CN111116688B - 普拉佐米星的制备方法 - Google Patents
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Abstract
本发明提供了一种普拉佐米星的制备方法。该方法使用磷酸溶液去除普拉佐米星前体中的‑Boc保护基,反应条件温和,经简单后处理即可制得普拉佐米星游离碱固体,且制得的普拉佐米星纯度在95%以上,满足工业化生产需求。
Description
技术领域
本发明属于药物制备技术领域,具体涉及氨基糖苷类抗生素普拉佐米星的制备方法。
背景技术
普拉佐米星(Plazomicin)是一种氨基糖苷类抗生素,由美国Achaogen公司开发,于2018年6月被FDA批准用于治疗复杂尿路感染、肾盂肾炎等。普拉佐米星是细菌蛋白质合成的抑制剂,对许多MDR革兰阴性细菌和MRSA具有很强的杀菌活性。与其他氨基糖苷类抗生素相比,普拉佐米星治疗鲍曼不动杆菌和耐碳青霉烯的肠杆菌类有更好的活性,其抑制大肠杆菌和克雷伯肺炎杆菌的活性比阿米卡星高4倍,对铜绿假单胞菌的活性与丁胺卡那霉素相似;对含有碳青霉烯酶和ESBL的菌株的杀伤性更显著。
普拉佐米星是在西索米星(sisomicin)的基础上进行化学改造而得,其化学名为(2“R,3”R,4“R,5”R)-2“-[(1S,2S,3R,4S,6R)-4-氨基-6-[(2'”S)-4'“-氨基-2'”-羟基丁酰胺基氨基)-3-[(2'S,3'R)-3'-氨基-6'-((2-羟基乙基氨基)甲基)-3',4'-二氢-2H-吡喃-2'-基氧基]-2-羟基环己基氧基]-5”-甲基-4”-(甲基氨基)四氢-2H-吡喃3”,5”-二羟基-2.5硫酸盐,结构式为:
在合成过程中,普拉佐米星结构中存在的多个氨基通常被保护基保护,故在最终得到普拉佐米星之前,会进行脱保护步骤。目前,已公开的普拉佐米星的合成工艺中主要有以下几种脱保护情况:
1、专利CN200880117193.1公开了使用三氟乙酸脱除普拉佐米星前体1中的-TBS及-Boc保护,再经反相高效液相色谱纯化,得到普拉佐米星游离碱:
该路线后处理时需加三次有机溶剂稀释再浓缩,操作复杂,最后使用反相高效液相色谱纯化,收率低,成本高,不适于工业化大量生产。
2、文献《Antimicrobial Agents and Chemotherapy,2010,54,11,4636-4642》中使用钯碳脱除普拉佐米星前体2中的-Cbz保护,得到普拉佐米星游离碱:
钯碳脱除-Cbz保护基时也产生结构中的双键被还原的杂质,增大了纯化难度。最后使用制备液相纯化,收率极低,且由于使用重金属氢化脱除保护基,易造成终产物重金属超标,同样不适于工业化生产。
3、上海医药工业研究院2017年硕士论文《普拉佐米星和维奈托克关键中间体的合成研究》中公开了使用氯化氢-乙酸乙酯溶液代替浓盐酸脱除-Boc保护,可以较高收率地获得纯度较高的普拉佐米星盐酸盐。但其整个普拉佐米星工艺使用不同的保护基对不同的氨基进行保护,再逐一脱保护,路线不节约。
4、文献ACS infectious diseases(2018),4(7),1114-1120使用三氟乙酸同时脱除普拉佐米星前体3中的苯联氮二烯、-TBS及-Boc保护,反应完成后经两次二氯甲烷稀释-浓缩后使用C-25色谱柱纯化,最后加冰醋酸冻干得到普拉佐米星醋酸盐,反应收率40%:
5、专利WO2019079613公开了用三氟乙酸脱除普拉佐米星前体4中的-Boc保护基,反应完成后用乙酸异丙酯多次洗涤至pH>2,得到普拉佐米星三氟乙酸盐。得到的普拉佐米星三氟乙酸盐经氨水中和至pH5.8-6.2后,用离子交换树脂柱纯化,除去其中的三氟乙酸,然后经过反渗透膜过滤得到普拉佐米星游离碱:
上述路线中,路线5因最后一步脱除的保护基种类单一,产生的杂质最少,最适于工业化大规模生产。但是,由于其在反应中使用了大量的三氟乙酸,后处理时需要使用有机溶剂反复洗涤,再经树脂柱纯化才能除去多余的三氟乙酸。操作繁琐,需要使用大量有机溶剂,成本高,环保压力大。
发明内容
本发明的目的在于克服现有技术中的缺陷,提供一种新的普拉佐米星的制备方法。该方法可简单高效地脱除普拉佐米星前体4中的-Boc保护基,制得纯度95%以上的普拉佐米星游离碱,操作简单,适于工业化大量生产。
本发明的目的可以通过以下技术方案实现:
一种制备普拉佐米星的方法,该方法将普拉佐米星前体4与磷酸溶液反应,以脱除其中的-Boc保护基:
优选地,上述反应中使用的磷酸溶液的浓度为45%~85%,优选80%~85%。
作为优选,磷酸溶液与普拉佐米星前体4的质量比为1-10:1,优选2-5:1。
本发明脱除-Boc保护基的反应可在二氯甲烷、四氢呋喃或乙腈等溶剂中进行,优选在二氯甲烷中进行,在醇类溶剂中进行时,反应基本不发生。
反应溶剂与普拉佐米星前体4的体积质量比为1-30:1,优选1-10:1。
作为优选,该脱除-Boc保护基的反应在10-40℃下进行,优选在室温下进行,所述的室温指20-25℃,反应时间以全部保护基脱除为准。
反应完成后,将反应体系加入另一有机溶剂中以析出普拉佐米星磷酸盐固体,加入方式优选为滴加;所述另一有机溶剂可以是甲醇、乙醇或异丙醇,优选乙醇。
为更好地析出普拉佐米星磷酸盐固体,有机溶剂与普拉佐米星前体4的体积质量比为5-30:1,优选10:1。
在得到普拉佐米星磷酸盐后,采用阴离子交换树脂脱除磷酸,使磷酸吸附于树脂中,即可获得普拉佐米星游离碱。
与现有技术相比,本发明取得了以下有益效果:
1、本发明提供的普拉佐米星游离碱的制备方法,工艺简单,条件温和,避免了强挥发性酸的使用,设备节约,环境友好;
2、本发明提供的制备方法,反应后处理简单,溶剂节约,易于操作,适用于工业化大规模生产;
3、本发明提供的制备方法,反应产生的杂质少,易于纯化,可高效地获得纯度95%以上的普拉佐米星游离碱,满足实际生产需要。
附图说明
图1为实施例1制得的纯度为99.08%的普拉佐米星的HPLC谱图。
具体实施方式
为了更好地理解本发明的内容,下面结合具体实施例对本发明的技术方案做进一步的说明,但具体的实施方式并不意味着对本发明有任何限制。
本发明所用式1化合物为参照专利WO2019079613的合成方法制备,其他试剂均可通过市售购得。
实施例1
氮气保护下,将普拉佐米星前体4(5g,5.03mmol)溶于二氯甲烷(50mL)中,室温下滴加85%的磷酸(10g),控制温度不高于25℃,室温反应3h。滴加乙醇(45mL),析出白色固体,滴毕继续搅拌12h。氮气保护下过滤,将滤饼溶于甲醇(50mL)中,加入阴离子交换树脂30g,缓慢搅拌10h。过滤,滤液减压浓缩,得到淡黄色普拉佐米星游离碱固体,HPLC纯度:99.08%。
实施例2
氮气保护下,将普拉佐米星前体4(5g,5.03mmol)溶于二氯甲烷(50mL)中,室温下滴加80%的磷酸(10g),控制温度不高于25℃,室温反应3h。滴加乙醇(45mL),析出白色固体,滴毕继续搅拌12h。氮气保护下过滤,将滤饼溶于甲醇(50mL)中,加入阴离子交换树脂30g,缓慢搅拌10h。过滤,滤液减压浓缩,得到淡黄色普拉佐米星游离碱固体,HPLC纯度:98.43%。
实施例3
氮气保护下,将普拉佐米星前体4(5g,5.03mmol)溶于二氯甲烷(50mL)中,室温下滴加60%的磷酸(10g),控制温度不高于25℃,室温反应5h。滴加乙醇(45mL),析出白色固体,滴毕继续搅拌12h。氮气保护下过滤,将滤饼溶于甲醇(50mL)中,加入阴离子交换树脂30g,缓慢搅拌10h。过滤,滤液减压浓缩,得到淡黄色普拉佐米星游离碱固体,HPLC纯度:96.79%。
实施例4
氮气保护下,将普拉佐米星前体4(5g,5.03mmol)溶于二氯甲烷(50mL)中,室温下滴加45%的磷酸(10g),控制温度不高于25℃,室温搅拌过夜。滴加乙醇(45mL),析出白色固体,滴完继续搅拌12h。氮气保护下过滤,将滤饼溶于甲醇(50mL)中,加入阴离子交换树脂30g,缓慢搅拌过夜。过滤,滤液减压浓缩,得到淡黄色普拉佐米星游离碱固体,HPLC纯度:95.62%。
实施例5
氮气保护下,将普拉佐米星前体4(1kg,1.01mol)溶于二氯甲烷(1000mL)中,室温下滴加85%的磷酸(2kg),控制温度不高于25℃,室温反应3h。滴加乙醇(10L),析出白色固体,滴毕继续搅拌12h。氮气保护下过滤,将滤饼溶于甲醇(10L)中,加入阴离子交换树脂6kg,缓慢搅拌10h。过滤,树脂用3kg甲醇漂洗2次,滤液减压浓缩,得到淡黄色普拉佐米星游离碱固体495.3g,收率:83.0%,HPLC纯度:96.93%。
实施例6
氮气保护下,将普拉佐米星前体4(5g,5.03mmol)溶于四氢呋喃(50mL)中,室温下滴加85%的磷酸(10g),控制温度不高于25℃,室温反应至液相检测反应完全。滴加乙醇(45mL),析出白色固体,滴毕继续搅拌12h。氮气保护下过滤,将滤饼溶于甲醇(50mL)中,加入阴离子交换树脂30g,缓慢搅拌过夜。过滤,滤液减压浓缩,得到淡黄色普拉佐米星游离碱固体,HPLC纯度:97.01%。
实施例7
氮气保护下,将普拉佐米星前体4(5g,5.0mmol)溶于二氯甲烷(50mL)中,40℃下滴加85%的磷酸(5g),控制温度不高于40℃,保温反应至液相检测反应完全。滴加异丙醇(100mL),析出白色固体,滴毕继续搅拌12h。氮气保护下过滤,将滤饼溶于甲醇(50mL)中,加入阴离子交换树脂30g,缓慢搅拌过夜。过滤,滤液减压浓缩,得到淡黄色普拉佐米星游离碱固体,HPLC纯度:95.82%。
实施例8
氮气保护下,将普拉佐米星前体4(1g,1.01mmol)溶于二氯甲烷(10mL)中,室温下滴加85%的磷酸(5g),控制温度不高于25℃,室温搅拌至液相检测反应完全。滴加乙醇(10mL),析出白色固体,滴毕继续搅拌12h。氮气保护下过滤,将滤饼溶于甲醇(10mL)中,加入阴离子交换树脂5g,缓慢搅拌过夜。过滤,滤液减压浓缩,得到淡黄色普拉佐米星游离碱固体,HPLC纯度:98.57%。
实施例9
氮气保护下,将普拉佐米星前体4(1g,1.01mmol)溶于二氯甲烷(10mL)中,室温下滴加85%的磷酸(10g),控制温度不高于25℃,室温反应至液相检测反应完全。滴加乙醇(30mL),析出白色固体,滴毕继续搅拌12h。氮气保护过滤,将滤饼溶于甲醇(5mL)中,加入阴离子交换树脂3g,缓慢搅拌过夜。过滤,滤液减压浓缩,得到淡黄色普拉佐米星游离碱固体,HPLC纯度:96.92%。
实施例10
氮气保护下,将普拉佐米星前体4(1g,1.01mmol)溶于乙腈(10mL)中,室温下滴加85%的磷酸(1g),控制温度不高于25℃,室温反应至液相检测反应完全。滴加乙醇(20mL),析出白色固体,滴毕继续搅拌12h。氮气保护下过滤,将滤饼溶于甲醇(10mL)中,加入阴离子交换树脂5g,缓慢搅拌过夜。过滤,滤液减压浓缩,得到淡黄色普拉佐米星游离碱固体,HPLC纯度:94.44%。
实施例11
氮气保护下,将普拉佐米星前体4(1g,1.01mmol)溶于二氯甲烷(10mL)中,室温下滴加85%的磷酸(5g),控制温度不高于25℃,室温搅拌至液相检测反应完全。滴加甲醇(5mL),析出白色固体,滴毕继续搅拌12h。氮气保护下过滤,将滤饼溶于甲醇(8mL)中,加入阴离子交换树脂4g,缓慢搅拌过夜。过滤,滤液减压浓缩,得到淡黄色普拉佐米星游离碱固体,HPLC纯度:96.31%。
实施例12
氮气保护下,将普拉佐米星前体4(1g,1.01mmol)溶于二氯甲烷(10mL)中,升温至回流,滴加85%的磷酸(2g),保温反应至液相检测反应完全。降温至室温滴加乙醇(10mL),析出白色固体,滴毕继续室温搅拌12h。氮气保护下过滤,将滤饼溶于甲醇(10mL)中,加入阴离子交换树脂5g,缓慢搅拌过夜。过滤,滤液减压浓缩,得到淡黄色普拉佐米星游离碱固体(0.42g,收率:70.1%,HPLC纯度:90.60%)。
实施例13
氮气保护下,将普拉佐米星前体4(1g,1.01mmol)溶于二氯甲烷(10mL)中,降温至内部为10℃,滴加85%的磷酸(2g),保温反应至液相检测反应完全。将滴加乙醇(10mL),析出白色固体,滴毕室温继续搅拌12h。氮气保护下过滤,将滤饼溶于甲醇(10mL)中,加入阴离子交换树脂5g,缓慢搅拌过夜。过滤,滤液减压浓缩,得到淡黄色普拉佐米星游离碱固体,HPLC纯度:96.11%。
对比实施例14
仅改变反应使用的酸性试剂,其他条件和操作与实施例1相同,考察不同酸性试剂脱除普拉佐米星前体4中-Boc保护基的效果,结果见下表:
以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
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CN108948107A (zh) * | 2018-07-30 | 2018-12-07 | 山东大学 | 一种普拉佐米星抗生素的制备方法 |
WO2019079613A1 (en) * | 2017-10-19 | 2019-04-25 | Achaogen, Inc. | SYNTHESIS OF ANTIBACTERIAL AMINOGLYCOSIDE ANALOGUES |
CN110642907A (zh) * | 2019-10-12 | 2020-01-03 | 上海博璞诺科技发展有限公司 | 普拉唑米星或其盐的合成方法 |
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CN108948107A (zh) * | 2018-07-30 | 2018-12-07 | 山东大学 | 一种普拉佐米星抗生素的制备方法 |
CN110642907A (zh) * | 2019-10-12 | 2020-01-03 | 上海博璞诺科技发展有限公司 | 普拉唑米星或其盐的合成方法 |
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"新型氨基糖苷类抗菌药plazomicin的合成;刘汉阳 等;《中国医药工业杂志》;20171231;第48卷(第5期);第657页图2,第660页左栏 * |
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