Preparation method of pramipexole dihydrochloride related substance BI-II786BS

Abstract

The invention belongs to the technical field of medicine production, and provides a preparation method of a pramipexole dihydrochloride related substance BI-II786BS. According to the method, a commercial reagent (S)-2, 6-diamino-4, 5, 6, 7-tetrahydrobenzothiazole is used as a raw material, the preparation process is simple, easy to implement, good in reproducibility and suitable for batch production of BI-II786BS, and the preparation method is suitable for large-scale production of pramipexole dihydrochloride related substances BI-II786BS. The pramipexole dihydrochloride related substance prepared by the method has high purity, and can be used as a reference substance (standard substance) for quality control of pramipexole dihydrochloride bulk drugs or preparations.

Description

Technical Field

[0001] The invention relates to a preparation method of BI-II786BS, a related substance of pramipexole hydrochloride, and belongs to the technical field of pharmaceutical production. Background Art

[0002] Pramipexole was developed by Boehringer Ingelheim in Germany and approved by the US FDA for marketing in the US in 1997 under the trade name Mirapex. It was later approved for marketing in Europe, Japan and other places, and was approved for entry into China in April 2005. Pramipexole hydrochloride is a non-ergotamine dopamine receptor agonist that relieves movement disorders in Parkinson's patients by stimulating dopamine receptors in the striatum, and is used to treat adult idiopathic Parkinson's disease. Among the 17 related substances of pramipexole hydrochloride, BI-II786BS and BI-II828BS have the most complex structures. They are the products of dimerization of pramipexole after oxidation at the C7 position, and a new chiral center is introduced.

[0003] There is currently only one synthetic route reported for BI-II786BS, as shown in the figure below, and its longest linear step sequence is 14 steps (Hu, T.; Yang, F.; Jiang, T.; Chen, W.; Zhang, J.; Li, J.; Jiang, X.; Shen, J. Synthesis of impurities of pramipexole dihydrochloride. Org. Process Res. Dev. 2016, 20, 1899-1905). It is reported that this synthetic route has the problem of low reproducibility (Sun Lantian, Synthesis Research of Pramipexole Hydrochloride and Its Related Impurities, Master's Degree Thesis of Beijing University of Technology, June 2018). Therefore, the development of the synthetic route of BI-II786BS, a substance related to pramipexole hydrochloride, in this patent can enrich the synthetic method of the substance in the prior art.

[0004]

[0005] Org.Process Res.Dev.2016,20,1899-1905 Summary of the invention

[0006] The object of the present invention is to provide a method for preparing BI-II786BS, a related substance of pramipexole hydrochloride. The method has a simple preparation process, is easy to implement, has readily available raw materials, has good reproducibility, and is suitable for mass production of BI-II786BS.

[0007] The above-mentioned purpose of the present invention is mainly achieved through the following route:

[0008] (1) reacting (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole with propionic anhydride in the presence of an organic base or an inorganic base to obtain (S)-2-amino-6-propionamido-4,5,6,7-tetrahydrobenzothiazole, i.e., intermediate M1;

[0009] (2) reacting the intermediate M1 with Boc2O in the presence of an organic base or an inorganic base to obtain (S)-2-tert-butoxyamido-6-propionamido-4,5,6,7-tetrahydrobenzothiazole, namely, the intermediate M2;

[0010] (3) The intermediate M2 is subjected to bromination reaction to obtain the intermediate M3, and the intermediate M3 is further cyclized to obtain (3aS, 8bS)-2-ethyl-7-tert-butoxyamido-3a,4,5,8b-tetrahydrothiazol[4,5-g]benzo[4,5-g] Azole, i.e. intermediate M4;

[0011] (4) reacting the intermediate M4 with the intermediate M1 obtained in step (1) under the condition of an organic acid or an inorganic acid to obtain (6S,7R)-2-tert-butoxyamido-6-propionamido-7-((S)-6-propionamido-4,5,6,7-tetrahydrobenzothiazole-2-amino)-4,5,6,7-tetrahydrobenzothiazole, i.e., intermediate M5;

[0012] (5) Removing the Boc protecting group from the intermediate M5 to obtain (6S,7R)-2-amino-6-propionamido-7-((S)-6-propionamido-4,5,6,7-tetrahydrobenzothiazole-2-amino)-4,5,6,7-tetrahydrobenzothiazole, namely, the intermediate M6;

[0013] (6) Reducing the intermediate M6 to obtain (6S,7R)-2-amino-6-propylamino-7-((S)-6-propylamino-4,5,6,7-tetrahydrobenzothiazole-2-amino)-4,5,6,7-tetrahydrobenzothiazole, i.e., pramipexole related substance BI-II786BS;

[0014] The structural formula is as follows:

[0015]

[0016] In the above method for preparing pramipexole hydrochloride-related substances, the organic base in step (1) is selected from triethylamine or diisopropylethylamine, and the inorganic base is selected from potassium carbonate or sodium carbonate, and the preferred base is triethylamine.

[0017] In the above method for preparing pramipexole hydrochloride-related substances, the molar ratio of (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole to propionic anhydride in step (1) is 1:1 to 1:5; and the reaction temperature in step (1) is -78 to 0°C, preferably -40 to -30°C.

[0018] In the above method for preparing related substances of pramipexole hydrochloride, the solvent used in the reaction of step (1) is selected from one or more of tetrahydrofuran, ether, diisopropyl ether, methyl tert-butyl ether, 1,4-dioxane, toluene, dichloromethane, chloroform, acetonitrile, DMF or DMSO, preferably tetrahydrofuran.

[0019] In the above method for preparing related substances of pramipexole hydrochloride, the organic base in step (2) is selected from triethylamine, diisopropylethylamine, pyridine or 4-dimethylaminopyridine, and the inorganic base is selected from potassium carbonate or sodium carbonate, etc., and the preferred base is 4-dimethylaminopyridine.

[0020] In the above-mentioned method for preparing pramipexole hydrochloride-related substances, the molar ratio of the intermediate M1 to Boc2O in the step (2) is 1:1 to 1:5, preferably 1:1.01 to 1:2; the reaction temperature in the step (2) is -20 to 100°C, preferably -5 to 60°C.

[0021] In the above-mentioned method for preparing related substances of pramipexole hydrochloride, the solvent used in the reaction of step (2) is selected from one or more of tetrahydrofuran, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,4-dioxane, toluene, dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, acetonitrile, DMF, DMSO or water, preferably dichloromethane.

[0022] In the above-mentioned method for preparing related substances of pramipexole hydrochloride, the brominating agent used in the bromination reaction in the step (3) is selected from one or more of N-bromosuccinimide (NBS), liquid bromine, dibromohydantoin, dibromoisocyanuric acid or 5,5-dibromobarbituric acid, preferably NBS; the catalyst or initiator is selected from one or more of azobisisobutyronitrile (AIBN), azobisisoheptanenitrile, dimethyl azobisisobutyrate, benzoyl peroxide or lauroyl peroxide, preferably AIBN; the solvent used is selected from one or more of carbon tetrachloride, dichloromethane, chloroform, 1,2-dichloroethane, toluene, acetonitrile, DMF or DMSO, preferably carbon tetrachloride; the molar ratio of the intermediate M2 to the brominating agent is 1:1 to 1:3, and the molar ratio of the intermediate M2 to the catalyst or initiator is 1:0.01 to 1:0.3.

[0023] In the above method for preparing pramipexole hydrochloride-related substances, the temperature of the bromination reaction in step (3) is 40 to 100° C., preferably 50 to 70° C.; and the reaction time is 1 to 3 hours.

[0024] In the above-mentioned method for preparing related substances of pramipexole hydrochloride, the inorganic salt used in the cyclization reaction in the step (3) is selected from one or more of ammonium chloride, sodium chloride, potassium carbonate, sodium carbonate, sodium bicarbonate, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium sulfite, sodium bisulfite or sodium thiosulfate, preferably a mixture of sodium bicarbonate and sodium thiosulfate.

[0025] In the above-mentioned method for preparing related substances of pramipexole hydrochloride, the solvent used for the cyclization reaction in step (3) is selected from one or more of DMSO, acetonitrile, tetrahydrofuran, diethyl ether, 1,4-dioxane, toluene, ethyl acetate, acetone, petroleum ether, methanol, ethanol, dichloromethane, chloroform, DMF, dimethylacetamide or water, preferably a mixed solvent of dichloromethane and water.

[0026] In the above method for preparing pramipexole hydrochloride-related substances, the reaction temperature of the cyclization reaction in step (3) is -20 to 60°C, preferably 20 to 40°C; the reaction time is 0 to 30 minutes, preferably 10 to 20 minutes.

[0027] In the above-mentioned method for preparing related substances of pramipexole hydrochloride, the molar ratio of intermediate M4 to intermediate M1 in step (4) is 3:1-1:10, and the ratio of reaction intermediate M4 to condensation reagent is 10:1-1:2; the reaction temperature in step (4) is 0-150°C, preferably 40-100°C; the condensation reagent in step (4) is selected from one or more of triethylamine hydrochloride, dimethylaminopyridine hydrochloride, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, p-toluenesulfonic acid pyridinium salt, hydrochloric acid, sulfuric acid or nitric acid, preferably p-toluenesulfonic acid pyridinium salt or triethylamine hydrochloride; the solvent used in the condensation reaction in step (4) is selected from one or more of dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, toluene, THF, methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane, acetonitrile, DMSO or DMF, preferably THF or chloroform.

[0028] In the above-mentioned method for preparing related substances of pramipexole hydrochloride, the acid reagent for removing the Boc protecting group of the intermediate M5 for deprotection reaction in step (5) is selected from one or more of trifluoroacetic acid (TFA), hydrochloric acid, sulfuric acid, camphorsulfonic acid, acetic acid or p-toluenesulfonic acid, preferably TFA; the molar ratio of the acid reagent to the intermediate M5 in step (5) is 500:1 to 1:100; the solvent for the deprotection reaction in step (5) is selected from one or more of dichloromethane, chloroform, 1,2-dichloroethane, toluene, THF, ether, dioxane, acetonitrile, DMF, DMSO or water, preferably dichloromethane; the reaction temperature in step (5) is -20 to 200°C, preferably 0 to 60°C.

[0029] In the above-mentioned method for preparing related substances of pramipexole hydrochloride, the reducing agent used in the reduction reaction of step (6) is selected from one or more of sodium borohydride, potassium borohydride, zinc borohydride, borane-tetrahydrofuran, borane-dimethyl sulfide, diisobutylaluminum hydride (DIBAL-H), red aluminum or lithium aluminum hydride, preferably DIBAL-H; the solvent used for the reduction reaction of intermediate M6 in step (6) is selected from one or more of tetrahydrofuran, toluene, dichloromethane, DMSO, ether, dioxane or methyl tert-butyl ether, preferably tetrahydrofuran; the molar ratio of intermediate M7 to reducing agent is 2:1 to 1:100; the temperature of the reduction reaction of intermediate M6 is -30 to 70°C, preferably 0 to 25°C.

[0030] In the above method for preparing related substances of pramipexole hydrochloride, the process for purifying the pramipexole related substance BI-II786BS prepared in step (6) is as follows:

[0031] After the reduction is completed, hydrochloric acid is added to the system in an ice-water bath to quench the reaction, and the pH is adjusted to 1-2. Then, a NaOH aqueous solution is added to adjust the pH to 13-14. Then, NaCl solid is added to the reaction solution, extracted with tetrahydrofuran, the organic phases are combined, dried, filtered, the filtrate is concentrated under reduced pressure, and then separated and purified by silica gel column chromatography to obtain a pure product; in this purification method, the concentration of the hydrochloric acid is 0.1%-38%, the concentration of the NaOH aqueous solution is 0.1%-40%, and the silica gel column chromatography separation and purification adopts a volume ratio of: dichloromethane / methanol containing 5% ammonia water = 20:1-0:1.

[0032] A pramipexole hydrochloride related substance is obtained by adopting the above preparation method.

[0033] Compared with the prior art, the present invention has the following beneficial effects:

[0034] (1) The present invention provides a novel method for preparing BI-II786BS, a related substance of pramipexole hydrochloride. The method for preparing BI-II786BS, a related substance of pramipexole hydrochloride, is simple in process, easy to implement, uses readily available raw materials, has good reproducibility, and is suitable for mass production of BI-II786BS.

[0035] (2) The present invention provides a method for preparing a novel pramipexole hydrochloride related substance BI-II786BS. The pramipexole hydrochloride related substance prepared by the method has high purity and can be used as a reference substance (standard substance) for quality control of pramipexole raw materials or preparations. DETAILED DESCRIPTION

[0036] The present invention is further described in detail below in conjunction with specific embodiments:

[0037] The structural formula of the pramipexole hydrochloride related substance BI-II786BS of the present invention is shown below:

[0038]

[0039] The chemical name of BI-II786BS is (6S,7R)-2-amino-6-propylamino-7-((S)-6-propylamino-4,5,6,7-tetrahydrobenzothiazole-2-amino)-4,5,6,7-tetrahydrobenzothiazole. The specific synthesis process is as follows:

[0040]

[0041] (1) (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole, i.e. S, reacts with propionic anhydride in the presence of an organic base or an inorganic base to obtain (S)-2-amino-6-propionamido-4,5,6,7-tetrahydrobenzothiazole, i.e. intermediate M1. The reaction process is as follows:

[0042]

[0043] The organic base is selected from triethylamine or diisopropylethylamine; the inorganic base is selected from potassium carbonate or sodium carbonate, etc. Preferably, the base is triethylamine.

[0044] The solvent used in the above reaction is selected from one or more of tetrahydrofuran, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,4-dioxane, toluene, dichloromethane, chloroform, acetonitrile, DMF, and DMSO. Preferably, the solvent used is tetrahydrofuran.

[0045] The above reaction temperature is -78 to 0°C, preferably, the reaction temperature is -40 to -30°C.

[0046] The molar ratio of the (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole to propionic anhydride is 1:1 to 1:5.

[0047] (2) The intermediate M1 obtained in step (1) reacts with Boc2O in the presence of an organic base or an inorganic base to perform Boc protection on the amine group to generate (S)-2-tert-butoxyamido-6-propionamido-4,5,6,7-tetrahydrobenzothiazole, i.e., intermediate M2. The reaction process is shown below:

[0048]

[0049] The organic base is selected from triethylamine, diisopropylethylamine, pyridine or 4-dimethylaminopyridine (DMAP), and the inorganic base is selected from potassium carbonate or sodium carbonate, etc. The preferred base is 4-dimethylaminopyridine.

[0050] The molar ratio of the intermediate M1 to Boc2O is 1:1 to 1:5, preferably 1:1.01 to 1:2.

[0051] In the above-mentioned amine protection reaction, the reaction temperature is -20 to 100°C, preferably, the reaction temperature is -5 to 60°C.

[0052] In the above-mentioned amine protection reaction, the solvent used is selected from one or more of tetrahydrofuran, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,4-dioxane, toluene, dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, acetonitrile, DMF, DMSO, and water. Preferably, the solvent used is dichloromethane.

[0053] (3) The intermediate M2 obtained in step (2) is brominated at the benzylic position to obtain the intermediate M3, and the intermediate M3 is further cyclized to obtain (3aS, 8bS)-2-ethyl-7-tert-butoxyamido-3a, 4, 5, 8b-tetrahydrothiazol[4, 5-g]benzo[4, 5-g] Azole, intermediate M4, the reaction process is as follows:

[0054]

[0055] The reaction temperature of the bromination reaction is 40-100°C, preferably, the reaction temperature is 50-70°C.

[0056] The reaction time of the bromination reaction is 0.5 to 3 hours, preferably, the reaction time is 1 hour.

[0057] The brominating agent used in the above bromination reaction is selected from one or more of N-bromosuccinimide (NBS), liquid bromine, dibromohydantoin, dibromoisocyanuric acid, and 5,5-dibromobarbituric acid, preferably NBS; the catalyst or initiator is selected from one or more of azobisisobutyronitrile (AIBN), azobisisoheptanenitrile, dimethyl azobisisobutyrate, benzoyl peroxide, and lauroyl peroxide, preferably AIBN; the molar ratio of the intermediate M2 to the brominating agent is 1:1 to 1:3, and the molar ratio of the intermediate M2 to the catalyst or initiator is 1:0.01 to 1:0.3.

[0058] The solvent used in the above bromination reaction is one or more selected from carbon tetrachloride, dichloromethane, chloroform, 1,2-dichloroethane, toluene, acetonitrile, DMF or DMSO, preferably carbon tetrachloride.

[0059] The reaction temperature of the above bromination reaction is 40 to 100° C., preferably 50 to 70° C., and the reaction time is 1 to 3 hours.

[0060] The inorganic salt in the above cyclization reaction is selected from one or more of ammonium chloride, sodium chloride, potassium carbonate, sodium carbonate, sodium bicarbonate, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium sulfite, sodium bisulfite or sodium thiosulfate, preferably a mixture of sodium bicarbonate and sodium thiosulfate.

[0061] The solvent used in the above cyclization reaction is selected from one or more of DMSO, acetonitrile, tetrahydrofuran, ether, 1,4-dioxane, toluene, ethyl acetate, acetone, petroleum ether, methanol, ethanol, dichloromethane, chloroform, DMF, dimethylacetamide or water, preferably a mixed solvent of dichloromethane and water.

[0062] The reaction temperature of the above cyclization reaction is -20 to 60°C, preferably 20 to 40°C; the reaction time is 0 to 30 minutes, preferably, the reaction time is 10 to 20 minutes.

[0063] (4) The intermediate M4 obtained in step (3) is subjected to a condensation reaction with the intermediate M1 obtained in step (1) to obtain (6S,7R)-2-tert-butoxyamido-6-propionamido-7-((S)-6-propionamido-4,5,6,7-tetrahydrobenzothiazole-2-amino)-4,5,6,7-tetrahydrobenzothiazole, i.e., intermediate M5. The reaction process is as follows:

[0064]

[0065] The condensation reagent of the above reaction is selected from one or more of triethylamine hydrochloride, dimethylaminopyridine hydrochloride, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, pyridinium p-toluenesulfonate, hydrochloric acid, sulfuric acid or nitric acid, preferably pyridinium p-toluenesulfonate or triethylamine hydrochloride.

[0066] The solvent for the above reaction is selected from one or more of dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, toluene, THF, methyltetrahydrofuran, ether, methyl tert-butyl ether, dioxane, acetonitrile, DMSO or DMF, preferably THF or chloroform.

[0067] The reaction temperature in the above condensation reaction is 0-150°C, preferably, the reaction temperature is 40-100°C.

[0068] In the above condensation reaction, the molar ratio of the intermediate M4 to the intermediate M1 is 3:1 to 1:10, and the ratio of the reaction intermediate M4 to the condensation reagent is 10:1 to 1:2.

[0069] (5) The intermediate M5 obtained in step (4) is deprotected from the Boc protecting group to obtain (6S,7R)-2-amino-6-propionamido-7-((S)-6-propionamido-4,5,6,7-tetrahydrobenzothiazole-2-amino)-4,5,6,7-tetrahydrobenzothiazole, i.e., intermediate M6. The reaction process is as follows:

[0070]

[0071] The reagent used in the above deprotection reaction is selected from one or more of trifluoroacetic acid (TFA), hydrochloric acid, sulfuric acid, camphorsulfonic acid, acetic acid, and p-toluenesulfonic acid, preferably TFA.

[0072] The molar ratio of the acid to the intermediate M5 in the above deprotection reaction is 500:1 to 1:100.

[0073] The solvent in the above deprotection reaction is selected from one or more of dichloromethane, chloroform, 1,2-dichloroethane, toluene, THF, ether, dioxane, acetonitrile, DMF, DMSO or water. Preferably, the solvent used is dichloromethane.

[0074] The reaction temperature in the above deprotection reaction is -20 to 200°C, preferably, the reaction temperature is 0 to 60°C.

[0075] (6) The intermediate M6 obtained in step (5) is reduced to obtain (6S,7R)-2-amino-6-propylamino-7-((S)-6-propylamino-4,5,6,7-tetrahydrobenzothiazole-2-amino)-4,5,6,7-tetrahydrobenzothiazole, i.e., pramipexole hydrochloride related substance BI-II786BS. The reaction process is as follows:

[0076]

[0077] In the above reduction reaction, the molar ratio of the intermediate M6 to the reducing agent is 2:1 to 1:100.

[0078] In the above reduction reaction, the reducing agent is selected from one or more of sodium borohydride, potassium borohydride, zinc borohydride, borane-tetrahydrofuran, borane-dimethyl sulfide, diisobutylaluminum hydride (DIBAL-H), red aluminum, and lithium aluminum hydride, and the preferred reducing agent is DIBAL-H.

[0079] In the above reduction reaction, the solvent is selected from one or more of tetrahydrofuran, toluene, dichloromethane, DMSO, ethyl ether, dioxane, and methyl tert-butyl ether. Preferably, the solvent is tetrahydrofuran.

[0080] In the above reduction reaction, the reaction temperature is -30 to 70°C, preferably, the temperature is 0 to 25°C.

[0081] (7) The purification process of the pramipexole hydrochloride related substance BI-II786BS prepared in step (6) is as follows: 0.1% to 38% hydrochloric acid is added to the system after reduction in an ice-water bath to quench the reaction, and the pH is adjusted to 1 to 2. Then, 0.1% to 40% NaOH aqueous solution is added to adjust the pH to 13 to 14. Then, NaCl solid is added to the reaction solution and extracted with tetrahydrofuran. The organic phases are combined, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated under reduced pressure, and then separated and purified by silica gel column chromatography (the solvent volume ratio used in the column chromatography is: dichloromethane / methanol containing 5% ammonia water = 20:1 to 0:1), to obtain a pure white powder product.

[0082] The structural formula is as follows:

[0083]

[0084] The pramipexole hydrochloride related substance BI-II786BS synthesized by the method of the present invention has high purity and can be used as a reference substance (standard substance) for quality control of pramipexole raw materials or preparations. In addition, the synthesis method of the present invention is simple to operate, the raw materials are easily available, and the reproducibility is good, so it is suitable for the production of the related substance BI-II786BS.

[0085] Example 1

[0086]

[0087] Add the commercial reagent (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole (24.99 g, 147.7 mmol) to a 1L round-bottom flask and dissolve it in tetrahydrofuran (290 mL) at room temperature. Add triethylamine (100.5 mL, 717 mmol) and propionic anhydride (18.9 mL, 147.7 mmol) in sequence under stirring at -40°C. Keep the reaction at this temperature for 3 hours. Add 1 mol / L NaOH aqueous solution (150 mL) to the reaction solution under an ice-water bath, move to room temperature and stir for 15 minutes. Extract with dichloromethane (250 mL × 3) and ethyl acetate (250 mL × 3) in sequence, combine the organic phases, dry with anhydrous sodium sulfate, and filter. The filtrate was concentrated under reduced pressure to obtain 31.83 g of white powdery solid (S)-2-amino-6-propionamido-4,5,6,7-tetrahydrobenzothiazole with a yield of 96%. 1 H NMR(300MHz, CDCl3)δ5.61(m,1H),4.93(br,2H),4.38(s,1H),

[0088] 2.96(d,J=15.3Hz,1H),2.74-2.57(m,2H),2.46(dd,J=15.3,5.4Hz,

[0089] 1H),2.19(q,J=7.5Hz,2H),2.01-1.82(m,2H),1.14(t,J=7.5Hz,

[0090] 3H).

[0091] HRMS(ESI):m / z 226.1009[M+H] + (calcd for C 10 H 16 N3OS + :226.1009).

[0092] Example 2

[0093]

[0094] Add (S)-2-amino-6-propionamido-4,5,6,7-tetrahydrobenzothiazole (20.02 g, 88.86 mmol) and DMAP (0.27 g, 2.22 mmol) to a 1L round-bottom flask and dissolve in dichloromethane (200 mL) at room temperature. Add Boc anhydride (22.4 mL, 97.74 mmol) under stirring at room temperature and keep the reaction at this temperature for 2 hours. The reaction solution is concentrated under reduced pressure to obtain a yellow-white solid. Add methanol (360 mL) to the reaction bottle containing the above solid at room temperature, stir and dissolve, then add anhydrous potassium carbonate (7.36 g, 53.3 mmol), keep the reaction at this temperature for 3 days. Add saturated NaHCO3 aqueous solution (250 mL) and extract with dichloromethane (300 mL×3). Combine the organic phases, add saturated NaCl aqueous solution (900 mL) to separate the liquids, and dry the organic phase with anhydrous sodium sulfate and filter. The filtrate was concentrated under reduced pressure to obtain a crude product. A small amount of dichloromethane was added to dissolve the crude product. Cyclohexane was then added to precipitate the product. The product was filtered and the filter residue was collected to obtain 21.3956 g of white solid (S)-2-tert-butoxyamido-6-propionamido-4,5,6,7-tetrahydrobenzothiazole. The yield was 74%.

[0095] 1 H NMR (300MHz, CDCl3) δ10.2(br,1H),5.52(d,J=6.9Hz,1H),4.41(m,1H),3.08(d,J=15.6Hz,1H),2.80-2.78(m,2H),2.56(d,J=16.5,

[0096] 6.3Hz,1H),2.19(q,J=7.5Hz,2H),1.99-1.92(m,2H),1.53(s,9H),

[0097] 1.15 (t, J = 7.5 Hz, 3H).

[0098] HRMS(ESI):m / z 326.1534[M+H] + (calcd for C 15 H 24 N3O3S + :326.1533).

[0099] Example 3

[0100]

[0101] Add (S)-2-tert-Butoxyamido-6-propionamido-4,5,6,7-tetrahydrobenzothiazole (3.00 g, 9.22 mmol), NBS (2.0576 g, 11.561 mmol) and AIBN (79.1 mg, 0.482 mmol) to a 500 mL round-bottom flask and mix with carbon tetrachloride (190 mL) at room temperature. Then raise the temperature to 55 °C and keep stirring vigorously for 1 hour. After the reaction solution is cooled to room temperature, it is concentrated under reduced pressure to obtain a yellow-brown solid.

[0102] Transfer the reaction flask to an ice-water bath, add dichloromethane (150 mL) to dissolve, then add saturated Na2S2O3 aqueous solution (150 mL) and saturated NaHCO3 aqueous solution (150 mL) to quench, and stir for 15 minutes. Move to room temperature, separate the organic phase from the aqueous phase, and extract the aqueous phase with dichloromethane (150 mL×3). Combine the organic phases, dry over anhydrous sodium sulfate, and filter. The filtrate is concentrated under reduced pressure to obtain a crude product. The crude product is separated and purified by neutral alumina column chromatography (dichloromethane / acetone = 100:1 to 1:1) to obtain a white solid compound (3aS, 8bS)-2-ethyl-7-tert-butoxyamido-3a,4,5,8b-tetrahydrothiazolo[4,5-g]benzo[4,5-g] 1.0680 g of oxazole, with a yield of 36%.

[0103] 1 H NMR (400MHz, Chloroform-d) δ10.52 (s, 1H), 5.41 (ddd, J = 3.6, 2.0,

[0104] 1.6Hz,1H),4.06(m,1H),3.06(dd,J=16.8,2.0Hz,1H),2.93(dd,J=

[0105] 16.8,4.4Hz,1H),2.15(m,1H),2.09(qd,J=7.6,3.6Hz,2H),1.95(ddd,

[0106] J=13.2,2.0,1.2Hz,1H),1.54(s,9H),1.00(t,J=7.6Hz,3H).

[0107] HRMS(ESI):m / z 324.1377[M+H] + (calcd for C 15 H 22 N3O3S + :324.1376).

[0108] Example 4

[0109]

[0110] In a 15 mL thick-walled screw-mouth glass tube, (3aS, 8bS)-2-ethyl-7-tert-butoxyamido-3a,4,5,8b-tetrahydrothiazolo[4,5-g]benzo[4,5-g] azole (201.4mg, 0.6227mmol), (S)-2-amino-6-propionamido-4,5,6,7-tetrahydrobenzothiazole (280.6mg, 1.245mmol), p-toluenesulfonic acid pyridinium salt (PPTS, 156.4mg, 0.6227mmol) and chloroform (1mL), and then seal the tube with a screw cap. Then heat to 80°C and react for 15 hours. After the reaction solution is cooled to room temperature, it is concentrated under reduced pressure to obtain a pale yellow-brown solid crude product. The crude product is separated and purified by silica gel column chromatography (dichloromethane / methanol=100:1 to 1:1) to obtain 432.7mg of crude compound (6S,7R)-2-tert-butoxyamido-6-propionamido-7-((S)-6-propionamido-4,5,6,7-tetrahydrobenzothiazole-2-amino)-4,5,6,7-tetrahydrobenzothiazole. Take a small amount of the above crude product and further separate and purify it to obtain a pure product for structural confirmation.

[0111] 1 H NMR (400MHz, Methanol-d4) δ4.89(m,1H),4.31(m,1H),4.14(m,1H),3.09(dd,J=16.0,5.6 Hz,1H),2.85(dd,J=15.6,5.2Hz,1H),2.68-2.61(m,2H),2.51(dd,J=16.0,5.6Hz,1H),2.4 4(dd,J=15.6,8.0Hz,1H),2.25(m,1H),2.21(q,J=7.6Hz,2H),2.20(q,J=7.6Hz,2H),2.01 -1.80(m,2H,H-6),1.82(m,1H),1.53(s,9H),1.13(t,J=7.6Hz,3H),1.12(t,J=7.6Hz,3H).

[0112] HRMS(ESI):m / z 549.2329[M+H] + (calcd for C 25 H 37 N6O4S2 + :549.2312).

[0113] Example 5

[0114]

[0115] In a 50 mL round-bottom flask, 355.8 mg of the crude product of (6S,7R)-2-tert-butoxyamido-6-propionamido-7-((S)-6-propionamido-4,5,6,7-tetrahydrobenzothiazole-2-amino)-4,5,6,7-tetrahydrobenzothiazole was added and dissolved in dichloromethane (10 mL) at room temperature. Trifluoroacetic acid (5 mL) was slowly added under stirring. After reacting at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure. The crude compound was separated and purified by silica gel column chromatography (dichloromethane / methanol=100:1 to 1:1) to obtain 79.6 mg of a yellow solid compound (6S,7R)-2-amino-6-propionamido-7-((S)-6-propionamido-4,5,6,7-tetrahydrobenzothiazole-2-amino)-4,5,6,7-tetrahydrobenzothiazole. The two-step yield was 29%.

[0116] 1 H NMR (400MHz, Methanol-d4) δ4.77 (dd, J=4.0, 3.6Hz, 1H), 4.29 (m,

[0117] 1H),4.16m,1H),2.96(dd,J=16.0,5.6Hz,1H),2.87(dd,J=16.0,5.2

[0118] Hz,1H),2.69-2.65(m,2H),2.50-2.40(m,2H),2.214(q,J=7.6Hz,

[0119] 2H),2.207(q,J=7.6Hz,2H),2.17(m,1H),2.04-1.97(m,2H),1.86(m,

[0120] 1H), 1.13(t,J=7.6Hz,6H), 1.12(t,J=7.6Hz,6H).

[0121] HRMS(ESI):m / z 449.1798[M+H] + (calcd for C 20 H 29 N6O2S2 + :449.1788).

[0122] Example 6

[0123]

[0124] Add (6S,7R)-2-amino-6-propionamido-7-((S)-6-propionamido-4,5,6,7-tetrahydrobenzothiazole-2-amino)-4,5,6,7-tetrahydrobenzothiazole (43.5 mg, 0.0970 mmol) to a 15 mL round-bottom flask and mix with tetrahydrofuran (2 mL) at room temperature under argon protection. Add DIBAL-H tetrahydrofuran solution (1 mol / L, 2 mL, 2 mmol) under stirring in an ice-water bath. Keep the reaction at this temperature for 10 minutes, then move to room temperature for 17 hours. Add 5% hydrochloric acid to quench the reaction under an ice-water bath, and adjust the pH to 1-2. Then add 10% NaOH aqueous solution to adjust the pH to 13-14. Then add NaCl solid (1.5 g) to the reaction solution and extract with tetrahydrofuran (20 mL×3). Combine the organic phases, dry over anhydrous sodium sulfate, and filter. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol containing 5% ammonia water = 20:1 to 0:1) to obtain 17.1 mg of a white solid compound (6S,7R)-2-amino-6-propylamino-7-((S)-6-propylamino-4,5,6,7-tetrahydrobenzothiazole-2-amino)-4,5,6,7-tetrahydrobenzothiazole (BI-II786BS), with a yield of 42%.

[0125] 1 H NMR (400MHz, Methanol-d4) δ4.74(m,1H),3.15(m,1H),2.98-2.93(m,2H),2.86(dd,J=15.2,5.2Hz,1H),2.67-2.63(m,2H),2.64-2.55(m,4H), 2.39-2.35(m,2H),2.32(m,1H),2.10(brd,J=13.2Hz,1H),1.76-1.61(m,2H),1.59-1.48(m,4H),0.97(t,J=7.6Hz,3H),0.93(t,J=7.6Hz,3H).

[0126] HRMS(ESI):m / z 421.2213[M+H] + (calcd for C 20 H 33 N6S2 + :421.2203).

Claims

1. A method for preparing a pramipexole hydrochloride related substance BI-II786BS, the method comprising the following steps: (1), (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole reacts with propionic anhydride in the presence of an organic base or an inorganic base to obtain (S)-2-amino-6-propionamido-4,5,6,7-tetrahydrobenzothiazole, i.e., intermediate M1; (2) reacting the intermediate M1 with Boc2O in the presence of an organic base or an inorganic base to obtain (S)-2-tert-butoxyamido-6-propionamido-4,5,6,7-tetrahydrobenzothiazole, namely, the intermediate M2; (3) The intermediate M2 is subjected to bromination reaction to obtain the intermediate M3, and M3 is further cyclized to obtain (3aS, 8bS)-2-ethyl-7-tert-butoxyamido-3a, 4, 5, 8b-tetrahydrothiazol[4, 5-g]benzo[4, 5-g] Azole, i.e. intermediate M4; (4) condensing the intermediate M4 with the intermediate M1 obtained in step (1) to obtain (6S,7R)-2-tert-butoxyamido-6-propionamido-7-((S)-6-propionamido-4,5,6,7-tetrahydrobenzothiazole-2-amino)-4,5,6,7-tetrahydrobenzothiazole, i.e., intermediate M5; (5) Removing the Boc protecting group from the intermediate M5 to obtain (6S,7R)-2-amino-6-propionamido-7-((S)-6-propionamido-4,5,6,7-tetrahydrobenzothiazole-2-amino)-4,5,6,7-tetrahydrobenzothiazole, namely, the intermediate M6; (6) Reducing the intermediate M6 to obtain (6S,7R)-2-amino-6-propylamino-7-((S)-6-propylamino-4,5,6,7-tetrahydrobenzothiazole-2-amino)-4,5,6,7-tetrahydrobenzothiazole, i.e., pramipexole related substance BI-II786BS; The structural formula is as follows:

2. The method for preparing the pramipexole hydrochloride related substance BI-II786BS according to claim 1, wherein: The organic base in step (1) is selected from triethylamine or diisopropylethylamine, and the inorganic base is selected from potassium carbonate or sodium carbonate, and the preferred base is triethylamine.

3. The method for preparing the pramipexole hydrochloride related substance BI-II786BS according to claim 1, wherein: In the step (1), the molar ratio of (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole to propionic anhydride is 1:1 to 1:5, preferably 1:1; The reaction temperature in step (1) is -78 to 0°C, preferably -40 to -30°C.

4. The method for preparing the pramipexole hydrochloride related substance BI-II786BS according to claim 1, wherein: The solvent used in the reaction of step (1) is one or more selected from tetrahydrofuran, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,4-dioxane, toluene, dichloromethane, chloroform, acetonitrile, DMF or DMSO, preferably tetrahydrofuran.

5. The method for preparing the pramipexole hydrochloride related substance BI-II786BS according to claim 1, wherein: The organic base in step (2) is selected from triethylamine, diisopropylethylamine, pyridine or 4-dimethylaminopyridine, and the inorganic base is selected from potassium carbonate or sodium carbonate, and the preferred base is 4-dimethylaminopyridine.

6. The method for preparing the pramipexole hydrochloride related substance BI-II786BS according to claim 1, wherein: In the step (2), the molar ratio of the intermediate M1 to Boc2O is 1:1 to 1:5, preferably 1:1.01 to 1:2; The reaction temperature in step (2) is -20 to 100°C, preferably -5 to 60°C.

7. The method for preparing the pramipexole hydrochloride related substance BI-II786BS according to claim 1, wherein: The solvent used in the reaction of step (2) is selected from one or more of tetrahydrofuran, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,4-dioxane, toluene, dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, acetonitrile, DMF, DMSO or water, preferably dichloromethane.

8. The method for preparing the pramipexole hydrochloride related substance BI-II786BS according to claim 1, wherein: The bromination reagent used in the bromination reaction in step (3) is selected from one or more of N-bromosuccinimide (NBS), liquid bromine, dibromohydantoin, dibromoisocyanuric acid or 5,5-dibromobarbituric acid, preferably NBS; the catalyst or initiator is selected from one or more of azobisisobutyronitrile (AIBN), azobisisoheptanenitrile, dimethyl azobisisobutyrate, benzoyl peroxide or lauroyl peroxide, preferably AIBN.

9. The method for preparing the pramipexole hydrochloride related substance BI-II786BS according to claim 1, wherein: The solvent used in the bromination reaction in step (3) is selected from one or more of carbon tetrachloride, dichloromethane, chloroform, 1,2-dichloroethane, toluene, acetonitrile, DMF or DMSO, preferably carbon tetrachloride.

10. The method for preparing the pramipexole hydrochloride related substance BI-II786BS according to claim 1, wherein: In the bromination reaction of step (3), the molar ratio of the intermediate M2 to the brominating agent is 1:1 to 1:3, and the molar ratio of the intermediate M2 to the catalyst or initiator is 1:0.01 to 1:0.

3.

11. The method for preparing the pramipexole hydrochloride related substance BI-II786BS according to claim 1, wherein: The temperature of the bromination reaction in step (3) is 40 to 100° C., preferably 50 to 70° C.; the reaction time is 0.5 to 3 hours.

12. The method for preparing the pramipexole hydrochloride related substance BI-II786BS according to claim 1, wherein: The inorganic salt used in the cyclization reaction in the step (3) is selected from one or more of ammonium chloride, sodium chloride, potassium carbonate, sodium carbonate, sodium bicarbonate, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium sulfite, sodium bisulfite or sodium thiosulfate, preferably a mixture of sodium bicarbonate and sodium thiosulfate. The solvent used for the cyclization reaction in step (3) is selected from one or more of DMSO, acetonitrile, tetrahydrofuran, diethyl ether, 1,4-dioxane, toluene, ethyl acetate, acetone, petroleum ether, methanol, ethanol, dichloromethane, chloroform, DMF, dimethylacetamide or water, preferably a mixed solvent of dichloromethane and water. The reaction temperature of the cyclization reaction in step (3) is -20 to 60°C, preferably 20 to 40°C; the reaction time is 0 to 30 minutes, preferably 10 to 20 minutes.

13. The method for preparing the pramipexole hydrochloride related substance BI-II786BS according to claim 1, wherein: In the step (4), the molar ratio of the reaction intermediate M4 to the intermediate M1 is 3:1 to 1:10, and the ratio of the reaction intermediate M4 to the condensation reagent is 10:1 to 1:

2.

14. The method for preparing the pramipexole hydrochloride related substance BI-II786BS according to claim 1, wherein: The condensation reagent used in step (4) is selected from one or more of triethylamine hydrochloride, dimethylaminopyridine hydrochloride, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, pyridinium p-toluenesulfonate, hydrochloric acid, sulfuric acid or nitric acid, preferably pyridinium p-toluenesulfonate or triethylamine hydrochloride.

15. The method for preparing the pramipexole hydrochloride related substance BI-II786BS according to claim 1, wherein: In step (4), the solvent is selected from one or more of dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, toluene, THF, methyltetrahydrofuran, ether, methyl tert-butyl ether, dioxane, acetonitrile, DMSO or DMF, preferably THF or chloroform; The reaction temperature in step (4) is 0 to 150°C, preferably 40 to 100°C.

16. The method for preparing the pramipexole hydrochloride related substance BI-II786BS according to claim 1, wherein: In the step (5), the acid reagent for removing the Boc protecting group of the intermediate M5 for deprotection reaction is selected from one or more of trifluoroacetic acid (TFA), hydrochloric acid, sulfuric acid, camphorsulfonic acid, acetic acid or p-toluenesulfonic acid, preferably TFA; In the step (5), the molar ratio of the acid reagent to the intermediate M5 is 500:1 to 1:100; The solvent for the deprotection reaction in step (5) is selected from one or more of dichloromethane, chloroform, 1,2-dichloroethane, toluene, THF, ether, dioxane, acetonitrile, DMF, DMSO or water, preferably dichloromethane; The reaction temperature in step (5) is -20 to 200°C, preferably 0 to 60°C.

17. The method for preparing the pramipexole hydrochloride related substance BI-II786BS according to claim 1, wherein: The reducing agent used in the reduction reaction of step (6) is one or more selected from the group consisting of sodium borohydride, potassium borohydride, zinc borohydride, borane-tetrahydrofuran, borane-dimethyl sulfide, diisobutylaluminum hydride (DIBAL-H), red aluminum or lithium aluminum hydride, preferably DIBAL-H; The solvent used for the reduction reaction of the intermediate M6 in step (6) is selected from one or more of tetrahydrofuran, toluene, dichloromethane, DMSO, ether, dioxane or methyl tert-butyl ether, preferably tetrahydrofuran; The molar ratio of the intermediate M6 to the reducing agent in step (6) is 2:1 to 1:100; The temperature of the reduction reaction of the intermediate M6 in step (6) is -30 to 70°C, preferably 0 to 25°C.

18. The method for preparing the pramipexole hydrochloride related substance BI-II786BS according to claim 1, characterized in that: The process for purifying the pramipexole related substance BI-II786BS prepared in step (6) is as follows: After the reduction is completed, hydrochloric acid is added to the system in an ice-water bath to quench the reaction and adjust the pH to 1-2. Then, an aqueous NaOH solution is added to adjust the pH to 13-14. Then, solid NaCl is added to the reaction solution, extracted with tetrahydrofuran, the organic phases are combined, dried, filtered, the filtrate is concentrated under reduced pressure, and then separated and purified by silica gel column chromatography to obtain a pure product.

19. The method for preparing the pramipexole hydrochloride related substance BI-II786BS according to claim 15, characterized in that: The concentration of the hydrochloric acid is 0.1% to 38%; the concentration of the NaOH aqueous solution is 0.1% to 40%; the silica gel column chromatography separation and purification adopts a solvent volume ratio of: dichloromethane / methanol containing 5% ammonia water = 20:1 to 0:

1.

20. A pramipexole hydrochloride related substance, characterized in that: The preparation method is obtained by the method according to any one of claims 1 to 19.

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