1-脱氧野尻霉素合成路线设计及工艺优化研究
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摘要
本研究以甲基-α-D-吡喃葡糖苷(methyl a-D-glucopyranoside)为起始反应原料,设计了一条合成1-脱氧野尻霉素(1-deoxynoj irimycin, DNJ)的工艺路线,然后根据这条工艺路线,以适应工业化大生产为标准,对其进行了优化,并在实验室条件下进行小试实验对优化工艺的可行性进行验证。而后,在实验室小试实验取得成功的基础上,对该优化工艺进行了中试放大试验,探索其工业化生产的可行性,结果如下：
1、通过调研文献,研究反应,设计了一条合成1-脱氧野尻霉素的工艺路线。这条工艺路线以甲基-α-D-吡喃葡糖苷为起始反应原料,经过苄基保护,脱甲基反应,开环形成双醇,通过Pfitzner-Moffatt氧化反应形成双羰基后再进行醛酮还原胺化反应关环,脱苄基保护等五步反应最后制得目标产物。然后通过实验室小试来对该设计路线的可行性进行实验验证,并取得了成功。小试投料77.6g,经过五步反应,最后得到6.79g目标产物DNJ,总收率为29.4%,各步收率分别为75%,65%,98.5%,72%和85%。
2、通过实验室小试实验,验证了该反应路线的可行性之后,本研究以能够进行工业化生产为标准对该条路线进行了工艺优化。优化内容有：验证了工艺中第一步反应生成的苄基醚副产对于第二步的反应没有影响,因而可以简化反应的后处理步骤；优化了原工艺中第二,四,五步反应的溶剂体系；将原工艺里的催化剂LiAlH4改变为NaBH4；将原工艺里第五步反应在工业化生产中操作比较困难的使用液氨和金属锂的反应条件,改变为使用Pd(OH)2和H2进行脱苄基保护。然后对优化后的工艺路线可行性进行了实验室小试验证,并取得了成功。小试投料195g,经过五步反应,最后得到7.4g目标产物DNJ,总收率为7.98%,各步收率分别为65%,52%,90.2%,35%和74.8%。
3、根据优化后的工艺路线进行了两批中试放大试验,进一步验证该优化路线的工业化生产可行性。两批中试试验均投料20kg,经过反应,分别得到目标产物0.67kg和1.63kg,总收率分别为8.03%和7.95%,平均收率为7.99%,与实验室小试收率相似。同时,两批中试试验所得到的产品能够达到100%的纯度,验证了优化工艺的可行性与稳定性。通过两批中试放大试验的结果可以看出,这条优化后的工艺,实验设计合理,反应条件适合,具备工业化生产的条件。
In this paper, we designed a route of synthesis of 1-deoxynojirimycin (DNJ) with methyl a-D-glucopyranoside as the start materials. Based on this route, we optimized it and carried out small scale experiments under laboratory conditions to verify the feasibility of the optimal procedure to meet the standards of industrialized production. Then on the basis of the success of small scale experiments in the laboratory, we did pilot scale of this optimized route to explore the feasibility of industrial production. Results are as follows:
1. We designed a route to synthesize 1-deoxynojirimycin after the literature review and reaction research. This route is taking methylα-D-glucopyranoside as the start materials, and the desired product has been gotten after five steps reactions. Each steps of the route were benzyl protected reaction, demethylation reaction, ring-opening reaction, the reaction of Pftizner-Moffat oxidation followed stereocontrolled intramolecular reductive aminaton, debenzylation reaction. Then we carried out small scale laboratory experiments with this route and got success finally. We used 77.6 gram reactant and got 6.79 gram desired product DNJ ultimately after five steps reactions. The general yield was 29.4% and the yields of each steps were:75%,65%,98.5%,72% and 85%.
2. After verifying the feasibility of the reaction route through small scale experiments in laboratory, this study optimized this procedure to the capable of industrial production as standard. The optimization contents:Verify the by-product benzyl ether of step 1 reaction in the procedure don't affect step 2 reaction, and so the processing steps after the reaction can be simplified; Optimize the solvent in step 2,4 and 5 reactions of original procedure; Change the catalyst LiAlH4 in original procedure to NaBH4; Change using lq. ammonia and lithium metal as reaction conditions in original procedure which is a bit difficult to be operated in industrial production to use Pd(OH)2 and H2 doing benzyl protection. Then we carried out small scale laboratory experiments with optimized procedure and got success finally. We used 195 gram reactant and got 7.4 gram desired product DNJ ultimately after five steps reactions. The general yield was 7.98% and the yields of each steps were:65%, 52%,90.2%,35% and 74.8%.
3. We carried on two batches of pilot scale experiments to further verify the feasibility of industrial production with the optimized procedure. We used 20kg reactant in each batch of pilot scale experiments, got desired product 0.67kg and 1.63kg after reactions, the general yield were 8.03% and 7.95%, the average yield was 7.99% and it's similar with the yield in small scale experiments. In the meantime, all the product we got from two batches of pilot scale experiments could reach 100% purity which verified the feasibility and stability of the optimized procedure. We can see from the results of the two batches pilot scale experiments that the experiments are designed reasonable and the reaction conditions are accurate in the optimized procedure, it's qualified for industrial production.
1、通过调研文献,研究反应,设计了一条合成1-脱氧野尻霉素的工艺路线。这条工艺路线以甲基-α-D-吡喃葡糖苷为起始反应原料,经过苄基保护,脱甲基反应,开环形成双醇,通过Pfitzner-Moffatt氧化反应形成双羰基后再进行醛酮还原胺化反应关环,脱苄基保护等五步反应最后制得目标产物。然后通过实验室小试来对该设计路线的可行性进行实验验证,并取得了成功。小试投料77.6g,经过五步反应,最后得到6.79g目标产物DNJ,总收率为29.4%,各步收率分别为75%,65%,98.5%,72%和85%。
2、通过实验室小试实验,验证了该反应路线的可行性之后,本研究以能够进行工业化生产为标准对该条路线进行了工艺优化。优化内容有：验证了工艺中第一步反应生成的苄基醚副产对于第二步的反应没有影响,因而可以简化反应的后处理步骤；优化了原工艺中第二,四,五步反应的溶剂体系；将原工艺里的催化剂LiAlH4改变为NaBH4；将原工艺里第五步反应在工业化生产中操作比较困难的使用液氨和金属锂的反应条件,改变为使用Pd(OH)2和H2进行脱苄基保护。然后对优化后的工艺路线可行性进行了实验室小试验证,并取得了成功。小试投料195g,经过五步反应,最后得到7.4g目标产物DNJ,总收率为7.98%,各步收率分别为65%,52%,90.2%,35%和74.8%。
3、根据优化后的工艺路线进行了两批中试放大试验,进一步验证该优化路线的工业化生产可行性。两批中试试验均投料20kg,经过反应,分别得到目标产物0.67kg和1.63kg,总收率分别为8.03%和7.95%,平均收率为7.99%,与实验室小试收率相似。同时,两批中试试验所得到的产品能够达到100%的纯度,验证了优化工艺的可行性与稳定性。通过两批中试放大试验的结果可以看出,这条优化后的工艺,实验设计合理,反应条件适合,具备工业化生产的条件。
In this paper, we designed a route of synthesis of 1-deoxynojirimycin (DNJ) with methyl a-D-glucopyranoside as the start materials. Based on this route, we optimized it and carried out small scale experiments under laboratory conditions to verify the feasibility of the optimal procedure to meet the standards of industrialized production. Then on the basis of the success of small scale experiments in the laboratory, we did pilot scale of this optimized route to explore the feasibility of industrial production. Results are as follows:
1. We designed a route to synthesize 1-deoxynojirimycin after the literature review and reaction research. This route is taking methylα-D-glucopyranoside as the start materials, and the desired product has been gotten after five steps reactions. Each steps of the route were benzyl protected reaction, demethylation reaction, ring-opening reaction, the reaction of Pftizner-Moffat oxidation followed stereocontrolled intramolecular reductive aminaton, debenzylation reaction. Then we carried out small scale laboratory experiments with this route and got success finally. We used 77.6 gram reactant and got 6.79 gram desired product DNJ ultimately after five steps reactions. The general yield was 29.4% and the yields of each steps were:75%,65%,98.5%,72% and 85%.
2. After verifying the feasibility of the reaction route through small scale experiments in laboratory, this study optimized this procedure to the capable of industrial production as standard. The optimization contents:Verify the by-product benzyl ether of step 1 reaction in the procedure don't affect step 2 reaction, and so the processing steps after the reaction can be simplified; Optimize the solvent in step 2,4 and 5 reactions of original procedure; Change the catalyst LiAlH4 in original procedure to NaBH4; Change using lq. ammonia and lithium metal as reaction conditions in original procedure which is a bit difficult to be operated in industrial production to use Pd(OH)2 and H2 doing benzyl protection. Then we carried out small scale laboratory experiments with optimized procedure and got success finally. We used 195 gram reactant and got 7.4 gram desired product DNJ ultimately after five steps reactions. The general yield was 7.98% and the yields of each steps were:65%, 52%,90.2%,35% and 74.8%.
3. We carried on two batches of pilot scale experiments to further verify the feasibility of industrial production with the optimized procedure. We used 20kg reactant in each batch of pilot scale experiments, got desired product 0.67kg and 1.63kg after reactions, the general yield were 8.03% and 7.95%, the average yield was 7.99% and it's similar with the yield in small scale experiments. In the meantime, all the product we got from two batches of pilot scale experiments could reach 100% purity which verified the feasibility and stability of the optimized procedure. We can see from the results of the two batches pilot scale experiments that the experiments are designed reasonable and the reaction conditions are accurate in the optimized procedure, it's qualified for industrial production.
引文
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[3]朱禧星,主编.现代糖尿病学.上海医科大学出版社,2000,5.380.
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