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CN-114438531-B - Electrochemical preparation method of rasagiline He Peiwei nisstat intermediate

CN114438531BCN 114438531 BCN114438531 BCN 114438531BCN-114438531-B

Abstract

The invention relates to an electroreduction preparation method of an anti-parkinsonism drug rasagiline and a drug ‌ for treating high-risk myelodysplastic syndrome Wei Nisi, namely an intermediate of 2, 3-dihydro-1H-indene-1-amine (I), which comprises the following preparation reaction: In a separated electrolytic tank, an alkaline solution of 2, 3-dihydro-1H-indene-1-ketoxime (A) and an organic solvent form a catholyte, the anolyte is an alkaline solution, and a catholyte product of 2, 3-dihydro-1H-indene-1-amine (I) is obtained through an electro-reduction reaction.

Inventors

  • HU AIXI
  • WANG MAN
  • YI YANGJIE
  • YE JIAO

Assignees

  • 湖南大学

Dates

Publication Date
20260508
Application Date
20210719

Claims (7)

  1. 1. An electroreduction preparation method of 2, 3-dihydro-1H-indene-1-amine shown in a formula I as an intermediate of rasagiline which is an anti-parkinsonism drug and a drug ‌ for treating high-risk myelodysplastic syndrome Wei Nisi, is characterized in that 2, 3-dihydro-1H-indene-1-amine (I) is prepared by an electroreduction method in an alkaline solution by the following preparation reaction: In a separated electrolytic tank, an alkaline solution of 2, 3-dihydro-1H-indene-1-ketoxime (A) and an organic solvent form a catholyte, the anolyte is an alkaline solution, a catholyte product of 2, 3-dihydro-1H-indene-1-amine (I) is obtained through an electroreduction reaction, and the catholyte product is subjected to post-treatment to obtain 2, 3-dihydro-1H-indene-1-amine, and HCl gas is introduced into the catholyte product to form salt, so that 2, 3-dihydro-1H-indene-1-amine hydrochloride is obtained; The voltage of the cathode working electrode is 7.0V-15.00V relative to a reference electrode, the current density of the cathode working electrode is 0.05 mA/cm 2 ~ 1.0 A/cm 2 , the electrolysis temperature is 25-85 ℃, the reference electrode of the separated electrolytic tank is a saturated potassium chloride calomel electrode or an Ag/AgCl electrode, alkali liquor in the cathode electrolyte is selected from potassium hydroxide solution or sodium hydroxide solution, and alkali liquor in the anode electrolyte is selected from potassium hydroxide solution or sodium hydroxide solution.
  2. 2. The process for the electroreduction preparation of 2, 3-dihydro-1H-inden-1-amine according to claim 1, wherein the cathode of the divided electrolytic cell is a brass electrode, a red copper electrode, a zinc sheet electrode, a nickel electrode, a lead electrode or a platinum electrode.
  3. 3. The method for preparing 2, 3-dihydro-1H-indene-1-amine by electroreduction according to claim 1, wherein the anode of the separation type electrolyzer is a platinum mesh electrode, a platinum sheet electrode or a graphite electrode, and the diaphragm of the separation type electrolyzer is an HF-101 strong acid type cation exchange membrane.
  4. 4. The method for preparing 2, 3-dihydro-1H-indene-1-amine according to claim 1, wherein the organic solvent in the catholyte is selected from any one or more of methanol, ethanol, tetrahydrofuran, and N, N-dimethylformamide.
  5. 5. The method for the electroreduction production of 2, 3-dihydro-1H-inden-1-amine according to claim 1, wherein the concentration of 2, 3-dihydro-1H-inden-1-one oxime (a) in the catholyte is between 5.0 g/L and 20.0 g/L.
  6. 6. The process for the electroreduction preparation of 2, 3-dihydro-1H-inden-1-amine according to claim 1, wherein the lye concentration is selected from 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. 7. The process for the electroreduction preparation of 2, 3-dihydro-1H-indene-1-amine according to claim 1, wherein the volume ratio of organic solvent to lye in the catholyte is selected from 1:1 to 1:10.

Description

Electrochemical preparation method of rasagiline He Peiwei nisstat intermediate Technical Field The invention relates to a novel method for preparing an intermediate of rasagiline mesylate serving as an anti-parkinsonism drug and ‌ -Wei Nisi serving as a drug for treating high-risk myelodysplastic syndrome by electroreduction, in particular to a method for preparing 2, 3-dihydro-1H-indene-1-amine and hydrochloride thereof by electroreduction of 2, 3-dihydro-1H-indene-1-ketoxime. Background Rasagiline mesylate (RASAGILINE MESYLATE), a monoamine oxidase B (MAO-B) inhibitor developed by the combination of israel Teva company and denmark Lundbeck company, is effective in the treatment of early Parkinson's Disease (PD) by blocking the decomposition of the neurotransmitter dopamine, is a second generation MAO-B selective inhibitor of Relay-selegiline, is superior to selegiline in terms of effectiveness, side effects, neuroprotection, is approved to be marketed in europe in 2005, and is approved to be marketed by the FDA in united states. The preparation method of rasagiline mesylate comprises the steps of Dai Ronghua and the like [ rasagiline mesylate synthesis process research [ J ]. Chinese modern application pharmacy [ 2016, 33 (1): 56-58] describes that 1-indenone is taken as a raw material, ammonium formate is selected in methanol, the mass ratio of substrate to zinc powder is 1:1, one-pot reduction-amination is carried out to prepare 2, 3-dihydro-1H-indene-1-amine (I), the 2, 3-dihydro-1H-indene-amine reacts with 3-bromopropyne under alkaline condition, and rasagiline mesylate is obtained by splitting L-tartaric acid and salifying methanesulfonic acid, wherein the yield of intermediate I (base) is 68 percent: Li Jie et al [ J ]. Shandong chemical 2020, 49 (11): 23-25] describe that 2, 3-dihydro-1H-inden-1-amine (I) can be prepared as intermediate I by reacting 1-indanone in methanol, ammonium formate at 48℃under 10% Pd/C catalysis, 4H to obtain N-propargyl-1-aminoindan hydrochloride from 2, 3-dihydro-1H-inden-1-amine under the actions of propargyl tosylate and hydrochloric acid. Wherein the yield of intermediate I (base) is 84%: The wuta pharmacy was announced at 7 and 30 months 2020, and the U.S. food and drug administration granted its breakthrough therapy at drug stack ‌ and Wei Nisi (Pevonedistat) for the treatment of patients with high risk myelodysplastic syndrome (HR-MDS). ‌ Pe Wei Nisi he is a "first-in-class" NEDD8 activating enzyme (NAE) inhibitor which is expected to be an innovative medicament for the first treatment of HR-MDS patients for more than ten years [An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature. 2009.4.9, 458(7239):732-736]. The preparation method of drug ‌ and Wei Nisi for treating high risk myelodysplastic syndrome on the market in 2020 [ synthetic method of tumor inhibitor MLN 4924. CN 106854208A 2017.06.16] comprises the steps of selecting compound 1 as a starting material, ammonifying with intermediate 2, 3-dihydro-1H-indene-1-amine (I) to synthesize compound 4, removing protecting group to obtain compound 5, and sulfonylating to obtain ‌ and Wei Nisi (Pevonedistat), wherein the preparation reaction is as follows: in the two new drug preparation methods, 2, 3-dihydro-1H-inden-1-amine (I) is found to be a key intermediate for preparing an anti-parkinsonism drug rasagiline and a drug ‌ culture Wei Nisi of high risk myelodysplastic syndrome (Pevonedistat): Dayong [ second generation monoamine oxidase inhibitor rasagiline mesylate, university of process study [ D ]. Jilin ], 2018] describes in its research paper that 2, 3-dihydro-1H-inden-1-one oxime in ethanol, 20% naoh was selected, substrate: nickel-aluminum alloy mass ratio of 1:2, reaction 6H at 60 ℃, to give intermediate I hydrochloride, yield 86.1%, roger et al [ an improved process for preparing 2, 3-dihydro-1H-inden-1-amine and derivatives, CN101062897 a 2007.10.31] also disclosed in chinese invention patent 2, 3-dihydro-1H-inden-1-one oxime in ethanol, 45% naoh was selected, substrate: nickel-aluminum alloy mass ratio of 3.5:5, reaction 8H at 50 ℃, intermediate I hydrochloride, yield 76.8%. The preparation of the 2, 3-dihydro-1H-indene-1-amine I adopts a catalytic hydrogenation method, wherein palladium is a catalyst, palladium or nickel is a complex which is difficult to separate from an amino compound intermediate which is a reduction product, so that the purity of the intermediate and the excessive heavy metal in the product of the anti-Parkinson medicament and the medicament ‌ for treating high-risk myelodysplastic syndrome Wei Nisi are influenced. The method adopts inorganic reducing agents zinc powder, metallic nickel-aluminum alloy (Raney nickel) and aluminum amalgam for reduction to prepare the 2, 3-dihydro-1H-indene-1-amine I, which is difficult to post-treat, has large wastewater quantity and large environmental pollution, and particularly has large toxicity to mercury. The inve