Preparation method of 1-(4-fluoro-3-pyridyl) ethanone

Abstract

The invention relates to the technical field of synthesis of pharmaceutical compounds, and particularly discloses a preparation method of 1-(4-fluoro-3-pyridyl) ethanone. According to the preparation method provided by the invention, 4-aminopyridine is taken as a starting material and reacts with fluoboric acid and sodium nitrite, fluorine is firstly applied to a pyridine ring to obtain 4-fluoropyridine hydrochloride, and then the 4-fluoropyridine hydrochloride reacts with lithium diisopropylamide and N-methoxy-N-methylacetamide to obtain 1-(4-fluoro-3-pyridyl) ethanone. According to the preparation method provided by the invention, the raw materials are cheap and easy to obtain, the operation in the preparation process is simple, and the yield is high.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical compound synthesis, in particular to a preparation method of 1-(4-fluoro-3-pyridyl)ethanone. BACKGROUND

[0002] 1-(4-fluoro-3-pyridyl)ethanone (or named as 1-(4-fluoropyridin-3-yl)ethan-1-one) and its derivatives are important chemical and pharmaceutical intermediates, which are widely used in the fields of pharmaceutical chemical industry and materials. For example, the patent document with publication number CN117897384A discloses that 1-(4-fluoro-3-pyridyl)ethanone is an important intermediate for preparing CDK2 inhibitors. The patent document also discloses a preparation method of 1-(4-fluoro-3-pyridyl)ethanone, and the process route adopted is as follows: The preparation method uses 4-fluoropyridine-3-carboxylic acid, methoxy(methyl)amine hydrochloride, N,N-diisopropylethylamine, methyl magnesium bromide as raw materials, and 1-(4-fluoro-3-pyridyl)ethanone is prepared through amidation reaction and hydrolysis reaction. The raw material 4-fluoropyridine-3-carboxylic acid adopted in the method has a high price, and the overall yield is also low, which is not suitable for industrial scale-up production.

[0003] Based on the above status, the present application aims to provide a new process for preparing 1-(4-fluoro-3-pyridyl)ethanone, so as to be used for industrial scale-up production. SUMMARY

[0004] The technical problem solved by the present application is to provide a preparation method of 1-(4-fluoro-3-pyridyl)ethanone.

[0005] To solve the above technical problem, the technical solution adopted by the present application is as follows: a preparation method of 1-(4-fluoro-3-pyridyl)ethanone, and the reaction formula of the preparation method is as follows: The preparation method comprises the following steps: (1) 4-aminopyridine is reacted with fluoroboric acid and sodium nitrite to obtain a reaction liquid 1; (2) The reaction liquid 1 is neutralized, and then an organic phase is obtained through extraction separation. The organic phase is contacted with hydrogen chloride to prepare 4-fluoropyridine hydrochloride; (3) The 4-fluoropyridine hydrochloride is reacted with diisopropyl lithium and N-methoxy-N-methylacetamide to obtain 1-(4-fluoro-3-pyridyl)ethanone.

[0006] As an embodiment of the present application, in step (1), the molar ratio of the 4-aminopyridine to the fluoroboric acid is 1: (1.1-3.0).

[0007] As an embodiment of the present application, in step (1), the molar ratio of the 4-aminopyridine to the sodium nitrite is 1: (1.1-2.5).

[0008] As an embodiment of the present application, in step (3), the molar ratio of the 4-fluoropyridine hydrochloride to the lithium diisopropylamide is 1: (1.2-2.2).

[0009] As an embodiment of the present application, in step (3), the molar ratio of the 4-fluoropyridine hydrochloride to the N-methoxy-N-methylacetamide is 1: (0.9-1.5).

[0010] As a preferred embodiment of the present application, in step (1), the molar ratio of the 4-aminopyridine to the fluoroboric acid is 1: (1.9-2.1).

[0011] As a preferred embodiment of the present application, in step (1), the molar ratio of the 4-aminopyridine to the sodium nitrite is 1: (1.9-2.1).

[0012] As a preferred embodiment of the present application, in step (3), the molar ratio of the 4-fluoropyridine hydrochloride to the lithium diisopropylamide is 1: (2.0-2.2).

[0013] As a preferred embodiment of the present application, in step (3), the molar ratio of the 4-fluoropyridine hydrochloride to the N-methoxy-N-methylacetamide is 1: (1.0-1.2).

[0014] As an embodiment of the present application, in step (2), the contacting reaction of the organic phase with hydrogen chloride is that hydrogen chloride gas is introduced into the organic phase until the pH value of the reaction system is 2-3.

[0015] As an embodiment of the present application, the reaction in step (3) is carried out in an inert gas atmosphere.

[0016] As a preferred embodiment of the present application, the preparation method provided by the present application comprises the following steps: S1: cooling fluoroboric acid with a mass percentage concentration of 40% to -20℃-10℃, adding 4-aminopyridine, stirring to react, then adding sodium nitrite, continuing to stir to react, monitoring during the reaction, and obtaining reaction liquid 1 when the 4-aminopyridine raw material is completely reacted; S2: keeping the temperature of the reaction liquid 1 at -20℃ to -10℃, adding sodium hydroxide to neutralize, until the pH value of the reaction liquid 1 is 7.0±0.3, the neutralization treatment is completed; extracting with an organic solvent and separating the organic phase, passing hydrogen chloride gas into the organic phase until the pH value of the reaction system is 2-3, and separating the obtained solid, which is 4-fluoropyridine hydrochloride; S3: mixing tetrahydrofuran with 4-fluoropyridine hydrochloride in an inert gas atmosphere, cooling the system to -78℃ to -60℃, adding lithium diisopropylamide, stirring and reacting, then adding N-methoxy-N-methylacetamide, and then warming to 20℃ to 30℃, stirring and reacting, and stopping the reaction after monitoring that the 4-fluoropyridine hydrochloride is completely reacted; then quenching the reaction liquid, and separating after treatment to obtain 1-(4-fluoro-3-pyridyl)ethanone.

[0017] The preparation method of 1-(4-fluoro-3-pyridyl)ethanone provided by the present application uses 4-aminopyridine as a starting material, reacts with fluoroboric acid and sodium nitrite to first fluorinate on the pyridine ring to obtain 4-fluoropyridine hydrochloride, and then reacts with lithium diisopropylamide and N-methoxy-N-methylacetamide to obtain 1-(4-fluoro-3-pyridyl)ethanone. The preparation method provided by the present application has the advantages that the raw materials are cheap and easy to obtain, the operation is simple during the preparation process, and the product yield is high.

[0018] In the preparation method provided by the present application, the 4-fluoropyridine hydrochloride obtained in the first step reaction is a solid, which can be separated by direct filtration, and the operation is simple; and the 4-fluoropyridine hydrochloride has high purity, which is convenient for obtaining the target product 1-(4-fluoro-3-pyridyl)ethanone with high purity in the next step, and has obvious production advantages and is suitable for large-scale production. BRIEF DESCRIPTION OF DRAWINGS

[0019] Figure 1 is the H-NMR spectrum of 1-(4-fluoro-3-pyridyl)ethanone prepared in Example 1 of the present application. 1 H-NMR spectrum; Figure 2 is the LCMS spectrum of 1-(4-fluoro-3-pyridyl)ethanone prepared in Example 1 of the present application. DETAILED DESCRIPTION

[0020] The technical solutions of the present application will be described in detail below through specific examples. The following examples are intended to further illustrate the content of the present application, rather than limit the scope of protection of the claims of the present application.

[0021] In the following examples, the reagents used are all commercially available products.

[0022] The technical solutions of the present application will be described in detail below through specific examples.

[0023] Example 1 The embodiment provides a preparation method of 1-(4-fluoro-3-pyridyl)ethanone, and a reaction formula is as follows: 1 2 3 The preparation method specifically comprises the following steps: Step 1: 466 g of fluoboric acid with a mass percentage concentration of 40% (2.12 mol) is added into a reaction bottle, and cooling is performed to-20 ℃, 100 g (1.06 mol) of 4-aminopyridine (a compound of formula 1) is added in stirring, after stirring for 15 min, the temperature of a reaction liquid system is kept at-10 ℃, sodium nitrite (147 g, 2.13 mol) aqueous solution is slowly added dropwise, and then stirring is continuously performed for 1 h, complete reaction is detected by GC, and reaction liquid 1 is obtained; The temperature of the reaction liquid 1 is kept at-20 ℃, sodium hydroxide aqueous solution is added dropwise in stirring for neutralization, until the pH value of the reaction liquid 1 is 7.1, then dichloromethane is used for extraction, an organic phase is separated, the organic phase is dried by using anhydrous sodium sulfate, then hydrogen chloride gas is introduced into the organic phase until the pH value is 2.4, and 127.9 g (0.96 mol) of white solid, that is, 4-fluoropyridine hydrochloride (a compound of formula 2) is obtained by filtration, and the yield is 91%; Step 2: 1100 mL of tetrahydrofuran is added into a reaction bottle in a nitrogen atmosphere, then 110.7 g (0.83 mol) of 4-fluoropyridine hydrochloride is added, the system is cooled and kept at about-68 ℃, 870 mL of diisopropylaminolithium with a concentration of 2 mol / L (1.74 mol) is added dropwise, stirring is performed for 3 h, then 94 g (0.91 mol) of N-methoxy-N-methylacetamide is added dropwise, then the temperature is slowly increased to 25 ℃, stirring is performed for 8 h, and complete reaction is detected by GC; The reaction liquid is slowly poured into ice water for quenching, then extraction is performed twice by using ethyl acetate, the organic phase is dried by using anhydrous sodium sulfate and then concentrated, and 97.3 g (0.70 mol) of product 1-(4-fluoro-3-pyridyl)ethanone (a compound of formula 3) is obtained by column chromatography purification, and the yield is 84%. The total yield is 76% in calculation.

[0024] Example 2 The embodiment provides a preparation method of 1-(4-fluoro-3-pyridyl)ethanone, and a reaction formula is as follows: Step 1: 257 g of fluoboric acid with a mass percentage concentration of 40% (1.17 mol) was added to a reaction bottle, cooled to -20°C, and 100 g (1.06 mol) of 4-aminopyridine was added under stirring. After stirring for 15 min, the temperature of the reaction liquid system was maintained at -10°C, and sodium nitrite (81 g, 1.17 mol) aqueous solution was slowly added dropwise. After 1 h of continuous stirring, the reaction was completed as detected by GC, and reaction liquid 1 was obtained; The temperature of reaction liquid 1 was maintained at -20°C, and sodium hydroxide aqueous solution was added dropwise under stirring for neutralization until the pH value of reaction liquid 1 was 7.0. Then, dichloromethane was used for extraction, and the organic phase was separated, dried with anhydrous sodium sulfate, and then hydrogen chloride gas was introduced into the organic phase until the pH was 2.8. After filtration, 100.7 g (0.75 mol) of white solid, i.e., 4-fluoropyridine hydrochloride, was obtained, and the yield was 71%. Step 2: 1100 mL of tetrahydrofuran was added to a reaction bottle under a nitrogen atmosphere, and then 110.7 g (0.83 mol) of 4-fluoropyridine hydrochloride was added. The system was cooled and maintained at about -68°C, and 566 mL of lithium diisopropylamide with a concentration of 2 mol / L (1.13 mol) was added dropwise. After stirring for 3 h, 78 g (0.76 mol) of N-methoxy-N-methylacetamide was added dropwise, and then the temperature was slowly increased to 25°C. After stirring for 8 h, the reaction was completed as detected by GC. The reaction liquid was slowly poured into ice water for quenching, and then extracted twice with ethyl acetate. After drying with anhydrous sodium sulfate, the organic phase was concentrated and purified by column chromatography to obtain 66.8 g (0.48 mol) of product 1-(4-fluoro-3-pyridyl)ethanone, and the yield was 58%. The total yield was 41%.

[0025] Example 3 The embodiment provides a preparation method of 1-(4-fluoro-3-pyridyl)ethanone, and the reaction formula is the same as that in Embodiment 1. The preparation method specifically includes the following steps. Step 1: 257 g of fluoboric acid with a mass percentage concentration of 40% (1.17 mol) was added to a reaction bottle, cooled to -20°C, and 100 g (1.06 mol) of 4-aminopyridine was added under stirring. After stirring for 15 min, the temperature of the reaction liquid system was maintained at -10°C, and sodium nitrite (81 g, 1.17 mol) aqueous solution was slowly added dropwise. After 1 h of continuous stirring, the reaction was completed as detected by GC, and reaction liquid 1 was obtained; The temperature of the reaction liquid 1 was maintained at -20°C, and sodium hydroxide aqueous solution was added dropwise for neutralization under stirring until the pH value of the reaction liquid 1 was 6.9, then extracted with dichloromethane, and the organic phase was separated, dried with anhydrous sodium sulfate, then hydrogen chloride gas was introduced into the organic phase until the pH was 2.1, and 106.4 g (0.80 mol) of white solid, i.e. 4-fluoropyridine hydrochloride, was obtained by filtration, with a yield of 75%; Step 2: 1100 mL of tetrahydrofuran was added to a reaction bottle under a nitrogen atmosphere, then 106.4 g (0.80 mol) of 4-fluoropyridine hydrochloride was added, the system was cooled and maintained at about -68°C, 598 mL of lithium diisopropylamide (1.20 mol) with a concentration of 2 mol / L was added dropwise, stirred for 3 h, then 123 g (1.19 mol) of N-methoxy-N-methylacetamide was added, then slowly raised to 25°C, stirred for 8 h, and GC detection showed that the reaction was complete; The reaction liquid was slowly poured into ice water for quenching, then extracted with ethyl acetate twice, the organic phase was dried with anhydrous sodium sulfate, then concentrated, and purified by column chromatography to obtain 67.6 g (0.49 mol) of product 1-(4-fluoro-3-pyridyl)ethanone, with a yield of 61%. The total yield was 46%.

[0026] The 1-(4-fluoro-3-pyridyl)ethanone prepared in Example 1 was detected by nuclear magnetic resonance analysis 1 The H-NMR spectrum is shown in Figure 1 The LCMS spectrum is shown in Figure 2 It can be seen from Figure 1 , Figure 2 that the target product 1-(4-fluoro-3-pyridyl)ethanone was successfully prepared in Example 1, and the product purity was greater than 95%.

[0027] Further scale-up experiments were carried out, which included the following steps: Step 1: 46.6 kg of fluoroboric acid with a mass percentage concentration of 40% (212 mol) was added to a reaction bottle, cooled and cooled to -20°C, then 10 kg (106 mol) of 4-aminopyridine was added under stirring, stirred for 30 min, then the temperature of the reaction liquid system was maintained at -15°C, and sodium nitrite (14.7 kg, 213 mol) aqueous solution was slowly added, then continued to stir for 2.5 h, and GC detection showed that the reaction was complete, obtaining reaction liquid 1; The temperature of the reaction liquid 1 was maintained at -20°C, and sodium hydroxide aqueous solution was added dropwise for neutralization under stirring until the pH value of the reaction liquid 1 was 6.9, then extracted with dichloromethane, and the organic phase was separated, dried with anhydrous sodium sulfate, then hydrogen chloride gas was introduced into the organic phase until the pH was 2.1, and 106.4 g (0.80 mol) of white solid, i.e. 4-fluoropyridine hydrochloride, was obtained by filtration, with a yield of 75%; Step 2: 30L of tetrahydrofuran was added into a reaction bottle under nitrogen atmosphere, then 11.1kg (83mol) of 4-fluoropyridine hydrochloride was added, the system was cooled and kept at about -70℃, 87L of 2mol / L diisopropylamine lithium (174mol) was added, stirred for 3h, then 9.4kg (91mol) of N-methoxy-N-methylacetamide was added, then slowly increased to 25℃, stirred for 12h, GC detection showed that the reaction was complete; The reaction solution was slowly poured into ice water for quenching, then extracted with ethyl acetate for 4 times, the organic phase was dried with anhydrous sodium sulfate and concentrated, then purified by column chromatography to obtain 9.8kg (70.5mol) of product 1-(4-fluoro-3-pyridyl)ethanone, the yield was 85%. The total yield was 75%.

[0028] The above only describes the embodiments of the present application, and does not limit the patent scope of the present application, any equivalent transformation or direct or indirect application in other related technical fields by using the content of the present application is included in the patent protection scope of the present application.

Claims

1. A process for the preparation of l-(4-fluoro-3-pyridyl)ethanone according to claim 1, characterized in that, The reaction formula is: ； The preparation method comprises the following steps: (1) 4-aminopyridine is reacted with fluoroboric acid and sodium nitrite to obtain a reaction solution 1; (2) The reaction solution 1 is neutralized, and then an organic phase is separated by extraction; the organic phase is reacted with hydrogen chloride to prepare 4-fluoropyridine hydrochloride; (3) The 4-fluoropyridine hydrochloride is reacted with diisopropylaminolithium and N-methoxy-N-methylacetamide to obtain 1-(4-fluoro-3-pyridyl) ethanone.

2. The production method according to claim 1, characterized by, In step (1), the molar ratio of the 4-aminopyridine to the fluoroboric acid is 1:(1.1-3.0).

3. The preparation method according to claim 1, characterized in that, In step (1), the molar ratio of the 4-aminopyridine to the sodium nitrite is 1:(1.1-2.5).

4. The method of claim 1, wherein, In step (3), the molar ratio of the 4-fluoropyridine hydrochloride to the diisopropylaminolithium is 1:(1.2-2.2).

5. The preparation method according to claim 1, characterized in that, In step (3), the molar ratio of the 4-fluoropyridine hydrochloride to the N-methoxy-N-methylacetamide is 1:(0.9-1.5).

6. The method of claim 1, wherein, In step (1), the molar ratio of the 4-aminopyridine to the fluoroboric acid is 1:(1.9-2.1); and / or, the molar ratio of the 4-aminopyridine to the sodium nitrite is 1:(1.9-2.1).

7. The preparation method according to claim 1, characterized in that, In step (3), the molar ratio of the 4-fluoropyridine hydrochloride to the diisopropylaminolithium is 1:(2.0-2.2); and / or, the molar ratio of the 4-fluoropyridine hydrochloride to the N-methoxy-N-methylacetamide is 1:(1.0-1.2).

8. The method of claim 1, wherein, In step (2), the reaction of the organic phase with hydrogen chloride is that hydrogen chloride gas is introduced into the organic phase until the pH value of the reaction system is 2-3.

9. The method of claim 1, wherein, The reaction in step (3) is carried out in an inert gas atmosphere.

10. The method of any one of claims 1-9, wherein, The preparation method comprises the following steps: S1: fluoroboric acid with a mass percentage concentration of 40% is cooled to-20℃ to-10℃, 4-aminopyridine is added, and stirring reaction is carried out, then sodium nitrite is added, and stirring reaction is continuously carried out to obtain a reaction solution 1; S2: the temperature of the reaction solution 1 is kept at-20℃ to-10℃, sodium hydroxide is added to neutralize, and the neutralization is completed when the pH value of the reaction solution 1 is 7.0±0.3; an organic phase is separated by extraction with an organic solvent, hydrogen chloride gas is introduced into the organic phase until the pH value of the reaction system is 2-3, and the obtained solid is separated, which is 4-fluoropyridine hydrochloride; S3: in an inert gas atmosphere, tetrahydrofuran is mixed with 4-fluoropyridine hydrochloride, the system is cooled to-78℃ to-60℃, diisopropylaminolithium is added, stirring reaction is carried out, then N-methoxy-N-methylacetamide is added, and then the temperature is raised to 20℃ to 30℃, and stirring reaction is carried out; then the reaction solution is quenched, and 1-(4-fluoro-3-pyridyl) ethanone is separated.

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