Novel method for preparing ropinirole hydrochloride intermediate 4-(beta-ethoxyl)-1,3-dihydro-2H-indolyl-2-ketone

Abstract

The invention discloses a novel method for preparing a ropinirole hydrochloride intermediate 4-(beta-ethoxyl)-1,3-dihydro-2H-indolyl-2-ketone, belonging to the technical field of pharmaceutical chemistry. The preparation method comprises the following steps: reducing 4-(2-benzoyloxyethyl)-3-chloro-1,3-dihydro-2H-indolyl-2-ketone in a solvent in inert gas shielding in the presence of a reduction catalyst by using a hydrogen donor to obtain the 4-(beta-ethoxyl)-1,3-dihydro-2H-indolyl-2-ketone. The whole synthetic technique does not need high-temperature high-pressure hydrogenation, has the advantages of mild reaction conditions, low cost, high product yield and the like, is simple to operate, and is suitable for industrial production.

Description

Technical field [0001] The invention belongs to the technical field of medicinal chemistry and relates to a preparation process of ropinirole hydrochloride intermediate 4-(β-hydroxyethyl)-1,3-dihydro-2H-indol-2-one. Background technique [0002] Parkinson's disease (PD) is a chronic progressive disease of extrapyramidal dysfunction of the central nervous system. It is a chronic neuronal degenerative disease that mainly occurs in middle-aged and elderly people. It seriously affects the quality of life of the people and gives rise to It brings huge psychological pressure and economic burden to society and families. Levodopa is the earliest therapeutic drug, but most patients will experience "switching phenomenon" after using treatment for a period of time, and even peripheral or central nervous side effects such as difficulty in movement and mental changes. Dopamine receptor agonists are a very important class of drugs in the anti-Parkinson's disease drug market. They are usu...

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Problems solved by technology

[0004] The synthetic route of ropinirole hydrochloride reported in the literature at present is mainly based on the halogen compound of 2-methyl-3-nitrophenylacetic acid, 3-aminophenethyl, isobenzodihydrofuran, 4-indole carboxaldehyde and o-bromoethylbenzaldehyde as raw materials to prepare, but these methods all have the shortcomings of expensive raw materials, high toxicity, harsh reaction conditions, low reaction yield, such as patent US4452808 with 2-methyl-3-nitrophenylacetic acid As the starting material, ropinirole is obtained through eleven-step reaction, the steps are too long, the raw material is not easy to obtain, and the highly toxic sodium cyanide is required; in addition, the patent articles with application numbers 200910029165, 2006100812218, and 200480040698 are also different. The problem of degree: 200910029165 mentioned that the intermediate 2-bromoethylbenzaldehyde was synthesized using bromine, which is highly irritating and harmful to production personnel

In 2006100812218, the preparation of the intermediate N, N-dipropyl-3-nitro-4-chlorophenethylamine uses highly active LiAlH 4 , LiAlH 4 It is hydrolyzed in humid air and causes combustion. When it meets water, it will react violently and cause an explosion. It is not suitable for industrial production. In addition, its intermediate 4-(N,N-dipropylethyl)-1,3-dihydro-2- Its preparation of indolinone (ropinirole) adopts catalytic hydrogenation reaction, the reaction time is up to 45 hours, the production cycle is longer, and the labor and energy consumption costs are relatively large during industrialized production

In 200480040698, it is mentioned that 4-(2'-aminoethyl)-1,3-dihydro-2H-indol-2-one hydrochloride and propionaldehyde are used to generate Schiff base, and then palladium carbon catalytic reduction occurs. Reductive amination reaction produces ropinirole hydrochloride, but its crude product yield is only 41%, purity 90%, finished product refined yield 85%, purity 95%, impurity amount is too large, can not be used for pharmaceutical preparations

[0008] According to the novelty search report of the Southwest Information Center of the Ministry of Science and Technology, the same literature report as the application of the present invention has not yet been retrieved in the open literature

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