Preparation method of rotigotine

Abstract

The invention relates to a preparation method of rotigotine, which solves the technical problems of unreasonable reaction steps and higher production cost in the prior art, and comprises the following steps: carrying out chiral amination reduction reaction on 5-methoxy-2-tetralone, chiral phosphate, pinacol borane and p-methoxyaniline to obtain a compound 1; reacting the compound 1 with bromopropane to obtain a compound 2; reacting the compound 2 with ceric ammonium nitrate to obtain a compound 3; dissolving the compound 3 in hydrobromic acid, and reacting to obtain a compound 4; and carrying out a reaction on the compound 4 and 2-thiophene ethyl methanesulfonate to obtain a crude product rotigotine. The method can be applied to the field of preparation of rotigotine.

Description

Technical Field

[0001] The present invention relates to a method for preparing a medicine, in particular to a method for preparing rotigotine. Background Art

[0002] Parkinson's disease (PD) is also known as tremor paralysis. Tremor refers to the shaking and trembling of the head and limbs, and paralysis refers to the inability to move part or all of the limbs independently. Its typical symptoms include movement disorders, tremors and muscle rigidity, or accompanied by some non-motor symptoms such as depression, constipation and sleep disorders. It often occurs in the elderly. The main pathological mechanism of Parkinson's disease is the gradual decline of brain cells that produce dopamine (DA) in the substantia nigra of the brain, which causes a significant decrease in the DA content in the mitochondria and causes the disease.

[0003] At present, there are nearly 2 million PD patients in my country, of which 1.7% are males and 1.6% are females over the age of 65. So far, the treatment of the disease is symptomatic, and there is no radical cure to restore the degenerated nerve cells.

[0004] Parkinson's disease is mainly treated with drugs and surgery. In the early stages of the disease, drugs can improve symptoms very well. The most commonly used and most effective drugs are levodopa preparations, but levodopa preparations can cause movement complications. Studies have shown that impulse-like striatal dopamine receptor stimulation is the main cause of movement complications. Drug treatment has certain limitations. Usually after 3-5 years of treatment, the condition becomes difficult to control. The side effects of the drugs are offset by their efficacy, and patients often feel that their daily living ability is greatly restricted. The biggest disadvantage of surgical treatment is that it is prone to relapse, it is an irreversible treatment, and its application is relatively limited.

[0005] Rotigotine is a new type of non-ergot dopamine receptor stimulator developed by Schwarz Biosciences of Germany. It has the effect of anti-Parkinson's disease by activating dopamine receptors in the body. Rotigotine is generally prepared as a long-acting sustained-release preparation, which has the following advantages in treating early idiopathic Parkinson's disease: it can continuously and sustainably release therapeutic drugs, provide a steady-state blood drug level, avoid pulsed stimulation of dopamine receptors, and prevent and delay neuronal degeneration.

[0006] Currently, the preparation methods of rotigotine mostly use 5-methoxy-2-tetralone as the starting material, and obtain the chiral target compound through splitting. When using traditional splitting agents, multiple splittings are required to meet the requirements, resulting in large loss of raw materials. At the same time, the key intermediates obtained by splitting have low purity, resulting in increased costs and difficulty in promoting industrial production.

[0007] The Chinese invention patent with application number CN201410380237.7 discloses a process for preparing rotigotine, which uses 5-methoxy-2-tetralone as a raw material and undergoes four steps of amination, asymmetric reduction, halogenation and demethoxylation to synthesize chiral rotigotine. The method uses stereoselective chemical reactions to synthesize compounds with a specific stereostructure. During the asymmetric reduction process, hensyl ester 1,4-dihydropyridine (HEH) is used as a reducing agent and chiral phosphoric acid is used as a catalyst to synthesize an important intermediate (S)-2-(N-n-propyl)amino-5-methoxytetralin (II) with a single stereostructure, avoiding the use of chiral reagents to split and obtain compounds with a single configuration, shortening the synthesis steps and improving the yield.

[0008] However, the above patent has the following problems:

[0009] (1) It condenses 5-methoxy-2-tetralone with n-propylamine and then uses chiral phosphate for reduction, which increases the reaction steps and is not conducive to industrial production;

[0010] (2) It uses halogenated ethylthiophene to introduce the thiophene ring. The price of halogenated ethylthiophene is relatively high, which increases the production cost by nearly 30 times. Summary of the invention

[0011] The present invention aims to solve the technical problems of unreasonable reaction steps and high production cost in the prior art, and provides a preparation method of rotigotine with reasonable steps, reduced production cost and high yield.

[0012] To this end, the present invention provides a method for preparing rotigotine, comprising the following steps:

[0013] (1) A chiral amination reduction reaction is carried out in a solution with 5-methoxy-2-tetralone, chiral phosphate, pinacol borane, and p-methoxyaniline at room temperature. After the reaction is completed, a single-configuration compound 1 is obtained by direct column chromatography;

[0014]

[0015] The structure of pinacol borane is as follows:

[0016]

[0017] The structure of the chiral phosphoric acid catalyst used in the reaction is as follows:

[0018]

[0019] (2) Compound 1 is used as a raw material to react with bromopropane to obtain compound 2;

[0020]

[0021] Compound 1 reacts with bromopropane and sodium tert-butoxide in a solution of N,N-dimethylformamide, and is washed and concentrated to obtain compound 2;

[0022] (3) Compound 2 reacts with ammonium cerium nitrate to obtain compound 3.

[0023]

[0024] Compound 2 and CAN are dissolved in a solvent and reacted at room temperature. After the reaction is completed, the mixture is washed and concentrated to obtain compound 3;

[0025] (4) Compound 3 was dissolved in hydrobromic acid, heated to reflux, and the solvent was dried after the reaction. The organic phase was extracted and dried to obtain Compound 4;

[0026]

[0027] (5) Compound 4 and 2-thiophene ethyl methanesulfonate are reacted with anhydrous sodium carbonate to obtain rotigotine.

[0028]

[0029] The chiral compound 4,2-thiophene ethyl methanesulfonate and anhydrous sodium carbonate are added to a reaction bottle containing xylene solvent, reacted, filtered, and the liquid is added to ice water. After extraction, the organic layers are combined, washed with water, dried, filtered, and the solvent is evaporated to obtain rotigotine.

[0030] The process route of the method for preparing rotigotine provided by the present invention is:

[0031]

[0032] Preferably, in the step (1), the reaction is carried out in a dichloromethane solution (or other solutions, such as tetrahydrofuran), and the molar ratio of the 5-methoxy-2-tetralone to p-methoxyaniline is 1:(1.2-1.5), wherein preferably, the molar ratio of 5-methoxy-2-tetralone, chiral phosphate, pinacol borane, and p-methoxyaniline is 1:0.1:3:(1.2-1.5), 1:0.1:3:1.2.

[0033] Preferably, in the step (2), compound 1 reacts with bromopropane and a basic catalyst in a solution of N,N-dimethylformamide, and the molar ratio of bromopropane to the basic catalyst is (1.5-2):1.5, wherein preferably, the molar ratio of compound 1, bromopropane and the basic catalyst is 1:(1.5-2):1.5. The basic catalyst is sodium tert-butoxide (or other catalysts, such as potassium tert-butoxide).

[0034] Preferably, in step (2), the reaction temperature is 50-70° C. When the reaction temperature is lower than 50° C. or higher than 70° C., the reaction yield will be significantly reduced.

[0035] Preferably, in step (3), the molar ratio of compound 2 to ammonium cerium nitrate is 1:(2.5-3), and the solvent is a mixed solvent of acetonitrile and water in a ratio of 1:1.

[0036] Preferably, in step (5), the reaction is carried out under the action of anhydrous sodium carbonate, and the molar ratio of compound 4 to 2-thiophene ethyl methanesulfonate is 1:(2-2.5), wherein preferably, the molar ratio of compound 4, anhydrous sodium carbonate and 2-thiophene ethyl methanesulfonate is 1:0.6:(2-2.5), 1:0.6:2.

[0037] Preferably, in step (5), the reaction temperature is 100-150° C. When the reaction temperature is lower than 100° C. or higher than 150° C., the reaction yield will be significantly reduced.

[0038] Preferably, the method further comprises the following steps:

[0039] (6) dissolving the crude rotigotine obtained in step (5) in dichloromethane, introducing HCl gas, filtering the solid, washing, and drying to obtain pure rotigotine hydrochloride;

[0040] (7) dissolving the rotigotine hydrochloride obtained in step (6) in water, adding sodium bicarbonate, stirring, filtering, washing, and drying to obtain pure rotigotine.

[0041] The present invention also provides rotigotine prepared by the method.

[0042] The present invention has the following beneficial effects:

[0043] (1) The present invention uses a novel chiral phosphate catalyst to directly convert 5-methoxy-2-tetralone into a chiral compound under the action of pinacol borane, which has a shorter process, avoids traditional chiral separation, and has higher efficiency.

[0044] (2) The present invention uses 2-(thiophen-2-yl)ethyl p-toluenesulfonate to replace halogenated ethylthiophene. Compared with halogenated ethylthiophene, 2-(thiophen-2-yl)ethyl p-toluenesulfonate is cheaper and can reduce the production cost by nearly thirty times.

[0045] (3) The target product obtained by the production process of the present invention has a single configuration, a total yield of 46.3%, simple operation and low cost. BRIEF DESCRIPTION OF THE DRAWINGS

[0046] Figure 1 Rotigotine prepared by the method provided by the present invention1 H-NMR spectrum;

[0047] Figure 2 Rotigotine prepared by the method provided by the present invention 13 C-NMR spectrum.

[0048] Figure 1 middle, 1 H NMR (400MHz, CDCl3, ppm) δ7.13(dd,J=5.2,1.1Hz,1H),7.00(t,J=7.8Hz,1H),6.93(dd,J =5.1,3.4Hz,1H),6.85-6.81(m,1H),6.69(d,J=7.5Hz,1H),6.59(d,J=7.8Hz,1H),3.03-2 .98(m,3H),2.94-2.89(m,1H),2.88-2.83(m,3H),2.80-2.73(m,1H),2.57(dd,J=8.5,6. 0Hz,3H),2.14-2.10(m,1H),1.66-1.60(m,1H),1.56-1.49(m,2H),0.91(t,J=7.4Hz,3H);

[0049] Figure 2 middle, 13 C NMR (100MHz, CDCl3, ppm) δ153.6,143.2,138.6,126.7,126.5,124.6,123.3,1 23.2,121.9,112.3,56.9,52.8,52.8,32.1,30.0,25.8,23.8,22.2,12.1.[α] D 20 = -42.7° (c = 1 in MeOH). DETAILED DESCRIPTION

[0050] The above scheme is further described below in conjunction with specific examples. It should be understood that these examples are used to illustrate the present invention and are not limited to the scope of the present invention. The implementation conditions adopted in the examples can be further adjusted according to the conditions of the specific manufacturer, and the unspecified implementation conditions are usually the conditions in conventional experiments.

[0051] Example 1

[0052] The present invention provides a method for preparing rotigotine, comprising the following steps:

[0053] (1) Preparation of compound 1: Chiral phosphoric acid catalyst (330 mg, 10 mol%) and pinacol borane (2.2 mL, 15 mmol) were dissolved in 20 mL of dichloromethane. Stirred at room temperature for about 2 minutes, then 5-methoxy-2-tetralone (881 mg, 5 mmol) and p-methoxyaniline (739 mg, 6 mmol) were added. After stirring at room temperature for about 24 hours, the reaction was directly separated and purified using a silica gel column to obtain 1.32 g of compound 1, with a yield of 93% and an ee value of 99.5%;

[0054] (2) Preparation of Compound 2: Compound 1 (1.3 g, 4.5 mmol) was dissolved in DMF, bromopropane (830 mg, 6.75 mmol) and t-BuONa (865 mg, 9 mmol) were added, the reaction system was heated to 60°C, and the reaction was carried out at this temperature for 4 h. After the reaction was complete, water was added to the system, and EA was extracted. The organic phase was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1.39 g of Compound 2 with a yield of 95%;

[0055] (3) Preparation of compound 3: Compound 2 (1.3 g, 4 mmol) was dissolved in CH3CN (20 ml) and H2O (20 ml), and ammonium cerium nitrate (5.3 g, 10 mmol) was added. The reaction was carried out at room temperature for 6 h. After the reaction was completed, ether was added, the organic phase was separated, dried, and concentrated under reduced pressure to obtain 772 mg of compound 3 with a yield of 88%;

[0056] (4) Preparation of Compound 4: Compound 3 (550 mg, 2.5 mmol) was dissolved in 5 ml of hydrobromic acid and heated under reflux for 4 h. The reaction liquid was then evaporated to dryness, and water was added to the residue to dissolve it. The pH was adjusted to 13 with sodium hydroxide, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 427 mg of Compound 4 with a yield of 83%.

[0057] (5) Preparation of crude rotigotine: Compound 4 (400 mg, 1.95 mmol), Na2CO3 (124 mg, 1.17 mmol), and 2-thiopheneethyl p-toluenesulfonate (1.1 g, 3.9 mmol) were dissolved in 10 mL of a xylene compound, heated to 140°C, and reacted for 24 h. After the reaction was complete as detected by TLC, the reaction system was cooled to room temperature, extracted with dilute hydrochloric acid, the aqueous phases were combined, alkalized with solid sodium hydroxide, extracted with DCM, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 492 mg of crude rotigotine with a yield of 80%.

[0058] (6) Preparation of rotigotine salt: The obtained crude rotigotine (1 g, 3.17 mmol) was dissolved in DCM, HCl gas was introduced for 10 min, and the mixture was stirred at room temperature for 0.5 h. The solid was filtered, washed with acetone, and dried to obtain pure rotigotine hydrochloride (1.09 g, 3.1 mmol) with a yield of 98%.

[0059] (7) Freeing of rotigotine salt: Rotigotine hydrochloride (11 g, 31 mmol) was dissolved in water, and sodium bicarbonate (2.86 g, 37.2 mmol) was added. The mixture was stirred at room temperature for 4 h, filtered, and the obtained compound was washed with water and dried in a vacuum oven to obtain 8.22 g of pure rotigotine with a yield of 91.5%.

[0060] Example 2

[0061] (1) Preparation of Compound 1: Dissolve chiral phosphoric acid catalyst (330 mg, 10 mol%) and pinacol borane (2.2 mL, 15 mmol) in 20 mL of tetrahydrofuran. Stir at room temperature for about 2 minutes, then add 5-methoxy-2-tetralone (881 mg, 5 mmol) and p-methoxyaniline (924 mg, 7.5 mmol). Stir at room temperature for about 24 hours. After the reaction is complete, directly use a silica gel column for separation and purification to obtain 1.28 g of Compound 1, with a yield of 90% and an ee value of 99.5%;

[0062] (2) Preparation of compound 2: Compound 1 (1.3 g, 4.5 mmol) was dissolved in DMF, bromopropane (1.11 g, 9 mmol) and t-BuOK (1.01 g, 9 mmol) were added, the reaction system was heated to 70°C, and the reaction was carried out at this temperature for 4 h. After the reaction was complete, water was added to the system, EA was extracted, the organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1.35 g of compound 2 with a yield of 92%;

[0063] (3) Preparation of compound 3: Compound 2 (1.3 g, 4 mmol) was dissolved in CH3CN (20 ml) and H2O (20 ml), and ammonium cerium nitrate (6.36 g, 12 mmol) was added. The reaction was carried out at room temperature for 6 h. After the reaction was completed, ether was added, the organic phase was separated, dried, and concentrated under reduced pressure to obtain 926 mg of compound 3 with a yield of 90%;

[0064] (4) Preparation of Compound 4: Compound 3 (550 mg, 2.5 mmol) was dissolved in 5 ml of hydrobromic acid and heated under reflux for 4 h. The reaction liquid was then evaporated to dryness, and water was added to the residue to dissolve it. The pH was adjusted to 13 with sodium hydroxide, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 427 mg of Compound 4 with a yield of 83%.

[0065] (5) Preparation of crude rotigotine: Compound 4 (400 mg, 1.95 mmol), Na2CO3 (124 mg, 1.17 mmol), and 2-thiopheneethyl p-toluenesulfonate (1.38 g, 4.88 mmol) were dissolved in 10 mL of a xylene compound, heated to 150°C, and reacted for 24 h. After the reaction was complete as detected by TLC, the reaction system was cooled to room temperature, extracted with dilute hydrochloric acid, the aqueous phases were combined, alkalized with solid sodium hydroxide, extracted with DCM, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 479 mg of crude rotigotine with a yield of 78%.

[0066] (6) Preparation of rotigotine salt: The obtained crude rotigotine (1.5 g, 4.76 mmol) was dissolved in DCM, HCl gas was introduced for 10 min, stirred at room temperature for 0.5 h, the solid was filtered, washed with acetone, and dried to obtain pure rotigotine hydrochloride (1.44 g, 4.57 mmol) with a yield of 98%;

[0067] (7) Freeing of rotigotine salt: Rotigotine hydrochloride (10 g, 28 mmol) was dissolved in water, and sodium bicarbonate (2.38 g, 31 mmol) was added. The mixture was stirred at room temperature for 4 h, filtered, and the obtained compound was washed with water and dried in a vacuum oven to obtain 8.22 g of pure rotigotine with a yield of 90.7%.

[0068] Example 3

[0069] (1) Preparation of compound 1: Dissolve chiral phosphoric acid catalyst (660 mg, 10 mol%) and pinacol borane (4.4 mL, 30 mmol) in 40 mL tetrahydrofuran. Stir at room temperature for about 2 minutes, then add 5-methoxy-2-tetralone (1.76 g, 10 mmol) and p-methoxyaniline (1.66 g, 13.5 mmol). Stir at room temperature for about 24 hours. After the reaction is complete, directly use a silica gel column for separation and purification to obtain 2.50 g of compound 1, with a yield of 89% and an ee value of 99.5%;

[0070] (2) Preparation of compound 2: Compound 1 (1.3 g, 4.5 mmol) was dissolved in DMF, bromopropane (971 mg, 7.88 mmol) and t-BuOK (1.01 g, 9 mmol) were added, the reaction system was heated to 70°C, and the reaction was carried out at this temperature for 4 h. After the reaction was complete, water was added to the system, EA was extracted, the organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1.28 g of compound 2 with a yield of 87%;

[0071] (3) Preparation of compound 3: Compound 2 (2.60 g, 4 mmol) was dissolved in CH3CN (20 ml) and H2O (20 ml), and ammonium cerium nitrate (11.7 g, 22 mmol) was added. The reaction was carried out at room temperature for 6 h. After the reaction was completed, ether was added, the organic phase was separated, dried, and concentrated under reduced pressure to obtain 1.84 g of compound 3, with a yield of 89%;

[0072] (4) Preparation of compound 4: Compound 3 (1 g, 1.38 mmol) was dissolved in 10 ml of hydrobromic acid and heated under reflux for 4 h. The reaction liquid was then evaporated to dryness, and water was added to the residue to dissolve it. The pH was adjusted to 13 with sodium hydroxide, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 770 mg of compound 4 with a yield of 82.3%.

[0073] (5) Preparation of crude rotigotine: Compound 4 (200 mg, 0.975 mmol), Na2CO3 (62 mg, 0.585 mmol), and 2-thiopheneethyl p-toluenesulfonate (620 mg, 2.2 mmol) were dissolved in 5 mL of a xylene compound, heated to 150°C, and reacted for 24 h. After the reaction was complete as detected by TLC, the reaction system was cooled to room temperature, extracted with dilute hydrochloric acid, the aqueous phases were combined, alkalized with solid sodium hydroxide, extracted with DCM, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 435 mg of crude rotigotine with a yield of 76%.

[0074] (6) Preparation of rotigotine salt: The obtained crude rotigotine (4.5 g, 14.3 mmol) was dissolved in DCM, HCl gas was introduced for 10 min, and the mixture was stirred at room temperature for 0.5 h. The solid was filtered, washed with acetone, and dried to obtain pure rotigotine hydrochloride (4.33 g, 13.7 mmol) with a yield of 98.2%.

[0075] (7) Freeing of rotigotine salt: Rotigotine hydrochloride (5 g, 14 mmol) was dissolved in water, and sodium bicarbonate (1.19 g, 15.5 mmol) was added. The mixture was stirred at room temperature for 4 h, filtered, and the obtained compound was washed with water and dried in a vacuum oven to obtain 4.10 g of pure rotigotine with a yield of 90.5%.

[0076] However, what is described above is only a specific embodiment of the present invention and should not be used to limit the scope of implementation of the present invention. Therefore, the replacement of equivalent components, or equivalent changes and modifications made according to the scope of protection of the present invention should still fall within the scope covered by the claims of the present invention.

Claims

1. A method for preparing rotigotine, Its characteristics are: The steps include: (1) using 5-methoxy-2-tetralone, chiral phosphate, pinacol borane, and p-methoxyaniline to carry out chiral amination reduction reaction to obtain compound 1 shown in formula 1; Formula 1: (2) reacting the compound 1 obtained in step (1) with bromopropane to obtain a compound 2 represented by formula 2; Formula 2: (3) reacting the compound 2 obtained in step (2) with ammonium cerium nitrate to obtain a compound 3 as shown in formula 3; Formula 3: (4) dissolving the compound 3 obtained in step (3) in hydrobromic acid to react to obtain the compound 4 shown in formula 4; Formula 4: (5) reacting the compound 4 obtained in step (4) with 2-thiophene ethyl methanesulfonate to obtain crude rotigotine.

2. The method for preparing rotigotine according to claim 1, It is characterized in that In the step (1), the reaction is carried out in a dichloromethane solution, and the molar ratio of the 5-methoxy-2-tetralone to p-methoxyaniline is 1:(1.2-1.5).

3. The method for preparing rotigotine according to claim 1, Features: In the step (2), the compound 1 reacts with bromopropane and an alkaline catalyst in a solution of N,N-dimethylformamide, and the molar ratio of bromopropane to the alkaline catalyst is (1.5-2):1.

5.

4. The method for preparing rotigotine according to claim 1, Features: In the step (2), the reaction temperature is 50-70°C.

5. The method for preparing rotigotine according to claim 1, Features: In the step (3), the molar ratio of the compound 2 to ammonium cerium nitrate is 1:(2.5-3).

6. The method for preparing rotigotine according to claim 1, Features: In the step (5), the reaction is carried out under the action of anhydrous sodium carbonate, and the molar ratio of the compound 4 to 2-thiopheneethyl methanesulfonate is 1:(2-2.5).

7. The method for preparing rotigotine according to claim 1, Features: In the step (5), the reaction temperature is 100-150°C.

8. The method for preparing rotigotine according to claim 1, It is characterized in that The following steps are also included: (6) dissolving the crude rotigotine obtained in step (5) in dichloromethane, introducing HCl gas, filtering the solid, washing, and drying to obtain pure rotigotine hydrochloride; (7) dissolving the rotigotine hydrochloride obtained in step (6) in water, adding sodium bicarbonate, stirring, filtering, washing, and drying to obtain pure rotigotine.

9. Rotigotine obtained by the method according to claims 1 to 8.

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