PL228268B1 - Method for obtaining (-)-enantiomer of (-)-(1R,4S)-2-azabicyclo[2.2.1]hept-5-en-3-one - Google Patents
Method for obtaining (-)-enantiomer of (-)-(1R,4S)-2-azabicyclo[2.2.1]hept-5-en-3-oneInfo
- Publication number
- PL228268B1 PL228268B1 PL408997A PL40899714A PL228268B1 PL 228268 B1 PL228268 B1 PL 228268B1 PL 408997 A PL408997 A PL 408997A PL 40899714 A PL40899714 A PL 40899714A PL 228268 B1 PL228268 B1 PL 228268B1
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- Prior art keywords
- azabicyclo
- hept
- enantiomer
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- obtaining
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- DDUFYKNOXPZZIW-UHFFFAOYSA-N 3-azabicyclo[2.2.1]hept-5-en-2-one Chemical compound C1C2C(=O)NC1C=C2 DDUFYKNOXPZZIW-UHFFFAOYSA-N 0.000 title claims description 16
- 238000000034 method Methods 0.000 title claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 241000233866 Fungi Species 0.000 claims description 4
- 241000228143 Penicillium Species 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 239000001888 Peptone Substances 0.000 claims description 3
- 108010080698 Peptones Proteins 0.000 claims description 3
- 239000002054 inoculum Substances 0.000 claims description 3
- 150000003951 lactams Chemical class 0.000 claims description 3
- 235000019319 peptone Nutrition 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 239000003814 drug Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000002777 nucleoside Substances 0.000 description 3
- -1 Γ-lactam enantiomers Chemical class 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 102000004157 Hydrolases Human genes 0.000 description 2
- 108090000604 Hydrolases Proteins 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- DDUFYKNOXPZZIW-UHNVWZDZSA-N (1s,4r)-3-azabicyclo[2.2.1]hept-5-en-2-one Chemical class C1[C@@H]2C(=O)N[C@H]1C=C2 DDUFYKNOXPZZIW-UHNVWZDZSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 102000004882 Lipase Human genes 0.000 description 1
- 108090001060 Lipase Proteins 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 241000589540 Pseudomonas fluorescens Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 238000005273 aeration Methods 0.000 description 1
- 230000002210 biocatalytic effect Effects 0.000 description 1
- 230000036983 biotransformation Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 235000019421 lipase Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000007003 mineral medium Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Description
(21) Numer zgłoszenia: 408997 (51) Int CI.(21) Filing Number: 408997 (51) Int CI.
C07D 471/08 (2006.01) C12P 41/00 (2006.01)C07D 471/08 (2006.01) C12P 41/00 (2006.01)
Urząd Patentowy Rzeczypospolitej Polskiej (22) Data zgłoszenia: 28.07.2014 (54) Sposób otrzymywania (-)-enancjomeru (-)-(1 R,4S)-2-azabicyklo[2.2.1]hept-5-en-3-onuPatent Office of the Republic of Poland (22) Date of application: 28.07.2014 (54) Method of obtaining the (-) - enantiomer (-) - (1 R, 4S) -2-azabicyclo [2.2.1] hept-5-en-3- onu
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PL 228 268 B1PL 228 268 B1
Opis wynalazkuDescription of the invention
Przedmiotem wynalazku jest sposób otrzymania (-)-enancjomeru (-)-(1 R,4S)-2-azabicyklo-[2.2.1]hept-5-en-3-onu, o wzorze 2, przedstawionym na rysunku.The present invention relates to the preparation of the (-) - enantiomer (-) - (1R, 4S) -2-azabicyclo [2.2.1] hept-5-en-3-one of the formula 2 shown in the drawing.
Wynalazek może znaleźć zastosowanie w przemyśle farmaceutycznym do syntezy leków.The invention may find application in the pharmaceutical industry for the synthesis of drugs.
Enancjomery 2-azabicyklo[2.2.1]hept-5-en-3-onu są prekursorami w syntezie leków, dlatego też ważnym elementem jest rozdział mieszaniny racemicznej tego laktamu (Singh, R.; Vince, R.; 2-Azabicyclo[2.2.1]hept-5-en-3-one: Chemical profile of a versatile synthetic building block and its impact on the development of therapeutics. Chem. Rev. 2012, 112, 4642-4686). Enancjomery γ-laktamu są szeroko stosowne jako prekursory karbocyklicznych nukleozydów, jak również wykorzystywane są jako reagenty w asymetrycznej syntezie chiralnej (Zhang, Y.; Yang, D.; Yao, S.; Cao, Y.; Song, H. HPLC determination of enantiomeric 2-azabicyclo[2.2.1]hept-5-en-3-one on chiral stationary phase. Journal of Chromatographic science 2011,49, 67-71).Enantiomers of 2-azabicyclo [2.2.1] hept-5-en-3-one are precursors in drug synthesis, therefore an important element is the resolution of the racemic mixture of this lactam (Singh, R .; Vince, R .; 2-Azabicyclo [2.2 .1] hept-5-en-3-one: Chemical profile of a versatile synthetic building block and its impact on the development of therapeutics. Chem. Rev. 2012, 112, 4642-4686). Γ-lactam enantiomers are widely used as precursors to carbocyclic nucleosides as well as being used as reagents in asymmetric chiral synthesis (Zhang, Y .; Yang, D .; Yao, S .; Cao, Y .; Song, H. HPLC determination of enantiomeric 2-azabicyclo [2.2.1] hept-5-en-3-one on chiral stationary phase. Journal of Chromatographic science 2011, 49, 67-71).
Znane są metody otrzymywania tego enacjomeru w biotransformacji enzymatycznej preparatami komercyjnie dostępnych lipaz (Forro, E.; Fulop, F. Enzymatic method for the synthesis of blockbuster drug intermediates - synthesis of five cyclic γ-amino acid and γ-lactam enantiomers. Eur. J. Org. Chem. 2008, 5263-5268) lub całymi komórkami bakterii Pseudomonas fluorescens (Palmer, C. F.; McMague, R. Conversion of one enantiomer of the carbocyclic nucleoside synthon 2-azabicyclo[2.2.1]hept-5-en-3-one into the other. J. Chem. Soc. Perkin. Trans. 1995, 1, 1201-1203).Methods of obtaining this enantiomer in enzymatic biotransformation with preparations of commercially available lipases are known (Forro, E .; Fulop, F. Enzymatic method for the synthesis of blockbuster drug intermediates - synthesis of five cyclic γ-amino acid and γ-lactam enantiomers. Eur. J. Org. Chem. 2008, 5263-5268) or Pseudomonas fluorescens whole cells (Palmer, CF; McMague, R. Conversion of one enantiomer of the carbocyclic nucleoside synthon 2-azabicyclo [2.2.1] hept-5-en-3 -one into the other. J. Chem. Soc. Perkin. Trans. 1995, 1, 1201-1203).
Brak jest doniesień literaturowych o otrzymywaniu (-)-enancjomeru (-)-2-azabicyklo[2.2.1]hept-5-en-3-onu przy użyciu grzybów strzępkowych.There are no reports in the literature on the preparation of the (-) - enantiomer of (-) - 2-azabicyclo [2.2.1] hept-5-en-3-one using filamentous fungi.
Istotą wynalazku jest, że do podłoża Czapka dodaje się inokulum grzyba strzępkowego Penicillium thomi AM91. Po narośnięciu grzybni dodaje się pepton w ilości pozwalającej otrzymać 1%-owy roztwór, następnie dodaje się mieszaninę racemiczną (±)-2-azabicyklo[2.2.1]hept-5-en-3-onu o wzorze 1, w ilości pozwalającej na osiągnięcie 0,033% stężenia laktamu. Po wykazaniu braku obecności (+)-enancjomeru na GC wyposażonym w kolumnę z wypełnieniem chiralnym, całość ekstrahuje się, osusza i oczyszcza. Otrzymuje się (-)-(1R,4S)-2-azabicyklo[2.2.1]hept-5-en-3-on o wzorze 2.The essence of the invention is that the inoculum of the Penicillium thomi AM91 filamentous fungus is added to the cap medium. After the mycelium has grown, an amount of peptone to obtain a 1% solution is added, then the racemic mixture of (±) -2-azabicyclo [2.2.1] hept-5-en-3-one of formula 1 is added in an amount sufficient to reaching 0.033% lactam concentration. After showing the absence of the (+) - enantiomer on the GC equipped with a chiral packed column, the whole is extracted, dried and purified. The (-) - (1R, 4S) -2-azabicyclo [2.2.1] hept-5-en-3-one of formula 2 is obtained.
Korzystne jest, gdy ekstrakcję prowadzi się chlorkiem metylenu albo chloroformem albo eterem dietylowym.It is preferable that the extraction is carried out with methylene chloride or with chloroform or diethyl ether.
Postępując zgodnie z wynalazkiem, w wyniku działania hydrolaz grzyba Penicillium thomi AM91 enancjomer (+) hydrolizuje szybciej pozostawiając nieprzereagowany enancjomer (-)-(1 R,4S)-2-azabicyklo[2.2.1]hept-5-en-3-onu o wzorze 2.Following the invention, the (+) enantiomer hydrolyzes faster by action of Penicillium thomi AM91 hydrolases, leaving the (-) - (1R, 4S) -2-azabicyclo [2.2.1] hept-5-en-3-one enantiomer unreacted formula 2.
Zasadniczą zaletą metody wytwarzania wspomnianego enancjomeru jest to, że otrzymuje się go w łagodnych warunkach z 70%-ową wydajnością, liczoną w stosunku do niezhydrolizowanego enancjomeru.The main advantage of the method of producing said enantiomer is that it is obtained under mild conditions with a yield of 70%, based on the non-hydrolysed enantiomer.
Wynalazek jest bliżej objaśniony na przykładach otrzymania (-)-enancjomeru (-)-2-azabicyklo[2.2.1 ]hept-5-en-3-onu.The invention is further illustrated by the preparation of the (-) - enantiomer of (-) - 2-azabicyclo [2.2.1] hept-5-en-3-one.
P r z y k ł a d. Do bioreaktora (Brunswick BioFlo®/CelliGen® 115, USA) o pojemności 7000 cm3, w którym znajduje się 3000 cm3 sterylnego podłoża o składzie: NaNO3-0.3%, KH2PO4-0.1%, KCI-0.05%, MgSO4x7 H2O-0.005%, FeSO4x7 H2O-0.001 g i sacharoza-3% (pH=4.2) wprowadza się 10% inokulum szczepu Penicillium thomi AM91. Proces prowadzi się w określonych warunkach: podłoże (3 dm3), napowietrzanie (1 v/m), szybkość obrotów (200-300 rpm), temperatura (299,15K). Po 4 dniach wzrostu mikroorganizmu w podłożu mineralnym, dodaje się 30 g peptonu, w celu indukcji hydrolaz enancjoselektywnie hydrolizujących pierścień (+)-;.'-laktamu, osiągając pH=8.3. Po 4 godzinach dodaje się 1 g substratu, jakim jest (±)-2-azabicyklo[2.2.1]hept-5-en-3-on o wzorze 1, rozpuszczonego w 2 cm3 acetonu. Po wykazaniu braku obecności (+)-enancjomeru na GC (Agilent 6890N, Cyclosil-B (30 m x 0,25 mm x 0,25 gm) zawartość bioreaktora przelewa się do czterech kolb o pojemności 2 dm3, każdą z nich trzykrotnie ekstrahuje sie mechanicznie chlorkiem metylenu (3 x 250 cm3). Ekstrakty osusza się bezwodnym siarczanem magnezu i następnie odparowuje rozpuszczalnik. Otrzymany surowy produkt wraz z metabolitami szczepu grzyba, oczyszcza się chromatograficznie na żelu krzemionkowym (Silica gel 60 (0,040-0,063 mm, Fluka), używając jako eluentu mieszaniny chlorek metylenu : metanol, w stosunku objętościowym 98:2,5. Po oczyszczeniu otrzymuje się 350 mg (-)enancjomeru (wydajność wynosiła 70%, a nadmiar enancjomeryczny ee=93% (GC chiralnej kolumny) (-)-(1R,4S)-2-azabicyklo[2.2.1]hept-5-en-3-onu w postaci stałej.Example: For a bioreactor (Brunswick BioFlo® / CelliGen® 115, USA) with a capacity of 7000 cm 3 , in which there is 3000 cm 3 of a sterile medium with the following composition: NaNO3-0.3%, KH2PO4-0.1%, KCI-0.05 %, MgSO4x7 H2O-0.005%, FeSO4x7 H2O-0.001 g and sucrose-3% (pH = 4.2) are introduced with 10% inoculum of Penicillium thomi AM91 strain. The process is carried out under certain conditions: substrate (3 dm 3 ), aeration (1 v / m), rotation speed (200-300 rpm), temperature (299.15K). After 4 days of growth of the microorganism in a mineral medium, 30 g of peptone are added to induce hydrolases that enantioselectively hydrolyze the (+) -; .'- lactam ring, reaching pH = 8.3. After 4 hours, add 1 g of the material, which is (±) -2-azabicyclo [2.2.1] hept-5-en-3-one of the formula 1, dissolved in 2 cm 3 of acetone. After demonstrating the absence of the (+) - enantiomer on the GC (Agilent 6890N, Cyclosil-B (30 mx 0.25 mm x 0.25 gm), the content of the bioreactor is poured into four 2 dm 3 flasks, each of them extracted three times mechanically with methylene chloride (3 x 250 cm 3 ). The extracts are dried with anhydrous magnesium sulfate and then the solvent is evaporated off. The obtained crude product, together with the metabolites of the fungus strain, is purified by chromatography on silica gel (Silica gel 60 (0.040-0.063 mm, Fluka), using methylene chloride: methanol as eluent, in a volume ratio of 98: 2.5. After purification, 350 mg of the (-) enantiomer were obtained (yield was 70%, ee = 93% enantiomeric excess (GC of chiral column) (-) - (1R, 4S) -2-azabicyclo [2.2.1] hept-5-en-3-one in solid form.
Uzyskany produkt charakteryzuje się następującymi danymi spektroskopowymi:The obtained product is characterized by the following spectroscopic data:
Temperatura topnienia: 54-55°C.Melting point: 54-55 ° C.
PL 228 268 Β1PL 228 268 Β1
Lit. [ajggg] = '565° (c=2.0, CHCb) (Taylor, S.J.C.; McCague, R.; Wisdom, R.; Lee, C.; Dickson, K.; Ruecroft, G.; 0’Brien, F.; Littlechild, J.; Bevan, J.; Roberts, S.M.; Evans, C.T. Development of the biocatalytic resolution of 2-azabicyclo[2.2.1]hept-5-en-3-one as an entry to single-enantiomer carbocyclic nucleosides. Tetrahedron Asymmetry 1993, 4, 6, 1117-11128) [a]^9] = -525.9° (c=1.0, CH3OH) 1H NMR (500 MHz, CDCIs), δ (ppm): 2,19-2,20 (m, 2, CH2-7); 3,19-3,23 (m, 1, CH-1); 4,31-4,35 (m, 1, CH-4); 5,85 (s, 1, NH); 6,63-6,65 (dt, 1, J = 7.4, 5.0 Hz, CH-6); 6;75-6;76 (dd, 1, J = 7.4, 5.0 Hz, CH-5);Lit. [ajgg6] = '565 ° (c = 2.0, CHClb) (Taylor, SJC; McCague, R .; Wisdom, R .; Lee, C .; Dickson, K .; Ruecroft, G .; O'Brien, F. ; Littlechild, J .; Bevan, J .; Roberts, SM; Evans, CT Development of the biocatalytic resolution of 2-azabicyclo [2.2.1] hept-5-en-3-one as an entry to single-enantiomer carbocyclic nucleosides . Tetrahedron Asymmetry 1993, 4, 6, 1117-11128), [a] ^ 9] = -525.9 ° (c = 1.0, CH3 OH) 1 H NMR (500 MHz, CDCl) δ (ppm): 2,19-2 . 20 (m, 2, CH 2 -7); 3.19-3.23 (m, 1, CH-1); 4.31-4.35 (m, 1, CH-4); 5.85 (s, 1, NH); 6.63-6.65 (dt, 1, J = 7.4, 5.0Hz, CH-6); 6; 75-6; 76 (dd, 1, J = 7.4, 5.0Hz, CH-5);
13C NMR (151 MHz), δ (ppm): 53,14 (CH2-7); 59,25 (CH-1); 60,21 (CH-4); 138,11 (CH-5); 141,05 (CH-6); 185,27 (C-3); 13 C NMR (151 MHz), δ (ppm): 53.14 (CH 2 -7); 59.25 (CH-1); 60.21 (CH-4); 138.11 (CH-5); 141.05 (CH-6); 185.27 (C-3);
IR (NaCI, cm1): 3019 (s), 2400 (m), 1709 (s), 1521 (m); GC-EIMS: 110 (M+1).IR (NaCl, cm 1 ): 3019 (s), 2400 (m), 1709 (s), 1521 (m); GC-EIMS: 110 (M + 1).
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| PL408997A PL228268B1 (en) | 2014-07-28 | 2014-07-28 | Method for obtaining (-)-enantiomer of (-)-(1R,4S)-2-azabicyclo[2.2.1]hept-5-en-3-one |
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| PL408997A PL228268B1 (en) | 2014-07-28 | 2014-07-28 | Method for obtaining (-)-enantiomer of (-)-(1R,4S)-2-azabicyclo[2.2.1]hept-5-en-3-one |
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| PL228268B1 true PL228268B1 (en) | 2018-03-30 |
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