913613-82-8

Usage

Uses

Used in Pharmaceutical Industry:
2(1H)-Quinolinone,7-(4-chlorobutoxy)is used as an impurity in the development and manufacturing process of Brexipiprazole (B677385) for its potential role in treating mental disorders, including CNS disorders. Its presence, however, needs to be carefully managed and controlled to ensure the safety and efficacy of the drug.

Upstream product

• 6940-78-9 4-chlorobutyl bromide 
• 70500-72-0 7-hydroxy-1H-quinolin-2-one 
• 591-27-5 m-Hydroxyaniline 
• 50297-40-0 3-chloro-N-(3-hydroxyphenyl)propanamide 
• 22246-18-0 7-hydroxy-3,4-dihydro-2-(1H)-quinolinone 
• 120004-79-7 7-(4-chlorobutoxy)-3,4-dihydroquinoline-2(1H)-one 
• 110-56-5 1,4-dichlorobutane 

Downstream Products

• 2094559-58-5 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)butoxy)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)quinoline-2(1H)-one 

Relevant academic research and scientific papers

Site-Selective Acceptorless Dehydrogenation of Aliphatics Enabled by Organophotoredox/Cobalt Dual Catalysis

The value of catalytic dehydrogenation of aliphatics (CDA) in organic synthesis has remained largely underexplored. Known homogeneous CDA systems often require the use of sacrificial hydrogen acceptors (or oxidants), precious metal catalysts, and harsh reaction conditions, thus limiting most existing methods to dehydrogenation of non- or low-functionalized alkanes. Here we describe a visible-light-driven, dual-catalyst system consisting of inexpensive organophotoredox and base-metal catalysts for room-temperature, acceptorless-CDA (Al-CDA). Initiated by photoexited 2-chloroanthraquinone, the process involves H atom transfer (HAT) of aliphatics to form alkyl radicals, which then react with cobaloxime to produce olefins and H2. This operationally simple method enables direct dehydrogenation of readily available chemical feedstocks to diversely functionalized olefins. For example, we demonstrate, for the first time, the oxidant-free desaturation of thioethers and amides to alkenyl sulfides and enamides, respectively. Moreover, the system's exceptional site selectivity and functional group tolerance are illustrated by late-stage dehydrogenation and synthesis of 14 biologically relevant molecules and pharmaceutical ingredients. Mechanistic studies have revealed a dual HAT process and provided insights into the origin of reactivity and site selectivity.

Method for preparing

The invention relates to a preparation method of brexpiprazole and an intermediate thereof; the method includes the steps of carrying out a reaction of a compound represented by the formula II with 1-bromo-4-chlorobutane in a reaction solvent to obtain a compound represented by the formula III, in the presence of 2,3-dicyano-5,6-dichlorobenzoquinone, oxidizing the compound represented by the formula III into a compound represented by the formula IV, carrying out a reaction of the compound represented by the formula IV with a compound represented by the formula V to obtain brexpiprazole, then carrying out hydrochloride formation and refining, adding an alkali, and allowing brexpiprazole to drift away. The purity of brexpiprazole obtained by the method is more than 99.5%, the total yield is more than 80%, the process is simple and the cost is low.

Preparation method of brexpiprazole intermediate 7-hydroxy-1H-quinoline-2-ketone

The invention belongs to the field of chemical engineering, and particularly relates to a preparation method of a brexpiprazole intermediate 7-hydroxy-1H-quinoline-2-ketone. According to the novel method for preparing the 7-hydroxy-1H-quinoline-2-ketone, DDQ is replaced with palladium on carbon, the obtained product is high in yield, few in impurity and easy to operate, the catalyst can be recycled, a target compound is synthesized through direct catalytic dehydrogenation, and the method has green atom economy and is suitable for industrial production.

Preparation method and application of substituted quinoline-2(1H)-one compound

The invention belongs to the field of pharmaceutical chemistry and chemical synthesis, and concretely relates to a preparation method of a substituted quinoline-2(1H)-one compound. The invention provides a preparation method of the substituted quinoline-2(1H)-one compound. The preparation method performs an oxidation reaction on a compound represented by a formula I and an oxidant in a solvent toobtain a compound represented by a formula II. The preparation method has the advantages of simple method, high yield and low cost and is suitable for industrial production. The substituted quinoline-2(1H)-one represented by the formula II is an important intermediate of a variety of pharmaceutical active ingredients.

Industry-Oriented Route Evaluation and Process Optimization for the Preparation of Brexpiprazole

Efforts toward route evaluation and process optimization for the preparation of brexpiprazole (1) are described. Starting from commercially available dihydroquinolinone 11, a three-step synthesis route composed of O-alkylation, oxidation, and N-alkylation was selected for industry-oriented process development aiming to reduce side reactions and achieve better impurity profiles. The reaction conditions of the three steps were investigated, and the control strategy for the process-related impurities was established. The optimized process was validated on the kilogram scale and now is viable for commercialization, with the results of not less than 99.90% purity of 1 (by HPLC) and not more than 0.05% of persistent impurities 15 and 16.

Oxidative Aromatization of 3,4-Dihydroquinolin-2(1 H)-ones to Quinolin-2(1 H)-ones Using Transition-Metal-Activated Persulfate Salts

Inorganic persulfate salts were identified as efficient reagents for the oxidative aromatization of 3,4-dihydroquinolin-2(1H)-ones through the activation of readily available transition metals, such as iron and copper. The feasible protocol conforming to the requirement of green chemistry was utilized in the preparation of the key intermediate (7-(4-chlorobutoxy)quinolin-2(1H)-one 2) of brexpiprazole in 80% isolated yield on a 100 g scale, and different quinolin-2(1H)-one derivatives with various functional groups were demonstrated in 52-89% yields.

Methods for preparing brexpiprazole intermediate and brexpiprazole with cheap metal copper

Methods for preparing a brexpiprazole intermediate and brexpiprazole with cheap metal copper are disclosed. The method for preparing the brexpiprazole intermediate includes dissolving 4-halogen benzo[b]thiophene and piperazine into a solvent under nitrogen protection, and adding an alkali, a ligand and a copper-based catalyst; stirring and reacting the mixture until TLC detection shows that the reaction is finished; after the reaction is finished, subjecting the system to extraction with ethyl acetate or dichloromethane; combining organic phases, and spin-drying the mixture; adding methanol todissolve solid; adding dropwise a hydrochloric acid methanol solution with a concentration of 2M to adjust the pH to 1-7 so that a target product forms a salt and then is precipitated; performing suction filtration to obtain white solid; and drying the white solid to obtain 4-piperazinyl benzothiophene hydrochloride. The methods have advantages of few side reactions, high product quality, low production cost, and the like, are suitable for industrial production and have good promotion and application prospects. The invention further provides a brexpiprazole bulk pharmaceutical chemical prepared from the brexpiprazole intermediate obtained with a low-cost technique, with the bulk pharmaceutical chemical having high purity.

PROCESS FOR THE PREPARATION OF BREXPIPRAZOLE AND ITS INTERMEDIATES

The present invention discloses to a process for the preparation of brexpiprazole and its pharmaceutically acceptable salt. The present invention further discloses novel intermediates and process for the preparation of the novel intermediates of brexpiprazole. The invention also discloses a process for purification of brexpiprazole to reduce or eliminate impurities.

Process for preparing Brexpiprazole

The invention relates to a method for preparing Brexpiprazole with a one-pot process. 7-hydroxyl-2-quinolone reacts with added 1-bromine-4-chlorobutane in the presence of alcohol and alkali, 1-(benzo[B]thiophen-4-yl) piperazine hydrochloride and water are added for a further reaction, finally, filtration, separation and drying are performed, and Brexpiprazole is obtained. Compared with the prior art, the method has the benefits as follows: 1, the problems of insufficient reaction and difficulty in purification in the prior art are solved; 2, the operation process is simplified, and the production efficiency is greatly improved; 3, used solvents are safe, and less environment pollution is caused.

Brexpiprazole derivative and preparation method thereof

The invention provides a brexpiprazole derivative, and a preparation method thereof. According to the chemical structure of the brexpiprazole derivative, the brexpiprazole derivative is prepared through following steps: brexpiprazole, and (HCHO) are reacted in the presence of a first alkaline catalyst to prepare N-hydroxymethyl brexpiprazole; and then N-hydroxymethyl brexpiprazole and an alkylformyl chloride compound are reacted in the presence of a second alkaline catalyst to obtain the brexpiprazole derivative. The brexpiprazole derivative is long in half life, and is capable of reducingmedicine administration frequency; and the brexpiprazole derivative prepared using the preparation method is low in impurity content and cost.