A method for synthesizing triene acetate

Abstract

This invention discloses a method for synthesizing acetate trienes. The method includes: adding compound A-1, potassium acetate, a catalyst, and a solvent to a reaction vessel, and refluxing the reaction under an inert gas atmosphere until complete to obtain the target compound A-2, i.e., acetate trienes; the solvent is an ether-based organic solvent; the catalyst is a quaternary ammonium acetate with the molecular formula R. 1 R 2 R 3 R 4 NOAc, where R 1 R 2 R 3 R 4 Each component is independently selected from C1 to C18 alkyl groups. This invention can generate the target product in low-boiling-point organic solvents with high yield and purity, avoiding the use of high-boiling-point solvents that are difficult to process, reducing the reaction temperature, reducing the occurrence of side reactions, and reducing environmental pollution.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry technology, specifically, it relates to a method for synthesizing acetate trienes, wherein acetate trienes are key intermediates in the synthesis and preparation of steroid hormone drugs. Background Technology

[0002] Acetate triene (CAS: 23460-76-6) is the starting material for the synthesis of the steroid hormone drug halcinonide. Further reaction of the acetate triene to remove hydrogen at the C1 and C2 positions yields acetate tetraene, an important intermediate in the synthesis of steroid drugs such as dexamethasone, prednisolone, budesonide, and triamcinolone. Existing literature on the synthesis of acetate triene uses glacial acetic acid to promote the reaction, but high-boiling-point organic solvents such as DMF and DMSO are used, and the reaction temperatures are high, which is not conducive to industrial production. Summary of the Invention

[0003] The purpose of this invention is to provide a method for synthesizing acetate trienes.

[0004] To achieve the above-mentioned objectives, the present invention adopts the following technical solution:

[0005] A method for synthesizing acetate trienes includes: adding compound A-1, potassium acetate, a catalyst and a solvent to a reaction vessel, and refluxing the reaction under an inert gas atmosphere until complete to obtain the target compound A-2, i.e., acetate trienes;

[0006] The solvent is an ether-based organic solvent;

[0007] The catalyst is a quaternary ammonium acetate, with the molecular formula R. 1 R 2 R 3 R 4 NOAc, where R 1 R 2 R 3 R 4 Each is independently selected from C1 to C18 alkyl groups;

[0008]

[0009] Preferably, the solvent is a C4-C6 cyclic ether, such as one or a mixture of tetrahydrofuran, 2-methyltetrahydrofuran, 2,5-dimethyltetrahydrofuran, 1,4-dioxane.

[0010] Preferably, the mass ratio of potassium acetate to compound A-1 is 0.5 to 2:1, more preferably 1.1 to 2:1; the mass ratio of quaternary ammonium acetate to compound A-1 is 0.05 to 0.5:1, more preferably 0.1 to 0.4:1.

[0011] Preferably, the ratio of the solvent to compound A-1 is 5 to 25 mL / g.

[0012] Preferably, the catalyst is tetrabutylammonium acetate.

[0013] After the invention is completed, the reaction solution is dropped into water to remove the ether organic solvent, then filtered and dried to obtain the target product, acetate triene A-2.

[0014] Compared with the prior art, the present invention has the following beneficial effects:

[0015] This invention boasts a high overall yield, utilizing quaternary ammonium acetate as a catalyst. This catalyst exhibits phase transfer catalysis and weak acidity, promoting the reaction. It can generate the target product in low-boiling-point organic solvents such as tetrahydrofuran and 1,4-dioxane with high yield and purity. It avoids the use of high-boiling-point solvents such as DMF and DMSO, which are difficult to process after post-treatment. This reduces the reaction temperature, minimizes side reactions, significantly reduces production costs, alleviates the pressure of waste treatment, and reduces environmental pollution. Detailed Implementation

[0016] The technical solution of the present invention will be further described below with reference to specific embodiments, but the scope of protection of the present invention is not limited thereto:

[0017] A method for synthesizing acetate trienes, using A-1 as a starting material, reacts in the presence of potassium acetate, a catalyst, and a solvent to generate A-2, i.e., acetate triene. The reaction route is as follows:

[0018]

[0019] Example 1:

[0020] 0.1 g of compound A-1, 0.13 g of potassium acetate, and 0.02 g of tetrabutylammonium acetate were added to a reaction flask, followed by 2 mL of tetrahydrofuran. The mixture was refluxed for 9.5 h under a nitrogen atmosphere and monitored by TLC. After the starting material spot disappeared, the reaction solution was brought to room temperature. The reaction solution was then added dropwise to water, filtered, and recrystallized from ethanol to give an off-white solid A-2 with a purity of 99% and a yield of 95%.

[0021] Example 2:

[0022] 1 g of compound A-1, 1.3 g of potassium acetate, and 0.2 g of tetrabutylammonium acetate were added to a reaction flask, followed by 20 mL of 1,4-dioxane. The mixture was refluxed for 3.5 h under a nitrogen atmosphere and monitored by TLC. After the starting material spot disappeared, the reaction solution was brought to room temperature. The reaction solution was then added dropwise to water, filtered, and recrystallized from ethanol to obtain a white solid A-2 with a purity of 99% and a yield of 95%.

[0023] Product identification data:

[0024] 2α-((10S,13S)-10,13-dimethyl-3-oxo-2,3,6,7,8,10,12,13,14,15-decahydro-1H-cy clopenta[α]phenanthren-17-yl)-2-oxoethyl acetate:off-whitesolid;1H NMR(500MHz,CDCl3)δ6.77(s,1H),5.75(s,1H),5.55-5.54(d,1H),5.05-5.02(d,1H),4.92-4.90(d,1H),0.99(s,3H),1.36(s,3H),1.61-1.56(m,1H),1.19-1.12(m,1H)ppm。

Claims

1. A method for synthesizing acetate trienes, characterized in that: The synthesis method includes: adding compound A-1, potassium acetate, catalyst and solvent to a reaction vessel, and refluxing the reaction under an inert gas atmosphere until complete to obtain target compound A-2, i.e., acetate triene; The solvent is one or a mixture of tetrahydrofuran, 2-methyltetrahydrofuran, 2,5-dimethyltetrahydrofuran, and 1,4-dioxane. The catalyst is a quaternary ammonium acetate, and the quaternary ammonium acetate is tetrabutylammonium acetate; 。 2. The synthesis method according to claim 1, characterized in that: The mass ratio of potassium acetate to compound A-1 is 0.5~2:1; the mass ratio of quaternary ammonium acetate to compound A-1 is 0.05~0.5:

1.

3. The synthesis method as described in claim 2, characterized in that: The mass ratio of potassium acetate to compound A-1 is 1.1~2:

1.

4. The synthesis method according to claim 2, characterized in that: The mass ratio of the quaternary ammonium acetate salt to compound A-1 is 0.1~0.4:1.

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