Synthesis method of pyridine drug intermediate

Abstract

The invention relates to a synthetic method of a pyridine drug intermediate. The synthetic method sequentially comprises the following steps: step S1, preparing 2-amino-5-bromopyridine from 2-aminopyridine; step S2, a step of preparing 2, 5-dibromopyridine from the 2-amino-5-bromopyridine; and step S3, a step of preparing the 2-bromo-5-iodopyridine from the 2, 5-dibromopyridine. 2-aminopyridine is used as a raw material, the raw material is easy to obtain, the cost is low, and the industrialization prospect is good; the method has the advantages of mild reaction conditions, high yield and few by-products in the reaction process, and can meet the requirements of industrial batch production.

Description

Technical Field

[0001] The present invention relates to the technical field related to the preparation of pyridine compounds, and in particular to a method for synthesizing a pyridine drug intermediate. Background Art

[0002] Pyridine and its derivatives are widely distributed in nature. Many plant components, such as alkaloids, contain pyridine ring compounds in their structures. They are the basis for the production of many important compounds and are indispensable raw materials in the production of medicines, pesticides, dyes, surfactants, rubber additives, feed additives, food additives, adhesives, etc.

[0003] 2,5-Dibromopyridine, English name 2,5-Dibromopyridine, is a light brown crystalline solid at room temperature and pressure. It is insoluble in water and soluble in highly polar organic solvents. 2,5-Dibromopyridine is a pyridine derivative with significant alkalinity. It is a common organic synthesis and pharmaceutical chemical reagent, mostly used in basic chemical research and the production of pyridine pesticide molecules.

[0004] 2,5-Dibromopyridine can be used as an organic synthesis reagent, and is often used in basic chemical research and pyridine drug molecular modification. The bromine atom in its structure can be easily arylated and alkylated through various metal-catalyzed coupling reactions to obtain the corresponding pyridine derivatives. The existing preparation of 2,5-pyridine compounds is generally through bromination and diazotization reactions, which has the disadvantages of high cost and low efficiency, which is not conducive to the needs of industrial mass production.

[0005] In view of the above-mentioned defects, the designers actively carried out research and innovation in order to create a synthesis method for pyridine drug intermediates to make them more valuable for industrial use. Summary of the invention

[0006] In order to solve the above technical problems, the purpose of the present invention is to provide a method for synthesizing a pyridine drug intermediate.

[0007] To achieve the above object, the present invention adopts the following technical solution:

[0008] A method for synthesizing a pyridine drug intermediate comprises the following steps in sequence:

[0009] Step S1, the step of preparing 2-amino-5-bromopyridine by 2-aminopyridine:

[0010] Step S11, adding 2-aminopyridine into a reaction container, and then adding acetic anhydride, heating to reflux for 2-6 hours after the addition, and detecting the reaction to be complete by thin layer chromatography;

[0011] Step S12, cooling the reaction liquid in the reaction container in the above step S11 to 15-20 degrees Celsius, then adding liquid bromine into the reaction container and stirring, heating at 50-60 degrees Celsius for 2-3 hours;

[0012] Step S13, adding pure water to the reaction container in the above step S12 until all the solids are dissolved for 0.5 to 1 hour, then adding sodium hydroxide solution to the reaction container and reacting for 0.5 to 1 hour, then adding catalyst 1 to the reaction container and continuing the reaction;

[0013] Step S14, subjecting the precipitate after the reaction in the reaction container in the above step S13 to sedimentation centrifugation in ethanol, and then drying and recrystallizing to obtain 2-amino-5-bromopyridine;

[0014] Step S2, the step of preparing 2,5-dibromopyridine by 2-amino-5-bromopyridine:

[0015] Step S21, adding the 2-amino-5-bromopyridine obtained in the above step S1 to water cooled to 5 to 10 degrees Celsius, and then adding an aqueous solution of hydrogen bromide thereto;

[0016] Step S22, adding liquid bromine to the mixed solution of step S21, and then adding sodium nitrite aqueous solution dropwise to the mixed solution;

[0017] Step S23, the reaction mixture of the above step S22 is continued to be stirred for 0.5 to 1 hour, the mixture is treated with an aqueous sodium hydroxide solution, and then the reaction mixture is extracted with diethyl ether, the organic layer is separated and dried over anhydrous sodium sulfate, the desiccant is filtered to remove the desiccant, and the solvent of the obtained filtrate is evaporated under reduced pressure;

[0018] Step S24, suspending the residue obtained in the above step S23 in heptane, filtering and collecting the residue to obtain the target product molecule 2,5-dibromopyridine;

[0019] Step S3, the step of preparing 2-bromo-5-iodopyridine by 2,5-dibromopyridine:

[0020] Step S31, slowly drop n-butyl lithium into the dry ether solution of 2,5-dibromopyridine obtained in the above step S2 at -80 to -50 degrees Celsius under argon protection, and stir the reaction for 0.5 to 1 hour;

[0021] Step S32, adding iodine ether solution to the reaction solution in the above step S31, then stirring the reaction for 2 to 3 hours, and then slowly heating to -40 to -30 degrees Celsius;

[0022] Step S33, quenching the reaction solution of the above step S32 with a saturated sodium sulfite solution, then extracting the reaction with ether, separating the organic layer and washing the obtained organic layer with brine;

[0023] Step S34, drying the organic layer obtained in the above step S33 with anhydrous magnesium sulfate, filtering and evaporating the filtrate, and separating and purifying the obtained residue by a chromatographic column to obtain 2-bromo-5-iodopyridine.

[0024] As a further improvement of the present invention, the molar ratio of 2-aminopyridine to acetic anhydride in step S11 is 1:1 to 1:2.

[0025] As a further improvement of the present invention, the catalyst 1 in step S13 is potassium carbonate.

[0026] As a further improvement of the present invention, the drying temperature in step S14 is 60 to 80 degrees Celsius.

[0027] As a further improvement of the present invention, the mass percentage of the aqueous hydrogen bromide solution in step S21 is 47%.

[0028] As a further improvement of the present invention, liquid bromine is added to the mixed solution in step S21, and the temperature of the reaction mixture is maintained at 0 to 10 degrees Celsius; an aqueous sodium nitrite solution is added dropwise to the mixed solution, and the reaction temperature is maintained at 0 to 5 degrees Celsius.

[0029] As a further improvement of the present invention, the reaction mixture in step S22 is continuously stirred and reacted for 0.5 to 1 hour at a reaction temperature of 20 to 25 degrees Celsius.

[0030] As a further improvement of the present invention, the chromatographic column in step S34 is a Sephadex LH-20 chromatographic column, 100mmX4.0mm, 3μm, column temperature 40 degrees Celsius, injection volume 5μL; mobile phase A is petroleum ether, mobile phase B is ethyl acetate, and isogradient elution is performed with an A:B phase volume ratio of 80:20.

[0031] By means of the above scheme, the present invention has at least the following advantages:

[0032] The present invention uses 2-aminopyridine as a raw material, the raw material is easy to obtain, the cost is low, and the industrialization prospect is good;

[0033] The reaction conditions of the present invention are relatively mild, the yield is high, and the by-products in the reaction process are relatively small, and the method can be applied to the needs of industrial batch production.

[0034] The above description is only an overview of the technical solution of the present invention. In order to more clearly understand the technical means of the present invention and implement it according to the contents of the specification, the preferred embodiments of the present invention are described in detail as follows. DETAILED DESCRIPTION

[0035] The following examples are used to illustrate the present invention, but are not intended to limit the scope of the present invention.

[0036] In order to make those skilled in the art better understand the scheme of the present invention, the technical scheme in the embodiment of the present invention will be clearly and completely described below in conjunction with the embodiment of the present invention. Obviously, the described embodiment is only a part of the embodiment of the present invention, rather than all the embodiments. The components of the embodiment of the present invention generally shown here can be arranged and designed in various configurations. Therefore, the following detailed description of the embodiment of the present invention is not intended to limit the scope of the invention claimed for protection, but merely represents the selected embodiment of the present invention. Based on the embodiment of the present invention, all other embodiments obtained by those skilled in the art without making creative work belong to the scope of protection of the present invention.

[0037] A method for synthesizing a pyridine drug intermediate comprises the following steps in sequence:

[0038] Step S1, the step of preparing 2-amino-5-bromopyridine by 2-aminopyridine:

[0039] Step S11, adding 2-aminopyridine into a reaction container, and then adding acetic anhydride, heating to reflux for 2-6 hours after the addition, and detecting the reaction to be complete by thin layer chromatography;

[0040] Step S12, cooling the reaction liquid in the reaction container in the above step S11 to 15-20 degrees Celsius, then adding liquid bromine into the reaction container and stirring, heating at 50-60 degrees Celsius for 2-3 hours;

[0041] Step S13, adding pure water to the reaction container in the above step S12 until all the solids are dissolved for 0.5 to 1 hour, then adding sodium hydroxide solution to the reaction container and reacting for 0.5 to 1 hour, then adding catalyst 1 to the reaction container and continuing the reaction;

[0042] Step S14, subjecting the precipitate after the reaction in the reaction container in the above step S13 to sedimentation centrifugation in ethanol, and then drying and recrystallizing to obtain 2-amino-5-bromopyridine;

[0043] Step S2, the step of preparing 2,5-dibromopyridine by 2-amino-5-bromopyridine:

[0044] Step S21, adding the 2-amino-5-bromopyridine obtained in the above step S1 to water cooled to 5 to 10 degrees Celsius, and then adding an aqueous solution of hydrogen bromide thereto;

[0045] Step S22, adding liquid bromine to the mixed solution of step S21, and then adding sodium nitrite aqueous solution dropwise to the mixed solution;

[0046] Step S23, the reaction mixture of the above step S22 is continued to be stirred for 0.5 to 1 hour, the mixture is treated with an aqueous sodium hydroxide solution, and then the reaction mixture is extracted with diethyl ether, the organic layer is separated and dried over anhydrous sodium sulfate, the desiccant is filtered to remove the desiccant, and the solvent of the obtained filtrate is evaporated under reduced pressure;

[0047] Step S24, suspending the residue obtained in the above step S23 in heptane, filtering and collecting the residue to obtain the target product molecule 2,5-dibromopyridine;

[0048] Step S3, the step of preparing 2-bromo-5-iodopyridine by 2,5-dibromopyridine:

[0049] Step S31, slowly drop n-butyl lithium into the dry ether solution of 2,5-dibromopyridine obtained in the above step S2 at -80 to -50 degrees Celsius under argon protection, and stir the reaction for 0.5 to 1 hour;

[0050] Step S32, adding iodine ether solution to the reaction solution in the above step S31, and then stirring the reaction for 2 to 3 hours, and then slowly heating to -40 to -30 degrees Celsius;

[0051] Step S33, quenching the reaction solution of the above step S32 with a saturated sodium sulfite solution, then extracting the reaction with ether, separating the organic layer and washing the obtained organic layer with brine;

[0052] Step S34, drying the organic layer obtained in the above step S33 with anhydrous magnesium sulfate, filtering and evaporating the filtrate, and separating and purifying the obtained residue by a chromatographic column to obtain 2-bromo-5-iodopyridine.

[0053] Preferably, in step S11, the molar ratio of 2-aminopyridine to acetic anhydride is 1:1 to 1:2.

[0054] Preferably, the catalyst 1 in step S13 is potassium carbonate.

[0055] Preferably, the drying temperature in step S14 is 60 to 80 degrees Celsius.

[0056] Preferably, the mass percentage of the aqueous hydrogen bromide solution in step S21 is 47%.

[0057] Preferably, liquid bromine is added to the mixed solution in step S21, and the temperature of the reaction mixture is maintained at 0 to 10 degrees Celsius; an aqueous sodium nitrite solution is added dropwise to the mixed solution, and the reaction temperature is maintained at 0 to 5 degrees Celsius.

[0058] Preferably, the reaction mixture in step S22 is stirred and reacted for 0.5 to 1 hour at a reaction temperature of 20 to 25 degrees Celsius.

[0059] Preferably, the chromatographic column in step S34 is a Sephadex LH-20 chromatographic column, 100 mm x 4.0 mm, 3 μm, a column temperature of 40 degrees Celsius, and an injection volume of 5 μL; mobile phase A is petroleum ether, mobile phase B is ethyl acetate, and an isocratic elution is performed with an A:B phase volume ratio of 80:20.

[0060] Embodiment 1:

[0061] A method for synthesizing a pyridine drug intermediate comprises the following steps in sequence:

[0062] Step S1, the step of preparing 2-amino-5-bromopyridine by 2-aminopyridine:

[0063] Step S11, adding 2-aminopyridine into a reaction container, and then adding acetic anhydride, heating to reflux for 2 hours after the addition, and detecting the reaction completion by thin layer chromatography;

[0064] Step S12, cooling the reaction liquid in the reaction container in the above step S11 to 15 degrees Celsius, then adding liquid bromine into the reaction container and stirring, heating at 50 degrees Celsius for 2 hours;

[0065] Step S13, adding pure water to the reaction container in the above step S12 until all solids are dissolved for 0.5 hours, then adding sodium hydroxide solution to the reaction container and reacting for 0.5 hours, then adding potassium carbonate to the reaction container and continuing the reaction;

[0066] Step S14, subjecting the precipitate after the reaction in the reaction container in the above step S13 to sedimentation centrifugation in ethanol, and then drying and recrystallizing to obtain 2-amino-5-bromopyridine, wherein the above drying temperature is 60 degrees Celsius;

[0067] Step S2, the step of preparing 2,5-dibromopyridine by 2-amino-5-bromopyridine:

[0068] Step S21, adding the 2-amino-5-bromopyridine obtained in the above step S1 into water cooled to 5 degrees Celsius, and then adding a 47% by mass aqueous solution of hydrogen bromide thereto;

[0069] In step S22, liquid bromine is added to the mixed solution of step S21, and the temperature of the reaction mixture is maintained at 5 degrees Celsius; an aqueous sodium nitrite solution is added dropwise to the mixed solution, and the reaction temperature is maintained at 2 degrees Celsius;

[0070] Step S23, the reaction mixture of the above step S22 is continued to be stirred for 0.5 hours, the reaction temperature is 20 degrees Celsius, the mixture is treated with an aqueous sodium hydroxide solution, and then the reaction mixture is extracted with ether, the organic layer is separated and dried over anhydrous sodium sulfate, the desiccant is filtered to remove the desiccant, and the obtained filtrate is evaporated to dryness of the solvent under reduced pressure;

[0071] Step S24, suspending the residue obtained in the above step S23 in heptane, filtering and collecting the residue to obtain the target product molecule 2,5-dibromopyridine;

[0072] Step S3, the step of preparing 2-bromo-5-iodopyridine by 2,5-dibromopyridine:

[0073] Step S31, under an argon protection environment at -80 degrees Celsius, n-butyl lithium is slowly added dropwise to the dry ether solution of 2,5-dibromopyridine obtained in the above step S2, and the mixture is stirred for reaction for 0.5 hours;

[0074] Step S32, adding iodine ether solution to the reaction solution in the above step S31, then stirring and reacting for 2 hours, and then slowly heating to -40 degrees Celsius;

[0075] Step S33, quenching the reaction solution of the above step S32 with a saturated sodium sulfite solution, then extracting the reaction with ether, separating the organic layer and washing the obtained organic layer with brine;

[0076] Step S34, drying the organic layer obtained in the above step S33 with anhydrous magnesium sulfate, filtering and evaporating the filtrate, and separating and purifying the obtained residue by chromatographic column to obtain 2-bromo-5-iodopyridine. The chromatographic column in the above step S34 is a Sephadex LH-20 chromatographic column, 100mmX4.0mm, 3μm, column temperature 40 degrees Celsius, injection volume 5μL; mobile phase A is petroleum ether, mobile phase B is ethyl acetate, and the volume ratio of A:B is 80:20 is used for isocratic elution.

[0077] Embodiment 2:

[0078] A method for synthesizing a pyridine drug intermediate comprises the following steps in sequence:

[0079] Step S1, the step of preparing 2-amino-5-bromopyridine by 2-aminopyridine:

[0080] Step S11, adding 2-aminopyridine into a reaction container, and then adding acetic anhydride, heating to reflux for 4 hours after the addition, and detecting the reaction completion by thin layer chromatography;

[0081] Step S12, cooling the reaction liquid in the reaction container in the above step S11 to 20 degrees Celsius, then adding liquid bromine into the reaction container and stirring, heating at 60 degrees Celsius for 3 hours;

[0082] Step S13, adding pure water to the reaction container in the above step S12 until all the solids are dissolved for 1 hour, then adding sodium hydroxide solution to the reaction container and reacting for 1 hour, then adding potassium carbonate to the reaction container and continuing the reaction;

[0083] Step S14, subjecting the precipitate after the reaction in the reaction container in the above step S13 to sedimentation centrifugation in ethanol, and then drying and recrystallizing to obtain 2-amino-5-bromopyridine, wherein the above drying temperature is 80 degrees Celsius;

[0084] Step S2, the step of preparing 2,5-dibromopyridine by 2-amino-5-bromopyridine:

[0085] Step S21, adding the 2-amino-5-bromopyridine obtained in the above step S1 into water cooled to 10 degrees Celsius, and then adding a 47% by mass aqueous solution of hydrogen bromide thereto;

[0086] In step S22, liquid bromine is added to the mixed solution of step S21, and the temperature of the reaction mixture is maintained at 10 degrees Celsius; an aqueous sodium nitrite solution is added dropwise to the mixed solution, and the reaction temperature is maintained at 5 degrees Celsius;

[0087] Step S23, the reaction mixture of the above step S22 is continued to be stirred for 1 hour, the reaction temperature is 25 degrees Celsius, the mixture is treated with an aqueous sodium hydroxide solution, and then the reaction mixture is extracted with ether, the organic layer is separated and dried over anhydrous sodium sulfate, the desiccant is filtered to remove the desiccant, and the obtained filtrate is evaporated to dryness of the solvent under reduced pressure;

[0088] Step S24, suspending the residue obtained in the above step S23 in heptane, filtering and collecting the residue to obtain the target product molecule 2,5-dibromopyridine;

[0089] Step S3, the step of preparing 2-bromo-5-iodopyridine by 2,5-dibromopyridine:

[0090] Step S31, under an argon protection environment at -50 degrees Celsius, n-butyl lithium is slowly added dropwise to the dry ether solution of 2,5-dibromopyridine obtained in the above step S2, and stirred for reaction for 1 hour;

[0091] Step S32, adding iodine ether solution to the reaction solution in the above step S31, then stirring and reacting for 3 hours, and then slowly heating to -30 degrees Celsius;

[0092] Step S33, quenching the reaction solution of the above step S32 with a saturated sodium sulfite solution, then extracting the reaction with ether, separating the organic layer and washing the obtained organic layer with brine;

[0093] Step S34, drying the organic layer obtained in the above step S33 with anhydrous magnesium sulfate, filtering and evaporating the filtrate, and separating and purifying the obtained residue by chromatographic column to obtain 2-bromo-5-iodopyridine. The chromatographic column in the above step S34 is a Sephadex LH-20 chromatographic column, 100mmX4.0mm, 3μm, column temperature 40 degrees Celsius, injection volume 5μL; mobile phase A is petroleum ether, mobile phase B is ethyl acetate, and the volume ratio of A:B is 80:20 is used for isocratic elution.

[0094] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. It should be pointed out that a person skilled in the art can make several improvements and modifications without departing from the technical principles of the present invention, and these improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A method for synthesizing a pyridine drug intermediate, characterized in that: The following steps are included in sequence: Step S1, the step of preparing 2-amino-5-bromopyridine by 2-aminopyridine: Step S11, adding 2-aminopyridine into a reaction container, and then adding acetic anhydride, heating to reflux for 2-6 hours after the addition, and detecting the reaction to be complete by thin layer chromatography; Step S12, cooling the reaction liquid in the reaction container in the above step S11 to 15-20 degrees Celsius, then adding liquid bromine into the reaction container and stirring, heating at 50-60 degrees Celsius for 2-3 hours; Step S13, adding pure water to the reaction container in the above step S12 until all the solids are dissolved for 0.5 to 1 hour, then adding sodium hydroxide solution to the reaction container and reacting for 0.5 to 1 hour, then adding catalyst 1 to the reaction container and continuing the reaction; Step S14, subjecting the precipitate after the reaction in the reaction container in the above step S13 to sedimentation centrifugation in ethanol, and then drying and recrystallizing to obtain 2-amino-5-bromopyridine; Step S2, the step of preparing 2,5-dibromopyridine by 2-amino-5-bromopyridine: Step S21, adding the 2-amino-5-bromopyridine obtained in the above step S1 to water cooled to 5 to 10 degrees Celsius, and then adding an aqueous solution of hydrogen bromide thereto; Step S22, adding liquid bromine to the mixed solution of step S21, and then adding sodium nitrite aqueous solution dropwise to the mixed solution; Step S23, the reaction mixture of the above step S22 is continued to be stirred for 0.5 to 1 hour, the mixture is treated with an aqueous sodium hydroxide solution, and then the reaction mixture is extracted with diethyl ether, the organic layer is separated and dried over anhydrous sodium sulfate, the desiccant is filtered to remove the desiccant, and the solvent of the obtained filtrate is evaporated under reduced pressure; Step S24, suspending the residue obtained in the above step S23 in heptane, filtering and collecting the residue to obtain the target product molecule 2,5-dibromopyridine; Step S3, the step of preparing 2-bromo-5-iodopyridine by 2,5-dibromopyridine: Step S31, slowly drop n-butyl lithium into the dry ether solution of 2,5-dibromopyridine obtained in the above step S2 at -80 to -50 degrees Celsius under argon protection, and stir the reaction for 0.5 to 1 hour; Step S32, adding iodine ether solution to the reaction solution in the above step S31, and then stirring the reaction for 2 to 3 hours, and then slowly heating to -40 to -30 degrees Celsius; Step S33, quenching the reaction solution of the above step S32 with a saturated sodium sulfite solution, then extracting the reaction with ether, separating the organic layer and washing the obtained organic layer with brine; Step S34, drying the organic layer obtained in the above step S33 with anhydrous magnesium sulfate, filtering and evaporating the filtrate, and separating and purifying the obtained residue by a chromatographic column to obtain 2-bromo-5-iodopyridine.

2. The method for synthesizing a pyridine drug intermediate according to claim 1, characterized in that: In the step S11, the molar ratio of 2-aminopyridine to acetic anhydride is 1:1 to 1:

2.

3. The method for synthesizing a pyridine drug intermediate according to claim 1, characterized in that: The catalyst 1 in step S13 is potassium carbonate.

4. The method for synthesizing a pyridine drug intermediate according to claim 1, characterized in that: The drying temperature in step S14 is 60 to 80 degrees Celsius.

5. The method for synthesizing a pyridine drug intermediate according to claim 1, characterized in that: The mass percentage of the aqueous hydrogen bromide solution in step S21 is 47%.

6. The method for synthesizing a pyridine drug intermediate according to claim 1, characterized in that: Liquid bromine is added to the mixed solution in step S21, and the temperature of the reaction mixture is maintained at 0 to 10 degrees Celsius; sodium nitrite aqueous solution is added dropwise to the mixed solution, and the reaction temperature is maintained at 0 to 5 degrees Celsius.

7. The method for synthesizing a pyridine drug intermediate according to claim 1, characterized in that: The reaction mixture in step S22 is continued to be stirred and reacted for 0.5 to 1 hour at a reaction temperature of 20 to 25 degrees Celsius.

8. The method for synthesizing a pyridine drug intermediate according to claim 1, characterized in that: The chromatographic column in step S34 is a Sephadex LH-20 chromatographic column, 100 mm x 4.0 mm, 3 μm, a column temperature of 40 degrees Celsius, and an injection volume of 5 μL; mobile phase A is petroleum ether, mobile phase B is ethyl acetate, and an isocratic elution is performed with an A:B phase volume ratio of 80:20.