CN114751855B - Preparation method of 2-bromo-4-amino-5-methylpyridine - Google Patents

Preparation method of 2-bromo-4-amino-5-methylpyridine Download PDF

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CN114751855B
CN114751855B CN202210561424.XA CN202210561424A CN114751855B CN 114751855 B CN114751855 B CN 114751855B CN 202210561424 A CN202210561424 A CN 202210561424A CN 114751855 B CN114751855 B CN 114751855B
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CN114751855A (en
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彭东杰
吴亮
钱鹏
高强
郑保富
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Shanghai Haohong Biomedical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals

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  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)

Abstract

The application provides a preparation method of 2-bromo-4-amino-5-methylpyridine, which comprises the following steps: step 1: adding a compound shown in the formula (I) into mixed acid to react for 0.1-1 h at 50-100 ℃ through a continuous flow reaction technology, and separating to obtain a compound shown in the formula (II); step 2: adding a compound shown in a formula (II) into a solvent, adding alkali and thiourea dioxide, reacting for 0.5-5 h at 50-100 ℃, and separating to obtain the compound 2-bromo-4-amino-5-methylpyridine shown in the formula (III). The preparation method improves the safety of the reaction and the yield of the product.

Description

Preparation method of 2-bromo-4-amino-5-methylpyridine
Technical Field
The application relates to the field of organic chemical synthesis, in particular to a preparation method of 2-bromo-4-amino-5-methylpyridine.
Background
2-Bromo-4-amino-5-methylpyridine is an important intermediate of pyrazolo [4,3-c ] pyridine derivatives, and the latter has good curative effects in preventing and treating tumors, cancers, neurological diseases, osteoporosis, senile dementia and the like. The existing preparation method of 2-bromo-4-amino-5-methylpyridine has low safety and low yield of the product. Therefore, how to improve the safety of the reaction and the yield of the product is a problem to be solved.
Disclosure of Invention
The application aims to provide a preparation method of 2-bromo-4-amino-5-methylpyridine, which is used for improving the safety of the reaction, the yield and the purity of the product.
The application provides a novel method for preparing 2-bromo-4-amino-5-methylpyridine, which adopts the following synthetic route:
The method specifically comprises the following steps:
Step 1: adding a compound shown in the formula (I) into mixed acid to react for 0.1-1 h at 50-100 ℃ through a continuous flow reaction technology, and separating to obtain a compound shown in the formula (II); the mixed acid is selected from at least two of concentrated nitric acid, concentrated sulfuric acid, fuming nitric acid and fuming sulfuric acid, preferably, the mixed acid is selected from mixed acid of concentrated nitric acid and concentrated sulfuric acid, mixed acid of concentrated sulfuric acid and fuming nitric acid, mixed acid of concentrated nitric acid and fuming sulfuric acid or mixed acid of fuming nitric acid and fuming sulfuric acid; the mass ratio of the mixed acid to the compound shown in the formula (I) is 0.5-4, and preferably, the mass ratio of the mixed acid to the compound shown in the formula (I) is 0.8-2;
Step 2: adding a compound shown in a formula (II) into a solvent, adding alkali and thiourea dioxide, reacting for 0.5-5 h at 50-100 ℃, and separating to obtain a compound shown in a formula (III) 2-bromo-4-amino-5-methylpyridine; the base is at least one selected from lithium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydrogen, sodium methoxide, sodium ethoxide, potassium carbonate, potassium hydroxide, potassium hydride and cesium carbonate, preferably at least one selected from lithium hydroxide, sodium hydroxide and potassium hydroxide; the mol ratio of the compound shown in the formula (II), the alkali and the thiourea dioxide is 1 (1-10): 3-6, preferably the mol ratio of the compound shown in the formula (II), the alkali and the thiourea dioxide is 1 (5-10): 4-6.
Preferably, step 1 comprises the steps of: adding the compound shown in the formula (I) into acid to obtain mixed solution, preheating, adding the mixed solution and the mixed acid into continuous flow reaction equipment at the flow rate of 0.3-10 mL/min for reaction for 0.1-1 h, and separating to obtain the compound shown in the formula (II), wherein the acid is at least one of concentrated sulfuric acid and fuming sulfuric acid, preferably concentrated sulfuric acid, and the mass ratio of the acid to the compound shown in the formula (I) is 0.5-4, preferably 0.8-2. By regulating the flow rates of the mixed solution and the mixed acid and the mass ratio of the acid to the compound shown in the formula (I) in the above range, the reaction can be smoothly carried out, the generated reaction heat can be transferred in a short time, and the safety of the reaction is improved.
More preferably, the temperature of the preheating treatment is 30 to 120℃for 0.1 to 0.5 hours, still more preferably 40 to 100℃for 0.1 to 0.4 hours, still more preferably 50 to 80℃for 0.1 to 0.3 hours. The preheating treatment can ensure that materials are easier to mix uniformly, and the reaction time is shortened.
Preferably, in step 2, the solvent is selected from at least one of methanol, ethanol, isopropanol, tert-butanol, ethylene glycol, tetrahydrofuran, methyltetrahydrofuran, acetone, acetonitrile, water, and more preferably ethanol.
Preferably, in step 2, the reaction temperature is 50℃to 80 ℃.
In the present application, the above-mentioned "continuous flow reaction technique" refers to a technique in which the reaction is performed after mixing liquid reactants at a constant flow rate during the reaction, for example, the reaction is performed in a continuous flow reaction apparatus.
Preferably, step 1 is carried out in a continuous flow reaction apparatus comprising a microreactor, preferably a pipeline reactor, comprising: the preheating device is used for preheating materials; a temperature detection device for monitoring the reaction temperature in the continuous reaction device; the temperature control system is used for adjusting the reaction temperature; pressure detection means for monitoring the reaction pressure in the continuous reaction means; an automated control system; the automatic control system is connected with the liquid pump, the temperature control system, the temperature detection equipment, the pressure detection equipment and the like. It will be appreciated that the microreactor described above may also include other necessary or optional components that make up the microreactor, and that the application is not limited to such components as long as the objects of the application are achieved. The microreactor may be a microreactor known in the art, and the present application is not limited thereto.
The concentrated nitric acid, the concentrated sulfuric acid, the fuming sulfuric acid and the fuming nitric acid refer to conventional concentrated nitric acid, concentrated sulfuric acid, fuming sulfuric acid and fuming nitric acid which are sold in the market, wherein the mass concentration of the concentrated nitric acid can be 68%, 75% or 95%; the mass concentration of the concentrated sulfuric acid can be 90% or 98%.
The separation step in the above steps is not particularly limited, and a separation step known in the art may be employed as long as the object of the present application can be achieved. For example, the separation step may include, but is not limited to: quenching reaction with water or other organic solvent, extracting, washing with water or other solvent, treating with active carbon, filtering, concentrating, recrystallizing, etc. The above-mentioned other organic solvents may be conventional organic solvents used in the separation known in the art, and the present application is not limited thereto as long as the object of the present application can be achieved.
The application has the beneficial effects that:
The continuous flow reaction technology is adopted in the step 1, so that the problem that a large amount of reaction heat is generated in a short time by the traditional kettle type reaction, so that safety accidents are easy to cause is solved, and the safety of the reaction is improved. Meanwhile, the compound shown in the formula (II) generated in the traditional kettle-type reaction is easy to destroy the structure by mixed acid to generate other byproducts, so that the yield is reduced, and the continuous flow reaction technology in the step 1 is adopted, so that the conversion efficiency can be improved, the generation of byproducts is reduced, the yield is further improved, and the purity of the obtained product is high. In addition, in the continuous flow reaction, the reaction volume is relatively determined, the contact area is large, the reaction can be effectively controlled, the channel temperature control effect is good, the reaction temperature can be effectively controlled, and the production safety is further improved.
The thiourea dioxide is used as the reducing agent in the step 2, so that the problems that the iron and ammonium chloride system, the iron and acetic acid system and the zinc and weak acid system used in the prior art generate a large amount of solid waste and residual iron or zinc are difficult to remove can be solved, and compared with the method that the cost of heavy metals such as palladium, platinum and nickel is lower, the heavy metal residues cannot be generated. The thiourea dioxide and the byproducts produced by the thiourea dioxide have good water solubility, simple and convenient post-treatment, low cost and low risk, are suitable for industrialized mass production, and also meet the requirements of green production.
Of course, it is not necessary for any one product or method of practicing the application to achieve all of the advantages set forth above at the same time.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings required for the description of the embodiments will be briefly described below, and it is apparent that the drawings in the following description are only some embodiments of the present application, and other embodiments may be obtained according to these drawings by those of ordinary skill in the art.
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of a compound represented by the formula (II) in example 1-1;
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of the compound represented by the formula (III) in example 1-1;
FIG. 3 is a High Performance Liquid Chromatography (HPLC) diagram of the compound shown by formula (II) in example 1-1;
FIG. 4 is an HPLC chart of the compound represented by the formula (III) in example 1-1.
Detailed Description
The following description of the embodiments of the present application will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present application, but not all embodiments. Based on the embodiments of the present application, all other embodiments obtained by the person skilled in the art based on the present application are included in the scope of protection of the present application.
In the present application, all raw materials are commercially available conventional raw materials unless otherwise specified.
Example 1-1
Step 1: 150g of 2-bromo-5-picoline nitrogen oxide is added into 150g of concentrated sulfuric acid (the mass concentration is 98%) to obtain a mixed solution, and then the mixed solution is pumped into preheating equipment at a flow rate of 0.5mL/min for preheating, wherein the preheating temperature is 70 ℃ and the time is 0.1h, and the mixed solution is directly pumped into a reactor after the preheating is finished. 150g of concentrated sulfuric acid (98% by mass) and 88.4g of concentrated nitric acid (95% by mass) were mixed to obtain a mixed acid, which was then pumped into a microreactor at a flow rate of 0.4mL/min, and the reactor temperature was set at 70 ℃. Then, the mixed solution and mixed acid were reacted for 0.5 hours, the reaction solution was added to ice water, the pH was adjusted to neutral with aqueous ammonia, and the mixture was filtered and dried to give 158g of the compound of formula (II) having a purity of 98.19% (as shown in FIG. 3 and Table 1) and a yield of 85%.
TABLE1 HPLC data for the compounds of formula (II)
Hydrogen spectrum of compound represented by formula (II): 1 H NMR (400 mhz, dmso) delta 8.70 (s, 1H), 8.60 (s, 1H), 2.45 (s, 4H), (as shown in fig. 1).
Step 2: 100g (0.46 mol) of the compound shown in the formula (II) obtained above is added with 500ml of ethanol, stirred and dissolved, 86g (2.15 mol) of sodium hydroxide is added, the mixture is heated to reflux, 232.5g (2.15 mol) of thiourea dioxide is added in batches, the mixture is reacted for 5 hours at 70 ℃, water is added for extraction with dichloromethane, drying, concentration, crystallization and drying are carried out, 77.6g of the compound shown in the off-white formula (III) is obtained, the purity is 100% (shown in the graph 4 and the table 2), and the yield is 90%.
TABLE 2 HPLC data for the compounds of formula (III)
Retention time (min) Peak area Area (%) Peak height USP tailing factor USP theoretical plate number
4.074 5107593 100.00 660094 0.934 6735.839
Hydrogen spectrum of the compound represented by formula (III): 1 H NMR (400 mhz, dmso) delta 7.65 (s, 1H), 6.63 (s, 1H), 6.15 (s, 2H), 1.94 (s, 3H); the spectrum is shown in figure 2.
Examples 1-2 to 1-9
The procedure of example 1-1 was repeated except that the relevant production parameters were adjusted as shown in Table 3.
Examples 2-1 to 2-5
The procedure of example 1-1 was repeated except that the relevant production parameters were adjusted as shown in Table 4.
Comparative example 1
Step 1: 2-bromo-5-methylpyridine oxynitride (5.1 g,27.2 mmol) was added to concentrated sulfuric acid (27.6 g,15 mL), followed by dropwise addition of concentrated nitric acid (33.6 g,24 mL); the mixture was heated to 100deg.C for 4h, the reaction was cooled to 0deg.C, and then added to water (300 mL). Adding 2mol/L NaOH aqueous solution, and adjusting the pH value of the reaction solution to be 9; the reaction solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to give a compound represented by formula (II) (4.6 g, yield 73%).
Step 2: the compound represented by the formula (II) (0.5 g,2.146 mmol) was dissolved in acetic acid (10 mL), and iron powder (0.476 g,8.58 mmol) was added at 25℃to raise the reaction temperature to 100℃and react for 30min. The reaction solution was cooled to room temperature, then added to an aqueous NaOH solution (1 mol/L,30 mL), extracted with ethyl acetate (3X 50 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the compound represented by formula (III) (213 mg, yield 53.1%).
The preparation parameters and performance tests of each example and comparative example are shown in tables 3 and 4.
TABLE 3 Table 3
Note that: table 1 the "concentrated sulfuric acid+concentrated nitric acid (150+88.4)" in example 1 means that the mass of concentrated sulfuric acid in the mixed acid is 150g, the mass of concentrated nitric acid is 88.4g, and so on. In comparative example 1, the amount of concentrated sulfuric acid was 15ml×1.84 g/ml=27.6 g, the amount of concentrated nitric acid was 24ml×1.4 g/ml=33.6 g, and the mass ratio of the sum of the amounts of concentrated sulfuric acid and concentrated nitric acid to the compound represented by formula (I) (27.6+33.6)/5.1=12. The "/" in table 1 indicates that no corresponding parameter exists.
TABLE 4 Table 4
Referring to Table 3, it can be seen from examples 1-1 to examples 1-9 and comparative example 1 that when the preparation method provided by the present application is used to prepare the compound of formula (III), the yield of the compound of formula (III) in step 2 and the yield of the compound of formula (III) in both steps are higher, thereby illustrating that the preparation method of the present application can improve the yield of the compound of formula (III).
Referring to tables 1,2,3 and 4, the purity of the compound of formula (II) in step 1 of example 1-1 was 98.19% (the peaks at 16.356min and 16.401min in FIG. 3 were impurity peaks), and the purity of the compound of formula (III) in step 2 was 100%, thereby demonstrating that the purity of the compound of formula (III) can be improved by the preparation method of the present application.
Referring to Table 3, it can be seen from examples 1-1 to 1-3 that when the kind of mixed acid and the mass ratio of the mixed acid to the compound represented by formula (I) are within the scope of the present application, the compound represented by formula (III) is produced with a higher yield. As can be seen from examples 1-1, examples 1-4 and examples 1-5, the compound of formula (III) was prepared in a higher yield when the reaction temperature and time of step 1 were within the scope of the present application. As can be seen from examples 1-1, examples 1-6 and examples 1-8, when the molar ratio of the compound of formula (II), the base and thiourea dioxide, and the reaction temperature and time of step 2 are within the scope of the present application, the compound of formula (III) is produced with a higher yield. As can be seen from examples 1-1 and examples 1-9, when the kind of the base in step 2 is within the scope of the present application, the compound represented by formula (III) is prepared with a higher yield. In the whole, the compound shown in the formula (III) prepared by the preparation method has higher yield.
The kind of acid in the mixed solution, the mass ratio of the acid to the compound represented by formula (I), the flow rate of the mixed solution, the flow rate of the mixed acid, the preheating treatment temperature and the preheating treatment time generally affect the yield of the compound represented by formula (III), and referring to Table 4, it can be seen from examples 1-1, 2-1 to 2-5 that the compound represented by formula (III) is produced with a higher yield when the above parameters are within the scope of the present application.
It should be noted that, in this document, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, or article that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, or article. Without further limitation, an element defined by the phrase "comprising one … …" does not exclude the presence of other like elements in a process, method or article that includes the element.
In this specification, each embodiment is described in a related manner, and identical and similar parts of each embodiment are all referred to each other, and each embodiment mainly describes differences from other embodiments.
The foregoing description is only of the preferred embodiments of the present application and is not intended to limit the scope of the present application. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application are included in the protection scope of the present application.

Claims (6)

1. A process for the preparation of 2-bromo-4-amino-5-methylpyridine, comprising the steps of:
Step 1: adding a compound shown in a formula (I) into acid through a continuous flow reaction technology to obtain a mixed solution, performing preheating treatment, then adding the mixed solution and the mixed acid into continuous flow reaction equipment at a flow rate of 0.3-10 mL/min respectively at a temperature of 70-100 ℃ to react for 0.5-1 h, and separating to obtain a compound shown in a formula (II); the mixed acid is selected from mixed acid of concentrated nitric acid and concentrated sulfuric acid, mixed acid of concentrated nitric acid and fuming sulfuric acid or mixed acid of concentrated sulfuric acid and fuming nitric acid; the mass ratio of the mixed acid to the compound shown in the formula (I) is 0.8-2; the acid is selected from concentrated sulfuric acid, and the mass ratio of the acid to the compound shown in the formula (I) is 0.8-2; the temperature of the preheating treatment is 30-120 ℃ and the time is 0.1-0.5 h;
step 2: adding a compound shown in a formula (II) into a solvent, adding alkali and thiourea dioxide, reacting for 0.5-5 h at 50-80 ℃, and separating to obtain a compound shown in a formula (III) 2-bromo-4-amino-5-methylpyridine; the alkali is selected from sodium hydroxide, and the molar ratio of the compound shown in the formula (II), the alkali and thiourea dioxide is 1 (5-7): 5-6);
2. The production method according to claim 1, wherein the temperature of the preheating treatment is 40 to 100 ℃ and the time is 0.1 to 0.4 hours.
3. The production method according to claim 2, wherein the temperature of the preheating treatment is 50 to 80 ℃ and the time is 0.1 to 0.3 hours.
4. The preparation method according to claim 1, wherein in step 2, the solvent is at least one selected from the group consisting of methanol, ethanol, isopropanol, t-butanol, ethylene glycol, tetrahydrofuran, methyltetrahydrofuran, acetone, acetonitrile, and water.
5. The preparation method according to claim 4, wherein in step 2, the solvent is ethanol.
6. The method of preparation of claim 1, wherein step 1 is performed in a continuous flow reaction apparatus comprising a microreactor comprising: preheating equipment, temperature detection equipment, an automatic control system, a liquid pump and a temperature control system.
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