Synthesis method of (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide

Abstract

The present invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide. The present invention uses the compound with the structure shown in Formula 1 and the compound with the structure shown in Formula 2 as starting reaction materials, and obtains the compound with the structure shown in Formula 4 through a condensation reaction and a decarboxylation reaction, avoiding the use of explosive nitroethane and high-temperature reactions; after obtaining the compound with the structure shown in Formula 4, the present invention uses reductive amination to obtain a reaction solution containing the compound with the structure shown in Formula 5 (intermediate), and directly synthesizes the target product (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide from the compound with the structure shown in Formula 4 without separating the intermediate, which simplifies the operation, improves the yield of the target product, reduces the discharge of three wastes, and the (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide obtained by the present invention has high purity and is suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide. Background Art

[0002] Tamsulosin hydrochloride, chemically named R-(+)-5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-2-methoxybenzenesulfonamide hydrochloride. This drug can selectively act on α1 receptors in the prostate and urethral smooth muscle, reduce the urethral pressure, and has low blood pressure side effects at therapeutic doses. It is applicable to the treatment of frequent urination, dysuria, etc. caused by prostate hyperplasia, with definite curative effect and low toxicity and side effects, and is the best therapeutic drug for benign prostatic hyperplasia clinically. The structure of tamsulosin hydrochloride is as follows:

[0003]

[0004] Among them, in the preparation process of tamsulosin hydrochloride, (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide is the key intermediate for synthesizing tamsulosin hydrochloride, and the structural formula is as follows:

[0005]

[0006] "Synthesis of Tamsulosin Hydrochloride" (Du Hongguang, Li Ming, etc. Chemical Reagents, 2007, 29(9), 541-543.) reported that (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide is mainly obtained from p-methoxyphenylacetone through chlorosulfonation, ammoniation, carbonyl asymmetric reductive amination, and reduction of benzyl group removal. The reaction route is as follows:

[0007]

[0008] Among them, the preparation process of the starting material p-methoxyphenylacetone used in the above synthesis route is reported in "Hass synthesis of pyridine and related compounds" (Ferd W, Hoover, Henry B.. J. Org. Chem, 1947, 12, 501-505.). Specifically, starting from p-methoxybenzaldehyde, through condensation with nitroethane, 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 an explosive precursor, and there are safety hazards in industrial production. Moreover, the total yield is only 36%, and it also needs to be purified by steam distillation, resulting in a large amount of three wastes, which is not suitable for industrial production.

[0011] The "Journal of Pharmacy" (Volume 63, Showa 18th year, 63, 376 - 80.) reported that starting from 1 - methoxy - 4-(prop - 1 - en - 1 - yl)benzene, through bromine addition, hydrolysis, epoxidation and ring - opening oxidation, the reaction route is as follows:

[0012]

[0013] The epoxide prepared by the synthesis route reported in the above "Journal of Pharmacy" needs to react at 180 - 220 °C, which has high requirements for equipment, and there is no reported yield in the literature, so it is not suitable for industrial production.

[0014] In summary, for the current synthetic route of (R)-5-(2 - aminopropyl)-2 - methoxybenzenesulfonamide, calculated from the source of the starting material p - methoxyphenylacetone used, either explosive - precursor nitroethane is used or high - temperature reaction is required, which is not suitable for industrial production. Summary of the Invention

[0015] The object of the present invention is to provide a synthetic method of (R)-5-(2 - aminopropyl)-2 - methoxybenzenesulfonamide. The synthetic method provided by the present invention avoids the use of explosive - precursor nitroethane and high - temperature reaction, and has a high yield and high purity of the target product. At the same time, the amount of three wastes in the reaction is reduced, which is suitable for industrial production.

[0016] To achieve the above object, the present invention provides the following technical solutions:

[0017] The present invention provides a synthetic method of (R)-5-(2 - aminopropyl)-2 - methoxybenzenesulfonamide, comprising the following steps:

[0018] (1) Mix the compound with the structure shown in Formula 1, the compound with the structure shown in Formula 2, an inorganic basic compound, cuprous iodide, L - proline and an organic solvent for a condensation reaction to obtain the compound with the structure shown in Formula 3;

[0019]

[0020] Wherein R in the compounds with the structures shown in Formula 2 and Formula 3 is a C1 - 5 alkyl group;

[0021] (2) Mix the compound with the structure shown in Formula 3, lithium chloride and a polar solvent for a decarboxylation reaction to obtain the compound with the structure shown in Formula 4;

[0022]

[0023] (3) Mix the compound with the structure shown in Formula 4, (R)-(+)-α-methylbenzylamine and an aromatic hydrocarbon organic solvent to carry out the first-stage reductive amination reaction. After removing the solvent from the obtained intermediate reaction solution, mix it with an alcohol solvent and a nickel catalyst, and carry out the second-stage reductive amination reaction in a hydrogen atmosphere to obtain a reductive amination reaction solution, and the reductive amination reaction solution contains the compound with the structure shown in Formula 5;

[0024]

[0025] (4) In a hydrogen atmosphere, mix the reductive amination reaction solution and a palladium catalyst to carry out a debenzylation reaction to obtain the (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide.

[0026] Preferably, R in the compounds with the structures shown in Formula 2 and Formula 3 is methyl or ethyl;

[0027] The mass ratio of the compound with the structure shown in Formula 1 to the compound with the structure shown in Formula 2 is 1:0.6 - 1.2.

[0028] Preferably, the inorganic basic compound includes one or more of cesium carbonate, potassium carbonate, potassium bicarbonate, sodium carbonate and sodium bicarbonate;

[0029] The mass ratio of the compound with the structure shown in Formula 1 to the inorganic basic compound is 1:1 - 3;

[0030] The mass ratio of the compound with the structure shown in Formula 1 to cuprous iodide is 1:0.2 - 1;

[0031] The mass ratio of the compound with the structure shown in Formula 1 to L-proline is 1:0.01 - 0.2.

[0032] Preferably, the temperature of the condensation reaction is 50 - 150 °C, and the heat preservation time is 6 - 12 h.

[0033] Preferably, the mass ratio of the compound with the structure shown in Formula 3 to lithium chloride is 1:0.1 - 1.

[0034] Preferably, the temperature of the decarboxylation reaction is 50 - 120 °C, and the heat preservation time is 5 - 10 h.

[0035] Preferably, in step (2), after the decarboxylation reaction is completed to obtain a decarboxylation reaction solution, it further includes removing the solvent from the decarboxylation reaction solution to obtain a crude product; mixing the crude product and an alcohol solvent to obtain a crude product solution; heating the crude product solution and then dropping it into water for crystallization, and separating the solid and liquid to obtain the compound with the structure shown in Formula 4; the temperature of the crystallization is 0 - 30 °C, and the time is 0.5 - 12 h.

[0036] Preferably, the nickel catalyst is Raney nickel; the mass ratio of the compound of the structure shown in Formula 4 to (R)-(+)-α-methylbenzylamine is 1:0.5-1; the mass ratio of the compound of the structure shown in Formula 4 to the nickel catalyst is 1:0.05-0.5.

[0037] Preferably, in step (3), the temperature of the first-stage reductive amination reaction and the second-stage reductive amination reaction is independently 30-120 °C; the pressure of hydrogen is 0.1-3.5 MPa.

[0038] Preferably, in step (4), the palladium catalyst is palladium on carbon, and the mass content of palladium in the palladium on carbon is 5-10%;

[0039] The mass ratio of the compound of the structure shown in Formula 4 to the palladium catalyst is 1:0.05-0.5;

[0040] The temperature of the debenzylation reaction is 30-80 °C; the pressure of hydrogen is 0.1-3.5 MPa.

[0041] The present invention provides a method for synthesizing (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide, which comprises the following steps: (1) Mixing a compound with the structure shown in Formula 1, a compound with the structure shown in Formula 2, an inorganic basic compound, cuprous iodide, L-proline and an organic solvent for a condensation reaction to obtain a compound with the structure shown in Formula 3; wherein R in the compounds with the structures shown in Formula 2 and Formula 3 is a C1-C5 alkyl group; (2) Mixing the compound with the structure shown in Formula 3, lithium chloride and a polar solvent for a decarboxylation reaction to obtain a compound with the structure shown in Formula 4; (3) Mixing the compound with the structure shown in Formula 4, (R)-(+)-α-methylbenzylamine and an aromatic hydrocarbon organic solvent for a first-stage reductive amination reaction, removing the solvent from the obtained intermediate reaction solution, and then mixing it with an alcohol solvent and a nickel catalyst for a second-stage reductive amination reaction in a hydrogen atmosphere to obtain a reductive amination reaction solution, wherein the reductive amination reaction solution contains a compound with the structure shown in Formula 5; (4) Mixing the reductive amination reaction solution and a palladium catalyst in a hydrogen atmosphere for a debenzylation reaction to obtain the (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide. The present invention uses the compound with the structure shown in Formula 1 and the compound with the structure shown in Formula 2 as starting reaction materials, and successively obtains the compound with the structure shown in Formula 4 through a condensation reaction and a decarboxylation reaction, avoiding the use of explosive nitroethane and high-temperature reactions; after obtaining the compound with the structure shown in Formula 4, the present invention uses a reductive amination reaction to obtain a reaction solution containing the compound with the structure shown in Formula 5 (intermediate), and directly synthesizes the target product (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide from the compound with the structure shown in Formula 4 without separating the intermediate, which simplifies the operation, improves the yield of the target product, reduces the discharge of three wastes, and the (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide obtained by the present invention has high purity and is suitable for industrial production. Description of the Drawings

[0042] Figure 1 is a synthesis flow chart of (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide provided by an embodiment of the present invention;

[0043] Figure 2 is a nuclear magnetic spectrum of the (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide product synthesized by the present invention;

[0044] Figure 3 is an HPLC detection spectrum of the (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide product synthesized by the present invention;

[0045] Figure 4 is a chiral purity detection chart of the (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide product synthesized by the present invention. Detailed Embodiments

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

[0047] (1) Mix a compound with the structure shown in Formula 1, a compound with the structure shown in Formula 2, an inorganic basic compound, cuprous iodide, L-proline and an organic solvent for a condensation reaction to obtain a compound with the structure shown in Formula 3;

[0048]

[0049] wherein R in the compounds with the structures shown in Formula 2 and Formula 3 is a C1-C5 alkyl group;

[0050] (2) Mix the compound with the structure shown in Formula 3, lithium chloride and a polar solvent for a decarboxylation reaction to obtain a compound with the structure shown in Formula 4;

[0051]

[0052] (3) Mix the compound with the structure shown in Formula 4, (R)-(+)-α-methylbenzylamine and an aromatic hydrocarbon organic solvent for a first-stage reductive amination reaction. After removing the solvent from the obtained intermediate reaction solution, mix it with an alcohol solvent and a nickel catalyst, and conduct a second-stage reductive amination reaction in a hydrogen atmosphere to obtain a reductive amination reaction solution, and the reductive amination reaction solution contains a compound with the structure shown in Formula 5;

[0053]

[0054] (4) In a hydrogen atmosphere, mix the reductive amination reaction solution and a palladium catalyst for a debenzylation reaction to obtain the (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide.

[0055] In the present invention, unless otherwise specified, all preparation raw materials / components are commercially available products well-known to those skilled in the art.

[0056] The present invention mixes a compound with the structure shown in Formula 1, a compound with the structure shown in Formula 2, an inorganic basic compound, cuprous iodide, L-proline and an organic solvent for a condensation reaction to obtain a compound with the structure shown in Formula 3;

[0057]

[0058] wherein R in the compounds with the structures shown in Formula 2 and Formula 3 is a C1-C5 alkyl group.

[0059] In the present invention, R in the compound of the structure shown in Formula 2 is a C1-C5 alkyl group, preferably a C1-C3 alkyl group, more preferably a methyl group or an ethyl group. The inorganic basic compound preferably includes one or more of cesium carbonate, potassium carbonate, potassium bicarbonate, sodium carbonate, and sodium bicarbonate, and more preferably cesium carbonate. The organic solvent preferably includes one or more of N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), and 1,4-dioxane, and more preferably DMF. The mass ratio of the compound of the structure shown in Formula 1 to the compound of the structure shown in Formula 2 is preferably 1:0.6-1.2, more preferably 1:0.7-1, and further preferably 1:0.88. The mass ratio of the compound of the structure shown in Formula 1 to the inorganic basic compound is preferably 1:1-3, more preferably 1:1.5-2, and further preferably 1:1.88. The mass ratio of the compound of the structure shown in Formula 1 to cuprous iodide is preferably 1:0.2-1, more preferably 1:0.25-0.6, and further preferably 1:0.36. The mass ratio of the compound of the structure shown in Formula 1 to L-proline is preferably 1:0.01-0.2, more preferably 1:0.02-0.15, and further preferably 1:0.04-0.13. The present invention has no special requirements for the dosage of the organic solvent, and it is only necessary to ensure the smooth progress of the condensation method.

[0060] In the present invention, the temperature of the condensation reaction is preferably 50-150 °C, more preferably 80-140 °C, and further preferably 120 °C; the heat preservation time is preferably 6-12 h, and more preferably 8 h. After the condensation reaction is completed, a condensation reaction solution is obtained. The present invention preferably performs post-treatment on the condensation reaction solution to obtain the compound of the structure shown in Formula 3. R in the compound of the structure shown in Formula 3 is preferably a C1-C3 alkyl group, more preferably a methyl group or an ethyl group. In the present invention, the post-treatment preferably includes: removing the solvent from the condensation reaction solution to obtain a crude product, dissolving the crude product in dichloromethane to obtain a crude product solution; washing the crude product solution successively with water and saturated brine, and concentrating the obtained organic solution to dryness to obtain the compound of the structure shown in Formula 3. The specific implementation method of removing the solvent is preferably vacuum distillation. The number of times of washing with water is preferably 1 time, and the number of times of washing with saturated brine is preferably 1 time. The compound of the structure shown in Formula 3 does not need to be further purified by column chromatography and directly undergoes the decarboxylation reaction.

[0061] After obtaining the compound of the structure shown in Formula 3, the present invention mixes the compound of the structure shown in Formula 3, lithium chloride, and a polar solvent to carry out a decarboxylation reaction to obtain the compound of the structure shown in Formula 4;

[0062]

[0063] In the present invention, the polar solvent preferably includes DMF, acetic acid or water, more preferably DMF. The mass ratio of the compound of the structure shown in Formula 3 to lithium chloride is preferably 1:0.1 - 1, more preferably 1:0.2 - 0.8, and further preferably 1:0.3 - 0.6. The present invention has no special requirements for the dosage of the polar solvent, as long as the decarboxylation reaction can proceed smoothly.

[0064] In the present invention, the temperature of the decarboxylation reaction is preferably 50 - 120 °C, more preferably 60 - 110 °C, and further preferably 100 °C; the heat preservation time is preferably 5 - 10 h, more preferably 6 h. In the present invention, after the decarboxylation reaction, a decarboxylation reaction solution is obtained. The present invention preferably further includes removing the solvent from the decarboxylation reaction solution to obtain a crude product; mixing the crude product with an alcohol solvent to obtain a crude product solution; heating the crude product solution and then dropping it into water for crystallization, and obtaining the compound of the structure shown in Formula 4 after solid-liquid separation. In the present invention, the solvent removal is preferably by vacuum distillation. The alcohol solvent is preferably ethanol. The temperature of the heated crude product solution is preferably 40 - 60 °C, more preferably 50 °C. A large amount of crystals will precipitate during the dropping process. After the dropping is completed, crystallization is carried out. The temperature of the crystallization is preferably 0 - 30 °C, more preferably 10 - 25 °C, and further preferably 15 °C; the crystallization time is preferably 0.5 - 12 h, more preferably 1 - 10 h, and further preferably 2 - 5 h. The crystallization is carried out under stirring conditions. The solid-liquid separation is preferably suction filtration. The present invention preferably washes the solid product obtained by the solid-liquid separation with water and then dries it to obtain the compound of the structure shown in Formula 4.

[0065] After obtaining the compound of the structure shown in Formula 4, the present invention mixes the compound of the structure shown in Formula 4, (R)-(+)-α-methylbenzylamine and an aromatic hydrocarbon organic solvent to carry out the first-stage reductive amination reaction. After removing the solvent from the obtained intermediate reaction solution, it is mixed with an alcohol solvent and a nickel catalyst, and the second-stage reductive amination reaction is carried out in a hydrogen atmosphere to obtain a reductive amination reaction solution, and the reductive amination reaction solution contains the compound of the structure shown in Formula 5;

[0066]

[0067] In the present invention, the aromatic hydrocarbon organic solvent is preferably toluene. The alcohol solvent is preferably methanol. The nickel catalyst is preferably Raney nickel. The mass ratio of the compound of the structure shown in Formula 4 to (R)-(+)-α-methylbenzylamine is preferably 1:0.5 - 1, more preferably 1:0.55 - 0.8, and further preferably 1:0.6. The mass ratio of the compound of the structure shown in Formula 4 to the nickel catalyst is preferably 1:0.05 - 0.5, more preferably 1:0.08 - 0.3, and further preferably 1:0.1.

[0068] In the present invention, the temperature of the first-stage reductive amination reaction is preferably 30 to 120°C, more preferably 50 to 105°C. In a specific embodiment of the present invention, the specific implementation manner of the first-stage reductive amination reaction is preferably: heating the above reaction raw materials to reflux for water separation, and carrying out heat preservation reaction after no water droplets drip out; the time of the heat preservation reaction is preferably 1 to 3 h, more preferably 2 h. The removal of the solvent is preferably carried out by vacuum distillation. The second-stage reductive amination reaction is preferably carried out in a high-pressure reaction kettle. The pressure of the hydrogen is preferably 0.1 to 3.5 MPa, more preferably 0.5 to 3 MPa, and further preferably 1 MPa. The temperature of the second-stage reductive amination reaction is preferably 30 to 120°C, more preferably 50 to 100°C, and further preferably 60°C; the second-stage reductive amination reaction preferably continues to carry out heat preservation reaction for 30 min after the pressure of the hydrogen is constant.

[0069] After the second-stage reductive amination reaction is completed, the present invention preferably post-treats the obtained initial reductive amination reaction to obtain a reductive amination reaction solution for carrying out the debenzylation reaction. The post-treatment preferably includes: cooling the initial reductive amination reaction solution to room temperature and then carrying out solid-liquid separation, and the obtained liquid product is the reductive amination reaction solution. The solid-liquid separation is preferably filtration.

[0070] After obtaining the reductive amination reaction solution, in the present invention, in a hydrogen atmosphere, the reductive amination reaction solution and a palladium catalyst are mixed to carry out the debenzylation reaction to obtain (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide.

[0071] In the present invention, the palladium catalyst is preferably palladium on carbon, and the mass content of palladium in the palladium on carbon is preferably 5 to 10%, more preferably 5%. The mass ratio of the compound shown in Formula 4 to the palladium catalyst is preferably 1:0.05 to 0.5, more preferably 1:0.1 to 0.4, and further preferably 1:0.2. The pressure of the hydrogen is preferably 0.1 to 3.5 MPa, more preferably 1 to 2.5 MPa, and further preferably 2 MPa. The temperature of the debenzylation reaction is preferably 30 to 80°C, more preferably 50 to 75°C. The debenzylation reaction preferably continues to carry out heat preservation reaction for 30 min after the pressure of the hydrogen is constant.

[0072] After the debenzylation reaction, a debenzylation reaction solution is obtained. The present invention preferably performs post-treatment on the debenzylation reaction solution to obtain the (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide. In the present invention, the post-treatment preferably includes: cooling the debenzylation reaction solution to room temperature for the first solid-liquid separation, concentrating the obtained liquid product to dryness to obtain a crude product; dissolving the crude product in n-hexane for the second solid-liquid separation, and drying the obtained solid product to obtain the (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide. The first solid-liquid separation is preferably filtration. The concentration is preferably vacuum concentration, and the second solid-liquid separation is preferably suction filtration.

[0073] To further illustrate the present invention, the technical solutions provided by the present invention will be described in detail below in conjunction with examples, but they should not be construed as limiting the protection scope of the present invention.

[0074] The following examples are all carried out according to Figure 1 the synthetic flow chart shown, wherein, Figure 1 SM-1 in is the compound shown in Formula 1, and its chemical name is 5-bromo-2-methoxybenzenesulfonamide; SM-2 is the compound shown in Formula 2, which is methyl acetoacetate in Example 1 and ethyl acetoacetate in Example 2; TX-1 is the compound shown in Formula 3, and its chemical name is methyl 2-(4-methoxy-3-sulfamoylphenyl)-3-oxobutyrate. TX-2 is the compound shown in Formula 4, and its chemical name is 2-methoxy-5-(2-oxopropyl)benzenesulfonamide, and TX-3 is the compound shown in Formula 5, and its chemical name is 5-[(R)-2-[[(R)-1-phenylethyl]amino]propyl]-2-methoxybenzenesulfonamide; TX-4 is (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide.

[0075] Example 1

[0076] (1) Add 100 g of 5-bromo-2-methoxybenzenesulfonamide, 500 g of DMF, 88 g of methyl acetoacetate, 185 g of cesium carbonate, 36 g of copper iodide, and 8.6 g of L-proline to a 1000 mL reaction flask, heat to 120 °C, react for 8 hours, remove the solvent under reduced pressure, add 500 g of dichloromethane, wash once with 200 mL of water and once with 100 mL of saturated brine, and concentrate the organic layer to dryness under reduced pressure to obtain 105 g of TX-1, which is directly used in the next step of the reaction. The yield is 92.4%.

[0077] (2) Add 105 g of TX-1, 400 g of DMF, and 37 g of lithium chloride into a 1000 mL reaction flask. Heat to 100 °C and keep the reaction for 6 hours. Remove the solvent under reduced pressure. Cool to room temperature, add 100 mL of ethanol, heat to 50 °C, and drip it into 500 mL of water. A large amount of solid precipitates. Keep stirring at 15 °C for 2 hours for crystal precipitation. Filter by suction, wash the filter cake with an appropriate amount of water, and dry to obtain 76.5 g of white solid TX-2, with a yield of 90.2%.

[0078] (3) Add 50 g of TX-2, 300 g of toluene, and 30 g of (R)-(+)-α-methylbenzylamine into a 500 mL reaction flask. Heat to reflux for water separation. After the reaction until no water droplets come out, continue to keep the reaction for 2 hours. Remove the solvent under reduced pressure, add it into a 500 mL high-pressure reaction kettle, add 250 g of methanol and 5 g of Raney nickel. The hydrogen pressure is 1 Mpa. Heat to 60 °C and keep the reaction. When the pressure remains unchanged, continue the reaction for 30 minutes. Cool to room temperature, filter, and the filtrate is directly used for the next step of the reaction. The filtrate contains TX-3.

[0079] (4) In a 500 mL high-pressure reaction kettle, add the filtrate obtained in Example 3, 10 g of 5% palladium-carbon, and the hydrogen pressure is 2 Mpa. Heat to 75 °C and keep the reaction. When the pressure remains unchanged, continue the reaction for 30 minutes. Cool to room temperature, filter, concentrate the filtrate under reduced pressure to dryness, add 50 g of n-hexane and stir evenly, then filter by suction and dry to obtain 44.5 g of white solid TX-4. The total yield of steps (3) and (4) is 88.6%.

[0080] The NMR spectrum of product TX-4 is as Figure 2 shown, and the NMR data are as follows: 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).

[0081] The HPLC detection spectrum of product TX-4 is as Figure 3 . It can be seen from Figure 3 that the purity of the (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide product prepared in this example is 99.919%.

[0082] The chiral purity detection of product TX-4 is shown in Figure 4 . It can be seen from Figure 4 that the chiral purity of the product prepared in this example is 100%.

[0083] Example 2

[0084] It is basically the same as the preparation method of Example 1, except that methyl acetoacetate is replaced by ethyl acetoacetate. The obtained results are basically the same as those of Example 1.

[0085] As can be seen from the above examples, the advantages of the present invention are that TX-2 is prepared by a conventional method, avoiding the use of explosive nitroethane and high-temperature reactions. The method of not separating intermediates is used to synthesize TX-4 from TX-2, which simplifies the operation process, has high yields in each step, reduces the amount of three wastes, and the obtained key intermediate TX-4 has high purity, making it suitable for industrial production.

[0086] Although the above examples have described the present invention in detail, they are only a part of the embodiments of the present invention, not all of them. Other embodiments can be obtained based on these embodiments without creative efforts, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A method for synthesizing (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide, characterized in that, It includes the following steps: (1) Mix the compound with the structure shown in Formula 1, the compound with the structure shown in Formula 2, an inorganic basic compound, cuprous iodide, L-proline and an organic solvent for a condensation reaction to obtain the compound with the structure shown in Formula 3; Formula 1, Formula 2, Formula 3; where R in the compounds with the structures shown in Formula 2 and Formula 3 is a C1-C5 alkyl group; (2) Mix the compound with the structure shown in Formula 3, lithium chloride and a polar solvent for a decarboxylation reaction. After the decarboxylation reaction is completed, a decarboxylation reaction solution is obtained. It also includes removing the solvent from the decarboxylation reaction solution to obtain a crude product; mixing the crude product with an alcohol solvent to obtain a crude product solution; heating the crude product solution and then dropping it into water for crystallization, and separating the solid and liquid to obtain the compound with the structure shown in Formula 4. The mass ratio of the compound with the structure shown in Formula 3 to lithium chloride is 1:0.1-0.8; Formula 4; (3) Mix the compound with the structure shown in Formula 4, (R)-(+)-α-methylbenzylamine and toluene, heat to reflux for water separation, and keep the temperature for reaction after no water drops out; the time for the heat preservation reaction is 1-3 h to obtain an intermediate reaction solution. After removing the solvent from the obtained intermediate reaction solution, mix it with an alcohol solvent and a nickel catalyst. The nickel catalyst is Raney nickel, and a second-stage reductive amination reaction is carried out in a hydrogen atmosphere to obtain a reductive amination reaction solution, and the reductive amination reaction solution contains the compound with the structure shown in Formula 5; Formula 5; (4) In a hydrogen atmosphere, mix the reductive amination reaction solution and a palladium catalyst for a debenzylation reaction. The palladium catalyst is palladium on carbon to obtain (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide.

2. The synthesis method according to claim 1, wherein R in the compounds with the structures shown in Formula 2 and Formula 3 is methyl or ethyl; The mass ratio of the compound with the structure shown in Formula 1 to the compound with the structure shown in Formula 2 is 1:0.6-1.

2.

3. The synthesis method according to claim 1, characterized in that, The inorganic basic compound includes one or more of cesium carbonate, potassium carbonate, potassium bicarbonate, sodium carbonate and sodium bicarbonate; The mass ratio of the compound with the structure shown in Formula 1 to the inorganic basic compound is 1:1-3; The mass ratio of the compound with the structure shown in Formula 1 to cuprous iodide is 1:0.2-1; The mass ratio of the compound with the structure shown in Formula 1 to L-proline is 1:0.01-0.

2.

4. The synthesis method according to any one of claims 1 to 3, characterized in that, The temperature of the condensation reaction is 50-150 °C, and the heat preservation time is 6-12 h.

5. The synthesis method according to claim 1, wherein The temperature of the decarboxylation reaction is 50-120 °C, and the heat preservation time is 5-10 h.

6. The synthesis method according to claim 1, wherein, In step (2), the temperature of the crystallization is 0-30 °C, and the time is 0.5-12 h.

7. The synthesis method according to claim 1, characterized in that, The mass ratio of the compound with the structure shown in Formula 4 to (R)-(+)-α-methylbenzylamine is 1:0.5-1; the mass ratio of the compound with the structure shown in Formula 4 to the nickel catalyst is 1:0.05-0.

5.

8. The synthesis method according to claim 1 or 7, characterized in that, In step (3), the temperature of the second-stage reductive amination reaction is 30-120 °C; the pressure of hydrogen is 0.1-3.5 MPa.

9. The synthesis method according to claim 1, characterized in that, In step (4), the mass content of palladium in the palladium on carbon is 5-10%; The mass ratio of the compound with the structure shown in Formula 4 to the palladium catalyst is 1:0.05-0.5; The temperature of the debenzylation reaction is 30-80 °C; the pressure of hydrogen is 0.1-3.5 MPa.

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