Preparation process for 2-chloro-4-amino-5-methylpyridine heterocyclic compound
By using hydrazine hydrate and ferric chloride hexahydrate as reducing agents to replace iron powder, the problems of low yield and equipment corrosion in the preparation of 2-chloro-4-amino-5-methylpyridine heterocyclic compounds in the prior art have been solved, and a high-purity and high-efficiency synthetic route has been realized.
Patent Information
- Application Number
- CN202410599079.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-05-15
- Publication Date
- 2025-11-18
AI Technical Summary
In the existing technology for preparing 2-chloro-4-amino-5-methylpyridine heterocyclic compounds, the use of iron powder as a reducing agent results in low yield of the target product, poor reduction effect, and easy corrosion of equipment.
Hydrazine hydrate (NH2·NH2·H2O) is used as a reducing agent, combined with ferric chloride hexahydrate and activated carbon, to generate 2-chloro-4-amino-5-methylpyridine heterocyclic compounds through a three-step reaction: oxidation, nitration and reduction, avoiding the use of iron powder.
It improves the yield and purity of the target product, avoids equipment corrosion, has a stable synthesis route with few byproducts, and uses inexpensive raw materials.
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Figure CN120965575A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the technical field, and in particular relates to a process for preparing 2-chloro-4-amino-5-methylpyridine heterocyclic compounds. Background Technology
[0002] 2-Chloro-4-amino-5-methylpyridine heterocyclic compounds are key intermediates in the synthesis of the pharmaceutical phenelzine. The synthesis of 2-chloro-4-amino-5-methylpyridine is difficult, and there is currently no mature process route. This compound can also be used as an intermediate in the pharmaceutical compound omeprazole. Additionally, it can be used as an intermediate in the preparation of protein kinase ERK2 inhibitors.
[0003] The existing technology for preparing 2-chloro-4-amino-5-methylpyridine heterocyclic compounds mainly includes the following steps: First, 2-chloro-5-methylpyridine is reacted with hydrogen peroxide under acetic acid conditions to generate 2-chloro-5-methylpyridine nitride; second, 2-chloro-5-methylpyridine nitride is reacted under nitric acid and sulfuric acid conditions to obtain the nitration product 2-chloro-4-nitro-5-methylpyridine nitride; third, 2-chloro-4-nitro-5-methylpyridine nitride is reduced to 2-chloro-4-methyl-5-aminopyridine heterocyclic compounds under iron powder and acetic acid or hydrochloric acid conditions.
[0004] However, the existing reaction mechanism still has some drawbacks. First, using iron powder as a reducing agent will result in a low yield of the target product. Second, iron powder as a reducing agent may not be able to effectively exert its reducing effect in materials with strong oxidation resistance, thereby reducing the reduction effect. At the same time, when iron powder is used as a reducing agent under hydrochloric acid or acetic acid conditions, the acidic conditions can easily corrode the equipment.
[0005] Therefore, based on the shortcomings of the existing technology, we have designed a novel preparation process for 2-chloro-4-amino-5-methylpyridine heterocyclic compounds, taking into account specific production needs. Summary of the Invention
[0006] The purpose of this invention is to provide a process for preparing 2-chloro-4-amino-5-methylpyridine heterocyclic compounds, which solves the problems of low yield of target product, poor reduction effect and easy corrosion and pollution of equipment caused by using iron powder as a reducing agent in existing preparation processes.
[0007] To solve the above-mentioned technical problems, the present invention is achieved through the following technical solution:
[0008] This invention discloses a process for preparing 2-chloro-4-amino-5-methylpyridine heterocyclic compounds, comprising the following steps:
[0009] Step 1, Oxidation Reaction: 12.8 g of 2-chloro-5-methylpyridine (0.1 mol) was placed in a 100 mL reaction flask, 20 mL of acetic acid and 2 mL of concentrated sulfuric acid were added, and the temperature was raised to 80 °C. Hydrogen peroxide (35% and 25 mL) was slowly added dropwise with stirring. After the addition was complete, the reaction was kept at this temperature for 4 h. After the reaction was complete, the temperature was lowered to 50 °C and the solution was removed under negative pressure, finally yielding 13.6 g of a deep yellow viscous liquid. In this step, 2-chloro-5-methylpyridine was mainly used as the raw material. It reacted with hydrogen peroxide under acetic acid conditions to generate 2-chloro-5-methylpyridine nitride. In the whole reaction process, the raw material was oxidized first to introduce the active oxygen atom.
[0010] Step 2, Nitration Reaction: The product from Step 1, 2-chloro-5-methylpyridine nitride (11.5 g, 0.08 mol), was placed in a 100 ml reaction flask. 5 ml of concentrated sulfuric acid was slowly added dropwise with stirring at room temperature. The temperature was then raised to 80 °C, and a mixture of concentrated sulfuric acid (32.5 ml) and concentrated nitric acid (32.2 ml) was added dropwise. The temperature was then raised to 100 °C, and the reaction was stirred for 5 hours. After the reaction was complete, the mixture was cooled to room temperature, and the reaction mixture was poured into 400 g of ice. The pH was adjusted to 2-3 with NaCO3. The mixture was filtered, and the filter cake was washed with ice water and dried to obtain 12.9 g of a yellow solid. In this step, 2-chloro-5-methylpyridine nitride reacts under nitric acid and sulfuric acid conditions to obtain the nitration product 2-chloro-4-nitro-5-methylpyridine nitride, which can introduce a more reactive nitro group into the product from the previous step, laying the foundation for subsequent reactions.
[0011] Step 3, Reduction reaction: Add 10g (0.05mol) of dried nitrate (2-chloro-4-nitro-5-methylpyridine nitrogen oxides) to a 250ml three-necked flask, add toluene (70ml), heat to about 40℃, add 1g of ferric chloride hexahydrate (dissolved in 3mL of ethanol before adding) and 2g of activated carbon, and add 10 drops of polyethylene glycol 400; then heat to 70℃ and slowly add 14.3g (0.35mol) of 80% NH2·NH2·H2O, i.e., hydrazine hydrate, while controlling the temperature at 70-80℃. After the addition is complete, heat to reflux for 3 hours.
[0012] Post-processing: After the reaction was completed, 45 ml of water was added, the solution was removed under negative pressure, the temperature was lowered to 50 °C, 80 ml of methane was added, the mixture was filtered, the filter cake was washed twice with 20 ml of dichloromethane, poured into a separatory funnel, the lower organic layer was collected, the upper aqueous layer was extracted twice with 30 ml of dichloromethane, the organic layer was collected, the solution was removed, the mixture was cooled and filtered to obtain a wet product, which was dried and then purified and decolorized by recrystallization with hot water until it met the requirements, and then dried to obtain 7.3 g of yellow solid. In this step, 2-chloro-4-nitro-5-methylpyridine nitrogen oxides were reduced to 2-chloro-4-methyl-5-aminopyridine under the conditions of ferric chloride and hydrazine hydrate. The product in step two was deoxygenated and aminated to the target product by the reducing agent.
[0013] The present invention has the following beneficial effects:
[0014] 1. The reaction of reducing nitro groups with hydrazine hydrate in the synthesis of 2-chloro-4-methyl-5-aminopyridine has not been reported.
[0015] 2. The synthesis method of the intermediate is stable, the raw materials are inexpensive, the synthesis route is reasonable, there are basically no by-products generated during the synthesis process, and the purity of the target product is high.
[0016] 3. This invention uses a novel synthetic route with inexpensive and readily available 2-chloro-5-methylpyridine as a raw material. After oxidation, pyridine oxide is generated, which allows the subsequent nitration reaction to be located at the fourth position of the pyridine ring. After nitration to obtain the nitro product, hydrazine hydrate is used to reduce the nitro group and the oxide to produce an amine.
[0017] 4. During the reduction of hydrazine hydrate, it is oxidized into nitrogen gas and escapes, thus not introducing impurities into the reaction products.
[0018] Of course, any product implementing this invention does not necessarily need to achieve all of the advantages described above at the same time. Attached Figure Description
[0019] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the description of the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.
[0020] Figure 1 The diagram shows the reaction formulas for the preparation of 2-chloro-4-amino-5-methylpyridine heterocyclic compounds in the prior art.
[0021] Figure 2 The diagram shows the reaction process for preparing the 2-chloro-4-amino-5-methylpyridine heterocyclic compound in this invention. Detailed Implementation
[0022] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.
[0023] In the description of this invention, it should be understood that the terms "upper," "middle," "outer," "inner," etc., which indicate orientation or positional relationship, are only for the convenience of describing this invention and simplifying the description, and do not indicate or imply that the components or elements referred to must have a specific orientation, or be constructed and operated in a specific orientation, and therefore should not be construed as limiting this invention.
[0024] Please see Figure 1-2 As shown, this invention provides a process for preparing 2-chloro-4-amino-5-methylpyridine heterocyclic compounds, comprising the following steps:
[0025] Step 1, Oxidation Reaction: 12.8 g of 2-chloro-5-methylpyridine (0.1 mol) was placed in a 100 mL reaction flask, 20 mL of acetic acid and 2 mL of concentrated sulfuric acid were added, and the temperature was raised to 80 °C. Hydrogen peroxide (35% and 25 mL) was slowly added dropwise with stirring. After the addition was complete, the reaction was kept at this temperature for 4 h. After the reaction was complete, the temperature was lowered to 50 °C and the solution was removed under negative pressure, finally yielding 13.6 g of a deep yellow viscous liquid. In this step, 2-chloro-5-methylpyridine was mainly used as the raw material. It reacted with hydrogen peroxide under acetic acid conditions to generate 2-chloro-5-methylpyridine nitride. In the whole reaction process, the raw material was oxidized first to introduce the active oxygen atom.
[0026] Step 2, Nitration Reaction: The product from Step 1, 2-chloro-5-methylpyridine nitride (11.5 g, 0.08 mol), was placed in a 100 ml reaction flask. 5 ml of concentrated sulfuric acid was slowly added dropwise with stirring at room temperature. The temperature was then raised to 80 °C, and a mixture of concentrated sulfuric acid (32.5 ml) and concentrated nitric acid (32.2 ml) was added dropwise. The temperature was then raised to 100 °C, and the reaction was stirred for 5 hours. After the reaction was complete, the mixture was cooled to room temperature, and the reaction mixture was poured into 400 g of ice. The pH was adjusted to 2-3 with NaCO3. The mixture was filtered, and the filter cake was washed with ice water and dried to obtain 12.9 g of a yellow solid. In this step, 2-chloro-5-methylpyridine nitride reacts under nitric acid and sulfuric acid conditions to obtain the nitration product 2-chloro-4-nitro-5-methylpyridine nitride, which can introduce a more reactive nitro group into the product from the previous step, laying the foundation for subsequent reactions.
[0027] Step 3, Reduction reaction: Add 10g (0.05mol) of dried nitrate (2-chloro-4-nitro-5-methylpyridine nitrogen oxides) to a 250ml three-necked flask, add toluene (70ml), heat to about 40℃, add 1g of ferric chloride hexahydrate (dissolved in 3mL of ethanol before adding) and 2g of activated carbon, and add 10 drops of polyethylene glycol 400; then heat to 70℃ and slowly add 14.3g (0.35mol) of 80% NH2·NH2·H2O, i.e., hydrazine hydrate, while controlling the temperature at 70-80℃. After the addition is complete, heat to reflux for 3 hours.
[0028] Post-processing: After the reaction was completed, 45 ml of water was added, the solution was removed under negative pressure, the temperature was lowered to 50 °C, 80 ml of methane was added, the mixture was filtered, the filter cake was washed twice with 20 ml of dichloromethane, poured into a separatory funnel, the lower organic layer was collected, the upper aqueous layer was extracted twice with 30 ml of dichloromethane, the organic layer was collected, the solution was removed, the mixture was cooled and filtered to obtain a wet product, which was dried and then purified and decolorized by recrystallization with hot water until it met the requirements, and then dried to obtain 7.3 g of yellow solid. In this step, 2-chloro-4-nitro-5-methylpyridine nitrogen oxides were reduced to 2-chloro-4-methyl-5-aminopyridine under the conditions of ferric chloride and hydrazine hydrate. The product in step two was deoxygenated and aminated to the target product by the reducing agent.
[0029] In the description of this specification, references to terms such as "an embodiment," "example," "specific example," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the invention. In this specification, illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples.
[0030] The preferred embodiments of the present invention disclosed above are merely illustrative of the invention. These preferred embodiments do not exhaustively describe all details, nor do they limit the invention to the specific implementations described. Clearly, many modifications and variations can be made based on the content of this specification. This specification selects and specifically describes these embodiments to better explain the principles and practical applications of the invention, thereby enabling those skilled in the art to better understand and utilize the invention. The invention is limited only by the claims and their full scope and equivalents.
Claims
1. A process for preparing 2-chloro-4-amino-5-methylpyridine heterocyclic compounds, characterized in that, Includes the following steps: Step 1, Oxidation reaction: 2-Chloro-5-methylpyridine (12.8g, 0.1mol) was placed in a 100mL reaction flask, 20mL of acetic acid and 2mL of concentrated sulfuric acid were added, and then the temperature was raised to 80℃. Hydrogen peroxide (35%, 25mL) was slowly added dropwise while stirring. After the addition was complete, the reaction was kept at this temperature for 4h. After the reaction was complete, the temperature was lowered to 50℃ and the solvent was removed under negative pressure, finally yielding a dark yellow viscous liquid. Step 2, Nitration reaction: 11.5 g of 2-chloro-5-methylpyridine nitrogen oxide (0.08 mol) from Step 1 was placed in a 100 ml reaction flask. 5 ml of concentrated sulfuric acid was slowly added dropwise with stirring at room temperature. Then, the temperature was raised to 80 °C and a mixture of concentrated sulfuric acid (32.5 ml) and concentrated nitric acid (32.2 ml) was added dropwise. The temperature was then raised to 100 °C and the reaction was stirred for 5 hours. After the reaction was complete, the mixture was cooled to room temperature and poured into 400 g of ice. The pH was adjusted to 2-3 with NaCO3. The mixture was filtered, and the filter cake was washed with ice water and dried to obtain a yellow solid. Step 3, Reduction reaction: Add 10g (0.05mol) of dried nitrate (2-chloro-4-nitro-5-methylpyridine nitrogen oxides) to a 250ml three-necked flask, add toluene (70ml), heat to about 40℃, add 1g of ferric chloride hexahydrate (dissolved in 3mL of ethanol before adding) and 2g of activated carbon, and add 10 drops of polyethylene glycol 400; then heat to 70℃ and slowly add 14.3g (0.35mol) of 80% NH2·NH2·H2O, i.e., hydrazine hydrate, while controlling the temperature at 70-80℃. After the addition is complete, heat to reflux for 3 hours. Post-processing: After the reaction is complete, add 45 ml of water, desolvent under negative pressure, cool to 50°C, add 80 ml of methane, filter, wash the filter cake twice with 20 ml of dichloromethane, pour into a separatory funnel, collect the lower organic layer, extract the upper aqueous layer twice with 30 ml of dichloromethane, collect the organic layer, desolvent, cool and filter to obtain the wet product, dry, recrystallize with hot water to purify and decolorize, and dry until qualified.
2. The preparation process for 2-chloro-4-amino-5-methylpyridine heterocyclic compounds according to claim 1, characterized in that, In step one, 2-chloro-5-methylpyridine is used as a raw material and reacts with hydrogen peroxide under acetic acid conditions to generate 2-chloro-5-methylpyridine nitrogen oxides.
3. The preparation process for 2-chloro-4-amino-5-methylpyridine heterocyclic compounds according to claim 1, characterized in that, In step two, 2-chloro-5-methylpyridine oxide reacts under nitric acid and sulfuric acid conditions to obtain the nitration product 2-chloro-4-nitro-5-methylpyridine oxide.
4. The preparation process for 2-chloro-4-amino-5-methylpyridine heterocyclic compounds according to claim 1, characterized in that, In step three, 2-chloro-4-nitro-5-methylpyridine nitrogen oxides are reduced to 2-chloro-4-methyl-5-aminopyridine under the conditions of ferric chloride and hydrazine hydrate.