A process for the preparation of (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide

Abstract

The application belongs to the technical field of organic synthesis and specifically relates to a preparation method of (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide. The application mixes p-bromoanisole, magnesium, an initiator and an organic solvent to perform a first-stage Grignard reaction, mixes the obtained first-stage Grignard reaction liquid and a compound shown in formula 2 to perform a second-stage Grignard reaction, performs chlorosulfonation reaction on the obtained compound shown in formula 3 and chlorosulfonic acid, mixes the obtained chlorosulfonation reaction liquid and ammonia water to perform an amination reaction, performs reduction reaction on the obtained compound shown in formula 4 in a hydrogen atmosphere, and (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide is obtained. The preparation method provided by the application simplifies the operation process, has less waste, and has high yield in each step, and the obtained (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide product has high purity and is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for preparing (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide. Background Technology

[0002] Tamsulosin hydrochloride, chemically named R-(+)-5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-2-methoxybenzenesulfonamide hydrochloride, selectively acts on α1 receptors in the smooth muscle of the prostate and urethra, reducing urethral pressure with minimal side effects at therapeutic doses. It is suitable for treating urinary frequency and difficulty urinating caused by benign prostatic hyperplasia (BPH), with definite efficacy and low toxicity, making it the best clinical treatment for BPH. The structure of tamsulosin hydrochloride is as follows:

[0003]

[0004] In the preparation of tamsulosin hydrochloride, (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide is a key intermediate in the synthesis of tamsulosin hydrochloride, with the following structural formula:

[0005]

[0006] The synthesis of tamsulosin hydrochloride (Du Hongguang, Li Ming, et al. Chemical Reagents, 2007, 29(9), 541-543.) reports that (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide is mainly obtained from p-methoxyphenylacetone via chlorosulfonation, amination, carbonyl asymmetric reductive amination, and reductive debenzylation. The reaction route is as follows:

[0007]

[0008] The preparation process of the starting material p-methoxyphenylacetone used in the above synthetic route is reported in "Hasssynthesis of pyridine and related compounds" (Ferd W, Hoover, Henry B..J.Org.Chem., 1947, 12, 501-505.). Specifically, it uses p-methoxybenzaldehyde as the starting material, which is obtained by condensation with nitrobenzene, reduction with iron / hydrochloric acid, hydrolysis, and then steam distillation. The reaction route is as follows:

[0009]

[0010] The nitroethane used in this route is easily explosive, posing safety hazards for industrial production. Furthermore, the total yield is only 36%, and purification is required through steam distillation, resulting in a large amount of waste and making it unsuitable for industrial production.

[0011] The Pharmaceutical Journal (Vol. 63, Showa 18, 63, 376-80) reported a method for obtaining the product from 1-methoxy-4-(prop-1-en-1-yl)benzene via bromine addition, hydrolysis, epoxidation, and ring-opening oxidation. The reaction route is as follows:

[0012]

[0013] The epoxides prepared by the synthetic route reported in the aforementioned pharmaceutical journal require reaction at 180–220°C, which places high demands on equipment, and the literature does not report yields, making them unsuitable for industrial production.

[0014] The paper "Purifying and Stabilizing alkoxyphenyl-oropan-a-ons" (Haene, Randolf, Albert, Frank Michael., Ger(East)DD, 206, 77.) reports the preparation of alkoxyphenyl-a-ons from p-methoxybenzaldehyde via a dachin reaction with methyl 3-chloropropionic acid. The reaction route is as follows:

[0015]

[0016] The above route requires condensation under sodium methoxide conditions followed by hydrochloric acid hydrolysis for decarboxylation. The reaction conditions are complicated, purification is carried out by distillation, and the overall yield is only 65%, which is not suitable for industrial production.

[0017] In summary, the current synthetic route for (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide, calculated from the starting material p-methoxyphenylacetone, suffers from long synthetic routes and low yields, making it unsuitable for industrial production. Summary of the Invention

[0018] The purpose of this invention is to provide a method for preparing (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide. The preparation method provided by this invention simplifies the operation steps, produces less waste, has high yields in each step, and the resulting (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide product has high purity and is suitable for industrial production.

[0019] To achieve the above objectives, the present invention provides the following technical solution:

[0020] This invention provides a method for preparing (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide, comprising the following steps:

[0021] (1) A first-stage Grignard reaction is carried out by mixing p-bromoanisole, magnesium metal, initiator and organic solvent to obtain a first-stage Grignard reaction solution; the first-stage Grignard reaction solution contains a Grignard product with the structure shown in Formula 1; the first-stage Grignard reaction solution and a compound with the structure shown in Formula 2 are mixed to carry out a second-stage Grignard reaction to obtain a compound with the structure shown in Formula 3.

[0022]

[0023] (2) Chlorosulfonic acid and the compound with the structure shown in Formula 3 are mixed to carry out a chlorosulfonation reaction. The resulting chlorosulfonation reaction solution is mixed with ammonia water to carry out an ammoniation reaction, and the compound with the structure shown in Formula 4 is obtained.

[0024]

[0025] (3) In a hydrogen atmosphere, the compound with the structure shown in Formula 4, an organic solvent and a palladium catalyst are mixed and reduced to obtain (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide.

[0026] Preferably, the mass ratio of p-bromoanisole to metallic magnesium is 1:0.1 to 0.2; and the mass ratio of p-bromoanisole to the compound with the structure shown in Formula 2 is 1:1 to 2.

[0027] Preferably, the initiator is 1,2-dibromoethane and iodine; the mass ratio of 1,2-dibromoethane to iodine is 1:0.2 to 0.3; and the mass ratio of p-bromoanisole to the initiator is 1:0.004 to 0.005.

[0028] Preferably, in step (1), the first stage Grignard reaction includes the following steps: in a protective gas atmosphere, a portion of organic solvent, a portion of p-bromoanisole, magnesium metal and an initiator are mixed and pre-reacted to obtain a pre-reaction solution; the pre-reaction solution, the remaining p-bromoanisole and the remaining organic solvent are mixed and reacted under reflux to obtain a Grignard reaction solution; the mass ratio of the portion of p-bromoanisole to the remaining p-bromoanisole is 1:24; the temperature of the pre-reaction is 30-35°C and the holding time is 30-60 min.

[0029] Preferably, in step (1), after the second-stage reaction is completed, a second-stage reaction solution is obtained, which contains a first intermediate; the chemical structural formula of the first intermediate is:

[0030]

[0031] The reaction solution of the second stage is mixed with hydrochloric acid, and the mixture is separated to obtain an organic phase and an aqueous phase. The aqueous phase is extracted with a first organic solvent, and the extracted organic phase and the organic phase obtained from the separation are combined to obtain an organic phase product. The organic phase product contains a second intermediate, the chemical structural formula of which is:

[0032]

[0033] The organic phase product, trifluoroacetic acid, and triethylsilane were mixed and reacted to obtain a compound with the structure shown in Formula 3.

[0034] Preferably, the temperature of the second stage reaction is 0–70°C, and the time is 1–2 days.

[0035] Preferably, the mass ratio of the compound with the structure shown in Formula 3 to chlorosulfonic acid is 1:5 to 15; the temperatures of the chlorosulfonation reaction and the amination reaction are independently 0 to 80°C.

[0036] Preferably, after the ammoniation reaction, the ammoniation reaction solution is obtained, and the mixture is further subjected to aeration and crystallization after cooling the ammoniation reaction solution, followed by solid-liquid separation to obtain a compound with the structure shown in Formula 4; the aeration and crystallization temperature is 0-30°C and the time is 1-24h.

[0037] Preferably, the palladium catalyst is palladium on carbon, and the palladium content in the palladium on carbon is 5-10% by mass;

[0038] The mass ratio of the compound with the structure shown in Formula 4 to the palladium catalyst is 1:0.01 to 0.5.

[0039] Preferably, the pressure of the hydrogen gas is 0.01 to 2 MPa.

[0040] This invention provides a method for preparing (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide, comprising the following steps: (1) mixing p-bromoanisole, magnesium metal, an initiator, and an organic solvent to carry out a first-stage Grignard reaction to obtain a first-stage Grignard reaction solution; the first-stage Grignard reaction solution contains a Grignard product with the structure shown in Formula 1; mixing the first-stage Grignard reaction solution and a compound with the structure shown in Formula 2 to carry out a second-stage Grignard reaction to obtain a compound with the structure shown in Formula 3; (2) mixing chlorosulfonic acid and a compound with the structure shown in Formula 3 to carry out a chlorosulfonation reaction, and mixing the obtained chlorosulfonation reaction solution with ammonia water to carry out an ammoniation reaction to obtain a compound with the structure shown in Formula 4; (3) in a hydrogen atmosphere, mixing the compound with the structure shown in Formula 4, an organic solvent, and a palladium catalyst to carry out a reduction reaction to obtain (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide. This invention uses a compound with the structure shown in Formula 2 as a reactant. A chiral center is constructed through a one-step reaction with the product of Formula 1, improving atom utilization. Then, chlorosulfonic acid is used as a raw material for a one-step chlorosulfonation and amination reaction. The resulting product is finally reduced to remove the protecting group, yielding (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide. The preparation method provided by this invention simplifies the operation process, reduces waste, and achieves high yields in each step. The obtained (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide product has high purity and is suitable for industrial production. Attached Figure Description

[0041] Figure 1 A flowchart illustrating the preparation process of (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide provided in this embodiment of the invention;

[0042] Figure 2 This is a mechanism diagram of the reaction in the embodiments of the present invention;

[0043] Figure 3 The NMR spectrum of the (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide product prepared in this invention;

[0044] Figure 4 The HPLC chromatogram of the (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide product prepared in this invention;

[0045] Figure 5 The image shows the chiral purity test result of the (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide product prepared in this invention. Detailed Implementation

[0046] This invention provides a method for preparing (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide, comprising the following steps:

[0047] (1) A first-stage Grignard reaction is carried out by mixing p-bromoanisole, magnesium metal, initiator and organic solvent to obtain a first-stage Grignard reaction solution; the first-stage Grignard reaction solution contains a Grignard product with the structure shown in Formula 1; the first-stage Grignard reaction solution and a compound with the structure shown in Formula 2 are mixed to carry out a second-stage Grignard reaction to obtain a compound with the structure shown in Formula 3.

[0048]

[0049] (2) Chlorosulfonic acid and the compound with the structure shown in Formula 3 are mixed to carry out a chlorosulfonation reaction. The resulting chlorosulfonation reaction solution is mixed with ammonia water to carry out an ammoniation reaction, and the compound with the structure shown in Formula 4 is obtained.

[0050]

[0051] (3) In a hydrogen atmosphere, the compound with the structure shown in Formula 4, an organic solvent and a palladium catalyst are mixed and reduced to obtain (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide.

[0052] In this invention, unless otherwise specified, all raw materials / components used in the preparation are commercially available products well known to those skilled in the art.

[0053] This invention involves mixing bromoanisole, magnesium metal, an initiator, and an organic solvent to conduct a first-stage Grignard reaction to obtain a first-stage Grignard reaction solution; the first-stage Grignard reaction solution contains a Grignard product with the structure shown in Formula 1; the first-stage Grignard reaction solution is then mixed with a compound with the structure shown in Formula 2 to conduct a second-stage Grignard reaction to obtain a compound with the structure shown in Formula 3.

[0054]

[0055] In this invention, the initiator is preferably 1,2-dibromoethane and iodine. The first organic solvent preferably includes one or more of tetrahydrofuran, methyltetrahydrofuran, and diethyl ether. The mass ratio of p-bromoanisole to magnesium is preferably 1:0.1-0.2, more preferably 1:0.12-0.17. The mass ratio of p-bromoanisole to the initiator is preferably 1:0.004-0.005, more preferably 1:0.0048. The mass ratio of 1,2-dibromoethane to iodine is preferably 1:0.2-0.3, more preferably 1:0.2. The mass ratio of p-bromoanisole to the compound with the structure shown in Formula 2 is preferably 1:1-2, more preferably 1:1.2-1.5, and most preferably 1:1.328. This invention does not have special requirements for the amount of the first organic solvent; it is sufficient to ensure the smooth progress of the reaction.

[0056] In this invention, the first stage Grignard reaction preferably includes the following steps: Pre-reaction is carried out by mixing a portion of a first organic solvent, a portion of p-bromoanisole, magnesium metal, and an initiator in a protective gas atmosphere to obtain a pre-reaction liquid; the pre-reaction liquid, the remaining p-bromoanisole, and the remaining first organic solvent are mixed, and the reaction is continued under reflux to obtain a Grignard reaction liquid. In this invention, the protective gas is preferably nitrogen. The volume ratio of the first organic solvent to the remaining first organic solvent is preferably 1:1. The mass ratio of the portion of p-bromoanisole to the remaining p-bromoanisole is 1:24. The temperature of the pre-reaction is preferably 30–35°C, more preferably 35°C; the holding time is preferably 30–60 min, more preferably 30 min. In this invention, the mixing of the pre-reaction liquid, the remaining p-bromoanisole, and the remaining first organic solvent is preferably carried out by: dissolving the remaining p-bromoanisole in the remaining first organic solvent to obtain a remaining p-bromoanisole solution; and adding the remaining p-bromoanisole solution dropwise to the pre-reaction liquid. The continued reaction is carried out under stirring conditions, and the stirring time is preferably 4 hours.

[0057] After obtaining the first-stage Grignard reaction solution, the present invention preferably cools the first-stage Grignard reaction solution to 0-5°C, and then mixes it with the compound with the structure shown in Formula 2 to carry out the second-stage Grignard reaction, so as to obtain the compound with the structure shown in Formula 3. Figure 2 This is a schematic diagram of the Grignard reaction mechanism in this invention. The intermediate obtained from the second-stage Grignard reaction does not need to be separated. In this invention, the compound with the structure shown in Formula 2 is preferably used in the form of an organic solution of the compound with the structure shown in Formula 2, wherein the organic solvent in the organic solution of the compound with the structure shown in Formula 2 is the first organic solvent. When the cooled first-stage Grignard reaction solution is mixed with the compound with the structure shown in Formula 2, this invention preferably adds the organic solution of the compound with the structure shown in Formula 2 dropwise to the first-stage Grignard reaction solution. The temperature of the second-stage Grignard reaction is preferably 0–70°C, more preferably 20–50°C, more preferably 25–35°C, and even more preferably 25–30°C; the time is preferably 1–2 days, more preferably 2 days. The second-stage Grignard reaction is carried out under stirring conditions.

[0058] In this invention, after the second-stage Grignard reaction is completed, a second-stage Grignard reaction solution is obtained, which contains a first intermediate; the chemical structural formula of the first intermediate is:

[0059]

[0060] After the second-stage Grignard reaction is completed, the present invention preferably adds the obtained second-stage Grignard reaction solution dropwise into hydrochloric acid and stirs to mix, then separates the liquid to obtain an organic phase and an aqueous phase; the aqueous phase is extracted with a first organic solvent, and the extracted organic phase and the separated organic phase are combined to obtain an organic phase product. In the present invention, the organic phase product contains a second intermediate, the chemical structural formula of which is:

[0061]

[0062] The organic phase product is subjected to a first drying and a first solid-liquid separation. The resulting liquid product is concentrated to dryness to obtain a first solid product. The first solid product is mixed with trifluoroacetic acid (TFA) and cooled to 0-5°C, preferably 5°C. Triethylsilane is then added dropwise to the mixture and the temperature is raised to 15-35°C, preferably 25°C, for reaction. The resulting reaction solution is concentrated to dryness under reduced pressure to obtain a second solid product. The second solid product is mixed with cyclohexane and subjected to a second solid-liquid separation. The resulting solid product is dried a second time to obtain a compound with the structure shown in Formula 3. The mass content of the hydrochloric acid is preferably 10%, the mass ratio of p-bromoanisole to the volume of hydrochloric acid is preferably 2.5 kg: 20 L, and the stirring time is preferably 1-3 h. The reagent used for the first drying is preferably anhydrous sodium sulfate. The first solid-liquid separation is preferably performed by filtration. The mass ratio of p-bromoanisole to trifluoroacetic acid is preferably 1:4-5.5, more preferably 1:4.5-5, and most preferably 1:4.8. The mass ratio of p-bromoanisole to triethylsilane is preferably 1:1 to 2.5, more preferably 1:1.2 to 2, and most preferably 1:1.4. The reaction time is preferably 1 to 3 hours, more preferably 2 hours. The stirring and mixing temperature is room temperature, and the time is 2 hours. The second solid-liquid separation is preferably performed by vacuum filtration.

[0063] After obtaining the compound with the structure shown in Formula 3, the present invention mixes chlorosulfonic acid and the compound with the structure shown in Formula 3 to carry out a chlorosulfonation reaction. The resulting chlorosulfonation reaction solution is mixed with ammonia water to carry out an ammoniation reaction to obtain the compound with the structure shown in Formula 4.

[0064] In this invention, the mass ratio of the compound with the structure shown in Formula 3 to chlorosulfonic acid is preferably 1:5 to 15, more preferably 1:6 to 12, and even more preferably 1:10. When the chlorosulfonic acid and the compound with the structure shown in Formula 3 are mixed: the compound with the structure shown in Formula 3 is preferably mixed in batches, the mixing temperature is preferably ≤15°C, the mixing is carried out under stirring conditions, and the stirring time is 5 minutes. The temperature of the chlorosulfonation reaction is preferably 0 to 80°C, more preferably 30 to 70°C, and even more preferably 40 to 60°C; the time is preferably 1 to 2 hours, more preferably 1 hour. In this invention, the chlorosulfonation reaction solution obtained from the chlorosulfonation reaction is preferably post-treated before being mixed with ammonia. In this invention, the post-treatment preferably includes: adding the chlorosulfonation reaction solution dropwise to crushed ice, and then adjusting the pH value to 7 to 8 with a pH adjuster. The pH adjuster is preferably first ammonia solution, and this invention does not have special requirements regarding the concentration of the first ammonia solution used to adjust the pH value.

[0065] In this invention, the mass concentration of the ammonia water is preferably 25-28 wt%. The ammonia water is industrial ammonia water. The mass ratio of the compound with the structure shown in Formula 3 to the ammonia water is preferably 1:4. The temperature of the ammoniation reaction is preferably 0-80°C, more preferably 20-50°C, and even more preferably 25-40°C; the time is preferably 1-2 hours, more preferably 1 hour.

[0066] In this invention, after the ammoniation reaction, an ammoniation reaction solution is obtained. The invention further includes cooling the ammoniation reaction solution and then maintaining it at a specific temperature for crystallization. After solid-liquid separation, a compound with the structure shown in Formula 4 is obtained. The preferred temperature for the crystallization is 0–30°C, more preferably 0–5°C; the preferred time is 1–24 h, more preferably 12 h. The crystallization is carried out under stirring conditions. After the crystallization is completed, the invention preferably involves solid-liquid separation of the obtained crystallization solution, and the resulting solid product is dried to obtain a compound with the structure shown in Formula 4. The solid-liquid separation is preferably performed by vacuum filtration.

[0067] After obtaining the compound with the structure shown in Formula 4, the present invention carries out a reduction reaction by mixing the compound with the structure shown in Formula 4, an organic solvent (hereinafter referred to as the second organic solvent) and a palladium catalyst in a hydrogen atmosphere to obtain (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide.

[0068] In this invention, the second organic solvent is preferably one or more of methanol, ethanol, isopropanol, and n-butanol, more preferably ethanol. The palladium catalyst is preferably palladium on carbon, and the mass content of palladium on the palladium on carbon is preferably 5-10%, more preferably 5%. The mass ratio of the compound with the structure shown in Formula 4 to the palladium catalyst is preferably 1:0.01-0.5, more preferably 1:0.02-0.1. This invention does not have special requirements on the amount of the second organic solvent used, as long as the reaction proceeds smoothly.

[0069] In this invention, the pressure of the hydrogen gas is preferably 0.01–2 MPa, more preferably 0.1–0.5 MPa. The temperature of the reduction reaction is preferably room temperature, and the time is preferably 2–3 hours, more preferably 2.5 hours.

[0070] Following the reduction reaction, the present invention preferably involves solid-liquid separation of the resulting reduction reaction solution, and the resulting liquid product is tested and concentrated to dryness to obtain (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide. In the present invention, the solid-liquid separation is preferably performed by filtration.

[0071] To further illustrate the present invention, the technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0072] The following embodiments are in accordance with Figure 1 The preparation process is carried out. Figure 1 SM-1 is p-bromoanisole; SM-2 is a compound with the structure shown in Formula 2, chemically named (S)-4-methyl-5-oxooxazolidine-3-carboxylic acid benzyl ester; TX-1 is a compound with the structure shown in Formula 1, chemically named (4-methoxyphenyl)magnesium bromide; TX-2 is a compound with the structure shown in Formula 3, chemically named (R)-(1-(4-methoxyphenyl)prop-2-yl)carbamate benzyl ester; TX-3 is a compound with the structure shown in Formula 4, chemically named (R)-(1-(4-methoxy-3-aminosulfonylphenyl)prop-2-yl)carbamate benzyl ester; and TX-4 is (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide.

[0073] Example 1

[0074] Add 10 L of tetrahydrofuran to a 50 L reactor. Under nitrogen protection, add 100 g of p-bromoanisole, 387 g of magnesium, 10 g of 1,2-dibromoethane, and 2 g of iodine. Heat to 35 °C and maintain the temperature for 30 minutes until the color disappears. Add 2.4 kg of p-bromoanisole in 10 L of tetrahydrofuran solution dropwise. After the addition is complete, reflux and stir for 4 hours. Cool to 0 °C and add 3.32 kg of (S)-4-methyl-5-oxooxazolidine-3-carboxylic acid benzyl ester in 10 L of tetrahydrofuran solution dropwise. After the addition is complete, heat to 28 °C and stir for 2 days. Add the reaction solution dropwise to 20 L of 10% hydrochloric acid and maintain the temperature and stir for 3 hours. Separate the layers. Extract the aqueous layer once with 10 L of tetrahydrofuran and combine the two layers with the organic layer. Dry the mixture with anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness under reduced pressure. Add TFA. 12 kg of cyclohexane was added, cooled to 5°C, and 3.5 kg of triethylsilane was added dropwise. After the addition was complete, the temperature was raised to 25°C and reacted for 2 hours. The mixture was concentrated to dryness under reduced pressure, 10 L of cyclohexane was added, and the mixture was stirred at room temperature for 2 hours. The mixture was filtered, and the resulting solid product was dried to obtain an off-white solid TX-23.54 kg, with a yield of 88.1%.

[0075] 30 kg of chlorosulfonic acid was added to a 50 L reactor, followed by 3 kg of TX-2 in batches, with the temperature controlled at 15 °C. After the addition was complete, the mixture was stirred for 5 minutes, and then heated to 50 °C for 1 hour. The mixture was then cooled to 25 °C and added dropwise to 75 kg of crushed ice. After the addition was complete, the pH was adjusted to 7–8 with ammonia water, and 12 kg of industrial ammonia water (25 wt%) was added. The mixture was kept at 25 °C for 1 hour, then cooled to 0–5 °C and stirred for 12 hours. The mixture was then filtered, and the resulting solid product was dried to obtain 33.5 kg of off-white solid TX-3, with a yield of 92.3%.

[0076] In a 5L high-pressure reactor, 3L of ethanol, 3kg of TX-3, 60g of 5% palladium on carbon, and hydrogen pressure of 0.2MPa were added. The reaction was carried out at room temperature for 2.5 hours. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 1.84kg of white solid TX-4, with a yield of 94.8%.

[0077] The NMR spectrum of the product TX-4 prepared in this embodiment is as follows: Figure 3 The NMR data are shown below: 1 H-NMR(500MHz,DMSO-d6)δ:7.55(1H,d),7.38(1H,m),7.12(1H,d),3.87(3H,s),2.97(1H,m),2.55(2H,m),0.94(3H,d).

[0078] The HPLC chromatogram of the product TX-4 prepared in this embodiment is as follows: Figure 4 As shown. By Figure 4 It can be seen that the purity of the (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide product prepared in this embodiment is 99.881%.

[0079] The chiral purity of the product TX-4 prepared in this embodiment was determined by [reference needed]. Figure 5 .Depend on Figure 5 It can be seen that the chiral purity of the product prepared in this embodiment is 100%.

[0080] As can be seen from Example 1, the present invention uses an amino acid derivative one-step method to construct chiral centers, which improves the atom utilization rate; the one-step method for chlorosulfonation and amination reactions reduces waste, increases reaction yield, and the obtained key intermediate TX-4 has high purity, making it suitable for industrial production.

[0081] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, and not all embodiments. Other embodiments can be obtained based on these embodiments without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A method for preparing (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide, characterized in that, Includes the following steps: In a 50L reactor, add 10L of tetrahydrofuran. Under nitrogen protection, add 100g of p-bromoanisole, 387g of magnesium, 10g of 1,2-dibromoethane, and 2g of iodine. Heat to 35℃ and maintain this temperature for 30 minutes until the color disappears. Add 2.4kg of p-bromoanisole in 10L of tetrahydrofuran solution dropwise. After the addition is complete, reflux and stir for 4 hours. Cool to 0℃ and add 3.32kg of (S)-4-methyl-5-oxooxazolidine-3-carboxylic acid benzyl ester in 10L of tetrahydrofuran solution dropwise. After the addition is complete, raise the temperature to 28℃ and stir for 2 days. Add the reaction solution dropwise to 20L. In hydrochloric acid, the mixture was stirred at a constant temperature for 3 hours, separated, and the aqueous layer was extracted once with 10 L of tetrahydrofuran. The extracts were combined with the organic layer, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. 12 kg of trifluoroacetic acid was added, the temperature was lowered to 5 °C, and 3.5 kg of triethylsilane was added dropwise. After the addition was complete, the temperature was raised to 25 °C and the reaction was carried out for 2 hours. The mixture was concentrated to dryness under reduced pressure, 10 L of cyclohexane was added, and the mixture was stirred at room temperature for 2 hours. The mixture was filtered, and the resulting solid product was dried to give 3.54 kg of (R)-(1-(4-methoxyphenyl)propyl-2-yl)carbamate, a white solid with a yield of 88.1%. 30 kg of chlorosulfonic acid was added to a 50 L reactor, followed by 3 kg of (R)-(1-(4-methoxyphenyl)prop-2-yl)carbamate benzyl ester in portions. The temperature was controlled at 15 °C. After the addition was complete, the mixture was stirred for 5 minutes. The temperature was then raised to 50 °C and reacted for 1 hour. The temperature was lowered to 25 °C and the mixture was added dropwise to 75 kg of crushed ice. After the addition was complete, the pH was adjusted to 7-8 with ammonia water. 12 kg of industrial ammonia water with a mass content of 25 wt% was added. The mixture was kept at 25 °C for 1 hour and then cooled to 0-5 °C. The mixture was stirred for 12 hours. The mixture was then filtered and the resulting solid product was dried to obtain 3.5 kg of (R)-(1-(4-methoxy-3-aminosulfonylphenyl)prop-2-yl)carbamate benzyl ester, with a yield of 92.3%. In a 5L high-pressure reactor, 3L of ethanol, 3kg of (R)-(1-(4-methoxy-3-aminosulfonylphenyl)propyl-2-yl)carbamate, 60g of 5% palladium on carbon, and hydrogen pressure of 0.2MPa were added. The reaction was carried out at room temperature for 2.5 hours, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 1.84kg of white solid (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide, with a yield of 94.8%.

Images