CN109627199B - 一种光学活性黄皮酰胺酮衍生物及其应用 - Google Patents

一种光学活性黄皮酰胺酮衍生物及其应用 Download PDF

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CN109627199B
CN109627199B CN201811420164.4A CN201811420164A CN109627199B CN 109627199 B CN109627199 B CN 109627199B CN 201811420164 A CN201811420164 A CN 201811420164A CN 109627199 B CN109627199 B CN 109627199B
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林汉森
庞涛
米俊儒
徐亚洲
许敬梓
罗旭娜
方成乔
张陆勇
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Abstract

本发明公开了一种光学活性黄皮酰胺酮衍生物及其应用。所述化合物的结构如式(Ⅰ)所示;其中,所述R为C1~C4烷烃基、C2~C4烯烃基、C2~C4炔烃基或‑COR1;所述R1选自C1~C4取代或非取代烷烃基、C1~C4取代或非取代烯烃基、取代或非取代苯基或杂环芳香环;所述R1中的取代基为苯基、卤代苯基、C1~C4烷基取代苯基、C1~C4烷卤基取代苯基、萘氧基、吡啶或噻吩。本发明所述化合物结构新颖,对谷氨酸诱导的小脑颗粒神经细胞损伤以及脑部缺血造成的神经细胞或组织损害具有较好的保护作用,可作为神经细胞保护剂,减轻谷氨酸或氧糖剥夺对神经细胞造成的损伤,从而预防和/或治疗由此引发的神经退行性疾病,如脑中风、外伤性脑损伤、老年性痴呆症等疾病。

Description

一种光学活性黄皮酰胺酮衍生物及其应用
技术领域
本发明涉及生物医药技术领域,更具体地,涉及一种光学活性黄皮酰胺酮衍生物及其应用。
背景技术
谷氨酸是中枢神经系统中主要的兴奋性神经递质,参与多种生理功能,比如快速突触传递,神经元可塑性,学习和记忆等。过量的谷氨酸会激活N-甲基-D-天冬氨酸受体(N-methyl-D-aspartate receptor,NMDAR),导致过多的Ca2+流入,造成线粒体功能损伤,活性氧(reactive oxygen species,ROS)快速增多,发生神经毒性,最终引起神经元细胞死亡。谷氨酸过多引起的神经细胞损伤机制在多种脑疾病的发生发展中起着重要的作用,比如神经退行性疾病,尤其是脑中风、外伤性脑损伤、老年性痴呆症等疾病。
缺血性卒中是由于脑血管狭窄或阻塞,引起脑组织供氧及能量代谢障碍,同样会导致神经细胞或组织受到损伤,出现局灶性神经系统症状和体征的临床综合症。
黄皮酰胺类化合物是从我国南方民间中草药黄皮[Clausena Lansium(Lour)skeelsJ]的叶、茎、果实中提取得到的具有生理活性的一类酰胺类化合物。目前已报道黄皮酰胺类化合物具有促智作用,对记忆障碍具有改善作用,能显著改善学习和记忆;而且能够显著增加基础突触传递和诱导突触长时程增强(long termpotentiation,LTP),已有部分化合物作为抗老年性痴呆症(AD)新药进行研究和引用。如专利CN200310123875.2中记载的黄皮酰胺光学活性异构体具有一定的促智和抗衰老作用。
但目前黄皮酰胺类化合物在抗AD、帕金森病、脑中风、外伤性脑损伤等疾病中的研究和应用仍存在较大的研究空白,对症的化合物结构或类型没有针对性的研究成果,有待进一步的研究和开发。
发明内容
本发明的目的在于提供一种光学活性黄皮酰胺酮衍生物。本发明所述化合物结构新颖,对谷氨酸诱导的小脑颗粒神经细胞损伤具有较好的保护作用,可作为谷氨酸损伤抑制剂,保护神经细胞免受谷氨酸的损伤;同时,所述化合物还具有保护神经组织或细胞免受或少受脑部缺氧造成的损害,可作为神经细胞保护剂,预防和/或治疗由脑组织供氧及能量代谢障碍造成神经细胞损伤疾病。
本发明的另一目的在于提供所述光学活性黄皮酰胺酮衍生物在制备治疗和/或预防神经退行性疾病药物中的应用。
本发明的再一目的在于提供所述光学活性黄皮酰胺酮衍生物作为神经保护剂的应用。
本发明的上述目的是通过以下方案予以实现的:
一种光学活性黄皮酰胺酮衍生物,所述化合物的结构如式(Ⅰ)所示:
Figure BDA0001880391130000021
其中,所述R为C1~C4烷烃基、C2~C4烯烃基、C2~C4炔烃基或-COR1;所述R1选自C1~C4取代或非取代烷烃基、C1~C4取代或非取代烯烃基、取代或非取代苯基或杂环芳香环;所述R1中的取代基为苯基、卤代苯基、C1~C4烷基取代苯基、C1~C4烷卤基取代苯基、萘氧基、吡啶或噻吩。
优选地,所述化合物的结构如式(Ⅱ)或如式(Ⅲ)所示:
Figure BDA0001880391130000022
其中,式(Ⅱ)或式(Ⅲ)中R各自独立地为C1~C4烷烃基、C2~C4烯烃基、C2~C4炔烃基或-COR1;所述R1选自C1~C4取代或非取代烷烃基、C1~C4取代或非取代烯烃基、取代或非取代苯基或杂环芳香环;所述R1中的取代基为苯基、卤代苯基、C1~C4烷基取代苯基、C1~C4烷卤基取代苯基、萘氧基、吡啶或噻吩。
优选地,所述式(Ⅱ)或式(Ⅲ)中R各自独立地为C1~C2烷烃基、C2~C3烯烃基、C2~C3炔烃基或-COR1;所述R1选自C1~C2取代或非取代烷烃基、C2~C3取代或非取代烯烃基、取代或非取代苯基或杂环芳香环;所述R1中的取代基为苯基、卤代苯基、C1~C2烷基取代苯基、C1~C2烷卤基取代苯基、萘氧基、吡啶或噻吩。
优选地,所述式(Ⅱ)或式(Ⅲ)中R各自独立地为甲基、乙基、丙烯基、丙炔基或-COR1;所述R1选自甲基、乙基、卤代甲基、卤代乙基、乙烯基、3-吡啶乙烯基、苯基、卤代苯基、卤甲基取代苯基、苯甲基、卤代苯甲基、卤甲基取代苯甲基、萘氧基或3-甲基噻吩;所述杂环芳香环为吡嗪。
优选地,所述式(Ⅱ)或式(Ⅲ)中R各自独立地为甲基、乙基、-CH2CH=CH2、-CH2C≡CH、
Figure BDA0001880391130000031
Figure BDA0001880391130000032
中的一种。
优选地,所述式(Ⅱ)或式(Ⅲ)中R各自独立地为
Figure BDA0001880391130000033
Figure BDA0001880391130000034
中的一种。
本发明同时还保护所述光学活性黄皮酰胺酮衍生物的制备方法,包括以下步骤:
S1.外消旋环氧肉桂酸((±)-β-苯基缩水甘油酸)的合成和拆分:以反式肉桂酸为原料制备(±)-β-苯基缩水甘油酸,然后分别用(R)-(+)-α-甲基苄胺(R-PEA)和(S)-(-)-α-甲基苄胺(S-PEA)拆分,得到(+)-(2S,3R)-环氧肉桂酸-(R)-α-甲基苄胺盐-2(即(+)-(2S,3R)-2)和(-)-(2R,3S)-环氧肉桂酸-(S)-α-甲基苄胺盐-2(即(-)-(2R,3S)-2);
反应过程示意如下:
Figure BDA0001880391130000035
S2.(+)-N-甲基-N-苯甲酰甲基-α,β-环氧-β-苯基丙酰胺(即(+)-(2S,3R)-1)和(-)-N-甲基-N-苯甲酰甲基-α,β-环氧-β-苯基丙酰胺(即(-)-(2R,3S)-1)的分别合成:
将(+)-(2S,3R)-环氧肉桂酸-(R)-α-甲基苄胺盐-2溶于无水有机溶剂中,然后在冰浴条件下,向其中加入二环己基碳二亚胺、三乙胺、2-(甲基氨基)-1-苯基-1-乙酮进行反应,待反应结束后萃取,分离有机层并洗涤和干燥得中间体(+)-(2S,3R)-1或(-)-(2R,3S)-1;反应过程示意如下:
Figure BDA0001880391130000041
将(-)-(2R,3S)-环氧肉桂酸-(S)-α-甲基苄胺盐-2(即(-)-(2R,3S)-2)参照中间体(+)-(2S,3R)-1的合成过程合成得到中间体(-)-(2R,3S)-1;
反应过程示意如下:
Figure BDA0001880391130000042
S3.(-)-黄皮酰胺酮和(+)-黄皮酰胺酮的分别合成:
将中间体(+)-(2S,3R)-1与氢氧化锂水溶液反应,反应结束后过滤,得白色固体,经重结晶得(-)-黄皮酰胺酮;
反应过程示意如下:
Figure BDA0001880391130000043
以中间体(-)-(2R,3S)-1为原料参照(-)-黄皮酰胺酮的合成过程合成得到(+)-黄皮酰胺酮;
反应过程示意如下:
Figure BDA0001880391130000051
S4.将(-)-黄皮酰胺酮或(+)-黄皮酰胺酮,和二环己基碳二亚胺、4-二甲氨基吡啶混溶于溶剂中,并加入羧酸化合物反应,待反应结束后分离、纯化即可得到光学活性黄皮酰胺酮衍生物(即(-)或(+)黄皮酰胺酮3-羟基羧酸酯类衍生物);
或,将(-)-黄皮酰胺酮或(+)-黄皮酰胺酮,和三乙胺混溶于溶剂中,并加入卤代烃反应,待反应结束后分离、纯化即可得到光学活性黄皮酰胺酮衍生物(即(-)或(+)黄皮酰胺酮3-羟基醚类衍生物)。
本发明提供的合成方法与现有技术中文献报道的相关合成方法缩短了反应步骤,各步反应均不需要进行柱层析分离,各步反应产物均可以通过重结晶方法进行分离纯化,而且不需要用到易燃易爆的金属钠,因此本发明整个合成方法更为高效、条件更为温和。
本发明合成方法利用对外消旋环氧肉桂酸进行拆分,得到最终产物(-)-黄皮酰胺酮或(+)-黄皮酰胺酮的光学纯度(即ee值)达到99.5%以上,其纯度明显高于现有技术文献的报道的合成方法所得的纯度。
本发明合成方法所用的起始原料外消旋反式肉桂酸的成本低廉,降低了目标产物的制造成本,所用到的溶剂均属于第三类有机溶剂(即属于对人体低毒或无毒的溶剂,是原料药生产过程允许使用的有机溶剂),因此本发明所述方法成本很低,对人体、对环境影响都很小,非常适合于工业化生产。
整个制备方法中制备(-)-黄皮酰胺酮和(+)-黄皮酰胺酮的过程示意如下:
Figure BDA0001880391130000061
优选地,步骤S1的具体过程为:反式肉桂酸与碳酸氢钠混溶于溶剂中,加入过硫酸氢钾水溶液进行反应;反应结束后滤去不溶盐类,去除水分;加入(R)-(+)-α-甲基苄胺(R-PEA),析出固体,过滤得(+)-(2S,3R)-环氧肉桂酸-(R)-α-甲基苄胺盐-2(即(+)-(2S,3R)-2);过滤后的滤液中加入另一异构体(S)-(-)-α-甲基苄胺(S-PEA),析出固体,过滤得(-)-(2R,3S)-环氧肉桂酸-(S)-α-甲基苄胺盐-2(即(-)-(2R,3S)-2)。
优选地,步骤S1所述反式肉桂酸与碳酸氢钠混溶于溶剂的过程中,保持温度在0~20℃。
优选地,步骤S1所述在加入过硫酸氢钾水溶液后,保持温度低于20℃进行反应。
优选地,步骤S2中将(+)-(2S,3R)-环氧肉桂酸-(R)-α-甲基苄胺盐-2溶于无水有机溶剂的过程为:将(+)-(2S,3R)-环氧肉桂酸-(R)-α-甲基苄胺盐-2先溶于水和有机溶剂中,调解为弱酸性,分层后分离有机层,并洗涤、干燥有机层。
优选地,步骤S2所述调节弱酸性为pH值为5~6;进一步优选地,步骤S2所述调节弱酸性采用盐酸。
优选地,步骤S2中所述有机溶剂为丙酮、二氯甲烷、丙二醇、甘油、乙醚或石油醚等。
优选地,步骤S2中将(+)-(2S,3R)-环氧肉桂酸-(R)-α-甲基苄胺盐-2或(-)-(2R,3S)-环氧肉桂酸-(S)-α-甲基苄胺盐-2溶于无水有机溶剂的过程中,分离有机层的过程为:反应液分离有机层,然后水相中加入二氯甲烷萃取,并萃取三次后合并有机层,用饱和氯化钠洗涤,无水硫酸钠干燥。
优选地,步骤S2中反应结束后,萃取和分离有机层的过程为:反应液加水萃取,分出有机层,依次用饱和碳酸氢钠溶液、饱和氯化钠溶液洗涤有机层,并用无水硫酸钠干燥有机层。
优选地,步骤S2整个反应在冰浴条件下进行。
更优选地,步骤S2的具体过程如下:
(1)将(+)-(2S,3R)-环氧肉桂酸-(R)-α-甲基苄胺盐-2或(-)-(2R,3S)-环氧肉桂酸-(S)-α-甲基苄胺盐-2溶于蒸馏水和二氯甲烷的混合溶剂中;然后在冰浴条件下下用1MHCl调节pH为5~6,分出有机层,水层用二氯甲烷萃取三次,合并有机层,用饱和氯化钠洗涤,无水硫酸钠干燥;
(2)滤除干燥剂后,冰浴冷却下向滤液加入二环己基碳二亚胺(DCC)、三乙胺,搅拌下将加入2-(甲基胺基)-1-苯基-1-乙酮进行反应,待反应结束后,加入蒸馏水搅拌,分出有机层,依次用饱和碳酸氢钠溶液,饱和氯化钠溶液洗涤,无水硫酸钠干燥,滤除干燥剂后旋除溶剂,即得中间体(+)-(2S,3R)-1或中间体(-)-(2R,3S)-1。
优选地,步骤S2中(+)-(2S,3R)-环氧肉桂酸-(R)-α-甲基苄胺盐-2或(-)-(2R,3S)-环氧肉桂酸-(S)-α-甲基苄胺盐-2,和二环己基碳二亚胺、三乙胺、2-(甲基氨基)-1-苯基-1-乙酮的摩尔比为0.1~1.5:0.3~2.1:0.8~3.5:0.2~1.8。
更优选地,步骤S2中(+)-(2S,3R)-环氧肉桂酸-(R)-α-甲基苄胺-2或(-)-(2R,3S)-环氧肉桂酸-(S)-α-甲基苄胺盐-2,和二环己基碳二亚胺、三乙胺、2-(甲基氨基)-1-苯基-1-乙酮的摩尔比为0.2~1.0:0.4~1.5:0.8~2.0:0.3~1.2。
优选地,步骤S3所述重结晶采用甲醇或乙醇,进一步优选地,所述乙醇采用体积比浓度为95%的乙醇。
优选地,步骤S3的具体过程如下:将中间体(+)-(2S,3R)-1或(-)-(2R,3S)-1加入溶有LiOH·H2O的蒸馏水中,室温搅拌进行反应,反应过程中采用TLC(乙酸乙酯:石油醚=2:1)进行监测,待反应完全后,反应液静置,过滤,得到白色固体干燥后,用乙酸乙酯进行重结晶,即可得到(-)-黄皮酰胺酮。
优选地,步骤S3中中间体(+)-(2S,3R)-1或中间体(-)-(2R,3S)-1与氢氧化锂的反应摩尔比为:0.5~1.5:0.8~3.0。
优选地,步骤S3中中间体(+)-(2S,3R)-1或中间体(-)-(2R,3S)-1与氢氧化锂的反应摩尔比为:0.8~1.3:0.9~3.0。
优选地,步骤S4中所述(-)-黄皮酰胺酮或(+)-黄皮酰胺酮,和二环己基碳二亚胺、4-二甲氨基吡啶、羧酸化合物的反应摩尔比为1~3:3~10:0.1~0.9:3~10。
更优选地,步骤S4中所述(-)-黄皮酰胺酮或(+)-黄皮酰胺酮,和二环己基碳二亚胺、4-二甲氨基吡啶、羧酸化合物的反应摩尔比为1~2:3~6:0.2~0.7:4~8。
优选地,步骤S4中所述(-)-黄皮酰胺酮或(+)-黄皮酰胺酮,和三乙胺、卤代烃的反应摩尔比为1~2.5:3~6.5:4~12。
更优选地,步骤S4中所述(-)-黄皮酰胺酮或(+)-黄皮酰胺酮,和三乙胺、卤代烃的反应摩尔比为1~2.0:3~5.5:6~12。
所述光学活性黄皮酰胺酮衍生物在制备治疗和/或预防神经退行性疾病药物中的应用也在本发明的保护范围内。
优选地,所述应用是应用于制备治疗和/或预防脑中风、外伤性脑损伤或老年性痴呆症药物中的应用。
本发明同时还保护光学活性黄皮酰胺酮衍生物作为神经保护剂的应用。
优选地,所述应用为作为谷氨酸损伤抑制剂或脑部缺氧损伤抑制剂的应用。
与现有技术相比,本发明具有以下有益效果:
(1)本发明所述化合物结构新颖,且对谷氨酸诱导的小脑颗粒神经细胞损伤具有较好的保护作用,可作为谷氨酸损伤抑制剂,保护神经细胞免受谷氨酸的损伤;同时所述化合物还具有减轻脑缺血对神经细胞或组织造成的损害,可作为神经细胞保护剂,减轻氧糖剥夺对神经细胞造成的损伤;本发明所述化合物可制备成为神经细胞保护剂,减轻由于脑组织供氧或能量代谢障碍造成的神经细胞损伤或谷氨酸诱导的神经细胞损伤,从而预防和/或治疗由上述原因导致的神经退行性疾病,如脑中风、外伤性脑损伤、老年性痴呆症等疾病。
(2)本发明所述化合物的制备方法过程简单、成本低廉,中间产物和目标产物分离简单,采用的溶剂安全,而且目标产物的光学纯度超过99.5%,适用于工业大规模化生产。
具体实施方式
下面结合具体实施例对本发明做出进一步地详细阐述,所述实施例只用于解释本发明,并非用于限定本发明的范围。下述实施例中所使用的试验方法如无特殊说明,均为常规方法;所使用的材料、试剂等,如无特殊说明,为可从商业途径得到的试剂和材料。
实施例1(-)-黄皮酰胺酮或(+)-黄皮酰胺酮的制备
(-)-黄皮酰胺酮或(+)-黄皮酰胺酮的制备过程如下:
1、外消旋环氧肉桂酸((±)-β-苯基缩水甘油酸)的合成和拆分:
Figure BDA0001880391130000091
①外消旋环氧肉桂酸((±)-β-苯基缩水甘油酸)的合成
称取148.20g反式肉桂酸,溶于650mL丙酮,搅拌下加入380.0g碳酸氢钠,用冰浴冷却至0~20℃,加入650mL水,再加入620.0g过硫酸氢钾的1250mL水溶液,保持温度低于20℃,反应3h后,滤去不溶盐类,滤液加入1.0L乙酸乙酯搅拌,用浓盐酸调节pH为5~6,分离出有机层,水层用3×500mL乙酸乙酯萃取,合并有机层,用1L蒸馏水、1L饱和氯化钠溶液洗涤,无水硫酸钠干燥,滤除干燥剂后浓缩至约750mL,直接用于下一步拆分反应。
②外消旋环氧肉桂酸((±)-β-苯基缩水甘油酸)的拆分
将121.18g(R)-(+)-α-甲基苄胺(R-PEA)加到上步得到的750mL液体中,出现大量白色固体,过滤,干燥得白色固体116.91g,用无水乙醇重结晶得白色针状晶体(+)-(2S,3R)-环氧肉桂酸-(R)-α-甲基苄胺化合物104.08g,收率:36.5%(理论收率50%);m.p159.3-160.5℃;
Figure BDA0001880391130000092
(c 1,EtOH);1H NMR(300MHz,Chloroform-d)δ7.50–7.15(m,10H),4.33(q,J=6.8Hz,1H),3.61(d,J=2.0Hz,1H),3.23(d,J=2.0Hz,1H),1.60(d,J=6.8Hz,3H)。
向滤液中加入60.59g(S)-(-)-α-甲基苄胺(S-PEA),室温下搅拌,反应液出现大量白色固体,静置后过滤,干燥得白色固体118.76g,用无水乙醇重结晶得白色针状晶体(-)-(2R,3S)-环氧肉桂酸-(S)-α-甲基苄胺化合物101.23g,收率:35.4%(理论收率50%);m.p159.9-161.0℃;
Figure BDA0001880391130000093
(c 1,EtOH);1H NMR(300MHz,Chloroform-d)δ7.49–7.15(m,9H),4.32(q,J=6.8Hz,1H),3.62(d,J=1.9Hz,1H),3.23(d,J=1.9Hz,1H),1.59(d,J=6.8Hz,3H)。
2、(+)-N-甲基-N-苯甲酰甲基-α,β-环氧-β-苯基丙酰胺(中间体(+)-(2S,3R)-1)
Figure BDA0001880391130000101
(1)114.06g(+)-(2S,3R)-环氧肉桂酸-(R)-α-甲基苄胺盐,溶于1.2L蒸馏水,加入1.0L二氯甲烷;冰浴下用1M HCl调节pH为5~6,分出有机层,水层用3×500mL二氯甲烷萃取,合并有机层,用500mL饱和氯化钠洗涤,无水硫酸钠干燥。
(2)滤除干燥剂后,冰浴冷却下向滤液加入84.36g二环己基碳二亚胺(DCC)、101.2g三乙胺,搅拌下将加入74.02g 2-(甲基胺基)-1-苯基-1-乙酮,反应5h后,加入1.5L蒸馏水搅拌,分出有机层,依次用500mL饱和碳酸氢钠溶液,500mL饱和氯化钠溶液洗涤,无水硫酸钠干燥,滤除干燥剂后旋除溶剂,得一浅黄色油状物(中间体(+)-(2S,3R)-1);
Figure BDA0001880391130000103
(c 1,CH3OH);HPLC分析:The enantiomeric excess was determined to be99.9%by HPLC with a Daicel Chiralcel AD-H column(4.6mm×25cm)(n-hexane/i-PrOH=85/15,λ=254nm,1mL/min),t=28.0min。)
3、(-)-黄皮酰胺酮的合成
Figure BDA0001880391130000102
向上述所得浅黄色油状物(中间体(+)-(2S,3R)-1)加入溶有16.80g LiOH·H2O的1.5L蒸馏水中,室温搅拌,TLC监测(乙酸乙酯:石油醚Ⅱ=2:1),反应完全后,静置,过滤,所得类白色固体干燥后,乙酸乙酯多次重结晶,得白色晶体(-)-黄皮酰胺酮:42.672g,
Figure BDA0001880391130000104
(c 0.5,CH3OH);m.p 196.6-198.4℃,收率:35.3%(理论收率50%);1H NMR(500MHz,Chloroform-d)δ7.56–7.50(m,2H),7.41(ddt,J=8.7,7.3,1.3Hz,1H),7.30–7.20(m,2H),7.14–7.09(m,2H),7.09–7.02(m,2H),7.04–6.97(m,1H),5.40(d,J=8.9Hz,1H),4.95–4.89(m,1H),3.87(t,J=9.4Hz,1H),3.55(d,J=2.7Hz,1H),2.89(s,3H).;13C NMR(126MHz,CDCl3)δ197.47,175.25,136.52,134.36,133.70,128.77,128.71,128.53,128.33,128.06,72.11,65.15,51.58,29.80;HRMS(ESI):m/z[M+1]+Calculated296.1281Found 296.1283;The enantiomeric excess was determined to be99.9%by HPLC with a Daicel Chiralcel OJ-H column(4.6mm×25cm)(n-hexane/i-PrOH=90/10,λ=254nm,1mL/min),t=20.7min。
4、(-)-N-甲基-N-苯甲酰甲基-α,β-环氧-β-苯基丙酰胺(中间体(-)-(2R,3S)-1)
过程同步骤2,不同之处在于用(-)-(2R,3S)-环氧肉桂酸-(S)-α-甲基苄胺盐替代(+)-(2S,3R)-环氧肉桂酸-(R)-α-甲基苄胺盐进行反应,得到中间体(-)-(2R,3S)-1。
5、(+)-黄皮酰胺酮的合成
过程同步骤3,不同之处在于用中间体2替代中间体(+)-(2S,3R)-1,得到(+)-黄皮酰胺酮。
实施例2化合物(+)-58和(-)-58的制备
1、(-)-58的制备:
Figure BDA0001880391130000111
称量0.590g(2mmol)(-)-黄皮酰胺酮、1.150g(6mmol)DCC(二环己基碳二亚胺)和0.049g(0.4mmol)DMAP(4-二甲氨基吡啶)溶于50mL二氯甲烷,室温搅拌下加入6mmol对三氟甲基苯甲酸,TLC监测(EA:PE=2:1),反应完全后,依次用30mL 1M HCl、30mL饱和碳酸氢钠和30mL饱和氯化钠溶液洗涤,无水硫酸钠干燥,滤除干燥剂,旋除溶剂得粗品,经柱层析,甲醇重结晶得化合物(-)-58,白色晶体;yield:0.748g(80.1%);m.p.131.5-132.0℃;
Figure BDA0001880391130000112
(c 0.2,CH3OH);1H NMR(500MHz,Chloroform-d)δ8.18–8.13(m,2H),7.70–7.64(m,2H),7.59–7.53(m,2H),7.48–7.41(m,1H),7.32–7.23(m,2H),7.21–7.15(m,2H),7.13–7.03(m,2H),7.05–6.98(m,1H),6.42(d,J=9.9Hz,1H),5.52(d,J=8.8Hz,1H),4.21(dd,J=10.0,8.8Hz,1H),2.95(s,3H);13C NMR(126MHz,CDCl3)δ197.19,170.61,164.53,136.43,133.86,133.15,132.82,130.63,128.85,128.74,128.60,128.37,128.30,125.54,125.51,122.68,73.27,64.87,49.26,30.04;HRMS(ESI):m/z[M+1]+Calculated 468.1417Found468.1420;The enantiomeric excess was determined to be 99.9%by HPLC with aDaicel Chiralcel OJ-H column(4.6mm×25cm)(n-hexane/i-PrOH=85/15,λ=254nm,1mL/min),t=11.4min。
2、(+)-58的制备:
Figure BDA0001880391130000121
(+)-58的制备过程同(-)-58,不同之处在于采用(+)-黄皮酰胺酮替代(-)-黄皮酰胺酮,制备得到化合物(+)-58,白色晶体;yield:0.758g(81.1%);m.p.130.9-131.5℃;
Figure BDA0001880391130000123
(c 0.2,CH3OH);1H NMR(500MHz,Chloroform-d)δ8.15(dq,J=7.7,0.8Hz,2H),7.73–7.64(m,2H),7.59–7.53(m,2H),7.44(ddt,J=8.7,7.3,1.2Hz,1H),7.30–7.23(m,2H),7.21–7.15(m,2H),7.10–7.03(m,2H),7.05–6.98(m,1H),6.42(d,J=9.9Hz,1H),5.55–5.50(m,1H),4.21(t,J=9.4Hz,1H),2.95(d,J=0.6Hz,3H);13C NMR(126MHz,CDCl3)δ197.20,170.62,164.54,136.42,133.87,133.14,132.81,130.63,128.85,128.74,128.60,128.37,128.30,125.54,125.51,73.26,64.87,49.26,30.04;HRMS(ESI):m/z[M+1]+Calculated 468.1417Found 468.1418;The enantiomeric excess was determined tobe 99.9%by HPLC with a Daicel Chiralcel OJ-H column(4.6mm×25cm)(n-hexane/i-PrOH=85/15,λ=254nm,1mL/min),t=14.6min。
化合物(+)-58-1~(+)-58-12、(-)-58-1~(-)-58-12的制备参照化合物化合物(+)-58和(-)-58的制备,不同之处在于替换相应的羧酸进行反应。
实施例3化合物(+)-58-1和(-)-58-1的制备
(-)-58-1:
Figure BDA0001880391130000122
白色针状晶体;yield:0.508g(75.4%);m.p.176.3-177.1℃;
Figure BDA0001880391130000124
(c 0.2,CH3OH);1H NMR(500MHz,Chloroform-d)δ7.55–7.49(m,2H),7.42(ddt,J=8.7,7.1,1.2Hz,1H),7.31–7.22(m,2H),7.15–7.10(m,2H),7.10–6.98(m,3H),6.18–6.12(m,1H),5.44(d,J=8.8Hz,1H),4.03(dd,J=9.8,8.9Hz,1H),2.90(d,J=0.6Hz,3H),2.09(s,3H);13C NMR(126MHz,Chloroform-d)δ197.17,171.03,169.99,136.46,133.75,133.38,128.78,128.76,128.55,128.26,72.21,64.88,49.16,29.95,21.02;HRMS(ESI):m/z[M+1]+Calculated 338.1387Found 338.1389;The enantiomeric excess was determined tobe 99.9%by HPLC with a Daicel Chiralcel AD-H column(4.6mm×25cm)(n-hexane/i-PrOH=80/20,λ=254nm,1mL/min),t=9.4min。
(+)-58-1:
Figure BDA0001880391130000131
白色针状晶体;yield:0.494g(73.4%);m.p.178.1-179.3℃;
Figure BDA0001880391130000133
(c0.2,CH3OH);1H NMR(500MHz,Chloroform-d)δ7.55–7.49(m,2H),7.46–7.39(m,1H),7.29–7.21(m,2H),7.15–7.09(m,2H),7.09–6.98(m,3H),6.15(dd,J=9.9,0.7Hz,1H),5.44(d,J=8.8Hz,1H),4.03(dd,J=9.9,8.8Hz,1H),2.90(d,J=0.6Hz,3H),2.09(s,3H);13C NMR(126MHz,Chloroform-d)δ197.16,171.02,169.99,136.45,133.75,133.38,128.78,128.76,128.55,128.25,72.21,64.88,49.16,29.96,21.03;HRMS(ESI):m/z[M+1]+Calculated 338.1387Found 338.1391;The enantiomeric excess was determined tobe 99.9%by HPLC with a Daicel Chiralcel AD-H column(4.6mm×25cm)(n-hexane/i-PrOH=80/20,λ=254nm,1mL/min),t=13.9min。
实施例4化合物(+)-58-2和(-)-58-2的制备
(-)-58-2:
Figure BDA0001880391130000132
白色晶体;yield:0.703g(75.2%);m.p.178.1-179.3℃;m.p.155.0-156.2℃;
Figure BDA0001880391130000134
Figure BDA0001880391130000135
(c 0.2,CH3OH);1H NMR(500MHz,Chloroform-d)δ7.91–7.86(m,1H),7.73–7.66(m,1H),7.64–7.53(m,4H),7.48–7.41(m,1H),7.33–7.24(m,2H),7.18–7.12(m,2H),7.11–7.03(m,2H),7.06–6.99(m,1H),6.34(d,J=9.5Hz,1H),5.51(d,J=8.8Hz,1H),4.18(t,J=9.1Hz,1H),2.94(s,3H);13C NMR(126MHz,CDCl3)δ197.06,170.45,165.80,136.44,133.80,133.25,131.93,131.61,131.04,130.49,128.72,128.61,128.28,128.24,126.76,126.72,124.48,73.94,65.07,48.88,30.03.;HRMS(ESI):m/z[M+1]+Calculated 468.1417Found468.1420;The enantiomeric excess was determined to be 99.9%by HPLC with aDaicel Chiralcel OJ-H column(4.6mm×25cm)(n-hexane/i-PrOH=85/15,λ=254nm,1mL/min),t=16.1min。
(+)-58-2:
Figure BDA0001880391130000141
白色晶体;yield:0.706g(75.6%);m.p.153.2-154.3℃;
Figure BDA0001880391130000143
(c 0.2,CH3OH);1H NMR(500MHz,Chloroform-d)δ7.92–7.86(m,1H),7.73–7.66(m,1H),7.64–7.53(m,4H),7.48–7.41(m,1H),7.31–7.24(m,2H),7.18–7.12(m,2H),7.11–7.04(m,2H),7.06–6.99(m,1H),6.34(d,J=9.5Hz,1H),5.51(d,J=8.8Hz,1H),4.18(t,J=9.1Hz,1H),2.95(s,3H);13C NMR(126MHz,Chloroform-d)δ197.05,170.45,165.80,136.43,133.80,133.25,131.93,131.62,131.04,128.72,128.61,128.28,128.24,126.72,73.94,65.07,48.88,30.03;HRMS(ESI):m/z[M+1]+Calculated 468.1417Found 468.1418;The enantiomericexcess was determined to be 99.9%by HPLC with a Daicel Chiralcel OJ-H column(4.6mm×25cm)(n-hexane/i-PrOH=85/15,λ=254nm,1mL/min),t=18.2min。
实施例5化合物(+)-58-3和(-)-58-3的制备
(-)-58-3:
Figure BDA0001880391130000142
白色晶体;yield:0.793g(84.9%);m.p.151.7-152.8℃;
Figure BDA0001880391130000144
(c 0.2,CH3OH);1H NMR(500MHz,Chloroform-d)δ8.30(tt,J=1.8,0.8Hz,1H),8.23(dt,J=7.7,1.5Hz,1H),7.80(ddt,J=7.9,1.8,1.0Hz,1H),7.61–7.52(m,3H),7.48–7.40(m,1H),7.33–7.23(m,2H),7.22–7.16(m,2H),7.10–7.04(m,2H),7.07–6.98(m,1H),6.44(d,J=9.9Hz,1H),5.53(d,J=8.8Hz,1H),4.23(dd,J=9.9,8.8Hz,1H),2.96(s,3H);13C NMR(126MHz,Chloroform-d)δ13CNMR(126MHz,CDCl3)δ197.23,170.61,164.44,136.45,133.85,133.50,133.16,131.34,131.08,130.44,130.00,129.97,129.20,128.85,128.76,128.60,128.36,128.30,127.14,127.11,124.89,122.72,73.21,64.88,49.22,30.03;HRMS(ESI):m/z[M+1]+Calculated 468.1417Found 468.1422;The enantiomeric excess was determined tobe 99.9%by HPLC with a Daicel Chiralcel OJ-H column(4.6mm×25cm)(n-hexane/i-PrOH=90/10,λ=254nm,1mL/min),t=15.2min。
(+)-58-3:
Figure BDA0001880391130000151
白色晶体;yield:0.745g(82.9%);m.p.153.3-154.2℃;
Figure BDA0001880391130000153
(c 0.2,CH3OH);1H NMR(500MHz,Chloroform-d)δ8.30(d,J=1.8Hz,1H),8.26–8.20(m,1H),7.82–7.77(m,1H),7.59–7.52(m,3H),7.48–7.40(m,1H),7.30–7.23(m,2H),7.22–7.16(m,2H),7.10–7.04(m,2H),7.04–6.98(m,1H),6.44(d,J=10.0Hz,1H),5.53(d,J=8.8Hz,1H),4.23(t,J=9.4Hz,1H),2.96(s,3H);13C NMR(126MHz,Chloroform-d)δ197.24,170.62,164.45,136.44,133.86,133.50,133.15,131.33,131.07,130.43,130.01,129.98,129.20,128.85,128.76,128.60,128.36,128.30,127.14,127.11,124.89,122.73,73.20,64.87,49.22,30.04;HRMS(ESI):m/z[M+1]+Calculated 468.1417Found 468.1421;The enantiomericexcess was determined to be 99.9%by HPLC with a Daicel Chiralcel OJ-H column(4.6mm×25cm)(n-hexane/i-PrOH=90/10,λ=254nm,1mL/min),t=17.8min。
实施例6化合物(+)-58-4和(-)-58-4的制备
(-)-58-4:
Figure BDA0001880391130000152
白色晶体;yield:0.801g(82.5%);m.p.107.5-108.0℃;
Figure BDA0001880391130000154
(c 0.2,CH3OH);1H NMR(500MHz,Chloroform-d)δ7.92(dd,J=8.2,1.4Hz,1H),7.87–7.81(m,1H),7.66(dd,J=8.2,6.8Hz,1H),7.59–7.53(m,2H),7.44(ddt,J=8.7,7.1,1.2Hz,1H),7.31–7.23(m,2H),7.21–7.15(m,2H),7.11–7.04(m,2H),7.06–6.99(m,1H),6.46–6.41(m,1H),5.52(d,J=8.8Hz,1H),4.21(dd,J=10.1,8.8Hz,1H),2.95(d,J=0.6Hz,3H);13C NMR(126MHz,Chloroform-d)δ197.15,170.41,163.47,158.64,136.38,135.27,135.21,133.92,132.90,128.90,128.71,128.62,128.46,128.31,127.54,125.81,125.78,123.33,121.16,118.67,118.49,73.47,64.79,49.25,30.05;HRMS(ESI):m/z[M+1]+Calculated486.1323Found 486.138;The enantiomeric excess was determined to be99.9%by HPLC with a Daicel Chiralcel OJ-H column(4.6mm×25cm)(n-hexane/i-PrOH=90/10,λ=254nm,1mL/min),t=17.4min。
(+)-58-4:
Figure BDA0001880391130000161
白色晶体;yield:0.806g(83.1%);m.p.111.5-113.0℃;
Figure BDA0001880391130000163
(c 0.2,CH3OH);1H NMR(500MHz,Chloroform-d)7.91(d,J=8.1Hz,1H),7.86–7.81(m,1H),7.65(t,J=7.5Hz,1H),7.59–7.53(m,2H),7.48–7.41(m,1H),7.30–7.23(m,2H),7.21–7.15(m,2H),7.11–7.05(m,2H),7.05–6.98(m,1H),6.44(d,J=10.1Hz,1H),5.53(d,J=8.8Hz,1H),4.21(dd,J=10.1,8.7Hz,1H),2.95(s,3H);13C NMR(126MHz,Chloroform-d)δ197.18,170.45,163.47,160.68,158.63,136.36,135.27,135.20,133.94,132.87,128.90,128.71,128.63,128.46,128.32,125.81,125.78,123.33,121.15,118.66,118.48,73.45,64.79,49.24,30.05;HRMS(ESI):m/z[M+1]+Calculated 486.1323Found 486.1324;The enantiomericexcess was determined to be 99.9%by HPLC with a Daicel Chiralcel OJ-H column(4.6mm×25cm)(n-hexane/i-PrOH=90/10,λ=254nm,1mL/min),t=20.5min。
实施例7化合物(+)-58-5和(-)-58-5的制备
(-)-58-5:
Figure BDA0001880391130000162
白色晶体;yield:0.743g(89.0%);m.p.174.3-175.0℃;
Figure BDA0001880391130000164
(c 0.2,CH3OH);1H NMR(500MHz,Chloroform-d)δ8.06(ddd,J=8.6,5.5,2.6Hz,2H),7.55(d,J=7.8Hz,2H),7.44(t,J=7.4Hz,1H),7.27(d,J=7.0Hz,2H),7.17(d,J=7.5Hz,2H),7.09(s,1H),7.07(td,J=7.9,7.4,5.5Hz,3H),7.01(dd,J=8.3,6.1Hz,1H),6.36(d,J=9.8Hz,1H),5.52(d,J=8.8Hz,1H),4.19(t,J=9.3Hz,1H),2.95(s,3H);13C NMR(126MHz,Chloroform-d)δ197.21,170.89,164.72,136.48,133.80,133.39,132.89,132.81,128.80,128.78,128.58,128.28,125.81,115.76,115.58,73.03,64.96,49.25,30.03;HRMS(ESI):m/z[M+1]+Calculated 418.1449Found 418.1453;The enantiomeric excess wasdetermined to be99.9%by HPLC with a Daicel Chiralcel OJ-H column(4.6mm×25cm)(n-hexane/i-PrOH=80/20,λ=254nm,1mL/min),t=11.2min。
(+)-58-5:
Figure BDA0001880391130000171
白色晶体;yield:0.727g(87.2%);m.p.178.3-179.4℃;
Figure BDA0001880391130000173
(c 0.2,CH3OH);1H NMR(500MHz,Chloroform-d)δ8.09–8.02(m,2H),7.58–7.52(m,2H),7.47–7.40(m,1H),7.30–7.23(m,2H),7.20–7.14(m,2H),7.13–7.04(m,4H),7.04–6.98(m,1H),6.36(d,J=9.8Hz,1H),5.52(d,J=8.9Hz,1H),4.19(t,J=9.3Hz,1H),2.95(s,3H);13C NMR(126MHz,Chloroform-d)δ197.21,170.89,164.72,136.47,133.80,133.39,132.89,132.81,128.80,128.78,128.58,128.28,125.81,115.76,115.59,73.03,64.96,49.24,30.04;HRMS(ESI):m/z[M+1]+Calculated 418.1449Found 418.1451;The enantiomericexcess was determined to be 99.9%by HPLC with a Daicel Chiralcel OJ-H column(4.6mm×25cm)(n-hexane/i-PrOH=80/20,λ=254nm,1mL/min),t=18.0min。
实施例8化合物(+)-58-6和(-)-58-6的制备
(-)-58-6:
Figure BDA0001880391130000172
白色晶体;yield:0.800g(83.1%);m.p.149.4-150.8℃;
Figure BDA0001880391130000174
(c 0.2,CH3OH);1H NMR(500MHz,Chloroform-d)δ7.54–7.48(m,2H),7.51–7.44(m,1H),7.46–7.33(m,4H),7.31–7.20(m,2H),7.09–6.96(m,5H),6.18(d,J=10.0Hz,1H),5.42(d,J=8.8Hz,1H),3.99(dd,J=10.1,8.8Hz,1H),3.79–3.68(m,2H),2.90(s,3H);13C NMR(126MHz,Chloroform-d)δ1197.11,170.62,169.94,136.37,134.58,133.82,133.03,132.89,130.84,129.16,128.78,128.66,128.57,128.30,128.28,124.21,72.89,64.78,49.16,40.73,29.94;HRMS(ESI):m/z[M+1]+Calculated 482.1574Found 482.1577;Theenantiomeric excess was determined to be 99.9%by HPLC with a DaicelChiralcel AD-H column(4.6mm×25cm)(n-hexane/i-PrOH=80/20,λ=254nm,1mL/min),t=13.3min。
(+)-58-6:
Figure BDA0001880391130000181
白色晶体;yield:0.791g(82.2%);m.p.147.9-149.1℃;
Figure BDA0001880391130000183
(c 0.2,CH3OH);1H NMR(500MHz,Chloroform-d)δ7.54–7.46(m,3H),7.48–7.33(m,4H),7.28–7.21(m,2H),7.09–6.97(m,5H),6.18(dd,J=10.1,0.7Hz,1H),5.41(d,J=8.8Hz,1H),3.98(dd,J=10.1,8.8Hz,1H),3.79–3.68(m,2H),2.90(d,J=0.6Hz,3H);13C NMR(126MHz,Chloroform-d)δ197.07,170.61,169.93,136.37,134.56,133.81,133.03,132.88,129.16,128.78,128.66,128.57,128.30,128.27,124.20,72.91,64.79,49.16,40.74,29.95;HRMS(ESI):m/z[M+1]+Calculated 482.1574Found 482.1578;The enantiomeric excess wasdetermined to be 99.9%by HPLC with a Daicel Chiralcel AD-H column(4.6mm×25cm)(n-hexane/i-PrOH=80/20,λ=254nm,1mL/min),t=16.1min。
实施例9化合物(+)-58-7和(-)-58-7的制备
(-)-58-7:
Figure BDA0001880391130000182
白色晶体;yield:0.595g(72.1%);m.p.200.7-202.1℃;
Figure BDA0001880391130000184
(c 0.2,CH3OH);1H NMR(500MHz,Chloroform-d)δ7.95–7.90(m,2H),7.60–7.52(m,2H),7.47–7.40(m,1H),7.29–7.23(m,2H),7.23–7.13(m,4H),7.08–7.01(m,2H),7.03–6.96(m,1H),6.32(d,J=9.5Hz,1H),5.52(d,J=8.9Hz,1H),4.19(t,J=9.2Hz,1H),2.95(s,3H),2.39(s,3H);13C NMR(126MHz,Chloroform-d)δ197.22,171.11,165.73,144.21,136.52,133.73,133.66,130.29,129.19,128.81,128.74,128.56,128.26,128.16,126.83,72.97,65.10,49.25,30.05,21.88;HRMS(ESI):m/z[M+1]+Calculated 414.1700Found 414.1703;Theenantiomeric excess was determined to be 99.9%by HPLC with a DaicelChiralcel OJ-H column(4.6mm×25cm)(n-hexane/i-PrOH=80/20,λ=254nm,1mL/min),t=10.9min。
(+)-58-7:
Figure BDA0001880391130000191
白色晶体;yield:0.586g(71.1%);m.p.201.8-213.0℃;
Figure BDA0001880391130000193
(c 0.2,CH3OH);1H NMR(500MHz,Chloroform-d)δ7.96–7.90(m,2H),7.58–7.52(m,2H),7.43(ddt,J=8.7,7.3,1.2Hz,1H),7.28–7.23(m,2H),7.23–7.17(m,2H),7.21–7.13(m,2H),7.09–7.01(m,2H),7.03–6.96(m,1H),6.32(d,J=9.5Hz,1H),5.52(d,J=8.8Hz,1H),4.19(t,J=9.2Hz,1H),2.96(d,J=0.5Hz,3H),2.39(s,3H);13C NMR(126MHz,Chloroform-d)δ197.20,171.11,165.73,144.22,136.51,133.73,133.65,130.30,129.19,128.82,128.74,128.57,128.27,128.17,126.82,72.97,65.10,49.25,30.05,21.89;HRMS(ESI):m/z[M+1]+Calculated 414.1700Found 414.1704;
The enantiomeric excess was determined to be 99.9%by HPLC with aDaicel Chiralcel OJ-H column(4.6mm×25cm)(n-hexane/i-PrOH=80/20,λ=254nm,1mL/min),t=20.4min。
实施例10化合物(+)-58-8和(-)-58-8的制备
(-)-58-8:
Figure BDA0001880391130000192
白色晶体;yield:0.652g(79.0%);m.p.156.2-157.5℃;
Figure BDA0001880391130000194
(c 0.2,CH3OH);1H NMR(500MHz,Chloroform-d)δ7.88–7.81(m,2H),7.58–7.52(m,2H),7.47–7.40(m,1H),7.38–7.32(m,1H),7.32–7.23(m,3H),7.19–7.13(m,2H),7.09–7.02(m,2H),7.05–6.96(m,1H),6.36(d,J=9.6Hz,1H),5.53(d,J=8.8Hz,1H),4.20(t,J=9.2Hz,1H),2.96(s,3H),2.37(s,3H);13C NMR(126MHz,Chloroform-d)δ197.23,171.06,165.85,138.27,136.51,134.23,133.75,133.57,130.76,129.48,128.82,128.75,128.57,128.38,128.27,128.19,127.41,72.94,65.07,49.29,30.04,21.40;HRMS(ESI):m/z[M+1]+Calculated414.1700Found 414.1703;The enantiomeric excess was determined to be 99.9%byHPLC with a Daicel Chiralcel OJ-H column(4.6mm×25cm)(n-hexane/i-PrOH=80/20,λ=254nm,1mL/min),t=10.1min。
(+)-58-8:
Figure BDA0001880391130000201
白色晶体;yield:0.665g(80.5%);m.p.155.4-156.7℃;
Figure BDA0001880391130000203
(c 0.2,CH3OH);1H NMR(500MHz,Chloroform-d)δ7.88–7.81(m,2H),7.58–7.52(m,2H),7.47–7.40(m,1H),7.38–7.32(m,1H),7.32–7.23(m,3H),7.21–7.13(m,2H),7.09–7.01(m,2H),7.03–6.97(m,1H),6.39–6.33(m,1H),5.53(dd,J=8.8,1.0Hz,1H),4.20(t,J=9.2Hz,1H),2.96(d,J=0.6Hz,3H),2.37(s,3H);13C NMR(126MHz,Chloroform-d)δ197.23,171.06,165.85,138.27,136.50,134.23,133.75,133.56,130.76,129.47,128.81,128.75,128.57,128.38,128.27,128.19,127.41,72.93,65.06,49.29,30.05,21.41;HRMS(ESI):m/z[M+1]+Calculated 414.1700Found 414.1702;The enantiomeric excess was determined tobe99.9%by HPLC with a Daicel Chiralcel OJ-H column(4.6mm×25cm)(n-hexane/i-PrOH=80/20,λ=254nm,1mL/min),t=16.7min。
实施例11化合物(+)-58-9和(-)-58-9的制备
(-)-58-9:
Figure BDA0001880391130000202
白色固体;yield:0.818g(85.4%);m.p.157.7-158.4℃;
Figure BDA0001880391130000204
(c 0.2,CH3OH);1H NMR(500MHz,Chloroform-d)δ7.78–7.70(m,2H),7.58(dd,J=8.3,1.2Hz,1H),7.53–7.47(m,2H),7.41(dddd,J=8.2,5.2,3.2,1.3Hz,2H),7.35(ddd,J=8.1,6.8,1.3Hz,1H),7.28–7.20(m,2H),7.17(dd,J=9.0,2.6Hz,1H),7.07(dq,J=6.6,2.9,2.4Hz,2H),7.05–6.95(m,4H),6.30(d,J=9.9Hz,1H),5.41(d,J=8.8Hz,1H),4.84(d,J=16.3Hz,1H),4.76(d,J=16.3Hz,1H),4.02(dd,J=10.0,8.8Hz,1H),2.91(s,3H);13C NMR(126MHz,Chloroform-d)δ197.07,170.31,168.17,155.79,136.35,134.41,133.83,132.85,129.81,129.60,128.83,128.64,128.57,128.35,128.27,127.74,127.30,126.57,124.25,118.70,107.53,72.90,65.44,64.77,49.07,29.99;HRMS(ESI):m/z[M+1]+Calculated480.1805Found 480.1810;The enantiomeric excess was determined to be99.9%by HPLC with a Daicel Chiralcel OJ-RH column(4.6mm×25cm)(H2O/Acetonitrile=75/25,λ=254nm,1mL/min),t=10.2min。
(+)-58-9:
Figure BDA0001880391130000211
白色固体;yield:0.811g(84.6%);m.p.155.4-156.7℃;
Figure BDA0001880391130000213
(c 0.2,CH3OH);1H NMR(500MHz,Chloroform-d)δ7.78–7.70(m,2H),7.58(dd,J=8.2,1.1Hz,1H),7.53–7.47(m,2H),7.46–7.38(m,2H),7.35(ddd,J=8.1,6.9,1.3Hz,1H),7.27–7.20(m,2H),7.18(dd,J=8.9,2.6Hz,1H),7.07(dq,J=6.7,2.9,2.4Hz,2H),7.05–6.96(m,4H),6.30(d,J=10.0Hz,1H),5.41(d,J=8.8Hz,1H),4.84(d,J=16.3Hz,1H),4.76(d,J=16.3Hz,1H),4.02(dd,J=10.0,8.8Hz,1H),2.91(d,J=0.6Hz,3H);13C NMR(126MHz,Chloroform-d)δ197.07,170.30,168.17,155.79,136.35,134.41,133.83,132.85,129.81,129.60,128.83,128.65,128.57,128.35,128.27,127.75,127.30,126.58,124.25,118.71,107.52,72.90,65.44,64.77,49.07,29.99;HRMS(ESI):m/z[M+1]+Calculated480.1805Found 480.1809;The enantiomeric excess was determined to be 99.9%byHPLC with a Daicel Chiralcel OJ-RH column(4.6mm×25cm)(H2O/Acetonitrile=75/25,λ=254nm,1mL/min),t=14.0min。
实施例12化合物(+)-58-10和(-)-58-10的制备
(-)-58-10:
Figure BDA0001880391130000212
白色晶体;yield:0.725g(86.5%);m.p.113.6-114.4℃;
Figure BDA0001880391130000214
(c 0.2,CH3OH);1H NMR(500MHz,Chloroform-d)δ7.55–7.49(m,2H),7.46–7.39(m,1H),7.30–7.19(m,3H),7.12–6.98(m,6H),6.94(dd,J=4.9,1.3Hz,1H),6.18(d,J=9.9Hz,1H),5.43(d,J=8.8Hz,1H),4.01(dd,J=9.9,8.9Hz,1H),3.76–3.65(m,2H),2.90(s,3H);13C NMR(126MHz,Chloroform-d)δ197.12,170.80,170.23,136.42,133.78,133.28,133.21,128.76,128.58,128.57,128.27,128.26,125.77,123.09,72.77,64.87,49.15,35.72,29.96;HRMS(ESI):m/z[M+1]+Calculated 420.1264Found 420.1268;The enantiomericexcess was determined to be 99.9%by HPLC with a Daicel Chiralcel OJ-H column(4.6mm×25cm)(n-hexane/i-PrOH=80/20,λ=254nm,1mL/min),t=19.9min。
(+)-58-10:
Figure BDA0001880391130000221
白色晶体;yield:0.704g(84.0%);m.p.112.8-113.5℃;
Figure BDA0001880391130000223
(c 0.2,CH3OH);1H NMR(500MHz,Chloroform-d)δ7.53(ddt,J=11.3,7.0,1.3Hz,2H),7.46–7.39(m,1H),7.24(ddt,J=17.7,7.9,2.3Hz,3H),7.15–6.98(m,6H),6.94(dd,J=5.0,1.3Hz,1H),6.17(d,J=9.9Hz,1H),5.42(t,J=9.2Hz,1H),4.01(dd,J=9.9,8.9Hz,1H),3.76–3.65(m,2H),2.91(s,3H);13C NMR(126MHz,Chloroform-d)δ197.10,170.82,170.23,136.41,133.78,133.27,133.20,128.79,128.76,128.59,128.56,128.27,125.77,123.09,72.77,64.88,49.15,35.71,29.97;HRMS(ESI):m/z[M+1]+Calculated 420.1264Found 420.1267;The enantiomeric excess was determined to be 99.9%by HPLC with a DaicelChiralcel OJ-H column(4.6mm×25cm)(n-hexane/i-PrOH=80/20,λ=254nm,1mL/min),t=22.0min。
实施例13化合物(+)-58-11和(-)-58-11的制备
(-)-58-11:
Figure BDA0001880391130000222
白色固体;yield:0.671g(80.9%);m.p.166.6-167.6℃;
Figure BDA0001880391130000224
(c 0.2,CH3OH);1H NMR(500MHz,Chloroform-d)δ9.18(d,J=1.4Hz,1H),8.55(d,J=1.4Hz,1H),7.58–7.52(m,2H),7.44(td,J=7.3,1.3Hz,1H),7.30–7.23(m,2H),7.21–7.15(m,2H),7.09–7.03(m,2H),7.03–6.97(m,1H),6.51(d,J=9.9Hz,1H),5.52(d,J=8.8Hz,1H),4.29(t,J=9.4Hz,1H),2.94(s,3H),2.65(s,3H);13C NMR(126MHz,Chloroform-d)δ197.22,170.23,163.40,158.22,146.01,144.46,140.16,136.43,133.84,133.10,128.83,128.80,128.59,128.33,128.30,73.54,64.88,49.03,30.03,22.17;HRMS(ESI):m/z[M+1]+Calculated 416.1605Found:416.1607;The enantiomeric excess was determined tobe 99.9%by HPLC with a Daicel Chiralcel AD-H column(4.6mm×25cm)(n-hexane/i-PrOH=80/20,λ=254nm,1mL/min),t=38.7min。
(+)-58-11:
Figure BDA0001880391130000231
白色固体;yield:0.664g(80.0%);m.p.163.1-164.6℃;
Figure BDA0001880391130000233
(c 0.2,CH3OH);1H NMR(500MHz,Chloroform-d)δ9.18(d,J=1.4Hz,1H),8.56(dd,J=1.4,0.6Hz,1H),7.58–7.53(m,2H),7.47–7.40(m,1H),7.30–7.23(m,2H),7.21–7.16(m,2H),7.10–7.02(m,2H),7.04–6.97(m,1H),6.51(d,J=9.8Hz,1H),5.52(d,J=8.8Hz,1H),4.29(t,J=9.3Hz,1H),2.94(d,J=0.6Hz,3H),2.65(s,3H);13C NMR(126MHz,Chloroform-d)δ197.20,170.24,163.40,158.23,146.03,144.45,140.17,136.44,133.83,133.11,128.83,128.81,128.59,128.34,128.30,73.56,64.90,49.03,30.04,22.17,;HRMS(ESI):m/z[M+1]+Calculated 416.1605Found:416.1609;The enantiomeric excess was determined tobe 99.9%by HPLC with a Daicel Chiralcel AD-H column(4.6mm×25cm)(n-hexane/i-PrOH=80/20,λ=254nm,1mL/min),t=44.0min。
实施例14化合物(+)-58-12和(-)-58-12的制备
(-)-58-12:
Figure BDA0001880391130000232
白色晶体;yield:0.724g(85.0%);m.p.140.3-141.6℃;
Figure BDA0001880391130000234
(c 0.2,CH3OH);1H NMR(500MHz,Chloroform-d)δ8.71(s,1H),8.60(s,1H),7.80(dt,J=8.0,1.9Hz,1H),7.69(d,J=16.1Hz,1H),7.58–7.52(m,2H),7.47–7.40(m,1H),7.33(dd,J=8.0,4.8Hz,1H),7.29–7.22(m,2H),7.19–7.14(m,2H),7.14–7.04(m,2H),7.04–6.98(m,1H),6.51(d,J=16.1Hz,1H),6.29(d,J=9.8Hz,1H),5.49(d,J=8.9Hz,1H),4.13(dd,J=9.9,8.8Hz,1H),2.93(s,3H);13C NMR(126MHz,Chloroform-d)δ197.18,170.90,165.25,151.13,149.75,142.39,136.45,134.66,133.80,133.31,130.35,128.79,128.58,128.29,124.04,119.71,72.66,64.92,49.29,30.02;HRMS(ESI):m/z[M+1]+Calculated 427.1652Found427.1656;The enantiomeric excess was determined to be 99.9%by HPLC with aDaicel Chiralcel OD-H column(4.6mm×25cm)(n-hexane/i-PrOH=75/25,λ=254nm,1mL/min),t=12.6min。
(+)-58-12:
Figure BDA0001880391130000241
白色晶体;yield:0.708g(83.1%);m.p.139.6-140.8℃;
Figure BDA0001880391130000243
(c 0.2,CH3OH);1H NMR(500MHz,Chloroform-d))δ8.85(d,J=2.2Hz,1H),8.57(dd,J=4.8,1.6Hz,1H),8.16(dt,J=8.1,2.0Hz,1H),7.73(d,J=16.1Hz,1H),7.70–7.64(m,2H),7.51–7.45(m,1H),7.45–7.39(m,1H),7.33–7.26(m,2H),7.18–7.12(m,2H),7.04(dd,J=8.4,6.9Hz,2H),7.01–6.94(m,1H),6.79(d,J=16.1Hz,1H),6.16(d,J=10.6Hz,1H),5.95(d,J=8.8Hz,1H),4.24(dd,J=10.6,8.7Hz,1H),2.77(s,3H);13C NMR(126MHz,Chloroform-d)δ197.18,170.90,165.25,151.12,149.73,142.39,136.45,134.66,133.80,133.31,130.35,128.79,128.58,128.29,124.04,119.71,72.66,64.92,49.28,30.02;HRMS(ESI):m/z[M+1]+Calculated 427.1652Found 427.1655;The enantiomeric excess was determined tobe 99.9%by HPLC with a Daicel Chiralcel OD-H column(4.6mm×25cm)(n-hexane/i-PrOH=75/25,λ=254nm,1mL/min),t=8.0min。
实施例15化合物(+)-58-13和(-)-58-13的制备
(-)-58-13的制备:
Figure BDA0001880391130000242
称量0.590g(2mmol)(-)-黄皮酰胺酮,置于一遮光圆底烧瓶内,加入0.304g(3mmol)三乙胺、30mL乙腈溶解,搅拌下滴加10mmol相应的溴甲烷,室温搅拌反应,TLC监测(EA:PE=1:1),反应完全后,硅藻土助滤,滤饼用70mL二氯甲烷洗涤,合并滤液,旋除后得粗品,经柱层析,甲醇-石油醚重结晶得化合物(-)-58-13,白色晶体;yield:0.589g(92.0%);m.p.122.1-123.0℃;
Figure BDA0001880391130000252
(c 0.2,CH3OH);1H NMR(300MHz,Chloroform-d)δ7.59–7.49(m,2H),7.48–7.36(m,1H),7.30–7.19(m,2H),7.13–6.95(m,5H),5.41(d,J=8.8Hz,1H),4.52(d,J=8.8Hz,1H),3.86(t,J=8.8Hz,1H),3.55(s,3H),2.87(s,3H);13C NMR(75MHz,Chloroform-d)δ197.32,173.27,136.21,134.97,133.51,128.58,128.42,128.35,128.05,127.81,80.54,64.96,59.19,49.99,29.50;HRMS(ESI):m/z[M+1]+Calculated310.1438Found 310.1440;The enantiomeric excess was determined to be 99.9%byHPLC with a Daicel Chiralcel OJ-H column(4.6mm×25cm)(n-hexane/i-PrOH=90/10,λ=254nm,1mL/min),t=22.1min。
(+)-58-13:
Figure BDA0001880391130000251
制备方法同(-)-58-13,不同之处在于用(+)-黄皮酰胺酮替代(-)-黄皮酰胺酮,得到化合物(+)-58-13,白色晶体;yield:0.560g(90.5%);m.p.122.7-123.7℃;
Figure BDA0001880391130000253
(c 0.2,CH3OH);1H NMR(300MHz,Chloroform-d)δ7.55–7.49(m,2H),7.44–7.37(m,1H),7.27–7.20(m,2H),7.10–6.97(m,5H),5.39(d,J=8.8Hz,1H),4.50(d,J=8.8Hz,1H),3.84(t,J=8.8Hz,1H),3.54(d,J=0.7Hz,3H),2.86(s,3H);13C NMR(75MHz,Chloroform-d)δ197.32,173.25,136.21,134.97,133.51,128.58,128.42,128.35,128.05,127.81,80.54,64.96,59.19,49.99,29.50;HRMS(ESI):m/z[M+1]+Calculated 310.1438Found 310.1439;The enantiomeric excess was determined to be 99.9%by HPLC with a DaicelChiralcel OJ-H column(4.6mm×25cm)(n-hexane/i-PrOH=90/10,λ=254nm,1mL/min),t=15.8min。
以下化合物的制备参照化合物(-)-58-13的制备,不同之处在于采用相应的碘代烃或溴代烃替代溴甲烷。
实施例16化合物(+)-58-14和(-)-58-14的制备
(-)-58-14:
Figure BDA0001880391130000261
白色晶体;yield:0.609g(94.2%);m.p.158.1-159.5℃;
Figure BDA0001880391130000263
(c 0.2,CH3OH);1H NMR(300MHz,Chloroform-d)δ7.58–7.48(m,2H),7.47–7.35(m,1H),7.29–7.18(m,2H),7.11–6.93(m,5H),5.42(d,J=8.8Hz,1H),4.58(d,J=8.6Hz,1H),3.97(dq,J=9.3,7.1Hz,1H),3.85(t,J=8.7Hz,1H),3.57(dq,J=9.3,7.0Hz,1H),2.86(s,3H),1.14(t,J=7.0Hz,3H;13C NMR(75MHz,Chloroform-d)δ197.41,173.52,136.23,135.11,133.48,128.49,128.45,128.34,128.03,127.70,79.13,66.88,65.03,50.15,29.51,15.33;HRMS(ESI):m/z[M+1]+Calculated 324.1594Found 324.1597;The enantiomeric excess wasdetermined to be 99.9%by HPLC with a Daicel Chiralcel OJ-H column(4.6mm×25cm)(n-hexane/i-PrOH=98/2,λ=254nm,1mL/min),t=38.8min。
(+)-58-14:
Figure BDA0001880391130000262
白色晶体;yield:0.606g(93.8%);m.p.156.1-157.7℃;
Figure BDA0001880391130000264
(c 0.2,CH3OH);1H NMR(300MHz,Chloroform-d)δ7.56–7.49(m,2H),7.45–7.38(m,1H),7.29–7.21(m,2H),7.08–6.97(m,5H),5.40(d,J=8.8Hz,1H),4.57(d,J=8.5Hz,1H),3.98(dq,J=9.3,7.0Hz,1H),3.84(t,J=8.7Hz,1H),3.58(dq,J=9.2,7.0Hz,1H),2.87(s,3H),1.15(t,J=7.0Hz,3H);13C NMR(75MHz,Chloroform-d)δ197.39,173.52,136.23,135.12,133.47,128.50,128.45,128.34,128.03,127.70,79.14,66.89,65.05,50.16,29.52,15.33;HRMS(ESI):m/z[M+1]+Calculated 324.1594Found 324.1596;The enantiomeric excess wasdetermined to be 99.9%by HPLC with a Daicel Chiralcel OJ-H column(4.6mm×25cm)(n-hexane/i-PrOH=98/2,λ=254nm,1mL/min),t=35.5min。
实施例17化合物(+)-58-15和(-)-58-15的制备
(-)-58-15:
Figure BDA0001880391130000271
白色晶体;yield:0.564g(84.2%);m.p.138.7-139.4℃;
Figure BDA0001880391130000273
(c 0.2,CH3OH);1H NMR(300MHz,Chloroform-d)δ7.55–7.49(m,2H),7.45–7.38(m,1H),7.28–7.20(m,2H),7.08–6.97(m,5H),5.80(ddt,J=17.3,10.4,5.8Hz,1H),5.40(d,J=8.8Hz,1H),5.17(dq,J=17.3,1.7Hz,1H),5.11(dq,J=10.4,1.4Hz,1H),4.63(d,J=8.7Hz,1H),4.39(ddt,J=12.7,5.5,1.5Hz,1H),4.23(ddt,J=12.8,6.1,1.4Hz,1H),3.87(t,J=8.8Hz,1H),2.86(s,3H);13C NMR(75MHz,Chloroform-d)δ197.33,173.51,136.21,134.81,134.18,133.48,128.56,128.47,128.34,128.05,127.76,117.88,77.94,71.73,65.01,50.14,29.50;HRMS(ESI):m/z[M+1]+Calculated 336.1594Found 331.1595;The enantiomericexcess was determined to be 99.9%by HPLC with a Daicel Chiralcel AD-H column(4.6mm×25cm)(n-hexane/i-PrOH=95/5,λ=254nm,1mL/min),t=70.2min。
(+)-58-15:
Figure BDA0001880391130000272
白色晶体;yield:0.561g(83.7%);m.p.140.4-141.3℃;
Figure BDA0001880391130000274
(c 0.2,CH3OH);1H NMR(300MHz,Chloroform-d)δ7.58–7.49(m,2H),7.48–7.36(m,1H),7.25(t,J=7.8Hz,2H),7.11–6.95(m,5H),5.81(ddt,J=17.3,10.3,5.8Hz,1H),5.42(d,J=8.8Hz,1H),5.24–5.12(m,1H),5.17–5.06(m,1H),4.64(d,J=8.7Hz,1H),4.39(ddt,J=12.8,5.5,1.4Hz,1H),4.24(ddt,J=12.8,6.0,1.4Hz,1H),3.88(t,J=8.8Hz,1H),2.87(s,3H);13CNMR(75MHz,Chloroform-d)δ197.34,173.51,136.21,134.81,134.18,133.49,128.56,128.47,128.34,128.05,127.76,117.89,77.94,71.73,65.00,50.13,29.50;HRMS(ESI):m/z[M+1]+Calculated 336.1594Found 336.1597;The enantiomeric excess wasdetermined to be99.9%by HPLC with a Daicel Chiralcel AD-H column(4.6mm×25cm)(n-hexane/i-PrOH=95/5,λ=254nm,1mL/min),t=78.5min。
实施例18化合物神经保护作用的测试
样品处理:样品用DMSO溶解,低温保存,DMSO在最终体系中的浓度控制在不影响检测活性的范围之内(0.1%)。
实验过程:原代大鼠小脑颗粒神经细胞完成培养后第六天加入要筛选的药物(加入96孔板时应1000倍稀释,终浓度均为10μM);第七天加入浓度为200μM的谷氨酸(加入96孔板时应100倍稀释);第八天用MTT(加入96孔板时终浓度应为0.5mg/ml)检测细胞存活率。以MK-801(为神经保护剂)为阳性对照,每个处理3个重复,设空白对照组CN,并统计结果为每个处理的平均值。
测得结果如表1所示。
表1
Figure BDA0001880391130000281
Figure BDA0001880391130000291
结果显示:在20uM浓度下,大多数化合物对于Glu损伤均有一定程度的保护,其中化合物(+)-58-11、(+)-58-9、(+)-58、(+)-58-2、(+)-58-3、(+)-58-10、(+)-58-12、(+)-58-4处理组的细胞存活率均高于Glu处理组,特别是化合物(+)-58-11、(+)-58-9、(+)-58-2处理组的细胞存活率与Glu处理相比有显著性差异。说明化合物具有很好的神经保护效果,可以作为谷氨酸损伤抑制剂应用,制备成为预防和/或治疗神经退行性疾病的药物,预防和/或治疗相关疾病,如脑中风、外伤性脑损伤、老年性痴呆症等。
实施例19化合物在PC12细胞氧糖剥夺损伤中的神经保护作用测试
待测化合物处理:待测化合物用DMSO溶解,-20℃低温保存。
PC12细胞是大鼠嗜铬细胞瘤细胞,具有很多神经细胞的特性,常代替神经细胞用于研究,广泛用于体外缺血损伤的研究。氧糖剥夺(Oxygen glucose deprivation,OGD)模型能较好地模拟在体脑缺血对神经组织造成的损害。因此,本实施例采用PC12构建OGD模型进行研究化合物对于氧糖剥夺环境下神经细胞的保护作用。
实验过程:PC12(大鼠嗜铬细胞瘤细胞)点于96孔板,状态稳定后加入待测化合物(加入96孔板时应1000倍稀释)。作用24h后换DMEM无糖培养基,置于缺氧孵箱中(5%CO2,1%O2)中2h,收集培养基上清测定LDH释放量。同时设空白对照组(Control)和氧糖剥夺损伤模型组(OGD)。
检测的结果如表2所示。
表2
Figure BDA0001880391130000292
Figure BDA0001880391130000301
其中,空白对照组(Control)乳酸脱氢酶(LDH)释放率为100%,氧糖剥夺损伤模型组(OGD)的LDH释放平均值为205.43%。从结果中可知,大多数化合物都具有降低PC12在氧糖剥夺环境下的LDH释放率,尤其是化合物58、(+)-58-4、(+)-58-8、(+)-58-15、(-)-58和(-)-58-12,经其处理后,LDH的释放率显著性地下降,表明化合物对于氧糖剥夺环境下的PC12具有很好的保护作用,能够减轻氧糖剥夺造成的损伤。上述结果表明,本发明所述化合物能够作为神经细胞保护剂,减轻氧糖剥夺对细胞造成的损伤。
综上,上述试验说明本发明化合物具有很好的神经保护效果,可以作为谷氨酸损伤抑制剂以及脑缺血引起神经细胞损伤的神经保护剂进行应用,制备成为预防和/或治疗神经退行性疾病的药物,预防和/或治疗相关疾病,如脑中风、外伤性脑损伤、老年性痴呆症等。
最后所应当说明的是,以上实施例仅用以说明本发明的技术方案而非对本发明保护范围的限制,对于本领域的普通技术人员来说,在上述说明及思路的基础上还可以做出其它不同形式的变化或变动,这里无需也无法对所有的实施方式予以穷举。凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等,均应包含在本发明权利要求的保护范围之内。

Claims (4)

1.一种光学活性黄皮酰胺酮衍生物,其特征在于,所述化合物的结构如式(Ⅱ)或如式(Ⅲ)所示:
Figure FDA0003479816730000011
其中,所述式(Ⅱ)或式(Ⅲ)中R各自独立地为
Figure FDA0003479816730000012
Figure FDA0003479816730000013
中的一种。
2.权利要求1所述光学活性黄皮酰胺酮衍生物在制备治疗和/或预防神经退行性疾病药物中的应用。
3.根据权利要求2所述应用,其特征在于,所述应用是应用于制备治疗和/或预防脑中风、外伤性脑损伤或老年性痴呆症药物中的应用。
4.权利要求1所述光学活性黄皮酰胺酮衍生物在制备神经保护剂中的应用。
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