Preparation method of Ternagnol intermediate

Abstract

The invention provides a preparation method of a Ternagnol intermediate. The method comprises the following steps: performing oxidative dehydrogenation on a compound as shown in a formula I in # imgabs0 # to obtain a compound as shown in a formula II; and carrying out catalytic reduction on the compound as shown in the formula II to obtain a target compound (S)-4-(3-bromophenyl)-6, 8-dichloro-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline as shown in a formula III. The method provided by the invention overcomes the defects of poor atom economy, complicated operation, difficulty in industrialization, high technical cost and the like in the existing resolution process, so that the preparation of the trinapanol intermediate is simpler and more convenient to operate, the raw materials are simple and easy to obtain, the cost is controllable, the industrialization is easier, and the product yield and the chiral purity are high.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis route design and raw material medicine and intermediate preparation, and particularly relates to a method for preparing an intermediate of Tenapanor, a new drug for treating constipation of irritable bowel syndrome. Background Art

[0002] Tenapanor is a new drug for the treatment of constipation-type irritable bowel syndrome (IBS-C). It was developed by Ardelyx Biopharmaceuticals in the United States and was approved by the FDA for marketing in September 2019. Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder syndrome, characterized by abdominal pain or abdominal discomfort, accompanied by changes in bowel habits and morphology such as constipation or diarrhea, and symptoms are mostly recurrent or chronic. The age of onset is mostly between 20 and 50 years old. The incidence rate in developed countries in Europe and the United States is 10% to 15%, and the incidence rate in the general population in my country is about 10%, mostly in young and middle-aged people, and the incidence rate in women is higher than that in men. In addition, nearly half of IBS patients also have upper gastrointestinal symptoms, such as stomach burning, nausea, vomiting, and extraintestinal symptoms such as back pain, headache, palpitations, frequent urination, urgency, sexual dysfunction, and heart and kidney diseases. There are also different degrees of psychological and mental abnormalities, such as anxiety, depression, tension, etc. According to the Bristol classification, IBS defecation habits and morphological changes such as constipation or diarrhea are mainly divided into diarrhea type (IBS-D), constipation type (IBS-C), mixed type (IBS-M) and undefined type (IBS-U). Constipation type irritable bowel syndrome (IBS-C) is a common gastrointestinal disease characterized by repeated abdominal pain and prolonged gastrointestinal transit. The pathogenesis of IBS-C has not been fully elucidated. Currently, the drugs used to treat IBS-C are mainly for relieving symptoms, and new targets are urgently needed. Tenapanor is an IBS sodium hydrogen exchanger-3 (NHE 3) inhibitor. By inhibiting the sodium / hydrogen exchange protein 3 (NHE3) molecule, it reduces the absorption of sodium in the small intestine and colon, promotes water secretion into the intestine, thereby promoting intestinal peristalsis, softening stool, and relieving abdominal pain, achieving the effect of treating constipation type irritable bowel syndrome. In addition, Fosun Pharma Holdings' subsidiary in my country is expanding its indications and conducting clinical trials for the treatment of hyperphosphatemia in patients with cardiorenal disease and dialysis.

[0003] Tenapanor (codenamed RDX5791, AZD1722) has a chemical name of 3-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-N-(26-(3-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacarbonyl)benzenesulfonamide; its molecular formula is C50 H 66 C l4 N8 10 S2, molecular weight is 1145.049, structural formula is as follows:

[0004]

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

[0006]

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

[0008]

[0009] The chiral separation using 4-(3-bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline has a low yield, poor atom economy, and the remaining by-products cannot be utilized.

[0010] Based on the above analysis, the present invention intends to design and synthesize an intermediate that can be used for the preparation of Tenapano. Through this synthetic route, the defects of the existing process technology such as high cost and poor atom economy are overcome, making the preparation of Tenapano intermediates simpler and more cost-controllable, and easier to industrialize. Summary of the invention

[0011] In order to overcome the defects of the prior art in the synthesis process of the tenapano intermediate (S)-4-(3-bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline, such as high cost and difficulty in industrialization, the present invention provides a preparation method of the tenapano intermediate as follows:

[0012]

[0013] In the compound represented by formula I, II or III, X is Br, F, Cl, I or NH2.

[0014] ① The compound represented by formula I is subjected to oxidative dehydrogenation to obtain the compound represented by formula II;

[0015] ② The compound represented by formula II is subjected to catalytic reduction to obtain the target compound represented by formula III (S)-4-(3-bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline.

[0016] As a specific implementation, in step ①, the dehydrogenation reagent is one or any combination of palladium acetate, 2-iodoacylbenzoic acid, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, tetrachlorobenzoquinone, and manganese dioxide.

[0017] As a specific implementation, in step ①, the ratio of the amount of the compound represented by formula I to the amount of the dehydrogenation reagent is 1.0:2.5-6.0.

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

[0019] As a specific implementation mode, in step ①, the reaction temperature is 20-110° C., and the reaction time is 2-24 h.

[0020] As a specific implementation manner, in step ②, the catalytic reduction reaction includes using a reduction catalyst and a ligand, wherein the reduction catalyst is one or any several of chiral rhodium (Rh), ruthenium (Ru) or iridium (Ir) acetate or fluoroborate; the ligand is (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, (S,S)-Et-DuPHOS.

[0021] As a specific implementation, in step ②, the ratio of the amount of the reduction catalyst to the ligand substance is 1.0:1.0-4.0, and / or the ratio of the amount of compound II to the catalyst substance is 1.0:0.1%-3.0%.

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

[0023] As a specific implementation, in step ②, the catalytic reduction reaction includes using a reaction solvent, and the reaction solvent is methanol, ethanol, isopropanol, toluene or water; further, the mass volume ratio of the compound II to the reaction solvent is 1.0:5-10.

[0024] As a specific implementation manner, 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, the reducing agent is hydrogen, 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 the prior splitting process such as poor atom economy, complex operation, difficulty in industrialization, and high technical cost, making the preparation of the Tenapano intermediate more convenient to operate, with simple and easy-to-obtain raw materials, controllable costs, easier to industrialize, and high product yield and chiral purity. DETAILED DESCRIPTION

[0026] The present invention is further described in detail below in conjunction with 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 without departing from the concept of the present invention are within the scope of protection of the present invention. The experimental methods in the embodiments of the present invention that do not specify specific conditions are usually conventional conditions, or according to the conditions recommended by the raw material or commodity manufacturer; reagents that do not specify the source are usually conventional reagents that can be purchased through commercial channels.

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

[0028] 20g (53.89mmol, 1.00eq.) of 4-(3-bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline was added to 200ml of dichloromethane and stirred to dissolve, and 14.68g (64.67mmol, 1.20eq.) of 2,3-dichloro-5,6-dicyanobenzoquinone was added at 20-30°C, and the mixture was kept warm for 4h. After the reaction was complete, the solid was removed by filtration, and 10% sodium sulfite was added dropwise to the filtrate to quench, the layers were separated, and the DCM phase was washed with water until neutral, the solvent was evaporated under reduced pressure, 100ml of water was added and stirred for 30min, and the mixture was filtered and dried to obtain 17.50g 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] 12g (36.74mmol, 1.00eq.) of 4-(3-chlorophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline was added to 200ml of dichloromethane and stirred to dissolve, and 10.84g (44.09mmol, 1.20eq.) of tetrachlorobenzoquinone was added at 20-30°C, and the reaction was kept warm for 3h. After the reaction was complete, the solid was removed by filtration, and the filtrate was quenched by adding 10% sodium sulfite dropwise, the layers were separated, and the DCM phase was washed with water until neutral, the solvent was evaporated under reduced pressure, 100ml of water was added and stirred for 30min, and the compound II was filtered and dried to obtain 10.88g, 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] 20g (53.89mmol, 1.00eq.) of 4-(3-bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline was added to 100ml of THF and stirred to dissolve. 14.68g (64.67mmol, 1.20eq.) of 2,3-dichloro-5,6-dicyanobenzoquinone was added at 20-30°C and the mixture was kept warm for 4h. After the reaction was complete, the solid was removed by filtration. 10% sodium sulfite was added dropwise to the filtrate to quench the reaction. THF was evaporated under reduced pressure and filtered to dryness to obtain 17.50g 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] 20g (53.89mmol, 1.00eq.) of 4-(3-bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline was added to 200ml of dichloromethane and stirred to dissolve. 9.37g (107.78mmol, 2.00eq.) of manganese dioxide was added at 20-30°C and the mixture was kept warm for 20h. The reaction was complete, the solid was removed by filtration, 10% sodium sulfite was added dropwise to the filtrate to quench, the layers were separated, the DCM phase was washed with water until neutral, the solvent was evaporated under reduced pressure, 100ml of water was added and stirred for 30min, and the compound II was obtained by filtration and drying to obtain 17.50g 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] Add 50 ml of isopropanol to 10 g of compound II in Example 1, stir, add 1.0% of rhodium acetate and 1.0% of (S,S)-(R,R)-PhTRAP, 0.52 g of cesium carbonate, replace with nitrogen 5 times, pass hydrogen to the pressure of 5.0 MPa, react for 24 hours, filter and evaporate to dryness to obtain 9.35 g 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] Add 50 ml of isopropanol to 10 g of compound II in Example 1, stir, add 1.0% ruthenium acetate and 1.0% (S)-BINAP, 0.44 g of DBU, replace with nitrogen 5 times, pass hydrogen to the pressure of 5.0 MPa, react for 24 hours, filter and evaporate to dryness to obtain 8.95 g 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] Add 50 ml of methanol to 10 g of compound II in Example 1, stir, add 1.0% of iridium acetate and 1.0% of (S,S)-Et-DuPHOS, 0.40 g of potassium carbonate, replace with nitrogen 5 times, pass hydrogen to the pressure of 5.0 MPa, react for 24 hours, filter and evaporate to dryness to obtain 9.46 g 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] Add 50 ml of toluene to 10 g of compound II in Example 1, stir, add 1.0% of rhodium acetate and 1.0% of (R,R)-DIOP, 0.31 g of diisopropylethylamine, replace with nitrogen 5 times, pass hydrogen to the pressure of 5.0 MPa, react for 8 h, filter and evaporate to dryness to obtain 9.06 g of the target compound with a yield of 90% and an ee value of 98.6%.

[0043] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example" or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, unless they are contradictory.

[0044] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims

1. A method for preparing a Tenapano intermediate, characterized in that: The method comprises the following steps: In the compound represented by formula I, II or III, X is Br, F, Cl, I or NH2, ① The compound represented by formula I is subjected to oxidative dehydrogenation to obtain the compound represented by formula II; ② The compound represented by formula II is subjected to catalytic reduction to obtain the target compound represented by formula III.

2. The method according to claim 1, characterized in that: In step ①, in the dehydrogenation reaction, the dehydrogenation reagent is one or a combination of any of palladium acetate, 2-iodoacylbenzoic acid, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, tetrachlorobenzoquinone, and manganese dioxide.

3. The method according to claim 1, characterized in that: In step ①, the ratio of the amount of the compound represented by formula I to the amount of the dehydrogenation reagent is 1.0:2.5-6.

0.

4. The method according to claim 1, characterized in that: In step ①, the solvent is one or any combination of 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.

5. The method according to claim 1, characterized in that: In step ①, the reaction temperature is 20-110° C. and the reaction time is 2-24 h.

6. The method according to claim 1, characterized in that: In step ②, the catalytic reduction reaction includes using a reduction catalyst and a ligand, wherein the reduction catalyst is one or any combination of chiral rhodium (Rh), ruthenium (Ru) or iridium (Ir) acetate or fluoroborate; and the ligand is one or any combination of (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.

7. The method according to claim 6, characterized in that: In step ②, the ratio of the amount of the reduction catalyst to the ligand substance is 1.0:1.0-4.0, and / or the ratio of the amount of compound II to the catalyst substance is 1.0:0.1%-3.0%.

8. The method according to claim 1, characterized in that: In step ②, the catalytic reduction includes the use of a base, wherein the base is one or any combination of cesium carbonate, potassium carbonate, potassium acetate, diisopropylethylamine, DBU, and triethylamine; and / or, the amount of the base added is 0.02 to 2.00 eq based on the amount of the compound II.

9. The method according to claim 1, characterized in that: In step ②, the catalytic reduction reaction includes using a reaction solvent, and the reaction solvent is methanol, ethanol, isopropanol, toluene or water; and / or, the mass volume ratio of the compound II to the reaction solvent is 1.0:5-10.

10. The method according to claim 1, characterized in that: 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, the reducing agent is hydrogen, and the required pressure is 0.1 MPa to 8.0 MPa.

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