CN1634961A - Improved process for preparing adenosine - Google Patents
Improved process for preparing adenosine Download PDFInfo
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- CN1634961A CN1634961A CN 200410084458 CN200410084458A CN1634961A CN 1634961 A CN1634961 A CN 1634961A CN 200410084458 CN200410084458 CN 200410084458 CN 200410084458 A CN200410084458 A CN 200410084458A CN 1634961 A CN1634961 A CN 1634961A
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Abstract
The invention discloses a method for preparing adenosine. The adenosine is obtained by functional group transition using cheap raw material inosine having an adenosine skeleton as an initiator. The invention have the advantages of reasonable synthetic route, temperate reaction condition, simple operation and friendly-to-environment.
Description
Technical field
The present invention relates to a kind of adenosine preparation method, particularly a kind of method that adopts chemical method to prepare adenosine.
Technical background
Adenosine is adenosine (adenosine), is a kind of endogenous nucleosides that spreads all over zooblast, plays regulating and controlling effect in the physiological metabolism process.Can directly enter cardiac muscle and generate adenylic acid (AMP) participation energy metabolism of myocardial through phosphorylation, also participate in dilating coronary blood vessel simultaneously, play the effect of blood flow increasing, can be used for treating illnesss such as stenocardia, myocardial infarction, arteriosclerosis, essential hypertension, apoplexy sequela.Adenosine also is important pharmaceutical intermediate, is the raw material of synthetic Triphosaden (ATP), adenylic acid (AMP) and many nucleoside medicines.Therefore adenosine has vast market development and application prospect.
It is the processing method of raw material chemosynthesis adenosine with the xanthoglobulin that Chinese patent literature (CN 1408720A) proposes a kind of: xanthoglobulin gets 6-chloropurine through the phosphorus oxychloride chloro; the condensation reaction under the catalysis of biconjugate nitrophenyl phosphate of 6-chloropurine and tetrem acyl ribose generate 6-chloro-9-(β-D-2 '; 3 '; 5 '-triacetyl ribofuranose glucoside) purine, the ammonia that pressurizes is then separated and is made adenosine.Its synthetic route is:
Though this synthetic method has cost advantage than the biological process synthesizing adenosine, it is loaded down with trivial details that its technological process still shows.Its maximum defective is: xanthoglobulin and tetrem acyl ribose are that raw material cracking glucoside key gets by inosine, price is than the inosine costliness, the formation that is raw material by the glucoside key with xanthoglobulin and tetrem acyl ribose comes synthesizing adenosine, does not obviously meet the composition principle of the simplest property, and production cost does not have advantage.Therefore seeking a kind of easy, cheap adenosine synthesis and production process becomes purpose of the present invention.
The content of invention
The object of the invention is, provides a kind of easy, low-cost and be easy to industrialized adenosine preparation method.
The said adenosine preparation method of the present invention is characterized in that, is starting raw material with inosine (Compound I), at first Compound I and acetic anhydride is carried out acylation reaction and makes triacetyl inosine (Compound I I); Then Compound I I is made 6-chloro-9-(β-D-2 ', 3 ', 5 '-triacetyl ribofuranose glucoside) purine (compound III) with chlorination reagent reaction in the organic bases solvent; At last with compound III at C
1～C
6Fatty Alcohol(C12-C14 and C12-C18)/NH
3Saturated solution in carry out ammonolysis reaction and make target compound one adenosine (compound IV); Its synthetic route is as follows:
Wherein: the temperature of acylation reaction is 0～200 ℃, and the reaction times is 0.1～10 hour; The temperature of chlorination is 0～100 ℃, and the reaction times is 3～30 hours; The temperature of ammonolysis reaction is 0～50 ℃, and reaction pressure is 0.1～0.4MPa, and the reaction times is 1～30 hour.
Embodiment
(1) inosine (Compound I) and acetic anhydride prepared in reaction triacetyl inosine (Compound I I):
Reaction solvent can use acetic anhydride itself or reaction is had the organic bases (as pyridine, N, accelerine, N, N-Diethyl Aniline etc.) of katalysis that as solvent, the consumption of solvent is 1～10 times of Compound I weight.Be fast reaction speed, can add weight is the sodium acetate or the DMAP (N, N-dimethyl-4-amido pyridine) of 0.005～0.2 times of Compound I weight.Acylation reaction is excessive acetic anhydride or the solvent of reclaim under reduced pressure after reacting 0.1～10 hour under 0～200 ℃, adds entry then, and freezing and crystallizing filters, and gets triacetyl inosine (Compound I I).
(2) triacetyl inosine (Compound I I) in the organic bases solvent with chlorination reagent prepared in reaction compound III:
This reacts employed organic bases solvent is pyridine, N, and accelerine is or/and N, the mixed solvent of N-Diethyl Aniline or they and tetrahydrofuran (THF) or dioxane, and consumption is 0.5～10 times of Compound I I weight.Employed chlorination reagent can be inorganic acyl chlorides, aliphatics acyl chlorides or aromatic series acyl chlorides as sulfur oxychloride, phosphorus oxychloride, phosphorus trichloride, Acetyl Chloride 98Min., propionyl chloride, oxalyl chloride or Benzoyl chloride etc., and the mol ratio of itself and Compound I I is 1: 0.3～5.0.Chlorination gets thick liquid russet in reaction under 0～100 ℃ after 3～30 hours, this thick liquid is the mix products of compound III, and the compound III mixture can separate, also can be without separating the aminolysis reaction that directly enter down the step.
(3) compound III ammonia is separated preparation adenosine compound IV:
Compound III that the last step makes or its mixture thick liquid are at C
1～C
6Fatty Alcohol(C12-C14 and C12-C18)/NH
3Saturated solution (particular methanol, ethanol or propyl alcohol/NH
3Saturated solution) in carry out ammonolysis reaction, the ammonolysis reaction temperature is 0～50 ℃, reaction pressure is 0.1～0.4MPa, the reaction times is 1～30 hour.Reclaim under reduced pressure NH after reaction finishes
3And solvent, the freezing solid of separating out of concentrated solution carries out recrystallization with water or ethanol/water mixed solvent and obtains adenosine (compound IV).
Characteristics of the present invention are:
1, employed raw and auxiliary material its cheap market price makes production cost drop to extremely low limit.
2, with the inosine be starting raw material, the fracture of no glucoside key and forming process, synthetic route are very reasonable.
3, easy and simple to handle, mild condition, reactions steps is few, does not have special pearl conversion unit, is easy to industrialization.
4, " three wastes " discharging is few, helps environment protection.
The invention will be further described below by embodiment, its objective is to better understanding content of the present invention.Therefore the cited case does not limit protection scope of the present invention:
Embodiment 1
(1) add the anhydrous sodium acetate of 100g and the inosine of 1Kg in the acetic anhydride of 2Kg, reacted 2 hours down at 130 ℃, excessive acetic anhydride is removed in underpressure distillation, add 2L water, be refrigerated to 0 ℃ of crystallization, filtration, dry triacetyl inosine (Compound I I) 1.41Kg, the yield 96% of getting;
(2) add the triacetyl inosine of 1.41Kg and the phosphorus oxychloride of 0.75Kg in the pyridine solvent of 2.8Kg, reacted 20 hours down at 30 ℃, get thick liquid russet, this thick liquid directly enters down the aminolysis reaction in step;
(3) will go up the thick liquid that makes of step slowly is added drop-wise to by 8L methyl alcohol and NH
3Form in the saturated solution, be controlled at the reaction 10 hours down of 50 ℃, the pressure of 0.4MPa.Ammonia excretion, steaming methyl alcohol remove pyridine under reduced pressure, and resistates is carried out secondary decolourization, recrystallization with water, get adenosine white crystal 0.55Kg, total recovery 55%.
Embodiment 2
(1) add the DMAP of 20g and the inosine of 1Kg in the acetic anhydride of 2Kg, at room temperature reacted 5 hours, excessive acetic anhydride is removed in underpressure distillation, adds 2L water, is refrigerated to 0 ℃ of crystallization, filtration, dry triacetyl inosine (Compound I I) 1.42Kg, the yield 97% of getting;
(2) add the triacetyl inosine of 1.42Kg and the phosphorus oxychloride of 0.75Kg in the mixed solvent of 0.8Kg pyridine and 2.0Kg dioxane composition, reacted 10 hours down at 50 ℃, get thick liquid russet, this thick liquid directly enters down the aminolysis reaction that goes on foot;
(3) will go up the thick liquid that makes of step slowly is added drop-wise to by 8L methyl alcohol and NH
3Form in the saturated solution, be controlled at the reaction 15 hours down of 25 ℃, the pressure of 0.2MPa.Ammonia excretion, steaming methyl alcohol remove pyridine and dioxane under reduced pressure, and resistates is carried out secondary decolourization, recrystallization with water, get adenosine white crystal 0.51Kg, total recovery 51%.
Claims (7)
1, a kind of adenosine preparation method is characterized in that, is starting raw material with inosine (Compound I), at first Compound I and acetic anhydride is carried out acylation reaction and makes triacetyl inosine (Compound I I); Then Compound I I is made 6-chloro-9-(β-D-2 ', 3 ', 5 '-triacetyl ribofuranose glucoside) purine (compound III) with chlorination reagent reaction in the organic bases solvent; At last with compound III at C
1～C
6Fatty Alcohol(C12-C14 and C12-C18)/NH
3Saturated solution in carry out ammonolysis reaction and make target compound-adenosine (compound IV); Its synthetic route is as follows:
Wherein: the temperature of acylation reaction is 0～200 ℃, and the reaction times is 0.1～10 hour; The temperature of chlorination is 0～100 ℃, and the reaction times is 3～30 hours; The temperature of ammonolysis reaction is 0～50 ℃, and reaction pressure is 0.1～0.4MPa, and the reaction times is 1～30 hour.
2, preparation method as claimed in claim 1 is characterized in that, wherein said chlorination reagent is sulfur oxychloride, phosphorus oxychloride, phosphorus trichloride, Acetyl Chloride 98Min., propionyl chloride, oxalyl chloride or Benzoyl chloride, and the mol ratio of itself and Compound I I is 1: 0.3～5.0.
3, preparation method as claimed in claim 1, it is characterized in that wherein said organic bases solvent is pyridine, N, accelerine or/and, N, N-Diethyl Aniline or they and tetrahydrofuran (THF) or dioxane mixed solvent, consumption is 0.5～10 times of Compound I I weight.
4, preparation method as claimed in claim 1 is characterized in that, wherein said alcohol/ammonia saturated solution is methyl alcohol, ethanol or propyl alcohol/NH
3Saturated solution.
5, preparation method as claimed in claim 2, it is characterized in that wherein the organic bases solvent is pyridine, N, accelerine is or/and N, N-Diethyl Aniline or they and tetrahydrofuran (THF) or dioxane mixed solvent, consumption is 0.5～10 times of Compound I I weight.
6, preparation method as claimed in claim 5 is characterized in that, wherein alcohol/ammonia saturated solution is methyl alcohol, ethanol or propyl alcohol/NH
3Saturated solution.
As described any one preparation method of claim 1～6, it is characterized in that 7, adding weight in acylation reaction is the sodium acetate or the N of 0.005～0.2 times of Compound I weight, N-dimethyl-4-amido pyridine is as catalyzer.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410084458 CN1634961A (en) | 2004-11-23 | 2004-11-23 | Improved process for preparing adenosine |
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|---|---|---|---|
| CN 200410084458 CN1634961A (en) | 2004-11-23 | 2004-11-23 | Improved process for preparing adenosine |
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Cited By (3)
| 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 |
| CN102675391A (en) * | 2011-12-20 | 2012-09-19 | 山东凯盛新材料股份有限公司 | Technique for synthesizing adenosin by chemical method |
| 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 |
-
2004
- 2004-11-23 CN CN 200410084458 patent/CN1634961A/en active Pending
Cited By (4)
| 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 |
| CN102675391A (en) * | 2011-12-20 | 2012-09-19 | 山东凯盛新材料股份有限公司 | Technique for synthesizing adenosin by chemical method |
| CN102675391B (en) * | 2011-12-20 | 2015-09-02 | 山东凯盛新材料有限公司 | Chemical method synthesizing adenosine technique |
| 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 |
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