Preparation method of dotenorad and intermediate thereof

Abstract

The invention discloses a preparation method of dotenorad and an intermediate thereof, and particularly discloses a preparation method of a compound as shown in a formula II, the preparation method comprises the following steps: in a solvent, in the presence of alkali metal tungstate and hydrogen peroxide, carrying out oxidation reaction as shown in the specification on a compound as shown in a formula I, and preparing to obtain a compound as shown in a formula II. The product prepared by the preparation method is high in purity, and the quality control of the dotenorad is facilitated.

Description

Technical Field

[0001] This invention belongs to the field of preparation of active pharmaceutical ingredients and intermediates, and specifically relates to a method for preparing dotenorazole and its intermediates. Background Technology

[0002] Dotinurad is a urate reabsorption inhibitor that targets and inhibits the activity of the urate reabsorption transporter (URAT1). By selectively inhibiting urate reabsorption in the kidneys (URAT1), it suppresses urate reabsorption and lowers blood uric acid levels. Dotinurad is an oral tablet available in strengths of 0.5 mg, 1 mg, or 2 mg per tablet, taken once daily. The initial adult dose is 0.5 mg daily, followed by a maintenance dose of 2 mg daily after uric acid testing, with a maximum dose not exceeding 4 mg daily.

[0003] The chemical name of dotenorazole is (3,5-dichloro-4-hydroxyphenyl)(1,1-dioxo-1,2-dihydro-3H-1λ6-1,3-benzothiazol-3-yl) methyl ketone.

[0004]

[0005] Patent CN102639518 discloses a method for synthesizing dotenoramide, which uses 2-aminobenzylthiol as the starting material, reacts with formaldehyde to obtain dihydrobenzothiazole, then condenses with 3,5-dichloro-4-methoxybenzoyl chloride to obtain benzothiazole benzamide intermediate, then oxidizes with m-chloroperoxybenzoic acid to obtain intermediate sulfone, and finally demethylates to obtain the finished product dotenoramide.

[0006]

[0007] Patents CN202010693795.4 and CN202010692765.1 report a new synthetic method for dotenoramide, in which 2-aminobenzylthiol is condensed with 3,5-dichloro-4-hydroxybenzoic acid to obtain an intermediate amide, which is then cyclized and oxidized with m-chloroperoxybenzoic acid to obtain dotenoramide.

[0008]

[0009] The main drawback of current methods for preparing dotenoroxetine is the low purity of the intermediate sulfone obtained from the oxidation step, which affects the final product quality and overall yield. Therefore, finding a simpler, more convenient, more selective, and cost-effective process is crucial for the economic and technological development of this active pharmaceutical ingredient. Summary of the Invention

[0010] This invention addresses the problem of low purity in existing dotenoroxetine and its intermediates by providing a method for preparing dotenoroxetine and its intermediates. The method uses hydrogen peroxide as an oxidant, adds an alkali metal tungstate catalyst, and synergistically oxidizes sulfides to sulfones. The product prepared by this method has high purity, which is beneficial for the quality control of dotenoroxetine.

[0011] The present invention provides a method for preparing a compound as shown in Formula II, the method comprising the following steps: in a solvent, in the presence of an alkali metal tungstate and hydrogen peroxide, the compound as shown in Formula I is subjected to the following oxidation reaction to prepare the compound as shown in Formula II;

[0012]

[0013] Where R represents H and C 1-6 Alkyl or hydroxyl protecting groups.

[0014] In some embodiments of the present invention, R is H or -CH3.

[0015] In some embodiments of the present invention, the solvent is one or more selected from water, alcohol solvents, ether solvents, ester solvents, and halogenated hydrocarbon solvents, preferably a mixture of alcohol solvent and water. The alcohol solvent is preferably methanol, ethanol, or isopropanol. The ether solvent is preferably tetrahydrofuran and methyl tert-butyl ether. The ester solvent is preferably ethyl acetate. The halogenated hydrocarbon solvent is preferably dichloromethane.

[0016] In some embodiments of the present invention, the solvent is a mixture of methanol and water or a mixture of ethanol and water.

[0017] In some embodiments of the present invention, when the solvent is a mixture of an alcohol solvent and water, the volume ratio of the alcohol solvent to water is (2.5-4):1.

[0018] In some embodiments of the present invention, the molar volume ratio of the compound as shown in Formula I to the solvent is 1-3 mol / L, for example 2.3 mol / L, 2.4 mol / L or 2.7 mol / L.

[0019] In some embodiments of the present invention, the alkali metal tungstate is sodium tungstate, sodium tungstate dihydrate, or potassium tungstate.

[0020] In some embodiments of the present invention, the molar ratio of the alkali metal tungstate to the compound as shown in Formula I is (0.01-0.2):1, preferably (0.04-0.12):1, for example 0.048:1, 0.051:1, 0.056:1 or 0.112:1.

[0021] In some embodiments of the present invention, the hydrogen peroxide is present in the form of a hydrogen peroxide solution of any concentration diluted with water or an organic solvent, preferably 10%-60% hydrogen peroxide, for example 30% hydrogen peroxide.

[0022] In some embodiments of the present invention, the molar ratio of the hydrogen peroxide and the compound as shown in Formula I is (2-6):1, for example 4:1.

[0023] In some embodiments of the present invention, the reaction temperature of the oxidation reaction is 0-100°C, preferably 30-65°C, and more preferably 35-60°C.

[0024] In some embodiments of the present invention, the reaction time of the oxidation reaction is monitored by conventional means in the art (e.g., TLC, HPLC or LC-MS); the reaction time of the oxidation reaction is preferably 3-16 h, more preferably 5-12 h, for example 10 h.

[0025] In some embodiments of the present invention, in the method for preparing the compound as shown in Formula II, the reaction substrate and reagent of the oxidation reaction are the compound as shown in Formula I, the solvent, the alkali metal tungstate, and hydrogen peroxide.

[0026] In some embodiments of the present invention, the preparation method of the compound shown in Formula II includes the following steps: (1) mixing the compound shown in Formula I with a solvent to obtain a mixture A; (2) mixing an alkali metal tungstate with the solvent to obtain a mixture B; (3) adding the mixture B to the mixture A, and then adding hydrogen peroxide thereto to carry out the reaction;

[0027] Steps (1) and (2) are not in any particular order.

[0028] In some embodiments of the present invention, the preparation method of the compound as shown in Formula II further includes the following post-treatment: adding a quenching agent to the reaction solution for neutralization, filtering, washing the filter cake with an organic solvent, and drying to obtain the compound as shown in Formula II.

[0029] In some embodiments of the present invention, the quenching agent in the post-processing is sodium thiosulfate, sodium sulfite, sodium bisulfite, or sodium metasulfite, such as an aqueous solution of sodium thiosulfate, or for example, a 10% aqueous solution of sodium thiosulfate.

[0030] In some embodiments of the present invention, the organic solvent in the post-processing is an alcohol solvent, such as methanol.

[0031] In some embodiments of the present invention, R is H or -CH3; the solvent is a mixture of methanol and water or a mixture of ethanol and water; the molar volume ratio of the compound of formula I to the solvent is 2.3-2.7 mol / L; specifically, it can be 2.3 mol / L, 2.4 mol / L, or 2.7 mol / L; the base Metal tungstates are sodium tungstate, sodium tungstate dihydrate, or tungsten. Potassium tungstate; the alkali metal tungstate and the The molar ratio of the compound shown in Formula I is (0.04-0.12):1; the hydrogen peroxide is present in the form of 30% hydrogen peroxide; the molar ratio of the hydrogen peroxide and the compound shown in Formula I is (4-6):1; the reaction temperature of the oxidation reaction is 30-60℃.

[0032] Terminology Definition

[0033] The term "hydroxyl protecting group" refers to a protecting group suitable for preventing hydroxyl side reactions. Representative hydroxyl protecting groups include, but are not limited to, acetyl, benzyl (Bn), p-methoxybenzyl (PMB), trimethylsilyl (TMS), and tert-butyldimethylsilyl (TBDMS).

[0034] The term "alkyl" refers to an alkyl group having a specified number of carbon atoms (e.g., C10, C20, C30, C40, C50, C60, C7 ...60, C70, C60, C60, C70, C60, C70, C60 1-6 Alkyl groups are straight-chain or branched alkyl groups. Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl.

[0035] The "-" at the end of a group indicates that the group is connected to other segments in the molecule through that site.

[0036] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0037] The reagents and raw materials used in this invention are all commercially available.

[0038] The significant advantages of this invention are as follows: It provides a method for preparing sulfones by oxidizing sulfides. The compound shown in Formula II is prepared via an oxidation reaction in the presence of alkali metal tungstate and hydrogen peroxide. The purity of the product is significantly improved compared to the reported m-chloroperoxybenzoic acid, and the final API is easier to control in terms of quality, with higher purity and yield. The preparation method of this invention is suitable for large-scale industrial production. Detailed Implementation

[0039] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0040] The preparation of 3-(3,5-dichloro-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole (compound 1) and (3,5-dichloro-4-hydroxyphenyl)(3(2H)-benzothiazole) methyl ketone (compound 2) are based on the preparation method of the same compounds in patent CN201080042866.9.

[0041] In this invention, 30% hydrogen peroxide refers to hydrogen peroxide in hydrogen peroxide having a mass percentage of 30%.

[0042] In the following embodiments, the purity detection methods for intermediate 3 and dotenoroxetine are as follows:

[0043]

[0044] Example 1: Oxidation of Intermediate 1

[0045]

[0046] 3-(3,5-dichloro-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole (intermediate 1, 3.5 g, 10.29 mmol) and 20 ml of methanol were added to a reaction flask and stirred until homogeneous. In a separate flask, sodium tungstate (170 mg) was dissolved in 5 ml of water and then added to the methanol solution of intermediate 1. The mixture was heated to 60 °C, and 30% hydrogen peroxide (4.7 g, 41.16 mmol) was added dropwise. After the addition was complete, the mixture was stirred at 60 °C for 5 h. The purity of intermediate 3 in the reaction solution was 95%. The solution was quenched with 10% sodium thiosulfate aqueous solution, filtered, and the filter cake was washed with methanol. The wet product was dried to obtain 3-(3,5-dichloro-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (intermediate 3, 3.44 g), with a yield of 89% and a purity of 98.8%. EI-MS m / z: 393.9 [M+Na] + The proton spectrum of intermediate 3: 1 H-NMR (400MHz, DMSO-d6) δ: 8.16 (1H, d), 7.93 (1H, dd), 7.87 (2H, s), 7.79 (1H, t), 7.47 (1H, t, J = 8.0 Hz), 5.34 (2H, s), 3.91 (3H, s).

[0047] Example 2: Oxidation of Intermediate 1

[0048] 3-(3,5-dichloro-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole (intermediate 1, 3.5 g, 10.29 mmol) and 20 ml of ethanol were added to a reaction flask and stirred until homogeneous. In a separate flask, sodium tungstate (170 mg) was dissolved in 5 ml of water and added to the ethanol solution of intermediate 1. The mixture was heated to 60 °C, and 30% hydrogen peroxide (7.0 g, 61.74 mmol) was added dropwise. After the addition was complete, the mixture was stirred at 60 °C for 10 h. The purity of intermediate 3 in the reaction solution was 90%. The solution was quenched with 10% sodium thiosulfate aqueous solution, filtered, and the filter cake was washed with ethanol. The wet product was dried to obtain 3-(3,5-dichloro-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (intermediate 3, 2.89 g), with a yield of 74% and a purity of 97.5%. EI-MS m / z: 393.9 [M+Na] + .

[0049] Example 3: Oxidation of Intermediate 1

[0050] 3-(3,5-dichloro-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole (intermediate 1, 3.5 g, 10.29 mmol) and 20 ml of methanol were added to a reaction flask and stirred until homogeneous. In a separate flask, sodium tungstate (170 mg) was dissolved in 5 ml of water and then added to the methanol solution of intermediate 1. The mixture was heated to 60 °C, and 30% hydrogen peroxide (7.0 g, 61.74 mmol) was added dropwise. After the addition was complete, the mixture was stirred at 30 °C for 5 h. The purity of intermediate 3 in the reaction solution was 80%. The solution was quenched with 10% sodium thiosulfate aqueous solution, filtered, and the filter cake was washed with methanol. The wet product was dried to obtain 3-(3,5-dichloro-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (intermediate 3, 2.66 g), with a yield of 69% and a purity of 91%.

[0051] Example 4: Oxidation of Intermediate 1

[0052] 3-(3,5-dichloro-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole (intermediate 1, 3.5 g, 10.29 mmol) and 20 ml of methanol were added to a reaction flask and stirred until homogeneous. In a separate flask, sodium tungstate (340 mg) was dissolved in 8 ml of water and then added to the methanol solution of intermediate 1. The mixture was heated to 60 °C, and 30% hydrogen peroxide (4.7 g, 41.16 mmol) was added dropwise. After the addition was complete, the mixture was stirred at 60 °C for 12 h. The purity of intermediate 3 in the reaction solution was 94%. The solution was quenched with 10% sodium thiosulfate aqueous solution, filtered, and the filter cake was washed with methanol. The wet product was dried to obtain 3-(3,5-dichloro-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (intermediate 3, 3.29 g), with a yield of 85% and a purity of 95%.

[0053] Example 5: Oxidation of Intermediate 1

[0054] 3-(3,5-dichloro-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole (intermediate 1, 3.5 g, 10.29 mmol) and 20 ml of methanol were added to a reaction flask and stirred until homogeneous. Separately, potassium tungstate (170 mg) was dissolved in 8 ml of water and added to the methanol solution of intermediate 1. The mixture was heated to 60 °C, and 30% hydrogen peroxide (4.7 g, 41.16 mmol) was added dropwise. After the addition was complete, the mixture was stirred at 60 °C for 5 h. The purity of intermediate 3 in the reaction solution was 95%. The solution was quenched with 10% sodium thiosulfate aqueous solution, filtered, and the filter cake was washed with methanol. The wet product was dried to obtain 3-(3,5-dichloro-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (intermediate 3, 3.2 g), with a yield of 83% and a purity of 95%.

[0055] Example 6: Oxidation of Intermediate 2

[0056]

[0057] Under nitrogen protection, (3,5-dichloro-4-hydroxyphenyl)(3(2H)-benzothiazolyl) methyl ketone (intermediate 2, 3.5 g, 10.73 mmol) and 20 ml of methanol were added to a reaction flask and stirred until homogeneous. In a separate flask, sodium tungstate dihydrate (170 mg, 0.52 mmol) was dissolved in 5 ml of water and added to the methanol solution of intermediate 2. The mixture was heated to 60 °C, and 30% hydrogen peroxide (4.7 g, 41.16 mmol) was added dropwise. After the addition was complete, the mixture was stirred at 60 °C for 5 h. The purity of dotenoroxetine in the reaction solution was 93%. The solution was neutralized with 10% sodium thiosulfate aqueous solution, filtered, and the filter cake was washed with methanol. The wet product was dried to obtain dotenoroxetine (compound 4, 3.35 g), with a yield of 87% and a purity of 99%. Dotenoroxetine 1H NMR spectrum: 1 H-NMR (400MHz, DMSO-d6) δ: 11.06 (1H, brs), 8.04 (1H, d, J = 8.0Hz), 7.90 (1H, dd), 7.76 (3H, m), 7.44 (1H, t, J = 8.0Hz), 5.37 (2H, s).

[0058] Example 7: Preparation of Dotenorolac

[0059] Under nitrogen protection, 3-(3,5-dichloro-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (intermediate 3, 3.0 g, 8.06 mmol), N,N-dimethylformamide (DMF, 10 mL), and anhydrous LiCl (1.37 g, 32.24 mmol) were added to a reaction flask. The mixture was heated to 120 °C and reacted for 16 h. After cooling to room temperature, 30 mL of water was added dropwise to induce crystallization. The crystals were filtered and dried to obtain 2.5 g of dotenoradine (compound 4), with a yield of 87% and a purity of 99%. Recrystallization from ethanol yielded 2.2 g of dotenoradine, with a yield of 88% and a purity of 99.9%.

Claims

1. A method for preparing a compound as shown in Formula II, characterized in that, The preparation method includes the following steps: in a solvent, in the presence of alkali metal tungstate and hydrogen peroxide, the compound shown in Formula I is subjected to the following oxidation reaction to prepare the compound shown in Formula II. Where R represents H and C 1-6 Alkyl or hydroxyl protecting groups.

2. The method for preparing the compound as shown in Formula II according to claim 1, characterized in that, The oxidation reaction satisfies one or more of the following conditions: (1) R is H or -CH3; (2) The solvent is one or more of water, alcohol solvents, ether solvents, ester solvents and halogenated hydrocarbon solvents; (3) The molar volume ratio of the compound shown in Formula I to the solvent is 1-3 mol / L; (4) The alkali metal tungstate is sodium tungstate, sodium tungstate dihydrate or potassium tungstate; (5) The molar ratio of the alkali metal tungstate to the compound shown in Formula I is (0.01-0.2):1; (6) The hydrogen peroxide is present in the form of 10%-60% hydrogen peroxide; (7) The molar ratio of the hydrogen peroxide and the compound shown in Formula I is (2-6):1; (8) The reaction temperature of the oxidation reaction is 0-100℃.

3. The method for preparing the compound as shown in Formula II according to claim 2, characterized in that, The oxidation reaction satisfies one or more of the following conditions: (1) The alcohol solvent is methanol, ethanol or isopropanol; (2) The ether solvents are tetrahydrofuran and methyl tert-butyl ether; (3) The ester solvent is ethyl acetate; (4) The halohydrocarbon solvent is dichloromethane; (5) The molar volume ratio of the compound as shown in Formula I to the solvent is 2.3 mol / L, 2.4 mol / L or 2.7 mol / L; (6) The molar ratio of the alkali metal tungstate to the compound shown in Formula I is (0.04-0.12):1; (7) The hydrogen peroxide is present in the form of 30% hydrogen peroxide; (8) The molar ratio of the hydrogen peroxide and the compound shown in Formula I is 4:1; (9) The reaction temperature of the oxidation reaction is 30-65℃.

4. The method for preparing the compound as shown in Formula II according to claim 2, characterized in that, The oxidation reaction satisfies one or more of the following conditions: (1) The solvent is a mixture of alcohol and water; the volume ratio of the alcohol to water is (2.5-4):1; (2) The molar ratio of the alkali metal tungstate to the compound shown in Formula I is 0.048:1, 0.051:1, 0.056:1 or 0.112:1; (3) The reaction temperature of the oxidation reaction is 35-60℃.

5. The method for preparing the compound as shown in Formula II according to claim 4, characterized in that, The solvent is a mixture of methanol and water or a mixture of ethanol and water.

6. The method for preparing the compound as shown in Formula II according to claim 1, characterized in that, The reaction substrates and reagents for the oxidation reaction are the compounds shown in Formula I, the solvent, the alkali metal tungstate, and hydrogen peroxide.

7. The method for preparing the compound of formula II as described in claim 1, characterized in that, The preparation method of the compound shown in Formula II includes the following steps: (1) mixing the compound shown in Formula I with a solvent to obtain a mixture A; (2) mixing an alkali metal tungstate with the solvent to obtain a mixture B; (3) adding the mixture B to the mixture A, and then adding hydrogen peroxide to it to carry out the reaction. Steps (1) and (2) are not in any particular order.

8. The method for preparing the compound of formula II as described in claim 1, characterized in that, The preparation method of the compound shown in Formula II further includes the following post-treatment: adding a quencher to the reaction solution for neutralization, filtering, washing the filter cake with an organic solvent, and drying to obtain the compound shown in Formula II.

9. The method for preparing the compound as shown in Formula II according to claim 8, characterized in that, The quenching agent is sodium thiosulfate, sodium sulfite, sodium bisulfite or sodium metasulfite, such as an aqueous solution of sodium thiosulfate, or for example, a 10% aqueous solution of sodium thiosulfate. Alternatively, the organic solvent may be an alcohol solvent, such as methanol.

10. The method for preparing the compound of formula II as described in claim 1, characterized in that, R is H or -CH3; the solvent is a mixture of methanol and water or a mixture of ethanol and water; the molar volume ratio of the compound of Formula I to the solvent is 2.3-2.7 mol / L; the alkali metal tungstate is sodium tungstate, sodium tungstate dihydrate, or potassium tungstate; the molar ratio of the alkali metal tungstate to the compound of Formula I is (0.04-0.12):1; the hydrogen peroxide is present in the form of 30% hydrogen peroxide; the molar ratio of the hydrogen peroxide to the compound of Formula I is (4-6):1; the reaction temperature of the oxidation reaction is 30-60℃.

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