WO2001030740A1

WO2001030740A1 - Process for the production of fluorodicarbonyl compounds

Info

Publication number: WO2001030740A1
Application number: PCT/JP2000/007393
Authority: WO
Inventors: Sumi Ishihara; Kenji Adachi
Original assignee: Daikin Industries Ltd.
Priority date: 1999-10-26
Filing date: 2000-10-23
Publication date: 2001-05-03

Abstract

A process for the production of fluorodicarbonyl compounds of general formula (2):R1 COCFR2 COR3 by fluorinating dicarbonyl compounds of general formula (1):R1 COCHR2 COR3 with fluorine, wherein at least part of the above fluorination is conducted while changing the molar ratio of fluorine gas to the dicarbonyl compound: (2) (wherein R1 is hydrogen, optionally substituted alkyl, or aryl; R2 is hydrogen, halogeno, optionally substituted alkyl, or aryl; and R3 is hydrogen, optionally substituted alkyl, aryl, alkoxy, or aryloxy, or alternatively at least two of R?1, R2 and R3¿ may be united to form a part of a ring structure which may involve a heteroatom). According to this process, the fluorination of dicarbonyl compounds (1) with fluorine gas into fluorodicarbonyl compounds (2) can be efficiently carried out.

Description

Description Method for producing fluorine-containing dicarbonyl compound

The present invention relates to a method for producing a fluorine-containing dicarbonyl compound by fluorinating a dicarbonyl compound with fluorine gas.

Art of obedience

A method for producing a fluorinated dicarbonyl compound by fluorinating a dicarbonyl compound with fluorine gas is known [Japanese Patent Application No. 6-510893 (WO 94Zl 0120), Japanese Patent Application Laid-Open No. 9-255611, 095/1 4646].

However, in either case, the amount of fluorine gas required for the completion of the fluorination reaction is unnecessarily large, and the reaction efficiency is often deteriorated. When these reactions are carried out industrially, the reaction efficiency is extremely important economically, and there is a problem that conventional techniques cannot cope with this.

Say of the day

Accordingly, an object of the present invention is to efficiently perform a reaction for producing a fluorine-containing dicarbonyl compound by fluorinating the dicarbonyl compound with fluorine gas.

Composition of departure date,

Under such circumstances, the present inventors have conducted intensive studies and found that in order to efficiently perform fluorination of a dicarbonyl compound with fluorine gas, in particular, when the number of moles of the dicarbonyl compound in the raw material was set to 100, The relative number of moles of fluorine introduced per minute is in the range of 0.0001 to 2.0. As described above, it has been found that the fluorination may be performed by controlling the flow rate and / or the concentration of the fluorine gas, and the present invention has been achieved. Furthermore, they have found that fluorination proceeds more efficiently by using a mixed solvent of acetonitrile and formic acid as a reaction solvent.

That is, the present invention provides a method for producing a fluorine-containing dicarbonyl compound represented by the following general formula (2) by fluorinating a raw material comprising a dicarbonyl compound represented by the following general formula (1) with fluorine: The present invention relates to a method for producing a fluorinated dicarbonyl compound, wherein the fluorination is performed at least in part while changing the relative number of moles of the fluorine gas with respect to the dicarbonyl compound.

General formula (1):

R ¹ CO CHR ² COR ³

(However, in this general formula (1), Ri is a hydrogen atom, a substituted or unsubstituted alkyl group, or an aryl group, and R2 is a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group, or an aryl group. And R ³ is a hydrogen atom, a substituted or unsubstituted alkyl group, an aryl group, an alkoxy group, or an aryloxy group, wherein at least ^{two of} R ¹ , R ^2, and R ³ are combined to form a heteroatom A part of the annular structure may be formed with or without interposition of a ring structure.)

General formula (2)

R ¹ CO CFR ² C OR ³

(In the general formula (2), R ¹ , R ² and R ³ have the same meanings as described above.)

In the production reaction of the fluorinated dicarbonyl compound of the present invention, when the number of moles of the dicarbonyl compound as the raw material is 100, The flow rate and / or concentration of the fluorine is controlled so that the relative mole number of the fluorine is in the range of 0.0001 to 2.0 (more preferably, 0.001 to 1.5). By doing so, the fluorination reaction can be performed efficiently. If the number of moles introduced is less than 0.0001, the reaction time becomes too long and the effect is poor, and if the number of moles introduced exceeds 2.0, the solvent is scattered from the reaction solution by the introduction of fluorine gas. It is easy and dangerous.

Further, in order to perform fluorination more efficiently, it is desirable to use a mixed solvent of acetonitrile and formic acid as a reaction solvent (particularly, increase the ratio of formic acid).

In the method for producing a fluorine-containing dicarbonyl compound of the present invention, the alkyl group in the general formulas (1) and (2) is preferably an alkyl group having 1 to 20 (more preferably 1 to 10) carbon atoms. Alkyl group represents a halogen atom, a hydroxyl group, a cyano group, an aryl group, an acyl group, an alkoxy group, an aryloxy group, an acyloxy group, an alkoxycarbonyl group, an aryloxycarbonyl group, or an alkane sulfonyl group, as the case may be. And it may be substituted by a substituent such as an arylsulfonyl group or an acylamino group. The aryl group is preferably an aromatic group having 6 to 14 carbon atoms (more preferably 6 to 10 carbon atoms), and the aryl group is also an alkyl group, a halogen atom, a cyano group, a nitro group, an acyl group, It may be substituted by a substituent such as an acyloxy group, an alkoxycarbonyl group, an aryloxycarbonyl group, an alkanesulfonyl group, or an arylsulfonyl group.

Further, the alkoxy group preferably means an alkoxy group having 1 to 20 (more preferably 1 to 10) carbon atoms, and the alkoxy group may be substituted by the same substituent as in the case of the above alkyl group. The aryloxy group preferably means an aryloxy group having 6 to 14 carbon atoms (more preferably, 6 to 10 carbon atoms), and the aryloxy group is also substituted by the same substituent as in the above aryl group. May be. Also, the halogen atom can be fluorine, chlorine, bromine or iodine. Examples of the cyclic structure that can be formed by combining R ¹ , R ^2, and R ³ include a monocyclic, bicyclic, or polycyclic structure having 3 to 20 members.

In the production method of the present invention, the dicalponyl compound represented by the general formula (1) as a raw material is a compound that can be easily obtained industrially or can be easily synthesized by a general synthesis method. Examples of the dicarbonate compound of the general formula (1) include the following.

HC 0 CH ₂ COH, CH ₃ C 0 CH ₂ COH, CH ₃ C 0 CH ₂ C

_{_{OCH 3, CH 3 C 0 CH}} 2 C_〇 _{_{_{C 2 H 5, CH 3 C}}} 0 CH 2 C_〇 _{_{_{C 5 H lls CH 3 C 0}}} CH 2 C 0 C 8 H i 7, CH 3 C 0 CH 2 CO CioH ₂ "

CH ₃ COCH (CH ₃ ) CO CH3, C Hs COCH (C ₈ H ₁₇ ) C

0 CH ₃ , CH ₃ CO CH F CO CH3, CH ₃ C0 CHC 1 C0 CH

3, CH ₃ COCHBr COCH ₃ , CH ₃ CO CH I CO CHs, P h C 0 CH ₂ C0 CH ₃ , CH ₃ COCHP h COC Hs, P h COC

H ₂ COP h, P h COCHFCOP h, CH ₃ C 0 CH ₂ C 0 CH ₂ P h, CH ₃ C 0 CH (CH ₂ P h) COCH ₃ , C l CH ₂ C 0 CH ₂ C

O CH3, Br CH ₂ COC H2 C0CH ₃ , CF ₃ C 0 CH ₂ C 0 C

H ₃ , CF ₃ C 0 CH ₂ C 0 CF ₃ , CF ₃ C 0 CHFC 0 CF ₃ , C

_{_{6 H 5 C 0 CH 2 C}} 0 C 6 F 5, Ce F 5 C 0 CH 2 C 0 C 6 F 5, Ce F 5 COCHFCO Ce F 5,

HC 0 CH ₂ COO CH3, HC 0 CH ₂ C 00 C ₂ H ₅ , CH ₃ C 0 CH ₂ C 00 C ₂ H ₅ , CH ₃ C 0 CH ₂ C 00 C ₃ H ₇ , CH ₃ C 0 CH ₂ _{_{COO C4 H 9, CH 3 C}} 0 CH 2 C 00 C 8 H 17, CH 3 C ◦ CH (CH 3) C 00 CH 3, P h CH 2 C 0 CH 2 C 00 CH 3, CH 3 CO CH2 COOP h, CH ₃ C 0 CH ₂ C 00 CH ₂ P h, CH ₃ CO CHP hCOO Ca H ₇ , CH ₃ CO CH (CH ₂ P h) CO 0 C ₂ H ₅ , CH ₃ CO CH F COO C2 H ₅ , CH ₃ CO CH C 1 C 00 C ₂ H ₅ , CH ₃ CO CHB r CO OC ₂ H ₅ , CH ₃ CO CH IC 00 C ₂ H ₅ , FCH ₂ C 0 CH ₂ COO C2 H ₅ , C 1 CH ₂ C 0 CH ₂ C 00 CH ₃

CO

According to the method for producing a fluorine-containing dicarbonyl compound of the present invention,

Two

The fluorination reaction proceeds as in R ¹ COCHR ² COR ³ R ¹ COCFR ² COR ^S , but when R ² = H in the dicarbonyl compound of the general formula (1), it is introduced as shown in the following reaction formula. Depending on the amount of fluorine, a product obtained by repeating the fluorination step twice, that is, a fluorinated dicarbonyl compound is obtained. Alternatively, also in the case where R ² = F in the general formula (1), the same dicarbonyl compound difluorinated in one step by the introduced fluorine can be obtained. F _{2 1} F ₂

R ¹ COCH ₂ COR ³ ~~ ^ R ^ OCHFCOR ³ ~ ^ R ¹ COCF ₂ COR ³ Fluorine (F ₂ ) used in the method for producing a fluorine-containing dicarbonyl compound of the present invention is used to suppress the violent reaction. Fluorine gas diluted with an inert gas such that the volume of the inert gas is in the range of 99.9% to 50% (preferably 9.9% to 70%, more preferably 97% to 80%) Good to use. Examples of the inert gas used for dilution include nitrogen, helium, argon, and carbon dioxide.

In the fluorination, the method of introducing fluorine is very important in order to efficiently fluorinate the dicarbonyl compound. As the fluorination proceeds, the amount of the raw material dicarbonyl compound in the reaction system gradually decreases, so in order to proceed with the fluorination efficiently, the amount of introduced fluorine must also be reduced. No. Otherwise, not only would excess fluorine be wasted, but it could also cause additional side reactions. This is extremely uneconomical and requires the disposal of excess fluorine, which is highly reactive, and poses both safety and environmental concerns.

When performing this reaction on a large scale, when starting the introduction of fluorine, the amount of fluorine introduced should be reduced at first to suppress side reactions due to the heat generated by fluorination, or to carry out the reaction safely. It is desirable to increase the amount gradually and then decrease it again as the amount of dicarbonyl compound in the reaction system decreases.

There are three ways to control the amount of fluorine introduced: controlling the flow rate of the diluted fluorine gas, controlling the concentration of the diluted fluorine gas, or controlling both the flow rate and the concentration. The method is conceivable. The amount of fluorine introduced can be represented by the relative number of moles introduced per minute, assuming that the number of moles of the starting dicarbonyl compound before reaction is 100, from 0.0001 to 2 The flow rate or the Z and concentration of the diluted fluorine gas may be controlled stepwise or / and continuously so as to fall within the range of 0.0 (preferably within the range of 0.001 to 1.5) ( The following is a summary of aspects of this control.

(1) At least a part of the fluorination is performed while changing the flow rate of the fluorine gas stepwise and / or continuously. At this time, the flow rate of the fluorine gas is reduced stepwise or / and continuously, or the flow rate of the fluorine gas is stepwise or / and continuously increased and then reduced.

(2) At least a part of the fluorination is performed while changing the concentration of the fluorine gas stepwise or / and continuously. At this time, the concentration of the fluorine gas is reduced stepwise and / or continuously. Alternatively, the concentration of the fluorine gas is increased stepwise or / and continuously, and then decreased.

(3) At least part of the fluorination is performed while changing the flow rate and the concentration of the fluorine gas stepwise or / and continuously. At this time, the flow rate and the concentration of the fluorine gas are reduced stepwise or / and continuously. Alternatively, the flow rate of the fluorine gas is decreased stepwise and / or continuously, and the concentration of the fluorine gas is increased stepwise and / or continuously and then decreased. Alternatively, the flow rate of the fluorine gas is increased stepwise or / and continuously, and then reduced, and the concentration of the fluorine gas is reduced stepwise or / and continuously. Alternatively, the flow rate and concentration of the fluorine gas may be varied stepwise or / and continuously. Increase continuously and then decrease.

The method of changing the flow rate and / or the concentration of the fluorine gas may be various other than the above embodiments. The period of the change may be a part of the whole fluorination reaction, or may be changed throughout. In this case, the change should start at a certain time after the start of the fluorination, but the initial stage of the fluorination is rather low and then raised to a high level, and the reaction proceeds smoothly. After confirming that the flow rate and / or concentration should be reduced. After this change, there may be a period during which the flow rate and / or concentration is increased, and this may be performed, for example, at the final stage of the fluorination reaction.

In the method for producing a fluorinated dicarbonyl compound of the present invention, the reaction may be performed in a batch system or a continuous system. In the case of a continuous reaction, the raw material dicarbonyl compound dissolved in a solvent together with an additive such as a salt or an acid, or in the case where an acid also serves as a solvent, together with fluorine gas without adding other solvents It can be introduced into a continuous reactor to perform at least part of the fluorination continuously.

In this case, the method of introducing the fluorine gas may be performed by appropriately changing the flow rate and / or the concentration as described above in accordance with the amount or concentration or the introduction rate of the dicarbonate compound as the raw material to be added at the same time.

In addition, examples of the continuous reaction apparatus include a reaction apparatus of a packed tower system and the like. In the case of a packed tower system, a parallel flow system in which the raw material and the fluorine gas flow in the same direction or a countercurrent system in which the raw material and the fluorine gas flow in the opposite direction can be adopted. When the co-current method is used, the relative concentration of the fluorine gas with respect to the raw material gradually decreases, so that the present invention can be implemented more effectively. In the method for producing a fluorinated dicarbonyl compound of the present invention, the conditions of the fluorination reaction (solvents, additives such as salts and acids, reaction temperatures, etc.) except for the method of introducing fluorine already include the fluorine of the dicarbonyl compound. Reference is made to Japanese Patent Application No. 6-51093 (W094 / 110120), which discloses gas fluorination, and Japanese Patent Application Laid-Open No. 9-255610, W095 / 14646. Conditions can be used.

The amount of the solvent to be used may be freely adjusted according to the substrate. Even if the amount is very small, for example, 5% by weight or less based on the substrate, the solvent is used as the solvent.

Among them, it is preferable to use an acid having a pKa of less than 4.5. Examples of the acid having a pKa of less than 4.5 include sulfuric acid, nitric acid, phosphoric acid, polyphosphoric acid, hydrogen fluoride, hydrofluoric acid, hydrogen chloride, hydrochloric acid, hydrogen bromide, hydrogen iodide, hypochlorous acid, and hypochlorous acid. Hydrogen halide or hydrohalic acid such as chloric acid, chloric acid, perchloric acid, perbronic acid, or periodic acid, hypohalous acid, hypohalous acid, halogenic acid, or perhalogenic acid;

Fluorosulfonic acid, chlorosulfonic acid, methanesulfonic acid, methanesulfonic acid, butanesulfonic acid, butanesulfonic acid, octanesulfonic acid, trifluoromethanesulfonic acid, difluorodomesulfonic acid, trichloromethanesulfonic acid, perfluorobenzosulfonic acid, perflu Sulfonic acid such as olooctanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, nitrobenzenesulfonic acid or polymer-supported sulfonic acid such as polystyrenesulfonic acid;

Carboxylic acids such as formic acid, chloroacetic acid, bromoacetic acid, dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid, glycolic acid, lactic acid, benzoic acid, oxalic acid, and succinic acid; _{_{BF 3, BC 1 3, B}} (0 CH 3) 3, B (0 COCH 3) 3, A 1 C 1 3, S b F 3, S b C 1 3, S b F 6, PF 3, PF 5 _{, a s F 3, a s} C 1 3, a s F 5, T i CI 4 Lewis acid such or complexes with its _{ether, HB F 5, HS b F} 6, HPF 6, HA s F 4, complex with HS b C l ₆ such as an acid or an ether such as consisting of a Lewis acid and a hydrogen halide;

Or mixtures thereof;

Can be exemplified.

In addition, these acids may be used in other solvents, halogenated hydrocarbons (e.g., chloroform, dichloromethane, carbon tetrachloride, chloroethane, dichloroethane, trichloroethane, tetrachloroethane, trichloromouth trifluoroethane, tetrafluoroethane). , Trifluoroacetane, perfluoropentane, etc.), nitrile compounds (eg, acetonitrile, propionitrile, etc.), water, acetic acid, propionic acid, butyric acid, isobutyric acid, alcohol (eg, methanol) , Ethanol, trifluoroethanol, propanol, isopropanol, hexafluoroisopropanol, HCF ₂ C F2 C H2 OH, H (CF ₂ CF ₂ ) 2 CH ₂ 0H, H (CF ₂ CF ₂ ) 3 CH ₂ OH, etc.).

Of these, a combination of formic acid and acetonitrile is particularly preferred. The reaction efficiency is further improved as compared with the case where only formic acid is used as a solvent. Further, the mixing ratio of formic acid and acetonitrile is also important, and the proportion of acetonitrile is preferably 80% or less, more preferably 35% or less. When a mixed solvent of formic acid and acetonitrile is used, the reaction efficiency is improved even if the flow rate and concentration of the diluted fluorine gas are constant, and the present invention makes it possible to control the amount of fluorine introduced. Thus, the reaction efficiency is further improved.

The reaction temperature may be appropriately set according to the reactivity of the substrate to be fluorinated and the solvent used, and can be selected from a range of 180 ° C to + 80 ° C. Economically preferred is -50 ° C to + 50 ° C, especially -30 ° C to + 30 ° C. The reaction temperature does not need to be kept constant, and may be freely changed during the reaction.

Il ffl ten cows

As described above, the present invention controls the amount of introduced fluorine gas (particularly, changes the flow rate and / or concentration) when fluorinating a dicarbonyl compound with fluorine gas. By using the dicarbonyl compound of the general formula (1), which is easy to synthesize, as a raw material and controlling the flow rate and concentration of the gas using inexpensive fluorine gas, the efficiency of the general formula (2) can be improved in a single step with high efficiency. Fluorine-containing dicarbonyl compounds can be produced with good yield.

A brief description of the screen

FIG. 1 is a graph showing the relationship between the equivalent number of fluorine, the production rate of a target substance, and the reaction time in Examples 1 and 9.

FIG. 2 is a graph showing the relationship between the number of equivalents of fluorine and the flow rate and concentration of the diluted fluorine gas in Example 1.

FIG. 3 is a graph showing the relationship between the number of equivalents of fluorine and the relative number of moles of fluorine introduced in Example 1.

FIG. 4 is a graph showing the relationship between the number of equivalents of fluorine, the production rate of the target substance, and the reaction time in Examples 2 and 9.

FIG. 5 is a graph showing the relationship between the number of equivalents of fluorine and the flow rate and concentration of the diluted fluorine gas in Example 2. FIG. 6 is a graph showing the relationship between the number of equivalents of fluorine and the relative number of moles of fluorine introduced in Example 2.

FIG. 7 is a graph showing the relationship between the equivalent number of fluorine, the production rate of the target substance, and the reaction time in Example 3 and Examples 10 and 11.

FIG. 8 is a graph showing the relationship between the number of equivalents of fluorine and the flow rate and concentration of the diluted fluorine gas in Example 3.

FIG. 9 is a graph showing the relationship between the number of equivalents of fluorine and the relative number of moles of fluorine introduced in Example 3.

FIG. 10 is a graph showing the relationship between the equivalent number of fluorine, the production rate of the target substance, and the reaction time in Example 4 and Examples 10 and 11.

FIG. 11 is a graph showing the relationship between the number of equivalents of fluorine and the flow rate and concentration of the diluted fluorine gas in Example 4.

FIG. 12 is a graph showing the relationship between the number of equivalents of fluorine and the relative number of moles of fluorine introduced in Example 4.

FIG. 13 is a graph showing the relationship between the number of equivalents of fluorine, the production rate of the target substance, and the reaction time in Examples 5 and 9.

FIG. 14 is a graph showing the relationship between the number of equivalents of fluorine and the flow rate and concentration of the diluted fluorine gas in Example 5.

FIG. 15 is a graph showing the relationship between the number of equivalents of fluorine and the relative number of moles of fluorine introduced in Example 5.

FIG. 16 is a graph showing the relationship between the equivalent number of fluorine, the production rate of the target substance, and the reaction time in Examples 6 and 12.

FIG. 17 is a graph showing the relationship between the number of equivalents of fluorine and the flow rate and concentration of the diluted fluorine gas in Example 6.

Figure 18 shows the number of fluorine equivalents and the relative moles of fluorine introduced in Example 6. It is a graph which shows the relationship with a number.

FIG. 19 is a graph showing the relationship between the number of equivalents of fluorine, the production rate of the target substance, and the reaction time in Examples 1, 6, and 13.

FIG. 20 is a graph showing the relationship between the number of equivalents of fluorine, the production rate of the target substance, and the reaction time in Examples 7 and 1.

FIG. 21 is a graph showing the relationship between the number of equivalents of fluorine and the flow rate and concentration of the diluted fluorine gas in Example 7.

FIG. 22 is a graph showing the relationship between the number of equivalents of fluorine and the relative number of moles of fluorine introduced in Example 7.

FIG. 23 is a graph showing the relationship between the equivalent number of fluorine, the production rate of the target substance, and the reaction time in Examples 8 and 9.

FIG. 24 is a graph showing the relationship between the number of equivalents of fluorine and the flow rate and concentration of the diluted fluorine gas in Example 8.

FIG. 25 is a graph showing the relationship between the number of equivalents of fluorine and the relative number of moles of fluorine introduced in Example 8.

FIG. 26 is a graph showing the relationship between the number of equivalents of fluorine and the flow rate and concentration of the diluted fluorine gas in Example 13.

FIG. 27 is a graph showing the relationship between the number of equivalents of fluorine and the relative number of moles of fluorine introduced in Example 13.

卖 Example

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to the following Examples.

First, the amount of fluorine in each of the following examples was calculated as 1 mol = 24.337 1 (24 ° C.). Tables 1 and 2 summarize the reaction conditions for each example.In Tables 3 to 15, `` Production rate '' refers to the unreacted The ratio of 2-fluoro-3-keto-n-methyl valerate to the total amount of the raw material and the target product (2-fluoro-3-keto n-methyl valerate) is expressed as a percentage. F2 flow rate "," F ₂ concentration "it it, the flow rate of the diluted fluorine gas, a fluorine concentration. The “relative mole number of F ₂ ” is defined as the relative mole number of fluorine introduced per minute when the mole number of the starting dicarbonyl compound before reaction is 100, and the flow rate of fluorine gas per minute. And concentration. Figures 1 to 27 are graphs of the experimental data in Tables 3 to 15, respectively.

The reaction mixture was poured into water, extracted with methylene chloride, washed with water, and then concentrated to obtain an oily substance, which was almost the desired product. Of the by-products contaminated, those other than 2,2-difluoro-3-keto-n-methyl valerate were traces, so the yield by ¹⁹ F-NMR was the desired product. In each example, only 2-fluoro-3-keto-n-methyl valerate and the by-product 2,2-difluoro-13-keto-n-methyl valerate are shown.

Ά ±.

A solution of 10.4 g (80 mmo 1) of 3-keto-η-methyl valerate in 27 ml of formic acid was cooled to 6 ° C and, with stirring, was diluted with nitrogen gas to 10% fluorine. The gas was introduced while changing the flow rate according to the method shown in Table 3 and Figure 2.

The production rate of the target product was determined by gas chromatography with respect to the number of equivalents of fluorine (Table 3). Fig. 1 shows the results together with Comparative Example 9 (introduced at a constant dilution fluorine gas flow rate of 190 ml / min). The results were graphed. Fluorine required for the target to raw material ratio to be 99.5: 0.5 was 132 mmo 1 (1.65 eq: equivalent), and the reaction time was 3 O Omin. Was. The raw material 3-keto_n-methyl valerate was set at 100 The relative number of moles of fluorine introduced per space was determined from the flow rate and concentration of fluorine gas, and plotted against the number of equivalents of fluorine to create Figure 3.

After the reaction, fluorobenzene 751 zl (8 mmo 1) was added as a reference substance, and ¹⁹ F-NMR was measured. The target substance, 2-fluoro-3-keto-1-n-methylvalerate, was 74.7%. It was confirmed that 2.3% of 2, 2-difluoro-3-keto-n-methyl valerate, a by-product, was produced. The procedure was the same as in Example 1, except that the flow rate of the diluted fluorine gas was in accordance with the method shown in Table 4 and FIG. The fluorine required for the target to raw material ratio to become 100: 0 was 124 mmo 1 (1.55 eq), and the reaction time was 298 min. ^{The 19} F-NMR yields were 77.3% for 2-fluoro-3-keto n-methyl valerate and 2.7% for 2,2-difluoro-3-keto-n-methyl valerate. Was. A solution of 6.5 g (50 mmo 1) of 3-keto-n-methyl valerate dissolved in 17 ml of formic acid was cooled to 6 ° C, and while stirring, the fluorine gas diluted with nitrogen gas was added to the solution in Table 5, Figure According to the method shown in FIG. 8, the fluorine gas was introduced at a flow rate of 10 Oml / min while changing the concentration of the fluorine gas.

The production rate of the desired product was determined by gas chromatography with respect to the number of equivalents of fluorine (Table 5). Fig. 7 shows a comparative example 10 (introduced at a constant fluorine concentration of 10%), and a comparative example. The results were graphed together with 1 1 (introduced at a constant fluorine concentration of 5%). Fluorine required for the ratio of the target substance to the raw material to be 96.8: 3.2 was 100 mmo 1 (2.0 eq), and the reaction time was 402 min. The relative number of moles of fluorine introduced per minute with respect to the starting material, 3-keto-n-methyl valerate, is 100. Calculated from the flow rate and concentration of raw gas, plotted against the number of fluorine equivalents,

Created 9.

After the reaction, fluorobenzene 469〃1 (5 mmo 1) was added as a reference substance, and ¹⁹ F_NMR was measured. The target substance, 2-fluoro-3-keto-1 n methyl monovalerate was 70.8%, It was confirmed that 2.4% of the product, 2,2-difluoro-3-keto-n-methyl valerate, was produced. ΆΑ.

The procedure was carried out in the same manner as in Example 3 except that the concentration of the diluted fluorine gas was in accordance with the method shown in Table 6 and FIG. The amount of fluorine required for the target to raw material ratio to be 97.4: 2.6 was lOOmmol (2.0 eq), and the reaction time was 420 min. ^The yield by ¹⁹ F-NMR was 73.0% for 2-fluoro-3-keto-n-methyl valerate, and 2.6% for 2,2-difluoro-13-keto-n-methyl valerate. The procedure was carried out in the same manner as in Example 1 except that the flow rate and concentration of the diluted fluorine gas were in accordance with the methods shown in Table 7 and FIG. The amount of fluorine required for the target to raw material ratio to become 100: 0 was 136 mmo 1 (1.7 eq), and the reaction time was 34 Omin. ^The yield by ¹⁹ F-NMR was 77.6% for 2-fluoro-3-keto-n-methyl valerate and 2.4% for 2,2-difluoro-3-keto-n-methyl valerate. .

Ά3.

The procedure was performed in the same manner as in Example 1 except that a mixed solvent of 27 ml of formic acid and 13.5 ml of acetonitrile was used as a solvent, and the flow rate of the diluted fluorine gas was in accordance with the method shown in Table 8 and FIG. Fluorine required for the ratio of the target substance to the raw material to become 100: 0 was 112 mmol (1.4 eq), and the reaction time was 189 min. ¹⁹ F—NMR yield is 2-fluoro-3-keto_n -Methyl valerate was 79.5%, and 2,2-difluoro-3-keto n-methyl valerate was 2.7%. When 1.3 equivalents of fluorine were introduced, 13.5 ml of acetonitrile was added, and the same procedure as in Example 1 was performed, except that the flow rate of the diluted fluorine gas was in accordance with the method shown in Table 9 and FIG. 21. Fluorine required for the target to raw material ratio to become 100: 0 was 124 mmol (1.55 eq), and the reaction time was 255 min. ^{The 19} F-NMR yields were 77.5% for 2-fluoro-3-keto-n-methyl valerate and 2.6% for 2,2-difluoro-3-keto-n-methyl valerate. . The flow rate and concentration of the diluted fluorine gas were set in accordance with the method shown in Table 10 and Figure 24, and the reaction temperature was further increased to 6 ° C and then to 12 ° C for up to 1.2 equivalents of fluorine. The procedure was as in Example 1, except that the temperature was increased from 4 equivalents to 20 ° C and from 15 equivalents to 27 ° C. Fluorine required for the ratio of the target substance to the raw material to be 96.5: 3.5 was 128 mmol (1.6 eq), and the reaction time was 397 min. The yield by i ⁹ F-NMR was 72.7% for 2-fluoro-3-keto-n-methyl valerate and 3.1% for 2,2-difluoro-3-keto-n-methyl valerate. Was. The procedure was the same as in Example 1, except that the flow rate of the diluted fluorine gas was fixed at 19 Oml / min and the concentration was fixed at 10%. Fluorine required for the ratio of the target substance to the raw material to be 97.2: 2.8 was 20 Omol (2.5 eq), and the reaction time was 257 min. ^{The 19} F-NMR yields were 73.5% for 2-fluoro-1,3-keto-n-methylvalerate and 2.6% for 2,2-difluoro-13-keto_n-methyl valerate. Was. Example 1 0

The procedure was the same as in Example 3, except that the flow rate of the diluted fluorine gas was fixed at 100 ml / min and the concentration was fixed at 10%. The ratio of target to raw material is 93.9:

The amount of fluorine required to reach 6.1 was 125 mmol (2.5 eq), and the reaction time was 304 min. ^The yield by ¹⁹ F-NMR was 2-fluoro-3_keto-n-methylvalerate 66.4%, 2,2-difluoro-3

—Keto n—methyl valerate was 2.2%.

Example 1 1

The procedure was performed in the same manner as in Example 3 except that the flow rate of the diluted fluorine gas was fixed at 100 m1 / min and the concentration was fixed at 5%. The ratio of the target substance to the raw material is 95.9:

The amount of fluorine required to reach 4.1 was 100 mmol (2.0 eq), and the reaction time was 485 min. ^{The 19} F-NMR yield was 2-1.6-keto-n-methylvalerate, 71.6%, 2,2-difluoro-3.

—Keto_n—methyl valerate was 2.5%.

Example 1

Except that a mixed solvent of 27 ml of formic acid and 13.5 ml of acetonitrile was used as the solvent, and the flow rate of the diluted fluorine gas was fixed at 190 m1 / min and the concentration was fixed at 10%. Performed as in Example 1. The ratio of target to raw material is 1

The fluorine required to reach 00: 0 was 13.6 mmo 1 (1.7 eq), and the reaction time was 174 min. ^The yield by ¹⁹ F-NMR was 77.4% for 2-fluoro-3-keto-n-methylvalerate and 2.7% for 2,2-difluoro-13-keto-n-methyl valerate. .

Example 1 3

The procedure was performed in the same manner as in Example 1, except that formic acid and acetonitrile, 27 ml of a 1: 5 mixed solvent were used as the solvent, and the flow rate of the diluted fluorine gas was introduced as shown in Table 15 and Figure 26. Was. It was necessary for the ratio of the target substance to the raw material to become 100: 0 The fluorine was 149 mmol (1.86 eq) and the reaction time was 258 min. ^{The 19} F-NMR yields were 61.1% for 2-fluoro-3-keto-n-methyl valerate and 5.6% for 2,2-difluoro-3-keto-n-methyl valerate. Was.

The results for each of the examples described above are shown in Figs. 1, 4, 7, 7, 10, 13, 16, 19, 20, and 23. [Here, the equivalent number of fluorine used (eq ) Of the desired product (2-fluoro-3-keto_n-methyl valerate) (the amount of 2-fluoro-13-keto-n-methyl valerate determined by gas chromatography Divided by the total amount of raw material and 2-fluoro-3-keto n-methyl valerate)) and the reaction time].

Fig. 2, Fig. 5, Fig. 8, Fig. 11, Fig. 11, Fig. 14, Fig. 17, Fig. 21, Fig. 24, and Fig. 26 show the flow rate and concentration of diluted fluorine gas for each example with respect to the number of equivalents of fluorine. . Furthermore, the amount of fluorine introduced per minute relative to the number of equivalents of fluorine (ie, the relative number of moles of fluorine introduced per minute when the number of moles before the reaction of the starting dicarbonyl compound is 100) is defined as Calculated from the flow rate and concentration of fluorine gas, and shown in Figure 3, Figure 6, Figure 9, Figure 12, Figure 15, Figure 18, Figure 22, Figure 25, and Figure 27.

Tables 1 and 2 list the reaction conditions for each case, and Tables 3 to 15 show the experimental data for each case.

For example, as can be seen in Figs. 1 and 4, in Examples 1 and 2 where the flow rate of the diluted fluorine gas (diluted fluorine gas) was controlled, there was much less fluorine than in Example 9 where the flow rate was constant. The reaction was able to be performed with the introduction amount of In addition, since the reaction proceeded efficiently, the increase in the reaction time due to the decrease in the flow rate of fluorine was slight. Dilution fluorine gas The flow rate of the gas was controlled as shown in Figs. 2 and 5, respectively, and the relative number of moles of fluorine introduced per minute was as shown in Figs.

Similar results were obtained in Examples 3 and 4 by controlling the fluorine concentration of the diluted fluorine gas (FIGS. 7 to 12). In both Examples 3 and 4, the reaction could be almost completed with less fluorine than in Example 10 (the fluorine concentration was constant at 10%). When the fluorine concentration was set low at 5% from the beginning and introduced in a fixed amount (Example 11), the reaction can be performed with the same amount of fluorine introduced as in Examples 3 and 4. As can be seen in Figure 10, the reaction time is longer and less efficient. In Example 5 where both the flow rate and the concentration of the diluted fluorine gas were reduced, a similarly high effect was observed (Figures 13 to 15).

Also, in Examples 1 to 5, the high effect was observed, so that the flow rate of the fluorine gas was decreased stepwise or / and continuously, and the concentration of the fluorine gas was decreased stepwise and / or It can be continuously increased and then decreased, or the flow rate of fluorine gas can be increased stepwise or / and continuously and then decreased and the concentration of fluorine gas can be increased stepwise and / or and / or It is clear that the same effect can be obtained by continuously decreasing or increasing the flow rate and concentration of fluorine gas stepwise or Z and continuously, and then decreasing. It is.

In addition, as can be seen in Fig. 19, in Example 6 using a mixed solvent of formic acid and acetonitrile, it can be seen that the reaction efficiency was further improved as compared with Example 1 using only formic acid as a solvent. .

Furthermore, as shown in FIG. 19, the mixing ratio of formic acid and acetonitrile is also important, and in Example 13 where the mixing ratio is 1: 5, the mixing ratio of 2: 1 is also important. The reaction efficiency is clearly lower than that of Example 6. Furthermore, the yield of 2-fluoro-3-keto-n-methyl valerate, which is the target substance, and 2,2-difluoro-3-keto-n-methyl valerate, which is a by-product, was 74 in Example 1. 7%, 2.3% and Example 6 are 79.5% and 2.7%, while Example 13 is 61.1% and 5.6%. The rate decreased and by-products increased.

Therefore, when a mixed solvent of formic acid and acetonitrile is used, the ratio of acetonitrile is preferably 80% or less, more preferably 35% or less. When a mixed solvent of formic acid and acetonitrile was used, the reaction efficiency was improved even when the flow rate and concentration of the diluted fluorine gas were constant (comparison between Example 9 and Example 12). By further controlling the amount of fluorine introduced, the reaction efficiency was further improved (Examples 6 and 12: Figure 16).

table 1

to

Table 2

Table 3—1 ^! LL

F ₂ Equivalents Reaction time Production rate F ₂ Flow rate F ₂ Concentration F ₂ Relative moles introduced (eq) (min) (%) (ml / mm) (%)

0.00 0 0.00 190 10 0.975

0.20 21 17.2

0.25 180 0.923

0.40 42 32.6

0.50 170 0.872

0.60 64 46.1

0.65 160 0.821

0.70 150 0.769

0.80 89 62.9 140 0.718

0.90 130 0.667

1.00 119 74.6

1.06 120 0.616

1.12 110 0.564

1.17 100 0.513

1.20 152 83.8 90 0.462

1.30 174 88.4

1.37 80 0.410

1.40 196 91.7 60 0.308

1.47 50 0.256

1.50 231 95.6

1.52 40 0.205

1.55 252 97.3 Table 3-2 βϋ.

F ₂ equivalents Reaction time Production rate F ₂ Flow rate F ₂ Concentration F ₂ Relative moles introduced

(eq) (min) (%) (ml / min) ()

1.60 276 98.8

1.65 300 99.5 40 10 0.205

Table 4— 1 _

F ₂ Equivalents Reaction time Production rate F ₂ Flow rate F ₂ Concentration F ₂ Relative moles introduced (eq) (min) (%) (ml / min) (%)

0.00 0 0.00 60 10 0.308

0.05 90 0.462

0.20 49 16.1 180 0.923

0.35 170 0.872

0.40 72 34.8

0.56 160 0.821

0.60 96 48.0

Π U.7 / Π U ν n 7fiQ

0.80 122 63.6 140 0.718

0.87 130 0.667

0.94 120 0.616

1.00 152 75.1

1.02 110 0.564

Table 4-2 i2J_2_

1.10 168 81.9 100 0.513

1.20 187 88.1 90 0.462

1.25 80 0.410

1.30 212 92.3

. OO 70

1.40 235 95.3

1.42 50 0.256

1.46 255 97.1

1.50 272 99.0 40 0.205

1.55 298 100 40 10 0.205

Table 5 Ά2.

(eq) (min) (%) (ml / min) (%)

0.00 0 0.00 100 10 0.821

0.20 24 15.6

0.40 49 30.3 9 0.739

0.60 76 43.2 8 0.657

0.80 107 55.2 7 0.574

1.00 140 65.1

1.10 6 0.492

1.20 179 75.9

1.40 219 82.4 5 0.410

1.50 244 85.3

1.60 268 87.4

1.65 4 0.328

1.70 294 90.4

1.80 324 92.3 3 0.246

1.90 364 94.9

1.95 382 95.9

2.00 402 96.8 100 3 0.246

Table 6 ΆΑ.

(eq) (min) (%) (ml / min) (%)

0.00 0 0.00 100 5 0.410

0.10 7 0.574

0.20 42 17.9 10 0.821

0.40 67 30.7 9 0.739

0.60 95 42.7 8 0.657

0.80 125 55.8 7 0.574

1.00 159 65.1

1.10 6 0.492

1.20 196 74.1

1.40 236 81.4 5 0.410

1 ^ ί) n

1.60 285 87.8 4 0.328

1.70 313 90.3

1.80 344 94.1 3 0.246

1.90 361 96.1

2.00 420 97.4 100 3 0.246

Table 7 _5_

(eq) (min) (%) (ml / min) (%)

0.00 0 0.00 190 10 0.975

0.10 180 0.923

0.20 21 17.1

0.30 170 0.872

0.40 44 30.4

0.45 160 0.821

0.55 150 0.769

0.60 68 46.3

0.70 140 0.718

0.80 95 61.0 9 0.646

0.90 130 0.600

1.00 128 71.7 8 0.533

1.05 120 0.492

1.10 147 77.0 110 0.451

1.20 169 82.6 7 0.395

1.30 194 85.8 100 0.359

1.40 223 90.1 6 0.308

1.50 254 93.7 5 0.256

1.60 292 96.9 80 0.205

1.65 316 98.3

1.70 340 100 80 5 0.205 Table 8.

Table 9 i.

F. Equivalent number Reaction time Production rate F ₂ Flow rate F ₂ Concentration F ₂ Relative moles introduced

(eq) (miru (%) (ml / min (%)

0.00 0 0.00 190 10 0.975

0.20 20 17.4

0.25 180 0.923

0.40 42 32.5

0.50 170 0.872

0.60 64 48.1

0.65 160 0.821

0.70 150 0.769

0.80 89 63.8 140 0.718

0.90 130 0.667

1.00 118 77.0

1.06 120 0.616

1.12 110 0.564

1.17 100 0.513

1.20 152 86.8 90 0.462

1.30 173 90.8

1.37 80 0.410

1.40 194 95.8 60 0.308

1.47 50 0.256

1.50 230 99.0

1.52 40 0.205

1.55 252 100 40 10 0.205 Table 1 o ω_

F ₂ equivalents Reaction time Production rate F ₂ Flow rate F ₂ Concentration F ₂ Relative induction Reaction temperature

(eq) (mm) (%) (ml / min) () Number of moles C)

0.00 0 0.00 180 10 1.00 6

0.10 170 0.949

0.14 160 0.893

0.20 23 17.6 150 0.837

0.24 140 0.781

0.30 9 0.703

0.35 130 0.653

0.40 54 30.5 8 0.580

0.50 120 0.536

0.60 91 46.8

0.70 110 0.491

0.80 135 63.8

0.85 7 0.430

1.01 186 70.6

1.02 100 0.391

1.10 210 75.2 6 0.335

1.20 242 79.3 5 0.279 12

1.30 281 84.5

1.40 319 89.1 20

1.50 358 93.2 27

1.60 397 96.5 100 5 0.279 27 Table 11

F ₂ equivalents Reaction time Production rate F ₂ Flow rate F ₂ Concentrated JF ₂ Relative moles introduced (eq) (min) (%) (ml / mm) (%)

0.00 0 0.00 190 10 0.975

0.20 21 16.8

0.40 41 31.8

0.60 62 43.1

0.80 82 59.5

1.00 103 68.7

1.10 113 72.3

1.20 123 74.1

1.30 133 78.7

1.40 143 81.6

1.50 153 83.4

o * r

1.60 163 86.0

1.80 184 89.6

2.00 204 92.4

2.20 225 95.1

2.40 246 96.5

2.50 256 97.2 190 10 0.975 Table 1 2 Example 10

0.00 0 0.00 100 10 0.821

0.20 24 16.4

0.40 50 31.0

0.60 73 43.2

0.80 97 54.0

1.00 122 62.5

1.20 146 70.3

1.40 170 76.0

1.50 183 79.1

1.60 195 80.5

1.80 219 85.4

2.00 243 87.7

2.20 267 91.3

2.40 292 93.8

2.50 304 93.9 100 10 0.821

Table 13 Example 1 1

0.00 0 0.00 100 5 0.410

0.20 48 16.1

0.40 97 30.6

0.60 148 45.9

0.80 198 59.2

1.00 243 68.8

9Q1 1.1

1.40 340 83.7

1.50 364 86.6

1.60 388 89.4

1.80 437 93.1

2.00 485 95.9 100 5 0.410

Table 14 Example 1 2

0.00 0 0.00 190 10 0.975

0.20 20 14.5

0.40 41 32.7

0.60 61 49.1

0.80 82 65.3

1.00 102 78.2

1.20 123 87.3

1 on 1 QQ no π

1.40 143 96.0

1.50 154 97.7

1.55 159 98.7

1.60 164 99.3

1.70 174 100 190 10 0.975

Table 15 Example 1

0.00 0 0.00 200 10 1.03

0.20 20 8.40 160 0.821

0.40 44 19.9

0.60 69 32.3

0.80 93 44.9

1.00 119 59.8 150 0.769

1.20 154 72.5

1.30 140 0.718

1 Q

丄 o 丄 1

1.50 195 88.4

1.64 213 93.9

1.70 223 96.0 110 0.564

1.80 242 98.7 70 0.359

1.86 258 100 70 10 0.359

Claims

The scope of the claims

1. When a dicarbonyl compound represented by the following general formula (1) is fluorinated with fluorine to produce a fluorine-containing dicarbonate compound represented by the following general formula (2), A method for producing a fluorinated dicarbonyl compound, wherein at least a part of the fluorination is performed while changing the relative number of moles of the raw gas.

General formula (1):

R ¹ CO CHR ² COR ³

(However, in this general formula (1), Ri is a hydrogen atom, a substituted or unsubstituted alkyl group, or an aryl group, and R ² is a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group, or an aryl group. And R ³ is a hydrogen atom, a substituted or unsubstituted alkyl group, an aryl group, an alkoxy group, or an aryloxy group, wherein at least two of R ¹ , R ² and R ³ are taken together to form a heteroatom A part of the annular structure may be formed with or without interposition of a ring structure.)

General formula (2):

2. Assuming that the number of moles of the dicarbonyl compound as the raw material is 100, the relative number of moles of fluorine introduced per minute is in the range of 0.0001 to 2.0. The method for producing a fluorinated dicarbonyl compound according to claim 1, wherein the fluorination is performed at least in part by controlling the flow rate and / or concentration of fluorine.

3. The method for producing a fluorinated dicarbonyl compound according to claim 1, wherein the fluorination is performed at least partially while changing the flow rate of the fluorine gas stepwise or / and continuously.

4. The method for producing a fluorinated dicarbonyl compound according to claim 3, wherein the flow rate of the fluorine gas is reduced stepwise or / and continuously.

5. The method for producing a fluorinated dicarbonyl compound according to claim 3, wherein the flow rate of the fluorine gas is increased stepwise or / and continuously, and then decreased.

6. The method for producing a fluorinated dicarbonyl compound according to claim 1, wherein the fluorination is performed at least partially while changing the concentration of the fluorine gas stepwise or / and continuously.

7. The method for producing a fluorine-containing dicarbonyl compound according to claim 6, wherein the concentration of the fluorine gas is reduced stepwise or continuously and continuously.

8. The method for producing a fluorine-containing dicarbonyl compound according to claim 6, wherein the concentration of the fluorine gas is increased stepwise or continuously and continuously, and thereafter reduced.

9. The fluorinated dicarbonyl according to claim 1, wherein at least a part of the fluorination is performed while changing the flow rate and the concentration of the fluorine gas stepwise or / and continuously. Method for producing compound <

10. The method for producing a fluorine-containing dicarbonyl compound according to claim 9, wherein the flow rate and the concentration of the fluorine gas are reduced stepwise or / and continuously.

11 1. Reduce the flow rate of the fluorine gas stepwise or / and continuously 10. The method for producing a fluorinated dicarbonyl compound according to claim 9, wherein the concentration is decreased and / or the concentration of the fluorine gas is increased stepwise or / and continuously, and thereafter decreased.

12. The flow rate of the fluorine gas is increased stepwise or / and continuously, and thereafter decreased, and the concentration of the fluorine gas is reduced stepwise / and / or continuously. 10. The method for producing a fluorinated dicarbonyl compound according to item 9 in the range.

13. The method for producing a fluorine-containing dicarbonyl compound according to claim 9, wherein the flow rate and the concentration of the fluorine gas are increased stepwise or / and continuously, and then reduced. .

14. The process for producing a fluorine-containing dicarbonyl compound according to any one of claims 1 to 13, wherein a mixed solvent of acetonitrile and formic acid is used as a reaction solvent.

15. The method according to claim 1, wherein at least a part of the fluorination is continuously performed by simultaneously introducing the raw material dicarbonyl compound and the fluorine gas into a continuous reaction apparatus. A method for producing a fluorine dicarbonate compound.