Preparation method of Elobixibat intermediate 2, 4-dibromo-5-methoxybenzene sulfonyl chloride

Abstract

The invention discloses a preparation method of an Elobixibat intermediate 2, 4-dibromo-5-methoxybenzene sulfonyl chloride (I), and belongs to the field of preparation of drug intermediates. The method comprises the following steps: oxidizing 3-methoxythiophenol serving as a raw material with hydrogen peroxide to generate a compound II, halogenating the compound II with bromine to generate a compound III, and finally oxidizing and chlorinating with zirconium chloride and hydrogen peroxide to generate the compound 2, 4-dibromo-5-methoxybenzenesulfonyl chloride (I). The preparation method of the intermediate compound III has the advantages of stable property, high yield, high purity, good product appearance, simple post-treatment, suitability for industrial production and the like.

Description

Technical Field

[0001] The invention relates to a method for preparing 2,4-dibromo-5-methoxybenzenesulfonyl chloride, an Elobixibat intermediate, in the field of pharmaceutical intermediate preparation. Background Art

[0002] Elobixibat is the first IBAT (ilealbile acid transporter) inhibitor to be marketed. Its mechanism of action is to inhibit the absorption of bile acid by bile acid transporters in the ileum (Curr Med Chem. 2006; 13(9): 997-1016.), thereby allowing bile acid to stimulate the intestinal mucosa to secrete mucus in the intestine, promote intestinal peristalsis, and make it easier for the human body to excrete feces (Cureus. 2024 Aug 18; 16(8), World J Gastroenterol. 2015 Jun 28; 21(24): 7436-42). Based on the aforementioned mechanism of action of Elobixibat, EAPharma Co., Ltd. first submitted its application for marketing approval in Japan on January 19, 2018 and was approved for constipation (Curr Ther Res Clin Exp. 2023 Oct 28; 99: 100724).

[0003] Elobixibat has a molecular weight of 695.27, which indicates it is slightly larger than typical small molecule drugs. Existing patents WO2019234077A1, pages 167-168, and WO2021110886A1, page 90, both report methods for preparing its key intermediate, 2,4-dibromo-5-methoxybenzenesulfonyl chloride, with a two-step total yield of 34%. Therefore, developing new technologies to increase the yield of 2,4-dibromo-5-methoxybenzenesulfonyl chloride, reduce medication costs, and improve the quality of life for constipation patients are urgent technical challenges to be addressed in the future. Summary of the Invention

[0004] The present invention aims to provide a method for preparing 2,4-dibromo-5-methoxybenzenesulfonyl chloride, an Elobixibat intermediate. The method has the characteristics of high total yield, simple post-treatment, readily available reaction raw materials, mild reaction conditions, etc.

[0005] 1. A method for preparing a compound represented by formula (I):

[0006]

[0007] It is characterized in that the preparation method comprises the following steps:

[0008] (1) In the presence of ethanol, 3-methoxythiophenol is used as a raw material and subjected to H2O2 oxidation reaction to obtain a compound represented by formula II:

[0009]

[0010] (2) The compound represented by formula II reacts with a bromine atom donor in the presence of dichloromethane solvent to produce the compound represented by formula III:

[0011]

[0012] (3) The compound represented by formula III reacts with hydrogen peroxide and zirconium chloride in the presence of acetonitrile solvent to produce the compound represented by formula I:

[0013]

[0014] 2. The method for preparing a compound of formula I according to claim 1, characterized in that, in step (1), the reaction time of the reaction is overnight; the mass ratio of the 3-methoxythiophenol to the ethanol solvent is 20:80-100, the unit of the mass is g, and the unit of the volume is mL; the molar ratio of the 3-methoxythiophenol to H2O2 is 1:1.5-3;

[0015] 3. The method for preparing a compound of formula I according to item 1, characterized in that, in step (2), the reaction temperature is -7°C to 0°C, and the reaction time is 1 to 3 hours; the volume ratio of the mass of the compound II to the dichloromethane solvent is 20:80 to 100, the unit of the mass is g, and the unit of the volume is mL; the bromine atom donor is selected from bromine, bromosuccinimide or dibromohydantoin; the molar ratio of the compound II to bromine is 1:4.5 to 6;

[0016] 4. The method for preparing a compound of formula I according to 1, characterized in that, in step (3), the reaction temperature is 0°C to 10°C, the reaction time is 0.5 to 2 hours; the volume ratio of the mass of the compound III to the acetonitrile solvent is 20:80 to 100, the unit of the mass is g, and the unit of the volume is mL; the molar ratio of the formula III to zirconium chloride is 1:2 to 3; the molar ratio of the formula III to H2O2 is 1:5 to 6;

[0017] 5. According to the above 3, the bromine atom donor is preferably selected from bromine.

[0018] In some preferred embodiments, the compound described in any one of the above, its deuterated form, its stereoisomer, its tautomer or a mixture thereof, is characterized in that the compound is selected from but not limited to the following compounds:

[0019]

[0020] The key point of the present invention is that the disulfide bond in formula II forms a large steric hindrance, and the bromide cation selectively undergoes electrophilic addition reaction at the 2, 2' and 4, 4' positions in formula II, thereby improving the raw material conversion rate. The total conversion rate of the key compound of formula III in two steps is 86%, which is more than 2 times higher than the 37% reported on page 90 of patent WO2021110886A1. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 This is a technical roadmap for the preparation of Elobixibat intermediate 2,4-dibromo-5-methoxybenzenesulfonyl chloride. DETAILED DESCRIPTION

[0022] The present invention is further described in detail below with reference to the embodiments, but is not intended to limit the present invention. Any equivalent substitutions in the art made according to the disclosure of the present invention shall fall within the scope of protection of the present invention.

[0023] The structures of the compounds were determined by mass spectrometry (MS) or nuclear magnetic resonance (NMR) 1 HNMR) to determine.

[0024] Nuclear magnetic resonance (NMR) 1 HNMR) shifts (δ) are given in parts per million (ppm); nuclear magnetic resonance ( 1 HNMR) was measured using a Bruker AVANCE-400 nuclear magnetic spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6) as the solvent and tetramethylsilane (TMS) as the internal standard. The chemical shift was calculated based on 10 -6 The units are given in ppm.

[0025] Mass spectrometry (MS) was performed using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: PLUS Technology, model: PLUS 5210).

[0026] Thin layer silica gel uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.

[0027] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0028] Unless otherwise specified in the present invention, the solution mentioned in the reaction of the present invention is an aqueous solution.

[0029] The term "room temperature" in the present invention refers to a temperature between 10°C and 25°C.

[0030] The term "overnight" in the present invention refers to a time period between 10 h and 12 h.

[0031] Example 1: Preparation of 2,4-dibromo-5-methoxybenzenesulfonyl chloride (Compound I)

[0032]

[0033] The preparation scheme is as follows:

[0034]

[0035] Step 1: Synthesis of 1,2-bis(3-methoxyphenyl)disulfane (Compound II)

[0036]

[0037] To a 250ml eggplant-shaped flask, 3-methoxythiophenol (7g, 0.05mol) and 28ml of EtOH were added dropwise in an ice bath. 30% H2O2 (3.4g, 0.10mol) was added dropwise. The mixture was stirred at room temperature overnight. After TLC monitoring, the reaction was complete, and the ethanol was removed by rotary evaporation to obtain 13.2g of a yellow liquid (1,2-bis(3-methoxyphenyl)disulfane) in a yield of 95%.

[0038] ESI-MS:m / z[M+H] + =279.1;

[0039] 1 H-NMR (400MHz, CDCl3) δ7.26(m,2H),7.16–7.10(m,4H),6.86–6.78(m,2H),3.82(s,6H).

[0040] Step 2: Synthesis of 1,2-bis(2,4-dibromo-5-methoxyphenyl)disulfane (Compound III)

[0041]

[0042] In a 250 ml eggplant-shaped flask, 1,2-bis(3-methoxyphenyl)disulfane (5 g, 18.0 mmol) was added and dissolved in 20 ml of dichloromethane. Under an ice-salt bath, a dichloromethane solution of bromine (12.8 g, 81 mmol, 4.5 eq.) was added dropwise. The mixture was stirred for 1 h, quenched with sodium thiosulfate solution, filtered, washed with water, and slurried with dichloromethane to obtain a light yellow solid 1,2-bis(2,4-dibromo-5-methoxyphenyl)disulfane (9.7 g, yield = 91%, HPLC = 96%).

[0043] ESI-MS: m / z [M+H] + = 591.1;

[0044] 1 H-NMR (400MHz, CDCl3) δ7.66(s,2H),7.15(s,2H),3.82(s,6H).

[0045] 2.3.3 Step 3: Synthesis of 2,4-dibromo-5-methoxybenzenesulfonyl chloride (Compound I)

[0046]

[0047] To a 50 ml eggplant-shaped flask, 1,2-bis(2,4-dibromo-5-methoxyphenyl)disulfane (5 g, 8.5 mmol) and 20 ml of acetonitrile were added, and ZrCl4 (4.3 g, 17.0 mmol, 2.2 eq.) were added in batches, stirred to dissolve, and 30% hydrogen peroxide (1.4 g, 42.5 mmol, 5 eq.) was added dropwise, keeping the temperature below 10°C. After the addition, the mixture was stirred at room temperature for half an hour, water was added, the mixture was filtered, and air-dried to give 2,4-dibromo-5-methoxybenzenesulfonyl chloride (2.5 g, yield = 80%, HPLC = 97%) as a white solid. The total yield of the three steps was 69%.

[0048] ESI-MS:m / z[M+H] + =363.2;

[0049] 1 HNMR (400MHz, DMSO-d6): δ8.06(s,1H),7.67(s,1H),4.02(s,3H).

[0050] Figure 1 This is a preparation route for compound I, which has a total of 3 steps, mild reaction conditions, and simple and readily available reagents.

Claims

1. A method for preparing a compound represented by formula (I): It is characterized in that The preparation method comprises the following steps: (1) In the presence of ethanol, 3-methoxythiophenol is used as a raw material and subjected to H2O2 oxidation reaction to obtain a compound represented by formula II: (2) The compound represented by formula II reacts with a bromine atom donor in the presence of dichloromethane solvent to produce the compound represented by formula III: (3) The compound represented by formula III reacts with hydrogen peroxide and zirconium chloride in the presence of acetonitrile solvent to produce the compound represented by formula I:

2. The method for preparing the compound of formula I according to claim 1, wherein In the step (1), the reaction time is overnight; the mass ratio of the 3-methoxythiophenol to the ethanol solvent is 20:80-100, the unit of the mass is g, and the unit of the volume is mL; the molar ratio of the 3-methoxythiophenol to H2O2 is 1:1.5-3.

3. The method for preparing the compound of formula I according to claim 1, wherein: In the step (2), the reaction temperature is -7°C to 0°C, and the reaction time is 1 to 3 hours; the volume ratio of the mass of the compound II to the dichloromethane solvent is 20:80 to 100, the unit of the mass is g, and the unit of the volume is mL; the bromine atom donor is selected from bromine, bromosuccinimide or dibromohydantoin; the molar ratio of the compound II to bromine is 1:4.5 to 6.

4. The method for preparing the compound of formula I according to claim 1, wherein: In the step (3), the reaction temperature of the reaction is 0°C to 10°C, and the reaction time of the reaction is 0.5 to 2 hours; the volume ratio of the mass of the compound III to the acetonitrile solvent is 20:80 to 100, the unit of the mass is g, and the unit of the volume is mL; the molar ratio of the formula III to zirconium chloride is 1:2 to 3; and the molar ratio of the formula III to H2O2 is 1:5 to 6.

5. According to claim 3, the bromine atom donor is preferably selected from bromine.

Images