【科普】雌酮和17β-雌二醇的生产方法(从大豆油工艺的副产品出发)

17β-雌二醇

悬浮2g(7.4mmol)雌酮在10ml水中,加入0.11g(0.37mmol)二甲基二辛 基氯化铵、0.4g(7.4mmol)KBH4,在油浴55℃中机械搅拌3小时。将反应物过 滤,粗品用甲醇重结晶得到β-雌二醇1.84g,收率91%。m.p.178-179℃,氢核 磁共振谱(400MHz,CDCl3)δ:7.95(m,1H,-OH),7.06(d,J=8Hz,1H,1-H) 6.53-6.61(m,2H,2-H,4-H),3.67(m,1H,17-H),0.73(s,3H,18-H)。

雌酮

雌酚酮的制备方法
Abstract

本发明提出了一种雌酚酮的制备方法,该合成工艺路线如下:本发明用大豆油的下脚料ADD作为原料替换双烯,仅通过两步化学反应,快速合成雌酚酮,降低能耗,减少污染,其三废产量仅为传统工艺的十分之一;而且原料来源广泛,成本低廉,适合于工业化推广运用。得到的产品,其总收率高;经过后处理之后纯度高达99.0%,单杂小于0.1%,符合美国药典标准;质量得率为60-65%。
CN105001293A.pdf (469.5 KB)

微生物转化植物甾醇为单产雄甾二烯二酮的菌株

CN101402928B

大豆油工艺

Woerfel, J. B. (1995). Soybean Oil Processing Byproducts and Their Utilization. Practical Handbook of Soybean Processing and Utilization, 297–313. doi:10.1016/b978-0-935315-63-9.50021-8
woerfel1995.pdf (1.9 MB)

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一些古早方法

A convenient synthesis of progesterone from stigmasterol

https://pubs.acs.org/doi/abs/10.1021/jo00442a044

A Synthesis of Progesterone from Ergosterol

https://pubs.acs.org/doi/10.1021/ja01610a036

The Preparation of Dehydroandrosterone from Cholesterol

https://pubs.acs.org/doi/10.1021/ja01311a036

The Synthesis of Estradiol and 1-Methylestradiol from Cholesterol

https://pubs.acs.org/doi/10.1021/ja01215a001

Butenandt, A., & Hanisch, G. (1935). Über Testosteron. Umwandlung des Dehydro-androsterons in Androstendiol und Testosteron; ein Weg zur Darstellung des Testosterons aus Cholesterin. Hoppe-Seyler´s Zeitschrift Für Physiologische Chemie, 237(1-3), 89–97. doi:10.1515/bchm2.1935.237.1-3.89

butenandt1935.pdf (1012.7 KB)

Ruzicka, L., & Wettstein, A. (1935). Sexualhormone VII. Über die künstliche Herstellung des Testikelhormons Testosteron (Androsten-3-on-17-ol). Helvetica Chimica Acta, 18(1), 1264–1275. doi:10.1002/hlca.193501801176


Synthesis of testosterone from dehydroandrosterone as described by Butenandt and Hanisch in 1935
https://eje.bioscientifica.com/view/journals/eje/180/6/EJE-19-0071.xml

Sondheimer, F., Mechoulam, R., & Sprecher, M. (1964). The synthesis of 10-hydroxy-10α-testosterone. Tetrahedron, 20(11), 2473–2485. doi:10.1016/s0040-4020(01)90827-0

Watanabe, Y., Mizuhara, Y., & Shiota, M. (1971). Synthesis of 19-hydroxy-19a-methyl-5-ene steroids via the 6.beta.,19-epoxy derivatives. The Journal of Organic Chemistry, 36(17), 2558–2560. doi:10.1021/jo00816a043

Kovganko, N. V., Kashkan, Z. N., & Chernov, Y. G. (1992). Synthesis of 19-hydroxysteroids I. New synthesis of 19-hydroxytestosterone. Chemistry of Natural Compounds, 28(6), 584–588. doi:10.1007/bf00630434

EHRENSTEIN, M., BARBER, G. W., & GORDON, M. W. (1951). INVESTIGATIONS ON STEROIDS. XIII. TRANSFORMATION OF STROPHANTHIDIN INTO COMPOUNDS STRUCTURALLY RELATED TO STEROID HORMONES1. The Journal of Organic Chemistry, 16(3), 349–375. doi:10.1021/jo01143a002

Mgr. Vojtěch Kapras
Syntéza a vlastnosti neuroaktivních steroidů
Synthesis and Properties of Neuroactive Steroids
PhD. Thesis

脱氢表雄酮 - 维基百科.pdf (612.0 KB)

DHEA很便宜
https://m.1688.com/offer/678717760967.html

补充:

1,4-雄二烯-3,17-二酮的合成

US2340388

雌酮

Estrone, 3-hydroxyestra-1,3,5(10)-trien-17-one (28.1.9), has been made synthetically in various ways. According to one of the first and most simple schemes, synthesis was carried out in the following manner. Condensation of 3-methoxyphenylacetylene with bicyclohexane-1,5-dione in a Favorskii reaction conditions lead to the corresponding carbinol (28.1.1). The triple bond was reduced by hydrogen over a palladium catalyst, forming the tertiary alcohol (28.1.2), which was then dehydrated in acidic conditions to give the compound (28.1.3). Intramolecular alkylation of this compound in the presence of anhydrous aluminum chloride formed a tetracyclic ketone (28.1.4), which during condensation with benzaldehyde was transformed into an eneone (28.1.5). This was methylated at the β-position relative to the keto-group by methyl iodide in the presence of potassium tert-butylate, and the resulting compound (28.1.6) underwent ozonolysis, forming the dicarboxylic acid (28.1.7). Cyclization of this compound to a cyclopentanone derivative lead to the formation of methyl ester of the desired estrone (28.1.8), and demethylation of the phenolic hydroxyl group by hydrobromic acid formed the desired estrone (28.1.9).

DD298107A5

  1. A process for the preparation of 3-hydroxy-1,3,5 (10) -estratrien-17-one by pyrolysis of 1,4-androstadiene-3,17-dione in the presence of 1,2,3,4-tetrahydronaphthaene as a hydrogen donor, by pre-heated to a temperature of 450-850 0 C 1,2,3,4-tetrahydronaphthalene in a mixing zone with a heated to a temperature of up to 300 0 C solution of 1,4-androstadiene-3 , 17-dione in 1,2,3,4-tetrahydronaphthalene, the Gomisch heated in a pyrolysis at a Verweiizeit 0.001 to 60 seconds to temperatures of 450-700 0 C and cools the product emerging from the pyrolysis, characterized that the pyrolysis is carried out under a pressure of 3.5 χ 10 e to 3 x 10 8 Pa. 2. Apparatus for carrying out the method according to claim 1, characterized in that it is designed according to German Patent 2537254.

US2280828
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HERSHBERG, E. B., RUBIN, M., & SCHWENK, E. (1950). SYNTHESIS OF ESTRONE FROM ANDROSTADIENEDIONE. The Journal of Organic Chemistry, 15(2), 292–300. doi:10.1021/jo01148a010
image

doi/10.1021/acs.oprd.6b00215
image

Russell Marker and the Mexican Steroid Hormone Industry
https://www.acs.org/content/acs/en/education/whatischemistry/landmarks/progesteronesynthesis.html

CN108003210A
US5741795

马烯雌酮及其衍生物的高效合成
http://www.ccspublishing.org.cn/article/doi/10.6023/cjoc201709005
(a) Zderic, J. A.; Bowers, A.; Carpio, H.; Djerassi, C. J. Am. Chem. Soc. 1958, 80, 2596.
(b) Zderic, J. A.; Carpio, H.; Bowers, A.; Djerassi, C. Steroids 1963, 1, 233.
(c) Bagli, J. F.; Morand, P. F.; Wiesner, K.; Gaudry, R. Tetrahedron Lett. 1964, 5, 387.
(d) Stein, R. P.; Buzby, G. C.; Smith, H. Tetrahedron Lett. 1966, (41), 5015.
(e) Stein, R. P.; Buzby, G. C.; Smith, H. Tetrahedron 1970, 26, 1917.
(f) Bailey, E. J.; Gale, A.; Phillipp, G.; Siddons, P. T.; Smith, G., Chem. Commun. 1967, 1253.
(g) Marshall, D. J.; Deghengh, R. Can. J. Chem. 1969, 47, 3127.



doi:10.1016/j.tetlet.2010.04.070
1a 是非常便宜的东西,而且不管制。

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总结:
1.直接热解法
2.碱金属还原法
3.逆羟醛缩合法

推荐前体物质:
53-43-0
510-64-5
846-48-0(在美国管制)

推荐直接购买雌二醇50-28-2(不管制),不要买成alpha 雌二醇。
(完结)

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竟然要两步反应[doge]

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果然不能买了

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Conformational dynamics of androgen receptors bound to agonists and antagonists
https://www.nature.com/articles/s41598-021-94707-2

Chemistry and Structural Biology of Androgen Receptor
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2096617/

Structure-based Virtual Screening and Identification of a Novel Androgen Receptor Antagonist
https://www.jbc.org/article/S0021-9258(20)63175-1/pdf

Structural basis for androgen receptor agonists and antagonists: Interaction of SPEED 98-listed chemicals and related compounds with the androgen receptor based on an in vitro reporter gene assay and 3D-QSAR

https://doi.org/10.1016/j.bmc.2006.06.064

In Vitro and in Vivo Structure-Activity Relationships of Novel Androgen Receptor Ligands with Multiple Substituents in the B-Ring

https://academic.oup.com/endo/article/146/12/5444/2500699

Structural basis of androgen receptor binding to selective androgen response elements
https://www.pnas.org/doi/10.1073/pnas.0401123101

Discovery of Novel Androgen Receptor Ligands by Structure-based Virtual Screening and Bioassays
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6411960/

Discovery of a Novel Androgen Receptor Antagonist Manifesting Evidence to Disrupt the Dimerization of the Ligand-Binding Domain via Attenuating the Hydrogen-Bonding Network Between the Two Monomers

https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c01287