A method for preparing (E)-oct-4-en-1,8-diacid

Abstract

To address the problems existing in the prior art, this invention provides a method for preparing (E)-oct-4-en-1,8-diacid. This method involves a condensation reaction of malonic acid ester or cyanoacetate (D) with 1,4-dibromo-2-butene in the presence of an alkali metal base to generate compound (B). B is then decarboxylated in the presence of an alkali metal hydroxide to generate an alkali metal salt of (E)-oct-4-en-1,8-diacid, which is subsequently acidified with hydrochloric acid to obtain (E)-oct-4-en-1,8-diacid. This invention eliminates the use of hazardous reagents (LDA) and cryogenic strips, reducing safety risks during production. The raw materials used are low in toxicity, inexpensive, and readily available. The operation does not require strictly anhydrous and oxygen-free conditions, facilitating industrial production. Compared with existing literature methods, the reaction steps of this invention are easier to control, the operation is convenient, the product quality and yield are more stable, the production cost is low, the process is green and environmentally friendly, economical and practical, and highly suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of chemical pharmaceuticals, and specifically relates to micuronium chloride intermediates. Background Technology

[0002] (E)-Octo-4-en-1,8-dicarboxylic acid is a key intermediate for micous chloride, with the following structural formula:

[0003]

[0004] Micuronium chloride is a non-depolarizing muscle relaxant with the following structure, belonging to the benzylisoquinoline class of compounds:

[0005]

[0006] Micuronium chloride is used for endotracheal intubation and maintaining muscle relaxation. After intravenous injection, muscle relaxation has a rapid onset (2 minutes) and a short duration (15 minutes). The onset of action is rapid with increasing dose, but the duration of action is not prolonged.

[0007] Methods for preparing micudium chloride have been reported in the prior art. For example, European patent EP0181055A1 reports the preparation of micudium chloride from 6,7-dimethoxy-2-methyl-1-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline in three steps: resolution, quaternization, and esterification. The key raw material for the final esterification step is (E)-oct-4-ene-1,8-dicarboxylic acid.

[0008] Sisido, K. et al. (Journal of Organic Chemistry, 1962, vol. 27, pp. 2681–2683) reported the synthesis of (E)-oct-4-en-1,8-diacid, with the following reaction:

[0009]

[0010] However, this process uses liquid ammonia, which is irritating, highly toxic, and volatile, as a solvent and requires the reaction to be carried out at -40°C; it also uses elemental lithium, which is highly flammable and deteriorates easily.

[0011] Pan Li, et al. (J.Org.Chem.1999,64,2259-2263) replaced the base with industrially available diisopropylaminolithium (LDA) in the process of making compound 2, but the reaction still required low temperature, and LDA is also a flammable and explosive substance.

[0012] In CN201811224813.3, Wei Wenguo et al. of Wuhan Jianuokang Pharmaceutical Technology Co., Ltd. proposed a method using bromoacetonitrile as a starting material, reacting it with a metal element to obtain a metal compound, then reacting it with 1,4-dibromo-2-butene to obtain (E)-oct-4-en-1,8-dionitrile, and finally hydrolyzing it to obtain (E)-oct-4-en-1,8-dicarboxylic acid. Although the reaction conditions of this method are relatively mild, the preparation of the metal compound requires strict anhydrous and oxygen-free conditions, and the post-reaction treatment is relatively troublesome, and the large amount of inorganic salts produced is detrimental to the environment. Summary of the Invention

[0013] To address the problems existing in the prior art, the present invention aims to provide a method for preparing (E)-oct-4-en-1,8-diacid, wherein compound (B) is synthesized from ester and 1,4-dibromo-2-butene:

[0014]

[0015] In some schemes, the ester is R=C n H 2n+1 n = 1, 2, 3; the solvents used are alcohols (C1-C5), tetrahydrofuran, 2-methylfuran, N,N-dimethylformamide, N,N-dimethylacetamide dimethyl sulfoxide, and hexamethylphosphoric triamine; the catalysts used are alkali (alkaline earth) metal hydrides; alkali metals (alkaline earth) are hydroxides; alkali metals (alkaline earth) are carbonates;

[0016] In some embodiments, the present invention uses malonate or cyanoacetate and 1,4-dibromo-2-butene as raw materials to synthesize compound (B).

[0017] In some embodiments, the present invention involves a condensation reaction of malonic acid ester or cyanoacetate (D) with 1,4-dibromo-2-butene in the presence of an alkali metal base to generate compound (B); B is decarboxylated in the presence of an alkali metal hydroxide to generate an alkali metal salt of (E)-oct-4-en-1,8-diacid, which is then acidified with hydrochloric acid to obtain (E)-oct-4-en-1,8-diacid.

[0018] In some embodiments, the present invention provides a method for preparing (E)-oct-4-en-1,8-dicarboxylic acid, with the following reaction formula:

[0019] Where E = CN, COOR; R = C n H 2n+1 , n=1, 2, 3; M=Li, Na, K

[0020] In this invention, B is used as a raw material, and decarboxylation is performed in the presence of alkali metal (Li, Na, K) hydroxides to generate (E)-oct-4-en-1,8-diacid alkali metal salt, which is then acidified with hydrochloric acid to obtain (E)-oct-4-en-1,8-diacid.

[0021] Compared with the method in J.Org.Chem.1999,64,2259, the method of this invention does not use hazardous reagents (LDA) and cryogenic strips, thus reducing safety risks in the production process.

[0022] Compared with the method in CN201811224813.3, the raw materials used in this invention are less toxic and inexpensive and readily available. The operation process does not require strict anhydrous and oxygen-free conditions, which facilitates industrial production.

[0023] Compared with existing literature methods, the reaction steps of this invention are easier to control, the operation is convenient, the product quality and yield are more stable, the production cost is low, the process is green and environmentally friendly, economical and practical, and it is very suitable for industrial production. Detailed Implementation

[0024] The following embodiments are for further illustration of some preferred embodiments of the present invention and are not all embodiments. Other embodiments based on the present invention made by those skilled in the art without inventive effort are all within the scope of protection of the present invention.

[0025] In this invention, unless otherwise specified, all abbreviations have the conventional meanings understood by those skilled in the art.

[0026] Example 1: Preparation of (E)-oct-4-en-1,8-diacid

[0027]

[0028] ① In a 500ml reaction flask, add ethyl cyanoacetate (56.6g, 0.5mol), N,N-dimethylformamide (250ml), and anhydrous sodium carbonate (106g, 1.0mol). Stir and heat to about 80℃. Slowly add 1,4-dibromo-2-butene (53.5g, 0.25mol). After the addition is complete, heat to 130-135℃ and stir to maintain the temperature for 30 hours. After the reaction is complete, remove the solvent (DMF) under reduced pressure, add 300ml of water, and extract with dichloromethane (200ml×2). Combine the organic layers, wash with semi-saturated brine (150ml), dry with anhydrous magnesium sulfate, filter off the drying agent, and concentrate to obtain 65.4g of yellow oily (E)-2,7-dicyanoctyl-4-enedia ethyl ester, with a yield of 94%.

[0029] ② Add (E)-2,7-dicyanooctyl-4-enediol diethyl ester (60g, 0.2336mol) obtained in the previous step to a 500ml reaction flask, followed by sodium hydroxide (60g, 1.5mol) and water (70ml) solution. Reflux the mixture for 6 hours. After the reaction is complete, add 150ml of water and stir to completely dissolve the hydrolysis product. Cool to 8-10℃, add dichloromethane (150ml), and acidify with hydrochloric acid to pH 1. Extract with rapid stirring for 20 minutes, separating the layers. Extract the aqueous layer again with dichloromethane (150ml), combine the organic layers, dry with anhydrous magnesium sulfate, filter to remove the drying agent, and distill the filtrate at atmospheric pressure to remove dichloromethane. Recrystallize the residue with n-hexane / ethyl acetate to obtain 32.0g of (E)-octyl-4-ene-1,8-diol (white solid), yield 79.6%.

[0030] Example 2: Preparation of (E)-oct-4-en-1,8-diacid

[0031]

[0032] ① In a 500ml reaction flask, add diethyl malonate (80.1g, 0.5mol), N,N-dimethylformamide (250ml), and anhydrous sodium carbonate (106g, 1.0mol). Stir and heat to about 80℃. Slowly add 1,4-dibromo-2-butene (53.5g, 0.25mol). After the addition is complete, heat to 130-135℃ and stir to maintain the temperature for 30 hours. After the reaction is complete, remove the solvent (DMF) under reduced pressure, add 300ml of water, and extract with dichloromethane (200ml×2). Combine the organic layers, wash with semi-saturated brine (150ml), dry with anhydrous magnesium sulfate, filter off the drying agent, and concentrate to obtain 84.7g of yellow oily (E)-tetraethylhexyl-3-ene-1,1,6,6-tetracarboxylic acid ester, with a yield of 91%.

[0033] ② Add (E)-tetraethylhexyl-3-ene-1,1,6,6-tetracarboxylic acid ester (80g, 0.2148mol) obtained in the previous step to a 500ml reaction flask, followed by sodium hydroxide (60g, 1.5mol) and water (70ml) solution. Reflux the mixture for 6 hours. After the reaction is complete, add 150ml of water and stir to completely dissolve the hydrolysis product. Cool to 8-10℃, add dichloromethane (150ml), and acidify with hydrochloric acid to pH 1. Extract with rapid stirring for 20 minutes, separating the layers. Extract the aqueous layer again with dichloromethane (150ml), combine the organic layers, dry with anhydrous magnesium sulfate, filter to remove the drying agent, and distill the filtrate at atmospheric pressure to remove dichloromethane. Recrystallize the residue with n-hexane / ethyl acetate to obtain (E)-oct-4-ene-1,8-dicarboxylic acid (white solid) 33.0g, yield 89.2%.

[0034] Example 3: Preparation of (E)-oct-4-ene-1,8-diacid

[0035]

[0036] ① Add diethyl malonate (80.1 g, 0.5 mol) and N,N-dimethylformamide (250 ml) to a 500 ml reaction flask. While stirring at room temperature, add 1,4-dibromo-2-butene (53.5 g, 0.25 mol). After the addition is complete, cool to 0-5℃ and add 60% sodium hydroxide (41.7 g, 1.0 mol) in portions. After the addition is complete, slowly raise the temperature to room temperature and maintain the reaction for 8 hours. Then raise the temperature of the reaction solution to 1... The reaction was carried out at 00-105℃ for 10 hours. After the reaction was completed, 20 ml of ethanol was carefully added, followed by removal of the solvent under reduced pressure. After distillation, 300 ml of water was added, and the mixture was extracted with dichloromethane (200 ml × 2). The organic layers were combined, washed with semi-saturated brine (150 ml), dried over anhydrous magnesium sulfate, filtered to remove the drying agent, and concentrated to obtain 87.0 g of yellow oily (E)-tetraethylhexyl-3-ene-1,1,6,6-tetracarboxylic acid ester, with a yield of 93.4%.

[0037] ② Add (E)-tetraethylhexyl-3-ene-1,1,6,6-tetracarboxylic acid ester (80g, 0.2148mol) obtained in the previous step to a 500ml reaction flask, followed by sodium hydroxide (84g, 1.5mol) and water (70ml) solution. Reflux the mixture for 6 hours. After the reaction is complete, add 150ml of water and stir to completely dissolve the hydrolysis product. Cool to 8-10℃, add dichloromethane (150ml), and acidify with hydrochloric acid to pH 1. Extract quickly with stirring for 20 minutes, separating the layers. Extract the aqueous layer again with dichloromethane (150ml), combine the organic layers, dry with anhydrous magnesium sulfate, filter to remove the drying agent, and distill the filtrate at atmospheric pressure to remove dichloromethane. Recrystallize the residue with n-hexane / ethyl acetate to obtain (E)-oct-4-ene-1,8-dicarboxylic acid (white solid) 33.5g, yield 90.6%.

[0038] Example 4: Preparation of (E)-oct-4-en-1,8-diacid

[0039]

[0040] ① In a 500ml reaction flask, add diethyl malonate (80.1g, 0.5mol) and tetrahydrofuran (250ml). While stirring at room temperature, add 1,4-dibromo-2-butene (53.5g, 0.25mol). After the addition is complete, cool to 0-5℃ and add 60% sodium hydroxide (41.7g, 1.0mol) in portions. After the addition is complete, slowly raise the temperature to room temperature and maintain the reaction for 8 hours. Then raise the temperature of the reaction solution to 60-65℃ and maintain the reaction for 10 hours. After the reaction is complete, carefully add 20ml of ethanol, then remove the solvent under reduced pressure. After distillation, add 300ml of water and extract with dichloromethane (200ml×2). Combine the organic layers, wash with semi-saturated brine (150ml), dry with anhydrous magnesium sulfate, filter off the drying agent, and concentrate to obtain 85.0g of yellow oily (E)-tetraethylhexyl-3-ene-1,1,6,6-tetracarboxylic acid ester, with a yield of 91.3%.

[0041] ② Add (E)-tetraethylhexyl-3-ene-1,1,6,6-tetracarboxylic acid ester (80g, 0.2148mol) obtained in the previous step to a 500ml reaction flask, followed by lithium hydroxide (36g, 1.5mol) and water (70ml) solution. Reflux the mixture for 6 hours. After the reaction is complete, add 150ml of water and stir to completely dissolve the hydrolysis product. Cool to 8-10℃, add dichloromethane (150ml), and acidify with hydrochloric acid to pH 1. Extract with rapid stirring for 20 minutes, separating the layers. Extract the aqueous layer again with dichloromethane (150ml), combine the organic layers, dry with anhydrous magnesium sulfate, filter to remove the drying agent, and distill the filtrate at atmospheric pressure to remove dichloromethane. Recrystallize the residue with n-hexane / ethyl acetate to obtain (E)-oct-4-ene-1,8-dicarboxylic acid (white solid) 34.0g, yield 91.9%.

[0042] It should be noted that the above preferred embodiments are merely illustrative of the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the content of the present invention and implement it accordingly. They should not be construed as limiting the scope of protection of the present invention. All equivalent changes or modifications made in accordance with the spirit and essence of the present invention should be covered within the scope of protection of the present invention.

Claims

1. A method for preparing (E)-oct-4-en-1,8-dioctic acid, characterized in that, In the method described, compound B is synthesized using ester and 1,4-dibromo-2-butene as raw materials. ； The method includes the following steps: (1) Condensation reaction: using diethyl malonate or ethyl cyanoacetate as raw material D, and 1,4-dibromo-2-butene in tetrahydrofuran solvent with sodium hydrogen as catalyst, the reaction is carried out at room temperature for 8 hours, and then heated to 60-65℃ and kept at room temperature for 10 hours to generate compound B. (2) Decarboxylation and acidification: Compound B was decarboxylated by reflux reaction in lithium hydroxide aqueous solution for 6 hours, water was added and stirred, the temperature was lowered to 8-10℃ and dichloromethane was added, and the solution was acidified with hydrochloric acid to pH=1. The mixture was stirred, dried, and the solvent was removed by distillation. The solution was then recrystallized from hexane / ethyl acetate to obtain (E)-oct-4-ene-1,8-diacid. The molar ratio of raw materials in step (1) is: diethyl malonate or ethyl cyanoacetate : 1,4-dibromo-2-butene : sodium hydrogen is 2 : 1 : 4; In step (2), the concentration of the lithium hydroxide aqueous solution is 1.5 mol / 70 ml water; The reaction formula for the method is as follows: 。

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