CN111072476B - Method for highly selective monofluoromethylation of β-ketoester compounds on oxygen - Google Patents

Abstract

The invention discloses a method for high-selectivity fluoromethylation of beta-keto ester compounds on oxygen. The method comprises the steps of adding a substrate alpha-position unsubstituted beta-keto ester derivative, a fluoromethylation reagent, namely monofluoroiodomethane and cesium fluoride into an organic solvent, stirring for reaction at 40-60 ℃, and separating to obtain an O-fluoromethylated olefine acid compound after the reaction is finished. The method has the advantages of simple process operation, no metal catalysis, no reducing agent, mild and easily controlled conditions, and is a synthetic method of alpha-unsubstituted beta-keto ester compounds with high oxygen selectivity and high yield of monofluoromethylation.

Description

Method for highly selective monofluoromethylation of β-ketoesters on oxygen

technical field

The invention relates to a method for highly selective oxygen-monofluoromethylation of α-position unsubstituted β-ketoester compounds, belonging to the technical field of organic chemical synthesis.

Background technique

Fluorine or fluorinated moieties in fluorinated organic compounds can significantly improve the lipophilicity, metabolic stability, and bioavailability of the parent molecule, and have been widely used in pharmaceuticals and agrochemicals. Among all fluorinated functional groups, monofluoromethyl (CH2F) is widely used in the synthesis of many drug molecules because of its widespread presence in many biologically active molecules and can mimic the CH3 and CH2OH groups often encountered in biologically active molecules. Such as fluoroquinone (a paralytic drug), fluticasone (an anti-inflammatory drug), and sevoflurane (an anesthetic), which have the following structural formulas:

Keto-enol tautomerism of β-ketoesters leading to high selectivity for monofluoromethylation has become a research hotspot. From the development history of monofluoromethoxylation reaction, the introduction method of monofluoromethoxy group belongs to indirect method, that is, the method of alkylating oxygen atom with a monofluoromethylating reagent. However, different types of oxygen-containing substrates and different monofluoromethylation reagents greatly limit the introduction range of functional groups.

Hu Jinbo et al. found that under the action of alkali, fluorochloromethane and phenol generate a monofluoromethyl product, which is also applicable to electron-rich aromatic rings (1-naphthol) or electron-deficient aromatic rings (2,4-dichlorophenol). The synthetic route is as follows:

但上述方法采用的一氟甲基化试剂CH₂FCl为气体，气体状态的试剂不便于使用，同时存在气体与溶剂溶解性等问题；这种方法可以进行O-CH₂F化，但对反应底物限制较大，仅能用于上述酚类衍生物底物(Zhang W,Zhu L,Hu J.Electrophilic monofluoromethylation of O-,S-,and N-nucleophiles with chlorofluoromethane[J].Tetrahedron,2007,63(43):10569-10575.)。

However, the monofluoromethylation reagent CH ₂ FCl used in the above method is gas, and the reagent in the gas state is inconvenient to use, and there are problems such as solubility of gas and solvent; this method can carry out O-CH ₂ F, but the reaction The substrate is limited and can only be used for the above-mentioned phenolic derivative substrates (Zhang W,Zhu L,Hu J.Electrophilic monofluoromethylation of O-,S-,and N-nucleophiles with chlorofluoromethane[J].Tetrahedron,2007, 63(43):10569-10575.).

Olah's group has developed a monofluoromethylation reagent, S-fluoromethyl-bisphenylsulfonium tetrafluoroborate, which can react with nucleophilic substrates such as imidazole and phenol to form the corresponding Monofluoromethyl product. The steps of this O-CH ₂ F method are cumbersome, and the reaction substrate is limited, and can only be used for the above-mentioned substrates (Prakash GKS, Ledneczki I, Chacko S, et al.Direct Electrophilic Monofluoromethylation [J]. Organic Letters, 2008, 10(4): 557-560.), the synthetic route of S-monofluoromethyl-bisphenylsulfonium tetrafluoroborate is as follows:

Norio Shibata's group developed a novel monofluoromethylation reagent, monofluoromethyl sulfoxide salt, for electrophilic monofluoromethylation. In the alkylation of α-substituted β-ketoesters, the CH ₂ F cation in the reagent exhibits a unique inherent preference for oxygen atoms, becoming a rare example of highly selective O-CH ₂ F in enolates (selectivity >80%), providing a new synthetic route for monofluoromethyl ethers relevant to the pharmaceutical and agrochemical industries. However, this O-CH ₂ F method is not only complicated in steps and difficult to prepare, but also has the problem of limiting the α-position of the substrate β-ketoester (Nomura Y, Tokunaga E, Shibata N. Inherent Oxygen Preference in Enolate Monofluoromethylation and a Synthetic Entry to Monofluoromethyl Ethers[J].Angewandte Chemie,2011,123(8):1925-1929.).

SUMMARY OF THE INVENTION

The purpose of the present invention is to provide a method for the highly selective oxygen monofluoromethylation of α-position unsubstituted β-ketoester compounds.

The technical scheme that realizes the object of the present invention is as follows:

A method for highly selective monofluoromethylation of β-ketoester compounds on oxygen, comprising the following steps:

Add the substrate α-position unsubstituted β-ketoester derivative, monofluoromethylation reagent monofluoroiodomethane and cesium fluoride to the organic solvent, stir the reaction at 40℃～60℃, after the reaction, filter, After distillation and column chromatography separation, an oxygen-monofluoromethylated alkenoic acid compound was obtained.

Preferably, the organic solvent is selected from N,N dimethylformamide or N,N dimethylacetamide.

Preferably, the α-position unsubstituted β-ketoester derivative is selected from ethyl benzoylacetate, ethyl p-methoxybenzoylacetate, ethyl p-fluorobenzoylacetate or p-nitrobenzene Ethyl formyl acetate.

Preferably, the reaction time is 2-3h.

Preferably, the molar ratio of the α-position unsubstituted β-ketoester derivative, monofluoroiodomethane, and cesium fluoride is 1:1.2-1.5:0.2-0.5.

Preferably, the eluent for the column chromatography separation is petroleum ether/ethyl acetate with a volume ratio of 95:5 to 99:1.

Compared with the prior art, the present invention has the following significant advantages:

(1) The method of the present invention can achieve high selectivity (selectivity up to 100%) and high yield (yield above 70%) of α-position unsubstituted β-ketoester for oxymonofluoromethylation.

(2) In the process of oxygen monofluoromethylation of β-keto ester compounds, only cesium fluoride is used as a catalyst, the system is simple, it is a one-pot reaction, no high temperature, no nitrogen protection is required, and the β-ketone is realized. Ester compounds can generate active substances containing "CH ₂ F" at the oxygen site with high selectivity.

Description of drawings

Fig. 1 is a ¹ H-NMR spectrum of ethyl β-monofluoromethoxybenzeneacrylate.

Figure 2 is a ¹ H-NMR spectrum of ethyl β-monofluoromethoxy-p-methoxyphenylacrylate.

FIG. 3 is a ¹ H-NMR spectrum of β-monofluoromethoxy-p-fluorophenylacrylate ethyl ester.

Figure 4 is a ¹ H-NMR spectrum of β-monofluoromethoxy-p-nitrophenylacrylate ethyl ester.

Detailed ways

The present invention will be described in further detail below with reference to specific embodiments and accompanying drawings.

The synthetic method of the α-position unsubstituted β-ketoester compounds of the present invention with high selectivity for monofluoromethylation on oxygen, the reaction formula is as follows:

Example 1

In a reactor containing solvent N,N-dimethylformamide (10ml), ethyl benzoylacetate (1.0g) and cesium fluoride (0.158g) were added, and after stirring at room temperature for 30 minutes, fluorine was slowly added dropwise Iodomethane (0.998g) was reacted at 40°C for 2.5 hours. After the reaction, the reaction solution was poured into saturated brine, extracted with dichloromethane three times (30 ml×3), dried over sodium sulfate, and filtered to obtain a dichloromethane solution of ethyl β-monofluoromethoxybenzeneacrylate. And using trifluorotoluene as a reference substance, its concentration was calibrated by fluorine spectrum, the yield was about 80%, and the selectivity was 100%.

Example 2

In a reactor containing solvent N,N-dimethylacetamide (10ml), ethyl benzoylacetate (1.0g) and cesium fluoride (0.158g) were added, and after stirring at room temperature for 30 minutes, fluorine was slowly added dropwise. Iodomethane (0.998g) was reacted at 40°C for 2.5 hours. After the reaction, the reaction solution was poured into saturated brine, extracted with dichloromethane three times (30 ml×3), dried over sodium sulfate, and filtered to obtain a dichloromethane solution of ethyl β-monofluoromethoxybenzeneacrylate. And using trifluorotoluene as a reference substance, its concentration was calibrated by fluorine spectrum, the yield was about 70%, and the selectivity was 100%.

Comparative Example 1

In a reactor containing solvent acetonitrile (10ml), add ethyl benzoylacetate (1.0g), cesium fluoride (0.158g), and after stirring at room temperature for 30 minutes, slowly dropwise add fluoroiodomethane (0.998g), 40 The reaction was carried out at °C for 2.5 hours. After the reaction, the reaction solution was poured into saturated brine, extracted with dichloromethane three times (30 ml×3), dried over sodium sulfate, and filtered to obtain a dichloromethane solution of ethyl β-monofluoromethoxybenzeneacrylate. And using trifluorotoluene as a reference substance, its concentration was calibrated by fluorine spectrum, the yield was about 35%, and the selectivity was 100%.

Comparative Example 2

In a reactor containing a solvent dimethyl sulfoxide (10 ml), ethyl benzoylacetate (1.0 g) and cesium fluoride (0.158 g) were added, and after stirring at room temperature for 30 minutes, fluoroiodomethane (0.998 g) was slowly added dropwise. g), react at 40°C for 2.5 hours. After the reaction, the reaction solution was poured into saturated brine, extracted with dichloromethane three times (30 ml×3), dried over sodium sulfate, and filtered to obtain a dichloromethane solution of ethyl β-monofluoromethoxybenzeneacrylate. And using trifluorotoluene as a reference substance, its concentration was calibrated by fluorine spectrum, the yield was about 40%, and the selectivity was 100%.

It can be seen from Examples 1 to 2 and Comparative Examples 1 and 2 that when N,N-dimethylformamide and N,N-dimethylacetamide are replaced with other aprotic polar solvents, the corresponding monofluoro The yield of the methoxylated product was significantly reduced, with little effect on the selectivity.

Comparative Example 3

In a reactor containing solvent N,N-dimethylformamide (10ml), ethyl benzoylacetate (1.0g) and potassium fluoride (0.06g) were added, and after stirring at room temperature for 30 minutes, fluorine was slowly added dropwise. Iodomethane (0.998g) was reacted at 40°C for 2.5 hours. After the reaction, the reaction solution was poured into saturated brine, extracted with dichloromethane three times (30 ml×3), dried over sodium sulfate, and filtered to obtain a dichloromethane solution of ethyl β-monofluoromethoxybenzeneacrylate. And using trifluorotoluene as a reference substance, its concentration was calibrated by fluorine spectrum, the yield was about 34%, and the selectivity was 83%.

Comparative Example 4

In a reactor containing solvent N,N-dimethylformamide (10ml), ethyl benzoylacetate (1.0g) and cesium hydroxide (0.156g) were added, and after stirring at room temperature for 30 minutes, fluorine was slowly added dropwise Iodomethane (0.998g) was reacted at 40°C for 2.5 hours. After the reaction, the reaction solution was poured into saturated brine, extracted with dichloromethane three times (30 ml×3), dried over sodium sulfate, and filtered to obtain a dichloromethane solution of ethyl β-monofluoromethoxybenzeneacrylate. And using trifluorotoluene as a reference substance, its concentration was calibrated by fluorine spectrum, the yield was about 54%, and the selectivity was 92%.

It can be seen from Example 1 and Comparative Examples 3 and 4 that the yield and selectivity of the corresponding monofluoromethoxylation product are significantly reduced by replacing cesium fluoride with other inorganic bases.

Comparative Example 5

In a reactor containing solvent N,N-dimethylformamide (10ml), ethyl benzoylacetate (1.0g) and cesium fluoride (0.158g) were added, and after stirring at room temperature for 30 minutes, fluorine was slowly added dropwise Iodomethane (0.998g) was reacted at 30°C for 2.5 hours. After the reaction, the reaction solution was poured into saturated brine, extracted with dichloromethane three times (30 ml×3), dried over sodium sulfate, and filtered to obtain a dichloromethane solution of ethyl β-monofluoromethoxybenzeneacrylate. And using trifluorotoluene as a reference substance, its concentration was calibrated by fluorine spectrum, the yield was about 40%, and the selectivity was 100%.

Example 3

In a reactor containing solvent N,N-dimethylformamide (10ml), ethyl benzoylacetate (1.0g) and cesium fluoride (0.158g) were added, and after stirring at room temperature for 30 minutes, fluorine was slowly added dropwise Iodomethane (0.998g) was reacted at 60°C for 2.5 hours. After the reaction, the reaction solution was poured into saturated brine, extracted with dichloromethane three times (30 ml×3), dried over sodium sulfate, and filtered to obtain a dichloromethane solution of ethyl β-monofluoromethoxybenzeneacrylate. And using trifluorotoluene as a reference substance, its concentration is calibrated by fluorine spectrum, the yield is about 60%, and the selectivity is 100%.

Comparative Example 6

In a reactor containing solvent N,N-dimethylformamide (10ml), ethyl benzoylacetate (1.0g) and cesium fluoride (0.158g) were added, and after stirring at room temperature for 30 minutes, fluorine was slowly added dropwise Iodomethane (0.998g) was reacted at 70°C for 2.5 hours. After the reaction, the reaction solution was poured into saturated brine, extracted with dichloromethane three times (30 ml×3), dried over sodium sulfate, and filtered to obtain a dichloromethane solution of ethyl β-monofluoromethoxybenzeneacrylate. And using trifluorotoluene as a reference substance, its concentration was calibrated by fluorine spectrum, the yield was about 30%, and the selectivity was 100%.

It can be seen from Examples 1, 3 and Comparative Examples 5 and 6 that the change of the reaction temperature has a great influence on the reaction yield, but has little effect on the selectivity, and the optimum reaction temperature is about 40°C-60°C.

Example 4

In a reactor containing solvent N,N-dimethylformamide (10ml), ethyl p-methoxybenzoylacetate (1.0g) and cesium fluoride (0.158g) were added, and after stirring at room temperature for 30 minutes, Fluoroiodomethane (0.998 g) was slowly added dropwise, and the mixture was reacted at 40°C for 2.5 hours. After the reaction, the reaction solution was poured into saturated brine, extracted with dichloromethane three times (30ml×3), dried over sodium sulfate, and filtered to obtain a dichloromethane solution of β-monofluoromethoxy-p-methoxybenzene ethyl acrylate . And using trifluorotoluene as a reference substance, its concentration was calibrated by fluorine spectrum, the yield was about 75%, and the selectivity was 100%.

Example 5

In a reactor containing solvent N,N-dimethylformamide (10ml), ethyl p-fluorobenzoylacetate (1.0g) and cesium fluoride (0.158g) were added, and after stirring at room temperature for 30 minutes, slowly dropwise Fluoroiodomethane (0.998 g) was added, and the mixture was reacted at 40° C. for 2.5 hours. After the reaction, the reaction solution was poured into saturated brine, extracted with dichloromethane three times (30 ml×3), dried over sodium sulfate, and filtered to obtain a dichloromethane solution of β-monofluoromethoxy-p-fluorobenzene ethyl acrylate. And using trifluorotoluene as a reference substance, its concentration was calibrated by fluorine spectrum, the yield was about 80%, and the selectivity was 100%.

Example 6

In a reactor containing solvent N,N-dimethylformamide (10ml), ethyl p-nitrobenzoylacetate (1.0g) and cesium fluoride (0.158g) were added, and after stirring at room temperature for 30 minutes, slowly Fluoroiodomethane (0.998 g) was added dropwise, and the mixture was reacted at 40°C for 2.5 hours. After the reaction, the reaction solution was poured into saturated brine, extracted with dichloromethane three times (30 ml×3), dried over sodium sulfate, and filtered to obtain a dichloromethane solution of ethyl β-monofluoromethoxy-p-nitrophenylacrylate. And using trifluorotoluene as a reference substance, its concentration was calibrated by fluorine spectrum, the yield was about 83%, and the selectivity was 100%.

It can be seen from Examples 1 and 4, 5 and 6 that the electron-withdrawing group or electron-donating group on the phenyl group has little effect on the reaction yield, and basically has no effect on the selectivity.

Comparative Example 7

In a reactor containing solvent N,N-dimethylformamide (10ml), methyl p-1-oxo-2-indancarboxylate (1.0g) and cesium fluoride (0.158g) were added, and the mixture was stirred at room temperature for 30 minutes. After that, fluoroiodomethane (0.998 g) was slowly added dropwise, and the mixture was reacted at 40° C. for 2.5 hours. After the reaction, the reaction solution was poured into saturated brine, extracted with dichloromethane three times (30ml×3), dried over sodium sulfate, and filtered to obtain 2-(fluoromethyl)-1-oxo-2,3-dihydro- 1H-Indene-2-carboxylate methyl ester. And using trifluorotoluene as a reference substance, its concentration was calibrated by fluorine spectrum, the yield was about 47%, and the selectivity was 83%.

It can be seen from Example 1 and Comparative Example 7 that when the same O-CH ₂ F synthesis method is used for β-keto ester compounds substituted at α position, the product will not have a higher yield.

Claims (4)

1. the method for highly selective monofluoromethylation on β-keto ester compound oxygen, is characterized in that, comprises the following steps: Add the substrate α-position unsubstituted β-ketoester derivative, the monofluoromethylation reagent monofluoroiodomethane and cesium fluoride to the organic solvent, stir the reaction at 40 ℃ ~ 60 ℃, after the reaction, filter, After distillation and column chromatography separation, the alkenoic acid compound of oxygen monofluoromethylation is obtained, and the organic solvent is selected from N,N-dimethylformamide or N,N-dimethylacetamide. The α-position unsubstituted β-ketoester derivative is selected from ethyl benzoylacetate, ethyl p-methoxybenzoylacetate, ethyl p-fluorobenzoylacetate or ethyl p-nitrobenzoylacetate. 2. method according to claim 1, is characterized in that, described reaction time is 2～3h. 3. The method according to claim 1, wherein the molar ratio of the α-position unsubstituted β-ketoester derivative, monofluoroiodomethane and cesium fluoride is 1:1.2～1.5:0.2～ 0.5. 4. method according to claim 1, is characterized in that, the eluent of described column chromatography separation is the petroleum ether/ethyl acetate that volume ratio is 95:5～99:1.

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