PL207193B1 - Method for the manufacture of (4aR,6R)-(-)-4,4a,5,6,7,8-hexahydro-6ß-hydroxyl-4a-methyl-2-(3H)-naphtalenone - Google Patents
Method for the manufacture of (4aR,6R)-(-)-4,4a,5,6,7,8-hexahydro-6ß-hydroxyl-4a-methyl-2-(3H)-naphtalenoneInfo
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- PL207193B1 PL207193B1 PL378553A PL37855305A PL207193B1 PL 207193 B1 PL207193 B1 PL 207193B1 PL 378553 A PL378553 A PL 378553A PL 37855305 A PL37855305 A PL 37855305A PL 207193 B1 PL207193 B1 PL 207193B1
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- hexahydro
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Description
Opis wynalazkuDescription of the invention
Przedmiotem wynalazku jest sposób wytwarzania (4aR,6R)-(-)-4,4a,5,6,7,8-heksahydro-6e-hydroksy-4a-metylo-2(3H)-naftalenonu, o wzorze 2 przedstawionym na rysunku.The subject of the invention is a process for the preparation of (4aR, 6R) - (-) - 4,4a, 5,6,7,8-hexahydro-6e-hydroxy-4a-methyl-2 (3H) -naphthalenone, with the formula 2 shown in the figure .
Związek ten może znaleźć zastosowanie jako chiralny substrat w totalnej syntezie związków o wysokiej aktywności biologicznej, np. terpenoidów oraz steroidów.This compound may find use as a chiral substrate in the total synthesis of compounds with high biological activity, e.g. terpenoids and steroids.
Otrzymanie (4aR,6R)-(-)-4,4a,5,6,7,8-heksahydro-6e-hydroksy-4a-metylo-2(3H)-naftalenonu z (S)-(-)-4,4a,5,6,7,8-heksahydro-4a-metylo-2(3H)-naftalenonu jest trudno osiągalne metodami chemicznymi.Preparation of (4aR, 6R) - (-) - 4,4a, 5,6,7,8-hexahydro-6e-hydroxy-4a-methyl-2 (3H) -naphthalenone from (S) - (-) - 4, 4 [alpha], 5,6,7,8-hexahydro-4 [alpha] -methyl-2 (3H) -naphthalenone is difficult to obtain by chemical means.
Znane jest otrzymywanie tego związku, w którym wykorzystano chiralny kompleks manganu w obecności imidazolu i H2O2. Wydajność tego procesu jest niska (poniżej 5%) (F. Estour, S. Menager, B. Akagah, O. Lafont; European Journal of Medicinal Chemistry, 2003 vol. 38).It is known to prepare this compound in which a chiral manganese complex was used in the presence of imidazole and H 2 O 2 . The yield of this process is low (less than 5%) (F. Estour, S. Menager, B. Akagah, O. Lafont; European Journal of Medicinal Chemistry, 2003 vol. 38).
Istota wynalazku polega na tym, że regioselektywną hydroksylację (S)-(-)-4,4a,5,6,7,8-heksahydro-4a-metylo-2(3H)-naftalenonu prowadzi się za pomocą kultury szczepu Chaetomium sp. 1.The essence of the invention lies in the fact that the regioselective hydroxylation of (S) - (-) - 4,4a, 5,6,7,8-hexahydro-4a-methyl-2 (3H) -naphthalenone is carried out with a culture of the Chaetomium sp. 1.
Korzystne jest, gdy hydroksylację prowadzi się wodną kulturą szczepu, przy ciągłym mieszaniu reagentów, w temperaturze 288 - 308 K.It is preferable that the hydroxylation is carried out with the aqueous culture of the strain under constant stirring of the reactants at a temperature of 288-308 K.
Postępując zgodnie z wynalazkiem, w wyniku działania układu enzymatycznego zawartego w komórkach grzyba Chaetomium sp. 1, następuje regioselektywna hydroksylacja pozycji 7β. Uzyskany w ten sposób produkt wydziela się z wodnej kultury mikroorganizmu, znanym sposobem przez ekstrakcję chloroformem.In accordance with the invention, regioselective hydroxylation of the 7β position occurs as a result of the enzyme system contained in the cells of the fungus Chaetomium sp. 1. The product obtained in this way is separated from the aqueous culture of the microorganism by a known method by extraction with chloroform.
Będący przedmiotem wynalazku (4aR,6R)-(-)-4,4a,5,6,7,8-heksahydro-7e-hydroksy-4a-metylo-2(3H)-naftalenon może znaleźć zastosowanie np. jako chiralny substrat w totalnej syntezie bardziej skomplikowanej związków o wysokiej aktywności biologicznej z grupy: steroidów, alkaloidów oraz terpenoidów (M. Pufa, G. Revial, A. Guingant, J. d'Angelo; J. Am. Chem. Soc, 1986, vol. 107)The (4aR, 6R) - (-) - 4,4a, 5,6,7,8-hexahydro-7e-hydroxy-4a-methyl-2 (3H) -naphthalenone being the subject of the invention can be used e.g. as a chiral substrate in total synthesis of more complex compounds with high biological activity from the group of: steroids, alkaloids and terpenoids (M. Pufa, G. Revial, A. Guingant, J. d'Angelo; J. Am. Chem. Soc, 1986, vol. 107)
Zasadniczą zaletą wynalazku jest otrzymywanie (4aR,6R)-(-)-4,4a,5,6,7,8-heksahydro-7e-hydroksy-4a-metylo-2(3H)-naftalenonu jako głównego produktu reakcji, z wydajnością 50%, w temperaturze pokojowej i pH bliskim obojętnemu.The main advantage of the invention is the preparation of (4aR, 6R) - (-) - 4,4a, 5,6,7,8-hexahydro-7e-hydroxy-4a-methyl-2 (3H) -naphthalenone as the main reaction product with the yield 50%, at room temperature and near neutral pH.
Wynalazek jest bliżej objaśniony w przykładzie wykonania.The invention is explained in more detail in an exemplary embodiment.
P r z y k ł a d. Do kolby Erlenmajera o pojemności 250 cm3 w której znajduje się 100 cm3 sterylnej pożywki zawierającej 3 g glukozy i 1 g aminobaku wprowadza się szczep Chaetomium sp. 1. Po sześciu dniach wzrostu dodaje się 50 mg (S)-(-)-4,4a,5,6,7,8-heksahydro-4a-metylo-2(3H)-naftalenonu, o wzorze 1, rozpuszczonego w 1 cm3 acetonu. Transformację prowadzi się przy ciągłym wstrząsaniu przez 6 dni. Następnie uzyskany roztwór transformacyjny ekstrahuje się trzykrotnie chloroformem, osusza bezwodnym siarczanem magnezu i odparowuje rozpuszczalnik. Otrzymuje się 61 mg surowego produktu, który oczyszcza się chromatograficznie. Jako eluentu używa się mieszaniny heksanaceton, w stosunku 2:1. Na tej drodze otrzymuje się 30,1 mg (4aR,6R)-(-)-4,4a,5,6,7,8-heksahydro-7e-hydroksy-4a-metylo-2(3H)-naftalenonu (wydajność przekracza 60%).Example A 250 cm 3 Erlenmajer flask containing 100 cm 3 of sterile medium containing 3 g of glucose and 1 g of aminobac is introduced with the Chaetomium sp. 1 strain. After six days of growth, 50 mg (S) is added - (-) - 4,4a, 5,6,7,8-hexahydro-4α-methyl-2 (3H) -naphthalenone, of the formula I, dissolved in 1 cm 3 of acetone. The transformation is carried out under continuous shaking for 6 days. The resulting transformation solution was then extracted three times with chloroform, dried with anhydrous magnesium sulfate, and the solvent was evaporated. 61 mg of crude product are obtained, which product is purified by chromatography. A 2: 1 mixture of hexanacetone is used as the eluent. In this way, 30.1 mg of (4aR, 6R) - (-) - 4.4a, 5,6,7,8-hexahydro-7e-hydroxy-4a-methyl-2 (3H) -naphthalenone are obtained (the yield exceeds 60%).
Strukturę otrzymanego związku określono za pomocą analizy krystalograficznej. Uzyskany produkt charakteryzuje się następującymi danymi spektralnymi: [α] D + 194° (CHCI3; c 0.700);The structure of the compound obtained was determined by crystallographic analysis. The obtained product is characterized by the following spectral data: [α] D + 194 ° (CHCl 3 ; c 0.700);
1H NMR (300 MHz, CDCI3): δ 1,24 (3H, s, H-4a); 1,33 (1H, dm, J= 12Hz, 5ax); 1,40 (1H, dm, J = 14 Hz, H-7ax); 1,80 (1H, ddd, J - 13,4 Hz, J = 5,5 Hz, J = 2,8 Hz, H-4ax); 1,88 (1H, dt, J = 14,2 Hz, J = 4,5 Hz, H-4eq); 1,96 (1H, dm, J = 12 Hz, H-5eq); 2,14 (1H, dm, J = 14 Hz, H-1); 2,34 (2H, m, H-3eq, and H-8eq); 2,46 (2H, m, H-3axand 8ax); 4,04 (1H, tt, J = 11,2 Hz, J = 4,2 Hz, H-6ax); 5,76 (1H, s, H-1); 13C NMR (300 MHz, CDCI3): δ 23,0 (CH3-4a); 31,0 (C-8); 33,4 (C-3); 35,7 (C-7); 36,6 (C-4a); 38,0 (C-4); 49,8 (C-5); 66,5 (C-6); 124,7 (C-1); 199,4 (C-2); 167,3 (C-8a); ElMS 70 eV, m/z (rel. int): 181 (59) [M+H]+, 162 (100) [M-H2O], 152 (31) [M-CO], 134 (81), 119 (47), 108 (47). 1 H NMR (300 MHz, CDCl 3): δ 1.24 (3H, s, H-4a); 1.33 (1H, dm, J = 12 Hz, 5ax); 1.40 (1H, dm, J = 14Hz, H-7ax); 1.80 (1H, ddd, J - 13.4 Hz, J = 5.5 Hz, J = 2.8 Hz, H-4ax); 1.88 (1H, dt, J = 14.2 Hz, J = 4.5 Hz, H-4eq); 1.96 (1H, dm, J = 12Hz, H -5eq); 2.14 (1H, dm, J = 14Hz, H -1); 2.34 (2H, m, H-3eq, and H-8eq); 2.46 (2H, m, H-3axand 8ax); 4.04 (1H, mp, J = 11.2 Hz, J = 4.2 Hz, H-6ax); 5.76 (1H, s, H -1); 13 C NMR (300 MHz, CDCl 3): δ 23.0 (CH3-4a); 31.0 (C-8); 33.4 (C-3); 35.7 (C-7); 36.6 (C-4a); 38.0 (C-4); 49.8 (C-5); 66.5 (C-6); 124.7 (C-1); 199.4 (C-2); 167.3 (C-8a); ElMS 70 eV, m / z (rel. Int): 181 (59) [M + H] + , 162 (100) [M-H2O], 152 (31) [M-CO], 134 (81), 119 (47), 108 (47).
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| PL378553A PL207193B1 (en) | 2005-12-28 | 2005-12-28 | Method for the manufacture of (4aR,6R)-(-)-4,4a,5,6,7,8-hexahydro-6ß-hydroxyl-4a-methyl-2-(3H)-naphtalenone |
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| PL378553A PL207193B1 (en) | 2005-12-28 | 2005-12-28 | Method for the manufacture of (4aR,6R)-(-)-4,4a,5,6,7,8-hexahydro-6ß-hydroxyl-4a-methyl-2-(3H)-naphtalenone |
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| PL378553A1 PL378553A1 (en) | 2006-06-26 |
| PL207193B1 true PL207193B1 (en) | 2010-11-30 |
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