CN102086222B - Preparation method of beta-thymidine - Google Patents
Preparation method of beta-thymidine Download PDFInfo
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Abstract
The invention provides a preparation method of beta-thymidine, belonging to the technical field of fine chemical industry. The preparation method is as follows: reacting 5-methyl uridine used as a raw material with dialkyl carbonate (RO)2CO for dehydration; generating halogenation reaction with a halogenation reagent; and finally, carrying out catalytic hydrogenation by reducing metal so as to prepare the beta-thymidine. The synthesis process is simple, and the cost is low; and only twice separations and purifications are carried out, thereby greatly reducing labor intensity and avoiding the defects that propionyl bromide is used, cost is high, yield is low, and equipment corrosion is severe in the original halogenation reaction process. By using a novel halogenation reaction system, raw material cost is reduced, conversion rate is high, yield is up to above 85%, the purity of the product is high, and high-performance liquid chromatography (HPLC) is larger than 99.8%.
Description
Technical field
The invention belongs to fine chemical technology, being specifically related to a kind of is the method that starting raw material prepares beta-thymidine with the 5-methyluridine.
Background technology
(β-Thymidine), claim deoxythymidine (Deoxythymidine) again is the key intermediate of treatment AIDS (AIDS) medicine " zidovudine " and " stavudine " to beta-thymidine, and no natural product exists.The method that manual work is at present produced has biosynthetic means and chemical synthesis process.Biosynthetic means (comprising DNA enzymolysis process, fermentation method, enzyme process) working condition equipment requirements is higher, and cost is expensive.At present, the preparation of beta-thymidine is main with chemosynthesis.
Early stage chemical process is synthesized beta-thymidine reaction lack stereospecificity, can generate a certain amount of alpha-isomer when generating beta-thymidine, makes raw material availability low, and separating technology is complicated, and cost improves greatly.Had the people to propose a kind of more perfect method for preparing beta-thymidine in 1998: through the synthetic beta-thymidine (CN1055293) of halo-acylations, catalytic hydrogenation and alcoholysis, though reaction has stereospecificity, yield is not very high with the 5-methyluridine.
Summary of the invention
The objective of the invention is to overcome the deficiency of prior art, provide one be suitable for industrialized easy, be the method for feedstock production beta-thymidine with the 5-methyluridine economically and reasonably.This method has realized the improvement at reaction process, has reduced the cost of raw and auxiliary material, has improved yield, is specially adapted to scale operation.
The preparation method of described a kind of beta-thymidine is characterized in that comprising following synthesis step:
1) described reaction equation is as follows:
2) being starting raw material with the 5-methyluridine (I) shown in the step 1), being dissolved in the polar solvent, under catalyst action, is 90-150 ℃ in temperature, with carbonic diester (RO)
2CO reaction 1-4 hour, processed obtains midbody compound (II), described carbonic diester (RO)
2The molar ratio of CO and 5-methyluridine (I) is 1.1-1.5:1; Described catalyzer is NaOH or KOH; Its charging capacity and 5-methyluridine (I) molar ratio are 0.0125-0.05:1, and midbody halides (III) is 2,2 '-dehydration-methyluridine;
3) with step 2) midbody compound (II) that obtains is dissolved in organic solvent; With halogenating agent be 50-80 ℃ in temperature; React and obtained midbody halides (III) in 2-10 hour; The molar ratio of described halogenating agent and midbody compound (II) is 1.2-1.5:1, and midbody halides (III) is 2 '-halo thymidine;
4) the midbody halides (III) that step 3) is obtained is dissolved in solvent; In the presence of reducing metal; Temperature is 20-60 ℃; Certain pressure reacted 10-20 hour down, and reduction obtains title product beta-thymidine (IV), and the consumption of described reducing metal is 0.1-0.3 a times of midbody halides (III) weight.
The preparation method of described a kind of beta-thymidine; It is characterized in that step 2) described in polar solvent be N; Dinethylformamide (DMF), N; The mixed solvent of one or more in N-N,N-DIMETHYLACETAMIDE (MDAC) or the acetonitrile, the mol ratio of its charging capacity and 5-methyluridine (I) is 6-8:1.
The preparation method of described a kind of beta-thymidine is characterized in that step 2) described in carbonic diester (RO)
2R among the CO is C
1-4Alkyl or phenyl.
The preparation method of described a kind of beta-thymidine is characterized in that the organic solvent described in the step 3) is a kind of among methyl alcohol, ethanol, chloroform, methylene dichloride or the DMSO, and the mol ratio of charging capacity and 5-methyluridine (I) is 10-20:1.
The preparation method of described a kind of beta-thymidine is characterized in that the halogenating agent described in the step 3) is a kind of among HBr or the HCl.
The preparation method of described a kind of beta-thymidine is characterized in that the halogenating agent described in the step 3) is NaBr-HCl system or NaBr-HBr system.
The preparation method of described a kind of beta-thymidine is characterized in that the reducing metal described in the step 4) is a kind of in zinc, nickel or the palladium charcoal.
The preparation method of described a kind of beta-thymidine is characterized in that the solvent described in the step 4) is one or more mixtures in methyl alcohol, ethanol or the water, and the mol ratio of charging capacity and 5-methyluridine (I) is 60-80:1.
The preparation method of described a kind of beta-thymidine is characterized in that the catalyzed reaction temperature described in the step 4) is for being 45-60 ℃.
The preparation method of described a kind of beta-thymidine is characterized in that the pressure described in the step 4) is 0.1～0.3mpa.
Compared with prior art, beneficial effect of the present invention is following:
1) this synthesis technique is through dehydrating condensation, halo, and catalytic hydrogenation prepares beta-thymidine, and technology is simple, and cost is low; Only need carry out twice separation and purify, greatly reduce labour intensity;
2) used PROPIONYL CHLORIDE in the halogenating reaction process, cost is high in the past, and yield is low, and equipment corrosion is serious.After adopting new halogenating reaction system, reduce raw materials cost, improved yield, reduced the corrosion on Equipment degree;
3) transformation efficiency is high, and total recovery is up to more than 85%, and product purity is high, HPLC>99.8%.
Embodiment
Below in conjunction with embodiment the present invention is further described, but protection scope of the present invention is not limited in this:
1. by 5-methyluridine (I) preparation midbody (II) 2,2 '-dehydration-methyluridine
Embodiment 1 joins 25.8g 5-methyluridine (0.1mol) and 25.7g diphenyl carbonate (0.12mol) among the 60ml MDAC, starts stirring and is warming up to 90 ℃, after solid dissolves clearly; Add 1gNaOH and reflux the guarantor after 1 hour; Behind the no raw material of TCL mensuration, solvent is fallen in the cooling underpressure distillation, and distillation finishes the postcooling crystallization; Filtration obtains the pulverous midbodys of 21.9 g clear crystals (II), and productive rate is 94%.
In the present embodiment, replace diphenyl carbonate with methylcarbonate, diethyl carbonate, dipropyl carbonate or dibutyl carbonate; Solvent replaces MDAC with one or more the mixed solvent in DMF, MDAC or the acetonitrile, replaces NaOH with KOH, all can obtain above-mentioned effect.
Embodiment 2 joins 25.8g 5-methyluridine (0.1mol) and 32.1g diphenyl carbonate (0.15mol) among the 60mlDMF, starts stirring and is warming up to 90 ℃, after solid dissolves clearly; Add 1.5gKOH and reflux insulation after 2 hours; Behind the no raw material of TCL mensuration, solvent is fallen in the cooling underpressure distillation, and distillation finishes the postcooling crystallization; Filtration obtains the pulverous midbodys of 22.1 g clear crystals (II), and productive rate is 95%.
Embodiment 3 joins 25.8g 5-methyluridine (0.1mol) and 10.8g methylcarbonate (0.12mol) among the 50mlDMF, starts stirring and is warming up to 120 ℃, after solid dissolves clearly; Add 1gKOH and reflux insulation after 3 hours; Behind the no raw material of TCL mensuration, solvent is fallen in the cooling underpressure distillation, and distillation finishes the postcooling crystallization; Filtration obtains the pulverous midbodys of 22.1 g clear crystals (II), and productive rate is 95%.
Embodiment 4 joins 25.8g 5-methyluridine (0.1mol) and 15.4g diethyl carbonate (0.13mol) among the 50mlDMF, starts stirring and is warming up to 150 ℃, after solid dissolves clearly; Add 1gNaOH and reflux insulation after 4 hours; Behind the no raw material of TCL mensuration, solvent is fallen in the cooling underpressure distillation, and distillation finishes the postcooling crystallization; Filtration obtains the pulverous midbodys of 22.1 g clear crystals (II), and productive rate is 95%.
Embodiment 5 joins 25.8g 5-methyluridine (0.1mol) and 20.44g dipropyl carbonate (0.12mol) among the 60mlDMF, starts stirring and is warming up to 150 ℃, after solid dissolves clearly; Add 1gNaOH and reflux insulation after 4 hours; Behind the no raw material of TCL mensuration, solvent is fallen in the cooling underpressure distillation, and distillation finishes the postcooling crystallization; Filtration obtains the pulverous midbody of 22.0g clear crystal (II), and productive rate is 94.5%.
2. by midbody (II) preparation halogenide (III) 2 '-halo thymidine
Embodiment 6 is suspended in midbody (II) 24g (0.1mol), 13gNaBr (0.127mol) in the 50ml methyl alcohol; Stirring also is warming up to 70 ℃; Slowly feed HCl gas, temperature is controlled at 70 ℃ of reactions 8 hours, with 70 ℃ of underpressure distillation behind the no midbody of TCL detection; Distill and finish postcooling and add 50ml methyl alcohol; Add an amount of NaOH adjusting PH again and be used for next step reaction to neutrality, yield is 93.5% (yield is bromo-derivative and chloro thing sum, and the bromo-derivative of generation and chloro thing mol ratio are 6.7:1).
In the present embodiment, solvent replaces methyl alcohol with ethanol, chloroform, methylene dichloride or DMSO, and halogenating agent replaces the NaBr-HCl system with HBr, HCl or NaBr-HBr system, all can obtain identical effect.
Embodiment 7 is suspended in midbody (II) 24g (0.1mol), 15.4gNaBr (0.15mol) in the 50ml methyl alcohol, stirs and be warming up to 70 ℃, slowly feeds HBr gas, and temperature is controlled at 70 ℃ of reactions 5 hours.Detect 70 ℃ of underpressure distillation behind the no midbody with TCL, finish postcooling and add 50ml methyl alcohol of distillation adds an amount of NaOH adjusting PH again and is used for next step reaction to neutrality, and yield is 94%.
Embodiment 8 is suspended in midbody (II) 24g (0.1mol), 12.3gNaBr (0.12mol) in the 100ml chloroform, stirs and be warming up to 70 ℃, slowly feeds HBr gas, and temperature is controlled at 70 ℃ of reactions 6 hours.Detect 70 ℃ of underpressure distillation behind the no midbody with TCL, finish postcooling and add the 100ml chloroform of distillation adds an amount of NaOH adjusting PH again and is used for next step reaction to neutrality, and yield is 93.5%.
Embodiment 9 is suspended in midbody (II) 24g (0.1mol), 14.4gNaBr (0.14mol) in the 60ml ethanol, stirs and be warming up to 70 ℃, slowly feeds HBr gas, and temperature is controlled at 70 ℃ of reactions 8 hours.Detect 70 ℃ of underpressure distillation behind the no midbody with TCL, finish postcooling and add 60ml ethanol of distillation adds an amount of NaOH adjusting PH again and is used for next step reaction to neutrality, and yield is 93.4%.
Embodiment 10 is suspended in midbody (II) 24g (0.1mol), 13.3gNaBr (0.13mol) in the 70ml methyl alcohol, stirs and be warming up to 70 ℃, slowly feeds HBr gas, and temperature is controlled at 70 ℃ of reactions 8 hours.Detect 70 ℃ of underpressure distillation behind the no midbody with TCL, finish postcooling and add 70ml methyl alcohol of distillation adds an amount of NaOH adjusting PH again and is used for next step reaction to neutrality, and yield is 94%.
Embodiment 11 is suspended in midbody (II) 24g (0.1mol), 13gNaBr (0.127mol) in the 50ml methyl alcohol, stirs and be warming up to 50 ℃, slowly feeds HBr gas, and temperature is controlled at 50 ℃ of reactions 8 hours.Detect 50 ℃ of underpressure distillation behind the no midbody with TCL, finish postcooling and add 50ml methyl alcohol of distillation adds an amount of NaOH adjusting PH again and is used for next step reaction to neutrality, and yield is 93.5%.
Embodiment 12 is suspended in midbody (II) 24g (0.1mol), 13gNaBr (0.127mol) in the 50ml methyl alcohol, stirs and be warming up to 80 ℃, slowly feeds HBr gas, and temperature is controlled at 80 ℃ of reactions 8 hours.Detect 80 ℃ of underpressure distillation behind the no midbody with TCL, finish postcooling and add 50ml methyl alcohol of distillation adds an amount of NaOH adjusting PH again and is used for next step reaction to neutrality, and yield is 94%.
Embodiment 13 is suspended in midbody (II) 24g (0.1mol), 13gNaBr (0.127mol) in the 50ml methyl alcohol, stirs and be warming up to 70 ℃, slowly feeds HCl gas, and temperature is controlled at 70 ℃ of reactions 2 hours.Detect 70 ℃ of underpressure distillation behind the no midbody with TCL, finish postcooling and add 50ml methyl alcohol of distillation adds an amount of NaOH adjusting PH again and is used for next step reaction to neutrality, and yield is 93.2%.
Embodiment 14 is suspended in midbody (II) 24g (0.1mol), 13gNaBr (0.127mol) in the 50ml methyl alcohol; Stirring also is warming up to 70 ℃, slowly feeds HCl gas, and temperature is controlled at 70 ℃ of reactions 10 hours; With 70 ℃ of underpressure distillation behind the no midbody of TCL detection; Finish postcooling and add 50ml methyl alcohol of distillation adds an amount of NaOH again and regulates PH and be used for next step reaction to neutrality, and yield is 94%.
Can the direct catalytic hydrogenation of reaction solution behind the adjusting PH be produced beta-thymidine in the industrial production.If need with the halides separation and Extraction; Can be with reaction solution underpressure distillation and the suction filtration after reacting completely, with saturated NaHCO3 and pure water elder generation after scouring repeatedly, oven dry gets final product; Halides (bromo-derivative with (or) chloro thing) content 99.3%, white powder or pale yellow powder.
3. by halogenide (III) preparation beta-thymidine (IV)
Embodiment 15 is adding aforesaid method gained halides 31.5g (containing halides 0.1mol) and 300ml methyl alcohol in the reaction flask among the embodiment 6, the nickel catalyzator after the 5g activation, and the 10ml sodium acetate stirs and is warming up to 45 ℃, logical H after the homo(io)thermism
2To balance, keep-up pressure at 0.3mpa, react after 10 hours with TCL detection reaction degree.After question response was complete, excessive catalyzer filtered through diatomite layer, the methanol wash filter cake, and merging filtrate, most of solvent is removed in underpressure distillation, activated carbon decolorizing, recrystallizing methanol gets white powder beta-thymidine 23.1g, yield 97%, measuring content is 99.8%.
Reducing metal replaces nickel with zinc or palladium charcoal in the present embodiment; Solvent is that one or more mixtures in methyl alcohol, ethanol or the water replace methyl alcohol, all can obtain above-mentioned experiment effect.
Embodiment 16 is with adding aforesaid method gained halides 31.5g (containing halides 0.1mol) and 360ml ethanol in the reaction flask among the embodiment 7; Nickel catalyzator after the 6g activation, the 10ml sodium acetate stirs and is warming up to 45 ℃; Logical H2 keep-ups pressure at 0.1mpa to balance after the homo(io)thermism.React after 10 hours with TCL detection reaction degree.After question response was complete, excessive catalyzer filtered through diatomite layer, the methanol wash filter cake, and merging filtrate, most of solvent is removed in underpressure distillation, activated carbon decolorizing, recrystallizing methanol gets white powder beta-thymidine 23.5g, yield 96.8%, measuring content is 99.7%.
Embodiment 17 is adding aforesaid method gained halides 31.5g (containing halides 0.1mol) and 400ml methyl alcohol in the reaction flask among the embodiment 8, the nickel catalyzator after the 5g activation, and the 10ml sodium acetate stirs and is warming up to 45 ℃.Logical H after the homo(io)thermism
2To balance, keep-up pressure at 0.3mpa, react after 10 hours with TCL detection reaction degree.After question response was complete, excessive catalyzer filtered through diatomite layer, the methanol wash filter cake, and merging filtrate, most of solvent is removed in underpressure distillation, activated carbon decolorizing, recrystallizing methanol gets white powder beta-thymidine 23.1g, yield 97%, measuring content is 99.7%.
Embodiment 18 is adding aforesaid method gained halides 31.5g (containing halides 0.1mol) and 300ml methyl alcohol in the reaction flask among the embodiment 9, the zinc catalyst after the 5g activation, and the 10ml sodium acetate stirs and is warming up to 45 ℃.Logical H after the homo(io)thermism
2To balance, keep-up pressure at 0.3mpa.React after 10 hours with TCL detection reaction degree.After question response was complete, excessive catalyzer filtered through diatomite layer, methanol wash filter cake, merging filtrate; Most of solvent, activated carbon decolorizing, recrystallizing methanol are removed in underpressure distillation; Get white powder beta-thymidine 22.98g, yield 96.5%, measuring content is 99.6%.
Embodiment 19 is adding aforesaid method gained halides 31.5g (containing halides 0.1mol) and 300ml methyl alcohol in the reaction flask among the embodiment 10, the nickel catalyzator after the 8g activation, and the 10ml sodium acetate stirs and is warming up to 45 ℃.Logical H after the homo(io)thermism
2To balance, keep-up pressure at 0.3mpa, react after 10 hours with TCL detection reaction degree, after question response is complete; Excessive catalyzer filters through diatomite layer, methanol wash filter cake, merging filtrate; Most of solvent, activated carbon decolorizing, recrystallizing methanol are removed in underpressure distillation; Get white powder beta-thymidine 23.1g, yield 97%, measuring content is 99.8%.
Embodiment 20 is adding aforesaid method gained halides 31.5g (containing halides 0.1mol) and 300ml methyl alcohol in the reaction flask among the embodiment 11, the nickel catalyzator after the 5g activation, and the 10ml sodium acetate stirs and is warming up to 20 ℃.Logical H after the homo(io)thermism
2To balance, keep-up pressure at 0.3mpa, react after 10 hours with TCL detection reaction degree; After question response was complete, excessive catalyzer filtered through diatomite layer, the methanol wash filter cake; Merging filtrate, underpressure distillation are removed most of solvent, activated carbon decolorizing; Recrystallizing methanol gets white powder beta-thymidine 22.62g.Yield 95%, measuring content is 99.5%.
Embodiment 21 is adding aforesaid method gained halides 31.5g (containing halides 0.1mol) and 300ml methyl alcohol in the reaction flask among the embodiment 12, the palladium carbon catalyst after the 5g activation, and the 10ml sodium acetate stirs and is warming up to 60 ℃, logical H after the homo(io)thermism
2To balance, keep-up pressure at 0.3mpa, react after 10 hours with TCL detection reaction degree, after question response is complete; Excessive catalyzer filters through diatomite layer, methanol wash filter cake, merging filtrate; Most of solvent, activated carbon decolorizing, recrystallizing methanol are removed in underpressure distillation; Get white powder beta-thymidine 23.1g, yield 97%, measuring content is 99.6%.
Embodiment 22 is adding aforesaid method gained halides 31.5g (containing halides 0.1mol) and 300ml methyl alcohol in the reaction flask among the embodiment 13, the zinc catalyst after the 5g activation, and the 10ml sodium acetate stirs and is warming up to 45 ℃, logical H after the homo(io)thermism
2To balance, keep-up pressure at 0.2mpa.React after 15 hours with TCL detection reaction degree, question response fully after, excessive catalyzer filters through diatomite layer; The methanol wash filter cake, merging filtrate, most of solvent is removed in underpressure distillation; Activated carbon decolorizing, recrystallizing methanol gets white powder beta-thymidine 22.98g; Yield 96.5%, measuring content is 99.65%.
Embodiment 23 is adding aforesaid method gained halides 31.5g (containing halides 0.1mol) and 300ml methyl alcohol in the reaction flask among the embodiment 14, the nickel catalyzator after the 5g activation, and the 10ml sodium acetate stirs and is warming up to 20 ℃, logical H after the homo(io)thermism
2To balance, keep-up pressure at 0.3mpa, react after 20 hours with TCL detection reaction degree, after question response is complete; Excessive catalyzer filters through diatomite layer, methanol wash filter cake, merging filtrate; Most of solvent, activated carbon decolorizing, recrystallizing methanol are removed in underpressure distillation; Get white powder beta-thymidine 22.86g, yield 96%, measuring content is 99.5%.
Claims (6)
1. the preparation method of a beta-thymidine is characterized in that comprising following synthesis step:
1) described reaction equation is as follows:
2) being starting raw material with the 5-methyluridine (I) shown in the step 1), being dissolved in the polar solvent, under catalyst action, is 90-150 ℃ in temperature, with carbonic diester (RO)
2CO reaction 1-4 hour, processed obtains midbody compound (II), described carbonic diester (RO)
2The molar ratio of CO and 5-methyluridine (I) is 1.1-1.5:1, and described catalyzer is NaOH or KOH, and its charging capacity and 5-methyluridine (I) molar ratio are 0.0125-0.05:1; Described carbonic diester (RO)
2R among the CO is C
1-4Alkyl or phenyl;
3) with step 2) midbody compound (II) that obtains is dissolved in organic solvent; With halogenating agent be 50-80 ℃ in temperature; React and obtained midbody halides (III) in 2-10 hour; The molar ratio of described halogenating agent and midbody compound (II) is 1.2-1.5:1, and described halogenating agent is NaBr-HCl system or NaBr-HBr system;
4) the midbody halides (III) that step 3) is obtained is dissolved in solvent; In the presence of reducing metal; Temperature is 20-60 ℃, and certain pressure reacted 10-20 hour down, and reduction obtains title product beta-thymidine (IV); The consumption of described reducing metal is 0.1-0.3 a times of midbody halides (III) weight, and described pressure is 0.1～0.3mpa.
2. the preparation method of a kind of beta-thymidine according to claim 1; It is characterized in that step 2) described in polar solvent be N; Dinethylformamide, N; The mixed solvent of one or more in N-N,N-DIMETHYLACETAMIDE or the acetonitrile, the mol ratio of its charging capacity and 5-methyluridine (I) is 6-8:1.
3. the preparation method of a kind of beta-thymidine according to claim 1; It is characterized in that the organic solvent described in the step 3) is a kind of among methyl alcohol, ethanol, chloroform, methylene dichloride or the DMSO, the mol ratio of charging capacity and 5-methyluridine (I) is 10-20:1.
4. the preparation method of a kind of beta-thymidine according to claim 1 is characterized in that the reducing metal described in the step 4) is a kind of in zinc, nickel or the palladium charcoal.
5. the preparation method of a kind of beta-thymidine according to claim 1 is characterized in that the solvent described in the step 4) is one or more mixtures in methyl alcohol, ethanol or the water, and the mol ratio of charging capacity and 5-methyluridine (I) is 60-80:1.
6. the preparation method of a kind of beta-thymidine according to claim 1 is characterized in that the catalyzed reaction temperature described in the step 4) is 45-60 ℃.
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| CN103450302B (en) * | 2012-05-29 | 2016-09-21 | 上海迪赛诺药业有限公司 | The method preparing beta-thymidine |
| CN102863493B (en) * | 2012-10-12 | 2014-12-03 | 安徽金太阳生化药业有限公司 | Preparation method of beta-thymidine |
| CN105566421A (en) * | 2014-10-09 | 2016-05-11 | 江苏笃诚医药科技股份有限公司 | Beta-thymidine preparation method |
| CN106366145A (en) * | 2015-07-25 | 2017-02-01 | 成都博腾药业有限公司 | Preparation method of (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine |
| CN106117287B (en) * | 2016-04-14 | 2019-10-29 | 安达市海纳贝尔化工有限公司 | The method for preparing 5- methyl deoxyuridine |
| CN106146587A (en) * | 2016-04-21 | 2016-11-23 | 上海艾美晶生物科技有限公司 | The method of preparation 2 '-deoxyuridine |
| CN105950689A (en) * | 2016-06-28 | 2016-09-21 | 焦作健康元生物制品有限公司 | Process for producing beta-thymidine through microbiological fermentation method |
| CN106967767B (en) * | 2017-04-25 | 2019-09-24 | 苏州笃美生物科技有限公司 | A kind of synthetic method of beta-thymidine |
| CN112210577A (en) * | 2020-11-04 | 2021-01-12 | 赤峰蒙广生物科技有限公司 | Method for producing beta-thymidine by fermentation method |
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| CN1216766A (en) * | 1998-10-06 | 1999-05-19 | 中国人民解放军第二军医大学 | Method for preparing beta-thymidine |
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| CN1216766A (en) * | 1998-10-06 | 1999-05-19 | 中国人民解放军第二军医大学 | Method for preparing beta-thymidine |
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