CN113735925A - 一种抗病毒药物Molnupiravir关键中间体及其制备方法 - Google Patents
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Abstract
本发明提供一种抗病毒药物Molnupiravir关键中间体为2',3'‑O‑亚异丙基胞苷甲磺酸盐,该关键中间体的制备方法是通过胞苷加入甲磺酸进行丙酮叉保护,同时甲磺酸与胞苷上裸露的胺基形成稳定的甲磺酸盐。本发明解决了现有硫酸盐不稳定的问题,方便放大生产,降低三废量;同时本发明的甲磺酸盐湿料或者干料在空气中放置48小时均不降解,在55℃放置15小时的降解在5%以内。
Description
技术领域
本发明属于医药制备技术领域,特别涉及一种抗病毒药物Molnupiravir关键中间体,以及该关键中间体的制备方法。
背景技术
Molnupiravir(本发明中翻译为:莫匹拉韦)是由University ofNorth Carolina,Vanderbilt University和Emory University联合研发的一种广谱口服抗病毒药物。该药物是一种SARS-CoV-2聚合酶抑制剂,对多种冠状病毒:SARS-CoV,MERS-CoV和SARS-CoV-2具有预防或治疗作用,并具有潜在抗COVID-19的作用。研究证实,在动物实验中,莫匹拉韦用于治疗感染SARS-CoV-2的雪貂,能有效抑制病毒并在24小时内阻止病毒的生长,从而抑制病毒传播。研究小组认为,如果莫匹拉韦在人体试验中也能取得类似效果,那么接受该口服药物治疗的新冠患者可在一天之内变得无传染性,应用市场广阔。其化学名为:((2R,3S,4R,5R)-3,4-二羟基-5-(4-(羟胺基)-2-氧嘧啶-1(2H)-基)四氢呋喃-2-基)异丁酸甲酯,结构式(IV)为:
该Molnupiravir原研专利WO2019113462报道了其合成路线(路线一),以尿苷为原料,经丙酮叉保护、酯化、取代、羟胺化、脱保护等反应得到目标物(IV),该路线因使用了较昂贵原料尿苷,且三废多,总收率只有17%,收率低、工艺成本高,不适合放大生产。
另外,有机合成化学期刊:Synlett,32(3),326-328;2021报道了另外一条合成路线(路线二),以胞苷为原料,经丙叉保护、酯化、羟胺化、脱保护四步反应得到目标物(IV),相比于原研路线(路线一)的起始物料更便宜、路线更短、收率更高(总收率44%),从中可以看出合成路线二更具优势。
不过在合成路线二的实际合成胞苷丙叉硫酸盐过程中,发现中间体(II)极其不稳定,在室温下存在自行脱保护功能,不适合放大生产,该路线中间体(II)仍需改进。为此,本发明提供一种抗病毒药物Molnupiravir关键中间体,以及该关键中间体的制备方法。
发明内容
本发明的目的在于克服现有技术的缺陷,提供一种更优化的制备抗病毒药物Molnupiravir关键中间体的制备方法,通过胞苷加入甲磺酸进行丙酮叉保护,同时甲磺酸与胞苷上裸露的胺基形成稳定的甲磺酸盐,解决了硫酸盐不稳定的问题,方便放大生产,降低三废量。
为了实现上述目的,本发明提供的一种抗病毒药物Molnupiravir关键中间体,所述关键中间体结构式为(I):
为了实现上述目的,本发明还提供一种抗病毒药物Molnupiravir关键中间体的制备方法,具体包括以下步骤:
步骤S1:通过将胞苷(III)、2,2-二甲氧基丙烷溶解在有机溶剂中,在甲磺酸存在下反应;反应过程如下:
步骤S2:反应完毕后,对溶液进行过滤得到滤饼,所述滤饼在10℃~70℃干燥得到Molnupiravir(莫匹拉韦)关键中间体(I)。
进一步的,所述2,2-二甲氧基丙烷摩尔数用量为所述胞苷摩尔数的1~20倍,优选为1~3倍,1.5倍,2倍,2.5倍。
进一步的,所述甲磺酸摩尔数用量为所述胞苷摩尔数的1~20倍,优选为1~3倍,1.5倍,2倍,2.5倍。
进一步的,所述有机溶剂为不含活泼氢的有机溶剂,包括含卤素的有机溶剂二氯甲烷、氯仿或氯苯;或不含卤素的有机溶剂苯、甲苯;或含其它杂原子的有机溶剂乙腈、丙酮、DMF(N,N-二甲基甲酰胺)、DMSO(二甲基亚砜)、THF(四氢呋喃)或***;或酯类有机溶剂甲酸乙酯、乙酸乙酯。
进一步的,所述有机溶剂重量用量为所述胞苷重量的3~50倍,优选为5~20倍,7.5倍,9.5倍,10倍,12.5倍,15倍,17.5倍,20倍;
进一步的,所述反应温度为-70℃~80℃,反应时间为2~3小时,优选为-10℃~40℃;所述干燥温度优选为20℃~50℃。
相比于现有技术,本发明具有如下有益效果:
1、本发明得到的关键中间体甲磺酸盐(式I)比已报道的硫酸盐(式II)的优势在于稳定性良好;经稳定性对比测试数据为:硫酸盐(式II)在湿料状态,放置在空气中2小时,降解55%;放置在氮气氛围15小时,降解70%。硫酸盐(式II)在干料状态,放置空气2小时,降解20%,加热至45℃,放置15小时,完全降解。而本发明的甲磺酸盐(式I)在湿料或者干料在空气中放置48小时均不降解;在55℃放置15小时,降解在5%以内。
2、本发明的制备方法采用胞苷加入甲磺酸进行丙酮叉保护,同时甲磺酸与胞苷上裸露的胺基成盐,形成稳定的甲磺酸盐,解决了其硫酸盐不稳定的问题,方便放大生产,降低三废量。
附图说明
图1是本发明一种抗病毒药物Molnupiravir关键中间体的1H-NMR曲线图;
图2是本发明一种抗病毒药物Molnupiravir关键中间体的质谱仪MS曲线图;
图3是本发明一种抗病毒药物Molnupiravir关键中间体的HPLC曲线图。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合实施例,对本发明作进一步的详细说明,以使本领域技术人员能够充分理解本发明的技术内容。应理解,以下实施例用于对本发明进行进一步说明,不能理解为对本发明保护范围的限制,本领域的技术人员根据本发明的上述内容作出的一些非本质的改进和调整均属于本发明的保护范围。下述示例具体的工艺参数等也仅是合适范围中的一个示例,即本领域技术人员可以通过本文的说明做合适的范围内选择,而并非要限定于下文示例的具体数值。
实施例1:
本发明的抗病毒药物Molnupiravir关键中间体的制备方法,该丙叉胞苷甲磺酸盐(I)的制备如下:在氮气保护下,于1000ml干燥的三颈烧瓶中加入500ml丙酮、50g胞苷、25.7g 2,2-二甲氧基丙烷,搅拌。然后将23.7g甲磺酸缓慢滴入烧瓶中,20℃反应2小时。反应完毕过滤,滤饼用100ml丙酮淋洗,45℃干燥得76g白色固体,收率97%,纯度98.6%。1HNMR(400MHz,DMSO-d6)δ9.58(s,1H),8.73(s,1H),8.14-8.12(d,1H,J=8),6.13-6.11(d,1H,J=8),5.79(m,1H),4.92-4.90(m,1H),4.76-4.74(m,1H),4.24-4.22(m,1H),3.65-3.54(m,2H),2.44(s,3H),1.48(s,3H),1.29(s,3H).LCMS:284.1(M+H).
实施例2:
本发明的抗病毒药物Molnupiravir关键中间体的制备方法,该丙叉胞苷甲磺酸盐(I)的制备如下:在氮气保护下,于1000ml干燥的三颈烧瓶中加入500ml二氯甲烷、50g胞苷、25.7g2,2-二甲氧基丙烷,搅拌。然后将23.7g甲磺酸缓慢滴入烧瓶中,80℃反应3小时。反应完毕过滤,滤饼用100ml二氯甲烷淋洗,45℃干燥得74g白色固体,收率95%,纯度98.3%。1HNMR(400MHz,DMSO-d6)δ9.58(s,1H),8.73(s,1H),8.14-8.12(d,1H,J=8),6.13-6.11(d,1H,J=8),5.79(m,1H),4.92-4.90(m,1H),4.76-4.74(m,1H),4.24-4.22(m,1H),3.65-3.54(m,2H),2.44(s,3H),1.48(s,3H),1.29(s,3H).LCMS:284.1(M+H)。
实施例3:
本发明的抗病毒药物Molnupiravir关键中间体的制备方法,该丙叉胞苷甲磺酸盐(I)的制备如下:在氮气保护下,于1000ml干燥的三颈烧瓶中加入500ml丙酮、50g胞苷、32.1g 2,2-二甲氧基丙烷,搅拌。然后将25.6g甲磺酸缓慢滴入烧瓶中,-70℃反应2.5小时。反应完毕过滤,滤饼用100ml丙酮淋洗,45℃干燥得72g白色固体,收率92%,纯度98.7%。1HNMR(400MHz,DMSO-d6)ε9.58(s,1H),8.73(s,1H),8.14-8.12(d,1H,J=8),6.13-6.11(d,1H,J=8),5.79(m,1H),4.92-4.90(m,1H),4.76-4.74(m,1H),4.24-4.22(m,1H),3.65-3.54(m,2H),2.44(s,3H),1.48(s,3H),1.29(s,3H).LCMS:284.1(M+H)。
实施例4:
本发明的抗病毒药物Molnupiravir关键中间体的制备方法,该丙叉胞苷甲磺酸盐(I)的制备如下:在氮气保护下,于1000ml干燥的三颈烧瓶中加入500ml四氢呋喃、50g胞苷、25.7g2,2-二甲氧基丙烷,搅拌。然后将23.7g甲磺酸缓慢滴入烧瓶中,-10℃反应2.7小时。反应完毕过滤,滤饼用100ml四氢呋喃淋洗,45℃干燥得70g白色固体,收率89.7%,纯度98.5%。1H NMR(400MHz,DMSO-d6)ε9.58(s,1H),8.73(s,1H),8.14-8.12(d,1H,J=8),6.13-6.11(d,1H,J=8),5.79(m,1H),4.92-4.90(m,1H),4.76-4.74(m,1H),4.24-4.22(m,1H),3.65-3.54(m,2H),2.44(s,3H),1.48(s,3H),1.29(s,3H).LCMS:284.1(M+H)。
实施例5:
本发明的抗病毒药物Molnupiravir关键中间体的制备方法,该丙叉胞苷甲磺酸盐(I)的制备具体方法为:在氮气保护下,于1000ml干燥的三颈烧瓶中加入500ml乙腈、50g胞苷、25.7g 2,2-二甲氧基丙烷,搅拌。然后将23.7g甲磺酸缓慢滴入烧瓶中,40℃反应2.2小时。反应完毕过滤,滤饼用100ml四氢呋喃淋洗,45℃干燥得71g白色固体,收率91.0%,纯度98.3%。1H NMR(400MHz,DMSO-d6)δ9.58(s,1H),8.73(s,1H),8.14-8.12(d,1H,J=8),6.13-6.11(d,1H,J=8),5.79(m,1H),4.92-4.90(m,1H),4.76-4.74(m,1H),4.24-4.22(m,1H),3.65-3.54(m,2H),2.44(s,3H),1.48(s,3H),1.29(s,3H).LCMS:284.1(M+H)。
需要指出的是,上述较佳实施例仅为说明本发明的技术构思及特点,其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施,并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰,都应涵盖在本发明的保护范围之内。
Claims (8)
3.根据权利要求2所述抗病毒药物Molnupiravir关键中间体的制备方法,其特征在于:所述反应的温度为-70℃~80℃,反应时间为2~3小时。
4.根据权利要求2所述抗病毒药物Molnupiravir关键中间体的制备方法,其特征在于:所述有机溶剂选自二氯甲烷、氯仿、氯苯、苯、甲苯、乙腈、丙酮、DMF、DMSO、THF、***、甲酸乙酯、乙酸乙酯中的一种或混合。
5.根据权利要求2所述抗病毒药物Molnupiravir关键中间体的制备方法,其特征在于:所述2,2-二甲氧基丙烷摩尔数用量为所述胞苷摩尔数的1~20倍。
6.根据权利要求2所述抗病毒药物Molnupiravir关键中间体的制备方法,其特征在于:所述甲磺酸摩尔数用量为所述胞苷摩尔数的1~20倍。
7.根据权利要求2所述抗病毒药物Molnupiravir关键中间体的制备方法,其特征在于:所述有机溶剂重量用量为所述胞苷重量的3~50倍。
8.根据权利要求2所述抗病毒药物Molnupiravir关键中间体的制备方法,其特征在于:所述干燥的温度为20℃~50℃。
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CN116041332A (zh) * | 2022-11-30 | 2023-05-02 | 山东诚汇双达药业有限公司 | 一种单一溶剂制备Molnupiravir的方法 |
CN116284183A (zh) * | 2022-06-07 | 2023-06-23 | 四川大学 | 一种抗病毒化合物及其制备方法和用途 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112552288A (zh) * | 2021-02-19 | 2021-03-26 | 南京桦冠生物技术有限公司 | 一种4-肟-5`-(2-甲基丙酰基)尿苷的制备方法 |
-
2021
- 2021-10-26 CN CN202111251257.0A patent/CN113735925A/zh active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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Non-Patent Citations (2)
Title |
---|
ROBERT WARNER CHAMBERS ET AL.: ""Synthesis of Cytidine 5"-Diphosphate and Guanosine 5"-Diphosphate"", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》》 * |
VIJAYAGOPAL GOPALSAMUTHIRAM ET AL.: ""A Concise Route to MK-4482 (EIDD-2801) from Cytidine: Part 2"", 《SYNLETT》 * |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN116284183A (zh) * | 2022-06-07 | 2023-06-23 | 四川大学 | 一种抗病毒化合物及其制备方法和用途 |
CN116041332A (zh) * | 2022-11-30 | 2023-05-02 | 山东诚汇双达药业有限公司 | 一种单一溶剂制备Molnupiravir的方法 |
CN116041332B (zh) * | 2022-11-30 | 2023-09-22 | 山东诚汇双达药业有限公司 | 一种单一溶剂制备Molnupiravir的方法 |
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