology aminating reaction temperature height, the problem that need carry out in high pressure resistant reactor has reduced facility investment, is easy to realize suitability for industrialized production.
(2) deacetylation of chloroacetylation inosine reaction, temperature of reaction is by changing into below 5 ℃ below 0 ℃.Be easy on the technology realize and be beneficial to reducing production costs.
(3) total reaction times of the deacetylation of chloroacetylation inosine and aminating reaction foreshortened to 15 hours by 20～100 hours, thereby had shortened the production cycle greatly.
(4) acetylize inosine halogenating reaction generates behind the chloro-acetylize inosine without concentrating and separating, and reaction solution is directly used in deacetylation and reacts, thereby has simplified production technique.
(5) in one step of acetylize of inosine, alkaline condition changes sodium acetate into by pyridine or sodium alkoxide, and weight yield reaches 141%, exceeds 16% than former technology.
Embodiment
Synthesis technique:
1, the triacetyl inosine is synthetic
Add the acetic anhydride and the anhydrous sodium acetate of calculated amount in the dry reaction still, when being heated to 82 ℃, repeatedly add inosine on a small quantity, temperature is controlled at below 120 ℃.After adding inosine, 120 ℃ of insulation reaction 30 minutes.Underpressure distillation to dripless produces.Be cooled to 0 ℃ centrifugal, wash with an amount of cold pure water and to crystallize to PH5.Oven dry.Get the crystallization of white triacetyl inosine.242～243 ℃ of fusing points, yield 96%, purity is more than 99%.
2, the halogenation of 6 hydroxyls of purine bases
(1) pyridine of adding triacetyl inosine and calculated amount in the exsiccant reactor, stirring is cooled to below 10 ℃, slowly drips (or stream adds) phosphorus oxychloride then, finishes and is warming up to 45～50 ℃, and insulation reaction 14 hours cools thereafter to 0 ℃.
(2) in the exsiccant reactor, add an amount of anhydrous methanol, be cooled to below 0 ℃, slowly add above-mentioned reaction solution.Stream add finish after, add an amount of morpholine again.Add in the process at stream, temperature should be controlled at below 10 ℃.
3, ammonolysis reaction, preparation adenosine crude product
The anhydrous methanol that in the exsiccant reactor, adds calculated amount.Logical ammonia is extremely saturated, and continues to be cooled to below 5 ℃.Above-mentioned reaction solution is slowly added in the methanol solution of saturated ammonia.Temperature is below 15 ℃ in the controlling tank.Stream adds the logical ammonia of back pressurization that finishes, and when the ammonia pressure reaches certain pressure in the jar, stops logical ammonia and closes into ammonia valve.In room temperature insulation reaction 15 hours (ammonia is pressed and can be raise in jar).Reaction finishes, and feed liquid is transferred in the concentration tank air distillation.Reclaim 72 ℃ of front-end volatiles and 72 ℃ of after cut respectively.When temperature in the jar rises to 92 ℃, in jar, add an amount of methyl alcohol, be cooled to below 5 ℃ centrifugal, the adenosine crude product.
4, the adenosine crude product is refining
The adenosine crude product is dropped in the reactor, add the purified water of calculated amount, under agitation be heated to molten clearly, add proper amount of active carbon then, refluxed 20～30 minutes.Filter, filtrate is cooled to below 5 ℃ centrifugal, with the crystallization oven dry, white adenosine crystallization.
Embodiments of the invention are not limited to so, as long as by the desired method steps of content of the present invention, all can implement.
Claims (6)
1, the technology of chemical synthesis of producing adenosine, with the inosine is starting raw material, it is characterized in that: with inosine at the sodium acetate, anhydrous existence condition, with excessive aceticanhydride acetylize, obtain the acetylize inosine, the acetylize inosine through the phosphorus oxychloride chlorination, obtains chloro-acetylize inosine in the solvent pyridine, chloro-acetylize inosine ammonia in the ammonia/methanol solution that keeps certain ammonia to press is separated reflection, obtains product adenosine crude product; Through refining get final product the qualified product of adenosine; Its synthetic route is:
2, the technology of chemical synthesis of producing adenosine is characterized in that, its synthesis step is:
(1) acylation reaction adds aceticanhydride and sodium acetate, anhydrous in the exsiccant reactor, when being heated to 80～85 ℃, adds inosine in batches; Feed in raw material and finish insulation reaction 0.5～1 hour; When underpressure distillation steams to dripless, add 1.5 times to the pure water of inosine, stir cooling, centrifugal when reducing to 5-10 ℃, the crystallization oven dry promptly gets white triacetyl inosine;
(2) chlorination reaction
A, in the exsiccant reactor, add triacetyl inosine and pyridine and under agitation be cooled to 5-10 ℃, slowly add phosphorus oxychloride, insulation reaction 10～20 hours is cooled to 10-15 ℃ thereafter;
B, above-mentioned reaction solution is slowly joined in the methyl alcohol that is cooled to 5 ℃, stream adds that control reaction temperature after stream adds end, adds an amount of morpholine at 15-20 ℃ again in the process;
(3) ammonolysis reaction
A, add methyl alcohol in exsiccant ammonolysis reaction still, logical ammonia adds thereafter and goes up the chlorination reaction liquid that the step obtains to saturated and cool to 5-10 ℃, and control ammonolysis reaction temperature in the kettle is at 10-15 ℃; With chlorination reaction liquid shift finish after, the logical ammonia of pressurization, heat-insulation pressure keeping reaction 10～20 hours;
After b, heat-insulation pressure keeping reaction finish, get rid of ammonia in the still, feed liquid is transferred in the still kettle; Solvent is reclaimed in air distillation; When temperature in the kettle reaches 90～95 ℃, stop the distillation, in still kettle, add 1～1.2 times of methyl alcohol to the acetylize inosine, after the stirring and dissolving, be cooled to 0-5 ℃ centrifugal, promptly get the adenosine crude product; Adenosine crude product pure water recrystallization, and, promptly get the adenosine after making with extra care with behind the activated carbon decolorizing.
3, the technology of chemical synthesis of producing adenosine according to claim 2 is characterized in that: the consumption of the middle aceticanhydride of synthesis step (1) is 1.5～2 times of inosine, and the consumption of sodium acetate, anhydrous is 8～9% of an inosine, and the insulation reaction temperature is 115 ℃～125 ℃.
4, the technology of chemical synthesis of producing adenosine according to claim 2, it is characterized in that: the consumption of the middle pyridine of synthesis step (2) is 1.5～2 times of triacetyl inosine, the consumption of methyl alcohol is 1～1.2 times of triacetyl inosine, the consumption of morpholine is 6.5～7% of a triacetyl inosine, and the insulation reaction temperature is 30～60 ℃.
5, the technology of chemical synthesis of producing adenosine according to claim 2 is characterized in that: heat-insulation pressure keeping ammonolysis reaction described in the synthesis step (3), and 10～30 ℃ of its temperature, pressure is 0.15～0.35Mpa; The consumption of described methyl alcohol is 3～5 times of triacetyl inosine.
6, the technology of chemical synthesis of producing adenosine according to claim 2 is characterized in that: the amount of used pure water was 5～7 times of adenosine crude product when crude product adenosine described in the synthesis step (3) was refining, and is centrifugal below 5 ℃, and with 50% washing with alcohol.
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| CN 200510044192 CN1727356A (en) | 2005-07-29 | 2005-07-29 | Technique of chemical synthesis of producing adenosine |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102464689A (en) * | 2010-11-17 | 2012-05-23 | 天津康鸿医药科技发展有限公司 | Preparation method of intermediate compound for synthesizing adenosine |
| CN111808157A (en) * | 2020-06-03 | 2020-10-23 | 北京先通国际医药科技股份有限公司 | Preparation method of adenosine bulk drug |
| CN113173960A (en) * | 2020-09-07 | 2021-07-27 | 远大生命科学(辽宁)有限公司 | Adenosine purification method |
| CN113527395A (en) * | 2021-09-17 | 2021-10-22 | 中国远大集团有限责任公司 | Adenosine crystal form and preparation method thereof |
| CN113683653A (en) * | 2021-06-28 | 2021-11-23 | 远大生命科学(辽宁)有限公司 | Adenosine crystal form, preparation method and application thereof |
-
2005
- 2005-07-29 CN CN 200510044192 patent/CN1727356A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102464689A (en) * | 2010-11-17 | 2012-05-23 | 天津康鸿医药科技发展有限公司 | Preparation method of intermediate compound for synthesizing adenosine |
| CN111808157A (en) * | 2020-06-03 | 2020-10-23 | 北京先通国际医药科技股份有限公司 | Preparation method of adenosine bulk drug |
| CN113173960A (en) * | 2020-09-07 | 2021-07-27 | 远大生命科学(辽宁)有限公司 | Adenosine purification method |
| CN113173960B (en) * | 2020-09-07 | 2023-06-30 | 远大生命科学(辽宁)有限公司 | Adenosine purification method |
| CN113683653A (en) * | 2021-06-28 | 2021-11-23 | 远大生命科学(辽宁)有限公司 | Adenosine crystal form, preparation method and application thereof |
| CN113683653B (en) * | 2021-06-28 | 2024-03-19 | 远大生命科学(辽宁)有限公司 | Adenosine crystal form, preparation method and application thereof |
| CN113527395A (en) * | 2021-09-17 | 2021-10-22 | 中国远大集团有限责任公司 | Adenosine crystal form and preparation method thereof |
| CN114106066A (en) * | 2021-09-17 | 2022-03-01 | 中国远大集团有限责任公司 | A kind of crystal form of adenosine and preparation method thereof |
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