CN1908003A - Method of synthesizing 9 alpha-bromine-11 beta-hydroxypregna-1,4,16-triene-3,20-diketone - Google Patents

Abstract

The synthesis method of 9α-bromo-11β-hydroxypregna-1,4,16-triene-3,20-dione belongs to the field of medicinal chemistry. Using pregnane-1,4,9(11),16-tetraene-3,20-dione as raw material, in the presence of N-bromoamide, organic solvent and perchloric acid, retain 1,4 in the molecule , 16-position double bond, selective hydroxybromination of 9(11)-position double bond to synthesize steroidal compound 9α-bromo-11β-hydroxypregna-1,4,16-triene-3,20-dione . The steroidal compound 9α-bromo-11β-hydroxypregna-1,4,16-triene-3,20-dione synthesized by the invention has no domestic and foreign literature reports, and is a new compound. The synthesis steps are simple, the reaction conditions are mild, the operation is simple and the yield is high.

Description

Synthesis of 9α-bromo-11β-hydroxypregna-1,4,16-triene-3,20-dione

technical field

The invention belongs to the field of chemical technology, and relates to drug synthesis, specifically a steroidal anti-inflammatory drug Rimexolone intermediate 9α-bromo-11β-hydroxypregna-1,4,16-triene-3 , Synthesis of 20-diketones.

Background technique

11β-hydroxypregna-1,4,16-triene-3,20-dione (compound 3) is an intermediate in the synthesis of the steroidal anti-inflammatory drug Rimexolone, which has anti-inflammatory properties , High anti-allergic effect, less side effects, long-term use will not cause intraocular pressure to rise, etc. It is the only safe ophthalmic steroidal anti-inflammatory drug at present. 11β-hydroxypregna-1,4,16-triene-3,20-dione can pass through 9α-bromo-11β-hydroxypregna-1,4,16-triene-3,20-dione (compound 2) Obtained after debromination.

The object of the present invention is to invent a method for synthesizing 9α-bromo-11β-hydroxypregna-1,4,16-triene-3,20-dione.

Contents of the invention

We use the intermediate pregnane-1,4,9(11),16-triene-3,20-dione (compound 1) as raw material for the synthesis of dexamethasone in N-bromoamide, organic solvent, high In the presence of chloric acid, the 1, 4, 16 double bonds in the molecule are retained, and the 9 (11) double bonds are selectively hydroxybrominated to synthesize 9α-bromo-11β-hydroxypregna-1,4,16- Triene-3,20-dione.

The aforementioned N-bromoamide refers to N-bromosuccinimide, one of N-bromoacetamides.

The above-mentioned organic solvent refers to tetrahydrofuran, one of dioxane.

The steroidal compound 9α-bromo-11β-hydroxypregna-1,4,16-triene-3,20-dione synthesized by the present invention has no domestic and foreign literature reports, and is a new compound. The synthesis steps are simple, the reaction conditions are mild, the operation is simple and the yield is high.

Detailed ways

example 1

In the reaction flask, add pregna-1,4,9(11), 16-tetraene-3,20-dione (3.08g, 0.01mol), 45 milliliters of tetrahydrofuran, N-bromosuccinimide ( 2.4g, 0.013mol), 28ml of 0.64mol/L perchloric acid aqueous solution, stirred at room temperature for 4 hours. Stop the reaction, add 6 ml of saturated sodium sulfite solution to the reaction bottle, concentrate under reduced pressure to remove tetrahydrofuran, add 200 ml of water, stir for 1 hour, and precipitate a solid, filter under reduced pressure, wash the solid with 100 ml of water three times, dry the resulting solid with methanol Recrystallized with dichloromethane to obtain 3.75 g of white solid with a yield of 95%. mp: 170°C (decomposition). ¹ H NMR (DMSO-d6): δ=1.15(s, 3H), 1.56(m, 1H), 1.69(s, 3H), 1.99(m, 1H), 2.05(m, 2H), 2.20(s, 3H), 2.22-2.40(m, 5H), 2.66-2.68(m, 1H), 4.55(s, 1H), 5.63(brs, 1H), 5.98(t, J=1.2Hz, 1H), 6.22(dd , J=1.6Hz, J=10Hz, 1H), 6.87 (dd, J=1.2Hz, J=2.8Hz, 1H), 7.34 (d, J=10Hz, 1H). MS: m/z = 404 (M ⁺ ), 406 (M ⁺ +2).

The melting point was determined by a Büchi Melting Point B-540 melting point apparatus, ^{the 1} HNMR was determined by a Bruker Avance DMX400 nuclear magnetic resonance instrument, and the mass spectrum was determined by a GC-HP-5989 mass spectrometer.

Example 2

In the reaction flask, add pregna-1,4,9(11), 16-tetraene-3,20-dione (3.08g, 0.01mol), 45 ml of tetrahydrofuran, N-bromoacetamide (1.79g, 0.013mol), 28 milliliters of 0.64mol/L perchloric acid aqueous solution, stirred at room temperature for 4 hours. Stop the reaction, add 6 ml of saturated sodium sulfite solution to the reaction bottle, concentrate under reduced pressure to remove tetrahydrofuran, add 200 ml of water, stir for 1 hour, and precipitate a solid, filter under reduced pressure, wash the solid with 100 ml of water three times, dry the resulting solid with methanol Recrystallized with dichloromethane to obtain 3.67 g of white solid with a yield of 93%.

Example 3

In the reaction flask, add pregna-1,4,9(11), 16-tetraene-3,20-dione (3.08g, 0.01mol), 45 ml of dioxane, N-bromosuccinyl Imine (2.4 g, 0.013 mol), 28 ml of 0.64 mol/L perchloric acid aqueous solution, stirred at room temperature for 4 hours. Stop the reaction, add 6 ml of saturated sodium sulfite solution to the reaction bottle, concentrate under reduced pressure to remove tetrahydrofuran, add 200 ml of water, stir for 1 hour, and precipitate a solid, filter under reduced pressure, wash the solid with 100 ml of water three times, dry the resulting solid with methanol Recrystallized with dichloromethane to obtain 3.60 g of white solid with a yield of 91%.

Example 4

In the reaction flask, add pregna-1,4,9(11), 16-tetraene-3,20-dione (3.08g, 0.01mol), 45 milliliters of dioxane, N-bromoacetamide ( 1.79g, 0.013mol), 28ml of 0.64mol/L perchloric acid aqueous solution, stirred at room temperature for 4 hours. Stop the reaction, add 6 ml of saturated sodium sulfite solution to the reaction bottle, concentrate under reduced pressure to remove tetrahydrofuran, add 200 ml of water, stir for 1 hour, and precipitate a solid, filter under reduced pressure, wash the solid with 100 ml of water three times, dry the resulting solid with methanol Recrystallized with dichloromethane to obtain 3.65 g of white solid with a yield of 92%.

Claims (3)

1,9 α-bromo-11 beta-hydroxies pregnant steroid-1,4,16-triolefin-3,20-diketone synthesis method is characterized in that: with pregnant steroid-1,4,9 (11), 16-tetraene-3,20-diketone are raw material, in the presence of N-bromo-acid amide, organic solvent, perchloric acid, keep 1,4 in the molecule, 16 two keys optionally carry out hydroxyl bromination synthesizing steroid compound 9 α-bromo-11 beta-hydroxies pregnant steroid-1,4 to 9 (11) two keys, 16-triolefin-3, the 20-diketone.

2, by described 9 α of claim 1-bromo-11 beta-hydroxies pregnant steroid-1,4,16-triolefin-3,20-diketone synthesis method is characterized in that: described N-bromo-acid amide refers to the N-bromo-succinimide, N-bromo ethanamide one.

3, by described 9 α of claim 1-bromo-11 beta-hydroxies pregnant steroid-1,4,16-triolefin-3,20-diketone synthesis method is characterized in that: described organic solvent refers to tetrahydrofuran (THF), the dioxane one.