Preparation method of sparsentan

Abstract

The invention belongs to the field of medicinal chemistry, and particularly relates to a sparsentan intermediate I and a preparation method thereof. And the structural formula of the intermediate I is # imgabs0 #. Compared with the prior art, the synthesis process provided by the invention has the advantages of low production cost, high target product yield, simplicity in operation and suitability for industrial production.

Description

Technical Field

[0001] The invention belongs to the field of medicinal chemistry and relates to a preparation method of sparsentan. Background Art

[0002] Sparsentan is an oral, single-molecule, dual-action endothelin-angiotensin receptor antagonist that selectively targets the endothelin A (ETA) receptor and the angiotensin II subtype 1 (AT1) receptor, blocking two pathways associated with the progression of IgA nephropathy. This helps protect glomerular podocytes, prevent glomerular sclerosis and mesangial cell proliferation, and reduce proteinuria. On February 17, 2023, sparsentan received accelerated approval from the U.S. Food and Drug Administration (FDA). The chemical structure of sparsentan is as follows:

[0003]

[0004] WO2010135350A2 discloses a series of intermediate compounds with biphenyl structures in sparsentan and their preparation methods, and specifically discloses the following key routes suitable for the synthesis of sparsentan:

[0005]

[0006] However, the intermediates in the preparation process of this route are mostly oily substances, which are not easy to purify and difficult to operate during scale-up production. They also introduce more impurities into the subsequent processes and cannot meet the needs of scale-up production of qualified raw materials. Summary of the Invention

[0007] The technical problem to be solved by the present invention is to provide an intermediate of sparsentan and a preparation method thereof in view of the deficiencies in the prior art. The method is simple to operate, has high yield and high product purity, and is suitable for large-scale industrial production.

[0008] In order to solve the above technical problems, the technical solutions adopted by the present invention are as follows:

[0009] The present invention provides a sparsentan intermediate I, the structural formula of the intermediate I is:

[0010]

[0011] Another aspect of the present invention provides a method for preparing the above-mentioned sparsentan intermediate I, comprising the following steps (I): subjecting 1-bromo-2-ethoxymethyl-4-hydroxymethylbenzene to a sulfonylation reaction with benzylsulfonyl chloride;

[0012]

[0013] The molar ratio of 1-bromo-2-ethoxymethyl-4-hydroxymethylbenzene to benzylsulfonyl chloride is 1:1.2-2, preferably 1:1.2-1.6, and more preferably 1:1.4-1.6.

[0014] Furthermore, the reaction temperature of step (I) is -5 to 10°C, preferably 0 to 10°C, more preferably 0 to 5°C, the reaction time is 0.5 to 8h, preferably 1 to 6h, more preferably 2 to 5h, and the reaction solvent is tetrahydrofuran; preferably, the reaction of step (I) is carried out in the presence of an organic base compound; further preferably, the organic base compound is selected from any one or more of triethylamine, N,N-diisopropylethylamine, and pyridine, preferably N,N-diisopropylethylamine.

[0015] Furthermore, the treatment method after the reaction of step (I) is as follows: after adding water to quench the reaction, adding ethyl acetate to extract and separate to obtain an ethyl acetate phase, adding a C4-C8 alkane solvent to the ethyl acetate phase, and crystallizing at low temperature to obtain intermediate I; preferably, the alkane solvent is n-heptane, and the crystallization temperature is -10 to 10°C, preferably -8 to 8°C, and more preferably -5 to 0°C.

[0016] In another aspect, the present invention provides a method for preparing sparsentan intermediate III, comprising the following steps (II): subjecting intermediate I to a substitution reaction with intermediate II under alkaline conditions, and then subjecting intermediate I to a salt-forming reaction with oxalic acid;

[0017]

[0018] Among them, the molar ratio of intermediate I, intermediate II and oxalic acid is 1: (1-1.5): (2-10), preferably 1: (1-1.2): (2.5-8), and more preferably 1: (1-1.1): (3-6).

[0019] Furthermore, the reaction solvent of step (II) is tetrahydrofuran, and the alkaline condition is provided by an alkaline solution, wherein the alkaline solution is a 5-15wt% aqueous sodium hydroxide solution, preferably an 8-12wt% aqueous sodium hydroxide solution, more preferably a 10-12wt% aqueous sodium hydroxide solution, the reaction temperature is 10-50°C, preferably 20-40°C, more preferably 25-35°C, and the reaction time is 1-10h; the reaction temperature of the salt-forming reaction is 40-60°C, preferably 45-60°C, more preferably 50-55°C, and the reaction time is 1-4h.

[0020] Furthermore, the post-treatment method of the substitution reaction in step (II) is: adding an organic solvent to the reaction system for extraction, concentrating the organic phase, washing with water, and directly performing a salt-forming reaction.

[0021] In another aspect, the present invention also provides use of the aforementioned sparsentan intermediate I in the preparation of sparsentan intermediate III or in the preparation of sparsentan.

[0022] In another aspect, the present invention also provides a method for preparing the aforementioned sparsentan intermediate V, comprising the following steps:

[0023] (I) 1-bromo-2-ethoxymethyl-4-hydroxymethylbenzene is subjected to a sulfonylation reaction with benzylsulfonyl chloride, followed by quenching the reaction with water, extraction with ethyl acetate, and separation to obtain an ethyl acetate phase. A C4-C8 alkane solvent is added to the ethyl acetate phase, and crystallization is performed at low temperature to obtain Intermediate I;

[0024]

[0025] Wherein, the molar ratio of 1-bromo-2-ethoxymethyl-4-hydroxymethylbenzene to benzylsulfonyl chloride is 1:1.2-2, preferably 1:1.2-1.6, more preferably 1:1.4-1.6;

[0026] (II) intermediate I is subjected to a substitution reaction with intermediate II under alkaline conditions, an organic solvent is added to the reaction system for extraction, the organic phase is concentrated, washed with water, and then reacted with oxalic acid to form a salt to obtain intermediate III;

[0027]

[0028] The molar ratio of intermediate I, intermediate II and oxalic acid is 1:(1-1.5):(2-10), preferably 1:(1-1.2):(2.5-8), and more preferably 1:(1-1.1):(3-6);

[0029] (III) reacting the intermediate III with the intermediate IV in the presence of a palladium catalyst, a base and an inert gas atmosphere to obtain the intermediate V;

[0030]

[0031] The molar ratio of intermediate III to intermediate IV is 1:(1-1.5), preferably 1:(1-1.2), and more preferably 1:(1-1.1).

[0032] Furthermore, in step (III), the palladium catalyst is Pd(PPh3)4, the base is selected from any one or more of potassium carbonate, sodium carbonate, and cesium carbonate, and the solvent for the substitution reaction is selected from any one or more of acetonitrile, 1,4-dioxane, toluene, DMF, ethylene glycol dimethyl ether, and 2-methyltetrahydrofuran.

[0033] In another aspect, the present invention further provides a method for preparing sparsentan, comprising the following steps:

[0034] (I) 1-bromo-2-ethoxymethyl-4-hydroxymethylbenzene is reacted with benzylsulfonyl chloride at -5 to 10°C to undergo sulfonylation reaction to obtain intermediate I;

[0035]

[0036] Wherein, the molar ratio of 1-bromo-2-ethoxymethyl-4-hydroxymethylbenzene to benzylsulfonyl chloride is 1:1.2-2, preferably 1:1.2-1.6, more preferably 1:1.4-1.6;

[0037] (II) intermediate I is subjected to a substitution reaction with intermediate II under alkaline conditions, an organic solvent is added to the reaction system for extraction, the organic phase is concentrated, washed with water, and then reacted with oxalic acid to form a salt to obtain intermediate III;

[0038]

[0039] The molar ratio of intermediate I, intermediate II and oxalic acid is 1: (1-1.5): (2-10), preferably

[0040] 1:(1-1.2):(2.5-8), more preferably 1:(1-1.1):(3-6);

[0041] (III) coupling reaction of intermediate III with intermediate IV in the presence of a palladium catalyst and a base to obtain intermediate V;

[0042]

[0043] Wherein, the molar ratio of intermediate III to intermediate IV is 1:(1-1.5), preferably 1:(1-1.2), more preferably 1:(1-1.1);

[0044] (IV) hydrolyzing the intermediate V under acidic conditions to obtain sparsentan;

[0045]

[0046] Beneficial effects:

[0047] Compared with the prior art, the synthesis process provided by the present invention has the advantages of low production cost, high yield of target product, simple operation and suitability for industrial production. DETAILED DESCRIPTION

[0048] The present invention will be described in more detail below through examples. These examples are used for further illustration to better understand the content of the present invention, but should not be regarded as limiting the present invention.

[0049] In the embodiments of the present invention, all concentrations expressed in % are by mass unless otherwise specified.

[0050] Example 1:

[0051] (1) Synthesis of Intermediate I:

[0052]

[0053] To a 500 mL three-necked flask, 1-bromo-2-ethoxymethyl-4-hydroxymethylbenzene (14.04 g, 57.28 mmol, 1 eq) and tetrahydrofuran (140 mL) were added. The temperature was lowered to 5°C, and N,N-diisopropylethylamine (20 mL) and benzylsulfonyl chloride (16.38 g, 85.92 mmol, 1.5 eq) were added. The reaction was allowed to proceed for 1 h. Water (150 mL) was added and stirred for 5 min. Ethyl acetate (200 mL x 3) was then added for extraction and separation to obtain the ethyl acetate phase. The ethyl acetate phase was concentrated to approximately 100 mL, and n-heptane (300 mL) was added. The mixture was crystallized at -5°C for 3 h, filtered, and dried to obtain 21.23 g of a solid with a yield of 92.82% and a purity of 98.15%.

[0054] 1 H NMR (400 MHz, d6-DMSO): δ1.21 (t, 3H), δ3.59 (m, 2H), δ3.59 (m, 2H), δ4.90 (s, 2H), δ5.28 (d, 2H), δ7.26-7.66 (phenyl ring region, 8H).

[0055] MS (m / z): 400.23 [M+H] + .

[0056] (2) Synthesis of Intermediate III:

[0057]

[0058] To a 500 mL three-necked flask were added intermediate I (11.30 g, 28.30 mmol, 1 eq), intermediate II (6.80 g, 29.50 mmol, 1.04 eq) and tetrahydrofuran (100 mL). 10% sodium hydroxide solution (100 mL) was added and the reaction was stirred at 30°C for 4 h before stopping the reaction. Ethyl acetate (200 mL × 3) was added for extraction, washed with water, and concentrated. The concentrate was dissolved in ethyl acetate (200 mL), and oxalic acid (9.40 g, 104.43 mmol, 3.69 eq) was added. The mixture was heated to 50°C for 2 h. A large amount of solid precipitated, which was filtered and dried to obtain 7.25 g of solid with a yield of 60.80% and a purity of 99.51%.

[0059] 1H NMR (400MHz, d6-DMSO): δ0.79 (t, 3H), δ1.16 (t, 3H), δ1.25 (t, 2H), δ1.46 (m, 2H), δ1.72 (t, 2H) , δ1.85 (m, 6H), δ2.35 (t, 2H), δ3.53 (m, 2H), δ4.46 (s, 2H), δ4.71 (s, 2H), δ7.05-7.61 (benzene ring region, 3H).

[0060] MS (m / z): 422.17 [M+H] + .

[0061] (3) Synthesis of intermediate V:

[0062]

[0063] To a 100 mL three-necked flask were added Intermediate III (2.32 g, 5.51 mmol, 1 eq), Intermediate IV (2.44 g, 5.78 mmol, 1.05 eq), Pd(PPh3)4 (0.11 g), toluene (20 mL), and a 20% aqueous cesium carbonate solution (20 mL). Nitrogen was introduced into the reaction flask and the mixture was heated to 85°C for 5 h. The reaction system was cooled to room temperature and extracted with ethyl acetate (20 mL x 3). The mixture was washed with water, dried, and concentrated to afford 3.41 g of an oil.

[0064] (4) Synthesis of Sparsentan:

[0065]

[0066] After removing the palladium catalyst, the crude intermediate V was mixed with 8 volumes of ethanol and 8 volumes of 6M hydrochloric acid, heated to 80°C and stirred for 5 hours. LCMS confirmed that the raw material conversion was complete, and the reaction solution was cooled to room temperature. 10M sodium hydroxide solution was added to adjust the pH to about 8, and stirring was continued for 2 hours. The pH was adjusted to 6 by adding acetic acid, and extracted with ethyl acetate (20 mL×3). The organic phase was washed with water, dried, concentrated, and column chromatography (petroleum ether / ethyl acetate = 1:2) was performed to obtain 3.19 g of a white solid. The yield of steps (3)-(4) was 97.15%, and the purity was 99.05%.

[0067] 1H NMR (400MHz, d6-DMSO): δ0.83 (t, 3H), δ1.02 (t, 3H), δ1.29 (h, 2H), δ1.53 (p, 2H), δ1.68 (s, 3H), δ1.71 (d, 2H), δ1.87 ( t, 6H), δ2.22 (s, 3H), δ2.36 (t, 2H), δ3.22 (t, 2H), δ4.02 (s, 2H), δ4.75 (s, 2H), δ6.94-8.07 (benzene ring region, 7H), δ10.48 (s, 1H).

[0068] MS (m / z): 593.35 [M+H] + .

[0069] Example 2:

[0070] (1) Synthesis of Intermediate I:

[0071] To a 250 mL three-necked flask, 1-bromo-2-ethoxymethyl-4-hydroxymethylbenzene (8.22 g, 33.53 mmol, 1 eq) and tetrahydrofuran (80 mL) were added. The temperature was lowered to 0°C, and N,N-diisopropylethylamine (11 mL) and benzylsulfonyl chloride (8.95 g, 46.95 mmol) were added. The reaction was allowed to react for 1 h. Water (80 mL) was added and stirred for 5 min. Ethyl acetate (100 mL x 3) was then added for extraction and separation to obtain the ethyl acetate phase. The ethyl acetate phase was concentrated to approximately 50 mL, and n-heptane (150 mL) was added. The mixture was crystallized at 0°C for 3 h, filtered, and dried to obtain 11.43 g of a solid with a yield of 85.36% and a purity of 97.23%.

[0072] (2) Synthesis of Intermediate III:

[0073] To a 50 mL three-necked flask were added intermediate I (1.32 g, 3.31 mmol, 1 eq), intermediate II (0.84 g, 3.64 mmol, 1.1 eq), and tetrahydrofuran (10 mL). 11% sodium hydroxide solution (10 mL) was added, and the reaction was stirred at 25°C for 4 h before stopping the reaction. Ethyl acetate (20 mL × 3) was added for extraction, washed with water, and concentrated. The concentrate was dissolved in ethyl acetate (20 mL), and oxalic acid (0.94 g, 10.44 mmol, 5 eq) was added. The mixture was heated to 55°C for 2 h. A large amount of solid precipitated, which was filtered and dried to obtain 0.95 g of solid, with a yield of 68.20% and a purity of 99.43%.

[0074] (3) Synthesis of Intermediate V: The mass of Pd(PPh3)4 in step (3) of Example 1 was replaced by Pd(dppf)Cl2, while other conditions remained unchanged, to obtain 2.91 g of an oily substance.

[0075] (4) Synthesis of sparsentan: The conditions were the same as those in Example 1 to obtain 2.32 g of a white solid. The yield of steps (3) and (4) was 71.22% and the purity was 99.13%.

[0076] Example 3:

[0077] (1) Synthesis of Intermediate I:

[0078] To a 100 mL three-necked flask, 1-bromo-2-ethoxymethyl-4-hydroxymethylbenzene (2.73 g, 11.14 mmol) and tetrahydrofuran (25 mL) were added. The temperature was lowered to 8°C, and N,N-diisopropylethylamine (3.5 mL) and benzylsulfonyl chloride (3.40 g, 17.82 mmol) were added. The reaction was allowed to react for 1 h. Water (30 mL) was added and stirred for 5 min. Ethyl acetate (50 mL x 3) was then added for extraction and separation to obtain the ethyl acetate phase. The ethyl acetate phase was concentrated to approximately 20 mL, and n-heptane (60 mL) was added. The mixture was crystallized at -8°C for 3 h, filtered, and dried to obtain 3.69 g of a solid with a yield of 82.97% and a purity of 98.53%.

[0079] (2) Synthesis of Intermediate III:

[0080] To a 50 mL three-necked flask were added intermediate I (1.48 g, 3.71 mmol, 1 eq), intermediate II (0.90 g, 3.89 mmol, 1.05 eq), and tetrahydrofuran (10 mL). 12% sodium hydroxide solution (10 mL) was added, and the reaction was stirred at 40°C for 4 h before stopping the reaction. Ethyl acetate (20 mL × 3) was added for extraction, washed with water, and concentrated. The concentrate was dissolved in ethyl acetate (20 mL), and oxalic acid (1.00 g, 11.12 mmol, 3 eq) was added. The mixture was heated to 53°C for 2 h. A large amount of solid precipitated, which was filtered and dried to obtain 1.16 g of solid, with a yield of 74.27% and a purity of 98.72%.

[0081] (3) Synthesis of intermediate V: The mass of Pd(PPh3)4 in step (3) of Example 1 was replaced by Pd(PPh3)Cl2, while other conditions remained unchanged, to obtain 2.75 g of an oily substance.

[0082] (4) Synthesis of sparsentan: The conditions were the same as those in Example 1 to obtain 2.25 g of a white solid. The yield of steps (3) and (4) was 68.95%, and the purity was 99.06%.

[0083] Example 4:

[0084] (1) Synthesis of Intermediate I:

[0085] To a 100 mL three-necked flask, 1-bromo-2-ethoxymethyl-4-hydroxymethylbenzene (2.76 g, 11.26 mmol, 1 eq) and tetrahydrofuran (25 mL) were added. The temperature was lowered to 10°C, and N,N-diisopropylethylamine (3.5 mL) and benzylsulfonyl chloride (3.01 g, 15.76 mmol, 1.4 eq) were added. The reaction was allowed to react for 1 h. Water (30 mL) was added and stirred for 5 min. Ethyl acetate (50 mL x 3) was then added for extraction and separation to obtain the ethyl acetate phase. The ethyl acetate phase was concentrated to approximately 00 mL, and n-heptane (60 mL) was added. The mixture was crystallized at 0°C for 3 h, filtered, and dried to obtain 3.78 g of a solid with a yield of 84.07% and a purity of 98.37%.

[0086] (2) Synthesis of Intermediate III:

[0087] To a 50 mL three-necked flask were added intermediate I (1.25 g, 3.13 mmol, 1 eq), intermediate II (0.78 g, 3.38 mmol, 1.08 eq), and tetrahydrofuran (10 mL). 10% sodium hydroxide solution (10 mL) was added, and the reaction was stirred at 35°C for 4 h before stopping the reaction. Ethyl acetate (20 mL × 3) was added for extraction, washed with water, and concentrated. The concentrate was dissolved in ethyl acetate (20 mL), and oxalic acid (0.85 g, 9.39 mmol, 3 eq) was added. The mixture was heated to 50°C for 2 h. A large amount of solid precipitated, which was filtered and dried to obtain 0.89 g of solid, with a yield of 67.47% and a purity of 99.39%.

[0088] (3) Synthesis of intermediate V: The mass of Pd(PPh3)4 in step (3) of Example 1 was replaced by Pd(OAc)2, and other conditions remained unchanged to obtain 2.87 g of an oily substance.

[0089] (4) Synthesis of sparsentan: The conditions were the same as those in Example 1 to obtain 1.09 g of a white solid. The yield of steps (3) and (4) was 3.34% and the purity was 99.34%.

[0090] Example 5:

[0091] (1) Synthesis of Intermediate I:

[0092] To a 50 mL three-necked flask, 1-bromo-2-ethoxymethyl-4-hydroxymethylbenzene (1.84 g, 7.51 mmol) and tetrahydrofuran (20 mL) were added. The temperature was cooled to -2°C, and N,N-diisopropylethylamine (3 mL) and benzylsulfonyl chloride (2.15 g, 11.23 mmol) were added. The reaction was allowed to react for 1 h. Water (20 mL) was added and stirred for 5 min. Ethyl acetate (50 mL x 3) was then added for extraction and separation to obtain the ethyl acetate phase. The ethyl acetate phase was concentrated to approximately 20 mL, and n-heptane (50 mL) was added. The mixture was crystallized at 5°C for 3 h, filtered, and dried to obtain 2.76 g of a solid with a yield of 92.08% and a purity of 98.05%.

[0093] (2) Synthesis of Intermediate III:

[0094] To a 50 mL three-necked flask were added intermediate I (1.37 g, 3.43 mmol, 1 eq), intermediate II (0.87 g, 3.77 mmol, 1.1 eq), and tetrahydrofuran (10 mL). 10% sodium hydroxide solution (10 mL) was added, and the reaction was stirred at 30°C for 4 h before stopping the reaction. Ethyl acetate (20 mL × 3) was added for extraction, washed with water, and concentrated. The concentrate was dissolved in ethyl acetate (20 mL), and oxalic acid (1.54 g, 17.16 mmol, 5 eq) was added. The mixture was heated to 50°C for 2 h. A large amount of solid precipitated, which was filtered and dried to obtain 1.06 g of solid, with a yield of 73.32% and a purity of 99.17%.

[0095] (3) Synthesis of Intermediate V: The mass of Pd(PPh3)4 in step (3) of Example 1 was replaced by a complex of Pd(dba)2 and PPh3, with other conditions remaining unchanged, to obtain 2.86 g of an oily substance.

[0096] (4) Synthesis of sparsentan: The conditions were the same as those in Example 1 to obtain 1.02 g of a white solid. The yield of steps (3) and (4) was 31.13%, and the purity was 99.37%.

[0097] Comparative Example 1

[0098] (1) Synthesis of Intermediate I'

[0099]

[0100] To a 500 mL three-necked flask, 1-bromo-2-ethoxymethyl-4-hydroxymethylbenzene (19.98 g, 81.51 mmol) and toluene (200 mL) were added. The temperature was lowered to 0-10°C, and N,N-diisopropylethylamine (30 mL) and ethylsulfonyl chloride (15.72 g, 122.27 mmol) were added. The reaction was allowed to proceed for 1 h. Water (250 mL) was added and stirred for 5 min. Ethyl acetate (300 mL x 3) was then added for extraction and separation. The ethyl acetate phase was concentrated and purified by column chromatography (petroleum ether / ethyl acetate) to yield 16.25 g of intermediate I' as an oil with a purity of 99.15%.

[0101] (2) Synthesis of Intermediate III:

[0102]

[0103] To a 50 mL three-necked flask were added Intermediate I' (2.57 g, 7.62 mmol), Intermediate II (1.83 g, 7.94 mmol), and tetrahydrofuran (20 mL). 10% sodium hydroxide solution (20 mL) was added, and the reaction was stirred at 30°C for 4 h before stopping the reaction. Ethyl acetate (40 mL x 3) was added for extraction, washed with water, and concentrated. The concentrate was dissolved in ethyl acetate (40 mL), and oxalic acid (2.40 g, 26.67 mmol) was added. The mixture was heated to 50°C for 2 h. A large amount of solid precipitated, which was filtered and dried to obtain 1.84 g of solid, with a yield of 57.30% and a purity of 99.03%.

[0104] Comparative Example 2

[0105] (1) Synthesis of Intermediate I"

[0106]

[0107] To a 500 mL three-necked flask, 1-bromo-2-ethoxymethyl-4-hydroxymethylbenzene (19.98 g, 81.51 mmol) and toluene (200 mL) were added. The temperature was lowered to 0-10°C, and N,N-diisopropylethylamine (30 mL) and p-nitrobenzylsulfonyl chloride (28.81 g, 122.27 mmol) were added. The reaction was allowed to proceed for 1 h. Water (250 mL) was added and stirred for 5 min. Ethyl acetate (300 mL x 3) was then added for extraction and separation to obtain the ethyl acetate phase. The ethyl acetate phase was concentrated to approximately 100 mL, and n-heptane (300 mL) was added. The mixture was crystallized at -5°C for 3 h, filtered, and dried to obtain 32.17 g of a solid with a yield of 88.83% and a purity of 84.36%.

[0108] (2) Synthesis of Intermediate III:

[0109]

[0110] To a 50 mL three-necked flask were added intermediate I (1.52 g, 3.42 mmol), intermediate II (0.82 g, 3.56 mmol) and tetrahydrofuran (10 mL), and 10% sodium hydroxide solution (10 mL) was added. After stirring at 30°C for 24 h, HPLC monitoring showed that no intermediate III was generated.

[0111] Comparative Example 3

[0112]

[0113] By replacing the p-nitrobenzylsulfonyl chloride in Comparative Example 2 with p-toluenesulfonyl chloride in equal moles, with other conditions remaining unchanged, Intermediate I'' was obtained with a yield of 82.71% and a purity of 91.23%. However, Intermediate I'' had poor stability and was completely converted into 1-bromo-2-ethoxymethyl-4-hydroxymethylbenzene during the next reaction with Intermediate II, and Intermediate III could not be generated.

[0114] The present invention provides an intermediate of sparsentan and a method for preparing the same. There are numerous methods and approaches for implementing this technical solution. The above description is merely a preferred embodiment of the present invention. It should be noted that those skilled in the art may make various improvements and modifications without departing from the principles of the present invention, and such improvements and modifications are also within the scope of protection of the present invention. Any components not specified in this embodiment may be implemented using existing technologies.

Claims

1. A sparsentan intermediate I, characterized in that: The structural formula of the intermediate I is:

2. The method for preparing the sparsentan intermediate I according to claim 1, characterized in that: The method comprises the following steps (I): 1-Bromo-2-ethoxymethyl-4-hydroxymethylbenzene is subjected to sulfonylation reaction with benzylsulfonyl chloride; The molar ratio of 1-bromo-2-ethoxymethyl-4-hydroxymethylbenzene to benzylsulfonyl chloride is 1:1.2-2, preferably 1:1.2-1.6, and more preferably 1:1.4-1.

6.

3. The method for preparing sparsentan intermediate I according to claim 2, characterized in that: The reaction temperature of step (I) is -5 to 10°C, preferably 0 to 10°C, more preferably 0 to 5°C, the reaction time is 0.5 to 8 hours, preferably 1 to 6 hours, more preferably 2 to 5 hours, and the reaction solvent is tetrahydrofuran; preferably, the reaction of step (I) is carried out in the presence of an organic base compound; further preferably, the organic base compound is selected from any one or more of triethylamine, N,N-diisopropylethylamine, and pyridine, preferably N,N-diisopropylethylamine; The treatment method after the reaction of step (I) is as follows: after adding water to quench the reaction, adding ethyl acetate to extract and separate to obtain an ethyl acetate phase, adding a C4-C8 alkane solvent to the ethyl acetate phase, and crystallizing at low temperature to obtain intermediate I; preferably, the alkane solvent is n-heptane, and the crystallization temperature is -10 to 10°C, preferably - 8~8℃, more preferably -5~0℃.

4. A method for preparing sparsentan intermediate III, characterized in that: The method comprises the following steps (II): The intermediate I undergoes a substitution reaction with the intermediate II under alkaline conditions, and then undergoes a salt-forming reaction with oxalic acid; Among them, the molar ratio of intermediate I, intermediate II and oxalic acid is 1: (1-1.5): (2-10), preferably 1: (1-1.2): (2.5-8), and more preferably 1: (1-1.1): (3-6).

5. The method for preparing sparsentan intermediate III according to claim 4, characterized in that: The reaction solvent of step (II) is tetrahydrofuran, and the alkaline condition is provided by an alkaline solution, which is a 5-15wt% sodium hydroxide aqueous solution, preferably an 8-12wt% sodium hydroxide aqueous solution, more preferably a 10-12wt% sodium hydroxide aqueous solution. The reaction temperature is 10-50°C, preferably 20-40°C, more preferably 25-35°C, and the reaction temperature of the salt-forming reaction is 40-70°C, preferably 45-60°C, more preferably 50-55°C.

6. The method for preparing sparsentan intermediate III according to claim 4, characterized in that: The post-treatment method of the substitution reaction in step (II) is: adding an organic solvent to the reaction system for extraction, concentrating the organic phase, washing with water, and directly performing a salt-forming reaction.

7. Use of the sparsentan intermediate I according to claim 1 in the preparation of sparsentan intermediate III or in the preparation of sparsentan.

8. A method for preparing sparsentan intermediate V, characterized in that: The following steps are involved: (I) 1-bromo-2-ethoxymethyl-4-hydroxymethylbenzene is subjected to a sulfonylation reaction with benzylsulfonyl chloride at -5 to 10°C, followed by quenching the reaction with water, extraction with ethyl acetate, and separation to obtain an ethyl acetate phase. A C4-C8 alkane solvent is added to the ethyl acetate phase, followed by crystallization at low temperature to obtain Intermediate I; Wherein, the molar ratio of 1-bromo-2-ethoxymethyl-4-hydroxymethylbenzene to benzylsulfonyl chloride is 1:1.2-2, preferably 1:1.2-1.6, more preferably 1:1.4-1.6; (II) intermediate I is subjected to a substitution reaction with intermediate II under alkaline conditions, an organic solvent is added to the reaction system for extraction, the organic phase is concentrated, washed with water, and then reacted with oxalic acid to form a salt to obtain intermediate III; The molar ratio of intermediate I, intermediate II and oxalic acid is 1:(1-1.5):(2-10), preferably 1:(1-1.2):(2.5-8), and more preferably 1:(1-1.1):(3-6); (III) reacting the intermediate III with the intermediate IV in the presence of a palladium catalyst, a base and an inert gas atmosphere to obtain the intermediate V; The molar ratio of intermediate III to intermediate IV is 1:(1-1.5), preferably 1:(1-1.2), and more preferably 1:(1-1.1).

9. The method for preparing sparsentan intermediate V according to claim 8, characterized in that: In step (III), the palladium catalyst is Pd(PPh3)4, the base is selected from any one or more of potassium carbonate, sodium carbonate, and cesium carbonate, and the solvent for the substitution reaction is selected from any one or more of acetonitrile, 1,4-dioxane, toluene, DMF, ethylene glycol dimethyl ether, and 2-methyltetrahydrofuran.

10. A method for preparing sparsentan, characterized in that: The following steps are involved: (I) 1-bromo-2-ethoxymethyl-4-hydroxymethylbenzene is subjected to a sulfonylation reaction with benzylsulfonyl chloride at -5 to 10°C, followed by quenching the reaction with water, extraction with ethyl acetate, and separation to obtain an ethyl acetate phase. A C4-C8 alkane solvent is added to the ethyl acetate phase, followed by crystallization at low temperature to obtain Intermediate I; Wherein, the molar ratio of 1-bromo-2-ethoxymethyl-4-hydroxymethylbenzene to benzylsulfonyl chloride is 1:1.2-2, preferably 1:1.2-1.6, more preferably 1:1.4-1.6; (II) intermediate I is subjected to a substitution reaction with intermediate II under alkaline conditions, an organic solvent is added to the reaction system for extraction, the organic phase is concentrated, washed with water, and then reacted with oxalic acid to form a salt to obtain intermediate III; The molar ratio of intermediate I, intermediate II and oxalic acid is 1:(1-1.5):(2-10), preferably 1:(1-1.2):(2.5-8), and more preferably 1:(1-1.1):(3-6); (III) coupling reaction of intermediate III with intermediate IV in the presence of a palladium catalyst and a base to obtain intermediate V; Wherein, the molar ratio of intermediate III to intermediate IV is 1:(1-1.5), preferably 1:(1-1.2), more preferably 1:(1-1.1); (IV) hydrolyzing the intermediate V under acidic conditions to obtain sparsentan;

Images