Process for the preparation of a tenuiparo intermediate

Abstract

The application provides a preparation method of a Tenapanib intermediate. The method comprises the following steps: obtaining a compound shown in formula II by oxidizing and dehydrogenating a compound shown in formula I; and obtaining a target compound (S)-4-(3-bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline shown in formula III by catalytically reducing the compound shown in formula II. The method provided by the application overcomes the defects of the existing separation process, such as poor atom economy, complex operation, difficulty in industrialization, high technical cost and the like, so that the preparation of the Tenapanib intermediate is more simple in operation, simple in raw material, controllable in cost, easier in industrialization, and high in product yield and chiral purity.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis route design and preparation technology of active pharmaceutical ingredients and intermediates, and specifically relates to a method for preparing an intermediate of Tenapanor, a new drug for treating constipation in irritable bowel syndrome. Background Technology

[0002] Tenapanor is a new drug for the treatment of constipation-predominant irritable bowel syndrome (IBS-C), developed by Ardelyx Biopharmaceuticals in the United States, and approved by the FDA in September 2019. IBS is a common functional gastrointestinal disorder characterized by abdominal pain or discomfort, accompanied by changes in bowel habits and stool form, such as constipation or diarrhea. Symptoms are often recurrent or chronic. In addition, nearly half of IBS patients also experience upper gastrointestinal symptoms, such as heartburn, nausea, and vomiting, as well as extraintestinal symptoms such as back pain, headache, palpitations, urinary frequency, urgency, sexual dysfunction, and cardiovascular and renal diseases. There are also varying degrees of psychological and mental abnormalities, such as anxiety, depression, and tension. According to the Bristol classification, IBS, including constipation or diarrhea, is mainly divided into diarrhea-predominant (IBS-D), constipation-predominant (IBS-C), mixed (IBS-M), and unpredictable (IBS-U). Constipation-predominant irritable bowel syndrome (IBS-C) is a common gastrointestinal disorder characterized by recurrent abdominal pain and prolonged gastrointestinal transit. The pathogenesis of IBS-C is not fully understood, and current treatments primarily focus on symptom relief, highlighting the urgent need for new therapeutic targets. Tenapanor is an inhibitor of sodium-hydrogen exchanger-3 (NHE3) in IBS. By inhibiting the NHE3 molecule, it reduces sodium absorption in the small intestine and colon, promoting water secretion into the intestine, thereby stimulating intestinal peristalsis, softening stool, and relieving abdominal pain, thus achieving a therapeutic effect on constipation-predominant irritable bowel syndrome. Furthermore, a subsidiary of Fosun Pharma in my country is expanding its indications, conducting clinical trials for the treatment of hyperphosphatemia in dialysis patients with cardiovascular and renal diseases.

[0003] Tenapanor (code RDX5791, AZD1722) has the chemical name 3-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-N-(26-(3-(((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl)sulfonamide)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacarbonyl)benzenesulfonamide; its molecular formula is C 50 H 66 C l4 N8 O10 S2, with a molecular weight of 1145.049, has the following structural formula:

[0004]

[0005] One of the key intermediates, (S)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzenesulfonyl chloride, has the following structural formula:

[0006]

[0007] The synthesis of this intermediate was first disclosed in a method in patent WO2010078449 filed by Ardelyx in the United States:

[0008]

[0009] Chiral resolution using 4-(3-bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline resulted in low yields, poor atom economy, and unusable byproducts.

[0010] Based on the above analysis, this invention aims to design and synthesize an intermediate that can be used for the preparation of tranapano. This synthetic route overcomes the shortcomings of existing processes, such as high cost and poor atom economy, making the preparation of tranapano intermediates simpler, more cost-controllable, and easier to industrialize. Summary of the Invention

[0011] To overcome the shortcomings of existing technologies, such as high cost and difficulty in industrialization of the synthesis process of the terapano intermediate (S)-4-(3-bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline, the present invention provides a method for preparing the terapano intermediate, with the following reaction formula:

[0012]

[0013] In the compounds represented by formula I, II, or III, X is Br, F, Cl, I, or NH. 2。

[0014] ① The compound shown in Formula I is oxidatively dehydrogenated to obtain the compound shown in Formula II;

[0015] ② The compound shown in Formula II was catalytically reduced to obtain the target compound shown in Formula III, (S)-4-(3-bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline.

[0016] In one specific implementation, the dehydrogenating agent in step ① is one or any combination of palladium acetate, 2-iodobenzoic acid, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, tetrachlorobenzoquinone, and manganese dioxide.

[0017] In one specific implementation, in step ①, the molar ratio of the compound represented by Formula I to the dehydrogenation reagent is 1.0:2.5~6.0.

[0018] In one specific implementation, in step ①, the solvent is one or any combination of dichloromethane, tetrahydrofuran, chloroform, 1,2-dichloroethane, methyltetrahydrofuran, 1,4-dioxane, and toluene; furthermore, the mass-volume ratio of the compound represented by Formula I to the solvent is 1.0:5.0~20.

[0019] In one specific implementation method, in step ①, the reaction temperature is 20~110℃ and the reaction time is 2~24h.

[0020] In one specific implementation, step ② involves the use of a reduction catalyst and ligands. The reduction catalyst is one or more of the acetate or fluoroborate of chiral rhodium (Rh), ruthenium (Ru), or iridium (Ir); the ligands are (S,S)-(R,R)-PhTRAP, (R,R)-DIPAMP, (S,S)-CHIRAPHOS, (S,S)-NORPHOS, (R,R)-DIOP, (S)-BINAP, (S,S)-BPPM, (S)-BPPFA, (S,S)-SKEWPHOS, (S,S)-CYCPHOS, and (S,S)-Et-DuPHOS.

[0021] In one specific implementation, in step ②, the molar ratio of the reduction catalyst to the ligand is 1.0:1.0~4.0, and / or the molar ratio of compound II to the catalyst is 1.0:0.1%~3.0%.

[0022] As a specific implementation method, in step ②, the catalytic reduction includes the use of an alkali, wherein the alkali is one or any combination of cesium carbonate, potassium carbonate, potassium acetate, diisopropylethylamine, DBU, and triethylamine; further, the amount of alkali added is 0.02~2.00 eq based on the molar amount of compound II.

[0023] In one specific implementation, in step ②, the catalytic reduction reaction includes the use of a reaction solvent, which is methanol, ethanol, isopropanol, toluene, or water; furthermore, the mass-volume ratio of compound II to the reaction solvent is 1.0:5~10.

[0024] In one specific implementation, in step ②, the reaction temperature is 20°C to 120°C, and the reaction time is 1 to 48 hours; and / or, the catalytic reduction reaction includes the use of a reducing agent, wherein the reducing agent is hydrogen gas, and the required pressure is 0.1 MPa to 8.0 MPa.

[0025] Compared with the prior art, the beneficial effects of the present invention are: overcoming the defects of existing resolution processes such as poor atom economy, complex operation, difficulty in industrialization, and high technical cost, making the preparation of terapano intermediates simpler to operate, with simple and readily available raw materials, controllable cost, easier industrialization, and high product yield and chiral purity. Detailed Implementation

[0026] The present invention will be further described in detail below with reference to specific embodiments. The following embodiments are used to understand the methods and core ideas of the present invention. For those skilled in the art, any possible changes or substitutions made without departing from the concept of the present invention are within the protection scope of the present invention. Experimental methods in the embodiments of the present invention that do not specify specific conditions are generally under conventional conditions or according to the conditions recommended by the raw material or product manufacturer; reagents whose source is not specified are generally commercially available conventional reagents.

[0027] Example 1: Preparation of Compound II (4-(3-bromophenyl)-6,8-dichloro-2-methyl-1,2-dihydroisoquinoline)

[0028] 20 g (53.89 mmol, 1.00 eq.) of 4-(3-bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline was dissolved in 200 ml of dichloromethane with stirring. 14.68 g (64.67 mmol, 1.20 eq.) of 2,3-dichloro-5,6-dicyanobenzoquinone was added at 20–30 °C, and the reaction was maintained at this temperature for 4 h. After the reaction was complete, the solid was removed by filtration. The filtrate was quenched dropwise with 10% sodium sulfite, and the layers separated. The DCM phase was washed with water until neutral. The solvent was evaporated under reduced pressure, and 100 ml of water was added and stirred for 30 min. The mixture was filtered and dried to give 17.50 g of compound II, with a yield of 88% and a purity of 98.25%.

[0029] Example 2 Preparation of Compound II (4-(3-bromophenyl)-6,8-dichloro-2-methyl-1,2-dihydroisoquinoline)

[0030] 12 g (36.74 mmol, 1.00 eq.) of 4-(3-chlorophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline was dissolved in 200 mL of dichloromethane with stirring. 10.84 g (44.09 mmol, 1.20 eq.) of tetrachlorobenzoquinone was added at 20–30 °C, and the reaction was maintained at this temperature for 3 h. After the reaction was complete, the solid was removed by filtration. The filtrate was quenched dropwise with 10% sodium sulfite, and the layers separated. The DCM phase was washed with water until neutral. The solvent was evaporated under reduced pressure, and 100 mL of water was added and stirred for 30 min. The mixture was filtered and dried to obtain 10.88 g of compound II, with a yield of 91% and a purity of 98.05%.

[0031] Example 3 Preparation of Compound II (4-(3-bromophenyl)-6,8-dichloro-2-methyl-1,2-dihydroisoquinoline)

[0032] 20 g (53.89 mmol, 1.00 eq.) of 4-(3-bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline was dissolved in 100 ml of THF with stirring. 14.68 g (64.67 mmol, 1.20 eq.) of 2,3-dichloro-5,6-dicyanobenzoquinone was added at 20–30 °C, and the reaction was maintained at this temperature for 4 h. After the reaction was complete, the solid was removed by filtration. The filtrate was quenched dropwise with 10% sodium sulfite, and the THF was removed by vacuum distillation. The residue was filtered and dried to give 17.50 g of compound II, with a yield of 89% and a purity of 98.21%.

[0033] Example 4: Preparation of Compound II (4-(3-bromophenyl)-6,8-dichloro-2-methyl-1,2-dihydroisoquinoline)

[0034] 20 g (53.89 mmol, 1.00 eq.) of 4-(3-bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline was dissolved in 200 mL of dichloromethane by stirring. 9.37 g (107.78 mmol, 2.00 eq.) of manganese dioxide was added at 20–30 °C, and the reaction was maintained at this temperature for 20 h. After the reaction was complete, the solid was removed by filtration. The filtrate was quenched dropwise with 10% sodium sulfite, and the layers separated. The DCM phase was washed with water until neutral. The solvent was evaporated under reduced pressure, and 100 mL of water was added and stirred for 30 min. The mixture was filtered and dried to give 17.50 g of compound II, with a yield of 86% and a purity of 97.20%.

[0035] Example 5 Preparation of compound III (S)-4-(3-bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline

[0036] 10g of compound II from Example 1 was added to 50ml of isopropanol and stirred. Then, 1.0% rhodium acetate and 1.0% (S,S)-(R,R)-PhTRAP and 0.52g of cesium carbonate were added. The mixture was purged with nitrogen five times and hydrogen was introduced to a pressure of 5.0 MPa. The reaction was carried out for 24 hours. The mixture was filtered and evaporated to dryness to obtain 9.35g of the target compound, with a yield of 93% and an ee value of 98%.

[0037] Example 6 Preparation of compound III (S)-4-(3-bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline

[0038] 10g of compound II from Example 1 was added to 50ml of isopropanol and stirred. Then, 1.0% ruthenium acetate and 1.0% (S)-BINAP and 0.44g of DBU were added. The mixture was purged with nitrogen five times and hydrogen was introduced to a pressure of 5.0 MPa. The reaction was carried out for 24 hours and then filtered and evaporated to dryness to obtain 8.95g of the target compound, with a yield of 89% and an ee value of 97%.

[0039] Example 7 Preparation of Compound III (S)-4-(3-bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline

[0040] 10g of compound II from Example 1 was added to 50ml of methanol and stirred. Then, 1.0% iridium acetate and 1.0% (S,S)-Et-DuPHOS and 0.40g of potassium carbonate were added. The mixture was purged with nitrogen five times and hydrogen was introduced to a pressure of 5.0 MPa. The reaction was carried out for 24 hours. The mixture was filtered and evaporated to dryness to obtain 9.46g of the target compound, with a yield of 94% and an ee value of 98.2%.

[0041] Example 8 Preparation of compound III (S)-4-(3-bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline

[0042] 10g of compound II from Example 1 was added to 50ml of toluene, stirred, and then 1.0% rhodium acetate and 1.0% (R,R)-DIOP and 0.31g of diisopropylethylamine were added. The mixture was purged with nitrogen five times, and hydrogen was introduced to a pressure of 5.0 MPa. The reaction was carried out for 8 hours, filtered, and evaporated to dryness to obtain 9.06g of the target compound, with a yield of 90% and an ee value of 98.6%.

[0043] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0044] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

1. A method for preparing a teraphen intermediate, characterized in that: The method includes the following steps: ； In the compounds represented by formula I, II, or III, X is Br, F, Cl, I, or NH2. ①The compound shown in Formula I is oxidatively dehydrogenated in the presence of a dehydrogenating agent and a solvent to obtain the compound shown in Formula II; the dehydrogenating agent is one or any combination of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, tetrachlorobenzoquinone, and manganese dioxide; ② The compound represented by Formula II is catalytically reduced to the target compound represented by Formula III under the action of a reducing catalyst, a ligand, a base, a reaction solvent, and a reducing agent; the reducing catalyst is one or any of the following: a chiral rhodium (Rh), ruthenium (Ru), or iridium (Ir) acetate or fluoroborate; the ligand is (S,S)-(R,R)-PhTRAP, (S)-BINAP, (S,S)-Et-DuPHOS, or (R,R)-DIOP; the base is one or any of the following: cesium carbonate, potassium carbonate, potassium acetate, diisopropylethylamine, DBU, or triethylamine; and the reducing agent is hydrogen.

2. The method as described in claim 1, characterized in that: In step ①, the molar ratio of the compound represented by Formula I to the dehydrogenation reagent is 1.0:2.5~6.

0.

3. The method as described in claim 1, characterized in that: In step ①, the solvent is one or any of the following: dichloromethane, tetrahydrofuran, chloroform, 1,2-dichloroethane, methyltetrahydrofuran, 1,4-dioxane, and toluene; and / or the mass-volume ratio of the compound represented by Formula I to the solvent is 1.0:5.0~20.

4. The method as described in claim 1, characterized in that: In step ①, the reaction temperature is 20~110℃ and the reaction time is 2~24h.

5. The method as described in claim 1, characterized in that: In step ②, the molar ratio of the reduction catalyst to the ligand is 1.0:1.0~4.0, and / or the molar ratio of compound II to the catalyst is 1.0:0.1%~3.0%.

6. The method as described in claim 1, characterized in that: In step ②, the amount of alkali added is 0.02~2.00 eq based on the amount of substance of compound II.

7. The method as described in claim 1, characterized in that: In step ②, the mass-to-volume ratio of compound II to the reaction solvent is 1.0:5~10.

8. The method as described in claim 1, characterized in that: In step ②, the reaction temperature is 20℃ to 120℃, and the reaction time is 1 to 48 hours; and / or, the pressure required for the catalytic reduction reaction is 0.1 MPa to 8.0 MPa.

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