CN101514184A - A kind of synthetic method of 5-bromo-2-picoline - Google Patents

Abstract

The invention discloses a method for synthesizing 5-bromo-2-methyl-pyridine: using 6-methyl-3-pyridinecarboxylic acid as a raw material to react with ethanol to generate 6-methyl-3-pyridinecarboxylic acid ethyl ester. Ammonolysis reaction with ammonia water to generate 6-methyl-3-pyridine carboxamide, then 6-methyl-3-aminopyridine through Hofmann degradation reaction, and finally react with brominating reagent to generate 5-bromo-2-methyl base pyridine. The route of the invention has mild reaction conditions, high yield, easy-to-obtain raw materials, low cost, and no 3-position by-products in the whole process, which reduces the load of later separation and has industrialization prospects.

Description

A kind of synthetic method of 5-bromo-2-picoline

technical field

The invention belongs to the technical field of chemical synthesis, and in particular relates to a synthesis method of 5-bromo-2-picoline.

Background technique

Pyridine and its derivatives are widely distributed in nature. Many plant components such as alkaloids contain pyridine ring compounds in their structures. They have a wide range of uses and can be used to produce high value-added fine chemical products, and play an important role in the pharmaceutical industry, pesticide industry and chemical industry. They are the basis for the production of many important compounds, and are indispensable and important raw materials in the production of medicines, pesticides, fuels, surfactants, rubber additives, feed additives, food additives, adhesives, and synthetic materials. 5-Bromo-2-picoline is an important pharmaceutical intermediate, which has broad prospects and huge market potential in the production of cardiovascular and cerebrovascular drugs and respiratory drugs. At present, its main synthetic method is the direct bromination method. Due to the positioning effect of the substituent, there will be a 3-position isomer during the reaction, and its ratio is 45:55. Separation and purification are carried out by traditional methods such as rectification. Most of the reports in the literature are purified by column chromatography to obtain pure products. This method wastes time and increases costs, and is not suitable for large-scale industrial production ^[1-4] .

references:

[1] Li, Yuexian; Plesescu, Mihaela; Prakash, Shimoga R.Synthesis of C-14 and C-13, H-2-labeled IKK inhibitor: [14C] and [13C4, D3]N-(6-chloro- 7-methoxy-9H-pyrido[3,4-b]indol-8-yl)-2-methyl-3-pyridinecarboxamide..Journal of Labeled Compounds and Radioph-armaceuticals(2006), 49(9), 789-799.

[2] Jagusch, Carsten; Negri, Matthias; Hille, Ulrike E.; Hu, Qingzhong; Bartels, Marc; Jahn-Hoffmann, Kerstin; Pinto-Bazurco Mendieta, Mariano A.E.; Rodenwaldt, Barbara; , Dirk; Lauterbach, Thomas; Recanatini, Maurizio; Cavalli, Andrea; Hartmann, Rolf W. Synthesis, biological evaluation and molecular modeling studies of methyleneimidazole substituted biaryls as inhibitors of human17-hydroxylase-17, 20-lycylase7 (CYP lyase7) of the core structure., Germany. Bioorganic & Medicinal Chemistry (2008), 16(4), 1992-2010.

[3] Guthikonda, Ravindra Nath; Cama, L.D.; Quesada, M.; Woods, M.F.; Salzmann, T.N.; Christensen, B.G. Structure-activity relationships in the 2-arylcarbapenem series. Medicinal Chemistry (1987), 30(5), 871-80.

[4] Du Zhenxia, Liu Cao, Separation and preparation of 5-bromo-2-methyl-pyridine and 3-bromo-2-methyl-pyridine, Journal of Beijing University of Chemical Technology 20023(3): 79-81

Contents of the invention

The technical problem to be solved by the present invention is to provide a new synthesis method of 5-bromo-2-picoline, so as to avoid the formation of its 3-position isomer and reduce the separation load.

In order to solve the problems of the technologies described above, the technical scheme adopted in the present invention is as follows:

A kind of synthetic method of 5-bromo-2-methyl-pyridine, comprises the steps:

(1) Using 6-methyl-3-pyridinecarboxylic acid as a raw material, reacting with ethanol at 30-80°C in the presence of acid to generate 6-methyl-3-pyridinecarboxylic acid ethyl ester;

(2) Add ethyl 6-methyl-3-pyridinecarboxylate into ammonia water and react at -5-60°C for 4-10 hours to obtain 6-methyl-3-pyridinecarboxamide;

(3) reacting 6-methyl-3-pyridinecarboxamide in a sodium hydroxide solution containing halogen at a temperature of 20-100° C. for 1-6 hours to obtain 6-methyl-3-aminopyridine;

(4) Add 6-methyl-3-aminopyridine to the HBr solution, in the presence of a catalytic amount of CuBr, add NaNO solution _dropwise , control the temperature at -10 to 20°C, and react for 1 to 6 hours to obtain 5- Bromo-2-methylpyridine.

The acid described in step (1) is hydrochloric acid, sulfuric acid or SOCl ₂ .

In step (1), add 5-10 g of 6-methyl-3-pyridinecarboxylic acid and 3-10 mL of acid per 100 mL of ethanol.

In step (2), the mass percent concentration of the ammonia water concentration is 25-28%.

In step (2), the amount of ethyl 6-methyl-3-pyridinecarboxylate added is 10-25 g per 100 mL of ammonia water.

In step (3), the halogen is Cl ₂ , Br ₂ , NaOCl or NaOBr.

In step (3), the molar ratio of 6-methyl-3-pyridinecarboxamide, halogen and sodium hydroxide is 1:1-1.3:2-5, and the mass percent concentration of NaOH solution is 3-10%.

In step (4), the mass percent concentration of the hydrohalic acid solution is 40-50%.

In step (4), the molar ratio of 6-methyl-3-aminopyridine to CuBr is 1: 1.0～1.5, and in every 100mL of HBr solution, the addition of 6-methyl-3-aminopyridine is 10～20g, saturated The amount of NaNO ₂ solution added is 15-30mL.

The reaction equation of the inventive method is:

Wherein, X=Cl, Br

Beneficial effects: the synthesis method of 5-bromo-2-picoline of the present invention, firstly, avoids the generation of a large number of 3-position by-products in the traditional preparation method, reduces the waste of raw materials and the load of later separation; secondly, in the preparation of amide In the reaction, the water solubility of 6-methyl-3-pyridinecarboxamide is not good, and the method of directly separating out from water is used, thereby avoiding the problem of serious environmental pollution caused by the use of acid chloride synthesis method in the traditional preparation of amides, and avoiding the problem of serious environmental pollution caused by acid chloride ammonium The solution reaction is very violent and difficult to control, leaving a potential safety hazard that is likely to cause splashing. The route of the invention has mild reaction conditions, high yield, easy-to-obtain raw materials, low cost, and no 3-position by-products in the whole process, which reduces the load of later separation and has industrialization prospects.

Description of drawings

Fig. 1 is the ¹ H NMR spectrum of the 5-bromo-2-picoline prepared according to the method of Example 1;

Fig. 2 is the MS spectrum of 5-bromo-2-picoline prepared according to the method of Example 1.

Detailed ways:

The present invention can be better understood from the following examples. However, those skilled in the art will readily understand that the specific material ratios, process conditions and results described in the examples are only used to illustrate the present invention, and should not and will not limit the present invention described in detail in the claims .

Example 1:

In a 500mL three-necked flask equipped with a stirrer and a thermometer, add 320mL of absolute ethanol, then add 25.6g (0.19mol) of 6-methyl-3-pyridinecarboxylic acid, 20mL of SOCl ₂ The temperature rise was controlled at 50-60°C, and the reaction was followed until the reaction was complete. The solvent was spin-dried, the solid was poured into 200mL saturated NaCO ₃ solution, extracted with CH ₂ Cl ₂ (100mL*2), the organic layers were combined, dried with 20g anhydrous sodium sulfate, filtered, and the brown liquid 6-methanol was spin-dried. 28 g of ethyl-3-pyridinecarboxylate, the yield was 91%, bp 116～117°C.

In a 250mL single-necked flask equipped with magnetic stirring, add 176mL of ammonia water (25% concentration), put 22g (0.13mol) ethyl 6-methyl-3-pyridinecarboxylate into the single-necked flask and stir at room temperature 10-15°C After 6-7 hours, put it in the refrigerator overnight, let the white crystals fully separate out, filter, and wash with water (50mL*2) to obtain 16.7g of white crystals of 6-methyl-3-pyridinecarboxamide with a yield of 92%. m.p.: 199-200°C.

In a 500mL three-neck flask equipped with a stirrer and a thermometer, add 300mL NaOH (concentration 5%) solution, then slowly add 17.3g (0.1mol) bromine, and then 13g (0.1mol) 6-methyl-3-pyridinecarboxamide Slowly add it into a three-necked flask, stir for 20 minutes, and control the temperature of the solution at 0-5°C. Then the oil bath was heated to 70-80°C for 4 hours, the reaction solution was extracted with CH ₂ Cl ₂ (100mL*2), washed with water (100mL*2), dried with 30g of anhydrous sodium sulfate, filtered, spin-dried, and Recrystallize from n-hexane-CH ₂ Cl ₂ (1:1), and filter to obtain 9.4 g of brown powder 6-methyl-3-aminopyridine with a yield of 91%. mp: 95-96°C.

Add 20 mL of 48% HBr into a 100 mL three-necked flask equipped with a stirrer and a thermometer, dissolve 3.1 g (0.022 mol) CuBr in the HBr solution, and slowly add 3 g (0.02 mol) of 6- Methyl-3-aminopyridine, keep the temperature for 10 minutes, slowly add 4.8mL of saturated NaNO ₂ solution dropwise, stir for 1h after the addition, neutralize the reaction solution with 10% sodium hydroxide solution to pH=7~8, and use steam to 3 g of the white product 5-bromo-2-picoline was distilled out, and the yield was 63%. mp: 33-34°C. ¹ H NMR (300MHz, CDCl ₃ ) δ: 2.44 (3H, s), δ: 7.25 (1H, s, J = 8Hz), δ: 7.91 (1H, q, J = 10Hz), δ: 8.55 (1H, d, J = 2.4 Hz). MS (m/z): 172/174 [M+H] ⁺ .

Example 2:

In a 500mL three-necked flask equipped with a stirrer and a thermometer, add 300mL of absolute ethanol, then add 25.6g (0.19mol) of 6-methyl-3-pyridinecarboxylic acid, 20mL of concentrated hydrochloric acid, and install a reflux condenser. The bath temperature was controlled at 70-80°C, and the reaction was followed until the reaction was complete. The solvent was spin-dried, the solid was poured into 200mL saturated NaCO ₃ solution, extracted with CH ₂ Cl ₂ (100mL*2), the organic layers were combined, dried with 20g anhydrous sodium sulfate, filtered, and the brown liquid 6-methanol was spin-dried. Base-3-pyridinecarboxylic acid ethyl ester 25g, the yield is 81%, bp 116～117 ℃.

In a 250mL single-necked flask equipped with magnetic stirring, add 100mL of ammonia water (concentration: 28%), put 22g (0.13mol) ethyl 6-methyl-3-pyridinecarboxylate into the single-necked flask and stir at room temperature 0-10°C After 4-5 hours, put it in the refrigerator overnight, let the white crystals fully separate out, filter, and wash with water (50mL*2) to obtain 13g of white crystals of 6-methyl-3-pyridinecarboxamide with a yield of 71.6%. m.p.: 199-200°C.

In a 500mL three-neck flask equipped with a stirrer and a thermometer, add 300mL NaOH (concentration 5%) solution, then slowly add 11.9g (0.1mol) NaOBr, then 13g (0.1mol) 6-methyl-3-pyridine formamide Slowly add it into a three-necked flask, stir for 20 minutes, and control the temperature of the solution at -5 to 5°C. Then the oil bath was heated to 60-70°C for 4 hours, the reaction solution was extracted with CH ₂ Cl ₂ (100mL*2), washed with water (100mL*2), dried with 30g of anhydrous sodium sulfate, filtered, spin-dried, and Recrystallize from n-hexane-CH ₂ Cl ₂ (1:1), and filter to obtain 9.8 g of brown powder 6-methyl-3-aminopyridine with a yield of 95%. mp: 95-96°C.

In a 100mL three-necked flask equipped with a stirrer and a thermometer, add 25mL of 48% HBr, dissolve 4.0g (0.028mol) CuBr in the HBr solution, and slowly add 3g (0.02mol) of 6- Methyl-3-aminopyridine, keep the temperature for 10 minutes, slowly add 5.2mL of saturated NaNO ₂ solution dropwise, stir for 1h after the addition, neutralize the reaction solution with 10% sodium hydroxide solution to pH=7~8, and use steam to 3 g of the white product 5-bromo-2-picoline was distilled out, and the yield was 67.2%. mp: 33-34°C. ¹ H NMR (300MHz, CDCl ₃ ) δ: 2.44 (3H, s), δ: 7.25 (1H, s, J = 8Hz), δ: 7.91 (1H, q, J = 10Hz), δ: 8.55 (1H, d, J = 2.4 Hz). MS (m/z): 172/174 [M+H] ⁺ .

Example 3:

In a 500mL three-necked flask equipped with a stirrer and a thermometer, add 350mL of absolute ethanol, then add 25.6g (0.19mol) of 6-methyl-3-pyridinecarboxylic acid and 15mL of H ₂ SO ₄ respectively, and install a reflux condenser. The oil bath temperature was controlled at 70-80°C, and the reaction was followed until the reaction was complete. The solvent was spin-dried, the solid was poured into 200mL saturated NaCO ₃ solution, extracted with CH ₂ Cl ₂ (100mL*2), the organic layers were combined, dried with 20g anhydrous sodium sulfate, filtered, and the brown liquid 6-methanol was spin-dried. 26 g of ethyl-3-pyridinecarboxylate, yield 84.5%, bp 116～117°C.

In a 250mL single-necked flask equipped with magnetic stirring, add 200mL of ammonia water (concentration: 25%), put 22g (0.13mol) ethyl 6-methyl-3-pyridinecarboxylate into the single-necked flask and stir at room temperature 15-25°C After 7-8 hours, put it in the refrigerator overnight, let the white crystals fully separate out, filter, and wash with water (50mL*2) to obtain 17g of white crystals of 6-methyl-3-pyridinecarboxamide with a yield of 94%. m.p.: 199-200°C.

Add 300mL NaOH (5%) solution in the 500mL three-neck flask equipped with stirrer, thermometer, then slowly add 7.45g g (0.1mol) NaOCl, then slowly add 13g (0.1mol) 6-methyl-3-pyridine formamide Add it into a three-neck flask, stir for 20 minutes, and control the temperature of the solution at 0-5°C. Then the oil bath was heated to 60-70°C for 5 hours, the reaction solution was extracted with CH ₂ Cl ₂ (100mL*2), washed with water (100mL*2), dried with 30g of anhydrous sodium sulfate, filtered, spin-dried, and Recrystallize from n-hexane-CH ₂ Cl ₂ (1:1), and filter to obtain 9.2 g of brown powder 6-methyl-3-aminopyridine with a yield of 89%. mp: 95-96°C.

Add 22mL of 48% HBr to a 100mL three-necked flask equipped with a stirrer and a thermometer, dissolve 3.7g (0.026mol) CuBr in the HBr solution, and slowly add 3g (0.02mol) in an ice bath to maintain the temperature at -3 to 5°C 6-Methyl-3-aminopyridine, keep the temperature for 10 minutes, slowly add 5mL of saturated _NaNO2 solution dropwise, stir for 1h after the addition, neutralize the reaction solution with 10% sodium hydroxide solution to pH=7~8, and add water 2.4 g of the white product 5-bromo-2-picoline was distilled by steam, and the yield was 50%. mp: 33-34°C. ¹ H NMR (300MHz, CDCl ₃ ) δ: 2.44 (3H, s), δ: 7.25 (1H, s, J = 8Hz), δ: 7.91 (1H, q, J = 10Hz), δ: 8.55 (1H, d, J = 2.4 Hz). MS (m/z): 172/174 [M+H] ⁺ .

Example 4:

The same as the preparation method of Example 3, the difference is: in a 500mL three-necked flask equipped with a stirrer and a thermometer, add 300mL of absolute ethanol, then add 15g of 6-methyl-3-pyridinecarboxylic acid, 9mL of H ₂ SO _4. Install a reflux condenser, control the temperature rise of the oil bath at 40-50°C, and track the reaction until the reaction is complete.

Example 5:

With the preparation method of embodiment 3, difference is: in the 250mL single-necked flask that magnetic stirring is housed, add 200mL ammoniacal liquor (concentration 25%), with 50g 6-methyl-3-pyridine carboxylate ethyl esters, drop into single-necked flask Stir at room temperature 40-50°C for 4-5 hours.

Embodiment 6:

With the preparation method of Example 3, the difference is: add 300mLNaOH (5%) solution in the 500mL there-necked flask equipped with stirrer, thermometer, then slowly add 0.13mol NaOCl, then add 0.1mol 6-methyl-3 - Pyridinecarboxamide was slowly added into the three-necked flask, stirred for 20 minutes, and the temperature of the solution was controlled at 0-5°C. Then the temperature of the oil bath was raised to 30-40° C. and kept for 5 hours.

Claims (9)

1, a kind of synthetic method of 5-bromo-2-methyl-pyridine is characterized in that this method comprises the steps:

(1) utilizes 6-methyl-3-pyridine carboxylic acid to be raw material, in the presence of acid, react generation 6-methyl-3-pyridine carboxylic acid ethyl ester down at 30～80 ℃ with ethanol;

(2) 6-methyl-3-pyridine carboxylic acid ethyl ester is added in the ammoniacal liquor, reacted 4～10 hours down, obtain 6-methyl-3-pyridine carboxamide at-5～60 ℃;

(3) with 6-methyl-3-pyridine carboxamide in containing the sodium hydroxide solution of halogen, temperature is 20～100 ℃ of down reactions 1～6 hour, obtains 6-methyl-3-aminopyridine;

(4) 6-methyl-3-aminopyridine is added in the HBr solution, in the presence of the CuBr of catalytic amount, drip NaNO ₂Solution, temperature are controlled at-10～20 ℃, react 1～6 hour, get 5-bromo-2-picoline.

2, the synthetic method of 5-bromo-2-methyl-pyridine according to claim 1, it is characterized in that: the acid described in the step (1) is hydrochloric acid, sulfuric acid or SOCl ₂

3, the synthetic method of 5-bromo-2-methyl-pyridine according to claim 1 and 2 is characterized in that: in the step (1), in the ethanol of every 100mL, add the 6-methyl-3-pyridine carboxylic acid of 5～10g and the acid of 3～10mL.

4, the synthetic method of 5-bromo-2-methyl-pyridine according to claim 1 is characterized in that: in the step (2), the mass percent concentration of described ammoniacal liquor is 25～28%.

5, according to the synthetic method of claim 1 or 4 described 5-bromo-2-methyl-pyridines, it is characterized in that: in the step (2), in every 100mL ammoniacal liquor, the add-on of 6-methyl-3-pyridine carboxylic acid ethyl ester is 10～25g.

6, the synthetic method of 5-bromo-2-methyl-pyridine according to claim 1 is characterized in that: in the step (3), described halogen is Cl ₂, Br ₂, NaOCl or NaOBr.

7, according to the synthetic method of claim 1 or 6 described 5-bromo-2-methyl-pyridines, it is characterized in that: in the step (3), the mol ratio of 6-methyl-3-pyridine carboxamide, halogen and sodium hydroxide is 1: 1～1.3: 2～5, and the mass percent concentration of NaOH solution is 3～10%.

8, the synthetic method of 5-bromo-2-methyl-pyridine according to claim 1 is characterized in that: in the step (4), the mass percent concentration of described HBr solution is 40～50%.

9, according to the synthetic method of claim 1 or 8 described 5-bromo-2-methyl-pyridines, it is characterized in that: in the step (4), the mol ratio of 6-methyl-3-aminopyridine and CuBr is 1: 1.0～1.5, in every 100mL HBr solution, 6-methyl-3-aminopyridine add-on is 10～20g, saturated NaNO ₂The add-on of solution is 15～30mL.

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