A method for synthesizing a tenapano hydrochloride intermediate

Abstract

This invention discloses a method for synthesizing a tenapano hydrochloride intermediate. The synthesis method includes the following steps: (1) condensing the compound 3-bromophenylacetaldehyde and the compound N-methyl-(2,4-dichlorophenyl)methylamine under dehydration conditions to obtain an enamine intermediate; (2) subjecting the enamine intermediate to an intramolecular cyclization reaction in the presence of an acid catalyst to obtain the tenapano hydrochloride intermediate 4-(3-bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline. The synthetic route provided by this invention requires only two steps to construct the key framework, and has the advantages of short reaction steps, high overall yield, and no need to use highly toxic liquid bromine. This process has high atom economy, reduces the emission of waste gas, wastewater, and solid waste, and is suitable for large-scale industrial production under mild conditions.

Description

Technical Field

[0001] This invention belongs to the field of chemical substance synthesis technology, specifically relating to a method for synthesizing a tenapano hydrochloride intermediate. Background Technology

[0002] Tenapanor, developed by the American pharmaceutical company Ardelyx, is an NHE3 receptor inhibitor. This drug lowers serum phosphorus by inhibiting phosphate uptake via the paracellular pathway. It can be used alone or in combination with existing phosphate binders to further synergistically lower phosphorus levels and improve constipation symptoms. It can be used to control hyperphosphatemia in adult patients with chronic kidney disease undergoing hemodialysis. Its chemical structure is as follows: .

[0003] 4-(3-Bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline is an important intermediate for tenapano hydrochloride. Its synthetic route is reported in patent WO2010078449A2 as follows: .

[0004] This synthetic route uses 3-bromoacetophenone as the starting material and synthesizes the target tetrahydroisoquinoline derivative through four steps: bromination, amination, reduction, and cyclization. This synthetic process has significant drawbacks for industrial application, mainly manifested in: low economic efficiency; severe dibromination side reactions in the first step of bromination, resulting in a yield of only 43%; and subsequent steps involving multiple recrystallizations and silica gel column chromatography, leading to poor overall yield and high purification costs, making large-scale production difficult; the strong acid cyclization followed by strong base neutralization generates large amounts of inorganic salt wastewater and environmental burden. Therefore, developing a synthetic method for the key intermediate 4 of tenapano, which uses readily available raw materials, has simple steps, mild conditions, and is easy to scale up, is of great significance for reducing pharmaceutical costs and improving product quality. Summary of the Invention

[0005] This invention addresses the technical problems of existing technologies, such as long synthetic routes, low yields, use of hazardous reagents, and high environmental impact. It provides a simple, mild, and environmentally friendly method for synthesizing the intermediate 4-(3-bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline of tenapano hydrochloride, which is achieved through the following technical solution: A method for synthesizing a tenapano hydrochloride intermediate, the synthetic route of which is as follows: ;

[0006] The specific synthesis steps are as follows: 1) Under dehydration conditions, the compound 3-bromophenylacetaldehyde shown in Formula 1 and the compound N-methyl-(2,4-dichlorophenyl)methylamine shown in Formula 2 were subjected to a condensation reaction to obtain the enamine intermediate N-methyl-N-((1E)-2-(3-bromophenyl)vinyl)-(2,4-dichlorophenyl)methylamine shown in Formula 3; 2) In the presence of an acid catalyst, the enamine intermediate 3 is subjected to an intramolecular cyclization reaction to obtain the tenapano hydrochloride intermediate 4-(3-bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline shown in Formula 4.

[0007] Furthermore, the dehydration conditions described in step 1) are selected from the use of a dehydrating agent or azeotropic dehydration.

[0008] Furthermore, the solvent used in the condensation reaction in step 1) is any one or a combination of more than one of dichloromethane, toluene, xylene, tetrahydrofuran, and acetonitrile.

[0009] Further, the dehydrating agent mentioned in step 1) is selected from one or more of anhydrous sodium sulfate, anhydrous magnesium sulfate, molecular sieve, and anhydrous calcium chloride.

[0010] Furthermore, the molecular sieve is a 3Å or 4Å molecular sieve.

[0011] Further, in step 2), the acid catalyst is a protic acid selected from one or more combinations of sulfuric acid, trifluoroacetic acid, methanesulfonic acid, and trifluoromethanesulfonic acid.

[0012] Furthermore, in step 2), the cyclization reaction is carried out under the catalysis of dichloromethane solvent and concentrated sulfuric acid, and the reaction temperature is controlled between -10℃ and 20℃.

[0013] This invention achieves efficient construction of the tetrahydroisoquinoline skeleton through an innovative two-step process. Compared to existing technologies, this process avoids the use of hazardous chemicals such as liquid bromine, significantly improving production safety and offering extremely high atom economy. By optimizing the acid dosage in the cyclization process, the pressure of inorganic salt waste and wastewater discharge from neutralization treatment is greatly reduced. The overall process features mild reaction conditions, excellent yields, and environmental friendliness, representing a highly efficient industrial synthesis route in line with the trend of green chemistry. Detailed Implementation

[0014] The present invention will be further described below with reference to specific embodiments in order to better understand the technical solution.

[0015] Preparation of intermediate 3 (N-methyl-N-((1E)-2-(3-bromophenyl)vinyl)-(2,4-dichlorophenyl)methylamine) Example

[0016] To a 500 mL three-necked flask equipped with a water separator and a reflux condenser, compound 1 (20.0 g, 100.5 mmol), compound 2 (19.1 g, 100.5 mmol), and 250 mL of toluene were added sequentially. Stirring was started, and the mixture was heated to 110-115 °C and refluxed, with water continuously removed through the water separator. The reaction was maintained at this temperature for 5 h until no significant water was expelled from the water separator and starting material 1 disappeared under TLC monitoring. The reaction solution was cooled to 50 °C, and toluene was removed by vacuum distillation to obtain a pale yellow oily substance 3 (33.8 g), which was used directly in the next step, with a yield of 90.7%.

[0017] Example 2 Under nitrogen protection, compound 1 (20.0 g, 100.5 mmol), compound 2 (21.0 g, 110.6 mmol), and 200 mL of dichloromethane were added to a 500 mL dry reaction flask. Then, 50 g of activated 4 Å molecular sieve was added. The reaction was stirred at 20–25 °C for 18 h. After the reaction was complete, the mixture was filtered through diatomaceous earth, and the filter cake was washed with dichloromethane (20 mL × 2). The filtrates were combined and concentrated to dryness under reduced pressure at 35 °C to obtain a pale yellow oily substance 3 (35.2 g), which was used directly in the next step, with a yield of 94.5%.

[0018] Example 3: Compound 1 (20.0 g, 100.5 mmol), compound 2 (19.1 g, 100.5 mmol), anhydrous magnesium sulfate (24.2 g, 201.0 mmol), and 250 mL of acetonitrile were added to a 500 mL reaction flask. The mixture was heated to 45–50 °C and stirred for 8 h. After the reaction mixture cooled to room temperature, it was filtered, and the filter cake was washed with acetonitrile. The filtrate was concentrated under reduced pressure at 45 °C to remove the solvent. 50 mL of isopropanol was added to the residue, and the mixture was stirred for 3 h, filtered, and dried to give a white solid 3 (24.9 g), with a yield of 66.9%.

[0019] Preparation of intermediate 4 (4-(3-bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline) Example

[0020] Add intermediate 3 (20.0 g, 53.9 mmol) and 200 mL of dichloromethane to a 500 mL three-necked flask and cool in a cold bath to -5 °C. Slowly add concentrated sulfuric acid (15.9 g, 161.7 mmol, 3.0 eq), keeping the internal temperature below 5 °C. After addition, raise the temperature to 15-20 °C and maintain the reaction for 6 h. Slowly pour the reaction solution into 200 g of crushed ice and stir for 20 min. Adjust the pH of the aqueous phase to 8-9 with 10% sodium hydroxide solution. Separate the liquids, washing the organic phase successively with saturated brine and drying it with anhydrous sodium sulfate. Filter, and concentrate the filtrate under reduced pressure to dryness to obtain yellow solid 4 (19.0 g), yield 95.0%.

[0021] Example 5 Intermediate 3 (20.0 g, 53.9 mmol) was added to a 250 mL reaction flask, and 100 mL of trifluoroacetic acid was added dropwise under ice bath conditions. After the addition was complete, the ice bath was removed, and the reaction mixture was stirred at 25-30 °C for 12 h. Most of the trifluoroacetic acid was recovered by vacuum distillation of the reaction solution. 150 mL of dichloromethane and 100 mL of purified water were added to the residue, and the pH was adjusted to neutral by adding sodium bicarbonate in portions. The mixture was separated, and the organic phase was decolorized with activated carbon, filtered, and concentrated. The residue was crystallized with a mixed solvent of n-heptane:ethyl acetate = 20:1 (v / v) to give a pale yellow solid 4 (13.6 g), with a yield of 68.0%.

[0022] Example 6 Intermediate 3 (20.0 g, 53.9 mmol) and 150 mL of dichloromethane were added to a 500 mL reaction flask. Methanesulfonic acid (10.4 g, 107.8 mmol, 2.0 eq) was added dropwise at 0-10 °C. After the addition was complete, the temperature was raised to 20-25 °C and the reaction was carried out for 10 h. 100 mL of purified water was added to the reaction mixture, and the mixture was stirred and separated. The organic phase was washed with 5% sodium carbonate solution until neutral. After concentrating the organic phase, it was crystallized with a mixed solvent of n-heptane:methyl tert-butyl ether = 10:1 (v / v) to give a pale yellow solid 4 (14.2 g), with a yield of 71.0%.

Claims

1. A process for the synthesis of an intermediate of Tenapanor hydrochloride characterized in that, The synthetic route for the tenapano hydrochloride intermediate is as follows: ； The specific synthesis steps are as follows: 1) Under dehydration conditions, the compound 3-bromophenylacetaldehyde shown in Formula 1 and the compound N-methyl-(2,4-dichlorophenyl)methylamine shown in Formula 2 were subjected to a condensation reaction to obtain the enamine intermediate N-methyl-N-((1E)-2-(3-bromophenyl)vinyl)-(2,4-dichlorophenyl)methylamine shown in Formula 3; 2) In the presence of an acid catalyst, the enamine intermediate 3 is subjected to an intramolecular cyclization reaction to obtain the tenapano hydrochloride intermediate 4-(3-bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline shown in Formula 4.

2. A process for the synthesis of a intermediate of Tenapanor hydrochloride as claimed in claim 1, wherein, The dehydration conditions described in step 1) are selected from using a dehydrating agent or azeotropic dehydration.

3. A process for the synthesis of a intermediate of Tenapanor hydrochloride as claimed in claim 1, wherein, The solvent used in the condensation reaction in step 1) is any one or a combination of more than one of dichloromethane, toluene, xylene, tetrahydrofuran, and acetonitrile.

4. The method for synthesizing a tenapano hydrochloride intermediate as described in claim 1, characterized in that, The dehydrating agent mentioned in step 1) is selected from one or more of anhydrous sodium sulfate, anhydrous magnesium sulfate, molecular sieve, and anhydrous calcium chloride.

5. The method for synthesizing a tenapano hydrochloride intermediate as described in claim 4, characterized in that, The molecular sieve is a 3Å or 4Å molecular sieve.

6. The method for synthesizing a tenapano hydrochloride intermediate as described in claim 1, characterized in that, In step 2), the acid catalyst is a protic acid selected from one or more combinations of sulfuric acid, trifluoroacetic acid, methanesulfonic acid, and trifluoromethanesulfonic acid.

7. The method for synthesizing a tenapano hydrochloride intermediate as described in claim 1, characterized in that, In step 2), the cyclization reaction is carried out under the catalysis of dichloromethane solvent and concentrated sulfuric acid, and the reaction temperature is controlled between -10℃ and 20℃.

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