CN112574106B

CN112574106B - Synthesis method of 7-amino-5-bromoquinoline

Info

Publication number: CN112574106B
Application number: CN202011251431.7A
Authority: CN
Inventors: 赵丽芳; 徐卫良; 徐炜政
Original assignee: SUZHOU KANGRUN PHARMACEUTICALS Inc
Current assignee: SUZHOU KANGRUN PHARMACEUTICALS Inc
Priority date: 2020-11-11
Filing date: 2020-11-11
Publication date: 2022-04-12
Anticipated expiration: 2040-11-11
Also published as: CN112574106A

Abstract

The invention discloses a synthesis method of 7-amino-5-bromoquinoline, which comprises the steps of carrying out bromination reaction on 7-nitro-1, 2,3, 4-tetrahydroquinoline serving as a raw material to obtain 5-bromo-7-nitro-1, 2,3, 4-tetrahydroquinoline, carrying out dehydrogenation reaction on the 5-bromo-7-nitroquinoline and DDQ to obtain the 5-bromo-7-nitroquinoline, and carrying out reduction reaction on iron powder to obtain the 7-amino-5-bromoquinoline. The method provides a new synthetic route for synthesizing the 7-amino-5-bromoquinoline, and the synthetic route is simple, reasonable in process selection, low in raw material cost, simple and easily available in raw materials, convenient to operate and post-treat, high in total yield, free of using highly toxic reagents, easy to amplify and capable of being produced in a large scale.

Description

Synthesis method of 7-amino-5-bromoquinoline

Technical Field

The invention belongs to the technical field of synthesis of drug intermediates, and particularly relates to a synthesis method of 7-amino-5-bromoquinoline.

Background

7-amino-5-bromoquinoline is an important medical intermediate. Because of the unique properties of 7-amino-5-bromoquinoline, it is widely used in drug design. Michael g. Kelly et al have developed benzamide derivatives as capsaicin receptor (VR) inhibitors for the treatment, prevention or amelioration of pain of various origins or etiologies, such as, without limitation, acute, chronic, inflammatory and neuropathic pain, dental pain and headache (e.g., migraine, cluster headache and tension headache). Compared with other VR-1 inhibitors, the novel VR-1 inhibitor has the characteristics of small toxicity, good absorbability, good half-life period, good solubility, low protein binding degree, strong affinity, less drug interaction and the like, wherein 7-amino-5-bromoquinoline is used as a modifying group to effectively improve the selectivity and the bioactivity of the original structure. (US 2006194801A 1) in addition, Mark G, BOCK et al have also developed a series of cyclic urea derivatives as 17 alpha-hydroxylase/C_17，20Lyase inhibitors (CYP 17 inhibitors) have good effect on treating prostate cancer and are one of the main means for clinically treating prostate cancer at present. Wherein, the 7-amino-5-bromoquinoline can be used as a modifying group to enhance the activity of the compound and has good selectivity. (US 2010331326A 1) therefore uses 7-amino-5-bromoquinoline as a modifying group to improve the properties of the original lead compound, so that the search for some candidate drug molecules with good activity has attracted attention and become one of the hot spots in the pharmaceutical chemistry community. However, no method for synthesizing 7-amino-5-bromoquinoline exists.

Disclosure of Invention

In order to solve the problems in the prior art, the invention aims to provide a synthesis method of 7-amino-5-bromoquinoline.

In order to achieve the purpose, the invention provides the following technical scheme:

the synthesis method of 7-amino-5-bromoquinoline comprises the following steps:

the first step is as follows: synthesis of 5-bromo-7-nitro-1, 2,3, 4-tetrahydroquinoline

Carrying out bromination reaction on 7-nitro-1, 2,3, 4-tetrahydroquinoline serving as a raw material and bromine to obtain 5-bromo-7-nitro-1, 2,3, 4-tetrahydroquinoline;

the second step is that: synthesis of 5-bromo-7-nitroquinoline

Carrying out dehydrogenation reaction on the 5-bromo-7-nitro-1, 2,3, 4-tetrahydroquinoline and DDQ to obtain 5-bromo-7-nitroquinoline;

the third step: synthesis of 7-amino-5-bromoquinoline

Iron powder is used as a reducing agent, and 5-bromo-7-nitroquinoline is subjected to reduction reaction to obtain 7-amino-5-bromoquinoline.

Further, the solvent used in the first step is concentrated sulfuric acid; the reactants were reacted first at-5 ℃ for 1 hour and then at 5 ℃ for 16 hours.

Further, after the reaction is finished in the first step, pouring the reaction mixture into crushed ice and adding ethyl acetate; after the pH of the mixed solution is adjusted to be =9 by sodium carbonate, carrying out suction filtration, and washing a filter cake by ethyl acetate until the filtrate is colorless; the mixed phase was extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate, concentrated under reduced pressure to give 5-bromo-7-nitro-1, 2,3, 4-tetrahydroquinoline.

Further, the reaction solvent used in the second step is dichloromethane, the reaction temperature is room temperature, and the reaction time is 1.5 hours.

Further, after the reaction is finished in the second step, the reaction liquid is filtered, and a filter cake is washed by dichloromethane; combining the filtrates, washing with 10% sodium hydroxide solution, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, stirring the residue and the mixed solvent for 1 h, filtering, washing the filter cake with the mixed solvent, and drying to obtain 5-bromo-7-nitroquinoline; wherein the mixed solvent is petroleum ether and ethyl acetate with the volume ratio of 5: 1.

Further, the reaction solvent used in the third step is absolute ethyl alcohol and acetic acid, and the reaction is carried out under the condition of heating reflux.

Has the advantages that: the invention provides a synthesis method of 7-amino-5-bromoquinoline, and provides a new synthesis route for synthesizing 7-amino-5-bromoquinoline, the synthesis route is simple, the process selection is reasonable, the raw material cost is low, the raw materials are simple and easy to obtain, the operation and the post-treatment are convenient, the total yield is high, no virulent reagent is used, the amplification is easy, and the large-scale production can be carried out.

Drawings

FIG. 1 is a reaction formula for synthesizing 7-amino-5-bromoquinoline according to the present invention.

Detailed Description

The present invention is further described below with reference to specific examples, which are only exemplary and do not limit the scope of the present invention in any way. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention, and that such changes and modifications may be made without departing from the spirit and scope of the invention.

The invention provides a synthesis process of 7-amino-5-bromoquinoline, which comprises the steps of carrying out bromination reaction on 7-nitro-1, 2,3, 4-tetrahydroquinoline serving as a raw material to obtain 5-bromo-7-nitro-1, 2,3, 4-tetrahydroquinoline, carrying out dehydrogenation reaction on the 5-bromo-7-nitroquinoline and DDQ to obtain the 5-bromo-7-nitroquinoline, and carrying out iron powder reduction reaction to obtain the 7-amino-5-bromoquinoline, wherein the reaction formula is shown in figure 1, and the specific synthesis steps are shown in the following.

A2L three-necked flask was charged with 1.4L of sulfuric acid and 7-nitro-1, 2,3, 4-tetrahydroquinoline (139.9 g, 0.786 mol). The reaction solution was cooled to-5 ℃ in an ice salt bath, and then bromine (169.5 g, 1.061 mol) was added. The mixture was stirred at-5 ℃ for 1 h and then at 5 ℃ for a further 16 h. After the reaction was complete, the reaction mixture was poured into a large amount of crushed ice and 2L of ethyl acetate was added. After the mixture was adjusted to pH =9 with sodium carbonate, it was filtered with suction and the filter cake was washed with ethyl acetate until the filtrate was colorless. The mixed phases were extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate, concentrated under reduced pressure to give 5-bromo-7-nitro-1, 2,3, 4-tetrahydroquinoline (186 g, 92.0%).

The second step is that: synthesis of 5-bromo-7-nitroquinoline

5-bromo-7-nitro-1, 2,3, 4-tetrahydroquinoline (62 g,0.2412 mol), 4.65L of dichloromethane were added to a 5L three-necked flask, stirred and dissolved, and 2, 3-dichloro-5, 6-dicyan-p-benzoquinone (DDQ) (109.5 g, 0.4825 mol) was added in portions at 5 ℃. The reaction mixture was stirred at room temperature for 1.5 h, the reaction solution was filtered with suction and the filter cake was washed 2 times with 500 mL of dichloromethane. The filtrates were combined and washed 2 times with 10% 1L sodium hydroxide solution, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, the residue was stirred with 400 mL of a mixed solvent (petroleum ether: ethyl acetate 5: 1) for 1 h, after filtration, the filter cake was washed with 200 mL of a mixed solvent (petroleum ether: ethyl acetate 5: 1) and dried to give 5-bromo-7-nitroquinoline (47 g, 77.0%).

The third step: synthesis of 7-amino-5-bromoquinoline

Reduced iron powder (86 g, 1.5 mol), 490 mL absolute ethanol, 610 mL water were charged to a 2L three-neck flask. Then heated to reflux and acetic acid (25.6 g, 0.426 mol) was added. 5-bromo-7-nitroquinoline (54 g, 0.21 mol) was added in portions and the reaction was refluxed for another 10 minutes. After the reaction is completed, 610 mL of ethanol is added, the mixture is heated to reflux and then is filtered, the filtrate is cooled to room temperature, and the ethanol is removed by decompression and concentration, so that brown crystals are precipitated. Filtration, filter cake washed with water and dissolved with 1100 mL of absolute ethanol and 610 mL of water at reflux temperature. And then filtered, and the filtrate was concentrated under reduced pressure to remove ethanol, and yellow crystals were precipitated. Filtration and washing of the filter cake with water until the filtrate was colourless and dried yielded 7-amino 5-bromoquinoline (42 g, 88.2%).

¹H NMR(400MHz,DMSO):6.009 (s, 2H), 6.965 (d, 1 H), 7.211 (q, 1 H) , 7.383( d, 1 H), 8.145 (d, 1 H) ,8.644(d, 1 H)。

Claims

The synthesis method of the 7-amino-5-bromoquinoline is characterized by comprising the following steps:

the first step is as follows: synthesis of 5-bromo-7-nitro-1, 2,3, 4-tetrahydroquinoline

Carrying out bromination reaction on 7-nitro-1, 2,3, 4-tetrahydroquinoline serving as a raw material and bromine to obtain 5-bromo-7-nitro-1, 2,3, 4-tetrahydroquinoline;

the second step is that: synthesis of 5-bromo-7-nitroquinoline

Carrying out dehydrogenation reaction on the 5-bromo-7-nitro-1, 2,3, 4-tetrahydroquinoline and DDQ to obtain 5-bromo-7-nitroquinoline;

the third step: synthesis of 7-amino-5-bromoquinoline

Iron powder is used as a reducing agent, and 5-bromo-7-nitroquinoline is subjected to reduction reaction to obtain 7-amino-5-bromoquinoline.
2. The method for synthesizing 7-amino-5-bromoquinoline according to claim 1, wherein the solvent used in the first step is concentrated sulfuric acid; the reactants were reacted first at-5 ℃ for 1 hour and then at 5 ℃ for 16 hours.
3. The method for synthesizing 7-amino-5-bromoquinoline according to claim 1, wherein in the first step, after the reaction is completed, the reaction mixture is poured into crushed ice and ethyl acetate is added; after the pH of the mixed solution is adjusted to be =9 by sodium carbonate, carrying out suction filtration, and washing a filter cake by ethyl acetate until the filtrate is colorless; the mixed phase was extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate, concentrated under reduced pressure to give 5-bromo-7-nitro-1, 2,3, 4-tetrahydroquinoline.
4. The method for synthesizing 7-amino-5-bromoquinoline according to claim 1, wherein the reaction solvent used in the second step is dichloromethane, the reaction temperature is room temperature, and the reaction time is 1.5 hours.
5. The method for synthesizing 7-amino-5-bromoquinoline according to claim 1, wherein in the second step, after the reaction is completed, the reaction solution is filtered with suction, and a filter cake is washed with dichloromethane; combining the filtrates, washing with 10% sodium hydroxide solution, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, stirring the residue and the mixed solvent for 1 h, filtering, washing the filter cake with the mixed solvent, and drying to obtain 5-bromo-7-nitroquinoline; wherein the mixed solvent is petroleum ether and ethyl acetate with the volume ratio of 5: 1.
6. The method for synthesizing 7-amino-5-bromoquinoline according to claim 1, wherein the reaction solvent used in the third step is absolute ethanol and acetic acid, and the reaction is performed under heating reflux.