A process for the preparation of a sertraline intermediate

Abstract

This invention relates to a method for preparing sertraline intermediates, specifically [(1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthylamine]. The method improves reaction selectivity and suppresses the generation of over-hydrogenation impurities by adding sulfur compounds during hydrogenation. This method offers advantages such as high diastereoselectivity, simple post-processing, high atom economy, and high yield, making it suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of organic chemical synthesis, specifically relating to a method for preparing (1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthylamine. Background Technology

[0002] Sertraline hydrochloride is an antidepressant newly developed and marketed by Pfizer in the early 1990s. It is a relatively new selective serotonin reuptake inhibitor (SSRI) that helps improve the body's ability to effectively alleviate depressive symptoms, including irritability, and can also reduce persistent fatigue and anxiety. It is widely used internationally to treat depressive and obsessive-compulsive disorders. Sertraline is characterized by its long-lasting effect, low hepatotoxicity, rapid digestion, and suitability for elderly patients, making it one of the most promising SSRIs for treating depression and increasingly favored in clinical practice.

[0003] Sertraline hydrochloride is (1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthylamine hydrochloride, and its structure is shown in Formula I:

[0004]

[0005] According to literature reports, the current synthetic route for sertraline hydrochloride is as follows:

[0006]

[0007] This route uses the intermediate 4-(3,4-dichlorophenyl)-1-tetrahydronaphthone as a starting material. It involves addition and dehydration with methylamine to give 4-(3,4-dichlorophenyl)-3,4-dihydro-N-methyl-1-naphthylimine, followed by palladium-catalyzed hydrogenation to yield 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthylimine. Resolution into salts yields the product (1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthylimine hydrochloride. This route, using 4-(3,4-dichlorophenyl)-1-tetrahydronaphthone as a starting material, has a shorter reaction time and is currently the mainstream process.

[0008] IV has two chiral centers, which will produce four isomers, as shown below:

[0009] cis-enantiomers

[0010] trans-enantiomers

[0011] The ratio of cis-enantiomers (IV-1 and IV-2) to trans-enantiomers (IV-3 and IV-4) is called selectivity. In this route, the transition from 4-(3,4-dichlorophenyl)-3,4-dihydro-N-methyl-1-naphthylimine (III) to 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthylamine (IV) is often accompanied by the formation of three dechlorination impurities: 4-(4-chlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthylamine (Formula V-1), 4-(3-chlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthylamine (Formula V-2), and 4-phenyl-1,2,3,4-tetrahydro-N-methyl-1-naphthylamine (Formula V-3), with the structures shown below:

[0012]

[0013] The diastereoselectivity of hydrogenation and dechlorination impurities are challenges affecting the current process. Since both isomer impurities and dechlorination impurities are known impurities as defined in the pharmacopoeia, they require complex post-processing to remove. Summary of the Invention

[0014] The technical problem to be solved by this invention is to overcome the shortcomings of the prior art and provide a method for preparing sertraline intermediates. By adding sulfur compounds during the hydrogenation process, the reaction selectivity is improved and the generation of over-hydrogenation impurities is suppressed. This method has the advantages of high diastereoselectivity, simple post-processing, high atom economy, and high yield, making it suitable for industrial production.

[0015] A method for preparing sertraline intermediates, comprising the following steps:

[0016] a) The 4-(3,4-dichlorophenyl)-3,4-dihydro-N-methyl-1-naphthylimine of Formula III is dissolved in an organic solvent in the presence of the organic solvent;

[0017] b) Under positive pressure and in the presence of palladium on carbon, an additive is added, and hydrogen gas is passed through the above reaction mixture to obtain a hydrogenation reaction solution containing four isomers (cis-enantiomers (IV-1, IV-2), trans-enantiomers (IV-3, IV-4) and dechlorination impurities (V-1, V-2, V-3).

[0018] c) Separate the desired IV-1 from the hydrogenation reaction solution of step b).

[0019] Preferably, the organic solvent in step a) is tetrahydrofuran.

[0020] Preferably, in step a), the weight-to-volume ratio (g / ml) of formula III to the organic solvent is 1:8.

[0021] Preferably, the additive in step b) is selected from sodium sulfide, potassium sulfide, diphenyl sulfide or thiophenol.

[0022] As a further preferred option, the additive in step b) is diphenyl sulfide.

[0023] Preferably, the weight ratio of palladium on carbon in step b) to formula III in step a) is 0.036:1.

[0024] Preferably, the weight ratio of palladium on carbon to additives in step b) is 200:1.

[0025] Preferably, the splitting step in step c) is as follows:

[0026] 1) First, evaporate the organic solvent in the hydrogenated liquid obtained in b) to dryness;

[0027] 2) Then add 500ml of methanol and stir to dissolve. Then heat to 60±5℃, add 20g of D-(-)-mandelic acid and keep warm and stir to crystallize for 5 hours±30 minutes. Then cool to room temperature, keep warm and stir for 3 hours±30 minutes, and filter. Dry the filter cake at 70±5℃ for 12±1 hours to obtain the product.

[0028] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0029] 1) The use of sulfur compounds as additives in this invention can significantly improve reaction selectivity and reduce the generation of dechlorination impurities; at the same time, the additive diphenyl sulfide used in this invention is more stable in air, less hygroscopic, and easier to weigh.

[0030] 2) The additives of this invention have simple post-processing. The target product can be obtained by recrystallization after separation, which reduces the generation of waste solvent.

[0031] 3) The present invention adds sulfur compounds as additives during the hydrogenation process, which can significantly improve the stereoselectivity of the reaction and inhibit the generation of excessive hydrogenation dechlorination impurities, bringing significant economic benefits. Detailed Implementation

[0032] The present invention will be further described in conjunction with embodiments. The following embodiments are merely illustrative and not intended to limit the invention in any way. The selectivity in the following embodiments refers to the content ratio of the cis-enantiomer to the trans-enantiomer.

[0033] Selectivity calculation: cis-enantiomers (IV-1 and IV-2) / trans-enantiomers (IV-3 and IV-4)

[0034] Determination of dechlorination impurities: The detection method is GC, and the specific detection method is as follows:

[0035] 1. Chromatographic conditions

[0036] Gas chromatograph: The gas chromatograph is equipped with an FID detector.

[0037] Chromatographic column: DB-17 (30m*0.53mm, 1.0μm) or equivalent column.

[0038] Vaporization chamber temperature: 250℃

[0039] Detector temperature: 280℃

[0040] Column temperature: Hold at 200℃ for 10 min, then increase to 240℃ at a rate of 1℃ / min and hold for 30 min.

[0041] Column flow rate: 5.0 ml / min

[0042] Flow split ratio: 10:1

[0043] Injection volume: 1.0 μl

[0044] 2. Reagents and solutions

[0045] Dichloromethane (chromatographic grade)

[0046] 3. Solution preparation

[0047] Blank solution: dichloromethane

[0048] Test solution: Transfer 400 μl of sample solution into a 10 ml volumetric flask and dilute to the mark with dichloromethane.

[0049] 4. After the baseline stabilizes, inject one blank solution and one test solution, and record the chromatogram.

[0050] 5. Requirements

[0051] In the chromatograms obtained from the tests, after deducting the dichloromethane solvent peak, the relative retention times of the main peak cis isomers (IV-1 and IV-2) were 1.00 (RT approximately 26 min), the relative retention times of 4-(3,4-dichlorophenyl)-3,4-dihydro-N-methyl-1-naphthylimine were approximately 1.31, the relative retention times of 4-(4-chlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthylamine (V-1) were approximately 0.71, the relative retention times of 4-(3-chlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthylamine (V-2) were approximately 0.69, and the relative retention times of 4-phenyl-1,2,3,4-tetrahydro-N-methyl-1-naphthylamine (V-3) were approximately 0.48, calculated using the area normalization method.

[0052] Example 1

[0053] 25g of 4-(3,4-dichlorophenyl)-3,4-dihydro-N-methyl-1-naphthylimine and 200mL of tetrahydrofuran were added to a 500ml hydrogenation reactor, followed by 0.90g of palladium on carbon (palladium content 7%; carbon content 37.60%; water content 55.40%). The reaction was carried out at room temperature under a pressure of 0.3-0.4MPa until hydrogen absorption ceased. The data obtained are shown in Table 1.

[0054] Table 1

[0055] Serial Number Selective Dechlorination impurities 1 4.66 3.34％

[0056] Example 2

[0057] Add 25g of 4-(3,4-dichlorophenyl)-3,4-dihydro-N-methyl-1-naphthylimine and 200mL of tetrahydrofuran to a 500ml hydrogenation reactor, then add 0.90g of palladium on carbon (palladium content 7%; carbon content 37.60%; water content 55.40%), followed by 2mg of additive. React at room temperature under a pressure of 0.3-0.4MPa until hydrogen absorption ceases. The resulting data are shown in Table 2.

[0058] Table 2

[0059]

[0060]

[0061] Example 3

[0062] Add 25g of 4-(3,4-dichlorophenyl)-3,4-dihydro-N-methyl-1-naphthylimine and 200mL of tetrahydrofuran to a 500mL hydrogenation reactor. Add 0.90g of palladium on carbon (palladium content 7%; carbon content 37.60%; water content 55.40%), followed by 2mg of diphenyl sulfide. React at room temperature under a pressure of 0.3-0.4MPa until no hydrogen absorption occurs, yielding the hydrogenation reaction solution. Evaporate the tetrahydrofuran to dryness, add 500mL of methanol and stir until dissolved. Heat to 60±5℃, add 20g of D-(-)-mandelic acid and maintain the temperature for crystallization for 5 hours±30 minutes. Then cool to room temperature and maintain the temperature with stirring for 3 hours±30 minutes. Filter the solution. The filter cake was dried at 70±5℃ for 12±1 hours to obtain 12.80 g of (1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthylamine-mandelate, with a yield of 45.5%.

[0063] Example 4

[0064] Add 25g of 4-(3,4-dichlorophenyl)-3,4-dihydro-N-methyl-1-naphthylimine and 200mL of tetrahydrofuran to a 500mL hydrogenation reactor. Add 0.90g of palladium on carbon (palladium content 7%; carbon content 37.60%; water content 55.40%), followed by 2mg of potassium sulfide. React at room temperature under a pressure of 0.3-0.4MPa until no hydrogen absorption occurs, yielding a hydrogenation reaction solution. Evaporate the tetrahydrofuran to dryness, add 500mL of methanol and stir until dissolved. Heat to 60±5℃, add 20g of D-(-)-mandelic acid, and maintain the temperature for crystallization for 5 hours±30 minutes. Then cool to room temperature, maintain the temperature and stir for 3 hours±30 minutes, and filter. The filter cake was dried at 70±5℃ for 12±1 hours to obtain 11.84 g of (1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthylamine-mandelate, with a yield of 42.1%.

[0065] Example 5

[0066] Add 25g of 4-(3,4-dichlorophenyl)-3,4-dihydro-N-methyl-1-naphthylimine and 200mL of tetrahydrofuran to a 500mL hydrogenation reactor. Add 0.90g of palladium on carbon (palladium content 7%; carbon content 37.60%; water content 55.40%), followed by 2mg of sodium sulfide. React at room temperature under a pressure of 0.3-0.4MPa until no hydrogen absorption occurs, yielding a hydrogenation reaction solution. Evaporate the tetrahydrofuran to dryness, add 500mL of methanol and stir until dissolved. Heat to 60±5℃, add 20g of D-(-)-mandelic acid and maintain the temperature for crystallization for 5 hours±30 minutes. Then cool to room temperature and maintain the temperature with stirring for 3 hours±30 minutes. Filter the solution. The filter cake was dried at 70±5℃ for 12±1 hours to obtain 11.79 g of (1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthylamine-mandelate, with a yield of 41.9%.

[0067] Example 6

[0068] Add 25g of 4-(3,4-dichlorophenyl)-3,4-dihydro-N-methyl-1-naphthylimine and 200mL of tetrahydrofuran to a 500mL hydrogenation reactor. Add 0.90g of palladium on carbon (palladium content 7%; carbon content 37.60%; water content 55.40%), followed by 2mg of thiophenol. React at room temperature under a pressure of 0.3-0.4MPa until no hydrogen absorption occurs, yielding the hydrogenation reaction solution. Evaporate the tetrahydrofuran to dryness, add 500mL of methanol and stir until dissolved. Heat to 60±5℃, add 20g of D-(-)-mandelic acid and maintain the temperature for crystallization for 5 hours±30 minutes. Then cool to room temperature and maintain the temperature with stirring for 3 hours±30 minutes. Filter the solution. The filter cake was dried at 70±5℃ for 12±1 hours to obtain 11.06 g of (1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthylamine-mandelate, with a yield of 39.3%.

[0069] Example 7

[0070] Add 25g of 4-(3,4-dichlorophenyl)-3,4-dihydro-N-methyl-1-naphthylimine and 200mL of tetrahydrofuran to a 500mL hydrogenation reactor. Add 0.90g of palladium on carbon (palladium content 7%; carbon content 37.60%; water content 55.40%), followed by 2mg of potassium iodide. React at room temperature under a pressure of 0.3-0.4MPa until no hydrogen absorption occurs, yielding the hydrogenation reaction solution. Evaporate the tetrahydrofuran to dryness, add 500mL of methanol and stir until dissolved. Heat to 60±5℃, add 20g of D-(-)-mandelic acid and maintain the temperature for crystallization for 5 hours±30 minutes. Then cool to room temperature and maintain the temperature with stirring for 3 hours±30 minutes. Filter the solution. The filter cake was dried at 70±5℃ for 12±1 hours to obtain 10.5 g of (1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthylamine-mandelate, with a yield of 37.3%.

[0071] Example 8

[0072] Add 25g of 4-(3,4-dichlorophenyl)-3,4-dihydro-N-methyl-1-naphthylimine and 200mL of tetrahydrofuran to a 500mL hydrogenation reactor. Add 0.90g of palladium on carbon (palladium content 7%; carbon content 37.60%; water content 55.40%), followed by 2mg of sodium iodide. React at room temperature under a pressure of 0.3-0.4MPa until no hydrogen is absorbed, yielding the hydrogenation reaction solution. Evaporate the tetrahydrofuran to dryness, add 500mL of methanol and stir until dissolved. Heat to 60±5℃, add 20g of D-(-)-mandelic acid and maintain the temperature for crystallization for 5 hours±30 minutes. Then cool to room temperature and maintain the temperature with stirring for 3 hours±30 minutes. Filter the solution. The filter cake was dried at 70±5℃ for 12±1 hours to obtain 11.3 g of (1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthylamine-mandelate, with a yield of 40.2%.

Claims

1. A method for preparing sertraline, characterized in that... Includes the following steps: a) The compound of Formula III dissolves in an organic solvent in the presence of the organic solvent; b) Under positive pressure and in the presence of palladium on carbon, add the additive diphenyl sulfide, and pass hydrogen gas into the above reaction mixture to obtain a hydrogenation reaction solution containing four isomers: cis-enantiomers IV-1, IV-2, trans-enantiomers IV-3, and IV-4, and dechlorination impurities V-1, V-2, and V-3. c) Evaporate the organic solvent in the hydrogenation reaction solution from step b) to dryness, and resolve and separate it with D-(-)-mandelic acid to obtain the desired sertraline as shown in Formula IV-1. The structural formulas of Formula III, Formula IV-1, Formula IV-2, Formula IV-3, Formula IV-4, Formula V-1, Formula V-2, and Formula V-3 are shown below:

2. The method for preparing sertraline according to claim 1, characterized in that... The organic solvent in step a) is tetrahydrofuran.

3. The method for preparing sertraline according to claim 1, characterized in that... In step a), the weight-to-volume ratio of formula III to the organic solvent is 1:8 g / ml.

4. The method for preparing sertraline according to claim 1, characterized in that... The weight ratio of palladium on carbon in step b) to formula III in step a) is 0.036:

1.

5. The method for preparing sertraline according to claim 1, characterized in that... In step b), the weight ratio of palladium on carbon to additives is 200:

1.

6. The method for preparing sertraline according to claim 1, characterized in that... The splitting step in step c) is as follows: 1) First, evaporate the organic solvent in the hydrogenation reaction solution obtained in b) to dryness; 2) Then add 500ml of methanol and stir to dissolve. Then heat to 60±5℃, add 20g of D-(-)-mandelic acid and keep warm and stir to crystallize for 5 hours±30 minutes. Then cool to room temperature, keep warm and stir for 3 hours±30 minutes, and filter. Dry the filter cake at 70±5℃ for 12±1 hours to obtain the product.

Images