CN109879815B - 2-bromo-6-aldehyde pyridine and preparation method thereof - Google Patents
2-bromo-6-aldehyde pyridine and preparation method thereof Download PDFInfo
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Abstract
The invention provides 2-bromo-6-aldehyde pyridine and a preparation method thereof, wherein the preparation method comprises the following steps: step S1, liquid bromine is dripped into the organic solution of the 2-bromine-6-methylpyridine to react to generate a mixture of the 2-bromine-6-bromomethylpyridine and the 2-bromine-6- (dibromomethyl) pyridine; step S2, adding the mixture into ethanol, adding urotropin into the ethanol, and reacting the mixture to obtain 2-bromo-6-formylpyridine; and step S3, adding acid into the reaction system to perform hydrolysis reaction to generate the 2-bromo-6-aldehyde pyridine. According to the preparation method of the 2-bromo-6-aldehyde pyridine, provided by the embodiment of the invention, a product with high purity can be obtained, and the method is safe, easy to process, simple in process and suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to 2-bromo-6-aldehyde pyridine and a preparation method thereof.
Background
2-bromo-6-aldehyde pyridine is an effective structural unit of tri [ (pyridyl) methyl ] amine ligand and is a very important organic intermediate.
At present, the preparation method of 2-bromo-6-aldehyde pyridine mainly comprises the following methods:
the method comprises the following steps: the 2-amino-6-methylpyridine is subjected to diazotization, bromination, hydrolysis and other steps of reactions, the method has many steps, many byproducts and low yield, and the diazotization reaction has risks, so that the method is not suitable for large-scale production.
The second method comprises the following steps: the 2, 6-dibromopyridine reacts with n-butyl lithium at the temperature of-78 ℃, the operation is not easy due to low temperature control, the use of n-butyl lithium is very dangerous, the purification needs to pass through a chromatographic column, the efficiency is low, the yield is low, and the industrial production is difficult.
The third method comprises the following steps: the 2-bromo-6-methylpyridine is oxidized by selenium dioxide, the oxidation degree of the method is not well controlled, the selenium dioxide can be further oxidized into acid, the yield is low, and the selenium dioxide is a highly toxic product and is not a preferred scheme.
Therefore, there is a high necessity to solve this problem.
Disclosure of Invention
In view of the above, the invention provides a preparation method of 2-bromo-6-aldehyde pyridine, which is safe, easy to process, simple in process and suitable for industrial production.
The invention also provides 2-bromo-6-aldehyde pyridine.
In order to solve the technical problems, the invention adopts the following technical scheme:
the preparation method of the 2-bromo-6-aldehyde pyridine according to the embodiment of the first aspect of the invention comprises the following steps:
step S1, adding 2-bromo-6-methylpyridine into a mixed solution of dichloromethane and water, cooling to 10-20 ℃ in an ice water bath, dropwise adding the liquid bromine at the temperature, heating to 40-60 ℃ after dropwise adding, and reacting for 8-12h to generate a mixture of 2-bromo-6-bromomethylpyridine and 2-bromo-6- (dibromomethyl) pyridine, wherein the molar ratio of the 2-bromo-6-methylpyridine to the liquid bromine is 1: 3;
step S2, adding the mixture into ethanol, adding urotropin into the ethanol, reacting the mixture to obtain a compound with a structural formula shown in the following formula,
and step S3, adding acid into the reaction system to perform hydrolysis reaction to generate the 2-bromo-6-aldehyde pyridine.
Wherein, preferably, the molar ratio of the 2-bromo-6-methylpyridine to the liquid bromine is 1: 3.
Preferably, the molar ratio of the 2-bromo-6-methylpyridine to the urotropin is 1: 2.
Further, the step S1 may further include:
after the reaction was completed, the pH was adjusted to 7 to 8, and thereafter, extraction was performed to obtain the mixture.
Preferably, the molar ratio of 2-bromo-6-bromomethylpyridine and 2-bromo-6- (dibromomethyl) pyridine in the mixture is 6: 1.
According to some embodiments of the present invention, the reaction temperature in the step S2 is 30-50 ℃ and the reaction time is 10-14 h.
According to some embodiments of the present invention, in the step S3, the reaction temperature is 80-100 ℃, the reaction time is 3-5h, and the acid in the step S3 is acetic acid and concentrated sulfuric acid.
According to some embodiments of the invention, the method of preparing further comprises the steps of:
step S4, after the reaction is finished, cooling to 0-10 ℃, carrying out suction filtration, washing a filter cake, and then adding ethanol: recrystallization was carried out with water at a ratio of 9:1 to obtain purified 2-bromo-6-formylpyridine.
The 2-bromo-6-formylpyridine according to the embodiment of the second aspect of the present invention is the 2-bromo-6-formylpyridine prepared by the preparation method according to any one of the above.
The technical scheme of the invention has at least one of the following effects:
(1) no use of very dangerous or virulent drugs;
(2) the experimental operation is simple and easy to process, and the industrial production can be realized;
(3) the three wastes are less, and the pollution to the environment is reduced.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the drawings of the embodiments of the present invention. It is to be understood that the embodiments described are only a few embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the described embodiments of the invention, are within the scope of the invention.
The method for preparing 2-bromo-6-formylpyridine according to the embodiment of the present invention will be described first.
The preparation method of the 2-bromo-6-aldehyde pyridine comprises the following steps:
step S1, liquid bromine is added dropwise to the organic solution of 2-bromo-6-methylpyridine to react, and a mixture of 2-bromo-6-bromomethylpyridine and 2-bromo-6- (dibromomethyl) pyridine is produced.
The reaction formula is shown as the following formula (1):
wherein the molar ratio of the 2-bromo-6-methylpyridine to the liquid bromine is preferably 1: 3.
The step S1 may include:
step S11, adding 2-bromo-6-methylpyridine into the mixed solution of dichloromethane and water, cooling to 10-20 ℃ in an ice water bath, dropwise adding the liquid bromine at the temperature, heating to 40-60 ℃ after dropwise adding, and reacting for 8-12 h.
Further, the step S1 may further include:
and step S12, after the reaction is finished, adjusting the pH value to 7-8, and extracting to obtain the mixture.
Preferably, the molar ratio of 2-bromo-6-bromomethylpyridine and 2-bromo-6- (dibromomethyl) pyridine in the mixture is 6: 1.
Specifically, for example, a sodium bicarbonate solution can be used to adjust the pH.
Step S2, adding the mixture into ethanol, adding urotropin into the ethanol, reacting the mixture to obtain a compound with a structural formula shown in the following formula,
the reaction formula is shown as the following formula (2):
wherein the molar ratio of the 2-bromo-6-methylpyridine to the urotropin may be, for example, 1: 2. This ratio enables the 2-bromo-6-bromomethylpyridine to react completely.
The reaction temperature in the step S2 is 30-50 ℃, the reaction time is 10-14h, preferably the reaction temperature is 40 ℃, the reaction time is 12h, and the reaction effect is the best.
And step S3, adding acid into the reaction system to perform hydrolysis reaction to generate the 2-bromo-6-aldehyde pyridine.
The reaction formula is shown as the following formula (3):
the acid in step S3 may be a mixture of acetic acid and concentrated sulfuric acid.
Further, in the step S3, the reaction temperature may be, for example, 80 to 100 ℃, and the reaction time may be, for example, 3 to 5 hours, and preferably, the hydrolysis may be completed at a hydrolysis temperature of 90 ℃ and a reaction time of 4 hours.
The preparation method according to the embodiment of the invention can further comprise the following steps:
and step S4, after the reaction is finished, cooling to 0-10 ℃, preferably cooling to 5 ℃ to precipitate a solid, then carrying out suction filtration, washing a filter cake, and then using ethanol: recrystallizing with water of 9:1 to obtain the purified 2-bromo-6-aldehyde pyridine with high purity.
According to the preparation method of the 2-bromo-6-aldehyde pyridine provided by the embodiment of the invention, the use of dangerous or extremely toxic medicines is avoided, the safety is improved, the experimental operation is simple and easy to process, the industrial production can be realized, the yield is high, the three wastes are less, and the environmental protection pressure is reduced.
In order to make the technical solution of the present invention better understood by those skilled in the art, the present invention is further described in detail with reference to the following examples.
Example 1:
(1) preparation of a mixture of the compounds 2-bromo-6-bromomethylpyridine and 2-bromo-6- (dibromomethyl) pyridine
Adding 2-bromo-6-methylpyridine (17.2g, 0.1mol, 1.0eq) and dichloromethane (34.4mL, 2P) and water (34.4mL, 2P) into a 250mL reaction bottle, cooling to 10 ℃ in an ice water bath, rapidly stirring, dropwise adding liquid bromine (48g, 0.3mol, 3.0eq), controlling the temperature to be 10-20 ℃, heating to 50 ℃ after dropwise adding, and reacting for 10 hours.
After cooling to room temperature, aqueous sodium bicarbonate was added to adjust the pH to 7-8, the aqueous phase was separated, extracted with dichloromethane (34.4mL, 2P), and the organic phases were combined, washed with saturated brine (34.4mL, 2P), dried over anhydrous sodium sulfate, filtered with suction, and concentrated to dryness to give 21.9g of a mixture of 2-bromo-6-bromomethylpyridine and 2-bromo-6- (dibromomethyl) pyridine.
Liquid phase detection shows that the ratio of 2-bromo-6-bromomethylpyridine to 2-bromo-6- (dibromomethyl) pyridine is 6: 1.
(2) Preparation of compound 2-bromo-6-aldehyde pyridine
A mixture of 2-bromo-6-bromomethylpyridine and 2-bromo-6- (dibromomethyl) pyridine (21.9g, theoretical molar amount 0.1mol, 1eq), and urotropin (28.04g, 0.2mol, 2.0eq) were added to ethanol (87mL, 4P), and heated to 40 ℃ for 12 hours.
Thereafter, the reaction mixture was cooled to room temperature, acetic acid (44mL, 2P) and concentrated sulfuric acid (3mL, 0.137P) were added thereto, the mixture was heated to 90 ℃ for 4 hours to react, the reaction mixture was cooled to 5 ℃ and filtered with suction, and the filter cake was washed with isopropyl ether to give 14.8g of a yellow solid.
The solid was recrystallized from ethanol (14.8 mL)/water (1.64mL) to give 12.1g of an off-white solid with a melting point of 77.8-79.2 ℃ and a liquid phase of 98.8% in 65% overall yield over two steps.
The reaction product was subjected to nmr experiments to confirm the structure of the product, and the data are as follows:
1H NMR (model: AVANCE III HD 400M, MeOD, 400MHz) at δ of 10.01(s, 1H), 7.942-7.921(M, 1H), 7.282-7.119(M, 2H), and the results of the measurements were in agreement with literature values.
Example 2:
(1) preparation of a mixture of the compounds 2-bromo-6-bromomethylpyridine and 2-bromo-6- (dibromomethyl) pyridine
Adding 2-bromo-6-methylpyridine (86g, 0.5mol, 1.0eq) and dichloromethane (172mL, 2P) and water (172mL, 2P) into a 1L reaction bottle, cooling to 10 ℃ in an ice water bath, rapidly stirring, dropwise adding liquid bromine (240g, 1.5mol, 3.0eq), controlling the temperature to be 10-20 ℃, heating to 50 ℃ after dropwise adding, and reacting for 10 hours.
Thereafter, the mixture was cooled to room temperature, an aqueous solution of sodium hydrogen carbonate was added to adjust the pH to 7 to 8, the aqueous phase was separated and extracted with methylene chloride (172mL, 2P), and the organic phase was combined, washed with a saturated saline solution (172mL, 2P), dried over anhydrous sodium sulfate, filtered with suction, and concentrated to dryness to give 110.8g of a mixture of 2-bromo-6-bromomethylpyridine and 2-bromo-6- (dibromomethyl) pyridine.
Liquid phase detection shows that the ratio of 2-bromo-6-bromomethylpyridine to 2-bromo-6- (dibromomethyl) pyridine is 6: 1.
(2) Preparation of compound 2-bromo-6-aldehyde pyridine
A mixture of 2-bromo-6-bromomethylpyridine and 2-bromo-6- (dibromomethyl) pyridine (110.8g, theoretical molar weight 0.5mol, 1eq), and urotropin (140.2g, 1.0mol, 2.0eq) were added to ethanol (435mL, 4P), and heated to 40 ℃ for 12 hours.
After that, after cooling to room temperature, acetic acid (220mL, 2P) and concentrated sulfuric acid (15mL, 0.137P) were added, and the mixture was heated to 90 ℃ to react for 4 hours, cooled to 5 ℃ and filtered with suction, and the filter cake was washed with isopropyl ether to obtain 75.3g of a yellow solid. The solid was recrystallized from ethanol (75.3 mL)/water (8.37mL) to give 62.3g of an off-white solid with a melting point of 78.9-80.2 deg.C, a liquid phase of 99.0%, and a total yield in two steps of 67%.
The reaction product was subjected to nmr experiments to confirm the structure of the product, and the data are as follows:
1H NMR (model: AVANCE III HD 400M, MeOD, 400MHz): delta-10.008 (s, 1H), 7.938-7.918(M, 1H), 7.290-7.113(M, 2H), and the detection results were in agreement with literature values.
Example 3:
(1) preparation of a mixture of the compounds 2-bromo-6-bromomethylpyridine and 2-bromo-6- (dibromomethyl) pyridine
Adding 2-bromo-6-methylpyridine (172g, 1.0mol, 1.0eq) and dichloromethane (344mL, 2P) and water (344mL, 2P) into a 2L reaction bottle, cooling to 10 ℃ in an ice water bath, rapidly stirring, dropwise adding liquid bromine (480g, 3.0mol, 3.0eq), controlling the temperature to be 10-20 ℃, heating to 50 ℃ after dropwise adding, and reacting for 10 hours.
Thereafter, the mixture was cooled to room temperature, the pH was adjusted to 7 to 8 by the addition of an aqueous solution of sodium hydrogen carbonate, the aqueous phase was separated and extracted with methylene chloride (344mL, 2P), and the organic phases were combined, washed with a saturated brine (344mL, 2P), dried over anhydrous sodium sulfate, filtered with suction, and concentrated to dryness to give 220.5g of a mixture of 2-bromo-6-bromomethylpyridine and 2-bromo-6- (dibromomethyl) pyridine.
Liquid phase detection shows that the ratio of 2-bromo-6-bromomethylpyridine to 2-bromo-6- (dibromomethyl) pyridine is 6: 1.
(2) Preparation of compound 2-bromo-6-aldehyde pyridine
A mixture of 2-bromo-6-bromomethylpyridine and 2-bromo-6- (dibromomethyl) pyridine (220.5g, theoretical molar weight 1.0mol, 1eq), and urotropin (280.4g, 2.0mol, 2.0eq) were added to ethanol (870mL, 4P), and heated to 40 ℃ for 12 hours.
After that, after cooling to room temperature, acetic acid (440mL, 2P) and concentrated sulfuric acid (30mL, 0.137P) were added, and the mixture was heated to 90 ℃ to react for 4 hours, cooled to 5 ℃ and filtered with suction, and the filter cake was washed with isopropyl ether to obtain 149.8g of a yellow solid. The solid was recrystallized from ethanol (150 mL)/water (16.7mL) to give 123.4g of an off-white solid with a melting point of 78.5-80.1 deg.C, a liquid phase of 98.7% and a total yield of 66% over two steps.
The reaction product was subjected to nmr experiments to confirm the structure of the product, and the data are as follows:
1H NMR (model: AVANCE III HD 400M, MeOD, 400MHz): delta-10.013 (s, 1H), 7.923-7.909(M, 1H), 7.285-7.103(M, 2H), and the detection results were in agreement with literature values.
While the foregoing is directed to the preferred embodiment of the present invention, it will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention as defined in the appended claims.
Claims (6)
1. A preparation method of 2-bromo-6-aldehyde pyridine is characterized by comprising the following steps:
step S1, adding 2-bromo-6-methylpyridine into a mixed solution of dichloromethane and water, cooling to 10-20 ℃ in an ice water bath, dropwise adding the liquid bromine at the temperature, heating to 40-60 ℃ after dropwise adding, and reacting for 8-12h to generate a mixture of 2-bromo-6-bromomethylpyridine and 2-bromo-6- (dibromomethyl) pyridine, wherein the molar ratio of the 2-bromo-6-methylpyridine to the liquid bromine is 1: 3;
step S2, adding the mixture into ethanol, adding urotropin into the ethanol, reacting the mixture to obtain a compound with a structural formula shown in the following formula,
the molar ratio of the 2-bromo-6-methylpyridine to the urotropine is 1: 2;
and step S3, adding acid into the reaction system to perform hydrolysis reaction to generate the 2-bromo-6-aldehyde pyridine.
2. The method for preparing 2-bromo-6-aldehydic pyridine according to claim 1, wherein said step S1 further comprises:
after the reaction was completed, the pH was adjusted to 7 to 8, and thereafter, extraction was performed to obtain the mixture.
3. The method for preparing 2-bromo-6-aldehyde pyridine according to claim 2, wherein the molar ratio of 2-bromo-6-bromomethylpyridine to 2-bromo-6- (dibromomethyl) pyridine in the mixture is 6: 1.
4. The method for preparing 2-bromo-6-aldehydic pyridine according to claim 1, wherein the reaction temperature in step S2 is 30-50 ℃ and the reaction time is 10-14 h.
5. The method for preparing 2-bromo-6-formylpyridine as claimed in claim 1, wherein the reaction temperature is 80-100 ℃ and the reaction time is 3-5h in step S3, and the acid in step S3 is acetic acid and concentrated sulfuric acid.
6. The method of preparing 2-bromo-6-aldehydic pyridines according to claim 1, characterized by the further steps of:
step S4, after the reaction is finished, cooling to 0-10 ℃, carrying out suction filtration, washing a filter cake, and then adding ethanol: recrystallization was carried out with water at a ratio of 9:1 to obtain purified 2-bromo-6-formylpyridine.
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