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Preparation method of 19-hydroxylated cortodone derivatives and 19-hydroxyandrostenedione

A technology of hydroxyandrostenedione and cortodolone, applied in the direction of steroids, organic chemistry, etc., can solve the problems of harsh reaction conditions, limited use range, low yield, etc., to achieve optimized synthesis steps, cost reduction, The effect of improving production efficiency

Active Publication Date: 2020-07-10
WUHAN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, most of these methods require pre-synthesis of special functional groups, harsh reaction conditions, and low yields, which greatly limit the scope of use of these methods.

Method used

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  • Preparation method of 19-hydroxylated cortodone derivatives and 19-hydroxyandrostenedione
  • Preparation method of 19-hydroxylated cortodone derivatives and 19-hydroxyandrostenedione
  • Preparation method of 19-hydroxylated cortodone derivatives and 19-hydroxyandrostenedione

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Embodiment 1: Preparation of 19-hydroxyl-cortodopine

[0033] (1) The strain Thanatephorus cucumeris NBRC 6298 was inoculated on PDA medium (potato 200g / L, glucose 20g / L and agar 15g / L) for activation culture in a constant temperature incubator at 30°C. After 6-10 days, inoculate the well-growth strains on the plate into a 250mL Erlenmeyer flask containing 100mL yeast liquid medium (glucose 25g / L, yeast extract 20g / L), and grow for about 2-3 days at 30°C and 200rpm , take 5mL of well-grown bacterial liquid and transfer it to a 250mL Erlenmeyer flask containing 100mL of fresh yeast liquid medium, continue to cultivate under the same conditions for 2-3 days, and put 25mg of cortodolone and ammonium ferrous sulfate into the In the bacterial culture medium (final iron ion concentration 1.5mmol / L), continue to cultivate and transform for about 3-4 days until the conversion rate reaches the highest, and obtain the compound 19-hydroxy-cortodone (conversion rate 45%).

[0034]...

Embodiment 2

[0037] Embodiment 2: the preparation of compound I-1

[0038]

[0039] 10 mg of 19-hydroxy-cortodone was dissolved in 1 mL of methanol, and then 10 μL of 3M aqueous sodium hydroxide solution and 20 μL of 30% hydrogen peroxide were added sequentially at 0°C. After stirring for 4 hours, the reaction solution was diluted with 5 mL of dichloromethane, and the organic phase was sequentially extracted with water and saturated brine. The combined organic phases were dried over anhydrous sodium sulfate, filtered under reduced pressure, and concentrated under reduced pressure. The obtained crude product was further separated and purified by silica gel column chromatography (eluent was dichloromethane:ethyl acetate=1:2, V / V ), yielding 6.6 mg of I-1 (58%). (c 0.46, CH 3 OH); HRMS(m / z): calcd for C 21 h 30 o 6 Na,[M+Na] + 401.1935; found, 401.1941; 1 H NMR (400MHz, Methanol-d 4 ( ddd,J=14.3,11.4,2.7Hz,1H),2.36–2.21(m,2H),2.20–2.10(m,1H),1.96–1.90(m,1H),1.86–1.73(m,3H), 1.68...

Embodiment 3

[0040] Embodiment 3: the preparation of compound 1-3

[0041]

[0042] 10 mg of 19-hydroxy-cortodone was dissolved in 1.5 mL of methanol, and 5.0 mg of 10% palladium on carbon was added under hydrogen atmosphere. The reaction was carried out at room temperature for 1 hour, and the reaction solution was filtered through celite to remove insoluble palladium carbon. The filtrate was concentrated under reduced pressure and dried to obtain the crude product I-2. I-2 obtained above was dissolved in 2 mL of dichloromethane, and then 10 mg of acetic anhydride and 3 mg of 4-dimethylaminopyridine (DMAP) were added. The reaction was stirred under argon at room temperature for 12 hours. The reaction solution was diluted with dichloromethane and extracted with saturated sodium bicarbonate and sodium chloride solutions successively. The obtained organic phase was dried over anhydrous sodium sulfate, filtered under reduced pressure, and concentrated, and the obtained crude product was fu...

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Abstract

The invention discloses a preparation method of 19 hydroxylated cortodoxone derivative and 19-hydroxy-4-androsten-3,17-dione, and belongs to the fields of organic synthesis and pharmacy. The preparation method provided by the invention comprises the following steps: using 19-hydroxy-cotondoxone as a raw material; performing at least one of the following reactions among 19-hydroxy-cotondoxone underrespective actions of hydrogen peroxide, trimethyl iodosilane, palladium on activated carbon, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, iodobenzene oxide, sodium borohydride, sodium periodate and other reagents: performing structural modification on a ring A and a ring B of 19 hydroxylated cortodoxone, substituting 17, 21 and / or 19 hydroxyl with substituents, and excising a side chain of 19 hydroxylated cortodoxone. The preparation method provided by the invention greatly improves preparation efficiency of an essential intermediate 19-hydroxy-4-androsten-3,17-dione for synthesizing norethindrone contraceptives, and reduces production costs of medicines.

Description

technical field [0001] The invention relates to the fields of organic synthesis and pharmacy, and more specifically relates to a preparation method of 19-hydroxylated cortodone derivatives and 19-hydroxyandrostenedione. Background technique [0002] Steroids are also known as steroids, and there are many kinds of such compounds, which occupy an important position clinically ([1]Fernandes P., Cruz A., Angelova B., Pinheiro H.M., Cabral J.M.S. Enzyme MicrobTechnol.2003,32,688-705. [2]Tong W.Y.,Dong X.Recent Pat.Biotechnol.,2009,3,141-153.[3]Donova M.V.,Egorova O.V.Appl.Microbiol.Biotechnol.,2012,94,1423-1447.[4]Bhatti H.N., Khera R.A. Steroids, 2012, 77, 1267-1290), can be roughly divided into sex hormones, corticosteroids and anabolic hormones according to their functions. At present, there are more than 300 kinds of steroid drugs in clinical use, accounting for about 15% of all clinically used drugs. [0003] The basic skeleton of a steroid consists of four fused carbocycl...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J5/00C07J1/00
CPCC07J1/0011C07J5/0053
Inventor 周强辉瞿旭东王军林张亚楠
Owner WUHAN UNIV
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