A method for preparing isobutyric acid derivatives

Abstract

This invention provides a synthetic method for preparing isobutyric acid derivatives (including bepidocrolic acid). The reaction steps of this invention are easily controlled, resulting in stable quality and yield, and the operation is convenient. This invention uses aliphatic aldehyde ethers and dimethyl ketene as raw materials to synthesize ethyl 6-bromo-2,2-dimethylhexanoate and ethyl 7-bromo-2,2-dimethylheptanoate; this invention also uses 2-(3-bromopropyl)-1,3-dioxane, acetone dicarboxylic acid diester (methyl / ethyl), and dimethyl ketene as raw materials to synthesize bepidocrolic acid and its intermediates (B, C, D, E, F, G, H). This method avoids the use of hazardous reagents (LDA), ultra-low temperature conditions, and expensive and limited-supply raw materials (TosMIC), thus reducing safety risks during the production process.

Description

Technical Field

[0001] This invention belongs to the field of chemical pharmaceuticals, and specifically relates to isobutyric acid derivatives (including bepidocaine). Background Technology

[0002] Most of the methods reported in the literature for preparing isobutyric acid derivatives involve the reaction of haloalkanes with isobutyrate esters at low temperatures in the presence of LDA, as follows:

[0003]

[0004] For example, the preparation of the key intermediate of bepidocrolic acid (ethyl 7-bromo-2,2-dimethylheptanoate) requires the use of LDA (hazardous reagent) and low temperature conditions (-40°C), and the reaction yield is not high (reported yield is only 60%).

[0005] In addition, during the construction of the bepidocrolic acid backbone, the literature used p-toluenesulfonylmethylisocyanate (TosMIC) and sodium hydrogen (a hazardous reagent), which are expensive and have limited market supply.

[0006] The above factors increase the risk of the synthesis process of bepidocalic acid, as well as the difficulty of operation and the production cost.

[0007] The main synthetic routes for bepidocalic acid in the literature are as follows:

[0008]

[0009] The literature route uses ethyl isobutyrate and 1,5-dibromopentane as starting materials. At low temperature, condensation with lithium diisopropylamino (LDA) yields ethyl 7-bromo-2,2-dimethylheptanoate. Ethyl 7-bromo-2,2-dimethylheptanoate is then used as an alkylating agent in a reaction with p-toluenesulfonylmethylisocyanate (TosMIC) under strongly alkaline conditions, catalyzed by tetrabutylammonium iodide (TBAI), to produce bis(2,2-dimethylheptanoate)-substituted p-toluenesulfonylmethylisocyanate. This is then hydrolyzed under acidic conditions to yield diethyl 8-carbonyl-2,2,14,14-tetramethylpentadecanedioate. Diethyl 8-carbonyl-2,2,14,14-tetramethylpentadecanedioate is hydrolyzed in an ethanol system to give 8-carbonyl-2,2,14,14-tetramethylpentadecanedioic acid. Reduction with NaBH4 finally yields the target product, bempedoic acid. It should be noted that ethyl isobutyrate and 1,5-dibromopentane inevitably produce a disubstituted product, 2,2,8,8-tetramethyl-nonanediol diethyl ester (structure shown below), under the action of LDA:

[0010]

[0011] This not only resulted in a large waste of raw materials, but also increased the pressure on environmental protection during the production process. Summary of the Invention

[0012] Research has shown that aliphatic aldehydes react with dimethyl ketene (a polymer industrial raw material) to form a four-membered ring lactone, which can be reduced with sodium borohydride to prepare isobutyric acid derivatives.

[0013]

[0014] Based on this, the present invention designs a new method for synthesizing the key raw materials of bepidocrolic acid (literature route), ethyl 6-bromo-2,2-dimethylhexanoate and ethyl 7-bromo-2,2-dimethylheptanoate:

[0015]

[0016] Aliphatic aldehyde ether (f) reacts with dimethyl ketene to generate tetracyclic lactone ether (d); d is reduced with sodium borohydride to give compound (c); c reacts with hydrobromic acid to generate compound (b); b reacts with ethanol to give the key raw materials for bepidocalic acid, ethyl 6-bromo-2,2-dimethylhexanoate (n=2) and ethyl 7-bromo-2,2-dimethylheptanoate (n=3).

[0017] In addition, during the exploration of methods for synthesizing beptopic acid, to avoid using the expensive and limited-supply p-toluenesulfonylmethylisocyanate (TosMIC), we designed a new synthetic route for beptopic acid:

[0018]

[0019] 2-(3-bromopropyl)-1,3-dioxane reacts with acetone dicarboxylic acid diester (A / B) to give a condensate (H); H is decarboxylated in the presence of sodium hydroxide to give compound (G); G is reduced with sodium borohydride to give compound (F); F reacts with benzyl bromo to give compound (E); E is hydrolyzed to give compound (D); D reacts with dimethyl ketene to give a bis-four-membered ring lactone (C); C is reduced with sodium borohydride to give compound (B); B is debenzylated with 10% Pd / C / ammonium formate to give bepidocal acid (A).

[0020] The reaction steps of this invention are easy to control, the quality and yield are relatively stable, and the operation is convenient.

[0021] The present invention provides a synthetic method for preparing isobutyric acid derivatives (including bepidocrolic acid), which avoids the use of hazardous reagents (LDA), ultra-low temperature conditions, and expensive and market-limited raw materials (TosMIC), thereby reducing safety risks in the production process.

[0022] This invention synthesizes ethyl 6-bromo-2,2-dimethylhexanoate and ethyl 7-bromo-2,2-dimethylheptanoate from aliphatic aldehyde ethers and dimethyl ketene.

[0023] This invention relates to a method for synthesizing bepidocrolic acid and its intermediates (B, C, D, E, F, G, H) using 2-(3-bromopropyl)-1,3-dioxane, acetone dicarboxylic acid diester (methyl / ethyl) and dimethyl ketene as raw materials. 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 ethyl 6-bromo-2,2-dimethylhexanoate:

[0027]

[0028] ① Add 35.7 g (0.2 mol) of 4-benzyloxybutanal and 150 ml of ethyl acetate to a 500 ml reaction flask, stir and cool to about 0 °C, maintain the internal temperature at 0–4 °C, add anhydrous zinc chloride (2.2 g, 0.016 mol), and dropwise add a solution of 14.00 g (0.2 mol) of dimethyl ketene in 100 ml of ethyl acetate. After the addition is complete, stir the reaction at 1–4 °C for 30 hours. After the reaction is complete, add 200 ml of 10% sodium bicarbonate aqueous solution and stir for 20 minutes. Separate the aqueous layer, wash the organic layer with 200 ml of 10% sodium bicarbonate aqueous solution, and separate the aqueous layer. Wash the organic layer with 200 ml of saturated brine, separate the aqueous layer, dry with anhydrous magnesium sulfate, and remove the solvent under reduced pressure to obtain 44.7 g of 4-(3-(benzyloxy)propyl)-3,3-dimethyloxetane-2-one, with a yield of 90%.

[0029] ② Add 4-(3-(benzyloxy)propyl)-3,3-dimethyloxetane-2-one (40.0 g, 0.161 mol) and dimethylformamide (DMF) (500 ml) to a 1000 ml reaction flask. Add sodium borohydride (15.2 g, 0.403 mol) at room temperature with stirring. Stir and react for 12 hours. Remove DMF under reduced pressure, add 600 ml of water, adjust pH to 1 with hydrochloric acid (3 M), extract with n-hexane (250 ml × 3), combine the extracts, dry with anhydrous magnesium sulfate, filter, and concentrate the filtrate to obtain 36.0 g of 6-benzyloxy-2,2-dimethylhexanoic acid (white solid), yield 90%.

[0030] ③ In a 500ml reaction flask equipped with a reflux condenser and a magnetic stirrer, add 33.1g (0.14mol) of 6-benzyloxy-2,2-dimethylhexanoic acid, 146ml (1.3mol) of 47% hydrobromic acid, and 6.5g (0.013mol) of hexadecyltributylphosphine bromide. Stir and heat, and reflux (internal temperature approximately 115℃) for 10 hours. After the reaction is complete, cool to room temperature, let stand for 30 minutes, and extract with ethyl acetate (300ml × 2), discarding the aqueous layer. Combine the organic layers, wash with saturated brine (150ml), separate the aqueous layer, and dry the organic layer with anhydrous sodium sulfate. Filter off the drying agent, concentrate the filtrate under reduced pressure, and obtain 28.7g of pale yellow liquid of 6-bromo-2,2-dimethylhexanoic acid, yield 92%.

[0031] ④ Add 27 g (0.121 mol) of 6-bromo-2,2-dimethylhexanoic acid, 300 ml of anhydrous ethanol, and 1.0 ml of concentrated sulfuric acid to a 500 ml reaction flask and reflux for 8 hours. After the reaction is complete, remove the solvent under reduced pressure and cool to room temperature. Add 150 ml of water and 200 ml of dichloromethane and stir for 30 minutes. Separate the layers, and extract the aqueous layer with 80 ml of dichloromethane. Combine the organic layers and wash with 10% sodium bicarbonate aqueous solution (100 ml). Separate the aqueous layer. Dry the organic layer with anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain 27.4 g of pale yellow liquid ethyl 6-bromo-2,2-dimethylhexanoate, with a yield of 90%.

[0032] Example 2) Preparation of ethyl 7-bromo-2,2-dimethylheptanoate:

[0033]

[0034] 5-Benzyloxypentanal (38.5 g, 0.2 mol) and ethyl acetate (150 ml) were added to a 500 ml reaction flask. The mixture was stirred and cooled to about 0 °C, maintaining the internal temperature at 0–4 °C. Anhydrous zinc chloride (2.2 g, 0.016 mol) was added, followed by dropwise addition of a 100 ml solution of dimethyl ketene (14.00 g, 0.2 mol) in ethyl acetate. After the addition was complete, the mixture was stirred at 1–4 °C for 30 hours. After the reaction was complete, 200 ml of 10% sodium bicarbonate aqueous solution was added and stirred for 20 minutes. The aqueous layer was separated, and the organic layer was washed again with 200 ml of 10% sodium bicarbonate aqueous solution. The aqueous layer was then separated. The organic layer was washed again with 200 ml of saturated brine. The aqueous layer was then separated, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 46.7 g of 4-(4-(Benzyloxy)butyl)-3,3-dimethyloxetane-2-one, with a yield of 89%.

[0035] ② Add 4-(4-(benzyloxy)butyl)-3,3-dimethyloxetane-2-one (42.3g, 0.161mol) and dimethylformamide (DMF) (500ml) to a 1000ml reaction flask. Add sodium borohydride (15.2g, 0.403mol) at room temperature with stirring. Stir and react for 12 hours. Remove DMF under reduced pressure, add 600ml of water, adjust pH to 1 with hydrochloric acid (3M), extract with n-hexane (250ml×3), combine the extracts, dry with anhydrous magnesium sulfate, filter, and concentrate the filtrate to obtain 37.5g of 7-benzyloxy-2,2-dimethylheptanoic acid (white solid), yield 88%.

[0036] ③ In a 500ml reaction flask equipped with a reflux condenser and a magnetic stirrer, add 37.0g (0.14mol) of 7-benzyloxy-2,2-dimethylheptanoic acid, 146ml (1.3mol) of 47% hydrobromic acid, and 6.5g (0.013mol) of hexadecyltributylphosphine bromide. Stir and heat, and reflux (internal temperature approximately 115℃) for 10 hours. After the reaction is complete, cool to room temperature, let stand for 30 minutes, and extract with ethyl acetate (300ml × 2), discarding the aqueous layer. Combine the organic layers, wash with saturated brine (150ml), separate the aqueous layer, and dry the organic layer with anhydrous sodium sulfate. Filter off the drying agent, concentrate the filtrate under reduced pressure, and obtain 29.9g of pale yellow liquid of 7-bromo-2,2-dimethylheptanoic acid, yield 90%.

[0037] ④ Add 28.7 g (0.121 mol) of 7-bromo-2,2-dimethylheptanoic acid, 300 ml of anhydrous ethanol, and 1.0 ml of concentrated sulfuric acid to a 500 ml reaction flask. Reflux the mixture for 8 hours. After the reaction is complete, remove the solvent under reduced pressure and cool to room temperature. Add 150 ml of water and 200 ml of dichloromethane and stir for 30 minutes. Separate the layers. Extract the aqueous layer with 80 ml of dichloromethane. Combine the organic layers and wash with 10% sodium bicarbonate aqueous solution (100 ml). Separate the aqueous layer. Dry the organic layer with anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain 29.2 g of pale yellow liquid ethyl 7-bromo-2,2-dimethylheptanoate, with a yield of 91%.

[0038] Example 3) Preparation of 1,9-bis(1,3-dioxolane-2-yl)nonane-5-one:

[0039]

[0040] In a 500ml reaction flask, 2-(3-bromopropyl)-1,3-dioxane (39g, 0.2mol) and dimethylformamide (200ml) were added separately. While stirring, dimethyl 1,3-propanone dicarboxylate (17.4g, 0.1mol), potassium carbonate (32g, 0.231mol), and potassium iodide (3.3g, 0.02mol) were added sequentially. The mixture was heated to 130±3℃ and maintained at this temperature for 24 hours. After the reaction was complete, the reaction solution was cooled to room temperature, filtered, and the filter cake was washed with DMF (20ml). The filtrates were combined, concentrated under reduced pressure to remove the solvent, and then ethanol (100ml) and purified water (150ml) were added. ), sodium hydroxide (36 g, 0.9 mol), heated to reflux and maintained under reflux for 4 hours; after the reaction was complete, concentrated to remove the solvent, added water (80 ml) while hot, cooled to room temperature, extracted with methyl tert-butyl ether (250 ml × 2), combined the extracts, washed with saturated brine (100 ml), separated the aqueous layer, dried the organic layer with anhydrous sodium sulfate, filtered to remove the filter cake; concentrated the filtrate to give 22.5 g of 1,9-bis(1,3-dioxolane-2-yl)nonane-5-one pale yellow liquid, two-step yield 78.5%.

[0041] Example 4) Preparation of 1,9-bis(1,3-dioxolane-2-yl)nonane-5-one

[0042] The formulation and operation were the same as in Example 3, except that dimethyl 1,3-propanone dicarboxylate (17.4 g, 0.1 mol) was replaced with diethyl 1,3-propanone dicarboxylate (20.2 g, 0.1 mol); the yield of 1,9-bis(1,3-dioxolane-2-yl)nonane-5-one was 22.0 g, with a yield of 76.8%.

[0043] Example 5) Preparation of 1,9-bis(1,3-dioxolane-2-yl)nonane-5-ol:

[0044]

[0045] In a 500 ml reaction flask, 20 g (0.07 mol) of 1,9-bis(1,3-dioxolane-2-yl)nonane-5-one, 80 ml of methanol, and 20 ml of water were added, stirred, and cooled to below -3 °C. Sodium borohydride (1.4 g, 0.037 mol) was added in portions while maintaining an internal temperature of -3 ± 3 °C. After the addition was complete, the reaction was carried out at the same temperature for 3 hours. After the reaction was complete, 100 ml of water was added, and the mixture was extracted with ethyl acetate (100 ml × 2). The extracts were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to give 19.0 g of 1,9-bis(1,3-dioxolane-2-yl)nonane-5-ol (colorless liquid). The yield was 94%.

[0046] Example 6) Preparation of 6-benzyloxy)nonanedialdehyde:

[0047]

[0048] In a 500 ml reaction flask, add tetrahydrofuran (200 ml), 1,9-bis(1,3-dioxolane-2-yl)nonane-5-ol (18.8 g, 0.065 mol), potassium carbonate (10.0 g, 0.072 mol), and benzyl bromide (12 g). The mixture was heated to 65±3℃ and kept at that temperature for 12 hours. The reaction solution was then cooled to room temperature. The mixture was filtered, and the filter cake was washed with THF (20 ml). The filtrates were combined. The solvent was removed by concentration under reduced pressure. Purified water (150 ml), ethanol (100 ml), and concentrated hydrochloric acid (20 g) were added. The mixture was heated to reflux and kept under reflux for 4 hours. After the reaction was completed, the solvent was removed by concentration. Water (80 ml) was added while the mixture was still hot. The mixture was cooled to room temperature and extracted with ethyl acetate (100 ml × 2). The extracts were combined and washed with saturated brine (100 ml). The aqueous layer was separated, and the organic layer was dried with anhydrous sodium sulfate. The filter cake was removed by filtration. The filtrate was concentrated to give 22.5 g of 6-benzyloxy)nonanedialdehyde, a pale yellow liquid. The yield of the two-step reaction was 79%.

[0049] Example 7) Preparation of 4,4'-(5-(benzyloxy)nonane-1,9-disubstituted)bis(3,3-dimethyloxetane-2-one):

[0050]

[0051] ① Add 22.0 g (0.076 mol) nonanal (6-benzyloxy) and 150 ml of ethyl acetate to a 500 ml reaction flask, stir and cool to about 0 °C, maintaining the internal temperature at 0–4 °C. Add anhydrous zinc chloride (1.0 g, 0.0073 mol), and dropwise add a solution of 11.00 g (0.157 mol) in ethyl acetate (60 ml). After the addition is complete, stir the reaction at 1–4 °C for 30 hours. After the reaction is complete, add 1 Stir 150 ml of 0% sodium bicarbonate aqueous solution for 20 minutes, separate the aqueous layer, add 100 ml of 10% sodium bicarbonate aqueous solution to the organic layer and wash, separate the aqueous layer; wash the organic layer with 100 ml of saturated brine, separate the aqueous layer, dry with anhydrous magnesium sulfate, remove the solvent under reduced pressure, and obtain 29.5 g of 4,4'-(5-(benzyloxy)nonane-1,9-disubstituted)bis(3,3-dimethyloxetane-2-one) oil, yield 90%.

[0052] Example 8) Preparation of 8-(benzyloxy)-2,2,14,14-tetramethylpentadecanedicarboxylic acid:

[0053]

[0054] In a 500 ml reaction flask, 28.0 g (5-(benzyloxy)nonane-1,9-bissubstituted)bis(3,3-dimethyloxetane-2-one) (200 ml) and 28.0 mol (0.065 ml) of N,N'-dimethylformamide (DMF) (200 ml) were added. Sodium borohydride (12.3 g, 0.325 mol) was added under stirring at room temperature, and the reaction was stirred for 12 hours. DMF was removed under reduced pressure, 200 ml of water was added, and the pH was adjusted to 1 with hydrochloric acid (3 M). The mixture was extracted with n-hexane (150 ml × 2), the extracts were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to give 24.5 g of 8-(benzyloxy)-2,2,14,14-tetramethylpentadecanedicarboxylic acid (white solid), yield 86.7%.

[0055] Example 9) Preparation of 2,2,14,14-tetramethyl-8-hydroxypentadecanedicarboxylic acid (Beppedic acid):

[0056]

[0057] In a 500 ml reaction flask equipped with a reflux condenser and magnetic stirrer, add 24 g (0.055 mol) of 8-(benzyloxy)-2,2,14,14-tetramethylpentadecanedicarboxylic acid, 300 ml of methanol, 17.5 g (0.275 mol) of ammonium formate, and 9.9 g of 10% Pd / C. Heat under reflux for 1 hour. Cool to room temperature, filter, wash the filter cake with 20 ml of methanol, combine the filtrates, concentrate to dryness under reduced pressure, and add 20 ml of 5% dilute hydrochloric acid aqueous solution. Disperse the residue with 0 ml of dichloromethane (150 ml × 3); extract with dichloromethane (150 ml × 3), and combine the dichloromethane layers; then back-extract with 10% potassium hydroxide aqueous solution (300 ml × 3); transfer the extract (aqueous layer) to a 2000 ml reaction flask, adjust the pH to 1 with concentrated hydrochloric acid, and then extract with methyl tert-butyl ether (250 ml × 3). Combine the extracts, add anhydrous magnesium sulfate to dry, filter, and concentrate the filtrate under reduced pressure to obtain 17.5 g of bepidocalic acid (A) white solid, yield 92.4%.

[0058] 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 isobutyric acid derivatives, wherein the isobutyric acid derivative is bepidocrolic acid, the method comprising: 2-(3-bromopropyl)-1,3-dioxane reacts with acetone dicarboxylic acid diester to give condensate H; H is decarboxylated in the presence of sodium hydroxide to give compound G; G is reduced with sodium borohydride to give compound F; F reacts with benzyl bromo to give compound E; E is hydrolyzed to give compound D; D reacts with dimethyl ketene to give a bis-four-membered ring lactone C; C is reduced with sodium borohydride to give compound B; B is debenzylated with 10% Pd / C / ammonium formate to give bepidocrolic acid A. The specific method route is as follows: 。

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