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Synthesis method and intermediates of pregnene-1,4,9 (11),16 (17)-tetraenol-3, 20-diketone

A synthetic method and intermediate technology, applied in the field of drug synthesis, to avoid the use of highly toxic reagent acetone cyanohydrin, easy to obtain and cheap raw materials

Active Publication Date: 2015-05-20
山东国九堂制药集团股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in the past, the commonly used method for introducing the carbonyl side chain at the C17 position is to use highly toxic acetone cyanohydrin.

Method used

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  • Synthesis method and intermediates of pregnene-1,4,9 (11),16 (17)-tetraenol-3, 20-diketone
  • Synthesis method and intermediates of pregnene-1,4,9 (11),16 (17)-tetraenol-3, 20-diketone
  • Synthesis method and intermediates of pregnene-1,4,9 (11),16 (17)-tetraenol-3, 20-diketone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Example 1: Preparation of the first intermediate (androst-4,9(11)-diene-3,17-dione);

[0027]

[0028] At 0°C, trifluoroacetic anhydride (10mL), acetic acid (12mL) and p-toluenesulfonic acid (6.85g) were added to 100mL of dichloromethane, and 9-α-hydroxyandroster (9.0g, 29.8mmol ) in dichloromethane 200mL, stirred at room temperature for 3 hours, added 100mL of water, 5N sodium hydroxide to adjust the pH to about 9, separated the organic layer, extracted the water layer with 100mL×2 dichloromethane, combined the organic layers, After washing with clear water, spin-dried, the first intermediate (7.2g, 85%) was obtained after methanol crystallization, and the nuclear magnetic resonance data of the first intermediate were as follows:

[0029] 1 H NMR (500MHz, CDCl 3 )δ5.76(d,J=1.4Hz,1H),5.63-5.44(m,1H),2.67-2.32(m,6H),2.24-2.03(m,7H),1.73-1.44(m,2H) ,1.35(s,3H),1.17(ddd,J=26.7,12.7,3.9Hz,1H),0.88(s,3H); 13C NMR (125MHz, CDCl3) δ221.18, 199.17, 169.06, 145.16, 124.25...

Embodiment 2

[0030] Example 2: Preparation of the second intermediate (androst-3-methoxy-3,5,9(11)-trien-17-one);

[0031]

[0032] The first intermediate (14 g, 4.9 mmol) was dissolved in tetrahydrofuran (THF) and trimethyl orthoformate ((CH 3 O) 3 CH) mixed solution 150mL, add p-toluenesulfonic acid (1.5g), stir and react at room temperature for 2.5 hours, add water 10mL and triethylamine 3mL, extract with dichloromethane, spin dry, the second intermediate after methanol crystallization body (10.0g, 83%), the nuclear magnetic resonance data of the second intermediate are as follows:

[0033] 1 H NMR (500MHz, CDCl 3 )δ5.52(d, J=5.9Hz, 1H), 5.29(d, J=4.3Hz, 1H), 5.18(s, 1H), 3.58(d, J=5.7Hz, 3H), 2.65-2.45( m, 3H), 2.40(ddd, J=17.7, 13.7, 7.4Hz, 1H), 2.25-2.04(m, 5H), 1.91(ddd, J=25.1, 14.9, 6.7Hz, 2H), 1.67-1.54( m,3H),1.15(s,3H),0.88(s,3H); 13 C NMR (125MHz, CDCl 3 )δ221.90,155.65,144.73,139.00,117.08,115.18,98.25,54.42,49.86,46.36,37.24,36.48,33.42,33.23,32.26,31.76,27.26,25.4...

Embodiment 3

[0034] Example 3: Preparation of the third intermediate (androst-3-methoxy-3,5,9(11)-triene-17-isocyano-p-toluenesulfonylmethylene);

[0035]

[0036] Dissolve p-toluenesulfonylmethylisonitrile (TosMIC) (4.3g, 21.9mmol) in 100mL dry tetrahydrofuran (THF), cool to -50°C, add potassium tert-butoxide tBuOK (2.96g, 26.2mmol), After reacting for 15 minutes, add 30 mL of THF solution of the second intermediate (5.0 g, 16.8 mmol), heat up to -40 to -35 ° C for 2.5 hours, add phosphorous acid (2.15 g, 26 mmol), and react for 15 minutes, add Phosphorus oxychloride (3.6ml, 39mmol), triethylamine (27ml, 194mmol), after heating up to 0°C for 1 hour, pour into 100mL of sodium chloride solution, extract with dichloromethane, spin dry, petroleum ether- Acetone column chromatography obtains the third intermediate (4.95g, 62%), and the nuclear magnetic resonance data of the third intermediate is as follows:

[0037] 1 H NMR (300MHz, CDCl 3 )δ7.83(d, J=8.3Hz, 2H), 7.38(d, J=8.0Hz, 2H), 5....

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Abstract

The invention relates to a synthesis method and main intermediates of pregnene-1,4,9 (11),16 (17)-tetraenol-3, 20-diketone. The synthesis method sequentially comprises the following steps of reacting a second intermediate and tosylmethyl isocyanide in an organic solvent at the temperature of lower than 35 DEG C below zero to generate a third intermediate; reacting the third intermediate and a methylated reagent in an organic solvent at the temperature of 70-90 DEG C, and then, removing methyl ether protecting groups and tosylmethyl isocyanide under the action of an acid to obtain a fourth intermediate; and reacting the fourth intermreidate under the action of 3-ketosteroid-1-dehydrogenase to generate pregnene-1,4,9 (11),16 (17)-tetraenol-3, 20-diketone. Raw materials of pregnene-1,4,9 (11),16 (17)-tetraenol-3, 20-diketone are cheap and available; the yield of pregnene-1,4,9 (11),16 (17)-tetraenol-3, 20-diketone is relatively high; a C17-position side chain is introduced by using tosylmethyl isocyanide, so that acetone cyanohydrin serving as a highly-toxic reagent is prevented from being used; and the synthesis method is safe, environment-friendly and suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and specifically relates to a synthesis method of pregna-1,4,9(11),16(17)-tetraene-3,20-dione and an intermediate thereof. Background technique [0002] Pregna-1,4,9(11),16(17)-tetraene-3,20-dione is a very important intermediate in the synthesis of progesterone and adrenocortical hormone drugs, which can be passed through 9-α- Hydroxyandroster is obtained as raw material. 9-α-Hydroxyandrosterol can be obtained by biodegrading phytosterols (such as stigmasterol in soybeans). However, the conventional method for introducing the carbonyl side chain at the C17 position is to use highly toxic acetone cyanohydrin. Acetone cyanohydrin is a highly toxic compound, and its toxicity is similar to that of hydrocyanic acid. Its vapor or liquid can enter the body through the respiratory tract, skin and digestive tract, causing acute poisoning. Mainly cause CNS damage, dizziness, headache, weakness, chest tig...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J7/00C07J1/00C07J41/00C07J75/00
CPCY02P20/55C07J1/0011C07J7/001C07J41/0094
Inventor 徐朝炜陶军华梁晓亮谢新开
Owner 山东国九堂制药集团股份有限公司
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