CN113087599A - 大麻二酚衍生物及其制备方法和在医药上的应用 - Google Patents
大麻二酚衍生物及其制备方法和在医药上的应用 Download PDFInfo
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- CN113087599A CN113087599A CN202110020576.4A CN202110020576A CN113087599A CN 113087599 A CN113087599 A CN 113087599A CN 202110020576 A CN202110020576 A CN 202110020576A CN 113087599 A CN113087599 A CN 113087599A
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Abstract
本发明涉及大麻二酚衍生物及其在医药上的应用,具体而言涉及如通式(I)所示的嘧啶衍生物,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共晶,其中,通式(I)中各取代基的定义与说明书的定义相同。
Description
技术领域
本发明涉及大麻二酚衍生物,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共晶,其药物组合物以及在制备药物中的应用。
背景技术
大麻(Cannabis sativa L.)为桑科大麻属一年生草本植物,起源于中亚和东亚,广泛分布于美国、印度、巴西等地。大麻的药用历史悠久,但成瘾性和精神致幻作用,使其临床应用受到极大限制。大麻包含数百种不同的化学物质,大约有70多种成分被称为大麻素,主要包括大麻二酚(cannabidiol,CBD)、大麻酚(cannabinol,CBN)、四氢大麻酚(Tetrahydrocannabinol,THC)及其同系物等,其中大麻二酚(CBD)含量最高。CBD不但能拮抗THC所引发的精神活性,而且具有广泛的治疗特征,对神经疾病包括焦虑、精神分裂、成瘾、神经退行性疾病、新生儿低氧缺血性脑病、癫痫均具有明显的改善作用,另外在抗肿瘤、抗炎、肝肝保护、疼痛、抗焦虑、抗失眠、抗惊厥、抗呕吐、抗痉挛、抗氧化、神经保护的治疗上,也表现出很好应用前景。
发明内容
本申请的目的是提供大麻二酚衍生物,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,其药物组合物以及其在制备药物中的应用。
本申请的一个或多个实施方式提供大麻二酚衍生物,其在具有良好药理活性的同时,具有更高的生物利用度(例如口服生物利用度)和更长的半衰期,给药后能够显著减少非活性或者毒性代谢产物的产生,同时延长药物作用时间、表现出更优的药代动力学特征、且降低毒副作用。
本申请的一个或多个实施方式提供了通式(I)所示的化合物,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共晶:
其中,
R0选自甲基、-CH2OH、-C(=O)OC1-6烷基、-C(=O)NRb1Rb2或者羧基,且R0至少一个氢原子被氘原子取代,且当R0选自-CD2H或者-CD3时,R不是-(CH2)4CH3;;
X选自氢、氘、羟基、C1-6烷基或者卤素;
R1选自C1-6烷基、C3-8碳环基或者C2-6烯基,所述的C1-6烷基、C2-6烯基、C3-8碳环基任选进一步被1至3个选自卤素、羟基、C3-8碳环基或者C1-6烷基的取代基所取代,R1任选被1个或者多个氘原子取代;
R2、R3各自独立地选自氢、羟基或者C1-6烷氧基,R2、R3各自独立地任选被1个或者多个氘原子取代,且其中R2、R3中的至少有一个不为H;
r选自0、1、2或者3;
n选自0、1或者2;
Y选自氢、羧基、C1-6烷基或者卤素,Y任选被1个或者多个氘原子取代;
R选自C1-12烷基、C1-12杂烷基、C2-12烯基、C2-12炔基、C3-12碳环基、C3-12杂环基、-C1-6亚烷基-C3-12碳环基、-C1-6亚烷基-C3-12杂环基、-NRb1Rb2、-C1-6亚烷基-C(=O)OC1-6烷基或者-C1-6亚烷基-C(=O)NRb1Rb2,且所述的C1-12烷基、C1-12杂烷基、C2-12烯基、C2-12炔基、C1-6亚烷基、C3-12碳环基、C3-12杂环基任选被1个或者多个选自羟基、羧基、卤素、氰基、=O、C1-6烷基、-NRb1Rb2、C3-12碳环基、C3-12杂环基、C2-6烯基、C2-6炔基、-C(=O)OC1-6烷基、-C(=O)C1-6烷基、-C(=O)NRb1Rb2、-S(=O)C1-6烷基或者-S(=O)2C1-6烷基的取代基所取代,且作为取代基的所述的C1-6烷基、C3-12碳环基、C3-12杂环基任选进一步被1个或者多个选自=O、羟基、羧基、卤素、氰基、-C(=O)OC1-6烷基或者-C(=O)C1-6烷基的取代基所取代,R任选被1个或者多个氘原子取代;
Rb1、Rb2各自独立地选自H、C1-6烷基、C3-12碳环基、C3-12杂环基、-C(=O)Rb3、-C(=O)NRb4Rb5,其中所述的C1-6烷基、C3-12碳环基、C3-12杂环基任选进一步被1个或者多个选自羟基、氘、卤素、C1-6烷基、C1-6烷氧基、C6-12芳基、C5-12杂芳基、C3-12环烷基或者C3-12杂环烷基的取代基所取代;或者Rb4与Rb5及N原子形成一个3至12元杂环,所述的杂环包含1个或者多个选自N、O或者S的杂原子,Rb1、Rb2任选被1个或者多个氘原子取代;
Rb3选自C1-6烷基、C1-6烷氧基或者C6-12芳基,Rb3任选被1个或者多个氘原子取代;
Rb4、Rb5选自H或者C1-6烷基,Rb4、Rb5任选被1个或者多个氘原子取代;
本申请的一个或多个实施方式提供以下的化合物,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共晶,其中所述化合物为以下结构之一:
本申请的一个或多个实施方式提供制备通式(I)所述化合物的中间体,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共晶,其中该中间体选自:
本发明还提供一种化合物A或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶的制备方法,其特征在于包括以下步骤:
第一步:化合物A-I、3,5-二羟基戊苯、质子酸在有机溶剂中反应,得到化合物A-II;
第二步:化合物A-II在有机溶剂中脱水反应制备得到化合物A。
所述有机溶剂是本领域根据本领域公知常识能够确定的。
本申请的一个或多个实施方式提供药物组合物,所述药物组合物包含:
(1)本申请所述的化合物或其立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或者前药;
(2)任选的一种或者多种其他活性成分;以及
(3)药学上可接受的载体和/或赋形剂。
在本申请的一个或多个实施方式中,所述的其他活性成分选自银杏内酯、抗肿瘤剂、抗凝血剂、抗癫痫剂、抗抑郁剂、抗焦虑剂、催眠剂、镇痛剂或者麻醉剂中的一种或多种,或者所述的其他活性成分的立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶。
在本申请的一个或多个实施方式中,所述银杏内酯为银杏内酯A、银杏内酯B、银杏内酯C、银杏内酯D、银杏内酯J、银杏内酯M、银杏内酯K、银杏内酯L、银杏内酯N、银杏内酯P、银杏内酯Q、白果内酯中的一种或任意两种及以上以任意比例的组合。
本申请的一个或多个实施方式提供本申请的化合物或其立体异构体、溶剂化物、代谢产物、药学上可接受的盐或共晶或者药物组合物在制备用于治疗创伤后应激障碍、面瘫、中风、偏头痛、冠心病稳定型心绞痛、脑梗塞、血栓栓塞、心肌梗塞、心脏缺血、冠状动脉疾病、高血压、脑缺血、改善性功能、痉挛、急性和慢性疼痛、纤维肌痛、术后疼痛、丛集性头痛、紧张性头痛、背疼、四肢痛、腰痛、颈部疼痛、神经性疼痛、癌痛、三叉神经痛、关节炎疼痛、炎性疼痛、Dravet综合征、Lennox-Gasta ut综合征、Prader-Willi综合征、Sturge-Weber综合征、脆性X综合征、焦虑、双相情感障碍、自闭症、广泛性焦虑症、社交焦虑症、癫痫、帕金森氏病、阿尔茨海默氏病、亨廷顿氏病、阿片类药物滥用、酗酒、尼古丁成瘾、厌食症、恶病质、化疗相关恶心呕吐、术后恶心和呕吐、肌萎缩性侧索硬化症(ALS)、Friedreich共济失调、精神分裂症、强迫症、多发性硬化症、抑郁、睡眠障碍、多发性硬化引起的痉挛、肌张力障碍、睡眠呼吸暂停、麻痹性痴呆、记忆力减退或者胶质母细胞瘤的药物中的用途。
本申请的一个或多个实施方式提供了用作药物使用的本申请的上述化合物。
本申请的一个或多个实施方式提供了在治疗以下疾病的方法中使用的本申请的上述化合物或其立体异构体、溶剂化物、代谢产物、药学上可接受的盐或共晶:创伤后应激障碍、面瘫、中风、偏头痛、冠心病稳定型心绞痛、脑梗塞、血栓栓塞、心肌梗塞、心脏缺血、冠状动脉疾病、高血压、脑缺血、改善性功能、痉挛、急性和慢性疼痛、纤维肌痛、术后疼痛、丛集性头痛、紧张性头痛、背疼、四肢痛、腰痛、颈部疼痛、神经性疼痛、癌痛、三叉神经痛、关节炎疼痛、炎性疼痛、Dravet综合征、Lennox-Gastaut综合征、Prader-Willi综合征、Sturge-Weber综合征、脆性X综合征、焦虑、双相情感障碍、自闭症、广泛性焦虑症、社交焦虑症、癫痫、帕金森氏病、阿尔茨海默氏病、亨廷顿氏病、阿片类药物滥用、酗酒、尼古丁成瘾、厌食症、恶病质、化疗相关恶心呕吐、术后恶心和呕吐、肌萎缩性侧索硬化症(ALS)、Friedreich共济失调、精神分裂症、强迫症、多发性硬化症、抑郁、睡眠障碍、多发性硬化引起的痉挛、肌张力障碍、睡眠呼吸暂停、麻痹性痴呆、记忆力减退或者胶质母细胞瘤。
本申请的一个或多个实施方式提供了治疗以下疾病的方法,其包括向有此需要的对象给予本申请的上述化合物或其立体异构体、溶剂化物、代谢产物、药学上可接受的盐或共晶:创伤后应激障碍、面瘫、中风、偏头痛、冠心病稳定型心绞痛、脑梗塞、血栓栓塞、心肌梗塞、心脏缺血、冠状动脉疾病、高血压、脑缺血、改善性功能、痉挛、急性和慢性疼痛、纤维肌痛、术后疼痛、丛集性头痛、紧张性头痛、背疼、四肢痛、腰痛、颈部疼痛、神经性疼痛、癌痛、三叉神经痛、关节炎疼痛、炎性疼痛、Dravet综合征、Lennox-Gastaut综合征、Prader-Willi综合征、Sturge-Weber综合征、脆性X综合征、焦虑、双相情感障碍、自闭症、广泛性焦虑症、社交焦虑症、癫痫、帕金森氏病、阿尔茨海默氏病、亨廷顿氏病、阿片类药物滥用、酗酒、尼古丁成瘾、厌食症、恶病质、化疗相关恶心呕吐、术后恶心和呕吐、肌萎缩性侧索硬化症(AL S)、Friedreich共济失调、精神分裂症、强迫症、多发性硬化症、抑郁、睡眠障碍、多发性硬化引起的痉挛、肌张力障碍、睡眠呼吸暂停、麻痹性痴呆、记忆力减退或者胶质母细胞瘤。
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、硫或氮任选进一步被一个或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。
“烃基”是指只含碳、氢两种原子的基团。
“烷基”是指1至20个碳原子的直链或支链饱和脂肪族烃基,优选为1至8个(例如1、2、3、4、5、6、7、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、新丁基、叔丁基、正戊基、异戊基、新戊基、正己基及其各种支链异构体;当烷基被取代基时,可以任选进一步被1个或者多个取代基所取代。
“杂烷基”是指烷基至少一个C原子被O、S、N或者P原子取代的基团。非限制性实施例包括硫代甲基、硫代乙基、硫代正丙基、硫代异丙基、硫代正丁基、硫代仲丁基、硫代叔丁基。所述的烷基定义与上文所述的“烷基”定义相同。
“烷氧基”是指烷基中至少1个碳原子被氧原子取代所形成的基团。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。所述的烷基定义与上文所述的“烷基”定义相同。
“烯基”是指包含1至10个(例如1、2、3、4、5、6、7、8、9、10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(例如2、3、4、5、6、7、8、9、10、11、12个)碳原子的烯基,更优选2至8个碳原子的烯基,进一步优选2至6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1个或者多个取代基所取代。
“炔基”是指包含1至10个(例如1、2、3、4、5、6、7、8、9、或10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(例如2、3、4、5、6、7、8、9、10、11或12个)碳原子的炔基,更优选2至8个碳原子的炔基,进一步优选2至6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1至多个取代基所取代。
“芳基”是指是指取代的或未取代的芳香环,其可以是5至8元(例如5、6、7、8元)的单环、5至12元(例如5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系,其可以是桥环或者螺环,非限制性实施例包括苯基、萘基。所述的芳基可以任选进一步被1个或者多个取代基所取代。
“杂芳基”是指取代的或未取代的芳香环,其可以是3至8元(例如3、4、5、6、7、8元)的单环、5至12元(例如5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系,且包含1至6个(例如1、2、3、4、5、6个)选自N、O或S的杂原子,优选5至8元杂芳基,杂芳基的环中选择性取代的1至4个(例如1、2、3、4个)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,杂芳基可以是桥环或者螺环,非限制性实施例包括环吡啶基、呋喃基、噻吩基、吡喃基、吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基苯并咪唑基、苯并吡啶基、吡咯并吡啶基。杂芳基任选进一步被1个或多个取代基所取代。
“碳环基”或“碳环”是指饱和或者不饱和的芳香环或者非芳香环。当为芳香环时,其定义与上文“芳基”的定义相同;当为非芳香环时,其可以是3至10元(例如3、4、5、6、7、8、9、10元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系,可以是桥环或者螺环,非限制性实施例包括环丙基、环丁基、环戊基、1-环戊基-1-烯基、1-环戊基-2-烯基、1-环戊基-3-烯基、环己基、1-环己基-2-烯基、1-环己基-3-烯基、环己烯基、环己二烯基、环庚基、环辛基、环壬基、环癸基、环十一烷基、环十二烷基、 所述的“碳环基”或“碳环”任选进一步被1个或者多个取代基所取代。
“杂环基”或“杂环”是指饱和或不饱和的芳香性杂环或者非芳香性杂环,当为芳香性杂环时,其定义与上文“杂芳基”定义相同;当为非芳香性杂环时,其可以是3至10元(例如3、4、5、6、7、8、9、10元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系,且包含1至4个选自N、O或S的杂原子,优选3至8元杂环基。“杂环基”或“杂环”的环中选择性取代的1至4个(例如1、2、3、4个)N、S可被氧化成各种氧化态;“杂环基”或“杂环”可以连接在杂原子或者碳原子上;“杂环基”或“杂环”可以为桥环或者螺环。“杂环基”或“杂环”的非限制性实施例包括环氧乙基、环氧丙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、硫杂环丁基、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、氧杂环庚基、硫杂环庚基、氧氮杂卓基、二氮杂卓基、硫氮杂卓基、吡啶基、哌啶基、高哌啶基、呋喃基、噻吩基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、哌嗪基、高哌嗪基、咪唑基、哌啶基、吗啉基、硫代吗啉基、噻噁烷基、1,3-二噻烷基、二氢呋喃基、二噻戊环基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、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、2-吡咯啉基、3-吡咯啉基、二氢吲哚基、2H-吡喃基、4H-吡喃基、二氧杂环己基、1,3-二氧戊基、吡唑啉基、二噻烷基、二噻茂烷基、二氢噻吩基、吡唑烷基、咪唑啉基、咪唑烷基、1,2,3,4-四氢异喹啉基、3-氮杂双环[3.1.0]己基、3-氮杂双环[4.1.0]庚基、氮杂双环[2.2.2]己基、3H-吲哚基喹嗪基、N-吡啶基尿素、1,1-二氧硫代吗啉基、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”或“杂环”任选进一步被0个或者多个取代基所取代。
“环烷基”是指饱和的环烃基,其环可以为3至10元(例如3、4、5、6、7、8、9、10元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至20元(例如4、5、6、7、8、9、10、11、12元)多环体系,环碳原子优选3至10个碳原子,进一步优选3至8个碳原子。“环烷基”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、环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基、1,5-环辛二烯基、1,4-环己二烯基和环庚三烯基等。当环烷基被取代时,可以任选进一步被1个或者多个取代基所取代。
“杂环烷基”是指取代的或未取代的饱和非芳香环基,其可以是3至8元(例如3、4、5、6、7、8元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系,且包含1、2或3个选自N、O或S的杂原子,优选3至8元杂环基。“杂环烷基”的环中选择性取代的N、S可被氧化成各种氧化态;“杂环烷基”可以连接在杂原子或者碳原子上;“杂环烷基”可以为桥环或者螺环。“杂环烷基”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、哌啶基、哌叮基、吗啉基、硫代吗啉基、1,3-二噻烷基、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、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。
当上文所述的“烷基”、“烷氧基”、“烯基”、“炔基”、“芳基”、“杂芳基”、“碳环基”、“碳环”、“杂环基”、“杂环”、“环烷基”、“杂环烷基”或者“杂环基”被取代时,可以任选进一步被0、1、2、3、4、5、6、7、8、9或者10个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、C1-6烷基氨基、=O、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、-NRq4Rq5、=NRq6、-C(=O)OC1-6烷基、-OC(=O)C1-6烷基、-C(=O)NRq4Rq5、C3-8环烷基、C3-8杂环烷基、C6-10芳基、C5-10杂芳基、-C(=O)OC6-10芳基、-OC(=O)C6-10芳基、-OC(=O)C5-10杂芳基、-C(=O)OC5-10杂芳基、-OC(=O)C3-8杂环烷基、-C(=O)OC3-8杂环烷基、-OC(=O)C3-8环烷基、-C(=O)OC3-8环烷基、-NHC(=O)C3-8杂环烷基、-NHC(=O)C6-10芳基、-NHC(=O)C5-10杂芳基、-NHC(=O)C3-8环烷基、-NHC(=O)C3-8杂环烷基、-NHC(=O)C2-6烯基或者-NHC(=O)C2-6炔基的取代基所取代,且其中所述的取代基C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、C3-8杂环烷基、C6-10芳基、C5-10杂芳基、-NHC(=O)C6-10芳基、-NHC(=O)C5-10杂芳基、-NHC(=O)C3-8杂环烷基或者-NHC(=O)C3-8环烷基任选进一步被1至3个选自OH、F、Cl、Br、I、C1-6烷基、C1-6烷氧基、-NRq4Rq5或者=O的取代基所取代;Rq1选自C1-6烷基、C1-6烷氧基或者C6-10芳基;Rq2、Rq3选自H或者C1-6烷基;其中,Rq4、Rq5选自H、C1-6烷基、-NH(C=N Rq1)NRq2Rq3、-S(=O)2NRq2Rq3、-C(=O)Rq1或者-C(=O)NRq2Rq3,其中所述的C1-6烷基任选进一步被1个或者多个选自OH、F、Cl、Br、I、C1-6烷基、C1-6烷氧基、C6-10芳基、C5-10杂芳基、C3-8环烷基或者C3-8杂环烷基的取代基所取代;或者Rq4与Rq5及N原子形成一个3至8元杂环,所述的杂环可以包含1个或者多个选自N、O或者S的杂原子。
“氨基酸侧链”是指氨基酸分子中除了氨基和羧基之外的基团。
“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反应获得的盐,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”是指一种或多种本发明所述化合物、其药学上可接受的盐或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/或一种或多种其它治疗剂。
“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氨基或者羧基来制备,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氨基或者羧基。
“共晶”是指活性药物成分(API)和共晶形成物(CCF)在氢键或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溶剂化物形成的多元共晶。
“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“任选地”或“选择性的”或“选择性地”是指随后所述的事件或状况可以但未必发生,该描述包括其中发生该事件或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。
具体实施方式
以下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(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Bruker 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或青岛GF254硅胶板,薄层色谱法(TLC)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按照本领域已知的方法来合成,或可购买于泰坦科技、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约1L容积的氮气气球;
氢气氛是指反应瓶连接约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℃;
DCM:二氯甲烷;
EA:乙酸乙酯;
HCl:盐酸;
THF:四氢呋喃;
DMF:N,N-二甲基甲酰胺;
PE:石油醚;
TLC:薄层色谱;
SFC:超临界流体色谱法;
NCS:N-氯代丁二酰亚胺;
Pd(dppf)Cl2:[1,1'-双(二苯基膦)二茂铁]二氯化钯;
DMSO:二甲基亚砜;
DTT:二硫苏糖醇;
ATP:三磷酸腺苷;
DNA:脱氧核糖核苷酸。
实施例
以下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。
实施例1
4-甲基-5'-(甲基-d3)-2'-(丙-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二醇(化合物1)
4-methyl-5'-(methyl-d3)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol
第一步:
3-乙氧基-6-(2-羟丙基-2-基)环己-2-烯-1-酮1b
3-ethoxy-6-(2-hydroxypropan-2-yl)cyclohex-2-en-1-one
在-70℃、氮气保护下,将3-乙氧基环己-2-烯-1-酮1a(10.0g,71.0mmol)滴加到二异丙基氨基锂(54mL,107.0mmol,2.0N)的四氢呋喃(100mL)溶液中,滴毕搅拌反应0.5h;滴加丙酮(9.2g,142.0mmol),滴毕继续搅拌3h;TLC检测至反应结束;滴加饱和氯化铵溶液(180mL)淬灭反应,分液,水相用乙酸乙酯(150mL×2)萃取,合并有机相用饱和食盐水(100mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到标题化合物1b(黄色油状物,18.0g,产率:99.0%)。
1H NMR(400MHz,DMSO)δ5.29(s,1H),4.93(s,1H),3.98–3.87(m,2H),2.46(dd,J=11.2,5.0Hz,1H),2.37(dt,J=17.4,4.5Hz,1H),2.21(dd,J=12.1,4.7Hz,1H),2.12–2.03(m,1H),1.67(ddd,J=24.2,12.3,5.1Hz,1H),1.27(t,J=7.0Hz,3H),0.99(s,3H),0.73(s,3H)。
LC-MS m/z(ESI)=199.2[M+1]。
第二步:
4-(2-羟基丙烷-2-基)环己-2-烯-1-酮1c
4-(2-hydroxypropan-2-yl)cyclohex-2-en-1-one
在0℃,氮气保护下,将红铝(67mL,234.1mmol,3.5N)滴加到化合物1b(17.0g,78.0mmol)的四氢呋喃(200mL)溶液中,滴毕缓慢升至室温搅拌反应2h;TLC检测至反应结束;降至0℃,滴加饱和氯化铵溶液(13mL)淬灭,抽滤,水相用乙酸乙酯(200mL×2)萃取,合并有机相用饱和食盐水(100mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品加入四氢呋喃(40mL)溶解,滴加盐酸水溶液(40mL,2N),滴毕室温搅拌反应1.5h;TLC检测至反应结束,滴加饱和碳酸氢钠溶液淬灭反应,减压浓缩,水相用乙酸乙酯(100mL×4)萃取,合并有机相用饱和食盐水(100mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩经硅胶柱层析(洗脱剂:乙酸乙酯/石油醚(v/v)=1/3)纯化,得到标题化合物1c(无色油状物,5.8g,产率:48.0%)。
1H NMR(400MHz,DMSO)δ7.19(dt,J=10.4,1.9Hz,1H),5.93(dd,J=10.4,2.8Hz,1H),4.58(s,1H),2.44–2.38(m,1H),2.38–2.29(m,2H),2.08–1.96(m,1H),1.62(tdd,J=12.9,9.4,5.0Hz,1H),0.99(s,3H),0.73(s,3H)。
LC-MS m/z(ESI)=155.4[M+1]。
第三步:
4-(2-羟基丙烷-2-基)-1-(甲基-d3)环己-2-烯-1-醇1d
4-(2-hydroxypropan-2-yl)-1-(methyl-d3)cyclohex-2-en-1-ol
在0℃,氮气保护下,将氘代甲基碘化镁(34mL,33.7mmol,1.0N)滴加到无水氯化锂(1.4g,33.7mmol)的四氢呋喃(20mL)溶液中,滴毕搅拌反应0.5h;滴加化合物1c(1.8g,11.2mmol)的四氢呋喃溶液(5mL),滴毕搅拌反应0.5h;TLC检测至反应结束;滴加饱和氯化铵溶液(20mL)淬灭,水相用乙酸乙酯(50mL×3)萃取,合并有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品,经硅胶柱层析(洗脱剂:乙酸乙酯/石油醚(v/v)=2/1)纯化,得到标题化合物1d(白色固体,1.2g,产率:60.0%)。
1H NMR(400MHz,DMSO)δ5.61(d,J=10.4Hz,1H),5.52(d,J=10.6Hz,1H),4.38(s,1H),4.17(s,1H),2.00(ddd,J=10.8,5.1,2.4Hz,1H),1.73–1.65(m,2H),1.57–1.48(m,1H),1.21(dd,J=10.1,6.8Hz,1H),0.99(s,3H),0.73(s,3H)。
LC-MS m/z(ESI)=174.6[M+1]。
第四步:
2'-(2-羟基丙烷-2-基)-4-甲基-5'-(甲基-d3)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二醇1e
2'-(2-hydroxypropan-2-yl)-4-methyl-5'-(methyl-d3)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol
将4-(2-羟基丙烷-2-基)-1-(甲基-d3)环己-2-烯-1-醇1d(500mg,2.9mmol),5-甲基苯-1,3-二醇(1080mg,8.7mmol),和4A分子筛(1.5g)溶于10mL二氯甲烷中,置换氮气,室温搅拌10分钟。最后加入左旋樟脑磺酸(67.34mg,0.29mmol)。室温搅拌1小时。向反应液中加入20mL饱和碳酸氢钠水溶液淬灭反应,乙酸乙酯萃取(10mL×4)。合并有机相,用无水硫酸钠干燥,过滤,浓缩得到700mg粗品。柱层析分离得到2'-(2-羟基丙烷-2-基)-4-甲基-5'-(甲基-d3)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二醇1e(白色固体,375mg,收率46%)。
1H NMR(400MHz,DMSO-d6)δ9.03(s,1H),8.79(s,1H),6.09(d,1H),5.95(d,1H),4.92(s,1H),3.90(d,1H),2.14(d,5H),1.37–1.21(m,2H),0.99(s,3H),0.91–0.79(m,2H),0.73(s,3H)。
第五步:
4-甲基-5'-(甲基-d3)-2'-(丙-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二醇(化合物1)
4-methyl-5'-(methyl-d3)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol
将2'-(2-羟基丙烷-2-基)-4-甲基-5'-(甲基-d3)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二醇1e(350mg,1.25mmol),用6mL四氢呋喃溶解,置换氮气,将体系降温至0℃,再将伯吉斯试剂(595mg,2.5mmol)加入体系中,迅速升温至室温。反应20分钟。向反应液中加入20mL饱和碳酸氢钠水溶液淬灭反应,乙酸乙酯萃取(10mL×4)。合并有机相,用无水硫酸钠干燥,过滤,浓缩得到500mg粗品,制备得到4-甲基-5'-(甲基-d3)-2'-(丙-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二醇(化合物1)(紫红色固体,30mg,收率9.2%)。
1H NMR(400MHz,Chloroform-d)δ6.28–6.15(m,2H),5.54(d,1H),4.65(p,1H),4.53–4.37(m,1H),3.61–3.46(m,1H),2.45(ddd,1H),2.22(ddt,1H),2.14(s,3H),2.10(q,1H),1.86–1.69(m,2H),1.56(t,3H)。
实施例2
4-乙基-5'-(甲基-d3)-2'-(丙-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯基]-2,6-二醇(化合物2)
4-ethyl-5'-(methyl-d3)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol
第一步:
((((5-乙烯基-1,3-亚苯基)双(氧基))双(亚甲基))二苯2b
(((5-vinyl-1,3-phenylene)bis(oxy))bis(methylene))dibenzene
在0℃下将t-BuOK(1.5g,13.0mmol)加入到溶于THF的甲基三苯基溴化磷(5.0g,13.0mmol)溶液中,在0℃下搅拌0.5h加入2a(3.0g,10.8mmol),随后将其移至室温继续搅拌至反应完全。待反应完全后经EA萃取,无水Na2SO4干燥,真空浓缩后得粗品,粗品经柱层析纯化后可得2b(白色固体,3.0g,88.8%)。
1H NMR(400MHz,DMSO):δ(ppm)7.58–7.30(m,10H),6.68(d,2H),6.67–6.60(m,1H),6.56(t,1H),5.72(d,1H),5.26(d,1H),5.05(s,4H)。
LC-MS m/z(ESI)=317.20[M+1]。
第二步:
5-乙基苯-1,3-二醇2c
5-ethylbenzene-1,3-diol
将2b(3.0g,9.5mmol)溶于EA和甲醇的混合溶液中(v1/v2=5/1),随后加入10%的Pd/C(600.0mg),H2条件下搅拌过夜。待其反应完全,过滤反应液,EA萃取滤液,有机相经无水Na2SO4干燥,真空浓缩,柱层析纯化可得2c(白色固体,1.2g,91.7%)。
1H NMR(400MHz,DMSO):δ(ppm)6.27(d,2H),6.20(t,1H),4.14(q,1H),2.51(q,2H),1.16(t,3H)。
LC-MS m/z(ESI)=139.10[M+1]。
第三步:
4-乙基-2'-(2-羟基丙烷-2-基)-5'-(甲基-d3)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二醇2d
4-ethyl-2'-(2-hydroxypropan-2-yl)-5'-(methyl-d3)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol
将2c(1.2g,8.7mmol)和左旋樟脑磺酸(69.7mg,0.3mmol)溶于干燥DCM溶液中搅拌10min后将1d(502.1mg,2.9mmol)加入至上述溶液中,换气三次后继续置于室温搅拌约1h。待反应完毕后用饱和NaHCO3将反应液pH调至7-8,二氯甲烷萃取,无水N a2SO4干燥,真空浓缩得其粗品。粗品经柱层析纯化可得2d(白色固体,200.0mg,23.5%)。
1H NMR(400MHz,DMSO):δ(ppm)6.50(s,1H),6.39–6.25(m,2H),5.70–5.62(m,1H),3.90–3.79(m,1H),2.50(q,2H),2.18–1.86(m,4H),1.75–1.64(m,1H),1.23(s,6H),1.18(t,3H)。
LC-MS m/z(ESI)=316.20[M+23]。
第四步:
4-乙基-5'-(甲基-d3)-2'-(丙-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二醇(化合物2)
4-ethyl-5'-(methyl-d3)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol
将2d(200.0mg,0.7mmol)称量至反应烧瓶中,换气三次,室温条件下加入5mL TH F搅拌至溶解完全,冰浴条件下缓慢加入伯吉斯试剂(333.6mg,1.4mmol),加入完毕后将其移至室温搅拌约20min。TLC检测至2d完全消耗完毕。加入饱和NaHCO3调节pH=7-8,乙酸乙酯萃取,有机相经饱和NaCl洗涤,无水Na2SO4干燥,浓缩,柱层析纯化可得粗品。将粗品经制备色谱柱提纯即得到目标产物化合物2(紫色固体,16.0mg,35.5%)。
1H NMR(400MHz,DMSO):δ(ppm)8.67(s,2H),6.04(s,2H),5.08(s,1H),4.50(d,1H),4.41(dd,1H),3.91–3.77(m,1H),3.09–2.98(m,1H),2.34(q,2H),2.21–2.02(m,1H),1.98–1.86(m,1H),1.73–1.60(m,2H),1.59(s,3H),1.08(t,3H)。
LC-MS m/z(ESI)=270.20[M+1]。
实施例3
4-乙基-5'-(甲基-d3)-2'-(丙-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二醇(化合物3)
4-ethyl-5'-(methyl-d3)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol
第一步:
(E)-((((5-(丙-1-烯-1-基)-1,3-亚苯基)双(氧基))双(亚甲基))二苯3a
(E)-(((5-(prop-1-en-1-yl)-1,3-phenylene)bis(oxy))bis(methylene))dibenzene
在0℃下将t-BuOK(1.4g,12.5mmol)加入到溶于THF的甲基三苯基溴化磷(4.5g,12.1mmol)溶液中,在0℃下搅拌0.5h加入2a(3.2g,10.1mmol),随后将其移至室温继续搅拌至反应完全。待反应完全后经EA萃取,无水Na2SO4干燥,真空浓缩后得粗品,粗品经柱层析纯化后可得3a(白色固体,3.0g,90.3%)。
1H NMR(400MHz,DMSO):δ(ppm)7.50–7.30(m,10H),6.61(d,1H),6.56(d,2H),6.54(t,1H),6.37(dd,1H),5.78(dd,1H),5.05(s,4H),1.85(dd,3H)。
LC-MS m/z(ESI)=331.20[M+1]。
第二步:
5-丙基苯-1,3-二醇3b
5-propylbenzene-1,3-diol
将3a(3.0g,9.1mmol)溶于EA和甲醇的混合溶液中(v1/v2=5/1),随后加入10%的Pd/C(300.0mg),H2条件下搅拌过夜。待其反应完全,过滤反应液,EA萃取萃取滤液,所得有机相经真空浓缩,柱层析纯化可得对应的目标化合物3b(白色固体,1.3g,96.3%)。
1H NMR(400MHz,DMSO):δ(ppm)(d,2H),6.18(t,1H),2.47(dd,2H),1.59(dt,2H),0.93(t,3H)。
LC-MS m/z(ESI)=153.10[M+1]。
第三步:
2'-(2-羟基丙烷-2-基)-5'-(甲基-d3)-4-丙基-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二醇3c
2'-(2-hydroxypropan-2-yl)-5'-(methyl-d3)-4-propyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol
将3b(1.3g,8.7mmol)和左旋樟脑磺酸(67.1mg,0.3mmol)溶于干燥DCM溶液中搅拌10min后将1d(502.1mg,2.9mmol)加入至上述溶液中,换气三次后继续置于室温搅拌约1h。待反应完毕后用饱和NaHCO3将反应液pH调至7-8,DCM萃取,无水Na2S O4干燥,真空浓缩得其粗品。粗品经柱层析纯化可得其目标化合物3c(白色固体,300.0mg,11.3%)。
1H NMR(400MHz,DMSO):δ(ppm)6.50(s,1H),6.29(d,2H),5.72–5.65(m,1H),3.89–3.81(m,1H),2.44(t,2H),2.18–1.87(m,4H),1.77–1.67(m,1H),1.66–1.53(m,2H),1.24(s,6H),0.92(t,3H)。
LC-MS m/z(ESI)=330.20[M+23]。
第四步:
5'-(甲基-d3)-2'-(丙-1-烯-2-基)-4-丙基-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二醇(化合物3)
5'-(methyl-d3)-2'-(prop-1-en-2-yl)-4-propyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol
将3c(350.0mg,1.2mmol)称量至反应烧瓶中,N2换气三次,室温条件下加入5mLTHF搅拌至溶解完全,冰浴条件下缓慢加入伯吉斯试剂(571.9mg,2.4mmol),加入完毕移至室温搅拌约20min。TLC检测至3c完全消耗完毕。饱和NaHCO3调节pH=7-8,乙酸乙酯萃取,有机相经饱和NaCl溶液洗涤,无水Na2SO4干燥,浓缩,柱层析纯化可得粗品。将粗品经制备色谱柱提纯得到目标产物化合物3(紫色固体,20.0mg,6.1%)。
1H NMR(400MHz,DMSO):δ(ppm)8.66(s,2H),6.01(s,2H),5.08(s,1H),4.49(d,1H),4.40(dd,1H),3.87–3.75(m,1H),3.09–2.96(m,1H),2.28(t,2H),2.14(s,1H),1.96–1.87(m,1H),1.73–1.60(m,2H),1.58(s,3H),1.55–1.41(m,2H),0.86(t,3H)。
LC-MS m/z(ESI)=290.20[M+23]。
实施例4
4-丁基-5'-(甲基-d3)-2'-(丙-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二醇(化合物4)
4-butyl-5'-(methyl-d3)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol
第一步:
(E)-((((5-(1--1-烯-1-基)-1,3-亚苯基)双(氧))双(亚甲基))二苯4a
(E)-(((5-(but-1-en-1-yl)-1,3-phenylene)bis(oxy))bis(methylene))dibenzene
在0℃下将t-BuOK(1.5g,13.0mmol)加入到溶于THF的甲基三苯基溴化磷(5.0g,13.0mmol)溶液中,在0℃下搅拌0.5h加入2a(3.4g,10.8mmol),随后将其移至室温继续搅拌至反应完全。待反应完全后经EA萃取,无水Na2SO4干燥,真空浓缩后得粗品,粗品经柱层析纯化后可得4a(白色固体,3.6g,96.7%)。
1H NMR(400MHz,DMSO):δ(ppm)7.47–7.29(m,10H),6.52(s,2H),6.34–6.23(m,1H),5.67–5.58(m,1H),5.04(s,4H),2.34–2.18(m,2H),1.02(t,3H)。
LC-MS m/z(ESI)=345.20[M+1]。
第二步:
5-丁基苯-1,3-二醇4b
5-butylbenzene-1,3-diol
将4a(3.6g,10.4mmol)溶于EA和甲醇的混合溶液中(v1/v2=5/1),随后加入10%的Pd/C(360.0mg),H2条件下搅拌过夜。待其反应完全,过滤反应液,EA萃取萃取滤液,所得有机相经真空浓缩,柱层析纯化可得对应的目标化合物4b(白色固体,1.4g,80.6%)。
1H NMR(400MHz,DMSO):δ(ppm)(d,2H),6.18(t,1H),2.47(dd,2H),1.59(dt,2H),0.93(t,3H)。
LC-MS m/z(ESI)=167.1[M+1]。
第三步:
4-丁基-2'-(2-羟基丙烷-2-基)-5'-(甲基-d3)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二醇4c
4-butyl-2'-(2-hydroxypropan-2-yl)-5'-(methyl-d3)-1',2',3',4'-tetrahydro-[1,1'-bi-phenyl]-2,6-diol
将4b(1.4g,4.3mmol)和左旋樟脑磺酸(67.1mg,0.3mmol)溶于干燥DCM溶液中搅拌10min后将1d(502.1mg,2.9mmol)加入至上述溶液中,换气三次后继续置于室温搅拌约1h。待反应完毕后用饱和NaHCO3将反应液pH调至7-8,DCM萃取,无水Na2S O4干燥,真空浓缩得其粗品。粗品经柱层析纯化可得其目标化合物4c(白色固体,250mg,9.2%)。
1H NMR(400MHz,Chloroform-d):δ(ppm)6.48(s,1H),6.36–6.24(m,2H),5.73–5.64(m,1H),3.88–3.80(m,1H),2.51–2.41(m,2H),2.20–1.86(m,4H),1.76–1.65(m,1H),1.61–1.49(m,2H),1.37–1.30(m,2H),1.23(s,6H),0.90(t,3H)。
LC-MS m/z(ESI)=343.20[M+23]。
第四步:
4-丁基-5'-(甲基-d3)-2'-(丙-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二醇(化合物4)
4-butyl-5'-(methyl-d3)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol
将4c(250.0mg,0.8mmol)称量至反应烧瓶中,换气三次,室温条件下加入5mL T HF搅拌至溶解完全,冰浴条件下缓慢加入伯吉斯试剂(381.3mg,1.6mmol),加入完毕后将其移至室温搅拌约20min。TLC检测4c完全消耗完毕。加入饱和NaHCO3调节pH=7-8,EA萃取,有机相经饱和NaCl洗涤,无水Na2SO4干燥,浓缩,柱层析纯化可得粗品。将粗品经制备色谱柱提纯即得到目标产物化合物4(紫色固体,25mg,10.6%)。
1H NMR(400MHz,DMSO):δ(ppm)8.66(s,2H),6.01(s,2H),5.07(s,1H),4.49(d,1H),4.40(dd,1H),3.90–3.75(m,1H),3.07–2.96(m,1H),2.30(t,2H),2.19–2.02(m,1H),1.99–1.84(m,1H),1.73–1.60(m,2H),1.58(s,3H),1.51–1.39(m,2H),1.36–1.20(m,2H),0.87(t,3H)。
LC-MS m/z(ESI)=304.20[M+23]。
实施例5
甲基-2,6-二羟基-5'-(甲基-d3)-4-戊基-2'-(丙-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-3-羧酸盐(化合物5)
Methyl-2,6-dihydroxy-5'-(methyl-d3)-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-3-carboxylate
第一步:
甲基-2,6-二羟基-2'-(2-羟基丙烷-2-基)-5'-(甲基-d3)-4-戊基-1’,2’,3’,4'-四氢-[1,1'-联苯]-3-羧酸盐5b
methyl-2,6-dihydroxy-2'-(2-hydroxypropan-2-yl)-5'-(methyl-d3)-4-pentyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-3-carboxylate
将1d(150mg,0.86mmol)、5a(619mg,2.6mmol)和4A分子筛(450mg)加入到烧瓶中,在氮气的保护下加入左旋樟脑磺酸(19mg,0.086mmol),在室温下搅拌反应,1.5h反应完毕,柱层析分离(PE:EA=15:1),得到目标产物5b(黄色油状产物,207mg,产率61.4%)。
1H NMR(400MHz,DMSO-d6)δ11.51(s,1H),9.87(s,1H),6.21(s,1H),4.87(d,1H),3.83(s,3H),3.75(d,1H),2.71-2.63(m,2H),2.38(td,1H),2.16–1.98(m,2H),1.92–1.81(m,1H),1.45(q,2H),1.28(ddd,10.5,6H),0.97(s,3H),0.86(t,3H),0.79(s,3H)。
第二步:
甲基-2,6-二羟基-5'-(甲基-d3)-4-戊基-2'-(丙-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-3-羧酸盐(化合物5)
methyl-2,6-dihydroxy-5'-(methyl-d3)-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-3-carboxylate
将5b(207mg,0.52mmol)和四氢呋喃(3mL)加入到烧瓶中,通入氮气保护,在0℃下加入伯吉斯试剂(250mg,1.01mmol),20min后反应完毕,加入5mL碳酸氢钠水溶液淬灭反应,柱层析分离得到目标产物化合物5(白色固体产物,66mg,产率33.5%)。
1H NMR(400MHz,DMSO-d6)δ11.54(s,1H),9.90(s,1H),6.20(s,1H),5.09(d,1H),4.52-4.36(m,2H),3.96–3.86(m,1H),3.83(s,4H),3.02(td,11.0,1H),2.73-2.62(m,2H),2.18-2.07(m,1H),2.00-1.91(m,1H),1.75-1.60(m,2H),1.58(s,3H),1.44(t,2H),1.32-1.26(m,4H),0.90-0.84(m,3H)。
实施例6
乙基-2,6-二羟基-5'-(甲基-d3)-4-戊基-2'-(丙-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-3-羧酸盐(化合物6)
ethyl-2,6-dihydroxy-5'-(methyl-d3)-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-3-carboxylate
第一步:
乙基-2,6-二羟基-2'-(2-羟基丙烷-2-基)-5'-(甲基-d3)-4-戊基-1’,2’,3’,4'-四氢-[1,1'-联苯]-3-羧酸盐6b
ethyl-2,6-dihydroxy-2'-(2-hydroxypropan-2-yl)-5'-(methyl-d3)-4-pentyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-3-carboxylate
将1d(150mg,0.86mmol)、6a(655mg,2.6mmol)和4A分子筛(450mg)加入到烧瓶中,在氮气的保护下加入左旋樟脑磺酸(19mg,0.086mmol),在室温下搅拌反应,1.5h反应完毕,柱层析分离(PE:EA=15:1),得到目标产物6b(黄色油状产物,200mg,产率57.1%)。
1H NMR(400MHz,DMSO-d6)δ11.77(d,1H),9.89(s,1H),6.21(s,1H),4.86(d,1H),4.32(q,2H),3.80(s,2H),2.71(s,2H),2.39(td,1H),2.16–1.99(m,2H),1.92–1.80(m,1H),1.49–1.42(m,2H),1.36–1.29(m,7H),0.97(s,4H),0.88–0.84(m,3H),0.79(s,3H)。
第二步:
乙基-2,6-二羟基-5'-(甲基-d3)-4-戊基-2'-(丙-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-3-羧酸盐(化合物6)
ethyl-2,6-dihydroxy-5'-(methyl-d3)-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-3-carboxylate
将6b(200mg,0.51mmol)和四氢呋喃(3mL)加入到烧瓶中,通入氮气保护,在0℃下加入伯吉斯试剂(254mg,1.02mmol),20min后反应完毕,加入5mL碳酸氢钠水溶液淬灭反应,柱层析分离得到目标产物化合物6(白色固体产物,66mg,产率33.5%)。
1H NMR(400MHz,DMSO-d6)δ11.78(s,1H),9.91(s,1H),6.19(s,1H),5.08(d,1H),4.47-4.42(m,2H),4.33(t,2H),3.90(d,1H),3.02(td,10.9,1H),2.69(d,2H),2.15-2.09(m,1H),1.98-1.91(m,1H),1.71-1.61(m,2H),1.58(s,3H),1.48-1.43(m,2H),1.31(d,3H),1.29-1.24(m,4H),0.87(q,3H)。
实施例7
(1'R,2'R)-5'-(甲基-d3)-4-戊基-2'-(丙-1-烯-2-基-d5)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二醇(化合物7)
(1'R,2'R)-5'-(methyl-d3)-4-pentyl-2'-(prop-1-en-2-yl-d5)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol
第一步:
3-乙氧基-6-(2-羟丙基-2-基-1,1,1,3,3,3-d6)环己-2-烯-1-酮7b
3-ethoxy-6-(2-hydroxypropan-2-yl-1,1,1,3,3,3-d6)cyclohex-2-en-1-one
在-70℃、氮气保护下,将3-乙氧基环己-2-烯-1-酮7a(10.0g,71.0mmol)滴加到二异丙基氨基锂(54mL,107.0mmol,2.0N)的四氢呋喃(100mL)溶液中,滴毕搅拌反应0.5h;滴加氘代丙酮(9.2g,142.0mmol),滴毕继续搅拌3h;TLC检测至反应结束;滴加饱和氯化铵溶液(180mL)淬灭反应,分液,水相用乙酸乙酯(150mL×2)萃取,合并有机相用饱和食盐水(100mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到标题化合物7b(黄色油状物,18.0g,产率:99.0%)。
1H NMR(400MHz,DMSO)。δ5.29(s,1H),4.93(s,1H),3.98–3.87(m,2H),2.46(dd,J=11.2,5.0Hz,1H),2.37(dt,J=17.4,4.5Hz,1H),2.21(dd,J=12.1,4.7Hz,1H),2.12–2.03(m,1H),1.67(ddd,J=24.2,12.3,5.1Hz,1H),1.27(t,J=7.0Hz,3H)。
LC-MS m/z(ESI)=205.1[M+1]。
第二步:
(R)-4-(2-羟基丙烷-2-基-1,1,1,3,3,3-d6)环己-2-烯-1-酮7c
(R)-4-(2-hydroxypropan-2-yl-1,1,1,3,3,3-d6)cyclohex-2-en-1-one
在0℃,氮气保护下,将红铝(67mL,234.1mmol,3.5N)滴加到化合物7b(17.0g,78.0mmol)的四氢呋喃(200mL)溶液中,滴毕缓慢升至室温搅拌反应2h;TLC检测至反应结束;降至0℃,滴加饱和氯化铵溶液(13mL)淬灭,抽滤,水相用乙酸乙酯(200mL×2)萃取,合并有机相用饱和食盐水(100mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品加入四氢呋喃(40mL)溶解,滴加盐酸水溶液(40mL,2N),滴毕室温搅拌反应1.5h;TLC检测至反应结束,滴加饱和碳酸氢钠溶液淬灭反应,减压浓缩,水相用乙酸乙酯(100mL×4)萃取,合并有机相用饱和食盐水(100mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩经硅胶柱层析(洗脱剂:乙酸乙酯/石油醚(v/v)=1/3)纯化。得到的消旋体用制备液相色谱分离纯化(AD柱,正己烷:异丙醇=95:5,214nm,25℃,保留时间:8.611分钟)得到标题化合物7c(无色油状物,5.8g,产率:48.0%)。
1H NMR(400MHz,DMSO)δ7.19(dt,J=10.4,1.9Hz,1H),5.93(dd,J=10.4,2.8Hz,1H),4.58(s,1H),2.44–2.38(m,1H),2.38–2.29(m,2H),2.08–1.96(m,1H),1.62(tdd,J=12.9,9.4,5.0Hz,1H)。
LC-MS m/z(ESI)=161.1[M+1]。
第三步:
(1R,4R)-4-(2-羟基丙烷-2-基-1,1,1,3,3,3-d6)-1-(甲基-d3)环己-2-烯-1-醇7d
(1R,4R)-4-(2-hydroxypropan-2-yl-1,1,1,3,3,3-d6)-1-(methyl-d3)cyclohex-2-en-1-ol
在0℃,氮气保护下,将氘代甲基碘化镁(34mL,33.7mmol,1.0N)滴加到无水氯化锂(1.4g,33.7mmol)的四氢呋喃(20mL)溶液中,滴毕搅拌反应0.5h;滴加化合物7c(1.8g,11.2mmol)的四氢呋喃溶液(5mL),滴毕搅拌反应0.5h;TLC检测至反应结束;滴加饱和氯化铵溶液(20mL)淬灭,水相用乙酸乙酯(50mL×3)萃取,合并有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品,经硅胶柱层析(洗脱剂:乙酸乙酯/石油醚(v/v)=2/1)纯化,得到标题化合物7d(白色固体,1.2g,产率:60.0%)。
1H NMR(400MHz,DMSO)δ5.61(d,J=10.4Hz,1H),5.52(d,J=10.6Hz,1H),4.38(s,1H),4.17(s,1H),2.00(ddd,J=10.8,5.1,2.4Hz,1H),1.73–1.65(m,2H),1.57–1.48(m,1H),1.21(dd,J=10.1,6.8Hz,1H)。
第四步:
(1'R,2'R)-2'-(2-羟基丙烷-2-基-1,1,1,3,3-d6)-5'-(甲基-d3)-4-戊基-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二醇7e
(1'R,2'R)-2'-(2-hydroxypropan-2-yl-1,1,1,3,3,3-d6)-5'-(methyl-d3)-4-pentyl-1',2',3',4'-tet-rahydro-[1,1'-biphenyl]-2,6-diol
在氮气保护下,将L-(-)樟脑磺酸(65mg,0.28mmol)滴加到化合物7d(500mg,2.79mmol)、3,5-二羟基戊苯(750mg,4.18mmol)和4A分子筛(1.5g)的二氯甲烷(10mL)溶液中,滴毕室温搅拌反应1.5h;TLC检测至反应结束;滴加饱和碳酸氢钠溶液(10mL)淬灭,水相用二氯甲烷(30mL×3)萃取,合并有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品经硅胶柱层析(洗脱剂:乙酸乙酯/石油醚(v/v)=1/10)纯化,得到标题化合物7e(白色固体,380mg,产率:39.0%)。
1H NMR(400MHz,DMSO)δ8.73(d,J=110.7Hz,2H),6.03(s,2H),4.88(s,1H),3.65(s,2H),2.38–2.28(m,3H),2.09(d,J=12.2Hz,1H),2.03–1.95(m,1H),1.83(d,J=16.8Hz,1H),1.51–1.43(m,2H),1.30–1.21(m,5H),0.85(t,J=7.0Hz,3H)。
LC-MS m/z(ESI)=342.3[M+1]。
第五步:
(1'R,2'R)-5'-(甲基-d3)-4-戊基-2'-(1-烯-2-基-d5)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二醇(化合物7)
(1'R,2'R)-5'-(methyl-d3)-4-pentyl-2'-(prop-1-en-2-yl-d5)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol
在0℃,氮气保护下,将伯吉斯试剂(390mg,1.66mmol)加到化合物7e(380mg,1.10mmol)的四氢呋喃(6mL)溶液中,升至室温搅拌反应20min;TLC检测至反应结束;滴加饱和碳酸氢钠溶液(10mL)淬灭,水相用乙酸乙酯(30mL×3)萃取,合并有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品经硅胶柱层析(洗脱剂:乙酸乙酯/石油醚(v/v)=1/30)纯化,得到标题化合物7(白色固体,44mg,HPLC:98%,产率:12.0%)。
1H NMR(400MHz,DMSO)δ8.64(s,2H),6.01(s,2H),5.08(s,1H),3.82(dd,J=8.8,1.8Hz,1H),3.07–2.97(m,1H),2.32–2.27(m,2H),2.14–2.04(m,1H),1.91(d,J=16.8Hz,1H),1.72–1.57(m,2H),1.47(dt,J=14.8,7.4Hz,2H),1.30–1.22(m,4H),0.86(t,J=7.0Hz,3H)。
LC-MS m/z(ESI)=323.3[M+1]。
实施例8
(1'S,2'S)-5'-(甲基-d3)-4-戊基-2'-(prop-1-en-2-yl-d5)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二醇(化合物8)
(1'S,2'S)-5'-(methyl-d3)-4-pentyl-2'-(prop-1-en-2-yl-d5)-1',2',3',4'-tetrahydro-[1,1'-biphe-nyl]-2,6-diol
第一步:
(S)-4-(2-羟基丙烷-2-基-1,1,1,3,3,3-d6)环己-2-烯-1-酮8a
(S)-4-(2-hydroxypropan-2-yl-1,1,1,3,3,3-d6)cyclohex-2-en-1-one
在0℃,氮气保护下,将红铝(67mL,234.1mmol,3.5N)滴加到化合物7b(17.0g,78.0mmol)的四氢呋喃(200mL)溶液中,滴毕缓慢升至室温搅拌反应2h;TLC检测至反应结束;降至0℃,滴加饱和氯化铵溶液(13mL)淬灭,抽滤,水相用乙酸乙酯(200mL×2)萃取,合并有机相用饱和食盐水(100mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品加入四氢呋喃(40mL)溶解,滴加盐酸水溶液(40mL,2N),滴毕室温搅拌反应1.5h;TLC检测至反应结束,滴加饱和碳酸氢钠溶液淬灭反应,减压浓缩,水相用乙酸乙酯(100mL×4)萃取,合并有机相用饱和食盐水(100mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩经硅胶柱层析(洗脱剂:乙酸乙酯/石油醚(v/v)=1/3)纯化。得到的消旋体用制备液相色谱分离纯化(AD柱,正己烷:异丙醇=95:5,214nm,25℃,保留时间:9.877分钟)得到标题化合物8a(无色油状物,5.8g,产率:48.0%)。
1H NMR(400MHz,DMSO)δ7.19(dt,J=10.4,1.9Hz,1H),5.93(dd,J=10.4,2.8Hz,1H),4.58(s,1H),2.44–2.38(m,1H),2.38–2.29(m,2H),2.08–1.96(m,1H),1.62(tdd,J=12.9,9.4,5.0Hz,1H)。
LC-MS m/z(ESI)=161.1[M+1]。
第二步:
(1S,4S)-4-(2-羟基丙烷-2-基-1,1,1,3,3,3-d6)-1-(甲基-d3)环己-2-烯-1-醇8b
(1S,4S)-4-(2-hydroxypropan-2-yl-1,1,1,3,3,3-d6)-1-(methyl-d3)cyclohex-2-en-1-ol
在0℃,氮气保护下,将氘代甲基碘化镁(34mL,33.7mmol,1.0N)滴加到无水氯化锂(1.4g,33.7mmol)的四氢呋喃(20mL)溶液中,滴毕搅拌反应0.5h;滴加化合物8a(1.8g,11.2mmol)的四氢呋喃溶液(5mL),滴毕搅拌反应0.5h;TLC检测至反应结束;滴加饱和氯化铵溶液(20mL)淬灭,水相用乙酸乙酯(50mL×3)萃取,合并有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品,经硅胶柱层析(洗脱剂:乙酸乙酯/石油醚(v/v)=2/1)纯化,得到标题化合物8b(白色固体,1.2g,产率:60.0%)。
1H NMR(400MHz,DMSO)δ5.61(d,J=10.4Hz,1H),5.52(d,J=10.6Hz,1H),4.38(s,1H),4.17(s,1H),2.00(ddd,J=10.8,5.1,2.4Hz,1H),1.73–1.65(m,2H),1.57–1.48(m,1H),1.21(dd,J=10.1,6.8Hz,1H)。
第三步:
(1'S,2'S)-2'-(2-羟基丙烷-2-基-1,1,1,3,3-d6)-5'-(甲基-d3)-4-戊基-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二醇8c
(1'S,2'S)-2'-(2-hydroxypropan-2-yl-1,1,1,3,3,3-d6)-5'-(methyl-d3)-4-pentyl-1',2',3',4'-tetr-ahydro-[1,1'-biphenyl]-2,6-diol
在氮气保护下,将L-(-)樟脑磺酸(65mg,0.28mmol)滴加到化合物8b(500mg,2.79mmol)、3,5-二羟基戊苯(0.75g,4.18mmol)和4A分子筛(1.5g)的二氯甲烷(10mL)溶液中,滴毕室温搅拌反应1.5h;TLC检测至反应结束;滴加饱和碳酸氢钠溶液(10mL)淬灭,水相用二氯甲烷(30mL×3)萃取,合并有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品经硅胶柱层析(洗脱剂:乙酸乙酯/石油醚(v/v)=1/10)纯化,得到标题化合物8c(白色固体,390mg,产率:40.0%)。
1H NMR(400MHz,DMSO)δ8.73(d,J=110.9Hz,2H),6.02(d,J=11.4Hz,2H),4.88(s,1H),3.66(d,J=5.5Hz,2H),2.33(dt,J=15.2,8.7Hz,3H),2.13–2.06(m,1H),2.02(s,1H),1.83(d,J=16.6Hz,1H),1.46(dd,J=14.6,7.2Hz,2H),1.25(ddd,J=11.6,11.1,5.5Hz,5H),0.85(t,J=7.0Hz,3H)。
LC-MS m/z(ESI)=342.3[M+1]。
第四步:
(1'S,2'S)-5'-(甲基-d3)-4-戊基-2'-(prop-1-en-2-yl-d5)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二醇(化合物8)
(1'S,2'S)-5'-(methyl-d3)-4-pentyl-2'-(prop-1-en-2-yl-d5)-1',2',3',4'-tetrahydro-[1,1'-biphe-nyl]-2,6-diol
在0℃,氮气保护下,将伯吉斯试剂(400mg,1.70mmol)加到化合物8c(390mg,1.13mmol)的四氢呋喃(8mL)溶液中,升至室温搅拌反应20min;TLC检测至反应结束;滴加饱和碳酸氢钠溶液(10mL)淬灭,水相用乙酸乙酯(30mL×3)萃取,合并有机相,用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品经硅胶柱层析(洗脱剂:乙酸乙酯/石油醚(v/v)=1/30)纯化,得到标题化合物8(白色固体,81mg,HPLC:95%,产率:23.0%)。
1H NMR(400MHz,DMSO)δ8.64(s,2H),6.01(s,2H),5.08(s,1H),3.82(d,J=10.5Hz,1H),3.12–2.95(m,1H),2.32–2.25(m,2H),2.15–2.04(m,1H),1.91(d,J=16.8Hz,1H),1.71–1.55(m,2H),1.47(dt,J=14.8,7.4Hz,2H),1.31–1.22(m,4H),0.86(t,J=7.0Hz,3H)。
LC-MS m/z(ESI)=323.3[M+1]。
实施例9
(1'R,2'R)-4-庚基-5'-(甲基-d3)-2'-(1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二醇(化合物9)
(1'R,2'R)-4-heptyl-5'-(methyl-d3)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol
第一步:
(E)-((5-(庚-1-烯-1-基)-1,3-亚苯基)双(氧基)双(亚甲基)二苯9a
(E)-(((5-(hept-1-en-1-yl)-1,3-phenylene)bis(oxy))bis(methylene))dibenzene
在0℃、氮气保护下,将双(三甲基硅基)氨基钠(113mL,226.1mmol,2.0N)滴加到n-溴代已基三苯基膦(100.0g,235.0mmol)的四氢呋喃(500mL)溶液中,滴毕升至10℃搅拌反应0.5h;滴加3,5-二苄氧基苯甲醛2a(30.0g,94.0mmol)的四氢呋喃(100mL)溶液,滴毕继续搅拌1.5h;TLC检测至反应结束;滴加饱和氯化铵溶液(300mL)淬灭反应,分液,水相用石油醚(300mL×2)萃取,合并有机相用饱和食盐水(200mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩经硅胶柱层析(洗脱剂:乙酸乙酯/石油醚(v/v)=1/10)纯化,得到标题化合物9a(无色油状物,47.0g,产率:99.0%)。
1H NMR(400MHz,DMSO)δ7.44–7.30(m,11H),6.60(t,J=2.1Hz,1H),6.53(t,J=7.6Hz,2H),6.32(d,J=12.0Hz,1H),5.60(dt,J=11.7,7.2Hz,1H),5.08(s,4H),2.24–2.14(m,2H),1.35(dd,J=14.2,7.2Hz,2H),1.27–1.18(m,4H),0.84(t,J=6.9Hz,3H)。
LC-MS m/z(ESI)=387.3[M+1]。
第二步:
5-庚基苯-1,3-二醇9b
5-heptylbenzene-1,3-diol
将钯碳(3.2g,10%)加到化合物9a(32.0g,83.0mmol)的无水甲醇(150mL)和乙酸乙酯(150mL)溶液中,氢化反应15h;TLC检测至反应结束;过滤,滤液减压浓缩经硅胶柱层析(洗脱剂:乙酸乙酯/石油醚(v/v)=1/3)纯化,得到标题化合物9b(白色固体,17.4g,产率:99.0%)
1H NMR(400MHz,DMSO)δ8.98(s,2H),6.02(s,3H),2.42–2.30(m,2H),1.47(dd,J=13.9,6.9Hz,2H),1.26(d,J=5.8Hz,8H),0.86(t,J=6.9Hz,3H)。
LC-MS m/z(ESI)=209.1[M+1]。
第三步:
(R)-4-(2-羟基丙烷-2-基)环己-2-烯-1-酮9c
(R)-4-(2-hydroxypropan-2-yl)cyclohex-2-en-1-one
消旋体1c用制备液相色谱分离纯化(AD柱,正己烷:异丙醇=95:5,214nm,25℃,保留时间:8.638分钟)得到标题手性化合物9c。
第四步:
(1R,4R)-4-(2-羟基丙烷-2-基)-1-(甲基-d3)环己-2-烯-1-醇9d
(1R,4R)-4-(2-hydroxypropan-2-yl)-1-(methyl-d3)cyclohex-2-en-1-ol
在0℃,氮气保护下,将氘代甲基碘化镁(34mL,33.7mmol,1.0N)滴加到无水氯化锂(1.4g,33.7mmol)的四氢呋喃(20mL)溶液中,滴毕搅拌反应0.5h;滴加化合物9c(1.8g,11.2mmol)的四氢呋喃溶液(5mL),滴毕搅拌反应0.5h;TLC检测至反应结束;滴加饱和氯化铵溶液(20mL)淬灭,水相用乙酸乙酯(50mL×3)萃取,合并有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品,经硅胶柱层析(洗脱剂:乙酸乙酯/石油醚(v/v)=2/1)纯化,得到标题化合物9d(白色固体,1.2g,产率:60.0%)。
1H NMR(400MHz,DMSO)δ5.61(d,J=10.4Hz,1H),5.52(d,J=10.6Hz,1H),4.38(s,1H),4.17(s,1H),2.00(ddd,J=10.8,5.1,2.4Hz,1H),1.73–1.65(m,2H),1.57–1.48(m,1H),1.21(dd,J=10.1,6.8Hz,1H),0.99(s,3H),0.73(s,3H)。
LC-MS m/z(ESI)=174.6[M+1]。
第五步:
(1'R,2'R)-4-庚基-2'-(2-羟基丙烷-2-基)-5'-(甲基-d3)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二醇9e
(1'R,2'R)-4-heptyl-2'-(2-hydroxypropan-2-yl)-5'-(methyl-d3)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol
在氮气保护下,将L-(-)樟脑磺酸(67mg,0.29mmol)加到化合物9b(1.6g,8.67mmol)、化合物9d(500mg,2.89mmol)和4A分子筛(1.5g)的二氯甲烷(10mL)溶液中,滴毕室温搅拌反应1.5h;TLC检测至反应结束;滴加饱和碳酸氢钠溶液(10mL)淬灭,水相用二氯甲烷(30mL×2)萃取,合并有机相用饱和食盐水(30mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品经硅胶柱层析(洗脱剂:乙酸乙酯/石油醚(v/v)=1/6)纯化,得到标题化合物9e(无色油状物,410mg,产率:41.0%)。
1H NMR(400MHz,DMSO)δ8.67(dd,J=96.6,46.4Hz,2H),6.03(s,2H),4.89(s,1H),3.66(d,J=10.8Hz,2H),2.40–2.28(m,3H),2.05(ddd,J=14.8,5.7,1.9Hz,2H),1.83(d,J=16.5Hz,1H),1.47(dd,J=14.1,7.2Hz,2H),1.28(d,J=24.3Hz,9H),0.97(s,3H),0.85(t,J=6.8Hz,3H),0.80(s,3H)。
LC-MS m/z(ESI)=364.3[M+1]。
第六步:
(1'R,2'R)-4-庚基-5'-(甲基-d3)-2'-(1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二醇(化合物9)
(1'R,2'R)-4-heptyl-5'-(methyl-d3)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol
在0℃,氮气保护下,将伯吉斯试剂(540mg,2.26mmol)加到化合物9e(410mg,1.13mmol)的四氢呋喃(5mL)溶液中,升至室温搅拌反应30min;TLC检测至反应结束;滴加饱和碳酸氢钠溶液(10mL)淬灭,水相用乙酸乙酯(30mL×3)萃取,合并有机相用饱和食盐水(30mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品经硅胶柱层析(洗脱剂:乙酸乙酯/石油醚(v/v)=1/30)纯化,得到标题化合物9(白色固体,245mg,HPLC:99.5%,产率:63%)。
1H NMR(400MHz,DMSO)δ8.63(s,2H),6.01(s,2H),5.08(s,1H),4.49(d,J=2.5Hz,1H),4.40(d,J=1.0Hz,1H),3.82(d,J=10.5Hz,1H),3.08–2.95(m,1H),2.30(dd,J=14.0,6.5Hz,2H),2.15–2.04(m,1H),1.91(d,J=16.6Hz,1H),1.72–1.63(m,1H),1.58(s,3H),1.50–1.42(m,2H),1.26(d,J=5.7Hz,9H),0.85(t,J=6.8Hz,3H)。
LC-MS m/z(ESI)=346.3[M+1]。
实施例10
(1'S,2'S)-4-庚基-5'-(甲基-d3)-2'-(1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二醇(化合物10)
(1'S,2'S)-4-heptyl-5'-(methyl-d3)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol
第一步:
(S)-4-(2-羟基丙烷-2-基)环己-2-烯-1-酮10a
(S)-4-(2-hydroxypropan-2-yl)cyclohex-2-en-1-one
消旋体1c用制备液相色谱分离纯化(AD柱,正己烷:异丙醇=95:5,214nm,25℃,保留时间:9.894分钟)得到标题手性化合物10a。
第二步:
(1S,4S)-4-(2-羟基丙烷-2-基)-1-(甲基-d3)环己-2-烯-1-醇10b
(1S,4S)-4-(2-hydroxypropan-2-yl)-1-(methyl-d3)cyclohex-2-en-1-ol
在0℃,氮气保护下,将氘代甲基碘化镁(34mL,33.7mmol,1.0N)滴加到无水氯化锂(1.4g,33.7mmol)的四氢呋喃(20mL)溶液中,滴毕搅拌反应0.5h;滴加化合物10a(1.8g,11.2mmol)的四氢呋喃溶液(5mL),滴毕搅拌反应0.5h;TLC检测至反应结束;滴加饱和氯化铵溶液(20mL)淬灭,水相用乙酸乙酯(50mL×3)萃取,合并有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品,经硅胶柱层析(洗脱剂:乙酸乙酯/石油醚(v/v)=2/1)纯化,得到标题化合物10b(白色固体,1.2g,产率:60.0%)。
1H NMR(400MHz,DMSO)δ5.61(d,J=10.4Hz,1H),5.52(d,J=10.6Hz,1H),4.38(s,1H),4.17(s,1H),2.00(ddd,J=10.8,5.1,2.4Hz,1H),1.73–1.65(m,2H),1.57–1.48(m,1H),1.21(dd,J=10.1,6.8Hz,1H),0.99(s,3H),0.73(s,3H)。
LC-MS m/z(ESI)=174.6[M+1]。
第三步:
(1'S,2'S)-4-庚基-2'-(2-羟基丙烷-2-基)-5'-(甲基-d3)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二醇10c
(1'S,2'S)-4-heptyl-2'-(2-hydroxypropan-2-yl)-5'-(methyl-d3)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol
在氮气保护下,将L-(-)樟脑磺酸(67mg,0.29mmol)加到化合物10b(500mg,2.89mmol)、5-庚苯-1,3-二醇9b(1.6g,8.67mmol)和4A分子筛(1.5g)的二氯甲烷(10mL)溶液中,滴毕室温搅拌反应1.5h;TLC检测至反应结束;滴加饱和碳酸氢钠溶液(10mL)淬灭,水相用二氯甲烷(30mL×2)萃取,合并有机相用饱和食盐水(30mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品经硅胶柱层析(洗脱剂:乙酸乙酯/石油醚(v/v)=1/6)纯化,得到标题化合物10c(无色油状物,400mg,产率:40.0%)。
1H NMR(400MHz,DMSO)δ8.67(dd,J=101.3,50.3Hz,2H),6.03(s,2H),4.89(s,1H),3.66(d,J=11.0Hz,2H),2.39–2.27(m,3H),2.14–1.97(m,2H),1.83(d,J=16.5Hz,1H),1.47(dd,J=14.2,7.2Hz,2H),1.30–1.18(m,9H),0.97(s,3H),0.85(t,J=6.9Hz,3H),0.80(s,3H)。
LC-MS m/z(ESI)=364.3[M+1]。
第四步:
(1'S,2'S)-4-庚基-5'-(甲基-d3)-2'-(1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二醇(化合物10)
(1'S,2'S)-4-heptyl-5'-(methyl-d3)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol
在0℃,氮气保护下,分别将4A分子筛(1.5g)、三乙胺(230mg,2.20mmol)和伯吉斯试剂(524mg,2.26mmol)加到化合物10c(400mg,1.10mmol)的四氢呋喃(5mL)溶液中,升至室温搅拌反应30min;TLC检测至反应结束;滴加饱和碳酸氢钠溶液(10mL)淬灭,水相用乙酸乙酯(30mL×3)萃取,合并有机相用饱和食盐水(30mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品经硅胶柱层析(洗脱剂:乙酸乙酯/石油醚(v/v)=1/30)纯化,得到标题化合物10(白色固体,220mg,HPLC:99.5%,产率:57%)。
1H NMR(400MHz,DMSO)δ8.63(s,2H),6.01(s,2H),5.08(s,1H),4.49(d,J=2.5Hz,1H),4.40(d,J=1.0Hz,1H),3.82(d,J=10.5Hz,1H),3.09–2.96(m,1H),2.34–2.21(m,2H),2.16–2.04(m,1H),1.99–1.85(m,1H),1.71–1.64(m,1H),1.58(s,3H),1.51–1.42(m,2H),1.26(d,J=5.6Hz,9H),0.85(t,J=6.8Hz,3H)。
LC-MS m/z(ESI)=346.3[M+1]。
实施例11
4-(庚基-1,1-d2)-5'-(甲基-d3)-2'-(1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二醇(化合物11)
4-(heptyl-1,1-d2)-5'-(methyl-d3)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol
第一步:
4-(庚基-1,1-d2)-2'-(2-羟基丙烷-2-基)-5'-(甲基-d3)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二醇11a
4-(heptyl-1,1-d2)-2'-(2-hydroxypropan-2-yl)-5'-(methyl-d3)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol
在氮气保护下,将L-(-)樟脑磺酸(67mg,0.29mmol)加到化合物1d(500mg,2.89mmol)、5-(庚基-1,1-d2)苯基-1,3-二醇(1.6g,8.67mmol)和4A分子筛(1.5g)的二氯甲烷(10mL)溶液中,滴毕室温搅拌反应1.5h;TLC检测至反应结束;滴加饱和碳酸氢钠溶液(10mL)淬灭,水相用二氯甲烷(30mL×2)萃取,合并有机相用饱和食盐水(30mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品经硅胶柱层析(洗脱剂:乙酸乙酯/石油醚(v/v)=1/6)纯化,得到标题化合物11a(无色油状物,400mg,产率:40.0%)。
1H NMR(400MHz,DMSO)δ8.67(dd,2H),6.03(s,2H),4.89(s,1H),3.66(d,2H),2.39–2.27(m,1H),2.14–1.97(m,2H),1.83(d,1H),1.47(dd,2H),1.30–1.18(m,9H),0.97(s,3H),0.85(t,3H),0.80(s,3H)。
LC-MS m/z(ESI)=366.3[M+1]。
第二步:
4-(庚基-1,1-d2)-5'-(甲基-d3)-2'-(1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二醇(化合物11)
4-(heptyl-1,1-d2)-5'-(methyl-d3)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol
在0℃,氮气保护下,分别将4A分子筛(1.5g)、三乙胺(230mg,2.20mmol)和伯吉斯试剂(524mg,2.26mmol)加到化合物11a(400mg,1.10mmol)的四氢呋喃(5mL)溶液中,升至室温搅拌反应30min;TLC检测至反应结束;滴加饱和碳酸氢钠溶液(10mL)淬灭,水相用乙酸乙酯(30mL×3)萃取,合并有机相用饱和食盐水(30mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品经硅胶柱层析(洗脱剂:乙酸乙酯/石油醚(v/v)=1/30)纯化,得到标题化合物11(白色固体,141mg,产率:37%)。
1H NMR(400MHz,DMSO)δ8.63(s,2H),6.01(s,2H),5.08(s,1H),4.49(d,1H),4.40(d,1H),3.82(d,1H),3.09–2.96(m,1H),2.16–2.04(m,1H),1.99–1.85(m,1H),1.71–1.64(m,1H),1.58(s,3H),1.51–1.42(m,2H),1.26(d,9H),0.85(t,3H)。
LC-MS m/z(ESI)=348.3[M+1]。
实施例12
(1'R,2'R)-5'-(甲基-d3)-4-戊基-2'-(丙基-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-4'-d-2,6-二醇(化合物12)
(1'R,2'R)-5'-(methyl-d3)-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-4'-d-2,6-diol
第一步:
(4R)-4-(2-羟基丙烷-2-基)环己-2-烯-1-酮-6-d 12a
(4R)-4-(2-hydroxypropan-2-yl)cyclohex-2-en-1-one-6-d
在氮气保护下,将重水(7mL,350.0mmol)和碳酸钾(54mg,0.4mmol)加到(R)-4-(2-羟基丙烷-2-基)环己-2-烯-1-酮9c(3.0g,19.5mmol)的四氢呋喃(14mL)和氘代甲醇(14mL)溶液中,室温搅拌反应48h;LC-MS检测反应完全;减压浓缩,水相用乙酸乙酯(30mL×3)萃取,合并有机相用饱和食盐水(30mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩经硅胶柱层析(洗脱剂:乙酸乙酯/石油醚(v/v)=1/1)纯化,得到标题化合物12a(无色油状物,2.4g,产率:79.0%)。
1H NMR(400MHz,DMSO)δ7.19(dt,J=10.3,1.9Hz,1H),5.99–5.88(m,1H),4.60(s,1H),2.44–2.38(m,1H),2.32(d,J=10.7Hz,1H),2.06–1.99(m,1H),1.67–1.56(m,1H),1.15(s,3H),1.05(s,3H)。
LC-MS m/z(ESI)=178.1[M+Na]。
第二步:
(1R,4R)-4-(2-羟基丙烷-2-基)-1-(甲基-d3)环己-2-烯-6-d-1-醇12b
(1R,4R)-4-(2-hydroxypropan-2-yl)-1-(methyl-d3)cyclohex-2-en-6-d-1-ol
在0℃,氮气保护下,将氘代甲基碘化镁(14mL,13.5mol,1.0N)滴加到无水氯化锂(570mg,13.5mol)的四氢呋喃(10mL)溶液中,滴毕搅拌反应0.5h;滴加化合物12a(700mg,4.0mmol)的四氢呋喃溶液(5mL),滴毕搅拌反应0.5h;TLC检测至反应结束;滴加饱和氯化铵溶液(20mL)淬灭,水相用乙酸乙酯(30mL×3)萃取,合并有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品,经硅胶柱层析(洗脱剂:乙酸乙酯/石油醚(v/v)=2/1)纯化,得到标题化合物12b(白色固体,430mg,产率:55.0%)。
1H NMR(400MHz,DMSO)δ5.66–5.58(m,1H),5.55–5.46(m,1H),4.40(d,J=1.8Hz,1H),4.21(s,1H),1.99(ddd,J=10.4,5.4,2.4Hz,1H),1.68(dd,J=12.9,5.5Hz,2H),1.24–1.20(m,1H),1.03(s,3H),0.97(s,3H)。
第三步:
(1'R,2'R)-2'-(2-羟基丙烷-2-基)-5'-(甲基-d3)-4-戊基-1’,2’,3’,4'-四氢-[1,1'-联苯]-4'-d-2,6-二醇12c
(1'R,2'R)-2'-(2-hydroxypropan-2-yl)-5'-(methyl-d3)-4-pentyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-4'-d-2,6-diol
在氮气保护下,将L-(-)樟脑磺酸(53mg,0.23mmol)加到化合物12b(400mg,2.29mmol)、3,5-二羟基戊苯(621mg,3.44mmol)和4A分子筛(1.2g)的二氯甲烷(10mL)溶液中,滴毕室温搅拌反应1.5h;TLC检测至反应结束;滴加饱和碳酸氢钠溶液(10mL)淬灭,水相用二氯甲烷(30mL×3)萃取,合并有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品经硅胶柱层析(洗脱剂:乙酸乙酯/石油醚(v/v)=1/6)纯化,得到标题化合物12c(白色固体,270mg,产率:35.0%)。
1H NMR(400MHz,DMSO)δ9.02–8.43(m,2H),6.03(s,2H),4.88(d,J=2.3Hz,1H),3.66(d,J=11.0Hz,2H),2.39–2.28(m,3H),2.09(d,J=12.6Hz,1H),1.81(s,1H),1.46(dt,J=14.6,7.4Hz,2H),1.32–1.22(m,6H),0.97(s,3H),0.85(t,J=7.0Hz,3H),0.79(s,3H)。
LC-MS m/z(ESI)=337.3[M+1]。
第四步:
(1'R,2'R)-5'-(甲基-d3)-4-戊基-2'-(丙基-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-4'-d-2,6-二醇(化合物12)
(1'R,2'R)-5'-(methyl-d3)-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-4'-d-2,6-diol
在0℃,氮气保护下,将伯吉斯试剂(284mg,1.12mmol)加到化合物12c(270mg,0.79mmol)的四氢呋喃(6mL)溶液中,升至室温搅拌反应30min;TLC检测至反应结束;滴加饱和碳酸氢钠溶液(10mL)淬灭,水相用乙酸乙酯(30mL×3)萃取,合并有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品经硅胶柱层析(洗脱剂:乙酸乙酯/石油醚(v/v)=1/30)纯化,得到标题化合物12(白色固体,73mg,HPLC:99%,产率:28.0%)。
1H NMR(400MHz,DMSO)δ8.64(s,2H),6.01(s,2H),5.08(s,1H),4.49(d,J=2.4Hz,1H),4.40(s,1H),3.82(d,J=10.4Hz,1H),3.08–2.95(m,1H),2.34–2.25(m,2H),1.89(s,1H),1.71–1.61(m,1H),1.58(s,3H),1.47(dt,J=14.7,7.4Hz,2H),1.36–1.20(m,5H),0.86(t,J=7.0Hz,3H)。
LC-MS m/z(ESI)=319.2[M+1]。
实施例13
(1'R,2'R)-5'-(甲基-d3)-4-戊基-2'-(丙基-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-4’,4'-d2,6-二醇(化合物13)
(1'R,2'R)-5'-(methyl-d3)-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-4',4'-d2-2,6-diol
第一步:
(R)-4-(2-羟丙基-2-基)环己-2-烯-1-酮-6,6-d2 13a
(R)-4-(2-hydroxypropan-2-yl)cyclohex-2-en-1-one-6,6-d2
在-70℃,氮气保护下,将二异丙基氨基锂(14mL,27.0mmol)滴加到(4R)-4-(2-羟基丙烷-2-基)环己-2-烯-1-酮-6-d 12a(2.0g,12.9mmol)的四氢呋喃(20mL)溶液中,滴毕搅拌反应0.5h;滴加重水(5mL,250.0mmol),回至室温搅拌反应20min,水相用乙酸乙酯(30mL×3)萃取,合并有机相用饱和食盐水(30mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩经硅胶柱层析(洗脱剂:乙酸乙酯/石油醚(v/v)=1/1)纯化,得到标题化合物13a(无色油状物,1.4g,产率:70.0%)。
1H NMR(400MHz,DMSO)δ7.19(dt,J=10.3,1.9Hz,1H),5.99–5.88(m,1H),4.60(s,1H),2.32(d,J=10.7Hz,1H),2.06–1.99(m,1H),1.67–1.56(m,1H),1.15(s,3H),1.05(s,3H)。
LC-MS m/z(ESI)=179.1[M+Na]。
第二步:
(1R,4R)-4-(2-羟基丙烷-2-基)-1-(甲基-d3)环己-2-烯-6,6-d2-1-醇13b
(1R,4R)-4-(2-hydroxypropan-2-yl)-1-(methyl-d3)cyclohex-2-en-6,6-d2-1-ol
在0℃,氮气保护下,将氘代甲基碘化镁(12mL,11.5mmol,1.0N)滴加到无水氯化锂(488mg,11.5mmol)的四氢呋喃(10mL)溶液中,滴毕搅拌反应0.5h;滴加化合物13a(600mg,3.8mmol)的四氢呋喃溶液(5mL),滴毕搅拌反应0.5h;TLC检测至反应结束;滴加饱和氯化铵溶液(20mL)淬灭,水相用乙酸乙酯(30mL×3)萃取,合并有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品,经硅胶柱层析(洗脱剂:乙酸乙酯/石油醚(v/v)=2/1)纯化,得到标题化合物13b(白色固体,410mg,产率:60.0%)。
1H NMR(400MHz,DMSO)δ5.66–5.58(m,1H),5.55–5.46(m,1H),4.40(d,J=1.8Hz,1H),4.21(s,1H),1.99(ddd,J=10.4,5.4,2.4Hz,1H),1.68(dd,J=12.9,5.5Hz,1H),1.24–1.20(m,1H),1.03(s,3H),0.97(s,3H)。
第三步:
(1'R,2'R)-2'-(2-羟基丙烷-2-基)-5'-(甲基-d3)-4-戊基-1’,2’,3’,4'-四氢-[1,1'-联苯]-4’,4'-d2-2,6-二醇13c
(1'R,2'R)-2'-(2-hydroxypropan-2-yl)-5'-(methyl-d3)-4-pentyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-4',4'-d2-2,6-diol
在氮气保护下,将L-(-)樟脑磺酸(53mg,0.23mmol)加到化合物13b(400mg,2.29mmol)、3,5-二羟基戊苯(621mg,3.44mmol)和4A分子筛(1.2g)的二氯甲烷(10mL)溶液中,滴毕室温搅拌反应1.5h;TLC检测至反应结束;滴加饱和碳酸氢钠溶液(10mL)淬灭,水相用二氯甲烷(30mL×3)萃取,合并有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品经硅胶柱层析(洗脱剂:乙酸乙酯/石油醚(v/v)=1/6)纯化,得到标题化合物13c(白色固体,250mg,产率:32.5%)。
1H NMR(400MHz,DMSO)δ9.02–8.43(m,2H),6.03(s,2H),4.88(d,J=2.3Hz,1H),3.66(d,J=11.0Hz,2H),2.39–2.28(m,3H),1.81(s,1H),1.46(dt,J=14.6,7.4Hz,2H),1.32–1.22(m,6H),0.97(s,3H),0.85(t,J=7.0Hz,3H),0.79(s,3H)。
LC-MS m/z(ESI)=338.3[M+1]。
第四步:
(1'R,2'R)-5'-(甲基-d3)-4-戊基-2'-(丙基-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-4’,4'-d2,6-二醇(化合物13)
(1'R,2'R)-5'-(methyl-d3)-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-4',4'-d2-2,6-diol
在0℃,氮气保护下,将伯吉斯试剂(264mg,1.11mmol)加到化合物13c(250mg,0.74mmol)的四氢呋喃(6mL)溶液中,升至室温搅拌反应30min;TLC检测至反应结束;滴加饱和碳酸氢钠溶液(10mL)淬灭,水相用乙酸乙酯(30mL×3)萃取,合并有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品经硅胶柱层析(洗脱剂:乙酸乙酯/石油醚(v/v)=1/30)纯化,得到标题化合物13(白色固体,55mg,产率:23.3%)。
1H NMR(400MHz,DMSO)δ8.64(s,2H),6.01(s,2H),5.08(s,1H),4.49(d,J=2.4Hz,1H),4.40(s,1H),3.82(d,J=10.4Hz,1H),3.08–2.95(m,1H),2.34–2.25(m,2H),1.89(s,1H),1.58(s,3H),1.47(dt,J=14.7,7.4Hz,2H),1.36–1.20(m,5H),0.86(t,J=7.0Hz,3H)。
LC-MS m/z(ESI)=320.2[M+1]。
实施例14
4-(甲基-d3)-5'-(甲基-d3)-2'-(丙-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二醇(化合物14)
4-(methyl-d3)-methyl-5'-(methyl-d3)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol
第一步:
2'-(2-羟基丙烷-2-基)-4-(甲基-d3)-5'-(甲基-d3)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二醇14b
2'-(2-hydroxypropan-2-yl)-4-(methyl-d3)-5'-(methyl-d3)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol
将4-(2-羟基丙烷-2-基)-1-(甲基-d3)环己-2-烯-1-醇1d(500mg,2.9mmol),5-(甲基-d3)-苯-1,3-二醇14a(1080mg,8.7mmol),和4A分子筛(1.5g)溶于10mL二氯甲烷中,置换氮气,室温搅拌10分钟。最后加入左旋樟脑磺酸(67.34mg,0.29mmol)。室温搅拌1小时。向反应液中加入20mL饱和碳酸氢钠水溶液淬灭反应,乙酸乙酯萃取(10mL×4)。合并有机相,用无水硫酸钠干燥,过滤,浓缩得到700mg粗品。柱层析分离得到2'-(2-羟基丙烷-2-基)-4-(甲基-d3)-5'-(甲基-d3)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二醇14b(白色固体,375mg,收率46%)。
1H NMR(400MHz,DMSO-d6)δ9.03(s,1H),8.79(s,1H),6.09(d,1H),5.95(d,1H),4.92(s,1H),3.90(d,1H),2.14(d,2H),1.37–1.21(m,2H),0.99(s,3H),0.91–0.79(m,2H),0.73(s,3H)。
第二步:
4-(甲基-d3)-5'-(甲基-d3)-2'-(丙-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二醇(化合物14)
4-(methyl-d3)-5'-(methyl-d3)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol
将2'-(2-羟基丙烷-2-基)-4-(甲基-d3)-5'-(甲基-d3)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二醇14b(350mg,1.25mmol),用6mL四氢呋喃溶解,置换氮气,将体系降温至0℃,再将伯吉斯试剂(595mg,2.5mmol)加入体系中,迅速升温至室温。反应20分钟。向反应液中加入20mL饱和碳酸氢钠水溶液淬灭反应,乙酸乙酯萃取(10mL×4)。合并有机相,用无水硫酸钠干燥,过滤,浓缩得到500mg粗品,制备得到4-(甲基-d3)-5'-(甲基-d3)-2'-(丙-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二醇(化合物14)(紫红色固体,30mg,收率9.2%)。
1H NMR(400MHz,Chloroform-d)δ6.28–6.15(m,2H),5.54(d,1H),4.65(p,1H),4.53–4.37(m,1H),3.61–3.46(m,1H),2.45(ddd,1H),2.22(ddt,1H),2.10(q,1H),1.86–1.69(m,2H),1.56(t,3H)。
实施例15
5'-(羟甲基-d2)-4-戊基-2'-(1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二醇(化合物15)
5'-(hydroxymethyl-d2)-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol
第一步:
2'-(2-羟基丙-2-基)-5'-(甲基-d3)-4-戊基-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二酚15a
2'-(2-hydroxypropan-2-yl)-5'-(methyl-d3)-4-pentyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol
将4-(2-羟基丙烷-2-基)-1-(甲基-d3)环己-2-烯-1-醇1d(2.37g,13.7mmol),3,5-二羟基戊苯(3.7g,20.6mmol)和4A分子筛(6g)溶于30mL二氯甲烷中,置换氮气,室温搅拌20分钟。最后加入左旋樟脑磺酸(317.8mg,1.37mmol)。室温搅拌1小时。向反应液中加入60mL饱和碳酸氢钠水溶液淬灭反应,乙酸乙酯萃取(30mL×4)。合并有机相,用无水硫酸钠干燥,过滤,浓缩得到粗品。经硅胶柱层析(洗脱剂:乙酸乙酯/石油醚(v/v)=1/6)纯化,得到标题化合物15a(无色油状物,1.3g,产率:28.5%)。
1H NMR(400MHz,DMSO)δ9.04–8.43(m,2H),6.03(s,2H),4.89(s,1H),3.66(m,2H),2.32(m,3H),2.14–2.06(m,1H),2.02(m,1H),1.88–1.79(m,1H),1.47(m,2H),1.32–1.19(m,5H),0.97(s,3H),0.85(t,3H),0.80(s,3H)。
LC-MS m/z(ESI)=336.20[M+1]
第二步:
5'-(甲基-d3)-4-戊基-2'-(丙-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二酚15b
5'-(methyl-d3)-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol
在0℃下,向反应瓶中依次加入化合物15a(1.3g,3.9mmol)、伯吉斯试剂(1.1g,4.7mmol)和四氢呋喃(10mL),氮气保护下搅拌反应3h;TLC检测至反应结束;加入乙酸乙酯(50mL),有机相用饱和食盐水(40mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品,经硅胶柱层析(洗脱剂:乙酸乙酯/石油醚(v/v)=1/15)纯化,得到标题化合物15b(无色油状物,794mg,产率:64.0%)
1H NMR(400MHz,DMSO)δ8.65(s,2H),6.01(s,2H),5.08(s,1H),4.49(d,1H),4.43–4.37(d,1H),3.85–3.78(m,1H),3.08–2.98(m,1H),2.32–2.26(m,2H),2.13–2.04(m,1H),1.95–1.87(m,1H),1.71–1.63(m,1H),1.58(s,3H),1.47(m,2H),1.35–1.22(m,5H),0.86(t,3H)。
LC-MS m/z(ESI)=318.20[M+1]。
第三步
5'-(羟甲基-d2)-4-戊基-2'-(1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二醇(化合物15)
5'-(hydroxymethyl-d2)-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol
将N-羟基邻苯二甲酰亚胺(0.5mmol)和无水t-BuOOH(1.5mmol)添加到15b(2.5mmol)和N-Bu4NI(0.05mml)的混合物中。在密封的空气气氛下,在75℃下搅拌反应混合物1小时。加入饱和Na2S2O8(10mL)使反应淬灭,用乙酸乙酯(3×30ml)萃取混合物。用盐水(20毫升)洗涤合并有机层,用无水硫酸钠干燥,在真空下去除溶剂。在室温下,缓慢地将HCl(1.5mL)放入装有上述混合物(140mg,0.5mmol)和锌粉(325mg,10mmol)于甲醇(3mL)中的烧瓶中。在室温下搅拌反应混合物20分钟。通过硅藻土过滤反应混合物,在真空下去除溶剂,用水稀释残留物,用EA(3×15mL)萃取。合并有机相,硫酸钠干燥。真空浓缩,然后用PE/EA硅胶柱纯化,得到化合物15(白色固体,51mg,31%)。
LC-MS m/z(ESI)=333.2[M+1]。
实施例22
2'-异丙基-5'-(甲基-d3)-4-戊基-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二醇(化合物22)
2'-isopropyl-5'-(methyl-d3)-4-pentyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol
在10psi下将15b(0.544g,1.73mmol)溶于乙酸乙酯(10ml)中,铂(0.021g)在10psi下氢化30min。使用石油醚和乙醚作为洗脱剂,通过硅胶色谱纯化混合物,得到化合物22(白色固体,534mg,98%)。
LC-MS m/z(ESI)=320.3[M+1]。
实施例24
2’,6'-二甲氧基-5-(甲基-d3)-4'-戊基-2-(丙基-1-烯-2-基)-1,2,3,4-四氢-1,1'-联苯(化合物24)
2',6'-dimethoxy-5-(methyl-d3)-4'-pentyl-2-(prop-1-en-2-yl)-1,2,3,4-tetrahydro-1,1'-biphenyl
将15b(1mmol)溶于DMF(55ml)中,向反应混合物中添加K2CO3(5mmol)和CH3I(3.6mmol),在室温下搅拌4小时。用薄层色谱法(10%乙醚/轻石油醚)监测反应,直到原料消失。向反应混合物中加入200ml水,用乙醚萃取溶液,用盐水冲洗有机相至中性pH,硫酸钠干燥,减压除去溶剂柱层析分离。得到化合物24(白色固体,342mg,99%)。
LC-MS m/z(ESI)=346.3[M+1]。
以下中间体按照表格中标注方法合成
以下化合物按照表格中标注方法合成
大鼠药代动力学
取健康成年SD大鼠3只(3只),禁食过夜(自由饮水)后,分别给予灌胃(p.o.,50mg/kg)给药,于给药后15min、30min、1h、2h、4h、6h、8h、24h从颈静脉丛采血0.1mL。所有血样使用K2EDTA抗凝,随后5℃,3500rpm离心10min分离血浆,于-20℃保存待测。建立LC/MS/MS法测定血浆中的原形药物浓度。测得化合物口服(p.o.)后在大鼠体内的药代动力学参数如下:
实验结果表明,本发明化合物口服给予大鼠后,其比CBD表现出更优的药代动力学特征,并且具有更好的口服生物利用度。
本发明说明书对具体实施方案进行了详细描述,本领域技术人员应认识到,上述实施方案是示例性的,不能理解为对本发明的限制,对于本领域技术人员来说,在不脱离本发明原理的前提下,通过对本发明进行若干改进和修饰,这些改进和修饰获得技术方案也落在本发明的权利要求书的保护范围内。
Claims (7)
1.通式(I)所示的化合物,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共晶:
其中,
R0选自甲基、C3-8碳环基、-CH2OH、-C(=O)OC1-6烷基、-C(=O)NRb1Rb2或者羧基,且R0至少一个氢原子被氘原子取代,且当R0选自-CD2H或者-CD3时,R不是-(CH2)4CH3;
X选自氢、氘、羟基、C1-6烷基或者卤素;
R1选自C1-6烷基、C3-8碳环基或者C2-6烯基,所述的C1-6烷基、C2-6烯基、C3-8碳环基任选进一步被1至3个选自卤素、羟基、C3-8碳环基或者C1-6烷基的取代基所取代,R1任选被1个或者多个氘原子取代;
R2、R3各自独立地选自氢、羟基或者C1-6烷氧基,R2、R3各自独立地任选被1个或者多个氘原子取代,且其中R2、R3中的至少有一个不为H;
r选自0、1、2或者3;
n选自0、1或者2;
Y选自氢、羧基、C1-6烷基或者卤素,Y任选被1个或者多个氘原子取代;
R选自C1-12烷基、C1-12杂烷基、C2-12烯基、C2-12炔基、C3-12碳环基、C3-12杂环基、-C1-6亚烷基-C3-12碳环基、-C1-6亚烷基-C3-12杂环基、-NRb1Rb2、-C1-6亚烷基-C(=O)OC1-6烷基或者-C1-6亚烷基-C(=O)NRb1Rb2,且所述的C1-12烷基、C1-12杂烷基、C2-12烯基、C2-12炔基、C1-6亚烷基、C3-12碳环基、C3-12杂环基任选被1个或者多个选自羟基、羧基、卤素、氰基、=O、C1-6烷基、-NRb1Rb2、C3-12碳环基、C3-12杂环基、C2-6烯基、C2-6炔基、-C(=O)OC1-6烷基、-C(=O)C1-6烷基、-C(=O)NRb1Rb2、-S(=O)C1-6烷基或者-S(=O)2C1-6烷基的取代基所取代,且作为取代基的所述的C1-6烷基、C3-12碳环基、C3-12杂环基任选进一步被1个或者多个选自=O、羟基、羧基、卤素、氰基、-C(=O)OC1-6烷基或者-C(=O)C1-6烷基的取代基所取代,R任选被1个或者多个氘原子取代;
Rb1、Rb2各自独立地选自H、C1-6烷基、C3-12碳环基、C3-12杂环基、-C(=O)Rb3、-C(=O)NRb4Rb5,其中所述的C1-6烷基、C3-12碳环基、C3-12杂环基任选进一步被1个或者多个选自羟基、氘、卤素、C1-6烷基、C1-6烷氧基、C6-12芳基、C5-12杂芳基、C3-12环烷基或者C3-12杂环烷基的取代基所取代;或者Rb4与Rb5及N原子形成一个3至12元杂环,所述的杂环包含1个或者多个选自N、O或者S的杂原子,Rb1、Rb2任选被1个或者多个氘原子取代;
Rb3选自C1-6烷基、C1-6烷氧基或者C6-12芳基,Rb3任选被1个或者多个氘原子取代;
Rb4、Rb5选自H或者C1-6烷基,Rb4、Rb5任选被1个或者多个氘原子取代;
5.药物组合物,所述药物组合物包含:
(1)权利要求1至3中任一项所述的化合物或其立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或者前药;
(2)任选的一种或者多种其他活性成分;以及
(3)药学上可接受的载体和/或赋形剂。
6.根据权利要求5的药物组合物,其特征在于,所述的其他活性成分选自银杏内酯、抗肿瘤剂、抗凝血剂、抗癫痫剂、抗抑郁剂、抗焦虑剂、催眠剂、镇痛剂或者麻醉剂中的一种或多种,或者所述的其他活性成分的立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶;优选地,所述银杏内酯为银杏内酯A、银杏内酯B、银杏内酯C、银杏内酯D、银杏内酯J、银杏内酯M、银杏内酯K、银杏内酯L、银杏内酯N、银杏内酯P、银杏内酯Q、白果内酯中的一种或任意两种及以上以任意比例的组合。
7.如权利要求1或2中任一项所述的化合物或其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶或者权利要求5或6所述的药物组合物在制备用于治疗创伤后应激障碍、面瘫、中风、偏头痛、冠心病稳定型心绞痛、脑梗塞、血栓栓塞、心肌梗塞、心脏缺血、冠状动脉疾病、高血压、脑缺血、改善性功能、痉挛、急性和慢性疼痛、纤维肌痛、术后疼痛、丛集性头痛、紧张性头痛、背疼、四肢痛、腰痛、颈部疼痛、神经性疼痛、癌痛、三叉神经痛、关节炎疼痛、炎性疼痛、Dravet综合征、Lennox-Gastaut综合征、Prader-Willi综合征、Sturge-Weber综合征、脆性X综合征、焦虑、双相情感障碍、自闭症、广泛性焦虑症、社交焦虑症、癫痫、帕金森氏病、阿尔茨海默氏病、亨廷顿氏病、阿片类药物滥用、酗酒、尼古丁成瘾、厌食症、恶病质、化疗相关恶心呕吐、术后恶心和呕吐、肌萎缩性侧索硬化症(ALS)、Friedreich共济失调、精神分裂症、强迫症、多发性硬化症、抑郁、睡眠障碍、多发性硬化引起的痉挛、肌张力障碍、睡眠呼吸暂停、麻痹性痴呆、记忆力减退或者胶质母细胞瘤的药物中的用途。
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