PL236000B1 - Chiral ebselen derivative of (1S, 3R, 4R)-2-[(S) -1-phenylethyl]-3-aminomethyl-2-azabicyclo[2.2.1]heptane and method of its preparation - Google Patents

Chiral ebselen derivative of (1S, 3R, 4R)-2-[(S) -1-phenylethyl]-3-aminomethyl-2-azabicyclo[2.2.1]heptane and method of its preparation Download PDF

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PL236000B1
PL236000B1 PL432309A PL43230918A PL236000B1 PL 236000 B1 PL236000 B1 PL 236000B1 PL 432309 A PL432309 A PL 432309A PL 43230918 A PL43230918 A PL 43230918A PL 236000 B1 PL236000 B1 PL 236000B1
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azabicyclo
phenylethyl
heptane
derivative
chiral
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Mariola Zielińska-Błajet
Elżbieta Wojaczyńska
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Politechnika Wroclawska
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Abstract

Przedmiotem wynalazku jest chiralny ebselen pochodna (1S,3R,4R)-2-[(S)-1-fenyloetylo]-3-ammometylo-2-azabicyklo[2.2.1]heptanu, o wzorze 1. Wynalazek dotyczy również sposobu wytwarzania chiralnego ebselenu pochodnej (1S,3R,4R)-2-[(S)-1-fenyloetylo]-3-aminometylo-2-azabicyklo[2.2.1]heptanu, o wzorze 1, który polega na tym, że chlorek 2-(chloroseleno)benzoilu poddaje się reakcji z równomolową ilością bicyklicznej aminy w obecności trójetyloaminy oraz 4-dimetyloaminopirydyny (DMAP), w temperaturze 295 K, w środowisku rozpuszczalnika organicznego.The subject of the invention is a chiral ebselene derivative of (1S,3R,4R)-2-[(S)-1-phenylethyl]-3-ammomethyl-2-azabicyclo[2.2.1]heptane, formula 1. The invention also relates to a method for preparing chiral ebselen derivative of (1S,3R,4R)-2-[(S)-1-phenylethyl]-3-aminomethyl-2-azabicyclo[2.2.1]heptane, of formula 1, which consists in the fact that the chloride 2-( chloroselene)benzoyl is reacted with an equimolar amount of bicyclic amine in the presence of triethylamine and 4-dimethylaminopyridine (DMAP), at a temperature of 295 K, in an organic solvent.

Description

Opis wynalazkuDescription of the invention

Przedmiotem wynalazku jest chiralny ebselen pochodna (1S,3R,4R)-2-[(S)-1-fenyloetylo]-3-aminometylo-2-azabicyklo[2.2.1]heptanu, znajdujący zastosowanie w farmakologii oraz jako katalizator w syntezie organicznej.The subject of the invention is a chiral ebselene derivative of (1S, 3R, 4R) -2 - [(S) -1-phenylethyl] -3-aminomethyl-2-azabicyclo [2.2.1] heptane, used in pharmacology and as a catalyst in organic synthesis .

Przedmiotem wynalazku jest również sposób wytwarzania chiralnego ebselenu pochodnej (1S,3R,4R)-2-[(S)-1-fenyloetylo]-3-aminometylo-2-azabicyklo[2.2.1] heptanu.The invention also relates to a process for the preparation of the chiral ebselene of the derivative (1S, 3R, 4R) -2 - [(S) -1-phenylethyl] -3-aminomethyl-2-azabicyclo [2.2.1] heptane.

W literaturze przedmiotu, m.in. opisano, że ebselen (2-fenylo-1,2-benzizoselenazol-3(2H)-on) oraz jego pochodne mogą być stosowane w farmakologii jako antyutleniacze, środki przeciwzapalne, antynowotworowe, antyinfekcyjne, oraz inhibitory enzymów [Mugesh, G.: Chem. Rev. 2001, 101,In the literature on the subject, incl. describes that ebselen (2-phenyl-1,2-benzisoselenazol-3 (2H) -one) and its derivatives can be used in pharmacology as antioxidants, anti-inflammatory, anti-cancer, anti-infective agents, and enzyme inhibitors [Mugesh, G .: Chem . Rev. 2001, 101,

2125; Chem. Eur. J. 2008, 14, 10603; J. Am. Chem. Soc. 2010, 132, 5364; Nogueira, C.W. Chem. Rev. 2004, 104, 6255; Uchida, K. Chem. Res. Toxicol. 2006, 19, 1196]. Ze stanu techniki wiadomo, że ebselen oraz jego pochodne znalazły praktyczne zastosowanie w farmakologii, m.in. w kardiologii [Wang, X. CN 1572295 A], jako środki przeciwzapalne w ginekologii [Yang, X. CN 1709243 A], w leczeniu łuszczycy [Xiong, Z. CN 101019863 A] oraz infekcji bakteryjnych [Billack, B.C. US 20100227899 A1]. W literaturze przedmiotu opisano również zastosowanie ebselenu oraz jego pochodnych jako katalizatora transferu tlenu w wielu reakcjach chemicznych [Młochowski, J.: Molecules 2015, 20, 10205; Tetrahedron 2001,57, 9743; Kumar, S. J. Org. Chem. 2012, 77, 9541; Wirth, T. Heteroat. Chem. 2014, 25, 320].2125; Chem. Eur. J. 2008, 14, 10603; J. Am. Chem. Soc. 2010, 132, 5364; Nogueira, C.W. Chem. Rev. 2004, 104, 6255; Uchida, K. Chem. Res. Toxicol. 2006, 19, 1196]. It is known from the prior art that ebselen and its derivatives have found practical application in pharmacology, incl. in cardiology [Wang, X. CN 1572295 A], as anti-inflammatory agents in gynecology [Yang, X. CN 1709243 A], in the treatment of psoriasis [Xiong, Z. CN 101019863 A] and bacterial infections [Billack, B.C. US 20100227899 A1]. The literature on the subject also describes the use of ebselene and its derivatives as a catalyst for oxygen transfer in many chemical reactions [Młochowski, J .: Molecules 2015, 20, 10205; Tetrahedron 2001, 57,9743; Kumar, S. J. Org. Chem. 2012, 77, 9541; Wirth, T. Heteroat. Chem. 2014, 25, 320].

Syntezę i aktywność biologiczną wybranych chiralnych pochodnych zawierających szkielet 2-azanorbornylowy opisano w artykułach [Wojaczyńska, E. Org. Biomol. Chem. 2015, 13, 6116; Tetrahedron: Asymmetry 2016, 27, 753]. W literaturze przedmiotu opisano również zastosowanie pochodnych opisanych na w/w szkielecie w wielu syntezach stereoselektywnych [Andersson, P.G.: Synlett 2000, 1092; J. Org. Chem. 2002, 67, 1567; Tetrahedron: Asymmetry, 2002, 13, 447; Chem. Soc. Rev. 2002, 31, 223; J. Org. Chem. 2004, 69, 4885; Chem. Eur, J. 2006, 12, 2318; Loh, T.P. Tetrahedron Lett. 2008, 49, 6007].The synthesis and biological activity of selected chiral derivatives containing the 2-azanorbornyl skeleton are described in the articles [Wojaczyńska, E. Org. Biomol. Chem. 2015, 13, 6116; Tetrahedron: Asymmetry 2016, 27, 753]. The literature on the subject also describes the use of the derivatives described on the above-mentioned framework in many stereoselective syntheses [Andersson, P.G .: Synlett 2000, 1092; J. Org. Chem. 2002, 67, 1567; Tetrahedron: Asymmetry, 2002, 13, 447; Chem. Soc. Rev. 2002, 31, 223; J. Org. Chem. 2004, 69, 4885; Chem. Eur, J. 2006, 12, 2318; Loh, T.P. Tetrahedron Lett. 2008, 49, 6007].

Chiralny ebselen pochodna (1S,3R,4R)-2-[(S)-1-fenyloetylo]-3-aminometylo-2-azabicyklo[2.2.1]heptanu, będący przedmiotem wynalazku, nie został dotychczas opisany w literaturze naukowej i patentowej.The chiral ebselene derivative (1S, 3R, 4R) -2 - [(S) -1-phenylethyl] -3-aminomethyl-2-azabicyclo [2.2.1] heptane, which is the subject of the invention, has not yet been described in the scientific and patent literature .

Istotę wynalazku stanowi chiralny ebselen pochodna (1S,3R,4R)-2-[(S)-1-fenyloetylo]-3-aminometylo-2-azabicyklo[2.2.1]heptanu, o wzorze 1.The present invention is based on the chiral ebselene derivative (1S, 3R, 4R) -2 - [(S) -1-phenylethyl] -3-aminomethyl-2-azabicyclo [2.2.1] heptane, of formula 1.

Sposób wytwarzania chiralnego ebselenu pochodnej (1S,3R,4R)-2-[(S)-1-fenyloetylo]-3-aminometylo-2-azabicyklo[2.2.1]heptanu, o wzorze 1, według wynalazku polega na tym, że chlorek 2-(chloroseleno)benzoilu o wzorze 2 poddaje się reakcji z równomolową ilością bicyklicznej aminy przedstawionej wzorem 3 w obecności trójetyloaminy oraz 4-dimetyloaminopirydyny (DMAP), w temperaturze 295 K, w środowisku rozpuszczalnika organicznego.The method of producing chiral ebselene of the derivative (1S, 3R, 4R) -2 - [(S) -1-phenylethyl] -3-aminomethyl-2-azabicyclo [2.2.1] heptane, according to the invention, consists in the following: 2- (chloroselene) benzoyl chloride of formula II is reacted with an equimolar amount of the bicyclic amine represented by formula 3 in the presence of triethylamine and 4-dimethylaminopyridine (DMAP) at 295 K in an organic solvent.

Korzystnie jako rozpuszczalnik stosuje się bezwodny acetonitryl.Preferably, anhydrous acetonitrile is used as the solvent.

Zaletą tego sposobu jest możliwość otrzymania chiralnego ebselenu pochodnej (1S,3R,4R)-2-[(S)-1-fenyloetylo]-3-aminometylo-2-azabicyklo[2.2.1]heptanu, posiadającego sztywny układ bicykliczny, jakim jest szkielet 2-azabicyklo[2.2.1]heptanu charakteryzujący się stabilną konfiguracją oraz odpowiednio umieszczonymi centrami donorowymi.The advantage of this method is the possibility of obtaining chiral ebselene of the derivative (1S, 3R, 4R) -2 - [(S) -1-phenylethyl] -3-aminomethyl-2-azabicyclo [2.2.1] heptane having a rigid bicyclic system, which is 2-azabicyclo [2.2.1] heptane skeleton characterized by a stable configuration and appropriately placed donor centers.

Sposób według wynalazku umożliwia wytworzenie chiralnego ebselenu pochodnej (1S,3R,4R)-2-[(S)-1-fenyloetylo]-3-aminometylo-2-azabicyklo[2.2.1]heptanu o wzorze 1, z wysoką wydajnością i czystością.The process according to the invention makes it possible to prepare chiral ebselene of the derivative (1S, 3R, 4R) -2 - [(S) -1-phenylethyl] -3-aminomethyl-2-azabicyclo [2.2.1] heptane of formula 1 with high yield and purity .

P r z y k ł a d 1P r z k ł a d 1

W celu wytworzenia 2-[(1S,3R,4R)-2[(S)-1-fenyloetylo-2-azabicyklo[2.2.1]hept-3-ylo]metylo]-benzizoselenazol-3(2H)-onu, przedstawionego wzorem numer 1, do roztworu 1 mmola aminy 2aza-norbornylowej (0,230 g) o wzorze 3, otrzymanej metodą znaną z publikacji: Wojaczyńska, E.: Tetrahedron: Asymmetry 2016, 27, str. 753, w 3,0 mL suchego acetonitrylu wkrapla się roztwór chlorku 2-(chloroseleno)benzoilu (1 mmol, 0,267 g) w 3,0 mL suchego acetonitrylu. Następnie dodaje się trójetyloaminę (2,5 mmol, 3,5 mL) oraz szczyptę 4-dimetyloaminopirydyny (DMAP). Reakcję prowadzi się w temperaturze pokojowej (295 K) przez kilka dni. Rozpuszczalnik usuwa się na wyparce a surowy produkt oczyszcza chromatograficznie na silikażelu, stosując mieszaninę dichlorometanu i metanolu (10:1). Uzyskuje się 0,312 g (76%) 2-[(1S,3R,4R)-2[(S)-1-fenyloetylo-2-azabicyklo[2.2.1]hept-3-ylo]metylo]-benzizoselenazol-3(2H)-onu, w postaci jasno żółtego ciała stałego, którego tożsamość potwierdzają analizy spektroskopowe. 1H NMR (600 MHz, CDCh): δ = 1,16-1,21 (m, 1H), 1,25 (d, J = 9,8 Hz, 1H), 1,38 (d, J = 6,5 Hz, 4H), 1,50-1,63 (m, 1H), 1,83 (d, J = 10,1 Hz, 1H), 1,93-2,03To make 2 - [(1S, 3R, 4R) -2 [(S) -1-phenylethyl-2-azabicyclo [2.2.1] hept-3-yl] methyl] -benzisoselenazol-3 (2H) -one, 1, to a solution of 1 mmol of 2-a-norbornyl amine (0.230 g) of formula 3, obtained by the method known from Wojaczyńska, E .: Tetrahedron: Asymmetry 2016, 27, p. 753, in 3.0 mL of dry acetonitrile a solution of 2- (chloroselene) benzoyl chloride (1 mmol, 0.267 g) in 3.0 mL of dry acetonitrile is added dropwise. Then triethylamine (2.5 mmol, 3.5 mL) and a pinch of 4-dimethylaminopyridine (DMAP) are added. The reaction is carried out at room temperature (295 K) for several days. The solvent is removed in an evaporator and the crude product is purified by chromatography on silica gel using a mixture of dichloromethane and methanol (10: 1). 0.312 g (76%) of 2 - [(1S, 3R, 4R) -2 [(S) -1-phenylethyl-2-azabicyclo [2.2.1] hept-3-yl] methyl] -benzisoselenazol-3 ( 2H) -one, in the form of a light yellow solid, the identity of which is confirmed by spectroscopic analyzes. 1 H NMR (600 MHz, CDCl 3): δ = 1.16-1.21 (m, 1H), 1.25 (d, J = 9.8 Hz, 1H), 1.38 (d, J = 6, 5 Hz, 4H), 1.50-1.63 (m, 1H), 1.83 (d, J = 10.1 Hz, 1H), 1.93-2.03

PL 236 000 B1 (m, 1H), 2,22 (dd, J = 9,0, 2,5 Hz, 1H), 2,29 (d, J = 4,3 Hz, 1H), 2,45 (dd, J = 14,2, 2,5 Hz, 1H), 3,44 (dd, J = 14,3, 8,8 Hz, 1H), 3,51 (q, J = 6,5 Hz, 1H), 3,63 (s, 1H), 7,29-7,36 (m, 2H), 7,39 (t, J = 7,7 Hz, 2H), 7,45-7,56 (m, 4H), 7,93 (d, J = 7,8 Hz, 1H). 13C NMR (150 MHz, CDCb): 22,4, 22,5, 29,0, 35,5, 40,3, 48,3, 58,7, 61,2, 69,5, 123,8, 125,9, 127,3, 127,8, 128,7, 128,9, 131,7, 138,7, 145,9, 167,2. HRMS (ESI): wartości teoretyczne dla [C22H24N2OSe+H]+: 413,1127; wartości doświadczalne: 413,1115.PL 236,000 B1 (m, 1H), 2.22 (dd, J = 9.0, 2.5 Hz, 1H), 2.29 (d, J = 4.3 Hz, 1H), 2.45 ( dd, J = 14.2, 2.5 Hz, 1H), 3.44 (dd, J = 14.3, 8.8 Hz, 1H), 3.51 (q, J = 6.5 Hz, 1H ), 3.63 (s, 1H), 7.29-7.36 (m, 2H), 7.39 (t, J = 7.7Hz, 2H), 7.45-7.56 (m, 4H), 7.93 (d, J = 7.8 Hz, 1H). 13 C NMR (150 MHz, CDCb): 22.4, 22.5, 29.0, 35.5, 40.3, 48.3, 58.7, 61.2, 69.5, 123.8, 125.9, 127.3, 127.8, 128.7, 128.9, 131.7, 138.7, 145.9, 167.2. HRMS (ESI): theoretical values for [C22H24N2OSe + H] +: 413.1127; experimental values: 413.1115.

Claims (3)

Zastrzeżenia patentowePatent claims 1. Chiralny ebselen pochodna (1S,3R,4R)-2-[(S)-1-fenyloetylo]-3-aminometylo-2-azabicyklo[2.2.1]heptanu, o wzorze 1.1. Chiral ebselene a (1S, 3R, 4R) -2 - [(S) -1-phenylethyl] -3-aminomethyl-2-azabicyclo [2.2.1] heptane derivative of formula 1. 2. Sposób wytwarzania chiralnego ebselenu pochodnej (1S,3R,4R)-2-[(S)-1-fenyloetylo]-3-aminometylo-2-azabicyklo[2.2.1]heptanu, o wzorze 1, znamienny tym, że chlorek 2-(chloroseleno)benzoilu o wzorze 2 poddaje się reakcji z równomolową ilością bicyklicznej aminy przedstawionej wzorem 3 w obecności trójetyloaminy oraz 4-dimetyloaminopirydyny (DMAP), w temperaturze 295 K, w środowisku rozpuszczalnika organicznego.2. A method for the preparation of chiral ebselene of the derivative (1S, 3R, 4R) -2 - [(S) -1-phenylethyl] -3-aminomethyl-2-azabicyclo [2.2.1] heptane, of formula 1, characterized in that the chloride 2- (chloroselene) benzoyl of formula 2 is reacted with an equimolar amount of the bicyclic amine represented by formula 3 in the presence of triethylamine and 4-dimethylaminopyridine (DMAP) at 295 K in an organic solvent. 3. Sposób według zastrz. 2, znamienny tym, że jako rozpuszczalnik organiczny stosuje się bezwodny acetonitryl.3. The method according to p. The process of claim 2, wherein the organic solvent is anhydrous acetonitrile.
PL432309A 2018-11-30 2018-11-30 Chiral ebselen derivative of (1S, 3R, 4R)-2-[(S) -1-phenylethyl]-3-aminomethyl-2-azabicyclo[2.2.1]heptane and method of its preparation PL236000B1 (en)

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