阅读说明：本技术 N-cf2h-1,2-二氢吡啶-2-酮化合物的合成方法 (N-CF2H-1, 2-dihydroSynthesis method of pyridine-2-ketone compound ) 是由 王光伟 周森 于 2020-12-31 设计创作，主要内容包括：本发明属于有机合成领域,具体涉及一种N-CF-2H-1,2-二氢吡啶-2-酮化合物的合成方法,采用下式(III)进行；其中,化合物1的母体骨架为未活化的吡啶、喹啉或者异喹啉,R为任何取代基。本发明实现了一种新的合成N-CF-2H-1,2-二氢吡啶-2-酮类化合物的方法。该方法对底物适用性广,收率高,不需要对吡啶类化合物进行预活化,极大地促进了N-CF-2H-1,2-二氢吡啶-2-酮类化合物的规模化生产和应用。(The invention belongs to the field of organic synthesis, and particularly relates to N-CF 2 The synthesis method of the H-1, 2-dihydropyridine-2-ketone compound is carried out by adopting the following formula (III); wherein, the parent skeleton of the compound 1 is unactivated pyridine, quinoline or isoquinoline, and R is any substituent. The invention realizes a new synthesis of N-CF 2 A method for preparing H-1, 2-dihydropyridine-2-ketone compounds. The method has wide applicability to substrates and high yield, does not need to pre-activate pyridine compounds, and greatly promotes N-CF 2 The scale production and application of H-1, 2-dihydropyridine-2-ketone compounds.)

1. N-CF₂A process for synthesizing an H-1, 2-dihydropyridin-2-one compound, which comprises reacting an H-1, 2-dihydropyridin-2-one compound represented by the following formula (III);

wherein, the parent skeleton of the compound 1 is unactivated pyridine, quinoline or isoquinoline, and R is any substituent.

2. The N-CF of claim 1₂The synthesis method of the H-1, 2-dihydropyridine-2-ketone compound is characterized in that R is H, an electron-withdrawing group or an electron-donating group.

3. The N-CF of claim 1₂The synthesis method of the H-1, 2-dihydropyridine-2-ketone compound is characterized in that R is an electron-withdrawing group.

4. The N-CF as claimed in claim 3₂The method for synthesizing the H-1, 2-dihydropyridine-2-ketone compound is characterized in that the electron-withdrawing group is one or more of acyl, aldehyde group, ester group, amide group, cyano group, sulfonyl group, fluorine-containing alkyl or halogen.

5. The N-CF of claim 1₂A process for synthesizing an H-1, 2-dihydropyridin-2-one compound characterized in that when the parent skeleton of compound 1 is an unactivated pyridine, the positions of the R substituents are 2-, 3-, 4-, 5-and 6-positions; when the parent skeleton of the compound 1 is an unactivated quinoline, the position of the R substituent is an arbitrary position.

6. The method of claim 1N-CF₂A process for synthesizing an H-1, 2-dihydropyridin-2-one compound, characterized in that when the parent skeleton of the compound 1 is an unactivated pyridine, the position of the R substituent is the 3-position or the 5-position; when the parent skeleton of compound 1 is an unactivated quinoline, the position of the R substituent is the 4-, 5-, or 6-position.

7. The N-CF of claim 1₂The method for synthesizing the H-1, 2-dihydropyridine-2-ketone compound is characterized by comprising the following steps: the compound 1 is used as a raw material, a difluoro reagent, alkali and an oxidant are added, and a target product is generated by reaction in a solvent.

8. The N-CF of claim 1₂A method for synthesizing an H-1, 2-dihydropyridin-2-one compound, which is characterized in that the compound 1: difluoro reagent: alkali: the molar ratio of the oxidant is 1: (1.5-2.5): (1.2-1.5): (2-4).

9. The N-CF of claim 7₂The synthesis method of the H-1, 2-dihydropyridine-2-ketone compound is characterized in that the difluoro reagent is BrCF₂CO₂Et,BrCF₂CO₂H,BrCF₂CO₂Na,ClCF₂CO₂Na,BrCF₂P(O)(OEt)₂,FSO₂CF₂CO₂H.

10. The N-CF of claim 7₂The method for synthesizing the H-1, 2-dihydropyridine-2-one compound is characterized in that the oxidant is tert-butyl peroxide, and H₂O₂Di-tert-butyl peroxide, m-chloroperoxybenzoic acid and peroxyacetic acid.

Technical Field

The invention belongs to the field of organic synthesis, and particularly relates to N-CF₂A method for synthesizing H-1, 2-dihydropyridine-2-ketone compound.

Background

In recent years, introduction of fluorine-containing functional groups into compounds has been one of the hot research focuses of synthetic chemistry. Researches show that the introduction of fluorine-containing functional groups into drug molecules can effectively improve the metabolic stability, lipophilicity, membrane permeability and the like of the drugs. Among the fluorine-containing functional groups, difluoromethyl (CF)₂H) Has received great attention because it is of the hydroxymethyl structure (CH)₂OH) in the electron isostere. In addition to this, it can act as a hydrogen donor through weak hydrogen bonding. Thus, the introduction of a difluoromethyl functionality is an advantageous means of improving the properties of biologically active molecules as well as drug molecules. There are studies showing that N-CF₂H-1, 2-dihydropyridin-2-one is a novel important building block for increasing the binding affinity of target receptors, and N-CF₂H-1, 2-dihydropyridin-2-one building blocks are also the pharmacophores of dual COX/5-LOX inhibitors, such as celecoxib analogs, and 1, 2-diarylacetylene 5-LOX inhibitors, among others.

Although N-CF₂H-1, 2-dihydropyridine-2-one structural unit has important application prospect in the aspects of drug molecules and the like, but currently, N-CF (N-CF) is involved₂The synthesis of H-1, 2-dihydropyridin-2-one compounds has been rarely reported. For example, the Ando topic group in 2006 reported a two-step synthesis of N-CF from 2-acetamidopyridine₂H-1, 2-dihydropyridin-2-one compounds (shown in formula (I)). In the reaction, pyridine compounds are in ClCF₂CO₂Na is used as a fluorine source, 18-crown-6 is used as a phase transfer catalyst, the N-difluoromethylation is completed by reflux reaction in acetonitrile, and then a target product is obtained by hydrolysis. This type of reaction was also reported in the 2010 Knaus topic group (as shown in formula (II)). 2-clopidogrel compound in FSO₂CF₂CO₂H is used as a fluorine source, and the target product is obtained by reflux reaction in acetonitrile under the condition that sodium bicarbonate is used as alkali. From aboveIn the two reactions, we can find that the pyridine compounds need to be pre-activated at the ortho position of the pyridine ring, the pyridine compounds used in the Ando subject group need to construct an amide structure at the ortho position of the pyridine ring, and the Knaus subject group needs to use 2-clopidogrel compounds as raw materials for reaction, so that the large-scale application of the methods is greatly limited. Therefore, more practical and efficient synthesis of N-CF has been developed₂The approach of the (1, 2-dihydropyridin-2-one) skeleton remains important and urgent.

Disclosure of Invention

The invention aims to provide N-CF₂A method for synthesizing H-1, 2-dihydropyridine-2-ketone compound.

In order to achieve the purpose, the invention adopts the technical scheme that:

N-CF₂The synthesis method of the H-1, 2-dihydropyridine-2-ketone compound is carried out by adopting the following formula (III);

wherein, the parent skeleton of the compound 1 is unactivated pyridine, quinoline or isoquinoline, and R is any substituent.

And R is H, an electron-withdrawing group or an electron-donating group.

And R is an electron-withdrawing group.

The electron-withdrawing group is one or more of acyl, aldehyde group, ester group, amide group, cyano group, sulfonyl group, fluorine-containing alkyl or halogen.

When the parent skeleton of the compound 1 is unactivated pyridine, the positions of R substituent are 2, 3, 4, 5 and 6; when the parent skeleton of compound 1 is an unactivated quinoline, the position of the R substituent may be any position.

When the parent skeleton of the compound 1 is unactivated pyridine, the position of the R substituent is 3 or 5; when the parent skeleton of compound 1 is an unactivated quinoline, the position of the R substituent is the 4-, 5-, or 6-position.

The method specifically comprises the following steps: the compound 1 is used as a raw material, a difluoro reagent, alkali and an oxidant are added, and a target product is generated by reaction in a solvent.

Compound 1: difluoro reagent: alkali: the molar ratio of the oxidant is 1: (1.5-2.5): (1.2-1.5): (2-4).

Compound 1: difluoro reagent: alkali: the molar ratio of the oxidant is 1: 2: 1.5: 2.

the difluoro reagent is BrCF₂CO₂Et,BrCF₂CO₂H,BrCF₂CO₂Na,ClCF₂CO₂Na,BrCF₂P(O)(OEt)₂,FSO₂CF₂CO₂H.

The base is 1, 8-diazabicycloundec-7-ene (DBU), Et₃N,ⁱPrNEt₂,NaOH,CH₃ONa,^tBuONa,K₂CO₃,Cs₂CO₃,Na₂CO₃One kind of (1).

The oxidant is tert-butyl peroxide (TBHP), H₂O₂Di-tert-butyl peroxide (DTBP), m-chloroperoxybenzoic acid (MCPBA) and peracetic acid.

The solvent is one of MeCN,1, 2-Dichloroethane (DCE), N, N-Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), Dioxane, Toluene and Tetrahydrofuran (THF).

Compared with the prior art, the invention has the beneficial effects that:

the invention realizes a new synthesis of N-CF₂A method for preparing H-1, 2-dihydropyridine-2-ketone compounds. The method has wide applicability to substrates and high yield, does not need to pre-activate pyridine compounds, and greatly promotes N-CF₂The scale production and application of H-1, 2-dihydropyridine-2-ketone compounds.

Detailed Description

In order to make the technical solutions of the present invention better understood by those skilled in the art, the present invention will be further described in detail with reference to the following preferred embodiments.

Example 1: 5-acetyl-N-CF₂Synthesis of H-1, 2-dihydropyridin-2-one Compound (3 a): (BrCF)₂CO₂Et as difluoro reagent for pyridone 3a synthesis).

The magneton was taken in a 25mL Schlenk flask, replaced with argon three times on a double calandria, then MeCN (3.0mL) was added, followed by 3-acetylpyridine (1a, 110. mu.L, 1.0mmol,1.0 equiv). Adding BrCF under stirring₂CO₂Et (2a, 256. mu.L, 2.0mmol,2.0equiv), then DBU (224. mu.L, 1.5mmol,1.5equiv) and finally 70% aqueous tert-butanol peroxide (290. mu.L, 2.0mmol,2.0equiv) were added and refluxed at 80 ℃ for 12 hours. After the reaction was complete, the reaction was transferred to a round bottom flask, acetonitrile solvent was removed by rotary evaporation, then 5mL of water was added, extraction was performed with 10mL of ethyl acetate, the aqueous phase was extracted three times with ethyl acetate (5mL x 3), the organic phases were combined, washed with 10mL of water, saturated aqueous sodium chloride solution (10mL x 2), and anhydrous MgSO₄Drying, filtration and rotary evaporation of the filtered organic phase followed by transfer of the rotary evaporated concentrate to a silica gel column and column chromatography (PE/EA 3/1) gave 148.8mg of pure product (yellow liquid). The yield was 81% yield.¹H NMR(400MHz,CDCl₃)δ8.17(d,J＝2.5Hz,1H),7.90(ddd,J＝9.8Hz,2.6Hz,1.3Hz,1H),7.63(t,J＝60.0Hz,1H),6.53(d,J＝10.1Hz,1H),2.45(s,3H).¹³C NMR(101MHz,CDCl₃)δ192.5,160.4,138.8,134.5(t,J＝3.3Hz),121.3,119.1,107.5(t,J＝254.0Hz),25.6.¹⁹F NMR(376MHz,CDCl₃)δ-103.66(d,²J_FH＝59.9Hz).HRMS(ESI):m/z calcd.for C₈H₈F₂NO₂ ⁺[M+H⁺]:188.0518,found:188.0521。

Example 2: 5-acetyl-N-CF₂Synthesis of H-1, 2-dihydropyridin-2-one Compound (3 a): (ClCF)₂CO₂Na as difluoro reagent for pyridone 3a synthesis).

Taking magneton into 25mL Schlenk bottle, adding ClCF₂CO₂Na (2b,305mg,2.0mmol,2.0equiv), was replaced three times with argon on double calandria, then MeCN (3.0mL) was added, followed by 3-acetylpyridine (1a, 110. mu.L, 1.0mmol,1.0 equiv). DBU (224. mu.L, 1.5mmol,1.5equiv) was added with stirring, and finally 70% aqueous tert-butanol peroxide (290. mu.L, 2.0mmol,2.0equiv) was added and refluxed at 80 ℃ for 12 hours. After the reaction was complete, the reaction was transferred to a round bottom flask, acetonitrile solvent was removed by rotary evaporation, then 5mL of water was added, extraction was performed with 10mL of ethyl acetate, the aqueous phase was extracted three times with ethyl acetate (5mL x 3), the organic phases were combined, washed with 10mL of water, saturated aqueous sodium chloride solution (10mL x 2), and anhydrous MgSO₄Drying, filtration and rotary evaporation of the filtered organic phase followed by transfer of the rotary evaporated concentrate to a silica gel column and column chromatography (PE/EA 3/1) gave 145.2mg of pure product (yellow liquid). The yield was 78% yield.

Example 3: 5-acetyl-N-CF₂Synthesis of H-1, 2-dihydropyridin-2-one Compound (3 a): (BrCF)₂P(O)(OEt)₂As difluoro reagent for the synthesis of pyridone 3 a).

The magneton was taken in a 25mL Schlenk flask, replaced with argon three times on a double calandria, then MeCN (3.0mL) was added, followed by 3-acetylpyridine (1a, 110. mu.L, 1.0mmol,1.0 equiv). Adding BrCF under stirring₂P(O)(OEt)₂(2c,356μL,2.0mmol,2.0equiv),DBU (224. mu.L, 1.5mmol,1.5equiv) was then added, and finally 70% aqueous tert-butanol peroxide (290. mu.L, 2.0mmol,2.0equiv) was added and refluxed at 80 ℃ for 12 hours. After the reaction was complete, the reaction was transferred to a round bottom flask, acetonitrile solvent was removed by rotary evaporation, then 5mL of water was added, extraction was performed with 10mL of ethyl acetate, the aqueous phase was extracted three times with ethyl acetate (5mL x 3), the organic phases were combined, washed with 10mL of water, saturated aqueous sodium chloride solution (10mL x 2), and anhydrous MgSO₄Drying, filtration, rotary evaporation of the filtered organic phase and transfer of the rotary evaporated concentrate to a silica gel column and column chromatography (PE/EA 3/1) gave 134.1mg of pure product (yellow liquid). The yield is 72% yield.

Example 4: 5-acetyl-N-CF₂Synthesis of H-1, 2-dihydropyridin-2-one Compound (3 a): (H)₂O₂As an oxidizing agent for the synthesis of pyridone 3 a).

The magneton was taken in a 25mL Schlenk flask, replaced with argon three times on a double calandria, then MeCN (3.0mL) was added, followed by 3-acetylpyridine (1a, 110. mu.L, 1.0mmol,1.0 equiv). Adding BrCF under stirring₂CO₂Et (2a, 256. mu.L, 2.0mmol,2.0equiv), then DBU (224. mu.L, 1.5mmol,1.5equiv), and finally 35% aqueous hydrogen peroxide (172. mu.L, 2.0mmol,2.0equiv) were added and refluxed at 80 ℃ for 12 hours. After the reaction was complete, the reaction was transferred to a round bottom flask, acetonitrile solvent was removed by rotary evaporation, then 5mL of water was added, extraction was performed with 10mL of ethyl acetate, the aqueous phase was extracted three times with ethyl acetate (5mL x 3), the organic phases were combined, washed with 10mL of water, saturated aqueous sodium chloride solution (10mL x 2), and anhydrous MgSO₄Drying, filtration, rotary evaporation of the filtered organic phase and transfer of the rotary evaporated concentrate to a silica gel column and column chromatography (PE/EA 3/1) gave 104.5mg of pure product (yellow liquid). The yield is 29% yield.

Example 5: 5-acetyl-N-CF₂Synthesis of H-1, 2-dihydropyridin-2-one Compound (3a) (Et)₃N doesUse of bases for the Synthesis of pyridones 3a)

The magneton was taken in a 25mL Schlenk flask, replaced with argon three times on a double calandria, then MeCN (3.0mL) was added, followed by 3-acetylpyridine (1a, 110. mu.L, 1.0mmol,1.0 equiv). Adding BrCF under stirring₂CO₂Et (2a, 256. mu.L, 2.0mmol,2.0equiv), then Et was added₃N (278. mu.L, 1.5mmol,1.5equiv), and finally 70% aqueous tert-butanol peroxide (290. mu.L, 2.0mmol,2.0equiv) was added and refluxed at 80 ℃ for 12 hours. After the reaction was complete, the reaction was transferred to a round bottom flask, acetonitrile solvent was removed by rotary evaporation, then 5mL of water was added, extraction was performed with 10mL of ethyl acetate, the aqueous phase was extracted three times with ethyl acetate (5mL x 3), the organic phases were combined, washed with 10mL of water, saturated aqueous sodium chloride solution (10mL x 2), and anhydrous MgSO₄The organic phase was dried, filtered, rotary evaporated and the concentrated solution transferred to a silica gel column and purified by column chromatography (PE/EA 3/1) to give 143.6mg (yellow liquid) of pure product. The yield was 77% yield.

Example 6: 5-acetyl-N-CF₂Synthesis of H-1, 2-dihydropyridin-2-one Compound (3a) (K)₂CO₃Use as bases for the synthesis of pyridones 3a

Taking magneton into a 25mL Schlenk bottle, adding K₂CO₃(207mg,1.5mmol,1.5equiv), three times with argon on double calandria, then MeCN (3.0mL) was added followed by 3-acetylpyridine (1a,110 μ L,1.0mmol,1.0 equiv). Adding BrCF under stirring₂CO₂Et (2a, 256. mu.L, 2.0mmol,2.0equiv), and finally 70% aqueous tert-butanol peroxide (290. mu.L, 2.0mmol,2.0equiv) was added and refluxed at 80 ℃ for 12 hours. After the reaction is completed, transferring the reaction solution into a round-bottom flask, removing the acetonitrile solvent by rotary evaporation, and then adding 5mL of acetonitrileWater, extracted with 10mL ethyl acetate, the aqueous phase extracted three times with ethyl acetate (5mL x 3), the organic phases combined, washed with 10mL water, saturated aqueous sodium chloride (10mL x 2), then anhydrous MgSO 2₄Drying, filtration, rotary evaporation of the filtered organic phase and transfer of the rotary evaporated concentrate to a silica gel column and column chromatography (PE/EA 3/1) gave 55.4mg of pure product (yellow liquid). The yield is 30% yield.

Example 7: 5-acetyl-N-CF₂Synthesis of H-1, 2-dihydropyridin-2-one Compound (3a) (Synthesis of pyridone 3a with DCE as solvent)

The magneton was taken in a 25mL Schlenk flask, replaced with argon three times on a double calandria, then DCE (3.0mL) was added, followed by 3-acetylpyridine (1a, 110. mu.L, 1.0mmol,1.0 equiv). Adding BrCF under stirring₂CO₂Et (2a, 256. mu.L, 2.0mmol,2.0equiv), then DBU (224. mu.L, 1.5mmol,1.5equiv) and finally 70% aqueous tert-butanol peroxide (290. mu.L, 2.0mmol,2.0equiv) were added and refluxed at 80 ℃ for 12 hours. After the reaction was complete, the reaction was transferred to a round bottom flask, acetonitrile solvent was removed by rotary evaporation, then 5mL of water was added, extraction was performed with 10mL of ethyl acetate, the aqueous phase was extracted three times with ethyl acetate (5mL x 3), the organic phases were combined, washed with 10mL of water, saturated aqueous sodium chloride solution (10mL x 2), and anhydrous MgSO₄Drying, filtration, rotary evaporation of the filtered organic phase and transfer of the rotary evaporated concentrate to a silica gel column and column chromatography (PE/EA 3/1) gave 153.2mg of pure product (yellow liquid). The yield was 82% yield.

Example 8: 5-acetyl-N-CF₂Synthesis of H-1, 2-dihydropyridin-2-one Compound (3a) (Synthesis of pyridone 3a with DMF as solvent)

Taking magneton in 25mLIn a Schlenk flask, argon was substituted three times on the double calandria, then DMF (3.0mL) was added followed by 3-acetylpyridine (1a, 110. mu.L, 1.0mmol,1 equiv). Adding BrCF under stirring₂CO₂Et (2a, 256. mu.L, 2.0mmol,2.0equiv), then DBU (224. mu.L, 1.5mmol,1.5equiv) and finally 70% aqueous tert-butanol peroxide (290. mu.L, 2.0mmol,2.0equiv) were added and refluxed at 80 ℃ for 12 hours. After the reaction was complete, the reaction was transferred to a round bottom flask, acetonitrile solvent was removed by rotary evaporation, then 5mL of water was added, extraction was performed with 10mL of ethyl acetate, the aqueous phase was extracted three times with ethyl acetate (5mL x 3), the organic phases were combined, washed with 10mL of water, saturated aqueous sodium chloride solution (10mL x 2), and anhydrous MgSO₄Drying, filtration, rotary evaporation of the filtered organic phase and transfer of the rotary evaporated concentrate to a silica gel column and column chromatography (PE/EA 3/1) gave 136.1mg of pure product (yellow liquid). Yield 73% yield.

Example 9: 5-amido-N-CF₂Synthesis of H-1, 2-dihydropyridin-2-one Compound (3b)

This procedure is analogous to that of example 1 and gives, by column chromatography (PE/EA-3/1), 199.3.8mg of pure product (yellow liquid). The yield was 78% yield.¹H NMR(400MHz,CDCl₃)δ7.66(d,J＝2.6Hz,1H),7.63(t,J＝59.8Hz,1H),7.42(dd,J＝9.8Hz,2.5Hz,1H),6.52(d,J＝9.6Hz,1H),3.63-3.37(m,4H),1.76-1.63(m,2H),1.62-1.45(m,4H).¹³C NMR(101MHz,CDCl₃)δ165.6,160.3,140.3,130.7(t,J＝3.6Hz),121.2,116.3,107.4(t,J＝253.1Hz),26.1,24.4.¹⁹F NMR(376MHz,CDCl₃)δ-103.62(d,²J_FH＝60.2Hz,2F).HRMS(ESI):m/z calcd.for C₁₂H₁₅F₂N₂O₂ ⁺[M+H⁺]:257.1096,found:257.1106.

Example 10: 5-Ts-N-CF₂Synthesis of H-1, 2-dihydropyridin-2-one Compound (3c)

This reaction procedure is analogous to that of example 1, giving 175.5mg of pure product by column chromatography (PE/EA 3/1) (pale yellow liquid). The yield was 59% yield.¹H NMR(400MHz,CDCl₃)δ8.29(d,J＝2.6Hz,1H),7.79(d,J＝8.4Hz,2H),7.59(t,J＝59.8Hz,1H),7.57(dd,J＝9.9Hz,2.6Hz,1H),7.35(d,J＝8.1Hz,2H),6.55(d,J＝9.9Hz,1H),2.42(s,3H).¹³C NMR(101MHz,CDCl₃)δ159.6,145.4,137.3,137.2,133.8(t,J＝3.9Hz),130.5,127.8,123.3,122.5,107.4(t,J＝255.5Hz),21.7.¹⁹F NMR(376MHz,CDCl₃)δ-103.61(d,²J_FH＝59.9Hz,2F).HRMS(ESI):m/z calcd.for C₁₃H₁₂F₂NO₃S⁺[M+H⁺]:300.0500,found:300.0507.

Example 11: 6-Br-N-CF₂Synthesis of H-1, 2-dihydroquinolin-2-one Compound (3d)

This procedure is analogous to that of example 1 and gives, by column chromatography (PE/EA 3/1), 144.3mg of pure product (yellow solid). Yield 53% yield. m.p.124-127 ℃.¹H NMR(600MHz,CDCl₃)δ8.08(t,J＝58.5Hz,1H),7.67(dt,J＝9.1Hz,2.9Hz,1H),7.65(d,J＝2.3Hz,1H),7.60(dd,J＝9.1Hz,2.3Hz,1H),7.58(d,J＝9.7Hz,1H),6.59(d,J＝9.6Hz,1H).¹³C NMR(151MHz,CDCl₃)δ161.2,140.7,134.0,133.7,131.4,122.3,122.1,118.1(t,J＝6.6Hz),117.0,109.8(t,J＝250.5Hz).¹⁹F NMR(565MHz,CDCl₃)δ-106.13(d,²J_FH＝58.5Hz,2F).HRMS(ESI):m/z calcd.for C₁₀H₇BrF₂NO⁺[M+H⁺]:273.9674,found:273.9677.

Example 12: 5-ester-N-CF₂Process for producing H-1, 2-dihydropyridin-2-one compound (3e)Synthesis of

The reaction procedure was similar to that of example 1 and column chromatography (PE/EA 3/1) gave 316.8mg of pure product as a yellow liquid. The yield is 72% yield.¹H NMR(400MHz,CDCl₃)δ8.47(d,J＝2.5Hz,1H),7.97(dd,J＝9.8Hz,2.5Hz,1H),7.67(t,J＝59.9Hz,1H),7.30(d,J＝8.5Hz,1H),6.92(dd,J＝8.4Hz,2.7Hz,1H),6.90-6.85(m,1H),6.59(d,J＝9.8Hz,1H),3.02-2.81(m,2H),2.48(dd,J＝18.7Hz,8.6Hz,1H),2.43-2.32(m,1H),2.34-2.21(m,1H),2.19-1.86(m,4H),1.72-1.54(m,2H),1.53-1.38(m,2H),0.89(s,3H).¹³C NMR(101MHz,CDCl₃)δ162.2,160.4,148.1,139.9,138.3,137.9,136.0(t,J＝3.4Hz),126.6,121.4,121.1,118.6,111.0,107.4(t,J＝254.5Hz),50.4,47.9,44.1,37.9,35.8,31.5,29.4,26.3,25.7,21.6,13.8.¹⁹F NMR(376MHz,CDCl₃)δ-103.57(d,²J_FH＝59.9Hz,2F).HRMS(ESI):m/z calcd.for C₂₅H₂₆F₂NO₄ ⁺[M+H⁺]:442.1824,found:442.1825.

Other N-CF₂The preparation of H-1, 2-dihydropyridin-2-ones is carried out analogously to example 1, the products and their yields are indicated in Table 1.

TABLE 1

There are many practical products that can be seen in the present invention which realize a novel synthesis of N-CF₂A method for preparing H-1, 2-dihydropyridine-2-ketone compounds. The method has wide applicability to substrates and high yield, does not need to pre-activate pyridine compounds, and greatly promotes N-CF₂The scale production and application of H-1, 2-dihydropyridine-2-ketone compounds.

The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.