CN1216526A - 3,4-二取代的苯基乙醇氨基1,2,3,4,-四氢化萘甲酰胺衍生物 - Google Patents
3,4-二取代的苯基乙醇氨基1,2,3,4,-四氢化萘甲酰胺衍生物 Download PDFInfo
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- CN1216526A CN1216526A CN97193866A CN97193866A CN1216526A CN 1216526 A CN1216526 A CN 1216526A CN 97193866 A CN97193866 A CN 97193866A CN 97193866 A CN97193866 A CN 97193866A CN 1216526 A CN1216526 A CN 1216526A
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- naphthane
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- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
通式(Ⅰ)表示的3,4-二取代的苯基乙醇氨基1,2,3,4-四氢化萘甲酰胺衍生物及其药用盐,其具有选择性的β2-肾上腺素能受体刺激作用,并能减轻心脏负担,如数脉。在该通式中,A表示低级亚烷基;B表示氨基,二(低级烷基)氨基或在环中可以含有氧原子的3至7-员脂环氨基;n是整数1或2;用“*”标记的碳原子指碳原子或其R或S构型或其混合物;而用“(S)”标记的碳原子指S构型的碳原子。这些化合物用作预防先兆性流产/早产的药剂,支气管扩张剂和在尿石病中缓解疼痛和除去结石的药剂。
Description
技术领域
本发明涉及可用作医药的新的3,4-二取代的苯基乙醇氨基1,2,3,4-四氢化萘甲酰胺衍生物。
更具体地,本发明涉及如下通式表示的3,4-二取代的苯基乙醇氨基1,2,3,4-四氢化萘甲酰胺衍生物:
(其中A表示低级亚烷基;B表示氨基,二(低级烷基)氨基或在环中可以含有氧原子的3至7-员脂环氨基;n是整数1或2;用*标记的碳原子表示R构型,S构型的碳原子或其混合物;用(S)标记的碳原子表示S构型的碳原子)和其药用盐,它们具有选择性的β2-肾上腺素能受体刺激作用,减轻心脏负担如心动过速。
背景技术
(其中用(R)标记的碳原子表示R构型的碳原子;而用(S)标记的碳原子表示S构型的碳原子)(参见日本公开特许平6-506676和日本公开特许平6-506955)。
但是,这些化合物是具有显著的β3-肾上腺素能受体刺激作用的β3-肾上腺素能受体刺激剂。
发明公开
本发明涉及由如下通式表示的3,4-二取代的苯基乙醇氨基1,2,3,4-四氢萘甲酰胺衍生物:
(其中A表示低级亚烷基;B表示氨基,二(低级烷基)氨基或在环中可以含有氧原子的3至7-员脂环氨基;n是整数1或2;用*标记的碳原子为R构型,S构型或其混合物;用(S)标记的碳原子表示S构型的碳原子)和其药用盐。
本发明涉及含有上述3,4-二取代的苯基乙醇氨基1,2,3,4-四氢萘甲酰胺衍生物或其药用盐的药物组合物。
本发明也涉及及含有上述3,4-二取代的苯基乙醇氨基1,2,3,4-四氢萘甲酰胺衍生物或其药用盐作为活性成分的,用于预防先兆流产和早产的药剂,支气管扩张药和用于在尿石病中疼痛缓解和除去结石的药剂。
本发明涉及预防先兆流产和早产的方法,预防和治疗与支气管狭窄和气道梗塞有关的疾病,尿石病中疼痛缓解和除去结石的方法,该方法包括施用上述3,4-二取代的苯基乙醇氨基1,2,3,4-四氢萘甲酰胺衍生物或其药用盐的药物组合物。
本发明涉及上述3,4-二取代的苯基乙醇氨基1,2,3,4-四氢萘甲酰胺衍生物或其药用盐在生产用于预防先兆流产和早产,预防和治疗与支气管狭窄和气道梗塞有关的疾病,尿石病中疼痛缓解和除去结石的药物组合物中的用途。
进一步地,本发明涉及上述3,4-二取代的苯基乙醇氨基1,2,3,4-四氢萘甲酰胺衍生物或其药用盐作为用于预防先兆流产和早产的药剂,支气管扩张药,尿石病中疼痛缓解和除去结石的药剂用途。
实施本发明的最佳方式
为了找到优秀的β2-肾上腺素能受体刺激剂,本发明的发明人进行了深入的研究,并且发现,某些由上述通式(Ⅰ)表示的3,4-二取代的苯基乙醇氨基1,2,3,4-四氢萘甲酰胺衍生物具有有力的和选择性的β2-肾上腺素能受体刺激作用,并明显地可以用作β2-肾上腺素能受体刺激剂,从而形成了本发明的基础。
因此,本发明涉及由如下通式表示的3,4-二取代的苯基乙醇氨基1,2,3,4-四氢萘甲酰胺衍生物:
(其中A表示低级亚烷基;B表示氨基,二(低级烷基)氨基或在环中含有氧原子的3至7-员脂环氨基;n是整数1或2;用*标记的碳原子为R构型,S构型或其混合物;用(S)标记的碳原子表示S构型的碳原子)和其药用盐,它具有与β1-肾上腺素能受体刺激作用相比更高选择性的β2-肾上腺素能受体刺激作用,并具有缓解心脏负担如心动过速的作用。
在这些由通式(Ⅰ)表示的本发明化合物中,术语“二(低级烷基)氨基”意思是用具有1至6个碳原子的直链或支链烷基(例如,甲基,乙基,丙基,异丙基)二取代的氨基,如二甲基氨基,二乙基氨基,乙基甲基氨基等等。术语“低级亚烷基”意思是具有1至3个碳原子的直链亚烷基如亚甲基,亚乙基和环丙烷,而术语“在环中可以含有氧原子的3至7-员脂环氨基”意思是1-吡咯烷基,哌啶子基,吗啉代基等等。
由上述通式(Ⅰ)表示的本发明化合物可以由如下工艺制备
例如,上述通式(Ⅰ)化合物可以如下制备:通过使由如下通式表示的胺化合物:
(其中R1是氢原子或羟基-保护剂;A,R,n和用(S)标记的碳原子如前定义),使产生的化合物以常规方式用由如下通式表示的胺化合物:
B-H (Ⅴ)
(其中B如前定义)酰胺化,如果必须,除去羟基-保护基。
(其中A,B和用(S)标记的碳原子如前面定义)用由上述通式(Ⅲ)表示的烷基化剂N-烷基化,以常规方式将产生的化合物还原,除去羟基-保护基。
(其中R0,n和用(S)标记的碳原子如前定义),如果必须,用试剂如三氟乙酸酐保护醇羟基和氨基,用如下通式表示的烷基化剂:
X-A-COB (Ⅺ)
(其中A,B和X如前定义),使化合物O-烷基化,并除去保护基。
在上述生产方法中用作原料的由上述通式(Ⅱ)表示的胺化合物可以通过在文献中所述的方法或与其类似的方法制备(例如,Eur.J.Med.Chem.,No.29,pp.259-267(1994);日本公开特许No.平3-14548)。
在盐酸存在下与福尔马林反应制备由下式表示的化合物:
(其中Ac和X如前定义)如果必须,以常规方式脱乙酰化,并用诸如丙酮二甲基缩醛的试剂往羟基上引入保护基。
(其中R0如前定义),然后使产生的化合物以常规的方式,用卤化剂卤化。
在上述生产方法中用作原料的由上述通式(Ⅳ)表示的胺化合物可以如下制备:通过使如下通式表示的酚化合物:
(其中R2是氨基-保护基;用(S)标记的碳原子如前定义)用由上述通式(Ⅺ)表示的烷基化剂进行O-烷基化,然后除去氨基-保护基,或通过用合适的试剂保护由上述通式(Ⅱ)表示的胺化合物的氨基,如果必须,将所产生的化合物转化为游离的羧酸或其反应活性功能衍生物,使产生的化合物用由上述通式(Ⅴ)表示的胺化合物在缩合剂存在或不存在下酰胺化,并除去氨基-保护基。
(其中R0,n和用(R)标记的碳原子和用(S)标记的碳原子如前定义)或其它由如下通式表示的化合物:
(其中R0,n和用(S)标记的碳原子如前定义),如果需要,用诸如三氟乙酸酐的试剂保护醇羟基和氨基,使产生的化合物用由上述通式(Ⅺ)表示的烷基化剂进行O-烷基化,并脱去保护基。
在由上述通式(Ⅰ)表示的本发明化合物中,单个异构体也可以如下制备:通过使在上述方法中作为中间体得到的非对映异构体混合物进行柱层析或分级结晶而分离相应的单个异构体,然后用所说的单个异构体进行相同的反应。
在上述生产方法中用作原料的通式(ⅩⅥ)所示的苯基乙酸酯衍生物可以通过在文献中所述的方法或与其类似的方法(例如,日本公开特许昭61-500915,日本公开特许昭57-135049)制备。
在上述生产方法中用作原料的通式(Ⅶ),(ⅩⅩ)和(ⅩⅪ)所示的光学活性扁桃酸衍生物和其混合物,可以从可购买到的相应的二羟基化合物衍生,或者可以通过使可以根据在文献中所述的方法或与其类似的方法得到的,由如下通式表示的溴化合物:
(其中R0和n如前定义),与草酸二乙酯反应,将产生的苯基二羟基乙酸衍生物用诸如硼氢化钠的试剂还原,并将酯化合物水解,给出由上述通式(Ⅶ)表示的扁桃酸衍生物,如果需要,并将衍生物进行光学拆分,以常规方式,用诸如光学活性的1-(1-萘基)乙基胺的拆分试剂。
(其中R0和n如前定义)氰基化,以常规方式将产生的氰基化合物水解,并将产生的化合物以类似于上述的方式光学拆分而制备。
通过上述生成方法得到的本发明化合物可以通过常规分离手段如分级重结晶分离和纯化,用柱层析,溶剂萃取等等纯化。
本发明由上述通式(Ⅰ)表示的3,4-二取代的苯基乙醇氨基四氢萘甲酰胺衍生物可以由常规方式转化为其药用盐。这类盐的例子包括与无机酸(例如,盐酸,氢溴酸,氢碘酸,硫酸,硝酸,磷酸等等)的酸加成盐,与有机酸(例如,甲酸,乙酸,甲磺酸,苯磺酸,对甲苯磺酸,丙酸,柠檬酸,丁二酸,酒石酸,富马酸,丁酸,草酸,丙二酸,马来酸,乳酸,苹果酸,碳酸,谷氨酸,天冬氨酸等等)的加成盐,和与无机碱的盐如钠盐和钾盐。产生的盐具有与游离形式相同的药理活性。
另外,本发明由上述通式(Ⅰ)表示的化合物也包括其水合物和其与药理上可接受的溶剂(例如,乙醇)的溶剂化物。
本发明由上述通式(Ⅰ)表示的化合物基于具有羟基的不对称碳原子存在R和S构型的两种异构体。无论是异构体之一还是其混合物都可以用于本发明,而R构型异构体是优选的。
当测量β2-肾上腺素能受体刺激活性的体外试验以常规方式用分离出的大鼠妊娠的子宫进行时,本发明由上述通式(Ⅰ)表示的化合物在大约5.0×10-10至5.0×10-7mol浓度显示松弛50%的大鼠子宫肌层的自发收缩(即,EC50)的活性。例如,2-[(2S)2-[[(2RS)2羟基-2-(4-羟基-3-羟基甲基苯基)乙基]氨基]1,2,3,4四氢萘-7-基氧基]-N,N-二甲基乙酰胺显示EC50值以mol浓度为5.3×10-9,而2-[(2S)2-[[(2R)-2-羟基-2-(4-羟基-3羟基甲基苯基)乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]-N,N-二甲基乙酰胺显示EC50值以mol浓度为2.6×10-9。因此,本发明的化合物具有很强的β2-肾上腺素能受体刺激作用,因此明显可以作为β2-肾上腺素能受体刺激剂。
当测量β1-肾上腺素能受体刺激活性的体外试验以常规方式用分离出的大鼠前房进行时,本发明由上述通式(Ⅰ)表示的化合物在大约5.0×10-7或更多的mol浓度显示每分钟大鼠心率增加20次搏动(即,EC20值)的活性。例如,2-[(2S)-2-[[(2RS)-2-羟基-2-(4-羟基-3-羟基甲基苯基)乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]-N,N-二甲基乙酰胺显示EC20值以mol浓度为2.5×10-6,而2-[(2S)-2-[[(2R)-2-羟基-2-(4-羟基-3-羟基甲基苯基)乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]-N,N-二甲基乙酰胺显示EC20值以mol浓度为9.4×10-7。因此,本发明的化合物与上述β2-肾上腺素能受体刺激作用相比,具有很弱的β1-肾上腺素能受体刺激作用。
结果是,本发明的化合物与β1-肾上腺素能受体刺激作用相比,具有具有很强的β2-肾上腺素能受体刺激作用和很高的选择性,这些是非常有用的和选择性的β2-肾上腺素能受体刺激剂,其中对心脏的负担由于抑制由β1-肾上腺素能受体刺激作用引起的心脏副作用(例如,心动过速)而降低。
本发明是选择性的β2-肾上腺素能受体刺激剂,非常有用于,例如,用于预防先兆流产,早产的药剂,支气管收缩药(预防和治疗与支气管狭窄和气道梗塞有关的疾病的药剂),尿石病中疼痛缓解和除去结石的药剂。
而且,由所述通式(Ⅰ)表示的化合物是非常稳定的化合物,因此具有良好的贮存稳定性。
当本发明由上述通式(Ⅰ)表示的3,4-二取代的苯基乙醇氨基四氢化萘甲酰胺化合物和其药用盐用于实际治疗时,它们以适当的药物组合物形式如片剂,粉剂,细粒剂,粒剂,胶囊,注射剂等等口服或肠胃外给药。这些药物组合物可以根据普通方法用普通药物载体,赋形剂和其它添加剂配制。
剂量根据需要各个治疗的患者的性别,年龄,体重,病症程度等等决定,在口服给药的情况下大约在每天每个成人1至1000mg的范围内,在肠胃外给药的情况下每天每个成人大约0.01至100mg范围内,而日剂量可以被分为每天一至几个剂量。
实施例
本发明的内容参考下列参考实施例,实施例和试验实施例更详细地说明,但本发明不受其限制。在参考实施例和实施例中所述的所有化合物的熔点都未经校正。
参考实施例1
(S)-4-(2-氨基-1,2,3,4-四氢萘-7-基氧基)-N,N-二甲基丁酰胺
将(S)-2-(叔丁氧羰基氨基)-7-羟基四氢萘(400mg)溶于8ml N,N-二甲基甲酰胺中,往溶液中加入3.16g碳酸铯和650μl4-溴代丁酸乙酯,混合物在室温下搅拌1.5小时。加入水后,反应混合物用乙酸乙酯萃取,萃取液用水洗涤然后用无水硫酸镁干燥。将溶剂减压蒸发,残余物通过硅胶中压液相柱色谱(洗脱剂:己烷/乙酸乙酯=1/1)纯化给出488mg(S)-4-[2-(叔丁氧羰基氨基)-1,2,3,4-四氢萘-7-基氧基]丁酸乙酯,熔点96-98℃。IR(KBr):3360,1723,1680cm-1 1H-NMR(CDCl3)δppm:1.26(3H,t,J=7.1Hz),1.45(9H,s),1.65-1.80(1H,m),2.00-2.15(3H,m),2.50(2H,t,J=7.3Hz),2.59(1H,dd,J=16.5,7.9Hz),2.75-2.85(2H,m),3.07(1H,dd,J=16.5,4.6Hz),3.90-4.05(3H,m),4.14(2H,q,J=7.1Hz),4.50-4.65(1H,m),6.58(1H,d,J=2.6Hz),6.68(1H,dd,J=8.4,2.6Hz),6.99(1H,d,J=8.4Hz)特定旋光度:[α]D 25=-50.7°(C=1.03,MeOH)
将(S)-4-[2-(叔丁氧羰基氨基)-1,2,3,4-四氢萘-7-基氧基]丁酸乙酯(988mg)溶于15ml乙醇和15ml甲醇的混合物中,往溶液中加入3.0ml 2N氢氧化钠水溶液,混合物在室温下搅拌2小时。将反应混合物减压浓缩,往残余物中加入10%柠檬酸水溶液,混合物用乙酸乙酯萃取。萃取液用食盐水洗涤并用无水硫酸镁干燥。减压蒸发溶剂,得到914mg(S)-4-[2-(叔丁氧羰基氨基)-1,2,3,4-四氢萘7-基氧基]丁酸,熔点150-153℃。IR (KBr):3452,3365,1691 cm-1 1H-NMR(CDCl3)δppm:1.45(9H,s),1.65-1.80(1H,m),2.00-2.20(3H,m),2.55-2.70(3H,m),2.75-2.85(2H,m),3.00-3.15(1H,m),3.90-4.10(3H,m),4.55-4.70(1H,m),6.58(1H,d,J=2.6Hz),6.68(1H,dd,J=8.4,2.6Hz),6.99(1H,d,J=8.4Hz)特定旋光度:[α]D 25=-53.5°(c=0.52,MeOH)
(S)-4-[2-(叔丁氧羰基氨基)-1,2,3,4-四氢萘-7-基氧基]丁酸(399mg)溶于5ml四氢呋喃,在冰-冷却,搅拌下加入204mg N,N’-羰基二咪唑,再反应2小时。然后,在冰-冷却,搅拌下加入1.40g在2ml四氢呋喃中的二甲基胺,混合物进行45分钟反应,然后在室温下反应45分钟。反应溶液在减压下浓缩,往残余物中加入水,混合物用乙醚萃取。萃取液依次用10%柠檬酸水溶液,水,饱和碳酸氢钠溶液和水洗涤,然后无水硫酸镁干燥。通过减压蒸发溶剂,得到396mg(S)-4-[2-(叔丁氧羰基氨基)-1,2,3,4-四氢萘-7-基氧基]-N,N-二甲基丁酰胺,熔点97-101℃。
IR(KBr):3325,1709,1624cm-1 1H-NMR(CDCl3)δppm:1.45(9H,s),1.65-1.80(1H,m),2.00-2.15(3H,m),2.51(2H,t,J=7.2Hz),2.59(1H,dd,J=16.5,8.1Hz),2.75-2.85(2H,m),2.95(3H,s),3.00-3.10(4H,m),3.90-4.00(3H,m),4.58(1H,brs),6.59(1H,d,J=2.6Hz),6.69(1H,dd,J=8.4,2.6Hz),6.98(1H,d,J=8.4Hz)
特定旋光度:[α]D 25=-50.0°(c=0.50,MeOH)
(S)-4[2-(叔丁氧羰基氨基)-1,2,3,4-四氢萘-7-基氧基]-N,N-二甲基丁酰胺(396mg)溶于5ml二氯甲烷,在冰-冷却,搅拌下往溶液中加入5ml二氯甲烷中的5ml三氟乙酸,混合物被搅拌15分钟,然后在室温下反应15分钟。反应溶液在减压下浓缩,往残余物中加入二氯甲烷,水和碳酸氢钠,混合物在室温下搅拌30分钟。分开有机层,无水硫酸镁干燥。通过减压蒸发溶剂,得到263mg油状形式的(S)-4-(2-氨基-1,2,3,4-四氢萘-7-基氧基]-N,N-二甲基丁酰胺。IR(neat):3404,1618cm-1 1H-NMR(CDCl3)δppm:1.75-1.90(1H,m),2.00-2.25(3H,m),2.45-2.55(2H,m),2.65-2.90(3H,m),2.94(3H,s),3.00(3H,s),3.05-3.20(1H,m),3.30-3.50(1H,m),3.96(2H,t,J=5.9Hz),5.89(2H,brs),6.60(1H,d,J=2.3Hz),6.68(1H,dd,J=8.4,2.3Hz),6.96(1H,d,J=8.4Hz)特定旋光度:[α]D 25=-46.2°(c=0.45,MeOH)
参考实施例2
(S)-2-(2-氨基-1,2,3,4-四氢萘-7-基氧基1)-N,N-二甲基乙酰胺乙酸酯
将(S)-2-(苄氧羰基氨基)-7-羟基四氢萘(13.4g)溶于120ml N,N-二甲基乙酰胺,往溶液中加入8.27g 2-溴-N,N-二甲基乙酰胺和22.0g碳酸铯,混合物在室温下搅拌6小时。将反应溶液倒入冰-水中,混合物用乙酸乙酯萃取,萃取液用水洗涤,无水硫酸镁干燥。减压蒸发溶剂,产生的残余物通过加入乙醚结晶给出14.0g(S)-2-(2-氨基-1,2,3,4-四氢萘-7-基氧基)-N,N-二甲基乙酰胺,熔点117-118℃。IR(KBr):3465,3284,1704,1667cm-1 1H-NMR(CDCl3)δppm:1.70-1.85(1H,m),2.00-2.10(1H,m),2.63(1H,dd,J=16.5,7.4Hz),2.75-2.85(2H,m),2.97(3H,s),3.05-3.15(4H,m),4.00-4.10(1H,m),4.64(2H,s),4.75-4.85(1H,m),5.10(2H,s),6.63(1H,d,J=2.7Hz),6.75(1H,dd,J=8.4,2.7Hz),6.99(1H,d,J=8.4Hz),7.25-7.40(5H,m)
特定旋光度:[α]D 25=-41.0°(c=1.02,甲醇)
(S)-2-(2-氨基-1,2,3,4-四氢萘-7-基氧基)-N,N-二甲基乙酰胺(100mg)和20mg 10%Pd/C悬浮于5ml乙酸中,悬浮液在室温下在氢气氛中搅拌3小时。滤出催化剂,减压浓缩滤液,残余物用乙醇-乙醚重结晶给出72mg(S)2-(2-氨基-1,2,3,4-四氢萘-7-基氧基)-N,N-二甲基乙酰胺乙酸盐,熔点135-142℃。IR(KBr):3431,2636,2158,1656cm-1 1H-NMR(DMSO-d6)δppm:1.40-1.60(1H,m),1.81(3H,s),1.85-2.00(1H,m),2.40-2.55(1H,m),2.60-3.15(10H,m),4.71(2H,s),5.60-6.55(3H,m),6.61(1H,d,J=2.7Hz),6.65(1H,dd,J=8.4,2.7Hz),6.95(1H,d,J=8.4Hz)
特定旋光度:[α]D 25=-46.8°(c=0.99,ACOH)
参考实施例3
2-溴-1-(2,2-二甲基苯并[1,2-d]-1,3-二噁烷-6-基)-1-乙酮
将2-乙酰氧基-4-溴乙酰基苯基乙酸酯(18.6g)溶于90ml甲醇中,在冰-冷却,搅拌下加入100ml47%氢溴酸,混合物在室温下反应16小时。在冰-冷却,搅拌下往溶液中加入水,过滤收集产生的沉淀,用水和己烷洗涤给出9.54g 2-溴-4’-羟基-3’-羟基甲基乙酰基苯,熔点117-119℃。IR(KBr):3440,1677cm-1 1H-NMR(DMSO-d6)δppm:4.50(2H,s),4.75(2H,s),5.10(1H,br s),6.87(1H,d,J=8.5Hz),7.79(1H,dd,J=8.5,2.4Hz),7.99(1H,d,J=2.4Hz),10.52(1H,s)
2-溴-4’-羟基-3’-羟基甲基乙酰基苯,124mg对甲苯磺酸一水合物和256ml丙酮二甲基缩酮溶于256ml丙酮中,混合物在回流下加热30分钟。冷却后,将饱和碳酸氢钠水溶液加入反应溶液中,混合物用乙酸乙酯萃取。萃取液用水和食盐水洗涤,然后用无水硫酸镁干燥。减压蒸发溶剂,产生的残余物通过硅胶中压液相柱色谱(洗脱剂:己烷/乙酸乙酯=7/1)纯化给出11.9g 2-溴-1-(2,2-二甲基苯并[1,2-d]-1,3-二噁烷-6-基)-1-乙酮,熔点52-54℃。IR(KBr):1693 cm-1 1H-NMR(CDCl3)δppm:1.57(6H,s),4.37(2H,s),4.89(2H,s),6.88(1H,d,J=8.6Hz),7.69(1H,d,J=2.2Hz),7.82(1H,dd,J=8.6,2.2Hz)
参考实施例4
(-)-2-[(2S)-2-[[(2R)-2-(2,2-二甲基苯并[1,2-d]-1,3-二噁烷6-基)-2羟基乙基]氨基]1,2,3,4-四氢萘-7-基氧基]-N,N-二甲基乙酰胺
将6-溴-2,2-二甲基苯并[1,2-d]-1,3-二噁烷(30.0g)溶于610ml四氢呋喃,在-80℃搅拌下将136ml 1.56M在己烷中的正丁基锂,混合物进行反应15分钟。在-80℃搅拌下,将反应混合物加入21.6g草酸二乙酯在200ml四氢呋喃中的溶液,混合物进行反应1小时。然后,依次加入100ml乙醇和1.40g硼氢化钠在100ml乙醇中的溶液。反应溶液在-30℃搅拌30分钟,加入8.26ml乙酸,混合物搅拌5分钟。然后,加入14.8g碳酸氢钾在50ml水中的溶液,反应混合物在减压下浓缩。将水加入残余物中,混合物用乙酸乙酯萃取。萃取液用食盐水洗涤,然后用无水硫酸镁干燥。减压蒸发溶剂,产生的残余物通过硅胶中压液相柱色谱(洗脱剂:己烷/乙酸乙酯=5/1)纯化给出25.1g 2-(2,2-二甲基苯并[1,2-d]-1,3-二噁烷-6-基)-2-羟基乙酸乙酯油状物。IR(neat):3467,1736 cm-1 1H-NMR(CDCl3)δppm:1.24(3H,t,J=7.1Hz),1.54(6H,s),3.39(1H,d,J=5.6Hz),4.10-4.35(2H,m),4.84(2H,s),5.06(1H,d,J=5.6Hz),6.80(1H,d,J=8.4Hz),7.03(1H,d,J=1.9Hz),7.19(1H,dd,J=8.4,1.9Hz)
将2-(2,2-二甲基苯并[1,2-d]-1,3-二噁烷-6-基)-2-羟基乙酸乙酯(78.3g)溶于145ml乙醇中,在在冰-冷却,搅拌下往溶液中加入176ml 2N氢氧化钠水溶液,混合物在室温下进行反应1.5小时。在冰-冷却,搅拌下,往溶液中加入174ml 2N硫酸溶液,水和食盐水,混合物用乙酸乙酯萃取。萃取液用食盐水洗涤,然后用无水硫酸镁干燥。减压蒸发溶剂,产生的残余物溶于210ml乙醇。然后,加入50.3g(R)-(+)-1-(1-萘基)乙基胺,在室温下放置给出48.3g沉淀的晶体。通过将产生的晶体用88ml乙醇重结晶,得到43.6g(-)-(R)-2-(2,2二甲基苯并[1,2-d]-1,3-二噁烷6基)-2-羟基乙酸,(R)-(+)-1-(1-萘基)乙基胺和乙醇的1∶1∶1盐,熔点164-165℃。IR(KBr):3327,1567cm-1 1H-NMR(CDCl3)δppm:1.15-1.30(9H,m),1.38(3H,s),3.70(2H,q,J=7.0Hz),4.15(1H,s),4.38(1H,d,J=15.2Hz),4.49(1H,d,J=15.2Hz),4.71(1H,q,J=6.7Hz),6.46(1H,d,J=8.4Hz),6.53(1H,d,J=1.8Hz),6.61(1H,dd,J=8.4,1.8Hz),7.30-7.45(2H,m),7.50-7.65(2H,m),7.75(1H,d,J=8.4Hz),7.84(1H,d,J=7.9Hz),7.91(1H,d,J=8.1Hz)
特定旋光度:[α]D 25=-33.7°(c=0.52,MeOH)
将(-)-(R)-2-(2,2-二甲基苯并[1,2-d]-1,3-二噁烷-6-基)-2-羟基乙酸,(R)-(+)-1-(1-萘基)乙基胺和乙醇的1∶1∶1盐(43.6g)悬浮于200ml水和300ml乙酸乙酯的两层混合物中,在冰-冷却,搅拌下,往溶液中加入47.9ml 2N硫酸溶液,将混合物搅拌30分钟。反应溶液滤过Celite,滤液的有机层用水洗涤并用无水硫酸镁干燥。减压蒸发溶剂,产生的残余物用乙酸乙酯-二异丙基醚重结晶给出22.8g(-)-(R)-2-(2,2-二甲基苯并[1,2-d]-1,3-二噁烷-6-基)-2-羟基乙酸,熔点115-118℃(分解)。IR (KBr):3397,2638,1701cm-1 1H-NMR(DMSO-d6)δppm:1.45(6H,s),4.81(2H,s),4.92(1H,s),5.80(1H,br),6.75(1H,d,J=8.4Hz),7.09(1H,d,J=1.8Hz),7.18(1H,dd,J=8.4,1.8Hz),12.50(1H,br)特定旋光度:[α]D 25=-113.3°(c=1.54,MeCN)
将(-)-(R)-2-(2,2-二甲基苯并[1,2-d]-1,3二噁烷-6-基)-2羟基乙酸(130mg),148mg(S)-2-氨基-7-羟基四氢萘氢溴酸盐和243mg苯并三唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐溶于1.4ml N,N二甲基甲酰胺,在冰-冷却,搅拌下,往溶液中加入0.15ml三乙胺,混合物进行反应15小时。将水加入反应混合物中,混合物用乙酸乙酯萃取。萃取液用水洗涤,无水硫酸镁干燥。减压蒸发溶剂,产生的残余物通过氨基丙基化的硅胶中压液相柱色谱(洗脱剂:乙酸乙酯/丙酮=4/1)纯化给出186mg(-)-2-(2R)-2-(2,2二甲基苯并[1,2-d]-1,3-二噁烷-6-基)-2-羟基-N-(2S)-7-羟基-1,2,3,4-四氢萘-2-基)乙酰胺,熔点169-170℃。IR(KBr):3373,3263,1642cm-1 1H-NMR(CDCl3)δppm:1.49(3H,s),1.51(3H,s),1.60-1.80(1H,m),1.90-2.00(1H,m),2.50(1H,dd,J=16.3,8.3Hz),2.60-2.80(2H,m),2.92(1H,dd,J=16.3,5.0Hz),3.60(1H,br),4.15-4.25(1H,m),4.73(2H,s),4.93(1H,s),6.20(1H,br),6.36(1H,d,J=2.5Hz),6.50(1H,d,J=8.0Hz),6.59(1H,dd,J=8.3,2.5Hz),6.77(1H,d,J=8.4Hz),6.88(1H,d,J=8.3Hz),6.93(1H,d,J=2.0Hz),7.12(1H,dd,J=8.4,2.0Hz)特定旋光度:[α]D 25=-101.2°(c=0.52,MeOH)
将(-)-2-(2R)-2-(2,2-二甲基苯并[1,2-d]-1,3-二噁烷-6-基)-2-羟基-N-(2S)-7-羟基-1,2,3,4-四氢萘-2-基)乙酰胺(686mg)溶于50ml四氢呋喃,加入3.58ml 2M硼烷-二甲基硫醚复合物的四氢呋喃溶液,混合物加热回流3小时。然后,加入1.34g三乙醇胺在5.0ml四氢呋喃中的溶液,混合物再加热回流15小时。冷却后,将水加入反应混合物中,混合物用乙酸乙酯萃取。萃取液用水洗涤,然后用无水硫酸镁干燥。减压蒸发溶剂,产生的残余物用乙酸乙酯重结晶给出(-)-(1R)-1-(2,2-二甲基苯并[1,2-d]-1,3-二噁烷-6-基)-2-[((2S)-7-羟基-1,2,3,4四氢萘-2-基)氨基]乙醇,熔点156-158℃。IR(KBr):3400cm-1 1H-NMR(CDCl3)δppm:1.50-1.70(7H,m),2.00-2.10(1H,m),2.55(1H,dd,J=17.5,10.4Hz),2.65-2.85(3H,m),2.90-3.10(3H,m),4.61(1H,dd,J=9.1,3.5Hz),4.84(2H,s),6.53(1H,d,J=2.3Hz),6.60(1H,dd,J=8.2,2.3Hz),6.80(1H,d,J=8.4Hz),6.94(1H,d,J=8.2Hz),7.02(1H,s),7.14(1H,d,J=8.4Hz)特定旋光度:[α]D 25=-59.0°(c=1.02,MeOH)
将(-)-(1R)-1-(2,2-二甲基苯并[1,2-d]-1,3-二噁烷-6-基)-2-[((2S)-7-羟基-1,2,3,4-四氢萘-2-基)氨基]乙醇(5.15g)和11.3mlN,N-二异丙基乙基胺加入125ml二氯甲烷中,在-15℃搅拌下5.51ml三氟乙酸酐在16ml二氯甲烷中的溶液,混合物进行反应30分钟。反应混合物用水洗涤,无水硫酸镁干燥。然后,减压蒸发溶剂。将产生的残余物溶于63ml N,N-二甲基甲酰胺,将5.0g分子筛4A粉末,3.24g2-溴-N,N-二甲基乙酰胺和19.0g碳酸铯加入到溶液中,混合物在室温下搅拌2小时。然后加入2.02ml二乙基胺,混合物在室温下进行反应20分钟。在冰冷却下往溶液中加入90ml水和180ml甲醇后,混合物在室温下搅拌1.5小时。然后,将食盐水加入,混合物用乙酸乙酯萃取。萃取液用食盐水洗涤,然后用硫酸镁干燥。减压蒸发溶剂,产生的残余物通过氨基丙基化的硅胶中压液相柱色谱(洗脱剂:乙酸乙酯)纯化给出3.22g(-)-(2R)-2-[(2S)-2-[[2-(2,2-二甲基苯并[1,2-d]-1,3-二噁烷-6-基)-2-羟基乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]-N,N-二甲基乙酰胺油状物。IR(neat):3401,1656 cm-1 1H-NMR(CDCl3)δppm:1.50-1.70(7H,m),2.00-2.10(1H,m),2.56(1H,dd,J=15.2,8.0Hz),2.65-3.10(12H,m),4,59(1H,dd,J=9.1,3.5Hz),4.64(2H,s),4.84(2H,s),6.65(1H,d,J=2.6Hz),6.73(1H,dd,J=8.4,2.6Hz),6.79(1H,d,J=8.4Hz),6.99(1H,d,J=8.4Hz),7.02(1H,d,J=2.0Hz),7.14(1H,dd,J=8.4,2.0Hz)特定旋光度:[α]D 25=-46.0°(c=1.23,MeOH)
参考实施例5
(-)-1-[2[(2S)-2-[[(2R)2-(2,2-二甲基苯并[1,2-d]-1,3-二噁烷-6-基)-2-羟基乙基]氨基]1,2,3,4-四氢萘-7-基氧基]乙酰基]吡咯烷
重复参考实施例4的反应和处理,只是用1-溴代乙酰基吡咯烷代替2-溴-N,N-二甲基乙酰胺,得到非晶状(-)-1-[2-[(2S)-2-[[(2R)-2-(2,2-二甲基苯并[1,2-d]1,3-二噁烷-6-基)-2-羟基乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]乙酰基]吡咯烷。IR(膜):3401,1649cm-1 1H-NMR(CDCl3)δppm:1.45-1.70(7H,m),1.80-2.10(5H,m),2.56(1H,dd,J=15.4,8.3Hz),2.70-3.05(6H,m),3.45-3.60(4H,m),4.55-4.65(3H,m),4.85(2H,s),6.65(1H,d,J=2.7Hz),6.73(1H,dd,J=8.4,2.7Hz),6.79(1H,d,J=8.4Hz),6.99(1H,d,J=8.4Hz),7.02(1H,d,J=1.9Hz),7.14(1H,dd,J=8.4,1.9Hz)特定旋光度:[α]D 25=-47.0°(c=1.13,MeOH)
(-)-1-[2-[(2S)-2-[[(2R)-2-(2,2-二甲基苯并[1,2-d]-1,3-二噁烷-6-基)-2-羟基乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]乙酰基]哌啶
重复参考实施例4的反应和处理,只是用1-溴代乙酰基吡啶代替2-溴-N,N-二甲基乙酰胺,得到非晶状 (-)-1-[2-(2S)-2-[[(2R)-2-(2,2-二甲基苯并[1,2-d]-1,3-二噁烷-6-基)-2-羟基乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]乙酰基]吡啶。IR(膜):3402,1649cm-1 1H-NMR(CDCl3)δppm:1.40-1.70(13H,m),1.95-2.10(1H,m),2.50-3.10(7H,m),3.40-3.60(4H,m),4.55-4.65(3H,m),4.85(2H,s),6.65(1H,d,J=2.7Hz),6.73(1H,dd,J=8.4,2.7Hz),6.80(1H,d,J=8.4Hz),6,99(1H,d,J=8.4Hz),7.02(1H,d,J=1.8Hz),7.14(1H,dd,J=8.4,1.8Hz)特定旋光度 :[α]D 25=-45.6°(c=1.00,MeOH)
(-)-4-[2-[(2S)-2-[[(2R)-2-(2,2-二甲基苯并[1,2-d]-1,3-二噁烷-6-基)-2-羟基乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]乙酰基]吗啉
重复参考实施例4的反应和处理,只是用4-溴代乙酰基吗啉代替2-溴-N,N-二甲基乙酰胺,得到非晶状(-)-4-[2-[(2S)-2-[[(2R)-2-(2,2-二甲基苯并[1,2-d]-1,3-二噁烷-6-基)-2-羟基乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]乙酰基]吗啉。IR(KBr):3438,1652 cm-1 1H-NMR(CDCl3)δppm:1.45-1.70(7H,m),2.00-2.10(1H,m),2.50-3.10(7H,m),3.55-3.75(8H,m),4.59(1H,dd,J=9.1,3.4Hz),4.65(2H,s),4.85(2H,s),6.65(1H,d,J=2.6Hz),6.72(1H,dd,J=8.4,2.6Hz),6.80(1H,d,J=8.4Hz),7.00(1H,d,J=8.4Hz),7.03(1H,d,J=1.8Hz),7.14(1H,dd,J=8.4,1.8Hz)特定旋光度[α]D 25=-52.2°(c=0.54,MeOH)
参考实施例6
重复参考实施例4的反应,只是用(S)-(-)-1-(1-萘基)乙基胺代替(R)-(+)-1-(1-萘基)乙基胺,给出(+)-(S)-2-(2,2-二甲基苯并[1,2-d]-1,3-二噁烷-6-基)-2-羟基乙酸,并随后得到如下化合物。
(-)-2-[(2S)-2-[[(2S)-2-(2,2-二甲基苯并[1,2-d]-1,3-二噁烷-6-基)-2-羟基乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]-N,N-二甲基乙酰胺
熔点:130-131℃(重结晶溶剂:乙酸乙酯)IR(KBr):3432,1652cm-1 1H-NMR(CDCl3)δppm:1.45-1.65(7H,m),2.00-2.10(1H,m),2.58(1H,dd,J=16.0,8.9Hz),2.65-3.10(12H,m),3.65(1H,br),4.60(1H,dd,J=9.2,3.5Hz),4.64(2H,s),4.85(2H,s),6.65(1H,d,J=2.6Hz),6.73(1H,dd,J=8.4,2.6Hz),6.80(1H,d,J=8.4Hz),6.99(1H,d,J=8.4Hz),7.02(1H,d,J=1.9Hz),7.14(1H,dd,J=8.4,1.9Hz)特定旋光度:[α]D 25=-25.6°(c=1.20,MeOH)
(-)-1-[2-[(2S)-2-[[(2S)-2-(2,2-二甲基苯并[1,2-d]-1,3-二噁烷-6-基)-2-羟基乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]乙酰基]吡咯烷
非晶状IR(KBr): 3415,1649cm-1 1H-NMR(CDCl3)δppm:1.50-1.70(7H,m),1.80-2.10(5H,m),2.55-3.10(7H,m),3.52(4H,t,J=6.6Hz),4.55-4.65(1H,m),4.58(2H,s),4.85(2H,s),6.65(1H,d,J=2.6Hz),6.74(1H,dd,J=8.4,2.7Hz),6.80(1H,d,J=8.4Hz),6.95-7.05(2H,m),7.10-7.15(1H,m)特定旋光度:[α]D 25=-26.9°(c=1.00,MeOH)
参考实施例7
2-[(2S)-2-[[(2RS)-2-[4-苄氧基-3-(2-苄氧基乙基)苯基]-2-羟基乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]-N,N-二甲基乙酰胺
将2-(5-乙酰基-2-羟基苯基)乙酸甲酯溶于120ml N,N-二甲基甲酰胺,将5ml溴化苄和5.8g碳酸钾加入溶液中,混合物在室温下搅拌16小时。将约100g冰和200ml己烷加入反应溶液中,在剧烈搅拌下往混合物中加入200ml水。然后通过过滤收集沉淀的晶体,用二氯甲烷-己烷重结晶给出10.1g2-(5-乙酰基-2-苄氧基苯基)乙酸甲酯,熔点85-87℃。IR(KBr):1747,1682cm-1 1H-NMR(CDCl3)δppm:2.55(3H,s),3.64(3H,s),3.71(2H,s),5.16(2H,s),6.96(1H,d,J=8.6Hz),7.30-7.40(5H,m),7.85(1H,d,J=2.3Hz),7.89(1H,dd,J=8.6,2.3Hz)
将2-(5-乙酰基-2-苄氧基苯基)乙酸甲酯(9.0g),18ml原甲酸甲酯和18ml乙二醇溶于300ml二氯甲烷中,将60mg对甲苯磺酸一水合物加入溶液中,混合物加热回流12小时。冷却后,将0.14ml三乙胺加入反应溶液中,将混合物搅拌15分钟。反应溶液通过硅胶快速柱层析(洗脱剂:二氯甲烷)部分纯化,然后进一步通过硅胶中压液相柱色谱(洗脱剂:己烷/乙醚=3/2)纯化,给出9.2g 2-[2-苄氧基-5-(2-甲基1,3二氧戊环-2-基)苯基]乙酸甲酯油状物。IR(neat):1742 cm-1 1H-NMR(CDCl3)δppm:1.65(3H,s),3.63(3H,s),3.68(2H,s),3.80-3.85(2H,m),4.00-4.05(2H,m),5.07(2H,s),6.88(1H,d,J=8.4Hz),7.30-7.45(7H,m)
将2-[2-苄氧基-5-(2-甲基-1,3-二氧戊环-2-基)苯基]乙酸甲酯(9.0g)溶于130ml乙醚,在冰冷却,搅拌下往溶液中以小批加入1.0g氢化铝锂,混合物进行反应1小时。在冰冷却,搅拌下往溶液中以小批加入水,滤出形成的沉淀。通过减压浓缩滤液,得到9.0g 2-[2-苄氧基-5-(2-甲基-1,3-二氧戊环-2-基)苯基]乙醇油状物。IR(neat):3442cm-1 1H-NMR(CDCl3)δppm:1.60-1.70(4H,m),2.96(2H,t,J=6.5Hz),3.75-3.90(4H,m),3.95-4.10(2H,m),5.08(2H,s),6.89(1H,dd,J=7.0,2.0Hz),7.30-7.45(7H,m)
将2-[2-苄氧基-5(2-甲基-1,3-二氧戊环-2-基)苯基]乙醇(9.0g)溶于100ml N,N-二甲基甲酰胺,在冰冷却,搅拌下往溶液中加入1.26g在60%油中的氢化钠,混合物在室温下进行反应1小时。然后,在冰冷却,搅拌下加入3.75ml溴化苄,混合物在室温下进行反应16小时。然后,将100g冰和100ml水加入反应溶液中,混合物用乙醚萃取,然后减压蒸发溶剂。将产生的残余物溶于50ml 1,2-二甲氧基乙烷,将10ml 1N盐酸加入溶液中,混合物在室温下搅拌30分钟。加入水,混合物用乙醚萃取,萃取液用无水硫酸镁干燥。减压蒸发溶剂,产生的残余物通过硅胶中压液相柱色谱(洗脱剂:己烷/乙醚=2/1)纯化,给出8.5g 4’-苄氧基-3’-(2-苄氧基乙基)乙酰基苯油状物。IR(neat):1677cm-1 1H-NMR(CDCl3)δppm:2.54(3H,s),3.05(2H,t,J=7.0Hz),3.73(2H,t,J=7.0Hz),4.52(2H,s),5.13(2H,s),6.92(1H,d,J=8.5Hz),7.20-7.40(10H,m),7.83(1H,dd,J=8.5,2.3Hz),7.86(1H,d,J=2.3Hz)
将4’-苄氧基-3’-(2-苄氧基乙基)乙酰基苯(8.0g)和0.4ml 30%溴化氢乙酸溶液溶于80ml氯仿中,在室温搅拌下,在2小时期间往溶液中滴加1.1ml溴在30ml氯仿中的溶液。减压浓缩反应溶液,产生的残余物通过硅胶中压液相柱色谱(洗脱剂:己烷/乙醚=2/1)纯化,给出3.9g4’-苄氧基-3’-(2-苄氧基乙基)-2-溴代乙酰基苯,熔点53-56℃。IR(KBr):1684cm-1 1H-NMR(CDCl3)δppm:3.04(2H,t,J=6.9Hz),3.73(2H,t,J=6.9Hz),4.38(2H,s),4.51(2H,s),5.14(2H,s),6.95(1H,d,J=8.4Hz),7.20-7.45(10H,m),7.85-7.90(2H,m)
在冰冷却,搅拌下将水(20ml)和二氯甲烷(20ml)加入600mg(S)-2-(2-氨基-1,2,3,4-四氢萘-7-基氧基)乙酸乙酯盐酸盐,300mg碳酸氢钠加入混合物中,混合物被搅拌30分钟。分出有机层,用无水硫酸镁干燥,减压蒸发溶剂。产生的残余物溶于0.5ml N,N-二甲基甲酰胺,在-10℃搅拌下,往溶液中加入440mg4’-苄氧基-3’-(2-苄氧基乙基)-2-溴代乙酰基苯在1ml N,N-二甲基甲酰胺中的溶液,混合物在0℃进行反应20分钟。反应溶液再冷却至-10℃,在搅拌下依次往溶液中加入190mg硼氢化钠和4ml乙醇,混合物在0℃进行反应10分钟。将反应混合物倒入冰水中,混合物用乙酸乙酯萃取。萃取液用水洗涤并用无水硫酸镁干燥,然后减压蒸发溶剂。将产生的残余物溶于10ml四氢呋喃中,往溶液中加入0.7ml三乙醇胺,混合物加热回流16小时。冷却后,加入水,混合物用乙酸乙酯萃取。萃取液用水洗涤并用无水硫酸镁干燥。减压蒸发溶剂,产生的残余物通过硅胶中压液相柱色谱(洗脱剂:二氯甲烷/乙醇=30/1)纯化,给出540mg2[(2S)-2-[[(2RS)-2-[4-苄氧基-3-(2-苄氧基乙基)苯基]-2-羟基乙基]氨基-1,2,3,4-四氢萘-7-基氧基]乙酸乙酯油状物。IR(neat):3297,1759,1736cm-1 1H-NMR(CDCl3)δppm:1.30(3H,t,J=7.1Hz),1.50-1.65(1H,m),2.00-2.10(1H,m),2.50-2.85(4H,m),2.90-3.10(5H,m),3.72(2H,t,J=7.3Hz),4.27(2H,q,J=7.1Hz),4.51(2H,s),4.57(2H,s),4.62(1H,dd,J=9.0,3.4Hz),5.06(2H,s),6.60(1H,s),6.69(1H,dd,J=8.4,2.7Hz),6.88(1H,d,J=8.4Hz),6.99(1H,d,J=8.4Hz),7.15-7.45(12H,m)
将2-[(2S)-2-[[(2RS)-2-[4-苄氧基-3-(2-苄氧基乙基)苯基]-2-羟基乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]乙酸乙酯(256mg)和2.2ml二甲基胺溶于2.2ml四氢呋喃,将溶液密封于管中,在60℃进行反应39小时。减压蒸发反应溶液,产生的残余物通过硅胶中压液相柱色谱(洗脱剂:乙酸乙酯/乙醇=1/1)纯化,给出230mg非晶状2-[(2S)-2-[[(2RS)-2-[4-苄氧基-3-(2-苄氧基乙基)苯基]-2-羟基乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]-N,N-二甲基乙酰胺。IR(neat):3381,1655,1649cm-1 1H-NMR(CDCl3)δppm:1.60-1.75(1H,m),2.05-3.15(18H,m),3.71(2H,t,J=7.2Hz),4.50(2H,s),4.63(2H,s),4.75(1H,d,J=7.4Hz),5.05(2H,s),6.63(1H,s),6.74(1H,dd,J=8.4,2.7Hz),6.87(1H,d,J=8.4Hz),6.99(1H,d,J=8.4Hz),7.15-7.45(12H,m)
参考实施例8
(-)-2-[(2S)2-[[(2R)-2-[4-苄氧基-3-(2-苄氧基乙基)苯基]-2-羟基乙基]氨基-1,2,3,4-四氢萘-7-基氧基]-N,N-二甲基乙酰胺
将苄基2-(2-苄氧基乙基)苯基醚(159mg)和123mg乙酸钠悬浮于2ml乙酸中,在室温搅拌下,往悬浮液中加入29μl溴,混合物进行反应1小时。然后,加入100mg亚硫酸钠七水合物在20ml水中的溶液,混合物用乙酸乙酯萃取。萃取液依次用水,饱和碳酸氢钠水溶液和水洗涤,然后用无水硫酸镁干燥。减压蒸发溶剂,产生的残余物通过硅胶中压液相柱色谱(洗脱剂:己烷/二氯甲烷=2/1)纯化,给出173mg苄基2-(2-苄氧基乙基)-4-溴代苯基醚油状物。1H-NMR(CDCl3)δppm:2.97(2H,t,J=7.0Hz),3.68(2H,t,J=7.0Hz),4.50(2H,s),5.02(2H,s),6.75(1H,d,J=8.7Hz),7.20-7.40(12H,m)
将苄基2-(2-苄氧基乙基)-4-溴代苯基醚(24.0g)溶于200ml四氢呋喃,在-95℃,搅拌下,往溶液中加入47.0ml 1.57M正丁基锂的己烷溶液,混合物进行反应15分钟。在-95℃,搅拌下,将反应溶液加入10.8g草酸二乙酯在300ml四氢呋喃中的溶液,草酸的溶液进行反应1小时。然后,依次加入200ml乙醇和755mg硼氢化钠。反应溶液在-35℃搅拌45分钟,加入4.70ml乙酸,将混合物搅拌15分钟。然后,加入6.9g碳酸氢钠在300ml水中的溶液,减压浓缩混合物。产生的浓缩物用乙酸乙酯萃取,萃取液用水洗涤,然后用无水硫酸镁干燥。然后减压蒸发溶剂,产生的残余物通过硅胶中压液相柱色谱(洗脱剂:己烷/乙酸乙酯=3/1)纯化,给出19.9g 2-[4-苄氧基-3-(2-苄氧基乙基)苯基]-2-羟基乙酸乙酯油状物。IR(neat): 3456,1735cm-1 1H-NMR(CDCl3)δppm:1.21(3H,t,J=7.1Hz),3.02(2H,t,J=7.3Hz),3.34(1H,d,J=5.9Hz),3.70(2H,t,J=7.3Hz),4.10-4.30(2H,m),4.51(2H,s),5.05(2H,s),5.08(1H,d,J=5.9Hz),6.87(1H,d,J=8.4Hz),7.20-7.40(12H,m)
将2-[4苄氧基-3-(2-苄氧基乙基)苯基]2-羟基乙酸乙酯(39.7g)悬浮于40ml乙醇中,在冰冷却,搅拌下往悬浮液中加入57ml 2N氢氧化钠水溶液,混合物在室温下进行反应1小时。然后,在冰冷却,搅拌下往反应溶液中加入57ml 2N硫酸水溶液,混合物用乙酸乙酯萃取。萃取液用水洗涤,然后用无水硫酸镁干燥。然后,减压蒸发溶剂给出35.1g 2-[4-苄氧基-3-(2-苄氧基乙基)苯基]-2-羟基乙酸油状物。IR(neat):3399,1734,1719cm-1 1H-NMR(CDCl3)δppm:3.01(2H,t,J=7.1Hz),3.71(2H,t,J=7.1Hz),4.50(2H,s),5.06(2H,s),5.16(1H,s),6.89(1H,d,J=8.4Hz),7.20-7.40(12H,m)
将2-[4-苄氧基-3-(2-苄氧基乙基)苯基]-2-羟基乙酸(1.73g),1.18g(S)-2-氨基-7-羟基四氢萘氢溴酸盐和1.95g苯并三唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐溶于11ml N,N-二甲基甲酰胺,在室温搅拌下往溶液中加入1.23ml三乙胺,将混合物进行反应3小时。将水加入反应混合物中,混合物用乙酸乙酯萃取。萃取液用水洗涤,然后用无水硫酸镁干燥。减压蒸发溶剂,产生的残余物通过硅胶中压液相柱色谱(洗脱剂:己烷/乙酸乙酯=1/1)部分纯化,给出2-[4-苄氧基-3-(2-苄氧基乙基)苯基]-2-羟基-N-((2S)-7-羟基-1,2,3,4-四氢萘-2-基)乙酰胺(非对映异构体混合物)。通过硅胶中压液相柱色谱(洗脱剂:乙醚)分开混合物给出1.08g非晶状(-)-(2R)-2-[4-苄氧基-3-(2-苄氧基乙基)苯基]-2-羟基-N-((2S)-7-羟基-1,2,3,4-四氢萘-2-基)乙酰胺(低极性异构体)和0.94g(-)-(2S)-2-[4-苄氧基-3-(2-苄氧基乙基)苯基]-2-羟基-N-((2S)-7-羟基-1,2,3,4-四氢萘-2-基)乙酰胺(高极性异构体)。
低极性异构体IR(film):3382,1650cm-1 1H-NMR(CDCl3)δppm:1.60-1.75(1H,m),1.85-2.00(1H,m),2.51(1H,dd,J=16.3,7.7Hz),2.55-2.80(2H,m),2.85-3.05(3H,m),3.49(1H,d,J=3.3Hz),3.66(2H,t,J=7.4Hz),4.15-4.25(1H,m),4.47(2H,s),4.89(1H,d,J=3.3Hz),5.00(2H,s),6.32(1H,br s),6.37(1H,d,J=2.5Hz),6.49(1H,d,J=8.0Hz),6.56(1H,dd,J=8.3,2.5Hz),6.81(1H,d,J=8.4Hz),6.85(1H,d,J=8.3Hz),7.10(1H,d,J=2.2Hz),7.14(1H,dd,J=8.4,2.2Hz),7.20-7.40(10H,m)Specific rotation:[α]D 31= -59.5°(c=1.08,MeOH)
高极性异构体IR(film):3387,1655cm-1 1H-NMR(CDCl3)δppm:1.60-1.75(1H,m),1.90-2.00(1H,m),2.49(1H,dd,J=16.3,8.3Hz),2.65-2.80(2H,m),2.90-3.05(3H,m),3.57(1H,br s),3.69(2H,t,J=7.1Hz),4.15-4.25(1H,m),4.49(2H,s),4.91(1H,d,J=3.4Hz),5.02(2H,s),6.02(1H,br s),6.35-6.45(2H,m),6.59(1H,dd,J=8.3,2.6Hz),6.84(1H,d,J=8.4Hz),6.88(1H,d,J=8.3Hz),7.10-7.40(12H,m)特定旋光度:[α]D 31=-4.8°(c=1.05,MeOH)
将(-)-(2R)-2-[4-苄氧基-3-(2-苄氧基乙基)苯基]-2-羟基-N-((2S)-7-羟基-1,2,3,4-四氢萘-2-基)乙酰胺(低极性异构体)(1.08g)溶于20ml四氢呋喃,438μl硼烷-二甲基硫醚复合物加入溶液中,混合物被加热回流3小时。然后,加入1.14g三乙醇胺在1ml四氢呋喃中的溶液,混合物再加热回流6小时。冷却后,往反应混合物中加入水,混合物用乙酸乙酯萃取。萃取液用水洗涤,然后用无水硫酸镁干燥。然后,减压蒸发溶剂,产生的残余物用乙酸乙酯重结晶,给出687mg(-)-(1R)-1-[4-苄氧基-3-(2-苄氧基乙基)苯基]-2-羟基-N-((2S)-7-羟基-1,2,3,4-四氢萘-2-基氨基)乙醇,熔点147-150℃。IR(KBr):3430,3290,3190cm-1 1H-NMR(CDCl3)δppm:1.50-1.65(1H,m),2.00-2.10(1H,m),2.54(1H,dd,J=17.7,10.6Hz),2.65-2.85(3H,m),2.90-3.10(5H,m),3.72(2H,t,J=7.2Hz),4.51(2H,s),4.62(1H,dd,J=9.0,3.4Hz)5.05(2H,s),6.52(1H,d,J=2.6Hz),6.60(1H,dd,J=8.2,2.6Hz),6.87(1H,d,J=8.3Hz),6.94(1H,d,J=8.2Hz),7.15-7.40(12H,m)特定旋光度:[α]D 31=-47.9°(c=1.10,tetrahydrofuran)
将(-)(1R)-1-[4-苄氧基-3(2苄氧基乙基)苯基]-2-羟基-N-((2S)-7羟基-1,2,3,4-四氢萘2基氨基)乙醇(450mg)溶于4ml二氯甲烷,在室温搅拌下,往溶液中依次加入860μl5N氢氧化钠水溶液和143mg 2溴-N,N-二甲基乙酰胺,混合物在室温下进行反应3小时。然后,再往溶液中加入143mg 2溴-N,N-二甲基乙酰胺,混合物在室温下进行反应1小时。然后,加入267μl二乙基胺,将混合物搅拌30分钟。将食盐水加入反应溶液中,混合物用乙酸乙酯萃取。萃取液用食盐水洗涤,然后用无水硫酸镁干燥。减压蒸发溶剂,产生的残余物通过氨基丙基化的硅胶中压液相柱色谱(洗脱剂:乙酸乙酯)纯化,给出410mg(-)-2-[(2S)-2-[[(2R)-2-[4-苄氧基-3-(2-苄氧基乙基)苯基]-2-羟基乙基]氨基]-1,2,3,4-四氢萘-7-基氧基)-N,N-二甲基乙酰胺油状物。IR(neat):3410,1656cm-1 1H-NMR(CDCl3)δppm:1.50-1.65(1H,m),2.00-2.10(1H,m),2.56(1H,dd,J=15.7,8.4Hz),2.65-3.10(14H,m),3.72(2H,t,J=7.5Hz),4.51(2H,s),4.60-4.70(3H,m),5.06(2H,s),6.58(1H,d,J=2.7Hz),6.74(1H,dd,J=8.4,2.7Hz),6.88(1H,d,J=8.4Hz),6.99(1H,d,J=8.4Hz),7.15-7.45(12H,m)特定旋光度:[α]D 25=-41.1°(c=1.00,MeOH)
参考实施例9
(-)-2-[(2S)-2-[[(2S)-2-[4-苄氧基-3-(2-苄氧基乙基)苯基]-2-羟基乙基]氨基]-1,2,3,4-四氢萘-7-基氧基)-N,N-二甲基乙酰胺
用在参考实施例8中得到的(-)-(2S)-2-[4-苄氧基-3-(2-苄氧基乙基)苯基]-2-羟基-N-((2S)7-羟基-1,2,3,4-四氢萘-2-基)乙酰胺(高极性异构体),重复参考实施例中的反应和处理,给出(-)-2-[(2S)-2-[[(2S)-2-[4-苄氧基-3-(2-苄氧基乙基)苯基]-2-羟基乙基]氨基]-1,2,3,4四氢萘-7-基氧基)-N,N-二甲基乙酰胺油状物。IR(neat):3409,1655cm-1 1H-NMR(CDCl3)δppm:1.50-1.65(1H,m),2.00-2.10(1H,m),2.57(1H,dd,J=16.0,8.8Hz),2.65-3.10(14H,m),3.71(2H,t,J=7.2Hz),4.50(2H,s),4.55-4.65(3H,m),5.05(2H,s),6.64(1H,d,J=2.7Hz),6.73(1H,dd,J=8.4,2.7Hz),6.87(1H,d,J=8.4Hz),6.98(1H,d,J=8.4Hz),7.15-7.45(12H,m)特定旋光度:[α]D 31=-24.2°(c=1.08,MeOH)
(-)-1-[2-[(2S)-2-[[(2R)-2-[4-苄氧基-3-(2-苄氧基乙基)苯基]-2-羟基乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]乙酰基]吡咯烷
用在参考实施例8中得到的(-)-(2R)-2-[4-苄氧基-3-(2-苄氧基乙基)苯基]-2-羟基-N-((2S)-7-羟基-1,2,3,4-四氢萘-2-基)乙酰胺(低极性异构体),重复参考实施例8中的反应和处理,给出(-)-1-[2-[(2S)-2-[[(2R)-2-[4-苄氧基-3-(2-苄氧基乙基)苯基]-2-羟基乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]乙酰基]比咯烷油状物。IR(neat):3401,1652cm-1 1H-NMR(CDCl3)δppm:1.40-1.75(1H,m),1.80-2.10(5H,m),2.50-2.60(1H,m),2.65-3.10(8H,m),3.45-3.55(4H,m),3.72(2H,t, J=7.3Hz)4.51(2H,s),4.55-4.65(3H,m),5.06(2H,s),6.65(1H,d,J=2.7Hz),6.74(1H,dd,J=8.4,2.7Hz),6.88(1H,d,J=8.4Hz),6.99(1H,d,J=8.4Hz),7.15-7.45(12H,m)特定旋光度:[α]D 25=-41.4°(c=0.59,MeOH)
(-)-1-[2-[(2S)-2-[[(2R)-2-[4-苄氧基-3-(2-苄氧基乙基)苯基]-2-羟基乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]乙酰基]哌啶
用在参考实施例8中得到的(-)-(2R)-2-[4-苄氧基-3-(2-苄氧基乙基)苯基]-2-羟基-N-((2S)-7-羟基-1,2,3,4-四氢萘-2-基)乙酰胺(低极性异构体)和1-溴代乙酰基哌啶,重复参考实施例8中的反应和处理,给出(-)-1-[2-[(2S)-2-[[(2R)-2-[4-苄氧基-3-(2-苄氧基乙基)苯基]-2-羟基乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]乙酰基]哌啶油状物。IR(neat):3395,649cm-1 1H-NMR(CDCl3)δppm:1.30-1.70(9H,m),1.95-2.05(1H,m),2.50-3.10(9H,m),3.45-3.60(4H,m),3.72(2H,t,J=7.2Hz),4.51(2H,s),4.55-4.65(3H,m),5.06(2H,s),6.65(1H,d,J=2.7Hz),6.73(1H,dd,J=8.4,2.7Hz),6.88(1H,d,J=8.4Hz),6.95-7.05(1H,m),7.15-7.45(12H,m)特定旋光度:[α]D 30=-78.1°(c=0.52,CHCl3)
(-)-4-[2-[(2S)-2-[[(2R)-2-[4-苄氧基-3-(2-苄氧基乙基)苯基]-2-羟基乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]乙酰基]吗啉
用在参考实施例8中得到的(-)-(2R)-2-[4-苄氧基-3-(2-苄氧基乙基)苯基]-2-羟基-N((2S)-7-羟基-1,2,3,4-四氢萘-2-基)乙酰胺(低极性异构体)和4-溴代乙酰基吗啉,重复参考实施例8中的反应和处理,给出(-)-4-[2-[(2S)-2-[[(2R)-2-[4-苄氧基-3-(2-苄氧基乙基)苯基]-2-羟基乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]乙酰基]吗啉油状物。IR(neat):3403,1655,1649cm-1 1H-NMR(CDCl3)δppm:1.40-1.80(4H,m),2.00-2.10(1H,m),2.50-3.10(9H,m),3.40-3.75(9H,m),4.51(2H,s),4.55-4.65(3H,m),5.06(2H,s),6.64(1H,d,J=2.7Hz),6.72(1H,dd,J=8.4,2.7Hz),6.88(1H,d,J=8.4Hz),6.95-7.05(1H,m),7.15-7.45(12H,m)特定旋光度:[α]D 30=-46.9°(c=0.52,CHCl3)
参考实施例10
2-[(2S)-2-[[(2RS)-2-羟基2-[4-羟基-3-羟基甲基苯基)乙基]氨基]-1,2,3,4四氢萘-7-基氧基]乙酸乙酯
将水(500ml)和二氯甲烷(1000ml)加入42.5g(S)-2-(2-氨基-1,2,3,4-四氢萘-7-基氧基]乙酸乙酯盐酸盐中,在冰冷却,搅拌下,往混合物中加入19.0g碳酸氢钠,将混合物搅拌1小时。分出有机层,无水硫酸镁干燥,然后减压蒸发溶剂。产生的残余物溶于370mlN,N-二甲基甲酰胺,在-10℃搅拌下,往溶液中加入;21.0g2-溴-1-(2,2-二甲基苯并[1,2-d]-1,3-二噁烷-6-基)-1-乙酮在220mlN,N-二甲基甲酰胺中的溶液,混合物在0℃进行反应1小时。将反应溶液冷却至-10℃,在搅拌下往溶液中依次加入14.0g硼氢化钠和180ml乙醇,混合物在0℃进行反应1小时。将混合物倒入冰-水中,混合物用乙酸乙酯萃取。萃取液用水洗涤,然后用无水硫酸镁干燥,减压蒸发溶剂。产生的残余物溶于350ml四氢呋喃,往溶液中加入22g三乙醇胺,混合物加热回流12小时。冷却后,往反应溶液中加入水,混合物用乙酸乙酯萃取。萃取液用水洗涤,然后用无水硫酸镁干燥。然后减压蒸发溶剂,产生的残余物通过硅胶中压液相柱色谱(洗脱剂:乙酸乙酯/乙醇=7/1)纯化,给出12.7g非晶状2-[(2S)-2-[[(2RS)-2-(2,2-二甲基苯并[1,2-d]-1,3-二噁烷-6-基)-2-羟乙基]-氨基]-1,2,3,4四氢萘-7-基氧基]乙酸乙酯。IR(KBr):3304,1758,1737cm-1 1H-NMR(CDCl3)δppm:1.30(3H,t,J=7.1Hz),1.45-1.70(7H,m),2.00-2.10(1H,m),2.50-3.10(7H,m),4.27(2H,q,J=7.1Hz),4.55-4.65(3H,m),4.84(2H,s),6.61(1H,s),6.69(1H,dd,J=8.4,2.6Hz),6.79(1H,d,J=8.4Hz),6.99(1H,d,J=8.4Hz),7.02(1H,s),7.13(1H.d,J=8.4Hz)
将2-[(2S)-2-[[(2RS)-2-(2,2-二甲基苯并[1,2-d]-1,3-二噁烷-6-基)-2-羟乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]乙酸乙酯(11.5g)悬浮于75ml1,2二甲基乙烷中,将温度保持在20℃或更低,往悬浮液中滴加252ml1N盐酸,产生的混合物在室温下进行反应30分钟。然后,在0℃搅拌下,加入23.3g碳酸氢钠,混合物用乙酸乙酯萃取。萃取液用饱和碳酸氢钠水溶液和食盐水洗涤,然后用无水硫酸镁干燥。然后,减压蒸发溶剂,产生的残余物通过硅胶中压液相柱色谱(洗脱剂:乙酸乙酯/乙醇=5/1)纯化,给出7.2g非晶状2-[(2S)-2[[(2RS)-2-羟基-2-(4-羟基-3-羟基甲基苯基)乙基)氨基]-1,2,3,4-四氢萘-7-基氧基]乙酸乙酯。IR(KBr):3191,1763,1752,1738cm-1 1H-NMR(DMSO-d6)δppm:1.15-1.25(3H,m),1.35-1.55(1H,m),1.70(1H,brs),1.85-2.00(1H,m),2.35-2.50(1H,m),2.55-3.00(6H,m),4.10-4.20(2H,m),4.40-4.55(3H,m),4.65-4.70(2H,m),4.94(1H,brs),5.08(1H,brs),6.55-6.70(2H,m),6.69(1H,d,J=8.2Hz),6.95(1H,d,J=8.2Hz),7.01(1H,d,J=8.2Hz),7.25-7.30(1H,m),9.17(1H,brs)
参考实施例11
4-[(2S)-2-[[(2RS)-2-(2,2-二甲基苯并[1,2-d]-1,3-二噁烷-6-基)-2-羟基乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]-N,N-二甲基丁酰胺
将(S)-4-(2-氨基-1,2,3,4-四氢萘-7-基氧基)-N,N-二甲基丁酰胺(263mg)和360μl三乙胺溶于5mlN,N-二甲基甲酰胺中,在冰冷却搅拌下,往溶液中加入245mg2-溴-1-(2,2-二甲基苯并[1,2-d]-1,3-二噁烷-6-基)-1-乙酮在2mlN,N-二甲基甲酰胺中的溶液,将混合物进行反应25分钟。在冰冷却搅拌下,往反应溶液中加入220mg硼氢化钠和5ml乙醇,将混合物搅拌1.5小时。将反应溶液倒入冰-水中,混合物用乙酸乙酯萃取。萃取液用水洗涤,用无水硫酸镁干燥。减压蒸发溶剂,将260mg三乙醇胺在7ml四氢呋喃中的溶液加入到产生的残余物中,混合物加热回流12小时。将水加入反应溶液中,混合物用乙酸乙酯萃取。萃取液用水洗涤,然后用无水硫酸镁干燥。减压蒸发溶剂,产生的残余物通过硅胶中压液相柱色谱(洗脱剂:乙酸乙酯/乙醇=6/1)纯化,给出165mg非晶状4-[(2S)-2-[[(2RS)2-(2,2-二甲基苯并[1,2-d]-1,3-二噁烷-6-基)2-羟基乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]-N,N-二甲基丁酰胺。IR(KBr):3445,1631cm-1 1H-NMR(CDCl3)δppm:1.53-1.70(7H,m),2.00-2.20(3H,m),2.4 5-3.10(15H,m),3.95-4.05(2H,m),4.60-4.65(1H,m),4.85(2H,s),6.60(1H,s),6.65-6.75(1H,m),6.80(1H,d,J=8.4Hz),6.98(1H,d,J=8.4Hz),7.03(1H,s),7.10-7.20(1H,m)
实施例1
2-[(2S)-2-[[(2RS)-2-羟基-2-(4-羟基-3-羟基甲基苯基)乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]-N,N-二甲基乙酰胺(化合物1)
将2-[(2S)-2-[[(2RS)-2-羟基-2-(4-羟基-3-羟基甲基苯基)乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]乙酸乙酯(2.00g)溶于17.9g二甲基胺在10ml四氢呋喃中的溶液,将溶液密封在管内,并在65℃反应36小时。减压蒸发反应溶液,产生的残余物通过氨基丙基化的硅胶中压液相柱色谱(洗脱剂:氯仿/甲醇=10/1)纯化,给出1.58g非晶状2-[(2S)-2-[[(2RS)-2-羟基-2-(4-羟基-3-羟基甲基苯基)乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]-N,N-二甲基乙酰胺(化合物1)。IR(KBr):3395,1652cm-1 1H-NMR(CDCl3)δppm:1.50-1.65(1H,m),1.95-2.10(1H,m),2.45-2.60(1H,m),2.65-2.85(3H,m),2.85-3.00(6H,m),3.05-3.10(3H,m),4.55-4.70(3H,m),4.75-4.85(2H,m),6.55-6.65(1H,m),6.65-6.75(1H,m),6.80-6.85(1H,m),6.90-7.05(2H,m),7.10-7.20(1H,m)
实施例2
以与实施例1所述相同的方式得到下列化合物。
2-[(2S)2-[[(2RS)-2-羟基-2-(4-羟基-3-羟基甲基苯基)乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]乙酰胺(化合物2)。
非晶状IR(KBr):3410,1666cm-1 1H-NMR(DMSO-d6)δppm:1.40-1.75(2H,m),1.85-2.00(1H,m),2.40-3.00(7H,m),4.30-4.35(2H,m),4.40-4.55(3H,m),4.93(1H,brs),5.08(1H,brs),6.60-6.75(3H,m),6.90-7.05(2H,m),7.25-7.30(1H,m),7.35(1H,brs),7.44(1H,brs),9.15(1H,brs)
4-[2[(2S)-2-[[(2RS)-2-羟基-2-(4-羟基-3-羟基甲基苯基)乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]乙酰基]吗啉(化合物3)。
非晶状IR(KBr):3400,1645cm-1 1H-NMR(DMSO-d6)δppm:1.35-1.80(2H,m),1.85-2.00(1H,m),2.35-2.95(7H,m),3.35-3.65(8H,m),4.40-4.55(3H,m),4.70-4.75(2H,m),4.89(1H,brs),5.03(1H,br),6.55-6.75(3H,m),6.90-7.05(2H,m),7.25-7.30(1H,m),9.13(1H,brs)
1-[2-[(2S)-2-[[(2RS)-2-羟基-2-(4-羟基-3-羟基甲基苯基)乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]乙酰基]哌啶(化合物4)。
非晶状IR(KBr):3381,1635cm-1 1H-NMR(CDCl3)δppm:1.35-1.80(7H,m),1.95-2.10(1H,m),2.40-3.10(7H,m),3.40-3.65(4H,m),4.55-4.65(3H,m),4.85(2H,s),6.60-6.75(2H,m),6.80-6.90(1H,m),6.97(1H,d,J=8.3Hz),7.06(1H,d,J=2.1Hz),7.17(1H,d,J=8.1Hz)
1-[2-[(2S)-2-[[(2RS)-2-羟基-2-(4-羟基-3-羟基甲基苯基)乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]乙酰基]吡咯烷(化合物5)。
非晶状IR(KBr):3374,3304,1645cm-1 1H-NMR(CDCl3)δppm:1.50-1.65(1H,m),1.80-2.10(5H,m),2.40-2.55(1H,m),2.65-3.00(6H,m),3.52(4H,t,J=6.9Hz),4.50-4.65(3H,m),4.75-4.85(2H,m),6.55-6.75(2H,m),6.80-6.85(1H,m),6.95-7.05(2H,m),7.10-7.15(1H,m)实施例3
(-)-2-[(2S)-2-[[(2R)-2-羟基-2-(4-羟基-3-羟基甲基苯基)乙基]氨基]-1,2,3,4-四氢萘-7基氧基)-N,N-二甲基乙酰胺(化合物6)
将(-)-2-[(2S)-2-[[(2R)-2-(2,2-二甲基苯并[1,2-d]-1,3-二噁烷-6-基)-羟基乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]-N,N-二甲基乙酰胺(192mg)溶于3.8ml1,2-二甲基乙烷,在冰-冷却,搅拌下往溶液中加入4.2ml1N盐酸,混合物在室温下进行反应2小时。反应溶液通过加入饱和碳酸氢钠水溶液中和,然后减压浓缩至干。往产生的残余物中加入四氢呋喃和乙醇,滤出不溶物。减压浓缩产生的滤液,产生残余物通过氨基丙基化的硅胶中压液相柱色谱(洗脱剂:乙酸乙酯/乙醇=5/1)纯化,然后用甲醇重结晶,给出142mg(-)-2-[(2S)-2-[[(2R)-2-羟基-2-(4-羟基-3-羟基甲基苯基)乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]-N,N-二甲基乙酰胺(化合物6),熔点175-176℃。IR(KBr):3363,1648cm-1 1H-NMR(DMSO-d6)δppm:1.40-1.50(1H,m),1.65(1H,brs),1.85-1.95(1H,m),2.43(1H,dd,J=15.8,8.4Hz),2.55-3.00(12H,m),4.40-4.55(3H,m),4.70(2H,s),4.95(1H,br)5.05-5.15(1H,m),6.55-6.70(3H,m),6.93(1H,d,J=8.3Hz),7.00(1H,dd,J=8.2,2.0Hz),7.27(1H,d,J=2.0Hz),9.201H,br)Specific rotation: [α]D 25=-80.0°(c=1.03, AcOH)
实施例4
(-)-1-[2-[(2S)-2-[[(2R)-2-羟基-2(4-羟基-3-羟基甲基苯基)乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]乙酰基]吡咯烷(化合物7)
用在参考实施例5中得到的(-)-1-[2-[(2S)-2-[[(2R)-2-(2,2-二甲基苯并[1,2-d]-1,3-二噁烷-6-基)-2-羟基乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]乙酰基]吡咯烷,重复实施例3的工艺,给出(-)-1-[2-[(2S)-2-[[(2R)-2-羟基-2-(4-羟基-3-羟基甲基苯基)乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]乙酰基]吡咯烷(化合物7),熔点192-195℃(重结晶溶剂:甲醇)IR(KBr):3327,1646cm-1 1H-NMR(DMSO-d6)δppm:1.40-2.00(7H,m),2.43(1H,dd,J=16.1,8.7Hz),2.55-3.00(6H,m),3.31(2H,t,J=6.8Hz),3.45(2H,t,J=6.8Hz),4.40-4.55(3H,m),4.62(2H,s),4.93(1H,brs),5.08(1H,d,J=3.7Hz),6.55-6.75(3H,m),6.93(1H,d,J=8.3Hz),7.00(1H,dd,J=8.2,2.0Hz),7.27(1H,d,J=2.0Hz),9.17(1H,brs)Specific rotation:[α]D 25=-71.3°(c=1.12,AcOH)
(-)-1-[2-[(2S)-2-[[(2S)-2-羟基-2-(4-羟基-3-羟基甲基苯基)乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]乙酰基]吡咯烷(化合物8)
用在参考实施例6中得到的(-)-1-[2-[(2S)-2-[[(2S)-2-(2,2-二甲基苯并[1,2-d]-1,3-二噁烷-6-基)-2-羟基乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]乙酰基]吡咯烷,重复实施例3的工艺,给出非晶状(-)-1-[2-[(2S)-2-[[(2S)-2-羟基-2-(4-羟基-3-羟基甲基苯基)乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]乙酰基]吡咯烷(化合物8)。IR(KBr):3297,1645cm-1 1H-N-MR(DMSO-d6+D2O)δppm:1.40-1.50(1H,m),1.70-2.00(5H,m),2.41(1H,dd,J=15.6,8.4Hz),2.55-2.95(6H,m),3.28(2H,t,J=6.8Hz),3.41(2H,t,J=6.8Hz),4.45(2H,s),4.51(1H,dd,J=8.4,4.1Hz),4.59(2H,s),6.58(1H,d,J=2.6Hz),6.63(1H,dd,J=8.4,2.6Hz),6.69(1H,d,J=8.2Hz),6.93(1H,d,J=8.4Hz),7.01(1H,dd,J=8.2,2.0Hz),7.25(1H,d,J=2.0Hz)特定旋光度:[α]D 25=-45.8°(c=1.00,ACOH)
(-)-2-[2-[(2S)-2-[[(2S)-2-羟基-2-(4-羟基-3-羟基甲基苯基)乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]-N,N-二甲基乙酰胺(化合物9)
用在参考实施例6中得到的(-)-2-[2-[(2S)-2-[[(2S)-2-(2,2-二甲基苯并[1,2-d]-1,3-二噁烷-6-基)-2-羟基乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]-N,N-二甲基乙酰胺,重复实施例3的工艺,给出非晶状(-)-2-[2-[(2S)-2-[[(2S)-2-羟基-2-(4-羟基-3-羟基甲基苯基)乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]-N,N-二甲基乙酰胺(化合物9)。IR(film):3297,1650cm-1 1H-NMR(CDCl3)δppm:1.50-1.65(1H,m),1.95-2.05(1H,m),2.46(1H,dd,J=15.6,8.7Hz),2.65-3.00(9H,m),3.07(3H,s),4.52(1H,dd,J=8.8,3.6Hz),4.62(2H,s),4.71(2H,s),6.58(1H,d,J=2.6Hz),6.69(1H,dd,J=8.4,2.6Hz),6.78(1H,d,J=8.3Hz),6.90-7.00(2H,m),7.07(1H,dd,J=8.3,1.9Hz)特定旋光度:[α]D 25=-25.6°(c=1.6,MeOH)
4-[(2S)-2-[[(2RS)-2-羟基-2-(4-羟基-3-羟基甲基苯基)乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]-N,N-二甲基丁酰胺(化合物10)
用在参考实施例11中得到的4-[(2S)-2[[(2RS)-2-(2,2-二甲基苯并[1,2-d]-1,3-二噁烷-6-基)-2-羟基乙基]氨基]-1,2,3,4-四氢萘-7基氧基]-N,N-二甲基丁酰胺,重复实施例3的工艺,给出非晶状4-[(2S)-2-[[(2RS)-2-羟基-2-(4-羟基-3-羟基甲基苯基)乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]-N,N-二甲基丁酰胺(化合物10)。IR(KBr):3438,1623cm-1 1H-NMR(DMSO-d6)δppm: 1.40-1.55(1H,m),1.85-2.00(3H,m),2.40-3.00(16H,m),3.85-3.95(2H,m),4.45-4.55(3H,m),4.90-5.00(1H,m),5.05-5.20(1H,m),6.60-6.75(3H,m),6.93(1H,d,J=8.5Hz),7.01(1H,d,J=6.8Hz),7.25-7.30(1H,m),9.17(1H,brs)
(-)-4-[(2S)-2-[[(2R)-2-羟基-2-(4-羟基-3-羟基甲基苯基)乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]乙酰基]吗啉(化合物11)
用在参考实施例5中得到的(-)-4-[2-[(2S)-2-[[(2R)-2-(2,2-二甲基苯并[1,2-d]-1,3-二噁烷-6-基)-2-羟基乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]乙酰基]吗啉,重复实施例3的工艺,给出非晶状(-)-4[(2S)-2-[[(2R)-2-羟基-2-(4-羟基-3-羟基甲基苯基)乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]乙酰基]吗啉(化合物11)。IR(KBr):3400,1647cm-1 1H-NMR(DMSO-d6)δppm:1.35-1.75(2H,m),1.85-1.95(1H,m),2.30-3.00(7H,m),3.40-3.65(8H,m),4.40-4.55(3H,m),4.73(2H,s),4.90-5.00(1H,m),5.08(1H,d,J=3.9Hz),6.60-6.75(3H,m),6.94(1H,d,J=8.2Hz),7.00(1H,dd,J=8.2,1.8Hz),7.27(1H,d,J=1.8Hz),9.18(1H,brs)特定旋光度:[α]D 25=-53.2°(c=0.53,MeOH)
(-)-1-[2-[(2S)-2-[[(2R)-2-羟基-2(4-羟基-3-羟基甲基苯基)乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]乙酰基]哌啶(化合物12)
用在参考实施例5中得到的(-)-1-[2-[(2S)-2-[[(2R)-2-(2,2-二甲基苯并[1,2-d]-1,3-二噁烷-6-基)-2-羟基乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]乙酰基]哌啶,重复实施例3的工艺,给出(-)-1-[2-[(2S)-2-[[(2R)-2-羟基-2-(4-羟基-3-羟基甲基苯基)乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]乙酰基]哌啶(化合物12),熔点167-170℃(不重结晶)。IR(KBr):3346,1645cm-1 1H-NMR(DMSO-d6)δppm:1.35-1.80(8H,m),1.85-1.95(1H,m),2.35-2.95(7H,m),3.30-3.45(4H,m),4.40-4.55(3H,m),4.68(2H,s),4.93(1H,br),5.07(1H,brs,6.62(1H,d,J=2.4Hz),6.64(1H,dd,J=8.2,2.7Hz),6.69(1H,d,J=8.2Hz),6.94(1H,d,J=8.3Hz),7.00(1H,dd,J=8.2,2.2Hz),7.27(1H,d,J=2.0Hz),9.17(1H,br)特定旋光度:[α]D 25=-60.3°(c=0.50,MeOH)
实施例5
(-)-2-[(2S)-2-[[(2R)-2-羟基-2-[4-羟基-3-(2-羟基乙基)苯基]乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]-N,N-二甲基乙酰胺(化合物13)
将在参考实施例8中得到的(-)-2-[(2S)-2-[[(2R)-2-[4-苄氧基-3-(2-苄氧基乙基)苯基]-2-羟基乙基]氨基]-1,2,3,4-四氢萘-7-基氧基)-N,N-二甲基乙酰胺(390mg)和30mg10%Pd/C悬浮于3ml乙酸中,混合物在氢气氛中在室温下搅拌16小时。滤出催化剂,减压浓缩滤液,产生残余物通过氨基丙基化的硅胶中压液相柱色谱(洗脱剂:乙酸乙酯/乙醇=5/1)纯化,给出235mg非晶状(-)-2[(2S)-2-[[(2R)-2-羟基-2-[4-羟基-3-(2-羟基乙基)苯基]乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]-N,N二甲基乙酰胺(化合物13)。IR(KBr):3310,1654cm-1 1H-NMR(CDCl3)δppm:1.50-1.65(1H,m),1.95-2.10(1H,m),2.52(1H,dd,J=17.5,9.8Hz),2.65-3.05(11H,m),3.09(3H,s),3.90-4.00(2H,m),4.61(1H, dd,J=8.8,3.8Hz),4.64(2H,s),6.62(1H,d,J=2.7Hz),6.71(1H, dd,J=8.4,2.7Hz),6.87(1H,d,J=8.2Hz),6.98(1H,d,J=8.4Hz),7.05-7.15(2H,m)特定旋光度:[α]D 25=-59.6°(c=1.10,MeOH)
实施例6
(-)-2-[(2S)-2-[[(2S)-2-羟基-2-[4-羟基-3-(2羟基乙基)苯基]乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]-N,N-二甲基乙酰胺(化合物14)
用在参考实施例9中得到的(-)-2-[(2S)-2-[[(2S)-2-[4-苄氧基-3-(2-苄氧基乙基)苯基]-2-羟基乙基]氨基]-1,2,3,4-四氢萘-7-基氧基)-N,N-二甲基乙酰胺,重复实施例5的工艺,给出非晶状(-)-2-[(2S)-2-[[(2S)-2-羟基-2-[4-羟基-3-(2-羟基乙基)苯基]乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]-N,N-二甲基乙酰胺(化合物14)。IR(film):3292,1652cm-1 1H-NMR(CDCl3)δppm:1.50-1.65(1H,m),1.95-2.05(1H,m),2.43(1H,dd,J=15.7,9.1Hz),2.65-2.95(8H, m),2.96(3H,s),3.06(3H,s),3.79(2H,brs),4.57(1H,dd,J=8.8,3.6Hz),4.61(2H,s),6.57(1H,d,J=2.6Hz),6.68(1H,dd,J=8.4,2.6Hz),6.78(1H,d,J=8.0Hz),6.95-7.05(3H,m)特定旋光度:[α]D 31=-28.7°(c=1.12,MeOH)
2-[(2S)-2-[[(2RS)-2-羟基-2-[4-羟基-3-(2-羟基乙基)苯基]乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]-N,N-二甲基乙酰胺(化合物15)
用在参考实施例7中得到的2-[(2S)-2-[[(2RS)-2-[4-苄氧基-3-(2-苄氧基乙基)苯基]-2-羟基乙基]氨基]-1,2,3,4-四氢萘-7-基氧基)-N,N-二甲基乙酰胺,重复实施例5的工艺,给出非晶状2-[(2S)-2-[[(2RS)-2-羟基-2-[4-羟基-3-(2-羟基乙基)苯基]乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]-N,N二甲基乙酰胺(化合物15)。1H-NMR(CDCl3)δppm:1.55-1.70(1H,m),2.00-2.10(1H,m),2.50-3.15(18H,m),3.50(1H,brs),3.96(2H,t,J=5.3Hz),4.55-4.70(3H,m),6.61(1H,s),6.71(1H,dd,J=8.4,2.5Hz),6.87(1H,d,J=8.1Hz),6.98(1H,d,J=8.4Hz),7.05-7.15(2H,m)IR(KBr):3416,1649cm-1
(-)-1-[2-[(2S)-2-[[(2R)-2-羟基-2-[4-羟基-3-(2-羟基乙基)苯基]乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]乙酰基]吡咯烷(化合物16)
用在参考实施例9中得到的(-)-1-[(2S)-2-[[(2R)-2-[4-苄氧基-3-(2-苄氧基乙基)苯基]-2-羟基乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]乙酰基]吡咯烷,重复实施例5的工艺,给出非晶状(-)-1-[2-[(2S)-2-[[(2R)-2-羟基-2-[4羟基-3-(2-羟基乙基]苯基]乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]乙酰基]吡咯烷(化合物16)。IR(KBr):3409,1643cm-1 1H-NMR(CDCl3)δppm:1.50-1.65(1H,m),1.80-2.05(5H,m),2.45-2.60(1H,m),2.65-3.05(8H,m),3.45-3.55(4H,m),3.90-4.00(2H,m),4.55-4.65(3H,m),6.62(1H,d,J=2.6Hz),6.71(1H,dd,J=8.4,2.6Hz),6.87(1H,d,J=8.1Hz),6.98(1H,d,J=8.4Hz),7.05-7.15(2H,m)特定旋光度:[α]D 25=-54.7°(c=0.57,MeOH)
(-)-1-[2-[(2S)-2-[[(2R)-2-羟基-2-[4-羟基-3-(2-羟基乙基)苯基]乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]乙酰基]哌啶(化合物17)
用在参考实施例9中得到的(-)-1-[2-[(2S)-2-[[(2R)-2-[4-苄氧基-3-(2-苄氧基乙基)苯基]-2-羟基乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]乙酰基]哌啶,重复实施例5的工艺,给出非晶状(-)-1-[2-[(2S)-2-[[(2R)-2-羟基-2-[4-羟基3-(2-羟基乙基)苯基]乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]乙酰基]哌啶(化合物17)。IR(KBr):3388,1640cm-1 1H-NMR(CDCl3)δppm:1.30-1.90(9H,m),2.00-2.10(1H,m),2.45-2.60(1H,m),2.65-3.10(9H,m),3.40-3.65(4H,m),3.98(2H,dd,J=5.8,4.8Hz),4.55-4.65(3H,m),6.63(1H,d,J=2.8Hz),6.71(1H,dd,J=8.5,2.8Hz),6.89(1H,d,J=8.1Hz),6.95-7.15(3H,m)特定旋光度:[α]D 30=-39.2°(c=0.50,CHCl3)(-)-4-[2-[(2S)-2-[[(2R)-2-羟基-2-[4-羟基-3-(2-羟基乙基)苯基]乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]乙酰基]吗啉(化合物18)
用在参考实施例9中得到的(-)-4-[2-[(2S)-2-[[(2R)-2-[4-苄氧基-3-(2-苄氧基乙基)苯基]-2-羟基乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]乙酰基]吗啉,重复实施例5的工艺,给出非晶状(-)-4-[2-[(2S)-2-[[(2R)-2-羟基-2-[4-羟基-3-(2-羟基乙基)苯基]乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]乙酰基]吗啉(化合物18)当用丙酮作溶剂重结晶时,此非晶状变成熔点为119-122℃的晶态。IR(KBr):3353,1651cm-1 1H-NMR(CDCl3)δppm:1.50-1.70(2H,m),2.00-2.10(1H,m),2.50-3.10(10H,m),3.50-3.75(8H,m),3.95-4.00(2H,m),4.55-4.70(3H,m),6.63(1H,d,J=2.8Hz),6.71(1H,dd,J=8.3,2.8Hz),6.89(1H,d,J=8.2Hz),6.95-7.15(3H,m)特定旋光度:[α]D 29=-60.8°(c=0.50,CHCl3)
实施例7
(-)-2-[(2S)-2-[[(2R)-2-羟基-2-(4-羟基-3羟基甲基苯基)乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]-N,N-二甲基乙酰胺0.5硫酸盐(化合物19)
将(-)-2-[(2S)-2-[[(2R)-2-羟基-2-(4-羟基-3-羟基甲基苯基)乙基]氨基]1,2,3,4-四氢萘7-基氧基]-N,N二甲基乙酰胺(化合物6)(600mg)悬浮于70ml乙醇中,往悬浮液中加入1.45ml1N硫酸水溶液,将混合物加热以溶解化合物。冷却后,过滤收集沉淀的晶体,给出649mg(-)-2-[(2S)-2-[[(2R)-2-羟基-2-(4-羟基-3-羟基甲基苯基)乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]-N,N-二甲基乙酰胺0.5硫酸盐(化合物19),熔点195-199℃。IR(KBr):3420,1640cm-1 1H-NMR(DMSO-d6)δppm:1.55-1.70(1H,m),2.00-2.15(1H,m),2.55-3.25(13H,m),4.48(2H,s),4.65-4.80(3H,m),5.00(1H,br),6.63(1H,d,J=2.6Hz),6.67(1H,dd,J=8.4,2.6Hz),6.73(1H,d,J=8.2Hz),6.96(1H,d,J=8.4Hz),7.06(1H,dd,J=8.2,2.0Hz),7.33(1H,d,J=2.0Hz),9.30(1H,br)特定旋光度:[α]D 28=-69.8°(c=0.52,H2O)
实施例8
用(-)-2-[(2S)-2-[[(2R)-2-羟基-2-(4-羟基-3-羟基甲基苯基)乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]-N,N-二甲基乙酰胺(化合物6)和L-酒石酸或D-酒石酸,以与实施例7中所述相同的方法,得到如下化合物。
(-)-2-[(2S)-2-[[(2R)-2-羟基-2-(4-羟基-3-羟基甲基苯基)乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]-N,N-二甲基乙酰胺0.5L-酒石酸盐(化合物20)
熔点:109-115℃(重结晶溶剂:乙醇)IR(KBr):3350,1646,1614cm-1 1H-NMR(DMSO-d6)δppm:1.55-1.70(1H,m),2.00-2.15(1H,m),2.60-3.25(13H,m),3.85(1H,s),4.48(2H,s),4.65-4.80(3H,m),6.64(1H,d,J=2.6Hz),6.67(1H,dd,J=8.4,2.6Hz),6.73(1H,d,J=8.2Hz),6.96(1H,d,J=8.4Hz),7.06(1H,dd,J=8.2,2.0Hz),7.33(1H,d,J=2.0Hz)特定旋光度:[α]D 28=-56.4°(c=0.50,H2O)
(-)-2-[(2S)-2-[[(2R)-2-羟基-2-(4-羟基-3-羟基甲基苯基)乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]-N,N-二甲基乙酰胺0.5D-酒石酸盐(化合物21)
熔点:123-124℃(重结晶溶剂:乙醇)IR(KBr):3400,1645,1613cm-1 1H-NMR(DMSO-d6)δppm:1.55-1.70(1H,m),2.00-2.15(1H,m),2.60-3.25(13H,m),3.84(1H,s),4.48(2H,s),4.65-4.80(3H,m),6.64(1H,d,J=2.6Hz),6.67(1H,dd,J=8.4,2.6Hz),6.73(1H,d,J=8.2Hz),6.96(1H,d,J=8.4Hz),7.06(1H,dd,J=8.2,2.0Hz),7.33(1H,d,J=2.0Hz)特定旋光度:[α]D 28=-68.5°(c=0.52,H2O)
用(-)-1-[2-[(2S)-2-[[(2R)-2-羟基-2-(4-羟基-3-羟基甲基苯基)乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]乙酰基]吡咯烷(化合物7)和硫酸,L-酒石酸或D-酒石酸,以与实施例7中所述相同的方法,得到如下化合物。
(-)-1-[2-[(2S)-2-[[(2R)-2-羟基-2-(4-羟基-3-羟基甲基苯基)乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]乙酰基]吡咯烷0.5硫酸盐(化合物22)
熔点:169-172℃(重结晶溶剂:乙醇)IR(KBr):3400,640cm-1 1H-NMR(DMSO-d6)δppm:1.55-1.95(5H,m),2.00-2.15(1H,m),2.55-3.50(11H,m),4.48(2H,s),4.63(2H,s),4.72(1H,dd,J=9.6,3.1Hz)4.99(1H,br),6.64(1H,d,J=2.6Hz)6.68(1H,dd,J=8.4,2.6Hz),6.73(1H,d,J=8.2Hz),6.96(1H,d,J=8.4Hz),7.06(1H,dd,J=8.2,2.0Hz),7.33(1H,d,J=2.0Hz),9.31(1H,br)特定旋光度:[α]D 28=-67.7°(c=0.52,H2O)
(-)-1-[2-[(2S)-2-[[(2R)-2羟基-2-(4-羟基-3-羟基甲基苯基)乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]乙酰基]吡咯烷0.5L-酒石酸(化合物23)熔点:130-134℃(重结晶溶剂:乙醇)IR(KBr):3400,1635,1614cm-1 1H-NMR(DMSO-d6)δppm:1.55-1.95(5H,m),2.00-2.15(1H,m),2.55-3.25(7H,m),3.30(2H,t,J=6.9Hz),3.40-3.50(2H,m),3.86(1H,s),4.48(2H,s),4.63(2H,s),4.65-4.75(1H,m),6.64(1H,d,J=2.5Hz),6.68(1H,dd,J=8.4,2.5Hz),6.73(1H,d,J=8.2Hz),6.97(1H,d,J=8.4Hz),7.06(1H,dd,J=8.2,2.0Hz),7.33(1H,d,J=2.0Hz)
特定旋光度:[α]D 28=-53.4°(c=0.55,H2O)
(-)-1-[2-[(2S)-2-[[(2R)-2-羟基-2-(4-羟基-3-羟基甲基苯基)乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]乙酰基]吡咯烷0.5 D-酒石酸(化合物24)
熔点:130-134℃(重结晶溶剂:乙醇)IR(KBr):3400,1635,1614cm-1 1H-NMR(DMSO-d6)δppm:1.55-1.95(5H,m),2.00-2.20(1H,m),2.55-3.25(7H,m),3.30(2H,t,J=6.8Hz),3.44(2H,t,J=6.8Hz),3.85(1H,s),4.48(2H,s),4.63(2H,s),4.70(1H,dd,J=9.2,2.8Hz),6.64(1H,d,J=2.6Hz),6.68(1H,dd,J=8.3,2.6Hz),6.73(1H,d,J=8.2Hz),6.97(1H,d,J=8.3Hz),7.06(1H,dd,J=8.2,2.0Hz),7.33(1H,d,J=2.0Hz)特定旋光度:[α]D 28=-66.2°(c=0.53,H2O)
实施例9
用(-)-2-[(2S)-2-[[(2R)-2羟基-2_[4-羟基-3-(2-羟基乙基)苯基]乙基]氨基]-1,2,3,4-四氢萘7基氧基]-N,N-二甲基乙酰胺(化合物13)和硫酸,以与实施例7中所述相同的方法,得到如下化合物。
(-)-2-[(2S)-2-[[(2R)-2-羟基-2-[4-羟基-3-(2-羟基乙基)苯基]乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]-N,N-二甲基乙酰胺0.5硫酸盐(化合物25)
熔点:211-215℃(分解)(重结晶溶剂:水)IR(KBr):3418,1636cm-1 1H-NMR(DMSO-d6)δ ppm:1.55-1.75(1H,m),2.05-2.15(1H,m),2.60-3.25(15H,m),3.56(2H,t,J=7.3Hz),4.60-4.80(3H,m),6.62(1H,d,J=2.6Hz),6.67(1H,dd,J=8.4,2.6Hz)6.75(1H,d,J=8.2Hz),6.96(1H,d,J=8.4Hz),7.03(1H,dd,J=8.2,2.1Hz),7.09(1H,d,J=2.1Hz),9.25(1H,br)特定旋光度:[α]D 25=-70.8°(c=1.0,H2O)
用(-)-4-[2-[(2S)-2-[[(2R)-2-羟基-2-[4-羟基-3-(2-羟基乙基)苯基]乙基]氨基]1,2,3,4-四氢萘-7-基氧基]乙酰基]吗啉(化合物18)和硫酸,以与实施例7中所述相同的方法,得到如下化合物。
(-)-4-[2-[(2S)-2-[[(2R)-2-羟基-2-[4-羟基-3-(2-羟基乙基)苯基]乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]乙酰基]吗啉0.5硫酸盐(化合物26)
熔点:129-134℃(分解)(重结晶溶剂:异丙醇-乙醇)IR(KBr):3394,1648cm-1 1H-NMR(DMSO-d6)δppm:1.50-1.75(1H,m),2.00-2.15(1H,m),2.40-3.90(19H,m),4.60-4.85(3H,m),6.60-6.80(3H,m),6.97(1H,d,J=7.9Hz),7.03(1H,dd,J=8.4,2.0Hz),7.08(1H,d,J=1.5Hz),9.25(1H,br)特定旋光度:[α]D 25=-58.3°(c=0.60,MeOH)
试验实施例1
药物对分离的子宫肌层的自发收缩上的作用
妊娠的SD大鼠(妊娠21天)子宫分离出,并制备不含基板(basal plate)的纵子宫肌条(约15mm长,约5mm宽)。实验根据Magnus法进行。标本在Locke-Ringer溶液中用1g张力制作,保持在37℃并用95%氧和5%二氧化碳通气。子宫肌层的自发收缩通过压力传感器等比例地诱导并在rectigram记录。通过在加入药物之前,5分钟期间子宫收缩总的程度与加入药物之后,5分钟期间子宫收缩总的程度比较,并且计算50%抑制浓度EC50而评价效力。
试验实施例2
药物对分离的前房的前房收缩上的作用
将SD雄性大鼠(350至400g体重)的前房分离出,实验根据Magnus法进行。标本在Krebs-Henseleit溶液中用1g张力制作,保持在37℃并用95%氧和5%二氧化碳通气。前房收缩通过压力传感器等比例地诱导并在rectigram上记录。加入药物之后,其效力通过计算每分钟心率增加20次搏击的药物浓度的EC20而评价。
试验实施例3
急性毒性
给5只4周龄的雄性ICR小鼠以20mg/kg的剂量静脉内给药生理盐水中的2-[(2S)-2-[[(2R)-2-羟基-2-(4-羟基-3-羟基甲基苯基)乙基]氨基]-1,2,3,4-四氢萘-7-基氧基]-N,N-二甲基乙酰胺0.5硫酸盐。给药后,24小时期间没有观察到动物死亡。
Claims (12)
1.由如下通式表示的3,4-二取代的苯基乙醇氨基1,2,3,4-四氢萘甲酰胺衍生物:
(其中A表示低级亚烷基;B表示氨基,二(低级烷基)氨基或在环中可以含有氧原子的3至7-员脂环氨基;n是整数1或2;用*标记的碳原子表示R构型,S构型的碳原子或其混合物;用(S)标记的碳原子表示S构型的碳原子)和其药用盐。
3.如权利要求2的3,4-二取代的苯基乙醇氨基1,2,3,4-四氢萘甲酰胺衍生物,如下通式表示:
(其中用(R)标记的碳原子表示R构型,用(S)标记的碳原子表示S构型的碳原子)和其药用盐。
7.用于预防先兆流产,早产的药剂,支气管扩张药,尿石病中疼痛缓解和除去结石的药剂,含有作为活性成分的如下通式表示的3,4-二取代的苯基乙醇氨基1,2,3,4-四氢萘甲酰胺衍生物:
(其中A表示低级亚烷基;B表示氨基,二(低级烷基)氨基或在环中可以含有氧原子的3至7-员脂环氨基;n是整数1或2;用*标记的碳原子表示R构型,S构型的碳原子或其混合物;用(S)标记的碳原子表示S构型的碳原子)或其药用盐。
10.用于预防先兆流产,早产,预防和治疗支气管狭窄和气道梗塞有关的疾病,尿石病中疼痛缓解和除去结石的方法,该方法包括施用如下通式表示的3,4-二取代的苯基乙醇氨基1,2,3,4-四氢萘甲酰胺衍生物:
(其中A表示低级亚烷基;B表示氨基,二(低级烷基)氨基或在环中可以含有氧原子的3至7-员脂环氨基;n是整数1或2;用*标记的碳原子表示R构型,S构型的碳原子或其混合物;用(S)标记的碳原子表示S构型的碳原子)和其药用盐。
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CN100435787C (zh) * | 2003-01-22 | 2008-11-26 | 橘生药品工业株式会社 | 预防或治疗子宫内生长迟缓和妊娠毒血症的药物 |
CN102365017A (zh) * | 2009-11-18 | 2012-02-29 | 美迪诺亚公司 | 哮喘急性恶化的治疗及减少哮喘患者住院治疗的可能性 |
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AU8562098A (en) * | 1997-08-19 | 1999-03-08 | Kissei Pharmaceutical Co. Ltd. | Phenylethanolaminotetralin derivatives and bronchodilators |
ZA994264B (en) | 1998-07-01 | 2000-01-25 | Warner Lambert Co | Stereoisomers with high affinity for adrenergic receptors. |
GB9913083D0 (en) | 1999-06-04 | 1999-08-04 | Novartis Ag | Organic compounds |
US7232837B2 (en) | 1999-06-29 | 2007-06-19 | Mcneil-Ppc, Inc. | Stereoisomers with high affinity for adrenergic receptors |
FR2809725B1 (fr) * | 2000-06-06 | 2004-05-07 | Sanofi Synthelabo | Propanolaminotetralines, leur preparation et compositions pharmaceutiques en contenant |
GB0029562D0 (en) | 2000-12-04 | 2001-01-17 | Novartis Ag | Organic compounds |
JPWO2006054514A1 (ja) * | 2004-11-19 | 2008-05-29 | キッセイ薬品工業株式会社 | 神経因性疼痛の予防又は治療用医薬組成物 |
JPWO2006054513A1 (ja) * | 2004-11-19 | 2008-05-29 | キッセイ薬品工業株式会社 | 神経因性疼痛の予防又は治療剤 |
EP2098511A1 (en) | 2008-03-07 | 2009-09-09 | Solvias AG | Process for preparing compounds containing a hydronaphtalene structure with an unsymmetrically substituted benzene ring |
WO2011112499A1 (en) * | 2010-03-08 | 2011-09-15 | Medicinova, Inc. | Compositions, methods, and devices for the treatment of dysmenorrhea |
BR112012025703A2 (pt) * | 2010-04-08 | 2016-07-05 | Medicinova Inc | métodos e composições para o tratamento de síndrome de intestino irritável |
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CN100435787C (zh) * | 2003-01-22 | 2008-11-26 | 橘生药品工业株式会社 | 预防或治疗子宫内生长迟缓和妊娠毒血症的药物 |
CN102365017A (zh) * | 2009-11-18 | 2012-02-29 | 美迪诺亚公司 | 哮喘急性恶化的治疗及减少哮喘患者住院治疗的可能性 |
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