CN117447461A - 一种吡唑并杂芳基类衍生物的制备方法 - Google Patents
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Abstract
本公开涉及一种吡唑并杂芳基类衍生物的制备方法。具体而言,所述的吡唑并杂芳基类衍生物的具体结构如下所示。本公开提供的制备方法收率高,适合于工业化放大生产。
Description
技术领域
本公开属于医药领域,涉及一种吡唑并杂芳基类衍生物的制备方法,属于制药领域。
背景技术
无论是正常细胞还是肿瘤细胞中,每天都会出现成千上万次DNA的损伤。这使得DNA损伤修复在维持基因组的稳定性和细胞存活方面起到至关重要的作用。相比较于正常细胞,肿瘤细胞承受了更大的复制压力,携带更多的内源性DNA损伤,并且经常出现一个或多个DNA损伤修复通路的缺失。这使得肿瘤细胞的存活更加依赖于DNA损伤修复的顺利进行。
同源重组修复是DNA双链断裂的主要修复方式,以未受损的姐妹染色单体的同源序列作为其修复的模板复制受损处的DNA序列,精确修复DNA。这种修复方式主要发生在细胞的G2期和S期。ATR是同源重组修复通路中的关键酶,属于PIKK家族。当ATR/ATRIP复合物与覆盖了复制蛋白A(RPA)的受损DNA结合后,ATR被激活并通过磷酸化下游蛋白Chk1和SMARCAL等,调节细胞周期各个检查点,引起细胞周期阻滞;保证受损DNA的稳定性;提高dNTP浓度,促使DNA损伤得以修复。细胞周期S期中出现的DNA损伤修复主要由ATR通路完成,说明ATR对于保证细胞增殖非常重要。对于临床肿瘤样品的分析结果表明在多种肿瘤组织中,例如胃癌、肝癌、结直肠癌、卵巢癌、胰腺癌等,均观察到ATR表达水平升高。并且在卵巢癌、胰腺癌病人中,高水平的ATR往往伴随着较低的存活率。由此可见ATR是一个重要的肿瘤治疗的靶标。
现已公开的ATR抑制剂的专利申请包括WO2010071837、WO2011154737、WO2016020320、WO2016130581、WO2017121684、WO2017118734、WO2018049400、WO2019050889、WO2014140644、WO2021098811A等。
发明内容
本公开提供一种式(VI)所示化合物的制备方法,可选的实施方案中,包含如下步骤:式(VII)所示化合物在催化剂作用下发生还原反应的步骤,
在其他的实施方案中,本公开提供的式(VI)所示化合物的制备方法包含如下步骤:式(X)所示化合物与式(VIII)所示化合物,在非亲核性碱性试剂作用下发生缩合反应的步骤,
在一些实施方案中,方法1中硝基还原的方式为氢化还原,可选地,所述的催化剂为Pd/C。
本公开中,式(VII)所示化合物可由式(IX)所示化合物与式(VIII)所示化合物在非亲核性碱性试剂作用下发生缩合反应制备得到,
可选的实施方案中,本公开中所述非亲核性碱性试剂选自双(三甲基硅基)胺基锂(LIHMDS)、二异丙基氨基锂(LDIA)、二乙基氨基锂(LDEA)、异丙基环己基氨基锂(LICA)、二环己基氨基锂(LDCA)或2,2,6,6-四甲基哌啶氨基锂(LTMP)。
一些实施方案中,所述非亲核性碱性试剂为双(三甲基硅基)胺基锂(LIHMDS)。
可选的实施方案中,式(X)所示化合物与非亲核性碱性试剂的物质的量比选自1:1-1:10,具体可选1:1、1:1.5、1:2、1:2.5、1:3、1:3.5、1:4、1:4.5、1:5、1:5.5、1:6、1:6.5、1:7、1:7.5、1:8、1:8.5、1:9、1:9.5或1:10,或任意两点之间的数值。
可选的实施方案中,式(IX)所示化合物与非亲核性碱性试剂的物质的量比选自1:1-1:10,具体可选1:1、1:1.5、1:2、1:2.5、1:3、1:3.5、1:4、1:4.5、1:5、1:5.5、1:6、1:6.5、1:7、1:7.5、1:8、1:8.5、1:9、1:9.5或1:10,或任意两点之间的数值。
可选的实施方案中,式(X)所示化合物与式(VIII)所示化合物在非亲核性碱性试剂作用下发生缩合反应的步骤,或式(IX)所示化合物与式(VIII)所示化合物在非亲核性碱性试剂作用下发生缩合反应的步骤的反应温度选自0℃至-50℃,具体地,可选0℃、-5℃、-10℃、-15℃、-20℃、-25℃、-30℃、-35℃、-40℃、-45℃或-50℃,或任意两点之间的数值;反应溶剂为非质子溶剂,具体可选自乙腈、四氢呋喃等。
可选的实施方案中,式(IX)所示化合物与式(VIII)所示化合物反应的步骤在惰性气体保护下发生,惰性气体具体可选氮气或氦气。
本公开另一方面提供一种式(V)所示化合物或其可药用盐的制备方法,包括式(VI)所示化合物在脱水剂和碱性试剂作用下环合的步骤,
进一步包括前述的式(VI)所示化合物的制备步骤。
可选的实施方案中,式(V)所示化合物或其可药用盐的制备方法中,所述脱水剂选自POCl3、PCl5,P2O5或SOCl2,所述碱性试剂选自二异丙基乙胺,三乙胺或吡啶。
可选的实施方案中,式(V)所示化合物或其可药用盐的制备方法中,所述脱水剂为POCl3,所述碱性试剂为二异丙基乙胺。
可选的实施方案中,式(VI)所示化合物与脱水剂的物质的量比选自1:1-1:10,具体可选1:1、1:1.5、1:2、1:2.5、1:3、1:3.5、1:4、1:4.5、1:5、1:5.5、1:6、1:6.5、1:7、1:7.5、1:8、1:8.5、1:9、1:9.5或1:10,或任意两点之间的数值。
可选的实施方案中,式(VI)所示化合物与碱性试剂的物质的量比选自1:1-1:10,具体可选1:1、1:1.5、1:2、1:2.5、1:3、1:3.5、1:4、1:4.5、1:5、1:5.5、1:6、1:6.5、1:7、1:7.5、1:8、1:8.5、1:9、1:9.5或1:10,或任意两点之间的数值。
可选的实施方案中,式(V)所示化合物或其可药用盐的制备方法中,反应的溶剂选自1,2-二氯乙烷、四氢呋喃或乙腈。
本公开另一方面提供一种式(I)所示化合物或其可药用盐的制备方法,包括前述的式(VI)所示化合物的制备步骤和/或前述的式(V)所示化合物或其可药用盐的制备步骤,任选进一步包括选自式(IV)所示化合物、式(III)所示化合物、式(II)所示化合物的一个或多个化合物的制备步骤,
在一些实施方案中,本公开提供的式(I)所示化合物或其可药用盐的制备方法,步骤如下所示:
可选的实施方案中,本公开提供的式(VI)所示化合物、式(V)所示化合物或其可药用盐、式(VII)所示化合物的制备方法,为大于500g级别(产物大于500g)的制备方法。
本公开另一方面提供一种式(VII)、(VI)所示的化合物,
本公开进一步提供一种经由前述方法制备得到的式(I)所示化合物或其可药用盐。
本公开进一步提供药物组合物,其包含经由前述方法制备得到的式(I)所示化合物或其可药用盐和一种或多种药学上可接受的赋形剂。
本公开中所述的“赋形剂”包括但不限于任何已经被美国食品和药物管理局批准对于人类或家畜动物使用可接受的任何助剂、载体、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、增香剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂或乳化剂。
具体实施方式
以下将结合实施例更详细地解释本公开,本公开的实施例仅用于说明本公开的技术方案,本公开的实质和范围并不局限于此。
本公开化合物结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR的测定是用Bruker AVANCE-400核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d6),氘代氯仿(CDCl3),氘代甲醇(CD3OD),内标为四甲基硅烷(TMS)。
MS的测定用FINNIGAN LCQAd(ESI)质谱仪(生产商:Thermo,型号:Finnigan LCQadvantage MAX)。
HPLC的测定使用WATER e2695-2489高效液相色谱仪。
本公开的已知的起始原料可以采用或按照本领域已知的方法来合成,或可购买自BEPHARM等公司。
实施例1.式(VI)所示化合物的制备
步骤1.式(VII)所示化合物的制备
氮气保护下向反应釜中加入9.0kg的四氢呋喃,开启搅拌,后分别加入1.0kg式(IX)所示化合物和0.85kg式(VIII)所示化合物,降温至-20℃,滴加双(三甲基硅基)胺基锂(1.0M in THF)10.8L,保温搅拌反应1小时,高效液相检测反应完全,滴加饱和的氯化铵水溶液(2.5vol),加入水(5vol),静置15-20分钟,分层,水相加入反应釜中,用6M HCl水溶液调至PH至2~3,后用二氯甲烷萃取,55℃下减压蒸馏,加入异丙醇溶剂,后滴加正庚烷析出,抽滤,真空干燥得产品1120g,纯度为99%,收率为70%。
MS m/z(ESI):297.10[M+l]。
1H NMR(400MHz,DMSO-d6)δ8.35(s,1H),6.20(s,2H),4.50-4.14(m,1H),3.93(s,3H),4.10-3.73(m,2H),3.68-3.50(m,2H),3.45-3.31(m,2H),1.25(d,3H)。
步骤2.式(VI)所示化合物的制备
氮气保护下,将乙酸乙酯(17kg)加入到反应釜中,开启搅拌,后依次将式(VII)所示化合物(0.9kg)和钯/碳(10%wt)(0.09kg)加入反应釜,氢气/真空将体系置换1次,持续加氢,搅拌反应48小时后抽滤,滤液浓缩至无液滴,后加入适量乙酸乙酯,回流搅拌1小时,向反应液中滴加正庚烷(4.5kg),室温搅拌3小时,冷却搅拌1小时,抽滤,真空干燥得到产物647g,纯度为99%,收率为80%。
MS m/z(ESI):267.20[M+l]。
1H NMR(400MHz,DMSO-d6)δ7.06(s,1),5.32(s,2H),4.40-4.37(m,1H),4.10-3.91(m,2H),3.88(s,3H),3.88-3.79(m,2H),3.64-3.43(m,2H),3.33(s,2),1.25(d,3H)。
实施例2.(R)-1-(4-氨基1-甲基-1H-吡唑-5-基)-3-(3-甲基吗啉)-1,3-丙二酮(式(VI)所示化合物)的制备
将1940mL的双(三甲基硅基)胺基锂和1.9336L的四氢呋喃加入到反应瓶中,降温到-10℃,将式(VIII)所示化合物(138.42g溶于240.0mL四氢呋喃中)滴加到上述溶液中,搅拌40分钟,将式(X)所示化合物(100.0g溶于800.0mL四氢呋喃),滴加到上述溶液中搅拌30分钟,LC-MS监测至反应完全,低温下滴加900mL 6N HCl水溶液至pH为7,分相,水相用甲基四氢呋喃萃取、饱和食盐水洗,有机相柱层析(乙酸乙酯:石油醚=0~90%)得到式(VI)所示化合物,108.0g,收率62.9%。
实施例3.(R)-4-(7-氯-1-甲基-1H-吡唑[4,3-b]吡啶-5-基)-3-甲基吗啉盐酸盐(式(V-1)所示化合物)的制备
氮气保护下,将乙腈(7000g)加入到反应釜中,开启搅拌,将式(VI)所示化合物(730.0g)、二异丙基乙基胺(1065.0)依次加入,开启冷却循环降温至-30℃,滴加POCl3(1680.0g),滴毕,低温搅拌0.5小时后升温至65℃,反应3小时至有固体析出,后室温搅拌至固体大量析出,加入甲基叔丁基醚(12200g),搅拌1小时,抽滤,真空干燥,得到产物,704.3g,纯度为99%,收率为85%。
MS m/z(ESI):267.10[M+l]。
实施例4.(R)-2-甲基-2-(1-甲基-5-(3-甲基吗啡啉)-3-(1H-吡唑-3-基)-1H-吡唑并[4,3-b]吡啶-7-基)丙腈的制备
参考已公开专利申请WO2021098811A中实施例1中相同制备方法,得到(R)-2-甲基-2-(1-甲基-5-(3-甲基吗啡啉)-3-(1H-吡唑-3-基)-1H-吡唑并[4,3-b]吡啶-7-基)丙腈。
Claims (10)
1.一种式(VI)所示化合物的制备方法,包含如下步骤:
方法1,式(VII)所示化合物在催化剂作用下发生还原反应的步骤,
或
方法2,式(X)所示化合物与式(VIII)所示化合物,在非亲核性碱性试剂作用下发生缩合反应的步骤,
2.根据权利要求1所述的制备方法,所述方法1中的催化剂为Pd/C。
3.根据权利要求1所述的制备方法,所述方法2进一步包括式(IX)所示化合物与式(VIII)所示化合物在非亲核性碱性试剂作用下发生缩合反应的步骤,
4.根据权利要求1或3所述的制备方法,所述的非亲核性碱性试剂选自双(三甲基硅基)胺基锂、二异丙基氨基锂、二乙基氨基锂、异丙基环己基氨基锂、二环己基氨基锂或2,2,6,6-四甲基哌啶氨基锂,优选双(三甲基硅基)胺基锂。
5.一种式(V)所示化合物或其可药用盐的制备方法,包括式(VI)所示化合物在脱水剂和碱性试剂作用下环合的步骤,
进一步包括权利要求1至4任一项所述的式(VI)所示化合物的制备步骤。
6.根据权利要求5所述的制备方法,所述脱水剂选自POCl3、PCl5,P2O5或SOCl2,优选POCl3,所述碱性试剂选自二异丙基乙胺,三乙胺或吡啶,优选二异丙基乙胺。
7.根据权利要求5所述的制备方法,所述反应的溶剂选自1,2-二氯乙烷、四氢呋喃或乙腈,优选乙腈。
8.一种式(I)所示化合物或其可药用盐的制备方法,包括权利要求1至4任一项所述的式(VI)所示化合物的制备步骤和/或权利要求5至8任一项所述的制备式(V)所示化合物或其可药用盐的步骤,任选进一步包括选自式(IV)所示化合物、式(III)所示化合物、式(II)所示化合物的一个或多个化合物的制备步骤,
9.一种式(VII)所示的化合物,
10.一种式(VI)所示的化合物,
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