Login Register Cart 0
Generic placeholder image

Combinatorial Chemistry & High Throughput Screening

Editor-in-Chief

ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

An Efficient Procedure for the Synthesis of 21-Acetoxypregna-1,4,9(11),16- tetraene-3,20-dione

Author(s): Luu D. Huy*, Nguyen T. Diep, Tran K. Vu, Tatiana S. Savinova and Marina V. Donova

Volume 23, Issue 3, 2020

Page: [225 - 231] Pages: 7

DOI: 10.2174/1386207323666200219122644

Price: $65

Abstract

Background: Halogenated corticosteroids are widely used in medicine, and the global need of these steroidal APIs is estimated to be 40 – 70 tons, annually. Vietnam currently imports the pharmaceutical compounds up to 90%, in particular 100% of steroidal drugs. Currently, industrial production is based on the chemical syntheses of corticosteroids from either 16- dehydropregnenolone acetate (obtained from diosgenin) or androstenedione (obtained from phytosterol). The development of shorter synthetic schemes and more economically feasible technologies is of great significance. Introduction of 1(2)-double bond at the final stages of the corticosteroids synthesis results inpoor yield. 21-Acetoxypregna-1,4,9(11),16-tetraene-3,20-dione (tetraene acetate) is a key intermediate in the synthesis of highly active halogenated corticosteroids such as dexamethasone and other halogenated corticosteroids. 21-acetoxypregna-1,4,9(11),16- tetraene-3,20-dione is a key intermediate in the synthesis of dexamethasone from the readily available and cheap 9α-hydroxyandrost-4-ene-3,17-dione.

Objective: The purpose of this study was the development of an efficient and shorter procedure for the synthesis of 21-acetoxypregna-1,4,9(11),16-tetraene-3,20-dione from 9α-hydroxyandrostenedione, which is a product of a bio-oxidative degradation of the side chain of phytosterols.

Methods: Pregnane side chain was constructed using cyanohydrin method. For 1(2)- dehydrogenation, selene dioxide was applied for the introduction of Δ1(2)-double bond. Other stages of the synthesis were epimerization, Stork’s iodination procedure and dehydration.

Result: 21-Acetoxypregna-1,4,9(11),16-tetraene-3,20-dione was prepared from 9α- hydroxyandrostenedione in yield more than 46%.

Conclusion: An efficient and practically feasible procedure for the synthesis of 21-acetoxypregna- 1,4,9(11),16-tetraene-3,20-dione from 9α-hydroxyandrostenedione, a key intermediate for the synthesis of 9-haloidated corticoids, has been developed. The procedure can be applied for the production of value-added 9-haloidated corticoids.

Keywords: 9α-hydroxyandrostenedione, 21-acetoxypregna-1, 4, 9(11), 16-tetraene-3, 20-dione, dehydration, hydrocyanation, acetoxylation, dehydrogenation.

« Previous Next »
[1]
Nagasawa, M.; Hashiba, H.; Watanabe, N.; Bae, M.; Tamura, G.; Arima, K. Microbial transformation of sterols. Part. IV. C19-steroid intermediates in the degradation of cholesterol by Arthrobacter simplex. Agric. Biol. Chem., 1970, 34(5), 801-804.
[http://dx.doi.org/10.1271/bbb1961.34.801]
[2]
John, S.C.; Wesenborn, F.L. Process for preparing 9alpha-hydroxy steroids. US. Patent 3,065,146, 1962 November 20.
[3]
Huy, L.D.; Diep, N.T.; Savinova, T.S.; Lukashev, N.V.; Beletskaya, I.P. Study on isolation of a phytosterol mixture from the by-product of soybean oil production. Vietnam J. Chem., 2010, 48(2), 203-210.
[4]
Van Rheenen, V. Cyanohydrin process. US. Patent 4,500,461, 1985 February 19 (Upjohn Co.).
[5]
Nitsuta, K. Preparation of 17α-cyanosteroid, Jpn. Patent 57062298, 1982 April 15 (Mitsubishi Chem. Ind.).
[6]
Walker, J.A. Corticosteroids from 17-ketosteroids via 20-cyano- Δ17(20)-pregnanes US. Patent 4600538, 1986 July;15.
[7]
Diep, N.T.; Huy, L.D. A novel scheme for the synthesis of 21-acetoxypregna-1,4,9(11)-triene-17α,21-diol-3,20-dione from 9α-hydroxyandrostenedione. Curr. Bioact. Compd., 2020. [e-pub ahead of print].
[8]
Fernández-Cabezón, L.; Galán, B.; García, J.L. New insights on steroid biotechnology. Front. Microbiol., 2018, 9(958), 958.
[http://dx.doi.org/10.3389/fmicb.2018.00958] [PMID: 29867863]
[9]
Bragin, E.Y.; Shtratnikova, V.Y.; Schelkunov, M.I.; Dovbnya, D.V.; Donova, M.V. Genome-wide response on phytosterol in 9-hydroxyandrostenedione-producing strain of Mycobacterium sp. VKM Ac-1817D. BMC Biotechnol., 2019, 19(1), 39.
[http://dx.doi.org/10.1186/s12896-019-0533-7] [PMID: 31238923]
[10]
Yao, K.; Xu, L.Q.; Wang, F.Q.; Wei, D.Z. Characterization and engineering of 3-ketosteroid-△1-dehydrogenase and 3-ketosteroid-9α-hydroxylase in Mycobacterium neoaurum ATCC 25795 to produce 9α-hydroxy-4-androstene-3,17-dione through the catabolism of sterols. Metab. Eng., 2014, 24, 181-191.
[http://dx.doi.org/10.1016/j.ymben.2014.05.005] [PMID: 24831710]
[11]
Savinova, T.S.; Diep, N.T.; Voishvillo, N.E.; Andryushina, V.A.; Karpova, N.V.; Beletskaya, I.P.; Huy, L.D. Extraction of a mixture of phytosterols from soybeanprocessing by-product and its use in the manufacture of 9alpha- hydroxyandrost-4-en-3,17-dione. Pharm. Chem. J., 2012, 46(3), 183-186.
[http://dx.doi.org/10.1007/s11094-012-0756-6]
[12]
Andryushina, V.A.; Rodina, N.V.; Stytsenko, T.S.; Huy, L.D.; Druzhinina, A.V.; Yaderetz, V.V.; Voishvillo, N.E. Conversion of soybean sterols into 3,17-diketosteroids using actinobacteria Mycobacterium neoaurum, Pymelobacter simplex and Rhodococcus erythropolis. Appl. Biochem. Microbiol., 2011, 47(3), 270-273.
[http://dx.doi.org/10.1134/S0003683811030021]
[13]
Karpova-Rodina, N.V. Andryushina, V.A.; Iaderez, V.V.; Druzhinina, A.V.; Stytsenko, T.S.; Shaskolskiy, B.L.; Lozinsky,V.I.; Huy, L.D. and Voishvillo. N.E. Transformation of Δ4-3-ketosteroids by free and immobilized cells of Rhodococcuserythropolis action bacterium. Appl. Biochem. Microbiol., 2011, 47(4), 386-392.
[14]
Kazantsev, A.V.; Savinova, T.S.; Lukashev, N.V.; Dovbnya, D.V.; Khomutov, S.M.; Sukhodolskaya, G.V.; Shutov, A.A.; Fokina, V.V.; Nikolayeva, V.M.; Donova, M.V.; Egorova, O.V.; Surovtsev, V.V. Method of obtaining 11β,17α,21-trihydroxy-16α-methyl-9α- fluoropregna-1,4-diene-3,20-dione (dexamethasone) from phytosterol. RU. Patent 2,532,902C1, 2014 November 20.
[15]
Andryushina, V.A.; Stytsenko, T.S.; Karpova, N.V.; Yaderetz, V.V.; Dzhavakhiya, V.V. Efficient synthesis of 21-aceroxypregna-1,4,9(11),16-tetraene-3,20-dione, a key intermediate in the synthesis of highly active fluorinated corticosteroids from 9α-hydroxyandrostenedione. Pharm. Chem. J., 2018, 52(9), 776-780.
[http://dx.doi.org/10.1007/s11094-018-1898-y]
[16]
Hazen, G.G.; Rosenburg, D.W. Preparation of 9(11)-unsaturated steroids. A novel reagent system. J. Org. Chem., 1964, 29(7), 1930-1932.
[http://dx.doi.org/10.1021/jo01030a065]
[17]
Shephard, K.P. Desulfinylation process for preparing androsta- 4,9(11)-diene-3,17-dione, US. Patent 4102907A, 1978 July 25 (Upjohn Co.).
[18]
Beaton, J.M.; Huber, J.E.; Padilla, A.G.; Breuer, M.E. Nonaromatic oxygenated strong acid dehydration of 9α- hydroxyandrostenediones, US. Patent 4127596A, 1978 November 28.
[19]
Savinova, T.S.; Kazantsev, A.V.; Huy, L.D.; Lukashev, N.V. Dehydration of 9α-Hydroxyandrost-4-ene-3,17-dione in organic solvents. Pharm. Chem. J., 2017, 51(7), 612-615.
[http://dx.doi.org/10.1007/s11094-017-1662-8]
[20]
Batist, J.N.M.; Marx, A.F. Process for the preparation of 9(11)- dehydroandrostanes, EP. Patent 0253415A1, 1988 January 20.
[21]
Batist, J.N.M.; Barendse, N.C.M.E.; Marx, A.F. Process for the preparation of 9(11)-dehydro steroids, EP. Patent 0294911A1, 1988 November 14.
[22]
Bergstrom, C.G.; Dodson, R.M. Acid-catalysed rearrangement of 9α-hydroxy-4-androstene-3,17-dion. Chem. Ind., 1961, 1530-1531.
[23]
Process for producing 4,9(11)-androstadiene-3,17-dione. HU. Patent 189,351 1986 June 30.
[24]
Solyom, S.; Szilagyi, K.; Toldy, L. A novel dehydration reaction of steroidal alcohols. J. Prakt. Chem., 1988, 330(2), 309-312.
[http://dx.doi.org/10.1002/prac.19883300220]
[25]
Andryushina, V.A.; Savinova, T.S.; Skryabin, K.G. Method of preparing pregnanes, RU. Patent 2,156,255, 2000 September 20.
[26]
Nitsuta, K. Preparation of 17α-cyanosteroid. Jpn. Patent 57,062,298, 1982 April 15.
[27]
Nitta, I.; Fujimori, Sh.; Haruyama, T.; Inoue, Sh.; Ueno, H. The syntheses of the corticoid side chain. III. A new synthesis of 17α,21-dihydroxypregna-1,4-diene-3,20-dione 17,21-diacetate from androsta-1,4-diene-3,17-dione. Bull. Chem. Soc. Jpn., 1985, 58(3), 981-986.
[http://dx.doi.org/10.1246/bcsj.58.981]
[28]
Westmijze, H.; Kleijn, H.; Vermeer, P.; Van Dịjck, L.A. Ag(I)-assisted hydrolysis of mestranolmethanesulfonate into epimestranol. Tetrahedron Lett., 1980, 21(27), 2665-2666.
[http://dx.doi.org/10.1016/S0040-4039(00)92834-X]
[29]
Reimann, H. Novel 1-methyl-1,3,5(10),9(11)-estratetraenes and methods for their manufacture. US Patent 3,082,225.
[30]
Andryushina, V.A.; Voishvillo, N.E.; Skryabin, K.G.; Stytsenko, T.S.; Savinova, T.S.; Sazonova, A.S. Strain pimelobacter simplex eliciting steroid-1,2-dehydrogenase activity, RU Patent 2,215,038, 2003 October 27.

Rights & Permissions Print Cite
Article Metrics
47
2
© 2024 Bentham Science Publishers | Privacy Policy