Synthesis method of rotigotine hydrochloride

Abstract

The invention discloses a method for synthesizing rotigotine hydrochloride, which is characterized in that (S)-2-amino-5-methoxyl tetrahydronaphthalene hydrochloride is used as a raw material, and the rotigotine hydrochloride is obtained through a one-pot acylation reaction, a reduction reaction and a demethylation reaction. The synthetic route is as follows: # imgabs0 #. The synthetic method comprises the following steps: step 1, taking (S)-2-amino-5-methoxy tetrahydronaphthalene hydrochloride as a raw material, and carrying out one-pot acylation reaction to obtain an intermediate I; step 2, carrying out reduction reaction on the intermediate I to obtain an intermediate II; 3, the intermediate II is subjected to a demethylation reaction, and the rotigotine hydrochloride is obtained. The method is mild in reaction condition, simple and convenient to operate, high in yield, high in product purity (greater than 99.8%) and suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and particularly relates to a method for synthesizing rotigotine hydrochloride. Background Art

[0002] Rotigotine is a selective dopamine D2-like receptor agonist first described and developed in the 1980s for the treatment of the signs and symptoms of early and late idiopathic Parkinson's disease, as well as for the treatment of moderate to severe idiopathic restless legs syndrome. It helps relieve symptoms in Parkinson's patients by stimulating dopamine receptors in the brain. Compared to other treatments, rotigotine not only improves motor function but may also provide significant relief of pain symptoms.

[0003] Currently disclosed synthetic routes all introduce propyl and 2-thienylethyl groups in steps, resulting in long reaction cycles and harsh reaction conditions. For example, in patent CN201280031707, the introduction of 2-thienylethyl groups via 2-thienylethanol toluenesulfonate requires a reflux reaction in xylene for more than 48 hours, making it unsuitable for industrial production.

[0004] Therefore, it is necessary to develop a simple and easy method for synthesizing rotigotine hydrochloride that is suitable for industrial production. Summary of the Invention

[0005] The present invention aims to overcome the deficiencies in the prior art and provides a method for synthesizing rotigotine hydrochloride.

[0006] The present invention is achieved through the following technical solutions:

[0007] A method for synthesizing rotigotine hydrochloride, the synthetic route is as follows:

[0008]

[0009] The following steps are involved:

[0010] Step 1: Using (S)-2-amino-5-methoxytetralin hydrochloride as starting material, a one-pot acylation reaction was performed to obtain intermediate I;

[0011] Step 2: Intermediate I is reduced to obtain intermediate II;

[0012] Step 3: Intermediate II is subjected to demethylation reaction to obtain rotigotine hydrochloride.

[0013] Furthermore, the step 1 is specifically as follows: (S)-2-amino-5-methoxytetralin hydrochloride is dissolved in pyridine, the temperature is controlled to -10 to 0°C under nitrogen protection, 2-thiopheneacetyl chloride is added, and the reaction is carried out at room temperature for 4 to 6 hours; the temperature is lowered to below 0°C, propionyl chloride is added dropwise, and after the addition, the mixture is stirred at room temperature for 10 to 12 hours. The reaction solution is poured into a large amount of crushed ice, filtered, and washed with water to obtain intermediate I.

[0014] Furthermore, the step 1 is specifically as follows: (S)-2-amino-5-methoxytetralin hydrochloride is added to pyridine, and propionyl chloride is added at a temperature of -10 to 0°C under nitrogen protection; after the addition, the mixture is naturally warmed to room temperature and reacted for 4 to 6 hours; the mixture is cooled to below 0°C, 2-thiopheneacetyl chloride is added dropwise, the mixture is naturally warmed to room temperature, and stirred at room temperature for 10 to 12 hours. The reaction solution is poured into a large amount of crushed ice, filtered, and washed with water to obtain intermediate I.

[0015] Furthermore, in step 1, the molar ratio of (S)-2-amino-5-methoxytetralin hydrochloride, 2-thiopheneacetyl chloride, and propionyl chloride is 1:1-1.5:2-3.

[0016] Furthermore, step 2 is specifically as follows: adding lithium aluminum tetrahydride to anhydrous tetrahydrofuran at 0-5°C and stirring for 15-45 minutes; controlling the temperature below 5°C, adding dropwise a tetrahydrofuran solution of intermediate I, stirring for 15-45 minutes after the addition, and then reflux at 50-80°C for 4-6 hours; the reaction is cooled to room temperature, water is added dropwise to quench the reaction, the pH is adjusted to 10-12, and after filtration, extraction, water washing, drying, and concentration, intermediate II is obtained.

[0017] Furthermore, in step 2, the molar ratio of the intermediate I to lithium aluminum tetrahydride is 1:2.5-3.5.

[0018] Furthermore, the step 2 is specifically as follows: adding intermediate I and sodium borohydride to anhydrous tetrahydrofuran, controlling the temperature at 0°C to 5°C with stirring, and adding boron trifluoride etherate dropwise; raising the temperature to 50°C to 80°C and refluxing with stirring for 4 to 6 hours after the addition, and completing the reaction; cooling to room temperature, adjusting the pH to 10 to 12, separating the liquids, extracting the aqueous phase with dichloromethane, combining the organic phases, washing with water, drying, filtering, and concentrating to obtain intermediate II.

[0019] Furthermore, in step 2, the molar ratio of intermediate I, sodium borohydride, and boron trifluoride etherate is 1:3.5-4.5:5-6.

[0020] Furthermore, step 3 is specifically as follows: adding thiourea and anhydrous aluminum chloride to toluene with stirring, controlling the temperature at 20-30°C; after the addition, stirring at room temperature for 15-45 minutes; diluting intermediate II with toluene and then adding it to the reaction system, controlling the temperature at 20-30°C, after the addition, heating to 60-65°C and reacting for 2-4 hours; after the reaction, cooling to 5-10°C, adjusting the pH to 8-9, filtering with diatomaceous earth pad, eluting with toluene, separating the liquid, washing the organic phase with water, drying with anhydrous sodium sulfate, filtering, adding a methanol solution of hydrogen chloride to the filtrate, filtering, and eluting with toluene to obtain rotigotine hydrochloride solid.

[0021] Furthermore, in step 3, the molar ratio of intermediate II, thiourea and aluminum trichloride is 1:2-3:3-4.

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] The technical solution of the present invention has mild reaction conditions, simple operation, high yield, high product purity (greater than 99.8%), and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 This is the HPLC chromatogram of Rotigotine hydrochloride in Example 1.

[0025] Figure 2 This is the HPLC chromatogram of Rotigotine hydrochloride in Example 2.

[0026] Figure 3 This is the HPLC chromatogram of rotigotine hydrochloride in Example 3. DETAILED DESCRIPTION

[0027] Exemplary embodiments of the present invention will be described in more detail below with reference to the accompanying drawings. Although exemplary embodiments of the present invention are shown in the accompanying drawings, it should be understood that the present invention can be implemented in various forms and should not be limited by the embodiments set forth herein. On the contrary, these embodiments are provided to enable a more thorough understanding of the present invention and to fully convey the scope of the present invention to those skilled in the art. It should be noted that, unless there is a conflict, the embodiments of the present invention and the features within the embodiments may be combined with each other. The present invention will be described in detail below with reference to the accompanying drawings and in conjunction with the embodiments.

[0028] Example 1:

[0029] S1: Add pyridine (500 ml) and (S)-2-amino-5-methoxytetralin hydrochloride (50.00 g, 0.234 mol) to a 2 L three-necked flask. Cool to -10°C under nitrogen, then add 2-thiopheneacetyl chloride (37.58 g, 0.234 mol). After addition, warm to room temperature and react for 5 hours. Cool to -5°C, add propionyl chloride (56.3 g, 0.608 mol) dropwise, warm to room temperature, and stir at room temperature for 10 hours. Pour the reaction solution into a large amount of crushed ice, filter, wash with water, and crystallize from methanol to obtain Intermediate I (71.10 g, 85.0% yield) as a white solid.

[0030] S2: Add anhydrous tetrahydrofuran (400 ml) to a 1L three-necked flask and cool to 5°C. Add lithium aluminum tetrahydride (20.34 g, 0.54 mol) and stir for 30 min. Control the temperature at 5°C and add a solution of intermediate I (63.63 g, 0.178 mol) in tetrahydrofuran (200 ml) dropwise. After the addition is complete, stir for 30 min, and then reflux at 67°C for 5 hours. The reaction is cooled to room temperature, water (80 ml) is added dropwise to quench the reaction, and NaOH solution is added to adjust the pH to 10. Filter out the solid (add diatomaceous earth), concentrate under reduced pressure to recover tetrahydrofuran, extract with dichloromethane (300 ml * 2), wash with water, wash with saturated brine, dry, and concentrate to obtain a light yellow oil intermediate II (59.31 g, yield 100%).

[0031] S3: Add toluene (400 ml) to a 2 L three-necked flask. Add thiourea (35.28 g, 0.46 mol) and anhydrous aluminum chloride (82.41 g, 0.62 mol) with stirring, maintaining the temperature at 20°C. The reaction system will gradually darken during the addition. Stir at room temperature for 30 minutes. Dilute Intermediate II (59.31 g, 0.178 mol) with toluene (110 ml) and add to the reaction system, maintaining the temperature at 20°C. After the addition, heat to 60°C and react for 3 hours.

[0032] After the reaction, cool to 5°C, add the ammonia-water mixture, adjust the pH to 8, and filter through a pad of diatomaceous earth. Rinse with toluene (200 ml). Separate the liquid, wash the organic phase with water (350 ml x 3), and dry over anhydrous sodium sulfate. Filter, and add a methanolic solution of hydrogen chloride to the filtrate. A large amount of white precipitate will form. Filter and rinse with toluene to obtain an off-white solid (50 g, 90% yield) with an HPLC purity of 99.2%.

[0033] Acetonitrile and methanol were crystallized to give a white solid (40 g) with an HPLC purity greater than 99.8% and a single impurity less than 0.1%. The HPLC chromatogram was as follows: Figure 1 shown.

[0034] Example 2:

[0035] S1: Add pyridine (500 ml) and (S)-2-amino-5-methoxytetralin hydrochloride (50.00 g, 0.234 mol) to a 2 L three-necked flask. Cool to below 0°C under nitrogen. Add propionyl chloride (21.65 g, 0.234 mol) at -5°C. After addition, allow to warm to room temperature and react for 6 hours. Cool to -10°C and add 2-thiopheneacetyl chloride (97.66 g, 0.608 mol) dropwise. Allow to warm to room temperature and stir at room temperature for 12 hours. Pour the reaction mixture into a large amount of crushed ice, filter, wash with water, and crystallize from methanol to obtain Intermediate I (69.00 g, 82.5% yield) as a white solid.

[0036] S2: Add anhydrous tetrahydrofuran (400 ml) to a 1L three-necked flask and cool to 0°C. Add lithium aluminum tetrahydride (16.91 g, 0.45 mol) and stir for 45 minutes. Control the temperature at 0°C and add a solution of intermediate I (63.63 g, 0.178 mol) in tetrahydrofuran (200 ml) dropwise. After the addition is complete, stir for 15 minutes and then reflux at 80°C for 6 hours. The reaction is cooled to room temperature, water (80 ml) is added dropwise to quench the reaction, and NaOH solution is added to adjust the pH to 12. Filter out the solid (add diatomaceous earth), concentrate under reduced pressure to recover tetrahydrofuran, extract with dichloromethane (300 ml * 2), wash with water, wash with saturated brine, dry, and concentrate to obtain a light yellow oil intermediate II (53.38 g, yield 90%).

[0037] S3: Add toluene (400 ml) to a 2 L three-necked flask. Add thiourea (27.40 g, 0.36 mol) and anhydrous aluminum chloride (70.67 g, 0.53 mol) with stirring, maintaining the temperature at 30°C. The reaction system will gradually darken during the addition. Stir at room temperature for 15 minutes. Dilute Intermediate II (59.31 g, 0.178 mol) with toluene (110 ml) and add to the reaction system, maintaining the temperature at 30°C. After the addition, heat to 65°C and react for 2 hours.

[0038] After the reaction, cool to 10°C, add ammonia solution, adjust the pH to 9, filter through diatomaceous earth pad, rinse with toluene (200ml), separate the liquid, wash the organic phase with water (350ml*3), and dry over anhydrous sodium sulfate. Filter, add methanol solution of hydrogen chloride to the filtrate, and a large amount of white precipitate will be generated. Filter and rinse with toluene to obtain an off-white solid (45g, yield 81%). After crystallization from acetonitrile and methanol, the HPLC purity is greater than 99.8%. The HPLC chromatogram is as shown below. Figure 2 shown.

[0039] Example 3:

[0040] S1: Add pyridine (500 ml) and (S)-2-amino-5-methoxytetralin hydrochloride (50.00 g, 0.234 mol) to a 2 L three-necked flask. Under nitrogen, add 2-thiopheneacetyl chloride (37.58 g, 0.234 mol) at 0°C. After addition, allow the mixture to warm to room temperature and react for 4 hours. Cool the mixture to 0°C and add propionyl chloride (64.95 g, 0.702 mol) dropwise. Allow the mixture to warm to room temperature and stir at room temperature for 11 hours. Pour the reaction mixture into a large amount of crushed ice, filter, wash with water, and crystallize from methanol to obtain Intermediate I (71.96 g, 86.0% yield) as a white solid.

[0041] S2: Add intermediate I (63.63 g, 0.178 mol), anhydrous tetrahydrofuran (600 ml), and sodium borohydride (27.05 g, 0.712 mol) to a 1L three-necked flask, control the temperature at 5°C with stirring, and add boron trifluoride etherate (136.42 g, 0.961 mol) dropwise. After the addition, the system becomes white and turbid. Heat to 67°C and reflux with stirring for 5 hours to complete the reaction. Cool to room temperature, adjust the pH to 11 with sodium hydroxide, separate the layers, extract the aqueous phase with dichloromethane (300 ml*2), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to obtain intermediate II (59.31 g, 82.5% yield) as a light yellow oil.

[0042] S3: Add toluene (400 ml) to a 2 L three-necked flask. Add thiourea (40.65 g, 0.53 mol) and anhydrous aluminum chloride (82.41 g, 0.62 mol) with stirring, maintaining the temperature at 25°C. The reaction system will gradually darken during the addition. Stir at room temperature for 45 minutes. Dilute Intermediate II (59.31 g, 0.178 mol) with toluene (110 ml) and add to the reaction system, maintaining the temperature at 25°C. After the addition, heat to 65°C and react for 4 hours.

[0043] After the reaction, cool to 5°C, add ammonia solution, adjust pH to 8, filter through diatomaceous earth pad, rinse with toluene (200ml), separate the liquid, wash the organic phase with water (350ml*3), and dry over anhydrous sodium sulfate. Filter, add methanol solution of hydrogen chloride to the filtrate, and a large amount of white precipitate will be generated. Filter and rinse with toluene to obtain an off-white solid (47.0g, yield 84%). After crystallization from acetonitrile and methanol, the HPLC purity is greater than 99.8%. The HPLC chromatogram is as shown below. Figure 3 shown.

[0044] The present invention has been described in detail above through the embodiments, but the contents described are only exemplary embodiments of the present invention and cannot be considered to limit the scope of implementation of the present invention. The scope of protection of the present invention is defined by the claims. Any use of the technical solution described in the present invention, or any person skilled in the art who, inspired by the technical solution of the present invention, designs a similar technical solution within the essence and scope of protection of the present invention to achieve the above-mentioned technical effects, or any equivalent changes and improvements made to the scope of application, shall still fall within the scope of protection covered by the patent of the present invention. It should be noted that for the sake of clarity, the description of some components and processes that have no direct and obvious connection with the scope of protection of the present invention but are known to those skilled in the art are omitted in the description of the present invention.

Claims

1. A method for synthesizing rotigotine hydrochloride, characterized in that: The synthetic route is as follows: The following steps are involved: Step 1: Using (S)-2-amino-5-methoxytetralin hydrochloride as starting material, a one-pot acylation reaction was performed to obtain intermediate I; Step 2: Intermediate I is reduced to obtain intermediate II; Step 3: Intermediate II is subjected to demethylation reaction to obtain rotigotine hydrochloride.

2. The method for synthesizing rotigotine hydrochloride according to claim 1, wherein The step 1 specifically comprises: dissolving (S)-2-amino-5-methoxytetralin hydrochloride in pyridine, controlling the temperature to -10 to 0°C under nitrogen protection, adding 2-thiopheneacetyl chloride, and reacting at room temperature for 4 to 6 hours; cooling below 0°C, adding propionyl chloride dropwise, stirring at room temperature for 10 to 12 hours after the addition, pouring the reaction solution into a large amount of crushed ice, filtering, and washing with water to obtain intermediate I.

3. The method for synthesizing rotigotine hydrochloride according to claim 1, wherein The step 1 specifically comprises: adding (S)-2-amino-5-methoxytetralin hydrochloride to pyridine, adding propionyl chloride under nitrogen protection at a temperature of -10 to 0°C; after the addition, naturally warming to room temperature and reacting for 4 to 6 hours; cooling to below 0°C, dropwise adding 2-thiopheneacetyl chloride, naturally warming to room temperature, stirring at room temperature for 10 to 12 hours, pouring the reaction solution into a large amount of crushed ice, filtering, and washing with water to obtain intermediate I.

4. The method for synthesizing rotigotine hydrochloride according to claim 2 or 3, wherein: In the step 1, the molar ratio of (S)-2-amino-5-methoxytetralin hydrochloride, 2-thiopheneacetyl chloride, and propionyl chloride is 1:1-1.5:2-3.

5. The method for synthesizing rotigotine hydrochloride according to claim 1, wherein: The step 2 specifically comprises: adding lithium aluminum tetrahydride to anhydrous tetrahydrofuran at 0-5°C and stirring for 15-45 minutes; controlling the temperature below 5°C, dropwise adding a tetrahydrofuran solution of intermediate I, stirring for 15-45 minutes after the addition, and then reflux at 50-80°C for 4-6 hours; cooling the reaction to room temperature, dropwise adding water to quench the reaction, adjusting the pH to 10-12, filtering, extracting, washing with water, drying, and concentrating to obtain intermediate II.

6. The method for synthesizing rotigotine hydrochloride according to claim 5, wherein: In the step 2, the molar ratio of the intermediate I to lithium aluminum tetrahydride is 1:2.5-3.

5.

7. The method for synthesizing rotigotine hydrochloride according to claim 1, wherein: The step 2 specifically comprises: adding intermediate I and sodium borohydride to anhydrous tetrahydrofuran, controlling the temperature at 0°C to 5°C with stirring, and dropwise adding boron trifluoride etherate; heating to 50°C to 80°C and refluxing with stirring for 4 to 6 hours after the addition, and completing the reaction; cooling to room temperature, adjusting the pH to 10 to 12, separating the liquids, extracting the aqueous phase with dichloromethane, combining the organic phases, washing with water, drying, filtering, and concentrating to obtain intermediate II.

8. The method for synthesizing rotigotine hydrochloride according to claim 7, wherein: In the step 2, the molar ratio of intermediate I, sodium borohydride, and boron trifluoride etherate is 1:3.5-4.5:5-6.

9. The method for synthesizing rotigotine hydrochloride according to claim 1, wherein: The step 3 specifically comprises: adding thiourea and anhydrous aluminum chloride to toluene with stirring, controlling the temperature at 20-30° C.; after the addition, stirring at room temperature for 15-45 minutes; diluting intermediate II with toluene and then adding it to the reaction system, controlling the temperature at 20-30° C., after the addition, heating to 60-65° C. and reacting for 2-4 hours; after the reaction, cooling to 5-10° C., adjusting the pH to 8-9, filtering with diatomaceous earth, eluting with toluene, separating the liquids, washing the organic phase with water, drying over anhydrous sodium sulfate, filtering, adding a methanol solution of hydrogen chloride to the filtrate, filtering, and eluting with toluene to obtain rotigotine hydrochloride solid.

10. The method for synthesizing rotigotine hydrochloride according to claim 9, wherein: In the step 3, the molar ratio of intermediate II, thiourea and aluminum trichloride is 1:2-3:3-4.

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