CN113382997A - 盐酸罗加替尼的一水合物及其固体状态 - Google Patents
盐酸罗加替尼的一水合物及其固体状态 Download PDFInfo
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- CN113382997A CN113382997A CN202080011813.4A CN202080011813A CN113382997A CN 113382997 A CN113382997 A CN 113382997A CN 202080011813 A CN202080011813 A CN 202080011813A CN 113382997 A CN113382997 A CN 113382997A
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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Abstract
本申请涉及化合物(III),其是[4‑{[4‑氨基‑6‑(甲氧基甲基)‑5‑(7‑甲氧基‑5‑甲基‑1‑苯并噻吩‑2‑基)吡咯并[2,1‑f][1,2,4]三嗪‑7‑基]甲基}哌嗪‑2‑酮盐酸盐]的结晶形式,其是一水合物,本申请还涉及其制备工艺、包含它的药物组合物及其在控制包括癌症在内的病症中的用途。
Description
背景技术
癌症产生的方式有很多种,这也是其治疗困难的原因之一。细胞转化的一种方式是遵循基因改变。人类基因组计划的完成表明人癌症基因具有基因组不稳定性和异质性。最近识别这些基因改变的策略加速了癌症基因的发现过程。例如,基因异常可导致蛋白过表达,从而导致这些蛋白的非生理性激活。酪氨酸激酶,特别是受体酪氨酸激酶(RTK)是许多癌蛋白的来源的一个蛋白家族。在过去的二十年中,许多研究途径已经证明RTK介导的信号传导在导致癌症的不利细胞生长中的重要性。近年来,酪氨酸激酶的选择性小分子抑制剂作为一类新型抗肿瘤药物在临床上取得了可喜的成果[Swinney和Anthony,NatureRev.Drug Disc.10(7),507-519(2011)]。
成纤维细胞生长因子(FGF)及其受体(FGFR)形成独特而多样的信号传导系统的一部分,该系统在涵盖胚胎发育和成人病理生理学各方面的各种生物过程中发挥着关键作用[Itoh和Ornitz,J.Biochem.149(2),121-130(2011)]。以时空的方式,FGF通过FGFR结合刺激广泛的细胞功能,包括迁移、增殖、分化和存活。
FGF家族包含18种分泌型多肽生长因子,其与在细胞表面表达的四种高度保守的受体酪氨酸激酶(FGFR-1至-4)结合。此外,FGFR 5可以与FGF结合,但没有激酶结构域,因此缺乏细胞内信号传导。许多转录和翻译过程增强了配体/受体相互作用的特异性,这些过程通过可变转录起始、可变剪接和C末端截断产生多种同工型。各种硫酸乙酰肝素蛋白聚糖(例如合成聚糖)可以是FGF/FGFR复合物的一部分,并强烈影响FGF诱导信号传导反应的能力[Polanska等人,Developmental Dynamics 238(2),277-293(2009)]。FGFR是细胞表面受体,由三个细胞外免疫球蛋白样结构域、单次跨膜结构域和细胞内二聚化酪氨酸激酶结构域组成。FGF的结合使细胞内激酶靠近,使它们能够相互转磷酸化。已识别七个磷酸化位点(例如,在FGFR 1 Tyr463、Tyr583、Tyr585、Tyr653、Tyr654、Tyr730和Tyr766中)。
这些磷酸酪氨酸基团中的一些充当下游信号传导分子的停泊位点,这些分子本身也可能被FGFR直接磷酸化,从而激活多个信号转导通路。因此,MAPK信号传导级联与细胞生长和分化有关,PI3K/Akt信号传导级联参与细胞存活和细胞命运决定,而PI3K和PKC信号传导级联在控制细胞极性方面具有功能。现在已识别几种FGF信号传导的反馈抑制剂,包括Spry(Sprouty)和Sef(与FGF表达相似)家族的成员。此外,在某些条件下,FGFR从前高尔基体膜释放到细胞质中。受体及其配体FGF-2通过涉及输入蛋白的机制协同转运进入细胞核,并参与CREB结合蛋白(CBP)复合物,这是一种常见且必不可少的转录共激活因子,其可作为基因激活门控因子。已观察到FGF-2、FGFR-1和FGFR-2的免疫组织化学表达与其细胞质和核肿瘤细胞定位之间的多重相关性。例如,在肺腺癌中,这种关联还在核水平上发现,强调复合物在核中的积极作用[Korc和Friesel,Curr.Cancer Drugs Targets 5,639-651(2009)]。
FGF在发育中和成体组织中广泛表达,并且在各种正常和病理过程中发挥重要作用,包括组织发育、组织再生、血管生成、肿瘤转化、细胞迁移、细胞分化和细胞存活。此外,FGF作为促血管生成因子,还与对血管内皮生长因子受体2(VEGFR-2)抑制产生耐药性的新兴现象有关[Bergers和Hanahan,Nat.Rev.Cancer 8,592-603(2008)]。
最近信号传导网络的致癌基因组谱证明了异常FGF信号传导在一些常见人癌症的出现中的重要作用[Wesche等人,Biochem.J.437(2),199-213(2011)]。配体非依赖性FGFR组成性信号传导已在许多人癌症(诸如脑癌、头颈癌、胃癌和卵巢癌)中描述。FGFR突变形式以及FGFR基因内易位已在恶性肿瘤诸如骨髓增殖性疾病中识别。有意思的是,在肿瘤细胞中也发现了被发现是许多发育障碍的原因的相同突变(例如,在软骨发育不全和致死性发育不良中发现的突变,导致二聚化并因此组成性激活FGFR-3,也经常在膀胱癌中发现)。促进二聚化的突变仅是可以增加来自FGFR的配体非依赖性信号传导的一种机制。位于FGFR激酶结构域内部或外部的其他突变可以改变结构域的构象,从而产生永久活性激酶。
染色体区8p11-12(FGFR-1的基因组位置)的扩增是乳腺癌中常见的局灶性扩增,在约10%的乳腺癌中发生,主要在雌激素受体阳性的癌症中发生。FGFR-1扩增在非小细胞肺鳞癌中也有报道,发现其在卵巢癌、膀胱癌和横纹肌肉瘤中的发生率很低。类似地,约10%的胃癌显示FGFR-2扩增,这与预后不良的弥漫型癌症有关。此外,发现位于FGFR-1至-4的多个单核苷酸多态性(SNP)与患选择性癌症的风险增加相关,或被报道与预后不良有关(例如,乳腺癌、结肠癌和肺腺癌中的FGFR-4G388R等位基因)。这些SNP促进癌症的直接作用尚存争议。
在2013年6月20日公开的WO 2013/087578中鉴别出通式(I)的强效FGFR抑制剂:
通式(A)的6,7-二取代的5-(1-苯并噻吩-2-基)-吡咯并[2,1-f]-[1,2,4]-三嗪-4-胺衍生物
更具体地,式(I)的化合物
4-{[4-氨基-6-(甲氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f]-[1,2,4]-三嗪-7-基]甲基}哌嗪-2-酮
或其药学上可接受的盐、水合物或溶剂化物,其用于生产药物和生产用于治疗和/或预防增殖性病症(诸如癌症和肿瘤疾病)的药物,是特别强效的FGFR抑制剂。
4-{[4-氨基-6-(甲氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1f]-[1,2,4]-三嗪-7-基]甲基}哌嗪-2-酮被给出的国际通用药物名称(INN)是罗加替尼(ROGARATINIB)。
罗加替尼(Rogaratinib)具有有价值的药理学特性,并且可用于预防和治疗人类和其他哺乳动物中的病症。
罗加替尼是受体酪氨酸激酶(特别是FGFR激酶,最明显的是FGFR-1和FGFR-3激酶)的活性或表达的强效抑制剂。在某些实施方案中,与FGFR激酶活性相关的病症是增殖性病症,特别是癌症和肿瘤疾病。
(I)的合成已经在WO 2013/087578中通过两条路线进行描述,在以下方案中示出。WO 2013/087578的合成路线如方案1所述:
方案1
方案2中示出了WO 2013/087578得到(I)的替代路线。
方案2:
4-氨基吡咯并[2,1-f][1,2,4]三嗪-6-甲腈的制备如WO2007/064883中所述并示于方案3中。
方案3:
式(I)的化合物的制备通用路线如WO 2013/087578中所述,但尚未应用于(I)的合成。它示于方案4。
方案4:
中间体(VII)的制备已在WO 2013/087578中根据该通用路线通过以下方案5中所示的顺序进行了描述。这种从(IX)到化合物(VII)的4步工艺的总收率仅为6%,并且使用了4次色谱纯化,这从经济角度来看是不利的。现有技术中尚未描述化合物(VII)向(I)的进一步转化。
方案5:
(IX)的制备已在WO 2007/064883中通过方案6中所示的反应顺序进行了描述。
方案6:
4-{[4-氨基-6-(甲氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-2-酮(XIV)的二盐酸盐及其制备工艺首次公开于WO2013/087578A1(Bayer)
二盐酸盐的制备如WO 2013/087578A1(Bayer)实施例II中所述。获得该化合物的唯一合适方法是在二噁烷中通过使用HCl。获得二盐酸盐的其他尝试,例如在各种溶剂中用浓HCl处理,产生不可分离的材料(高度吸湿;胶状物等)。从监管方面,二噁烷不是合成的最后一步中使用的有利溶剂,因为残留溶剂的限度极低。此外,HCl与二噁烷反应的开环副产物可产生基因毒性杂质,这些杂质必须降至ppm级。
二盐酸盐具有极强吸湿性并在空气中静置时失去HCl(即,它在化学上不稳定),这产生各种水合物和盐酸盐化学计量的不确定混合物。二盐酸盐的规模化处理非常困难,尤其是在生产规模上。
二盐酸盐的不利性质导致大规模制备4-{[4-氨基-6-(甲氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-2-酮的固体形式存在问题。因此,需要罗加替尼的稳定盐和结晶形式。
虽然现有技术公开的工艺本身对于制备式(I)的化合物及其合成中间体是有效的,但是因素(诸如纯度、产物收率、工艺效率、安全性和经济性)对于医药产品的工业规模工艺来说是非常重要的。还需要以高收率制备式(I)的化合物及其盐和各种结晶形式的有效工艺。
本发明的目的是提供用于制备式(I)的化合物或其药学上可接受的盐、水合物或溶剂化物(罗加替尼)的具有高收率的有效工艺
本发明的目的是提供工业规模(公斤至公吨范围)制备式(I)的化合物的工艺,该工艺满足适用于生产的标准并且提供纯度、环境相容性、工业可用性、安全方面和产量的改进。纯度和安全性方面被认为与药物的制备特别相关。
本发明的目的是提供固体状态形式的(I),其与已知的二盐酸盐相比表现出优异性质。
本发明解决了如下所述的那些问题。
发明内容
本发明涉及化合物(III)
其是化合物(I)的一氯化物的一水合物
本发明还涉及药物组合物,其包含化合物I的一氯化物的一水合物(其是化合物(III))和任选另外的药学上可接受的赋形剂。
本发明还涉及制备式(III)的化合物的工艺,该化合物是化合物(I)的一氯化物一水合物,该工艺包括在溶剂的存在下悬浮或溶解(I)并且用酸或酸前体处理所得溶液。
具体实施方式
4-{[4-氨基-6-(甲氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-2-酮对应于式(I),[4-{[4-氨基-6-(甲氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-2-酮盐酸盐]对应于式(II)的化合物并且其一水合物对应于式(III)。
本发明的式(III)的化合物(其是以其优势结晶形式的化合物(I)的一氯化物一水合物)的制备,先前尚未描述,如以下方案所示:
方案7:(III)的合成
本发明的一个方面是用于制备罗加替尼的具有高收率的有效工艺,其以极高纯度获得而无需使用色谱技术。此外,(I)转化为其盐酸盐(II),更具体地为具有如式(III)中的化学组成的结晶一水合物形式,具有将其用作药物成分的优势特性。
4-{[4-氨基-6-(甲氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-2-酮-单盐酸盐对应于式(II)的化合物。
本发明提供固体状态的式(II)的化合物,其是
-物理上和化学上稳定的
-可以配制成片剂而没有过度的负担
-可以以可重现的方式制备,也可以大规模制备
-易于以高化学纯度分离,通过离心或通过过滤
-易于按规模干燥
-表现出比游离碱更好的溶解度
-吸湿性低于二盐酸盐(现有技术)
-具有良好的按规模处理特性,例如,静电低于二盐酸盐
-易于微粉化且收率高
-可长期储存(如果仅限定一年内的生产档期,则很重要)
现已发现4-{[4-氨基-6-(甲氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-2-酮[A]的单盐酸盐的一水合物提供了上述益处。
除了优选的新一水合物形式外,还发现了几种其他新的水合物。式(II)的化合物可以四种不同的水合物形式和无定形形式存在。发现3/4-水合物(2.6%水)、一水合物(3.5%水)、二水合物(6.7%水)和三水合物(9.7%水)。在高湿度下储存期间,3/4-水合物、三水合物以及无定形形式转变为一水合物。在封闭容器中储存期间,二水合物在两周内转化为一水合物。已鉴别式(I)的化合物的化合物II的以下水合物形式是:
1.一水合物(一当量水):A(化合物(III))
2.二水合物(二当量水):B
3.三水合物(三当量水):C
4.3/4-水合物(0.75当量水):D
5.无定形形式:E
总之–水合物形式和无定形形式–是式(II)的化合物的不同固体形式。
式(II)的化合物的一水合物是优选形式并且在本文中称为化合物(III)。出乎意料的是,化合物(III)在以下方面显示出优于式(II)的化合物的其他固体形式的有益特性:
-物理稳定性:在25℃和50℃下储存12个月未显示出稳定性变化;
-化学稳定性:一水合物在储存数年期间具有化学稳定性
-可以通过干混、湿法制粒、干燥和干磨、总混、压片和包衣的工艺步骤配制成片剂而没有过度的负担;
-未观察到与片剂成分的相互作用。一水合物形式在片剂基质中稳定,并且在储存期间未发生变化(见表5)–给出了与其他成分的相容性;
-可以以可重现的方式制备,也可以大规模制备。这在几个中试工厂(pilotplant)活动中得到证明,其中制备了>100kg的原料药(drug substance);
-易于分离,通过离心或通过过滤。这在几个中试工厂活动中得到体现。一水合物形式的分离没有技术问题;
-以高化学纯度和高化学收率分离。这在几个中试工厂活动中得到体现。材料质量优良并且符合质量标准(specification);
-易于按规模干燥。这在几个中试工厂活动中得到证明。该材料可以易于在真空下干燥而未显著损失HCl和水。HCl和水值符合质量标准;
-比游离碱更易溶解。一水合物形式在水中具有显著更好的溶解性。这导致生物利用度提高;
-吸湿性低于二盐酸盐。吸湿试验(实验部分4.4.)使用一水合物形式进行。该化合物在15%r.h.、85%r.h.和97%r.h.(r.h.=相对湿度)下储存12个月,未见吸水,这清楚地表明一水合物形式不具有吸湿性。值得一提的是,所有其他形式在储存条件下均变成一水合物形式(见表4)。
-具有良好的按规模处理特性并且静电较低。一水合物形式易于批量处理。化合物的称重和倾倒容易进行,未观察到静电特性;
-易于微粉化且收率高。大批量微粉化的收率通常>95%(th.)。在微粉化过程中未观察到问题。目标粒径以可重现的方式易于获得;
-可长期存储(如果仅限定一年内的生产档期,则很重要)。稳定性数据表明一水合物形式在储存期间非常稳定;
-在过滤和分离方面,晶体的习性是可接受的。过滤时间极短,这对于在中试工厂中进行处理是很大的优势。
因此,一水合物形式(III)比式I的化合物的其他固体形式更适合且优选用于大规模生产。
特别地,式(III)的化合物减少向式(II)的化合物的另一种形式的任何非期望转化,并且使上述特性的相关变化最小化。这应提高包含式(II)的化合物的制备和制剂的安全性和质量,并且降低对患者的风险。
根据本发明的药物组合物包含化合物(III)和任选另外的药学上可接受的赋形剂。
优选地,该药物组合物包含化合物(III),并且不包含显著分数(significantfractions)的式(II)的化合物的另一种形式,和任选包含另外的药学上可接受的赋形剂。更优选地,该药物组合物包含相对于存在于该组合物中式(II)的化合物的所有形式的总量,超过85重量%,更优选超过90重量%,最优选超过95重量%的化合物(III)。
式(II)的化合物的不同形式可以通过X射线粉末衍射,差示扫描量热法(DSC),IR-、拉曼-、NIR-、FIR-和13C-固态-NMR-光谱进行区分。
式(I)的化合物的化合物(III)可以通过X射线粉末衍射图(在25℃下并且使用Cu-Kα1作为放射源)明确表征,其至少显示以下反射:9.3、10.6、13.3,优选至少以下反射:9.3、10.6、13.3、20.7、23.3,更优选至少以下反射:9.3、10.6、11.4、13.3、20.7、23.3、26.0,最优选至少以下反射:6.8、9.3、10.6、11.4、13.3、20.7、23.3、24.6、26.0、27.6,各自引用为2θ值±0.2°。
化合物(III)也可以通过X射线粉末衍射图(在25℃下并且使用Cu-Kα1作为放射源)明确表征,如图1所示。
式(II)的化合物的二水合物形式[B]可以通过X射线粉末衍射图(在25℃下并且使用Cu-Kα1作为放射源)明确表征,其至少显示以下反射:6.7、13.9、14.5,优选至少以下反射:6.7、11.7、13.5、13.9、14.5,更优选至少以下反射:6.2、6.7、11.7、12.6、13.5、13.9、17.9,最优选至少以下反射:6.2、6.7、11.7、12.6、13.5、13.9、14.5、16.4、17.9、25.9,各自引用为2θ值±0.2°。二水合物形式[B]的式(I)的化合物也可以通过X射线粉末衍射图(在25℃下并且使用Cu-Kα1作为放射源)明确表征,如图2所示。
式(II)的化合物的三水合物形式[C]可以通过X射线粉末衍射图(在25℃下并且使用Cu-Kα1作为放射源)明确表征,其至少显示以下反射:6.8、12.9、14.6,优选至少以下反射:6.8、7.6、12.9、14.6、26,更优选至少以下反射:6.8、7.6、11.2、12.9、14.6、22.、26.5,最优选至少以下反射:6.8、7.6、11.2、12.9、13.5、14.6、17.4、22.5、23.3、26.5,各自引用为2θ值±0.2°。三水合物形式[C]的式(I)的化合物也可以通过X射线粉末衍射图(在25℃下并且使用Cu-Kα1作为放射源)明确表征,如图3所示。
式(II)的化合物的3/4-水合物形式[D]可以通过X射线粉末衍射图(在25℃下并且使用Cu-Kα1作为放射源)明确表征,其至少显示以下反射:7.3、12.2、14.0,优选至少以下反射:7.3、12.2、13.1、13.4、14.0,更优选至少以下反射:7.3、12.2、13.1、13.4、14.0、20.3、22.4,最优选至少以下反射:7.3、12.2、13.1、13.4、13.6、14.0、20.3、21.2、22.4、26.3,各自引用为2θ值±0.2°。3/4-水合物形式[D]的式(I)的化合物也可以通过X射线粉末衍射图(在25℃下并且使用Cu-Kα1作为放射源)明确表征,如图4所示。
氯化氢一水合物(III)的制备工艺
本发明的一个方面涉及制备一氯化物盐(II)的工艺,更具体地是其具有如式(III)的化学组成的结晶一水合物形式。
与现有技术的工艺相比,本发明的一般优势在于它以令人满意的收率提供化合物(I)和(III),具有极低的杂质水平,这符合后期临床开发或市场供应对API的要求。根据本发明的工艺可以在不使用色谱纯化步骤的情况下进行。此外,现有技术的工艺具有某些缺陷,这些缺陷阻碍了工业规模生产的应用,诸如工艺安全性问题、产品分解和由于放大规模时增加的加工时间而导致的杂质形成增加,以及由于高度稀释导致的生产量有限。以下描述的本发明的工艺可用于在用于化学合成的标准工业多用途设备中的大规模API生产,而无需不相称的财政和人力资源。这是通过优化生产量以及通过在合成的每个阶段应用优化且简化的工艺和/或定制的纯化工艺以避免杂质形成来实现。总之,使用如下所示的从(IV)开始至(III)的本发明的工艺的最终步骤实现的总收率为36%:
下表给出了现有技术的工艺与具有本发明工艺的最终合成步骤的(I)的直接比较:
*通过4-氨基吡咯并[2,1-f][1,2,4]三嗪-6-腈得到实例8a的长合成路线,在方案2和本发明的工艺之间无共同的中间体
方法1:
根据本发明的这个方面,如上所示的(I)至(III)的转化通过在合适的溶剂的存在下,优选在水或醇中,更优选在水混溶性有机溶剂(诸如醇或醚,最优选乙醇或THF)与水的混合物中悬浮或溶解(I),并且将其用氯化氢或氯化氢前体,最优选氯化氢处理进行。
优选首先将式(I)的化合物进料至溶剂或溶剂混合物中,随后加入酸,最优选氯化氢。将氯化氢加入该混合物中,优选作为水溶液,优选在20℃和回流条件之间的温度下,更优选在40℃至60℃下,更优选在45至55℃下。
通过过滤分离反应产物并用水混溶的有机溶剂(诸如醇或醚,优选乙醇)洗涤。产物可以被干燥或在不干燥的情况下递送至下一工艺步骤。
然后在升高的温度下将产物悬浮于水或低浓度氯化氢水溶液中,优选在水中的0.13%氯化氢,以将固体状态形式调节为具有如式(III)中的化学组成的期望结晶一水合物形式。将混合物冷却至20±3℃并通过过滤分离。
化合物(III)优选在50℃的温度和减压下干燥,更优选在低于30毫巴的压力下且不施加副气(by-gas)。
该工艺,在本文中称为“制备化合物(III)的方法1”,具有将(I)转化为其一氯化物,更具体地为一氯化物一水合物(III)的优点,其在作为活性药物成分的应用过程中显示出有利的特性。此外,该工艺具有可靠地产生作为一水合物(III)的一氯化物(II)的优点。在该工艺的盐形成步骤过程中最初可能形成的其他形式,在升高的温度下用稀释的氯化氢水溶液处理过程中转化为期望形式。
方法2:
根据本发明的这个方面,(I)至(III)的转化通过在合适的溶剂的存在下悬浮或溶解(I)并且用酸或酸前体对其进行处理而进行。优选地,溶剂是水或醇,更优选水混溶性有机溶剂(诸如醇或醚,最优选乙醇或THF)与水的混合物。酸或酸前体优选是氯化氢。优选首先将式(I)的化合物进料至溶剂或溶剂混合物中,随后加入酸。
将氯化氢加入该混合物中,优选作为水溶液,优选在20℃至回流条件下,更优选在40℃至60℃下,最优选在45至55℃下。
将一水合物(III)(例如通过方法1制备)的小等分试样,优选相对于(I)的初始量的1质量%,优选通过预先研磨或微粉化具有细粒度,加入悬浮液中以进行种晶,以便引导产物至期望的固体状态形式。
冷却反应混合物并在过滤干燥器上分离产物。滤饼用与水混溶的有机溶剂,优选醇或醚,最优选乙醇或乙醇和水的混合物洗涤。然后在20-35℃下用水或低浓度氯化氢水溶液(优选在水中的0.13%氯化氢)洗涤滤饼。
产物在减压和升高的温度下干燥,诸如在30毫巴和50℃下且不施加副气。
该工艺,在本文中称为“制备(III)的方法2”,具有在加入氯化氢步骤中立即可靠地形成(II)作为优选的一水合物(III)的优点,无需通过进行再浆化或其他单元操作来手动处理固体中间体,以调整到期望的固体状态。出乎意料地发现,在(I)的氯化氢盐已经以其他固体状态形式析出之后,可以通过将晶种加入悬浮液中以调节假多晶型。与制备(III)的方法1相比,该种晶工艺具有在大规模时改进过滤和干燥特性的优点。
该工艺的优点在于极大减少了(I)与酸性条件接触期间形成的杂质,诸如(XV)和(XVI)的形成:
这是通过最小化加工和处理时间实现的-特别是在大规模时-特别是通过避免额外的酸处理以将产物调整为期望的多晶型。这使得杂质水平符合后期临床开发或市场供应API的要求。
根据本发明的工艺,潜在的副产物,特别是式(XV)和(XVI)的化合物以及进一步的,可以非常有效地与(III)分离,因为这些副产物或其盐在根据本申请工艺的条件下未析出并保留在滤液中。
本发明的另一个实施方案是基本上不含钯的式(III)化合物,其中钯以至多100ppm,优选至多60ppm,最优选0-2ppm的量存在,并且具有极高纯度,其含有一种或多种结构上与(I)相关的吡咯并-三嗪物质,基于式(I)的化合物的量,各自从0%至最大0.15%,优选地各自从0%至最大0.06%(按HPLC面积%)。结构上与(I)相关的吡咯并-三嗪物质包括,但不限于式(XV)、(XVI)、(XVII)、(XVIII)和(VI)的化合物。
式(I)的化合物的制备
本发明的一个方面涉及制备式(I)的化合物的工艺,其可以通过在合适的催化剂存在下,使式(VIIb)的化合物(其中R1是卤素或其他合适的离去基团,最优选为溴)与式(VIIIb)的化合物(其中R2是合适的金属有机取代基诸如Li、MgR、Sn和B,羧酸,氢或硼衍生物诸如硼酯、硼酰胺、MIDA,优选为氢或硼衍生物,最优选为硼酸)反应进行制备。在产生式(I)的化合物的催化C-H活化反应中,取代基R2还可以包含氢。
(VIIb)和(VIIIb)的混合物在碱(诸如氢氧化物、(氢-)碳酸盐、氟化物或胺)的存在下,在合适的有机溶剂或与水的混合物中,在升高的温度下用过渡金属催化剂(优选用合适的钯催化剂)处理。
优选将式(VII)和(VIII)的化合物在THF和水中的混合物用K2CO3(作为碱)和催化剂在60℃的温度下处理回流30min至300min。
合适的钯催化剂是但不限于:
X-Phos催化剂前体=(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯)[2-(2'-氨基-1,1'-联苯)]二氯化钯(II)
和
Pd(dbpf)Cl2=[1,1'-双(二叔丁基膦基)二茂铁]二氯化钯(II)
和
PdCl2(Amphos)2=双(二叔丁基(4-二甲氨基苯基)膦)二氯化钯(II)。
该工艺产生式(I)的化合物与副产物和剩余试剂的混合物,称为粗反应混合物。该粗反应混合物可以通过以下方法处理:
本发明的另一方面是获得式(I)的化合物的固体和纯化形式的工艺。该工艺包括通过在20℃至回流温度,最优选在60℃下加入钯清除剂(诸如乙酰半胱氨酸)的水溶液处理粗反应混合物1h至24h。反应过程中使用的溶剂,诸如THF,可以通过蒸馏除去,任选地在减压下。可以在蒸馏之前或之后加入合适的溶剂,优选为容易萃取痕量(XIX)的非水混溶性溶剂,最优选为MTBE或EtOAc。冷却后,优选冷却至0℃至30℃,优选20℃的温度,通过过滤分离化合物。该纯化的化合物(I)可以进行进一步的纯化工艺。
为了提供高度纯化形式的式(I)的化合物,在诸如50℃至回流的温度下将其进料至合适的有机溶剂或溶剂混合物中并加热至升高的温度,最优选THF与水或乙醇与水的混合物。在高于-10℃和低于回流温度,优选在0℃和20℃之间的温度下通过过滤分离式(I)的化合物。
优选将式(I)的化合物进料至四氢呋喃与水的混合物(以85体积四氢呋喃与15体积水的比例)中并加热该混合物直至获得溶液。通过蒸馏除去THF,优选在减压下并加入乙醇以改变溶剂组成以主要包含乙醇和水。将混合物冷却至15℃并过滤分离式(I)的化合物。可以重复该纯化程序以进一步降低杂质水平。
该化合物在减压和升高的温度下干燥。
潜在的副产物,特别是痕量钯、苯并噻吩副产物,诸如(XIX):
和一种或多种结构上与(I)相关的吡咯并-三嗪物质诸如起始化合物(XII)、(VI)和(XVIII)在根据本申请工艺的条件下未析出并保留在滤液中。
本发明的另一个实施方案是具有极高纯度的式(I)的化合物,其含有一种或多种结构上与(I)相关的吡咯并-三嗪物质,基于式(I)的化合物的量,各自从0%至最大0.15%,优选地各自从0%至最大0.06%(按HPLC面积%)。结构上与(I)相关的吡咯并-三嗪物质包括,但不限于式(XII)、(VI)和(XVIII)的化合物。
本发明的另一个实施方案是具有极高纯度的式(I)的化合物,其含有痕量钯(通过适当的痕量方法测定,从0ppm至最大60ppm,通常低于2ppm)。
式(VII)的化合物的制备
本发明的另一方面是制备式(VIIb)的化合物的工艺,其中R1可以是氯、溴或碘,最优选为溴,其通过在酸存在下,使式(V)和(XIII)的化合物与多聚甲醛反应生成式(VI)的中间产物。式(VI)的产物不是分离的,而用卤化剂处理,诸如溴化剂、碘化剂或氯化剂。优选地,在与一锅反应相同的反应容器中使用溴化剂,最优选为N-溴代琥珀酰亚胺(NBS)。虽然中间体(VI)难以分离和纯化,尤其是使用更大规模的标准工业操作,但具有化学结构(VII)的溴化衍生物很容易从反应混合物中以良好的纯度结晶。通过在升高的温度下将(VII)悬浮于合适的溶剂或溶剂混合物中,可以进一步提高纯度。
在制备式(VII)的化合物的工艺的优选实施方案中,将式(V)和(XIII)的化合物进料至合适的溶剂中,优选为甲醇、乙醇、异丙醇、正丙醇、正丁醇及其与水的混合物,最优选在MeOH中。
甲醛源,优选多聚甲醛、福尔马林溶液或其他甲醛源,最优选多聚甲醛,酸剂,优选羧酸(诸如乙酸、苯甲酸、丙酸、三氟乙酸),磺酸(诸如对甲苯磺酸、苯磺酸),无机酸(诸如氯化氢、硫酸、亚磷酸,最优选乙酸)并加热至升高的温度,优选40-100℃,最优选至60℃以回流1h至48h,优选20-24h。
在反应中配置1eq至4eq哌嗪-2-酮(XIII)、1eq至3eq多聚甲醛和1eq至10eq乙酸。优选在反应中配置1eq至2eq哌嗪-2-酮(XIII)、1eq至1.5eq多聚甲醛和3eq至7eq乙酸。最优选在反应中配置1.5eq哌嗪-2-酮(XIII)、1.1eq多聚甲醛和6eq乙酸。
在转化为(VI)之后,可以任选地加入另外的合适溶剂,诸如质子和非质子有机溶剂和水,与或不与无机或有机碱,诸如三乙胺、吡啶、许尼希碱(Hünig’s base)、2,6-二甲基吡啶、N-甲基咪唑,或无机碱,诸如氢氧化钠、氢氧化钾、氢氧化钙、碳酸钠或碳酸钾组合。
最优选地,加入氢氧化钠水溶液直至达到微酸性或中性pH。出乎意料的是,通过在溴化过程中应用5.5至6.5的pH值,可以实现最佳转化率、有限杂质形成、良好的搅拌特性和通过减少细颗粒形成而增强分离特性之间的优化。
将溴化剂,优选NBS或1,3-二溴-5,5-二甲基乙内酰脲(DBDMH),最优选NBS,以固体或以在合适溶剂(优选为乙腈)中的溶液加入。分批加入固体NBS或缓慢加入NBS在乙腈中的溶液是有利的,以减少杂质的形成。
溴化在-20℃至20℃下,优选在-10℃至10℃下,最优选在-8℃至-2℃下进行。有利的是将反应混合物加热至回流并在反应完成后再次冷却,以改善分离。
为了提供高度纯化的式(VII)的化合物,将反应产物进料至合适的有机溶剂或溶剂混合物中,优选醇、醚、腈、水及其混合物,最优选甲醇、THF以及甲醇和THF与水的混合物并加热至升高的温度(诸如50℃)以回流。在高于-10℃和低于回流温度,优选在0℃和20℃之间的温度下通过过滤分离式(VII)的化合物。最后用水或与水混合的溶剂混合物(优选MeOH或THF)洗涤过滤器。最优选MeOH和水的混合物。
为了制备式(VII)的化合物,优选在环境温度和任选在减压下干燥经过滤和洗涤的产物。式(VII)的化合物以含有约5%水的水合物获得。
潜在的副产物,特别是副产物诸如式(XX)、(XXI)和(VI)的化合物在根据本申请工艺的条件下未析出并保留在滤液中。
本发明的另一个实施方案是具有极高纯度的式(XII)的化合物。副产物包括,但不限于(XX)、(XXI)和(VI),其量诸如:基于式(VII)的化合物的量,(XX)为0%至0.50%,优选为0%至0.30%,(XXI)为0%至0.70%,优选为0%至0.30%,以及(VI)为0%至0.30%,优选为0%至0.20%(按HPLC面积%)。
式(V)的化合物的制备
本发明的另一方面是制备式(V)的化合物的工艺
其从式(IV)的化合物经由式(XXII)和(XXIII)的反应中间体,
通过BOC取代基的酸性断裂、醇部分的氯化和醚化,以及用含有甲脒的试剂环化和进行或不进行中间体分离的反应顺序。
在制备式(XII)的化合物的工艺的优选实施方案中,将式(V)的化合物进料至合适酸在合适溶剂中的溶液中直至形成中间体(XXII)。然后在存在或不存在合适碱的情况下使反应混合物与甲醇或碱金属甲醇化物反应以形成反应中间体(XXIII)。然后加入甲脒或甲脒前体并将混合物加热至升高的温度,优选在40℃和回流之间,最优选至60-66℃。向(V)的转化可以通过优选以水溶液的形式加入碱来完成。
在制备式(V)的化合物的工艺中,将式(VII)化合物在19℃至25℃下进料至13-14%HCl在二噁烷中的溶液。在完成向中间体(XXII)的转化后,通常约6h,在20℃至30℃的温度下将反应混合物进料至甲醇和合适的碱(诸如K3PO4、碱金属甲醇化物、无机碳酸盐、无机碳酸氢盐、氢氧化物、有机胺碱,优选1eq至2eq K3PO4或2eq至3eq甲醇钠,最优选2.5eq甲醇钠)的混合物中并搅拌直至完全转化为中间体(XXIII),通常持续1h。然后将甲脒或甲脒前体,最优选为6eq乙酸甲脒加入反应混合物中,并将混合物加热至55℃以回流(约67℃)直至中间体(XXIII)完全转化,通常持续16h至20h。加入合适的碱(诸如K3PO4、碱金属甲醇化物、无机碳酸盐、无机碳酸氢盐、氢氧化物、有机胺碱,最优选为4eq K3PO4)的水溶液,并将混合物加热至55℃以回流(67℃)直至完全转化为式(V)化合物,通常持续2h。通过蒸馏除去有机溶剂,优选在减压下,并加入乙酸异丙酯。优选在45℃的温度下分离水相和有机相,并且优选在45℃的温度下用乙酸异丙酯萃取水相。合并的有机相通过蒸馏浓缩,优选在中等温度和减压下进行。将得到的悬浮液加热至80℃直至大部分产物再次溶解并缓慢冷却至0℃至20℃。通过过滤分离产物。为了制备式(XII)的化合物,优选在40℃至60℃的温度下和任选地在减压下干燥。
该工艺具有避免形成杂质的一般优势。具体地,当中间体(XXII)的酸性溶液在不存在碱的情况下与甲醇反应时,在该工艺的产物(V)中发现式(XXIV)的副组分。产物(V)中式(XXIV)的副组分的水平取决于该工艺步骤的时间。在中试工厂规模的典型反应中,该工艺步骤在1h内转化120kg(VII),形成约11%的(XXIV),在终产物中产生高达7%的这种杂质。通过将中间体(XXII)的酸性溶液进料至具有合适碱的甲醇溶液中,可以极大减少式(XXIV)和(XXV)的副组分的形成。
此外,该工艺极大减少了处理时间并且极大减少了焦油形成,尤其是在工业规模上,从而避免了(V)的后处理、纯化和分离工作量增加。这通过在中间体(XXII)与甲醇的反应过程中施加有限量的碱实现,从而在与甲脒的转化过程中避免强碱性条件。因此,可以减少试剂分解。通过在与甲脒反应后以水溶液形式加入过量的碱,引发向(V)的完全转化并且其残留的甲脒副产物在过量焦油形成发生之前被立即去除到水面上。
根据本申请工艺,潜在的副产物,特别是副产物,诸如式(XXIII)、(XXIV)和(XXV)的化合物在根据本申请工艺的条件下未析出并保留在滤液中。
本发明的另一个实施方案是具有极高纯度的式(V)的化合物。副产物包括,但不限于(XXIII)、(XXIV)和(XXV),其量诸如:基于式(I)的化合物的量,(XXIII)为0%至0.15%和(XXIV)为0%至0.15%以及(XXV)为0%至0.15%(按HPLC面积%)。
本发明的另一个实施方案是用于纯化式(V)的化合物的重结晶工艺。如果(V)不是通过此处描述的本发明的工艺生产的,则(V)可以以降低质量获得,例如含有大量副组分和盐,并且使用量低。为了提高此类样品的质量,(V)可通过在直至回流的升高的温度将其溶解于醇与非质子溶剂的混合物中,优选在乙醇与乙酸异丙酯的混合物中并再次缓慢冷却进行重结晶。可以以良好的收率和高纯度分离纯化的化合物(V)。
式(IV)的化合物的制备
本发明的另一方面是制备式(IV)的化合物的工艺
方案8中描述的反应顺序概述了经由中间体(XI)、(XII)和(IX)制备化合物(IV)。它通常遵循类似于WO 2007/064883的合成顺序直至获得中间体(VII),并且化合物(VII)至(VII)的转化类似于WO2013/087578中描述的工艺进行。与现有技术的工艺相比,本发明的工艺通过改进的方法和工艺提供(IV),用于工业规模的高效和安全生产并且无需色谱纯化步骤。
方案8:
在制备式(XI)的化合物的工艺中,在吡啶盐酸盐的存在下,在二噁烷和吡啶的溶剂混合物中,在102℃±3℃的温度下,使2,5-二甲氧基四氢呋喃(X)与肼羧酸叔丁酯反应。在这些条件下,通过蒸馏除去反应过程中形成的甲醇。在完全转化后,加入水和非水混溶的有机溶剂,优选为二正丁基醚,并且可以从该混合物中分离产物。本发明获得化合物(XI)的工艺已应用于大规模生产,并且通过使用吡啶和吡啶盐酸盐作为试剂,具有减少副组分形成的优点,尤其是大规模生产。
式(XII)的化合物通过使化合物(XI)与氯磺酰异氰酸酯在DMF中反应制备。可以通过将反应混合物加入无机盐(诸如氢氧化物和碳酸盐,最优选为碳酸氢铵)的水溶液中,随后过滤来分离粗产物。通过将粗产物溶解于合适的有机化合物,优选为甲醇中来纯化粗产物,并且通过将溶液与水混合以析出产物。本发明制备化合物(XII)的工艺已应用于大规模生产并且具有无需色谱纯化即可以提供具有良好纯度的(XII)的优点。
式(IX)的化合物通过使化合物(XII)与N-溴代琥珀酰亚胺在DMF和甲基叔丁基醚的混合物中反应制备。反应混合物水解后,产物用甲基四氢呋喃萃取,化合物(IX)在甲基四氢呋喃中的溶液未经分离或纯化即用于下一阶段。本发明制备化合物(IX)的工艺已应用于大规模生产并且具有通过避免(IX)以固体分离并将其嵌入(IV)的制备中而简化工艺的优点。
式(IV)的化合物通过使化合物(IX)与金属有机试剂,优选与甲基溴化镁和丁基锂反应并且加入多聚甲醛中来制备。已经观察到收率和质量的变化,这取决于多聚甲醛的不同批次。这可以通过在使用前用甲基四氢呋喃处理多聚甲醛来克服。水解和结晶后获得纯化的式(IV)的化合物。本发明制备化合物(IV)的工艺已应用于大规模生产并且具有无需色谱纯化即可提供具有良好纯度的(IV)的优点。
式(VIII)的化合物的制备
该制备描述于欧洲专利申请号15180755.9,其全部内容在此通过引用并入。优选的方法详述如下:
步骤1:
如上所示的(XXXV)与(XXXIV)反应得到(XXXIII)通过(XXXV)与(XXXIV)的缩合进行。这通过在25-40℃下将碱金属醇化物(诸如甲醇钠)在醇(优选为甲醇)中的溶液加入琥珀酸二甲酯溶液中完成。可以使用其他琥珀酸酯代替(XXXV),因为酯在以下步骤中被断裂。
将混合物加热至回流并加入噻吩-3-醛溶液。完全转化后,加入水使混合物水解并且产物用甲苯萃取(或其他非水溶性溶剂)。除去溶剂后,粗品(XXXIII)通过从甲苯(或其他合适的溶剂)结晶和/或再浆化以纯化。
·通过将噻吩-3-醛缓慢加入反应混合物中,该工艺具有相对于醛而言的高转化率的优点。
·该工艺具有应用减少的过量琥珀酸二甲酯以实现完全转化的优点。
·该工艺具有通过结晶或/再浆化纯化后得到极纯固体中间体(XXXIII),有助于避免在后期通过例如制备色谱进行纯化的优点。
步骤2:
如步骤2所示,(XXXIII)经由(XXXII)得到羧酸中间体(XXXI)的反应通过在脱水条件下闭环获得苯并噻吩衍生物(XXXII)和酯部分的水解进行,从而产生7-羟基-1-苯并噻吩-5-羧酸(XXXI)。这通过将(XXXIII)与乙酸酐和乙酸钠在甲苯中在70-75℃下加热7h(其他脱水剂:例如酸酐(三氟乙酸酐)、氯甲酸甲酯;乙酸钠以外的其他碱(乙酸钾;所有工艺步骤的T&t均可变化)完成。通过在25-30℃下加入水使混合物水解。分离有机相,用水洗涤,再次用水洗涤,通过减压蒸馏除去部分溶剂。(XXXII)在甲苯中的剩余溶液用MeOH和水稀释,在低于45℃的温度下缓慢加入氢氧化钠水溶液(其他碱,主要是无机物),最后加热至50-55℃持续5h。分离水相并进一步用水稀释,通过加入强质子酸(诸如HCl、HNO3、磺酸、CH3COOH和H2SO4,优选为H2SO4),在10-15℃下直至pH值达到2-3以析出产物。将悬浮液加热至40-45℃并在2h内冷却至25-30℃以改善产物的过滤行为,并通过过滤分离。
·该工艺具有不使用大量过量的乙酸酐作为溶剂,而是通过在甲苯中稀释来限制过量使用,从而提高工业规模的工艺安全性的优点。通过在稀释条件下水解乙酸酐过程中能量的受控释放来实现安全后处理。
·该工艺具有通过在向(XXXII)的闭环步骤过程中仅使用适中的反应温度来减少副产物的量的优点。
·通过在分离前的温度处理过程中改善固体状态特性,该工艺在工业规模的(XXXI)分离过程中具有可接受的过滤时间的优点。
·该工艺具有能以极高收率获得具有极高纯度的结晶良好的中间体(XXXI)的固体产物,避免中间体(XXXII)或合成后期的额外纯化步骤的优点。
步骤3:
如方案所示,(XXXI)得到7-甲氧基-1-苯并噻吩-5-羧酸甲酯(XXX)的反应通过将酯和苯酚部分甲基化进行。这通过将(XXXI)溶解于丙酮和甲苯(其他溶剂)的混合物中进行。加入碳酸钾(其他无机碱、胺类)后,将悬浮液加热至50-60℃,并缓慢加入硫酸二甲酯(其他甲基化剂:甲基碘)。完全转化后,在85℃下将溶剂部分蒸馏并加入水。分离各相并用甲苯另外萃取水相。用水洗涤合并的有机相并在60℃下减压除去溶剂。粗产物被送至下一步。
步骤4:
(XXX)得到7-甲氧基-5-甲基-1-苯并噻吩(XXVII)的反应通过将酯部分还原为甲基得到(XXVII)进行。这优先通过将(XXX)的酯部分还原为醇(XXIX),随后将醇部分氯化为(XXVIII),随后还原为(XXVII)的逐步还原来实现,如步骤4中所示。这通过将粗产物(XXX)溶解于惰性溶剂(诸如醚类,例如二噁烷、Me-THF、CPME和MTBE,芳香族和脂肪族烃类,例如苯、甲苯、二甲苯、环己烷)中进行;优选使用THF,并在25-30℃下加入双(2-甲氧基-乙氧基)-二氢化铝钠在甲苯中的溶液。其他合适的还原剂包括氢(及合适的催化剂)、LAH、硼烷和硅烷。
混合物通过加入氢氧化钠水溶液(其他碱水溶液)水解并且产物用甲苯(其他非水混溶的溶剂或通过加入反溶剂析出/结晶)萃取,并通过在60℃下减压除去溶剂进行分离。
将粗品(XXIX)溶解于甲苯中,并在50-55℃下缓慢加入HCl水溶液。可以使用其他氯化试剂,诸如SOCl2。完全转化后,混合物用碳酸氢钠水溶液水解。通过用盐水、Na2SO4处理和通过在60℃减压除去溶剂共沸干燥来干燥有机相。
另外,其他离去基团可用作结构(XXVIII)中的替代氯,诸如Br、I、F、RSO3。
将粗产物(XXVIII)溶解于惰性溶剂中,诸如醚类,例如二噁烷、Me-THF、CPME和MTBE,芳香族和脂肪族烃类,例如苯、甲苯、二甲苯、环己烷;优选使用THF,并在25-30℃下加入还原剂诸如双(2-甲氧基-乙氧基)-二氢化铝钠在甲苯中的溶液。其他合适的还原剂包括氢(及合适的催化剂)、LAH、硼烷和硅烷。
混合物通过加入氢氧化钠水溶液(其他碱水溶液)水解并且产物用甲苯(其他非水混溶的溶剂或通过加入反溶剂析出/结晶)萃取,并通过在60℃下减压除去溶剂进行分离。(XXVIII)通过在125-160℃下真空蒸馏纯化。
·根据方案1,该工艺具有以高收率和高纯度获得7-甲氧基-5-甲基-1-苯并噻吩(XXVII)而无杂质的优点,这对于临床应用的最终药物成分(I)的质量至关重要,并且不能在以下得到(I)的工艺步骤中的一个步骤中轻易清除。
·该工艺具有可以使用标准的多用途设备和工业规模的安全试剂获得7-甲氧基-5-甲基-1-苯并噻吩(XXVII)的优点。避免使用剧烈的反应条件,如高温>160℃,和不利的试剂,如未完全溶解于反应混合物中的糖浆状多磷酸。因此避免了工业规模上成本非常高的安全和工程考虑。
步骤5:
根据本发明的第一方面,(XXVII)得到式(VIII)的苯并噻吩-2-基硼酸酯的反应通过硼酸化进行。将(XXVII)溶解于惰性溶剂诸如THF中并通过在-73至-80℃下加入金属有机碱诸如正丁基锂在THF/己烷中的溶液进行金属化。将反应物料搅拌30分钟后,在-73至-80℃下缓慢加入硼酸三异丙酯。在30分钟的反应时间后,在<10℃下用氢氧化钾水溶液水解混合物,并在20-30℃下进行相分离。水相用甲苯洗涤并且产物通过在0-5℃下加入硫酸水溶液(其他酸)析出。(XXVIII)通过过滤分离并用水洗涤。产物在40-45℃下用溶剂诸如环己烷再浆化,分离并在40-45℃下减压干燥。
·根据方案1,该工艺具有以高收率和高纯度获得(7-甲氧基-5-甲基-1-苯并噻吩-2-基)硼酸(VIII)而无杂质的优点,这对于临床应用的最终药物成分(I)的质量至关重要,并且不能在以下得到(I)的工艺步骤中的一个步骤中轻易清除。
除了欧洲专利申请号15180755.9中描述的由(XXVII)制备(VIII)的方法之外,由(XXVII)制备(VIII)的第二种方法是将(XXVII)溶解于惰性溶剂(诸如THF)和通过在-55至-80℃下加入金属有机碱(诸如正丁基锂在THF/己烷中的溶液)进行金属化。将反应物料搅拌30分钟后,在-55至-80℃下加入硼酸三异丙酯。在30分钟的反应时间后,将混合物升温至-10℃并在<30℃下用氢氧化钾水溶液水解,并在20-30℃下进行相分离。水相用甲苯洗涤,混合物通过在20℃下加入硫酸水溶液酸化。加入2-丙醇并通过在升高的温度和减压下蒸馏有机溶剂以结晶产物。(XXVIII)通过过滤分离并用水洗涤。产物在40-45℃下用溶剂(诸如环己烷)再浆化,分离并在40-45℃下减压干燥。
定义
在本发明的上下文中,溶剂化物被指定为通过与溶剂分子的化学计量配位形成固体或液体状态复合物的本发明化合物的那些形式。
水合物是特殊形式的溶剂化物,其中与水发生配位。在本发明的上下文中,水合物是优选的溶剂化物。
由于不对称中心的性质或受限的旋转,本发明的化合物可以以异构体(对映异构体、非对映异构体)的形式存在。可以存在其中不对称中心处于(R)-、(S)-或(R,S)-构型的任何异构体。
本发明化合物的所有异构体,无论是分离的、纯的、部分纯的还是外消旋混合物,均涵盖在本发明的范围内。所述异构体的纯化和所述异构体混合物的分离可以通过本领域已知的标准技术完成。例如,非对映体混合物可以通过色谱法或结晶分离成单独的异构体,并且外消旋体可以通过手性相的色谱法或拆分分离成各自的对映体。
此外,根据本发明包括上述化合物的所有可能的互变异构形式。
本发明还涵盖根据本发明的化合物的所有合适的同位素变体。根据本发明的化合物的同位素变体被理解为是指其中根据本发明的化合物中的至少一个原子已被交换为具有相同原子序数但具有与通常或主要在自然界中发生的原子质量不同的原子质量的另一个原子的化合物。可掺入根据本发明的化合物中的同位素的实例是氢、碳、氮、氧、氟、氯、溴和碘的同位素,诸如2H(氘)、3H(氚)、13C、14C、15N、17O、18O、18F、36Cl、82Br、123I、124I、129I和131I。根据本发明的化合物的特定同位素变体,尤其是其中已掺入一种或多种放射性同位素的那些,可能有益于例如检查作用机制或活性化合物在体内的分布。由于相对容易制备和检测,特别是用3H或14C同位素标记的化合物适用于这一目的。此外,由于化合物具有更高的代谢稳定性,例如体内半衰期的延长或所需活性剂量的减少,因此掺入同位素(例如氘)可产生特定的治疗益处。因此,根据本发明的化合物的这种修饰在一些情况下也可以构成本发明的优选实施方案。根据本发明的化合物的同位素变体可以通过本领域技术人员已知的工艺制备,例如通过以下描述的方法和工作实例中描述的方法,通过使用特定试剂和/或其中起始化合物的相应同位素修饰。
除非另有说明,必要时用于偶联反应的合适碱特别是碱金属碳酸盐,诸如碳酸钠、碳酸钾或碳酸铯,碱金属磷酸盐,诸如磷酸钠或磷酸钾,或碱金属氟化物,诸如氟化钾或氟化铯。通常,这些碱以水溶液的形式使用。反应在反应条件下呈惰性的有机溶剂中进行。优选地,使用与水混溶的有机溶剂,诸如1,2-二甲氧基乙烷、四氢呋喃、1,4二噁烷、乙腈、N,N-二甲基甲酰胺(DMF)或二甲亚砜(DMSO),但也可以使用其他惰性溶剂,诸如二氯甲烷或甲苯。
除非另有说明,适用于工艺步骤的缩合剂,如有必要,包括,例如,碳二亚胺诸如N,N'-二乙基-、N,N'-二丙基-、N,N'-二异丙基-、N,N'-二环己基碳二亚胺(DCC)或N-(3-二甲氨基丙基)-N'-乙基-碳二亚胺(EDC),光气衍生物诸如N,N'-羰基二咪唑(CDI)或氯甲酸异丁酯,α-氯烯胺诸如1-氯-2-甲基-1-二甲基氨基-1-丙烯,磷化合物诸如丙烷膦酸酐、氰基膦酸二乙酯、双(2-氧代-3-噁唑烷基)磷酰氯、苯并三唑-1-基氧基-三(二甲氨基)鏻六氟磷酸盐(BOP)或苯并三唑-1-基氧基-三(吡咯烷子基)鏻六氟磷酸盐(PyBOP),以及铀化合物诸如O-(苯并三唑-1-基)-N,N,N',N'-四甲基脲鎓四氟硼酸盐(TBTU)、O-(苯并三唑-1-基)-N,N,N',N'-四甲基脲鎓六氟磷酸盐(HBTU)、2-(2-氧代-1-(2H)-吡啶基)-1,1,3,3-四甲基脲鎓四氟硼酸盐(TPTU)、O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲鎓六氟磷酸盐(HATU)或O-(1H-6-氯-苯并-三唑-1-基)-1,1,3,3-四甲基-脲鎓四氟硼酸盐(TCTU),如果合适,与另外的助剂组合使用,诸如1-羟基苯并三唑(HOBt)或N-羟基琥珀酰亚胺(HOSu),和/或碱诸如碱金属碳酸盐,例如碳酸钠或碳酸钾,或有机胺碱,诸如三乙胺、N-甲基哌啶、N-甲基吗啉(NMM)、N,N-二异丙基乙胺(DIPEA)、吡啶或4-N,N-二甲氨基吡啶(DMAP)。优选使用O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基甲脲鎓六氟磷酸盐(HATU)或O-(苯并三唑-1-基)-N,N,N',N'-四甲基脲鎓四氟硼酸盐(TBTU)与N,N-二异丙基乙胺(DIPEA)和任选的1-羟基苯并三唑(HOBt)组合使用。
除非另有说明,用于工艺(必要时)的可接受的惰性溶剂是,例如,醚诸如乙醚、叔丁基甲基醚(MTBE)、四氢呋喃(THF)、1,4-二噁烷或1,2-二甲氧基乙烷,烃诸如苯、甲苯、二甲苯、己烷或环己烷,卤代烃诸如二氯甲烷、三氯甲烷、四氯化碳、1,2-二氯乙烷、三氯乙烯或氯苯,或其他溶剂诸如丙酮、乙腈、乙酸乙酯(EtOAC)、吡啶、二甲亚砜(DMSO)、N,N-二甲基甲酰胺(DMF)、N,N'-二甲基丙烯脲(DMPU)或N-甲基吡咯烷酮(NMP)。还可以使用这些溶剂的混合物。优选使用二氯甲烷、四氢呋喃、N,N-二甲基甲酰胺或其混合物。
治疗方法:
根据本发明的式(I)的化合物的结晶形式,优选结晶形式(III)可以具有有用的药理学特性并且可以用于预防和治疗人和动物的疾病。根据本发明的式(I)的化合物的形式可以开辟进一步的治疗选择并且因此可以丰富药学。
本发明式(I)的化合物的结晶形式可用于抑制、阻断、降低、减少等细胞增殖和/或细胞分裂,和/或产生凋亡。该方法包括向有需要的哺乳动物(包括人)给予一定量的本发明的通式(I)的化合物,所述量有效治疗病症。过度增殖性病症包括,但不限于,例如:银屑病,瘢痕疙瘩和其他影响皮肤的增生,良性前列腺增生(BPH),实体瘤,诸如乳腺癌、呼吸道癌、脑癌、生殖器官癌、消化道癌、泌尿道癌、眼癌、肝癌、皮肤癌、头颈癌、甲状腺癌、甲状旁腺癌及其远端转移。这些病症还包括淋巴瘤、肉瘤和白血病。
乳腺癌的实例包括,但不限于浸润性导管癌、浸润性小叶癌、原位导管癌和原位小叶癌。
呼吸道癌的实例包括,但不限于小细胞和非小细胞肺癌,以及支气管腺瘤和胸膜肺母细胞瘤。
脑癌的实例包括,但不限于脑干和下丘脑(hypophtalmic)神经胶质瘤、小脑和大脑星形细胞瘤、成神经管细胞瘤、室管膜瘤,以及神经外胚层和松果体肿瘤。
男性生殖器官的肿瘤包括,但不限于前列腺癌和睾丸癌。
女性生殖器官的肿瘤包括,但不限于子宫内膜癌、宫颈癌、卵巢癌、阴道癌和外阴癌,以及子宫肉瘤。
消化道肿瘤包括,但不限于肛门癌、结肠癌、结肠直肠癌、食道癌、胆囊癌、胃癌、胰腺癌、直肠癌、小肠癌和唾液腺癌。
泌尿道肿瘤包括,但不限于膀胱癌、阴茎癌、肾癌、肾盂癌、输尿管癌、尿道癌和人乳头状肾癌。
眼癌包括,但不限于眼内黑素瘤和成视网膜细胞瘤。
肝癌的实例包括,但不限于肝细胞癌(肝细胞癌伴有或未伴有纤维板层变体)、胆管癌(肝内胆管癌)和混合性肝细胞胆管癌。
皮肤癌包括,但不限于鳞状细胞癌、卡波西肉瘤、恶性黑素瘤、默克尔细胞皮肤癌和非黑素瘤皮肤癌。
头颈癌包括,但不限于喉癌、下咽癌、鼻咽癌、口咽癌、唇癌和口腔癌以及鳞状细胞癌。
淋巴瘤包括,但不限于AIDS-相关的淋巴瘤、非霍奇金淋巴瘤、皮肤T细胞淋巴瘤、伯基特淋巴瘤、霍奇金病和中枢神经系统的淋巴瘤。
肉瘤包括,但不限于软组织肉瘤、骨肉瘤、恶性纤维组织细胞瘤、淋巴肉瘤和横纹肌肉瘤。
白血病包括,但不限于急性髓样白血病、急性淋巴母细胞性白血病、慢性淋巴细胞白血病、慢性髓性白血病和毛细胞性白血病。
在一些实施方案中,本发明进一步涉及使用有效量的根据本发明的式(I)的化合物的形式中的至少一种治疗和/或预防疾病,特别是前述疾病的方法。
在一些实施方案中,本发明进一步涉及使用有效量的根据本发明的式(I)的化合物的形式中的至少一种治疗和/或预防膀胱癌的方法。
在一些实施方案中,本发明进一步涉及使用有效量的根据本发明的式(I)的化合物的形式中的至少一种治疗和/或预防头颈癌的方法。
在一些实施方案中,本发明进一步涉及使用有效量的根据本发明的式(I)的化合物的形式中的至少一种治疗和/或预防肺癌的方法。
根据本发明的式(I)的化合物的形式可以单独使用或如有需要与其他活性物质联合使用。本发明进一步涉及含有根据本发明的式(I)的化合物的形式中的至少一种和一种或多种另外的活性物质的医药产品,特别是用于治疗和/或预防前述疾病。作为合适的其他活性物质,可以提及以下:
131I-chTNT、阿巴瑞克(abarelix)、玻玛西林(abemaciclib)、阿比特龙、阿卡替尼(acalabrutinib)、阿柔比星、阿达木单抗、曲妥珠单抗-美坦新偶联物(ado-trastuzumabemtansine)、阿法替尼、阿柏西普、阿地白介素、阿来替尼、阿仑单抗(alemtuzumab)、阿仑膦酸、阿利维A酸(alitretinoin)、六甲蜜胺、氨磷汀、氨鲁米特、氨基乙酰丙酸己酯、氨柔比星、安吖啶、阿那曲唑、安西司亭、茴三硫(anethole ditholethione)、anetumabravtansine、血管紧张素II、抗凝血酶III、阿帕鲁胺、阿瑞吡坦、阿西莫单抗、阿加来必(arglabin)、三氧化二砷、门冬酰胺酶、阿特珠单抗、阿维鲁单抗、axicabtageneciloleucel、阿西替尼、阿扎胞苷、巴利昔单抗(basiliximab)、贝洛替康(belotecan)、苯达莫司汀、贝索单抗、贝利司他、贝伐单抗(bevacizumab)、贝沙罗汀(bexarotene)、比卡鲁胺、比生群、博来霉素、博纳吐单抗、硼替佐米、博舒替尼、布舍瑞林、博舒替尼、本妥昔单抗(brentuximab vedotin)、布加替尼、白消安、卡巴他赛(cabazitaxel)、卡博替尼、降钙素(calcitonine)、甲酰四氢叶酸钙(calcium folinate)、左亚叶酸钙、卡培他滨、卡罗单抗、卡马西平、卡铂、卡波醌、卡非佐米、卡莫氟、卡莫司汀、卡妥索单抗(catumaxomab)、塞来昔布、西莫白介素、色瑞替尼、西妥昔单抗、苯丁酸氮芥、氯地孕酮、氮芥、西多福韦、西那卡塞、顺铂、克拉屈滨、氯膦酸、氯法拉滨(clofarabine)、考比替尼、copanlisib、克立他酶(crisantaspase)、克里唑蒂尼、环磷酰胺、环丙孕酮、阿糖胞苷、达卡巴嗪、放线菌素D、达雷木单抗(daratumumab)、阿法达贝泊汀(darbepoetin alfa)、达拉非尼、达沙替尼、柔红霉素、地西他滨、地加瑞克、地尼白介素-毒素连接物(denileukin diftitox)、狄诺塞麦(denosumab)、地普奥肽、地洛瑞林、二去水卫矛醇(dianhydrogalactitol)、右雷佐生、二溴螺氯铵、二去水卫矛醇、双氯芬酸、dinutuximab、多西他赛、多拉司琼、去氧氟尿苷、多柔比星、多柔比星+雌酮、屈大麻酚、durvalumab、依库丽珠单抗(eculizumab)、依决洛单抗、依利醋铵、埃罗妥珠单抗(elotuzumab)、伊屈泼帕(eltrombopag)、enasidenib、内皮抑素、依诺他滨、恩扎鲁胺、表柔比星、环硫雄醇、依泊汀α、依泊汀β、依泊汀ζ、依铂、艾日布林(eribulin)、埃洛替尼、埃索美拉唑、雌二醇、雌莫司汀、炔雌醇、依托泊苷、依维莫司、依西美坦、法屈唑、芬太尼、非格司亭、氟羟甲睾酮、氟尿苷、氟达拉滨、氟尿嘧啶、氟他胺、亚叶酸、福美坦、福沙吡坦、福莫司汀、氟维司群、钆布醇、加多利道、钆特酸葡胺、钆弗塞胺、钆塞酸、硝酸镓、加尼瑞克、吉非替尼、吉西他滨、吉妥单抗(gemtuzumab)、羧肽酶、氧化型谷胱甘肽(glutoxim)、GM-CSF、戈舍瑞林、格拉司琼、粒细胞集落刺激因子、二盐酸组胺、组氨瑞林(histrelin)、羟基脲、I-125粒子、兰索拉唑、依班膦酸、替伊莫单抗(ibritumomabtiuxetan)、依鲁替尼、伊达比星、异环磷酰胺、伊马替尼、咪喹莫特、英丙舒凡(improsulfan)、吲地司琼、英卡膦酸、巨大戟醇甲基丁烯酸酯、inotuzumab ozogamicin、干扰素α、干扰素β、干扰素γ、碘比醇、碘苄胍(123I)、碘美普尔、易普利姆玛(ipilimumab)、伊立替康、伊曲康唑、伊沙匹隆(ixabepilone)、伊沙佐米、兰瑞肽、兰索拉唑、拉帕替尼(lapatinib)、Iasocholine、来那度胺(lenalidomide)、乐伐替尼、来格司亭、香菇多糖、来曲唑、亮丙瑞林、左旋咪唑、左炔诺孕酮、左甲状腺素钠、麦角乙脲、乐铂、洛莫司汀、氯尼达明、lutetium Lu 177dotatate、马索罗酚、甲羟孕酮、甲地孕酮、美拉胂醇、美法仑、美雄烷、巯基嘌呤、美司钠、美沙酮、氨甲喋呤、甲氧沙林(methoxsalen)、甲基氨基酮戊酸盐、甲基泼尼松龙、甲基睾酮、甲酪氨酸、米哚妥林、米伐木肽(mifamurtide)、米替福辛、米铂(miriplatin)、二溴甘露醇、丙脒腙、二溴卫矛醇、丝裂霉素、米托坦、米托蒽醌、mogamulizumab、莫拉司亭、莫哌达醇、盐酸吗啡、硫酸吗啡、mvasi、大麻隆、nabiximols、那法瑞林、纳洛酮+戊唑辛、纳曲酮、那托司亭、耐昔妥珠单抗(necitumumab)、奈达铂、奈拉滨(nelarabine)、neratinib、奈立膦酸、奈妥匹坦(netupitant)/帕洛诺司琼、纳武单抗、喷曲肽、尼洛替尼(nilotinib)、尼鲁米特、尼莫唑、尼妥珠单抗(nimotuzumab)、尼莫司丁、尼达尼布、尼拉帕尼、二胺硝吖啶(nitraerine)、纳武单抗、奥滨尤妥珠单抗(obinutuzumab)、奥曲肽、奥法木单抗(ofatumumab)、奥拉帕尼、olaratumab、高三尖杉酯碱(omacetaxinemepesuccinate)、奥美拉唑、昂丹司琼、奥普瑞白介素(oprelvekin)、奥古蛋白、orilotimod、奥西替尼、奥沙利铂、羟考酮、羟甲烯龙、ozogamicine、p53基因治疗、紫杉醇、帕博西尼、帕利夫明、钯-103粒子、帕洛诺司琼、帕米膦酸、帕尼单抗(panitumumab)、帕比司他、泮托拉唑、帕唑帕尼(pazopanib)、培门冬酶、PEG-倍他依泊汀(甲氧基PEG-倍他依泊汀)、派姆单抗(pembrolizumab)、聚乙二醇非格司亭(pegfilgrastim)、聚乙二醇干扰素α-2b、派姆单抗、培美曲塞、喷他佐辛、喷司他丁、培洛霉素、全氟丁烷、培磷酰胺、帕妥株单抗、溶链菌制剂(picibanil)、毛果芸香碱、吡柔比星、匹克生琼、普乐沙福(plerixafor)、普卡霉素、聚氨葡糖(poliglusam)、磷酸聚雌二醇、聚乙烯吡咯烷酮+透明质酸钠、多糖-K、泊马度胺、帕纳替尼、卟吩姆钠、普拉曲沙(pralatrexate)、泼尼莫司汀、泼尼松、甲基苄肼、丙考达唑、普萘洛尔、喹高利特(quinagolide)、雷贝拉唑、racotumomab、氯化镭223、拉多替尼、雷洛昔酚、雷替曲塞(raltitrexed)、雷莫司琼、雷莫芦单抗、雷莫司汀(ranimustine)、拉布立酶、雷佐生、refametinib、瑞戈非尼(regorafenib)、瑞博西尼(ribociclib)、利塞膦酸、铼-186依替膦酸盐、利妥昔单抗(rituximab)、罗拉吡坦(rolapitant)、罗米地辛(romidepsin)、罗米司亭(romiplostim)、罗莫肽、瑞卡帕布(rucaparib)、来昔决南钐(153Sm)、沙莫司亭、sarilumab、沙妥莫单抗、分泌素、司妥昔单抗(siltuximab)、sipuleucel-T、西佐喃、索布佐生、甘氨双唑钠(sodium glycididazole)、索尼德吉、索拉非尼(sorafenib)、司坦唑醇、链脲霉素、舒尼替尼、他拉泊芬(talaporfin)、talimogenelaherparepvec、他米巴罗汀(tamibarotene)、他莫昔芬、他喷他多、他索纳明(tasonermin)、替西白介素(teceleukin)、锝(99mTc)巯诺莫单抗、99mTc-HYNIC-[Tyr3]-奥曲肽、替加氟、替加氟+吉美嘧啶(gimeracil)+奥替拉西(oteracil)、替莫卟吩、替莫唑胺、西罗莫司(temsirolimus)、替尼泊苷、睾酮、替曲膦(tetrofosmin)、沙利度胺、噻替派、胸腺法新(thymalfasin)、促甲状腺素α、硫鸟嘌呤(tioguanine)、tisagenlecleucel、托珠单抗(tocilizumab)、托泊替康、托瑞米芬、托西莫单抗(tositumomab)、曲贝替定(trabectedin)、曲美替尼、曲马多、曲妥珠单抗、曲妥珠单抗美坦辛偶联物、曲奥舒凡(treosulfan)、维甲酸、曲氟尿苷+tipiracil、曲洛司坦、曲普瑞林、曲美替尼、曲磷胺、促血小板生成素、色氨酸、乌苯美司、瓦他拉尼、戊柔比星(valrubicin)、凡德他尼(vandetanib)、伐普肽、维罗非尼(vemurafenib)、长春碱、长春新碱、长春地辛、长春氟宁、长春瑞宾、维莫德吉、伏立诺他(vorinostat)、伏氯唑、钇-90玻璃微球、净司他丁、净司他丁斯酯、唑来膦酸和佐柔比星。
药物组合物:
根据本发明的式(I)的化合物的晶体形式可以具有全身和/或局部活性。为了该目的,它可以以合适的方式给药,诸如,例如通过口服、肠胃外、肺、鼻、舌下、舌、含服、直肠、阴道、皮肤、透皮、结膜、耳途径或作为植入物或支架。
对于这些给药途径,根据本发明的式(I)的化合物的结晶形式可以以合适的给药形式给予。
对于口服给药,可以将根据本发明的式(I)的化合物的结晶形式配制成本领域已知的剂型,其快速和/或以改良的方式递送本发明的化合物,诸如,例如,片剂(未包衣或包衣片剂,例如具有延迟溶解或不溶解的肠溶或控释包衣)、口腔崩解片、薄膜/薄片、薄膜/冻干剂、胶囊(例如硬或软明胶胶囊)、糖衣片剂、颗粒剂、丸剂、粉剂、乳剂、悬浮剂、气溶胶或溶液剂。可以将根据本发明的化合物以结晶和/或无定形和/或溶解形式掺入所述剂型中。
肠胃外给药可以通过避免吸收步骤(例如静脉内、动脉内、心内、脊柱内或腰椎内)或包括吸收(例如肌内、皮下、皮内、经皮或腹膜内)来实现。适合肠胃外给药的给药形式尤其是溶液剂、悬浮液、乳剂、冻干剂或无菌粉剂形式的注射和输注制剂。
适用于其他给药途径的实例是用于吸入的药物形式[尤其是粉末吸入器、雾化器]、滴鼻剂、鼻用溶液、鼻喷雾剂;用于舌、舌下或含服给药的片剂/薄膜/薄片/胶囊;栓剂;滴眼液、眼药膏、眼部浴液、眼部插入物、滴耳剂、耳喷雾剂、耳用粉剂、洗耳剂、耳塞;阴道胶囊、水性悬浮液(洗剂、振荡混合物)、亲脂性悬浮液、乳液、软膏、乳膏、透皮治疗系统(诸如,例如,贴剂)、乳剂、糊剂、泡沫、扑粉、植入物或支架。
式(I)的化合物的结晶形式可以掺入所述的给药形式中。这可以通过与药学上合适的赋形剂混合以本身已知的方式实现。除了其他之外,药学上合适的赋形剂包括,
·软膏基质(例如凡士林、石蜡、甘油三酯、蜡、羊毛蜡、羊毛蜡醇、羊毛脂、亲水性软膏、聚乙二醇),
·栓剂基质(例如聚乙二醇、可可脂、硬脂),
·溶剂(例如水、乙醇、异丙醇、甘油、丙二醇、中链甘油三酯脂肪油、液态聚乙二醇、石蜡),
·表面活性剂、乳化剂、分散剂或润湿剂(例如十二烷基硫酸钠)、卵磷脂、磷脂、脂肪醇(诸如,例如,),去水山梨糖醇脂肪酸酯(诸如,例如,)、聚氧乙烯去水山梨糖醇脂肪酸酯(诸如,例如,)、聚氧乙烯脂肪酸甘油酯(诸如,例如,)、聚氧乙烯脂肪酸酯、聚氧乙烯脂肪醇醚、甘油脂肪酸酯、泊洛沙姆(诸如,例如,),
·缓冲剂、酸和碱(例如磷酸盐、碳酸盐、柠檬酸、乙酸、盐酸、氢氧化钠溶液、碳酸铵、氨丁三醇、三乙醇胺),
·等张剂(例如葡萄糖、氯化钠),
·吸附剂(例如高分散二氧化硅),
·包衣物质(例如糖、虫胶)和用于以快速或以改性方式溶解的薄膜或扩散膜的成膜剂(例如聚乙烯吡咯烷酮(诸如,例如,)、聚乙烯醇、羟丙基甲基纤维素、羟丙基纤维素、乙基纤维素、羟丙基甲基纤维素邻苯二甲酸酯、醋酸纤维素、醋酸纤维素邻苯二甲酸酯、聚丙烯酸酯、聚甲基丙烯酸酯诸如,例如,)),
·胶囊物质(例如明胶、羟丙基甲基纤维素),
·增塑剂(例如聚乙二醇、丙二醇、甘油、三醋酸甘油酯、柠檬酸三乙酯、邻苯二甲酸二丁酯),
·渗透增强剂,
·稳定剂(例如抗氧化剂诸如,例如,抗坏血酸、抗坏血酸棕榈酸酯、抗坏血酸钠、丁基羟基苯甲醚、丁基羟基甲苯、没食子酸丙酯),
·防腐剂(例如对羟基苯甲酸酯、山梨酸、硫柳汞、苯扎氯铵、醋酸氯己定、苯甲酸钠),
·着色剂(例如无机颜料诸如,例如,氧化铁、二氧化钛),
·调味剂、甜味剂、味道和/或气味遮蔽剂。
本发明还涉及药物组合物,其至少包含根据本发明的式(I)的化合物的结晶形式,通常连同一种或多种药学上合适的赋形剂,和涉及它们的根据本发明的用途。
本发明的药物组合物的剂量:
基于已知用来评价用于治疗病症的化合物的实验室技术,通过药理学测定来确定对哺乳动物中以上识别的病状的治疗,并且通过将这些结果与用于治疗这些病状的已知药物的结果进行比较,可以容易地确定用于治疗每一种期望适应症的本发明化合物的有效剂量。在这些病状之一的治疗中所给药的活性成分的量可以根据如下考量而发生很宽泛的变化:所使用的具体化合物和剂量单位、给药方式、治疗时间、受治疗患者的年龄和性别以及被治疗病状的性质和程度。
当然,对于每名患者来说,具体的初始和连续给药方案将根据主治医生所确定的病状的性质和严重程度、使用的具体化合物的活性、患者的年龄和一般状况、给药时间、给药途径、药物的排泄率、组合用药等而变化。治疗的目标模式和本发明化合物或其药学上可接受的盐或酯或组合物的剂量数,可以由本领域技术人员使用常规治疗试验来确定。
除非另有说明,以下试验和实施例中的重量数据均为重量百分比;份数是重量份数。液体/液体溶液的溶剂比、稀释比和浓度数据是基于体积的每种情况。
实施例
缩写和首字母缩略词:
Ac 乙酰基
Ac2O 乙酸酐
AcOH 乙酸
aq. 含水(溶液)
Boc 叔丁氧羰基
br. 宽(1H-NMR信号)
Bu 丁基
cat. 催化
conc. 浓的
d 双峰(1H-NMR信号)
DBDMH 1,3-二溴-5,5-二甲基乙内酰脲
DCI 直接化学电离(MS)
DCM 二氯甲烷
戴斯-马丁高碘烷 1,1,1-三乙酰氧基-1,1-二氢-1,2-苯碘酰-3(1H)-酮
DIPEA N,N-二异丙基乙胺
DMF N,N-二甲基甲酰胺
DMSO 二甲基亚砜
EI 电子碰撞电离(MS)
eq. 当量
ESI 电喷雾电离(MS)
Et 乙基
EtOAc 乙酸乙酯
GC-MS 气相色谱-耦合质谱
h 小时
Hal 卤素
1H-NMR 质子核磁共振光谱
HPLC 高效液相色谱
iPr 异丙基
LC-MS 液相色谱-耦合质谱
Me 甲基
MeOH 甲醇
min 分钟
MS 质谱
m/z 质荷比(MS)
NBS N-溴代琥珀酰亚胺
n-Bu 正丁基
NCS N-氯琥珀酰亚胺
of th. 理论(化学收率)
Pd/C 钯/炭
PdCl2(dppf) [1,1'-双(二苯基-膦基)-二茂铁]二氯化钯(II)
Pd(dba)2 双(二亚苄基丙酮)钯
Ph 苯基
PPA 多聚磷酸
q 四重峰(1H-NMR信号)
quant. 定量(收率)
rac 外消旋的
Rf TLC保留因子
RP 反相(HPLC)
rt 室温
Rt 保留时间(HPLC)
s 单峰(1H-NMR信号)
sat. 饱和(溶液)
t 三峰(1H-NMR信号)
TBAF 四正丁基氟化铵
TBDMS 叔丁基二甲基甲硅烷基
TBTU N-[(1H-苯并三唑-1-基氧基)(二甲氨基)亚甲基]-N-甲基甲铵四氟硼酸盐
tBu 叔丁基
tert 叔
TFA 三氟乙酸
THF 四氢呋喃
TLC 薄层色谱法
方法:
DSC/TG
使用来自Perkin-Elmer的差示扫描量热计(型号DSC7、Pyris-1或Diamond)记录DSC热谱图。使用非气密铝盘以20Kmin-1的加热速率进行测量,最终达到2Kmin-1。流动气体为氮气。没有样品制备。
使用来自Perkin-Elmer的热天平(型号TGA7和Pyris 1)记录TGA热谱图。使用开放式铂盘以10Kmin-1的加热速率进行测量。流动气体为氮气。没有样品制备。
XRPD
使用XRD衍射仪X`Pert PRO(PANalytical)和STOE STADI-P(放射Cu Kα1,波长)在室温下记录X射线衍射图。没有样品制备。所有X射线反射均引用为°2θ(theta)值(峰值最大值),分辨率为±0.2°。
拉曼
使用来自Bruker的FT-拉曼分光光度计(型号RFS 100和MultiRam,波数范围:3500-100cm-1)在室温下记录拉曼光谱。分辨率为2cm-1。扫描次数:64。在玻璃小瓶或铝盘中进行测量。没有样品制备。
IR
在室温下使用配有HATR装置的IR光谱仪Bruker Tensor 37在4000至550cm-1的波数范围内记录IR光谱。分辨率为2cm-1。扫描次数:64。没有样品制备。
HPLC(方法1):
系统:高效液相色谱仪,配备梯度泵、UV检测器,并附有数据记录器和积分器软件;柱:Waters XBridge Phenyl(150mm*2.1mm,3.5μm);流速:0.5mL/min;柱温:25℃;检测226nm,运行时间:30min;流动相A:在1L去离子水中的385mg CH3COONH4,pH 8.5,用NH4OH25%(约70μl)调节;流动相B:乙腈;
HPLC(方法2):
系统:高效液相色谱仪,配备梯度泵、UV检测器,并附有数据记录器和积分器软件;柱:Waters XBridge Phenyl(150mm*2.1mm,3.5μm);流速:0.4mL/min;柱温:25℃;检测226nm,运行时间:30min;流动相A:在1L去离子水中的385mg CH3COONH4,pH 8.5,用NH4OH25%(约70μl)调节;流动相B:乙腈;
HPLC(方法3):
系统:高效液相色谱仪,配备梯度泵、UV检测器,并附有数据记录器和积分器软件;柱:Waters XBridge Phenyl(150mm*2.1mm,3.5μm);流速:0.4mL/min;柱温:25℃;检测226nm,运行时间:30min;流动相A:在0.7L去离子水中的770mg CH3COONH4,pH 8.5,用NH4OH25%(约200μl)调节;流动相B:乙腈;
HPLC(方法4):
系统:高效液相色谱系统,配备脱气机,延迟体积(停留体积)约为850μL,UV-VIS检测器和色谱数据系统。固定相:Meteoric Core C18(150mm长,3.0mm ID,2.7μm粒径);流动相A:1.15g NH4H2PO4+155μL H3PO4 85%/1L水(pH 3.0);流动相B:乙腈/甲醇52:48v/v;226nm UV检测;烘箱温度:65℃,进样量:6μl;线性梯度:
HPLC(方法5):
系统:高效液相色谱仪,配备梯度泵、UV检测器,并附有数据记录器和积分器软件;柱:Kromasil C18(250mm*4.6mm,5μm);流速:0.4mL/min;柱温:25℃;检测226nm,运行时间:30min;流动相A:含0.1%H3PO4的去离子水,流动相B:乙腈;
残留溶剂(通过GC方法1确定):
系统:顶空进样器,气相色谱仪,其配有分流器、自动进样器、2个火焰离子化检测器(FID)和数据分析系统。
残留元素:ICP-MS
实施例1:1H-吡咯-1-基氨基甲酸叔丁酯(XI)
首先将1045kg二噁烷、350kg肼羧酸叔丁酯和420kg 2,5-二甲氧基四氢呋喃进料至搅拌的反应容器中,然后加入21.4kg吡啶盐酸盐和343kg吡啶。输送管路用总量为40L的二噁烷冲洗。将反应混合物加热至102±3℃持续7h并蒸馏出1620L溶剂。将批料冷却至25±5℃,并在1h内将1750kg水进料至反应器中,保持温度在22±3℃。将混合物搅拌至少30min,然后加入270kg二正丁基醚并将温度调节至10±3℃。将悬浮液搅拌2h,然后在离心机上分离成两部分。每部分用67kg二正丁基醚和60kg庚烷的混合物洗涤,随后用175L庚烷洗涤。产物在60℃下干燥,得到288kg 1H-吡咯-1-基氨基甲酸叔丁酯(XI),理论收率为60%。
HPLC(方法2):纯度98.66%(Rt=15.47min)1H-吡咯-1-基氨基甲酸叔丁酯
实施例2:(2-氰基-1H-吡咯-1-基)氨基甲酸叔丁酯(XII)
将190kg 1H-吡咯-1-基氨基甲酸叔丁酯(XII)和678kg无水DMF在反应容器中在22±3℃下搅拌直至产物溶解。将批料冷却至0±3℃,并在2.5h的最短时间段内缓慢加入163kg氯磺酰异氰酸酯,将混合物保持在该温度。将混合物再搅拌一小时。在第二个搅拌反应容器中,提供272kg碳酸氢铵在2660kg水中的溶液,并通过保持温度低于25℃将反应混合物转移到该溶液上。第一个反应器和输送管路用20L DMF冲洗,随后用20L水冲洗。
将混合物在22±3℃下持续搅拌2h,在离心机上将粗产物分离成两部分,每部分用760L水洗涤两次。
在搅拌的反应容器中,在37±3℃下将粗产物溶解于452kg甲醇中。在第二个反应器中提供1197kg水,保温度为22±3℃,并在1h内将甲醇溶液加液至水中,保持温度在22±3℃。第一反应器和输送管路用20L水冲洗并将混合物搅拌2h。产物在离心机上分离成两部分,每部分用143L 4:1体积的水和甲醇混合物洗涤。在50℃下干燥后,以80%的理论收率得到173kg(2-氰基-1H-吡咯-1-基)氨基甲酸叔丁酯(XII)。
HPLC(方法3):纯度98.7%(Rt=17.28min)(2-氰基-1H-吡咯-1-基)氨基甲酸叔丁酯
实施例3:(4-溴-2-氰基-1H-吡咯-1-基)氨基甲酸叔丁酯(IX)
在反应容器中搅拌180kg(2-氰基-1H-吡咯-1-基)氨基甲酸叔丁酯(XII)和508kgDMF,并加入666kg甲基叔丁基醚。将批料冷却至2±3℃,并在该温度下在2.5h内将171kg N-溴代琥珀酰亚胺分成15份加入。
通过在40-50min内加入13.1kg亚硫酸钠在740L水中的溶液以水解混合物,保持温度低于25℃。将批料在22±3℃下搅拌30-60min,然后弃去下层水相。有机相用360L水洗涤两次,通过在45±5℃下减压蒸馏除去约540L溶剂。残留混合物用310kg甲基四氢呋喃稀释,通过在45±5℃下减压蒸馏除去约360L溶剂。
加入310kg甲基四氢呋喃并得到733kg(4-溴-2-氰基-1H-吡咯-1-基)氨基甲酸叔丁酯(IX)的溶液,并在没有进一步纯化的情况下在下一化学步骤中转化。
实施例4:[2-氰基-4-(羟甲基)-1H-吡咯-1-基]氨基甲酸叔丁酯(IV)
(4-溴-2-氰基-1H-吡咯-1-基)氨基甲酸叔丁酯(IX)在前一阶段的四氢呋喃甲酯中的溶液,对应于140kg(2-氰基-1H-吡咯-1-基)氨基甲酸叔丁酯(XII),在第一反应容器中搅拌,用950kg甲基四氢呋喃稀释并冷却至-40±3℃。加入88.6kg 35%甲基溴化镁在甲基四氢呋喃中的溶液,保持温度在-40±3℃,随后加入10L甲基四氢呋喃。将混合物在-43±6℃下搅拌30min,然后加入123kg 23%丁基锂在己烷中的溶液,保持温度在-43±6℃,随后加入10L甲基四氢呋喃。在该温度下搅拌混合物45-60min。
多聚甲醛的处理:在环境温度下将81kg多聚甲醛在243L甲基四氢呋喃中搅拌,过滤分离,得到约88kg溶剂湿性多聚甲醛。
将546kg甲基四氢呋喃和溶剂湿性多聚甲醛进料至第二搅拌反应容器中。将温度调节至24±3℃,在2h内将来自第一个反应容器的冷反应混合物通过绝缘管转移到多聚甲醛浆液中,同时将批料温度保持在24±3℃。第一个反应器和输送管路用40L甲基四氢呋喃冲洗,在24±3℃下搅拌该批料1.5h。
在第三个搅拌反应容器中,在12±3℃下制备193kg氯化铵在840L水中的溶液,并将反应混合物加料至该溶液中,随后加入40L甲基四氢呋喃,温度保持在12±3℃。加入155kg柠檬酸在280L水中的溶液,并将混合物在12±3℃下搅拌至少15min。弃去下层水层,有机相用280kg 15%氯化钠水溶液洗涤。将批料通过减压蒸馏浓缩,保持批料温度在45±5℃,直至残留体积约为560L。
以类似的方式将程序的开始再重复一次并且将两批在搅拌的反应容器中合并。
现在总批量对应于通过溴化和金属化以及加入多聚甲醛的顺序转化的280kg(2-氰基-1H-吡咯-1-基)氨基甲酸叔丁酯(XII)的总量。
将两批所得的混合物通过减压蒸馏浓缩至约600L残留体积,保持批料温度在45±5℃,然后加入1400L正庚烷。通过在减压下保持批料温度在45±5℃,通过蒸馏除去约1400L溶剂。停止蒸馏并将批料冷却至25±5℃。然后加入1400L正庚烷并通过减压蒸馏除去约1400L溶剂,保持批料温度在45±5℃。在50±3℃下加入140L乙酸乙酯并将该批料在该温度下保持20-30min,冷却至2±3℃并搅拌1h。在离心机上分离产物并用140L 2体积的正庚烷和1体积的乙酸乙酯的混合物洗涤两次。产物在40℃下干燥,得到184kg(理论收率为57%)。
HPLC(方法2):纯度97.8%(Rt=13.83min)[2-氰基-4-(羟甲基)-1H-吡咯-1-基]氨基甲酸叔丁酯
实施例5:6-(甲氧基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺(V)
将905kg 13.6%HCl在二噁烷中的溶液进料至搅拌的反应容器中,并将温度调节至25+/-5℃。在140min内将200kg[2-氰基-4-(羟甲基)-1H-吡咯-1-基]氨基甲酸叔丁酯(IV)分成5份加入,保持温度低于30℃。在22+/-3℃下搅拌混合物6h。在另一个搅拌的反应容器中,提供948kg MeOH和380kg 30%甲醇钠在甲醇中的溶液的混合物,并将反应混合物加料至该溶液中,保持温度在15-30℃。反应器和输送管路用102kg二噁烷冲洗,反应混合物在22+/-3℃下搅拌1h。加入526kg乙酸甲脒并将批料加热至63+/-3℃并在该温度下保持18.5h。
加入1163kg K3PO4在2597kg水中的溶液并将反应混合物保持在63+/-3℃下2h。
通过在500-100毫巴下于40℃最高内部温度下蒸馏浓缩混合物,直至不再收集到馏出物(约2450L馏出物)。将反应混合物加热至45+/-3℃并加入1390kg乙酸异丙酯。在该温度下将两相混合物搅拌30min,然后分离各层并且在45+/-3℃下再次用1390kg乙酸异丙酯萃取水层。合并有机相并在45+/-3℃下通过过滤器进入搅拌的反应容器中以除去不溶物。
在<300毫巴下于45℃最高内部温度下将溶液浓缩至约600-800L的残留体积。
将混合物在95℃下加热至回流,在此温度下保持至少30min直至获得溶液,然后缓慢冷却至0+/-3℃并在此温度下保持4h。然后通过过滤分离产物。滤饼用176kg乙酸异丙酯洗涤并在50℃烘箱中干燥。得到102.5kg固体形式的(V),收率为68%。
HPLC(方法5):纯度99.7%(6-(甲氧基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺)(Rt=4.6min),在RRT下为0.09%(XXIV)1.55,0.05%(XXV)
使用含量测定:99.0%(相对于外标)
重结晶工艺
将510g(V)(hplc纯度:89.7面积%和85.2%使用含量测定)、1020mL乙酸异丙酯和331mL乙醇进料至搅拌的反应容器中并加热至回流并保持1h。将混合物在3h内冷却至0℃,并在0℃下再搅拌2h。通过过滤分离纯化的(V)并用510mL冷乙酸异丙酯洗涤3次。(V)在30℃下减压干燥,得到331g(V)(66.7%收率)
HPLC(方法1:纯度99.6%(6-(甲氧基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺)
使用含量测定:100.6%(相对于外标)
实施例7:4-{[4-氨基-5-溴-6-(甲氧基甲基)吡咯并[2,1-f][1,2,4]三嗪-7-基]
甲基}哌嗪-2-酮(VII)
方法1:pH 7.2:
将93.8kg 6-(甲氧基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺(V)、78.8kg哌嗪-2-酮和726kg甲醇进料至搅拌的反应容器中,加热至22±3℃并在此温度下搅拌至少30min。使混合物通过过滤器以除去不溶物并将滤液收集在另一个搅拌的反应容器中。第一个容器和过滤器用178kg甲醇冲洗。将温度调节至22±3℃,在此温度下加入188kg乙酸,随后加入20kg甲醇。加入17.4kg多聚甲醛并将批料加热至回流并保持24h。将混合物冷却至25±5℃,并在反应完成后(根据HPLC,化合物(V)≤6.0%)将反应混合物中和至pH 7.2±0.2,保持批料温度在25±5℃,加入146kg 50%氢氧化钠水溶液,随后加入20kg甲醇。
将混合物冷却至-5±3℃,并在不少于2h的时间内将103.2kg N-溴代琥珀酰亚胺分成小份加入反应器,将批料温度保持在-5±3℃。加入结束后,将混合物搅拌至少15min,然后加热至回流并保持1h,在2h内再次冷却至22±3℃并在该温度下再保持1h。通过离心分离粗产物,母液可以通过离心机再循环以完成所有物料的分离。分离的粗产物用148kg甲醇洗涤两次。
将粗反应产物与741kg甲醇一起转移到搅拌的反应容器中,加热至25±5℃并在该温度下搅拌至少10min。将混合物加热至回流并保持3h至3.5h,在3h内再次冷却至10±3℃并在该温度下再保持一小时。通过离心分离纯化产物,滤饼用148kg甲醇洗涤两次。
将纯化产物与741kg甲醇一起转移到搅拌的反应容器中,加热至25±5℃并在该温度下搅拌至少10min。将混合物加热至回流并保持3h至3.5h,在3h内再次冷却至10±3℃并在该温度下再保持一小时。离心分离纯产物,滤饼用74kg甲醇和94kg水的混合物洗涤两次。
产物在托盘干燥器中的托盘上(约2.9kg/m2)通过空气通风在环境温度下以薄层干燥,得到以水合物形式的94.9kg 4-{[4-氨基-5-溴-6-(甲氧基甲基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-2-酮(VII)(45%收率),每mol(VII)含约1mol水。
HPLC(方法3):纯度99.8%(4-{[4-氨基-5-溴-6-(甲氧基甲基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-2-酮)(RT=10.8min),相关副产物:(XXI)在RRT(相对保留时间)1.05:0.09%;(XX)在RRT 1.38:0.07%;(VI)在RRT 0.74:未检出
使用含量测定:96.1%(相对于外标)
TGA:5.0%重量损失
方法2:
将140.0kg 6-(甲氧基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺(V)、117.6kg哌嗪-2-酮和1106kg甲醇进料至搅拌的反应容器中,并将混合物在22±3℃下搅拌1h。使混合物通过过滤器以除去不溶物并将滤液收集在另一个搅拌的反应容器中。第一个容器和过滤器用266kg甲醇冲洗。在22±3℃温度下加入280kg乙酸,然后加入20L甲醇。加入26kg多聚甲醛并将批料加热至回流并保持24h。将混合物冷却至25±5℃,并在反应完成后(根据hplc,化合物(V)≤6.0%),通过加入84kg 50%氢氧化钠水溶液使反应混合物中和至pH 6.0±0.2,将批料温度保持在<25℃,随后加入20L甲醇。将混合物在22±3℃下搅拌至少15min,然后冷却至-5±3℃。
在单独的搅拌容器中,在20℃下将154kg N-溴代琥珀酰亚胺溶解于934kg乙腈中。通过将温度保持在-5±3℃(加料时间>4h),将NBS溶液转移到反应混合物中。NBS溶液的残留物用50L乙腈冲洗。然后将混合物在此温度下搅拌30至40min,然后加热至回流并保持1h,在1h内再次冷却至22±3℃并在此温度下再保持一小时。通过过滤分离粗产物。滤饼用221kg甲醇洗涤两次。
将粗反应产物与1106kg甲醇一起转移到搅拌的反应容器中,加热至25±5℃并在该温度下搅拌至少10min。将混合物加热至回流并保持3h至3.5h,在3h内再次冷却至10±3℃并在该温度下再保持一小时。过滤分离纯化产物,滤饼用221kg甲醇洗涤两次。
将纯化产物与995kg甲醇和140kg水一起转移到搅拌的反应容器中,加热至25±5℃并在该温度下搅拌至少10min。将混合物加热至回流并保持3h至3.5h,在3h内冷却至10±3℃并在此温度下再保持一小时。过滤分离纯产物,滤饼用111kg甲醇和140kg水的混合物洗涤两次。
产物在托盘干燥器中的托盘上(约2.9kg/m2)通过空气通风在环境温度下以薄层干燥,得到以水合物形式的208kg 4-{[4-氨基-5-溴-6-(甲氧基甲基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-2-酮(72%收率),每mol(VII)含约1mol水。
HPLC(方法3):批次14纯度99.5%(4-{[4-氨基-5-溴-6-(甲氧基甲基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-2-酮)(RT=11.1min),相关副产物:(XXI)在RRT(相对保留时间)1.05:0.15%;(XX)在RRT 1.38min:0.16%;(VI)在RRT 0.74:<0.05%
使用含量测定:95.1%(相对于外标,水合物含约1mol/5%水)
实施例8:4-{[4-氨基-6-(甲氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)
吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-2-酮(I)
在10℃夹套温度下,将27.1kg 4-{[4-氨基-5-溴-6-(甲氧基甲基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-2-酮(VII)置于搅拌反应容器中的425kg THF中。加入74kg水、22.1kg(7-甲氧基-5-甲基-1-苯并噻吩-2-基)硼酸(VIII)和20.5kg碳酸钾,通过将内压降低至200毫巴使反应混合物惰性化并用氩气重新填充至环境压力。加入0.47kg[1,1'-双(二-叔丁基膦基)二茂铁]二氯化钯(II)并通过将内压降低至200毫巴使反应器惰性化并用氩气重新填充至环境压力。在90min内将反应混合物加热至回流(约64℃内部温度)并在该温度下再搅拌2h。在55℃至回流温度下加入24.1kg乙酰半胱氨酸在274kg水中的溶液。将反应混合物在该温度下搅拌2h,然后在55℃至回流温度下加入242kg乙酸乙酯。夹套温度设置为50℃
搅拌60min后,通过在48℃至50℃和500毫巴下从反应混合物中蒸馏出366kg溶剂以浓缩反应混合物。加入另外的239kg乙酸乙酯并通过在46℃至50℃和500毫巴下从反应混合物中蒸馏出147kg溶剂以浓缩反应混合物。蒸馏结束后,将夹套温度调至75℃,搅拌60min。在2h内将混合物冷却至20℃内部温度并再搅拌2h。过滤分离产物并用196kg乙醇和22kg水的混合物洗涤。
将产物置于搅拌的反应容器中的456kg THF和91kg水的混合物中并加热至65℃直至得到溶液。夹套温度设置为50℃,反应混合物通过在500至200毫巴下蒸馏浓缩,直至不再收集到馏出物(约469kg馏出物)。加入238kg乙醇并通过在140毫巴下从反应混合物中蒸馏出46kg溶剂以浓缩反应混合物。
夹套温度设置为80℃,将混合物搅拌3h,然后在3h内冷却至15℃的内部温度。将混合物搅拌1h,在离心机上分离产物并用298kg乙醇和39kg水的混合物洗涤。产物在45℃和30毫巴下干燥,得到28.3kg(I)。
按照方法1以类似方式通过转化27.4kg 4-{[4-氨基-5-溴-6-(甲氧基甲基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-2-酮(VII)和22.1kg(7-甲氧基-5-甲基-1-苯并噻吩-2-基)硼酸(VIII)重复该程序以产生第二批次(I),得到28.5kg(I)。
纯化:
将来自第一批次(I)的28.3kg(I)置于搅拌的反应容器中的413kg THF和81kg水的混合物中,并在65℃下加热至回流直至获得溶液。然后将夹套温度设置为60℃,并将混合物通过加热的颗粒过滤器(60℃)进入另一个搅拌的反应容器中。
将来自第二批次(I)的28.5kg(I)置于搅拌的反应容器中的410kg THF和81kg水的混合物中,并在65℃下加热至回流直至获得溶液。然后将夹套温度设置为60℃,并将混合物通过加热的颗粒过滤器(60℃)进入已含有第一部分(I)溶液的搅拌反应容器中。
夹套温度设置为50℃,反应混合物通过在200毫巴下蒸馏浓缩,直至不再收集到馏出物(约798kg馏出物)。加入429kg乙醇并通过在140毫巴下从反应混合物中蒸馏出90kg溶剂以浓缩反应混合物。
夹套温度设置为85℃,将混合物搅拌90min,然后3h内冷却至15℃内部温度。将混合物搅拌1h并在过滤干燥器上分离产物并用354kg乙醇和45kg水的混合物洗涤。最后将产物在45℃和30毫巴下干燥,产生53.6kg(I),理论收率为78%。
HPLC(方法4):
纯度:99.8%(Rt=11.6min),相关副产物:(VI)在RRT(相对保留时间)0.16:n.d.;(XVIII)在RRT 1.02min:0.09%;(XV)在RRT 0.77:n.d.(XVI)在RRT 0.98:n.d.
使用含量测定:97.8%(相对于外标)
残留溶剂(通过GC方法1确定):0.4%四氢呋喃
残留元素(通过ICP-MS测定):0.9mg/kg钯
实施例9:4-{[4-氨基-6-(甲氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)
吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-2-酮盐酸盐水合物(III)一水合物[A]
方法1:
将16.1kg 4-{[4-氨基-6-(甲氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-2-酮(I)通过在反应容器中搅拌悬浮于106kg乙醇和13kg水的混合物中。将混合物加热至50±5℃并搅拌1h。加入5.4±0.2kg 25%HCl在水中的溶液,然后加入10kg乙醇,在此温度下搅拌该批料1h。在2.5h内将混合物冷却至0±3℃,并在0±3℃下搅拌1h。过滤分离产物并通过冷反应容器用48kg乙醇洗涤过滤器。粗产物未经干燥即进行进一步加工。
该工艺进行四次,因此总共转化64.4kg。在下一工艺步骤中合并四次粗产物。
2.5kg 10%HCl水溶液在搅拌的反应容器中用193kg水稀释并将4次粗产物悬浮于该混合物中。将批料加热至75±3℃,在该温度下搅拌1h,然后在3h内冷却至20±3℃。产物在过滤干燥器上分离,残留产物通过反应容器循环滤液从反应容器冲洗到过滤器中。将产物在30毫巴和50℃夹套温度下干燥,得到以期望的一水合物[A]固体状态形式的63.7kg(89%收率)4-{[4-氨基-6-(甲氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩)-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-2-酮盐酸盐水合物(III)。
HPLC(方法4):
纯度:99.7%(Rt=11.9min),相关副产物:(VI)在RRT(相对保留时间)0.16:n.d.(XVIII)在RRT 1.02min:n.d.;(XV)在RRT 0.77:0.07%;(XVI)在RRT 0.98:0.16%
使用含量测定:98.2%(相对于外标,基于一氯化物,一水合物)
残留溶剂(通过GC方法1测定):0.3%乙醇
残留元素(通过ICP-MS测定):1mg/kg钯
水含量(Karl Fischer比色法):3.5%
离子色谱:6.4%氯
方法2:
将51.1kg 4-{[4-氨基-6-(甲氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-2-酮(I)在搅拌的反应容器中悬浮于336kg乙醇和41kg水的混合物中。将混合物加热至50℃并加入17.3kg25%HCl在水中的溶液,随后加入32kg乙醇。0.48kg 4-{[4-氨基-6-(甲氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-2-酮盐酸盐水合物(III)以一水合物[A]的形式作为晶种加入(例如根据方法1或方法2制备并另外通过气流粉碎机研磨至低于20μm粒径),并且反应混合物在50℃下搅拌1h。
在2.5h内将混合物冷却至0℃并在0℃下搅拌1h。产物通过过滤干燥器过滤分离,过滤器用107kg冷乙醇洗涤。然后停止过滤。
将2.0kg 10%HCl在水中的溶液的混合物用154kg水稀释并在搅拌的反应容器中加热至30℃并通过管路输送至过滤干燥器中。通过搅拌将滤饼悬浮于32℃的过滤干燥器上60min,然后过滤。
将产物在50℃夹套温度和30毫巴下干燥,直至达到45℃的产物温度。然后继续干燥2h。得到以期望的一水合物[A]固体状态形式的54.0kg(95%收率)4-{[4-氨基-6-(甲氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-2-酮盐酸盐水合物(III)。
HPLC(方法4):
纯度:99.9%(Rt=11.6min),相关副产物:(VI)在RRT(相对保留时间)0.16:n.d.(XVIII)在RRT 1.02min:n.d.;(XV)在RRT 0.77:0.04%;(XVI)在RRT 0.98:n.d.
使用含量测定:98.2%(相对于外标,基于一氯化物,一水合物)
残留溶剂(通过GC方法1测定):0.2%乙醇
残留元素(通过ICP-MS测定):0.6mg/kg钯
水含量(Karl Fischer比色法):3.8%
离子色谱:6.8%氯
实施例10:制备用于实验室规模表征的不同固体状态形式样品的工艺:
一水合物(A)的制备
如上所述制备作为式(I)的化合物的一水合物[A]的结晶形式(III)(根据方法1,实施例9)
二水合物(B)的制备
将1g式(II)的化合物的一水合物形式[A](水含量为3.1%)悬浮于10mL甲醇中并在0℃下搅拌五周。随后过滤悬浮液并将残留物在室温下储存直至溶剂蒸发。它在两周内转化为一水合物。
三水合物(C)的制备
在回流下将1g式(II)的化合物的一水合物形式[A](水含量为3.5%)溶解于100mL甲醇中。将溶液过滤并储存在冰箱中直至溶剂蒸发。
3/4-水合物(D)的制备
将3.5g式(II)的化合物的一水合物形式[A](水含量为3.1%)悬浮于35mL甲醇中并在0℃下搅拌一周。随后将悬浮液过滤并将残留物在室温下储存直至溶剂蒸发。
无定形物料(E)的制备
式(II)的化合物的一水合物形式[A](水含量为3.1%)用乙醇/水(1:1)喷雾干燥。
式(II)的化合物的水合物形式的物理表征
XRPD
13C固态NMR光谱
结晶形式[A]:一水合物
结晶形式[D]:3/4-水合物
结晶形式[C]:三水合物
结晶形式[E]:无定形化合物
关于(II)的水合物形式的制备和表征的额外数据
式(II)的化合物的4-{[4-氨基-6-(甲氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-2-酮-单盐酸盐的水合物形式的制备
在各种溶剂中制备一水合物(A)的悬浮液并在0℃和25℃下搅拌。滤出残留物并在室温和环境湿度下干燥。表1总结了结果。不可能对所有固体状态形式进行可重现的制备。
表1:浆液实验
式(II)的化合物4-{[4-氨基-6-(甲氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-2-酮-单盐酸盐的水合物形式的特性
储存
一水合物、3/4-水合物、三水合物和无定形形式在25℃和50℃(湿度未设置)下储存在密闭容器中。结果总结在表2中。
表2:在25℃和50℃下储存
吸湿性
一水合物、3/4-水合物、三水合物和无定形形式在各种湿度下储存。然后通过热重分析测定它们的含水量。结果总结在表3中。
表3
*在一个月的储存期间已发生向一水合物的转变。
含有化合物(III)的药物组合物(600mg)
表4:200mg(API)片剂的组成
片剂制造工艺的描述
干混
将微晶纤维素、化合物(III)、乳糖一水合物和交聚维酮按表1的比例称量到合适的容器中并共混。
湿法造粒
共混后,在高剪切造粒机中将混合物与粘合剂溶液(在纯化水中的共聚维酮)造粒。造粒后,将颗粒湿筛分。
干燥和干磨
将过筛的颗粒转移到流化床干燥器中并干燥,直至达到3-4%LOD。
干燥后,颗粒通过0.9mm筛。
总混(final blend)
将微晶纤维素、交聚维酮和无水胶体二氧化硅加入总混物中并在料仓共混器中混合。
最后将硬脂酸镁加入总混物中并混合。
压片
将混合物在旋转压机上压制成重量为680.0mg的片剂。
包衣
使片剂在滚筒包衣机中用包衣悬浮液(在纯净水中的羟丙甲纤维素、聚乙二醇、氧化铁红、二氧化钛)进行包衣。
含有化合物(III)的药物组合物的特性
方法:
根据以下方法评估片剂:
表5:包衣片200mg,包装在HDPE瓶中
根据上述方法制造含有化合物III的片剂并记录初始XRPD。在48个月的时间里,XRPD图案在研究的所有储存条件下均保持不变。
表6:在棕色玻璃瓶中的稳定性
表7:片剂的稳定性
a 溶解方法变更的生效日期
b 7个月后检测溶解度
c 降解产物更新评价方法的首次应用
图:
图1:根据实施例10的一水合物(A)的X射线粉末衍射图。
图2:根据实施例10的二水合物(B)的X射线粉末衍射图。
图3:根据实施例10的三水合物(B)的X射线粉末衍射图。
图4:根据实施例10的3/4-水合物(D)的X射线粉末衍射图。
Claims (18)
2.根据权利要求1的化合物的形式,其特征在于在25℃下并且使用Cu-Kα1作为放射源测量的X射线粉末衍射图至少显示以下反射,引用为2θ值±0.2°:9.3、10.6和13.3。
3.根据权利要求1的化合物的形式,其特征在于在25℃下并且使用Cu-Kα1作为放射源测量的X射线粉末衍射图至少显示以下反射,引用为2θ值±0.2°:9.3、10.6、13.3、20.7和23.3。
4.根据权利要求1的化合物的形式,其特征在于在25℃下并且使用Cu-Kα1作为放射源测量的X射线粉末衍射图至少显示以下反射,引用为2θ值±0.2°:9.3、10.6、11.4、13.3、20.7、23.3和26.0。
5.根据权利要求1的化合物的形式,其特征在于在25℃下并且使用Cu-Kα1作为放射源测量的X射线粉末衍射图至少显示以下反射,引用为2θ值±0.2°:6.8、9.3、10.6、11.4、13.3、20.7、23.3、24.6、26.0和27.6。
6.一种药物组合物,其包含式(I)的化合物的假多晶型(III)和任选另外的药学上可接受的赋形剂。
7.根据权利要求6的药物组合物,其主要包含式(I)的化合物的结晶形式(III)并且不包含显著分数的式(I)的化合物的另一种形式和任选包含另外的药学上可接受的赋形剂。
8.权利要求1至5中任一项的化合物的结晶形式,用于治疗和/或预防癌症。
9.权利要求6至7中任一项的药物组合物,用于治疗和/或预防增殖性病症,诸如癌症和肿瘤疾病。
10.如权利要求1至5中任一项所限定的化合物在制造用于治疗或预防增殖性病症诸如癌症和肿瘤疾病的药物组合物中的用途。
11.如权利要求1至5中任一项所限定的化合物在制造物理上和化学上稳定的片剂中的用途。
12.一种治疗或预防哺乳动物中的增殖性病症,诸如癌症和肿瘤疾病的方法,其包括向有需要的哺乳动物给予治疗有效量的如权利要求1至5中任一项所定义的化合物。
13.一种生产式(I)的化合物的结晶形式(III)的工艺,其包括通过将式(I)的化合物溶解或悬浮于惰性溶剂中并且添加酸或酸前体,使式(I)的化合物反应的步骤。
14.根据权利要求13的工艺,其中通过将式(I)的化合物溶解或悬浮于THF或EtOH和水中,并且添加HCl,使式(I)的化合物反应。
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EP19154781 | 2019-01-31 | ||
PCT/EP2020/051884 WO2020156982A1 (en) | 2019-01-31 | 2020-01-27 | The monohydrate of rogaratinib hydrochloride and solid states thereof |
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CN113720956A (zh) * | 2021-09-08 | 2021-11-30 | 广州国标检验检测有限公司 | 一种气质联用检测药物中硫酸酯的方法 |
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- 2020-01-27 EP EP20702012.4A patent/EP3917929A1/en not_active Withdrawn
- 2020-01-27 KR KR1020217024012A patent/KR20210119994A/ko unknown
- 2020-01-27 CA CA3128073A patent/CA3128073A1/en active Pending
- 2020-01-27 WO PCT/EP2020/051884 patent/WO2020156982A1/en active Application Filing
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JP2022519081A (ja) | 2022-03-18 |
KR20210119994A (ko) | 2021-10-06 |
WO2020156982A1 (en) | 2020-08-06 |
DOP2021000162A (es) | 2021-09-15 |
JOP20210204A1 (ar) | 2023-01-30 |
EP3917929A1 (en) | 2021-12-08 |
ECSP21056314A (es) | 2021-08-31 |
CO2021009660A2 (es) | 2021-08-09 |
AU2020214188A1 (en) | 2021-07-15 |
TW202035413A (zh) | 2020-10-01 |
GEP20237531B (en) | 2023-08-25 |
US20220098201A1 (en) | 2022-03-31 |
CA3128073A1 (en) | 2020-08-06 |
MA54856A (fr) | 2022-05-04 |
EA202192133A1 (ru) | 2022-02-09 |
MX2021009173A (es) | 2021-09-10 |
IL284927A (en) | 2021-09-30 |
SG11202107919YA (en) | 2021-08-30 |
BR112021012876A2 (pt) | 2021-09-08 |
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