A preparation method of pramipexole hydrochloride related substances
The pramipexole hydrochloride-related substance BI-II828BS was prepared by a multi-step synthesis method, which solved the problems of difficult synthesis and low reproducibility and achieved high-purity batch production and quality control.
Patent Information
- Application Number
- CN202210488858.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2022-05-07
- Publication Date
- 2025-10-10
- Estimated Expiration
- 2042-05-07
AI Technical Summary
In the prior art, the impurity BI-II828BS of pramipexole hydrochloride is difficult to synthesize, has low reproducibility, and lacks an effective synthetic route.
A multi-step synthesis method is adopted, including reaction with propionic anhydride in the presence of an organic base or an inorganic base, Boc protection, bromination, oxidation, condensation, reduction and the like, to prepare a pramipexole hydrochloride related substance BI-II828BS.
The invention provides a simple and easy preparation method, the raw materials are readily available, the reproducibility is good, and the method is suitable for batch production. The prepared BI-II828BS has high purity and can be used for quality control.
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Abstract
Description
Technical Field
[0001] The present invention relates to a method for preparing a pramipexole hydrochloride related substance, in particular to a method for preparing a pramipexole hydrochloride related substance BI-II828BS, and belongs to the technical field of pharmaceutical production. Background Art
[0002] Pramipexole hydrochloride is a non-ergot alkaloid dopamine receptor agonist originally developed by Boehringer Ingelheim. It was approved by the U.S. FDA in 1997 and subsequently approved for marketing in Europe, Japan, and other regions. It is currently used primarily for the treatment of Parkinson's disease at all stages and for the treatment of restless legs syndrome. Pramipexole hydrochloride was approved for entry into China in 2005 and has been included in the National Medical Insurance Class B Catalog. In 2019, pramipexole ranked first in the list of terminal anti-Parkinson's disease drugs in China's public medical institutions with annual sales of nearly 700 million yuan, with Boehringer Ingelheim accounting for more than 90% of the market. Since the patent protection for pramipexole has expired, the development of generic drugs for it has significant economic and social value.
[0003]
[0004] During the application and post-approval production process for generic pramipexole hydrochloride, qualitative and quantitative studies of related substances (i.e., impurities) are required for quality control of the pramipexole hydrochloride API and formulation. Because the original manufacturer, Boehringer Ingelheim, specifies as many as 17 related substances in its quality standards for pramipexole hydrochloride, a sufficient number of impurity standard samples are required for comparison. Among these, impurities BI-II786BS and BI-II828BS have the most complex structures, representing dimerization products of pramipexole following oxidation at the C7 position, and also introduce a new chiral center into the molecule. Currently, only one synthetic route has been reported for the trans-impurity BI-II786BS, with the longest linear sequence consisting of 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). The synthesis of the cis-impurity BI-II828BS has not yet been reported. The structures of these two impurities are complex, making their synthesis difficult. The only reported synthetic route for the trans-impurity BI-II786BS also suffers from low reproducibility (Sun Lantian, Synthesis of pramipexole hydrochloride and its related impurities, Master's thesis, Beijing University of Technology, June 2018).
[0005]
[0006] Org.Process Res.Dev.2016,20,1899–1905 Summary of the Invention
[0007] The present invention aims to provide a method for preparing a pramipexole hydrochloride-related substance. The method can obtain the pramipexole hydrochloride-related substance BI-II828BS, and the preparation process is simple and easy to implement, the raw materials are readily available, the reproducibility is good, and the method is suitable for batch production of BI-II828BS.
[0008] The above-mentioned purpose of the present invention is mainly achieved through the following technical solutions:
[0009] A method for preparing a related substance of pramipexole hydrochloride comprises the following steps:
[0010] (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;
[0011] (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, i.e., intermediate M2;
[0012] (3) The intermediate M2 is subjected to bromination reaction to obtain the intermediate M3, which is further oxidized to obtain (S)-2-tert-butoxyamido-6-propionamido-7-oxo-4,5,6,7-tetrahydrobenzothiazole, namely the intermediate M4;
[0013] (4) Condensing the intermediate M4 with the intermediate M1 obtained in step (1) to obtain a dimer intermediate M5, which is further reduced to obtain (6S,7S)-2-tert-butoxyamido-6-propionamido-7-((S)-6-propionamido-4,5,6,7-tetrahydrobenzothiazole-2-amino)-4,5,6,7-tetrahydrobenzothiazole, i.e., intermediate M6;
[0014] (5) Removing the Boc protecting group from the intermediate M6 to obtain (6S,7S)-2-amino-6-propionamido-7-((S)-6-propionamido-4,5,6,7-tetrahydrobenzothiazole-2-amino)-4,5,6,7-tetrahydrobenzothiazole, namely, intermediate M7;
[0015] (6) Reducing the intermediate M7 to obtain (6S,7S)-2-amino-6-propylamino-7-((S)-6-propylamino-4,5,6,7-tetrahydrobenzothiazole-2-amino)-4,5,6,7-tetrahydrobenzothiazole, i.e., the pramipexole related substance BI-II828BS;
[0016] The structural formula is as follows:
[0017]
[0018] In the above-mentioned method for preparing related substances of pramipexole hydrochloride, the organic base in step (1) or step (2) is selected from triethylamine or diisopropylethylamine, and the inorganic base is selected from potassium carbonate or sodium carbonate, and the preferred base is triethylamine.
[0019] In the above-mentioned method for preparing related substances of pramipexole hydrochloride, 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.
[0020] In the above-mentioned method for preparing related substances of pramipexole hydrochloride, 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.
[0021] In the above-mentioned method for preparing pramipexole hydrochloride-related substances, the molar ratio of the intermediate M1 to Boc2O in step (2) is 1:1 to 1:5; and the reaction temperature in step (2) is -20 to 100°C, preferably -5 to 60°C.
[0022] 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, acetonitrile, DMF, DMSO or water, preferably a mixed solvent of tetrahydrofuran and water.
[0023] In the above-mentioned method for preparing related substances of pramipexole hydrochloride, 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), 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.
[0024] In the above method for preparing pramipexole hydrochloride-related substances, the temperature of the bromination reaction in step (3) is 40-100° C., preferably 50-70° C.; and the reaction time is 1-3 hours.
[0025] In the above-mentioned method for preparing related substances of pramipexole hydrochloride, the oxidant for the oxidation reaction in step (3) is selected from trimethylamine oxide (TMANO) or N-methylmorpholine N-oxide (NMO), preferably TMANO; and the molar ratio of the intermediate M2 to the oxidant in step (3) is 1:1 to 1:15.
[0026] In the above-mentioned method for preparing related substances of pramipexole hydrochloride, the solvent used in the oxidation reaction in step (3) is selected from one or more of DMSO, acetonitrile, tetrahydrofuran, diethyl ether, 1,4-dioxane, toluene, dichloromethane, chloroform, DMF, dimethylacetamide or water, preferably DMSO; the temperature of the oxidation reaction in step (3) is 40-100° C., preferably 50-70° C.; and the reaction time is 3-7 hours.
[0027] In the above-mentioned method for preparing related substances of pramipexole hydrochloride, the molar ratio of the condensation reaction intermediate M4 to the intermediate M1 in step (4) is 3:1 to 1:10; the temperature of the condensation reaction in step (4) is 0 to 150° C., preferably 40 to 80° C.; the condensation agent in the condensation reaction in step (4) is selected from one or more of tetraethyl titanate, tetraisopropyl titanate, titanium tetrachloride, titanium tetrafluoride, tin tetrachloride, molecular sieves, boron trifluoride ether or p-toluenesulfonic acid, preferably tetraethyl titanate; 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, diethyl ether, methyl tert-butyl ether, dioxane, acetonitrile, DMSO or DMF, preferably THF.
[0028] In the above-mentioned method for preparing related substances of pramipexole hydrochloride, the reducing agent for the reduction reaction of the intermediate M5 in step (4) 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 sodium borohydride; the molar ratio of the intermediate M5 to the reducing agent is 4:1 to 1:10; the temperature for the reduction reaction of the intermediate M5 is -30 to 70°C, preferably 0 to 30°C; the solvent added for the reduction reaction of the intermediate M5 is selected from one or more of methanol, ethanol, tetrahydrofuran, toluene, boron trifluoride etherate, ether or water, preferably methanol.
[0029] In the above-mentioned method for preparing related substances of pramipexole hydrochloride, the acid reagent for removing the Boc protecting group of the intermediate M6 in step (5) 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; the molar ratio of the acid reagent to the intermediate M6 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.
[0030] In the above-mentioned method for preparing related substances of pramipexole hydrochloride, 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 M7 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 reducing agent is 2:1 to 1:100; and the temperature for the reduction reaction of intermediate M7 is -30 to 70°C, preferably 0 to 25°C.
[0031] In the above-mentioned method for preparing related substances of pramipexole hydrochloride, the process for purifying the pramipexole related substance BI-II828BS prepared in step (6) is as follows:
[0032] After the reduction is complete, hydrochloric acid is added to the system in an ice-water bath to quench the reaction and adjust the pH to 2-3. Aqueous NaOH solution is then added to adjust the pH to 13-14. Solid NaCl is then added to the reaction solution, and extraction is performed with tetrahydrofuran. The organic phases are combined, dried, filtered, and the filtrate is concentrated under reduced pressure. Purification is then performed by silica gel column chromatography to obtain a pure product. In this purification method, the concentration of hydrochloric acid is 0.1% to 38%, and the concentration of aqueous NaOH solution is 0.1% to 40%. The silica gel column chromatography separation and purification employs a volume ratio of dichloromethane to methanol containing 5% ammonia water = 20:1 to 0:1.
[0033] A pramipexole hydrochloride-related substance is obtained by adopting the above preparation method.
[0034] Compared with the prior art, the present invention has the following beneficial effects:
[0035] (1) The present invention provides a novel method for preparing BI-II828BS, a related substance of pramipexole hydrochloride. The method is simple and easy to implement, uses readily available raw materials, has good reproducibility, and is suitable for mass production of BI-II828BS.
[0036] (2) The present invention provides a novel method for preparing BI-II828BS, a related substance of pramipexole hydrochloride. 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
[0037] The present invention will be described in further detail below in conjunction with specific embodiments:
[0038] The structural formula of the pramipexole hydrochloride related substance BI-II828BS of the present invention is shown in formula (I):
[0039]
[0040] The chemical name of BI-II828BS is (6S,7S)-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:
[0041]
[0042] (1) (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole (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 (intermediate M1). The reaction process is shown below:
[0043]
[0044] 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.
[0045] 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.
[0046] The reaction temperature is -78 to 0°C, preferably, the reaction temperature is -40 to -30°C.
[0047] The molar ratio of the (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole to propionic anhydride is 1:1 to 1:5.
[0048] (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 as follows:
[0049]
[0050] 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.
[0051] The molar ratio of the intermediate M1 to Boc2O is 1:1 to 1:5.
[0052] In the above-mentioned amino protection reaction, the reaction temperature is -20 to 100°C, preferably, the reaction temperature is -5 to 60°C.
[0053] 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, acetonitrile, DMF, DMSO, and water. Preferably, the solvent used is a mixed solvent of tetrahydrofuran and water.
[0054] (3) The intermediate M2 obtained in step (2) is brominated at the benzyl position to obtain the intermediate M3, which is further oxidized to obtain (S)-2-tert-butoxyamido-6-propionamido-7-oxo-4,5,6,7-tetrahydrobenzothiazole, i.e., the intermediate M4. The reaction process is as follows:
[0055]
[0056] The reaction temperature of the bromination reaction is 40-100°C, preferably 50-70°C.
[0057] The reaction time of the bromination reaction is 0.5 to 3 hours, preferably, the reaction time is 1 hour.
[0058] The brominating agent used in the above-mentioned 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.
[0059] The solvent used in the bromination reaction is one or more selected from carbon tetrachloride, dichloromethane, chloroform, 1,2-dichloroethane, toluene, acetonitrile, DMF or DMSO, preferably carbon tetrachloride.
[0060] The reaction temperature of the bromination reaction is 40 to 100° C., preferably 50 to 70° C., and the reaction time is 1 to 3 hours.
[0061] The oxidant in the above oxidation reaction is selected from trimethylamine oxide (TMANO) and N-methylmorpholine nitrogen oxide (NMO), preferably TMANO; the molar ratio of the intermediate M2 to the oxidant is 1:1 to 1:15.
[0062] The solvent used in the above oxidation reaction is selected from one or more of DMSO, acetonitrile, tetrahydrofuran, diethyl ether, 1,4-dioxane, toluene, dichloromethane, chloroform, DMF, dimethylacetamide or water, preferably DMSO.
[0063] The reaction temperature of the above oxidation reaction is 40-100° C., preferably 50-70° C.; the reaction time is 3-7 hours, preferably 5 hours.
[0064] (4) The intermediate M4 obtained in step (3) is subjected to a condensation reaction with the intermediate M1 obtained in step (1) to obtain the intermediate M5, which is further reduced to obtain (6S,7S)-2-tert-butoxyamido-6-propionamido-7-((S)-6-propionamido-4,5,6,7-tetrahydrobenzothiazole-2-amino)-4,5,6,7-tetrahydrobenzothiazole, i.e., the intermediate M6. The reaction process is as follows:
[0065]
[0066] In the above condensation reaction, the condensing agent is selected from one or more of tetraethyl titanate, tetraisopropyl titanate, titanium tetrachloride, titanium tetrafluoride, tin tetrachloride, molecular sieves, boron trifluoride etherate, and p-toluenesulfonic acid, preferably tetraethyl titanate.
[0067] The solvent in the above condensation reaction is selected from one or more of dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, toluene, THF, ether, methyl tert-butyl ether, dioxane, acetonitrile, DMF, and DMSO. Preferably, the solvent used is THF.
[0068] The reaction temperature in the above condensation reaction is 0-150°C, preferably, the reaction temperature is 40-80°C.
[0069] The molar ratio of the intermediate M4 to the intermediate M1 in the above condensation reaction is 3:1 to 1:10.
[0070] 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; preferably, the reducing agent is sodium borohydride.
[0071] In the above reduction reaction, the solvent is selected from one or more of methanol, ethanol, tetrahydrofuran, toluene, boron trifluoride etherate, ether, and water. Preferably, the solvent is methanol.
[0072] In the above reduction reaction, the reaction temperature is -30 to 70°C, preferably, the temperature is 0 to 30°C.
[0073] In the above reduction reaction, the molar ratio of the intermediate M5 to the reducing agent is 4:1 to 1:10.
[0074] (5) The intermediate M6 obtained in step (4) is deprotected by removing the Boc protecting group to obtain (6S,7S)-2-amino-6-propionamido-7-((S)-6-propionamido-4,5,6,7-tetrahydrobenzothiazole-2-amino)-4,5,6,7-tetrahydrobenzothiazole, i.e., intermediate M7. The reaction process is as follows:
[0075]
[0076] 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.
[0077] The molar ratio of the acid to the intermediate M6 in the above deprotection reaction is 500:1 to 1:100.
[0078] 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.
[0079] The reaction temperature in the above deprotection reaction is -20 to 200°C, preferably, the reaction temperature is 0 to 60°C.
[0080] (6) The intermediate M7 obtained in step (5) is reduced to obtain (6S,7S)-2-amino-6-propylamino-7-((S)-6-propylamino-4,5,6,7-tetrahydrobenzothiazole-2-amino)-4,5,6,7-tetrahydrobenzothiazole, i.e., the pramipexole hydrochloride related substance BI-II828BS represented by formula (I). The reaction process is as follows:
[0081]
[0082] In the above reduction reaction, the molar ratio of the intermediate M7 to the reducing agent is 2:1 to 1:100.
[0083] 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.
[0084] In the above reduction reaction, the solvent is selected from one or more of tetrahydrofuran, toluene, dichloromethane, DMSO, diethyl ether, dioxane, and methyl tert-butyl ether. Preferably, the solvent is tetrahydrofuran.
[0085] In the above reduction reaction, the reaction temperature is -30 to 70°C, preferably, the temperature is 0 to 25°C.
[0086] (7) The purification process of the pramipexole hydrochloride-related substance BI-II828BS 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 adjust the pH to 2 to 3. 0.1% to 40% NaOH aqueous solution is then 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 column chromatography is: dichloromethane / methanol containing 5% ammonia water = 20:1 to 0:1) to obtain a pure white powder product.
[0087] The structural formula is as follows:
[0088]
[0089] The pramipexole hydrochloride related substance BI-II828BS 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, uses readily available raw materials, and has good reproducibility, making it suitable for the production of the related substance BI-II828BS.
[0090] Example 1:
[0091]
[0092] To a 1 L round-bottom flask, add the commercial reagent (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole (25.22 g, 149.0 mmol) and dissolve it in tetrahydrofuran (290 mL) at room temperature. Add triethylamine (101.4 mL, 724 mmol) and propionic anhydride (19.1 mL, 149.0 mmol) sequentially at -40°C with stirring. Maintain this temperature for 3 hours. Add 1 mol / L aqueous NaOH (150 mL) to the reaction mixture in an ice-water bath, bring to room temperature, and stir for 15 minutes. Extract with dichloromethane (250 mL x 3) and ethyl acetate (250 mL x 3), sequentially. Combine the organic phases, dry over anhydrous sodium sulfate, and filter. The filtrate was concentrated under reduced pressure to obtain 33.29 g of (S)-2-amino-6-propionamido-4,5,6,7-tetrahydrobenzothiazole as a white powdery solid with a yield of 99.3%.
[0093] 1 H NMR (300MHz, CDCl3) δ5.61 (m, 1H), 4.93 (br, 2H), 4.38 (s, 1H), 2.96 (d, J = 15.3Hz, 1H), 2.74-2.57 (m ,2H),2.46(dd,J=15.3,5.4Hz,1H),2.19(q,J=7.5Hz,2H),2.01-1.82(m,2H),1.14(t,J=7.5Hz,3H). HRMS(ESI):m / z 226.1009[M+H] + (calcd forC 10 H 16 N3OS + :226.1009).
[0094] Example 2:
[0095]
[0096] In a 500 mL round bottom flask, (S)-2-amino-6-propionamido-4,5,6,7- tetrahydrobenzothiazole (8.24 g, 36.6 mmol) was mixed with tetrahydrofuran (125 mL) and water (125 mL) at room temperature. Triethylamine (15.2 mL, 110 mmol) and Boc anhydride (20.5 mL, 89.3 mmol) were added successively under ice-water bath stirring. The reaction was kept at this temperature for 1 hour. It was then allowed to reach room temperature and heated to 60 °C for 12 hours. The reaction was cooled to room temperature and quenched with 1 mol / L hydrochloric acid to pH 4 under ice-water bath. The reaction was extracted with dichloromethane (250 mL x 3). The organic phase was combined and dried over anhydrous sodium sulfate after being partitioned with saturated aqueous sodium chloride solution. The filtrate was concentrated under reduced pressure to give the product (S)-2-tert-butoxyamido-6-propionamido-4,5,6,7- tetrahydrobenzothiazole as a white solid, 10.20 g, 85.7% yield.
[0097] 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, 6.3 Hz, 1H), 2.19 (q, J = 7.5 Hz, 2H), 1.99-1.92 (m, 2H), 1.53 (s, 9H), 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 (3.74 g, 11.49 mmol) was mixed with carbon tetrachloride (190 mL) at room temperature. NBS (2.05 g, 11.5 mmol) and AIBN (94.4 mg, 0.575 mmol) were added successively under stirring. The reaction was then heated to 55 °C and stirred vigorously for 1 hour. The reaction was cooled to room temperature and concentrated under reduced pressure to give a yellow-brown solid.
[0102] DMSO (103 mL) was added to the reaction flask containing the above solid at room temperature. After stirring and dissolving, TMANO (8.63 g, 114.9 mmol) was added, and the temperature was then raised to 55°C and stirred for 5 hours. After the reaction solution was cooled to room temperature, saturated aqueous NaHCO₃ (100 mL) was added and stirred at room temperature for 10 minutes. The organic phases were extracted with dichloromethane (250 mL × 3), combined, washed with saturated aqueous NaCl (500 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (cyclohexane / acetone = 10:1 to 1:1) to obtain 1.37 g of (S)-2-tert-butoxyamido-6-propionamido-7-oxo-4,5,6,7-tetrahydrobenzothiazole as a yellow-white solid, with a total yield of 35.2% over the two steps.
[0103] 1 H NMR (300MHz, CDCl3) δ8.50(br,1H),5.98(d,J=6.6Hz,1H),4.77(m,1H),3.40(d,J=16.2Hz,1H),3.07(dd,J=16.8,6.6H z, 1H), 2.87 (d, J = 15.3Hz, 1H), 2.72 (dd, J = 16.2, 7.5Hz, 1H), 2.19 (q, J = 7.2Hz, 2H), 1.54 (s, 9H), 1.14 (t, J = 7.2Hz, 3H).
[0104] HRMS(ESI):m / z 340.1328[M+H] + (calcd for C 15 H 22 N3O4S + :340.1326).
[0105] Example 4:
[0106]
[0107] To a 15 mL thick-walled screw-cap glass tube, (S)-2-tert-Butoxyamido-6-propionamido-7-oxo-4,5,6,7-tetrahydrobenzothiazole (100 mg, 0.30 mmol), (S)-2-amino-6-propionamido-4,5,6,7-tetrahydrobenzothiazole (99.85 mg, 0.44 mmol), and tetrahydrofuran (1 mL) were added sequentially. Ti(OEt)4 (0.19 mL, 0.89 mmol) was added while stirring in an ice-water bath, and the tube was sealed with a screw cap. The reaction was maintained at this temperature for 20 minutes, then the temperature was raised to 60°C for 17 hours. After cooling the reaction solution to room temperature, methanol (6 mL) was added. NaBH4 (45.4 mg, 1.20 mmol) was added while stirring in an ice-water bath. The reaction was maintained at this temperature for 10 minutes, then the temperature was raised to room temperature for 3 hours. Acetone (3 mL) was added to the reaction solution to quench the reaction and stirred for 15 minutes. Saturated aqueous NaHCO3 solution (15 mL) was then added to the reaction solution. Extraction was performed with ethyl acetate (15 mL × 3). The organic phases were combined, dried over 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 = 100:1 to 15:1) to obtain 67.2 mg of a white solid compound (6S,7S)-2-tert-butoxyamido-6-propionamido-7-((S)-6-propionamido-4,5,6,7-tetrahydrobenzothiazole-2-amino)-4,5,6,7-tetrahydrobenzothiazole, with a total yield of 41.4% over the two steps. 1 H NMR (300MHz, CD3OD) δ4.86(d,J=10.5Hz,1H),4.24(m,1H),4.12(m,1H),3.06(d,J=12.6Hz,1H),2.86(d,J=12.6Hz,1H ),2.62(m,3H),2.49-2.41(m,2H),2.25-2.17(m,4H),1.97(m,1H),1.91-1.80(m,2H),1.52(s,9H),1.16-1.11(m,6H).
[0108] HRMS(ESI):m / z 549.2313[M+H] + (calcd for C 25 H 37 N6O4S2 + :549.2312).
[0109] Example 5:
[0110]
[0111] To a 25 mL conical-bottom flask, add (6S,7S)-2-tert-butoxyamido-6-propionamido-7-((S)-6-propionamido-4,5,6,7-tetrahydrobenzothiazol-2-amino)-4,5,6,7-tetrahydrobenzothiazole (169 mg, 0.31 mmol) and dissolve in dichloromethane (3.5 mL) at room temperature. Add trifluoroacetic acid (3.5 mL, 46 mmol) while stirring in an ice-water bath. Maintain the reaction temperature for 10 minutes, then bring the mixture to room temperature for 2 hours. Concentrate the reaction mixture under reduced pressure to yield 243 mg of the crude product.
[0112] A small amount of the crude product was separated and purified by alkaline alumina and silica gel column chromatography (dichloromethane / methanol = 100:1 to 1:1) to obtain a yellow-white solid compound (6S,7S)-2-amino-6-propionamido-7-((S)-6-propionamido-4,5,6,7-tetrahydrobenzothiazole-2-amino)-4,5,6,7-tetrahydrobenzothiazole. 1 H NMR(300MHz,CD3OD)δ8.06(br,2H),4.77(m,1H),4.21(m,1H),4.13(m,1H),2.92-2.82(m,2H ),2.62-2.41(m,5H),2.25-2.16(m,4H),1.99(m,1H),1.90-1.79(m,2H),1.15-1.09(m,6H).
[0113] HRMS(ESI):m / z 449.1793[M+H] + (calcd for C 20 H 29 N6O2S2 + :449.1788).
[0114] Example 6:
[0115]
[0116] The above crude product was transferred to a 100 mL round bottom flask and mixed with tetrahydrofuran (6.2 mL) under argon at room temperature. A solution of DIBAL-H in tetrahydrofuran (1 mol / L, 6.2 mL, 6.2 mmol) was added with stirring in an ice water bath. After 10 minutes of reaction at this temperature, the reaction was moved to room temperature for 17 hours. The reaction was quenched with 5% hydrochloric acid in an ice water bath and the pH was adjusted to 1-2. The pH was then adjusted to 13-14 by adding 10% aqueous NaOH solution. Then NaCl solid (5 g) was added to the reaction solution and extracted with tetrahydrofuran (50 mL x 3). The organic phase was combined and dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product 195.0 mg. The crude product was purified by silica gel column chromatography (dichloromethane / methanol containing 5% ammonia water = 20:1 to 0:1) to obtain the product (6S,7S)-2-amino-6-propylamino-7-((S)-6-propylamino-4,5,6,7-tetrahydrobenzo[d]thiazol-2-ylamino)-4,5,6,7-tetrahydrobenzo[d]thiazole (BI-II828BS) 75.1 mg as a white powder with a total yield of 58.0% for two steps.
[0117] 1 H NMR (300 MHz, CD3OD) δ 4.74 (m, 1H), 3.06-3.02 (m, 2H), 2.91-2.86 (m, 2H), 2.67-2.62 (m, 5H), 2.54-2.34 (m, 4H), 2.11 (d, J = 11.7 Hz, 1H), 1.68-1.53 (m, 6H), 0.97-0.95 (m, 6H).
[0118] HRMS (ESI): m / z 421.2218 [M+H] + (calcd for C 20 H 33 N6S2 + :421.2203).
Claims
1. A method for preparing a related substance of pramipexole hydrochloride, characterized in that: The steps include: (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; (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, i.e., intermediate M2; (3) The intermediate M2 is subjected to bromination reaction to obtain the intermediate M3, which is further oxidized to obtain (S)-2-tert-butoxyamido-6-propionamido-7-oxo-4,5,6,7-tetrahydrobenzothiazole, namely the intermediate M4; (4) Condensing the intermediate M4 with the intermediate M1 obtained in step (1) to obtain a dimer intermediate M5, which is further reduced to obtain (6S,7S)-2-tert-butoxyamido-6-propionamido-7-((S)-6-propionamido-4,5,6,7-tetrahydrobenzothiazole-2-amino)-4,5,6,7-tetrahydrobenzothiazole, i.e., intermediate M6; (5) Removing the Boc protecting group from the intermediate M6 to obtain (6S,7S)-2-amino-6-propionamido-7-((S)-6-propionamido-4,5,6,7-tetrahydrobenzothiazole-2-amino)-4,5,6,7-tetrahydrobenzothiazole, namely, intermediate M7; (6) Reducing the intermediate M7 to obtain (6S,7S)-2-amino-6-propylamino-7-((S)-6-propylamino-4,5,6,7-tetrahydrobenzothiazole-2-amino)-4,5,6,7-tetrahydrobenzothiazole, i.e., the pramipexole related substance BI-II828BS; The structural formula is as follows:
2. The method for preparing the related substances of pramipexole hydrochloride according to claim 1, wherein: The organic base in step (1) or step (2) is selected from triethylamine and diisopropylethylamine, and the inorganic base is selected from potassium carbonate and sodium carbonate.
3. The method for preparing the related substances of pramipexole hydrochloride according to claim 2, wherein: The base in step (1) or step (2) is triethylamine.
4. The method for preparing the related substances of pramipexole hydrochloride 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°C.
5. The method for preparing the related substances of pramipexole hydrochloride according to claim 4, wherein: The reaction temperature in step (1) is -40 to -30°C.
6. The method for preparing the related substances of pramipexole hydrochloride 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 and DMSO.
7. The method for preparing the related substances of pramipexole hydrochloride according to claim 6, wherein: The solvent used in the reaction of step (1) is tetrahydrofuran.
8. The method for preparing the related substances of pramipexole hydrochloride according to claim 1, wherein: In step (2), the molar ratio of the intermediate M1 to Boc2O is 1:1 to 1:5; The reaction temperature in the step (2) is -20 to 100°C.
9. The method for preparing the related substances of pramipexole hydrochloride according to claim 8, wherein: The reaction temperature in step (2) is -5 to 60°C.
10. The method for preparing the related substances of pramipexole hydrochloride according to claim 1, wherein: The solvent used in the reaction of step (2) is one or more selected from tetrahydrofuran, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,4-dioxane, toluene, dichloromethane, chloroform, acetonitrile, DMF, DMSO and water.
11. The method for preparing the related substances of pramipexole hydrochloride according to claim 10, characterized in that: The solvent used in the reaction of step (2) is a mixed solvent of tetrahydrofuran and water.
12. The method for preparing the related substances of pramipexole hydrochloride according to claim 1, wherein: The bromination reagent used in the bromination reaction in step (3) is one or more selected from N-bromosuccinimide, liquid bromine, dibromohydantoin, dibromoisocyanuric acid and 5,5-dibromobarbituric acid; the catalyst or initiator is one or more selected from azobisisobutyronitrile, azobisisoheptanenitrile, dimethyl azobisisobutyrate, benzoyl peroxide and lauroyl peroxide; The solvent used in the bromination reaction in step (3) is one or more selected from carbon tetrachloride, dichloromethane, chloroform, 1,2-dichloroethane, toluene, acetonitrile, DMF and DMSO; 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.
13. The method for preparing the related substances of pramipexole hydrochloride according to claim 12, characterized in that: The bromination reagent used in the bromination reaction in step (3) is N-bromosuccinimide.
14. The method for preparing the related substances of pramipexole hydrochloride according to claim 12, wherein: The catalyst or initiator used in the bromination reaction in step (3) is azobisisobutyronitrile.
15. The method for preparing the related substances of pramipexole hydrochloride according to claim 12, wherein: The solvent used in the bromination reaction in step (3) is carbon tetrachloride.
16. The method for preparing the related substances of pramipexole hydrochloride according to claim 1, characterized in that: The temperature of the bromination reaction in step (3) is 40-100° C., and the reaction time is 0.5-3 hours.
17. The method for preparing the related substances of pramipexole hydrochloride according to claim 16, characterized in that: The temperature of the bromination reaction in step (3) is 50-70°C.
18. The method for preparing related substances of pramipexole hydrochloride according to claim 1, characterized in that: The oxidant for the oxidation reaction in step (3) is selected from trimethylamine oxide and N-methylmorpholine nitrogen oxide; The molar ratio of the intermediate M2 to the oxidant in the oxidation reaction of step (3) is 1:1 to 1:
15.
19. The method for preparing the related substances of pramipexole hydrochloride according to claim 18, characterized in that: The oxidant for the oxidation reaction in step (3) is trimethylamine oxide.
20. The method for preparing related substances of pramipexole hydrochloride according to claim 1, wherein: The solvent used for the oxidation reaction in step (3) is one or more selected from DMSO, acetonitrile, tetrahydrofuran, diethyl ether, 1,4-dioxane, toluene, dichloromethane, chloroform, DMF, dimethylacetamide and water; The temperature of the oxidation reaction in step (3) is 40 to 100° C., and the reaction time is 3 to 7 hours.
21. The method for preparing the related substances of pramipexole hydrochloride according to claim 20, characterized in that: The solvent used in the oxidation reaction in step (3) is DMSO.
22. The method for preparing the related substances of pramipexole hydrochloride according to claim 20, characterized in that: The temperature of the oxidation reaction in step (3) is 50-70°C.
23. The method for preparing the related substances of pramipexole hydrochloride according to claim 1, characterized in that: In step (4), the molar ratio of the condensation reaction intermediate M4 to the intermediate M1 is 3:1 to 1:10; The temperature of the condensation reaction in step (4) is 0 to 150° C.; The condensing agent for the condensation reaction in step (4) is one or more selected from tetraethyl titanate, tetraisopropyl titanate, titanium tetrachloride, titanium tetrafluoride, tin tetrachloride, molecular sieves, boron trifluoride etherate and p-toluenesulfonic acid; The solvent for the condensation reaction in step (4) is one or more selected from dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, toluene, THF, ether, methyl tert-butyl ether, dioxane, acetonitrile, DMSO and DMF.
24. The method for preparing the related substances of pramipexole hydrochloride according to claim 23, wherein: The temperature of the condensation reaction in step (4) is 40-80°C.
25. The method for preparing the related substances of pramipexole hydrochloride according to claim 23, wherein: The condensation agent for the condensation reaction in step (4) is tetraethyl titanate.
26. The method for preparing the related substances of pramipexole hydrochloride according to claim 23, wherein: The solvent for the condensation reaction in step (4) is THF.
27. The method for preparing the related substances of pramipexole hydrochloride according to claim 1, characterized in that: The reducing agent for the reduction reaction of the intermediate M5 in step (4) is one or more selected from sodium borohydride, potassium borohydride, zinc borohydride, borane-tetrahydrofuran, borane-dimethyl sulfide, diisobutylaluminum hydride, red aluminum and lithium aluminum hydride; The molar ratio of the intermediate M5 to the reducing agent in step (4) is 4:1 to 1:10; The temperature of the reduction reaction of the intermediate M5 in step (4) is -30 to 70°C; The solvent added for the reduction reaction of the intermediate M5 in step (4) is one or more selected from methanol, ethanol, tetrahydrofuran, toluene, boron trifluoride etherate, ether and water.
28. The method for preparing the related substances of pramipexole hydrochloride according to claim 27, wherein: The reducing agent for the reduction reaction of the intermediate M5 in step (4) is sodium borohydride.
29. The method for preparing the related substances of pramipexole hydrochloride according to claim 27, wherein: The temperature of the reduction reaction of the intermediate M5 in step (4) is 0-30°C.
30. The method for preparing the related substances of pramipexole hydrochloride according to claim 27, wherein: The solvent added in the reduction reaction of the intermediate M5 in step (4) is methanol.
31. The method for preparing the related substances of pramipexole hydrochloride according to claim 1, characterized in that: The acid reagent for the deprotection reaction of removing the Boc protecting group of the intermediate M6 in step (5) is one or more selected from trifluoroacetic acid, hydrochloric acid, sulfuric acid, camphorsulfonic acid, acetic acid and p-toluenesulfonic acid; In step (5), the molar ratio of the acid reagent to the intermediate M6 is 500:1 to 1:100; The solvent for the deprotection reaction in step (5) is one or more selected from dichloromethane, chloroform, 1,2-dichloroethane, toluene, THF, ether, dioxane, acetonitrile, DMF, DMSO and water; The reaction temperature in step (5) is -20 to 200°C.
32. The method for preparing the related substances of pramipexole hydrochloride according to claim 31, characterized in that: In the step (5), the acid reagent used for the deprotection reaction of removing the Boc protecting group of the intermediate M6 is trifluoroacetic acid.
33. The method for preparing the related substances of pramipexole hydrochloride according to claim 31, wherein: The solvent for the deprotection reaction in step (5) is dichloromethane.
34. The method for preparing the related substances of pramipexole hydrochloride according to claim 31, wherein: The reaction temperature in step (5) is 0-60°C.
35. The method for preparing the related substances of pramipexole hydrochloride according to claim 1, characterized in that: 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, red aluminum and lithium aluminum hydride; The solvent used for the reduction reaction of the intermediate M7 in step (6) is one or more selected from tetrahydrofuran, toluene, dichloromethane, DMSO, diethyl ether, dioxane and methyl tert-butyl ether; The molar ratio of the intermediate M7 to the reducing agent in step (6) is 2:1 to 1:100; The temperature of the reduction reaction of the intermediate M7 in step (6) is -30 to 70°C.
36. The method for preparing the related substances of pramipexole hydrochloride according to claim 35, characterized in that: The reducing agent used in the reduction reaction of step (6) is diisobutylaluminum hydride.
37. The method for preparing the related substances of pramipexole hydrochloride according to claim 35, characterized in that: The solvent used for the reduction reaction of the intermediate M7 in step (6) is tetrahydrofuran.
38. The method for preparing the related substances of pramipexole hydrochloride according to claim 35, wherein: The temperature of the reduction reaction of the intermediate M7 in step (6) is 0-25°C.
39. The method for preparing the related substances of pramipexole hydrochloride according to claim 1, wherein: The process for purifying the pramipexole related substance BI-II828BS 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 the pH is adjusted to 2-3. Then, a NaOH aqueous solution is added to adjust the pH to 13-14. Then, solid NaCl is added to the reaction solution, and extraction is performed with tetrahydrofuran. The organic phases are combined, dried, and filtered. The filtrate is concentrated under reduced pressure and then separated and purified by silica gel column chromatography to obtain a pure product.
40. The method for preparing the related substances of pramipexole hydrochloride according to claim 39, wherein: 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 volume ratio of: dichloromethane: methanol containing 5% ammonia water = 20:1 to 0:1.