A preparation method of 3-fluoro-4-aminopyridine

Abstract

The invention discloses a method for preparing 3-fluoro-4-aminopyridine, wherein 4-halopyridine and ammonia water are used as raw materials to react in the presence of a copper catalyst to generate 4-aminopyridine, and then a substitution reaction is carried out with a fluorinated reagent in the presence of 1,10-phenanthroline, ZnCl2 and n-butyl lithium to generate 3-fluoro-4-aminopyridine. The route has mild reaction conditions, a short reaction route, low cost, good safety, and good industrial production application prospects.

Description

Technical Field

[0001] The invention relates to the field of drug synthesis, and in particular to a method for preparing 3-fluoro-4-aminopyridine. Background Art

[0002] 3-Fluoro-4-aminopyridine, its structural formula is: , is a very important fluorinated intermediate in the pharmaceutical field, and representative drugs include transforming growth factor β inhibitors and coagulation inhibitors .

[0003] The preparation methods of 3-fluoro-4-aminopyridine in the prior art are mainly as follows:

[0004] US20030092679A discloses a method for synthesizing 3-fluoro-4-aminopyridine: 3-fluoropyridine is used as a raw material, oxidized with hydrogen peroxide to obtain pyridine nitrogen oxide, nitrated with mixed acid at high temperature to obtain a nitro compound, and then the nitro compound is reduced to obtain 3-fluoro-4-aminopyridine. The reaction route is as follows: ;

[0005] However, the above method has a low total yield, generates a lot of by-products in the nitration reaction, and is not easy to separate and purify. In addition, the intermediate product pyridine nitrogen oxide is prone to explosion, and the nitration reaction needs to be carried out at high temperature, which is extremely dangerous. Therefore, this method cannot meet the needs of industrial production safety.

[0006] CN101863829A discloses a method for synthesizing 3-fluoro-4-aminopyridine: 1) using 3-fluoropyridine (1A) as a raw material, deprotonating the raw material with a strong base, and reacting the resulting mixture with carbon dioxide to obtain 3-fluoro-4-pyridinecarboxylic acid or a metal salt thereof (1B); 2) subjecting the compound (1B) to an esterification reaction to obtain a formate ester thereof (1C); 3) subjecting the 3-fluoro-4-pyridinecarboxylate ester (1C) to an aminolysis reaction to obtain 3-fluoro-4-pyridinecarboxamide (1D); and 4) subjecting the 3-fluoro-4-pyridinecarboxamide (1D) to a Hofmann degradation reaction to obtain 3-fluoro-4-aminopyridine (1). The reaction route is as follows: ;

[0007] However, the above method has a long process route, resulting in many by-products and a low overall yield of only 98%, which is not conducive to industrial production.

[0008] In summary, the existing technologies generally have problems such as low yield and purity, long reaction route, and low safety. Therefore, there is an urgent need to provide a new method for preparing 3-fluoro-4-aminopyridine with high yield, high purity, mild reaction conditions, and suitable for industrial production. Summary of the invention

[0009] The purpose of the present invention is to provide a preparation process of 3-fluoro-4-aminopyridine to solve the problems of low yield and purity, long reaction route, low safety and the like in the prior art.

[0010] In order to solve the above technical problems, the present invention provides the following technical solutions: ;

[0011] The specific steps are:

[0012] 1) Using 4-halopyridine and ammonia as raw materials, 4-aminopyridine is reacted in the presence of a copper catalyst;

[0013] 2) Using 4-aminopyridine as a raw material, a substitution reaction is carried out with a fluorinated reagent in the presence of 1,10-phenanthroline, ZnCl2, and n-butyl lithium to generate 3-fluoro-4-aminopyridine;

[0014] Wherein, R is Cl, Br, I;

[0015] Step 1) the copper catalyst is selected from copper powder, CuI, CuCl, and copper acetate;

[0016] Step 2) The fluorination agent is selected from KF and CsF.

[0017] As a preferred embodiment of the present invention, the mass fraction of aqueous ammonia is 30-50%, preferably 30%.

[0018] As a preferred embodiment of the present invention, step 1) and step 2) are carried out in an inert gas, wherein the inert gas is argon or nitrogen, preferably argon.

[0019] As a preferred embodiment of the present invention, the molar ratio of the 4-halopyridine to aqueous ammonia is 1: (5-10), preferably 1: (7-10); the molar ratio of the 4-halopyridine to the copper catalyst is 1: (0.05-0.1).

[0020] As a preferred embodiment of the present invention, the 1,10-phenanthroline, ZnCl2 and n-butyl lithium form an efficient Li-Zn composite catalyst. Preferably, the molar ratio of 1,10-phenanthroline, ZnCl2 and n-butyl lithium is 3:1:3, the molar ratio of the 4-halopyridine to 1,10-phenanthroline is 1: (0.1~0.5), and the molar ratio of the 4-halopyridine to the fluorinated reagent is 1: (1~1.5), preferably 1: (1.1~1.3).

[0021] Preferably, 1,10-phenanthroline (5.4 g, 0.03 mol), ZnCl2 (1.36 g, 0.01 mol), anhydrous tetrahydrofuran (100 mL) are added to a reactor at 0°C, and then the n-butyllithium solution is slowly added dropwise.

[0022] As a preferred embodiment of the present invention, in step 1), the reaction temperature is 60-100° C., preferably 80-100° C.; and the reaction time is 5-15 h.

[0023] As a preferred embodiment of the present invention, in step 2), the reaction temperature is 20-50°C, preferably room temperature; and the reaction time is 5-10 hours.

[0024] As a preferred embodiment of the present invention, the solvent in step 2) is selected from DMSO, DMF, THF, ethyl acetate, dichloromethane, chloroform, acetonitrile, preferably THF.

[0025] As a preferred embodiment of the present invention, in step 1), after the reaction is completed, the mixture is cooled to room temperature, extracted, and the organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude 4-aminopyridine product, which is directly subjected to the next step of reaction without further purification. Preferably, the solvent used for extraction is ethyl acetate.

[0026] As a preferred embodiment of the present invention, in step 2), after the reaction is completed, sodium thiosulfate aqueous solution is added to quench the reaction, extraction is performed, the organic phases are combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by silica gel column chromatography to obtain 3-fluoro-4-aminopyridine as a light yellow solid. Preferably, the solvent used for extraction is ethyl acetate; the eluent for silica gel column chromatography is DCM:PE=1:2.

[0027] The present invention has achieved the following beneficial effects:

[0028] 1) The present invention uses 4-halopyridine and ammonia water as raw materials to react in the presence of a copper catalyst to generate 4-aminopyridine, and then undergoes a substitution reaction with a fluorinated reagent in the presence of 1,10-phenanthroline, ZnCl2, and n-butyl lithium to generate 3-fluoro-4-aminopyridine. This route prepares 4-aminopyridine in two steps, with a total yield of more than 90% and a purity of more than 99.5%. The reaction conditions are mild, the reaction route is short, the cost is low, the safety is good, and it has good prospects for industrial production and application.

[0029] 2) In particular, the 1,10-phenanthroline, ZnCl2 and n-butyl lithium of the present invention can form a highly efficient Li-Zn composite catalyst, which makes the ortho-fluorination reaction highly selective, thereby ensuring a high yield and purity. DETAILED DESCRIPTION

[0030] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0031] The present invention is further explained below in conjunction with specific implementation modes.

[0032] Example 1

[0033] Step 1: Synthesis of 4-aminopyridine

[0034] Under argon environment, 4-bromopyridine (15.80 g, 0.1 mol) and 30% ammonia solution (60 mL) were slowly added to a 250 mL reaction vessel, followed by copper powder catalyst (0.64 g, 0.01 mol), and the mixture was heated to 100 °C for 10 h. After the reaction, the mixture was cooled to room temperature, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude 4-aminopyridine product, which was directly subjected to the next step without further purification.

[0035] Step 2: Synthesis of 3-fluoro-4-aminopyridine

[0036] Under argon atmosphere, 1,10-phenanthroline (5.4 g, 0.03 mol), ZnCl2 (1.36 g, 0.01 mol), anhydrous tetrahydrofuran (100 mL) were added to the reactor at 0°C, and then n-butyl lithium solution (1.92 g, 0.03 mol) was slowly added dropwise. After stirring for 1 hour, 4-aminopyridine and KF (6.96 g, 0.12 mol) prepared in step 1 were added, and the reaction was stirred at room temperature for 6 hours. After the reaction, sodium thiosulfate aqueous solution was added to quench the reaction, and the mixture was extracted with dichloromethane (3×100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (eluent DCM:PE (v / v) = 1:2) to obtain 9.83 g of a light yellow solid, with a total yield of 87.8% in two steps and a purity of 99.6% by HPLC.

[0037] LC-MS (ESI): [M+H] + =113.2.

[0038] 1 H-NMR (500 MHz, DMSO-d6): δ(ppm): 8.31 (d,1H), 7.92 (d,1H), 6.77-6.65(m,1H), 6.33 (s,2H).

[0039] Example 2

[0040] Step 1: Synthesis of 4-aminopyridine

[0041] Under argon environment, 4-chloropyridine (11.40 g, 0.1 mol) and 30% ammonia solution (50 mL) were slowly added to a 250 mL reaction vessel, followed by the addition of CuI catalyst (0.95 g, 0.005 mol), and the mixture was heated to 80 °C for 12 h. After the reaction, the mixture was cooled to room temperature, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude 4-aminopyridine product, which was directly subjected to the next step without further purification.

[0042] Step 2: Synthesis of 3-fluoro-4-aminopyridine

[0043] Under argon atmosphere, 1,10-phenanthroline (10.8 g, 0.06 mol), ZnCl2 (2.72 g, 0.02 mol), anhydrous tetrahydrofuran (100 mL) were added to the reactor at 0°C, and then n-butyl lithium solution (3.84 g, 0.06 mol) was slowly added dropwise. After stirring for 1 hour, 4-aminopyridine and CsF (16.7 g, 0.11 mol) prepared in step 1 were added, and the reaction was stirred at room temperature for 5 hours. After the reaction, sodium thiosulfate aqueous solution was added to quench the reaction, and the mixture was extracted with dichloromethane (3×100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (eluent DCM:PE (v / v) = 1:2) to obtain 10.25 g of a light yellow solid, with a total yield of 91.5% in two steps and a purity of 99.7% by HPLC.

[0044] LC-MS (ESI): [M+H] + =113.2.

[0045] 1 H-NMR (500 MHz, DMSO-d6): δ(ppm): 8.31 (d,1H), 7.92 (d,1H), 6.77-6.65(m,1H), 6.33 (s,2H).

[0046] Example 3

[0047] Step 1: Synthesis of 4-aminopyridine

[0048] Under argon atmosphere, 4-iodopyridine (20.50 g, 0.1 mol) and 30% ammonia solution (70 mL) were slowly added to a 250 mL reaction vessel, followed by copper acetate catalyst (18.2 g, 0.01 mol), and the mixture was heated to 90 °C for 7 h. After the reaction, the mixture was cooled to room temperature, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude 4-aminopyridine product, which was directly subjected to the next step without further purification.

[0049] Step 2: Synthesis of 3-fluoro-4-aminopyridine

[0050] Under argon atmosphere, 1,10-phenanthroline (5.4 g, 0.03 mol), ZnCl2 (1.36 g, 0.01 mol), anhydrous tetrahydrofuran (100 mL) were added to the reactor at 0°C, and then n-butyl lithium solution (1.92 g, 0.03 mol) was slowly added dropwise. After stirring for 1 hour, 4-aminopyridine and KF (8.7 g, 0.15 mol) prepared in step 1 were added, and the reaction was stirred at room temperature for 8 hours. After the reaction, sodium thiosulfate aqueous solution was added to quench the reaction, and the mixture was extracted with dichloromethane (3×100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (eluent DCM: PE (v / v) = 1:2) to obtain 10.1 g of light yellow solid, with a total yield of 90.2% in two steps and a purity of 99.5% by HPLC.

[0051] LC-MS (ESI): [M+H] + =113.2.

[0052] 1 H-NMR (500 MHz, DMSO-d6): δ(ppm): 8.31 (d,1H), 7.92 (d,1H), 6.77-6.65(m,1H), 6.33 (s,2H).

[0053] The above embodiments are merely examples for clear explanation, and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived from these are still within the protection scope of the invention.

Claims

1. A method for preparing 3-fluoro-4-aminopyridine, characterized in that: Its synthetic route is: The specific steps are: 1) Using 4-halopyridine and ammonia water as raw materials, reacting in the presence of a copper catalyst to generate 4-aminopyridine; 2) Using 4-aminopyridine as a raw material, a substitution reaction is carried out with a fluorination reagent in the presence of 1,10-phenanthroline, ZnCl2 and n-butyl lithium to generate 3-fluoro-4-aminopyridine; Wherein, R is Cl, Br, I; Step 1) The copper catalyst is selected from copper powder, CuI, CuCl, and copper acetate; Step 2) The fluorination agent is selected from KF and CsF.

2. The preparation method according to claim 1, characterized in that: The mass fraction of ammonia water is 30-50%.

3. The preparation method according to claim 1, characterized in that: Step 1) and step 2) are carried out in an inert gas, which is argon or nitrogen.

4. The preparation method according to claim 1, characterized in that: The molar ratio of the 4-halopyridine to the ammonia water is 1:(5-10), and the molar ratio of the 4-halopyridine to the copper catalyst is 1:(0.05-0.1).

5. The preparation method according to claim 1, characterized in that: The molar ratio of the 1,10-phenanthroline, ZnCl2 and n-butyl lithium is 3:1:3, the molar ratio of the 4-halopyridine to 1,10-phenanthroline is 1:(0.1-0.5), and the molar ratio of the 4-halopyridine to the fluorinated reagent is 1:(1-1.5).

6. The preparation method according to claim 1, characterized in that: In step 1), the reaction temperature is 60-100° C. and the reaction time is 5-15 h.

7. The preparation method according to claim 1, characterized in that: In step 2), the reaction temperature is 20-50° C. and the reaction time is 5-10 h.

8. The preparation method according to claim 1, characterized in that: In step 1), after the reaction is completed, the mixture is cooled to room temperature, extracted, and the organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude 4-aminopyridine product, which is directly subjected to the next step of reaction without further purification.

9. The preparation method according to claim 1, characterized in that: In step 2), after the reaction is completed, an aqueous sodium thiosulfate solution is added to quench the reaction, and the organic phases are extracted and combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by silica gel column chromatography to obtain 3-fluoro-4-aminopyridine as a light yellow solid.

10. The preparation method according to claim 1, characterized in that: The solvent in step 2) is selected from DMSO, DMF, THF, ethyl acetate, dichloromethane, chloroform, and acetonitrile.

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