Synthetic method of 17z-(1-hydroxyl-2-oxo-1-ethylene) androstenone derivatives

A technology for the synthesis of androstenone and its synthesis method, which is applied in the field of synthesis of 17Z-androstenone, can solve the problems of difficult separation, difficult separation of isomers, and low stereoselectivity of products, and achieve high yield, highly selective effect

Inactive Publication Date: 2018-01-09
TAIZHOU POLYTECHNIC COLLEGE +1
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  • Abstract
  • Description
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Problems solved by technology

[0004] Previously reported chemical syntheses of this class of steroids (Beyler, R.E.; Hoffman, F.J. Am. Chem. Soc. 1957, 79, 9297. Herzog, H.L.; Gentles, M.J.; Marshall, H.; Hershberg, E.B.J. Am. Chem. Soc.1961,83,4073.), harsh reaction conditions are often used, the yield of the target compound is relatively low, and the stereoselectivity of the product is not high, and the isomers of E and Z are difficult to separate, which cannot meet the requirements of research and application
Equally using zinc acetate and glacial acetic acid system also can not improve the yield of target compound (Lewbart, M.L.; Monder, C.; Boyko, W.J.; Singer, C.J.; Iohan, F.J.Org.Chem.1989,54,1332-1338. )
And use p-toluenesulfonic acid to promote above-mentioned reaction, can obviously improve the yield of target compound, but still give the isomer mixture of E and Z, also have the difficulty of separation (M.L.D.Gioia, A.Leggio, A.L. Pera, A. Liguori, A. Napoli, C. Siciliano, G. Sindona, Tetrahedron Lett. 2001, 42, 7413–7415)

Method used

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  • Synthetic method of 17z-(1-hydroxyl-2-oxo-1-ethylene) androstenone derivatives
  • Synthetic method of 17z-(1-hydroxyl-2-oxo-1-ethylene) androstenone derivatives
  • Synthetic method of 17z-(1-hydroxyl-2-oxo-1-ethylene) androstenone derivatives

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preparation example Construction

[0013] A kind of synthetic method of 17Z-(1-hydroxyl-2-oxo-1-ethylene) androstenone derivative of the present invention comprises the following steps:

[0014] A mixture of glucocorticoids is produced by mixing the catalyst o-iodobenzoic acid and the oxidant potassium persulfate, adding the solvent DMSO, reacting with mixing and stirring, quenching the reaction, and then extracting, washing, drying, and evaporating the solvent to obtain the target compound 17Z- (1-Hydroxy-2-oxo-1-ethylidene)androstenone derivatives.

[0015]

[0016] a: X=H, Y=H; b: X, Y=O; c: X=OH, Y=H

[0017] The reaction temperature in the step of the present invention is 75° C., the reaction time is 12 hours, and the yield is 89%-92%.

[0018] test instrument

[0019] Infrared spectral analysis: Bruker tensor 27 infrared spectrometer, KBr tablet method, the detection range is 4000 ~ 400cm -1 ; Melting point measurements: WRR melting point apparatus, data uncorrected. 1 H-NMR and 13 C-NMR analysis:...

Embodiment 117

[0022] Example 1 17Z-(1-hydroxy-2-oxo-1-ethylidene)androstenone (2a)

[0023] Take 1.038g (3mmol) of compound 1a, 0.93g (3.75mmol) of o-iodobenzoic acid, 2.30g (3.75mmol) of potassium hydrogen persulfate, add 3.5mL of DMSO, and stir the reaction at 75°C for 12h under nitrogen protection. The reaction mixture was quenched with 3 mL of water, extracted twice with 20 mL of chloroform each time, the combined organic phases were washed successively with 10% NaOH, water and saturated brine, Na 2 SO 4 dry. The solvent was evaporated and the residue was chromatographed (silica gel, EtOAc / DCM: 1 / 12) to give the product 17Z-(1-hydroxy-2-oxo-1-ethylidene)androstenone (2a) as a white solid 878 mg, 89% yield: mp 150-152°C (EtOAc / hexanes): 149-152°C); 1 H-NMR (CDCl 3 ,ppm):δ9.586(s,1H),5.746(s,1H),5.587(s,1H),1.218(s,3H),1.023(s,3H); 1 H-NMR (CDCl 3 +D 2 O, ppm): δ9.583 (s, 1H), 5.748 (s, 1H), 1.219 (s, 3H), 1.023 (s, 3H); 13 C-NMR (CDCl 3 ,ppm): δ199.52,186.09,170.87,147.02,141.83...

Embodiment 217

[0024] Example 2 17Z-(1-hydroxy-2-oxo-1-ethylene)-4-androst-3,11-enedione (2b)

[0025]Take 1.083g (3mmol) of compound 1a, 0.93g (3.75mmol) of o-iodobenzoic acid, 2.30g (3.75mmol) of potassium hydrogen persulfate, add DMSO 3.5mL, and stir at 75°C for 12h under nitrogen protection. The reaction mixture was quenched with 3 mL of water, extracted twice with 20 mL of chloroform each time, the combined organic phases were washed successively with 10% NaOH, water and saturated brine, Na 2 SO 4 dry. The solvent was evaporated and the residue was chromatographed (silica gel, EtOAc / DCM: 1 / 12) to give the product 17Z-(1-hydroxy-2-oxo-1-ethylidene)-4-androst-3 as a white solid , 11-enedione (2b) 0.946mg, yield 92%: mp190-192°C (EtOAc / Hexanes): 188-192°C); 1 H-NMR (CDCl 3 ,ppm): δ9.595(d,J=0.9Hz,1H),5.740(s,1H),5.630(d,J=0.9Hz,1H),3.250(d,J=13.2Hz,1H),1.432 (s,3H),0.978(s,3H); 1 H-NMR (CDCl 3 +D 2 0, ppm): δ9.592(s, 1H), 5.746(s, 1H), 3.248(d, J=13.2Hz, 1H), 1.432(s, 3H), 0.979(s,...

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Abstract

The invention relates to a synthetic method for a 17Z-(1-hydroxy-2-oxo-1- ethylidene) androstenone derivative. The synthetic method comprises the following steps of mixing a catalyst 2-iodobenzoic acid and an oxidant potassium hydrogen persulfate to produce a mixture glucocorticoid, adding a DMSO solvent, performing a mixing and stirring reaction and a quenching reaction, and conducting extraction, washing and drying to boil off the solvent, then performing column chromatography to obtain the target compound 17Z-(1-hydroxy-2-oxo-1- ethylidene) androstenone derivative. (Please see the formula in the description) The synthetic method for the 17Z-(1-hydroxy-2-oxo-1- ethylidene) androstenone derivative has the advantages of being high in selectivity, capable of preparing a single stereoselective product, high in the target compound yield and capable of meeting the needs in scientific researches and practical application.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, and in particular relates to a synthesis method of 17Z-(1-hydroxyl-2-oxo-1-ethylidene)androstenone. Background technique [0002] Due to their strong biological activity, many steroid compounds in nature have been widely used as drugs in clinical treatment. After proper structural design and modification, many steroids can become new drugs with better physiological functions than the parent steroids, such as improved drug properties and reduced side effects. Through years of experimental research, it was found that the change of the 17-position substituent of the steroid core has a more important effect on the drug activity than the change of the substituent at other positions (Chowdhury P, Borah JM, Goswami1P, Das AM.A convenient synthesis of the side chain of loteprednol etabonate-An ocular soft corticosteroid from20-oxopregnanes using metal-mediated halogenation as a key reaction. Steroids20...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J7/00
CPCC07J7/009
Inventor 王立中王存德卞小琴
Owner TAIZHOU POLYTECHNIC COLLEGE
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