A method for the synthesis of an elobixibat intermediate

Abstract

The application provides a synthesis method of an intermediate of elobixibat. The intermediate shown in formula V is prepared from ethyl cyanoacetate by substitution reaction with a halogenated alkane, ester reduction, and bromine substitution and cyano hydrolysis reaction. The method has simple steps, low cost and high yield and purity of raw materials, and does not need purification operation in the intermediate step, thereby reducing solvent use, being more economical and environmentally friendly, and being conducive to industrial application.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis, specifically relating to a method for synthesizing an ixobart intermediate. Background Technology

[0002] Constipation is a common and chronic condition worldwide, with high prevalence among young women, older men, and women. In Japan, the estimated number of people suffering from constipation is approximately 4.5 million. In addition to reduced bowel movement frequency, constipation is characterized by symptoms such as difficulty in defecation and hard, dry stools. When these symptoms become chronic, many patients experience a significant decline in their quality of life.

[0003] Elobixibat hydrate, jointly developed by EA Pharmaceuticals (a gastroenterology subsidiary of Eisai Co., Ltd.) and Mochida Pharmaceutical, was officially launched in Japan on April 19, 2018, under the brand name GOOFICE. It is used to treat chronic constipation and is the world's first bile acid transport inhibitor. This drug works by inhibiting bile acid transport, which regulates bile acid reabsorption, thereby increasing the flow of bile acids to the colon. This, in turn, promotes increased water secretion in the intestines and facilitates defecation, thus naturally improving bowel regularity. Elobixibat is an approved bile acid transport inhibitor.

[0004] The synthesis of ilexibarb mainly follows the synthetic methods reported in WO2002050051A1 and WO2016064082A2, and the routes are as follows: 2-(bromomethyl)-2-butylhexanoic acid (compound V) is an important intermediate in the synthesis of icoxibate, and its structural formula is as follows: Currently, there are two main reported synthetic methods for 2-(bromomethyl)-2-butylhexanoic acid (compound V). One is the synthetic method reported in WO2002008211A2, as follows: The disadvantages of this method are: (1) The starting material 2,2-di-n-butyl-1,3-propanediol is not easy to buy on the market. Only reagent-grade small packages are available on the market, and the price is relatively high; (2) Sodium periodate used in the second oxidation reaction is a strong oxidant and is a dangerous chemical, which is unsafe. Ruthenium trichloride is a precious metal and has a high cost; (3) The post-processing of each step of this route requires column chromatography purification, which is cumbersome, requires a large amount of solvent, and puts great pressure on environmental protection.

[0005] Another synthetic method is reported in the Journal of Chemical and Pharmaceutical Research, 2015, 7(12), 733-740, as follows: The disadvantages of this method are: (1) the first reduction reaction needs to be carried out at a low temperature of -60~-70°C, which requires high-quality equipment and is difficult to operate; (2) selective single reduction inevitably results in double reduction byproducts, which affect the purity of the final product; (3) the overall yield of this method is low, only 24.5%. Therefore, it is necessary to provide a method that uses readily available raw materials, is simple to operate, has a high yield, and is of good quality, suitable for industrial application. The synthesis method of 2-(bromomethyl)-2-butylhexanoic acid for large-scale production is of great significance. Summary of the Invention

[0006] The purpose of this invention is to provide a method for synthesizing icoxibate intermediates.

[0007] This invention provides a method for synthesizing the ixobart intermediate shown in Formula V, comprising the following steps: (1) Compound I reacts with compound II under the action of a base to give compound III; (2) Compound III reacts with a reducing agent to give compound IV; (3) Compound IV reacts with a brominating reagent to give compound V; the reaction formula is as follows: Further, the base in step (1) is sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride, 1,8-diazabicycloundec-7-ene, potassium carbonate, or cesium carbonate; the molar ratio of compound I, compound II, and base is 1:(2~10):(2~10), preferably 1:(2.1~2.2):(2.5~3.5).

[0008] Furthermore, the reaction conditions in step (1) are as follows: in an organic solvent, the reaction is carried out at 10~80℃ for 2~7h; the organic solvent is methanol, ethanol, tert-butanol, tetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile or acetone; preferably, the reaction conditions are as follows: in tetrahydrofuran, the reaction is carried out at 20~50℃ for 3~5h.

[0009] Further, the reducing agent in step (2) is sodium borohydride, potassium borohydride or lithium borohydride; the molar ratio of the compound of formula III to the reducing agent is 1:(1~5), preferably 1:(1.5~1.8).

[0010] Furthermore, the reaction conditions in step (2) are as follows: in an organic solvent, the reaction is carried out at 0-50°C for 1-5 hours; the organic solvent is methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, ethylene glycol dimethyl ether, tetrahydrofuran or 1,4-dioxane; preferably, the reaction conditions are as follows: in ethanol, the reaction is carried out at 20-30°C for 1-3 hours.

[0011] Further, the brominating reagent in step (3) is hydrobromic acid, phosphorus tribromide, or phosphorus tribromooxy; the reaction conditions are: under solvent-free conditions or in a solvent, reaction at 60~120℃ for 2~7h; the mass concentration of the hydrobromic acid is 40%~68%; the solvent is water or an organic solvent; the organic solvent is N,N-dimethylformamide, dimethyl sulfoxide, or acetonitrile; the molar ratio of compound IV to the brominating reagent is 1:(1~10), preferably 1:(1.5~5).

[0012] Furthermore, the brominating agent in step (3) is hydrobromic acid; the reaction conditions are: reaction at 80~100℃ for 4~6h under solvent-free conditions; preferably, the concentration of the hydrobromic acid is 48%.

[0013] Furthermore, the brominating reagent in step (3) is phosphorus tribromide or phosphorus tribromooxy; the reaction conditions are: at 60~120℃, react in an organic solvent for 2~4 hours, and then add water to react for 1~3 hours.

[0014] Furthermore, step (3) also includes the following post-processing steps: adjusting the pH to alkaline, extracting to remove impurities, adjusting the pH to acidic, extracting the product, and concentrating; preferably, the extractant used to extract to remove impurities is methyl tert-butyl ether; the extractant used to extract the product is ethyl acetate.

[0015] Furthermore, the alkalinity is a pH value of 9-10, and the acidity is a pH value of 2-3.

[0016] The hydrobromic acid described in this invention is an aqueous solution of hydrogen bromide with a mass concentration of 40% to 68%.

[0017] The present invention has the following advantages: (1) The synthesis route is short, with only three steps, and the raw materials are cheap and readily available; (2) The first and second steps do not require purification and can proceed directly to the next step. Purification is only carried out in the last step by extracting impurities, which reduces the use of solvents and is more environmentally friendly; (3) The third step is a one-pot reaction, in which bromine substitution and cyano hydrolysis are carried out together, which simplifies the operation and saves costs.

[0018] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0019] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Attached Figure Description

[0020] Figure 1 For the compound of formula V of the present invention 1 H-NMR spectrum. Detailed Implementation

[0021] The raw materials and equipment used in this invention are all known products, obtained by purchasing commercially available products.

[0022] Example 1: Preparation of the icoxibate intermediate of the present invention (1) Ethyl cyanoacetate (20 g, 0.177 mol, 1 eq), sodium hydride (14.87 g, 0.620 mol, 3.5 eq), tetrahydrofuran (200 ml), and 1-chlorobutane (36.05 g, 0.389 mol, 2.2 eq) were added to a reaction flask and heated to 50°C for 4 h. The reaction was quenched with 200 ml of water, extracted with ethyl acetate (100 ml x 3), dried over anhydrous sodium sulfate, and concentrated to dryness to obtain ethyl 2-butyl-2-cyanohexanoate (compound III), which was directly used in the next reaction.

[0023] (2) The ethyl 2-butyl-2-cyanohexanoate (0.177 mol, 1 eq), sodium borohydride (12.12 g, 0.319 mol, 1.8 eq), and ethanol (300 ml) obtained in the first step were added to a reaction flask and reacted at room temperature for 2 h. The reaction was quenched with water (300 ml), extracted with ethyl acetate (200 ml x 3), dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 2-butyl-2-(hydroxymethyl)hexanonitrile (compound IV), which was directly used in the next step of the reaction.

[0024] (3) The 2-butyl-2-(hydroxymethyl)hexanonitrile (0.177 mol, 1 eq) and 48% hydrobromic acid (149.18 g, 0.885 mol, 5 eq) obtained in the second step were added to a reaction flask and heated to 100°C for 5 h. After cooling to room temperature, 4N NaOH aqueous solution (about 350 ml) was added to adjust the pH to 9-10. Impurities were extracted with methyl tert-butyl ether (100 ml x 3). The pH of the aqueous phase was adjusted to 2-3 with 6N HCl (about 250 ml). The product was extracted with ethyl acetate (100 ml x 3) and dried over anhydrous sodium sulfate. After filtration, the product was concentrated to dryness to obtain 38.6 g of the target compound 2-(bromomethyl)-2-butylhexanoic acid (compound V), with a purity of 99.5% and an overall yield of 82.2% for the three steps. The overall yield is calculated as follows: (molar amount of ethyl cyanoacetate as the starting material / molar amount of compound V obtained) 100%, the molar amount of compound V = the mass of compound V obtained from the reaction / the molecular weight of compound V, and the molecular weight of compound V is 265.19 g / mol.

[0025] 1 H-NMR (400 MHz, CDCl3): δ0.88-0.93 (t, 6H), 1.11-1.25 (m, 4H), 1.26-1.38 (m, 4H), 1.67-1.69 (m, 4H), 3.58 (s, 2H). 1 See H-NMR spectrum Figure 1 .

[0026] Example 2: Preparation of the icoxibate intermediate of the present invention (1) Ethyl cyanoacetate (20 g, 0.177 mol, 1 eq), sodium hydride (12.74 g, 0.531 mol, 3 eq), tetrahydrofuran (200 ml) and 1-bromobutane (53.30 g, 0.389 mol, 2.2 eq) were added to a reaction flask and heated to 50°C for 3 h. The reaction was quenched with 200 ml of water, extracted with ethyl acetate (100 ml x 3), dried over anhydrous sodium sulfate, and concentrated to dryness to obtain ethyl 2-butyl-2-cyanohexanoate (compound III), which was directly used in the next reaction.

[0027] (2) The ethyl 2-butyl-2-cyanohexanoate (0.177 mol, 1 eq), potassium borohydride (17.21 g, 0.319 mol, 1.8 eq), and ethanol (300 ml) obtained in the first step were added to a reaction flask and reacted at room temperature for 2 h. The reaction was quenched with water (300 ml), extracted with ethyl acetate (200 ml x 3), dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 2-butyl-2-(hydroxymethyl)hexanonitrile (compound IV), which was directly used in the next step of the reaction.

[0028] (3) The 2-butyl-2-(hydroxymethyl)hexanonitrile (0.177 mol, 1 eq), phosphorus tribromide (71.87 g, 0.266 mol, 1.5 eq), and N,N-dimethylformamide (300 ml) obtained in the second step were added to a reaction flask and heated to 80°C for 4 h. 100 ml of water was slowly added, and the reaction was continued at 80°C for 2 h. The mixture was cooled to room temperature, and 4N NaOH aqueous solution (about 300 ml) was added to adjust the pH to 9-10. Impurities were extracted with methyl tert-butyl ether (100 ml x 3). The pH of the aqueous phase was adjusted to 2-3 with 6N HCl (about 250 ml). The product was extracted with ethyl acetate (100 ml x 3) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to dryness to obtain 39.8 g of the target compound 2-(bromomethyl)-2-butylhexanoic acid (compound V), with a purity of 99.1% and an overall yield of 84.8% for the three steps.

[0029] Example 3: Preparation of the icoxibate intermediate of the present invention (1) Ethyl cyanoacetate (20 g, 0.177 mol, 1 eq), sodium hydride (10.62 g, 0.443 mol, 2.5 eq), tetrahydrofuran (200 ml) and 1-iodobutane (68.40 g, 0.372 mol, 2.1 eq) were added to a reaction flask and reacted at room temperature for 5 h. The reaction was quenched with 200 ml of water, extracted with ethyl acetate (100 ml x 3), dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 41.8 g of ethyl 2-butyl-2-cyanohexanoate (compound of formula III), which was directly used in the next reaction.

[0030] (2) The ethyl 2-butyl-2-cyanohexanoate (0.177 mol, 1 eq), potassium borohydride (14.34 g, 0.266 mol, 1.5 eq), and ethanol (300 ml) obtained in the first step were added to a reaction flask and reacted at room temperature for 2 h. The reaction was quenched with water (300 ml), extracted with ethyl acetate (200 ml x 3), dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 2-butyl-2-(hydroxymethyl)hexanonitrile (compound IV), which was directly used in the next step of the reaction.

[0031] (3) The 2-butyl-2-(hydroxymethyl)hexanonitrile (0.177 mol, 1 eq), phosphorus tribromide (76.26 g, 0.266 mol, 1.5 eq), and N,N-dimethylformamide (300 ml) obtained in the second step were added to a reaction flask and heated to 80°C for 3 h. 100 ml of water was slowly added and the reaction was continued at 80°C for 2 h. The mixture was cooled to room temperature, and 4N NaOH aqueous solution (about 300 ml) was added to adjust the pH to 9-10. Impurities were extracted with methyl tert-butyl ether (100 ml x 3). The pH of the aqueous phase was adjusted to 2-3 with 6N HCl (about 250 ml). The product was extracted with ethyl acetate (100 ml x 3) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to dryness to obtain 37.3 g of the target compound 2-(bromomethyl)-2-butylhexanoic acid (compound V), with a purity of 99.3% and an overall yield of 79.4% for the three steps.

[0032] In summary, this invention provides a method for preparing icoxibate intermediates that is simple in procedure, uses inexpensive and readily available raw materials, and yields high-purity products. Moreover, it eliminates the need for purification in intermediate steps, reducing solvent usage and making it more economical and environmentally friendly, thus facilitating its industrial application.

Claims

1. A method for synthesizing the ixobart intermediate shown in Formula V, characterized in that, Includes the following steps: (1) Compound I reacts with compound II under the action of a base to give compound III; (2) Compound III reacts with a reducing agent to give compound IV; (3) Compound IV reacts with a brominating reagent to give compound V; The reaction formula is as follows: ； The brominating agent in step (3) is phosphorus tribromide; the reaction conditions are: reacting in an organic solvent at 60~120℃ for 2~4 hours, followed by adding water for 1~3 hours.

2. The synthesis method according to claim 1, characterized in that, The base mentioned in step (1) is sodium methoxide, sodium ethoxide, potassium tert-butoxide or sodium hydride; the molar ratio of compound I and compound II to base is 1:(2~10):(2~10).

3. The synthesis method as described in claim 1 or 2, characterized in that, The reaction conditions described in step (1) are as follows: reaction at 10~80℃ for 2~7h in an organic solvent; the organic solvent is methanol, ethanol, tert-butanol, tetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile or acetone.

4. The synthesis method as described in claim 3, characterized in that, The reaction conditions are: in tetrahydrofuran, the reaction is carried out at 20~50℃ for 3~5 hours.

5. The synthesis method as described in claim 1, characterized in that, The reducing agent in step (2) is sodium borohydride, potassium borohydride or lithium borohydride; the molar ratio of compound III to reducing agent is 1:(1~5).

6. The synthesis method according to claim 1 or 5, characterized in that, The reaction conditions in step (2) are: reaction at 0~50℃ for 1~5h in an organic solvent; the organic solvent is methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, ethylene glycol dimethyl ether, tetrahydrofuran or 1,4-dioxane.

7. The synthesis method according to claim 6, characterized in that, The reaction conditions are: in ethanol, at 20-30°C for 1-3 hours.

8. The synthesis method according to claim 1, characterized in that, The organic solvent in step (3) is N,N-dimethylformamide or dimethyl sulfoxide; the molar ratio of compound IV to the brominated reagent is 1:(1~10).

9. The synthesis method according to claim 1, characterized in that, Step (3) also includes the following post-processing steps: adjusting the pH to alkaline, extracting to remove impurities, adjusting the pH to acidic, extracting the product, and concentrating.

10. The synthesis method according to claim 9, characterized in that, The alkalinity is pH 9-10, and the acidity is pH 2-3.

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