CN109485647B - 一种抗焦虑药物帕戈隆或帕秦克隆的制备方法 - Google Patents
一种抗焦虑药物帕戈隆或帕秦克隆的制备方法 Download PDFInfo
- Publication number
- CN109485647B CN109485647B CN201811437849.XA CN201811437849A CN109485647B CN 109485647 B CN109485647 B CN 109485647B CN 201811437849 A CN201811437849 A CN 201811437849A CN 109485647 B CN109485647 B CN 109485647B
- Authority
- CN
- China
- Prior art keywords
- clone
- reaction
- paroxetine
- preparing
- rhodium
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 239000002249 anxiolytic agent Substances 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 34
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 13
- 239000010948 rhodium Substances 0.000 claims abstract description 12
- 229910052703 rhodium Inorganic materials 0.000 claims abstract description 11
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims abstract description 11
- 150000001336 alkenes Chemical class 0.000 claims abstract description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 8
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims abstract description 8
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000002904 solvent Substances 0.000 claims abstract description 8
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims abstract description 6
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 5
- 238000011065 in-situ storage Methods 0.000 claims abstract description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 4
- 150000003930 2-aminopyridines Chemical class 0.000 claims abstract description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- AHOUBRCZNHFOSL-YOEHRIQHSA-N (+)-Casbol Chemical compound C1=CC(F)=CC=C1[C@H]1[C@H](COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-YOEHRIQHSA-N 0.000 claims description 9
- AHOUBRCZNHFOSL-UHFFFAOYSA-N Paroxetine hydrochloride Natural products C1=CC(F)=CC=C1C1C(COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-UHFFFAOYSA-N 0.000 claims description 9
- 229960002296 paroxetine Drugs 0.000 claims description 9
- -1 2-aminopyridine compound Chemical class 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- ICSNLGPSRYBMBD-UHFFFAOYSA-N alpha-aminopyridine Natural products NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 claims description 5
- NPPQSCRMBWNHMW-UHFFFAOYSA-N Meprobamate Chemical compound NC(=O)OCC(C)(CCC)COC(N)=O NPPQSCRMBWNHMW-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000012298 atmosphere Substances 0.000 claims description 4
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical group [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 229940125713 antianxiety drug Drugs 0.000 claims 3
- 230000000949 anxiolytic effect Effects 0.000 claims 1
- XTBAPWCYTNCZTO-UHFFFAOYSA-N isoindol-1-one Chemical group C1=CC=C2C(=O)N=CC2=C1 XTBAPWCYTNCZTO-UHFFFAOYSA-N 0.000 abstract description 6
- 238000005580 one pot reaction Methods 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000001338 self-assembly Methods 0.000 abstract description 2
- 239000004215 Carbon black (E152) Substances 0.000 abstract 1
- 230000004913 activation Effects 0.000 abstract 1
- 238000010640 amide synthesis reaction Methods 0.000 abstract 1
- 230000003197 catalytic effect Effects 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 abstract 1
- 229930195733 hydrocarbon Natural products 0.000 abstract 1
- 150000002430 hydrocarbons Chemical class 0.000 abstract 1
- 238000006467 substitution reaction Methods 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- 239000000047 product Substances 0.000 description 10
- 239000000758 substrate Substances 0.000 description 7
- 239000000203 mixture Substances 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000010949 copper Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 229910001873 dinitrogen Inorganic materials 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 150000003953 γ-lactams Chemical class 0.000 description 2
- CRADWWWVIYEAFR-UHFFFAOYSA-N 1,8-naphthyridin-2-amine Chemical compound C1=CC=NC2=NC(N)=CC=C21 CRADWWWVIYEAFR-UHFFFAOYSA-N 0.000 description 1
- 238000010499 C–H functionalization reaction Methods 0.000 description 1
- 238000007341 Heck reaction Methods 0.000 description 1
- 238000006845 Michael addition reaction Methods 0.000 description 1
- 159000000021 acetate salts Chemical class 0.000 description 1
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000003934 aromatic aldehydes Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- FXLOVSHXALFLKQ-UHFFFAOYSA-N p-tolualdehyde Chemical compound CC1=CC=C(C=O)C=C1 FXLOVSHXALFLKQ-UHFFFAOYSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- PZSJYEAHAINDJI-UHFFFAOYSA-N rhodium(3+) Chemical compound [Rh+3] PZSJYEAHAINDJI-UHFFFAOYSA-N 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Neurology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Indole Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
本发明公开了一种利用Rh(III)催化合成抗焦虑药物帕戈隆或者帕秦克隆及其类似物的方法，包括如下步骤：在铑催化剂和醋酸盐存在的条件下，苯甲醛与2‑氨基吡啶类化合物类化合物在溶剂中发生反应，原位产生一个有效的导向基团。该导向基团再在铑催化下与取代烯烃反应，反应完成后，经过后处理得到所述的氮杂环骨架的化合物。该制备方法使用铑进行催化两个独立的反应(酰胺形成和碳氢活化)，成功实现了自组装高效导向基的合成策略。反应从更简单的原料出发，在简洁温和的催化体系中，利用“一锅法”合成了新型取代特征的异吲哚酮骨架，操作简便，反应条件温和，收率高，原子经济性高。
Description
技术领域
本发明属于药物合成领域，具体涉及一种抗焦虑药物帕戈隆或帕秦克隆的制备方法。
背景技术
异吲哚酮(γ-内酰胺)是一个较多见而又重要的母核，在很多具有生物活性的分子中都有所体现，如下图所示。
因α位是具有较强络合力的N原子，故利用苯甲酰胺中的氮原子作为导向原子，并且参与形成γ-内酰胺的研究已多有报道。李兴伟课题组最早在2010年尝试使用N-苯基取代的芳甲酰胺作为底物，与丙烯酸酯反应构建起异吲哚酮骨架(Org.Lett.,2010,12,5430)。反应中首先生成了Heck产品中间体，进而发生迈克尔加成而环化。但底物中芳环若是呋喃、吲哚等杂环时不利于形成异吲哚酮产品，多是停留在了氧化Heck反应产品上,且反应条件较为苛刻。反应式如下：
2014年，于金权课题组对以上反应进行了改良。他们使用了N-全氟取代苯基芳甲酰胺作为底物(Chem.Sci.,2015,6,1923)，实际上就是增大酰胺中氮原子上取代基的拉电子能力，减弱酰胺键的异构化而增加其亲核性。这一工作虽然扩宽了底物类别，对于杂环如噻吩、呋喃、吡啶都有很好的适用性，且反应条件变得较为温和，但其底物的普适性仍不够广泛，且原料较为复杂，制备过程不够简单。
发明内容
本发明提供了一种抗焦虑药物帕戈隆或帕秦克隆的制备方法，该制备方法通过该“一锅法”合成策略可以一步从苯甲醛作为原料制备药物帕戈隆和帕秦克隆。
一种抗焦虑药物帕戈隆或帕秦克隆的制备方法，包括如下步骤：
包括如下步骤：在铑催化剂和醋酸盐存在的条件下，苯甲醛与2-氨基吡啶类化合物在溶剂中发生反应，原位生成含导向基团的中间体；该中间体再在铑催化下与取代烯烃反应，反应完成后，经过后处理得到所述的抗焦虑药物，所述的抗焦虑药物为抗焦虑药物帕戈隆和帕秦克隆；
作为优选，所述的铑催化剂为[Cp*RhCl2]2(CAS：12354-85-7)，用量为2.5mol％，该种铑催化剂对本发明中的底物的催化效率高。
作为优选，所述的醋酸盐为醋酸铜，用量为2eq。该醋酸盐起到氧化剂的作用，有助于铑催化剂在反应中的催化。
作为优选，以摩尔量计，苯甲醛、2-氨基吡啶类化合物和取代烯烃用量比为1:1.2～2:1.2～2。
作为优选，所述的溶剂为乙腈、水、甲醇、乙醇、DMF、DMSO和THF中的至少一种，这些溶剂都为极性溶剂，有利于底物中C-H键的断裂，作为进一步的优选，所述的溶剂为乙腈。
作为优选，反应的温度为80～110℃，反应温度过高，会使得副反应增多，反应温度过低，会降低反应物的转化率，作为进一步的优选，反应的温度为80℃。
作为优选，反应的氛围为空气、氮气中的一种，在这些氛围中，均能使反应更好进行，具有较高产率，作为进一步的优选，反应的氛围为N2氛围。
本发明中，反应的时间可以通过TLC进行监测，在80℃下搅拌4～12小时反应能够发生完全。
为了提高反应的收率，可以先将苯甲醛类化合物、2-氨基吡啶类化合物、Cu(OAc)2和[Cp*RhCl2]2加入Schlenk瓶中，然后对其进行抽真空处理再通入氮气，操作三次后，再加入溶剂和取代烯烃。
同现有技术相比，本发明的有益效果体现在：该反应采用“一锅法”制备，操作简单。反应中可自生成高效导向基团。
所述的反应式如下：
推测该反应机理为：
首先，芳香醛与2-氨基吡啶发生缩合反应生成中间体A，在原位产生一个有效的新型导向基团。接着，自组装导向基与取代烯烃在金属铑(III)催化下发生C-H活化、烯烃插入以及环内加成等反应，得到异吲哚酮衍生物。
附图说明
图1为实施例1制得的产物的1HNMR谱图；
图2为实施例1制得的产物的13CNMR谱图；
图3为实施例2制得的产物的1HNMR谱图；
图4为实施例2制得的产物的13CNMR谱图。
具体实施方式
实施例1
在25mL的Schlenk瓶中，称入22mg(0.2mmol)对甲基苯甲醛(1.0eq)，Cu(OAc)265mg(2.0eq)，2-氨基1,8-二氮杂萘54mg(1.5eq)，[Cp*RhCl2]2 6mg(5％)。然后对其进行抽真空处理再通入氮气，操作三次后，加入2mL乙腈和不饱和羰基化合物50mg(2.0eq)，在80℃下氮气氛围中恒温搅拌。约10h后TLC检测反应完毕，加入些许硅胶，蒸出溶剂，固化，固体上样，进行柱色谱分离。可以制备得到帕戈隆(cas：133737-32-3)总收率约15％。
产物核磁共振数据：1H NMR(CDCl3,600MHz),δ:8.98(d,J＝9.0Hz,1H),8.23(d,J＝8.4Hz,1H),8.11(d,J＝8.4Hz,1H),7.95(d,J＝7.2Hz,1H),7.67–7.60(m,2H),7.55–7.50(m,1H),7.43(d,J＝8.4Hz,1H),6.18(dd,J1＝7.8Hz,J2＝3.0Hz,1H),3.64(dd,J1＝16.8Hz,J2＝3.6Hz,1H),3.09(dd,J1＝17.2Hz,J2＝7.8Hz,1H),2.40–2.31(m,2H),1.46–1.37(m,3H),0.80(d,J＝6.0Hz,6H).
13C NMR(CDCl3,150MHz),δ:208.4,168.6,154.5,154.2,154.0,146.0,139.1,138.7,133.8,131.4,128.8,124.7,123.5,122.3,119.1,116.5,57.0,45.4,41.9,32.4,27.7,22.4。
实施例2
依据实施例1一样的步骤，更换为如下反应物，可以制备得到帕秦克隆，收率为20％。而如果首先制备反应中生成的中间体下酰胺(通过酰氯和胺缩合)，既是通过如下第二个反应式可以以更高的效率得到帕秦克隆，产率可以达到68％。具体来讲，在25mL的Schlenk瓶中，称入56.6mg(0.2mmol)酰胺(1.0eq)，Cu(OAc)2 65mg(2.0eq)，[Cp*RhCl2]26mg(5％)。然后对其进行抽真空处理再通入氮气，操作三次后，加入2mL乙腈和不饱和酰胺化合物78mg(2.0eq)，在80℃下氮气氛围中恒温搅拌。约10h后TLC检测反应完毕，加入些许硅胶，蒸出溶剂，固化，固体上样，进行柱色谱分离(乙酸乙酯与石油醚体积比例为1:1，TLC检测发现产品极性比不饱和酰胺稍微大一些)。
产物核磁共振数据：1H NMR(CDCl3,600MHz),δ:8.94(d,J＝9.0Hz,1H),8.20(d,J＝9.0Hz,1H),8.08(d,J＝8.4Hz,1H),7.91(d,J＝7.8Hz,1H),7.67(d,J＝7.8Hz,1H),7.62(t,J＝7.2Hz,1H),7.50(t,J＝7.2Hz,1H),7.38(d,J＝7.8Hz,1H),6.09(dd,J1＝9.0Hz,J2＝3.0Hz,1H),3.97–3.92(m,4H),3.85–3.77(m,2H),3.70(dd,J1＝15.0Hz,J2＝3.0Hz,1H),3.65–3.56(m,2H),2.74(dd,J1＝14.4Hz,J2＝9.0Hz,1H),1.71–1.52(m,4H).
13C NMR(CDCl3,150MHz),δ:168.6,167.8,154.3,154.1,153.9,145.7,139.0,138.7,133.6,131.1,128.8,124.5,123.9,122.1,119.0,116.3,106.9,64.5,57.8,44.0,40.0,36.9,35.6,34.9。
Claims (6)
1.一种抗焦虑药物帕戈隆或帕秦克隆的制备方法，其特征在于，包括如下步骤：在铑催化剂和醋酸盐存在的条件下，苯甲醛与2-氨基吡啶类化合物在溶剂中发生反应，原位生成含导向基团的中间体；该中间体再在铑催化下与取代烯烃反应，反应完成后，经过后处理得到所述的抗焦虑药物，所述的抗焦虑药物为帕戈隆或帕秦克隆；
所述的2-氨基吡啶类化合物的结构如式(I)所示：
所述的取代烯烃的结构如式(II)或(III)所示：
所述的铑催化剂为[Cp*RhCl2]2；
所述的醋酸盐为醋酸铜。
2.根据权利要求1所述的抗焦虑药物帕戈隆或帕秦克隆的制备方法，其特征在于，所述的铑催化剂的用量为苯甲醛的2-6mol％。
3.根据权利要求1或2所述的抗焦虑药物帕戈隆或帕秦克隆的制备方法，其特征在于，所述的醋酸盐的用量为苯甲醛摩尔量的1.2～2.0倍。
4.根据权利要求1所述的抗焦虑药物帕戈隆或帕秦克隆的制备方法，其特征在于，所述的溶剂为乙腈、水、甲醇、乙醇、DMF、DMSO和THF中的至少一种。
5.根据权利要求1所述的抗焦虑药物帕戈隆或帕秦克隆的制备方法，其特征在于，反应的温度为60～110℃。
6.根据权利要求1所述的抗焦虑药物帕戈隆或帕秦克隆的制备方法，其特征在于，反应的氛围为空气、氮气中的一种。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811437849.XA CN109485647B (zh) | 2018-11-28 | 2018-11-28 | 一种抗焦虑药物帕戈隆或帕秦克隆的制备方法 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811437849.XA CN109485647B (zh) | 2018-11-28 | 2018-11-28 | 一种抗焦虑药物帕戈隆或帕秦克隆的制备方法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109485647A CN109485647A (zh) | 2019-03-19 |
| CN109485647B true CN109485647B (zh) | 2021-04-13 |
Family
ID=65698501
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811437849.XA Active CN109485647B (zh) | 2018-11-28 | 2018-11-28 | 一种抗焦虑药物帕戈隆或帕秦克隆的制备方法 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109485647B (zh) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113201006B (zh) * | 2021-05-20 | 2022-05-17 | 四川大学 | 一种铑催化的碳氢活化反应合成酰基硅取代的异吲哚-1-酮类似物的方法 |
-
2018
- 2018-11-28 CN CN201811437849.XA patent/CN109485647B/zh active Active
Non-Patent Citations (7)
| Title |
|---|
| Cu/Fe Catalyzed Intermolecular Oxidative Amination of Benzylic C-H Bonds;Cong Liu 等;《Chemistry-A European Journal》;20160226;第22卷(第18期);6208-6212 * |
| Multicomponent Synthesis of Isoindolinone Frameworks via RhIII-Catalysed in situ Directing Group-Assisted Tandem Oxidative Olefination/Michael Addition;Liang Wang 等;《Chemistry-AN ASIAN JOURNAL》;20180202;第13卷(第7期);765-769 * |
| Pd(TFA)2-catalyzed oxidative coupling of anilides with olefins through C-H bond activation under non-acidic conditions;Xiaoli Yu 等;《Journal of Organometallic Chemistry》;20160824;第822卷;100-103 * |
| Rh(III)-catalyzed C–H olefination of N-pentafluoroaryl oxidant;Yi Lu 等;《Chemical Science》;20150108;第6卷(第3期);1923-1927 * |
| Rh(III)-Catalyzed Tandem Oxidative Olefination-Michael Reactions between Aryl Carboxamides and Alkenes;Fen Wang 等;《Organic Letters》;20101101;第12卷(第23期);5430-5433 * |
| Rhodium(III)-catalyzed oxidative mono- and di-olefination of isonicotinamides;Xiaohong Wei 等;《Organic&Biomolecular Chemistry》;20120613;第10卷(第29期);5521-5524 * |
| Ruthenium-catalyzed ortho-C–H bond alkylation of aromatic amides with a,b-unsaturated ketones via bidentate-chelation assistance;Guy Rouquet 等;《Chemical Science》;20130319;第4卷(第5期);2201-2208 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109485647A (zh) | 2019-03-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5738185B2 (ja) | アルコールおよびアンモニアからアミンを調製する方法 | |
| CN112898192B (zh) | 一种n-酰基吲哚化合物的制备方法 | |
| Yang et al. | Highly efficient synthesis of primary amides via aldoximes rearrangement in water under air atmosphere catalyzed by an ionic ruthenium pincer complex | |
| Jiang et al. | Asymmetric transfer hydrogenation catalysed by hydrophobic dendritic DACH–rhodium complex in water | |
| Liu et al. | Dendritic Chiral Phosphine Lewis Bases‐Catalyzed Asymmetric Aza‐Morita–Baylis–Hillman Reaction of N‐Sulfonated Imines with Activated Olefins | |
| Li et al. | Palladium (ii)-catalyzed C–C and C–O bond formation for the synthesis of C 1-benzoyl isoquinolines from isoquinoline N-oxides and nitroalkenes | |
| Wu et al. | Rhodium (III)-catalyzed regioselective C (sp2)–H activation of indoles at the C4-position with iodonium ylides | |
| CN109232529B (zh) | 一种Rh(III)催化具有氮杂环骨架的化合物的制备方法 | |
| CN109485647B (zh) | 一种抗焦虑药物帕戈隆或帕秦克隆的制备方法 | |
| Willis et al. | Intermolecular hydroacylation of acrylate esters: a new route to 1, 4-dicarbonylsElectronic supplementary information (ESI) available: experimental details. See http://www. rsc. org/suppdata/cc/b1/b107852f | |
| CN113620918B (zh) | 一种通过路易斯酸催化[3+2]环加成反应合成螺环类化合物的方法 | |
| JP4822844B2 (ja) | エナンチオ選択的なエナミドのカルボニル基への求核付加反応方法と光学活性α−ヒドロキシ−γ−ケト酸エステル、ヒドロキシジケトンの合成方法 | |
| CN112574041B (zh) | 一种手性β羟基1,3-二羰基类化合物的合成方法 | |
| JP4917064B2 (ja) | スルホニルイミデートのアリル化反応方法 | |
| Shan et al. | Copper-catalyzed desymmetric silylative-cyclization of 1, 6-diynes for synthesis of spirocyclic compounds | |
| JP2001526111A (ja) | モリブデン、タングステンまたはクロムを有するキラル配位子をベースとする触媒組成物およびアリル性基質の不斉アルキル化の方法 | |
| CN111018779B (zh) | 一种2-(3-异喹啉基)-丙酸乙酯衍生物及合成方法 | |
| EP1439159B1 (en) | Process for producing optically active compound | |
| CN108623439B (zh) | 一种由芳基重氮盐和芳基磺酰肼制备联芳烃的方法 | |
| CN111662202A (zh) | 一种α-酮酰胺类化合物的合成方法 | |
| CN111285846B (zh) | 一种2-(2-吲哚基)-乙酸酯衍生物及其合成方法 | |
| JP4307106B2 (ja) | ５−アルキリデン−２−オキサゾリジノン類の製造方法 | |
| Mercy et al. | Facile synthesis of N-(α-furanyl) alkyl sulfoximines via gold catalyzed Michael addition/cyclization of enynones and sulfoximines | |
| CN113087689B (zh) | 5-氨基-γ-内酯衍生物的简便合成方法 | |
| JPH08208655A (ja) | ヘキサアザイソウルチタン誘導体の製造方法 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |