CN107286212B - Preparation method of high-purity didanosine impurity - Google Patents

Preparation method of high-purity didanosine impurity Download PDF

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CN107286212B
CN107286212B CN201610220005.4A CN201610220005A CN107286212B CN 107286212 B CN107286212 B CN 107286212B CN 201610220005 A CN201610220005 A CN 201610220005A CN 107286212 B CN107286212 B CN 107286212B
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didanosine
anhydroinosine
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高明
王俊臣
陈风
朱秋晟
钱丹
殷恒亮
杨秋燕
陈金春
卢廷贵
赵臻
李翠平
马珍珍
年蓓蕾
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Abstract

The invention discloses a preparation method of high-purity didanosine impurities, which is characterized by easy acquisition of adopted reagents, simple synthesis operation, mild reaction conditions and high product purity. Which comprises the following steps: 1) taking 2-acetoxy isobutyryl chloride and inosine as initial raw materials, and carrying out bromination reaction and acylation reaction in a solvent under the catalysis of lithium bromide; 2) concentrating the reaction solution obtained in the step 1, removing the solvent, and dissolving the reaction solution in a polar solvent to be directly used in the next step; 3) adding an alkaline reagent into the mixture at low temperature, adjusting the pH value to be in a strong alkali condition, and reacting to obtain the 2 ', 3' -anhydroinosine.

Description

一种高纯度去羟肌苷杂质的制备方法A kind of preparation method of high-purity didanosine impurity

技术领域technical field

本发明涉及有机合成领域,特别涉及一种高纯度去羟肌苷杂质的制备方法。The invention relates to the field of organic synthesis, in particular to a method for preparing a high-purity didanosine impurity.

背景技术Background technique

去羟肌苷(DDI)化学名为2,3-双脱氧肌苷。该药是由美国Bristol-Myers Squibb公司开发,并于1991年首次在美国上市的一种HIV-1逆转录酶抑制剂。The chemical name of didanosine (DDI) is 2,3-dideoxyinosine. The drug is an HIV-1 reverse transcriptase inhibitor developed by Bristol-Myers Squibb Company in the United States and first listed in the United States in 1991.

本品通过干扰逆转录酶而阻止病毒的复制而使艾滋病患者的CD4细胞数目增多,从而延长患者的生存时间和减少致病菌感染发生率。临床已用于不能耐受齐多夫定(AZT)、A ZT治疗无效或无症状HIV感染的艾滋病患者。This product prevents the replication of the virus by interfering with reverse transcriptase and increases the number of CD4 cells in AIDS patients, thereby prolonging the survival time of patients and reducing the incidence of pathogenic bacterial infection. It has been clinically used for AIDS patients who cannot tolerate zidovudine (AZT), who are ineffective in AZT treatment or asymptomatic HIV infection.

虽然去羟肌苷上市二十多年,但关于其生产过程中的杂质研究还相对较少。特别是2’,3’-脱水肌苷的发现,申请人在去羟肌苷生产过程中发现了杂质2’,3’-脱水肌苷,并通过大量化学实验验证了该杂质的多少与反应进行程度有关,其结构式如下:Although didanosine has been on the market for more than two decades, there are relatively few studies on impurities in its production process. Especially the discovery of 2',3'-anhydroinosine, the applicant discovered the impurity 2',3'-anhydroinosine in the production process of didanosine, and verified the amount and reaction of this impurity through a large number of chemical experiments The degree of progress is related, and its structural formula is as follows:

Figure BDA0000961955360000021
Figure BDA0000961955360000021

站在安全用药的角度,2’,3’-脱水肌苷标准样品(即对照品)的合成对于合成高品质去羟肌苷、减少副作用、提高艾滋病人的存活率和生活质量显得尤为重要。对于药厂来说,高纯度的杂质对照能为我们监测生产过程、减少副反应的发生、提高产品收率和纯度提供数据支撑和理论依据。另一方面,国际竞争越来越激烈,高品质的产品能够提高产品的竞争力。From the perspective of safe drug use, the synthesis of 2', 3'-anhydroinosine standard samples (that is, the reference substance) is particularly important for synthesizing high-quality didanosine, reducing side effects, and improving the survival rate and quality of life of AIDS patients. For pharmaceutical factories, high-purity impurity control can provide data support and theoretical basis for us to monitor the production process, reduce the occurrence of side reactions, and improve product yield and purity. On the other hand, international competition is becoming more and more intense, and high-quality products can improve the competitiveness of products.

发明内容SUMMARY OF THE INVENTION

本发明的目的在于提供一种高纯度去羟肌苷杂质2’,3’-脱水肌苷的制备方法,该方法所采用的试剂易得,合成操作简单,反应条件温和,产物纯度高。The purpose of the present invention is to provide a kind of preparation method of high-purity didanosine impurity 2', 3'-dehydroinosine, the reagent that this method adopts is easy to obtain, the synthesis operation is simple, the reaction condition is mild, and the product purity is high.

本发明的目的是通过以下技术方案实现的:The purpose of this invention is to realize through the following technical solutions:

一种去羟肌苷杂质2’,3’-脱水肌苷的制备方法,包括以下步骤:A kind of preparation method of didanosine impurity 2', 3'-dehydrated inosine, comprises the following steps:

1、以2-乙酰氧基异丁酰氯和肌苷为起始原料,在溴化锂催化下在溶剂中发生反应;1. Take 2-acetoxyisobutyryl chloride and inosine as starting materials, and react in a solvent under the catalysis of lithium bromide;

该步骤发生溴化反应和酰化反应得到5-O-(2,4,4-三甲基-1,3-二氧-环戊酮基)-2-溴-3-乙酰氧基-肌苷和5-O-(2,4,4-三甲基-1,3-二氧环戊酮基)-3-溴-2-乙酰氧基-肌苷;In this step, bromination reaction and acylation reaction occur to obtain 5-O-(2,4,4-trimethyl-1,3-dioxo-cyclopentanonyl)-2-bromo-3-acetoxy-carboxyl glycosides and 5-O-(2,4,4-trimethyl-1,3-dioxolanone)-3-bromo-2-acetoxy-inosine;

2、步骤1所得反应液浓缩除去溶剂后溶于极性溶剂中直接用于下一步;2. The reaction solution obtained in step 1 is concentrated to remove the solvent and then dissolved in a polar solvent to be directly used in the next step;

3、低温条件下向步骤2)所得极性溶剂中加入碱性试剂,调pH至强碱条件下进行反应,过滤即得2’,3’-脱水肌苷。3. Add an alkaline reagent to the polar solvent obtained in step 2) under low temperature conditions, adjust the pH to react under strong alkaline conditions, and filter to obtain 2',3'-dehydrated inosine.

上述步骤用反应式表达为:The above steps are expressed as:

Figure BDA0000961955360000031
Figure BDA0000961955360000031

优选地,上述技术方案中,步骤1的操作步骤为:在溶剂中加入无水溴化锂升温,待无水溴化锂溶解;然后再加入2-乙酰氧基异丁酰氯进行反应;所得反应液降温后再加入肌苷进行反应。Preferably, in the above technical solution, the operation steps of step 1 are: adding anhydrous lithium bromide to the solvent to heat up, and waiting for the anhydrous lithium bromide to dissolve; then adding 2-acetoxyisobutyryl chloride to react; Inosine was added for the reaction.

优选地,上述技术方案中,步骤1中无水溴化锂、2-乙酰氧基异丁酰氯和肌苷的质量比为30-40:50-60:25-35,可以是35-40:55-58:28-32,如:37.5:55:30。Preferably, in the above technical solution, in step 1, the mass ratio of anhydrous lithium bromide, 2-acetoxyisobutyryl chloride and inosine is 30-40:50-60:25-35, which can be 35-40:55- 58:28-32, eg: 37.5:55:30.

优选地,上述技术方案中,步骤1中所述升温为升至70-75℃,步骤1中所述降温为降至10℃以下。Preferably, in the above technical solution, the temperature increase in step 1 is to increase to 70-75°C, and the temperature decrease in step 1 is to decrease to below 10°C.

优选地,上述技术方案中,步骤1中加入2-乙酰氧基异丁酰氯后反应0.5-2h,如:1h;步骤1中再加入肌苷后反应3-6h,如:4h。Preferably, in the above technical solution, 2-acetoxyisobutyryl chloride is added in step 1 and reacted for 0.5-2h, such as 1h; in step 1, inosine is added and reacted for 3-6h, such as 4h.

优选地,上述技术方案中,步骤1中所述溶剂为乙腈。Preferably, in the above technical solution, the solvent in step 1 is acetonitrile.

优选地,上述技术方案中,步骤1中每使用1g肌苷对应使用5-15g乙腈。Preferably, in the above technical solution, 5-15g of acetonitrile is used for every 1g of inosine used in step 1.

优选地,上述技术方案中,步骤1和步骤2中还包括将步骤1所得反应液中和至中性或弱碱性环境,如:以无水乙酸钠中和至pH6.5-7.0。Preferably, in the above technical solution, steps 1 and 2 further include neutralizing the reaction solution obtained in step 1 to a neutral or weakly alkaline environment, such as: neutralizing to pH 6.5-7.0 with anhydrous sodium acetate.

优选地,上述技术方案中,步骤2中除去溶剂后、溶于极性溶剂前还包括以下步骤:将中间产物加入二氯甲烷和水的混合物中,搅拌,静止分层,取二氯甲烷层并将二氯甲烷蒸干,所得产物待用。二氯甲烷和水的比例可以为1:10~10:1,还可以为1:3~3:1,杂质部分溶于水,中间产物溶于二氯甲烷中;步骤2除去溶剂后所得的每1g中间产物加入6-10ml,可以为6-8ml二氯甲烷和水的混合物中。Preferably, in the above technical scheme, after removing the solvent in step 2 and before dissolving in the polar solvent, the following steps are further included: adding the intermediate product to the mixture of dichloromethane and water, stirring, and statically layering, and taking the dichloromethane layer The dichloromethane was evaporated to dryness, and the obtained product was used. The ratio of dichloromethane to water can be 1:10~10:1, or 1:3~3:1, the impurities are partially dissolved in water, and the intermediate product is dissolved in dichloromethane; Add 6-10ml, can be 6-8ml of a mixture of dichloromethane and water per 1g of the intermediate product.

优选地,上述技术方案中,步骤2中所述极性溶剂为甲醇、乙醇、异丙醇或叔丁醇。Preferably, in the above technical solution, the polar solvent in step 2 is methanol, ethanol, isopropanol or tert-butanol.

优选地,上述技术方案中,步骤3中所述低温条件为-20~10℃,如:5-10℃。Preferably, in the above technical solution, the low temperature condition in step 3 is -20-10°C, such as: 5-10°C.

优选地,上述技术方案中,步骤3中所述碱性试剂为氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、甲胺及其相应水溶液。Preferably, in the above technical solution, the alkaline reagents in step 3 are sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, methylamine and their corresponding aqueous solutions.

优选地,上述技术方案中,步骤3中所述强碱条件为pH值≥10,可以是pH值12-14。Preferably, in the above technical solution, the strong alkali condition in step 3 is that the pH value is greater than or equal to 10, which may be pH value 12-14.

优选地,上述技术方案中,步骤3中所述反应所需时间为8-16h,如:12h。低温条件下保温反应使脱保护、环氧键的形成、结晶同时进行。Preferably, in the above technical solution, the time required for the reaction in step 3 is 8-16h, such as 12h. The heat preservation reaction at low temperature enables deprotection, formation of epoxy bonds, and crystallization to proceed simultaneously.

与现有技术相比,本发明具有如下有益效果:该方法所采用的试剂易得,合成操作简单,反应条件温和,同时产物纯度高,可达99.5%以上,重量收率也可达84%以上,摩尔收率可达90%以上。并且通过对2’,3’-脱水肌苷的合成,为去羟肌苷杂质检验的定性及定量提供了标准样品。Compared with the prior art, the invention has the following beneficial effects: the reagents used in the method are easy to obtain, the synthesis operation is simple, the reaction conditions are mild, and the product purity is high, which can reach more than 99.5%, and the weight yield can also reach 84%. Above, the molar yield can reach more than 90%. And through the synthesis of 2', 3'-anhydroinosine, a standard sample is provided for the qualitative and quantitative detection of didanosine impurities.

附图说明Description of drawings

图1是本发明去羟肌苷杂质2’,3’-脱水肌苷核磁共振氢谱图谱,1H NMR(400MHz,DMSO):δ=8.30(s,1H,1-H),8.10(s,1H,2-H),6.17(s,1H,3-H),4.46(d,J=4.0Hz,1H,4-H),4.21-4.18(m,J=8.0Hz,2H,5-H),3.53(d,J=4.0Hz,2H,6-H)。2.50的峰为DMSO溶剂峰。Fig. 1 is the hydrogen nuclear magnetic resonance spectrum of didanosine impurity 2', 3'-anhydroinosine of the present invention, 1 H NMR (400MHz, DMSO): δ=8.30(s, 1H, 1-H), 8.10(s ,1H,2-H),6.17(s,1H,3-H),4.46(d,J=4.0Hz,1H,4-H),4.21-4.18(m,J=8.0Hz,2H,5- H), 3.53 (d, J=4.0 Hz, 2H, 6-H). The peak at 2.50 is the DMSO solvent peak.

图2是本发明去羟肌苷杂质2’,3’-脱水肌苷的质谱图谱。Fig. 2 is the mass spectrum of didanosine impurity 2', 3'-anhydroinosine of the present invention.

具体实施方式Detailed ways

下面结合附图,对本发明的具体实施方式进行详细描述,但应当理解本发明的保护范围并不受具体实施方式的限制。The specific embodiments of the present invention will be described in detail below with reference to the accompanying drawings, but it should be understood that the protection scope of the present invention is not limited by the specific embodiments.

实施例1Example 1

1)将250g乙腈投入干燥的反应瓶中,搅拌下加入无水溴化锂37.5g升温至70-75℃,待无水溴化锂溶解;然后再加入55g的2-乙酰氧基异丁酰氯反应1小时;所得反应液降温至10℃以下后,再加入30g肌苷进行反应4h;1) 250g of acetonitrile was dropped into a dry reaction flask, 37.5g of anhydrous lithium bromide was added under stirring and the temperature was raised to 70-75°C, until the anhydrous lithium bromide was dissolved; then 55g of 2-acetoxyisobutyryl chloride was added to react for 1 hour; After the obtained reaction solution was cooled to below 10 °C, 30 g of inosine was added to carry out the reaction for 4 h;

2)加无水乙酸钠中和pH至6.5-7.0,真空浓缩除去乙腈,得乳白色固体稠状物;每1g乳白色固体稠状物加入8ml二氯甲烷与水的混合物,二氯甲烷和水的体积比为1:1,搅拌15分钟,静止分层,取二氯甲烷层,将二氯甲烷层蒸干,所得产物溶于150ml乙醇中;2) Add anhydrous sodium acetate to neutralize the pH to 6.5-7.0, and concentrate in vacuo to remove acetonitrile to obtain a milky white solid thick substance; add 8 ml of a mixture of dichloromethane and water, a mixture of dichloromethane and water per 1 g of the milky white solid thick substance The volume ratio was 1:1, stirring for 15 minutes, static layering, taking the dichloromethane layer, evaporating the dichloromethane layer to dryness, and dissolving the obtained product in 150 ml of ethanol;

3)在5-10℃条件下向其中加入碱性试剂5%氢氧化钠水溶液120ml,调节pH至pH值13,反应12h,过滤,烘干即得2’,3’-脱水肌苷25.8g,纯度99.0%以上,重量收率86%(摩尔收率92.2%)。3) Add 120ml of alkaline reagent 5% sodium hydroxide aqueous solution to it at 5-10°C, adjust the pH to pH 13, react for 12h, filter, and dry to obtain 25.8g of 2',3'-anhydroinosine , the purity is above 99.0%, and the weight yield is 86% (molar yield 92.2%).

实施例2Example 2

1)将250g乙腈投入干燥的反应瓶中,搅拌下加入无水溴化锂37.5g升温至70-75℃,待无水溴化锂溶解;然后再加入55g的2-乙酰氧基异丁酰氯反应1小时;所得反应液降温至10℃以下后,再加入30g肌苷进行反应4h;1) 250g of acetonitrile was dropped into a dry reaction flask, 37.5g of anhydrous lithium bromide was added under stirring and the temperature was raised to 70-75°C, until the anhydrous lithium bromide was dissolved; then 55g of 2-acetoxyisobutyryl chloride was added to react for 1 hour; After the obtained reaction solution was cooled to below 10 °C, 30 g of inosine was added to carry out the reaction for 4 h;

2)加无水乙酸钠中和pH至6.5-7.0,真空浓缩除去乙腈,得乳白色固体稠状物;每1g乳白色固体稠状物加入8ml二氯甲烷与水的混合物,二氯甲烷和水的体积比为1:1,搅拌15分钟,静止分层,将二氯甲烷层蒸干,所得产物溶于150ml甲醇中;2) Add anhydrous sodium acetate to neutralize the pH to 6.5-7.0, and concentrate in vacuo to remove acetonitrile to obtain a milky white solid thick substance; add 8 ml of a mixture of dichloromethane and water, a mixture of dichloromethane and water per 1 g of the milky white solid thick substance The volume ratio was 1:1, stirred for 15 minutes, separated into layers, and the dichloromethane layer was evaporated to dryness, and the obtained product was dissolved in 150 ml of methanol;

3)在5-10℃条件下向其中加入碱性试剂甲胺水溶液120ml,调节pH至强碱pH值12,反应12h,过滤,烘干即得2’,3’-脱水肌苷25.2g,纯度99.5%以上,重量收率84%以上(摩尔收率90.1%)。3) Add 120ml of alkaline reagent methylamine aqueous solution to it at 5-10°C, adjust the pH to a strong base pH value of 12, react for 12h, filter, and dry to obtain 25.2g of 2',3'-anhydroinosine, The purity is 99.5% or more, and the weight yield is 84% or more (molar yield 90.1%).

实施例3Example 3

1)将300g乙腈投入干燥的反应瓶中,搅拌下加入无水溴化锂40g升温至70-75℃,待无水溴化锂溶解;然后再加入60g的2-乙酰氧基异丁酰氯反应1小时;所得反应液降温至10℃以下后,再加入30g肌苷进行反应4h;1) 300g of acetonitrile was dropped into a dry reaction flask, 40g of anhydrous lithium bromide was added under stirring and the temperature was raised to 70-75°C, until the anhydrous lithium bromide was dissolved; then 60g of 2-acetoxyisobutyryl chloride was added to react for 1 hour; the obtained After the reaction solution was cooled to below 10°C, 30g of inosine was added to react for 4h;

2)加无水乙酸钠中和pH至6.5-7.0,真空浓缩除去乙腈,得乳白色固体稠状物;每1g乳白色固体稠状物加入6ml二氯甲烷与水的混合物,二氯甲烷和水的体积比为1:3,搅拌15分钟,静止分层,取二氯甲烷层,将二氯甲烷层蒸干,所得产物溶于150ml叔丁醇中;2) Add anhydrous sodium acetate to neutralize the pH to 6.5-7.0, and concentrate in vacuo to remove acetonitrile to obtain a milky white solid thick substance; add 6 ml of a mixture of dichloromethane and water, a mixture of dichloromethane and water per 1 g of the milky white solid thick substance The volume ratio was 1:3, stirring for 15 minutes, static layering, taking the dichloromethane layer, evaporating the dichloromethane layer to dryness, and dissolving the obtained product in 150 ml of tert-butanol;

3)在5-10℃条件下向其中加入碱性试剂5%氢氧化钠水溶液130ml,调节pH至强碱pH值14,反应12h,过滤,烘干即得2’,3’-脱水肌苷22.5g,纯度99.0%以上,重量收率75%(摩尔收率80.4%)。3) Add 130ml of alkaline reagent 5% sodium hydroxide aqueous solution to it at 5-10°C, adjust the pH to a strong base pH value of 14, react for 12h, filter, and dry to obtain 2',3'-anhydroinosine 22.5 g, purity 99.0% or more, weight yield 75% (molar yield 80.4%).

前述对本发明的具体示例性实施方案的描述是为了说明和例证的目的。这些描述并非想将本发明限定为所公开的精确形式,对示例性实施例进行选择和描述的目的在于解释本发明的特定原理及其实际应用,从而使得本领域的技术人员能够实现并利用本发明的各种不同的示例性实施方案以及各种不同的选择和改变。本发明的范围意在由权利要求书及其等同形式所限定。The foregoing descriptions of specific exemplary embodiments of the present invention have been presented for purposes of illustration and description. These descriptions are not intended to limit the invention to the precise forms disclosed, but the exemplary embodiments were chosen and described for the purpose of explaining certain principles of the invention and their practical application, to enable those skilled in the art to make and utilize the invention Various exemplary embodiments of the invention, as well as various choices and modifications. The scope of the invention is intended to be defined by the claims and their equivalents.

Claims (9)

1. A method for preparing didanosine impurity 2 ', 3' -anhydroinosine is characterized by comprising the following steps:
1) taking 2-acetoxy isobutyryl chloride and inosine as initial raw materials, and carrying out bromination reaction and acylation reaction in a solvent under the catalysis of lithium bromide;
wherein, the operation steps of the step 1) are as follows: adding anhydrous lithium bromide into the solvent, and heating until the anhydrous lithium bromide is dissolved; then adding 2-acetoxy isobutyryl chloride for reaction; cooling the obtained reaction liquid, and then adding inosine for reaction; the temperature is raised to 70-75 ℃, and the temperature is lowered to below 10 ℃;
in the step 1), the mass ratio of the anhydrous lithium bromide to the 2-acetoxyisobutyryl chloride to the inosine is 30-40:50-60: 25-35;
2) concentrating the reaction solution obtained in the step 1), removing the solvent, and dissolving the reaction solution in a polar solvent to be directly used in the next step;
3) adding an alkaline reagent into the mixture at low temperature, adjusting the pH value to be in a strong alkali condition for reaction, and filtering to obtain 2 ', 3' -anhydroinosine;
wherein, before the reaction solution is concentrated to remove the solvent in the step 2), the method also comprises the step of neutralizing the reaction solution obtained in the step 1) to a neutral environment;
after the solvent is removed in the step 2) and before the solvent is dissolved in the polar solvent, the method also comprises the step of removing impurities, wherein the step of removing the impurities comprises the following steps: adding the intermediate product into a mixture of dichloromethane and water, stirring, standing for layering, taking a dichloromethane layer, and evaporating dichloromethane to dryness;
in the step 3), the low-temperature condition is 0-10 ℃, and the strong alkali condition is that the pH is 10-14.
2. The method for preparing didanosine impurity, 2 ', 3' -anhydroinosine, according to claim 1, wherein the mass ratio of the anhydrous lithium bromide, the 2-acetoxyisobutyryl chloride, and the inosine in the step 1) is 37.5:55: 30.
3. The method for preparing didanosine impurity 2 ', 3' -anhydroinosine according to claim 1, wherein the step 1) is performed for 0.5 to 2 hours after 2-acetoxyisobutyryl chloride is added; adding inosine in the step 1) and reacting for 3-6 h.
4. The method for preparing didanosine impurity, 2 ', 3' -anhydroinosine, according to claim 3, wherein the reaction time after adding 2-acetoxyisobutyryl chloride in the step 1) is 1 hour; inosine was added in step 1) and the reaction was carried out for 4 h.
5. The method for preparing didanosine impurity, 2 ', 3' -anhydroinosine, according to claim 1, wherein the solvent used in step 1) is acetonitrile, and 5-15g of acetonitrile is used for every 1g of inosine used in step 1).
6. The method for preparing didanosine impurity 2 ', 3' -anhydroinosine according to claim 1, wherein the polar solvent in the step 2) is methanol or ethanol.
7. The method for preparing didanosine impurity, 2 ', 3' -anhydroinosine, according to claim 1, wherein the low temperature condition in the step 3) is 5 to 10 ℃; the time required for the reaction in the step 3) is 8-16 h.
8. The method for preparing didanosine impurity, 2 ', 3' -anhydroinosine, according to claim 7, wherein the time required for the reaction in the step 3) is 12 hours.
9. The method for preparing didanosine impurity 2 ', 3' -anhydroinosine according to claim 1, wherein the alkaline reagent in the step 3) is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, methylamine and corresponding aqueous solutions thereof.
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Nucleic Acid-Related Compounds.88.Efficient Conversions of Ribonucleosides into Their 2,3-Anhydro, 2(and 3)-Deoxy, 2,3-Didehydro-2,3-dideoxy,and 2,3-Dideoxynucleoside Analogs;Morris J. Robins et al.;《Journal of Organic Chemistry》;19951231;第60卷(第24期);第7902-7908页 *
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