PL218587B1 - Process for preparing 17a-oxa-D-homo-androst-1,4-diene-3,17-dione - Google Patents
Process for preparing 17a-oxa-D-homo-androst-1,4-diene-3,17-dioneInfo
- Publication number
- PL218587B1 PL218587B1 PL400947A PL40094712A PL218587B1 PL 218587 B1 PL218587 B1 PL 218587B1 PL 400947 A PL400947 A PL 400947A PL 40094712 A PL40094712 A PL 40094712A PL 218587 B1 PL218587 B1 PL 218587B1
- Authority
- PL
- Poland
- Prior art keywords
- carried out
- androst
- oxa
- dione
- homo
- Prior art date
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- OSVMTWJCGUFAOD-KZQROQTASA-N formestane Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1O OSVMTWJCGUFAOD-KZQROQTASA-N 0.000 title claims description 9
- 238000004519 manufacturing process Methods 0.000 title 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 230000009466 transformation Effects 0.000 claims description 6
- 239000000758 substrate Substances 0.000 claims description 5
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 4
- 239000002609 medium Substances 0.000 claims description 4
- 230000000813 microbial effect Effects 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 241001465752 Purpureocillium lilacinum Species 0.000 claims description 3
- 230000036983 biotransformation Effects 0.000 claims description 3
- RSIHSRDYCUFFLA-DYKIIFRCSA-N boldenone Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 RSIHSRDYCUFFLA-DYKIIFRCSA-N 0.000 claims description 3
- 238000004587 chromatography analysis Methods 0.000 claims description 3
- 239000012043 crude product Substances 0.000 claims description 3
- RSIHSRDYCUFFLA-UHFFFAOYSA-N dehydrotestosterone Natural products O=C1C=CC2(C)C3CCC(C)(C(CC4)O)C4C3CCC2=C1 RSIHSRDYCUFFLA-UHFFFAOYSA-N 0.000 claims description 3
- 239000003480 eluent Substances 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 238000006220 Baeyer-Villiger oxidation reaction Methods 0.000 claims description 2
- 239000012736 aqueous medium Substances 0.000 claims description 2
- 238000011097 chromatography purification Methods 0.000 claims description 2
- 125000000422 delta-lactone group Chemical group 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 230000003647 oxidation Effects 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 230000007062 hydrolysis Effects 0.000 claims 1
- 238000006460 hydrolysis reaction Methods 0.000 claims 1
- 150000002576 ketones Chemical class 0.000 claims 1
- 239000000376 reactant Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- AEMFNILZOJDQLW-QAGGRKNESA-N androst-4-ene-3,17-dione Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 AEMFNILZOJDQLW-QAGGRKNESA-N 0.000 description 2
- 229960005471 androstenedione Drugs 0.000 description 2
- AEMFNILZOJDQLW-UHFFFAOYSA-N androstenedione Natural products O=C1CCC2(C)C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 AEMFNILZOJDQLW-UHFFFAOYSA-N 0.000 description 2
- 239000000262 estrogen Substances 0.000 description 2
- DBPWSSGDRRHUNT-CEGNMAFCSA-N 17α-hydroxyprogesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)C)(O)[C@@]1(C)CC2 DBPWSSGDRRHUNT-CEGNMAFCSA-N 0.000 description 1
- 229940122815 Aromatase inhibitor Drugs 0.000 description 1
- 241000134719 Aspergillus tamarii Species 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 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
- 206010028980 Neoplasm Diseases 0.000 description 1
- PDMMFKSKQVNJMI-BLQWBTBKSA-N Testosterone propionate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CC)[C@@]1(C)CC2 PDMMFKSKQVNJMI-BLQWBTBKSA-N 0.000 description 1
- 241000227728 Trichoderma hamatum Species 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 229940030486 androgens Drugs 0.000 description 1
- 239000003886 aromatase inhibitor Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 201000000079 gynecomastia Diseases 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229960001712 testosterone propionate Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Landscapes
- Steroid Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Description
Opis wynalazkuDescription of the invention
Przedmiotem wynalazku jest sposób wytwarzania 17a-oxa-D-homo-androst-1,4-dien-3,17-dionu, o wzorze 2 przedstawionym na rysunku.The present invention relates to a process for the preparation of 17a-oxa-D-homo-androst-1,4-dien-3,17-dione of the formula (2) shown in the drawing.
Wynalazek może znaleźć zastosowanie w przemyśle farmaceutycznym do otrzymywania związków biologicznie aktywnych.The invention may find application in the pharmaceutical industry for the preparation of biologically active compounds.
17a-oxa-D-homo-androst-1,4-dien-3,17-dion jest związkiem stosowanym głównie jako inhibitor aromatazy przekształcającej androgeny w estrogeny. Dzięki jego własnościom terapeutycznym można farmakologicznie zapobiegać rozwojowi raka piersi, który może być aktywowany przez estrogeny u kobiet po menopauzie. Związek ten stosowany jest również w profilaktyce przerostu i nowotworu prostaty, przy ginekomastii oraz przedwczesnym dojrzewaniu (G. E. Serafini, S. Moslemi, Molecular and Cellular Endocrinology, 2001, 178, s. 117-131).17a-oxa-D-homo-androst-1,4-dien-3,17-dione is a compound mainly used as an aromatase inhibitor that converts androgens into estrogens. Due to its therapeutic properties, it is possible to pharmacologically prevent the development of breast cancer, which can be activated by oestrogens in postmenopausal women. This compound is also used in the prevention of prostate hyperplasia and cancer, in gynecomastia and premature puberty (G. E. Serafini, S. Moslemi, Molecular and Cellular Endocrinology, 2001, 178, pp. 117-131).
Wynalazek dotyczy mikrobiologicznego, konkurencyjnego w stosunku do chemicznego, utleniania typu Baeyera-Villigera 1,4-dien-3-okso substratu steroidowego do 17a-oxa-D-homo-androst-1,4-dien-3,17-dionu, z układem δ-laktonu w pierścieniu D.The invention relates to microbial, competitive to the chemical, Baeyer-Villiger type oxidation of 1,4-dien-3-oxo steroid substrate to 17a-oxa-D-homo-androst-1,4-dien-3,17-dione, with δ-lactone system in the D ring
Znany jest sposób otrzymywania 17a-oxa-D-homo-androst-1,4-dien-3,17-dionu w mieszaninie produktów na drodze mikrobiologicznej transformacji propionianu testosteronu oraz androstendionu przez Trichoderma hamatum KCH25 z niską wydajnością. W ciągu 4 dni z propionianu uzyskano 5% tego produktu a z androstendionu w ciągu 6 dni 13% (A. Bartmańska, J. Dmochowska-Gładysz, Enzyme and Microbial Technology, 2007, 40, s. 1615-1621). Związek ten otrzymano również z niską wydajnością jako jeden z produktów przekształcenia 17(a-hydroksyprogesteronu w kulturze Aspergillus tamarii KITA (A. Ch. Hunter, N. E. Carragher, Journal of Steroid Biochemistry & Molecular Biology, 2003, 87, s. 301-308).It is known to obtain 17a-oxa-D-homo-androst-1,4-dien-3,17-dione in a mixture of products by microbial transformation of testosterone propionate and androstenedione by Trichoderma hamatum KCH25 with low yield. Within 4 days, 5% of this product was obtained from propionate and 13% from androstenedione within 6 days (A. Bartmańska, J. Dmochowska-Gładysz, Enzyme and Microbial Technology, 2007, 40, pp. 1615-1621). This compound was also obtained in low yield as one of the transformation products of 17 (α-hydroxyprogesterone in Aspergillus tamarii KITA culture (A. Ch. Hunter, NE Carragher, Journal of Steroid Biochemistry & Molecular Biology, 2003, 87, pp. 301-308) .
Przedmiotem wynalazku jest sposób otrzymywania 17a-oxa-D-homo-androst-1,4-dien-3,17-dionu, opracowany w wyniku badań prowadzonych w ramach projektu finansowanego przez Unię Europejską z Europejskiego Funduszu Rozwoju Regionalnego, Grant Nr POIG. 01 .03.01 -00- 1 58/09 „Biotransformacje użyteczne w przemyśle farmaceutycznym i kosmetycznym.The subject of the invention is a method of obtaining 17a-oxa-D-homo-androst-1,4-dien-3,17-dione, developed as a result of research conducted as part of a project financed by the European Union from the European Regional Development Fund, Grant No. POIG. 01 .03.01 -00- 1 58/09 "Biotransformations useful in the pharmaceutical and cosmetic industries.
Istota wynalazku polega na tym, że wodną pożywkę zaszczepia się szczepem Penicillium lilacinum AM111, po czym hodowlę prowadzi się przez 3 doby. Propionian 1-dehydrotestosteronu roz3 puszczony w acetonie, dodaje się w ilości od 10 do 25 mg na 100 cm3 pożywki i transformację prowadzi się przez kolejne 3 doby. Roztwór ekstrahuje się rozpuszczalnikiem organicznym niemieszającym się z wodą, osusza się i odparowuje rozpuszczalnik. Surowy produkt oczyszcza się chromatograficznie, przy czym proces biotransformacji substratu prowadzi się przy ciągłym wstrząsaniu reagentów i w temperaturze od 18 do 27°C.The essence of the invention lies in the fact that the aqueous medium is inoculated with the Penicillium lilacinum AM111 strain, after which the cultivation is carried out for 3 days. Propionate, 1-dehydrotestosterone striped 3 released in acetone, is added in an amount of from 10 to 25 mg per 100 cm 3 of culture medium and the transformation is carried out for a further 3 days. The solution is extracted with a water-immiscible organic solvent, dried and the solvent is evaporated off. The crude product is purified by chromatography, with the biotransformation process of the substrate carried out by shaking the reagents continuously and at a temperature of 18 to 27 ° C.
33
Korzystnie jest, gdy do hodowli dodaje się 25 mg substratu na 100 cm3 pożywki.Preferably, 25 mg of substrate per 100 cm 3 of medium are added to the culture.
Korzystnie także jest, gdy oczyszczanie chromatograficzne prowadzi się przy pomocy eluentu o składzie heksan: aceton: chloroform: octan etylu, w proporcji objętościowej składnikówIt is also preferred that the chromatographic purification is carried out with the eluent of the composition hexane: acetone: chloroform: ethyl acetate, in the proportion by volume of the components
1,5:1:0,5:0,25.1.5: 1: 0.5: 0.25.
Zasadniczą zaletą wynalazku jest otrzymanie 17a-oxa-D-homo-androst-1,4-dien-3,17-dionu z wydajnością 92%, w temperaturze pokojowej.The main advantage of the invention is the preparation of 17a-oxa-D-homo-androst-1,4-dien-3,17-dione with a yield of 92%, at room temperature.
Wynalazek jest bliżej objaśniony na przykładzie wykonania.The invention is explained in more detail using an exemplary embodiment.
P r z y k ł a dP r z k ł a d
Do kolby Erlenmajera o pojemności 300 cm3, w której znajduje się 100 cm3 sterylnej pożywki zawierającej 3 g glukozy i 1 g aminobaku, wprowadza się szczep Penicillium lilacinum AM111. Hodowlę prowadzi się przy stałym wstrząsaniu w temperaturze 20°C. Po trzech dniach wzrostu mikroor3 ganizmu dodaje się 25 mg propionianu 1-dehydrotestosteronu, o wzorze 1, rozpuszczonego w 1 cm3 acetonu. Transformację prowadzi się przy ciągłym wstrząsaniu przez kolejne 72 godziny w warunkach, w których prowadzona była hodowla mikroorganizmu. Następnie uzyskany roztwór transformacyjny ekstrahuje się trzykrotnie chloroformem, osusza bezwodnym siarczanem magnezu i odparowuje rozpuszczalnik. Otrzymuje się 35 mg surowego produktu, który oczyszcza się chromatograficznie używając jako eluent mieszaninę: heksan: aceton: chloroform: octan etylu (1,5:1:0,5:0,25 v/v/v/v). Na tej drodze otrzymuje się 23 mg 17a-oxa-D-homo-androst-1,4-dien-3,17-dionu, o wzorze 2 (wydajność 92%).Penicillium lilacinum AM111 strain is introduced into an Erlenmajer flask with a capacity of 300 cm 3 , in which there is 100 cm 3 of a sterile medium containing 3 g glucose and 1 g aminobac. The cultivation is carried out under constant agitation at a temperature of 20 ° C. After three days of growth mikroor 3 ganizmu added 25 mg of 1-dehydrotestosterone propionate of the formula 1, dissolved in 1 cm 3 of acetone. The transformation is carried out under continuous shaking for a further 72 hours under the conditions in which the microorganism was grown. The resulting transformation solution was then extracted three times with chloroform, dried with anhydrous magnesium sulfate, and the solvent was evaporated. 35 mg of crude product are obtained which are purified by chromatography using as eluent: hexane: acetone: chloroform: ethyl acetate (1.5: 1: 0.5: 0.25 v / v / v / v). In this way, 23 mg of 17a-oxa-D-homo-androst-1,4-dien-3,17-dione of formula 2 are obtained (92% yield).
Uzyskany produkt charakteryzuje się następującymi danymi spektralnymi:The obtained product is characterized by the following spectral data:
1H NMR: δ (ppm): 1,20 (3H, s, 19-CHs); 1,37 (3H, s, I8-CH3); 6,09 (1H, br s, C=C4H); 6,26 (1H, dd, J = 2,1; 10,2 Hz, C=C2H); 7,02 (1H, d, J = 10,2 Hz, C=C1H) 1 H NMR: δ (ppm): 1.20 (3H, s, 19-CHs); 1.37 (3H, s, 18-CH3); 6.09 (1H, br s, C = C4H); 6.26 (1H, dd, J = 2.1; 10.2 Hz, C = C2H); 7.02 (1H, d, J = 10.2Hz, C = C1H)
PL 218 587 B1 13C NMR: δ (ppm): 185,9 (C-3); 170,6 (C-17); 166,3 (C-5); 154,1 (C-1); 128,1 (C-2); 124,0 (C-4); 82,2 (C-13); 51,0 (C-9); 45,3 (C-14); 42,7 (C-10); 38,8 (C-12); 37,5 (C-8); 32,1 (C-7); 32,0 (C-6); 28,3 (C-16); 23,4 (C-11); 20,2 (C-15); 19,9 (C-18); 18,5 (C-19).GB 218 587 B1 13 C NMR: δ (ppm): 185.9 (C-3); 170.6 (C-17); 166.3 (C-5); 154.1 (C-1); 128.1 (C-2); 124.0 (C-4); 82.2 (C-13); 51.0 (C-9); 45.3 (C-14); 42.7 (C-10); 38.8 (C-12); 37.5 (C-8); 32.1 (C-7); 32.0 (C-6); 28.3 (C-16); 23.4 (C-11); 20.2 (C-15); 19.9 (C-18); 18.5 (C-19).
Claims (3)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PL400947A PL218587B1 (en) | 2012-09-27 | 2012-09-27 | Process for preparing 17a-oxa-D-homo-androst-1,4-diene-3,17-dione |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PL400947A PL218587B1 (en) | 2012-09-27 | 2012-09-27 | Process for preparing 17a-oxa-D-homo-androst-1,4-diene-3,17-dione |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| PL400947A1 PL400947A1 (en) | 2013-05-27 |
| PL218587B1 true PL218587B1 (en) | 2015-01-30 |
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| PL400947A PL218587B1 (en) | 2012-09-27 | 2012-09-27 | Process for preparing 17a-oxa-D-homo-androst-1,4-diene-3,17-dione |
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| Country | Link |
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2012
- 2012-09-27 PL PL400947A patent/PL218587B1/en unknown
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| Publication number | Publication date |
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| PL400947A1 (en) | 2013-05-27 |
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