Electrochemical process for the preparation of rasagiline and a pevenistat intermediate

Abstract

The present application relates to the preparation method of 2,3-dihydro-1H-inden-1-amine (I) which is an intermediate of anti-Parkinson drug rasagiline and high-risk myelodysplastic syndrome drug pevonedishe, and the preparation reaction is as follows: in a divided electrolytic cell, the cathode electrolyte is composed of the alkaline solution of 2,3-dihydro-1H-inden-1-ketoxime (A) and an organic solvent; the anode electrolyte is an alkaline solution; the cathode electrolysis product of 2,3-dihydro-1H-inden-1-amine (I) is obtained through the electro-reduction reaction.

Description

Technical Field

[0001] This invention relates to a novel method for the electroreduction preparation of intermediates of the anti-Parkinson's drug rasagiline mesylate and the drug pervirnisstat for treating high-risk myelodysplastic syndromes. Specifically, it relates to a method for the electroreduction preparation of 2,3-dihydro-1H-indene-1-amine and its hydrochloride from 2,3-dihydro-1H-indene-1-one oxime. Background Technology

[0002] Rasagiline mesylate is a monoamine oxidase B (MAO-B) inhibitor jointly developed by Teva Pharmaceutical Industries of Israel and Lundbeck Pharmaceutical Industries of Denmark. By blocking the breakdown of the neurotransmitter dopamine, it can effectively treat early-stage Parkinson's disease (PD). As a second-generation selective MAO-B inhibitor following selegiline, rasagiline is superior to selegiline in terms of efficacy, side effects, and neuroprotection. It was approved for marketing in Europe in February 2005 and received FDA approval in the United States.

[0003] Preparation method of rasagiline mesylate: Dai Ronghua et al. [Study on the synthetic process of rasagiline mesylate [J]. Chinese Journal of Modern Applied Pharmacy. 2016, 33(1): 56-58] described the preparation of 2,3-dihydro-1H-inden-1-amine (Ⅰ) by one-pot reduction-amination in methanol with 1-indanone as raw material and ammonium formate selected, substrate:zinc powder mass ratio of 1:1. The latter reacted with 3-bromopropyne under alkaline conditions, and after resolution by L-tartaric acid and salt formation by mesylate, rasagiline mesylate was obtained, with intermediate Ⅰ (base) in a yield of 68%.

[0004]

[0005] Li Jie et al. [Optimization of Synthesis Process of N-Propynyl-1-aminoindane Hydrochloride [J]. Shandong Chemical Industry. 2020, 49(11): 23-25] described that 2,3-dihydro-1H-indane-1-amine (I) can be prepared by reacting 1-indone in methanol with ammonium formate under 10% Pd / C catalysis at 48℃ for 4 h to obtain intermediate I. 2,3-dihydro-1H-indane-1-amine is then reacted with propynyl p-toluenesulfonic acid and hydrochloric acid to obtain N-propynyl-1-aminoindane hydrochloride. The yield of intermediate I (base) was 84%.

[0006]

[0007] On July 30, 2020, Takeda Pharmaceutical announced that the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation to its investigational drug pevonedistat for the treatment of patients with high-risk myelodysplastic syndromes (HR-MDS). Pevonedistat is a first-in-class NEDD8-activating enzyme (NAE) inhibitor and is expected to be the first innovative drug to treat HR-MDS patients in more than a decade [An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature. 2009.4.9, 458(7239):732-736].

[0008] The preparation method of pevonedistat, a drug for treating high-risk myelodysplastic syndromes that was launched in 2020 [Synthetic method of tumor inhibitor MLN4924. CN106854208 A. 2017.06.16]: Starting with compound 1, compound 4 was synthesized by amination with intermediate 2,3-dihydro-1H-inden-1-amine (Ⅰ). The protecting group was then removed to obtain compound 5, which was subsequently sulfonated to obtain pevonedistat. The preparation reaction is as follows:

[0009]

[0010] In the two new drug preparation methods mentioned above, 2,3-dihydro-1H-indene-1-amine (Ⅰ) was found to be a key intermediate in the preparation of the anti-Parkinson's drug rasagiline and the drug pevonedistat for treating high-risk myelodysplastic syndromes:

[0011]

[0012] Gong Dayong [Research on the Synthetic Process of Rasagiline Mesylate, a Second-Generation Monoamine Oxidase Inhibitor [D]. Jilin University, 2018] described in his graduate thesis the reaction of 2,3-dihydro-1H-indene-1-one oxime in ethanol with 20% NaOH, a substrate-to-nickel-aluminum alloy mass ratio of 1:2, at 60℃ for 6 h to obtain the hydrochloride salt of intermediate I, with a yield of 86.1%. Luo Jie et al. [An Improved Method for Preparing 2,3-Dihydro-1H-indene-1-amine and its Derivatives. CN101062897 A. 2007.10.31] also disclosed in Chinese invention patent the reaction of 2,3-dihydro-1H-indene-1-one oxime in ethanol with 45% NaOH, a substrate-to-nickel-aluminum alloy mass ratio of 3.5:5, at 50℃ for 8 h to obtain the hydrochloride salt of intermediate I, with a yield of 76.8%.

[0013]

[0014] The preparation of 2,3-dihydro-1H-indene-1-amine I involves catalytic hydrogenation. Palladium, the catalyst, is expensive. Furthermore, the palladium or nickel catalyst forms complexes with the reduction product—an amino compound intermediate—that are difficult to separate, affecting the purity of the intermediate and leading to heavy metal contamination in products like the anti-Parkinson's drug and the high-risk myelodysplastic syndrome drug, pevinistat. Another method involves the reduction of 2,3-dihydro-1H-indene-1-amine I using inorganic reducing agents such as zinc powder, a nickel-aluminum alloy (Raney nickel), and aluminum amalgam. This method is difficult to process, generates large amounts of wastewater, and causes significant environmental pollution; mercury, in particular, is highly toxic.

[0015] This invention selects a green and environmentally friendly method to prepare the intermediate 2,3-dihydro-1H-indene-1-amine (Ⅰ) of the anti-Parkinson's drug rasagiline and the drug pevinistat for treating high-risk myelodysplastic syndromes.

[0016] Summary of the Invention

[0017] The technical problem solved by this invention is to provide an electroreduction method for preparing 2,3-dihydro-1H-indene-1-amine (Ⅰ) and its salts, which are intermediates of the anti-Parkinson's drug rasagiline and the drug pevinistat for treating high-risk myelodysplastic syndromes, in order to overcome the problems of classical reduction reactions.

[0018] To solve the technical problem of this invention, the present invention provides the following technical solution:

[0019] This invention provides an electroreduction method for preparing 2,3-dihydro-1H-indene-1-amine (Ⅰ), an intermediate between rasagiline and pevinistat, characterized in that 2,3-dihydro-1H-indene-1-one oxime (A) is electroreduced in an alkaline solution to obtain 2,3-dihydro-1H-indene-1-amine (Ⅰ): its preparation reaction is as follows:

[0020]

[0021] In a separate electrolytic cell, an alkaline solution of 2,3-dihydro-1H-indene-1-one oxime (A) and an organic solvent are used to form the cathode electrolyte; the anolyte is an alkaline solution; the cathode electrolyte product of 2,3-dihydro-1H-indene-1-amine (I) is obtained by electroreduction reaction; the cathode electrolyte product is post-treated to obtain 2,3-dihydro-1H-indene-1-amine, which is then precipitated with HCl gas to form a salt, yielding 2,3-dihydro-1H-indene-1-amine hydrochloride.

[0022] The cathode working electrode voltage is 7.0V~15.00V relative to the reference electrode; the cathode working electrode current density is 0.05 mA / cm². 2~ 1.0 A / cm 2 Between; the current is between 0.4 and 1.0 A, and the electrolysis temperature is between 25℃ and 85℃.

[0023] The concentration of 2,3-dihydro-1H-inden-1-one oxime (A) was between 5.0 g / L and 20.0 g / L;

[0024] The alkaline solution is selected from: potassium hydroxide solution and sodium hydroxide solution;

[0025] Alkali concentration selection: 0.1 mol / L, 0.2 mol / L, 0.5 mol / L, 1 mol / L, 2 mol / L, 3 mol / L or 5 mol / L;

[0026] The reference electrode for the partitioned electrolytic cell is either a saturated potassium chloride calomel electrode or an Ag / AgCl electrode.

[0027] The cathode of the partitioned electrolytic cell is: a brass electrode, a copper electrode, a zinc sheet, a nickel electrode, a lead electrode, or a platinum electrode.

[0028] The anode of the partitioned electrolytic cell is a platinum mesh electrode, a platinum sheet electrode, or a graphite electrode.

[0029] The diaphragm of the partitioned electrolytic cell is: HF-101 strong acid type cation exchange membrane;

[0030] The organic solvent in the cathode electrolyte is selected from: methanol, ethanol, tetrahydrofuran, and N,N-dimethylformamide;

[0031] The volume ratio of organic solvent to alkaline solution in the cathode electrolyte is selected from 1:1 to 1:10.

[0032] Beneficial technical effects:

[0033] This invention relates to an electroreduction method for preparing intermediate I of the Parkinson's disease drug rasagiline and the drug pevinistat for treating high-risk myelodysplastic syndromes. The electroreduction method for preparing 2,3-dihydro-1H-inden-1-amine (I) of this invention has the following advantages:

[0034] (1) No toxic or dangerous reducing agents are needed in the reduction reaction. "Electrons" are clean reaction reagents and are an important part of the development of "green pharmaceutical industry".

[0035] (2) No additional catalyst is needed during the electroreduction process; high purity and high yield intermediates can be obtained simply in an alkaline solution.

[0036] (3) In industrial production, it simplifies the process flow, reduces production costs, and is safe and environmentally friendly, making it suitable for large-scale promotion and application.

[0037] Electroreduction reactions do not require toxic or hazardous reducing agents, making them an important component of the development of a "green pharmaceutical industry." High-purity and high-yield intermediates can be obtained simply in an alkaline solution without the need for additional catalysts.

[0038] The electroreduction preparation method of 2,3-dihydro-1H-indene-1-amine and its hydrochloride (Ⅰ) of the present invention simplifies the process and reduces production costs in the industrial production of rasagiline, a Parkinson's disease drug, and pervirnisstat, a drug for treating high-risk myelodysplastic syndromes, while also being virtually pollution-free to the environment, making it suitable for large-scale application.

[0039] Attached Figure Description

[0040] Figure 1. Schematic diagram of a partitioned electrolytic cell. Detailed Implementation

[0041] The following examples are intended to illustrate the invention and not to further limit it.

[0042] Example 1

[0043] Electroreduction preparation of 2,3-dihydro-1H-inden-1-amine

[0044]

[0045] Separated electrolytic cell ( Figure 1 A proton exchange membrane is used. At the cathode (zinc sheet 2×2 cm)... 2 Add 0.44 g (3 mmol) of 2,3-dihydro-1H-inden-1-one oxime, 10 mL of methanol, and 40 mL of 0.2 mol / L KOH to the anode chamber (platinum mesh 1 × 1 cm). 2 50 mL of 5 mol / L KOH solution; reaction at 50℃ with a constant current of 0.6 A and a current density of 0.15 A / cm². 2 A saturated calomel electrode was used as a reference electrode to monitor the cathode reaction potential, which ranged from 7.0 to 15.0 V. The electroreduction reaction was carried out for 6.5 h. The cathode liquid was extracted three times with ethyl acetate. The organic layer was collected, dried with anhydrous sodium sulfate, and dissolved by rotary evaporation to obtain an oily compound. HCl gas was then introduced to form a salt, yielding 0.46 g of 2,3-dihydro-1H-indene-1-amine hydrochloride (white solid) with a melting point of 210–212 °C and a yield of 90.6%.

[0046] Example 2

[0047] Electroreduction preparation of 2,3-dihydro-1H-inden-1-amine

[0048]

[0049] Separated electrolytic cell ( Figure 1 A proton exchange membrane is used. At the cathode (zinc sheet 2×2 cm)... 2 Add 0.88 g (6 mmol) of 2,3-dihydro-1H-inden-1-one oxime, 5 mL of methanol: 45 mL of 0.5 mol / L KOH to the anode chamber (platinum mesh 1 × 1 cm). 2 50 mL of 5 mol / L KOH solution; reaction at 55℃ with a constant current of 0.6 A and a current density of 0.15 A / cm². 2 A saturated calomel electrode was used as a reference electrode to monitor the cathode reaction potential, which ranged from 7.0 to 15.0 V. The electroreduction reaction was carried out for 6.5 h. The cathode liquid was extracted three times with ethyl acetate. The organic layer was collected, dried with anhydrous sodium sulfate, and dissolved by rotary evaporation to obtain an oily compound. HCl gas was then introduced to form a salt, yielding 0.92 g of 2,3-dihydro-1H-indene-1-amine hydrochloride (white solid) with a melting point of 210–212 °C and a yield of 90.6%.

[0050] Example 3 (Control Experiment 1)

[0051] Preparation by reduction of 2,3-dihydro-1H-inden-1-amine

[0052]

[0053] 2,3-Dihydro-1H-indene-1-amine was prepared according to the method described in the literature [Research on the Synthesis Process of Rasagiline Mesylate, a Second-Generation Monoamine Oxidase Inhibitor [D]. Jilin University, 2018]: 50.0 g (0.34 mol) of 2,3-dihydro-1H-indene-1-one oxime, 250 mL of ethanol, and 150 g of 20% NaOH aqueous solution were added. The reaction temperature was controlled at 60~65℃. 100 g of nickel-aluminum alloy was added in batches, and the addition time was controlled within 2 h. After the addition was completed, the temperature was maintained at 60~65℃ for 6 h. After the reaction was complete, the solution was filtered. The resulting solution was extracted three times with dichloromethane, the organic phase was washed with water, and the dichloromethane was concentrated to about half of the remaining volume. The solution was extracted twice with 4 mol / L hydrochloric acid solution. The solutions were combined and concentrated under reduced pressure to dryness. The solid was recrystallized from ethanol and crystallized for 2 h. The solid was filtered to obtain a white solid, which was dried to give 49.6 g of 2,3-dihydro-1H-indene-1-amine hydrochloride, with a yield of 86.1%.

[0054] Example 4 (Control Experiment 2)

[0055] Preparation by reduction of 2,3-dihydro-1H-inden-1-amine

[0056]

[0057] Separated electrolytic cell ( Figure 1A proton exchange membrane is used. The cathode (zinc sheet 2×2 cm) 2 Add 0.66 g (4.5 mmol) of 2,3-dihydro-1H-inden-1-one oxime to the cathode chamber, along with ethanol:KOH (20%) = 1:9 (total solvent in the cathode chamber is 50 mL). Add 0.99 g of nickel-aluminum alloy in portions to the anode chamber (platinum mesh 1 × 1 cm). 2 50 mL of 20% KOH solution; reaction at 40℃ with a constant current of 0.5 A and a current density of 0.13 A / cm². 2 A saturated calomel electrode was used as a reference electrode to monitor the cathode reaction potential, which ranged from 7.0 to 15.0 V. The electroreduction reaction was carried out for 6.5 h. The cathode liquid was extracted three times with ethyl acetate. The organic layer was collected, dried with anhydrous sodium sulfate, and dissolved by rotary evaporation to obtain an oily compound. HCl gas was then introduced to form a salt, yielding 0.590 g of 2,3-dihydro-1H-indene-1-amine hydrochloride, a white solid with a yield of 77.6% and a melting point of 210–212 °C.

[0058] Example 5 (Control Experiment 3)

[0059] Preparation by reduction of 2,3-dihydro-1H-inden-1-amine

[0060]

[0061] 2,3-Dihydro-1H-inden-1-amine was prepared according to the method described in the literature [Study on the Synthetic Process of Rasagilan Methanesulfonate [J]. Chinese Journal of Modern Applied Pharmacy. 2016, 33(1): 56-58]: 13.2 g (100 mmol) of 1-indenone was dissolved in 150 mL of methanol, and 18.9 g (300 mmol) of ammonium formate and 9.6 g (100 mmol) of zinc powder were added sequentially, followed by stirring and reflux. After the reaction was completed, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated. The residue was dissolved in 5% hydrochloric acid, washed with ethyl acetate, and the aqueous phase was adjusted to pH 10 with concentrated ammonia. It was then extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 9.1 g of a pale yellow liquid, with a yield of 68%.

[0062] In this specification, the invention has been described with reference to specific embodiments thereof. However, it will be apparent that various modifications and variations can be made without departing from the spirit and scope of the invention. Therefore, the specification and drawings should be considered illustrative rather than restrictive.

Claims

1. A method for the electroreduction preparation of 2,3-dihydro-1H-indene-1-amine, an intermediate of the anti-Parkinson's drug rasagiline and the drug pevinistat for treating high-risk myelodysplastic syndromes, as shown in Formula I; characterized in that... In alkaline solution, 2,3-dihydro-1H-inden-1-one oxime (A) is electroreduced to prepare 2,3-dihydro-1H-inden-1-amine (I): its preparation reaction is as follows: In a partitioned electrolytic cell, an alkaline solution of 2,3-dihydro-1H-indene-1-one oxime (A) and an organic solvent are used to form the cathode electrolyte; the anode electrolyte is an alkaline solution; and the cathode electrolyte of 2,3-dihydro-1H-indene-1-amine (I) is obtained by electroreduction reaction. The cathode electrolysis product was post-treated to obtain 2,3-dihydro-1H-indene-1-amine, which was then precipitated with HCl gas to form a salt, yielding 2,3-dihydro-1H-indene-1-amine hydrochloride. The cathode working electrode voltage is 7.0V~15.00V relative to the reference electrode; the cathode working electrode current density is 0.05 mA / cm². 2 ~ 1.0 A / cm 2 The electrolysis temperature is between 25℃ and 85℃; the reference electrode of the partitioned electrolytic cell is a saturated potassium chloride calomel electrode or an Ag / AgCl electrode; the alkaline solution in the cathode electrolyte is selected from potassium hydroxide solution or sodium hydroxide solution; the alkaline solution in the anolyte is selected from potassium hydroxide solution or sodium hydroxide solution.

2. The method for preparing 2,3-dihydro-1H-inden-1-amine by electroreduction as described in claim 1, characterized in that, The cathode of the partitioned electrolytic cell is a brass electrode, a copper electrode, a zinc sheet electrode, a nickel electrode, a lead electrode, or a platinum electrode.

3. The method for preparing 2,3-dihydro-1H-inden-1-amine by electroreduction as described in claim 1, characterized in that, The anode of the partitioned electrolytic cell is a platinum mesh electrode, a platinum sheet electrode, or a graphite electrode; the diaphragm of the partitioned electrolytic cell is an HF-101 strong acid type cation exchange membrane.

4. The method for preparing 2,3-dihydro-1H-inden-1-amine by electroreduction as described in claim 1, characterized in that, The organic solvent in the cathode electrolyte is selected from any one or more of methanol, ethanol, tetrahydrofuran, and N,N-dimethylformamide.

5. The method for preparing 2,3-dihydro-1H-inden-1-amine by electroreduction as described in claim 1, characterized in that, The concentration of 2,3-dihydro-1H-indene-1-one oxime (A) in the cathode electrolyte is between 5.0 g / L and 20.0 g / L.

6. The method for preparing 2,3-dihydro-1H-inden-1-amine by electroreduction as described in claim 1, characterized in that, The selection of the alkaline solution concentration is as follows: 0.1 mol / L, 0.2 mol / L, 0.5 mol / L, 1mol / L, 2 mol / L, 3 mol / L or 5 mol / L.

7. The method for preparing 2,3-dihydro-1H-inden-1-amine by electroreduction as described in claim 1, characterized in that, The volume ratio of organic solvent to alkaline solution in the cathode electrolyte is selected from 1:1 to 1:10.

Images