Process for the preparation of a rotigotine intermediate

Abstract

The application provides a preparation method of a rotigotine intermediate. Specifically, the application takes 5-methoxy-2-norbornanone as a raw material, adopts biological enzyme reduction to obtain a chiral formula II compound, and performs amination on the formula II compound to obtain a formula III target product (S)-2-(N-benzylamino)-5-methoxynorbornane.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to a method for preparing a key intermediate of rotigotine ((S)-2-(N-benzylamino)-5-methoxytetrahydronaphthalene). Background Technology

[0002] Rotigotine, also known as Neupro, was originally developed by Schwarz AG in Germany. It is a dopamine receptor agonist administered via a skin patch and is highly effective in treating early-stage Parkinson's disease. The drug was approved by the US FDA in May 2007 and by the Chinese FDA in July 2018. Currently, there are several main methods for preparing rotigotine:

[0003] 1. WO201102638 reports a method for preparing 5-methoxy-2-tetrahydronaphthone as a raw material.

[0004]

[0005] This method has a long synthesis route, high raw material costs, low yield due to chiral resolution, and complex processing.

[0006] 2. Chinese patent CN201310013996 reports a preparation method using 2-amino-5-methoxytetrahydronaphthalene as a raw material.

[0007]

[0008] This method also involves chiral catalyst separation, resulting in low yields and high costs.

[0009] 3. Chinese patent CN2104130238A reports a preparation method using 5-methoxy-2-tetrahydronaphthone as a raw material.

[0010]

[0011] The post-processing of this method is difficult, requiring chromatography to obtain the product, making it unsuitable for industrial production.

[0012] In summary, all reported routes have practical flaws. The key issue in all routes is the low yield or difficulty in scaling up chiral separation. Therefore, the key to synthesizing high-purity, high-yield rotigotine lies in the synthesis of chiral intermediates. Summary of the Invention

[0013] The purpose of this invention is to provide a new method for preparing a chiral intermediate ((S)-2-(N-benzylamino)-5-methoxytetrahydronaphthalene) with a high yield.

[0014] In a first aspect, the present invention provides a method for preparing a compound of formula III, the method comprising the following steps:

[0015]

[0016] (i) The compound of formula I is reduced in an inert solvent under the catalysis of a biological enzyme and a reducing agent to obtain the chiral compound of formula II.

[0017] (ii) In an inert solvent, the compound of formula II is catalytically amination to obtain the compound of formula III.

[0018] In another preferred embodiment, in step (i), the biological enzyme is selected from the group consisting of: piracetamine, coenzyme NADPH, glucose dehydrogenase, or combinations thereof.

[0019] In another preferred embodiment, in step (i), when the bioenzyme is rauvolfine, the concentration of the bioenzyme is 0.5-1.3 mg / ml; and / or

[0020] When the bioenzyme is the coenzyme NADPH, the molar ratio of the coenzyme NADPH to the compound of formula I is 0.02‰-0.03‰; and / or

[0021] When the bioenzyme is glucose dehydrogenase, the mass ratio of glucose dehydrogenase to the compound of formula I is 1:150-250, preferably 1:180-200.

[0022] In another preferred embodiment, the reaction temperature is 20-30°C.

[0023] In another preferred embodiment, the reducing agent is selected from the group consisting of glucose, or combinations thereof.

[0024] In another preferred embodiment, in step (i), the molar ratio of glucose to the compound of formula I is 0.01-0.02.

[0025] In another preferred embodiment, the pH of the reaction in step (i) is 6-8, preferably, the pH of the reaction is 7.

[0026] In another preferred embodiment, step (i) is performed in the presence of NADPH.

[0027] In another preferred embodiment, in step (i), the pH of the reaction is adjusted using a Kpi buffer solution.

[0028] In another preferred embodiment, in step (i), the inert solvent is water.

[0029] In another preferred embodiment, in step (ii), the catalytic amination is carried out in the presence of an amination agent selected from the group consisting of ammonium hydroxide, ammonium sulfite, ammonia, ammonium bicarbonate, urea, or combinations thereof; preferably, the amination agent is selected from the group consisting of ammonium hydroxide and ammonium sulfite.

[0030] In another preferred embodiment, in step (ii), the molar ratio of the compound of formula II to the amination agent is 1:10-15, preferably 1:12.

[0031] In another preferred embodiment, in step (ii), the reaction is carried out in the presence of a base; preferably, the base is sodium sulfite.

[0032] In another preferred embodiment, in step (ii), the reaction temperature is 110-130°C.

[0033] A second aspect of the present invention provides a method for preparing a key intermediate of rotigotine ((S)-2-(N-benzylamino)-5-methoxytetrahydronaphthalene), said method using the method of the first aspect of the present invention to prepare a compound of formula III, and

[0034] ((S)-2-(N-benzylamino)-5-methoxytetrahydronaphthalene was prepared using compound of formula III.

[0035] In another preferred embodiment, the preparation is carried out according to the method of reference patent 201310013996.

[0036] In another preferred embodiment, the preparation method includes the following steps:

[0037] (iii) Reaction of compound III with bromopropane yields (S)-2-(N-n-propyl)amino-5-methoxytetrahydronaphthalene:

[0038]

[0039] (iv) Reaction of (S)-2-(N-n-propyl)amino-5-methoxytetrahydronaphthalene with 2-(2-bromoethyl)thiophene yields (S)-2-[N-propyl-N-[2-(2-thiophene)ethyl]amino]-5-methoxy-1,2,3,4-tetrahydronaphthalene;

[0040] and

[0041]

[0042] (v) Using (S)-2-[N-propyl-N-[2-(2-thiophene)ethyl]amino]-5-methoxy-1,2,3,4-tetrahydronaphthalene as a starting material, the methyl group is removed under the action of hydrobromic acid to obtain the final product (-)-(S)-2-[N-propyl-N-[2-(2-thiophene)ethyl]amino]-5-hydroxy-1,2,3,4-tetrahydronaphthalene].

[0043] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0044] Through long-term and extensive research, the inventors of this application have developed a method for preparing the key intermediate of rotigotine ((S)-2-(N-benzylamino)-5-methoxytetrahydronaphthalene), which is simple to operate, has a high yield, and is extremely low in cost. Based on this, the present invention was completed.

[0045] In a first aspect, the present invention provides a method for preparing a compound of formula III, the method comprising the following steps:

[0046]

[0047] (i) In an inert solvent, under the catalysis of a biological enzyme, the compound of formula I is reduced to give the chiral compound of formula II;

[0048] (ii) In an inert solvent, the compound of formula II undergoes an amination reaction in the presence of a catalyst to give the compound of formula III.

[0049] In another preferred embodiment, in step (i), the bioenzyme is piracetamine, coenzyme NADPH, and glucose dehydrogenase.

[0050] In another preferred embodiment, in step (i), the concentration of glucose dehydrogenase is 0.5-1.3 mg / ml, more preferably 0.8-1.1 mg / ml, and most preferably 0.9-1.0 mg / ml.

[0051] In another preferred embodiment, in step (i), the mass ratio of glucose dehydrogenase to the compound of formula I is 1:150-250, preferably 1:180-200.

[0052] In another preferred embodiment, in step (i), the concentration of the bioenzyme pilifurucin is 0.5-1.3 mg / ml.

[0053] In another preferred embodiment, in step (i), the concentration of the bioenzyme pilifuruin is 0.8-1.1 mg / ml.

[0054] In another preferred embodiment, in step (i), the concentration of the bioenzyme pilifurucin is 0.9-1.0 mg / ml.

[0055] In another preferred embodiment, in step (i), the molar ratio of the compound to Formula I is 1:250-500, preferably 1:260-450.

[0056] In another preferred embodiment, in step (i), the pH of the reaction is 7.

[0057] In another preferred embodiment, in step (i), the pH of the reaction is adjusted using a Kpi buffer solution.

[0058] In another preferred embodiment, in step (i), the molar ratio of the coenzyme NADPH to the compound of formula I is 0.02‰-0.03‰.

[0059] In another preferred embodiment, in step (i), the inert solvent is water.

[0060] In another preferred embodiment, in step (i), glucose is dissolved in an inert solvent.

[0061] In another preferred embodiment, in step (i), the molar ratio of glucose to compound of formula I is 1-2:1, preferably 1.5:1.

[0062] In another preferred embodiment, in step (ii), the catalyst is selected from one or a combination of ammonium hydroxide, ammonium sulfite, ammonia, ammonium bicarbonate, and urea.

[0063] In another preferred embodiment, in step (ii), the amination agent is ammonium hydroxide and ammonium sulfite.

[0064] In another preferred embodiment, in step (ii), the reaction temperature is 110-130°C.

[0065] In another preferred embodiment, in step (ii), the reaction temperature is 110-130°C.

[0066] Main advantages of this invention:

[0067] 1. This invention greatly shortens the synthesis method provided in previous reports, simplifies the operation, improves the yield, and significantly reduces the cost.

[0068] 2. This invention avoids the use of chemical methods for racemic resolution and adopts a method using biological enzymes as catalysts. It is environmentally friendly, simple, has a high yield, and produces no side reactions, which greatly improves product quality.

[0069] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise specified, all experimental materials used in this invention are commercially available; the biological enzymes perakine, glucose dehydrogenase, and NADPH were purchased from Shanghai Runtian Pharmaceutical Technology Co., Ltd.

[0070] Example

[0071] Example 1: Preparation of Compound II

[0072]

[0073] Compound I (14.6 g, 82.9 mmol) was added to water (100 mL), followed by perakine reductase (100 mg), glucose dehydrogenase (100 mg), 50 mM Kpi buffer (pH 7) (30 mL), glucose (0.03 g, 0.13 mol), and NADPH (1.48 mg, 0.002 mmol). The mixture was stirred at 20-30 °C for approximately 10 h. The mixture was extracted twice with ethyl acetate (50 mL + 30 mL). The ethyl acetate extracts were combined and concentrated under reduced pressure to remove the solvent, yielding 14.2 g of a pale yellow solid. Yield: 96.2% (relative to Formula I). ​​MS (ESI): [M+1] + =179.23, and HPLC analysis showed a chiral purity of 99.80%.

[0074] Example 2 Preparation of Compound II

[0075] Compound I (14.6 g, 82.9 mmol) was added to water (100 mL), followed by perakine reductase (110 mg), glucose dehydrogenase (100 mg), and 50 mM Kpi buffer (pH 7, 30 mL). Glucose (0.03 g, 0.13 mol) and NADPH (1.48 mg, 0.002 mmol) were then added. The mixture was stirred at 20-30 °C for approximately 10 h. Ethyl acetate (50 mL) was added for extraction, followed by extraction with ethyl acetate (30 mL). The ethyl acetate mixtures were combined and concentrated under reduced pressure to remove the solvent, yielding 12.4 g of a pale yellow solid. Yield: 84.3% (relative to Formula I). ​​MS (ESI): [M+1] + =179.23, and the chiral purity obtained by HPLC testing was 99.62%.

[0076] Example 3 Preparation of Compound III

[0077]

[0078] Compound II (20 g, 0.11 mol) was placed in a three-necked flask (250 ml), and ammonium hydroxide (200 ml) was added. The mixture was stirred until homogeneous, then sodium sulfite (52.7 g, 0.42 mol) was added. The mixture was heated in an oil bath to 120 °C and stirred for 12 h until the reaction was essentially complete. The mixture was then allowed to cool slowly to room temperature (20 °C), and water (100 ml) was added. After the addition was complete, ethyl acetate (150 ml) was added with stirring. The mixture was extracted and separated to obtain the organic phase. Saturated brine (100 ml) was added, and the organic phase was collected, dried over anhydrous sodium sulfate, and the solvent was removed by distillation to obtain 17.66 g of solid, with a yield of 88.8% (relative to Formula II). MS (ESI): [M+1] + =178.24.

[0079] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A method for preparing a compound of formula III, characterized in that, The method includes the following steps: (i) The compound of formula I is reduced in a solvent under the catalysis of a biological enzyme and a reducing agent to obtain the chiral compound of formula II; (ii) In a solvent, the compound of formula II undergoes catalytic amination to obtain the compound of formula III; The bio-enzyme is a combination of pili-rauvoloxine reductase and glucose dehydrogenase. The reducing reagents are glucose and coenzyme NADPH; The catalytic amination is carried out in the presence of an amination agent selected from the group consisting of: ammonium hydroxide; The reaction is carried out in the presence of a base; Furthermore, in step (i), the concentration of the piriformis reductase is 0.5-1.3 mg / ml; The molar ratio of the coenzyme NADPH to the compound of formula I is 0.02‰-0.03‰; The mass ratio of glucose dehydrogenase to compound of formula I is 1:150-250; Step (i) is performed in the presence of NADPH; The solvent is water; In step (ii), the molar ratio of the compound of formula II to the amination agent is 1:10-15.

2. The method as described in claim 1, characterized in that, In step (ii), the alkali is sodium sulfite.

3. A method for preparing a key intermediate of rotigotine ((S)-2-(N-benzylamino)-5-methoxytetrahydronaphthalene), characterized in that, Compound III was prepared by the method of claim 1, and ((S)-2-(N-benzylamino)-5-methoxytetrahydronaphthalene was prepared using compound of formula III.

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