JP6236630B6 - Method for producing monofluoromalonic acid derivative - Google Patents

Description

  The present invention relates to a novel process for producing monofluoromalonic ester derivatives. Monofluoromalonic acid ester derivatives are useful compounds as raw materials for electronic materials and as intermediates for production of medicines and agricultural chemicals.

Conventionally, as a method of directly fluorinating with fluorine gas to obtain a monofluoromalonic acid ester derivative, a method carried out in the presence of a copper nitrate catalyst (for example, see Patent Document 1 and Non-Patent Document 1), diethyl malonate with sodium hydride is used. A method to be carried out after forming a sodium salt (for example, see Patent Document 2) is known.
In addition, a method of fluorine-substituting ethyl chloromalonate with an amine hydrofluoride (see, for example, Patent Document 3), a method in which trifluoroacrylate can be reacted with ethanol (for example, see Non-Patent Document 2), etc. Are known.

Further, as a fluorinating agent, a method using an N-fluoropyridinium salt (see, for example, Non-Patent Document 3), a method using xenon difluoride (for example, see Non-Patent Document 4), and 1-fluoro-2-pyridone are used. A method (for example, see Non-Patent Document 5) is known.
Since the methods described in Patent Document 1 and Non-Patent Document 2 use fluorine gas, there are safety problems, and in many cases, the yield is low. The method described in Patent Document 2 has a problem of becoming a mixture of diethyl monofluoromalonate and diethyl difluoromalonate, in which separation of the product is difficult.

On the other hand, in the method described in Patent Document 3, it is necessary to prepare ethyl chloromalonate in advance, and there is a problem that the production process becomes long in a multistage reaction. The method described in Non-Patent Document 2 is produced by decomposing a raw material into which three fluorine atoms have been introduced, and has a problem that two expensive fluorines are discarded as waste liquid.
Furthermore, the methods described in Non-Patent Document 3, Non-Patent Document 4, and Non-Patent Document 5 may not be applicable to production on an industrial scale because an expensive fluorinating agent is used.

Special table 2001-510173 gazette Japanese National Patent Publication No. 11-507938 JP-T-2004-537502

R. D. R. D. Chambers et al., Journal of Fluorine Chem., 1988, 92, 45 T.A. F. Fuchikami et al., Chemical Letters, 1573 (1984) T.A. T. Umemoto et al., Journal of American Chemistry Society, 1990, 112, 8563 T.A. B. T. B. Patrick et al., Journal of Fluorine Chem., 1988, 39, 415 S. T.A. S. T. Purrington et al., Journal of Organic Chemistry (J. Org. Chem.), 1983, 48, 761

  An object of the present invention is to overcome the conventional problems and provide a process for producing a monofluoromalonic ester derivative that can be carried out industrially.

As a result of intensive studies on a method for producing a monofluoromalonic acid ester derivative, the present inventors found that the malonic acid ester derivative was converted to hydrogen fluoride in the presence of an iodosylbenzene derivative or in the presence of a catalytic amount of an iodobenzene derivative and an oxidizing agent. It has been found that a monofluoromalonic acid ester derivative can be obtained by reacting with a source, and the present invention has been completed.
That is, the present invention provides the following general formula (1)

(In the formula (1), R ¹ and R ² each independently represent a methyl group, an ethyl group, a linear, branched or cyclic alkyl group having 3 to 6 carbon atoms, a phenyl group or a benzyl group; ³ represents a hydrogen atom, a methyl group or an ethyl group.)
General formula (2)

(In the formula (2), R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently a hydrogen atom, a methyl group, an ethyl group, a linear or branched alkyl having 3 to 4 carbon atoms. A group, a methoxy group, an ethoxy group, a linear, branched or cyclic alkoxy group having 3 to 4 carbon atoms, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a cyano group or a nitro group.)
In the presence of an iodosylbenzene derivative represented by:
The following general formula (3)

(In the formula (3), R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are the same as the formula (2).)
Reacting with a source of hydrogen fluoride in the presence of an iodobenzene derivative represented by
The following general formula (4)

(In formula (4), R ¹ , R ² and R ³ are the same as those in formula (1).)
The manufacturing method of the monofluoromalonic acid derivative represented by these is provided.

  INDUSTRIAL APPLICABILITY According to the present invention, an industrial production method of a monofluoromalonic acid derivative useful as an electronic material raw material or a synthetic intermediate for medical and agricultural chemicals is provided.

Hereinafter, the present invention will be described in detail.
Examples of the malonic ester derivative represented by the general formula (1) used in the present invention include dimethyl malonate, diethyl malonate, di-n-propyl malonate, di-iso-propyl malonate, and dimalonate malonate. -N-butyl, di-iso-butyl malonate, di-tert-butyl malonate, di-n-pentyl malonate, di-cyclopentyl malonate, di-n-hexyl malonate, di-cyclohexyl malonate, Tert-Butyl-ethyl malonate, diphenyl malonate, dibenzyl malonate, dimethyl 2-methylmalonate, diethyl 2-methylmalonate, di-n-propyl 2-methylmalonate, di-iso-methyl 2-methylmalonate Propyl, 2-methylmalonate di-n-butyl, 2-methylmalonate di-iso-butyl, 2-methylmalonate -Tert-butyl, 2-methylmalonate di-n-pentyl, 2-methylmalonate di-cyclopentyl, 2-methylmalonate di-n-hexyl, 2-methylmalonate di-cyclohexyl, 2-methylmalon Tert-butyl-ethyl acid, diphenyl 2-methylmalonate, dibenzyl 2-methylmalonate dimethyl 2-ethylmalonate, diethyl 2-ethylmalonate, di-n-propyl 2-ethylmalonate, 2-ethylmalonic acid Di-iso-propyl, di-n-butyl 2-ethylmalonate, di-iso-butyl 2-ethylmalonate, di-tert-butyl 2-ethylmalonate, di-n-pentyl 2-ethylmalonate, 2-Ethylmalonic acid di-cyclopentyl, 2-ethylmalonic acid di-n-hexyl, 2-ethylmalonic acid di-cyclohexyl Butyl tert ethyl-malonate - ethyl, 2-ethyl malonic acid diphenyl, 2-ethyl malonic acid dibenzyl, and the like.

  Examples of the iodosylbenzene derivative represented by the general formula (2) used in the present invention include iodosylbenzene, 2-iodosyltoluene, 3-iodosyltoluene, 4-iodosyltoluene, 2,4,6. -Trimethyliodosylbenzene, 2-ethyliodosylbenzene, 3-ethyliodosylbenzene, 4-ethyliodosylbenzene, 2-iodosylanisole, 3-iodosylanisole, 4-iodosylanisole, 1-chloro-2 -Iodosylbenzene, 1-chloro-3-iodosylbenzene, 1-chloro-4-iodosylbenzene, 1,2-diiodosylbenzene, 1,3-diiodosylbenzene, 1,4-diiodosyl Benzene, 1-iodosyl-2-nitrobenzene, 1-iodosyl-3-nitrobenzene, 1-iodine Examples include dosyl-4-nitrobenzene, 1-iodosyl-2-cyanobenzene, 1-iodosyl-3-cyanobenzene, 1-iodosyl-4-cyanobenzene, and the like, which are represented by the general formula (1) included in the reaction. It is good to use 0.1-10 mol times with respect to a malonic ester derivative, and when using less than 1.0 mol times, an oxidizing agent may be required.

  Examples of the iodobenzene derivative represented by the general formula (3) used in the present invention include iodobenzene, 2-iodotoluene, 3-iodotoluene, 4-iodotoluene, 2,4,6-trimethyliodobenzene, 2-ethyliodobenzene, 3-ethyliodobenzene, 4-ethyliodobenzene, 2-iodoanisole, 3-iodoanisole, 4-iodoanisole, 1-chloro-2-iodobenzene, 1-chloro-3-iodobenzene 1-chloro-4-iodobenzene, 1,2-diiodobenzene, 1,3-diiodobenben, 1,4-diiodobenzene, 1-iodo-2-nitrobenzene, 1-iodo-3-nitrobenzene, 1-iodo-4-nitrobenzene, 1-iodo-2-cyanobenzene, 1-iodo-3-cyano Benzene or 1-iodo-4-cyano benzene and the like, with respect to malonic acid ester derivative represented by the general formula Gusuru the reaction (1), using 0.1 to 10 mols.

  In the present invention, the monofluoromalonic acid ester derivative represented by the general formula (4) is a malonic acid ester derivative represented by the general formula (1) in the presence of an iodosylbenzene derivative represented by the general formula (2). Alternatively, it can be obtained by reacting with a hydrogen fluoride source in the presence of an iodobenzene derivative represented by the general formula (3) and an oxidizing agent. Examples of the monofluoromalonic acid ester derivative include the following compounds.

  Dimethyl fluoromalonate, diethyl fluoromalonate, di-n-propyl fluoromalonate, di-iso-propyl fluoromalonate, di-n-butyl fluoromalonate, di-iso-butyl fluoromalonate, fluoromalon Di-tert-butyl acid, di-n-pentyl fluoromalonate, di-cyclopentyl at fluoromalonic acid, di-n-hexyl fluoromalonate, di-cyclohexyl fluoromalonate, tert-butyl-ethyl fluoromalonate, fluoro Diphenyl malonate, dibenzyl fluoromalonate, dimethyl 2-fluoro-2-methylmalonate, diethyl 2-fluoro-2-methylmalonate, di-n-propyl 2-fluoro-2-methylmalonate, 2-fluoro- 2-Methylmalonic acid di-iso-propyl 2-fluoro-2-methylmalonate di-n-butyl, 2-fluoro-2-methylmalonate di-iso-butyl, 2-fluoro-2-methylmalonate di-tert-butyl, 2-fluoro-2 -Di-n-pentyl methylmalonate, di-cyclopentyl at 2-fluoro-2-methylmalonic acid, di-n-hexyl 2-fluoro-2-methylmalonic acid, di-fluoro-2-methylmalonic acid di- Cyclohexyl, tert-butyl-ethyl 2-fluoro-2-methylmalonate, diphenyl 2-fluoro-2-methylmalonate, dibenzyl 2-fluoro-2-methylmalonate, dimethyl 2-fluoro-2-ethylmalonate, 2-fluoro-2-ethylmalonate diethyl, 2-fluoro-2-ethylmalonate di-n-propyl, 2-fluoro-2-ethyl Di-iso-propyl ronate, di-n-butyl 2-fluoro-2-ethylmalonate, di-iso-butyl 2-fluoro-2-ethylmalonate, di-tert-2-fluoro-2-ethylmalonate -Butyl, 2-fluoro-2-ethylmalonate di-n-pentyl, 2-fluoro-2-ethylmalonic acid di-cyclopentyl, 2-fluoro-2-ethylmalonate di-n-hexyl, 2-fluoro 2-ethylmalonate di-cyclohexyl, 2-fluoro-2-ethylmalonate tert-butyl-ethyl, 2-fluoro-2-ethylmalonate diphenyl, 2-fluoro-2-ethylmalonate dibenzyl, etc. .

Examples of the hydrogen fluoride source used in the present invention include anhydrous hydrofluoric acid, a hydrofluoric acid aqueous solution having a concentration of 10 to 70% by weight, a hydrogen fluoride-triethylamine salt [Et ₃ N · (HF) ₂ to _5. ], Hydrogen fluoride-pyridine salt [Py · (HF) ₂ to ₁₀ ] or hydrogen fluoride-tetraethylammonium fluoride salt [Et ₄ NF · (HF) ₁ to ₅ ]. These may be used alone or in combination. Moreover, 1.5-30 mol is used in conversion of hydrogen fluoride with respect to the malonic ester derivative represented by General formula (1) with which reaction is provided.

  Examples of the oxidizing agent used in the present invention include hydrogen peroxide, peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, tert-butyl hydroperoxide, cumene hydroperoxide, potassium persulfate, potassium hydrogen persulfate- Examples thereof include peracids and / or peroxides such as potassium hydrogen sulfate-potassium sulfate mixture (trade name: Oxone, manufactured by Sigma-Aldrich Co., Ltd.). These may be used alone or in combination. Moreover, 1.0-5.0 mol amount is used with respect to the malonic ester derivative represented by General formula (1) with which reaction is provided.

  Examples of the solvent applicable to the present invention include halogenated hydrocarbon solvents such as dichloromethane, 1,2-dichloroethane, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chlorobenzene, and o-dichlorobenzene. And halogenated aromatic hydrocarbon solvents such as m-dichlorobenzene. These may be used alone or in combination. Further, it is used in an amount of 5 to 100 times by weight based on the malonic ester derivative represented by the general formula (1) provided for the reaction.

The reaction temperature and time in the present invention vary depending on the type of iodosylbenzene to be used, the type of iodobenzene derivative, the type of hydrogen fluoride source, and the type of oxidizing agent, but are usually in the temperature range of 20 to 80 ° C., The reaction is completed by carrying out the reaction for 48 hours.
The post-treatment after the reaction in the present invention can be carried out by a well-known method, for example, by neutralization with an aqueous sodium hydrogen carbonate solution, etc., extraction with a solvent such as dichloromethane, drying with sodium sulfate, etc. A crude product may be obtained, and further purification may be performed by a known method such as silica gel column chromatography as appropriate or by combining a plurality of formulations.

EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited only to these examples.
The Agilent Technologies 400 MHz NMR system ( ¹ H-NMR, ¹³ C-NMR and ¹⁹ F-NMR described below) manufactured by Agilent was used for calculation of yield and identification of the compound.
Example 1 Preparation of diethyl fluoromalonate (5)

  A 10 ml Teflon test tube equipped with a stir bar was charged with iodosylbenzene (550 mg, 2.50 mmol), triethylamine pentahydrofluoride (804 mg, 4.00 mmol) and 1,2-dichloroethane (2 ml). ) And stirred at room temperature for 15 minutes, and then diethyl malonate (160 mg, 1.00 mmol) was added thereto. Subsequently, after sealing a test tube with a septum cap, it heated at 70 degreeC on the oil bath, and reacted for 24 hours.

After completion of the reaction, the reaction solution was returned to room temperature, added to a saturated aqueous sodium hydrogen carbonate solution (50 ml), neutralized, extracted three times with dichloromethane (10 ml), and the organic layers were combined and washed with saturated brine (10 ml). After drying, filtration and concentration, a crude product was obtained.
When the obtained crude product was quantified in ¹ H-NMR measurement using 1,4-dimethoxybenzene as an internal standard substance, the reaction yield was 100%.

Subsequently, the obtained crude product was purified by silica gel column chromatography to obtain the target diethyl fluoromalonate in a yield of 38%.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.34 (t, J = 7 Hz, 6H, CH ₃ ), 4.33 (q, J = 7 Hz, 4H, CH ₂ ), 5.28 (d, J = 48.5Hz, 1H, CHF).
¹³ C-NMR (100 MHz, CDCl ₃ ) δ 13.9, 62.6, 85.2 (d, J = 195 Hz), 163.9 (d, J = 24 Hz).
¹⁹ F-NMR (376 MHz, CDCl ₃ ) δ-195.17 (d, J = 48.5 Hz).

  Example 2 Preparation of dimethyl fluoromalonate (6)

The same operation as in Example 1 was performed except that dimethyl malonate (132 mg, 1.00 mmol) was replaced with diethyl malonate (160 mg, 1.00 mmol) in Example 1.
When the obtained crude product was quantified by ¹ H-NMR measurement using 1,4-dimethoxybenzene as an internal standard substance, the reaction yield was 53%.
Subsequently, the obtained crude product was purified by silica gel column chromatography to isolate the target dimethyl fluoromalonate.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.88 (s, 6H, CH ₃ ), 5.34 (d, J = 48.5 Hz, 1H, CHF).
¹³ C-NMR (100 MHz, CDCl ₃ ) δ 53.3, 85.0 (d, J = 196 Hz), 164.2 (d, J = 24 Hz).
¹⁹ F-NMR (376 MHz, CDCl ₃ ) δ-195.23 (d, J = 48.5 Hz).
¹⁹ F-NMR (376 MHz, CDCl ₃ ) δ-195.17 (d, J = 48.5 Hz).

  Example 3 Preparation of dibenzyl fluoromalonate (7)

The same operation as in Example 1 was performed except that dibenzyl malonate (284 mg, 1.00 mmol) was replaced with diethyl malonate (160 mg, 1.00 mmol) in Example 1.
When the obtained crude product was quantified by ¹ H-NMR measurement using 1,4-dimethoxybenzene as an internal standard substance, the reaction yield was 58%.
Subsequently, the obtained crude product was purified by silica gel column chromatography to isolate the target dibenzyl fluoromalonate.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 5.24 (s, 4H, CH ₂ ), 5.36 (d, J = 48 Hz, 1H, CHF), 7.29-7.35 (m, 10H, Ph ).
¹³ C-NMR (100 MHz, CDCl ₃ ) δ 68.2, 85.2 (d, J = 196 Hz), 128.4, 128.65, 128.7, 134.2, 163.6 (d, J = 24 Hz) ).
¹⁹ F-NMR (376 MHz, CDCl ₃ ) δ-195.03 (d, J = 48 Hz).

  Example 4 Preparation of di-n-butyl fluoromalonate (8)

The same operation as in Example 1 was performed except that di-n-butyl malonate (216 mg, 1.00 mmol) was replaced with diethyl malonate (160 mg, 1.00 mmol) in Example 1.
When the obtained crude product was quantified by ¹ H-NMR measurement using 1,4-dimethoxybenzene as an internal standard substance, the reaction yield was 58%.

Subsequently, the obtained crude product was purified by silica gel column chromatography to isolate the target di-n-butyl fluoromalonate.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.94 (t, J = 7 Hz, 6H, CH ₃ ), 1.35-1.42 (m, 4H, CH ₂ ), 1.64-1.71 ( _{m, 4H, CH 2),} 4.28 (dt, J = 4, 6Hz, 4H, CH 2), 5.29 (d, J = 48Hz, 1H, CHF).
¹³ C-NMR (100 MHz, CDCl ₃ ) δ 13.5, 18.8, 30.3, 66.4, 85.2 (d, J = 195 Hz), 164.0 (d, J = 24 Hz).
¹⁹ F-NMR (376 MHz, CDCl ₃ ) δ-194.91 (d, J = 48 Hz).

  Example 5 Preparation of di-n-hexyl fluoromalonate (9)

The same operation as in Example 1 was performed, except that di-n-hexyl malonate (272 mg, 1.00 mmol) was replaced with diethyl malonate (160 mg, 1.00 mmol) in Example 1.
The obtained crude product was quantified by ¹ H-NMR measurement using 1,4-dimethoxybenzene as an internal standard substance, and the reaction yield was 61%.

Next, the obtained crude product was purified by silica gel column chromatography to isolate the target di-n-hexyl fluoromalonate.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.89 (t, J = 7 Hz, 6H, CH ₃ ), 1.31-1.38 (m, 12H, CH ₂ ), 1.65-1.72 ( _{m, 4H, CH 2),} 4.26 (dt, J = 4, 7Hz, 4H, CH 2), 5.28 (d, J = 48Hz, 1H, CHF).
¹³ C-NMR (100 MHz, CDCl ₃ ) δ 13.8, 22.4, 25.2, 28.2, 31.2, 66.6, 85.2 (d, J = 195 Hz), 164.0 (d , J = 24 Hz).
¹⁹ F-NMR (376 MHz, CDCl ₃ ) δ-194.90 (d, J = 48 Hz).

  Example 6 Preparation of diethyl 2-fluoro-2-methylmalonate (10)

The same operation as in Example 1 was performed except that diethyl 2-methylmalonate (174 mg, 1.00 mmol) was replaced with diethyl malonate (160 mg, 1.00 mmol) in Example 1.
The obtained crude product was quantified by ¹ H-NMR measurement using 1,4-dimethoxybenzene as an internal standard substance, and the reaction yield was 18%.

Next, the obtained crude product was purified by silica gel column chromatography to isolate the objective diethyl 2-fluoro-2-methylmalonate.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.31 (t, J = 7 Hz, 6H, CH ₃ ), 1.76 (d, J = 22 Hz, 3H, CH ₃ ), 4.27 (q, J = 7Hz, 4H, CH _2).
¹⁹ F-NMR (376 MHz, CDCl ₃ ) δ-157.53 (d, J = 22 Hz).

[Example 7] Preparation of diethyl fluoromalonate In a 10-ml Teflon (registered trademark) test tube equipped with a stirrer, iodobenzene (102 mg, 0.50 mmol), triethylamine pentahydrofluoride (804 mg, 4. 00 mmol), m-chloroperbenzoic acid (518 mg, 3.00 mmol) and 1,2-dichloroethane (2 ml), and after stirring at room temperature for 15 minutes, diethyl malonate (160 mg, 1.00 mmol) was added thereto. Added. Subsequently, after sealing a test tube with a septum cap, it heated at 70 degreeC on the oil bath, and reacted for 24 hours.

After completion of the reaction, the reaction solution was returned to room temperature, added to a saturated aqueous sodium hydrogen carbonate solution (50 ml), neutralized, extracted three times with dichloromethane (10 ml), and the organic layers were combined and washed with saturated brine (10 ml). After drying, filtration and concentration, a crude product was obtained.
When the obtained crude product was quantified in ¹ H-NMR measurement using 1,4-dimethoxybenzene as an internal standard substance, the reaction yield was 3%.

[Example 8]
The same procedure as in Example 7 was performed, except that o-methoxyiodobenzene (117 mg, 0.50 mmol) was replaced with iodobenzene (102 mg, 0.50 mmol) in Example 7 to obtain a crude product.
When the obtained crude product was quantified in ¹ H-NMR measurement using 1,4-dimethoxybenzene as an internal standard substance, the reaction yield was 3%.

  Since the production method of the present invention uses a hydrogen fluoride source that is relatively easy to handle, it is possible to produce monofluoromalonic acid ester derivatives on an industrial scale.

Claims (3)

The following general formula (1)
(In the formula (1), R ¹ and R ² each independently represents a methyl group, an ethyl group, a linear, branched or cyclic alkyl group having 3 to 6 carbon atoms, a phenyl group or a benzyl group; Represents a hydrogen atom, a methyl group or an ethyl group.)
General formula (2)
(In the formula (2), R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently a hydrogen atom, a methyl group, an ethyl group, a linear or branched alkyl having 3 to 4 carbon atoms. A group, a methoxy group, an ethoxy group, a linear, branched or cyclic alkoxy group having 3 to 4 carbon atoms, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a cyano group or a nitro group.)
In the presence of an iodosylbenzene derivative represented by:
The following general formula (3)
(In the formula (3), R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are the same as the formula (2).)
Reacting with a source of hydrogen fluoride in the presence of an iodobenzene derivative represented by
The following general formula (4)
(In formula (4), R ¹ , R ² and R ³ are the same as those in formula (1).)
The manufacturing method of the monofluoromalonic acid derivative represented by these. The hydrogen fluoride source is one or more selected from the group consisting of anhydrous hydrogen fluoride, hydrogen fluoride aqueous solution, hydrogen fluoride-pyridine complex, hydrogen fluoride-triethylamine complex, and hydrogen fluoride-tetraethylammonium fluoride salt. The manufacturing method of the monofluoromalonic acid derivative of Claim 1. The method for producing a monofluoromalonic acid derivative according to claim 1 or 2, wherein the oxidizing agent is a peracid and / or a peroxide.