CN108017559A - 苯环衍生物及其在医药上的应用 - Google Patents

苯环衍生物及其在医药上的应用 Download PDF

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CN108017559A
CN108017559A CN201710956142.9A CN201710956142A CN108017559A CN 108017559 A CN108017559 A CN 108017559A CN 201710956142 A CN201710956142 A CN 201710956142A CN 108017559 A CN108017559 A CN 108017559A
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alkyl
alkoxy
radical
carbocylic
hydroxyl
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CN108017559B (zh
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秦琳琳
魏用刚
刘国亮
王伟
罗新峰
万松林
宣兆利
任磊
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Sichuan Haisco Pharmaceutical Co Ltd
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Abstract

本发明涉及一种苯环衍生物及其制备方法和在医药上的应用，具体而言涉及如通式(A)所示的苯环衍生物，或者其立体异构体、溶剂化物、代谢产物、前药、药学上可接受的盐或者共晶，其制备方法、包含其的药物组合物以及本发明化合物或者组合物在中枢神经领域的用途，其中，通式(A)中各取代基的定义与说明书的定义相同。

Description

苯环衍生物及其在医药上的应用
技术领域
本发明涉及一种通式(A)所示的苯环衍生物，或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或者共晶，其制备方法、药物组合物以及本发明化合物在中枢神经领域的用途。
背景技术
GABAA受体是中枢神经系统中主要的抑制性神经递质受体。GABAA受体由跨膜多肽亚基的五聚体构成，19种不同的亚基组成了多种不同的GABAA受体亚型。GAB AA受体涉及麻醉、抑郁、焦虑、癫痫、记忆障碍、药物依赖等多种疾病的发病机制和诊断治疗。因此，GABAA受体是药理学和临床上重要的药物作用靶点。丙泊酚及其衍生物8即是一类重要的以GABAA为靶点的化合物。
丙泊酚可激活多种GABAA受体亚型，是一个临床上成熟的静脉麻醉药，广泛用于全身麻醉的诱导和维持。临床剂量相关的丙泊酚可直接激活哺乳动物神经元中的GAB AA受体-氯离子通道复合体，增加氯离子传导，降低神经网络的兴奋性，进而引起全身麻醉(Manami Hara等(1993).Anesthesiology,79,781-788)。丙泊酚的显著药代动力学和药效学性质是起效快，维持时间短和快速可逆。静脉给药后，丙泊酚迅速从血液进入心、肺和肝等高灌注区，高脂溶性使丙泊酚容易跨越血脑屏障进入大脑发挥全身麻醉作用。
然而，丙泊酚也有显而易见的局限性和缺点。据报道，约70％的病人在注射丙泊酚时有一定程度的疼痛或者不适(Pascale Picard(2000).Anesthesia&Analgesia,90,963-969)，有报道认为是脂质乳剂水相中的丙泊酚导致的注射疼痛(Klement W等，1991，Br JAnaesth 67，281)，几项研究报道了与DIPRIVAN的水相中的丙泊酚含量相比，当丙泊酚的水相浓度降低时注射疼痛显著降低(Doenicke AW等，1996，Anesth Analg 82，472；Ueki R等，2007，J Anesth 21，325)。虽然有报道用其他药物预处理或者联合用药的方法可降低丙泊酚注射疼痛的发生率和严重程度(C.H.Tan等(1998).Anaesthesia,53,302–305)，但这种疼痛仍难以避免。丙泊酚已被证明可降低收缩压，舒张压和平均动脉血压，因此在临床上会引起低血压。同时，呼吸抑制也是使用丙泊酚时不可忽视的风险。这些不良反应很大程度上阻碍了丙泊酚在一些临床病例中的应用，如心血管疾病，脑损伤和慢性低血压。
鉴于丙泊酚的局限性和缺点，需要开发新的具有更好药代动力学和药效学特性，且有较少副作用的GABAA受体激动剂。
发明内容
本发明的目的在于提供一种结构新颖、药效好、安全、可口服的GABAA受体激动剂，或者其立体异构体、药学上可接受的盐或前药，制备方法、药物组合物以及其在中枢神经领域上的用途，以便促进镇静催眠，治疗和预防焦虑、恶心、呕吐、偏头痛、惊厥、癫痫、神经变性疾病、脑保护以及中枢神经系统相关的疾病提供更多更优的药物选择途径。
本发明涉及一种通式(A)所示的化合物，或者其所有的立体异构体、溶剂化物、代谢产物、前药、药学上可接受的盐或者共晶：
其中：
X选自H、F、Cl、Br、I、氰基、异氰基、氨基、羧基、-C(＝O)(WRa)、NRcRd、3-12元碳环基、3-12元杂环基或者与R1相结合形成3-12元碳环基或者3-12元杂环基，所述的碳环基或杂环基任选进一步被0至12个Rf所取代，所述的杂环基含有1至6个选自N、O或者S的杂原子；
Rf选自H、F、Cl、Br、I、(＝O)、(＝S)、(＝C)、羟基、巯基、氨基、氰基、羧基、酯基、酰胺基、C1-6烷基、C1-6烷氧基、C1-6硫烷基、C2-6烯基、C2-6炔基、-C＝O-C1-6烷基、3至8元碳环基或者3至8元杂环基取代，所述的杂环基含有1至6个选自N、O或者S的杂原子，所述的烷基、烷氧基、烯基、碳环基或杂环基任选进一步被0至4个选自H、F、Cl、Br、I、羟基、C1-4烷基或C1-4烷氧基的取代基所取代；
W选自NRb、O、S或者不存在；
Ra、Rb、Rc、Rd各自独立选自H、C1-6烷基、C3-8碳环基或者3至8元杂环基，所述的烷基、碳环基或者杂环基可以任选进一步被被0至5个选自H、F、Cl、Br、I、(＝O)、羟基、氨基、氰基、羧基、C1-6烷基、C1-6烷氧基、C3-8碳环基或者3至8元杂环基的取代基所取代，所述的杂环基含有1至2个选自N、O或者S的杂原子；
R1、R2、R3、R7、R8、R9和R10各自独立选自H、F、Cl、Br、I、羟基、C1-8烷基、C1-8烷氧基、3至8元碳环基或者3至8元杂环基，所述的烷基、烷氧基、碳环基或者杂环基任选进一步被0至5个选自F、Cl、Br、I、羟基、C1-8烷基、C1-8烷氧基、3至8元碳环基或者3至8元杂环基的取代基所取代，所述的杂环基含有1至2个选自N、O或者S的杂原子，且R1、R2和R3不同时为H，当X与R1相结合形成3-12元碳环基或者3-12元杂环基时，R2和R3不同时为H；
作为选择，R1与R2、R1与R3、R2与R3、R7与R8或者R9与R10任意一组可以与其相连接的碳原子形成一个3至8元碳环基或者3至8元杂环基，所述3至8元碳环基或者3至8元杂环基任选进一步被0至5个选自F、Cl、Br、I、羟基、C1-8烷基、C 1-8烷氧基、3至8元碳环基或者3至8元杂环基取代，所述的杂环基含有1至2个选自N、O或者S；
R4或者R5各自独立选自H、F、Cl、Br、I、C1-8烷基、C1-8烷氧基、3至8元碳环基或者3至8元杂环基，所述的烷基、烷氧基、碳环基或者杂环基任选进一步被0至5个选自F、Cl、Br、I、羟基、C1-8烷基、C1-8烷氧基、3至8元碳环基或者3至8元杂环基的取代基所取代，所述的杂环基含有1至2个选自N、O或者S的杂原子，且R4和R5不同时为H；
条件是，当X选自H时，R4、R5不为烷氧基取代的烷基，且不同时为F；
Y选自H、F、Cl、Br、I、醛基或者羧基，优选为H；
R6选自H、F、Cl、Br、I、羟基、C1-8烷基或者C1-8烷氧基；
n选自1、2或者3，优选1或者2，更优选1。
本发明优选方案，包括通式(A-I)或者(A-II)所示的化合物，或者其所有的立体异构体、溶剂化物、代谢产物、前药、药学上可接受的盐或者共晶：
其中：
X1选自H、F、Cl、Br、I、氰基、异氰基、氨基、羧基、-C(＝O)(WRa)、NRcRd、3-12元碳环基或3-12元杂环基，优选H、Br、I、氰基、异氰基、氨基、羧基、-C(＝O)(WRa)、NRcRd、3-12元碳环基、3-12元杂环基，更优选Br、I、氰基、异氰基、 氨基、羧基、-C(＝O)(WRa)、NRcRd、3-12元杂环基，所述的碳环基或杂环基任选进一步被0至12个Rf所取代，所述的杂环基含有1至6个选自N、O或者S的杂原子；
Cy选自3-12元碳环基或者3-12元杂环基，所述的碳环基或杂环基任选进一步被0至12个Rf所取代，优选进一步被0至12个选自F、Cl、Br、羟基、巯基、氨基、氰基、羧基、羧酸酯基、酰胺基、C1-6烷基、C1-6烷氧基、C2-6烯基、3至8元碳环基或者3至8元杂环基所取代，所述的杂环含有1至6个选自N、O或者S的杂原子；
Rf选自H、F、Cl、Br、I、(＝O)、(＝S)、(＝C)、羟基、巯基、氨基、氰基、羧基、酯基、酰胺基、C1-6烷基、C1-6烷氧基、C2-6烯基、-C＝O-C1-6烷基、3至8元碳环基或者3至8元杂环基取代，所述的杂环基含有1至6个选自N、O或者S的杂原子，所述的烷基、烷氧基、烯基、碳环基或杂环基任选进一步被0至4个选自H、F、Cl、Br、I、羟基、C1-4烷基或C1-4烷氧基的取代基所取代；
W选自NRb、O、S或者不存在；
Ra、Rb、Rc、Rd各自独立选自H、C1-6烷基、C3-8碳环基或者3至8元杂环基，所述的烷基、碳环基或者杂环基可以任选进一步被被0至5个选自H、F、Cl、Br、I、(＝O)、羟基、氨基、氰基、羧基、C1-6烷基、C1-6烷氧基、C3-8碳环基或者3至8元杂环基的取代基所取代，所述的杂环基含有1至2个选自N、O或者S的杂原子；
R1、R2、R3、R7、R8、R9和R10各自独立选自H、F、Cl、Br、I、羟基、C1-8烷基、C1-8烷氧基、3至8元碳环基或者3至8元杂环基，所述的烷基、烷氧基、碳环基或者杂环基任选进一步被0至5个选自F、Cl、Br、I、羟基、C1-8烷基、C1-8烷氧基、3至8元碳环基或者3至8元杂环基的取代基所取代，所述的杂环基含有1至2个选自N、O或者S的杂原子，且R1、R2和R3不同时为H，当X1与R1相结合形成3-12元碳环基或者3-12元杂环基时，R2和R3不同时为H；
作为选择，R1与R2、R1与R3、R2与R3、R7与R8或者R9与R10任意一组可以与其相连接的碳原子形成一个3至8元碳环基或者3至8元杂环基，所述3至8元碳环基或者3至8元杂环基任选进一步被0至5个选自F、Cl、Br、I、羟基、C1-8烷基、C 1-8烷氧基、3至8元碳环基或者3至8元杂环基取代，优选进一步被0至5个选自F、Cl、Br、羟基、C1-8烷基、C1-8烷氧基或者3至8元碳环基所取代，所述的杂环基含有1至2个选自N、O或者S；
R4或者R5各自独立选自H、F、Cl、Br、I、C1-8烷基、C1-8烷氧基、3至8元碳环基或者3至8元杂环基，所述的烷基、烷氧基、碳环基或者杂环基任选进一步被0至5 个选自F、Cl、Br、I、羟基、C1-8烷基、C1-8烷氧基、3至8元碳环基或者3至8元杂环基的取代基所取代，所述的杂环基含有1至2个选自N、O或者S的杂原子，且R4和R5不同时为H；
条件是，当X1选自H时，R4、R5不为烷氧基取代的烷基，且不同时为F；
Y选自H、F、醛基或者羧基，优选为H、醛基或者羧基，更优选H；
R6选自H、F、Cl、Br、I、羟基、C1-8烷基或者C1-8烷氧基，优选H、F、Cl、羟基、C1-8烷基或者C1-8烷氧基，更优选H、羟基或者C1-8烷基；
n选自1、2或者3，优选1或者2，更优选1。
本发明优选方案，包括通式(A-I)或者(A-II)所示的化合物，或者其所有的立体异构体、溶剂化物、代谢产物、前药、药学上可接受的盐或者共晶：
其中：
X1选自H、F、Cl、Br、I、氰基、异氰基、氨基、羧基、-C(＝O)(Ra)、-C(＝O)(OR a)、-C(＝O)(NRaRb)、NRcRd、 所述各环任选进一步被0至10个Rf取代；
Ra、Rb各自独立选自H、CF3、甲基、乙基、正丙基或异丙基；
Cy选自氮杂五元环，所述环任选进一步被0至4个Rf取代；
Rf各自独立的选自H、F、Cl、Br、I、(＝O)、(＝S)、(＝C)、羟基、巯基、氨基、氰基、羧基、酯基、甲基、乙基、异丙基、叔丁基、甲氧基、乙氧基、异丙氧基、乙烯基、丙烯基、烯丙基、羟甲基、羟乙基、-C(＝O)CH3,优选Cl、Br、甲基、乙基、异丙基、叔丁基、羟基、巯基、羟基甲基、羟基乙基、甲氧基、乙氧基、异丙氧基、氨基、羰基甲基、-C(＝O)NH2、乙烯基、烯丙基、乙炔基、环丙基、环戊基；；
R1、R2、R3、R7、R8、R9和R10各自独立地选自H、F、Cl、Br、CH2F、CHF2、C F3、CH2CH2F、CHFCH3、CHFCH2F、羟基、甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、羟基甲基、羟基乙基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、环丙基、环丁基、环戊基、环己基、氧杂环戊基、氮杂环戊基、氧杂环己基或者氮杂环己基，优选H、甲基、乙基、正丙基、异丙基、环丙基或环丁基，且通式(A-I)中，R1、R2和R3不同时为H，通式(A-II)中，R2和R3不同时为H；
R4或者R5各自独立选自H、F、Cl、Br、CH2F、CHF2、CF3、CH2CH2F、CHFCH3、CHFCH2F、甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、羟基甲基、羟基乙基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、环丙基、环丁基、环戊基或者环己基，优选H、甲基、乙基、正丙基或异丙基，且R4和R5不同时为H，当X1选自H时，R4、R5不同时为F；
R6选自H、F、Cl、Br、I、羟基、甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基或者叔丁氧基，优选H、羟基、甲基、乙基、正丙基或异丙基；
Y选自H、F、醛基或者羧基，优选为H；
n选自1、2或者3，优选1或者2，更优选1。
本发明优选方案，本发明涉及的化合物及其立体异构体、溶剂化物、代谢产物、前药、药学上可接受的盐或者共晶，其中所述的化合物包括但不限于:
本发明涉及一种药物组合物，所述的药物组合物包括通式通式(A)所述的化合物或者其所有的立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或者前药，和一种或者多种药学上可接受的载体和/或者赋形剂。
本发明涉及一种通式(A)所示的化合物，或者其所有的立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或者前药，在制备诱导和维持动物或者人类的麻醉、促进动物或者人类的镇静催眠、脑保护、脑卒中、治疗和/或者预防焦虑、抑郁、失眠、恶心、呕吐、偏头痛、精神分裂、惊厥或者癫痫药物中的用途，优选在制备诱导和维持动物或者人类的麻醉药物中的用途。
除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或者F、Cl、Br、I均包括它们的同位素情况，及本发明所述基团和化合物中所涉及的碳、氢、氧、硫或者氮任选进一步被一个或者多个它们对应的同位素所替代，其中碳的同位素包括12C、13C和14C，氢的同位素包括氕(H)、氘(D，又叫重氢)、氚(T，又叫超重氢)，氧的同位 素包括16O、17O和18O，硫的同位素包括32S、33S、34S和36S，氮的同位素包括14N和 15N，氟的同位素包括17F和19F，氯的同位素包括35Cl和37Cl，溴的同位素包括79Br和 81Br。
“烷基”是指1至20个碳原子的直链或者支链饱和脂肪族烃基，优选为1至8个碳原子的烷基，更优选为1至6个碳原子的烷基，进一步优选为1至4个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、正己基及其各种支链异构体；所述的烷基可以任选进一步被0至5个选自F、Cl、Br、I、＝O、羟基、巯基、-SR11、硝基、氰基、氨基、烷基氨基、酰胺基、烯基、炔基、C1-6烷基、C1-6羟基烷基、C1-6烷氧基、3至8元碳环基、3至8元杂环基、3至8元碳环基氧基、3至8元杂环基氧基、羧基或者羧酸酯基的取代基所取代，其中R11选自C1-6烷基、3至8元碳环基或者3至8元杂环基，本文中出现的烷基，其定义与本定义一致。
“烷氧基”是指-O-烷基。非限制性实施例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基、环丙氧基和环丁氧基。所述的烷基可以任选进一步被0至5个选自F、Cl、Br、I、＝O、羟基、巯基、-SR11、硝基、氰基、氨基、烷基氨基、酰胺基、烯基、炔基、烷基、羟基烷基、烷氧基、碳环基、杂环基、碳环基氧基、杂环基氧基、羧基或者羧酸酯基的取代基所取代，其中R11如上文定义。本文中出现的烷氧基，其定义与本定义一致。
“氨基”是指-NH2。
“羟基”是指-OH。
“巯基”是指-SH。
“羧基”是指-COOH。
“羰基”是指-(C＝O)-。
“羧酸酯基”是指-COOR12，其中R12为C1-6烷基。
“酰胺基”是指-CONR13R14，其中R13和R14各自独立选自H、烷基或者碳环基，R13和R14可以任选进一步被0至3个选自F、Cl、Br、I、羟基、巯基、-SR11、硝基、氰基、氨基、烷基氨基、酰胺基、烯基、炔基、烷基、羟基烷基、烷氧基、碳环基、杂环基、碳环基氧基、杂环基氧基、羧基或者羧酸酯的取代基所取代，其中R11如上文定义。
“＝O”为本领域通常习惯用法，是指以双键相连的氧原子，譬如羰基中与碳原子相连 的双键氧原子。
“烯基”是指含有1至3个碳-碳双键，由2至20个碳原子组成的直链或者支链不饱和脂肪族烃基，优选2至12个碳原子的烯基，更优选2至8个碳原子的烯基。非限制性实施例包括乙烯基、丙烯-2-基、丁烯-2-基、丁烯-2-基、戊烯-2-基、戊烯-4-基、己烯-2-基、己烯-3基、庚烯-2-基、庚烯-3-基、庚烯-4-基、辛烯-3-基、壬烯-3-基、癸烯-4-基和十一烯-3-基。所述的烯基可以任选进一步被0至4个选自F、Cl、Br、I、烷基、烷氧基、直链烯基、直链炔基、氨基、硝基、氰基、巯基、酰胺基、碳环基或者杂环基的取代基所取代。
“炔基”是指含有1至3个碳-碳叁键，由2至20个碳原子组成的直链或者支链不饱和脂肪族烃基，优选2至12个碳原子的炔基，更优选2至8个碳原子的炔基。非限制性实施例包括乙炔基、丙炔-1-基、丙炔-2-基、丁炔-1-基、丁炔-2-基、丁炔-3-基、3,3-二甲基丁炔-2-基、戊炔-1-基、戊炔-2-基、己炔-1-基、1-庚炔-1-基、庚炔-3-基、庚炔-4-基、辛炔-3-基、壬炔-3-基、癸炔-4-基、十一炔-3-基、十二炔-4-基。所述的炔基可以任选进一步被0至4个选自F、Cl、Br、I、烷基、烷氧基、直链烯基、直链炔基、氨基、硝基、氰基、巯基、酰胺基、碳环基或者杂环基的取代基所取代。
“碳环基”是指饱和或者不饱和的芳香环或者非芳香环，芳香环或者非芳香环可以是3至8元的单环、4至12元双环或者10至15元三环体系，碳环基可以连接有桥环或者螺环，非限制性实施例包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环癸基和环十二烷基、环己烯、所述的碳环基可以任选进一步被0至8个选自F、Cl、Br、I、＝O、羟基、巯基、-SR11、硝基、氰基、氨基、烷基氨基、酰胺基、烯基、炔基、烷基、羟基烷基、烷氧基、碳环基、杂环基、碳环基氧基、杂环基氧基、羧基或者羧酸酯基所取代，其中R11如上文定义。本文中出现的碳环基，其定义与本定义一致。
“杂环基”是指取代的或者未取代的饱和或者不饱和的芳香环或者非芳香环，芳香环或者非芳香环可以是3至8元的单环、4至12元双环或者10至15元三环体系，且包含1至6个选自N、O或者S的杂原子，杂环基的环中选择性取代的N、S可被氧化成各种氧化态。杂环基可以连接在杂原子或者碳原子上，杂环基可以连接有桥环或者螺环，非限制性实施例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、吡啶基、呋喃基、噻吩基、 吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基、哌叮基、吗啉基、硫代吗啉基、1,3-二噻基、二氢呋喃基、二氢吡喃基、二噻戊环基、四氢呋喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、苯并咪唑基、苯并吡啶基、吡咯并吡啶基、苯并二氢呋喃基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基和氧杂螺[3.3]庚烷基。所述的杂环基可以任选进一步被0至5个选自F、Cl、Br、I、＝O、羟基、巯基、-SR11、硝基、氰基、氨基、烷基氨基、酰胺基、烯基、炔基、烷基、羟基烷基、烷氧基、碳环基、杂环基、碳环基氧基、杂环基氧基、羧基或者羧酸酯基的取代基所取代，其中R11如上文定义。本文中出现的杂环基，其定义与本定义一致。
“药学上可接受的盐”或者“其药学上可接受的盐”是指本发明化合物保持游离酸或者游离碱的生物有效性和特性，且所述的游离酸通过与无毒的无机碱或者有机碱，所述的游离碱通过与无毒的无机酸或者有机酸反应获得的盐。
“药物组合物”是指一种或者多种本发明所述化合物、其药学上可接受的盐或者前药和其它化学组分形成的混合物，其中，“其它化学组分”是指药学上可接受的载体、赋形剂和/或者一种或者多种其它治疗剂。
“载体”是指不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的材料。
“赋形剂”是指加入到药物组合物中以促进化合物给药的惰性物质。非限制性实施例包括碳酸钙、磷酸钙、糖、淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂和崩解剂。
“前药”是指可经体内代谢转化为具有生物活性的本发明化合物。本发明的前药通过修饰本发明化合物中的酚基团来制备，该修饰可以通过常规的操作或者在体内被除去，而得到母体化合物。当本发明的前药被施予哺乳动物个体时，前药被割裂形成游离的羟基。
“共晶”是指活性药物成分(API)和共晶形成物(CCF)在氢键或者其他非共价键的作用下结合而成的晶体，其中API和CCF的纯态在室温下均为固体，并且各组分间存在固定的化学计量比。共晶是一种多组分晶体，既包含两种中性固体之间形成的二元共晶，也包含中性固体与盐或者溶剂化物形成的多元共晶。
“动物”是指包括哺乳动物，例如人、陪伴动物、动物园动物和家畜，优选人、马或者犬。
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体和构象异构体。
“任选”或者“任选地”或者“选择性的”或者“选择性地”是指随后所述的事件或者状况可以但未必发生，该描述包括其中发生该事件或者状况的情况及其中未发生的情况。例如，“选择性地被烷基取代的杂环基”是指该烷基可以但未必存在，该描述包括其中杂环基被烷基取代的情况，及其中杂环基未被烷基取代的情况。
本文所述“作为选择”是指一种并列的存在关系，比如“Ra与Rb各自独立选自烷基、烷氧基；作为选择，Ra与Rb形成芳环”，表示的Ra与Rb形成芳环与Ra与Rb各自独立选自烷基或烷氧基是一种并列的关系，不受彼此定义的限制。
麻醉诱导时间和麻醉维持时间：给药后开始计时，密切观察动物一般症状和给药局部、呼吸的变化。如正常动物将其推倒或者呈背位仰卧时，能立即翻正过来，这种反射判为翻正反射。反之，则视为翻正反射消失，记录反射消失时间，待动物重新出现翻正反射时，记录反射恢复时间。将给药结束至翻正反射的时间记为麻醉起效时间，自翻正反射消失至反射恢复时间记为麻醉维持时间。
具体实施方式
以下结合实施例详细说明本发明的技术方案，但本发明的保护范围包括但是不限于此。
化合物的结构是通过核磁共振(NMR)或者(和)质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和Bruke r Avance 300)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3)，氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)；
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))；
HPLC的测定使用Agilent 1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm，3.5μM)；
薄层层析硅胶板使用烟台黄海HSGF254或者青岛GF254硅胶板，薄层色谱法(T LC)使用的硅胶板采用的规格是0.15mm～0.20mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm；
柱层析一般使用烟台黄海硅胶200～300目硅胶为载体；
本发明的己知起始原料可以采用或者按照本领域已知的方法来合成，或者可购买于泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、百灵威科技等 公司；
氮气氛是指反应瓶连接一个约1L容积的氮气气球；
氢气氛是指反应瓶连接一个约1L容积的氢气气球；
氢化反应通常抽真空，充入氢气，反复操作3次；
实施例中无特殊说明，反应在氮气氛下进行；
实施例中无特殊说明，溶液是指水溶液；
实施例中无特殊说明，反应的温度为室温，室温最适宜的反应温度，为20℃～30℃；
中间体1
2-[(1R)-1-环丙基乙基]-6-异丙基苯胺(中间体1)
2-[(1R)-1-cyclopropylethyl]-6-isopropyl-aniline
第一步：2-(1-环丙基乙基)-6-异丙基苯胺(1B)
2-(1-cyclopropylvinyl)-6-isopropyl-aniline
向反应瓶中依次加入2-溴-6-异丙基苯胺(1A)(6.70g，31.29mmol)，2-(1-环丙基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(9.10g，46.88mmol))，七水磷酸钾(31.76g，93.87mmol)，甲苯(100mL)和水(50mL)，用水泵抽真空，氮气置换3次，加入醋酸钯(0.35g，1.56mmol)和2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(Ruphos，1.46g，3.12mmol)，再次用水泵抽真空，氮气置换3次，升温至90℃，氮气氛围下反应4小时。冷却至室温，过滤后分液，水相用乙酸乙酯(50mL x 3)萃取，合并有机相，用水(100mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(V/V)＝50:1-20:1)得到淡黄色油状液体2-(1-环丙基乙基)-6-异丙基苯胺(13B)(4.86g，产率：77.1％)。
MS m/z(ESI):202.2(M+1).
1HNMR(400MHz,CDCl3):δ7.07(dd,1H),6.82(dd,1H),6.72(dd,1H),5.22(dd,1H),4.94(d,1H),3.83(s,2H),2.95-2.84(m,1H),1.68-1.62(m,1H),1.26(d,6H),0.73-0.68(m,2H),0.47-0.43(m,2H).
第二步：2-[(1R)-1-环丙基乙基]-6-异丙基苯胺(中间体1)
2-[(1R)-1-cyclopropylethyl]-6-isopropyl-aniline
250mL的高压反应釜中室温下加入2-(1-环丙基乙基)-6-异丙基苯胺(1B)(2.0g，9.94mmol)，二氯甲烷(20mL)和[(R)-2,2'-双(二苯基膦)-1,1'-联萘]二乙酸钌(0.34g，0.40mmol)，加毕将高压釜装置拧紧密封，用氢气置换3次，充入氢气，高压釜上的压力表压力显示为20atm，室温下反应30小时。减压浓缩除去溶剂，残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(V/V)＝30:1)得到淡黄色油状液体2-[(1R)-1-环丙基乙基]-6-异丙基苯胺(中间体1)(1.52g，产率：75.3％，cHPLC：98.53％)。
MS m/z(ESI):204.2(M+1).
1HNMR(400MHz,CDCl3):δ7.14(dd,1H),7.04(dd,1H),6.81(dd,1H),3.74(s,2H),2.98-2.90(m,1H),2.36-2.29(m,1H),1.30(d,3H),1.27(d,6H),1.12-1.04(m,1H),0.59-0.52(m,1H),0.48-0.41(m,1H),0.18-0.07(m,2H).
中间体2
2,6-双[(1R)-1-环丙基乙基]苯胺(中间体2)
2,6-bis[(1R)-1-cyclopropylethyl]aniline
第一步：2,6-双(1-环丙基乙烯基)苯胺(2B)
2,6-bis(1-cyclopropylvinyl)aniline
向反应瓶中依次加入2,6-二溴苯胺(2A)(10.0g，39.9mmol)，2-(1-环丙基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(23.2g，120.0mmol)，七水磷酸钾(40.5g，120.0mmol)，甲苯(100mL)和水(50mL)，用水泵抽真空，氮气置换3次，加入醋酸钯(0.45g，2.0mmol)和2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(Ruphos，1.86g，4.0mmol)，再次用水泵抽真空，氮气置换3次，升温至90℃，氮气氛围下反应8小时。冷却至室温，过滤后分液，水相用乙酸乙酯(50mL x 3)萃取，合并有机相，用水(150mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(V/V)＝50:1-20:1)得到淡黄色油状液体2,6-双(1-环丙基乙烯基)苯胺(2B)(7.58g，产率：84.4％)。
1HNMR(400MHz,CDCl3):δ6.87(d,2H),6.64(dd,1H),5.19(d,2H),4.94(d,2H),4.00(s,2H),1.68-1.62(m,2H),0.74-0.69(m,4H),0.48-0.45(m,4H).
第二步：2,6-双[(1R)-1-环丙基乙基]苯胺(中间体2)
2,6-bis[(1R)-1-cyclopropylethyl]aniline
室温下，向250mL的高压反应釜中加入2,6-双(1-环丙基乙烯基)苯胺(11B)(4.0g，17.8mmol)和二氯甲烷(30mL)，加入催化剂[(R)-2,2'-双(二苯基膦)-1,1'-联萘]二乙酸钌(0.7g，0.83mmol)，加完后将高压釜装置拧紧密封，用氢气置换3次，充入氢气，高压釜上的压力表压力显示为22atm，室温下反应30小时。减压浓缩除去溶剂，残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(V/V)＝30:1)得到白色固体2,6-双[(1R)-1-环丙基乙基]苯胺(中间体2)(3.2g,产率：78.6％，cHPLC：93.0％)。
MS m/z(ESI):230.2(M+1).
1HNMR(400MHz,CDCl3):δ7.14(d,2H),6.80(t,1H),3.62(s,2H),2.27-2.34(m,2H),1.29(d,6H),1.04-1.12(m,2H),0.52-0.59(m,2H),0.41-0.48(m,2H),0.06-0.17(m,4H).
中间体3
2-[(1S)-1-环丙基乙基]-6-异丙基苯胺(中间体3)
2-[(1S)-1-cyclopropylethyl]-6-isopropyl-aniline
第一步：2-[(1S)-1-环丙基乙基]-6-异丙基苯胺(中间体3)
2-[(1S)-1-cyclopropylethyl]-6-isopropyl-aniline
室温下，250mL的高压反应釜中室温下加入2-(1-环丙基乙基)-6-异丙基苯胺(1B)(2.0g，9.94mmol)，二氯甲烷(20mL)和[(S)-2,2'-双(二苯基膦)-1,1'-联萘]二乙酸钌(0.34g，0.40mmol)，加毕将高压釜装置拧紧密封，置换氢气3次后充入氢气，高压釜上的压力表压力显示为20atm，室温下反应30小时。减压浓缩除去溶剂，残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(V/V)＝30:1)得到淡黄色油状液体2-[(1S)-1-环丙基乙基]-6-异丙基苯胺(中间体3)(1.54g，产率：76.2％，cHPLC：96.95％)。
MS m/z(ESI):204.2(M+1).
1HNMR(400MHz,CDCl3):δ7.14(dd,1H),7.03(dd,1H),6.80(dd,1H),3.74(s,2H),2.98-2.89(m,1H),2.36-2.29(m,1H),1.30(d,3H),1.27(d,6H),1.15-1.04(m,1H),0.59-0.52(m,1H),0.48-0.41(m,1H),0.18-0.07(m,2H).
实施例1
1-[2-[(1R)-1-环丙基乙基]-6-异丙基-苯基]吡咯(化合物1)
1-[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenyl]pyrrole
第一步：1-[2-[(1R)-1-环丙基乙基]-6-异丙基-苯基]吡咯(化合物1)
1-[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenyl]pyrrole
反应瓶中依次加入2-[(1R)-1-环丙基乙基]-6-异丙基-苯胺(中间体1)(0.812g，4m mol)，2,5-二甲氧基四氢呋喃(0.53g，4mmol)，醋酸钠(0.035g，0.44mmol)和醋酸(5mL)，80℃下搅拌3小时，将体系冷却至室温，加入水(10mL)稀释，用乙酸乙酯(20mL×2)萃取，合并有机相，用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚)得到无色液体1-[2-[(1R)-1-环丙基乙基]-6-异丙基-苯基]吡咯(化合物1)(0.7g，产率：70％)。
MS M/Z(ESI):254.2(M+1).
1H NMR(400MHz,CDCl3):δ7.42(t,1H)，7.34-7.32(m,1H),7.24-7.23(m,1H),6.61(t,2H)，6.29-6.27(m,2H),2.48-2.40(m,1H),1.53-1.45(m,1H),1.21(d,3H)，1.17(d,3H)，1.14(d,3H),0.99-0.91(m,1H),0.52-0.45(m,1H),0.39-0.30(m,1H),0.07-0.05(m,2H).
实施例2
1-[2-[(1R)-1-环丙基乙基]-6-异丙基-苯基]四氢吡咯(化合物2)
1-[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenyl]pyrrolidine
第一步：1-[2-[(1R)-1-环丙基乙基]-6-异丙基-苯基]四氢吡咯(化合物2)
1-[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenyl]pyrrolidine
将2-[(1R)-1-异丙基乙基]-6-异丙基-苯胺(中间体1)(2.03g，10mmol)，1,4-二溴丁烷(2.37g，11mmol)，碳酸钾(3.04g，22mmol)，碘化钠(1.65g，11mmol)溶于N，N-二甲基甲酰胺(10mL)中，80℃下搅拌3小时，反应结束，加入水(10mL)稀释，用乙酸乙酯(20mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚)，得到黄色液体1-[2-[(1R)-1-环丙基乙基]-6-异丙基-苯基]四氢吡咯(化合物2)(1.50g，产率：58.4％)。
MS M/Z(ESI):256.3(M-1).
1H NMR(400MHz,CDCl3):δ7.24-7.19(m,2H),7.14-7.12(m,1H),3.18-3.13(m,5H),2.53-2.49(m,1H),2.06-1.98(m,4H),1.27-1.22(m,9H),1.06-0.97(m,1H),0.59-0.52(m,1H),0.40-0.34(m,1H),0.23-0.20(m,1H),0.13-0.0.07(m,1H).
实施例3
1-[2,6-双[(1R)-1-环丙基乙基]苯基]吡咯(化合物3)
1-[2,6-bis[(1R)-1-cyclopropylethyl]phenyl]pyrrole
第一步：1-[2,6-双[(1R)-1-环丙基乙基]苯基]吡咯(化合物3)
1-[2,6-bis[(1R)-1-cyclopropylethyl]phenyl]pyrrole
反应瓶中加入2,6-双[(1R)-1-环丙基乙基]苯胺(中间体2)(2.3g，10mmol)，2,5-二 甲氧基四氢呋喃(1.32g，10mmol)和醋酸钠(0.082g，1.0mmol)，加入醋酸(10mL)，80℃下搅拌3小时，冷却至室温后加入水(20mL)，用乙酸乙酯(40mL×2)萃取，合并有机相，用饱和食盐水(40mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚)，得到无色液体1-[2,6-双[(1R)-1-环丙基乙基]苯基]吡咯(化合物3)(1.4g，产率：40％)。
1H NMR(400MHz,CDCl3):δ7.48-7.41(m,1H),7.35-7.32(m,2H),6.55(t,2H)，6.23(t,2H),1.48-1.41(m,2H),1.22(d,6H)，0.98-0.89(m,2H),0.49-0.44(m,2H),0.32-0.28(m,2H),0.05-0.08(m,4H).
实施例4
1-[2,6-双[(1R)-1-环丙基乙基]苯基]四氢吡咯(化合物4)
1-[2,6-bis[(1R)-1-cyclopropylethyl]phenyl]pyrrolidine
第一步：1-[2,6-双[(1R)-1-环丙基乙基]苯基]四氢吡咯(化合物4)
1-[2,6-bis[(1R)-1-cyclopropylethyl]phenyl]pyrrolidine
将2,6-双[(1R)-1-环丙基乙基]苯胺(中间体2)(2.03g，10mmol)，1,4-二溴丁烷(2.37g，11mmol)，碳酸钾(3.04g，22mmol)和碘化钠(1.65g，11mmol)溶于N，N-二甲基甲酰胺(10mL)中，80℃下反应3小时，冷却至室温后加入水(10mL)，用乙酸乙酯(20mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚)，得到无色液体1-[2,6-双[(1R)-1-环丙基乙基]苯基]四氢吡咯(化合物4)(0.8g，产率：30％)。
MS M/Z(ESI):284.2(M+1).
1H NMR(400MHz,CDCl3):δ7.26-7.23(m,3H),3.17-3.07(m,4H),2.43-2.40(m,2H),1.99-1.90(m,4H),1.27(d,6H),1.04-0.97(m,2H),0.58-0.51(m,2H),0.39-0.33(m,2H),0.23-0.19(m,2H),0.17-0.08(m,2H).
实施例5
1-[2-[(1R)-1-环丙基乙基]-6-异丙基-苯基]四氮唑(化合物5)
1-[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenyl]tetrazole
第一步：1-[2-[(1R)-1-环丙基乙基]-6-异丙基-苯基]四氮唑(化合物5)
1-[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenyl]tetrazole
将2-[(1R)-1-环丙基乙基]-6-异丙基-苯胺(中间体1)(1.016g,5.0mmol)和叠氮化钠(0.39g,6.0mmol)加入到原甲酸三甲酯中(0.796g，7.5mmol)，加入冰醋酸(2mL)，加热至80℃搅拌4小时，冷却至室温后减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝20:1～5:1)得到白色固体1-[2-[(1R)-1-环丙基乙基]-6-异丙基-苯基]四氮唑(化合物5)(0.512g,产率：40％)。
MS M/Z(ESI):257.1(M+1).
1HNMR(400MHz,CDCl3):δ8.62(s,1H),7.57(dd,1H),7.44(dd,1H),7.34(dd,1H),2.14-2.04(m,1H),1.27-1.19(m,1H),1.18-111(m,9H),0.97-0.88(m,1H),0.56-0.46(m,1H),0.43-0.32(m,1H)，0.07-0.01(m,2H).
实施例6
1-[2,6-双[(1R)-1-环丙基乙基]苯基]四氮唑(化合物6)
1-[2,6-bis[(1R)-1-cyclopropylethyl]phenyl]tetrazole
第一步：1-[2,6-双[(1R)-1-环丙基乙基]苯基]四氮唑(化合物6)
1-[2,6-bis[(1R)-1-cyclopropylethyl]phenyl]tetrazole
反应瓶中加入原甲酸三甲酯(0.955g，9.0mmol)，加入1-[2,6-双[(1R)-1-环丙基乙基]苯胺(中间体2)(1.376g,6.0mmol)，叠氮化钠(0.468g,7.2mmol)和冰醋酸(4mL)，加毕于90℃下反应5小时，冷却至室温后减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝20:1～5:1)得到淡黄色固体产物1-[2,6-双[(1R)-1-环丙基乙基]苯基]四氮唑(化合物6)(0.801g,产率：47.3％)。
MS M/Z(ESI):283.2(M+1).
1HNMR(400MHz,CDCl3):δ8.57(s,1H),7.59(dd,1H),7.44(dd,2H),1.30-1.21(m,1H),1.17(d,6H),0.95-0.88(m,2H),0.55-0.41(m,2H),0.40-0.31(m,2H),0.04-0.01(m,4H),(-0.21)-(-0.27)(m,1H).
实施例7
2-[(1R)-1-环丙基乙基]-6-异丙基-苯甲腈(化合物7)
2-[(1R)-1-cyclopropylethyl]-6-isopropyl-benzonitrile
第一步：2-[(1R)-1-环丙基乙基]-6-异丙基-苯甲腈(化合物7)
2-[(1R)-1-cyclopropylethyl]-6-isopropyl-benzonitrile
将氰化亚铜(1.145g，12.79mmol)加入到二甲亚砜(20mL)中，升至60℃，氰化亚铜溶解后，一次性加入亚硝酸叔丁酯(3.043g，29.51mmol)，滴加2-[(1R)-1-环丙基乙基]-6-异丙基-苯胺(中间体1)(2.0g，9.84mmol)的二甲亚砜(10mL)溶液，继续搅拌1小时后冷却至45℃，滴加4M的盐酸溶液(5mL)，搅拌10分钟，加入水(40mL)，用二氯甲烷(50mL×3)萃取，合并有机相，用水(100mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝100:1)得到棕色液体2-[(1R)-1-环丙基乙基]-6-异丙基-苯甲腈(化合物7)(0.854g，产率：40.7％)。
MS M/Z(ESI):236.1(M+23).
1HNMR(400MHz,CDCl3):δ7.50(dd,1H),7.32(dd,1H),7.23(dd,1H),3.45-3.35(m,1H),2.57-2.49(m,1H),1.36(d,3H),1.32(d,3H),1.30(d,3H),1.07-0.98(m,1H),0.64-0.57(m,1H),0.44-0.38(m,1H)，0.32-0.20(m,2H).
实施例8
2-[(1R)-1-环丙基乙基]-6-异丙基-苯甲醛(化合物8)
2-[(1R)-1-cyclopropylethyl]-6-isopropyl-benzaldehyde
第一步：2-[(1R)-1-环丙基乙基]-6-异丙基-苯甲醛(化合物8)
2-[(1R)-1-cyclopropylethyl]-6-isopropyl-benzaldehyde
反应瓶中加入2-[(1R)-1-环丙基乙基]-6-异丙基-苯甲腈(化合物7)(2.133g，10.0mmol)和干燥的甲苯(40mL)，冷却至0℃，滴加二异丁基氢化铝(1M in toluene,20.0mL,20.0mmol)溶液，滴毕升至室温搅拌过夜，小心加入水(5mL)淬灭反应，搅拌10分钟后生成白色沉淀，过滤，用乙酸乙酯(20mL)洗涤滤饼，所得滤液用无水硫酸钠干燥，减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝50:1)得到淡黄色液体2-[(1R)-1-环丙基乙基]-6-异丙基-苯甲醛(化合物8)(1.612g，产率：74.5％)。
MS M/Z(ESI):239.1(M+23).
1HNMR(400MHz,CDCl3):δ10.64(s,1H),7.47-7.28(m,3H),3.57-3.47(m,1H),2.74-2.66(m,1H),1.32(d,3H),1.28(dd,6H),1.08-1.00(m,1H),0.62-0.54(m,1H),0.44-0.37(m,1H),0.27-0.21(m,1H)，0.13-0.06(m,1H).
实施例9
2-[(1R)-1-环丙基乙基]-6-异丙基-苯甲酸(化合物9)
2-[(1R)-1-cyclopropylethyl]-6-isopropyl-benzoic acid
2-[(1R)-1-环丙基乙基]-6-异丙基-苯甲酸(化合物9)
2-[(1R)-1-cyclopropylethyl]-6-isopropyl-benzoic acid
将2-[(1R)-1-环丙基乙基]-6-异丙基-苯甲醛(化合物8)(1.49g，6.89mmol)溶于叔丁醇(20mL)和异丁烯(15％in THF，20mL)的混合溶液中，冷却至0℃，滴加亚氯酸钠(1.869g，20.67mmol)和磷酸二氢钾(2.479g，20.67mmol)的水溶液(10mL)，滴毕缓慢升至室温搅拌过夜，加入1M的氢氧化钠溶液(20mL)，继续搅拌10分钟，分离水相，加入4M的盐酸(10mL)酸化体系，用甲基叔丁醚(20mL×3)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石 油醚/乙酸乙酯(v/v)＝5:1)得淡黄色液体2-[(1R)-1-环丙基乙基]-6-异丙基-苯甲酸(化合物9)(1.067g，产率：66.6％)。
MS M/Z(ESI):255.1(M+23).
1HNMR(400MHz,CDCl3):δ8.84(s,1H),7.39(dd,1H),7.31(dd,1H),7.21(dd,1H),3.08-2.98(m,1H),2.15-2.08(m,1H),1.33(d,3H),1.30(d,3H),1.28(d,3H),1.08-1.00(m,1H)，0.61-0.56(m,1H),0.40-0.35(m,1H),0.25-0.16(m,2H).
实施例10
2-[(1S)-1-环丙基乙基]-6-异丙基-苯甲腈(化合物10)
2-[(1S)-1-cyclopropylethyl]-6-isopropyl-benzonitrile
2-[(1S)-1-环丙基乙基]-6-异丙基-苯甲腈(化合物10)
2-[(1S)-1-cyclopropylethyl]-6-isopropyl-benzonitrile
将氰化亚铜(1.145g，12.79mmol)加入到二甲亚砜(20mL)中，升至60℃，待氰化亚铜溶解后，一次性加入亚硝酸叔丁酯(3.043g，29.51mmol)，滴加2-[(1S)-1-环丙基乙基]-6-异丙基-苯胺(中间体3)(2.0g，9.84mmol)的二甲亚砜(10mL)溶液，搅拌1小时，冷却至45℃，滴加4M的盐酸溶液(5mL)，继续搅拌10分钟，加入水(40mL)，用二氯甲烷(50mL×3)萃取，合并有机相，用水(100mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝100:1)得到棕色液体2-[(1S)-1-环丙基乙基]-6-异丙基-苯甲腈(化合物10)(0.925g，产率：44.1％)。
MS M/Z(ESI):236.1(M+23).
1HNMR(400MHz,CDCl3):δ7.50(dd,1H),7.31(dd,1H),7.22(dd,1H),3.45-3.35(m,1H),2.57-2.49(m,1H),1.37(d,3H),1.32(d,3H),1.30(d,3H),1.07-1.00(m,1H),0.64-0.57(m,1H),0.44-0.38(m,1H)，0.32-0.20(m,2H).
实施例11
2-[(1S)-1-环丙基乙基]-6-异丙基-苯甲醛(化合物11)
2-[(1S)-1-cyclopropylethyl]-6-isopropyl-benzaldehyde
第一步：2-[(1S)-1-环丙基乙基]-6-异丙基-苯甲醛(化合物11)
2-[(1S)-1-cyclopropylethyl]-6-isopropyl-benzaldehyde
将2-[(1S)-1-环丙基乙基]-6-异丙基-苯甲腈(化合物10)(2.133g，10.0mmol)溶于干燥甲苯(40mL)中，冷却至0℃，滴加二异丁基氢化铝(1M in toluene，20.0mL，20.0mmol)溶液，滴毕升至室温搅拌过夜，小心加水(5mL)淬灭反应，继续搅拌10分钟，生成白色沉淀物，过滤，用乙酸乙酯(20mL)洗涤滤饼，所得滤液用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝50:1)，得淡黄色液体2-[(1S)-1-环丙基乙基]-6-异丙基-苯甲醛(化合物11)(1.532g，产率：70.8％)。
MS M/Z(ESI):239.1(M+23).
1HNMR(400MHz,CDCl3):δ10.64(s,1H),7.47-7.28(m,3H),3.55-3.46(m,1H),2.73-2.66(m,1H),1.31(d,3H),1.27(dd,6H),1.07-0.99(m,1H),0.62-0.55(m,1H),0.44-0.37(m,1H),0.27-0.21(m,1H)，0.12-0.06(m,1H).
实施例12
2-[(1S)-1-环丙基乙基]-6-异丙基-苯甲酸(化合物12)
2-[(1S)-1-cyclopropylethyl]-6-isopropyl-benzoic acid
2-[(1S)-1-环丙基乙基]-6-异丙基-苯甲酸(化合物12)
2-[(1S)-1-cyclopropylethyl]-6-isopropyl-benzoic acid
将2-[(1S)-1-环丙基乙基]-6-异丙基-苯甲醛(化合物11)(1.49g，6.89mmol)溶于叔丁醇(20mL)和异丁烯(15％in THF,20mL)的混合溶液中，冷却至0℃，滴加亚氯酸钠(1.869g，20.67mmol)和磷酸二氢钾(2.479g，20.67mmol)的水溶液(10mL)溶液，滴毕缓慢升至室温搅拌过夜，加入1M氢氧化钠溶液(20mL)，继续搅拌10分钟，分离水相，用4M的盐酸溶液(10mL)酸化，甲基叔丁醚(20mL×3)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝5:1)得淡黄色液体2-[(1S)-1-环丙基乙基]-6-异丙基-苯甲酸(化合物12)(0.824g，产率：51.5％)。
MS M/Z(ESI):255.1(M+23).
1HNMR(400MHz,DMSO-D6):δ12.99(s,1H),7.36-7.29(m,2H),7.20(dd,1H),2.93-2.83(m,1H),1.97-1.91(m,1H),1.23(d,3H),1.19(dd,6H),1.09-1.01(m,1H),0.54-0.47(m,1H)，0.32-0.25(m,1H),0.18-0.05(m,2H).
实施例13
3-[2,6-二[(1R)-1-环丙基乙基]苯基]恶唑烷酮(化合物13)
3-[2,6-bis[(1R)-1-cyclopropylethyl]phenyl]oxazolidin-2-one
第一步：2-氯乙基N-[2,6-二[(1R)-1-环丙基乙基]苯基]碳酸酯(13B)
2-chloroethyl N-[2,6-bis[(1R)-1-cyclopropylethyl]phenyl]carbamate
圆底烧瓶中加入2,6-二[(1R)-1-环丙基乙基]苯胺(中间体2)(1.0g，4.36mmol)，甲苯(5mL)和水(2mL)，搅拌下加入氢氧化钠(1.92g，4.80mmol)，滴加氯甲酸氯乙酯(0.65g，4.58mmol)，室温下反应20小时，加入水(2mL)，用甲基叔丁基醚(5mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩得到白色固体2-氯乙基N-[2,6-二[(1R)-1-环丙基乙基]苯基]碳酸酯(13B)(1.4g，产率：96％)。
第二步：3-[2,6-二[(1R)-1-环丙基乙基]苯基]恶唑烷酮(化合物13)
3-[2,6-bis[(1R)-1-cyclopropylethyl]phenyl]oxazolidin-2-one
反应瓶瓶中放入2-氯乙基N-[2,6-二[(1R)-1-环丙基乙基]苯基]碳酸酯(13B)(1.40g,4.17mmol)和甲醇(5mL)，加入甲醇钠(0.68g，12.5mmol)，室温反应20小时，加入水(10mL)，用二氯甲烷(10mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝10：1)得白色固体3-[2,6-二[(1R)-1-环丙基乙基]苯基]恶唑烷酮(化合物13)(0.8g，产率：60％)。
MS m/z(ESI):300.2(M+1).
1HNMR(400MHz,CDCl3):δ7.40-7.26(m,3H),4.50-4.46(m,2H),3.81-3.76(m,1H),3.74-3.69(m,1H),2.16-2.09(m,2H),1.30-1.28(m,6H),1.06-1.03(m,2H),0.60-0.35(m,4H),0.26-0.21(m,3H),0.01-0.00(m,1H).
实施例14
(R)-4-(2-(1-环丙基乙基)-6-异丙基苯基)吗啉(化合物14)
(R)-4-(2-(1-cyclopropylethyl)-6-isopropylphenyl)morpholine
第一步：(R)-4-(2-(1-环丙基乙基)-6-异丙基苯基)吗啉(化合物14)
(R)-4-(2-(1-cyclopropylethyl)-6-isopropylphenyl)morpholine
反应瓶中依次加入(R)-2-(1-环丙基乙基)-6-异丙基苯胺(中间体1)(1.0g，4.92mmol)，N,N-二甲基甲酰胺(10mL)，2,2'-二溴二乙醚(1.71g，7.38mmol)，碳酸钾(1.02g，7.38mmol)和碘化钾(0.816g，4.92mmol)，加热到90℃反应8小时，将反应液倒入水(50mL)中，充分搅拌后用乙酸乙酯(30mL×3)萃取，饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝10:1)得到粉色固体(R)-4-(2-(1-环丙基乙基)-6-异丙基苯基)吗啉(化合物14)(1.0g，产率：74.4％)。
MS M/Z(ESI):274.3(M+1)
1HNMR:(400MHz,CDCl3):δ7.24-7.17(m,2H),7.12-7.10(m,1H),3.83-3.70(m,4H),3.48-3.42(m,1H),3.21-3.15(m,2H),3.00-2.93(m,2H),2.74-2.67(m,1H),1.25-1.21(m,9H),1.08-0.99(m,1H),0.61-0.54(m,1H),0.38-0.33(m,1H),0.28-0.22(m,1H),0.08-0.01(m,1H).
实施例15
4-(2,6-二((R)-1-环丙基乙基)苯基)吗啉(化合物15)
4-(2,6-bis((R)-1-cyclopropylethyl)phenyl)morpholine
第一步：4-(2,6-二((R)-1-环丙基乙基)苯基)吗啉(化合物15)
4-(2,6-bis((R)-1-cyclopropylethyl)phenyl)morpholine
反应瓶中加入2,6-二((R)-1-环丙基乙基)苯胺(1.0g，4.36mmol)(中间体2)，N,N-二甲基甲酰胺(10mL)和2,2'-二溴二乙醚(1.52g，6.54mmol)，加入碳酸钾(0.904g，6.54mmol)，碘化钾(0.724g，4.36mmol)，加热到90℃搅拌8小时，反应完毕后将反应液倒入水(50mL)中，充分搅拌后用乙酸乙酯(30mL×3)萃取，饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝10:1)得到粉色固体4-(2,6-二((R)-1-环丙基乙基)苯基)吗啉(化合物15)(1.0g，产率：76.6％)。
MS M/Z(ESI):300.2(M+1).
1HNMR:(400MHz,CDCl3):δ7.23-7.21(m,3H),3.77-3.67(m,4H),3.09-2.97(m,4H),2.71-2.64(m,2H),1.24(d,6H),1.07-0.99(m,2H),0.61-0.54(m,2H),0.38-0.32(m,2H),0.28-0.22(m,2H),0.09-0.03(m,2H).
实施例16
1-[2-[(1R)-1-环丙基乙基]-6-异丙基-苯基]咪唑
1-[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenyl]imidazole
第一步：1-[2-[(1R)-1-环丙基乙基]-6-异丙基-苯基]咪唑(化合物16)
1-[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenyl]imidazole
向装有甲醇(10mL)的反应瓶中加入2-[(1R)-1-环丙基乙基]-6-异丙基-苯胺(中间体1)(2.04g，10mmol)和乙二醛(0.58g，10mmol)，室温搅拌16小时，向体系中加入甲醛(1.6mL)和氯化铵(1.07g，20mmol)后加入甲醇(40mL)稀释，回流1小时，10分钟内加入85％的磷酸溶液(1.4mL)，继续回流4小时，将体系冷却至室温，减压浓缩除去溶剂，加入冰(30g)和乙酸乙酯(30mL)，用10％的氢氧化钠水溶液调节pH至9，分液，水层用乙酸乙酯(50mL×2)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝10∶1)得到白色固体1-[2-[(1R)-1-环丙基乙基]-6-异丙基-苯基]咪唑(化合物16)(0.82g，产率：32％).
MS m/z(ESI):255.2(M+1).
1H NMR(400MHz,CDCl3):δ7.47-7.43(m,2H),7.35(d,1H),7.27-7.25(m,1H),7.22(d,1H),6.89(t,1H),2.42-2.33(m,1H),1.50-1.40(m,1H),1.18(q,3H),1.15(dd,3H),1.12(d,3H),0.95-0.86(m,1H),0.51-0.46(m,1H),0.36-0.30(m,1H),0.02-0.02(m,1H),(-0.07)-(-0.13)(m,1H).
实施例17
3-[2-[(1R)-1-环丙基乙基]-6-异丙基-苯基]唑烷-2-酮(化合物17)
3-[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenyl]oxazolidin-2-one
第一步：2-氯乙基N-[2-[(1R)-1-环丙基乙基]-6-异丙基-苯基]氨基甲酸酯(17B)
2-chloroethyl N-[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenyl]carbamate
反应瓶中加入2-[(1R)-1-环丙基乙基]-6-异丙基-苯胺(中间体1)(1.0g，4.92mmol)和甲苯(5mL)，加入氢氧化钠(0.22g,5.5mmol)的水溶液(4mL)，缓慢滴加氯甲酸氯乙酯(0.74g,5.2mmol)，保持内温不超过25℃，室温反应1小时，分液，有机相减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝10：1)得到白色固体2-氯乙基N-[2-[(1R)-1-环丙基乙基]-6-异丙基-苯基]氨基甲酸酯(17B)(1.35g，产率：89％).
MS m/z(ESI):310.6(M+1).
1H NMR(400MHz,CDCl3):δ7.34-7.27(m,2H),7.20-7.18(m,1H),6.07(s,1H),4.42-4.29(m,2H),3.75-3.56(m,2H),3.19-3.12(m,1H),2.36-2.32(m,1H),1.26(d,3H),1.22(d,6H),1.01-0.99(m,1H),0.56-0.54(m,1H),0.41-0.38(m,1H),0.20-0.17(m,1H),0.13-0.09(m,1H).
第二步：3-[2-[(1R)-1-环丙基乙基]-6-异丙基-苯基]唑烷-2-酮(化合物17)
3-[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenyl]oxazolidin-2-one
向反应瓶中依次加入甲醇(5mL)，2-氯乙基N-[2-[(1R)-1-环丙基乙基]-6-异丙基-苯基]氨基甲酸酯(17B)(1.07g,3.45mmol)和甲醇钠(0.66g,12mmol)的甲醇溶液(10mL)，室温反应过夜，减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝6：1)得到白色固体3-[2-[(1R)-1-环丙基乙基]-6-异丙基-苯基]唑烷-2-酮
(化合物17)(0.86g，产率：91％).
MS m/z(ESI):274.2(M+1).
1H NMR(400MHz,CDCl3):δ7.39-7.26(m,2H),7.23-7.21(m,1H),4.55-4.47(m,2H),3.82-3.71(m,2H),2.97-2.92(m,1H),2.18-2.12(m,1H),1.13-1.12(m,9H),1.08-1.04(m,1H),0.65-0.48(m,1H),0.45-0.32(m,1H),0.28-0.19(m,1H),0.24-0.00(m,1H).
实施例18
N-[2-[(1R)-1-环丙基乙基]-6-异丙基-苯基]甲酰胺(化合物18)
N-[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenyl]formamide
第一步：N-[2-[(1R)-1-环丙基乙基]-6-异丙基-苯基]甲酰胺(化合物18)
N-[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenyl]formamide
搅拌下将乙酸酐(0.6mL)加入到甲酸(0.66mL)的反应瓶中，室温搅拌15min，滴加2-[(1R)-1-异丙基乙基]-6-异丙基-苯胺(中间体1)(1.016g，5mmol)的二氯甲烷溶液(10mL)，室温搅拌2h，停止反应。减压浓缩反应液的黄棕色固体，用石油醚(10mL)洗涤，减压浓缩除去残留溶剂得白色固体产物，用正庚烷(25mL)重结晶得白色固体N-[2-[(1R)-1-环丙基乙基]-6-异丙基-苯基]甲酰胺(化合物18)(0.816g,产率：70.6％，cHPL C：98.75％)。
MS M/Z(ESI):232.2(M+1).
1H NMR(400MHz,CDCl3):δ8.45(0.34H,s),8.00(0.66H,d),7.37-7.29(2H,m),7.23-7.19(1H,m),7.00(0.58H,d,J＝1.2Hz),6.75(0.42H,s),3.22-3.10(1H,m),2.42-2.38(1H,m),1.26-1.21(9H,m),1.03-0.97(1H,m),0.59-0.54(1H,m),0.43-0.37(1H,m),0.21-0.14(1H,m),0.09-0.0.00(1H,m).
实施例19
N-[2-[(1S)-1-环丙基乙基]-6-异丙基-苯基]甲酰胺(化合物19)
N-[2-[(1S)-1-cyclopropylethyl]-6-isopropyl-phenyl]formamide
第一步：N-[2-[(1S)-1-环丙基乙基]-6-异丙基-苯基]甲酰胺(化合物19)
N-[2-[(1S)-1-cyclopropylethyl]-6-isopropyl-phenyl]formamide
搅拌下将乙酸酐(0.6mL)加入到甲酸(0.66mL)的反应瓶中，室温搅拌15min，滴加2-[(1S)-1-异丙基乙基]-6-异丙基-苯胺(中间体3)(1.016g，5mmol)的二氯甲烷溶液(10mL)，室温搅拌2h，停止反应。减压浓缩反应液的黄棕色固体，用石油醚(10mL)洗涤，减压浓缩除去残留溶剂得白色固体产物，用正庚烷(25mL)重结晶得白色固体N-[2-[(1S)-1-环丙基乙基]-6-异丙基-苯基]甲酰胺(化合物19)(0.832g,产率：72.0％，cHPLC：98.70％)。
MS M/Z(ESI):232.2(M+1).
1H NMR(400MHz,CDCl3):δ8.45(0.34H,s),8.00(0.66H,d,J＝1.2Hz),7.37-7.29(2H,m),7.23-7.19(1H,m),7.00(0.58H,d,J＝1.2Hz),6.75(0.42H,s),3.22-3.10(1H,m),2.42-2.38(1H,m),1.26-1.21(9H,m),1.03-0.97(1H,m),0.59-0.54(1H,m),0.43-0.37(1H,m),0.21-0.14(1H,m),0.09-0.0.00(1H,m).
实施例20
2-[(1R)-1-环丙基乙基]-6-异丙基-苯甲酸甲酯(化合物20)
methyl 2-[(1R)-1-cyclopropylethyl]-6-isopropyl-benzoate
第一步：2-[(1R)-1-环丙基乙基]-6-异丙基-苯甲酸甲酯(化合物20)
methyl 2-[(1R)-1-cyclopropylethyl]-6-isopropyl-benzoate
将中间体1(0.42g,1.82mmol)溶于DCM(10ml)中，滴加一滴DMF，加入草酰氯(1ml)，室温搅拌4h.减压浓缩除去溶剂及多余的草酰氯，将残余物溶于甲醇(10ml)，室温搅拌5h.减压浓缩除去溶剂，残余物经柱层析(PE/EA＝20:1)得到黄色油状产品2-[(1R)-1-环丙基乙基]-6-异丙基-苯甲酸甲酯(化合物20)(0.40g,产率：91.0％)。
MS M/Z(ESI):247.2(M+1).
1H NMR(400MHz,CDCl3):δ7.35-7.33(m,1H),7.25(m,1H),7.18-7.16(m,1H),3.85(s,3H),2.82-2.77(m,1H),1.92-1.88(m,1H),1.28-1.22(m,9H),1.03-1.00(m,1H),0.56-0.52(m,1H),0.38-0.33(m,1H),0.20-0.12(m,2H).
实施例21
N-[2-[(1R)-1-环丙基乙基]-6-异丙基-苯基]环丙基甲酰胺(化合物21)
N-[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenyl]cyclopropanecarboxamide
第一步：N-[2-[(1R)-1-环丙基乙基]-6-异丙基-苯基]环丙基甲酰胺(化合物21)
N-[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenyl]cyclopropanecarboxamide
将中间体1(2.03g,10.00mmol)溶于DCM(10ml)中，依次加入三乙胺(1.11g,11.00mmol)和环丙基甲酰氯(1.05g,10.0mmol)，室温搅拌4h。反应液直接减压浓缩后柱层析(PE/EA＝20:1to 5:1)得白色固体N-[2-[(1R)-1-环丙基乙基]-6-异丙基-苯基]环丙基甲酰胺(化合物21)(1.124g,产率：41.4％)。
MS M/Z(ESI):272.2(M+1).
实施例22
2-溴-1,3-双[(R)-1环丙基乙基]苯(化合物22)
2-bromo-1,3-bis((R)-1-cyclopropylethyl)benzene
第一步：2-溴-1,3-双[(R)-1环丙基乙基]苯(化合物22)
2-bromo-1,3-bis((R)-1-cyclopropylethyl)benzene
将2,6-双[(1R)-1-环丙基乙基]苯胺(中间体2)(4.60g，20.1mmol)和溴化亚铜(3.45g，24.1mmol)加入到二甲亚砜(10mL)中，升至50℃，待氰化亚铜溶解后，慢慢滴加亚硝酸叔丁酯的二甲亚砜溶液(10.0mL，40.1mmol)，50℃搅拌4小时，冷却至室温，滴加4M的盐酸溶液至澄清，继续搅拌10分钟，加入水(40mL)，用乙酸乙酯(50mL×3)萃取，合并有机相，用水(100mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝30:1)得到无色液体2-溴-1,3-双[(R)-1环丙基乙基]苯(化合物22)(3.85g，产率：65.5％)。
GM M/Z(EI):292.20[M(Br79)]+,294.20[M(Br81)]+
1H NMR(400MHz,DMSO-d6):δ7.37-7.31(m,3H),2.68-2.61(m,2H),1.22(d,J＝6.9Hz,6H),1.14-1.06(m,2H),0.58-0.51(m,2H),0.39-0.32(m,2H),0.26-0.20(m,2H),0.10-0.04(m,2H).
实施例23
1,3-双[(R)-1环丙基乙基]-2-碘苯(化合物23)
1,3-bis[(1R)-1-cyclopropylethyl]-2-iodo-benzene
第一步：1,3-双[(R)-1环丙基乙基]-2-碘苯(化合物23)
1,3-bis[(1R)-1-cyclopropylethyl]-2-iodo-benzene
将碘化钾(0.67g，4.01mmol)和碘(0.05g，0.20mmol)溶于DMSO(5mL)中，然后加入铜粉(0.01g，0.20mmol)，升至60℃，缓慢加入亚硝酸叔丁酯(0.41g，4.01mmol)和2,6-双[(1R)-1-环丙基乙基]苯胺(中间体2)(0.46g，2.01mmol)的 DMSO溶液(5mL)，60℃下搅拌1.5h。冷却至室温，加入乙酸乙酯(10mL),水(10mL)，分液，水相用乙酸乙酯(10mL*2)萃取，合并有机相，用水(20mL)洗涤，无水硫酸钠干燥，减压浓缩后柱层析(PE/EA＝100/1)得无色液体1,3-双[(R)-1环丙基乙基]-2-碘苯(化合物23)(0.42g，62.0％)。
1H NMR(400MHz,DMSO-d6):δ7.34-7.27(m,3H),2.65-2.57(m,2H),1.19(d6H),1.15-1.08(m,2H),0.58-0.51(m,2H),0.39-0.32(m,2H),0.26-0.20(m,2H),0.12-0.06(m,2H).
实施例24
2,6-双[(1R)-1-环丙基乙基]苯甲腈(化合物24)
2,6-bis[(1R)-1-cyclopropylethyl]benzonitrile
第一步：2,6-双[(1R)-1-环丙基乙基]苯甲腈(化合物24)
2,6-bis[(1R)-1-cyclopropylethyl]benzonitrile
将2,6-双[(1R)-1-环丙基乙基]苯胺(中间体2)(2.35g，10.30mmol)和氰化亚铜(1.01g，11.30mmol)加入到二甲亚砜(4mL)中，升至40℃，待氰化亚铜溶解后，慢慢滴加亚硝酸叔丁酯(3.70mL，30.70mmol)，50℃搅拌4小时，冷却至室温，滴加4M的盐酸溶液(2.5mL)，继续搅拌10分钟，加入水(40mL)，用二氯甲烷(50mL×3)萃取，合并有机相，用水(100mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝30:1)得到棕色液体2-[(1S)-1-环丙基乙基]-6-异丙基-苯甲腈(化合物24)(1.00g，产率：40.8％)。
MS M/Z(ESI):262.1[M+23]+.
1HNMR(400MHz,CDCl3):7.52(t,1H),7.34(d,2H),2.57-2.49(m,2H),1.37(d,6H),1.07-0.99(m,2H),0.64-0.58(m,2H),0.45-0.38(m,2H),0.33-0.26(m,2H),0.26-0.20(m,2H).
实施例25
2,6-双[(R)-1-环丙基乙基]苯甲醛(化合物25)
2,6-bis((R)-1-cyclopropylethyl)benzaldehyde
第一步：2,6-双[(R)-1-环丙基乙基]苯甲醛(化合物25)
2,6-bis((R)-1-cyclopropylethyl)benzaldehyde
将2,6-双[(1R)-1-环丙基乙基]苯甲腈(化合物24)(2.80g，11.7mmol)溶于干燥甲苯(15mL)中，冷却至0℃，滴加二异丁基氢化铝(1.5M in toluene，16mL，23.4mmol)溶液，滴毕升至室温搅拌过夜，小心加4M的盐酸(2.0mL)淬灭反应，继续搅拌10分钟，用乙酸乙酯萃取(20mL*2)，无水硫酸钠干燥，减压浓缩，残得淡黄色液体2,6-双[(R)-1-环丙基乙基]苯甲醛(化合物25)(3.20g，产率：90.0％)。
MS M/Z(ESI):262.1(M+23).
实施例26
2,6-双[(R)-1-环丙基乙基]苯甲酸(化合物26)
2,6-bis[(1R)-1-cyclopropylethyl]benzoic acid
第一步：2,6-双[(R)-1-环丙基乙基]苯甲酸(化合物26)
2,6-bis[(1R)-1-cyclopropylethyl]benzoic acid
将原料2,6-双[(R)-1-环丙基乙基]苯甲醛(化合物25)(3.22g，13.3mmol)溶于叔丁醇(10mL)和异丁烯(10mL)，0℃下加入亚氯酸钠(3.60g，39.9mmol)和磷酸二氢钠(6.22g，39.9mmol)的混合水溶液(25mL)，加完后移走冰水浴，自然升至室温反应6h。冷至室温后乙酸乙酯萃取(20mL*3),饱和氯化钠洗(20mL*1),无水硫酸钠干燥,过滤,减压浓缩后柱层析(PE:EA＝20:1)得土黄色固体2,6-双[(R)-1-环丙基乙基]苯甲酸(化合物26)(0.63g，收率：18.4％)。
MS M/Z(ESI):257.1(M-1).
1HNMR(400MHz,CDCl3):7.43-7.39(m,1H),7.32-7.30(m,2H),2.13-2.06(m,2H),1.33(d,J＝7.0Hz,6H),1.07-1.00(m,2H),0.60-0.54(m,2H),0.41-0.34(m,2H),0.25-0.14(m,4H).
实施例27
1,3-双[(R)-1-环丙基乙基]-2-异氰基苯(化合物27)
1,3-bis((R)-1-cyclopropylethyl)-2-isocyanobenzene
第一步：1,3-双[(R)-1-环丙基乙基]-2-异氰基苯(化合物27)
1,3-bis((R)-1-cyclopropylethyl)-2-isocyanobenzene
搅拌下将原料(R)-N-[2-(1-环丙基乙基)-6-异丙基苯基]甲酰胺(化合物18)(0.69g，3.0mmol)加入到THF(10mL)中，冷却至0℃，一次加入三乙胺(2.0mL，14.3 mmol)和三氯氧磷(0.5mL，5.4mmol)，室温搅拌2h，停止反应。小心加入饱和NaHCO3调pH＝7～8，分离有机相，乙酸乙酯(10mL×2)萃取，合并有机相并用无水硫酸钠干燥，减压浓缩后柱层析(PE/EA＝20:1)得1,3-双[(R)-1-环丙基乙基]-2-异氰基苯(化合物27)(0.52g，收率78.9％)
MS M/Z(ESI):214.1(M+1).
1HNMR:(400MHz,CDCl3):δ7.36-7.28(m,2H),7.17(dd,1H),3.40-3.33(m,1H),2.58-2.51(m,1H),1.33(d,3H),1.28(dd,6H),1.08-0.99(m,1H),0.64-0.57(m,1H),0.45-0.39(m,1H),0.31-0.25(m,1H),0.21-0.15(m,1H).
实施例28
4-氨基-3-[(1R)-1-环丙基乙基]-5-异丙基-苯甲醛(化合物28)
4-amino-3-[(1R)-1-cyclopropylethyl]-5-isopropyl-benza
第一步：4-氨基-3-[(1R)-1-环丙基乙基]-5-异丙基-苯甲醛(化合物28)
4-amino-3-[(1R)-1-cyclopropylethyl]-5-isopropyl-benza
100ml三口瓶中，加入10ml乙酸溶液，将六甲基四胺(4.206g,30.0mmol)加入到反应瓶中，加热至70℃，搅拌1.5h，滴加(R)-2-(1-环丙基乙基)-6-异丙基苯胺(2.033g,10.0mmol)的乙酸(10ml)溶液，滴加完毕升温至80℃，搅拌5h。反应完毕后加水(50ml)淬灭，继续搅拌1h，EA(50ml*3)萃取，水(50ml*2)洗涤有机相，无水硫酸钠干燥。减压浓缩得粗品，柱层析纯化PE：EA＝30:1，得淡黄色固体产物4-氨基-3-[(1R)-1-环丙基乙基]-5-异丙基-苯甲醛(化合物28)(0.615g，Y：26.6％)。
MS:232.2(+1)
实施例29
4-氨基-3-[(1R)-1-环丙基乙基]-5-异丙基-苯甲酸(化合物29)
4-amino-3-[(1R)-1-cyclopropylethyl]-5-isopropyl-benzoicacid
第一步：4-氨基-3-[(1R)-1-环丙基乙基]-5-异丙基-苯甲酸(化合物29)
4-amino-3-[(1R)-1-cyclopropylethyl]-5-isopropyl-benzoicacid
0℃下，50ml单瓶中，加入4-氨基-3-[(1R)-1-环丙基乙基]-5-异丙基-苯甲醛(0.823g,3.56mmol)，20ml丙酮，加入高锰酸钾(1.69g,10.7mmol)，缓慢升至室温继续搅拌30h。反应完成后，抽滤，滤饼用甲醇(35ml)洗涤合并滤液，减压浓缩得粗品，柱层析纯化PE：EA＝10:1到PE：EA＝5:1，得淡棕色粘稠液体产物4-氨基-3-[(1R)-1-环丙基乙基]-5-异丙基-苯甲酸(化合物29)(0.212g，Y：24.1％)。
MS:248.2(+1)
实施例30
1-[2-[(1R)-1-环丙基乙基]-6-异丙基-苯基]-2-哌啶酮(化合物30)
1-[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenyl]piperidin-2-one
第一步：5-氯-N-[(1R)-1-环丙基乙基]-6-异丙基-苯基]戊酰胺(化合物30A)
5-chloro-N-[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenyl]pentanamide
将2-[(1R)-1-环丙基乙基]-6-异丙基苯胺(1.02g,5.00mmol)溶于DCM(10mL)中，依次加入三乙胺(0.56g,5.50mmol)和5-氯戊酰氯(0.78g,5.00mmol)，35℃搅拌8h，减压浓缩，柱层析(PE/EA＝20:1to 5:1)分离得5-氯-N-[(1R)-1-环丙基乙基]-6-异丙基-苯基]戊酰胺(化合物30A)(1.24g，产率：76.83％)。
MS m/z(ESI):322.2(M+1).
第二步：1-[2-[(1R)-1-环丙基乙基]-6-异丙基-苯基]-2-哌啶酮(化合物30)
1-[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenyl]piperidin-2-one
将5-氯-N-[(1R)-1-环丙基乙基]-6-异丙基-苯基]戊酰胺(0.10g,0.31mmol)溶于乙醇(3mL)中，加入叔丁醇钠(45mg,0.47mmol)，60℃搅拌4h,减压浓缩，柱层析(PE/EA＝5:1)分离得1-[2-[(1R)-1-环丙基乙基]-6-异丙基-苯基]-2-哌啶酮(化合物30)(71mg，产率：80％)。
MS m/z(ESI):286.9(M+1).
生物测试例
1、小鼠翻正反射实验
SPF级ICR小鼠(SCXY(川)-2008-24-成都达硕生物科技有限公司)，18-22g，雌雄各半。利用成熟的小鼠麻醉模型研究受试化合物的全身麻醉效果(Ratnakumari Lingamaneni等(2001).Anesthesiology,2001,94,1050-7)。用生理盐水将待测化合物配制为所需浓度备用。将实验动物在实验室环境中适应后禁食12小时。次日以50、100mg/kg口服给药后，记录翻正反射消失时间，给药后到翻正反射消失的时间为麻醉诱导时间，翻正反射消失到翻正反射恢复的时间为麻醉持续时间，以麻醉诱 导时间和麻醉持续时间表示麻醉作用的强弱。以麻醉诱导时间、麻醉维持时间、翻正反射消失率等指标评价麻醉效果。
翻正反射消失时间：翻正反射消失，使之处于仰卧位并能够持续60s的时间；
翻正反射恢复时间：翻正反射能力恢复，使之处于仰卧位翻正时间小于2s。
实验结果表明，小鼠通过口服给药后能够产生明显的麻醉效果，本发明化合物具有良好的药效活性和口服特性。

Claims (8)

1.一种通式(A)所示的化合物，或者其立体异构体、溶剂化物、代谢产物、前药、药学上可接受的盐或者共晶：
其中：
X选自H、F、Cl、Br、I、氰基、异氰基、氨基、羧基、-C(＝O)(WRa)、NRcRd、3-12元碳环基、3-12元杂环基或者与R1相结合形成3-12元碳环基或者3-12元杂环基，所述的碳环基或杂环基任选进一步被0至12个Rf所取代，所述的杂环基含有1至6个选自N、O或者S的杂原子；
Rf选自H、F、Cl、Br、I、(＝O)、(＝S)、(＝C)、羟基、巯基、氨基、氰基、羧基、酯基、C1-6烷基、C1-6烷氧基、C2-6烯基、-C＝O-C1-6烷基、3至8元碳环基或者3至8元杂环基取代，所述的杂环基含有1至6个选自N、O或者S的杂原子，所述的烷基、烷氧基、烯基、碳环基或杂环基任选进一步被0至4个选自H、F、Cl、Br、I、羟基、C1-4烷基或C1-4烷氧基的取代基所取代；
W选自NRb、O、S或者不存在；
Ra、Rb、Rc、Rd各自独立选自H、C1-6烷基、C3-8碳环基或者3至8元杂环基，所述的烷基、碳环基或者杂环基可以任选进一步被被0至5个选自H、F、Cl、Br、I、(＝O)、羟基、氨基、氰基、羧基、C1-6烷基、C1-6烷氧基、C3-8碳环基或者3至8元杂环基的取代基所取代，所述的杂环基含有1至2个选自N、O或者S的杂原子；
R1、R2、R3、R7、R8、R9和R10各自独立选自H、F、Cl、Br、I、羟基、C1-8烷基、C1-8烷氧基、3至8元碳环基或者3至8元杂环基，所述的烷基、烷氧基、碳环基或者杂环基任选进一步被0至5个选自F、Cl、Br、I、羟基、C1-8烷基、C1-8烷氧基、3至8元碳环基或者3至8元杂环基的取代基所取代，所述的杂环基含有1至2个选自N、O或者S的杂原子，且R1、R2和R3不同时为H，当X与R1相结合形成3-12元碳环基或者3-12元杂环基时，R2和R3不同时为H；
作为选择，R1与R2、R1与R3、R2与R3、R7与R8或者R9与R10任意一组可以与其相连接的碳原子形成一个3至8元碳环基或者3至8元杂环基，所述3至8元碳环基或者3至8元杂环基任选进一步被0至5个选自F、Cl、Br、I、羟基、C1-8烷基、C1-8烷氧基、3至8元碳环基或者3至8元杂环基取代，所述的杂环基含有1至2个选自N、O或者S；
R4或者R5各自独立选自H、F、Cl、Br、I、C1-8烷基、C1-8烷氧基、3至8元碳环基或者3至8元杂环基，所述的烷基、烷氧基、碳环基或者杂环基任选进一步被0至5个选自F、Cl、Br、I、羟基、C1-8烷基、C1-8烷氧基、3至8元碳环基或者3至8元杂环基的取代基所取代，所述的杂环基含有1至2个选自N、O或者S的杂原子，且R4和R5不同时为H；
条件是，当X选自H时，R4、R5不为烷氧基取代的烷基，且不同时为F；
Y选自H、F、Cl、Br、I、醛基或者羧基；
R6选自H、F、Cl、Br、I、羟基、C1-8烷基或者C1-8烷氧基；
n选自1、2或者3。
2.根据权利要求1所述的的化合物，或者其立体异构体、溶剂化物、代谢产物、前药、药学上可接受的盐或者共晶，其中该化合物选自通式(A-I)或者(A-II)所示的化合物：
其中:
X1选自H、F、Cl、Br、I、氰基、异氰基、氨基、羧基、-C(＝O)(WRa)、NRcRd、3-12元碳环基或3-12元杂环基，所述的碳环基或杂环基任选进一步被0至12个Rf所取代，所述的杂环基含有1至6个选自N、O或者S的杂原子；
Cy选自3-12元碳环基或者3-12元杂环基，所述的碳环基或杂环基任选进一步被0至12个Rf所取代；所述的杂环含有1至6个选自N、O或者S的杂原子。
3.根据权利要求2所示的化合物，或者其立体异构体、溶剂化物、代谢产物、前药、药学上可接受的盐或者共晶，其中：
X1选自H、F、Cl、Br、I、氰基、异氰基、氨基、羧基、-C(＝O)(WRa)、NRcRd、3-12元碳环基或3-12元杂环基，所述的碳环基或杂环基任选进一步被0至12个Rf所取代；
Cy选自3-12元碳环基或者3-12元杂环基，所述的碳环基或杂环基任选进一步被0至12个Rf所取代，所述的杂环基含有1至6个选自N、O或者S的杂原子；
Rf选自H、F、Cl、Br、I、(＝O)、(＝S)、(＝C)、羟基、巯基、氨基、氰基、羧基、酯基、C1-6烷基、C1-6烷氧基、C2-6烯基、-C＝O-C1-6烷基，所述的烷基、烷氧基或烯基任选进一步被0至4个选自H、F、Cl、Br、I、羟基、C1-4烷基或C1-4烷氧基的取代基所取代；
W选自NRb、O、S或者不存在；
Ra、Rb各自独立选自H或C1-6烷基，所述的烷基可以任选进一步被0至5个选自H、F、Cl、Br、I、C1-6烷基或C1-6烷氧基的取代基所取代，
Rc、Rd各自独立选自H或C1-6烷基，所述的烷基可以任选进一步被0至5个选自H、(＝O)、C1-6烷基或C3-8碳环基的取代基所取代；
R1、R2、R3、R7、R8、R9和R10各自独立选自H、F、Cl、Br、I、羟基、C1-8烷基、C1-8烷氧基、3至8元碳环基或者3至8元杂环基，所述的烷基、烷氧基、碳环基或者杂环基任选进一步被0至5个选自F、Cl、Br、I、羟基、C1-4烷基或C1-4烷氧基的取代基所取代，所述的杂环基含有1至2个选自N、O或者S的杂原子，且R1、R2和R3不同时为H，当X1与R1相结合形成3-12元碳环基或者3-12元杂环基时，R2和R3不同时为H；
R4或者R5各自独立选自H、C1-4烷基，且R4和R5不同时为H；
Y选自H、F、Cl、Br、I、醛基或者羧基；
R6选自H、F、Cl、Br、I、羟基、C1-8烷基或者C1-8烷氧基；
n选自1、2或者3。
4.根据权利要求3所示的化合物，或者其立体异构体、溶剂化物、代谢产物、前药、药学上可接受的盐或者共晶，其中:
X1选自H、F、Cl、Br、I、氰基、异氰基、氨基、羧基、-C(＝O)(Ra)、-C(＝O)(ORa)、-C(＝O)(NRaRb)、NRcRd、 所述各环任选进一步被0至10个Rf取代；
Ra、Rb各自独立选自H、CF3、甲基、乙基、正丙基或异丙基；
Cy选自氮杂五元环，所述环任选进一步被0至4个Rf取代；
Rf各自独立的选自H、F、Cl、Br、I、(＝O)、(＝S)、(＝C)、羟基、巯基、氨基、氰基、羧基、酯基、甲基、乙基、异丙基、叔丁基、甲氧基、乙氧基、异丙氧基、乙烯基、丙烯基、烯丙基、羟甲基、羟乙基、-C＝OCH3；
R1、R2、R3、R7、R8、R9和R10各自独立地选自H、甲基、乙基、正丙基、异丙基、环丙基或环丁基，且通式(A-I)中，R1、R2和R3不同时为H，通式(A-II)中，R2和R3不同时为H；
R4或者R5各自独立选自H、甲基、乙基、正丙基或异丙基，且R4和R5不同时为H；
R6选自H、羟基、甲基、乙基、正丙基或异丙基；
Y选自H、F、醛基或者羧基；
n选自1。
5.根据权利要求4所述的化合物，或者其立体异构体、溶剂化物、代谢产物、前药、药学上可接受的盐或者共晶，其中所述的化合物选自：
6.一种药物组合物，所述药物组合物包含权利要求1-5中任一项所述的化合物或者其立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或者前药，和一种或者多种药学上可接受的载体和/或者赋形剂。
7.根据权利要求1-5中任一项所述的化合物、或者其立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或者前药，在制备诱导和维持动物或者人类的麻醉、促进动物或者人类的镇静催眠、治疗和/或者预防焦虑、抑郁、失眠、恶心、呕吐、偏头痛、精神分裂、惊厥和癫痫药物中的用途。
8.根据权利要求1-5所述的化合物在制备诱导和维持动物或者人类的麻醉、促进动物或者人类的镇静催眠、治疗和/或者预防焦虑、抑郁、失眠、恶心、呕吐、偏头痛、精神分裂、惊厥和癫痫药物中的用途，其特征在于通过口服给药。
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