CN118251404A - 药物中间体及其制备方法 - Google Patents
药物中间体及其制备方法 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D229/00—Heterocyclic compounds containing rings of less than five members having two nitrogen atoms as the only ring hetero atoms
- C07D229/02—Heterocyclic compounds containing rings of less than five members having two nitrogen atoms as the only ring hetero atoms containing three-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种药物中间体及其制备方法,具体公开了式(I)化合物及其制备方法。
Description
本申请要求申请日为2022/10/18的中国专利申请2022112756796的优先权。本申请引用上述中国专利申请的全文。
本发明涉及一种药物中间体及其制备方法,具体涉及式(I)化合物及其制备方法。
2022年是人类与新冠大流行抗争的第3年,全球累计确诊病例已超6亿,累计死亡人数超600万,约70个国家新冠确诊病例超过100万例,其流行病学传播的模式、蔓延态势和大流行的程度远远超过了2009年的H1N1甲型流感。SARS-CoV-2属于单正链的RNA病毒,和SARS-CoV以及MERS-CoV具有较高的同源性。该病毒感染进入宿主细胞后,在宿主细胞的帮助下,其遗传物质RNA首先翻译表达出两条多聚蛋白前体(pp1a和pp1ab),多聚蛋白前体在3CL蛋白酶和PL蛋白酶的作用下发生分子内的切割产生多个非结构蛋白,由于3CL蛋白酶至少负责11个位点的切割,故又称之为主蛋白酶(main protease,Mpro)。非结构蛋白参与了病毒亚基因RNA和四个结构蛋白(E蛋白、M蛋白、S蛋白和N蛋白)的产生,进而完成子代病毒的繁衍与释放;3CL蛋白酶属于半胱氨酸蛋白酶,活性形式为同源二聚体。3CL蛋白酶在冠状病毒中较为保守,并且不同冠状病毒3CL蛋白酶的底物之间具有共同特征;由于人体内不存在与3CL蛋白酶同源的蛋白酶,因此3CL蛋白酶成为理想的抗冠状病毒靶标之一。
开发能够有效抗新型冠状病毒的药物是目前临床用药所亟需的。专利PCT/CN2022/087511发现了一种具有良好的抗新型冠状病毒活性的3CL蛋
白酶抑制剂。为了进一步提高药物的可及性和更有利于放大生产,有必要开发用于获得该3CL蛋白酶抑制剂的中间体的新方法,以克服与PCT/CN2022/087511中已知方法相关的问题,包括使用试剂商业可及性及价格问题,规模化生产可放大性问题,工艺生产安全性问题,总体生产成本问题等。3CL蛋白酶抑制剂的分子结构如下:
发明内容
本发明提供了式(I)化合物的制备方法,
其特征在于,包含以化合物A为原料合成化合物D的步骤:
其中,
R1选自H、C1-4烷基和苄基;
R2为氨基保护基。
本发明的一些方案中,上述R1选自H、甲基、乙基、异丙基、叔丁基和苄基,优选甲基。
本发明的一些方案中,上述R2选自Boc。
本发明的一些方案中,式(I)化合物的制备方法还包含由化合物D合成式(I)化合物的步骤。
本发明的一些方案中,式(I)化合物的制备方法还包含如下的步骤:
本发明的一些方案中,式(I)化合物的制备方法还包括将步骤5反应后所得化合物的粗品打浆纯化的过程:
1)向粗品中加入醋酸异丙酯和正庚烷的混合溶剂,所述醋酸异丙酯和正庚烷的混合溶剂的比例为1:4~2:3,优选1:3;
2)在40~60℃下打浆1~2小时,优选50℃;
3)降温至10-20℃;
4)过滤。
本发明还提供下式中间体、其盐酸盐或硫酸盐,
定义和说明:
除非另有说明,本文所用的下列术语和短语旨在含有下列含义。一个特定的短语或术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的,而应该按照普通的含义去理解。当本文出现商品名时,旨在指代其对应的商品或其活性成分。
本发明的中间体化合物可以通过本领域技术人员所熟知的多种合成方
法来制备,包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式,优选的实施方式包括但不限于本发明的实施例。本领域技术人员可以借鉴本发明的内容适当改变原料、工艺条件等环节来实现相应的其它目的,其相关改变都没有脱离本发明的内容,所有类似的替换和改动对于本领域技术人员来说是显而易见的,都被视为包括在本发明的范围之内。
本发明具体实施方式的化学反应是在合适的溶剂中完成的,所述的溶剂须适合于本发明的化学变化及其所需的试剂和物料。为了获得本发明的化合物,有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
本领域任何合成路线规划中的一个重要考量因素是为反应性官能团(如本发明中的氨基)选择合适的保护基。
术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于:甲酰基;酰基,例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基);烷氧基羰基,如叔丁氧基羰基(Boc);芳基甲氧羰基,如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc);芳基甲基,如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基;甲硅烷基,如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
除非另有规定,术语“C1-4烷基”用于表示直链或支链的由1至4个碳原子组成的饱和碳氢基团。所述C1-4烷基包括C1-2、C1-3和C2-3烷基等;其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C1-4烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)、丁基(包括n-丁基,异丁基,s-丁基和t-丁基)等。
本发明所使用的所有溶剂可经市售获得。
本发明采用下述缩略词:Me代表甲基;Boc代表叔丁氧羰基;TFAA代表三氟乙酸酐;EtOAc代表乙酸乙酯;IBX代表2-碘酰基苯甲酸;EDCI代
表1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐;HOBt代表1-羟基苯并三唑。
化合物经本领域常规命名方法或者软件命名,市售化合物采用供应商目录名称。
技术效果
本发明给出的中间体的合成工艺,有益效果为:原料价格便宜易得,生产成本低,消除了生产过程中的安全隐患,更适于规模化生产。
具体地:
1、成本更低:新路线中Boc-叔亮氨酸使用效率更高,各步收率更优,成本较高的缩合步骤更靠后,物料成本大大降低。
2、试剂更廉价易得:原工艺路线中,烯烃化步骤采用的TEBBE试剂;新工艺路线更换为更为广泛易得的Wittig试剂。
3、工艺安全:原工艺路线中使用的IBX在生产过程中均存在安全隐患,新工艺路线分别用Tempo试剂进行了替代,消除了安全隐患。
4、更适合规模化生产:新工艺路线涉及的工艺条件更常规,纯化过程更简便,更适于规模化生产。
为了更好的理解本发明的内容,下面结合具体实施例来做进一步的说明,但具体的实施方式并不是对本发明的内容所做的限制。
实施例1
合成路线:
步骤1:中间体1-B的合成
将中间体1-A(70g)和2,2,6,6-四甲基哌啶氮氧化物(0.2g)溶于二氯甲烷(700mL)中,降温至0-5℃,将碳酸氢钠(33.81g)、溴化钠(2.65g)溶于水(420mL)中,加入到反应液中,将次氯酸钠溶液(372.12g,8%含量),水(200mL),混合均匀,于0~10℃滴加到反应液中,搅拌反应1小时,反应结束后,将亚硫酸钠(100g)溶于水(1000mL)中,加入反应液中淬灭0.5小时,分液,有机相加入二氯甲烷(1L)再萃取一遍,合并有机相,加入食盐水(1L)洗涤一遍,浓缩得到中间体1-B(68g,收率:98%)。1H NMR(400MHz,CDCl3)δppm major[4.66(s,1H),4.00(s,1H),3.69(s,3H),2.94(s,1H),2.37–2.12(m,3H),1.80(s,1H),1.33(s,9H)].minor[4.53(s,1H),4.09(s,1H),3.69(s,3H),2.96(s,1H),2.37–2.12(m,3H),1.77(s,1H),1.41(s,9H)].MS m/z:168.0[M-Boc]+步骤2:中间体1-C的合成
将甲基三苯基溴化膦(103.47g)溶于甲苯(650mL)中,氮气置换3次,降温至0-5℃,加入叔丁醇钾(29.79g),升温至20-25℃,搅拌反应1小时,加入中间体1-B(65g),20-25℃搅拌反应16小时,反应结束后,加入水(1000mL),萃取分液,水相加入甲基叔丁基醚再萃取一遍,合并有机相,用食盐水(1000mL)洗涤,有机相减压浓缩至干,浓缩物用石油醚-乙酸乙酯进行柱层析纯化,得到中间体1-C(33g,收率:51%)。1H NMR(400MHz,CDCl3)δppm major[5.15(d,J=6.0Hz,1H),4.85(d,J=6.0Hz,1H),4.45(s,1H),3.87(s,1H),3.72(s,3H),3.09(s,1H),2.41–2.22(m,3H),1.84(s,1H),1.37(s,9H)].
minor[5.15(d,J=6.0Hz,1H),4.85(d,J=6.0Hz,1H),4.31(s,1H),3.97(s,1H),3.72(s,3H),3.11(s,1H),2.37–2.12(m,3H),2.06(s,1H),1.40(s,9H)].MS m/z:166.0[M-Boc]+
步骤3:中间体1-D的合成
氯苯(250mL)中降温至-10-0℃,加入二乙基锌正己烷溶液(1mol/L,561mL),滴加完毕后,再滴加三氟化硼乙醚(119.46g),滴加完毕后继续搅拌0.5小时,降温至-10℃,滴加二碘甲烷(300.57g),滴加完毕后继续搅拌0.5小时,将中间体1-C(50g)溶解于氯苯(50mL)中,滴加到反应液中,滴加完毕升温至35-40℃反应4小时,反应结束后,降温至-10~-5℃,滴加20%柠檬酸水溶液(1000mL),滴加完毕后,加入乙酸乙酯(500mL),继续搅拌10分钟,分液,有机相用20%柠檬酸水溶液(250mL)洗涤,合并水相,水相用乙酸乙酯(300mL*2)萃取,水相加入酒石酸钾钠水溶液[酒石酸钾钠(316g)+水(750mL)],用氨水调节pH至9-10,加入二氯甲烷(500mL),萃取分液,水相用二氯甲烷(300mL)再萃取一遍,合并有机相减压浓缩得到中间体1-D(24g,收率:70%)。1H NMR(400MHz,CDCl3)δppm 3.71(s,3H),3.69(s,1H),3.64(d,J=3.6Hz,1H),1.86(s,1H),1.72–1.67(m,2H),1.52–1.47(m,2H),0.70–0.59(m,3H),0.40–0.38(m,1H).MS m/z:182.1[M+H]+
步骤4:中间体1-E的合成
将中间体1-D(137g)、(S)-N-Boc叔亮氨酸(192.32g)溶解于乙腈(1370mL)和N,N-二甲基甲酰胺(137mL)的混合溶液中,25℃条件下加入1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(159.41g)、N-甲基吗啉(152.93g)、1-羟基苯并三唑(102.14g),继续反应16小时,反应完成后,减压浓缩除去大部分乙腈后,加入乙酸乙酯(1000mL),水(1000mL),萃取,分液,有机相用10%柠檬酸(500mL*2)洗涤,饱和碳酸氢钠(500mL)洗涤,饱和食盐水(500mL)洗涤,减压浓缩至干,浓缩物于10-15℃下加入盐酸乙酸乙酯溶液(4mol/L,1.89L),甲醇(200mL),加完后于20-25℃搅拌反应0.5小时,反应完成后,浓缩
除1L溶剂,于25℃下搅拌0.5小时,过滤,滤饼加入乙酸乙酯(200mL)洗涤,滤饼除溶残后得到中间体1-E(212g,收率:85%)。1H NMR(400MHz,CDCl3)δppm 8.49(s,3H),4.51(s,1H),4.42(s,1H),4.03(d,J=4.8Hz,1H),3.70(s,3H),2.26(d,J=10.8Hz,1H),2.07(s,1H),1.97(s,1H),1.90(d,J=10.0Hz,1H),1.90(d,J=10.0Hz,1H),1.80(d,J=12.4Hz,1H),1.23(s,9H),0.81–0.64(m,3H),0.48–0.46(m,1H).MS m/z:294.9[M+H]+
步骤5:中间体1的合成
将中间体1-E(211.59g)溶解于二氯甲烷(1300mL)中,于10-15℃下加入三氟乙酸酐(201.48g),继续加入三乙胺(64.71g),加完后于20-25℃继续反应1小时,反应结束后,将反应液降温至10-15℃,滴加水(500mL),分液,有机相用10%柠檬酸水溶液(500mL)洗涤,饱和碳酸氢钠水溶液(500mL)洗涤,饱和食盐水(500mL)洗涤,浓缩至干得到中间体1的粗品,向粗品中加入醋酸异丙酯(50mL)、正庚烷(500mL)于50℃下打浆1-2小时,降温至10-20℃,过滤,得到中间体1(212g,收率:85%)。1H NMR(400MHz,CDCl3)δppm 8.49(d,J=8.8Hz,1H),4.68(d,J=9.6Hz,1H),4.59(s,1H),4.37(s,1H),3.72(s,3H),2.10(d,J=10.0Hz,1H),1.99(s,1H),1.92–1.86(m,2H),1.59(dd,J=12.4Hz,2.4Hz,1H),1.10(s,9H),0.75–0.63(m,3H),0.49–0.47(m,1H).MS m/z:391.1[M+H]+.
实施例2中间体1-A的合成
氮气保护下,将S1(39g,141.6mmol,1eq)投入1000mL圆底烧瓶中,加入甲醇160g,乙酸(10.2g,170mmol,1.2eq)搅拌溶解;加入10%钯碳4.0g,将氢气压力设定0.3~0.5MPa,温度10~20℃,保温搅拌8~10hr;中控TLC
点板显示原料点消失;过滤;滤液转移至1000mL圆底烧瓶中,5~5℃滴加三乙胺,0~10℃滴加二碳酸二叔丁酯,滴毕升温至15~20℃,保温搅拌2~2.5hr,TLC中控至原料点消失;反应液减压浓缩,加入乙酸乙酯180g,饮用水100g萃洗分层;水相用乙酸乙酯复萃;合并有机相,依次用12%碳酸氢钠水溶液,和30%氯化钠水溶液洗涤;有机相用无水硫酸钠干燥2hr,过滤;减压浓缩干,浓缩结束加入正庚烷80.4g室温打浆2-3hr,过滤,收集滤饼40-45℃真空干燥,得到目标产物中间体1-A(33.0g,收率:85.9%),1H NMR(400MHz,DMSO-d6,298K,δin ppm):5.03(m,1H,CH),3.94(m,1H,CH),3.71(s,9H,C(CH3)3),3.64(d,3H,CH3),3.60(d,1H,CH),3.34(m,2H,CH2),2.41(m,1H,OH),1.86(m,1H,CH),1.63(m,2H,CH2)。
Claims (7)
- 式(I)化合物的制备方法,其特征在于,包含以化合物A为原料合成化合物D的步骤:其中,R1选自H、C1-4烷基和苄基;R2为氨基保护基。
- 根据权利要求1所述式(I)化合物的制备方法,其中R1选自H、甲基、乙基、异丙基、叔丁基和苄基,优选甲基。
- 根据权利要求1所述式(I)化合物的制备方法,其中R2选自Boc。
- 根据权利要求1所述式(I)化合物的制备方法,其还包含由化合物D合成式(I)化合物的步骤。
- 根据权利要求1所述式(I)化合物的制备方法,其包含如下的步骤:
- 权利要求5所述式(I)化合物的制备方法,其中,还包括将步骤5反 应后所得化合物的粗品打浆纯化的过程:1)向粗品中加入醋酸异丙酯和正庚烷的混合溶剂,所述醋酸异丙酯和正庚烷的混合溶剂的比例为1:4~2:3,优选1:3;2)在40~60℃下打浆1~2小时,优选50℃;3)降温至10-20℃;4)过滤。
- 下式中间体、其盐酸盐或硫酸盐,
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