Process for the preparation of pramipexole hydrochloride

Abstract

The application relates to the field of drug synthesis and discloses a preparation and purification method of pramipexole hydrochloride. The method is characterized in that 4-amino phenol is used as raw material, transition metal catalyzed hydrogenation reaction is used to reduce 4-amino cyclohexanol into a mixture of each epimer, a low-load catalyst or no catalyst is used to oxidize the cyclohexanol derivative into a cyclohexanone derivative by using a cheap and easily available oxidant, pramipexole is obtained through bromination and thiourea reaction, most of the R configuration pramipexole hydrochloride is removed through a purification method of multiple reactions with different chiral acids, and high-purity S configuration pramipexole hydrochloride is obtained. The preparation method is simple, the reaction condition requirement is not high, mass synthesis is easy to realize, the method has the advantages of low cost, greenness, low toxicity and the like, and is suitable for industrialized production of pramipexole hydrochloride, related derivatives and pramipexole isomers.

Description

Technical Field

[0001] This invention relates to the field of drug synthesis, and more specifically to a method for preparing pramipexole hydrochloride. Background Technology

[0002] Pramipexole hydrochloride is a non-ergot dopamine agonist, chemically named (S)-2-amino-4,5,6,7-tetrahydro-6-propylaminobenzothiazole dihydrochloride monohydrate. It was first marketed in the United States in 1997, used alone or in combination with levodopa for the treatment of early to late-stage idiopathic Parkinson's disease. In 2006, it was approved for the treatment of primary restless legs syndrome, and in 2007, it was launched in China under the brand name Sifrol. Pramipexole hydrochloride is a top-level recommended anti-Parkinson's drug by the European Federation of Neurological Societies and the International Society for Movement Disorders, and has been proven to be the only anti-Parkinson's drug capable of improving depression associated with Parkinson's disease. Pramipexole hydrochloride is used in clinical treatment in more than 50 countries worldwide, serving over 2 million patients annually, and is the most prescribed dopamine receptor agonist for the treatment of Parkinson's disease globally.

[0003] The aging population is becoming an increasingly prominent issue in modern society. Parkinson's disease, a disease closely related to aging, has an incidence rate that increases significantly with age. Currently, there are over 5.7 million patients worldwide, and this number is projected to rise to 8.7 million by 2030, placing a heavy burden on patients' families and society. Therefore, optimizing the synthesis methods and processes of therapeutic drugs and reducing production costs is of great significance.

[0004] Currently, most existing methods for preparing pramipexole hydrochloride are based on chemical synthesis. Most of these methods involve the use of heavy metal catalysts, oxidants, and highly toxic reducing agents. Some of these methods also cause serious environmental pollution and result in high raw material costs, which is detrimental to overall process cost control. Summary of the Invention

[0005] The purpose of this invention is to overcome the problems of high toxicity, heavy pollution, and high cost of existing synthetic routes, and to provide a method for preparing pramipexole hydrochloride. The method described in this invention is characterized by low cost, safety, non-toxicity, and good environmental compatibility, and can prepare pramipexole hydrochloride with extremely high purity in the S-configuration.

[0006] To achieve the above objectives, the present invention provides a method for preparing pramipexole hydrochloride, the method comprising the following steps:

[0007] (1) 4-aminophenol is reacted with hydrogen chloride to obtain hydrochloride, and then the hydrochloride is hydrogenated and reduced in the presence of a first solvent and a transition metal catalyst. The resulting product is then neutralized with a first base to obtain 4-aminocyclohexanol.

[0008] (2) The 4-aminocyclohexanol was mixed with the first acylation reagent and reacted to obtain the first acylation product shown in formula (I);

[0009] (3) The first acylated product is reacted with a reducing agent in the presence of a first catalyst and an organic solvent to obtain the reduced product shown in formula (II);

[0010] (4) The reduction product is subjected to an acylation reaction to obtain the second acylated product shown in formula (III);

[0011] (5) In the presence of an optional second catalyst, the second acylated product is oxidized to obtain the oxidized product shown in formula (IV);

[0012] (6) In the presence of an acidic solvent, the oxidation product is first brominated with bromine, and then mixed with thiourea for reaction;

[0013]

[0014] Wherein, R is a protecting group for hydroxyl and amino groups, preferably acetyl, propionyl or tert-butyloxycarbonyl.

[0015] Preferably, in step (1), the mass ratio of the transition metal catalyst to the hydrochloride is 0.05-10:1, more preferably 0.4-0.6:1.

[0016] Preferably, the transition metal catalyst is at least one of palladium catalyst, nickel catalyst and platinum catalyst, more preferably at least one of palladium on carbon, palladium hydroxide, palladium chloride, palladium black, Raney nickel and platinum oxide.

[0017] Preferably, the first solvent is at least one of water, a C1-C5 alcohol, tetrahydrofuran, dioxane, and ethyl acetate.

[0018] Preferably, the first base is at least one selected from sodium bicarbonate, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium phosphate, potassium dihydrogen phosphate, pyridine, and triethylamine.

[0019] Preferably, the conditions for hydrogenation reduction include: a temperature of 20-50°C, a time of 4h-7d, and a hydrogen partial pressure of 10-100 atm.

[0020] Preferably, the molar ratio of 4-aminocyclohexanol to the first acylation reagent is 1:0.5-1.5.

[0021] Preferably, the first acylation reagent is propionic anhydride and / or propionyl chloride.

[0022] Preferably, the reaction conditions include a temperature of -10 to 50°C and a time of 10 min to 4 h.

[0023] Preferably, in step (3), the molar ratio of the first acylation product, the reducing agent and the first catalyst is 1:(2-5):(2-10), more preferably 1:(2-3):(2-4).

[0024] Preferably, the reducing agent is at least one selected from sodium borohydride, potassium borohydride, boranetetrahydrofuran, diisobutylaluminum hydride, and red aluminum.

[0025] Preferably, the first catalyst is at least one selected from boron trifluoride diethyl ether, elemental iodine, nickel chloride, magnesium chloride, zinc chloride, cobalt chloride, zinc acetate, and cobalt acetate.

[0026] Preferably, the organic solvent is at least one selected from tetrahydrofuran, diethyl ether, dioxane, benzene, and toluene.

[0027] Preferably, the reaction conditions include a temperature of 5-70°C and a time of 0.5-6 hours.

[0028] Preferably, in step (4), the process of performing the acylation reaction on the reduction product includes: reacting the reduction product with a second acylation reagent.

[0029] Preferably, the molar ratio of the reduction product to the second acylation reagent is 1:0.8-1.2.

[0030] Preferably, the second acylation agent is at least one of ditert-butyl dicarbonate and tert-valerate chloride.

[0031] Preferably, the reaction conditions include a temperature of -10 to 50°C and a time of 0.5 to 4 hours.

[0032] Preferably, in step (4), the process of carrying out the acylation reaction of the reduction product includes: reacting the reduction product with a third acylation reagent in the presence of a third catalyst, and then hydrolyzing it in the presence of a second base.

[0033] Preferably, the molar ratio of the reduction product, the third catalyst, and the third acylation reagent is 1:(0.05-6):(1-3), more preferably 1:(0.2-1):(1.5-2.5).

[0034] Preferably, the third acylation agent is at least one selected from acetic anhydride, acetyl chloride, propionic acid glycoside, and propionyl chloride.

[0035] Preferably, the third catalyst is at least one of sodium acetate, pyridine, and elemental iodine.

[0036] Preferably, the second alkali is at least one selected from potassium carbonate, sodium carbonate, potassium hydroxide, and sodium hydroxide.

[0037] Preferably, the reaction conditions include a temperature of -10 to 70°C and a time of 10 min to 4 h.

[0038] Preferably, in step (5), the specific process of oxidizing the second acylated product includes: mixing the second acylated product with a second catalyst, a phase transfer catalyst, a first oxidant and a third base in the presence of a second solvent.

[0039] Preferably, the molar ratio of the second acylation product, the second catalyst, the phase transfer catalyst, the first oxidant and the third base is 100:(0.01-20):(0.1-20):(120-500):(1-50), more preferably 100:(1-5):(0.5-5):(150-200):(5-20).

[0040] Preferably, the second catalyst is at least one selected from sodium tungstate, ruthenium trichloride, ruthenium tetroxide, and tetra-n-propyl perruthenium.

[0041] Preferably, the phase transfer catalyst is at least one selected from tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, triethylbenzylammonium chloride, and triethylbenzylammonium bromide.

[0042] Preferably, the first oxidant is at least one of hydrogen peroxide, sodium hypochlorite, sodium periodate, potassium peroxymonosulfate, and N-methylmorpholine nitrogen oxides.

[0043] Preferably, the third alkali is at least one selected from potassium carbonate, sodium carbonate, potassium hydroxide, and sodium hydroxide.

[0044] Preferably, the second solvent is at least one selected from water, dichloromethane, trichloromethane, dichloroethane, ethyl acetate, tetrahydrofuran, and dioxane.

[0045] Preferably, the reaction conditions include a temperature of 15-60°C and a time of 0.5-8 hours.

[0046] Preferably, in step (5), the specific process of oxidizing the second acylated product includes: mixing and reacting the second acylated product with a second oxidant in the presence of a third solvent, and then quenching it with a reducing agent.

[0047] Preferably, the molar ratio of the second acylated product to the second oxidant is 1:1.2-10, more preferably 1:2-4.

[0048] Preferably, the second oxidant is at least one selected from hydrogen peroxide, sodium hypochlorite, sodium periodate, potassium peroxymonosulfate, and N-methylmorpholine nitrogen oxides.

[0049] Preferably, the reducing agent is at least one selected from sodium thiosulfate, sodium sulfite, sodium bisulfite, potassium bisulfite, and zinc powder.

[0050] Preferably, the third solvent is at least one of water and a C1-C5 acid.

[0051] Preferably, the reaction conditions include a temperature of -10 to 40°C and a time of 10 min to 4 h.

[0052] Preferably, in step (6), the molar ratio of the oxidation product, the bromine and the thiourea is 1:(0.5-1.5):(0.5-1.5).

[0053] Preferably, the acidic solvent is a C1-C5 acid.

[0054] Preferably, the conditions for the bromination reaction include: a temperature of -10 to 40°C and a time of 0.5 to 4 hours.

[0055] Preferably, the conditions for the mixing reaction include: a temperature of 30-100℃ and a time of 1-12h.

[0056] Preferably, the method further includes purifying the product obtained in step (6) to obtain the S-configuration of pramipexole hydrochloride, wherein the purification process includes the following steps:

[0057] S1: In the presence of the fourth solvent, the product obtained in step (6) is mixed with the first hydrochloric acid, then heated to dissolve and mixed with the first chiral acid, filtered to obtain pramipexole chiral acid salt A1, then mixed with the second hydrochloric acid, and neutralized with the fourth base to obtain pramipexole free base B1.

[0058] S2: Replace pramipexole with pramipexole free base B1 and repeat step S1 to obtain pramipexole free base B2;

[0059] S3: Mix the filtrates from S1 and S2, neutralize with the fifth base, and filter to obtain pramipexole free base L1. Then, in the presence of the fifth solvent, mix pramipexole free base L1 with the third hydrochloric acid, heat to dissolve, mix with the second chiral acid, and filter to obtain pramipexole chiral acid salt L2; then recrystallize.

[0060] Preferably, in step S1, the molar ratio of the product obtained in step (6), the first hydrochloric acid, and the first chiral acid is 1:(0.5-1.5):(0.5-1.5).

[0061] Preferably, the first chiral acid is at least one of D-tartaric acid, D-malic acid, and L-camphorsulfonic acid.

[0062] Preferably, the concentration of the first hydrochloric acid is 10-15 mol / L.

[0063] Preferably, the concentration of the second hydrochloric acid is 0.5-3 mol / L.

[0064] Preferably, the fourth solvent is at least one of C1-C5 alcohols, ethyl acetate, tetrahydrofuran, and dioxane.

[0065] Preferably, the fourth alkali is at least one selected from sodium bicarbonate, potassium carbonate, sodium carbonate, potassium hydroxide, and sodium hydroxide.

[0066] Preferably, the heating temperature is 40-100℃.

[0067] Preferably, in step S3, the molar ratio of the pramipexole free base L1, the third hydrochloric acid, and the second chiral acid is 1:(0.5-1.5):(0.5-1.5).

[0068] Preferably, the second chiral acid is at least one of L-tartaric acid, L-malic acid, and D-camphorsulfonic acid.

[0069] Preferably, the concentration of the third hydrochloric acid is 10-15 mol / L.

[0070] Preferably, the fifth solvent is at least one of C1-C5 alcohols, ethyl acetate, tetrahydrofuran, and dioxane.

[0071] Preferably, the fifth alkali is at least one selected from sodium bicarbonate, potassium carbonate, sodium carbonate, potassium hydroxide, and sodium hydroxide.

[0072] Preferably, the heating temperature is 40-100℃.

[0073] Preferably, in step S3, the specific process of recrystallization includes: heating and dissolving pramipexole chiral acid salt L2, cooling to room temperature and filtering, neutralizing the solid product with a sixth base, then dissolving it in an alcohol solvent, mixing it with a fourth hydrochloric acid, and filtering.

[0074] Preferably, the sixth alkali is at least one selected from sodium bicarbonate, potassium carbonate, sodium carbonate, potassium hydroxide, and sodium hydroxide.

[0075] Preferably, the alcohol solvent is a C1-C5 alcohol.

[0076] Preferably, the concentration of the fourth hydrochloric acid is 10-15 mol / L.

[0077] Preferably, the recrystallization temperature is 40-100℃.

[0078] The above technical solution uses 4-aminophenol as a raw material, which is mixed with hydrochloric acid to form a hydrochloride salt. This salt is then reduced to a mixture of 4-aminocyclohexanol epiomers via a transition metal-catalyzed hydrogenation reaction. The cyclohexanol derivative is then oxidized to a cyclohexanone derivative using an inexpensive and readily available oxidant, even in the presence of a low-load catalyst or even without a catalyst. Finally, the derivative reacts with bromine and thiourea to obtain pramipexole hydrochloride, with each configuration (R / S) comprising 50%. A chiral acid is then used to react with the pramipexole to form a solid product. Most of the R-configured pramipexole is removed, and the filtrate is reacted with a chiral acid to obtain the S-configured pramipexole, which is then further purified. This significantly improves the optical purity of the product, reduces the number of recrystallizations, and increases the purity and yield of the S-configured pramipexole. This preparation and purification method is simple, has low requirements for conditions, and facilitates the purification of intermediates. It is easy to achieve large-scale synthesis and has advantages such as low cost, greenness, and low toxicity. It is a suitable preparation method for industrial production, especially applicable to the preparation and purification of pramipexole hydrochloride, related derivatives, and pramipexole isomers. Attached Figure Description

[0079] Figure 1 This is a flowchart of the preparation method of pramipexole hydrochloride according to the present invention;

[0080] Figure 2 This is a flowchart of the purification method for pramipexole hydrochloride described in this invention. Detailed Implementation

[0081] The following provides a detailed description of specific embodiments of the present invention. It should be understood that the specific embodiments described herein are for illustrative and explanatory purposes only and are not intended to limit the scope of the invention.

[0082] The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

[0083] In the description of this application, the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating relative importance or implying the number of technical features indicated. Therefore, unless otherwise stated, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature; "multiple" means two or more. The term "comprising" and any variations thereof mean non-exclusive inclusion, allowing for the presence or addition of one or more other features, integers, steps, operations, units, components, and / or combinations thereof.

[0084] The preparation method of pramipexole hydrochloride according to the present invention includes the following steps:

[0085] (1) 4-aminophenol is reacted with hydrogen chloride to obtain hydrochloride, and then the hydrochloride is hydrogenated and reduced in the presence of a first solvent and a transition metal catalyst. The resulting product is then neutralized with a first base to obtain 4-aminocyclohexanol.

[0086] (2) The 4-aminocyclohexanol was mixed with the first acylation reagent and reacted to obtain the first acylation product shown in formula (I);

[0087] (3) The first acylated product is reacted with a reducing agent in the presence of a first catalyst and an organic solvent to obtain the reduced product shown in formula (II);

[0088] (4) The reduction product is subjected to an acylation reaction to obtain the second acylated product shown in formula (III);

[0089] (5) In the presence of an optional second catalyst, the second acylated product is oxidized to obtain the oxidized product shown in formula (IV);

[0090] (6) In the presence of an acidic solvent, the oxidation product is first brominated with bromine, and then mixed with thiourea for reaction;

[0091]

[0092] Wherein, R is a protecting group for the hydroxyl and amino groups, preferably acetyl, propionyl, or tert-butyloxycarbonyl. The method described in this invention uses low-cost 4-aminophenol as a raw material, and the synthesis route is safe and environmentally friendly, with no toxic reagents or heavy metal residues, making it more suitable for industrial production.

[0093] According to the method of the present invention, in step (1), the mass ratio of the transition metal catalyst to the hydrochloride is 0.05-10:1, preferably 0.1-5:1, and more preferably 0.4-0.6:1.

[0094] According to the method of the present invention, in step (1), the transition metal catalyst can be a commonly used transition metal catalyst in the art, preferably at least one of palladium catalyst, nickel catalyst and platinum catalyst, more preferably at least one of palladium on carbon, palladium hydroxide, palladium chloride, palladium black, Raney nickel and platinum oxide.

[0095] According to the method of the present invention, in step (1), the first solvent may be at least one of water, C1-C5 alcohol, tetrahydrofuran, dioxane and ethyl acetate.

[0096] According to the method of the present invention, in step (1), the first base may be at least one of sodium bicarbonate, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium phosphate, potassium dihydrogen phosphate, pyridine and triethylamine.

[0097] According to the method of the present invention, in step (1), the conditions for hydrogenation reduction may include: a temperature of 20-50°C, a time of 4h-7d, and a hydrogen partial pressure of 10-100atm; preferably, the conditions for hydrogenation reduction include: a temperature of 30-50°C, a time of 1-3d, and a hydrogen partial pressure of 20-50atm.

[0098] According to the method described in this invention, in step (1), the hydrogen chloride can be hydrogen chloride gas or commercially available hydrochloric acid. In a specific embodiment, the hydrogen chloride gas is prepared by in-situ reaction of acetyl chloride and an alcohol.

[0099] According to the method described in this invention, in step (1), 4-aminocyclohexanol is synthesized using 4-aminophenol as a raw material to synthesize pramipexole hydrochloride. In the prior art, trans-p-aminocyclohexanol is generally purchased directly as a raw material, which is costly. However, the inventors have found that whether trans- or cis-p-aminocyclohexanol is used is not important for the subsequent reaction results. Both will cause the product to racemize in the subsequent reaction. Therefore, although the 4-aminophenol used in this application is a mixture of several p-aminocyclohexanols, it has no effect on the final synthesis of pramipexole hydrochloride and greatly reduces the production cost. This is a significant advantage for reducing the overall production cost of industrially synthesized pramipexole.

[0100] According to the method of the present invention, in step (2), the molar ratio of 4-aminocyclohexanol to the first acylation reagent can be 1:0.5-1.5; preferably 1:0.8-1.2.

[0101] According to the method of the present invention, in step (2), the first acylation reagent may be propionic anhydride and / or propionyl chloride.

[0102] According to the method of the present invention, in step (2), the reaction conditions may include: a temperature of -10 to 50°C and a time of 10 min to 4 h; in a preferred case, the reaction conditions include: a temperature of -5 to 5°C and a time of 0.5 to 1.5 h.

[0103] According to the method of the present invention, in step (2), the reaction can be carried out under solvent-free conditions or in the presence of a solvent. When a solvent is used, the solvent is at least one of C1-C5 alcohols, tetrahydrofuran, dioxane, and dichloromethane.

[0104] According to the method of the present invention, in step (3), the molar ratio of the first acylation product, the reducing agent and the first catalyst can be 1:(2-5):(2-10), preferably 1:(2-4):(2-6), and more preferably 1:(2-3):(2-4).

[0105] According to the method of the present invention, in step (3), the reducing agent can be at least one of sodium borohydride, potassium borohydride, boranetetrahydrofuran, diisobutylaluminum hydride and red aluminum.

[0106] According to the method of the present invention, in step (3), the first catalyst may be at least one of boron trifluoride ether, elemental iodine, nickel chloride, magnesium chloride, zinc chloride, cobalt chloride, zinc acetate, and cobalt acetate.

[0107] According to the method of the present invention, in step (3), the organic solvent can be a commonly used organic solvent in the art, preferably at least one of tetrahydrofuran, diethyl ether, dioxane, benzene and toluene.

[0108] According to the method of the present invention, in step (3), the reaction conditions may include: a temperature of 5-70°C and a time of 0.5-6h; preferably, the reaction conditions include: a temperature of 25-50°C and a time of 1-3h.

[0109] According to the method described in this invention, in step (3), the reaction process further includes: after the reduction reaction, quenching with acid, and then neutralizing with alkali. The acid can be hydrochloric acid or sulfuric acid, and the alkali can be at least one of sodium bicarbonate, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium phosphate, and potassium dihydrogen phosphate. In a specific embodiment, neutralization with alkali adjusts the pH of the system to 8-9.

[0110] According to the method of the present invention, in step (4), the process of carrying out the acylation reaction of the reduction product may include: reacting the reduction product with a second acylation reagent. This reaction may be carried out in a solvent, which may be at least one of water, a C1-C5 alcohol, tetrahydrofuran, and dioxane.

[0111] According to the method of the present invention, in step (4), the molar ratio of the reduction product to the second acylation reagent can be 1:0.8-1.2, preferably 1:1-1.2.

[0112] According to the method of the present invention, in step (4), the second acylation agent can be at least one of ditert-butyl dicarbonate and tert-valerate chloride.

[0113] According to the method of the present invention, in step (4), the reaction conditions may include: a temperature of -10 to 50°C and a time of 0.5 to 4 hours; in a preferred case, the reaction conditions include: a temperature of 10 to 30°C and a time of 1 to 3 hours.

[0114] According to the method of the present invention, in step (4), the process of carrying out the acylation reaction of the reduction product may further include: reacting the reduction product with a third acylation reagent in the presence of a third catalyst, and then hydrolyzing it in the presence of a second base. The reaction can be carried out under solvent-free conditions or in a solvent. When a solvent is used, the solvent may be at least one of dichloromethane, tetrahydrofuran, dioxane, benzene, and toluene.

[0115] According to the method of the present invention, in step (4), the molar ratio of the reduction product, the third catalyst and the third acylation reagent can be 1:(0.05-6):(1-3), preferably 1:(0.1-3):(1.2-2.8), and more preferably 1:(0.2-1:(1.5-2.5).

[0116] According to the method of the present invention, in step (4), the third acylation agent can be at least one of acetic anhydride, acetyl chloride, propionic acid glycoside and propionyl chloride.

[0117] According to the method of the present invention, in step (4), the third catalyst can be at least one of sodium acetate, pyridine and iodine, preferably sodium acetate.

[0118] According to the method described in this invention, in step (4), the second alkali can be at least one of potassium carbonate, sodium carbonate, potassium hydroxide, and sodium hydroxide.

[0119] According to the method of the present invention, in step (4), the reaction conditions may include: a temperature of -10 to 70°C and a time of 10 min to 4 h; in a preferred case, the reaction conditions include: a temperature of 60 to 70°C and a time of 3 to 4 h.

[0120] According to the method described in this invention, in step (4), depending on the acylation reagent used, there are two routes for the reaction: when a second acylation reagent is used, the reduction product and the second acylation reagent directly undergo an acylation reaction in the presence of a solvent to obtain the second acylation product; when a third acylation reagent is used, the reduction product needs to react with the third acylation reagent first under the action of a third catalyst, and then hydrolyze under the action of a second base to obtain the second acylation product. This reaction can be carried out in a solvent or without a solvent.

[0121] According to the method of the present invention, in step (5), the specific process of oxidizing the second acylated product may include: mixing the second acylated product with a second catalyst, a phase transfer catalyst, a first oxidant and a third base in the presence of a second solvent.

[0122] According to the method of the present invention, in step (5), the molar ratio of the second acylation product, the second catalyst, the phase transfer catalyst, the first oxidant and the third base can be 100:(0.01-20):(0.1-20):(120-500):(1-50), preferably 100:(0.1-10):(0.3-10):(130-300):(3-30), and more preferably 100:(1-5):(0.5-5):(150-200):(5-20).

[0123] According to the method of the present invention, in step (5), the second catalyst may be at least one of sodium tungstate, ruthenium trichloride, ruthenium tetroxide and tetra-n-propyl perruthenium.

[0124] According to the method of the present invention, in step (5), the phase transfer catalyst can be at least one selected from tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, triethylbenzylammonium chloride, and triethylbenzylammonium bromide. Using a phase transfer catalyst allows the catalyst and oxidant, which are insoluble in the organic phase, to be transferred to the organic phase, thereby accelerating the reaction rate.

[0125] According to the method of the present invention, in step (5), the first oxidant can be at least one of hydrogen peroxide, sodium hypochlorite, sodium periodate, potassium peroxymonosulfate and N-methylmorpholine nitrogen oxides.

[0126] According to the method described in this invention, in step (5), the third alkali can be at least one of potassium carbonate, sodium carbonate, potassium hydroxide, and sodium hydroxide.

[0127] According to the method of the present invention, in step (5), the second solvent can be at least one of water, dichloromethane, trichloromethane, dichloroethane, ethyl acetate, tetrahydrofuran, and dioxane.

[0128] According to the method of the present invention, in step (5), the reaction conditions may include: a temperature of 15-60°C and a time of 0.5-8h; preferably, the reaction conditions include: a temperature of 35-45°C and a time of 0.5-1.5h.

[0129] According to the method of the present invention, in step (5), the specific process of oxidizing the second acylated product may further include: reacting the second acylated product with a second oxidizing agent in the presence of a third solvent, and then quenching it with a reducing agent.

[0130] According to the method of the present invention, in step (5), the molar ratio of the second acylated product to the second oxidant is 1:1.2-10, preferably 1:1.5-6, and more preferably 1:2-4.

[0131] According to the method of the present invention, in step (5), the second oxidant can be at least one of hydrogen peroxide, sodium hypochlorite, sodium periodate, potassium peroxymonosulfate and N-methylmorpholine nitrogen oxides.

[0132] According to the method of the present invention, in step (5), the reducing agent can be at least one of sodium thiosulfate, sodium sulfite, sodium bisulfite, potassium bisulfite and zinc powder.

[0133] According to the method of the present invention, in step (5), the third solvent can be at least one of water and C1-C5 acids.

[0134] According to the method of the present invention, in step (5), the reaction conditions may include: a temperature of -10 to 40°C and a time of 10 min to 4 h; in a preferred case, the reaction conditions include: a temperature of 15 to 30°C and a time of 0.5 to 1 h.

[0135] According to the method of the present invention, in step (6), the molar ratio of the oxidation product, the bromine and the thiourea can be 1:(0.5-1.5):(0.5-1.5), preferably 1:(0.8-1.2):(0.8-1.2), and most preferably 1:(0.9-1.1):(0.9-1.1).

[0136] According to the method of the present invention, in step (6), the acidic solvent can be a C1-C5 acid.

[0137] According to the method of the present invention, in step (6), the conditions for the bromination reaction may include: a temperature of -10 to 40°C and a time of 0.5 to 4 h; preferably, the conditions for the bromination reaction include: a temperature of 15 to 30°C and a time of 0.5 to 1.5 h.

[0138] According to the method of the present invention, in step (6), the conditions for the mixed reaction include: a temperature of 30-100°C and a time of 1-12h; preferably, the conditions for the bromination reaction include: a temperature of 60-80°C and a time of 3-6h.

[0139] According to the method described in this invention, in step (6), after the mixing reaction, a post-treatment is further included. The specific process of the post-treatment is as follows: when R in the oxidation product is acetyl or propionyl, the product after the thiourea mixing reaction is filtered out, mixed with an acidic reagent to remove the amino protecting group, and then mixed with a base for neutralization to obtain pramipexole hydrochloride; when R in the oxidation product is tert-butyloxycarbonyl, the filtered product after the thiourea mixing reaction is directly mixed with a base for neutralization to obtain pramipexole hydrochloride. The acidic reagent can be sulfuric acid or hydrochloric acid with a concentration of 1-6 mol / L; the base can be at least one of sodium bicarbonate, potassium carbonate, sodium carbonate, potassium hydroxide, and sodium hydroxide; the reaction conditions for removing the amino protecting group can include: a temperature of 70-100℃, a solvent of water, and a time of 1-7 days.

[0140] The method of the present invention further includes: purifying the product obtained in step (6) to obtain pramipexole hydrochloride of the S configuration, wherein the purification process includes the following steps:

[0141] S1: In the presence of the fourth solvent, the product obtained in step (6) is mixed with the first hydrochloric acid, then heated to dissolve and mixed with the first chiral acid, filtered to obtain pramipexole chiral acid salt A1, then mixed with the second hydrochloric acid, and neutralized with the fourth base to obtain pramipexole free base B1.

[0142] S2: Replace pramipexole with pramipexole free base B1 and repeat step S1 to obtain pramipexole free base B2;

[0143] S3: Mix the filtrates from S1 and S2, neutralize with the fifth base, and filter to obtain pramipexole free base L1. Then, in the presence of the fifth solvent, mix pramipexole free base L1 with the third hydrochloric acid, heat to dissolve, mix with the second chiral acid, and filter to obtain pramipexole chiral acid salt L2; then recrystallize.

[0144] According to the method described in this invention, most of the R-configuration pramipexole hydrochloride in the product is first converted into a solid salt and removed by a first chiral acid. Then, the filtrate is reacted with a second chiral acid to extract the S-configuration pramipexole hydrochloride. After recrystallization for further purification, high-purity S-configuration pramipexole hydrochloride can finally be obtained.

[0145] According to the method of the present invention, in step S1, the molar ratio of the product obtained in step (6), the first hydrochloric acid and the first chiral acid can be 1:(0.5-1.5):(0.5-1.5), preferably 1:(0.8-1.2):(0.8-1.2).

[0146] According to the method of the present invention, in step S1, the first chiral acid can be at least one of D-tartaric acid, D-malic acid and L-camphorsulfonic acid.

[0147] According to the method described in this invention, in step S1, the concentration of the first hydrochloric acid can be 10-15 mol / L, preferably 11-13 mol / L. In a specific embodiment, commercially available concentrated hydrochloric acid with a concentration of 12 mol / L is used.

[0148] According to the method described in this invention, in step S1, the concentration of the second hydrochloric acid can be 0.5-3 mol / L, preferably 0.5-1.5 mol / L.

[0149] According to the method of the present invention, in step S1, the fourth solvent can be at least one of C1-C5 alcohols, ethyl acetate, tetrahydrofuran and dioxane, preferably methanol and / or ethanol.

[0150] According to the method described in this invention, in step S1, the fourth alkali can be at least one of sodium bicarbonate, potassium carbonate, sodium carbonate, potassium hydroxide, and sodium hydroxide.

[0151] According to the method described in this invention, in step S1, the heating temperature can be 40-100℃, preferably 40-60℃.

[0152] According to the method of the present invention, in step S3, the molar ratio of the pramipexole free base L1, the third hydrochloric acid and the second chiral acid can be 1:(0.5-1.5):(0.5-1.5), preferably 1:(0.8-1.2):(0.8-1.2).

[0153] According to the method of the present invention, in step S3, the second chiral acid is at least one of L-tartaric acid, L-malic acid and D-camphorsulfonic acid;

[0154] According to the method described in this invention, in step S3, the concentration of the third hydrochloric acid can be 10-15 mol / L, preferably 11-13 mol / L. In a specific embodiment, commercially available concentrated hydrochloric acid with a concentration of 12 mol / L is used.

[0155] According to the method of the present invention, in step S3, the fifth solvent can be at least one of C1-C5 alcohols, ethyl acetate, tetrahydrofuran and dioxane, preferably methanol and / or ethanol.

[0156] According to the method described in this invention, in step S3, the fifth alkali can be at least one of sodium bicarbonate, potassium carbonate, sodium carbonate, potassium hydroxide, and sodium hydroxide.

[0157] According to the method described in this invention, in step S3, the heating temperature can be 40-100℃, preferably 40-60℃.

[0158] According to the method described in this invention, in step S3, the specific process of recrystallization includes: heating and dissolving pramipexole chiral acid salt L2, cooling to room temperature and filtering, neutralizing the solid product with a sixth base, then dissolving it in an alcohol solvent, mixing it with a fourth hydrochloric acid, and filtering.

[0159] According to the method described in this invention, in step S3, the sixth alkali can be at least one of sodium bicarbonate, potassium carbonate, sodium carbonate, potassium hydroxide, and sodium hydroxide.

[0160] According to the method of the present invention, in step S3, the alcohol solvent can be a C1-C5 alcohol, preferably isopropanol.

[0161] According to the method described in this invention, in step S3, the concentration of the fourth hydrochloric acid can be 10-15 mol / L, preferably 11-13 mol / L. In a specific embodiment, commercially available concentrated hydrochloric acid with a concentration of 12 mol / L is used.

[0162] According to the method described in this invention, in step S3, the recrystallization temperature can be 40-100℃, preferably 50-80℃.

[0163] According to the method of the present invention, in step S3, the solvent for heating and dissolving can be a mixture of an organic solvent and water; wherein, the organic solvent can be at least one of C1-C5 alcohols; the volume ratio of the organic solvent to water can be 1-50:1, preferably 5-20:1.

[0164] The preparation method of pramipexole hydrochloride described in this invention is as follows: Figure 1 and Figure 2 As shown, where Figure 1 Figure 1 This is a flowchart of the preparation method of pramipexole hydrochloride according to the present invention; Figure 2 This is a flowchart of the purification method for pramipexole hydrochloride according to the present invention. Figure 1 As shown, 4-aminophenol is first converted to hydrochloride under the action of hydrogen chloride, and then undergoes hydrogenation reduction under the action of a transition metal catalyst. After neutralization with a base, it yields 4-aminocyclohexanol. 4-Aminocyclohexanol then reacts with a first acylation reagent to give the first acylated product. The first acylated product undergoes a reduction reaction with a reducing agent under the action of a first catalyst to give the reduced product. The reduced product can directly react with a second acylation reagent to generate the second acylated product; alternatively, it can first react with a third acylation reagent under the action of a third catalyst, and then hydrolyze under the action of a second base to obtain the second acylated product. The oxidation of the second acylated product to an oxidation product can also be divided into two systems: when using a catalyst system, the second acylated product is mixed with a second catalyst, a phase transfer catalyst, a first oxidant, and a third base to react and generate the oxidation product; when not using a catalyst system, the second acylated product is mixed with a second oxidant, and then quenched with a reducing agent to obtain the oxidation product. Finally, the oxidation product is first reacted with bromine to complete bromination, then reacted with thiourea, the product is filtered, the amino protecting group is removed under acidic conditions and then neutralized with alkali, or the filtered product is directly neutralized with alkali to obtain pramipexole, which is then purified to obtain pramipexole hydrochloride.

[0165] In a specific implementation, the purification process is as follows: Figure 2 As shown, pramipexole reacts with a first chiral acid in the presence of a first hydrochloric acid to generate pramipexole chiral acid salt A1. The chiral acid salt A1 is filtered out and redissolved in a second hydrochloric acid. After neutralization with a fourth base, pramipexole free base B1 is generated. The above steps are repeated with pramipexole free base B1. At this point, most of the R-configuration pramipexole hydrochloride reacts with the first chiral acid to form a solid product, which is removed. The solution then contains mostly S-configuration pramipexole hydrochloride. The mother liquors from both filtrations are mixed, and a fifth base is added for neutralization to obtain solid pramipexole free base L1. This L1 is then mixed with a third hydrochloric acid, heated to dissolve, and then reacted with a second chiral acid. Pramipexole chiral acid salt L2 is generated. At this point, solid pramipexole chiral acid salt L2 is a salt formed by pramipexole hydrochloride with S configuration and a second chiral acid. The solid pramipexole chiral acid salt L2 is then dissolved by heating in a mixed solvent of organic solvent and water. After cooling to room temperature, the precipitated solid is filtered to obtain a recrystallized product. The recrystallized product is neutralized with a sixth base to obtain the free base of pramipexole chiral acid salt L3. The recrystallization and base addition steps can be repeated 1-3 times. The final free base of pramipexole chiral acid salt is mixed with an alcohol solvent, dissolved by heating, and then a fourth hydrochloric acid is added dropwise. After cooling, the solid produced is filtered to obtain pramipexole hydrochloride with S configuration.

[0166] The following examples further illustrate the preparation and purification method of pramipexole hydrochloride according to the present invention. These examples are implemented based on the technical solution of the present invention, providing detailed implementation methods and specific operating procedures; however, the scope of protection of the present invention is not limited to the following examples.

[0167] Unless otherwise specified, the experimental methods used in the following embodiments are conventional methods in the art. Unless otherwise specified, the experimental materials used in the following embodiments are commercially available.

[0168] Example 1

[0169] (1) Dissolve 20g of 4-aminophenol in 50mL of ethyl acetate to obtain an ethyl acetate solution of 4-aminophenol. Then, add 19.6mL of acetyl chloride dropwise to 75mL of anhydrous methanol under an ice-water bath. After maintaining the solution for 1h, add the resulting solution dropwise to the ethyl acetate solution of 4-aminophenol. Continue the reaction under an ice-water bath for 2h. After the reaction is complete, remove methanol and excess acid by rotary evaporation to obtain 26.5g of 4-aminophenol hydrochloride. Dissolve 1g of 4-aminophenol hydrochloride in 30mL of anhydrous methanol and add 0.5... g of PtO2 was added, then argon gas was used for protection, followed by vacuuming and then hydrogen gas. This process was repeated three times until the hydrogen pressure was 20 atm. The temperature was raised to 50℃ and reacted for 2 days. The catalyst was removed by filtration. 0.6 g of sodium bicarbonate was added to the resulting hydrochloride methanol solution to neutralize the acidity, and then the methanol was removed by rotary evaporation. The resulting product was dissolved in 50 mL of ethyl acetate, and the insoluble matter was removed by filtration. The product was washed three times with ethyl acetate, and the filtrate was evaporated to dryness to obtain 4-aminocyclohexanol. The conversion rate was 100% as determined by 1H NMR spectroscopy. The 4-aminocyclohexanol and hydrochloric acid ratio was: δ H (300MHz; D2O)3.99(0.33H,s),3.82-3.54(0.44H,m),3.25-3.13(1.13H,m),2.03-1.97(2H,m),1.80-1.66(4H,m),1.61-1.17(3.6H,m);

[0170] (2) 0.87 mol of 4-aminocyclohexanol was dissolved in 300 mL of methanol. 0.87 mol of propionic anhydride was added under ice-water bath conditions. After reacting for 1 h, TLC showed the reaction was complete. The solvent and acid were removed by rotary evaporation to obtain 4-propionylaminocyclohexanol. The conversion rate was 100% as determined by 1H NMR spectroscopy. 4-Propionylaminocyclohexanol: mp 159-161℃; δ H (300MHz; D2O)3.59-3.44(2H,m),2.23(2H,dd,J=15.3Hz,7.5Hz),1.90-1.78(4H,m),1.34-1.15(4H,m),1.01(3H,t,J=7.7Hz);

[0171] (3) 0.74 mol of 4-propionylaminocyclohexanol was dissolved in 1 L of dry tetrahydrofuran. 2.21 mol of sodium borohydride was added at 5 °C. After stirring for 5 minutes, 2.65 mol of boron trifluoride diethyl ether was added dropwise. The mixture was heated to room temperature for 0.5 h, then heated to 50 °C and reacted for another 2 h. After the reaction was confirmed to be complete by TLC, the mixture was cooled to room temperature and quenched by slowly pouring in 1.5 L of 1 mol / L hydrochloric acid at 0 °C. The solvent and some water were removed by rotary evaporation. Sodium hydroxide solution was added to neutralize the pH of the system to 8-9. Most of the water was removed by rotary evaporation. The residue was dissolved in 800 mL of a mixed solvent of ethyl acetate and methanol in a ratio of 5:1. After filtering out the insoluble matter, the filtrate was evaporated to dryness to obtain 4-propionylaminocyclohexanol. The conversion rate was 77% as determined by 1H NMR spectroscopy. Among them, 4-propionylaminocyclohexanol: δ H (300MHz; D2O)3.64-3.56(1H,m),3.11-3.01(1H,m),2.96(2H,t,J=7.7Hz),2.11-2.06(2H,m) ,2.03-1.98(2H,m),2.23(2H,dd,J=23.1Hz,7.8Hz),1.48-1.23(4H,m),0.91(3H,t,J=7.5Hz);

[0172] (4) 166.7 mmol of 4-propylaminocyclohexanol was dissolved in 50 mL of dichloromethane, 95.1 mmol of sodium acetate and 190 mmol of acetic anhydride were added, and the mixture was reacted at 50 °C for 3 h. After the reaction was complete as detected by TLC, the mixture was cooled to room temperature, and pyridine and solvent were removed by rotary evaporation. Sodium hydroxide solution was added to adjust the pH of the system to 10, and the mixture was stirred for 0.5 h until the diacetylation product was completely reacted as shown by TLC. The mixture was then extracted with dichloromethane, dried over anhydrous magnesium sulfate, and rotary evaporated to obtain 4-(N-propylacetamido)cyclohexanol. The conversion rate was 84.3% as detected by 1H NMR. 4-(N-propylacetamido)cyclohexanol: δ H (300MHz; CDCl3)6.52(0.5H,s,br),6.03(0.5H,s,br),4.26-4.16(1H,m),3.58-3.52(1H,m),3.12-3.05 (2H,m),2.11-2.00(6H,m),1.77-1.66(2H,m),1.57-1.47(4H,m),1.46-1.36(2H,m),0.94-0.84(3H,m);

[0173] (5) 95.48 mmol of 4-(N-propylacetamido)cyclohexanol was dissolved in 80 mL of glacial acetic acid. The temperature was kept below 20 °C. 190 mmol of 5 wt% sodium hypochlorite solution was added dropwise. The reaction was allowed to proceed for 0.5 h. After the reaction was confirmed to be complete by TLC, saturated sodium thiosulfate solution was added to quench the reaction. The system was extracted with ethyl acetate, and the pH of the system was adjusted to 8 with sodium hydroxide solution. The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness to obtain 4-(N-propylacetamido)cyclohexanone. The conversion rate was 98.4% as determined by 1H NMR spectroscopy. Mp 46-48 °C; δ H (300MHz; CDCl3)4.71-4.65(0.7H,m),4.04-3.96(0.2H,m),3.09-3.02(2H,m),2.50-2.32(4H ,m),2.13(0.7H,s),2.05(2.3H,s),2.03-1.80(4H,m),1.59-1.46(2H,m),0.88-0.78(3H,m).

[0174] (6) 0.15 mol of 4-(N-propylacetamido)cyclohexanone was dissolved in 100 mL of glacial acetic acid. 0.15 mol of bromine was added dropwise at a temperature below 20 °C. After reacting for 1 h, and confirming complete reaction by TLC, 0.15 mmol of thiourea was added. The temperature was raised to 70 °C and stirred vigorously for 4 h. After the bromine intermediate disappeared as confirmed by TLC, the mixture was cooled to room temperature and filtered to obtain a white solid. The solid was washed with acetone and dried to obtain (±)-N6-acetylprapraxol hydrobromide. The obtained product was dissolved in 50 mL of water, and 8 mL of 18 mol / L sulfuric acid was added dropwise. The mixture was refluxed for 7 days until TLC confirmed complete reaction. After cooling to room temperature, the pH of the system was adjusted to 9-10 with sodium hydroxide solution. After stirring for 1 h, the mixture was filtered. The obtained solid was washed with water and dried to obtain (±)-prapraxol, with a yield of 93.8%. (±)-prapraxol: δ H (300MHz; MeOD)2.93-2.91(1H,m),2.84(1H,dd,J=15.0Hz,4.5Hz),2.65-2.60(2H,m),2.56-2.40(2 H,m),2.36(1H,dd,J=15.0Hz,9.0Hz),2.17-2.06(1H,m),1.71-1.50(3H,m),0.96(3H,t,J=7.5Hz);

[0175] (7) Purification

[0176] S1: Dissolve 0.96 mol of (±)-prapixol in 2 L of methanol. Add 0.96 mol of 12 mol / L hydrochloric acid dropwise at room temperature. After stirring for 5 min, a large number of white particles appear. Heat to 50 °C to dissolve the white particles. Add 0.96 mol of D-tartaric acid. Stir for 1 h and cool to room temperature. A white solid is formed. Filter the solid and wash it with methanol. Collect the filtrate for later use. Dissolve the white solid in 500 mL of 1 mol / L hydrochloric acid. Adjust the pH of the system to 9-10 with sodium hydroxide solution. Stir for 0.5 h and filter. Wash the obtained solid with water and dry it to obtain pramipexole free base B1.

[0177] S2: The pramipexole free base B1 obtained in S1 was dissolved in 2L of methanol. 0.96 mol of 12 mol / L hydrochloric acid was added dropwise at room temperature. After stirring for 5 min, the temperature was raised to 50℃ to dissolve the generated white particles. Then, 0.96 mol of D-tartaric acid was added, and the mixture was stirred for 1 h. After cooling to room temperature, the white solid was filtered off and washed with methanol. The filtrate was collected for later use. The white solid was dissolved in 500 mL of 1 mol / L hydrochloric acid. The pH of the system was adjusted to 9-10 with sodium hydroxide solution. After stirring for 0.5 h, the mixture was filtered. The resulting solid was washed with water and dried to obtain pramipexole free base B2. Polarimetry analysis showed that B2: [α] D 20 +88.5 (c 1.13in MeOH);

[0178] S3: Combine the filtrates collected in S1 and S2, adjust the pH of the system to 9-10 with sodium hydroxide solution, stir for 0.5 h, filter, wash the obtained solid with water, dry to obtain 126.5 g of 0.6 mol of pramipexole free base L1, then add 0.6 mol of 12 mol / L hydrochloric acid dropwise at room temperature, stir for 5 minutes, heat to 50 °C to dissolve the white solid, then add 0.6 mol of L-tartaric acid, stir for 1 h, cool to room temperature, filter the resulting white solid, wash with methanol, then dissolve in sodium hydroxide solution, adjust the pH of the solution to 9-10, stir for 0.5 h, filter, wash the obtained solid with water, dry to obtain pramipexole L-tartrate L2; wherein, the purity of L1, as determined by liquid chromatography and polarimetry, is 41.9 ee%. [α] D 20 -59.5 (c 1.13 in MeOH); L2, HPLC purity: 87.6 ee%. [α] D 20 -78.4 (c 1.02in MeOH);

[0179] S4: Recrystallization: Pramipexole L-tartrate L2 was dissolved in 900 mL of a methanol-water mixture (methanol:water ratio 10:1). After stirring at 60 °C for 2 h, the mixture was cooled to room temperature, resulting in the precipitation of a large amount of white solid. This solid was filtered and washed with methanol to obtain the recrystallized product. The product was then dissolved in sodium hydroxide solution, and the pH was adjusted to 9-10. After stirring for 0.5 h, the mixture was filtered to obtain the free base L3 of Pramipexole L-tartrate. The resulting solid was then washed with water, dried, and the above operation was repeated. Finally, the solid was dissolved in 300 mL of 1 mol / L hydrochloric acid, and sodium hydroxide solution was added to adjust the pH... The solution was prepared with a pH of 9-10. After stirring for 0.5 h, the mixture was filtered. The resulting solid was washed with water and dried to obtain pramipexole L-tartrate free base L4. Pramipexole L-tartrate free base L4 was dissolved in 600 mL of isopropanol, heated to 75 °C and stirred for 20 min. 1.14 mmol of 12 mol / L hydrochloric acid was added dropwise, and stirring continued for 30 min. After cooling to room temperature, a white solid was filtered off and washed with isopropanol to obtain 105.6 g of (S)-pramipexole hydrochloride, with a yield of 92.3%. The purity of L3 was determined by liquid chromatography and polarimetry to be 96.9 ee%. [α] D 20 -86.9 (c 0.99 in MeOH); L4, HPLC purity: 99.1 ee%; [α] D 20 -93.9 (c 0.98in MeOH).

[0180] Example 2

[0181] (1) Dissolve 20g of 4-aminophenol in 50mL of ethyl acetate to obtain an ethyl acetate solution of 4-aminophenol. Then, add 19.6mL of acetyl chloride dropwise to 75mL of anhydrous methanol under an ice-water bath. After maintaining the solution for 1 hour, add the resulting solution dropwise to the ethyl acetate solution of 4-aminophenol and continue the reaction under an ice-water bath for 2 hours. After the reaction is complete, remove methanol and excess acid by rotary evaporation to obtain 26.5g of 4-aminophenol hydrochloride. Dissolve 10g of 4-aminophenol hydrochloride in 150mL of anhydrous methanol. 0.5 g of PtO2 was added to water-methanol, and then argon gas was added for protection. After evacuation, hydrogen gas was added. This process was repeated three times until the hydrogen pressure was 50 atm. The temperature was raised to 50 °C and the reaction was carried out for 7 days. The catalyst was removed by filtration. 6 g of sodium bicarbonate was added to the resulting hydrochloride-methanol solution to neutralize the acidity. Then, methanol was removed by rotary evaporation. The resulting product was dissolved in 50 mL of ethyl acetate. The insoluble matter was removed by filtration and the product was washed three times with ethyl acetate. The filtrate was dried by rotary evaporation to obtain 4-aminocyclohexanol. The conversion rate was 100% as detected by 1H NMR.

[0182] Steps (2) to (7) are the same as in Example 1.

[0183] Example 3

[0184] (1) Dissolve 20g of 4-aminophenol in 50mL of ethyl acetate to obtain an ethyl acetate solution of 4-aminophenol. Then, add 19.6mL of acetyl chloride dropwise to 75mL of anhydrous methanol under an ice-water bath. After maintaining the solution for 1h, add the resulting solution dropwise to the ethyl acetate solution of 4-aminophenol and continue the reaction under an ice-water bath for 2h. After the reaction is complete, remove methanol and excess acid by rotary evaporation to obtain 26.5g of 4-aminophenol hydrochloride. Dissolve 1g of 4-aminophenol hydrochloride in 30mL of anhydrous methanol. 0.33 g of PtO2 was added to the alcohol, and then argon gas was used for protection. After evacuation, hydrogen gas was used instead. This process was repeated three times until the hydrogen pressure was 40 atm. The temperature was raised to 50 °C and the reaction was carried out for 7 days. The catalyst was removed by filtration. 0.6 g of sodium bicarbonate was added to the resulting hydrochloride methanol solution to neutralize the acidity. Then, methanol was removed by rotary evaporation. The product was dissolved in 50 mL of ethyl acetate, and the insoluble matter was removed by filtration. The product was washed three times with ethyl acetate. The filtrate was dried by rotary evaporation to obtain 4-aminocyclohexanol. The conversion rate was 77% as detected by 1H NMR.

[0185] Steps (2) to (7) are the same as in Example 1.

[0186] Example 4

[0187] (1) and (2) are the same as in Example 1;

[0188] (3) 95.3 mmol of 4-propionylaminocyclohexanol was dissolved in 100 mL of dry tetrahydrofuran. 290 mmol of sodium borohydride was added at 5 °C. After stirring for 5 minutes, 340 mmol of boron trifluoride diethyl ether was added dropwise. The mixture was heated to room temperature for 0.5 h and then heated to 50 °C for another 2 h. After the reaction was confirmed to be complete by TLC, the mixture was cooled to room temperature and quenched by slowly pouring in 300 mL of 1 mol / L hydrochloric acid at 0 °C. The solvent and some water were removed by rotary evaporation. Sodium hydroxide solution was added to neutralize the pH of the system to 8-9. Most of the water was removed by rotary evaporation. The residue was dissolved in 100 mL of a mixed solvent of ethyl acetate and methanol in a ratio of 5:1. After filtering out the insoluble matter, the filtrate was evaporated to dryness to obtain 4-propionylaminocyclohexanol. The conversion rate was 80% as determined by 1H NMR.

[0189] (4) to (7) are the same as in Example 1.

[0190] Example 5

[0191] (1) and (2) are the same as in Example 1;

[0192] (3) 5.85 mmol of 4-propionylaminocyclohexanol was dissolved in 20 mL of dry tetrahydrofuran. 17.57 mmol of sodium borohydride was added at 5 °C. After stirring for 5 minutes, 17.56 mmol of nickel chloride was added dropwise. The mixture was heated to room temperature for 0.5 h and then heated to 50 °C for another 2 h. After the reaction was confirmed to be complete by TLC, the mixture was cooled to room temperature and quenched by slowly pouring in 20 mL of 1 mol / L hydrochloric acid at 0 °C. The solvent and some water were removed by rotary evaporation. Sodium hydroxide solution was added to neutralize the pH of the system to 8-9. Most of the water was removed by rotary evaporation. The residue was dissolved in 30 mL of a mixed solvent of ethyl acetate and methanol in a ratio of 5:1. After filtering out the insoluble matter, the filtrate was evaporated to dryness to obtain 4-propionylaminocyclohexanol. The conversion rate was 77% as determined by 1H NMR.

[0193] (4) to (7) are the same as in Example 1.

[0194] Example 6

[0195] (1) and (2) are the same as in Example 1;

[0196] (3) 5.85 mmol of 4-propionylaminocyclohexanol was dissolved in 20 mL of dry tetrahydrofuran. 17.57 mmol of sodium borohydride was added at 5 °C. After stirring for 5 minutes, 17.56 mmol of elemental iodine was added dropwise. The mixture was heated to room temperature for 0.5 h and then heated to 50 °C for another 2 h. After the reaction was confirmed to be complete by TLC, the mixture was cooled to room temperature and quenched by slowly pouring in 20 mL of 1 mol / L hydrochloric acid at 0 °C. The solvent and some water were removed by rotary evaporation. Sodium hydroxide solution was added to neutralize the pH of the system to 8-9. Most of the water was removed by rotary evaporation. The residue was dissolved in 30 mL of a mixed solvent of ethyl acetate and methanol in a ratio of 5:1. After filtering out the insoluble matter, the filtrate was evaporated to dryness to obtain 4-propionylaminocyclohexanol. The conversion rate was 56% as detected by 1H NMR.

[0197] (4) to (7) are the same as in Example 1.

[0198] Example 7

[0199] (1) to (3) are the same as in Example 1;

[0200] (4) 0.12 mol of 4-propylaminocyclohexanol was dissolved in 50 mL of dichloromethane, 0.58 mol of pyridine and 0.25 mol of acetic anhydride were added, and the mixture was reacted at 70 °C for 3 h. After the reaction was complete as detected by TLC, the mixture was cooled to room temperature, and pyridine and solvent were removed by rotary evaporation. Sodium hydroxide solution was added to adjust the pH of the system to 10, and the mixture was stirred for 0.5 h until the diacetylated product was completely reacted as shown by TLC. The mixture was then extracted with dichloromethane, dried over anhydrous magnesium sulfate, and rotary evaporated to obtain 4-(N-propylacetamido)cyclohexanol. The conversion rate was 89.6% as detected by 1H NMR.

[0201] (5) to (7) are the same as in Example 1.

[0202] Example 8

[0203] (1) to (3) are the same as in Example 1;

[0204] (4) 11.4 mmol of 4-propylaminocyclohexanol was dissolved in 20 mL of dichloromethane, 25.46 mmol of elemental iodine and 25.46 mmol of acetic anhydride were added, and the mixture was reacted at 70 °C for 3 h. After the reaction was complete as detected by TLC, the mixture was cooled to room temperature, pyridine and solvent were removed by rotary evaporation, sodium hydroxide solution was added to adjust the pH of the system to 10, and the mixture was stirred for 0.5 h until the diacetylation product was completely reacted as shown by TLC. The mixture was then extracted with dichloromethane, dried over anhydrous magnesium sulfate, and evaporated by rotary evaporation to obtain 4-(N-propylacetamido)cyclohexanol. The conversion rate was 82% as detected by 1H NMR.

[0205] (5) to (7) are the same as in Example 1.

[0206] Example 9

[0207] (1) to (4) are the same as in Example 1;

[0208] (5) 5.03 mmol of 4-(N-propylacetamido)cyclohexanol and 0.44 mmol of triethylbenzylammonium chloride were added to 40 mL of a mixed solvent of dichloromethane and water, wherein the volume ratio of dichloromethane to water was 1:1. Then, 0.72 mmol of potassium carbonate and 9.35 mmol of sodium periodate were added sequentially. After stirring for 5 min, 0.04 mmol of ruthenium trichloride trihydrate was added under vigorous stirring. The mixture was heated to 40 °C and reacted for 1 h. After the reaction was confirmed to be complete by TLC, the mixture was cooled to room temperature, separated, and the aqueous phase was extracted with dichloromethane and dried with anhydrous magnesium sulfate. The organic phase was then evaporated to dryness to obtain 4-(N-propylacetamido)cyclohexanone. The conversion rate was 83% as determined by 1H NMR.

[0209] (6) and (7) are the same as in Example 1.

[0210] Example 10

[0211] (1) to (4) are the same as in Example 1;

[0212] (5) 0.8 mol of 4-(N-propylacetamido)cyclohexanol and 7.93 mmol of tetrabutylammonium chloride were added to 750 mL of a mixed solvent of dichloromethane and water, wherein the volume ratio of dichloromethane to water was 2:1. Then, 79.7 mmol of potassium carbonate and 1.21 mol of sodium periodate were added sequentially. After stirring for 5 min, 0.76 mmol of ruthenium trichloride trihydrate was added under vigorous stirring. The mixture was heated to 40 °C and reacted for 1 h. After the reaction was confirmed to be complete by TLC, the mixture was cooled to room temperature, separated, and the aqueous phase was extracted with dichloromethane and dried with anhydrous magnesium sulfate. The organic phase was then evaporated to dryness to obtain 4-(N-propylacetamido)cyclohexanone. The conversion rate was 85.4% as determined by 1H NMR.

[0213] (6) and (7) are the same as in Example 1.

[0214] Example 11

[0215] (1) to (3) are the same as in Example 1;

[0216] (4) 0.88 mol of 4-propylaminocyclohexanol was dissolved in 500 mL of methanol, and 0.97 mol of di-tert-butyl dicarbonate was added. The mixture was reacted at room temperature for 2 h. After the reaction was complete as detected by TLC, 500 mL of water was added, and the mixture was extracted with dichloromethane, dried over anhydrous magnesium sulfate, and rotary evaporated to obtain 4-(N-propyltert-butyloxycarbonylamino)cyclohexanol. The conversion rate was 88.7% as detected by 1H NMR spectroscopy. Among them, 4-(N-propyltert-butyloxycarbonylamino)cyclohexanol was obtained. Carbonylamino)cyclohexanol: δH (300MHz; CDCl3) 3.83 (1H,s,br), 3.58-3.51 (1H,m), 2.98 (2H,s), 2.63 (1H,s), 2.01 (2H,t,J=11.7Hz), 1.74-1.65 (2H,m), 1.56-1.35 (15H,m), 0.86 (3H,t,J=7.4Hz);

[0217] (5) 3.9 mmol of 4-(N-propyltert-butyloxycarbonylamino)cyclohexanol and 0.4 mmol of tetrabutylammonium chloride were added to 30 mL of a mixed solvent of dichloromethane and water in a ratio of 2:1. Then, 0.4 mmol of potassium carbonate and 6.1 mmol of sodium periodate were added sequentially. After stirring for 5 minutes, 0.19 mmol of ruthenium trichloride trihydrate was added under vigorous stirring. The temperature was then raised to 40 °C and reacted for 1 h. The reaction was monitored by TLC until complete, and then cooled to 40 °C. At room temperature, the aqueous phase was extracted with dichloromethane, and the organic phase was dried with anhydrous magnesium sulfate and evaporated to dryness to obtain 4-(N-propyl tert-butoxycarbonylamino)cyclohexanone. The conversion rate was 96.8% as determined by 1H NMR spectroscopy. The 4-(N-propyl tert-butoxycarbonylamino)cyclohexanone values ​​were: Mp 65-67℃; δH (300MHz; CDCl3) 4.33 (1H, s, br), 3.03 (2H, t, J = 7.4Hz), 2.48-2.40 (4H, m), 2.04 (2H, dd, J = 12.3Hz, 3.0Hz), 1.91 (2H, dd, J = 12.0Hz, 5.1Hz), 1.56-1.48 (12H, m), 0.87 (3H, t, J = 7.4Hz).

[0218] (6) 0.46 mol of 4-(N-propyltert-butyloxycarbonylamino)cyclohexanone was dissolved in 500 mL of glacial acetic acid. 0.46 mol of bromine was added dropwise at a temperature below 20 °C. After reacting for 1 h, 0.46 mmol of thiourea was added after the reaction was confirmed to be complete by TLC. The temperature was then raised to 70 °C and stirred vigorously for 8 h. A large number of white particles appeared. After the bromine intermediate disappeared by TLC, the temperature was lowered to room temperature and filtered to obtain a white solid. After washing with acetone, the product was dissolved in 300 mL of water. The pH of the system was adjusted to 9-10 with sodium hydroxide solution. After stirring for 1 h, the product was filtered. The obtained solid was washed with water and dried to obtain (±)-praxexole. The conversion rate was 84.2% as determined by 1H NMR.

[0219] (7) Same as Example 1.

[0220] Example 12

[0221] (1) to (4) are the same as in Example 11;

[0222] (5) 3.9 mmol of 4-(N-propyl tert-butyloxycarbonylamino)cyclohexanol and 0.4 mmol of tetrabutylammonium chloride were added to 30 mL of a mixed solvent of dichloromethane and water, wherein the ratio of dichloromethane to water was 2:1. Then, 0.4 mmol of potassium carbonate and 6.1 mmol of sodium periodate were added sequentially. After stirring for 5 minutes, 0.004 mmol of ruthenium trichloride trihydrate was added under vigorous stirring. The temperature was then raised to 40 °C and reacted for 3 h. After the reaction was complete as detected by TLC, the temperature was lowered to room temperature. The aqueous phase was extracted with dichloromethane and the organic phase was dried with anhydrous magnesium sulfate. The organic phase was dried by rotary evaporation to obtain 4-(N-propyl tert-butyloxycarbonylamino)cyclohexanone. The conversion rate was 85.7% as detected by 1H NMR.

[0223] (6) and (7) are the same as in Example 11.

[0224] Example 13

[0225] (1) to (4) are the same as in Example 11;

[0226] (5) 3.9 mmol of 4-(N-propyl tert-butyloxycarbonylamino)cyclohexanol and 0.4 mmol of tetrabutylammonium chloride were added to 30 mL of a mixed solvent of ethyl acetate and water, wherein the ratio of ethyl acetate to water was 2:1. Then, 0.4 mmol of potassium carbonate and 6.1 mmol of sodium periodate were added sequentially. After stirring for 5 minutes, 0.004 mmol of ruthenium trichloride trihydrate was added under vigorous stirring. The temperature was then raised to 40 °C and reacted for 4 h. After the reaction was complete as detected by TLC, the temperature was lowered to room temperature. The aqueous phase was extracted with dichloromethane and the organic phase was dried with anhydrous magnesium sulfate. The organic phase was dried by rotary evaporation to obtain 4-(N-propyl tert-butyloxycarbonylamino)cyclohexanone. The conversion rate was 81.6% as detected by 1H NMR.

[0227] (6) and (7) are the same as in Example 11.

[0228] Example 14

[0229] (1) to (4) are the same as in Example 11;

[0230] (5) 3.9 mmol of 4-(N-propyl tert-butyloxycarbonylamino)cyclohexanol and 0.4 mmol of tetrabutylammonium chloride were added to 30 mL of a mixed solvent of dichloromethane and water, wherein the ratio of dichloromethane to water was 2:1. Then, 0.4 mmol of potassium carbonate and 6.1 mmol of sodium periodate were added sequentially. After stirring for 5 minutes, 0.0004 mmol of ruthenium trichloride trihydrate was added under vigorous stirring. The temperature was then raised to 40 °C and reacted for 8 h. After the reaction was complete as detected by TLC, the temperature was lowered to room temperature. The aqueous phase was extracted with dichloromethane and the organic phase was dried with anhydrous magnesium sulfate. The organic phase was dried by rotary evaporation to obtain 4-(N-propyl tert-butyloxycarbonylamino)cyclohexanone. The conversion rate was 80.6% as detected by 1H NMR.

[0231] (6) and (7) are the same as in Example 11.

[0232] Example 15

[0233] (1) to (4) are the same as in Example 11;

[0234] (5) 6.3 mmol of 4-(N-propyl tert-butyloxycarbonylamino)cyclohexanol was dissolved in 10 mL of glacial acetic acid. 11.5 mmol of 5 wt% sodium hypochlorite solution was added dropwise at a temperature below 20 °C. The reaction was allowed to proceed for 0.5 h. After the reaction was confirmed to be complete by TLC, saturated sodium thiosulfate solution was added to quench the reaction. The mixture was then extracted with ethyl acetate. The organic phases were combined and the pH of the organic phase was adjusted to 8 with sodium hydroxide solution. The organic phases were collected by separation. The aqueous phase was extracted again with ethyl acetate and combined with the previous organic phase. The mixture was dried with anhydrous magnesium sulfate and evaporated to dryness to obtain 4-(N-propyl tert-butyloxycarbonylamino)cyclohexanone. The conversion rate was 96.4% as determined by 1H NMR spectroscopy.

[0235] (6) and (7) are the same as in Example 11.

[0236] Example 16

[0237] (1) to (4) are the same as in Example 11;

[0238] (5) 0.14 mol of 4-(N-propyl tert-butyloxycarbonylamino)cyclohexanol was dissolved in 500 mL of glacial acetic acid. 0.37 mol of 5 wt% sodium hypochlorite solution was added dropwise at a temperature below 20 °C. After reacting for 0.5 h, the reaction was detected by TLC to be complete. Saturated sodium thiosulfate solution was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic phases were combined. The pH of the organic phase was adjusted to 8 with sodium hydroxide solution. The organic phases were collected by separation, and the aqueous phase was extracted again with ethyl acetate. The aqueous phase was combined with the previous organic phase, dried with anhydrous magnesium sulfate, and evaporated to dryness to obtain 4-(N-propyl tert-butyloxycarbonylamino)cyclohexanone. The conversion rate was detected by 1H NMR spectroscopy to be 89.8%.

[0239] (6) and (7) are the same as in Example 11.

[0240] Comparative Example 1

[0241] (1) to (6) are the same as in Example 1;

[0242] (7) Purification: 0.85 mol of (±)-prapiphoroxane was dissolved in 1800 mL of methanol, and 0.84 mol of 12 mol / L hydrochloric acid was added dropwise. After stirring for 5 min, a large number of white particles appeared. The temperature was raised to 50 °C to dissolve the white solid. Then, 0.85 mol of L-tartaric acid was added, and after stirring for 1 h, the mixture was cooled to room temperature. The resulting white solid was filtered and washed with methanol. Then, recrystallization was carried out in methanol. This process was repeated 15 times to obtain (S)-prapiphoroxane hydrochloride with a yield of 15.6%. The HPLC purity was 96.5%.

[0243] Comparative Example 2

[0244] (1) Dissolve 87 mmol of trans-4-aminocyclohexanol in 200 mL of dichloromethane, add 87 mmol of propionic anhydride dropwise at a temperature of 5-10 °C, and then heat to 25 °C and react for 2 hours. After TLC shows that the reaction is complete, remove the solvent by rotary evaporation to obtain trans-4-propionylaminocyclohexanol. The conversion rate was 100% as detected by 1H NMR.

[0245] (2) 58 mmol of trans-4-propionylaminocyclohexanol was dissolved in 100 mL of acetone. 0.12 mol of Jones reagent was added at 5-10 °C for oxidation. After 2 hours of reaction, the reaction was shown to be complete by TLC. 40 mL of isopropanol was added to quench the reaction. Then, 50 mL of ethyl acetate was added to dilute the solution. The solution was filtered through diatomaceous earth to remove insoluble matter and washed three times with 30 mL of ethyl acetate. 50 mL of ethyl acetate was added to the filter cake and stirred at 40-50 °C for 30 min. The solution was filtered again and the above operation was repeated twice to remove insoluble salt byproducts. Finally, the ethyl acetate filtrate was evaporated to dryness and 50 mL of n-hexane was added. The solution was then crystallized at 0-5 °C to obtain 4-propionylaminocyclohexanone. The conversion rate was 77% as detected by 1H NMR.

[0246] (3) Dissolve 0.10 mol of 4-propionylaminocyclohexanone in 70 mL of glacial acetic acid, add 0.10 mol of bromine dropwise at a temperature below 20 °C, react for 1 h, and after the reaction is complete as detected by TLC, add 0.10 mmol of thiourea, heat to 70 °C and stir vigorously for 4 h. After the bromine intermediate disappears as detected by TLC, cool to room temperature, filter to obtain a white solid, wash with ethyl acetate, and dry to obtain 2-amino-6-(N-propionyl)-4,5,6,7-tetrahydrobenzothiazole hydrobromide; dissolve the obtained product in 50 mL of water, adjust the pH of the system to 9-10 with sodium hydroxide solution, stir for 0.5 h and filter, wash the obtained solid with water and dry to obtain 2-amino-6-(N-propionyl)-4,5,6,7-tetrahydrobenzothiazole, with a yield of 92%;

[0247] (4) 10 mmol of 2-amino-6-(N-propionyl)-4,5,6,7-tetrahydrobenzothiazole was dissolved in 50 mL of dry tetrahydrofuran. 50 mL of a 1 mol / L borane tetrahydrofuran complex solution was added under nitrogen protection at 5 °C. The mixture was heated to 50 °C and reacted for 1 h. After TLC showed complete reaction, the mixture was cooled to room temperature, and 5 mL of water and 10 mL of 12 mol / L hydrochloric acid were added to quench the reaction. After evaporating the solvent, the pH was adjusted to 9-10 with sodium hydroxide solution. The mixture was extracted three times with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure to obtain (±)-praxexole, with a yield of 90%.

[0248] (5) Dissolve 10 mmol of (±)-prapixol in 20 mL of methanol, add 0.10 mol of 12 mol / L hydrochloric acid dropwise at room temperature, stir for 5 min and a large number of white particles appear. Heat to 50 °C to dissolve the white particles, then add 0.10 mol of L-tartaric acid, stir for 1 h and cool to room temperature. A white solid is formed. Filter it out and wash it with cold methanol to obtain a white solid. The solution was dissolved in 20 mL of water, and the pH of the system was adjusted to 9-10 with sodium hydroxide solution. After stirring for 0.5 h, the mixture was filtered. The resulting solid was washed with water and dried to obtain pramipexole free base. The pramipexole free base was dissolved in 600 mL of isopropanol, heated to 75 °C and stirred for 20 min. 1.14 mmol of 12 mol / L hydrochloric acid was added dropwise, and stirring was continued for 30 min. The mixture was then cooled to room temperature, and a white solid was filtered off. The solid was washed with isopropanol to obtain (S)-pramipexole hydrochloride with a yield of 32%. The HPLC purity was determined to be 35.1 ee% by liquid chromatography and polarimetry. [α] D 20 -45.1 (c 0.90in MeOH).

[0249] The results from the examples and comparative examples show that the preparation and purification method of pramipexole hydrochloride in this invention has higher reaction efficiency and better purity of the final synthesized S-configuration pramipexole hydrochloride. In addition, this method has the advantages of low cost, greenness, convenient post-processing, and suitability for large-scale production, and has excellent application prospects.

[0250] The preferred embodiments of the present invention have been described in detail above; however, the present invention is not limited thereto. Within the scope of the inventive concept, various simple modifications can be made to the technical solutions of the present invention, including combinations of various technical features in any other suitable manner. These simple modifications and combinations should also be considered as the content disclosed in the present invention and are all within the protection scope of the present invention.

Claims

1. A method for preparing pramipexole hydrochloride, characterized in that, The method includes the following steps: (1) 4-aminophenol is reacted with hydrogen chloride to obtain hydrochloride, and then the hydrochloride is hydrogenated and reduced in the presence of a first solvent and a transition metal catalyst. The resulting product is then neutralized with a first base to obtain 4-aminocyclohexanol. (2) The 4-aminocyclohexanol was mixed with the first acylation reagent and reacted to obtain the first acylation product shown in formula (I); (3) The first acylated product is reacted with a reducing agent in the presence of a first catalyst and an organic solvent to obtain the reduced product shown in formula (II); (4) The reduction product is subjected to an acylation reaction to obtain the second acylated product shown in formula (III); (5) In the presence of an optional second catalyst, the second acylated product is oxidized to obtain the oxidized product shown in formula (IV); (6) In the presence of an acidic solvent, the oxidation product is first brominated with bromine, and then mixed with thiourea for reaction; Wherein, R is a protecting group for hydroxyl and amino groups, preferably acetyl, propionyl or tert-butyloxycarbonyl.

2. The method according to claim 1, characterized in that, In step (1), the mass ratio of the transition metal catalyst to the hydrochloride is 0.05-10:1, preferably 0.4-0.6:1; Preferably, the transition metal catalyst is at least one of palladium catalyst, nickel catalyst and platinum catalyst, more preferably at least one of palladium on carbon, palladium hydroxide, palladium chloride, palladium black, Raney nickel and platinum oxide; Preferably, the first solvent is at least one selected from water, C1-C5 alcohols, tetrahydrofuran, dioxane, and ethyl acetate; Preferably, the first base is at least one selected from sodium bicarbonate, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium phosphate, potassium dihydrogen phosphate, pyridine, and triethylamine. Preferably, the conditions for hydrogenation reduction include: a temperature of 20-50°C, a time of 4h-7d, and a hydrogen partial pressure of 10-100 atm.

3. The method according to claim 1 or 2, characterized in that, In step (2), the molar ratio of 4-aminocyclohexanol to the first acylation reagent is 1:0.5-1.5; Preferably, the first acylation reagent is propionic anhydride and / or propionyl chloride; Preferably, the reaction conditions include a temperature of -10 to 50°C and a time of 10 min to 4 h.

4. The method according to any one of claims 1-3, characterized in that, In step (3), the molar ratio of the first acylation product, the reducing agent and the first catalyst is 1:(2-5):(2-10), preferably 1:(2-3):(2-4); Preferably, the reducing agent is at least one selected from sodium borohydride, potassium borohydride, boranetetrahydrofuran, diisobutylaluminum hydride, and red aluminum; Preferably, the first catalyst is at least one selected from boron trifluoride diethyl ether, elemental iodine, nickel chloride, magnesium chloride, zinc chloride, cobalt chloride, zinc acetate, and cobalt acetate; Preferably, the organic solvent is at least one selected from tetrahydrofuran, diethyl ether, dioxane, benzene, and toluene; Preferably, the reaction conditions include a temperature of 5-70°C and a time of 0.5-6 hours.

5. The method according to any one of claims 1-4, characterized in that, In step (4), the process of performing the acylation reaction on the reduction product includes: reacting the reduction product with a second acylation reagent; Preferably, the molar ratio of the reduction product to the second acylation reagent is 1:0.8-1.2; Preferably, the second acylation agent is at least one of ditert-butyl dicarbonate and tert-valerate chloride; Preferably, the reaction conditions include a temperature of -10 to 50°C and a time of 0.5 to 4 hours.

6. The method according to any one of claims 1-4, characterized in that, In step (4), the process of carrying out the acylation reaction of the reduction product includes: reacting the reduction product with a third acylation reagent in the presence of a third catalyst, and then hydrolyzing it in the presence of a second base; Preferably, the molar ratio of the reduction product, the third catalyst, and the third acylation reagent is 1:(0.05-6):(1-3), more preferably 1:(0.2-1):(1.5-2.5); Preferably, the third acylation agent is at least one selected from acetic anhydride, acetyl chloride, propionic acid glycoside, and propionyl chloride; Preferably, the third catalyst is at least one selected from sodium acetate, pyridine, and elemental iodine; Preferably, the second alkali is at least one selected from potassium carbonate, sodium carbonate, potassium hydroxide, and sodium hydroxide; Preferably, the reaction conditions include a temperature of -10 to 70°C and a time of 10 min to 4 h.

7. The method according to any one of claims 1-6, characterized in that, In step (5), the specific process of oxidizing the second acylated product includes: mixing the second acylated product with a second catalyst, a phase transfer catalyst, a first oxidant and a third base in the presence of a second solvent; Preferably, the molar ratio of the second acylation product, the second catalyst, the phase transfer catalyst, the first oxidant, and the third base is 100:(0.01-20):(0.1-20):(120-500):(1-50), more preferably 100:(1-5):(0.5-5):(150-200):(5-20); Preferably, the second catalyst is at least one selected from sodium tungstate, ruthenium trichloride, ruthenium tetroxide, and tetra-n-propylammonium perruthenate; Preferably, the phase transfer catalyst is at least one selected from tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, triethylbenzylammonium chloride, and triethylbenzylammonium bromide; Preferably, the first oxidant is at least one selected from hydrogen peroxide, sodium hypochlorite, sodium periodate, potassium peroxymonosulfate, and N-methylmorpholine nitrogen oxides; Preferably, the third alkali is at least one selected from potassium carbonate, sodium carbonate, potassium hydroxide, and sodium hydroxide. Preferably, the second solvent is at least one selected from water, dichloromethane, trichloromethane, dichloroethane, ethyl acetate, tetrahydrofuran, and dioxane; Preferably, the reaction conditions include a temperature of 15-60°C and a time of 0.5-8 hours.

8. The method according to any one of claims 1-6, characterized in that, In step (5), the specific process of oxidizing the second acylated product includes: reacting the second acylated product with a second oxidizing agent in the presence of a third solvent, and then quenching it with a reducing agent; Preferably, the molar ratio of the second acylated product to the second oxidant is 1:1.2-10, more preferably 1:2-4; Preferably, the second oxidant is at least one selected from hydrogen peroxide, sodium hypochlorite, sodium periodate, potassium peroxymonosulfate, and N-methylmorpholine nitrogen oxides; Preferably, the reducing agent is at least one selected from sodium thiosulfate, sodium sulfite, sodium bisulfite, potassium bisulfite, and zinc powder; Preferably, the third solvent is at least one of water and a C1-C5 acid; Preferably, the reaction conditions include a temperature of -10 to 40°C and a time of 10 min to 4 h.

9. The method according to any one of claims 1-8, characterized in that, In step (6), the molar ratio of the oxidation product, the bromine, and the thiourea is 1:(0.5-1.5):(0.5-1.5); Preferably, the acidic solvent is a C1-C5 acid; Preferably, the conditions for the bromination reaction include: a temperature of -10 to 40°C and a time of 0.5 to 4 hours; Preferably, the conditions for the mixing reaction include: a temperature of 30-100℃ and a time of 1-12h.

10. The method according to any one of claims 1-9, characterized in that, The method further includes purifying the product obtained in step (6) to obtain the S-configuration of pramipexole hydrochloride, wherein the purification process includes the following steps: S1: In the presence of the fourth solvent, the product obtained in step (6) is mixed with the first hydrochloric acid, then heated to dissolve and mixed with the first chiral acid, filtered to obtain pramipexole chiral acid salt A1, then mixed with the second hydrochloric acid, and neutralized with the fourth base to obtain pramipexole free base B1. S2: Replace pramipexole with pramipexole free base B1 and repeat step S1 to obtain pramipexole free base B2; S3: Mix the filtrates from S1 and S2, neutralize with the fifth base, and filter to obtain pramipexole free base L1. Then, in the presence of the fifth solvent, mix pramipexole free base L1 with the third hydrochloric acid, heat to dissolve, mix with the second chiral acid, and filter to obtain pramipexole chiral acid salt L2; then recrystallize.

11. The method according to claim 10, characterized in that, In process S1, the molar ratio of the product obtained in step (6), the first hydrochloric acid, and the first chiral acid is 1:(0.5-1.5):(0.5-1.5); Preferably, the first chiral acid is at least one selected from D-tartaric acid, D-malic acid, and L-camphorsulfonic acid; Preferably, the concentration of the first hydrochloric acid is 10-15 mol / L; Preferably, the concentration of the second hydrochloric acid is 0.5-3 mol / L; Preferably, the fourth solvent is at least one of C1-C5 alcohols, ethyl acetate, tetrahydrofuran, and dioxane; Preferably, the fourth alkali is at least one selected from sodium bicarbonate, potassium carbonate, sodium carbonate, potassium hydroxide, and sodium hydroxide; Preferably, the heating temperature is 40-100℃.

12. The method according to claim 10 or 11, characterized in that, In step S3, the molar ratio of the pramipexole free base L1, the third hydrochloric acid, and the second chiral acid is 1:(0.5-1.5):(0.5-1.5); Preferably, the second chiral acid is at least one selected from L-tartaric acid, L-malic acid, and D-camphorsulfonic acid; Preferably, the concentration of the third hydrochloric acid is 10-15 mol / L; Preferably, the fifth solvent is at least one of C1-C5 alcohols, ethyl acetate, tetrahydrofuran, and dioxane; Preferably, the fifth alkali is at least one selected from sodium bicarbonate, potassium carbonate, sodium carbonate, potassium hydroxide, and sodium hydroxide; Preferably, the heating temperature is 40-100℃.

13. The method according to any one of claims 10-12, characterized in that, In step S3, the specific process of recrystallization includes: heating and dissolving pramipexole chiral acid salt L2, cooling to room temperature and filtering, neutralizing the solid product with the sixth base, then dissolving it in an alcohol solvent, mixing it with the fourth hydrochloric acid, and filtering.

14. The method according to claim 13, characterized in that, The sixth alkali is at least one selected from sodium bicarbonate, potassium carbonate, sodium carbonate, potassium hydroxide, and sodium hydroxide; and / or The alcohol solvent is a C1-C5 alcohol; and / or The concentration of the fourth hydrochloric acid is 10-15 mol / L; and / or The recrystallization temperature is 40-100℃.

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