Synthesis method of triene acetate

Abstract

The invention discloses a synthesis method of triene acetate, which comprises the following steps: adding a compound A-1, potassium acetate, a catalyst and a solvent into a reaction container, and carrying out reflux reaction in an inert gas atmosphere until complete reaction to obtain a target compound A-2, namely the triene acetate, the solvent is an ether organic solvent; the catalyst is quaternary ammonium acetate, the molecular formula of the catalyst is R1R2R3R4NOAc, and R1, R2, R3 and R4 are respectively and independently selected from C1-C18 alkyl groups. According to the invention, the target product can be generated in the low-boiling-point organic solvent, the yield and the purity are high, the use of a high-boiling-point solvent with difficulty in post-treatment is avoided, the reaction temperature is reduced, the side reaction is reduced, and the pollution to the environment is reduced. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemistry, and specifically relates to a method for synthesizing an acetate triene, wherein the acetate triene is a key intermediate for synthesizing and preparing steroid hormone drugs. Background Art

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

[0003] The present invention aims to provide a method for synthesizing triene acetate.

[0004] In order to achieve the above-mentioned invention object, the present invention adopts the following technical scheme:

[0005] A method for synthesizing an acetate triene, comprising: adding a compound A-1, potassium acetate, a catalyst and a solvent into a reaction container, and performing a reflux reaction under an inert gas atmosphere until the reaction is complete, to obtain a target compound A-2, i.e., an acetate triene;

[0006] The solvent is an ether organic solvent;

[0007] The catalyst is quaternary ammonium acetate, and its molecular formula is 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;

[0008]

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

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

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

[0012] Preferably, the catalyst is tetrabutylammonium acetate.

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

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

[0015] The invention has high comprehensive yield, uses quaternary ammonium acetate as a catalyst, has phase transfer catalysis and weak acidity to promote reaction, can generate target products in low-boiling point organic solvents such as tetrahydrofuran and 1,4-dioxane, and has high yield and purity, avoids using solvents such as DMF and DMSO which have high boiling points and are difficult to post-treat, reduces reaction temperature, reduces occurrence of side reactions, greatly reduces production costs, alleviates treatment pressure of three wastes, and reduces pollution to the environment. DETAILED DESCRIPTION

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

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

[0018]

[0019] Embodiment 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 bottle, and then 2 mL of tetrahydrofuran was added. Under a nitrogen atmosphere, the reaction was refluxed for 9.5 h and monitored by TLC. After the raw material spot disappeared, the reaction solution was restored to room temperature, and the reaction solution was dropped into water, filtered, and recrystallized from ethanol to obtain an off-white solid A-2 with a purity of 99% and a yield of 95%.

[0021] Embodiment 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, and then 20 mL of 1.4-dioxane was added. Under a nitrogen atmosphere, the reaction was refluxed for 3.5 h and monitored by TLC. After the raw material spot disappeared, the reaction solution was restored to room temperature, and the reaction solution was dropped into water, filtered, and recrystallized from ethanol to obtain an off-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 an acetic acid triene, characterized in that: The synthesis method comprises: adding compound A-1, potassium acetate, a catalyst and a solvent into a reaction container, and performing a reflux reaction under an inert gas atmosphere until the reaction is complete, thereby obtaining a target compound A-2, namely, acetate triene; The solvent is an ether organic solvent; The catalyst is quaternary ammonium acetate, and its molecular formula is 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; 2. The synthesis method according to claim 1, characterized in that: The solvent is C4-C6 cyclic ether.

3. The synthesis method according to claim 2, characterized in that: The solvent is one of tetrahydrofuran, 2-methyltetrahydrofuran, 2,5-dimethyltetrahydrofuran, 1,4-dioxane or a mixture thereof.

4. The synthesis method according to any one of claims 1 to 3, characterized in that: The mass ratio of the potassium acetate to the compound A-1 is 0.5 to 2:1; the mass ratio of the quaternary ammonium acetate to the compound A-1 is 0.05 to 0.5:

1.

5. The synthesis method according to claim 4, characterized in that: The mass ratio of the potassium acetate to the compound A-1 is 1.1 to 2:

1.

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

1.

7. The synthesis method according to claim 1, characterized in that: The catalyst is tetrabutylammonium acetate.

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