Process for the preparation of (dithiodiylbis(4-hydroxy-5-methoxy-2,1-phenylene))bis(phenyl methanone)

Abstract

The application discloses a preparation method of (dithiodibenzophenone) bis(4-hydroxy-5-methoxy-2,1-benzyl) (III), and belongs to the field of preparation of pharmaceutical intermediates. The application takes 3,4-dimethoxy benzene thiol as raw material, and generates compound II through hydrogen peroxide oxidation; and the compound II generates compound III through benzoic anhydride reaction. The preparation of the intermediate compound III has the advantages of stable property, simple synthesis, high purity, good product appearance, and suitability for industrial production.

Description

Technical Field

[0001] This invention relates to a method for preparing (dithiodimethylbis(4-hydroxy-5-methoxy-2,1-benzylmethyl))bis(phenyl ketone) in the field of pharmaceutical intermediate preparation. Background Technology

[0002] IBAT (ileal bile acid transporter) inhibitors are marketed drugs whose mechanism of action is to inhibit the absorption of bile acids by bile acid transporters in the ileum (Curr Med Chem. 2006;13(9):997-1016.), thereby stimulating the intestinal mucosa to secrete mucus, promoting intestinal peristalsis, and making it easier for the body to excrete waste (Cureus. 2024 Aug 18;16(8), World J Gastroenterol. 2015 Jun 28;21(24):7436-42). The latest IBAT inhibitor, Linerixibat, developed by GSK, was first approved for marketing in the United States on March 17, 2026, with the approved indication being cholestatic pruritus.

[0003] The (dithiodimethylbis(4-hydroxy-5-methoxy-2,1-benzylmethyl))bis(phenyl) ketone reported in this study is a promising pharmaceutical intermediate. Its reduction product, (2-mercapto-4,5-methoxyphenyl)(phenyl) ketone, can serve as an important intermediate in the process route of the IBAT inhibitor drug Linerixibat (as shown in step k on page 22 of the original patent WO9605188A1). Existing technology 1, WO9605188A1, requires 11 steps to synthesize the intermediate (2-mercapto-4,5-methoxyphenyl)(phenyl) ketone, a lengthy process that poses a significant challenge to the cost of Linerixibat. Existing technology 2 reports a method for preparing (2-mercapto-4,5-methoxyphenyl)(phenyl) ketone, but the raw materials are difficult to obtain, and the technical route also presents considerable challenges (Szabó, J., Bernáth, G. and Sohár, P. (1989), Alkaline hydrolysis of 3-methyl-2H-1, 3-benzothiaziniumiodides. Journal of Heterocyclic Chemistry, 26: 789-791. https: / / doi.org / 10.1002 / jhet.5570260352).Therefore, developing a method for preparing (disulfide dimethyl bis(4-hydroxy-5-methoxy-2,1-benzylmethyl))bis(phenyl ketone) has great potential significance. It is an urgent technical problem to be solved in the future in order to reduce the cost of medication for patients and improve the quality of life for patients with cholestasis. Summary of the Invention

[0004] The purpose of this invention is to provide a method for preparing the potential intermediate of Linerixibat (dithiodimethylbis(4-hydroxy-5-methoxy-2,1-phenylmethylene))bis(phenyl ketone), which has the advantages of simple synthetic route, simple post-processing, readily available reaction raw materials, and mild reaction conditions.

[0005] 1. A method for preparing a compound of formula (III):

[0006]

[0007] The preparation method is characterized by comprising the following steps:

[0008] (1) In the presence of ethanol, using 3,4-dimethoxythiophenol as a raw material, the compound shown in Formula II was obtained by oxidation with H2O2:

[0009]

[0010] (2) The compound shown in Formula II reacts with benzoyl chloride or benzoic anhydride donor under acidic conditions, using dichloromethane or 1,2-dichloroethane as solvent, to produce the compound shown in Formula III:

[0011]

[0012] 2. The method for preparing a compound of formula III according to claim 1, characterized in that, in step (1), the reaction time is 12 h; the mass ratio of 3,4-dimethoxythiophenol to ethanol solvent is 20:80-100, the mass is in g, and the volume is in mL; the molar ratio of 3,4-dimethoxythiophenol to H2O2 is 1:1.5-3;

[0013] 3. The method for preparing a compound of formula III according to claim 1, characterized in that, in step (2), the reaction temperature is -7°C. oThe reaction temperature is C~25℃, and the reaction time is 24 hours; the mass ratio of compound II to dichloromethane or 1,2-dichloroethane solvent is 20:80~100, where the mass is in g and the volume is in mL, and the solvent is preferably dichloromethane; the benzoyl donor is selected from benzoyl chloride or benzoic anhydride, preferably benzoic anhydride; the molar ratio of formula II to benzoyl or benzoic anhydride is 1:2.5~3; the acid is preferably methanesulfonic acid, and the molar ratio of formula II to methanesulfonic acid is 1:2.5~3;

[0014] In some preferred embodiments, the compound, its deuterated form, its stereoisomer, its tautomer, or mixture thereof described in any one of the preceding embodiments is characterized in that the compound is selected from, but is not limited to, the following compounds:

[0015] Example 1

[0016] The key point of this invention is that the disulfide bond in Formula II forms a large steric hindrance, and the benzoyl cation selectively performs a selective electrophilic addition reaction on the ortho position of the disulfide bond with small steric hindrance in Formula II, thereby selectively and rapidly preparing the compound of Formula III. Attached Figure Description

[0017] Figure 1 The technical route for the preparation of (dithiodimethylbis(4-hydroxy-5-methoxy-2,1-benzylmethyl))bis(phenyl ketone) is shown. Detailed Implementation

[0018] The present invention will be further described in detail below with reference to the embodiments, but this is not intended to limit the present invention. Any equivalent substitutions made in the art based on the disclosure of the present invention shall fall within the protection scope of the present invention.

[0019] The structure of the compound was determined by mass spectrometry (MS) or nuclear magnetic resonance (NMR). 1 It was determined by HNMR.

[0020] Nuclear magnetic resonance (NMR) 1 HNMR shift (δ) is given in parts per million (ppm); nuclear magnetic resonance (NMR) 1 The ¹H NMR (hydrocarbon NMR) measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvent was deuterated dimethyl sulfoxide (DMSO-d6), and the internal standard was tetramethylsilane (TMS). Chemical shifts were expressed in terms of 10⁻¹⁰ NMR values. -6 (ppm) is given as the unit.

[0021] Mass spectrometry (MS) measurements were performed using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Spectrum Technology, model: Spectrum 5210).

[0022] Thin-layer silicone uses Yantai Huanghai HSGF254 or Qingdao GF254 silicone sheets.

[0023] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0024] Unless otherwise specified in this invention, the solution mentioned in the reaction of this invention is an aqueous solution.

[0025] In the terminology of this invention, "room temperature" refers to a temperature between 10°C and 25°C.

[0026] In the terminology of this invention, "overnight" refers to a time between 10 h and 12 h.

[0027] Example 1: Preparation of (dithiodimethylbis(4-hydroxy-5-methoxy-2,1-benzylmethyl))bis(phenyl ketone) (Compound III)

[0028]

[0029] The preparation method is as follows:

[0030]

[0031] Step 1: Synthesis of 1,2-bis(3,4-dimethoxyphenyl)dithione (Compound II)

[0032] In a 100 mL pear-shaped flask, 5 g of 3,4-dimethoxyphenylthiophenol and 20 mL of EtOH were added. 9.8 g of 30% H₂O₂ was added dropwise in an ice bath. After the addition was complete, the mixture was stirred overnight at room temperature. A large amount of solid precipitated. The reaction was monitored by TLC. 100 mL of water was added, and the mixture was stirred for 30 min. The mixture was then filtered to obtain 4.8 g of 1,2-bis(3,4-dimethoxyphenyl)dithioethane (white solid, 97% yield). ESI-MS: m / z [M+H] + =339.0; 1 H NMR (400 MHz, DMSO) δ 7.08-7.02 (M, 4H), 6.98–6.94 (m, 2H), 3.75 (s, 6H), 3.72 (s, 6H).

[0033] Step 2: Synthesis of 1,2-bis(2,4-dibromo-5-methoxyphenyl)dithion (Compound III)

[0034] In a 50 mL pear-shaped flask, under ice bath conditions, 1,2-bis(3,4-dimethoxyphenyl)dithione (MW = 338.06, 300 mg, 0.89 mmol) was added sequentially to dissolve in dichloromethane. Trifluoromethanesulfonic acid (270 mg, 1.78 mmol, 2 eqv.) was then added dropwise, followed by the addition of a dichloromethane solution of benzoic anhydride (500 mg, 2.23 mmol). After the addition was complete, the mixture was brought to room temperature and stirred overnight. The reaction was monitored by TLC. After the reaction was complete, the solution was concentrated and separated by column chromatography to give compound III (120 mg, white solid, 25% yield). ESI-MS: m / z [M+H] + =546.97; 1 H NMR (400 MHz, DMSO) δ 7.97 (d, J = 8.1 Hz, 4H), 7.60 (t, J = 7.6 Hz, 4H), 7.08 (s, 6H), 3.82 (s, 6H), 3.77 (s, 6H).

[0035] Figure 1 This is the preparation route diagram for compound III, which consists of two steps, with mild reaction conditions and simple and readily available reagents.

Claims

1. A method for preparing a compound of formula (III): Its features are, The preparation method includes the following steps: (1) In the presence of ethanol, using 3,4-dimethoxythiophenol as a raw material, the compound shown in Formula II was obtained by oxidation with H2O2: (2) The compound shown in Formula II reacts with benzoyl chloride or benzoic anhydride donor under acidic conditions, using dichloromethane or 1,2-dichloroethane as solvent, to produce the compound shown in Formula III:

2. The method for preparing the compound of formula III according to claim 1, characterized in that, In step (1), the reaction time is 12 hours; the mass ratio of 3,4-dimethoxythiophenol to ethanol solvent is 20:80-100, the mass unit is g, and the volume unit is mL; the molar ratio of 3,4-dimethoxythiophenol to H2O2 is 1:1.5-3.

3. The method for preparing a compound of formula III according to claim 1, characterized in that, In step (2), the reaction temperature is -7°C. o The reaction temperature is C~25℃, and the reaction time is 24 hours; the mass ratio of compound II to the volume ratio of dichloromethane or 1,2-dichloroethane solvent is 20:80~100, where mass is in g and volume is in mL; the benzoyl donor is selected from benzoyl chloride or benzoic anhydride; the molar ratio of formula II to benzoyl or benzoic anhydride is 1:2.5~3; the selected acid is methanesulfonic acid, and the molar ratio of formula II to methanesulfonic acid is 1:2.5~3.

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