A preparation method of pramipexole hydrochloride related substance BI-II786BS

Abstract

The application belongs to the technical field of medicine production, and provides a preparation method of pramipexole hydrochloride related substance BI-II 786BS, which takes commercial reagent (S)-2, 6-diamino-4, 5, 6, 7-tetrahydrobenzothiazole as raw material, has simple preparation process, is easy to realize, has good reproducibility, is suitable for batch production of BI-II 786BS, and has high purity of pramipexole hydrochloride related substance prepared by the method, and can be used as a control (standard) for quality control of pramipexole hydrochloride bulk drug or preparation.

Description

TECHNICAL FIELD

[0001] The application relates to a preparation method of pramipexole hydrochloride related substance BI-II786BS and belongs to the technical field of medicine production. BACKGROUND

[0002] Pramipexole is developed by Boehringer Ingelheim in Germany and approved by the FDA of the United States in 1997 and marketed in the United States under the trade name Mirapex. It is also approved for marketing in Europe, Japan and other places. In April 2005, it was approved to enter China. Pramipexole hydrochloride is a non-ergot dopamine receptor agonist. It can reduce the motor disorders of Parkinson's disease patients by stimulating the dopamine receptors of the striatum and is used for treating adult idiopathic Parkinson's disease. Among the 17 related substances of pramipexole hydrochloride, BI-II786BS and BI-II828BS have the most complex structure. They are the dimeric products of pramipexole after oxidation at the C7 position and introduce a new chiral center.

[0003] There is only one reported synthesis route for BI-II786BS, which is shown in the following figure. The 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 has been reported that this synthesis route has the problem of low reproducibility (Sun, Lan Tian, Synthesis of pramipexole hydrochloride and related impurities, Master's Degree Thesis of Beijing University of Technology, June 2018). Therefore, the development of the synthesis route of pramipexole hydrochloride related substance BI-II786BS in the present application can realize the synthesis method of the substance in the prior art.

[0004]

[0005] Org. Process Res. Dev. 2016, 20, 1899-1905 SUMMARY

[0006] The purpose of the present application is to provide a preparation method of pramipexole hydrochloride related substance BI-II786BS. The method has the advantages of simple preparation process, easy implementation, easy-to-obtain raw materials, good reproducibility and suitability for batch production of BI-II786BS.

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

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

[0009] (2), intermediate M1 is reacted with Boc2O in the presence of an organic base or an inorganic base to obtain (S) -2-tert-butoxycarbonylamino-6-propionamido-4, 5, 6, 7-tetrahydrobenzothiazole, i. e. intermediate M2;

[0010] (3), intermediate M2 is subjected to bromination to obtain intermediate M3, and intermediate M3 is further subjected to cyclization to obtain (3aS, 8bS) -2-ethyl-7-tert-butoxycarbonylamino-3a, 4, 5, 8b-tetrahydrothiazolo [4, 5-g] benzothiazole, i. e. intermediate M4;

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

[0012] (5), intermediate M5 is subjected to Boc removal to obtain (6S, 7R) -2-aminopropionamido-7- ( (S) -6-propionamido-4, 5, 6, 7-tetrahydrobenzothiazol-2-ylamino) -4, 5, 6, 7-tetrahydrobenzothiazole, i. e. intermediate M6;

[0013] (6), intermediate M6 is subjected to reduction to obtain (6S, 7R) -2-aminopropylamino-7- ( (S) -6-propylamino-4, 5, 6, 7-tetrahydrobenzothiazol-2-ylamino) -4, 5, 6, 7-tetrahydrobenzothiazole, i. e. pramipexole related substance BI-II786BS;

[0014] The structure is as follows:

[0015]

[0016] In the preparation method of the pramipexole hydrochloride related substance, 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 preferably the base is triethylamine.

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

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

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

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

[0021] In the above preparation method of pramipexole hydrochloride related substances, 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 preparation method of pramipexole hydrochloride related substances, the brominating 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), azobisisoheptyl nitrile, dimethyl azobis isobutyrate, benzoyl peroxide or lauryl 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 intermediate M2 to the brominating agent is 1:1-1:3, and the molar ratio of intermediate M2 to the catalyst or initiator is 1:0.01-1:0.3.

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

[0024] In the above preparation method of pramipexole hydrochloride related substances, the inorganic salt used in the cyclization reaction in 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 preparation method of pramipexole hydrochloride related substances, the solvent used in 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 mixture of dichloromethane and water.

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

[0027] In the above preparation method of pramipexole hydrochloride related substances, the molar ratio of intermediate M4 to intermediate M1 in step (4) is 3:1-1:10, and the ratio of intermediate M4 to condensing reagent in the reaction is 10:1-1:2; the temperature of the reaction in step (4) is 0-150°C, preferably 40-100°C; the condensing reagent used in step (4) is selected from one or more of triethylamine hydrochloride, dimethylamino pyridine hydrochloride, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, p-toluenesulfonic acid pyridine salt, hydrochloric acid, sulfuric acid or nitric acid, preferably p-toluenesulfonic acid pyridine 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 preparation method of pramipexole hydrochloride related substances, the acid reagent for the deprotection reaction of intermediate M5 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 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, diethyl 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 preparation method of pramipexole hydrochloride related substances, the reducing agent used in the reduction reaction in 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, diethyl ether, dioxane or methyl tert-butyl ether, preferably tetrahydrofuran; the molar ratio of intermediate M7 to the reducing agent is 2:1 to 1:100; the temperature for the reduction reaction of intermediate M6 is -30 to 70°C, preferably 0 to 25°C.

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

[0031] After the reduction is completed, hydrochloric acid is added to quench the reaction under an ice water bath, and the pH is adjusted to 1 to 2. Then, an aqueous NaOH solution is added to adjust the pH to 13 to 14. Then, NaCl solid is added to the reaction solution, and tetrahydrofuran is used for extraction. The organic phases are combined, dried, filtered, and the filtrate is concentrated under reduced pressure. Then, the product is obtained by silica gel column chromatography separation and purification. In this purification method, the concentration of the hydrochloric acid is 0.1% to 38%, the concentration of the aqueous NaOH solution is 0.1% to 40%, and the silica gel column chromatography separation and purification uses dichloromethane / methanol containing 5% ammonia water in a volume ratio of 20:1 to 0:1.

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

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

[0034] (1), the application provides a preparation method of new pramipexole hydrochloride related substance BI-II786BS, the method of the pramipexole hydrochloride related substance is simple in process, easy to realize, raw materials are easy to obtain, has good reproducibility, and is suitable for batch production of BI-II786BS.

[0035] (2), the application provides a preparation method of new pramipexole hydrochloride related substance BI-II786BS, the pramipexole hydrochloride related substance prepared by the method has high purity, and can be used as a control (standard) for quality control of pramipexole raw drugs or preparations. DETAILED DESCRIPTION

[0036] The application will be further described in detail below in combination with specific embodiments:

[0037] The structural formula of the pramipexole hydrochloride related substance BI-II786BS of the application is shown in the following formula:

[0038]

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

[0040]

[0041] (1), (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole, namely S, is reacted with propionic anhydride in the presence of an organic base or an inorganic base to obtain (S)-2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole, namely intermediate M1, and the reaction process is shown in the following formula:

[0042]

[0043] The above-mentioned organic base is selected from triethylamine or diisopropyl ethylamine; the inorganic base is selected from potassium carbonate or sodium carbonate, and preferably, the base is triethylamine.

[0044] The solvent used in the above-mentioned 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, and preferably, the solvent used is tetrahydrofuran.

[0045] The reaction temperature is -78-0 ℃, and preferably, the reaction temperature is -40--30 ℃.

[0046] The molar ratio of (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 or inorganic base to protect the amine group with Boc, generating (S)-2-tert-butoxyamido-6-propamido-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., with 4-dimethylaminopyridine being the preferred base.

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

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

[0052] In the above-mentioned amino 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 intermediate M3, and intermediate M3 is further cyclized to obtain (3aS,8bS)-2-ethyl-7-tert-butoxyamido-3a,4,5,8b-tetrahydrothiazo[4,5-g]benzo[3aS,8bS] ... The reaction process of azole, namely intermediate M4, is shown below:

[0054]

[0055] The reaction temperature for the above bromination reaction is 40–100°C, preferably 50–70°C.

[0056] The reaction time for the above bromination reaction is 0.5 to 3 hours, preferably 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, dibromo isocyanuric acid, 5,5-dibromobarbituric acid, preferably NBS; the catalyst or initiator is selected from one or more of azobisisobutyronitrile (AIBN), azobisisoheptanenitrile, dimethyl azodicarboxylate, benzoyl peroxide, lauryl peroxide, preferably AIBN; the molar ratio of intermediate M2 to the brominating agent is 1:1 to 1:3, and the molar ratio of 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 selected from one or more of 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 used 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, 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.

[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 condensation reaction with the intermediate M1 obtained in step (1) to obtain (6S,7R)-2-tert-butoxycarbonylamino-6-propionamido-7-((S)-6-propionamido-4,5,6,7-tetrahydrobenzothiazol-2-ylamino)-4,5,6,7-tetrahydrobenzothiazole, i.e. intermediate M5, and the reaction process is as shown below:

[0064]

[0065] The condensing agent used in the above reaction is selected from one or more of triethylamine hydrochloride, dimethylamino pyridine hydrochloride, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, p-toluenesulfonic acid pyridine salt, hydrochloric acid, sulfuric acid or nitric acid, preferably p-toluenesulfonic acid pyridine salt or triethylamine hydrochloride.

[0066] The solvent used in the above reaction 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.

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

[0068] The molar ratio of intermediate M4 to intermediate Ml in the above condensation reaction is 3:1-1:10, and the ratio of intermediate M4 to condensing agent in the reaction is 10:1-1:2.

[0069] (5) The intermediate M5 obtained in step (4) is deprotected to obtain (6S,7R)-2-amino-6-propionamido-7-((S)-6-propionamido-4,5,6,7-tetrahydrobenzothiazol-2-ylamino)-4,5,6,7-tetrahydrobenzothiazole, i.e. intermediate M6, and the reaction process is shown 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, p-toluenesulfonic acid, preferably TFA.

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

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

[0074] The reaction temperature in the above deprotection reaction is -20-200°C, preferably the reaction temperature is 0-60°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-tetrahydrobenzothiazol-2-ylamino)-4,5,6,7-tetrahydrobenzothiazole, i.e. pramipexole hydrochloride related substance BI-II 786BS, and the reaction process is shown as follows:

[0076]

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

[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-dimethylsulfide, diisobutylaluminum hydride (DIBAL-H), red aluminum, lithium aluminum hydride, and preferably the reducing agent is DIBAL-H.

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

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

[0081] (7) The purification process of pramipexole hydrochloride related substance BI-II786BS prepared in step (6) is as follows: after the reduction is completed, 0.1% to 38% hydrochloric acid is added to quench the reaction under an ice water bath, 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 liquid, and extracted with tetrahydrofuran. The organic phases are combined, dried with anhydrous sodium sulfate, and filtered. The filtrate is concentrated under reduced pressure, and then separated and purified by silica gel column chromatography (column chromatography uses solvents with a volume ratio of dichloromethane / methanol containing 5% ammonia water = 20:1 to 0:1), to obtain a 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 application has high purity, and can be used as a control (standard) for quality control of pramipexole raw material or preparation. In addition, the synthesis method of the present application is simple to operate, the raw materials are easy to obtain, and the reproducibility is good, and is suitable for the production of pramipexole hydrochloride related substance BI-II786BS.

[0085] Example 1

[0086]

[0087] In a 1 L round bottom flask, commercial reagent (S)-2,6-diamino-4,5,6,7- tetrahydrobenzothiazole (24.99 g, 147.7 mmol) was dissolved in tetrahydrofuran (290 mL) at room temperature. Triethylamine (100.5 mL, 717 mmol) and propionic anhydride (18.9 mL, 147.7 mmol) were added successively under stirring at -40 °C. The reaction was maintained at this temperature for 3 hours. 1 mol / L aqueous NaOH solution (150 mL) was added to the reaction under ice-water bath, and after stirring for 15 minutes at room temperature, the reaction was extracted successively with dichloromethane (250 mL x 3) and ethyl acetate (250 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give (S)-2-amino-6-propionamido-4,5,6,7- tetrahydrobenzothiazole as a white powder, 31.83 g, yield 96%. 1 H NMR (300 MHz, CDC13) δ 5.61 (m, 1H), 4.93 (br, 2H), 4.38 (s, 1H),

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

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

[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] In a 1 L round bottom flask, (S)-2-amino-6-propionamido-4,5,6,7- tetrahydrobenzothiazole (20.02 g, 88.86 mmol) and DMAP (0.27 g, 2.22 mmol) were dissolved in dichloromethane (200 mL) at room temperature. Boc anhydride (22.4 mL, 97.74 mmol) was added with stirring at room temperature and the reaction was allowed to proceed for 2 h at this temperature. The reaction was concentrated under reduced pressure to give a yellow-white solid. Methanol (360 mL) was added to the reaction flask containing the above solid at room temperature and after stirring to dissolve, anhydrous potassium carbonate (7.36 g, 53.3 mmol) was added and the reaction was allowed to proceed for 3 days at this temperature. Saturated aqueous NaHCO3(250 mL) was added and the mixture was extracted with dichloromethane (300 mL x 3). The organic phases were combined and the mixture was partitioned with saturated aqueous NaCl (900 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a crude product which was dissolved in a small amount of dichloromethane and the product was precipitated by the addition of cyclohexane. The precipitate was filtered to give (S)-2-tert-butoxyamido-6-propionamido-4,5,6,7- tetrahydrobenzothiazole as a white solid (21.3956 g, 74% yield).

[0095] 1 H NMR (300 MHz, CDC13) δ 10.2 (br, 1H), 5.52 (d, J = 6.9 Hz, 1H), 4.41 (m, 1H), 3.08 (d, J = 15.6 Hz, 1H), 2.80-2.78 (m, 2H), 2.56 (d, J = 16.5,

[0096] 6.3 Hz, 1H), 2.19 (q, J = 7.5 Hz, 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] In a 500 mL round bottom flask, (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) were added and mixed with carbon tetrachloride (190 mL) at room temperature. The reaction was then warmed to 55 °C and stirred vigorously for 1 hour. After the reaction was cooled to room temperature, it was concentrated under reduced pressure to give a yellow-brown solid.

[0102] The reaction flask was transferred to an ice-water bath and dissolved in dichloromethane (150 mL). The reaction was quenched by the addition of saturated aqueous Na2S203 (150 mL) and saturated aqueous NaHC03 (150 mL) and stirred for 15 minutes. The reaction was allowed to warm to room temperature and the organic phase was separated from the aqueous phase and the aqueous phase was extracted with dichloromethane (150 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography on neutral alumina (dichloromethane / acetone = 100:1 to 1:1) to give compound (3aS,8bS)-2-ethyl-7-tert-butoxyamido-3a,4,5,8b-tetrahydrothiazolo[4,5- g]benzothiazole 1.0680 g in 36% yield as a white solid.

[0103] 1 H NMR (400 MHz, Chloroform-d) δ 10.52 (s, 1H), 5.41 (ddd, J = 3.6, 2.0, 1.6 Hz, 1H), 4.06 (m, 1H), 3.06 (dd, J = 16.8, 2.0 Hz, 1H), 2.93 (dd, J = 16.8, 4.4 Hz, 1H), 2.15 (m, 1H), 2.09 (qd, J = 7.6, 3.6 Hz, 2H), 1.95 (ddd, J = 13.2, 2.0, 1.2 Hz, 1H), 1.54 (s, 9H), 1.00 (t, J = 7.6 Hz, 3H).

[0104] 1.6 Hz, 1H), 4.06 (m, 1H), 3.06 (dd, J = 16.8, 2.0 Hz, 1H), 2.93 (dd, J = 16.8, 4.4 Hz, 1H), 2.15 (m, 1H), 2.09 (qd, J = 7.6, 3.6 Hz, 2H), 1.95 (ddd, J = 13.2, 2.0, 1.2 Hz, 1H), 1.54 (s, 9H), 1.00 (t, J = 7.6 Hz, 3H).

[0105] 16.8, 4.4 Hz, 1H), 2.15 (m, 1H), 2.09 (qd, J = 7.6, 3.6 Hz, 2H), 1.95 (ddd, J = 13.2, 2.0, 1.2 Hz, 1H), 1.54 (s, 9H), 1.00 (t, J = 7.6 Hz, 3H).

[0106] 16.8, 4.4 Hz, 1H), 2.15 (m, 1H), 2.09 (qd, J = 7.6, 3.6 Hz, 2H), 1.95 (ddd, J = 13.2, 2.0, 1.2 Hz, 1H), 1.54 (s, 9H), 1.00 (t, J = 7.6 Hz, 3H).

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

[0108] Example 4

[0109] ​

[0110] (3aS,8bS)-2-ethyl-7-tert-butoxyamido-3a,4,5,8b-tetrahydrothiazo[4,5-g]benzo[3aS,8bS] ... The reaction mixture was prepared with 201.4 mg (0.6227 mmol), (S)-2-amino-6-propamido-4,5,6,7-tetrahydrobenzothiazole (280.6 mg, 1.245 mmol), pyridinium p-toluenesulfonate (PPTS, 156.4 mg, 0.6227 mmol), and chloroform (1 mL), and the tube was then sealed with a screw cap. The temperature was then raised to 80 °C and the reaction was allowed to proceed for 15 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to obtain a pale yellow-brown crude solid. The crude solid was purified by silica gel column chromatography (dichloromethane / methanol = 100:1 to 1:1) to give 432.7 mg of the crude compound (6S,7R)-2-tert-butoxyamido-6-propamido-7-((S)-6-propamido-4,5,6,7-tetrahydrobenzothiazole-2-amino)-4,5,6,7-tetrahydrobenzothiazole. Take a small amount of the above crude product, 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, was placed the above crude (6S,7R)-2-tert-butoxy- carbonylamino-6-propionamido-7-((S)-6-propionamido-4,5,6,7-tetrahydrobenzo- thiazol-2-ylamino)-4,5,6,7-tetrahydrobenzothiazole 355.8 mg, which was dissolved in dichloromethane (10 mL) at room temperature, and trifluoroacetic acid (5 mL) was added slowly with stirring. After the reaction was carried out at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure, and the crude compound obtained was purified by column chromatography on silica gel (dichloromethane / methanol = 100:1 to 1:1) to give a yellow solid compound (6S,7R)-2-amino-6-propionamido-7-((S)-6-propionamido- 4,5,6,7-tetrahydrobenzothiazol-2-ylamino)-4,5,6,7-tetrahydrobenzothiazole 79.6 mg in a two-step yield of 29%.

[0116] 1 H NMR (400 MHz, Methanol-d4) δ 4.77 (dd, J = 4.0, 3.6 Hz, 1H), 4.29 (m,

[0117] 1H), 4.16m, 1H), 2.96 (dd, J = 16.0, 5.6 Hz, 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 = 7.6 Hz,

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

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

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

[0122] Example 6

[0123]

[0124] In a 15 mL round bottom flask, (6S,7R)-2-amino-6-(propylamino)-7-((S)-6- propylamino-4, 5, 6, 7-tetrahydrobenzo thiazol-2-ylamino)-4, 5, 6, 7- tetrahydrobenzothiazole (43.5 mg, 0.0970 mmol) was mixed with tetrahydrofuran (2 mL) under argon protection at room temperature. DIBAL-H solution in tetrahydrofuran (1 mol / L, 2 mL, 2 mmol) was added under stirring in ice water bath. After 10 minutes of reaction at this temperature, it was removed to room temperature for 17 hours of reaction. The reaction was quenched by 5% hydrochloric acid under ice water bath, and the pH was adjusted to 1-2. 10% NaOH aqueous solution was added to adjust the pH to 13-14. Then NaCl solid (1.5 g) was added to the reaction solution, which was extracted with tetrahydrofuran (20 mL x 3). The organic phase was combined, dried with anhydrous sodium sulfate, and filtered. 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 white solid compound (6S,7R)-2-amino-6-(propylamino)-7-((S)-6-propylamino-4, 5, 6, 7- tetrahydrobenzothiazol-2-ylamino)-4, 5, 6, 7-tetrahydrobenzothiazole (BI-II786BS) 17.1 mg, yield 42%.

[0125] 1 H NMR (400 MHz, Methanol-d4) δ 4.74 (m, 1H), 3.15 (m, 1H), 2.98-2.93 (m, 2H), 2.86 (dd, J = 15.2, 5.2 Hz, 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 (br d, J = 13.2 Hz, 1H), 1.76-1.61 (m, 2H), 1.59-1.48 (m, 4H), 0.97 (t, J = 7.6 Hz, 3H), 0.93 (t, J = 7.6 Hz, 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 or inorganic base to give (S)-2-amino-6-propamido-4,5,6,7-tetrahydrobenzothiazole, i.e. intermediate M1. (2) React intermediate M1 with Boc2O in the presence of an organic or inorganic base to obtain (S)-2-tert-butoxyamido-6-propamido-4,5,6,7-tetrahydrobenzothiazole, i.e. intermediate M2. (3) Intermediate M2 was brominated to obtain intermediate M3, and M3 was further cyclized to obtain (3aS,8bS)-2-ethyl-7-tert-butoxyamido-3a,4,5,8b-tetrahydrothiazo[4,5-g]benzo[]. Azole, namely intermediate M4; (4) The intermediate M4 is condensed with the intermediate M1 obtained in step (1) to obtain (6S,7R)-2-tert-butoxyamido-6-propamido-7-((S)-6-propamido-4,5,6,7-tetrahydrobenzothiazole-2-amino)-4,5,6,7-tetrahydrobenzothiazole, i.e., intermediate M5; (5) Remove the Boc protecting group from intermediate M5 to obtain (6S,7R)-2-amino-6-propamido-7-((S)-6-propamido-4,5,6,7-tetrahydrobenzothiazole-2-amino)-4,5,6,7-tetrahydrobenzothiazole, i.e. intermediate M6. (6) Reduce 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 structure is as follows:

2. The method for preparing 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.

3. The method for preparing pramipexole hydrochloride related substance BI-II786BS according to claim 2, characterized in that: The base in step (1) is triethylamine.

4. The method for preparing pramipexole hydrochloride related substance BI-II786BS according to claim 1, wherein: In step (1), the molar ratio of (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole to propionic anhydride is 1:1 to 1:

5. The reaction temperature in step (1) is -78 to 0℃.

5. The method for preparing pramipexole hydrochloride related substance BI-II786BS according to claim 4, characterized in that: In step (1), the molar ratio of (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole to propionic anhydride is 1:

1.

6. The method for preparing pramipexole hydrochloride related substance BI-II786BS according to claim 4, characterized in that: The reaction temperature in step (1) is -40 to -30℃.

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

8. The method for preparing pramipexole hydrochloride related substance BI-II786BS according to claim 7, characterized in that: The solvent used in step (1) is tetrahydrofuran.

9. The method for preparing 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.

10. The method for preparing pramipexole hydrochloride related substance BI-II786BS according to claim 9, characterized in that: The base in step (2) is 4-dimethylaminopyridine.

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

12. The method for preparing pramipexole hydrochloride related substance BI-II786BS according to claim 11, characterized in that: In step (2), the molar ratio of intermediate M1 to Boc2O is 1:1.01 to 1:

2.

13. The method for preparing pramipexole hydrochloride related substance BI-II786BS according to claim 11, characterized in that, The reaction temperature in step (2) is -5 to 60°C.

14. The method for preparing pramipexole hydrochloride related substance BI-II786BS according to claim 1, wherein: The solvent used in 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.

15. The method for preparing pramipexole hydrochloride related substance BI-II786BS according to claim 14, characterized in that: The solvent used in step (2) is dichloromethane.

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

17. The method for preparing pramipexole hydrochloride related substance BI-II786BS according to claim 16, characterized in that: The brominating reagent used in step (3) is N-bromosuccinimide.

18. The method for preparing pramipexole hydrochloride related substance BI-II786BS according to claim 16, characterized in that: The catalyst or initiator used in the bromination reaction in step (3) is azobisisobutyronitrile.

19. The method for preparing 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.

20. The method for preparing pramipexole hydrochloride related substance BI-II786BS according to claim 19, characterized in that: The solvent used in the bromination reaction in step (3) is carbon tetrachloride.

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

3.

22. The method for preparing pramipexole hydrochloride related substance BI-II786BS according to claim 1, wherein: The bromination reaction in step (3) is carried out at a temperature of 40–100°C and for a reaction time of 0.5–3 hours.

23. The method for preparing pramipexole hydrochloride related substance BI-II786BS according to claim 22, characterized in that: The bromination reaction in step (3) is carried out at a temperature of 50–70 °C.

24. The method for preparing pramipexole hydrochloride related substance BI-II786BS according to claim 1, wherein: The inorganic salt used in the cyclization reaction in step (3) is selected from one or more of the following: 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. The solvent used in 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. The cyclization reaction in step (3) has a reaction temperature of -20 to 60°C and a reaction time of 0 to 30 minutes.

25. The method for preparing pramipexole hydrochloride related substance BI-II786BS according to claim 24, characterized in that: The inorganic salt used in the cyclization reaction in step (3) is a mixture of sodium bicarbonate and sodium thiosulfate.

26. The method for preparing pramipexole hydrochloride related substance BI-II786BS according to claim 24, characterized in that: The solvent used in step (3) for the cyclization reaction is a mixture of dichloromethane and water.

27. The method for preparing pramipexole hydrochloride related substance BI-II786BS according to claim 24, characterized in that: The cyclization reaction in step (3) is carried out at a temperature of 20–40 °C.

28. The method for preparing pramipexole hydrochloride related substance BI-II786BS according to claim 24, characterized in that: The cyclization reaction time in step (3) is 10 to 20 minutes.

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

2.

30. The method for preparing 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 the following: triethylamine hydrochloride, dimethylaminopyridine hydrochloride, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, p-toluenesulfonic acid pyridine salt, hydrochloric acid, sulfuric acid, or nitric acid.

31. The method for preparing pramipexole hydrochloride related substance BI-II786BS according to claim 30, characterized in that: The condensation reagent used in step (4) is p-toluenesulfonic acid pyridinium salt or triethylamine hydrochloride.

32. The method for preparing pramipexole hydrochloride related substance BI-II786BS according to claim 1, wherein: The solvent 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. The reaction temperature in step (4) is 0 to 150°C.

33. The method for preparing pramipexole hydrochloride related substance BI-II786BS according to claim 32, characterized in that: The solvent used in step (4) is tetrahydrofuran or chloroform.

34. The method for preparing pramipexole hydrochloride related substance BI-II786BS according to claim 32, characterized in that: The reaction temperature in step (4) is 40–100°C.

35. The method for preparing pramipexole hydrochloride related substance BI-II786BS according to claim 1, wherein: In step (5), the acid reagent used to remove the Boc protecting group from intermediate M5 for deprotection reaction is selected from one or more of trifluoroacetic acid, hydrochloric acid, sulfuric acid, camphor sulfonic acid, acetic acid or p-toluene sulfonic acid. In step (5), the molar ratio of the acid reagent to intermediate M5 is 500:1 to 1:

100. The solvent used in the deprotection reaction in step (5) is selected from one or more of dichloromethane, chloroform, 1,2-dichloroethane, toluene, THF, diethyl ether, dioxane, acetonitrile, DMF, DMSO, or water. The reaction temperature in step (5) is -20 to 200℃.

36. The method for preparing pramipexole hydrochloride related substance BI-II786BS according to claim 35, characterized in that: The acid reagent used in the deprotection reaction in step (5) is trifluoroacetic acid.

37. The method for preparing pramipexole hydrochloride related substance BI-II786BS according to claim 35, characterized in that: The solvent for the deprotection reaction in step (5) is dichloromethane.

38. The method for preparing pramipexole hydrochloride related substance BI-II786BS according to claim 35, characterized in that: The reaction temperature in step (5) is 0 to 60°C.

39. The method for preparing pramipexole hydrochloride related substance BI-II786BS according to claim 1, wherein: 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, red aluminum, or lithium aluminum hydride. The solvent used for the reduction reaction of intermediate M6 in step (6) is selected from one or more of tetrahydrofuran, toluene, dichloromethane, DMSO, diethyl ether, dioxane, or methyl tert-butyl ether. The molar ratio of intermediate M6 to reducing agent in step (6) is 2:1 to 1:100; The temperature for the reduction reaction of intermediate M6 in step (6) is -30 to 70°C.

40. The method for preparing pramipexole hydrochloride related substance BI-II786BS according to claim 39, characterized in that: The reducing agent used in the reduction reaction in step (6) is diisobutylaluminum hydride.

41. The method for preparing pramipexole hydrochloride related substance BI-II786BS according to claim 39, characterized in that: The solvent used in the reduction reaction in step (6) is tetrahydrofuran.

42. The method for preparing pramipexole hydrochloride related substance BI-II786BS according to claim 39, characterized in that: The reduction reaction temperature in step (6) is 0–25 °C.

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

44. The method for preparing pramipexole hydrochloride related substance BI-II786BS according to claim 43, 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 uses a solvent volume ratio of dichloromethane / methanol containing 5% ammonia = 20:1 to 0:1.

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