CN108137543A - 选择性nr2b拮抗剂 - Google Patents
选择性nr2b拮抗剂 Download PDFInfo
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- CN108137543A CN108137543A CN201680060583.4A CN201680060583A CN108137543A CN 108137543 A CN108137543 A CN 108137543A CN 201680060583 A CN201680060583 A CN 201680060583A CN 108137543 A CN108137543 A CN 108137543A
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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Abstract
本公开总体而言涉及式I的化合物,包括其盐,以及使用该化合物的组合物和方法。该化合物是NR2B受体的配体且可用于治疗各种中枢神经***疾病。
Description
相关申请的交叉引用
本申请要求2015年10月14号提交的印度临时专利申请序列号3308/DEL/2015的权益,该申请通过整体引用结合到本文中。
技术领域
总体而言,本公开涉及式I的化合物,包括其盐,以及使用该化合物的组合物和方法。该化合物是NR2B NMDA受体的配体且可用于治疗各种中枢神经***疾病。
背景
N-甲基-D-天冬氨酸盐(NMDA)受体是通过结合中枢神经***中的兴奋性神经递质谷氨酸盐门控的离子通道。其被认为在多种神经疾病的发展中起关键作用,该疾病包括抑郁症、神经性疼痛、阿兹海默氏(Alzheimer’s)病及帕金森氏(Parkinson’s)病。功能性NMDA受体是主要由两个NR1及两个NR2亚单位构成的四聚体结构。NR2亚单位进一步细分成四个单独的亚型:NR2A、NR2B、NR2C及NR2D,其差异性地分布在整个脑中。已研究了NMDA受体、尤其是含有NR2B亚单位的通道的拮抗剂或别构调节剂作为治疗重度抑郁症的治疗剂(G.Sanacora,2008,Nature Rev.Drug Disc.7:426-437)。
NR2B受体含有除针对谷氨酸盐的配体结合位点之外的额外配体结合位点。非选择性NMDA拮抗剂,诸如***(Ketamine)是孔阻断剂,干扰Ca++运输通过通道。***在人类临床试验中作为静脉内药物已展示快速且持久的抗抑郁性质。另外,采用重复、间歇输注***维持功效(Zarate等人,2006,Arch.Gen.Psychiatry 63:856-864)。但此类药物因其CNS副作用(包括解离作用)而具有有限的治疗价值。
在NR2B的N末端结构域中也已鉴别出别构、非竞争性结合位点。选择性在该位点结合的试剂(例如塔索普迪(Traxoprodil))在人类临床试验中作为静脉内药物展现持续的抗抑郁反应及改进的副作用特征(Preskorn等人,2008,J.Clin.Psychopharmacol.,28:631-637及F.S.Menniti等人,1998,CNS Drug Reviews,4,4,307-322)。然而,对此类药物的研发因低生物利用度、较差药代动力学及缺乏针对其它药理学靶(包括hERG离子通道)的选择性而受阻。阻断hERG离子通道可导致心率失常,包括潜在致死性尖端扭转型室性心动过速(Torsades de pointe),因此针对此通道的选择性至关重要。因此,在治疗重度抑郁症中,仍存在研发具有有利的耐受特征的有效NR2B选择性负向别构调节剂的未满足的临床需要。
NR2B受体拮抗剂已公开在PCT公布WO 2009/006437中。
本发明提供技术优点,例如该化合物是新型的且是NR2B受体的配体并可用于治疗各种中枢神经***疾病。另外,该化合物在例如以下一个或多个方面为药物用途提供优点:其作用机制、结合、抑制功效、靶选择性、溶解度、安全特征或生物利用度。
概述
在第一实施方案中,本公开提供了式I化合物:
其中:
Ar1是苯基并且被0-3个选自氰基、卤素、烷基、卤代烷基和卤代烷氧基的取代基取代;
Ar2是吡啶基或嘧啶基,并且被1个OR取代基且被0-2个卤素或烷基取代基取代;
R是氢或选自以下的前药部分:烷基酯、氨基酸酯、烷氧基酯、膦酸、膦酸烷基酯、烷氧基膦酸酯酸(alkoxyphosphononate acid)、烷氧基膦酸酯烷基酯(alkoxyphosphonatealkyl esters)、烷基氨基甲酸酯、氨基酸氨基甲酸酯、烷基氨基磷酸酯(alkylphosporamidates)、芳基氨基磷酸酯(aryl phosphoramidates)和氨基磺酸酯;
X是键或C1-C3亚烷基;
n是1或2;
环A是哌嗪基、高哌嗪基或2,5-二氮杂双环[2.2.1]庚烷、哌嗪-2-酮并且被0-4个选自卤素、烷基、羟基或烷氧基的取代基取代;
或其药学上可接受的盐。
描述
应理解的是,任何给定的示例性实施方案可以与一个或多个另外的示例性实施例组合。
除非另有规定,否则这些术语具有以下含义。“烷基”是指包含1至6个碳的直链或支链烷基。“烯基”是指具有至少一个双键的包含2至6个碳的直链或支链烷基。“炔基”是指具有至少一个三键的包含2至6个碳的直链或支链烷基。“环烷基”是指包含3至7个碳的单环体系。具有烃部分的术语(例如烷氧基)包括烃部分的直链和支链异构体。“卤素”包括氟、氯、溴和碘。“卤代烷基”和“卤代烷氧基”包括从单卤代到全卤代的所有卤代异构体。“芳基”是指具有6至12个碳原子的单环或双环芳族烃基,或者其中一个或两个环为苯基的双环稠合环体系。双环稠合环体系由与四至六元芳族或非芳族碳环稠合的苯基组成。芳基的代表性实例包括但不限于茚满基、茚基、萘基、苯基和四氢萘基。“杂芳基”是指具有1-5个独立地选自氮、氧和硫的杂原子的5至7元单环或8至11元双环芳族环体系。加括号和多重括号的术语旨在向本领域技术人员阐明键合关系。例如,术语如((R)烷基)是指被取代基R进一步取代的烷基取代基。
本发明包括所述化合物的所有药学上可接受的盐形式。药学上可接受的盐是其中抗衡离子对所述化合物的生理学活性或毒性没有显著贡献并且因此起药理学等价物作用的盐。这些盐可以使用市售可得的试剂根据常用有机技术制备。一些阴离子盐形式包括乙酸盐、醋硬脂酸盐、苯磺酸盐、溴化物、氯化物、柠檬酸盐、富马酸盐、葡糖醛酸盐、氢溴酸盐、盐酸盐、氢碘酸盐、碘化物、乳酸盐、马来酸盐、甲磺酸盐、硝酸盐、双羟萘酸盐、磷酸盐、琥珀酸盐、硫酸盐、酒石酸盐、甲苯磺酸盐和昔萘酸盐(xinofoate)。一些阳离子盐形式包括铵、铝、苄星(benzathine)、铋、钙、胆碱、二乙胺、二乙醇胺、锂、镁、葡甲胺、4-苯基环己胺、哌嗪、钾、钠、氨丁三醇和锌。
一些式I化合物含有至少一个不对称碳原子,其实例如下所示。本发明包括化合物的所有立体异构形式,即混合物和分离的异构体二者。立体异构体的混合物可以通过本领域已知的方法分离成单独的异构体。这些化合物包括所有互变异构形式。
本发明旨在包括存在于本发明化合物中的原子的所有同位素。同位素包括具有相同原子序数但不同质量数的那些原子。作为一般例子而非限制,氢的同位素包括氘和氚。碳的同位素包括13C和14C。本发明的同位素标记的化合物通常可以通过本领域技术人员已知的常规技术或通过与本文所述类似的方法使用适当的同位素标记的试剂代替否则使用的未标记的试剂来制备。这样的化合物可能具有多种潜在用途,例如作为确定生物活性的标准和试剂。在稳定同位素的情况下,这些化合物可能具有有利地改变生物学、药理学或药代动力学性质的潜力。
本申请中使用的缩写是本领域技术人员公知的。
本发明的一个方面是式I的化合物
其中:
Ar1是苯基并且被0-3个选自氰基、卤素、烷基、卤代烷基和卤代烷氧基的取代基取代;
Ar2是吡啶基或嘧啶基,并且被1个OR取代基且被0-2个卤素或烷基取代基取代;
R是氢或选自以下的前药部分:烷基酯、氨基酸酯、烷氧基酯、膦酸、膦酸烷基酯、烷氧基膦酸酯酸、烷氧基膦酸酯烷基酯、烷基氨基甲酸酯、氨基酸氨基甲酸酯、烷基氨基磷酸酯、芳基氨基磷酸酯和氨基磺酸酯;
X是键或C1-C3亚烷基;
n是1或2;
环A是哌嗪基、高哌嗪基或2,5-二氮杂双环[2.2.1]庚烷、哌嗪-2-酮并且被0-4个选自卤素、烷基、羟基或烷氧基的取代基取代;
或其药学上可接受的盐。
本发明的另一方面是式I化合物,其中n是1且环A是被0-2个烷基取代基取代的哌嗪基。
本发明的另一方面是式I化合物,其中Ar1是被0-3个选自氰基、卤素、烷基、卤代烷基和卤代烷氧基的取代基取代的苯基。
本发明的另一方面是式I的化合物,其中Ar2选自
且R选自氢、氨基酸酯、膦酸、烷氧基膦酸酯酸、烷基氨基甲酸酯、氨基酸氨基甲酸酯、烷基氨基磷酸酯、芳基氨基磷酸酯和氨基磺酸酯。
本发明的另一方面是式I的化合物,其中X是亚甲基。
本发明的另一方面是式I的化合物,其中R是氢。
本发明的另一方面是式I的化合物,其中R是P(=O)(OH)2。
本发明的另一方面是选自以下的式I化合物:
或其药学上可接受的盐。
在第二方面,提供了包含式I化合物或其药学上可接受的盐和药学上可接受的载体的药物组合物。
第三方面,治疗抑郁症、阿尔茨海默氏病、神经性疼痛或帕金森病的方法,其包括给患者施用治疗有效量的式I化合物。
在第三方面的第二个实施方案中,式I化合物涉及治疗抑郁症。
在第三方面的第三个实施方案中,式I化合物涉及治疗阿尔茨海默氏病。
在第三方面的第四个实施方案中,式I化合物涉及治疗神经性疼痛。
实施例
现在将结合某些实施方案来描述本公开,所述实施方案并非意在限制其范围。相反,本公开涵盖可包括在权利要求范围内的所有替代物、修改和等同物。因此,包括具体实施方案的以下实施例将说明本公开的一个实践,应当理解的是,实施例是为了说明某些实施方案的目的,并且被呈现以提供被认为是其程序和概念方面最有用和容易理解的描述。
本公开的化合物可以使用本章节中描述的反应和技术以及本领域普通技术人员已知的其他合成方法来制备。反应在适合于所用试剂和材料并且适合于受影响的转变的溶剂中进行。另外,在下面描述的合成方法的描述中,应该理解,所有建议的反应条件,包括溶剂的选择、反应温度、实验的持续时间和后处理程序被选择为本领域技术人员应容易认识到的该反应的条件标准。有机合成领域的技术人员应理解,存在于分子各部分上的官能团必须与所建议的试剂和反应相容。这种对与反应条件相容的取代基的限制对于本领域技术人员是显而易见的并且因此必须使用替代方法。
在本发明的一个优选实施方案中,本公开化合物的合成可以在以下示意型表述中阐述。
流程1:
步骤1:4-(5-(苄基氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯
在室温下往搅拌的哌嗪-1-甲酸酯叔丁酯(5.99g,32.2mmol)的甲苯(100mL)溶液中加入5-(苄基氧基)-2-溴吡啶(8.5g,32.2mmol)、叔丁醇钠(7.73g,80mmol)和BINAP(4.01g,6.44mmol)且反应混合物用氮气吹扫15min,随后加入Pd2(dba)3(2.95g,3.22mmol)。反应在100℃下加热18小时。反应的完成通过LCMS监测。反应混合物通过硅藻土过滤并用乙酸乙酯(200ml)洗涤;将滤液浓缩以去除乙酸乙酯和甲苯。向残余物加入水(250ml)并且产物用乙酸乙酯(3*100mL)萃取,合并的有机层经无水硫酸钠干燥,过滤并浓缩以得到粗品20g。粗产物通过使用120g硅胶柱ISCO纯化,产物用40%乙酸乙酯/石油醚洗脱以得到黄色固体形式的4-(5-(苄基氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(5g,12.99mmol,40.4%产率)。
LCMS:缓冲液:10mM乙酸铵pH-5用HCOOH调节,流动相A:缓冲液:ACN(95:5),流动相B:缓冲液:ACN(5:95),方法:%B:0min-5%:1.1min-95%:1.7min-95%。柱名称:AcquityBEH C18(2.1x 50mm)1.7u,方法:C:\MassLynx,流速:0.8ml/min,RT-1.28min,M(+1)-370。
步骤2:4-(5-羟基吡啶-2-基)哌嗪-1-甲酸叔丁酯
往搅拌的4-(5-(苄基氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(2.00g,5.41mmol)的甲醇(10mL)溶液中加入Pd/C(0.576g,5.41mmol),在通过真空弯管的氢气气囊压力下搅拌并在室温下搅拌18小时。反应的完成通过LCMS监测。反应混合物通过硅藻土过滤并浓缩滤液以得到棕色胶状物形式的4-(5-羟基吡啶-2-基)哌嗪-1-甲酸叔丁酯(1.4g,5.01mmol,93%产率)。
LCMS:%B:0min-2%:1.0min-98%:1.6min-98%,流动相B:乙腈,流动相A:0.1%TFA/水,方法:C:\MassLynx,RT-0.64min,M(+1)-280。
步骤3:6-(哌嗪-1-基)吡啶-3-醇.HCl
在室温下往搅拌的4-(5-羟基吡啶-2-基)哌嗪-1-甲酸叔丁酯(1.5g,5.37mmol)的1,4-二氧六环(15mL)溶液中加入4M HCl/1,4-二氧六环(5mL,5.37mmol)。反应混合物在室温下搅拌12小时。反应的完成通过LCMS监测。将反应混合物浓缩以得到灰白色固体形式的6-(哌嗪-1-基)吡啶-3-醇.HCl(1g,4.08mmol,76%产率)。
LCMS:缓冲液:10mM乙酸铵pH-5用HCOOH调节,流动相A:缓冲液:ACN(95:5),流动相B:缓冲液:ACN(5:95),方法:%B:0min-5%:1.1min-95%:1.7min-95%。柱名称:AcquityBEH C18(2.1x 50mm)1.7u,方法:C:\MassLynx,流速:0.8ml/min,RT-0.35min,M(+1)-180。
流程2:
步骤1:4-(5-甲氧基嘧啶-2-基)哌嗪-1-甲酸叔丁酯
在密封管中往搅拌的2-氯-5-甲氧基嘧啶(1g,6.92mmol)的DMF(20mL)溶液中加入哌嗪-1-甲酸叔丁酯(1.2g,6.44mmol)和TEA(3mL,21.52mmol),混合物在60℃下搅拌48小时。反应的完成通过LCMS监测。减压去除溶剂以得到粗残余物,将粗残余物溶解在乙酸乙酯(100mL)中并用水(2*100mL)洗涤,有机层经无水硫酸钠干燥,过滤并减压蒸发以得到棕色液体形式的粗品(1.5g)。粗化合物通过Combi(24g硅胶柱,用15%乙酸乙酯/石油醚洗脱)纯化以得到灰白色固体形式的4-(5-甲氧基嘧啶-2-基)哌嗪-1-甲酸叔丁酯(550mg,1.738mmol,25.1%产率)。
LCMS:Column-Ascentis Express C18(50X2.1mm-2.7μm),流动相A:10mMNH4COOH/水:ACN(98:02),流动相B:10mM NH4COOH/水:ACN(02:98),流速=1ml/min,时间:%B::0.0:0.0::1.7:100.0::3.0:100.0::3.2:0.0,LCMS RT=2.2min M(+1)-295。
步骤2:
在0℃下往搅拌的4-(5-甲氧基嘧啶-2-基)哌嗪-1-甲酸叔丁酯(330mg,1.121mmol)的1,4-二氧六环(10mL)溶液中加入HCl/1,4二氧六环(1.121mL,1.121mmol)。反应混合物在室温下搅拌12小时。反应的完成通过LCMS监测。减压去除溶剂以得到粗化合物,粗化合物用乙酸乙酯(2*10mL)研磨并过滤得到的固体,以得到灰白色固体形式的5-甲氧基-2-(哌嗪-1-基)嘧啶盐酸盐(200mg,0.607mmol,54.1%产率)。
LCMS:Column-Ascentis Express C18(50X2.1mm-2.7μm),流动相A:10mMNH4COOH/水:ACN(98:02),流动相B:10mM NH4COOH/水:ACN(02:98),流速=1ml/min,时间:%B::0.0:0.0::1.7:100.0::3.0:100.0::3.2:0.0,RT-0.946min,M(+1)-195。
步骤3:
往搅拌的5-甲氧基-2-(哌嗪-1-基)嘧啶盐酸盐(50mg,0.217mmol)溶液中加入在干燥的DMF(1.5mL)中的DIPEA(0.114mL,0.650mmol)和3-溴-1-(4-氯-3-氟苯基)吡咯烷-2-酮(95mg,0.325mmol)。反应混合物在微波下在120℃下加热90分钟。反应的完成通过LCMS监测。减压浓缩反应混合物以得到1-(4-氯-3-氟苯基)-3-(4-(5-甲氧基嘧啶-2-基)哌嗪-1-基)吡咯烷-2-酮(60mg,0.093mmol,43%产率)粗化合物,通过LCMS测得纯度为63%,其无需纯化用于下一步骤。
LCMS:Column-Ascentis Express C18(50X2.1mm-2.7μm),流动相A:10mMNH4COOH/水:ACN(98:02),流动相B:10mM NH4COOH/水:ACN(02:98),流速=1ml/min,时间:%B::0.0:0.0::1.7:100.0::3.0:100.0::3.2:0.0,RT-2.2min,M(+1)-406。
流程3:
步骤1:1-(5-(苄基氧基)吡啶-2-基)-1,4-二氮杂环庚烷。
在室温下往搅拌的1,4-二氮杂环庚烷(4.10g,41.0mmol)的甲苯(10mL)溶液中加入5-(苄基氧基)-2-氯吡啶(3.00g,13.66mmol)和叔丁醇钾(3.06g,27.3mmol)。反应混合物用氮气吹扫15分钟,随后在室温下加入Tetrakis(1.578g,1.366mmol)。反应在110℃下加热4小时。反应的完成通过LCMS监测。反应混合物通过硅藻土过滤并将滤液浓缩以得到粗品9g。粗产物通过ISCO纯化,使用40g碱性氧化铝柱,产物用75%乙酸乙酯/石油醚洗脱以得到棕色胶状物形式的1-(5-(苄基氧基)吡啶-2-基)-1,4-二氮杂环庚烷(1.5g,4.29mmol,31.4%产率)。
LCMS:%B:0min-2%:1.0min-98%:1.6min-98%,流动相B:乙腈,流动相A:0.1%TFA/水,方法:C:\MassLynx,RT-0.66min,M(+1)-284。
步骤2a:
在室温下往搅拌的1-(5-(苄基氧基)吡啶-2-基)-1,4-二氮杂环庚烷(0.200g,0.169mmol)的DMF(3mL)溶液中加入TEA(0.071mL,0.508mmol)和(S)-甲磺酸1-(4-甲基苄基)-2-氧代吡咯烷-3-基酯(0.096g,0.339mmol)。反应混合物在120℃下在微波中搅拌2小时。反应的完成通过LCMS监测。将反应混合物浓缩以得到粗品0.45g。粗品通过制备型TLC纯化;板用乙酸乙酯展开以得到灰白色固体形式的(R)-3-(4-(5-(苄基氧基)吡啶-2-基)-1,4-二氮杂环庚烷-1-基)-1-(4-甲基苄基)吡咯烷-2-酮(0.04g,0.085mmol,50.2%产率)。
LCMS:缓冲液:10mM乙酸铵pH-5用HCOOH调节,流动相A:缓冲液:ACN(95:5),流动相B:缓冲液:ACN(5:95),方法:%B:0min-5%:1.1min-95%:1.7min-95%。柱名称:AcquityBEH C18(2.1x 50mm)1.7u,方法:C:\MassLynx,流速:0.8ml/min,RT-1.3min,M(+1)-471。
步骤2b:
在室温下往搅拌的1-(5-(苄基氧基)吡啶-2-基)-1,4-二氮杂环庚烷(0.05g,0.176mmol)的DMF(3mL)溶液中加入TEA(0.074mL,0.529mmol)和甲磺酸1-(4-氯-3-氟苯基)-2-氧代吡咯烷-3-基酯(0.081g,0.265mmol)。反应混合物在120℃下在微波中搅拌2小时。通过LCMS质谱测得28%所需产物。反应混合物在高真空下浓缩以得到棕色胶状物形式的粗3-(4-(5-(苄基氧基)吡啶-2-基)-1,4-二氮杂环庚烷-1-基)-1-(4-氯-3-氟苯基)吡咯烷-2-酮(0.2g,0.113mmol,64.1%产率)并且该粗品无需进一步纯化原样用于下一个步骤。
LCMS:缓冲液:10mM乙酸铵pH-5用HCOOH调节,流动相A:缓冲液:ACN(95:5),流动相B:缓冲液:ACN(5:95),方法:%B:0min-5%:1.1min-95%:1.7min-95%。柱名称:AcquityBEH C18(2.1x 50mm)1.7u,方法:C:\MassLynx,流速:0.8ml/min,RT-1.25min,M(+1)-495。
流程4:
步骤1:(1S,4S)-5-(5-(苄基氧基)吡啶-2-基)-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯
向(1S,4S)-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯(2.5g,12.61mmol)的1,4-二氧六环(50mL)溶液中加入5-(苄基氧基)-2-氯吡啶(3.05g,13.87mmol)和碳酸铯(8.22g,25.2mmol)。用氮气将反应混合物脱气15分钟,随后加入XANTPHOS(1.094g,1.891mmol),随后PdOAc2(0.283g,1.261mmol)并加热至110℃过夜。反应的完成通过LCMS监测。反应物质通过硅藻土过滤并用乙酸乙酯(100mL)洗涤。真空浓缩滤液以得到粗品5.5g。该粗品通过ISCO体系纯化(25%EA:己烷,40g硅胶柱)以得到黄色固体形式的(1S,4S)-5-(5-(苄基氧基)吡啶-2-基)-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯(0.8g,2.097mmol,16.63%产率)。
LCMS:Column-Ascentis Express C18(50X2.1mm-2.7μm),流动相A:10mM乙酸铵/水,流动相B:CAN,流速=1ml/min,时间:%A:%B::0.0:100.0:0.0::1.7:0.0:100.0::3.2:0.0:100.0,RT-2.505min,M(+1)–382。
步骤2:(1S,4S)-2-(5-(苄基氧基)吡啶-2-基)-2,5-二氮杂双环[2.2.1]庚烷
向(1S,4S)-5-(5-(苄基氧基)吡啶-2-基)-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯(0.8g,2.097mmol)的1,4-二氧六环(5mL)溶液中加入4M HCl/二氧六环(5mL,20.00mmol)并在室温下搅拌过夜。反应的完成通过LCMS监测。真空浓缩反应物质以得到粗固体。该固体用乙酸乙酯(2x 50mL)研磨。往该固体化合物中加入10%碳酸氢钠溶液(50mL)并且用乙酸乙酯(3x 50mL)萃取产物,合并的有机层经硫酸钠干燥,过滤并真空浓缩以得到棕色固体形式的(1S,4S)-2-(5-(苄基氧基)吡啶-2-基)-2,5-二氮杂双环[2.2.1]庚烷(0.5g,1.066mmol,50.8%产率)。
LCMS:Column-Ascentis Express C8(50X2.1mm-2.7μm),流动相A:2%ACN-98%H2O-10mM NH4COOH,流动相B:98%ACN-2%H2O-10mM NH4COOH,流速=1ml/min,时间:%B::0.0:0.0::1.7:100.0::4.0:100.0,RT-1.726min,M(+1)–282。
步骤3:(R)-3-((1S,4S)-5-(5-(苄基氧基)吡啶-2-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-1-(4-氟苄基)吡咯烷-2-酮。
向(1S,4S)-2-(5-(苄基氧基)吡啶-2-基)-2,5-二氮杂双环[2.2.1]庚烷(0.075g,0.267mmol)的乙腈(3mL)溶液中加入DIPEA(0.140mL,0.800mmol)和(S)-甲磺酸1-(4-氟苄基)-2-氧代吡咯烷-3-基酯(0.115g,0.400mmol),随后加热到85℃过夜。减压浓缩反应物质并在硫酸氢钠溶液(10%)(50mL)和乙酸乙酯(50mL)之间分配,有机层经硫酸钠干燥并真空浓缩以得到棕色胶状物形式的(R)-3-((1S,4S)-5-(5-(苄基氧基)吡啶-2-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-1-(4-氟苄基)吡咯烷-2-酮(0.18g,0.194mmol,72.9%产率)。
LCMS:%B:0min-2%:1.0min-98%:1.6min-98%,流动相B:乙腈,流动相A:0.1%TFA/水,方法:C:\MassLynx,RT-1.21min,M(+1)-473。
流程5:
步骤1:3-甲基-4-((R)-1-(4-甲基苄基)-2-氧代吡咯烷-3-基)哌嗪-1-甲酸叔丁酯。
向3-甲基哌嗪-1-甲酸叔丁酯(0.530g,2.65mmol)的乙腈(30mL)溶液中加入(S)-甲磺酸1-(4-甲基苄基)-2-氧代吡咯烷-3-基酯(1.5g,5.29mmol)并将温度升高至130℃历时2小时。反应混合物用水(30mL)稀释并用乙酸乙酯(2x 50mL)萃取。合并的有机层经硫酸钠干燥并减压浓缩。粗产物经C18,40g反相Combiflash纯化,用80%乙腈+20%10mM乙酸铵混合物洗脱以得到灰白色固体形式的粗3-甲基-4-((R)-1-(4-甲基苄基)-2-氧代吡咯烷-3-基)哌嗪-1-甲酸叔丁酯(950mg,2.255mmol,85%产率)。
LCMS:RT:2.368min ACN/(H2O+HCOONH4),Ascentis Express C18(50x2.1mm-2.7μm),梯度=1.7min,波长=220nm;MS(ES):m/z 388.M+H。
步骤2:1-(4-甲基苄基)-3-(2-甲基哌嗪-1-基)吡咯烷-2-酮.TFA
在室温下往搅拌的3-甲基-4-(1-(4-甲基苄基)-2-氧代吡咯烷-3-基)哌嗪-1-甲酸叔丁酯(1g,2.58mmol)的DCM(25mL)溶液中加入TFA(1.988mL,25.8mmol)。反应混合物在室温下搅拌2小时。反应的完成通过LCMS监测。减压蒸发反应混合物并用***(20mL)洗涤并减压使固体干燥以得到1-(4-甲基苄基)-3-(2-甲基哌嗪-1-基)吡咯烷-2-酮.TFA(856mg,1.919mmol,74.4%产率)。
LCMS:ACN/(H2O+HCOONH4),Ascentis Express C18(50x2.1mm-2.7μm),梯度-1.7min,波长-220nm,RT-1.75min,M(+1)-288。
步骤3:
往搅拌的5-(苄基氧基)-2-氯吡啶(650mg,2.96mmol)溶液中加入1-(4-甲基苄基)-3-(2-甲基哌嗪-1-基)吡咯烷-2-酮(850mg,0.696mmol)、BINAP(43.3mg,0.070mmol)和叔丁醇钠(201mg,2.088mmol)。反应混合物用氮气吹扫10分钟,随后加入Pd2(dba)3(51.0mg,0.056mmol)。反应混合物在110℃下搅拌18小时。反应的完成通过LCMS监测。反应混合物用饱和氯化铵溶液稀释并用乙酸乙酯(100mL)萃取。有机层经硫酸钠干燥,过滤并减压蒸发以得到粗品1.5g。该粗品经C18(24gms,反相柱,silicycle)纯化,用40%乙腈/10mM乙酸铵洗脱以得到浅黄色液体形式的3-(4-(5-(苄基氧基)吡啶-2-基)-2-甲基哌嗪-1-基)-1-(4-甲基苄基)吡咯烷-2-酮(650mg,0.994mmol,33.6%产率),通过LCMS测得纯度为72%。
LCMS:Column-Ascentis Express C18(50X2.1mm-2.7μm),流动相A:10mMNH4COOH/水:ACN(98:02),流动相B:10mM NH4COOH/水:ACN(02:98),流速=1ml/min,时间:%B::0.0:0.0::1.7:100.0::3.0:100.0,3.2:0.0,RT-2.489min,M(+1)-471。
流程6:
步骤1:1-(5-(苄基氧基)吡啶-2-基)-3,3-二甲基哌嗪
向5-(苄基氧基)-2-氯吡啶(1.731g,7.88mmol)的1,4-二氧六环(20mL)溶液中加入2,2-二甲基哌嗪(1g,8.76mmol)、BINAP(0.545g,0.876mmol)、叔丁醇钠(2.104g,21.89mmol)。反应混合物用氮气吹扫15分钟并加入Pd2(dba)3(0.642g,0.701mmol)。在氮气下使反应混合物回流5小时。反应的完成通过LCMS监测。反应混合物用水50mL稀释并且产物用乙酸乙酯(3*50mL)萃取。合并的有机层用盐水溶液(100mL)洗涤、经硫酸钠干燥并减压蒸发以得到粗残余物3g。该粗品通过120g C18Redisep反相柱纯化,用40%乙腈+60%10mM乙酸铵洗脱以得到1-(5-(苄基氧基)吡啶-2-基)-3,3-二甲基哌嗪(1.3g,4.33mmol,49.4%产率)。
LCMS:ACN/(H2O+HCOONH4),Ascentis Express C18(50x2.1mm-2.7μm),梯度=1.7min,波长=220nm,RT-1.94min,M(+1)-298。
步骤2:(R)-3-(4-(5-(苄基氧基)吡啶-2-基)-2,2-二甲基哌嗪-1-基)-1-(4-甲基苄基)吡咯烷-2-酮。
在室温下向3-溴-1-(4-甲基苄基)吡咯烷-2-酮(135mg,0.504mmol)的DMF(2mL)溶液中加入1-(5-(苄基氧基)吡啶-2-基)-3,3-二甲基哌嗪(100mg,0.336mmol)和TEA(0.047mL,0.336mmol)。反应混合物在120℃下在CEN微波中加热1.5小时。反应的完成通过LCMS监测。往反应混合物中加入水(25mL)并且产物用乙酸乙酯(3*15mL)萃取,合并的有机层经硫酸钠干燥、过滤并减压蒸发以得到粗残余物0.3g。粗产物经历反相C18,24g硅胶柱纯化,用80%乙腈+20%10mM TFA洗脱以得到(R)-3-(4-(5-(苄基氧基)吡啶-2-基)-2,2-二甲基哌嗪-1-基)-1-(4-甲基苄基)吡咯烷-2-酮(25mg,0.046mmol,13.81%产率)。
LCMS:ACN/(H2O+HCOONH4),Ascentis Express C18(50x2.1mm-2.7μm),梯度=1.7min,波长=220nm,RT–2.562min,M(+1)-485。
通用中间体
实施例1(外消旋体):1-(4-氯-3-氟苯基)-3-(4-(5-羟基嘧啶-2-基)哌嗪-1-基)吡咯烷-2-酮。
在-78℃下往搅拌的1-(4-氯-3-氟苯基)-3-(4-(5-甲氧基嘧啶-2-基)哌嗪-1-基)吡咯烷-2-酮(60mg,0.148mmol)的DCM(8mL)溶液中缓慢加入BBr3/DCM(5mL,5.00mmol)。反应混合物在室温下搅拌12小时。反应的完成通过LCMS监测。将反应混合物冷却至0℃并用饱和碳酸氢钠溶液(25mL)猝灭。产物用DCM(2*25mL)萃取,合并的有机层经无水硫酸钠干燥,过滤并减压蒸发以得到粗化合物。粗化合物送至SCP。采用以下条件通过制备型LC/MS纯化粗物质:Waters Xbridge C18,19x150mm,5μm;Guard柱:Waters XBridge C18,19x10mm,5μm;流动相A:5:95乙腈:(10mM NH4OAc/水);流动相B:95:5乙腈:(10mM NH4OAc/水);梯度:5-35%B经25分钟,接着在35%B下保持10分钟并在100%B下保持5分钟;流速:15ml/min。合并含有所需产物的级分并使用Genevac离心蒸发器干燥以得到浅黄色固体形式的1-(4-氯-3-氟苯基)-3-(4-(5-羟基嘧啶-2-基)哌嗪-1-基)吡咯烷-2-酮(29.1mg,0.148mmol,50.2%产率)。使用两次分析型LC/MS注射来确定最终纯度。
注射1条件:柱:Ascentis Express C18(50x2.1)mm,2.7μm;流动相A:5:95乙腈:(10mM NH4OAc/水);流动相B:95:5乙腈:(10mM NH4OAc/水);温度:50℃;梯度:0-100%B经3分钟;流速:1.1ml/min。
注射2条件:柱:Ascentis Express C18(50x2.1)mm,2.7μm;流动相A:5:95乙腈:(0.1%TFA/水);流动相B:95:5乙腈:(0.1%TFA/水);温度:50℃;梯度:0-100%B经3分钟;流速:1.1ml/min。
LCMS:A:95%水:5%乙腈;10mM NH4OAc,B:5%水:95%乙腈;10mM NH4OAc,流速:1.1ml/min,温度:50℃,柱:Ascentis Express C18(50x2.1)mm,2.7μm,时间(min):0---3,%B:0---100,LCMS RT=1.34min(M+H,392)。
1H NMR:(400MHz,甲醇-d4)δ=8.03(s,2H),7.87-7.81(m,1H),7.54-7.39(m,2H),3.90-3.70(m,7H),3.04-2.95(m,2H),2.76-2.68(m,2H),2.39-2.31(m,1H),2.27-2.16(m,1H)。
实施例2(P1&P2):
往搅拌的(S)-甲磺酸1-(4-甲基苄基)-2-氧代吡咯烷-3-基酯(0.108g,0.382mmol)的ACN(5mL)溶液中加入6-(哌嗪-1-基)吡啶-3-醇(0.057g,0.318mmol)和DIPEA(0.139mL,0.795mmol)并加热至80℃历时16小时。反应的完成通过LCMS监测。将反应混合物冷却至RT。反应混合物用水(15mL)稀释,分离水层并用EtOAc(3×25mL)萃取。合并的有机层用水(15mL)和盐水(15mL)洗涤并经硫酸钠干燥。过滤混合物,真空去除溶剂以得到粗产物。粗化合物通过SCP纯化。采用以下条件经由制备型LC/MS纯化粗物质:Waters Xbridge C18,19x150mm,5μm;Guard Column:Waters XBridge C18,19x10mm,5μm;流动相A:5:95乙腈:(10mM NH4OAc/水);流动相B:95:5乙腈:(10mM NH4OAc/水);梯度:5-30%B经25分钟,接着在30%B下保持10分钟并在100%B下保持5分钟;流速:15ml/min。合并含有所需产物的级分并使用Genevac离心蒸发器干燥以得到浅黄色固体形式的2;3-(4-(5-羟基吡啶-2-基)哌嗪-1-基)-1-(4-甲基苄基)吡咯烷-2-酮(30mg,0.0816mmol,25.74%产率)。使用两次分析型LC/MS注射来确定最终纯度。
注射1条件:柱:Ascentis Express C18(50x2.1)mm,2.7μm;流动相A:5:95乙腈:(10mM NH4OAc/水);流动相B:95:5乙腈:(10mM NH4OAc/水);温度:50℃;梯度:0-100%B经3分钟;流速:1.1ml/min。
注射2条件:柱:Ascentis Express C18(50x2.1)mm,2.7μm;流动相A:5:95乙腈:(0.1%TFA/水);流动相B:95:5乙腈:(0.1%TFA/水);温度:50℃;梯度:0-100%B经3分钟;流速:1.1ml/min。
化合物2的手性筛选示出了两个峰,表明外消旋化。外消旋混合物2送去SPC进行手性分离。收集来自SFC的级分并浓缩以得到P1;(S)-3-(4-(5-羟基吡啶-2-基)哌嗪-1-基)-1-(4-甲基苄基)吡咯烷-2-酮和P2;(R)-3-(4-(5-羟基吡啶-2-基)哌嗪-1-基)-1-(4-甲基苄基)吡咯烷-2-酮。
该化合物记作BMT-17328301-003(57%ee)。
通过SFC纯化BMT-173283-01-003(98564-126-02)ee:57%。
手性筛选:注射体积:10,共溶剂:0.3%DEA/甲醇,柱:Chiralcel OD-H(4.6X250)mm,5u,柱温:23.2,总流速:3,CO2流速:1.8,共溶剂流速:1.2,共溶剂%:40,背压:101。
峰信息:
SFC纯化方法:
分析型SFC条件:柱/尺寸:Chiralcel OD-H(250X 4.6)mm,5u,%CO2:60%,%共溶剂:40%(0.25%DEA/甲醇),总流速:3.0g/min,背压:100bar,温度:25℃,UV:244。
制备型SFC条件:柱/尺寸:Chiralcel OD-H(250X 21)mm,5u,%CO2:60%,%共溶剂:40%(0.25%DEA/甲醇),总流速:75.0g/min,背压:100bar,温度:25℃,UV:244,峰号:保留时间::峰1:3.00::峰2:4.00,溶解度:5ml甲醇(5ml in methanol),加载能力/注射:9.00mg/mL,总注射No:15,总纯化时间1.0小时,仪器详情:Make/型号:Thar SFC-80。
对于P1(同手性):(S)-3-(4-(5-羟基吡啶-2-基)哌嗪-1-基)-1-(4-甲基苄基)吡咯烷-2-酮
LCMS:Column-Ascentis Express C18(50X2.1mm-2.7μm),流动相A:0.1%HCOOH/水,流动相B:CAN,流速=1ml/min,时间:%A:%B::0.0:100.0:0.0::1.7:0.0:100.0::3.2:0.0:100.0,RT–1.669,M(+1)-367。
手性纯度:注射体积:10,共溶剂:0.3%DEA/甲醇,柱:Chiralcel OD-H(4.6X250)mm,5u,柱温:23.7,总流速:3,CO2流速:1.8,共溶剂流速:1.2,共溶剂%:40,背压:99,RT-2.9min。
1H NMR:400MHz,MeOD:δ2.03-2.09(m,1H),2.22(t,J=7.60Hz,1H),2.32(s,3H),2.78(t,J=11.20Hz,2H),3.11(t,J=21.20Hz,2H),3.21-3.27(m,2H),3.42-3.43(m,4H),3.71(t,J=17.20Hz,1H),4.37(d,J=14.80Hz,1H),4.49(d,J=14.40Hz,1H),6.81(d,J=10.00Hz,1H),7.13-7.19(m,5H),7.73(d,J=2.80Hz,1H)。
对于P2(同手性):(R)-3-(4-(5-羟基吡啶-2-基)哌嗪-1-基)-1-(4-甲基苄基)吡咯烷-2-酮
手性纯度:注射体积:10,共溶剂:0.3%DEA/甲醇,柱:Chiralcel OD-H(4.6X250)mm,5u,柱温:23.7,总流速:3,CO2流速:1.8,共溶剂流速:1.2,共溶剂%:40,背压:99,RT-4.95min。
LCMS:Column-Ascentis Express C8(50X2.1mm-2.7μm),流动相A:2%ACN-98%H2O-10mM NH4COOH,流动相B:98%ACN-2%H2O-10mM NH4COOH,流速=1ml/min,时间:%A::0.0:0.0::1.5:100.0::3.2:100.0,RT–1.733,M(+1)-367。
1NMR:400MHz,MeOD:δ2.01-2.08(m,1H),2.15-2.20(m,1H),2.32(s,3H),2.67-2.73(m,2H),2.98-3.03(m,2H),3.19-3.26(m,2H),3.38(t,J=10.40Hz,4H),3.62(t,J=17.60Hz,1H),4.36(d,J=14.40Hz,1H),4.49(d,J=14.40Hz,1H),6.77(d,J=8.80Hz,1H),7.13-7.73(m,5H),7.73(d,J=2.80Hz,1H)。
实施例3(外消旋体):3-(4-(5-羟基嘧啶-2-基)哌嗪-1-基)-1-(4-甲基苄基)吡咯烷-2-酮
在-78℃往搅拌的3-(4-(5-甲氧基嘧啶-2-基)哌嗪-1-基)-1-(4-甲基苄基)吡咯烷-2-酮(60mg,0.157mmol)的DCM(8mL)溶液中缓慢加入BBr3/DCM(5mL,5.00mmol)。反应混合物在室温下搅拌12小时。反应的完成通过LCMS监测。将反应混合物冷却至0℃并用饱和NaHCO3溶液猝灭并用DCM(2x25mL)萃取,有机层经硫酸钠干燥并减压蒸发以得到粗化合物75mg。粗化合物送至SCP。采用以下条件经由制备型LC/MS纯化粗物质:Waters XbridgeC18,19x150mm,5μm;Guard柱:Waters XBridge C18,19x10mm,5μm;流动相A:5:95乙腈:(10mM NH4OAc/水);流动相B:95:5乙腈:(10mMNH4OAc/水);梯度:5-35%B经25分钟,接着在35%B下保持10分钟并在100%B下保持5分钟;流速:15ml/min。合并含有所需产物的级分并使用Genevac离心蒸发器干燥以得到浅黄色固体形式的3-(4-(5-羟基嘧啶-2-基)哌嗪-1-基)-1-(4-甲基苄基)吡咯烷-2-酮(15.1mg,0.041mmol,26.1%产率)。使用两次分析型LC/MS注射来确定最终纯度。
注射1条件:柱:Ascentis Express C18(50x2.1)mm,2.7μm;流动相A:5:95乙腈:(10mM NH4OAc/水);流动相B:95:5乙腈:(10mM NH4OAc/水);温度:50℃;梯度:0-100%B经3分钟;流速:1.1ml/min。
注射2条件:柱:Ascentis Express C18(50x2.1)mm,2.7μm;流动相A:5:95乙腈:(0.1%TFA/水);流动相B:95:5乙腈:(0.1%TFA/水);温度:50℃;梯度:0-100%B经3分钟;流速:1.1ml/min。
1H NMR:(400MHz,甲醇-d4)δ=8.03(s,2H),7.17(d,J=2.0Hz,4H),4.53-4.46(m,1H),4.41-4.33(m,1H),3.74-3.59(m,5H),3.30-3.19(m,3H),2.97-2.88(m,4H),2.68-2.59(m,2H),2.34(s,3H),2.24-2.14(m,1H),2.10-1.98(m,1H)。
LCMS方法信息:A:95%水:5%乙腈;10mM NH4OAc,B:5%水:95%乙腈;10mMNH4OAc,流速:1.1ml/min,温度:50℃,柱:Ascentis Express C18(50x2.1)mm,2.7μm,时间(min):0---3,%B:0---100,LCMS RT=1.24min,M(+1)-368。
手性筛选:注射体积:10,共溶剂:0.3%DEA/甲醇,柱:Lux Cellulose 4(250X4.6)mm,5u,柱温;27.1,总流速:4,CO2流速:2.4,共溶剂流速:1.6,共溶剂%:40,背压:99,手性保留时间:5.59min。
实施例4:
1-(3-氟-4-(三氟甲氧基)苯基)-3-(4-(5-羟基吡啶-2-基)哌嗪-1-基)吡咯烷-2-酮
经1分钟向加热至80℃的6-(哌嗪-1-基)吡啶-3-醇盐酸盐(20mg,0.093mmol)的乙腈(2mL)溶液和DIPEA(0.049mL,0.278mmol)中加入甲磺酸1-(3-氟-4-(三氟甲氧基)苯基)-2-氧代吡咯烷-3-基酯(43.1mg,0.121mmol)的乙腈(1mL)溶液。随后将混合物在80℃下搅拌16小时。让混合物冷却至室温并随后浓缩。残余物通过SCP纯化。采用以下条件经由制备型LC/MS纯化粗物质:Waters Xbridge C18,19x150mm,5μm;Guard Column:Waters XBridgeC18,19x10mm,5μm;流动相A:5:95乙腈:(10mM NH4OAc/水);流动相B:95:5乙腈:(10mMNH4OAc/水);梯度:10-45%B经25分钟,接着在45%B下保持10分钟并在100%B下保持5分钟;流速:15ml/min。合并含有所需产物的级分并使用Genevac离心蒸发器干燥以得到浅黄色固体形式的1-(3-氟-4-(三氟甲氧基)苯基)-3-(4-(5-羟基吡啶-2-基)哌嗪-1-基)吡咯烷-2-酮(1.5mg,3.34μmol,3.60%产率)。使用两次分析型LC/MS注射来确定最终纯度。
注射1条件:柱:Ascentis Express C18(50x2.1)mm,2.7μm;流动相A:5:95乙腈:(10mM NH4OAc/水);流动相B:95:5乙腈:(10mM NH4OAc/水);温度:50℃;梯度:0-100%B经3分钟;流速:1.1ml/min。
注射2条件:柱:Ascentis Express C18(50x2.1)mm,2.7μm;流动相A:5:95乙腈:(0.1%TFA/水);流动相B:95:5乙腈:(0.1%TFA/水);温度:50℃;梯度:0-100%B经3分钟;流速:1.1ml/min。
1H NMR:(400MHz,DMSO-d6)δppm 8.87-9.06(m,1H)7.90-7.99(m,1H)7.71-7.78(m,1H)7.53-7.64(m,2H)6.98-7.13(m,2H)6.67-6.76(m,1H)3.64-3.87(m,3H)2.89-2.99(m,2H)2.57-2.71(m,2H)2.18-2.37(m,1H)2.00-2.13(m,1H)。
LCMS:方法信息:A:95%水:5%乙腈;10mM NH4OAc,B:5%水:95%乙腈;10mMNH4OAc,流速:1.1ml/min,温度:50℃,柱:Ascentis Express C18(50x2.1)mm,2.7μm,时间(min):0---3,%B:0---100,RT-1.49min,M(+1)-441。
实施例5:
经1分钟向加热至80℃的6-(哌嗪-1-基)吡啶-3-醇盐酸盐(20mg,0.093mmol)的乙腈(2mL)溶液和DIPEA(0.049mL,0.278mmol)中加入甲磺酸1-(3-氟-4-(三氟甲氧基)苯基)-2-氧代吡咯烷-3-基酯(25mg,0.070mmol)的ACN(1mL)溶液。反应混合物在80℃下搅拌12小时。反应的完成通过LCMS监测。将反应混合物冷却至室温并减压蒸发以得到粗化合物,将粗化合物送至SCP。采用以下条件经由制备型LC/MS纯化粗物质:Waters Xbridge C18,19x150mm,5μm;Guard Column:Waters XBridge C18,19x10mm,5μm;流动相A:5:95乙腈:(10mM NH4OAc/水);流动相B:95:5乙腈:(10mMNH4OAc/水);梯度:10-45%B经25分钟,接着在45%B下保持10分钟并在100%B下保持5分钟;流速:15ml/min。合并含有所需产物的级分并使用Genevac离心蒸发器干燥以得到浅黄色固体形式的1-(3-氟-4-(三氟甲氧基)苯基)-3-(4-(5-羟基吡啶-2-基)哌嗪-1-基)吡咯烷-2-酮(4.7mg,10.25μmol,11.05%产率)。使用两次分析型LC/MS注射来确定最终纯度。
注射1条件:柱:Ascentis Express C18(50x2.1)mm,2.7μm;流动相A:5:95乙腈:(10mM NH4OAc/水);流动相B:95:5乙腈:(10mM NH4OAc/水);温度:50℃;梯度:0-100%B经3分钟;流速:1.1ml/min。
注射2条件:柱:Ascentis Express C18(50x2.1)mm,2.7μm;流动相A:5:95乙腈:(0.1%TFA/水);流动相B:95:5乙腈:(0.1%TFA/水);温度:50℃;梯度:0-100%B经3分钟;流速:1.1ml/min。
LCMS:方法信息:A:95%水:5%乙腈;10mM NH4OAc,B:5%水:95%乙腈;10mMNH4OAc,流速:1.1ml/min,温度:50℃,柱:Ascentis Express C18(50x2.1)mm,2.7μm,时间(min):0---3,%B:0---100,RT-1.484min,M(+1)-441。
1H NMR:400MHz,DMSO-d6:δ8.98(br s,1H),7.93-7.69(m,2H),7.73-7.74(m,1H),7.59(s,2H),6.95-7.20(m,1H),6.71-6.95(m,1H),3.71-3.81(m,3H),3.32-3.37(m,4H),2.89-2.94(m,2H),2.60-2.73(m,2H),2.24-2.45(m,2H)。
实施例6(P1&P2):
将搅拌的3-溴-1-(4-氟苄基)吡咯烷-2-酮(0.042g,0.153mmol)、6-(哌嗪-1-基)吡啶-3-醇.HCl(0.03g,0.139mmol)和DIPEA(0.024mL,0.139mmol)的乙腈(5mL)溶液在90℃下加热18小时。反应的完成通过LCMS监测。将反应混合物冷却至室温。反应混合物用水(15mL)稀释和分离水层并用EtOAc(3×25mL)萃取。合并的有机层用水(15mL)和盐水(15mL)洗涤并经硫酸钠干燥。过滤混合物,真空去除溶剂以得到粗产物。粗品送至SCP。采用以下条件经由制备型LC/MS纯化粗物质:Waters Xbridge C18,19x150mm,5μm;Guard Column:Waters XBridge C18,19x10mm,5μm;流动相A:5:95乙腈:(10mM NH4OAc/水);流动相B:95:5乙腈:(10mM NH4OAc/水);梯度:10-30%B经25分钟,接着在30%B下保持10分钟并在100%B下保持5分钟;流速:15ml/min。合并含有所需产物的级分并使用Genevac离心蒸发器干燥以得到浅黄色固体形式的(+/-)1-(4-氟苄基)-3-(4-(5-羟基吡啶-2-基)哌嗪-1-基)吡咯烷-2-酮(45.1mg,0.122mmol,88%产率)。使用两次分析型LC/MS注射来确定最终纯度。
注射1条件:柱:Ascentis Express C18(50x2.1)mm,2.7μm;流动相A:5:95乙腈:(10mM NH4OAc/水);流动相B:95:5乙腈:(10mM NH4OAc/水);温度:50℃;梯度:0-100%B经3分钟;流速:1.1ml/min。
注射2条件:柱:Ascentis Express C18(50x2.1)mm,2.7μm;流动相A:5:95乙腈:(0.1%TFA/水);流动相B:95:5乙腈:(0.1%TFA/水);温度:50℃;梯度:0-100%B经3分钟;流速:1.1ml/min。
外消旋化合物通过手性SFC分离。
SFC纯化方法:
分析型SFC条件:柱/尺寸:Chiralcel OD-H(250X 4.6)mm,5u,%CO2:60%,%共溶剂:40%(0.25%DEA/甲醇),总流速:3.0g/min,背压:100bar,温度:25℃,UV:243。
制备型SFC条件:柱/尺寸:Chiralcel OD-H(250X 21)mm,5u,%CO2:60%,%共溶剂:40%(0.25%DEA/甲醇),总流速:70.0g/min,背压:100bar,温度:25℃,UV:243,峰号:保留时间::峰1:3.00::峰2:4.00,溶解度:甲醇+THF(1:1)5ml,加载能力/注射:8.00mg/mL,总注射No:15,总纯化时间1.0小时,仪器详情:Make/型号:Thar SFC-80
手性纯化产生1-(4-氟苄基)-3-(4-(5-羟基吡啶-2-基)哌嗪-1-基)吡咯烷-2-酮(17mg,0.046mmol,33.0%产率)和1-(4-氟苄基)-3-(4-(5-羟基吡啶-2-基)哌嗪-1-基)吡咯烷-2-酮(14mg,0.038mmol,27.2%产率)。
对于P1(同手性):1-(4-氟苄基)-3-(4-(5-羟基吡啶-2-基)哌嗪-1-基)吡咯烷-2-酮
LCMS:Column-Ascentis Express C18(50X2.1mm-2.7μm),流动相A:10mMNH4COOH/水:ACN(98:02),流动相B:10mM NH4COOH/水:ACN(02:98),流速=1ml/min,时间:%B::0.0:0.0::1.7:100.0::3.0:100.0::3.2:0.0,RT-2.182min,M(+1)–371。
手性纯度:注射体积:10,共溶剂:0.3%DEA/甲醇,柱:Chiralcel OD-H(4.6X250)mm,5u,柱温:23.4,总流速:3,CO2流速:1.8,共溶剂流速:1.2,共溶剂%:40,背压:100,RT-2.57min。
1H NMR:400MHz,MeOD:δ2.05(t,J=15.20Hz,1H),2.15-2.20(m,1H),2.67-2.71(m,2H),2.97-3.00(m,2H),3.23-3.28(m,2H),3.42-3.43(m,2H),3.60(t,J=17.60Hz,1H),4.40(d,J=14.40Hz,1H),4.51(d,J=14.80Hz,1H),6.76(d,J=8.80Hz,1H),7.06-7.10(m,2H),7.12-7.15(m,1H),7.28-7.32(m,2H),7.73-7.74(m,1H)。
对于P2(同手性):1-(4-氟苄基)-3-(4-(5-羟基吡啶-2-基)哌嗪-1-基)吡咯烷-2-酮
LCMS:Column-Ascentis Express C18(50X2.1mm-2.7μm),流动相A:10mMNH4COOH/水:ACN(98:02),流动相B:10mM NH4COOH/水:ACN(02:98),流速=1ml/min,时间:%B::0.0:0.0::1.7:100.0::3.0:100.0::3.2:0.0,RT-2.188min,M(+1)–371。
手性纯度:注射体积:10,共溶剂:0.3%DEA/甲醇,柱:Chiralcel OD-H(4.6X250)mm,5u,柱温:23.4,总流速:3,CO2流速:1.8,共溶剂流速:1.2,共溶剂%:40,背压:100,RT-4.11min。
1H NMR:400MHz,MeOD:δ2.02-2.11(m,1H),2.16-2.20(m,1H),2.65-2.71(m,2H),2.96-3.02(m,2H),3.21-3.28(m,2H),3.30-3.38(m,4H),3.60(t,J=17.60Hz,1H),4.43(d,J=-8.40Hz,1H),4.51(d,J=14.80Hz,1H),6.76(d,J=8.80Hz,1H),7.06-7.10(m,2H),7.12-7.15(m,1H),7.28-7.32(m,2H),7.74(d,J=2.80Hz,1H)。
实施例7(P1&P2):
在室温下向6-(哌嗪-1-基)吡啶-3-醇(250mg,1.395mmol)的乙腈(10mL)溶液中加入三乙胺(706mg,6.97mmol)和3-溴-1-(3-氯-4-(二氟甲氧基)苯基)吡咯烷-2-酮(475mg,1.395mmol)。反应混合物在90℃下在CEM微波下搅拌1.5小时。反应的完成通过LCMS监测。反应混合物用饱和氯化铵(50mL)稀释并且产物用乙酸乙酯(50mL)萃取。有机层经硫酸钠干燥并减压蒸发以得到粗残余物0.9g。粗品纯度:51%。粗品通过反相HPLC纯化以得到(+/-)1-(3-氯-4-(二氟甲氧基)苯基)-3-(4-(5-羟基吡啶-2-基)哌嗪-1-基)吡咯烷-2-酮(100mg,0.227mmol,16.33%产率)。
HPLC方法信息:柱:SUNFIRE C18250X3010u,流动相A:10mM NH4OAc/水,流动相B:CAN溶解度:CAN+THF,流速:30ml/min,加载能力:50mg,T/%B:0/30,10/60,注射No:16,总纯化时间:8min。
LCMS(TFA):RT0.67min;{流动相A:0.1%TFA/水,流动相B:乙腈}Acquity BEH C18(2.1x 50mm)1.7u,梯度=2.25min,波长=220nm;MS(ES):m/z 439M+H。
外消旋混合物经历SFC纯化以得到异构体P1、异构体P2。
制备型SFC条件:柱/尺寸:Luxcellulose-2(250X 21.5)mm,5u,%CO2:60%,%共溶剂:40%(0.25%DEA/甲醇),总流速:70.0g/min,背压:100bar,温度:25℃,UV:247,峰号:保留时间::峰1:4.30::峰2:5.90,溶解度:甲醇30.0ml。
对于P1(同手性):1-(3-氯-4-(二氟甲氧基)苯基)-3-(4-(5-羟基吡啶-2-基)哌嗪-1-基)吡咯烷-2-酮
HPLC:95/5至5/95H2O/CH3CN/0.05%TFA,流速=1mL/min,梯度=15min,SunfireC18 4.6x150mm:RT=5.59min;纯度@220nm:94.033%;@254nm:94.16%.Xbridge Phenyl3.5um,4.6x150mm:RT=6.55min;纯度@220nm:89.82%;@254nm:92.52%。
LCMS:Column-Ascentis Express C18(50X2.1mm-2.7μm),流动相A:10mMNH4COOH/水:ACN(98:02),流动相B:10mM NH4COOH/水:ACN(02:98),流速=1ml/min,时间:%B::0.0:0.0::1.7:100.0::3.0:100.0::3.2:0.0,RT-2.072min,M(+1)-439。
SFC:CO23.0_Colvent_100.met;流速:-总流速3,CO2流速2.1,共溶剂(0.3%DEA/甲醇)0.9;柱:-ChiralpakAD H(250x 4.6)mm 5μ;RT 3.17min,纯度@217nm:100%。
1H NMR:400MHz,MeOD:δ2.18-2.24(m,1H),2.31-2.35(m,1H),2.73-2.78(m,2H),3.02-3.07(m,2H),3.31-3.41(m,4H),3.72-3.85(m,3H),6.65-7.02(m,2H),7.13-7.16(m,1H),7.32(d,J=9.20Hz,1H),7.57-7.60(m,1H),7.74(d,J=3.20Hz,1H),7.89(d,J=75.60Hz,1H)。
对于P2(同手性):(1-(3-氯-4-(二氟甲氧基)苯基)-3-(4-(5-羟基吡啶-2-基)哌嗪-1-基)吡咯烷-2-酮。
HPLC:95/5至5/95H2O/CH3CN/0.05%TFA,流速=1mL/min,梯度=15min,SunfireC184.6x150mm:RT=5.6min;纯度@220nm:93.02%;@254nm:93.29%.Xbridge Phenyl3.5um,4.6x150mm:RT=6.536min;纯度@220nm:91.18%;@254nm:93.24%。
LCMS:Column-Ascentis Express C18(50X2.1mm-2.7μm),流动相A:10mMNH4COOH/水:ACN(98:02),流动相B:10mM NH4COOH/水:ACN(02:98),流速=1ml/min,时间:%B::0.0:0.0::1.7:100.0::3.0:100.0::3.2:0.0,RT:2.068min,M(+1)-439。
SFC:CO23.0_Colvent_100.met;流速:-总流速3,CO2流速2.1,共溶剂(0.3%DEA/甲醇)0.9;柱:-ChiralpakAD H(250x 4.6)mm 5μ;RT 4min;纯度@217nm:98.86%。
1H NMR:400MHz,MeOD:δ2.16-2.26(m,1H),2.32-2.38(m,1H),2.73-2.78(m,2H),3.03-3.07(m,2H),3.38-3.41(m,4H),3.72-3.84(m,3H),6.65-7.02(m,2H),7.13-7.16(m,1H),7.32(d,J=9.20Hz,1H),7.57-7.60(m,1H),7.74(d,J=3.20Hz,1H),7.89(d,J=75.60Hz,1H)。
实施例8(P1&P2):
程序:在室温下将DIPEA(0.039mL,0.223mmol)加入搅拌的6-(哌嗪-1-基)吡啶-3-醇(0.04g,0.223mmol)的乙腈(5mL)溶液中并加热至50℃,在5分钟后,将甲磺酸1-(4-氯-3-氟苯基)-2-氧代吡咯烷-3-基酯(0.124g,0.402mmol)溶解于乙腈(5mL)。反应在85℃下加热18小时。反应的完成通过LCMS监测。将反应混合物蒸发至干并送至SCP纯化。8的手性筛分显示了两个主要峰,表明外消旋化。外消旋混合物8;1-(4-氯-3-氟苯基)-3-(4-(5-羟基吡啶-2-基)哌嗪-1-基)吡咯烷-2-酮(20mg,0.051mmol,22.8%产率)通过SFC分离,得到P1;1-(4-氯-3-氟苯基)-3-(4-(5-羟基吡啶-2-基)哌嗪-1-基)吡咯烷-2-酮和P2;1-(4-氯-3-氟苯基)-3-(4-(5-羟基吡啶-2-基)哌嗪-1-基)吡咯烷-2-酮。
8的手性筛选:注射体积:10,共溶剂:0.3%DEA/甲醇,柱:Chiralcel OD-H(4.6X250)mm,5u,柱温:26,总流速:4,CO2流速:2.4,共溶剂流速:1.6,共溶剂%:40,背压:129。
峰信息
SFC纯化方法
分析型SFC条件:柱/尺寸:Chiralcel OD-H(250X 4.6)mm,5u,%CO2:60%,%共溶剂:40%(0.25%DEA/甲醇),总流速:4.0g/min,背压:100bar,温度:25℃,UV:247。
制备型SFC条件:柱/尺寸:Chiralcel OD-H(250X 21)mm,5u,%CO2:60%,%共溶剂:40%(0.25%DEA/甲醇),总流速:70.0g/min,背压:100bar,温度:25℃,UV:247。
对于P1(同手性):
1H NMR:(400MHz,甲醇-d4)δ=7.85(dd,J=2.5,12.0Hz,1H),7.76(d,J=2.5Hz,1H),7.53-7.40(m,2H),7.20-7.10(m,1H),6.79(d,J=9.0Hz,1H),3.94-3.71(m,3H),3.53-3.39(m,4H),3.20-3.00(m,3H),2.78(s,2H),2.27-2.16(m,2H)。
LCMS:Column-Ascentis Express C18(50X2.1mm-2.7μm),流动相A:10mMNH4COOH/水:ACN(98:02),流动相B:10mM NH4COOH/水:ACN(02:98),流速=1ml/min,时间:%B::0.0:0.0::1.7:100.0::3.0:100.0::3.20.0,RT-2.18min,M(+1)-391。
手性纯度:注射体积:5,共溶剂:0.3%DEA/甲醇,柱:chiralpak-ODH(4.6*250)mm5u,柱温:22.6,CO2流速:2.4,共溶剂流速:1.6,共溶剂:40,总流速:4,背压:97,RT-3.15min。*****
对于P2(同手性):
LCMS:Column-Ascentis Express C18(50X2.1mm-2.7μm),流动相A:10mMNH4COOH/水:ACN(98:02),流动相B:10mM NH4COOH/水:ACN(02:98),流速=1ml/min,时间:%B::0.0:0.0::1.7:100.0::3.0:100.0::3.2:0.0,RT-2.21min,M(+1)-391。
1H NMR:(400MHz,甲醇-d4)δ=7.85(dd,J=2.5,12.0Hz,1H),7.76(d,J=2.5Hz,1H),7.53-7.40(m,2H),7.20-7.10(m,1H),6.79(d,J=9.0Hz,1H),3.94-3.71(m,3H),3.53-3.39(m,4H),3.20-3.00(m,3H),2.78(s,2H),2.27-2.16(m,2H)。
手性纯度:注射体积:5,共溶剂:0.3%DEA/甲醇,柱:chiralpak-ODH(4.6*250)mm5u,柱温:22.1,CO2流速:2.4,共溶剂流速:1.6,共溶剂:40,总流速:4,背压:101,RT–6.6min。
实施例9(P1&P2):
经1分钟向加热至80℃的6-(哌嗪-1-基)吡啶-3-醇(40mg,0.185mmol)的乙腈(2mL)溶液和DIPEA(0.097mL,0.556mmol)中加入(S)-甲磺酸1-(3-氟-4-甲基苄基)-2-氧代吡咯烷-3-基酯(84mg,0.278mmol))的乙腈(1mL)溶液。随后将混合物在80℃下搅拌16小时。让反应混合物冷却至室温并随后浓缩。残余物通过SCP纯化。采用以下条件经由制备型LC/MS纯化粗物质:Waters Xbridge C18,19x150mm,5μm;Guard柱:WatersXBridge C18,19x10mm,5μm;流动相A:5:95乙腈:(10mM NH4OAc/水);流动相B:95:5乙腈:(10mM NH4OAc/水);梯度:5-35%B经25分钟,接着在35%B下保持10分钟并在100%B下保持5分钟;流速:15ml/min。合并含有所需产物的级分并使用Genevac离心蒸发器干燥以得到浅黄色固体形式的(+/-)1-(3-氟-4-甲基苄基)-3-(4-(5-羟基吡啶-2-基)哌嗪-1-基)吡咯烷-2-酮(20mg,0.052mmol,27.8%产率)。
使用两次分析型LC/MS注射来确定最终纯度。
注射1条件:柱:Ascentis Express C18(50x2.1)mm,2.7μm;流动相A:5:95乙腈:(10mM NH4OAc/水);流动相B:95:5乙腈:(10mM NH4OAc/水);温度:50℃;梯度:0-100%B经3分钟;流速:1.1ml/min。
注射2条件:柱:Ascentis Express C18(50x2.1)mm,2.7μm;流动相A:5:95乙腈:(0.1%TFA/水);流动相B:95:5乙腈:(0.1%TFA/水);温度:50℃;梯度:0-100%B经3分钟;流速:1.1ml/min。
SFC纯化方法:
分析型SFC条件:柱/尺寸:Chiralcel OD-H(250X 4.6)mm,5u,%CO2:60%,%共溶剂:40%(0.25%DEA/甲醇),总流速:3.0g/min,背压:100bar,温度:25℃,UV:245。
制备型SFC条件:柱/尺寸:Chiralcel OD-H(250X 21)mm,5u,%CO2:60%,%共溶剂:40%(0.25%DEA/甲醇),总流速:60.0g/min,背压:100bar,温度:25℃,UV:245,峰号:保留时间,峰1:3.00::峰2:4.00,溶解度:甲醇10.0ml,加载能力/注射:5.00mg/mL,总注射No:10,总纯化时间1.0小时,仪器详情:Make/型号:Thar SFC-80。
对于P1(同手性):
LCMS:Column-Kinetex XB-C18(75X3mm-2.6μm),流动相A:10mM NH4COOH/水:ACN(98:02),流动相B:10mM NH4COOH/水:ACN(02:98),时间:%B:流速::0:20:1::4:100:1::4.6:100:1.5::4.7201.5,RT–1.653min,M(+1)–385。
1H NMR:(400MHz,DMSO-d6)δ=9.06-8.88(m,1H),7.79-7.68(m,1H),7.33-7.19(m,1H),7.10-7.03(m,1H),7.00-6.90(m,2H),6.76-6.65(m,1H),4.43-4.24(m,2H),3.52-3.40(m,1H),3.29-3.23(m,4H),3.20-3.01(m,2H),2.95-2.84(m,2H),2.22(d,J=1.5Hz,3H),2.15-2.02(m,1H),1.99-1.81(m,1H)。
手性纯度:注射体积:10,共溶剂:0.3%DEA/甲醇,
柱:Chiralcel OD-H(250X 4.6)mm,5u,柱温;27.1,总流速:4,CO2流速:2.4,共溶剂流速:1.6,共溶剂%:40,背压:99,RT-4.94min。
对于P2(同手性):
LCMS:Column-Kinetex XB-C18(75X3mm-2.6μm),流动相A:10mM NH4COOH/水:ACN(98:02),流动相B:10mM NH4COOH/水:ACN(02:98),时间:%B:流速::0:20:1::4:100:1::4.6:100:1.5::4.7201.5,RT–1.656min,M(+1)–385。
1H NMR:(400MHz,DMSO-d6)δ=9.02-8.90(m,1H),7.80-7.67(m,1H),7.34-7.23(m,1H),7.11-7.03(m,1H),7.00-6.90(m,1H),6.76-6.63(m,1H),4.44-4.24(m,2H),3.55-3.44(m,1H),3.30-3.22(m,4H),3.20-3.10(m,2H),2.96-2.87(m,2H),2.60-2.53(m,2H),2.22(d,J=1.0Hz,3H),2.16-2.03(m,1H),2.00-1.83(m,1H)。
手性纯度:注射体积;10,共溶剂:0.3%DEA/甲醇,柱:Chiralcel OD-H(4.6X250)mm,5u,柱温:23.5,总流速:3,CO2流速:1.8,共溶剂流速:1.2,共溶剂%:40,背压;100,RT-5.42min。
实施例10(同手性):
在80℃下经1.5小时向6-(哌嗪-1-基)吡啶-3-醇(0.111g,0.622mmol)的1.0mLCH3CN溶液和DIPEA(0.271mL,1.554mmol)中加入(S)-甲磺酸1-(4-氯-3-氟苄基)-2-氧代吡咯烷-3-基酯(0.2g,0.622mmol)的0.5mL CH3CN溶液。随后将混合物在80℃下搅拌16小时。反应的完成通过LCMS监测。将反应混合物冷却至室温并浓缩以得到粗品0.3g。粗残余物通过SCP纯化。采用以下条件经由制备型LC/MS纯化粗物质:Waters Xbridge C18,19x150mm,5μm;Guard Column:Waters XBridge C18,19x10mm,5μm;流动相A:5:95乙腈:(10mM NH4OAc/水);流动相B:95:5乙腈:(10mM NH4OAc/水);梯度:5-35%B经25分钟,接着在35%B下保持10分钟并在100%B下保持5分钟;流速:15ml/min。合并含有所需产物的级分并使用Genevac离心蒸发器干燥以得到(R)-1-(4-氯-3-氟苄基)-3-(4-(5-羟基吡啶-2-基)哌嗪-1-基)吡咯烷-2-酮(45mg,0.111mmol,16.63%产率)。使用两次分析型LC/MS注射来确定最终纯度。
注射1条件:Column:Ascentis Express C18(50x2.1)mm,2.7μm;流动相A:5:95乙腈:(10mM NH4OAc/水);流动相B:95:5乙腈:(10mM NH4OAc/水);温度:50℃;梯度:0-100%B经3分钟;流速:1.1ml/min。
注射2条件:柱:Ascentis Express C18(50x2.1)mm,2.7μm;流动相A:5:95乙腈:(0.1%TFA/水);流动相B:95:5乙腈:(0.1%TFA/水);温度:50℃;梯度:0-100%B经3分钟;流速:1.1ml/min。
手性筛选:注射体积:10,共溶剂:0.3%DEA/甲醇,柱:Chiralcel OD-H(4.6X250)mm,5u,柱温:24.3,总流速:3,CO2流速:1.95,共溶剂流速:1.05,共溶剂%:35,背压:101,RT-6.12min。
1H NMR:400MHz,DMSO-d6:δ7.73(s,1H),7.56(t,J=-8.00Hz,1H),7.26(d,J=12.00Hz,1H),7.06(t,J=36.00Hz,2H),6.69-6.71(m,4H),4.38(d,J=4.00Hz,2H),3.47(t,J=20.00Hz,1H),3.31-3.28(m,5H),3.27-3.19(m,2H),2.90(t,J=24.00Hz,2H),2.53(t,J=24.00Hz,2H),2.29-2.01(m,1H),1.95-1.89(m,1H)。
LCMS:A:95%水:5%乙腈;10mM NH4OAc,B:5%水:95%乙腈;10mM NH4OAc,流速:1.1ml/min,温度:50℃,柱:Ascentis Express C18(50x2.1)mm,2.7μm,时间(min):0---3,%B:0---100,RT-2.27min,M(+1)–405。
实施例11(P1&P2):
往搅拌的6-(哌嗪-1-基)吡啶-3-醇盐酸盐(70mg,0.325mmol)的干燥DMF(1.5mL)溶液中加入DIPEA(0.170mL,0.974mmol)和3-溴-1-(4-(三氟甲基)苄基)吡咯烷-2-酮(209mg,0.649mmol)。反应混合物在微波下在120℃下加热90分钟。反应的完成通过LCMS监视。反应混合物原样送至SCP。采用以下条件经由制备型LC/MS纯化粗物质:Waters XbridgeC18,19x150mm,5μm;Guard柱:Waters XBridge C18,19x10mm,5μm;流动相A:5:95乙腈:(10mM NH4OAc/水);流动相B:95:5乙腈:(10mM NH4OAc/水);梯度:5-35%B经25分钟,接着在35%B下保持10分钟并在100%B下保持5分钟;流速:15ml/min。合并含有所需产物的级分并使用Genevac离心蒸发器干燥以得到浅黄色固体形式的产物(60mg,0.142mmol,4.39%产率)。使用两次分析型LC/MS注射来确定最终纯度。
注射1条件:柱:Ascentis Express C18(50x2.1)mm,2.7μm;流动相A:5:95乙腈:(10mM NH4OAc/水);流动相B:95:5乙腈:(10mM NH4OAc/水);温度:50℃;梯度:0-100%B经3分钟;流速:1.1ml/min。
注射2条件:柱:Ascentis Express C18(50x2.1)mm,2.7μm;流动相A:5:95乙腈:(0.1%TFA/水);流动相B:95:5乙腈:(0.1%TFA/水);温度:50℃;梯度:0-100%B经3分钟;流速:1.1ml/min。
SFC纯化方法:
分析型SFC条件:柱/尺寸:chiralcel OD-H(250X 4.6)mm,5u,%CO2:60%,%共溶剂:40%(0.25%DEA/甲醇),总流速:3.0g/min,背压:100bar,温度:24℃,UV:210。
制备型SFC条件:柱/尺寸:chiralcel OD-H(250X 21.5)mm,5u,%CO2:60%,%共溶剂:40%(0.25%DEA/甲醇),总流速:60.0g/min,背压:100bar,温度:25℃,UV:210,峰号:保留时间::峰1:2.50::峰2:4.20,溶解度:甲醇6.0ml,加载能力/注射:2.5mg/mL,总注射No:12,总纯化时间1.0小时,仪器详情:Make/型号:Thar SFC-80。
对于P1(同手性):
3-(4-(5-羟基吡啶-2-基)哌嗪-1-基)-1-(4-(三氟甲基)苄基)吡咯烷-2-酮
LCMS:方法信息:Column-Ascentis Express C8(50X2.1mm-2.7μm),流动相A:2%ACN-98%H2O-10mM NH4COOH,流动相B:98%ACN-2%H2O-10mM NH4COOH,流速=1ml/min,时间:%B::0.0:0.0::1.7:100.0::4.0:100.0,RT-1.798min,M(+1)-421。
1H NMR:(400MHz,DMSO-d6)δ=9.10-8.88(m,1H),7.74(s,3H),7.50-7.41(m,2H),7.10-7.00(m,1H),6.76-6.65(m,1H),4.58-4.36(m,2H),3.64-3.44(m,2H),3.25-3.08(m,4H),2.99-2.87(m,3H),2.55(br.s.,4H),2.20-2.05(m,1H),2.01-1.80(m,1H)。
手性纯度:注射体积:10,共溶剂:0.3%DEA/甲醇,柱:Chiralcel OD-H(4.6X250)mm,5u,柱温:25.9,总流速:3,CO2流速:1.8,共溶剂流速:1.2,共溶剂%:40,背压:44,RT–3.05min。
对于P2(同手性):
3-(4-(5-羟基吡啶-2-基)哌嗪-1-基)-1-(4-(三氟甲基)苄基)吡咯烷-2-酮
LCMS:方法信息:Column-Ascentis Express C8(50X2.1mm-2.7μm),流动相A:2%ACN-98%H2O-10mM NH4COOH,流动相B:98%ACN-2%H2O-10mM NH4COOH,流速=1ml/min,时间:%B::0.0:0.0::1.7:100.0::4.0:100.0,RT-1.793min,M(+1)-421。
1H NMR:(400MHz,DMSO-d6)δ=9.04-8.92(m,1H),7.74(br.s.,3H),7.51-7.42(m,2H),7.10-7.02(m,1H),6.76-6.66(m,1H),4.57-4.38(m,2H),3.54-3.44(m,1H),3.26-3.13(m,3H),2.97-2.86(m,2H),2.63-2.54(m,5H),2.18-2.07(m,1H),2.01-1.92(m,1H)。
手性纯度:注射体积:10,共溶剂:0.3%DEA/甲醇,柱:Chiralcel OD-H(4.6X250)mm,5u,柱温:25.8,总流速:3,CO2流速:1.8,共溶剂流速:1.2,共溶剂%:40,背压:52,RT–3.94min。
实施例12(同手性):
经1分钟向加热至80℃的6-(哌嗪-1-基)吡啶-3-醇(20mg,0.112mmol)的乙腈(2mL)溶液和DIPEA(0.058mL,0.335mmol)中加入((S)-甲磺酸1-(4-氯苄基)-2-氧代吡咯烷-3-基酯(50.8mg,0.167mmol)的乙腈(1mL)溶液。随后将混合物在80℃下搅拌16小时。将混合物冷却至室温。随后浓缩以得到粗化合物。粗品通过SCP纯化。采用以下条件经由制备型LC/MS纯化粗物质:Waters Xbridge C18,19x150mm,5μm;Guard柱:Waters XBridge C18,19x10mm,5μm;流动相A:5:95乙腈:(0.1%TFA/水);流动相B:95:5乙腈:(0.1%TFA/水);梯度:5-25%B经25分钟,接着在25%B下保持10分钟并在100%B下保持5分钟;流速:15ml/min。合并含有所需产物的级分并使用Genevac离心蒸发器干燥以得到浅黄色固体形式的(R)-1-(4-氯苄基)-3-(4-(5-羟基吡啶-2-基)哌嗪-1-基)吡咯烷-2-酮(26mg,0.064mmol,57.2%产率)。使用两次分析型LC/MS注射来确定最终纯度。
注射1条件:柱:Ascentis Express C18(50x2.1)mm,2.7μm;流动相A:5:95乙腈:(10mM NH4OAc/水);流动相B:95:5乙腈:(10mM NH4OAc/水);温度:50℃;梯度:0-100%B经3分钟;流速:1.1ml/min。
注射2条件:柱:Ascentis Express C18(50x2.1)mm,2.7μm;流动相A:5:95乙腈:(0.1%TFA/水);流动相B:95:5乙腈:(0.1%TFA/水);温度:50℃;梯度:0-100%B经3分钟;流速:1.1ml/min。
1H NMR:(400MHz,甲醇-d4)δ=7.70-7.69(m,1H),7.47-7.44(m,1H),7.41-7.38(m,2H),7.33-7.29(m,2H),7.12-7.09(m,1H),4.59-4.45(m,2H),4.25-4.19(m,1H),3.74-3.60(m,6H),3.44-3.35(m,3H),3.29-3.23(m,2H),2.50-2.42(m,1H),2.27-2.18(m,1H)。
LCMS:A:95%水:5%乙腈;10mM NH4OAc,B:5%水:95%乙腈;10mM NH4OAc,流速:1.1ml/min,温度:50℃,柱:Ascentis Express C18(50x2.1)mm,2.7μm,时间(min):0---3,%B:0---100,RT-1.33min,M(+1)–387。
手性筛选:注射体积:10,共溶剂:0.3%DEA/甲醇,柱:ChiralpakAS H 4(250X4.6)mm,5u,柱温:26.7,总流速:3,CO2流速:1.95,共溶剂流速:1.05,共溶剂%:35,背压:97,RT-3.16min。
实施例13P1(同手性):
1-(4-(二氟甲氧基)-3-氟苯基)-3-(4-(5-羟基吡啶-2-基)哌嗪-1-基)吡咯烷-2-酮
向6-(哌嗪-1-基)吡啶-3-醇(39.6mg,0.221mmol)在乙腈(10mL)中的悬浮液中加入DIPEA(0.116ml,0.663mmol)并将反应物质加热到50℃历时10分钟。在该温度下加入甲磺酸1-(4-(二氟甲氧基)-3-氟苯基)-2-氧代吡咯烷-3-基酯(75mg,0.221mmol)的乙腈(1mL)溶液并在80℃下将反应物质搅拌18小时。将混合物冷却至室温。随后浓缩以得到粗化合物。粗品通过SCP纯化。采用以下条件经由制备型LC/MS纯化粗物质:Waters Xbridge C18,19x150mm,5μm;Guard柱:Waters XBridge C18,19x10mm,5μm;流动相A:5:95乙腈:(0.1%TFA/水);流动相B:95:5乙腈:(0.1%TFA/水);梯度:5-25%B经25分钟,接着在25%B下保持10分钟并在100%B下保持5分钟;流速:15ml/min。合并含有所需产物的级分并使用Genevac离心蒸发器干燥以得到浅黄色固体形式的1-(4-(二氟甲氧基)-3-氟苯基)-3-(4-(5-羟基吡啶-2-基)哌嗪-1-基)吡咯烷-2-酮(8.5mg,0.020mmol,9.01%产率)。使用两次分析型LC/MS注射来确定最终纯度。
注射1条件:柱:Ascentis Express C18(50x2.1)mm,2.7μm;流动相A:5:95乙腈:(10mM NH4OAc/水);流动相B:95:5乙腈:(10mM NH4OAc/水);温度:50℃;梯度:0-100%B经3分钟;流速:1.1ml/min。
注射2条件:柱:Ascentis Express C18(50x2.1)mm,2.7μm;流动相A:5:95乙腈:(0.1%TFA/水);流动相B:95:5乙腈:(0.1%TFA/水);温度:50℃;梯度:0-100%B经3分钟;流速:1.1ml/min。
LCMS:A:95%水:5%乙腈;10mM NH4OAc,B:5%水:95%,乙腈;10mM NH4OAc,流速:1.1ml/min,温度:50℃,柱:Ascentis Express C18(50x2.1)mm,2.7μm,时间(min):0---3,%B:0---100,RT-1.331min M(+1)-423。
1H NMR:(400MHz,甲醇-d4)δ=7.85(dd,J=2.5,13.1Hz,1H),7.77(d,J=2.5Hz,1H),7.45-7.40(m,1H),7.37-7.30(m,1H),7.17(dd,J=3.0,9.0Hz,1H),7.03-6.64(m,2H),3.91-3.74(m,3H),3.42(t,J=5.0Hz,4H),3.07(td,J=5.1,10.8Hz,2H),2.82-2.74(m,2H),2.42-2.32(m,1H),2.29-2.16(m,1H)。
手性筛选:注射体积:5,共溶剂:0.3%DEA/甲醇,柱:Lux cellulose-2(4.6*250)mm 5u,柱温:21.2,CO2流速:2.4,共溶剂流速:1.6,共溶剂:40,总流速:4,背压:98,RT-3.86min。
实施例13P2(同手性):1-(4-(二氟甲氧基)-3-氟苯基)-3-(4-(5-羟基吡啶-2-基)哌嗪-1-基)吡咯烷-2-酮。
往6-(哌嗪-1-基)吡啶-3-醇(39.6mg,0.221mmol)在乙腈(10mL)中的悬浮液中加入DIPEA(0.116ml,0.663mmol)并加热反应物质至50℃历时10分钟。在该温度下加入甲磺酸1-(4-(二氟甲氧基)-3-氟苯基)-2-氧代吡咯烷-3-基酯(75mg,0.221mmol)的乙腈(1mL)溶液并将反应物质在80℃下搅拌18小时。反应的完成通过LCMS监测。将反应物冷却至室温。随后浓缩以得到粗化合物。粗品通过SCP纯化。采用以下条件经由制备型LC/MS纯化粗物质:Waters Xbridge C18,19x150mm,5μm;Guard柱:Waters XBridge C18,19x10mm,5μm;流动相A:5:95乙腈:(0.1%TFA/水);流动相B:95:5乙腈:(0.1%TFA/水);梯度:5-25%B经25分钟,接着在25%B下保持10分钟并在100%B下保持5分钟;流速:15ml/min。合并含有所需产物的级分并使用Genevac离心蒸发器干燥以得到浅黄色固体形式的1-(4-(二氟甲氧基)-3-氟苯基)-3-(4-(5-羟基吡啶-2-基)哌嗪-1-基)吡咯烷-2-酮(21mg,0.049mmol,22.27%产率)。使用两次分析型LC/MS注射来确定最终纯度。
注射1条件:柱:Ascentis Express C18(50x2.1)mm,2.7μm;流动相A:5:95乙腈:(10mM NH4OAc/水);流动相B:95:5乙腈:(10mM NH4OAc/水);温度:50℃;梯度:0-100%B经3分钟;流速:1.1ml/min。
注射2条件:柱:Ascentis Express C18(50x2.1)mm,2.7μm;流动相A:5:95乙腈:(0.1%TFA/水);流动相B:95:5乙腈:(0.1%TFA/水);温度:50℃;梯度:0-100%B经3分钟;流速:1.1ml/min。
LCMS:A:95%水:5%乙腈;10mM NH4OAc,B:5%水:95%,乙腈;10mM NH4OAc,流速:1.1ml/min,温度:50℃,柱:Ascentis Express C18(50x2.1)mm,2.7μm,时间(min):0---3,%B:0---100,RT-1.332min M(+1)–423。
1H NMR:(400MHz,甲醇-d4)δ=7.85(dd,J=2.5,12.5Hz,1H),7.76(d,J=3.0Hz,1H),7.45-7.40(m,1H),7.36-7.31(m,1H),7.19-7.15(m,1H),7.02-6.64(m,2H),3.89-3.74(m,3H),3.44-3.40(m,4H),3.07(td,J=5.3,10.9Hz,2H),2.78(td,J=5.1,10.8Hz,2H),2.41-2.33(m,1H),2.29-2.18(m,1H)。
手性筛选:注射体积:5,共溶剂:0.3%DEA/甲醇,柱:Lux cellulose-2(4.6*250)mm 5u,柱温:21.2,CO2流速:2.4,共溶剂流速:1.6,共溶剂:40,总流速:4,背压:98,RT-3.17min。
实施例14(P1&P2):
实施例14P1(同手性):
在室温下往搅拌的6-(哌嗪-1-基)吡啶-3-醇(0.04g,0.223mmol)的乙腈(6mL)溶液中加入DIPEA(0.117mL,0.670mmol)。将反应混合物加热至50℃并缓慢滴加甲磺酸1-(3-氟-4-甲基苯基)-2-氧代吡咯烷-3-基酯(0.115g,0.402mmol)的乙腈(2mL)溶液。将反应混合物加热至80℃历时18小时。反应的完成通过LCMS监测。使混合物为室温。随后浓缩以得到粗化合物。粗品通过SCP纯化。采用以下条件经由制备型LC/MS纯化粗物质:Waters XbridgeC18,19x150mm,5μm;Guard Column:Waters XBridge C18,19x10mm,5μm;流动相A:5:95乙腈:(10mM NH4OAc/水);流动相B:95:5乙腈:(10mM NH4OAc/水);梯度:10-35%B经25分钟,接着在35%B下保持10分钟并在100%B下保持5分钟;流速:15ml/min。合并含有所需产物的级分并使用Genevac离心蒸发器干燥以得到浅黄色固体形式的1-(3-氟-4-甲基苯基)-3-(4-(5-羟基吡啶-2-基)哌嗪-1-基)吡咯烷-2-酮(16.5mg,0.0445mmol,19.95%)。使用两次分析型LC/MS注射来确定最终纯度。
注射1条件:柱:Ascentis Express C18(50x2.1)mm,2.7μm;流动相A:5:95乙腈:(10mM NH4OAc/水);流动相B:95:5乙腈:(10mM NH4OAc/水);温度:50℃;梯度:0-100%B经3分钟;流速:1.1ml/min。
注射2条件:柱:Ascentis Express C18(50x2.1)mm,2.7μm;流动相A:5:95乙腈:(0.1%TFA/水);流动相B:95:5乙腈:(0.1%TFA/水);温度:50℃;梯度:0-100%B经3分钟;流速:1.1ml/min。
1H NMR:(400MHz,甲醇-d4)δ=7.76(d,J=3.0Hz,1H),7.57(d,J=12.0Hz,1H),7.32-7.23(m,1H),7.16(dd,J=3.0,9.0Hz,1H),6.80(d,J=9.0Hz,1H),4.60(s,1H),3.88-3.71(m,2H),3.51(s,1H),3.42(t,J=5.0Hz,1H),3.16(d,J=1.5Hz,1H),3.10-3.00(m,1H),2.77(dd,J=5.5,10.5Hz,1H),2.32-2.20(m,1H)。
LCMS:A:95%水:5%乙腈;10mM NH4OAc,B:5%水:95%乙腈;10mM NH4OAc,流速:1.1ml/min,温度:50℃,柱:Ascentis Express C18(50x2.1)mm,2.7μm,时间(min):0---3,%B:0---100,RT-1.32min,M(+1)-371。
手性筛选:注射体积:5,共溶剂:0.3%DEA/甲醇,柱:Lux cellulose-4(4.6X250)mm 5u,柱温:18.8,CO2流速:2.4,共溶剂流速:1.6,共溶剂%:40,总流速:4,背压:102,RT-4.09min,97.6%ee。
实施例14P2(同手性):
在室温下往搅拌的6-(哌嗪-1-基)吡啶-3-醇(0.04g,0.223mmol)的乙腈(6mL)溶液中加入DIPEA(0.117mL,0.670mmol)。反应混合物加热至50℃并缓慢滴加甲磺酸1-(3-氟-4-甲基苯基)-2-氧代吡咯烷-3-基酯(0.115g,0.402mmol)的乙腈(2mL)溶液。反应混合物加热至80℃历时18小时。反应的完成通过LCMS监测。让混合物冷却至室温。随后浓缩以得到粗化合物。粗品通过SCP纯化。采用以下条件经由制备型LC/MS纯化粗物质:Waters XbridgeC18,19x150mm,5μm;Guard柱:Waters XBridge C18,19x10mm,5μm;流动相A:5:95乙腈:(0.1%TFA/水);流动相B:95:5乙腈:(0.1%TFA/水);梯度:5-25%B经25分钟,接着在25%B下保持10分钟并在100%B下保持5分钟;流速:15ml/min。合并含有所需产物的级分并使用Genevac离心蒸发器干燥以得到1-(3-氟-4-甲基苯基)-3-(4-(5-羟基吡啶-2-基)哌嗪-1-基)吡咯烷-2-酮(13mg,0.035mmol,15.10%产率)。
1H NMR:(400MHz,甲醇-d4)δ=7.76(d,J=2.5Hz,1H),7.63–7.50(m,1H),7.33–7.23(m,2H),7.16(dd,J=3.0,9.0Hz,1H),6.80(d,J=9.0Hz,1H),4.60(s,1H),3.89–3.69(m,3H),3.50(d,J=1.5Hz,1H),3.42(t,J=5.3Hz,2H),3.19–3.14(m,1H),3.06(dd,J=5.3,11.3Hz,2H),2.83–2.67(m,2H),2.36(br.S.,1H),2.28–2.11(m,2H)。
LCMS:A:95%水:5%乙腈;10mM NH4OAc,B:5%水:95%乙腈;10mM NH4OAc,流速:1.1ml/min,温度:50℃,柱:Ascentis Express C18(50x2.1)mm,2.7μm,时间(min):0---3,%B:0---100,LCMS RT-1.32min,M(+1)-371。
手性筛选:注射体积:5,共溶剂:0.3%DEA/甲醇,
柱:Lux cellulose-4(4.6X250)mm 5u,柱温:21.6,CO2流速:2.4,共溶剂流速:1.6,共溶剂%:40,总流速:4,背压:97,RT-4.73min。
实施例15(同手性):
在室温下往搅拌的6-(哌嗪-1-基)吡啶-3-醇(0.015g,0.084mmol)的DMF(3mL)溶液中加入TEA(0.035mL,0.251mmol)和(S)-甲磺酸1-苄基-2-氧代吡咯烷-3-基酯(0.045g,0.167mmol)。反应混合物在120℃下在微波下搅拌2小时。通过LCMS测定对主要所需产物进行质谱分析(Major desiredproduct mass by LCMS)。反应混合物原样送至SCP。粗化合物通过SCP纯化以得到浅黄色固体形式的(R)-1-苄基-3-(4-(5-羟基吡啶-2-基)哌嗪-1-基)吡咯烷-2-酮(2mg,5.39μmol,6.44%产率)。
LCMS:A:95%水:5%乙腈;10mM NH4OAc,B:5%水:95%乙腈;10mM NH4OAc,流速:1.1ml/min,温度:50℃,柱:Ascentis Express C18(50x2.1)mm,2.7μm,时间(min):0---3,%B:0---100,RT-1.161min,M(+1)-353。
手性筛选:注射体积:5,共溶剂:0.3%DEA/甲醇,柱:chiralcel-ASH(250*4.6)5u,柱温:24.6,CO2流速:2.4,共溶剂流速:1.6,共溶剂%:40,总流速:4,背压:103,RT-2.3min。
1H NMR:400MHz,DMSO-d6:δ2.08(s,2H),2.92(bs,2H),3.18-3.22(m,6H),3.37-3.42(m,2H),4.34-4.46(m,3H),6.75(s,1H),6.96(s,1H),7.07-7.09(m,1H),7.22-7.25(m,2H),7.28-7.31(m,1H),7.35-7.39(m,2H),7.75(d,J=2.80Hz,1H)。
实施例16(P1,P2,P3&P4):
3-(4-(5-羟基吡啶-2-基)-2-甲基哌嗪-1-基)-1-(4-甲基苄基)吡咯烷-2-酮
在室温下向3-(4-(5-(苄基氧基)吡啶-2-基)-2-甲基哌嗪-1-基)-1-(4-甲基苄基)吡咯烷-2-酮(650mg,1.381mmol)的甲醇(20mL)溶液中加入Pd/C(147mg,1.381mmol)。反应混合物在氢气压力下搅拌18小时。反应混合物经硅藻土过滤并用甲醇(100mL)洗涤,滤液经硫酸钠干燥并减压蒸发以得到粗残余物。粗品经C18反相silicycle柱纯化,用50%乙腈+10mM乙酸铵洗脱以得到纯级分,蒸发该级分得到浅黄色固体形式的3-(4-(5-羟基吡啶-2-基)-2-甲基哌嗪-1-基)-1-(4-甲基苄基)吡咯烷-2-酮(420mg,0.993mmol,71.9%产率)。
LCMS:RT:1.93min ACN/(H2O+HCOONH4),Ascentis Express C18(50x2.1mm-2.7μm),梯度=1.7min,波长=220nm;MS(ES):m/z 381.M+H。
SFC:CO23.0_Colvent_100.met;流速:-总流速3,CO2流速2.1,共溶剂(0.3%DEA/甲醇)0.9;柱:-Chiralpak AD H(250x 4.6)mm 5μ;RT 3.9min;纯度@217nm:32%,RT 4.7min;纯度@217nm:16%,RT 6min;纯度@217nm:16%,RT 10min;纯度@217nm:33%。
制备型SFC条件:柱/尺寸:Chiralcel OD-H(250X 21)mm,5u,%CO2:75%,%共溶剂:25%(0.25%DEA/甲醇),总流速:60.0g/min背压:100bar,温度:25℃,UV:245,峰号:保留时间::峰1:3.90::峰2:4.70::峰3:6.00::峰4:10.00,溶解度:60ml甲醇,加载能力/注射:5.0mg/mL,总注射No:120;总纯化时间15.0小时。仪器详情:Make/型号:Thar SFC-80。
对于P1(同手性):
3-(4-(5-羟基吡啶-2-基)-2-甲基哌嗪-1-基)-1-(4-甲基苄基)吡咯烷-2-酮
LCMS:Column-Ascentis Express C8(50X2.1mm-2.7μm),流动相A:2%ACN-98%H2O-10mM NH4COOH,流动相B:98%ACN-2%H2O-10mM NH4COOH,流速=1ml/min,时间:%B::0.0:0.0::1.7:100.0::4.0:100.0,RT-1.774min,M(+1)-381。
1H NMR:(400MHz,甲醇-d4)dppm 7.75(dd,J=3.01,0.50Hz,1H)7.13-7.21(m,5H)6.77(dd,J=9.04,0.44Hz,1H)4.55(s,1H)4.42(s,1H)4.13(t,J=9.00Hz,1H)3.77-3.88(m,2H)3.36-3.39(m,2H)3.24-3.30(m,2H)3.02(d,J=0.25Hz,1H)2.95(td,J=11.66,3.17Hz,1H)2.88(d,J=0.69Hz,1H)2.58-2.73(m,4H)2.34(s,3H)2.07-2.19(m,1H)1.95-2.05(m,3H)1.18-1.24(m,3H)。
手性纯度:注射体积:10,共溶剂:0.3%DEA/甲醇,柱:Chiralcel OD-H(4.6X250)mm,5u,柱温:26,总流速:3,CO2流速:2.25,共溶剂流速:0.75,共溶剂%:25,背压:99,RT–5.3min。
对于P2(同手性):
3-(4-(5-羟基吡啶-2-基)-2-甲基哌嗪-1-基)-1-(4-甲基苄基)吡咯烷-2-酮
LCMS:Column-Ascentis Express C8(50X2.1mm-2.7μm),流动相A:2%ACN-98%H2O-10mM NH4COOH,流动相B:98%ACN-2%H2O-10mM NH4COOH,流速=1ml/min,时间:%B::0.0:0.0::1.7:100.0::4.0:100.0,RT-1.751min,M(+1)-381。
1H NMR:(400MHz,甲醇-d4)dppm 7.75(dd,J=2.98,0.53Hz,1H)7.13-7.20(m,7H)6.77(dd,J=9.04,0.50Hz,1H)4.49(d,J=14.56Hz,1H)4.30-4.35(m,1H)4.05(dd,J=9.60,7.72Hz,1H)3.74-3.86(m,3H)3.36-3.45(m,3H)3.21-3.31(m,2H)2.99-3.03(m,2H)2.89-2.99(m,3H)2.88(d,J=0.63Hz,2H)2.57-2.70(m,3H)2.23-2.35(m,3H)1.94-2.08(m,3H)1.24(s,3H)。
手性纯度:注射体积:10,共溶剂:0.3%DEA/甲醇,柱:Chiralcel OD-H(4.6X250)mm,5u,柱温:25.9,总流速:3,CO2流速:2.25,共溶剂流速:0.75,共溶剂%:25,背压:103,RT–6.4min。
对于P3(同手性):
3-(4-(5-羟基吡啶-2-基)-2-甲基哌嗪-1-基)-1-(4-甲基苄基)吡咯烷-2-酮
LCMS:Column-Ascentis Express C8(50X2.1mm-2.7μm),流动相A:2%ACN-98%H2O-10mM NH4COOH,流动相B:98%ACN-2%H2O-10mM NH4COOH,流速=1ml/min,时间:%B::0.0:0.0::1.7:100.0::4.0:100.0,RT-1.774min,M(+1)-381。
1H NMR:(400MHz,甲醇-d4)dppm 7.75(dd,J=3.01,0.44Hz,1H)7.14-7.22(m,5H)6.75-6.80(m,1H)4.50-4.56(m,1H)4.38-4.44(m,1H)4.13(t,J=9.00Hz,1H)3.78-3.88(m,2H)3.36-3.38(m,2H)3.24-3.30(m,2H)3.02(d,J=0.31Hz,1H)2.95(td,J=11.64,3.20Hz,1H)2.88(d,J=0.63Hz,1H)2.59-2.74(m,6H)2.34(s,4H)2.08-2.19(m,1H)1.94-2.06(m,4H)1.19-1.24(m,3H)。
手性纯度:注射体积:10,共溶剂:0.3%DEA/甲醇,柱:Chiralcel OD-H(4.6X250)mm,5u,柱温:25.9,总流速:3,CO2流速:2.25,共溶剂流速:0.75,共溶剂%:25,背压:100,RT–7.6min。
对于P4(同手性):
3-(4-(5-羟基吡啶-2-基)-2-甲基哌嗪-1-基)-1-(4-甲基苄基)吡咯烷-2-酮
LCMS:Column-Ascentis Express C8(50X2.1mm-2.7μm),流动相A:2%ACN-98%H2O-10mM NH4COOH,流动相B:98%ACN-2%H2O-10mM NH4COOH,流速=1ml/min,时间:%B::0.0:0.0::1.7:100.0::4.0:100.0,RT-1.750min,M(+1)-381。
1H NMR:(400MHz,甲醇-d4)dppm 7.75(dd,J=3.01,0.50Hz,1H)7.13-7.20(m,5H)6.77(d,J=8.66Hz,1H)4.49(d,J=14.56Hz,1H)4.29-4.35(m,1H)4.05(dd,J=9.60,7.72Hz,1H)3.75-3.86(m,2H)3.37-3.44(m,4H)3.21-3.31(m,1H)2.87-3.02(m,1H)2.57-2.69(m,1H)2.34(s,2H)2.22-2.31(m,1H)1.98-2.07(m,1H)1.93-1.96(m,6H)1.24(s,3H)。
手性纯度:注射体积:10,共溶剂:0.3%DEA/甲醇,柱:Chiralcel OD-H(4.6X250)mm,5u,柱温:24.8,总流速:3,CO2流速:2.25,共溶剂流速:0.75,共溶剂%:25,背压:100,RT–15.1min。
实施例17(同手性):
制备:
在室温下往搅拌的(R)-3-(4-(5-(苄基氧基)吡啶-2-基)-1,4-二氮杂环庚烷-1-基)-1-(4-甲基苄基)吡咯烷-2-酮(0.1g,0.212mmol)的甲醇(10mL)溶液中加入Pd/C(0.023g,0.212mmol)。反应混合物通过真空弯管与氢气气囊连接并在室温下搅拌18小时。通过LCMS对主要所需产物进行质谱分析。反应混合物通过硅藻土过滤并将滤液浓缩以得到粗品0.04g。将粗品送至SCP。粗化合物通过SCP纯化以得到浅黄色固体形式的(R)-3-(4-(5-羟基吡啶-2-基)-1,4-二氮杂环庚烷-1-基)-1-(4-甲基苄基)吡咯烷-2-酮(6.5mg,0.017mmol,7.88%产率)。
LCMS:溶剂A:5%ACN,95%水,10mM NH4OAc,溶剂B:95%ACN,5%水,10mM NH4OAc,流速:4ml/min,温度:50℃,柱:Ascentis Express C18(50x4.6)mm,2.7μm,时间(min):0---4,%B:0---100,RT-1.93min,M(+1)-381。
手性筛选:注射体积:3,共溶剂:0.3%DEA/甲醇,柱:ChiralpakAD H(250X 4.6)mm5u,柱温:26.4,总流速:4,CO2流速:1.95,共溶剂流速:1.05,共溶剂%:35,背压:99,RT-9.73min。
1H NMR:400MHz,DMSO-d6:δ1.80(bs,3H),2.08(d,J=6.40Hz,1H),2.29(s,3H),2.68-2.68(m,2H),2.91(bs,1H),3.02-3.10(m,2H),3.11-3.19(m,2H),3.52-3.55(m,3H),3.60(s,2H),4.24-4.35(m,2H),6.47(d,J=9.20Hz,1H),7.01-7.04(m,1H),7.08-7.16(m,4H),7.68(d,J=2.80Hz,1H),8.66(s,1H)。
实施例18(同手性):
向(R)-4-(5-(苄基氧基)吡啶-2-基)-1-(1-(4-甲基苄基)-2-氧代吡咯烷-3-基)哌嗪-2-酮(0.15g,0.182mmol)的MeOH(5mL)溶液中加入Pd/C(0.12g,0.113mmol)并在室温下在氢气气囊压力下搅拌12小时。反应的完成通过LCMS监测。反应物质通过硅藻土过滤并减压浓缩以得到粗品0.12g。粗品送至SCP。粗品通过SCP纯化。采用以下条件经由制备型LC/MS纯化粗物质:Waters Xbridge C18,19x150mm,5μm;Guard柱:Waters XBridge C18,19x10mm,5μm;流动相A:5:95甲醇:(10mM NH4OAc/水);流动相B:95:5甲醇:(10mM NH4OAc/水);梯度:15-60%B经25分钟,接着在60%B下保持10分钟并在100%B下保持5分钟;流速:15ml/min。合并含有所需产物的级分并使用Genevac离心蒸发器干燥以得到浅黄色固体形式的(R)-4-(5-羟基吡啶-2-基)-1-(1-(4-甲基苄基)-2-氧代吡咯烷-3-基)哌嗪-2-酮(21mg,0.055mmol,30.1%产率)。
LCMS:溶剂A:5%ACN,95%水,10mM NH4OAc,溶剂B:95%ACN,5%水,10mM NH4OAc,流速:4ml/min,温度:50℃,
柱:Ascentis Express C18(50x4.6)mm,2.7μm,时间(min):0---4,%B:0---100,RT-1.735min,M(+1)–381。
H-NMR:400MHz,DMSO-d6:δ1.98-2.05(m,1H),2.15-2.22(m,1H),2.29(s,3H),3.19-3.22(m,2H),3.24-3.28(m,1H),3.36-3.43(m,1H),3.65(t,J=28.00Hz,2H),3.91-4.02(m,2H),4.30(d,J=14.80Hz,1H),4.41(d,J=14.80Hz,1H),5.06(t,J=19.20Hz,1H),6.76(d,J=8.80Hz,1H),7.10(dd,J=11.60,Hz,1H),7.13-7.17(m,4H),7.76(d,J=3.20Hz,1H),9.05(s,1H)。
手性筛选:注射体积:3,共溶剂:0.3%DEA/甲醇,柱:Chiralcel OD-H(4.6X250)mm,5u,柱温:25,总流速:3,CO2流速:1.95,共溶剂流速:1.05,共溶剂%:35,背压:99,RT-3.97min。
实施例19(同手性):
向1-(5-羟基吡啶-2-基)哌嗪-2-酮.HCl(0.03g,0.131mmol)的乙腈(5mL)溶液中加入DIPEA(0.068mL,0.392mmol),加热至60oC历时30分钟,随后加入(S)-甲磺酸1-(4-甲基苄基)-2-氧代吡咯烷-3-基酯(0.041g,0.144mmol)的乙腈(1mL)溶液,加热至85℃过夜。减压浓缩反应物质,随后溶解于2mLDMF并送至SCP。采用以下条件经由制备型LC/MS纯化粗物质:Waters Xbridge C18,19x150mm,5μm;Guard柱:Waters XBridge C18,19x10mm,5μm;流动相A:5:95乙腈:(10mM NH4OAc/水);流动相B:95:5乙腈:(10mM NH4OAc/水);梯度:5-30%B经25分钟,接着在30%B下保持10分钟并在100%B下保持5分钟;流速:15ml/min。合并含有所需产物的级分并使用Genevac离心蒸发器干燥以得到浅黄色固体形式的(R)-1-(5-羟基吡啶-2-基)-4-(1-(4-甲基苄基)-2-氧代吡咯烷-3-基)哌嗪-2-酮(5mg,0.013mmol,10.06%产率)。
LCMS:溶剂A:5%ACN,95%水,10mM NH4OAc,溶剂B:95%ACN,5%水,10mM NH4OAc,流速:4ml/min,温度:50℃,柱:Ascentis Express C18(50x4.6)mm,2.7μm,时间(min):0---4,%B:0---100,RT-1.677min,M(+1)–381。
H-NMR:1H NMR:400MHz,MeOD:δ2.03-2.09(m,1H),2.25-2.26(m,1H),2.34(s,3H),2.97-3.00(m,1H),3.24-3.30(m,2H),3.34-3.35(m,1H),3.47(d,J=16.80Hz,1H),3.72-3.81(m,2H),3.85(t,J=10.80Hz,2H),4.40(d,J=14.40Hz,1H),4.51(d,J=14.80Hz,1H),7.18-7.21(m,4H),7.28(dd,J=12.00,Hz,1H),7.44(d,J=9.20Hz,1H),8.01-8.02(m,1H)。
手性筛选:注射体积:5,共溶剂:0.3%DEA/甲醇,柱:Lux cellulose-2(4.6X250)mm,5u,柱温:29.1,总流速:4,CO2流速:2.4,共溶剂流速:1.6,共溶剂%:40,背压:98,RT-5.76min。
实施例20(同手性):
向1-(5-羟基吡啶-2-基)哌嗪-2-酮盐酸盐(0.03g,0.131mmol)的乙腈(5mL)溶液中加入DIPEA(0.068mL,0.392mmol),加热至60℃历时30分钟,随后加入(S)-甲磺酸1-(4-氟苄基)-2-氧代吡咯烷-3-基酯(0.041g,0.144mmol)的乙腈(1mL)溶液,随后加热至85℃过夜。反应的完成通过LCMS监测。减压浓缩反应物质,随后溶解于2mL DMF并送至SCP。采用以下条件经由制备型LC/MS纯化粗物质:Waters Xbridge C18,19x150mm,5μm;Guard Column:Waters XBridge C18,19x10mm,5μm;流动相A:5:95乙腈:(10mM NH4OAc/水);流动相B:95:5乙腈:(10mM NH4OAc/水);梯度:5-30%B经25分钟,接着在30%B下保持10分钟并在100%B下保持5分钟;流速:15ml/min。合并含有所需产物的级分并使用Genevac离心蒸发器干燥以得到浅黄色固体形式的(R)-4-(1-(4-氟苄基)-2-氧代吡咯烷-3-基)-1-(5-羟基吡啶-2-基)哌嗪-2-酮(1mg,2.55μmol,1.952%产率)。
LCMS:溶剂A:5%ACN,95%水,10mM NH4OAc,溶剂B:95%ACN,5%水,10mM NH4OAc,流速:4ml/min,温度:50℃,
柱:Ascentis Express C18(50x4.6)mm,2.7μm,时间(min):0---4,%B:0---100,RT-1.551min,M(+1)–385。
H-NMR:400MHz,MeOD:δ2.04-2.10(m,1H),2.25-2.30(m,1H),2.97-3.02(m,1H),3.26-3.30(m,2H),3.34-3.37(m,1H),3.47(d,J=16.40Hz,1H),3.72-3.81(m,2H),3.85(t,J=11.20Hz,2H),4.45(d,J=14.80Hz,1H),4.53(d,J=14.40Hz,1H),7.09-7.13(m,2H),7.28(dd,J=11.60,Hz,1H),7.31-7.35(m,2H),7.44(d,J=9.20Hz,1H),8.02(d,J=2.80Hz,1H)。
手性筛选:注射体积:4,共溶剂:0.3%DEA/甲醇,柱:Lux cellulose-2(4.6X250)mm,5u,柱温:23,总流速:4,CO2流速:2.4,共溶剂流速:1.6,共溶剂%:40,背压:99,RT-4.64min。
实施例21(P1&P2):
在室温下向3-(4-(5-(苄基氧基)吡啶-2-基)-2,2-二甲基哌嗪-1-基)-1-(4-甲基苄基)吡咯烷-2-酮(25mg,0.052mmol)的MeOH(10mL)溶液中加入Pd/C(1.098mg,10.32μmol)。反应混合物在氢气气囊压力下搅拌过夜。反应的完成通过LCMS监测。反应混合物通过硅藻土过滤并且滤液减压蒸发以得到粗品30mg。粗化合物通过SCP纯化。采用以下条件经由制备型LC/MS纯化粗物质:Waters Xbridge C18,19x150mm,5μm;Guard Column:WatersXBridge C18,19x10mm,5μm;流动相A:5:95乙腈:(10mM NH4OAc/水);流动相B:95:5乙腈:(10mM NH4OAc/水);梯度:10-40%B经25分钟,接着在40%B下保持10分钟并在100%B下保持5分钟;流速:15ml/min。合并含有所需产物的级分并使用Genevac离心蒸发器干燥以得到浅黄色固体形式的(+/-)(4-(5-羟基吡啶-2-基)-2,2-二甲基哌嗪-1-基)-1-(4-甲基苄基)吡咯烷-2-酮(4mg,0.0101mmol,19.65%产率)。
使用两次分析型LC/MS注射来确定最终纯度。
注射1条件:柱:Ascentis Express C18(50x2.1)mm,2.7μm;流动相A:5:95乙腈:(10mM NH4OAc/水);流动相B:95:5乙腈:(10mM NH4OAc/水);温度:50℃;梯度:0-100%B经3分钟;流速:1.1ml/min。
注射2条件:柱:Ascentis Express C18(50x2.1)mm,2.7μm;流动相A:5:95乙腈:(0.1%TFA/水);流动相B:95:5乙腈:(0.1%TFA/水);温度:50℃;梯度:0-100%B经3分钟;流速:1.1ml/min。
外消旋混合物通过SFC分离。
制备型SFC条件:柱/尺寸:Chiralpak AD-H(250X 21)mm,5u,%CO2:60%,%共溶剂:40%(0.25%DEA/甲醇),总流速:60.0g/min,背压:100bar,温度:25℃,UV:220,峰号:保留时间::峰1:3.40::峰2:4.40,溶解度:4ml甲醇。
对于P1(同手性):(4-(5-羟基吡啶-2-基)-2,2-二甲基哌嗪-1-基)-1-(4-甲基苄基)吡咯烷-2-酮。
HPLC:95/5至5/95H2O/CH3CN/0.05%TFA,流速=1mL/min,梯度=15min,SunfireC184.6x150mm:RT=10.32min;纯度@220nm:89.04%;@254nm:91.96%.Xbridge Phenyl3.5um,4.6x150mm:RT=11.57min;纯度@220nm:90.7%;@254nm:94.77%。
LCMS:Column-Ascentis Express C18(50X2.1mm-2.7μm),流动相A:10mMNH4COOH/水:ACN(98:02),流动相B:10mM NH4COOH/水:ACN(02:98),流速=1ml/min,时间:%B::0.0:0.0::1.7:100.0::3.0:100.0::3.2:0.0,RT-2.136min,M(+1)-395。
SFC:CO23.0_Colvent_100.met;流速:-总流速3,CO2流速2.1,共溶剂(0.3%DEA/甲醇)0.9;柱:-Chiralpak AD H(250x 4.6)mm 5μ;RT 4.12;纯度@217nm:100%。
1H NMR:(400MHz,甲醇-d4)δppm 7.72(dd,J=3.01,0.56Hz,1H)7.12-7.21(m,4H)6.75(dd,J=9.10,0.56Hz,1H)4.49-4.55(m,1H)4.36-4.42(m,1H)4.11(t,J=9.25Hz,1H)3.65-3.71(m,1H)3.51(dt,J=3.29,1.62Hz,1H)3.42(dd,J=11.92,1.63Hz,1H)3.04-3.27(m,3H)2.86-2.96(m,2H)2.48(dt,J=11.40,3.58Hz,1H)2.04-2.15(m,3H)1.29(s,3H)1.17(s,3H)。
对于P2(同手性):3-(4-(5-羟基吡啶-2-基)-2,2-二甲基哌嗪-1-基)-1-(4-甲基苄基)吡咯烷-2-酮。
HPLC:95/5至5/95H2O/CH3CN/0.05%TFA,流速=1mL/min,梯度=15min,SunfireC18 4.6x150mm:RT=10.32min;纯度@220nm:86.63%;@254nm:88.45%.Xbridge Phenyl3.5um,4.6x150mm:RT=11.566min;纯度@220nm:89.57%;@254nm:92.52%。
LCMS:Column-Ascentis Express C18(50X2.1mm-2.7μm),流动相A:10mMNH4COOH/水:ACN(98:02),流动相B:10mM NH4COOH/水:ACN(02:98),流速=1ml/min,时间:%B::0.0:0.0::1.7:100.0::3.0:100.0::3.2:0.0,RT-2.133min,M(+1)-395。
SFC:CO23.0_Colvent_100.met;流速:-总流速3,CO2流速2.1,共溶剂(0.3%DEA/甲醇)0.9;柱:-Chiralpak AD H(250x 4.6)mm 5μ;RT 6.07;纯度@217nm:100%。
1H NMR:(400MHz,甲醇-d4)δppm 7.71(dd,J=3.04,0.60Hz,1H)7.11-7.21(m,5H)6.76(d,J=0.56Hz,1H)4.53(s,1H)4.34-4.42(m,1H)4.11(t,J=9.19Hz,1H)3.65-3.71(m,1H)3.38-3.51(m,1H)3.18-3.25(m,2H)3.03-3.16(m,1H)2.86-2.96(m,2H)2.47(dt,J=11.28,3.55Hz,1H)2.04-2.11(m,1H)1.27-1.33(m,3H)1.16(s,3H)。
实施例22(P1&P2):
实施例22(P1)(同手性):1-(4-氯-3-氟苯基)-3-(4-(5-羟基吡啶-2-基)-1,4-二氮杂环庚烷-1-基)吡咯烷-2-酮
在室温下往搅拌的3-(4-(5-(苄基氧基)吡啶-2-基)-1,4-二氮杂环庚烷-1-基)-1-(4-氯-3-氟苯基)吡咯烷-2-酮(0.186g,0.376mmol)的甲醇(10mL)溶液中加入Pd/C(0.04g,0.376mmol)。反应混合物通过真空弯管连接于氢气气囊并在室温下搅拌18小时。对主要所需产物进行质谱分析(major desiredproduct mass),反应物质经硅藻土过滤并将滤液浓缩以得到粗产物0.15g。粗化合物通过SCP纯化以得到浅黄色固体形式的1-(4-氯-3-氟苯基)-3-(4-(5-羟基吡啶-2-基)-1,4-二氮杂环庚烷-1-基)吡咯烷-2-酮(4mg,9.39μmol,2.497%产率)。
LCMS:溶剂A:5%ACN,95%水,10mM NH4OAc,溶剂B:95%ACN,5%水,10mM NH4OAc,流速:4ml/min,温度:50℃,柱:Ascentis Express C18(50x4.6)mm,2.7μm,时间(min):0---4,%B:0---100,RT-1.474min,M(+1)-405。
手性筛选:注射体积:7,共溶剂:0.3%DEA/甲醇,柱:Chiralcel OJ-H(4.6X250)mm,5u,柱温:26.6,总流速:4,CO2流速:2.4,共溶剂流速:1.6,共溶剂%:40,背压:99,RT–2.78min。
1H NMR:400MHz,DMSO-d6:δ2.12-2.16(m,2H),2.31-2.34(m,1H),2.45-2.49(m,1H),3.19-3.22(m,1H),3.35-3.38(m,1H),3.43-3.45(m,2H),3.53-3.64(m,3H),3.80-3.92(m,4H),4.59(t,J=19.60Hz,1H),6.85(d,J=9.20Hz,1H),7.30-7.33(m,1H),7.54-7.57(m,1H),7.64-7.69(m,2H),7.86(dd,J=12.00,Hz,1H)。
实施例22(P2)(同手性):1-(4-氯-3-氟苯基)-3-(4-(5-羟基吡啶-2-基)-1,4-二氮杂环庚烷-1-基)吡咯烷-2-酮。
在室温下往搅拌的3-(4-(5-(苄基氧基)吡啶-2-基)-1,4-二氮杂环庚烷-1-基)-1-(4-氯-3-氟苯基)吡咯烷-2-酮(0.186g,0.376mmol)的甲醇(10mL)溶液中加入Pd/C(0.04g,0.376mmol)。反应混合物通过真空弯管连接于氢气气囊并在室温下搅拌18小时。对主要所需产物进行质谱分析,反应物质经硅藻土过滤并将滤液浓缩以得到粗产物。粗化合物通过SCP纯化以得到浅黄色固体形式的1-(4-氯-3-氟苯基)-3-(4-(5-羟基吡啶-2-基)-1,4-二氮杂环庚烷-1-基)吡咯烷-2-酮(10mg,0.023mmol,6.18%产率)。
LCMS:溶剂A:5%ACN,95%水,10mM NH4OAc,溶剂B:95%ACN,5%水,10mM NH4OAc,流速:4ml/min,温度:50℃,
柱:Ascentis Express C18(50x4.6)mm,2.7μm,时间(min):0---4,%B:0---100,RT-1.468min,M(+1)-405。
手性筛选:注射体积:4,共溶剂:0.3%DEA/甲醇,柱:Chiralcel OJ-H(4.6X250)mm,5u,柱温:26.5,总流速:3,CO2流速:1.95,共溶剂流速:1.05,共溶剂%:35,背压:99,RT–6.14min。
1H NMR:400MHz,DMSO-d6:δ2.12-2.16(m,2H),2.31-2.34(m,1H),2.45-2.49(m,1H),3.19-3.22(m,1H),3.35-3.38(m,1H),3.43-3.45(m,2H),3.53-3.64(m,3H),3.80-3.92(m,4H),4.59(t,J=19.60Hz,1H),6.85(d,J=9.20Hz,1H),7.30-7.33(m,1H),7.54-7.57(m,1H),7.64-7.69(m,2H),7.86(dd,J=12.00,Hz,1H)。
实施例23(同手性):
向(R)-3-((1S,4S)-5-(5-(苄基氧基)吡啶-2-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-1-(4-甲基苄基)吡咯烷-2-酮(0.18g,0.142mmol)的MeOH(5mL)溶液中加入Pd/C(0.15g,0.141mmol)并在室温下在氢气气囊压力下搅拌过夜。反应的完成通过LCMS监测。反应物质通过硅藻土过滤并减压浓缩以得到粗品,将粗品溶解于2mL DMF并送至SCP。采用以下条件经由制备型LC/MS纯化粗物质:Waters Xbridge C18,19x150mm,5μm;Guard柱:Waters XBridge C18,19x10mm,5μm;流动相A:5:95乙腈:(10mM NH4OAc/水);流动相B:95:5乙腈:(10mM NH4OAc/水);梯度:10-45%B经25分钟,接着在45%B下保持10分钟并在100%B下保持5分钟;流速:15ml/min。合并含有所需产物的级分并使用Genevac离心蒸发器干燥以得到浅黄色固体形式的(R)-3-((1S,4S)-5-(5-羟基吡啶-2-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-1-(4-甲基苄基)吡咯烷-2-酮(4mg,9.83μmol,6.92%产率)。
LCMS:A:95%水:5%乙腈;10mM NH4OAc,B:5%水:95%乙腈;10mM NH4OAc,流速:1.1ml/min,温度:50℃,柱:Ascentis Express C18(50x2.1)mm,2.7μm,时间(min):0---3,%B:0---100,RT-1.171min,M(+1)–379。
H-NMR:400MHz,DMSO-d6:δ1.71-1.81(m,3H),2.07-2.11(m,1H),2.27(s,3H),2.73(d,J=10.00Hz,1H),3.00-3.17(m,4H),3.22(d,J=9.60Hz,1H),3.35-3.37(m,1H),3.88(s,1H),4.24(d,J=14.80Hz,1H),4.30(d,J=14.80Hz,1H),4.40(s,1H),6.39(d,J=8.80Hz,1H),7.02(dd,J=12.00,Hz,1H),7.06(d,J=7.60Hz,2H),7.13(d,J=8.00Hz,2H),7.67(d,J=2.80Hz,1H),8.73(s,1H)。
手性筛选:注射体积:5,共溶剂:0.3%DEA/甲醇,柱:Whelk-01(R,R)(250X4.6)mm5u,柱温:26.7,总流速:4,CO2流速:2.4,共溶剂流速:1.6,共溶剂%:40,背压:101。RT-5.7min。
实施例24(同手性):
向(R)-3-((1S,4S)-5-(5-(苄基氧基)吡啶-2-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-1-(4-氟苄基)吡咯烷-2-酮(0.18g,0.194mmol)的MeOH(5mL)溶液中加入Pd/C(0.15g,0.141mmol)并在室温下在氢气气囊压力下搅拌过夜。反应的完成通过LCMS监测。反应物质通过硅藻土过滤并减压浓缩以得到粗品,将粗品溶解于2ml DMF中并送至SCP。采用以下条件经由制备型LC/MS纯化粗物质:Waters Xbridge C18,19x150mm,5μm;Guard柱:Waters XBridge C18,19x10mm,5μm;流动相A:5:95乙腈:(10mM NH4OAc/水);流动相B:95:5乙腈:(10mM NH4OAc/水);梯度:10-35%B经25分钟,接着在35%B下保持10分钟并在100%B下保持5分钟;流速:15ml/min。合并含有所需产物的级分并使用Genevac离心蒸发器干燥,得到浅黄色固体形式的(R)-1-(4-氟苄基)-3-((1S,4S)-5-(5-羟基吡啶-2-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)吡咯烷-2-酮(11mg,0.028mmol,14.66%产率)。
LCMS:A:95%水:5%乙腈;10mM NH4OAc,B:5%水:95%乙腈;10mM NH4OAc,流速:1.1ml/min,温度:50℃,柱:Ascentis Express C18(50x2.1)mm,2.7μm,时间(min):0---3,%B:0---100,RT-1.07min,M(+1)–383。
1H-NMR:400MHz,MeOD:δ1.91-1.98(m,3H),2.27-2.31(m,1H),2.99(d,J=11.60Hz,1H),3.20-3.30(m,3H),3.34-3.43(m,2H),3.50(d,J=10.00Hz,1H),4.09(s,1H),4.35(d,J=14.80Hz,1H),4.45(d,J=15.20Hz,1H),4.50(s,1H),6.51(d,J=9.60Hz,1H),7.05-7.09(m,2H),7.15(dd,J=12.00,Hz,1H),7.27-7.30(m,2H),7.68(d,J=2.80Hz,1H)。
手性筛选:注射体积:5,共溶剂:0.3%DEA/甲醇,柱:Lux cellulose-2(4.6X250)mm,5u,柱温:26.8,总流速:4,CO2流速:2.4,共溶剂流速:1.6,共溶剂%:40,背压:101,RT-3.75min。
实施例25(P1&P2):
往搅拌的6-(哌嗪-1-基)吡啶-3-醇.盐酸盐(70mg,0.325mmol)的干燥DMF(1.5mL)溶液中加入DIPEA(0.170mL,0.974mmol)和3-溴-1-(3-氟-4-甲基苄基)哌啶-2-酮(97mg,0.325mmol)。混合物在120℃微波下加热90分钟。反应的完成通过LCMS监测。将反应混合物浓缩以去除DMF。粗品原样通过ISCO纯化。粗化合物通过ISCO纯化(40g硅胶柱,用50%乙酸乙酯/石油醚洗脱)以得到25(外消旋体混合物);棕色胶状物形式的1-(3-氟-4-甲基苄基)-3-(4-(5-羟基吡啶-2-基)哌嗪-1-基)哌啶-2-酮(60mg,0.151mmol,46.4%产率)。外消旋混合物送至手性SFC以得到P1:1-(3-氟-4-甲基苄基)-3-(4-(5-羟基吡啶-2-基)哌嗪-1-基)哌啶-2-酮(11.1mg,0.026mmol,8.07%产率)和P2:1-(3-氟-4-甲基苄基)-3-(4-(5-羟基吡啶-2-基)哌嗪-1-基)哌啶-2-酮(9.6mg,0.023mmol,7.13%产率)。
SFC纯化方法:
分析型SFC条件:柱/尺寸:Luxcellulose-2(250X 4.6)mm,5u,%CO2:60%,%共溶剂:40%(0.25%DEA/甲醇),总流速:4.0g/min,背压:100bar,温度:25℃,UV:244。
制备型SFC条件:柱/尺寸:Luxcellulose-2(250X 21.5)mm,5u,%CO2:60%,%共溶剂:45%(0.25%DEA/甲醇),总流速:75.0g/min,背压:100bar,温度:25℃,UV:244,峰号:保留时间::峰1:4.20::峰2:6.00,溶解度:10ml甲醇,加载能力/注射:6mg/mL,总注射No:6,总纯化时间0.50小时,仪器详情:Make/型号:Thar SFC-80。
对于P1(同手性):
1H NMR:(400MHz,DMSO-d6)d=8.98-8.92(m,1H),7.75-7.71(m,1H),7.28-7.21(m,1H),7.08-7.04(m,1H),7.01-6.95(m,2H),6.73-6.67(m,1H),4.52-4.40(m,3H),3.29-3.17(m,6H),3.16-3.08(m,1H),2.98-2.90(m,2H),2.70-2.62(m,2H),2.23-2.19(m,3H),1.91-1.75(m,4H)。
LCMS:Column-Ascentis Express C18(50X2.1mm-2.7μm),流动相A:10mMNH4COOH/水:ACN(98:02),流动相B:10mM NH4COOH/水:ACN(02:98),流速=1ml/min,时间:%B::0.0:0.0::1.7:100.0::3.0:100.0::3.2:0.0,RT-1.99min,M(+1)-399。
手性纯度:注射体积:7,共溶剂:0.3%DEA/甲醇,柱:Lux cellulose-2(4.6X250)mm,5u,柱温:26.4,总流速:4,CO2流速:2.4,共溶剂流速:1.6,共溶剂%:40,背压:100,RT-4.12min。
对于P2(同手性):
1H NMR:(400MHz,DMSO-d6)d=9.05-8.90(m,1H),7.73(d,J=2.5Hz,1H),7.25(s,1H),7.05(dd,J=9.0,3.0Hz,1H),7.00-6.95(m,2H),6.70(d,J=9.0Hz,1H),4.46(d,J=13.1Hz,2H),3.28-3.08(m,7H),2.94(d,J=5.0Hz,2H),2.66(d,J=6.0Hz,2H),2.21(d,J=1.5Hz,3H),1.86(br.s.,3H),1.75-1.65(m,1H)。
LCMS:Column-Ascentis Express C18(50X2.1mm-2.7μm),流动相A:10mMNH4COOH/水:ACN(98:02),流动相B:10mM NH4COOH/水:ACN(02:98),流速=1ml/min,时间:%B::0.0:0.0::1.7:100.0::3.0:100.0::3.2:0.0,RT-1.99min,M(+1)-399。
手性纯度:注射体积:7,共溶剂:0.3%DEA/甲醇,柱:Lux cellulose-2(4.6X250)mm,5u,柱温:26.3,总流速:4,CO2流速:2.4,共溶剂流速:1.6,共溶剂%:40,背压:94,RT-4.67min。
实施例26(同手性):
向3-((1S,4S)-5-(5-(苄基氧基)吡啶-2-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-1-(4-氯-3-氟苯基)吡咯烷-2-酮(0.18g,0.215mmol)的MeOH(5mL)溶液中加入Pd/C(0.11g,0.103mmol)并在室温下在氢气气囊压力下搅拌过夜。反应的完成通过LCMS监测。反应物质通过硅藻土过滤并减压浓缩以得到粗品,将粗品溶解于2mL DMF中并送至SCP。采用以下条件经由制备型LC/MS纯化粗物质:Waters Xbridge C18,19x150mm,5μm;GuardColumn:Waters XBridge C18,19x10mm,5μm;流动相A:5:95乙腈:(0.1%TFA/水);流动相B:95:5乙腈:(0.1%TFA/水);梯度:0-20%B经25分钟,接着在20%B下保持10分钟并在100%B下保持5分钟;流速:15ml/min。合并含有所需产物的级分并使用Genevac离心蒸发器干燥以得到浅黄色固体形式的1-(4-氯-3-氟苯基)-3-((1S,4S)-5-(5-羟基吡啶-2-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)吡咯烷-2-酮(2mg,4.96μmol,2.305%产率)。
LCMS:A:95%水:5%乙腈;10mM NH4OAc,B:5%水:95%乙腈;10mM NH4OAc,流速:1.1ml/min,温度:50℃,柱:Ascentis Express C18(50x2.1)mm,2.7μm,时间(min):0---3,%B:0---100,RT-1.302min,M(+1)–403。
1H NMR:400MHz,MeOD:δ2.12-2.26(m,4H),2.61(t,J=12.00Hz,1H),3.51-3.54(m,1H),3.72(bs,3H),3.80-3.93(m,3H),4.17(bs,1H),6.86(d,J=9.20Hz,1H),7.38-7.51(m,3H),7.55(s,1H),7.78-7.81(m,1H)。
手性筛选:注射体积:7,共溶剂:0.3%DEA/甲醇,柱:Lux cellulose-4(250X4.6)mm,5u,柱温:26,总流速:4,CO2流速:2.4,共溶剂流速:1.6,共溶剂%:40,背压:98,RT-4.43min。
实施例27(同手性):
向(R)-3-(4-(5-(苄基氧基)-3-甲基吡啶-2-基)哌嗪-1-基)-1-(4-甲基苄基)吡咯烷-2-酮(0.15g,0.169mmol)的MeOH(5mL)溶液中加入Pd/C(0.1g,0.094mmol)并在室温下在氢气气囊压力下搅拌过夜。反应的完成通过LCMS监测。反应物质通过硅藻土过滤并减压浓缩以得到粗品,将粗品溶解于2mLDMF中并送至SCP。采用以下条件经由制备型LC/MS纯化粗物质:Waters Xbridge C18,19x150mm,5μm;Guard柱:Waters XBridge C18,19x10mm,5μm;流动相A:5:95乙腈:(10mM NH4OAc/水);流动相B:95:5乙腈:(10mM NH4OAc/水);梯度:10-45%B经25分钟,接着在45%B下保持10分钟并在100%B下保持5分钟;流速:15ml/min。合并含有所需产物的级分并使用Genevac离心蒸发器干燥以得到浅黄色固体形式的(R)-3-(4-(5-羟基-3-甲基吡啶-2-基)哌嗪-1-基)-1-(4-甲基苄基)吡咯烷-2-酮(6mg,0.015mmol,9.15%产率)。
LCMS:溶剂A:5%ACN,95%水,10mM NH4OAc,溶剂B:95%ACN,5%水,10mM NH4OAc,流速:4ml/min,温度:50℃,
柱:Ascentis Express C18(50x4.6)mm,2.7μm,时间(min):0---4,%B:0---100,RT-2.112min,M(+1)-381。
1H NMR:400MHz,DMSO-d6:δ2.08(s,3H),2.21(s,1H),2.31(s,3H),2.35-2.41(m,2H),3.26-3.32(m,8H),4.36-4.49(m,4H),6.98-7.11(m,1H),7.16-7.23(m,4H),7.72(d,J=2.80Hz,1H)。
手性筛选:注射体积:5,共溶剂:0.3%DEA/甲醇,柱:Lux cellulose-4(250X 4.6)mm,5u,柱温:26.9,总流速:4,CO2流速:2.4,共溶剂流速:1.6,共溶剂%:40,背压:100,RT-4.58min。
实施例28:
2:6-(4-(1-(3-氟-4-甲基苯基)-2-氧代吡咯烷-3-基)哌嗪-1-基)吡啶-3-基磷酸二氢盐
在-20℃下向1-(3-氟-4-甲基苯基)-3-(4-(5-羟基吡啶-2-基)哌嗪-1-基)吡咯烷-2-酮(55mg,0.148mmol)在1.0mL干燥DCM和三乙胺(0.145mL,1.039mmol)中的溶液中加入POCl3(0.069mL,0.742mmol)。反应混合物在室温下搅拌3小时。往反应混合物中加入水2mL。反应混合物在室温下搅拌18小时。反应的完成通过LCMS监测。将反应混合物浓缩以得到粗残余物0.1g。粗品通过反相制备型HPLC纯化。在纯化完成后,将级分冻干以得到灰白色固体形式的6-(4-(1-(3-氟-4-甲基苯基)-2-氧代吡咯烷-3-基)哌嗪-1-基)吡啶-3-基二氢磷酸盐(23.56mg,0.051mmol,34.5%产率)。
HPLC:柱:CHIRALPAKADH(250X4.6mm),5微米,流动相:0.2%DEA正己烷:乙醇:80:20,RT-26.88min。
LCMS:Column-Ascentis Express C8(50X2.1mm-2.7μm),流动相A:10mMNH4COOH/水:ACN(98:02),流动相B:10mM NH4COOH/水:ACN(02:98),RT-0.8min,M(+1)–451。
1H NMR:(400MHz,DMSO-d6)dppm 1.99-2.13(m,4H)2.21(d,J=1.51Hz,2H)2.31-2.37(m,4H)2.57-2.71(m,2H)2.88-3.01(m,2H)3.61-3.81(m,3H)6.74(d,J=8.53Hz,1H)7.04-7.20(m,1H)7.25-7.44(m,3H)7.63(dd,J=12.80,2.26Hz,1H)7.91(br.s.,1H)。
生物学方法
放射性配体结合测定。使用3HRo 25-6981对8-10周龄雄性Sprague Dawley大鼠(Harlan,Netherlands)的前脑进行确定与NR2B-亚型NMDA受体结合的结合实验(Mutel V;BuchyD;Klingelschmidt A;Messer J;Bleuel Z;Kemp JA;Richards JG.Journal ofNeurochemistry,1998,70(5):2147-2155)。使用断头器(Guillotine)对大鼠实施无麻醉断头术(经动物伦理委员会(animal ethics committee)批准)且将所收集的脑速冻并在-80℃下储存3-6个月用于膜制备。
对于膜制备,将大鼠前脑在冰上在由50mM KH2PO4(用KOH将pH调节至7.4)、1mMEDTA、0.005%Triton×100及蛋白酶抑制剂混合液(SigmaAldrich)构成的均质化缓冲液中解冻20分钟。使用Dounce均质器将所解冻的脑均质化且在48000×g下离心20min。将沉淀(pellet)再悬浮在冷缓冲液中并使用Dounce均质器再均质化。随后,将均质物等分,速冻且在-80℃下储存不超过3-4个月。
为进行竞争性结合测定,将解冻的膜均质物添加至96孔板的每个孔中(20μg/孔)。在100%DMSO中连续稀释实验化合物且添加至测定板的每一排中以达成所需化合物浓度,使测定板中的DMSO浓度保持在1.33%最终反应体积下。然后,将3H Ro 25-6981(4nM)添加至测定板中。在室温下培育1hr后,将膜结合放射性配体收获至GF/B过滤板(在室温下用0.5%PEI处理1hr)上。在50℃下将过滤板干燥20min,与microscint 20一起培育10分钟,且最后,在TopCount(Perkin Elmer)上读取计数。使用MK-0657(此化合物的制备作为实施例1描述在WO 2004108705中(40μM)测定非特异性结合。将CPM值转换成抑制%,且使用特制软件绘制浓度响应曲线。将每一实验重复至少两次以获得实验化合物的最终结合Ki值。使用此测定,实施例14,P-1的化合物显示4nM的结合Ki。
体外占据测定。此测定证实在给药后实施例1化合物占据动物中的脑常驻NR2B亚型受体。向7-9周龄雄性CD-1小鼠静脉给药具有实验化合物的由10%二甲基乙酰胺、40%PEG-400、30%羟丙基β环糊精及30%水组成的溶媒,且在给药后15分钟通过断头术收获前脑。立即将脑样品速冻且储存在-80℃下。在第二天,将给药的脑样品在冰上解冻15-20分钟,然后在由50mM KH2PO4(用KOH将pH调节至7.4)、1mM EDTA、0.005%Triton×100及蛋白酶抑制剂混合液(SigmaAldrich)构成的冷均质化缓冲液中使用Polytron均质化10秒。使用Dounce均质器使粗均质物进一步均质化,且将来自所有动物的均质化膜等份速冻并储存在-80℃下直至进一步使用。在冰上进行整个均质化过程。
为确定占据,首先将膜均质物在冰上解冻,且然后使用25号针进行针均质化。将均质化膜(6.4mg/ml)添加至96孔板上,然后添加3H Ro 25-6981(6nM)。在振荡器上在4℃下将反应混合物培育5分钟,且然后收获至GF/B过滤板(在室温下用0.5%PEI处理1hr)上。在50℃下将过滤板干燥20分钟,与microscint 20一起培育10分钟,且在TopCount(PerkinElmer)上读取。每次给药或化合物组由4-5只动物组成。向对照动物组仅给予溶媒。将来自每一动物的膜一式三份添加至测定板中。使用添加至含有来自给药溶媒的动物的膜均质物的孔中的10μM Ro 25-6981来测定非特异性结合。使用以下方程式将特异性计数/分钟转换成每一动物的每剂量化合物下的占据%:
使用此程序,实施例14,P1的化合物在3mg/Kg i.v.剂量后显示86%的NR2B受体占据。通过质谱以常用方式测定药物水平。在此剂量下,血浆中的药物水平为1018nM,且均质化脑组织中的药物水平为1342nM。
hERG电生理学测定。使用膜片钳技术评价实验化合物对稳定表达hERG通道的HEK293细胞的hERG活性。在室温下,将平铺(plate)有表达hERG的细胞的盖玻片置于实验腔室中,且灌注由以下物质(以mM计)组成的溶液:140NaCl、4KCl、1.8CaCl2、1MgCl2、10葡萄糖、10HEPES(pH 7.4,NaOH)。硼硅酸盐膜片吸量管在填充有含有以下物质的内部溶液时具有2-4MΩ的端电阻:130KCl、1MgCl2、1CaCl2、10EGTA、10HEPES、5ATP-K2(pH 7.2,KOH)。使用由pClamp(Axon instruments)软件控制的Axopatch 200B(Axon instruments,Union City,CA)膜片钳放大器在-80mV下以全细胞结构钳制细胞。形成吉伽封口(gigaseal)时,重复(0.05Hz)施加以下电压方案以记录尾电流:自-80mV至+20mV持续2秒的去极化步骤,然后至-65mV(3秒)的超极化步骤以引发尾电流,且然后返回至保持电位。在尾电流稳定后施加化合物。首先,在单独细胞外溶液存在下(对照)且随后在含有递增化合物浓度的细胞外溶液中记录尾电流。每一化合物浓度施加2-5分钟。每一浓度下的抑制百分比计算为峰值尾电流相对于在对照溶液存在下记录的峰值尾电流的减小。在定制软件中进行数据分析。绘制不同浓度下的抑制百分比以获得浓度响应曲线,随后使用四参数方程式拟合该曲线来计算hERG IC50值。使用此程序,实施例14,P-1的化合物是hERG通道的差抑制剂,且IC50=8.9μM。
小鼠强迫游泳测试(mFST)。强迫游泳测试(FST)是在临床前研究中用于评价抗抑郁化合物的动物模型。FST以与经修改的Porsolt等人(Porsolt RD、Bertin A、JalfreM.Behavioral despair in mice:a primary screening test forantidepressants.Arch IntPharmacodyn Thér 1977;229:327-36)类似的方法进行。在此范例中,强迫小鼠在填充有水的不可逃脱的圆筒中游泳。在这些条件下,小鼠最初将尽力逃脱且最终产生不动行为;此行为解释为被动压力应对策略或抑郁症样行为。将游泳罐置于由塑料制成的箱内部。通过达到圆筒高度的不透明塑料片将每个罐彼此分离。使三只小鼠同时经历测试。通过将小鼠置于含有水(20cm深,维持在24℃-25℃下)的单独玻璃圆筒(46cm高度×20cm直径)中实施6min的游泳期。在此水位下,小鼠尾不会接触容器底部。当小鼠保持被动漂浮且在水中不挣扎并仅做出为保持其鼻/头在水上方且保持其漂浮所必需的那些运动时,则将小鼠判断为不动的。在总共6min的测试期间评估不动性的持续时间,且表示为不动性的持续时间(sec)。对每一小鼠仅测试一次。在每一期结束时,使用干布弄干小鼠且使其返回置于热毯上的圈养笼中以防止体温降低。每一试验后更换水。使用摄影机(Sony Handicam,型号:DCR-HC38E;PAL)记录所有测试期,且使用Forced Swim Scan 2.0版软件(Clever Systems公司,Reston,VA,USA;参见Hayashi E、ShimamuraM、Kuratani K、KinoshitaM、Hara H.Automated experimental system capturing three behavioralcomponents during murine forced swim test.Life Sci.2011年2月28日;88(9-10):411-7及Yuan P、Tragon T、Xia M、Leclair CA、Skoumbourdis AP、Zheng W、Thomas CJ、Huang R、Austin CP、Chen G、Guitart X.Phosphodiesterase 4inhibitors enhancesexual pleasure-seeking activity in rodents.Pharmacol Biochem Behav.2011;98(3):349-55)完成评分。对于NCE测试:在游泳期前15min在小鼠中通过i.v.途径给药测试化合物,且在后续6min内记录不动时间。在FST结束时,通过快速断头方法对小鼠实施安乐死,且收集血浆及脑样品并储存在-80℃下直至进一步分析。在小鼠强迫游泳测定中,实施例1的化合物在30%羟丙基β环糊精/70%柠檬酸盐缓冲液(pH4)的溶媒中以5mL/Kg给药体积静脉给药。在这些条件下在3mg/Kg下,实施例14,P-1化合物展示统计上显著的不动时间减少。在此剂量下,药物水平在血浆中为314nM且在脑中为410nM。如上文所报导测定NR2B受体占据且测定为67%。
对于本领域技术人员显而易见的是,本公开不限于上述公开,并且在不偏离其基本属性的情况下其可以涵盖在其他具体形式中。因此,期望的是,在所有方面本公开为示例性的而不是限制性的,参考随附权利要求,而不是参考上述公开,因此在权利要求的等同物的意义和范围内的所有变化意欲涵盖在本文中。
Claims (13)
1.式I化合物:
其中:
Ar1是苯基并且被0-3个选自氰基、卤素、烷基、卤代烷基和卤代烷氧基的取代基取代;
Ar2是吡啶基或嘧啶基,并且被1个OR取代基且被0-2个卤素或烷基取代基取代;
R是氢或选自以下的前药部分:烷基酯、氨基酸酯、烷氧基酯、膦酸、膦酸烷基酯、烷氧基膦酸酯酸(alkoxyphosphononate acid)、烷氧基膦酸酯烷基酯(alkoxyphosphonate alkyl esters)、烷基氨基甲酸酯、氨基酸氨基甲酸酯、烷基氨基磷酸酯、芳基氨基磷酸酯和氨基磺酸酯;
X是键或C1-C3亚烷基;
n是1或2;
环A是哌嗪基、高哌嗪基或2,5-二氮杂双环[2.2.1]庚烷、哌嗪-2-酮并且被0-4个选自卤素、烷基、羟基或烷氧基的取代基取代;
或其药学上可接受的盐。
2.权利要求1的化合物,其中n是1且环A是被0-2个烷基取代基取代的哌嗪基。
3.权利要求1的化合物,其中Ar1是被0-3个选自氰基、卤素、烷基、卤代烷基和卤代烷氧基的取代基取代的苯基。
4.权利要求1的化合物,其中Ar2选自
且R选自氢、氨基酸酯、膦酸、烷氧基膦酸酯酸、烷基氨基甲酸酯、氨基酸氨基甲酸酯、烷基氨基磷酸酯、芳基氨基磷酸酯和氨基磺酸酯。
5.权利要求1的化合物,其中X是亚甲基。
6.权利要求1的化合物,其中R是氢。
7.权利要求1的化合物,其中R是P(=O)(OH)2。
8.权利要求1的化合物,其选自:
和
或其药学上可接受的盐。
9.一种药物组合物,其包含权利要求1的化合物或其药学上可接受的盐和药学上可接受的载体。
10.一种治疗抑郁症、阿尔茨海默氏病、神经性疼痛或帕金森病的方法,其包括给患者施用治疗有效量的权利要求1的化合物。
11.权利要求10的方法,涉及治疗抑郁症。
12.权利要求10的方法,涉及治疗阿尔茨海默氏病。
13.权利要求10的方法,涉及治疗神经性疼痛。
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- 2016-10-13 BR BR112018006537A patent/BR112018006537A2/pt not_active Application Discontinuation
- 2016-10-13 EP EP16790475.4A patent/EP3362441B1/en active Active
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020169167A1 (en) * | 2001-03-09 | 2002-11-14 | Cowart Marlon D. | Benzimidazoles that are useful in treating sexual dysfunction |
WO2015105929A1 (en) * | 2014-01-09 | 2015-07-16 | Bristol-Myers Squibb Company | (r)-3-((3s,4s)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one and its prodrugs for the treatment of psychiatric disorders |
WO2015105772A1 (en) * | 2014-01-09 | 2015-07-16 | Bristol-Myers Squibb Company | Selective nr2b antagonists |
Non-Patent Citations (1)
Title |
---|
尤启冬主编: "《药物化学》", 31 January 2004, 化学工业出版社 * |
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IL258603A (en) | 2018-06-28 |
EP3362441B1 (en) | 2020-08-12 |
BR112018006537A2 (pt) | 2018-10-16 |
WO2017066366A1 (en) | 2017-04-20 |
MX2018004256A (es) | 2018-05-16 |
US10961229B2 (en) | 2021-03-30 |
ES2818254T3 (es) | 2021-04-09 |
CN108137543B (zh) | 2021-11-23 |
EA201890946A1 (ru) | 2018-09-28 |
US10344020B2 (en) | 2019-07-09 |
KR20180063306A (ko) | 2018-06-11 |
CA3001890A1 (en) | 2017-04-20 |
JP2018536637A (ja) | 2018-12-13 |
US20200071304A1 (en) | 2020-03-05 |
AU2016340237A1 (en) | 2018-05-31 |
EP3362441A1 (en) | 2018-08-22 |
US20180312491A1 (en) | 2018-11-01 |
JP6938485B2 (ja) | 2021-09-22 |
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