CN113121430B - Preparation method of 5- (alpha-halogenated butyryl) -8-hydroxyquinoline-2-ketone - Google Patents
Preparation method of 5- (alpha-halogenated butyryl) -8-hydroxyquinoline-2-ketone Download PDFInfo
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- CN113121430B CN113121430B CN202110501529.1A CN202110501529A CN113121430B CN 113121430 B CN113121430 B CN 113121430B CN 202110501529 A CN202110501529 A CN 202110501529A CN 113121430 B CN113121430 B CN 113121430B
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/24—Oxygen atoms attached in position 8
- C07D215/26—Alcohols; Ethers thereof
Abstract
The application provides a preparation method of 5- (alpha-halogenated butyryl) -8-hydroxyquinoline-2-ketone, which comprises the following steps: step 1: in the presence of an acid-binding agent, carrying out acylation reaction on 8-hydroxyquinoline-2-ketone shown in a formula (I) and an acylating agent shown in a formula (II) to obtain 8- (alpha-halogenated butyryloxy) -quinoline-2-ketone shown in a formula (III); step 2: and (3) carrying out rearrangement reaction on the 8- (alpha-halogenated butyryloxy) -quinoline-2-ketone in methanesulfonic acid to obtain the 5- (alpha-halogenated butyryl) -8-hydroxyquinoline-2-ketone shown in the formula (IV). The method has the advantages of simple process, low production cost, good product quality and high yield, and is beneficial to industrial production.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of 5- (alpha-halogenated butyryl) -8-hydroxyquinoline-2-ketone.
Background
The 5- (alpha-halogenated butyryl) -8-hydroxyquinoline-2-ketone is used as a medical intermediate and is a key intermediate for synthesizing a medicine procaterol hydrochloride, and the procaterol hydrochloride is used for preventing and treating asthmatic symptoms caused by bronchial asthma, asthmatic bronchitis and chronic obstructive pulmonary diseases. Developed by tsukamur pharmaceuticals, marketed in japan in 1981. In tsukamur junior patent US4026897, 8-hydroxyquinolin-2-one is used as a starting material, and a Friedel-crafts reaction is adopted to prepare an intermediate 5- (alpha-bromobutyryl) -8-hydroxyquinolin-2-one, the Friedel-crafts reaction uses a large excess of 2-bromobutyryl bromide and anhydrous aluminum trichloride, a reaction product forms a viscous oily precipitate, and a large amount of aluminum salt wastewater is generated in post-treatment, so that environmental protection pressure is brought. Chinese patent CN111217746 adopts 8-hydroxyquinoline oxynitride to react with 2-bromobutyryl halide to obtain 5- (2-bromobutyryl) -8-hydroxyquinolone, and the reaction condition still needs a large amount of Lewis acid, generates excessive waste brine and is not beneficial to industrial production.
Therefore, the technical personnel in the field have a need to solve the problem of providing a preparation method of 5- (alpha-halogenated butyryl) -8-hydroxyquinoline-2-ketone with simple process, low production cost and good product quality.
Disclosure of Invention
In order to solve the technical problems, the invention provides a preparation method of 5- (alpha-halogenated butyryl) -8-hydroxyquinoline-2-ketone, which has the advantages of simple process, low production cost, good product quality and high yield and is beneficial to industrial production.
A process for the preparation of 5- (α -halobutyryl) -8-hydroxyquinolin-2-one, comprising the steps of:
step 1: in the presence of an acid-binding agent, carrying out acylation reaction on 8-hydroxyquinoline-2-ketone shown in a formula (I) and an acylating agent shown in a formula (II) to obtain 8- (alpha-halogenated butyryloxy) -quinoline-2-ketone shown in a formula (III);
and 2, step: carrying out rearrangement reaction on the 8- (alpha-halogenated butyryloxy) -quinoline-2-ketone in methanesulfonic acid to obtain 5- (alpha-halogenated butyryl) -8-hydroxyquinoline-2-ketone shown as a formula (IV);
the preparation process of the 5- (alpha-halogenated butyryl) -8-hydroxyquinoline-2-ketone is shown as follows:
according to the scheme, 8-hydroxyquinoline-2-ketone reacts with an acylating agent shown in a formula (II), then a rearrangement reaction is carried out in methanesulfonic acid to prepare a 5- (alpha-halogenated butyryl) -8-hydroxyquinoline-2-ketone intermediate, the obtained intermediate does not need to be purified, and the content of liquid chromatography is over 97%.
Preferably, the molar ratio of the 8-hydroxyquinolin-2-one to the acylating agent is 1 (1-1.5).
In the acylation reaction, when the acylating agent is excessive, the excessive acylating agent is often removed by a post-treatment process; when the amount of the acylating agent is insufficient, the starting material remains to be unfavorable for the separation by the post-treatment, and the reaction yield is impaired. According to the invention, through adding an appropriate amount of acylating agent, on one hand, the complete reaction of the acylating agent can be ensured, and on the other hand, through reducing the amount of the acylating agent, the raw materials are saved, and the three wastes are reduced.
Preferably, the molar ratio of the 8- (alpha-halobutyryloxy) -quinolin-2-one to methanesulfonic acid is 1 (5-15).
During the rearrangement reaction: 1. methanesulfonic acid acts as a solvent first, the solubility of quinoline compounds is poor, and a sufficient amount of methanesulfonic acid is needed to ensure that the solid dissolves and the reaction is stable 2. The dehydration capacity of methanesulfonic acid promotes the occurrence of free rearrangement of the substrate molecules, which requires lower moisture and lower concentration (reduces the occurrence of side reactions). In view of this, the molar ratio of 8- (alpha-halobutyryloxy) -quinolin-2-one to methanesulfonic acid is chosen to be 1 (5-15), taking into account differences in molecular weight, solubility factors, reaction concentrations, raw material costs, and the like.
Preferably, the molar ratio of the 8- (alpha-halobutyryloxy) -quinolin-2-one to methanesulfonic acid is from 1 (7) to 12.
Preferably, the acylating agent comprises one or more of 2-chlorobutyryl chloride, 2-bromobutyryl chloride, 2-chlorobutyryl bromide and 2-bromobutyryl bromide.
Preferably, the acid-binding agent comprises one or more of trimethylamine, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, imidazole and 2-methylimidazole.
Preferably, the step 1 specifically comprises: dispersing the 8-hydroxyquinoline-2-ketone in an inert solvent, adding the acylating agent and the acid-binding agent, reacting for a period of time at the temperature of 20-60 ℃, and cooling to room temperature; washing with water, filtering and drying to obtain the 8- (alpha-halogenated butyryloxy) -quinoline-2-ketone.
The effect of the water wash here is: 1. hydrolysis breaks down the binding of excess acylating agent to the product; 2. hydrolyzing the excess acylating agent to carboxylic acid; 3. excess carboxylic acid (carboxylic acid dissolved in water) is removed.
Preferably, in the step 1, after the filtration is completed, the filter cake is washed with an appropriate amount of water. The effect of the washing here is: (1) removing mother liquor in the filter cake, and (2) removing impurities adsorbed by the mother liquor and the filter cake.
Preferably, the step 2 specifically comprises: putting the 8- (alpha-halogenated butyryloxy) -quinoline-2-ketone into methanesulfonic acid, reacting at 20-65 ℃ for a period of time, and cooling to room temperature; then, pouring into water for hydrolysis, filtering and drying to obtain the 5- (alpha-halogenated butyryl) -8-hydroxyquinoline-2-ketone.
Preferably, in the step 2, the hydrolysis, filtration, drying and the like can be repeatedly performed.
Preferably, in the step 2, after the filtration is completed, the filter cake is washed with a proper amount of water. The effect of the washing here is: (1) removing mother liquor in the filter cake, and (2) removing impurities adsorbed by the mother liquor and the filter cake.
Preferably, the inert solvent comprises one or more of dichloromethane, dichloroethane, trichloromethane, carbon tetrachloride, carbon disulfide, nitrobenzene and nitromethane.
Preferably, in the step 1, the reaction temperature is 35-45 ℃; more preferably 40 deg.c.
Preferably, in the step 2, the reaction temperature is 45-55 ℃; more preferably 50 deg.c.
Preferably, in the step 1, the reaction time is 1 to 6 hours.
Preferably, in the step 2, the reaction time is 1 to 4 hours.
Compared with the prior art, the method provided by the invention optimizes the process conditions and simplifies the preparation process, thereby saving the preparation time and improving the preparation efficiency; and the used raw materials are easy to obtain, the reaction conditions are controllable, the production cost is greatly reduced, the obtained product has good quality and high yield, and the method is suitable for large-scale industrial production.
Drawings
FIG. 1 shows the NMR spectrum of 5- (. Alpha. -halobutyryl) -8-hydroxyquinolin-2-one, solvent: methanol-d 4;
FIG. 2 is an HPLC detection spectrum of 5- (alpha-halobutyryl) -8-hydroxyquinolin-2-one, and the chromatographic conditions are as follows: octadecyl bonded silica gel column chromatography 4.6X 250mm, mobile phase methanol-buffer solution (35).
Detailed Description
In order to make those skilled in the art better understand the technical solutions in the present application, the present application will be clearly and completely described below with reference to specific embodiments, and it is obvious that the described embodiments are only a part of the embodiments of the present application, and not all embodiments. All other embodiments obtained by a person of ordinary skill in the art based on the embodiments in the present application without making any creative effort shall fall within the protection scope of the present application.
The invention provides a preparation method of 5- (alpha-halogenated butyryl) -8-hydroxyquinoline-2-ketone, which comprises the following steps:
step 1: in the presence of an acid-binding agent, carrying out acylation reaction on 8-hydroxyquinoline-2-ketone shown in a formula (I) and an acylating agent shown in a formula (II) to obtain 8- (alpha-halogenated butyryloxy) -quinoline-2-ketone shown in a formula (III);
step 2: carrying out rearrangement reaction on 8- (alpha-halogenated butyryloxy) -quinoline-2-ketone in methanesulfonic acid to obtain 5- (alpha-halogenated butyryl) -8-hydroxyquinoline-2-ketone shown as a formula (IV);
preferably, the molar ratio of 8-hydroxyquinolin-2-one to acylating agent is 1 (1-1.5).
Preferably, the molar ratio of 8- (. Alpha. -halobutyryloxy) -quinolin-2-one to methanesulfonic acid is from about 1 (5) to about 15.
Preferably, the acylating agent comprises one or more of 2-chlorobutyryl chloride, 2-bromobutyryl chloride, 2-chlorobutyryl bromide and 2-bromobutyryl bromide.
Preferably, the acid-binding agent comprises one or more of trimethylamine, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, imidazole and 2-methylimidazole.
Preferably, step 1 specifically comprises: dispersing 8-hydroxyquinoline-2-ketone in an inert solvent, adding an acylating agent and an acid-binding agent, reacting for a period of time at 20-60 ℃, and cooling to room temperature; washing with water, filtering and drying to obtain 8- (alpha-halogenated butyryloxy) -quinoline-2-ketone.
The effect of the water wash here is: 1. hydrolyzing to break the bond of the excess acylating agent to the product; 2. hydrolyzing the excess acylating agent to carboxylic acid; 3. excess carboxylic acid (carboxylic acid dissolved in water) is removed.
Preferably, in step 1, after the filtration is completed, the filter cake is washed with an appropriate amount of water. The effect of the washing here is: (1) removing mother liquor in the filter cake, and (2) removing impurities adsorbed by the mother liquor and the filter cake.
Preferably, step 2 specifically comprises: putting 8- (alpha-halogenated butyryloxy) -quinoline-2-ketone into methanesulfonic acid, reacting at 20-65 ℃ for a period of time, and cooling to room temperature; then, pouring into water for hydrolysis, filtering and drying to obtain the 5- (alpha-halogenated butyryl) -8-hydroxyquinoline-2-ketone.
In the step 2, heat is released in the hydrolysis process, and as the product is sensitive to temperature, generally, the water temperature is higher, the impurities are increased along with the decomposition of the product in the hydrolysis process. To avoid this, the hydrolysis process may be carried out in cold water.
The purpose of the hydrolysis is to hydrolyze the methanesulfonic acid and product complex and then separate them by water.
Preferably, step 2 specifically comprises: putting 8- (alpha-halogenated butyryloxy) -quinoline-2-ketone into methanesulfonic acid, reacting at 20-65 ℃ for a period of time, and cooling to room temperature; then, pouring into cold water for hydrolysis, filtering and drying to obtain the 5- (alpha-halogenated butyryl) -8-hydroxyquinoline-2-ketone.
Preferably, the temperature of the cold water is-10-10 ℃.
Preferably, the temperature of the cold water is 0-10 ℃.
Preferably, in step 2, the hydrolysis, filtration, drying, etc. may be repeated.
Preferably, in step 2, after the filtration is completed, the filter cake is washed with an appropriate amount of water. The effect of the washing here is: (1) removing mother liquor in the filter cake, and (2) removing impurities adsorbed by the mother liquor and the filter cake.
Preferably, the inert solvent comprises one or more of dichloromethane, dichloroethane, trichloromethane, carbon tetrachloride, carbon disulfide, nitrobenzene and nitromethane.
Preferably, in the step 1, the reaction temperature is 35-45 ℃; more preferably 40 deg.c.
Preferably, in the step 2, the reaction temperature is 45-55 ℃; more preferably 50 deg.c.
Preferably, in step 1, the reaction time is 1 to 6 hours.
Preferably, in step 2, the reaction time is 1 to 4 hours.
In the examples of the present invention, 8-hydroxyquinolin-2-one was supplied from An Naiji chemical company, 2-bromobutyryl bromide and methanesulfonic acid were supplied from Shandong West Asia chemical company, and the remaining raw materials were either analytically pure or chemically pure or self-made.
Example 1:8- (alpha-chlorobutyryloxy) -quinolin-2-ones
16.1g (0.10 mol) of 8-hydroxyquinoline-2-ketone is put into 150ml of anhydrous dichloromethane, 34.6g (0.30 mol) of diisopropylethylamine is added, 15.5g (0.11 mol) of 2-chlorobutyryl chloride is slowly dropped at room temperature, the temperature is maintained at 40 ℃ after the addition is finished, the stirring is carried out for 4h, 200ml of water is added, the stirring is carried out for 0.5h, the mixed solution is directly filtered, the filter cake is washed by proper amount of water, and the filter cake is dried in vacuum at 50 ℃ to obtain 24.7g of white powder, wherein the yield is 93.0%.
Example 2:8- (alpha-bromobutyryloxy) -quinolin-2-one
16.1g (0.10 mol) of 8-hydroxyquinoline-2-ketone is put into 150ml of anhydrous dichloromethane, 17.7g (0.30 mol) of triethylamine is added, 25.3g (0.11 mol) of 2-bromobutyryl bromide is slowly dropped at room temperature, the temperature is maintained at 40 ℃ and stirred for 4h after the addition is finished, 200ml of water is added and stirred for 0.5h, the mixed solution is directly filtered, the filter cake is washed by proper amount of water and is dried in vacuum at 50 ℃ to obtain 25.5g of white powder, and the yield is 82.2%.
Example 3:5- (alpha-chlorobutyryl) -8-hydroxyquinolin-2-one
Adding 13.3g (0.05 mol) of 8- (alpha-chlorobutyryloxy) -quinoline-2-ketone into 38.4g (0.4 mol) of anhydrous methanesulfonic acid, heating to 50 ℃, stirring for reaction for 2 hours, cooling to room temperature, pouring into 200ml of cold water, stirring for 0.5 hour, filtering, washing a filter cake with a proper amount of water, and draining. The filter cake is put into 200ml cold water again and stirred for 2 hours, filtered, the filter cake is washed by proper amount of water and dried to obtain 8.8g of light yellow powder with yield of 66.2 percent.
Example 4:5- (alpha-bromobutyryl) -8-hydroxyquinolin-2-one
Adding 15.5g (0.05 mol) of 8- (alpha-bromo-butyryloxy) -quinoline-2-ketone into 38.4g (0.4 mol) of anhydrous methanesulfonic acid, heating to 50 ℃, stirring for reacting for 2 hours, cooling to room temperature, pouring into 200ml of cold water, stirring for 0.5 hour, filtering, washing a filter cake with proper amount of water, and draining. The filter cake was put into 200ml of cold water again and stirred for 2 hours, filtered, and the filter cake was washed with an appropriate amount of water and dried to obtain 9.1g of pale yellow powder with a yield of 58.7%.
1 HNMR(400MHz,MeOH-d4)δ:8.73(d,J＝10Hz,1H),7.81(d,J＝8.4Hz,1H),7.04(d,J＝8.4Hz,1H),6.73(d,J＝10Hz,1H),5.38(t,1H),2.15(m,2H),1.08(t,3H)。
According to a nuclear magnetic resonance hydrogen spectrogram, d8.73 and 6.73 are adjacent hydrogen, d7.81 and 7.04 are adjacent hydrogen, one group of hydrogen belongs to a benzene ring, the other group of hydrogen belongs to a nitrogen heterocyclic ring, the active hydroxyl and amino hydrogen are replaced by methanol without signals, and the displacement of three groups of hydrogen atoms of the halogenated butyryl group conforms to the rule. Since the benzene ring of the test substance has only two adjacent hydrogens, and the starting material and the intermediate have three benzene ring hydrogens, the product can be excluded from being the raw material or the intermediate.
The content of 5- (alpha-bromo-butyryl) -8-hydroxyquinoline-2-ketone in the product is detected as follows: 97.26% (HPLC normalization method).
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (8)
1. A method for preparing 5- (α -halobutyryl) -8-hydroxyquinolin-2-one, comprising the steps of:
step 1: in the presence of an acid-binding agent, carrying out acylation reaction on 8-hydroxyquinoline-2-ketone shown in a formula (I) and an acylating agent shown in a formula (II) to obtain 8- (alpha-halogenated butyryloxy) -quinoline-2-ketone shown in a formula (III);
step 2: carrying out rearrangement reaction on the 8- (alpha-halogenated butyryloxy) -quinoline-2-ketone in methanesulfonic acid to obtain 5- (alpha-halogenated butyryl) -8-hydroxyquinoline-2-ketone shown as a formula (IV);
wherein the molar ratio of the 8-hydroxyquinolin-2-one to the acylating agent is 1 (1-1.5);
the molar ratio of the 8- (alpha-halogenated butyryloxy) -quinoline-2-ketone to the methanesulfonic acid is 1 (5-15).
2. The preparation method of claim 1, wherein the acylating agent comprises one or more of 2-chlorobutyryl chloride, 2-bromobutyryl chloride, 2-chlorobutyryl bromide and 2-bromobutyryl bromide.
3. The preparation method of claim 1, wherein the acid-binding agent comprises one or more of trimethylamine, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, imidazole and 2-methylimidazole.
4. The method according to any one of claims 1 to 3, wherein step 1 is specifically: dispersing the 8-hydroxyquinoline-2-ketone in an inert solvent, adding the acylating agent and the acid-binding agent, reacting for a period of time at the temperature of 20-60 ℃, and cooling to room temperature;
washing with water, filtering and drying to obtain the 8- (alpha-halogenated butyryloxy) -quinoline-2-ketone.
5. The preparation method according to claim 4, wherein the step 2 is specifically: putting the 8- (alpha-halogenated butyryloxy) -quinoline-2-ketone into methanesulfonic acid, reacting at 20-65 ℃ for a period of time, and cooling to room temperature;
then, pouring into water for hydrolysis, filtering and drying to obtain the 5- (alpha-halogenated butyryl) -8-hydroxyquinoline-2-ketone.
6. The method of claim 4, wherein the inert solvent comprises one or more of dichloromethane, dichloroethane, chloroform, carbon tetrachloride, carbon disulfide, nitrobenzene, and nitromethane.
7. The method according to claim 5, wherein in the step 1, the reaction temperature is 35-45 ℃;
in the step 2, the reaction temperature is 45-55 ℃.
8. The method according to claim 7, wherein in the step 1, the reaction temperature is 40 ℃;
in the step 2, the reaction temperature is 50 ℃.
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