Preparation method of rotigotine

A technology of methoxyl and tetrahydronaphthalene, applied in the field of drug preparation, can solve the problems of large consumption of raw materials, corrosion of equipment, difficulty in disassembly, etc., and achieve the effects of reducing loss, easy operation and good application prospects

Active Publication Date: 2021-08-10
CHENGDU TECH UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In the current preparation process of rotigotine, there are problems such as difficult disassembly, large consumption of raw materials, high cost, and easy corrosion of equipment

Method used

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  • Preparation method of rotigotine
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  • Preparation method of rotigotine

Examples

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preparation example Construction

[0025] The invention provides a kind of preparation method of rotigotine, comprises the steps:

[0026] S1 dissolves 5-methoxyl-2-tetralone in an organic solvent, adds R-alpha-methylbenzylamine dropwise to react, and then adds a reducing agent to obtain 5-methoxyl-N(( R)-1-phenethyl)-1,2,3,4-tetrahydronaphthalene-2-amine hydrochloride;

[0027] S2 debenzylation reaction of 5-methoxy-N((R)-1-phenylethyl)-1,2,3,4-tetrahydronaphthalene-2-amine hydrochloride, after the end, in the base Reactive conditions are processed to obtain 5-methoxy-1,2,3,4-tetrahydronaphthalene-2-amine;

[0028] S3 Dissolve 5-methoxy-1,2,3,4-tetrahydronaphthalene-2-amine in an organic solvent, add S-mandelic acid solution dropwise, after the dropwise addition, suction filter after reaction to obtain a solid, After separation, (S)-5-methoxy-1,2,3,4-tetrahydronaphthalene-2-amine was obtained;

[0029] S4 reacts (S)-5-methoxy-1,2,3,4-tetrahydronaphthalene-2-amine with propionyl chloride reagent to generate ...

Embodiment 1

[0055] Example 1 (preparation of 5-methoxy-N-((R)-1-phenylethyl)-1,2,3,4-tetrahydronaphthalene-2-amine hydrochloride)

[0056] Dissolve MPTN-0 (0.948mol, 167.0g) in 1.4kg of absolute ethanol, and add R-α-methylbenzylamine (1.137mol, 137.8g) dropwise at room temperature (25°C). After the addition is complete, Raise the temperature to 30-35°C and stir for 5 hours; after the stirring, cool down to 5-10°C, add sodium borohydride (0.948mol, 35.9g) in batches, control the system temperature at 10-15°C, and stir for 6h; the stirring is over Finally, keep the temperature of the system at 10-15°C, add 200g of concentrated hydrochloric acid dropwise to adjust the pH of the system to <3, stir for 2 hours, a large amount of solids precipitate, filter, and dry to constant weight to obtain 270.0g of off-white solid MPTN-1, with a yield of 89.6 %, HPLC analysis purity is 98.2%.

Embodiment 2

[0057] Embodiment 2 (preparation of 5-methoxy-1,2,3,4-tetrahydronaphthalene-2-amine)

[0058] Add MPTN-1 (270.0g, 0.85mol) into a 5L hydrogenation kettle, add 2kg of methanol, 25g of 10% palladium carbon wet product, control the hydrogen pressure at 2-5atm, stir at 60°C for 5h, and debenzylation is completed. Add sodium hydroxide powder equivalent to MPTN-1 into the reaction kettle, and stir for 3h. Then the reaction solution was filtered, and the solvent was removed from the filtrate under reduced pressure to obtain 0.0 g of brown oil MPTN-2 with a yield of 66.4% and a purity of 97.6% by HPLC analysis.

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Abstract

The invention relates to the technical field of medicine preparation, and discloses a preparation method of rotigotine, which comprises the following steps: by taking 5-methoxy-2-tetralone as an initial raw material, reacting with R-alpha-methylbenzylamine, performing debenzylation reduction and S-mandelic acid chiral resolution, then reacting with a propionyl chloride reagent to generate an amide compound, and then reducing by a sodium borohydride reagent to obtain the rotigotine; and finally, reacting with 2-(thiophene-2-yl) 2-nitric acid benzene sulfonic acid ethyl ester to obtain the rotigotine. The preparation process route is as follows: the rotigotine is mild in preparation condition, simple and convenient to operate, relatively high in yield of key intermediates, high in optical purity and easy for industrial large-scale production, and has a very good application prospect.

Description

technical field [0001] The invention belongs to the technical field of medicine preparation, and in particular relates to a preparation method of rotigotine. Background technique [0002] Parkinson's disease (PD) is a neurodegenerative disease that often occurs in the elderly. The main pathological mechanism of Parkinson's disease is the degeneration and death of dopamine (DA) neurons in the substantia nigra of the midbrain. As a result, the DA content of the linear body is significantly reduced and the disease is caused. The clinical manifestations of the disease are resting tremor, bradykinesia, postural gait disturbance, and muscle rigidity, or some non-motor symptoms such as depression, constipation, and sleep disturbance. The most important treatment for Parkinson's disease is drug therapy, and the most effective drug is levodopa preparation, which can cause motor complications. Studies have shown that stimulation of pulsatile striatal dopamine receptors is the main c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/20C07C213/10C07C217/74C07C213/08C07C213/02C07C231/02C07C233/23
CPCC07D333/20C07C213/10C07C213/08C07C213/02C07C231/02C07B2200/07C07C2602/28C07C217/74C07C233/23Y02P20/55
Inventor 韩卫华陆艳红熊武蒋卓成
Owner CHENGDU TECH UNIV
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