CN103601780A - Synthetic method of 3-acetylpyridine adenine dinucleotide - Google Patents
Synthetic method of 3-acetylpyridine adenine dinucleotide Download PDFInfo
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- CN103601780A CN103601780A CN201310520771.9A CN201310520771A CN103601780A CN 103601780 A CN103601780 A CN 103601780A CN 201310520771 A CN201310520771 A CN 201310520771A CN 103601780 A CN103601780 A CN 103601780A
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Abstract
The invention discloses a chemical synthesis method of 3-acetylpyridine adenine dinucleotide, comprising the following steps: (1) D-ribose is used as a starting material to prepare monophosphate-3-acetylpyridine-alpha-D-nucleoside; (2) adenosine is used as a main raw material to prepare morpholine adenosine monophosphate; and (3) a docking reaction between morpholine adenosine monophosphate and monophosphate-3-acetylpyridine-alpha-D-nucleoside is carried out to prepare 3-acetylpyridine adenine dinucleotide. According to the chemical synthesis method, a commercial industrial product D-ribose is used as the starting raw material; any enzyme is not used during the preparation process of an intermediate; price of raw materials is low and the raw materials are easy to purchase; and production cost of the product is reduced greatly. In addition, by the chemical synthesis method, yield of the product is high, and total yield of the reaction is 4.2% and is remarkably higher than product yield of a present biosynthesis method.
Description
Technical field
The present invention relates to a kind of synthetic method of purine derivative, relate in particular to the chemical synthesis process of 3-acetylpyridine adenine dinucleotide, belong to the synthetic field of 3-acetylpyridine adenine dinucleotide.
Background technology
3-acetylpyridine adenine dinucleotide can be widely used in various fields as biochemical reagents raw material.That the synthetic method of the relevant 3-acetylpyridine adenine dinucleotide of report is one piece of document of 1956 (The Journal of Biological Chemistry the earliest, 1956,221,823-832.), the synthetic method of the disclosed 3-acetylpyridine adenine dinucleotide of the method belongs to biosynthetic means.After this, the people such as Nathan O.Kaplan disclose a kind of biosynthetic means of preparing 3-acetylpyridine adenine dinucleotide from Reduced nicotinamide-adenine dinucleotide (NAD), the method be take NAD as raw material, utilize the glucosides transferance of pig brain NPD enzyme, thereby become 3-acetylpyridine to make 3-acetylpyridine adenine dinucleotide niacinamide Partial Conversion.All there is the problem that is difficult for acquisition in above-mentioned these biosynthetic meanss raw material used---Reduced nicotinamide-adenine dinucleotide (NAD)---.The chemical synthesis process of NAD sees the people's such as Todd report the earliest.Yet, this semisynthesis that is just also raw material from AMP and monophosphate niacinamide nucleosides.Afterwards, it was raw material that the people such as David R.Walt be take the AMP dissociating, and through an one-step hydrolysis, sloughed VITAMIN B4.Pass into again ammonia and form amido sugar.Amido sugar reacts with the niacinamide activating, and forms monophosphate niacinamide nucleosides.Under the effect of enzyme and adenosine disodium triphosphate effect, form Reduced nicotinamide-adenine dinucleotide (NAD) (JACS, 1980,102,7805.JACS, 1984,106,234) again;
Biosynthetic means needs special-purpose place and equipment, and needed specificity enzyme can only be prepared in laboratory, and not having business-like enzyme can buy.If aftertreatment is processed bad, be easy to cause product enzymolysis.The cost of raw material NAD and various enzymes is all very high.
Therefore, in practice, urgently need to develop that a kind of preparation cost is relatively cheap, product yield is high, do not need the chemical synthesis process of the 3-acetylpyridine adenine dinucleotide of specificity enzyme.
Summary of the invention
Main purpose of the present invention is to provide the chemical synthesis process of the 3-acetylpyridine adenine dinucleotide that a kind of preparation cost is relatively cheap, product yield is high.
Main purpose of the present invention is achieved through the following technical solutions:
A chemical synthesis process for 3-acetylpyridine adenine dinucleotide, comprises the following steps:
(1) take D-ribose prepares monophosphate-3-acetylpyridine-α-D-nucleosides as starting raw material;
(2) take adenosine prepares morpholine AMP as main raw material;
(3) morpholine AMP and monophosphate-3-acetylpyridine-α-D-nucleosides are docked to reaction, prepare 3-acetylpyridine adenine dinucleotide.
Wherein, preferred, in step (3) at methane amide, under manganous chloride and anhydrous magnesium sulfate exist, by morpholine AMP and monophosphate-3-acetylpyridine-α-D-nucleosides mix and blend, under room temperature, react, prepare 3-acetylpyridine adenine dinucleotide; Described room temperature is preferably 20-25 ℃.
Wherein, the consumption of each composition is preferably: count in molar ratio manganous chloride: anhydrous magnesium sulfate: morpholine AMP; Monophosphate-3-acetylpyridine-α-D-nucleosides=1:(2-3): (0.9-1): 1, methane amide is excessive;
Described monophosphate-3-acetylpyridine-α-D-nucleosides can prepare by the following method:
(1) protecting group, with triphenylmethyl chloride as D-ribose 5-position, prepares 5-Tr-D-ribose;
Preferably, under anhydrous pyridine exists, by D-ribose and triphenylmethyl chloride mix and blend, at 60-85 ℃, stirring reaction; Preferably, meter in molar ratio, by D-ribose and triphenylmethyl chloride according to 1:(1-1.2) mole dosage proportioning stirring reaction 4 hours under 75 ℃ of conditions.
(2), by 5-Tr-D-ribose, prepare 5-Tr-1-amido-D-ribose;
Preferably, in step (2), by following reaction, prepare 5-Tr-1-amido-D-ribose:
By the 0-4 ℃ of reaction in excessive saturated methanolic ammonia solution of 5-Tr-D-ribose, prepare 5-Tr-1-amido-D-ribose.
(3) 5-Tr-1-amido-D-ribose is reacted with 3-acetylpyridine, make 3-acetylpyridine-5-Tr-α-D-nucleosides;
Preferably, in step (3), under the condition of anhydrous methanol and the existence of trifluoromethanesulfonic acid trimethylsilyl group, the methanol solution of 5-Tr-1-amido-D-ribose is joined in 3-acetylpyridine, under room temperature, stir and react; Reacting coarse product is used column chromatography, obtain 3-acetylpyridine-5-Tr-α-D-nucleosides.
Wherein the mol ratio of 5-Tr-1-amido-D-ribose and 3-acetylpyridine is preferably 1:(1-1.2);
(4) 3-acetylpyridine-5-Tr-α-D-nucleosides is taken off to protecting group, obtain 3-acetylpyridine-α-D-nucleosides (compound 4).
Preferably, in step (4), by 3-acetylpyridine-5-Tr-α-D-nucleosides stirring reaction in methyl alcohol-dilute hydrochloric acid, slough protecting group.
(5) by 3-acetylpyridine-α-D-nucleosides under the effect of phosphorus oxychloride and trimethyl phosphite 99, make monophosphate-3-acetylpyridine-α-D-nucleosides (compound 5).
Preferably, in step (5), keeping, under 0-4 ℃ of temperature condition, 3-acetylpyridine-α-D-nucleosides being joined to stirring reaction in phosphorus oxychloride and trimethyl phosphite 99, obtain;
Further, the invention provides the method that from above-mentioned reaction product separation and purification obtains monophosphate-3-acetylpyridine-α-D-nucleosides, comprising: in reaction product, add the resin moderated pH to 5 of Dowex; After Dowex resin water rinses, merge the concentrated rear upper ion column of water, wash with water, by elutriant evaporate to dryness water, separate out solid, obtain.
Preferably, the present invention be take by the following method adenosine and is prepared morpholine AMP as main raw material:
(1) by adenosine under the effect of phosphorus oxychloride and trimethyl phosphite 99, make monophosphate adenosine (compound 6).
At keeping 0-4 ℃, in phosphorus oxychloride and trimethyl phosphite 99, add adenosine.Keep 0-4 ℃ of reaction; Obtain;
The present invention also further provides from above-mentioned reaction product separation and purification to obtain the method for monophosphate adenosine, comprising: in reaction product, add the resin moderated pH to 5 of Dowex; After Dowex resin water rinses, merge the concentrated rear upper ion column of water, wash with water, by elutriant evaporate to dryness water, separate out solid, obtain.
(2) by monophosphate adenosine under DCC, morpholine effect, make morpholine AMP.
Existing 3-acetylpyridine adenine dinucleotide synthetic method is biosynthetic means, and the present invention is with adopting the method for chemosynthesis to prepare 3-acetylpyridine adenine dinucleotide completely, and starting raw material is commercial industrial goods D-ribose.In intermediate preparation process, not using any enzyme, is all conventional chemical reagent, and chemical feedstocks is cheap, be easy to buy, so total cost is well below biosynthetic means, greatly reduces the production cost of product; In addition, the product yield of the inventive method is high, and the total recovery of eight step reactions is 4.2%, existing biosynthetic means (The Journal of Biological Chemistry, 1956,221,823-832.JACS, 1980,102,7805) from full acetyl-D-ribose, calculate, total recovery only has 2% left and right, and the total recovery of chemical synthesis process of the present invention is significantly higher than existing biosynthetic means.
The present invention compared with prior art, mainly possesses following advantage:
The first, the present invention adopts chemical process synthetic completely, has avoided comparatively expensive enzyme catalyst.All there is sale in selected chemical feedstocks Ge great reagent company.Chemical feedstocks is cheap, be easy to buy, so total cost is well below biosynthetic means, greatly reduces the production cost of product.
Second, in synthetic route, the present invention has designed two key intermediate: monophosphate-3-acetylpyridine-α-D-nucleosides and morpholine AMP, with route independently, synthesize one of them key intermediate respectively, and then dock, the effective like this synthetic risk of having avoided linear synthetic route to bring, has also significantly improved the yield of product.
Accompanying drawing explanation
The process route chart of the chemical synthesis process of Fig. 1 3-acetylpyridine adenine dinucleotide of the present invention.
Embodiment
Below in conjunction with specific embodiment, further describe the present invention, advantage and disadvantage of the present invention will be more clear along with description.But these embodiment are only exemplary, scope of the present invention are not formed to any restriction.It will be understood by those skilled in the art that lower without departing from the spirit and scope of the present invention and can the details of technical solution of the present invention and form be modified or be replaced, but these modifications and replacement all fall within the scope of protection of the present invention.
Synthesizing of embodiment 15-Tr-D-ribose (compound 1).
15.0g D-ribose is joined in 250ml there-necked flask, add 100ml anhydrous pyridine, open and stir.Add 27.8g triphenylmethyl chloride.Be heated to 75 ℃, stirring reaction 4 hours.Under decompression, steam most of pyridine, then with toluene band three times, evaporate to dryness obtains brown syrup shape product.With 200ml chloroform, dissolve again, with frozen water and saturated common salt, wash three times successively.Organic phase anhydrous magnesium sulfate drying, filters, and is spin-dried for, and ethyl alcohol recrystallization obtains 39.4g product.Be 5-Tr-D-ribose.
LC-MS：【M+Na】
+=415。HNMR（MeOH-d4）：δ：7.605-7.104(m,15H)；6.260(d,1H);5.832(d,1H);5.201(d,1H);5.006(d,1H)ppm.
Synthesizing of embodiment 2:5-Tr-1-amido-D-ribose (compound 2).
39.4g5-Tr-D-ribose is dissolved in 200ml anhydrous methanol, is placed in the water-bath of constant temperature low temperature, keep 0 ℃.Under stirring, constantly pass into dry ammonia, after 20 hours, detect raw material and disappear, almost the quantitative 5-Tr-1-amido-D-ribose that is transformed into.Obtain 39.2g yellow solid, be product.
LC-MS：【M+H】
+=392。HNMR（MeOH-d4）：δ：7.523-7.078(m,15H)；5.891(d,1H);5.755(d,1H);4.568(d,1H);4.306(d,1H)ppm.
Synthesizing of embodiment 3:3-acetylpyridine-5-Tr-α-D-nucleosides (compound 3).
Under room temperature, in 250ml there-necked flask, add 50ml anhydrous methanol, under stirring, splash into 6.0g3-acetylpyridine.Slowly drip 11.6g trifluoromethanesulfonic acid trimethylsilyl group (TMSOTf).After half an hour, add the methanol solution (19.6 grams of 5-Tr-1-amido-D-riboses are dissolved in 50ml methyl alcohol) of 5-Tr-1-amido-D-ribose.Dropwise stirring at room 5 hours.Decompression steams solvent.With lack the dissolve with methanol of volume as far as possible, slowly add anhydrous diethyl ether, there is solid to separate out.Filter, dry, obtain thick product.Column chromatography, with methylene dichloride and methanol system wash-out, obtains 3-acetylpyridine-5-Tr-α-D-nucleosides 9.65g.
LC-MS:[M]
+after=496(deduction trifluoromethanesulfonic acid root).HNMR（DMSO-d6）：δ：9.472(s,1H);9.387(s,1H);9.165(d,1H);9.076(d,1H);8.245-8.134(m,1H);7.412-7.305(m,15H);6.784(d,1H);6.543(d,1H);4.851-4.741(m,1H);4.562-4.021(m,2H);3.623-3.268(m,2H);2.656(s,3H)ppm.
Synthesizing of embodiment 4:3-acetylpyridine-α-D-nucleosides (compound 4).
Under room temperature, 10.0g3-acetylpyridine-5-Tr-α-D-nucleosides is dissolved in 50ml anhydrous methanol, opens and stir, slowly add the dilute hydrochloric acid of 25ml1%.Stir about 15 minutes, occur precipitation in a large number.Filter, filtrate decompression steams solvent.With lack the water dissolution of volume as far as possible, with C-2 reversed-phase column (Merck, 70-230 order), do column chromatography.Chromatographic solution is spin-dried for, almost quantitative 3-acetylpyridine-α-D-nucleosides that obtains.Dry weighing: 6.22g.
LC-MS:[M]
+after=254(deduction trifluoromethanesulfonic acid root).HNMR（DMSO-d6）：δ：10.512(s,1H);9.772(s,1H);9.310(d,2H);8.642(s,1H);8.154(t,1H);7.220(d,1H);5.985(t,1H);5.532(t,1H);5.218(d,1H);4.496(dd,1H);4.348(dd,1H);2.716(s,3H)ppm.
Synthesizing of embodiment 5 monophosphates-3-acetylpyridine-α-D-nucleosides (compound 5)
At 0 ℃, in reaction flask, add 0.06ml phosphorus oxychloride and 0.36ml trimethyl phosphite 99.Open and stir, add 100mg3-acetylpyridine-α-D-nucleosides.Reactant keeps 0 degree, reacts 4 hours.Add several dripping, then add Dowex resin (Dowex resin1 * 8, HCO
3-type, 20-50 order) adjusting pH to 5.Resin rinses with 200ml water.Water merges, and is concentrated into 10ml, is loaded to ion column.Filler is Dowex resin1 * 2, CH
3cOO-type, 200-400 order, 8 * 1cm, washes with water.By comparing with standard model, determine the chromatographic solution at product place, merge the lower evaporate to dryness water of 30 degree.Add acetone to separate out solid, filter and obtain amorphous powder 56mg.
LC-MS：【M-1】
-=332。HNMR（D
2O）：δ：9.987(s,1H);9.885(d,1H);9.654(d,1H);8.876(t,1H);5.223(d,1H);4.865(t,2H);4.436(d,1H);3.912(d,1H);3.658(t,1H);2.665(s,3H)ppm.
Embodiment 6: monophosphate adenosine (compound 6) synthetic.
At 0 ℃, in reaction flask, add 0.6ml phosphorus oxychloride and 3.6ml trimethyl phosphite 99.Open and stir, add 801mg adenosine.Reactant keeps 0 ℃, reacts 5 hours.Add 2ml water, then add Dowex resin (Dowex resin1 * 8, HCO
3-type, 20-50 order) adjusting pH to 5.Resin rinses with 1000ml water.Water merges, and is concentrated into 50ml, is loaded to ion column.Filler is Dowex resin1 * 2, CH
3cOO-type, 200-400 order, 8 * 1cm, washes with water.By comparing with standard model, determine the chromatographic solution at product place, merge evaporate to dryness water at 30 ℃.Add acetone to separate out solid, filter and obtain amorphous powder 0.56g.Yield 54%.
LC-MS：【M-1】
-=346。HNMR（D
2O）：δ：8.956(s,1H);8.458(s,1H);6.054(d,1H);5.147(t,1H);4.763(t,2H);4.261(d,1H);4.013(d,1H);3.657(d,1H)ppm.
Synthesizing of embodiment 7 morpholine monophosphate adenosines (compound 7).
In reaction flask, add 347mg AMP and 10ml water, the 10ml trimethyl carbinol, the morpholine that 0.34ml(4mmol) purifying is crossed.Be heated to reflux.Slowly drip the t-butanol solution of DCC.(824mg, 4mmolDCC is dissolved in the 15ml trimethyl carbinol.) the about 3-4 hour of whole dropping process.Reaction solution continues to stir several hours, until show a principal point on HPLC.Now, reaction solution is cooled to room temperature, and the solid of separating out is removed by the method for filtering, and uses trimethyl carbinol washing leaching cake.Filtrate is evaporate to dryness under vacuum, until most of trimethyl carbinol is removed.Ether extraction three times of remaining water.If needed can solids removed by filtration in leaching process.Ether phase evaporate to dryness, last remaining little water is drained with oil pump, obtains glass residue.With the least possible dissolve with methanol, transfer in single port bottle.Slowly steam methyl alcohol, add dry ether, precipitation, obtains white solid powder.Dry, weigh: 295mg, yield: 71%.
LC-MS：【M-1】
-=415。HNMR（D
2O）：δ：9.235(s,1H);8.391(s,1H);5.964(d,1H);4.648(t,1H);4.542(t,2H);4.139(d,1H);4.007(d,1H);3.912(d,1H);3.689(m,4H);3.457(m,4H)ppm.
Synthesizing of embodiment 83-acetylpyridine adenine dinucleotide (compound 8).
In reaction flask, add 20ml methane amide, add 187mg manganous chloride and 240mg anhydrous magnesium sulfate.The morpholine monophosphate adenosine that adds again 416mg, stirs 15 minutes.3-acetylpyridine-α-D-the nucleosides that adds again 362mg.Stirring at room 16 hours.React complete, reaction solution adds acetonitrile, and thick product is separated out.Use again resin (Sephadex QAE A-25) purifying, with the ammonium bicarbonate soln wash-out of 0.25M.With Amberite XAD-16, purify again, use water-methanol gradient elution.Afterwards, lyophilize.Obtain yellow powder 355mg.HPLC purity 98%.
LC-MS：【M+1】
+=663。HNMR（D
2O）：δ：9.332(s,1H);9.156(d,1H);8.965(d,1H);8.440(s,1H);8.241(s,1H);8.110(t,1H);6.100(t,2H);4.614(t,1H);4.465-4.102(9H);2.756(s,3H)ppm。
Claims (10)
1. a chemical synthesis process for 3-acetylpyridine adenine dinucleotide, comprises the following steps:
(1) take D-ribose prepares monophosphate-3-acetylpyridine-α-D-nucleosides as starting raw material;
(2) take adenosine prepares morpholine AMP as main raw material;
(3) morpholine AMP and monophosphate-3-acetylpyridine-α-D-nucleosides are docked to reaction, prepare 3-acetylpyridine adenine dinucleotide.
2. in accordance with the method for claim 1, it is characterized in that: in step (3) under methane amide, manganous chloride and anhydrous magnesium sulfate exist, by morpholine AMP and monophosphate-3-acetylpyridine-α-D-nucleosides mix and blend, under room temperature, react, prepare 3-acetylpyridine adenine dinucleotide; Wherein, the consumption of each composition is preferably: count in molar ratio manganous chloride: anhydrous magnesium sulfate: morpholine AMP; Monophosphate-3-acetylpyridine-α-D-nucleosides=1:(2-3): (0.9-1): 1, methane amide is excessive.
3. it is characterized in that in accordance with the method for claim 1: described monophosphate-3-acetylpyridine-α-D-nucleosides can prepare by the following method:
(1) protecting group, with triphenylmethyl chloride as D-ribose 5-position, prepares 5-Tr-D-ribose;
(2), by 5-Tr-D-ribose, prepare 5-Tr-1-amido-D-ribose;
(3) 5-Tr-1-amido-D-ribose is reacted with 3-acetylpyridine, make 3-acetylpyridine-5-Tr-α-D-nucleosides;
(4) 3-acetylpyridine-5-Tr-α-D-nucleosides is taken off to protecting group, obtain 3-acetylpyridine-α-D-nucleosides;
(5) by 3-acetylpyridine-α-D-nucleosides under the effect of phosphorus oxychloride and trimethyl phosphite 99, make monophosphate-3-acetylpyridine-α-D-nucleosides.
4. in accordance with the method for claim 3, it is characterized in that: in step (1) under anhydrous pyridine exists, by D-ribose and triphenylmethyl chloride mix and blend, at 60-85 ℃, stirring reaction; Preferably, meter in molar ratio, by D-ribose and triphenylmethyl chloride according to 1:(1-1.2) mole dosage proportioning stirring reaction 4 hours under 75 ℃ of conditions.
5. it is characterized in that in accordance with the method for claim 3: step prepares 5-Tr-1-amido-D-ribose by following reaction in (2): by the 0-4 ℃ of reaction in excessive saturated methanolic ammonia solution of 5-Tr-D-ribose.
6. in accordance with the method for claim 3, it is characterized in that: under the condition existing at anhydrous methanol and trifluoromethanesulfonic acid trimethylsilyl group in step (3), the methanol solution of 5-Tr-1-amido-D-ribose is joined in 3-acetylpyridine, under room temperature, stir and react; Reacting coarse product is used column chromatography, obtain 3-acetylpyridine-5-Tr-α-D-nucleosides.
7. in accordance with the method for claim 3, it is characterized in that: in step (4), by 3-acetylpyridine-5-Tr-α-D-nucleosides stirring reaction in methyl alcohol-dilute hydrochloric acid, slough protecting group; In step (5), keeping, under 0-4 ℃ of temperature condition, 3-acetylpyridine-α-D-nucleosides being joined to stirring reaction in phosphorus oxychloride and trimethyl phosphite 99, obtain monophosphate-3-acetylpyridine-α-D-nucleosides crude product.
8. it is characterized in that in accordance with the method for claim 7: in step (5), also comprise in monophosphate-3-acetylpyridine-α-D-nucleosides crude product and add the resin moderated pH to 5 of Dowex; After Dowex resin water rinses, merge the concentrated rear upper ion column of water, wash with water, by elutriant evaporate to dryness water, separate out solid, obtain monophosphate-3-acetylpyridine-α-D-nucleosides sterling.
9. it is characterized in that in accordance with the method for claim 1: the method that the adenosine of take in step (2) is prepared morpholine AMP as main raw material comprises:
(1) by adenosine under the effect of phosphorus oxychloride and trimethyl phosphite 99, make monophosphate adenosine;
(2) by monophosphate adenosine under DCC, morpholine effect, make morpholine AMP.
10. in accordance with the method for claim 9, it is characterized in that: step (1), keeping, under 0-4 ℃ of temperature condition, adding adenosine in phosphorus oxychloride and trimethyl phosphite 99, keeps 0-4 ℃ of temperature to react, and obtains monophosphate adenosine;
Wherein, monophosphate adenosine crude product is prepared into the method for monophosphate adenosine sterling, comprises: in crude product, add the resin moderated pH to 5 of Dowex; After Dowex resin water rinses, merge the concentrated rear upper ion column of water, wash with water, by elutriant evaporate to dryness water, separate out solid, obtain sterling.
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| CN109053838A (en) * | 2018-07-26 | 2018-12-21 | 四川大学 | Prepare β-nicotinamide mononucleotide or β-niacinamide ribose method |
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| CN102477057A (en) * | 2010-11-26 | 2012-05-30 | 北京利德曼生化股份有限公司研发中心 | Thio-nicotinamide adenine dinucleotide, intermediates thereof and preparation methods of thio-nicotinamide adenine dinucleotide and intermediates |
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| CN109053838A (en) * | 2018-07-26 | 2018-12-21 | 四川大学 | Prepare β-nicotinamide mononucleotide or β-niacinamide ribose method |
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