Preparation method of tamsulosin chiral amine

Abstract

The invention relates to tamsulosin, in particular to a tamsulosin chiral amine preparation method. According to the method, Fmoc-p-methoxy-L-phenylalanine which is low in cost and can be commercially purchased is used as a raw material, and the Fmoc-p-methoxy-L- The method comprises the following steps: 1) carrying out a reduction reaction on a compound A (Fmoc-p-methoxy-L-phenylalanine) and borane to obtain a compound B; 2) carrying out Appel reaction on the compound B to obtain a compound C; 3) performing hydrodehalogenation reaction on the compound C to obtain a compound D; the invention provides a preparation method of tamsulosin chiral amine, which comprises the following steps: (1) carrying out a sulfonation reaction on a compound D and chlorosulfonic acid, and reacting with ammonia water to obtain a compound E. (5) carrying out deprotection on the compound E to obtain a compound F (tamsulosin chiral amine). The preparation method of tamsulosin chiral amine is a brand new preparation method of tamsulosin chiral amine, and has the advantages of simple route, cheap and easily available raw materials, mild conditions and high reaction yield, and greatly reduces the production cost of tamsulosin.

Description

TECHNICAL FIELD

[0001] The present application relates to tamsulosin, in particular to a preparation method of tamsulosin chiral amine. BACKGROUND

[0002] Tamsulosin is a drug for treating benign prostatic hyperplasia (BPH), which is a selective alpha 1 adrenergic receptor blocker. Its main mechanism of action is to selectively block alpha 1A adrenergic receptors in the prostate, relax prostate smooth muscle, and thus improve symptoms such as dysuria caused by benign prostatic hyperplasia. It is the first high-selectivity alpha 1A adrenergic receptor antagonist for treating benign prostatic hyperplasia, developed by Yamanouchi Pharmaceutical Co., Ltd. of Japan, and marketed in Japan in 1993 under the trade name Harnal. It was marketed in China in 1996. 5-[2-[2-(2-ethoxyphenoxy)ethylamino]propyl]-2-methoxy-benzenesulfonamide, CAS Registry Number: 106133-20-4, structural formula as follows: Through the literature retrieval tool Reaxys and Scifingder, etc. Retrieval, in the prior art, the method for synthesizing tamsulosin usually needs to use expensive metal catalyst, and the reaction post-treatment is complex, resulting in high cost and low yield. The main synthesis route is: EP0380144 discloses that 5-propionyl-2-methoxybenzenesulfonamide is synthesized from p-methoxyphenylpropanone as a raw material, (R)-1-phenylethylamine is used as a chiral introducing agent, and hydrogenation is carried out under the condition of platinum dioxide to form a salt, and then debenzylization, free substitution to obtain tamsulosin free base.

[0003] This route uses expensive platinum catalyst due to the presence of catalytic toxic sulfur element, and the chiral construction of isomers is not single, and the corresponding isomer configuration exists, and the chiral purification process is complicated. The overall path cost is high.

[0004] WO2012101648 discloses the following route: This route synthesizes the target structure from p-methoxyphenylpropanone as a raw material in 4 steps, but the chiral isomers need to be separated, which increases the process difficulty, and high temperature and high pressure conditions are also required due to the presence of catalytic toxic sulfur element.

[0005] WO200563701 discloses the following route: This route uses low-cost amino acids as raw materials, and overcomes the problem of chiral structure, but the route is as long as 7 steps, involves Friedel-Crafts reaction, and the reaction has isomerism, which leads to difficult separation and significantly low overall yield.

[0006] CN117024315 discloses the following route: The amino acid derivative used in this route is not commonly used, and the chiral structure is constructed by Grignard reaction, which is significantly longer in steps, and the raw material is difficult to obtain, and the Grignard reaction has certain danger.

[0007] The reaction conditions in the above route are harsh, the danger coefficient is high, the chemical purity or optical purity of the obtained product is low, or the product quality is unstable, so it is necessary to develop a new process to solve the problems in the prior art. SUMMARY

[0008] One object of the present application is to overcome the problems of complex synthesis process, high cost, and impure product in the prior art, and to provide a preparation method of an intermediate of high optical purity of tamsulosin absolute chiral amine, which can be reacted in one step to generate tamsulosin. Compared with the prior art, the present application significantly reduces the production cost, simplifies the process, and has green and environmentally friendly reaction conditions, high safety factor, and important industrial application value.

[0009] The specific technical solutions are as follows: Comprising the following steps: S1: Synthesis of compound B Compound A is dissolved in a solvent, a reducing agent is added at-10-0℃, and the reaction is carried out at 10-30℃. The disappearance of the raw material is monitored, the reducing agent is quenched at-10-0℃, extracted, filtered and concentrated to remove the solvent, and compound B is obtained. S2: Synthesis of compound C Compound B is dissolved in an organic solvent, and iodine, triphenylphosphine and imidazole are added under nitrogen. The reaction is carried out at 10-30℃, and the disappearance of the raw material is monitored by TLC. The reaction is quenched, extracted, filtered and concentrated to remove the solvent, and compound C is obtained by slurry purification. S3: Synthesis of compound D Compound C is dissolved in an organic solvent, and a catalytic amount of palladium on carbon and a base are added. The reaction is carried out under hydrogen atmosphere at 10-30℃, and the disappearance of the raw material is monitored by TLC. The palladium on carbon is recovered by filtration, and the solvent is concentrated under vacuum to obtain compound D. S4: Synthesis of compound E Compound D is dissolved in dichloromethane, chlorosulfonic acid is added under nitrogen at -10-0 ℃, and the reaction is carried out at 10-30 ℃, and the disappearance of the raw material is monitored, the reaction is quenched at -10-0 ℃, and the solvent is removed by washing, drying, filtering and concentrating; the product after concentration is dissolved in acetonitrile, and ammonia water is added at -10-0 ℃, and the disappearance of the raw material is monitored, the reaction is quenched at -10-0 ℃, and the solvent is removed by washing, drying, filtering and concentrating; and the target compound E is obtained by purification. S5: Synthesis of compound F Compound E is dissolved in an organic solvent, a base is added and reacted at 10-30 ℃, and the disappearance of the raw material is monitored, and the solvent is removed by washing, drying, filtering and concentrating; and the target compound F, i.e. the chiral amine of tamsulosin, is obtained by purification.

[0010] The method is characterized in that the solvent used in step S1 is any one or several of tetrahydrofuran and 2-methyltetrahydrofuran; the reducing agent is any one or several of borane tetrahydrofuran, diisobutylaluminum hydride and lithium aluminum hydride; and the molar ratio of compound A to the borane tetrahydrofuran reducing agent is 1:1.5-1:2.

[0011] The method is characterized in that the organic solvent used in step S2 is any one or several of toluene and dichloromethane; the molar ratio of compound B to iodine to triphenylphosphine to imidazole is 1:1.1:1.2:2-1:2:2.5:5; and nitrogen protection is provided.

[0012] The method is characterized in that the organic solvent used in step S3 is any one or several of methanol, ethanol, isopropanol and tetrahydrofuran; the base is any one or several of triethylamine, ammonia water and N-methylmorpholine; the molar ratio of compound C to Pd / C to the base is 1:0.05:1-1:0.1:3; and the displacement gas is hydrogen.

[0013] The method is characterized in that the organic solvent used in step S4 is any one or several of acetonitrile, dichloromethane, 1,2-dichloroethane and tetrahydrofuran; the base is ammonia water; and the molar ratio of compound D to chlorosulfonic acid to ammonia water is 1:1:1-1:2:4.

[0014] The method is characterized in that the organic solvent used in step S5 is any one or several of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide and tetrahydrofuran; the base is any one or several of dimethylamine, piperidine and methylamine; and the molar ratio of compound E to the base is 1:0.5-1:2.

[0015] Advantages 1) A completely new synthetic route is adopted, low-cost Fmoc-p-methoxy-L-phenylalanine is used as the raw material, and the target product is obtained in 5 steps with a total yield of 48%. The operation is simple and easy to scale up, and the synthesized intermediate can synthesize tamsulosin in one step. 2) The key step of the present application is S3, i.e. synthesis of compound D, which innovatively uses amino acids to construct an absolutely chiral amine, and there is no report of application in the synthesis of tamsulosin. The raw material is cheap and easy to obtain, and the operation is simple and easy to implement. 3) Another advantage of the present application is that the reducing agent Pd / C is used for hydrogenation and dehalogenation, which has the advantages of convenient purification and recycling of palladium-carbon for repeated use, and is suitable for industrial production.

[0016] 4) The process of the present application is simple, the reaction conditions are green and environmentally friendly, the production safety factor is high, and it has important industrial application value, which is obviously superior to the routes reported in the literature. DETAILED DESCRIPTION

[0017] In order to make the purpose, technical scheme and advantages of the present application more clear and explicit, the following specific examples are used to further illustrate the present application. In the present application, the experimental methods are conventional methods unless otherwise specified. It should be understood that the specific examples described herein are used to explain the present application, and are not used to limit the present application.

[0018] The reaction progress of the present application can be monitored by conventional monitoring methods in the art (such as TLC, LCMS or NMR), and the disappearance of the raw material is generally used as the reaction endpoint.

[0019] Example 1 Example 1 of the present application provides a preparation method of compound B, and the route is as follows: Compound A (1000 g, 2.40mol) was dissolved in dry 2-THF (10L), and nitrogen was replaced. Borane (1M tetrahydrofuran solution, 3.59L, 3.59mol) was slowly added dropwise at -10-0°C. The reaction was allowed to warm to 10-30°C for 2h, and the disappearance of the raw material was monitored by TLC. The reaction was quenched by adding dilute hydrochloric acid (1M) under stirring at 0°C, and the layers were separated after standing. The aqueous phase was extracted with 2-methyltetrahydrofuran 5000mL*2, and the white solid was obtained after standing and drying, 869.0 g of compound B, yield: 90%, purity: 95%.

[0020] The compound B prepared in this example was identified, and the following results were obtained: ESI-MS (m / z): 403.18 Example 2 Example 2 of the present application provides a preparation method of compound B, and the route is as follows: Compound A (100 g, 239.81 mmol) was dissolved in dry 2-THF (1000 mL) and replaced with nitrogen. Borane (10 M dimethyl sulfide complex, 719 mL, 0.719 mol) was slowly added dropwise at 0 °C. The reaction was warmed to reflux for 4 h, and TLC was used to monitor the disappearance of the starting material. The reaction was cooled to 0 °C, and dilute hydrochloric acid (1 M) was added with stirring until the reaction was completely quenched. The layers were allowed to separate, and the aqueous phase was extracted with 2-methyltetrahydrofuran (500 mL x 2). The mixture was allowed to separate, and the organic phase was concentrated to give a white solid, 89.8 g of compound B, in a yield of 93% and a purity of 94%.

[0021] Compound B prepared in this example was identified, and the following results were obtained: ESI-MS (m / z): 403.18 Example 3 Example 3 of the present application provides a method for preparing compound C, as shown in the following route: Compound B (860 g, 2.13 mol) and toluene (8.6 L) were added to a 10 L three-necked flask, and nitrogen was bubbled through. Iodine (380 g, 2.99 mol) was added, followed by triphenylphosphine (840 g, 3.20 mol) and imidazole (435.0 g, 6.4 mol). The reaction was carried out at 10-30 °C for 1.5 h, and TLC showed that the starting material had completely reacted. The reaction mixture was poured into 10 L of water, and the mixture was separated. The aqueous phase was extracted with toluene (2500 mL x 2), and the combined organic phase was concentrated to give a white solid, 1040 g of compound C, in a yield of 95% and a purity of 96%.

[0022] Compound C prepared in this example was identified, and the following results were obtained: ESI-MS (m / z): 513.08 Example 4 Example 4 of the present application provides a method for preparing compound D, as shown in the following route: Compound C (1000 g, 1.95 mol) was dissolved in methanol (10 L), and triethylamine (394 g, 3.89 mol) was added. After replacement with nitrogen, Pd / C (10 g) was added, and the mixture was stirred under H2 at 10-30 °C for 5 h. TLC showed that the starting material had completely reacted. The reaction mixture was filtered, and the filtrate was concentrated to give a yellow oil, 640 g of compound C, in a yield of 85% and a purity of 93%.

[0023] The compound C obtained in this embodiment was identified, and the following results were obtained: ESI-MS (m / z): 387.18 Example 5 Example 5 of the present invention provides a method for preparing compound E, the route of which is as follows: Compound D (600 g, 1.55 mol) was dissolved in dichloromethane (6 L), purged with nitrogen, and cooled to 0 °C. Chlorosulfonic acid (360 g, 3.10 mol) was diluted with 5 L of dichloromethane and slowly added dropwise to the reaction mixture. The mixture was stirred at 0 °C for 1 h, then heated to 10-30 °C and stirred for 1 h. TLC showed that the starting material had reacted completely. The reaction mixture was slowly poured into 6 L of ice water, stirred, and allowed to stand for separation. The aqueous phase was washed with 5 L of dichloromethane. The organic phases were combined and concentrated. The crude product was dissolved in acetonitrile (3 L), and ammonia (600 mL) was slowly added dropwise at 0 °C. The mixture was allowed to rise naturally to 10-30 °C and reacted for 10 h. LCMS showed that the starting material had reacted completely. The solvent was concentrated at -10-0 °C, water (2 L) was added, and the mixture was slurried, filtered, and the filter cake was collected and dried to give 544 g of white solid, compound E. Yield: 76%, purity: 90%.

[0024] The compound E obtained in this embodiment was identified, and the following results were obtained: ESI-MS (m / z): 466.16 Example 6 Example 6 of the present invention provides a method for preparing compound F, the route of which is as follows: Compound E (400 g, 857 mmol) was dissolved in 2-THF (4000 mL). Dimethylamine solution (2.0 M inTHF, 850 mL, 1.71 mol) was added dropwise to the reaction mixture. The reaction was carried out at 10-30 °C for 2 h. LC-MS showed that the starting material had reacted completely. After concentration under reduced pressure, 600 mL of n-hexane was added and the mixture was stirred. The mixture was filtered, and the filter cake was dried to give 180 g of compound F. Yield: 87%, purity: 95%.

[0025] The compound F obtained in this embodiment was identified, and the following results were obtained: ESI-MS (m / z) 244.09 1 HNMR(400MHz,DMSO-d6).δ:7.53(1H,d, J =2.0Hz), 7.36(1H,dd, J =2.4,8.4Hz),7.11(1H,d, J= 8.4 Hz), 3.87 (3H, s), 3.34 (1H, s), 2.95 (2H, dd, J = 6.4, 12.8 Hz), 0.94 (3H, d, J = 6.4 Hz).

Claims

1. A process for the preparation of a chiral amine of tamsulosin, characterized in that, The following steps are taken: The following steps are taken: S1: Synthesis of compound B Compound A is dissolved in a solvent, a reducing agent is added at -10-0°C, and the reaction is carried out at 10-30°C until the starting material disappears. The reducing agent is quenched at -10-0°C, extracted, filtered, and the solvent is concentrated to obtain compound B. S2: Synthesis of compound C Compound B is dissolved in an organic solvent, and iodine, triphenylphosphine, and imidazole are added under nitrogen at -10-0°C. The reaction is carried out at 10-30°C until the starting material disappears, the reaction is quenched, extracted, and the solvent is concentrated to obtain compound C. S3: Synthesis of compound D Compound C is dissolved in an organic solvent, and a catalytic amount of palladium on carbon and a base are added. The reaction is carried out under a hydrogen atmosphere at 10-30°C until the starting material disappears. The palladium on carbon is recovered by filtration, and the solvent is concentrated under vacuum to obtain compound D. S4: Synthesis of compound E Compound D is dissolved in dichloromethane, and chlorosulfonic acid is added under nitrogen at -10-0°C. The reaction is carried out at 10-30°C until the starting material disappears. The reaction is quenched at -10-0°C, washed, dried, filtered, and the solvent is concentrated. The concentrated product is dissolved in acetonitrile, and ammonia is added at -10-0°C. The reaction is monitored until the starting material disappears, and the reaction is quenched at -10-0°C. The reaction is washed, dried, filtered, and the solvent is concentrated to obtain compound E. S5: Synthesis of compound F Compound E is dissolved in an organic solvent, and a base is added under nitrogen. The reaction is carried out at 10-30°C until the starting material disappears. The reaction is washed, filtered, and the solvent is concentrated to obtain compound F, which is a chiral amine of tamsulosin.

2. The method of claim 1, wherein, The solvent used in step S1 is any one or several of tetrahydrofuran, 2-methyltetrahydrofuran; the reducing agent is any one or several of borane, diisobutylaluminum hydride, lithium aluminum hydride; the molar ratio of compound A:reducing agent is 1:1.5-1:

2.

3. The method of claim 1, wherein, The organic solvent used in step S2 is any one or several of toluene, dichloromethane; the molar ratio of compound B:iodine:triphenylphosphine:imidazole is 1:1.1:1.2:2-1:2:2.5:5; nitrogen protection is used.

4. The method of claim 1, wherein, The organic solvent used in step S3 is any one or several of methanol, ethanol, isopropanol, tetrahydrofuran; the base is any one or several of triethylamine, ammonia, and N-methylmorpholine; the molar ratio of compound C:Pd / C:base is 1:0.05:1-1:0.1:3; the displacement gas is hydrogen.

5. The method of claim 1, wherein, The organic solvent used in step S4 is any one or several of acetonitrile, dichloromethane, 1,2-dichloroethane, and tetrahydrofuran; the base is ammonia; the molar ratio of compound D:chlorosulfonic acid:ammonia is 1:1:1-1:2:

4.

6. The method of claim 1, wherein, The organic solvent used in step S5 is any one or several of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, and tetrahydrofuran; the base is any one or several of dimethylamine, piperidine, and methylamine; the molar ratio of compound E:base is 1:0.5-1:2.

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