JP6359906B2 - Method for producing fluoromalonic ester derivative - Google Patents

Description

  The present invention relates to a novel process for producing a fluoromalonic ester derivative. Fluoromalonate derivatives are useful compounds as raw materials for electronic materials and as intermediates for the production of medicines and agricultural chemicals.

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

Furthermore, as a fluorinating agent, a method using an N-fluoropyridinium salt (see, for example, Non-Patent Document 3), a method using xenon difluoride (see, for example, 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 fluoromalonate 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 diethyl 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. Chambers et al., Journal of Fluorine Chem., 1988, 92, 45 T. Fuchikami et al., Chemistry Lett., 1573 (1984) T. Umemoto et al., Journal of American Chemical Society (J. Am. Chem. Soc.), 1990, 112, 8563 T. B. Patrick et al., Journal of Florine Chem., 1988, 39, 415 S. T. Purrington et al., The Journal of Organic Chemistry, 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 reacted a malonic acid ester derivative with N-fluorobis (methanesulfonyl) imide, which can be prepared at low cost, in the presence of a Lewis acid. Thus, a method for obtaining a monofluoromalonic acid ester derivative with a relatively high yield was found, and the present invention was 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 4 carbon atoms, a phenyl group or a benzyl group; ³ represents a hydrogen atom, a methyl group or an ethyl group)
Is reacted with N-fluorobis (methanesulfonyl) imide in the presence of a Lewis acid, and the following general formula (2):

(In the formula (2), R ¹ , R ² and R ³ are the same as the formula (1))
It concerns on the manufacturing method of the monofluoromalonic acid ester derivative represented by these.

  INDUSTRIAL APPLICABILITY According to the present invention, a simple method for producing a fluoromalonic ester 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.
The tetraalkyl orthotitanates of the present invention are tetramethyl orthotitanate, tetraethyl orthotitanate, tetra-n-propyl orthotitanate, tetra-iso-propyl orthotitanate, tetra-n-butyl orthotitanate, tetra-iso-butyl ortho. Titanate is shown.

  Specific examples of the malonic acid ester derivative represented by the general formula (1) used in the present invention include dimethyl malonate, diethyl malonate, di-n-propyl malonate, and di-iso-propyl malonate. Di-n-butyl malonate, di-iso-butyl malonate, di-tert-butyl malonate, di-n-pentyl malonate, di-cyclopentyl malonate, di-n-hexyl malonate, malonic acid Di-cyclohexyl, tert-butyl-ethyl malonate, diphenyl malonate, dibenzyl malonate, dimethyl 2-methylmalonate, diethyl 2-methylmalonate, di-n-propyl 2-methylmalonate, 2-methylmalonic acid Di-iso-propyl, 2-methylmalonate di-n-butyl, 2-methylmalonate di-iso-butyl, 2-methylmalo Di-tert-butyl acid, di-n-pentyl 2-methylmalonate, di-cyclopentyl at 2-methylmalonic acid, di-n-hexyl 2-methylmalonate, di-cyclohexyl 2-methylmalonate, 2- Tert-butyl-ethyl methylmalonate, diphenyl 2-methylmalonate, dibenzyl 2-methylmalonate, dimethyl 2-ethylmalonate, diethyl 2-ethylmalonate, di-n-propyl 2-ethylmalonate, 2-ethyl Di-iso-propyl malonate, di-n-butyl 2-ethylmalonate, di-iso-butyl 2-ethylmalonate, di-tert-butyl 2-ethylmalonate, di-n-2-ethylmalonate Pentyl, 2-ethylmalonic acid di-cyclopentyl, 2-ethylmalonic acid di-n-hexyl, 2-ethylmalonic acid di-cyclohexyl Le, butyl tert 2-ethyl malonate - ethyl, 2-ethyl malonic acid diphenyl, 2-ethyl malonic acid dibenzyl, and the like.

  Specific examples of the fluoromalonic acid ester derivative represented by the general formula (2) obtained by the present invention include dimethyl fluoromalonate, diethyl fluoromalonate, di-n-propyl fluoromalonate, and difluoromalonate. -Iso-propyl, di-n-butyl fluoromalonate, di-iso-butyl fluoromalonate, di-tert-butyl fluoromalonate, di-n-pentyl fluoromalonate, di-cyclopentyl at fluoromalonic acid, fluoro Di-n-hexyl malonate, di-cyclohexyl fluoromalonate, tert-butyl-ethyl fluoromalonate, diphenyl fluoromalonate, dibenzyl fluoromalonate, dimethyl 2-fluoro-2-methylmalonate, 2-fluoro-2 -Diethyl methylmalonate, 2-fluoro 2-methylmalonate di-n-propyl, 2-fluoro-2-methylmalonate di-iso-propyl, 2-fluoro-2-methylmalonate di-n-butyl, 2-fluoro-2-methylmalon Di-iso-butyl acid, di-tert-butyl 2-fluoro-2-methylmalonate, di-n-pentyl 2-fluoro-2-methylmalonate, di-cyclopentyl 2-fluoro-2-methylmalonate, 2-fluoro-2-methylmalonate di-n-hexyl, 2-fluoro-2-methylmalonate di-cyclohexyl, 2-fluoro-2-methylmalonate tert-butyl-ethyl, 2-fluoro-2-methyl Diphenyl malonate, dibenzyl 2-fluoro-2-methylmalonate, dimethyl 2-fluoro-2-ethylmalonate, 2-fluoro-2-ethylmalonate Diethyl diethyl, 2-fluoro-2-ethylmalonate di-n-propyl, 2-fluoro-2-ethylmalonate di-iso-propyl, 2-fluoro-2-ethylmalonate di-n-butyl, 2 -Fluoro-2-ethylmalonate di-iso-butyl, 2-fluoro-2-ethylmalonate di-tert-butyl, 2-fluoro-2-ethylmalonate di-n-pentyl, 2-fluoro-2- Di-cyclopentyl at the time of ethylmalonic acid, di-n-hexyl 2-fluoro-2-ethylmalonate, di-cyclohexyl 2-fluoro-2-ethylmalonate, tert-butyl-ethyl 2-fluoro-2-ethylmalonate , 2-fluoro-2-ethylmalonate diphenyl, 2-fluoro-2-ethylmalonate dibenzyl and the like.

The amount of N-fluorobis (methanesulfonyl) imide used in the present invention is 1.0 mol times to 5.0 mol with respect to the malonic ester derivative represented by the general formula (1) included in the reaction. The amount is preferably doubled, but since excessive use may not be economical, it is preferably in the range of 1.0 mole-fold to 3.0 mole-fold.
Specific examples of the Lewis acid applicable to the present invention include tetraalkyl orthotitanate, tetramethyl orthotitanate, tetraethyl orthotitanate, tetra-n-propyl orthotitanate, tetra-iso-propyl orthotitanate, tetra -N-butyl orthotitanate, tetraalkyl orthotitanates such as tetra-iso-butyl orthotitanate, scandium (III) triflate, lanthanum (III) triflate, rare earth triflates such as ytterbium (III) triflate, etc. It is good to use 0.3 mol fold amount-3.0 mol fold amount with respect to the malonic ester derivative represented by General formula (1) with which reaction is carried out.

  The solvent that can be used in the present invention is not particularly limited as long as it is inert to the reaction. Specifically, for example, chlorinated aliphatic hydrocarbon solvents such as dichloromethane, chloroform, 1,2-dichloroethane, etc. Non-polar solvents such as benzene, toluene, ethylbenzene, xylene, cumene, mesitylene and other aromatic hydrocarbon solvents, and fluorinated aromatic hydrocarbon solvents such as benzotrifluoride, etc. It is recommended to use 5 to 100 times by weight of the malonic ester derivative represented by 1).

The reaction temperature and time of the present invention are 0 to 40 ° C., and the reaction is completed by carrying out the reaction for 6 to 24 hours.
The post-treatment after the reaction of the present invention can be carried out by a known method. For example, after adding water or an aqueous sodium hydrogen carbonate solution, extraction with a solvent such as dichloromethane, washing with a saturated saline solution, sodium sulfate, etc. The crude product may be obtained by drying and concentrating on. Furthermore, you may refine | purify with silica gel column chromatography etc. as needed.

EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited only to these examples.
For calculation of yield and identification of compounds, ¹ H-NMR and ¹⁹ F-NMR used Varian Oxford 300 (Varian Oxford 300), and MS spectrum was Shimadzu LCMS-2010EV (Shimadzu LCMS-2010EV). )It was used. In the measurement of ¹ H-NMR, tetramethylsilane (0.00 ppm) was used as the reference substance, and in the measurement of ¹⁹ F-NMR, hexafluorobenzene (-162.2 ppm) was used as the reference and internal standard substance. It was.

Further, N-fluorobis (methanesulfonyl) imide was prepared according to JP-A-8-512286.
Example 1 Preparation of diethyl fluoromalonate (3)

  A test tube equipped with a stirrer was charged with N-fluorobis (methanesulfonyl) imide (382.4 mg, 2.0 mmol) and 1,2-dichloroethane (10 mL) and dissolved at room temperature. Next, diethyl malonate (160.2 mg, 1.0 mmol) and tetra-iso-propoxyorthotitanate (0.16 mL, 0.5 mmol) were added to the solution, and the reaction was performed at room temperature for 12 hours. After completion of the reaction, water was added, dichloromethane extraction (three times), the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product.

In the ¹⁹ F-NMR measurement of the obtained crude product using hexafluorobenzene as an internal standard, the objective diethyl fluoromalonate (3) was produced in a yield of 57%. Subsequently, the product was purified by silica gel column chromatography (toluene / dichloromethane = 50/50 vol / vol) to obtain purified diethyl fluoromalonate as a colorless transparent liquid (89.0 mg, 0.50 mmol, yield 50%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ 1.34 (t, J = 7.2 Hz, 6H), 4.32 (q, J = 6.9 Hz, 4H), 5.28 (d, J = 48. 3Hz, 1H).
¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ-195.5 (d, J = 48.5 Hz).
LCMS (ESI, m / z) 201 [(M + Na) ⁺ ].
The physical property data of the product is that of diethyl fluoromalonate (3) described in Janal of Organic Chemistry, 1991, 56, 213-277 (J. Org. Chem., 1991, 56, 213-277). Consistent with physical property values.
Example 2 Preparation of dibenzyl fluoromalonate (4)

Using the same reactor as in Example 1, the same procedure as in Example 1 was performed, except that dibenzyl malonate (284.3 mg, 1.0 mmol) was used instead of diethyl malonate (160.2 mg, 1.0 mmol). A crude product was obtained.
The obtained crude product was subjected to ¹⁹ F-NMR measurement using hexafluorobenzene as an internal standard, and the target dibenzyl fluoromalonate (4) was produced in a yield of 63%. Subsequently, the product was purified by silica gel column chromatography (hexane / dichloromethane = 50/50 vol / vol) to obtain purified dibenzyl fluoromalonate as a colorless transparent liquid (178.4 mg, 0.59 mmol, yield 59%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ 5.19-5.35 (m, 5H), 7.33 (bs, 10H).
¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ-192.2 (d, J = 50.0 Hz).
LCMS (ESI, m / z) 325 [(M + Na) ⁺ ].
The physical property data of the product coincided with the physical property values of dibenzyl fluoromalonate (4) described in Tetrahedron, 1991, 47, 1001-1012 (Tetrahedron, 1991, 47, 1001-1012).
Example 3 Preparation of di-tert-butyl fluoromalonate (5)

The same reactor as in Example 1 was used, except that di-tert-butyl malonate (216.3 mg, 1.0 mmol) was used instead of diethyl malonate (160.2 mg, 1.0 mmol). The same operation was performed to obtain a crude product.
The obtained crude product was subjected to ¹⁹ F-NMR measurement using hexafluorobenzene as an internal standard, and the target product, di-tert-butyl fluoromalonate (5), was produced in a yield of 47%. Subsequently, the residue was purified by silica gel column chromatography (toluene / hexane = 80/20 vol / vol) to obtain purified di-tert-butyl fluoromalonate as a colorless transparent liquid (93.7 mg, 0.40 mmol, yield 40). %).
¹ H-NMR (300 MHz, CDCl ₃ ) δ 1.49 (s, 18 H), 5.00 (d, J = 48.9 Hz, 1 H).
¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ-193.2 (d, J = 49.4 Hz).
LCMS (ESI, m / z) 257 [(M + Na) ⁺ ].
The physical property data of the product was consistent with the physical property values of di-tert-butyl fluoromalonate (5) described in Tetrahedron, 1991, 47, 1001-1012 (Tetrahedron, 1991, 47, 1001-1012).
Example 4 Preparation of dimethyl fluoromalonate (6)

Using the same reactor as in Example 1, the same operation as in Example 1 was performed except that dimethyl malonate (150.1 mg, 1.0 mmol) was used instead of diethyl malonate (160.2 mg, 1.0 mmol). A crude product was obtained.
The obtained crude product was subjected to ¹⁹ F-NMR measurement using hexafluorobenzene as an internal standard, and the target product, dimethyl fluoromalonate (6), was produced in a yield of 45%.
Example 5 Preparation of diethyl 2-fluoro-2-methylmalonate (7)

  A test tube equipped with a stirrer was charged with N-fluorobis (methanesulfonyl) imide (38.2 mg, 0.2 mmol) and 1,2-dichloroethane (1.0 mL) and dissolved at room temperature. Subsequently, diethyl 2-methylmalonate (17.4 mg, 0.1 mmol) and tetra-iso-propoxyorthotitanate (0.016 mL, 0.05 mmol) were added to the solution, and the reaction was performed at room temperature for 12 hours. . After completion of the reaction, water was added, dichloromethane extraction (three times), the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product.

In the ¹⁹ F-NMR measurement of the obtained crude product using hexafluorobenzene as an internal standard, the objective diethyl 2-fluoro-2-methylmalonate was produced quantitatively.
Subsequently, the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 10/90 vol / vol) to obtain purified diethyl 2-fluoro-2-methylmalonate (7) as a colorless transparent liquid (18.7 mg, 0 0.097 mmol, 97% yield).
¹ H-NMR (300 MHz, CDCl ₃ ) δ 1.29 (t, J = 7.2 Hz, 6H), 1.79 (d, J = 21.9 Hz, 3H), 4.30 (q, J = 7. 2Hz, 4H).
¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ-157.9 (q, J = 21.7 Hz).
LCMS (ESI, m / z) 215 [(M + Na) ⁺ ].
The physical property data of the product was consistent with the physical property value of diethyl 2-fluoro-2-methylmalonate (7) described in Dalton Transition, 2005, 1637-1643 (Dalton Trans., 2005, 1637-1643).

Example 6 Preparation of diethyl fluoromalonate (3) A test tube equipped with a stir bar was charged with N-fluorobis (methanesulfonyl) imide (191.2 mg, 1.0 mmol) and dichloromethane (10 mL), and dissolved at room temperature. I let you. Next, diethyl malonate (160.2 mg, 1.0 mmol) and tetra-iso-propoxyorthotitanate (0.10 mL, 0.3 mmol) were added to the solution, and the reaction was performed at room temperature for 12 hours. After completion of the reaction, water was added, dichloromethane extraction (three times), the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product.

In the ¹⁹ F-NMR measurement of the obtained crude product using hexafluorobenzene as an internal standard, the target diethyl fluoromalonate (3) was produced in a yield of 36%.
Example 7 Preparation of diethyl fluoromalonate (3) Using the same reactor as in Example 6, the amount of N-fluorobis (methanesulfonyl) imide (191.2 mg, 1.0 mmol) was (382.4 mg, 2. Except for changing to 0 mmol), the same reaction operation as in Example 6 was performed to obtain a crude product.

In the ¹⁹ F-NMR measurement of the obtained crude product using hexafluorobenzene as an internal standard, the target diethyl fluoromalonate (3) was produced in a yield of 49%.
Example 8 Preparation of diethyl fluoromalonate (3) Using the same reactor as in Example 6, the amount of N-fluorobis (methanesulfonyl) imide (191.2 mg, 1.0 mmol) was (382.4 mg, 2. The reaction was performed in the same manner as in Example 6 except that the amount of tetra-iso-propoxyorthotitanate (0.10 mL, 0.3 mmol) was changed to (0.16 mL, 0.5 mmol). Obtained.

In the ¹⁹ F-NMR measurement of the obtained crude product using hexafluorobenzene as an internal standard, the objective diethyl fluoromalonate (3) was produced in a yield of 75%.
Example 9 Preparation of diethyl fluoromalonate (3) Using the same reactor as in Example 6, the amount of N-fluorobis (methanesulfonyl) imide (191.2 mg, 1.0 mmol) was (382.4 mg, 2. The reaction was performed in the same manner as in Example 6 except that the amount of tetra-iso-propoxyorthotitanate (0.10 mL, 0.3 mmol) was changed to (0.36 mL, 1.0 mmol). Obtained.

In the ¹⁹ F-NMR measurement of the obtained crude product using hexafluorobenzene as an internal standard, the objective diethyl fluoromalonate (3) was produced in a yield of 73%.
Example 10 Preparation of diethyl fluoromalonate (3) Using the same reactor as in Example 6, the amount of N-fluorobis (methanesulfonyl) imide (191.2 mg, 1.0 mmol) was (382.4 mg, 2. The reaction was performed in the same manner as in Example 6 except that the amount of tetra-iso-propoxyorthotitanate (0.10 mL, 0.3 mmol) was changed to (0.72 mL, 2.0 mmol). Obtained.

In the ¹⁹ F-NMR measurement of the obtained crude product using hexafluorobenzene as an internal standard, the target diethyl fluoromalonate (3) was produced in a yield of 76%.
Example 11 Preparation of diethyl fluoromalonate (3) A test tube equipped with a stir bar was charged with N-fluorobis (methanesulfonyl) imide (383.4 mg, 2.0 mmol) and dichloroethane (10 mL) and dissolved at room temperature. I let you. Next, diethyl malonate (160.2 mg, 1.0 mmol) and ytterbium triflate (310.1 mg, 0.5 mmol) were added to the solution, and the reaction was performed at room temperature for 12 hours. After completion of the reaction, water was added, dichloromethane extraction (three times), the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product.

In the ¹⁹ F-NMR measurement of the obtained crude product using hexafluorobenzene as an internal standard, the objective diethyl fluoromalonate (3) was produced in a yield of 9%.
Example 12 Preparation of diethyl fluoromalonate (3) N-fluorobis (methanesulfonyl) imide (383.4 mg, 2.0 mmol) and chloroform (10 mL) were charged into a test tube equipped with a stir bar and dissolved at room temperature. I let you. Next, diethyl malonate (160.2 mg, 1.0 mmol) and tetra-iso-propoxyorthotitanate (0.16 mL, 0.5 mmol) were added to the solution, and the reaction was performed at room temperature for 12 hours. After completion of the reaction, water was added, dichloromethane extraction (three times), the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product.

In the ¹⁹ F-NMR measurement of the obtained crude product using hexafluorobenzene as an internal standard, the objective diethyl fluoromalonate (3) was produced in a yield of 75%.
Example 13 Preparation of diethyl fluoromalonate (3) Using the same reaction apparatus as in Example 12, except that toluene (10 mL) was used instead of chloroform (10 mL), the crude product was obtained. Obtained.

In the ¹⁹ F-NMR measurement of the obtained crude product using hexafluorobenzene as an internal standard, the objective diethyl fluoromalonate (3) was produced in a yield of 81%.
Example 14 Preparation of diethyl fluoromalonate (3) Using the same reaction apparatus as in Example 12, except that benzotrifluoride (10 mL) was used instead of chloroform (10 mL), the same reaction operation as in Example 12 was performed. I got a thing.

In the ¹⁹ F-NMR measurement of the obtained crude product using hexafluorobenzene as an internal standard, the objective diethyl fluoromalonate was produced in a yield of 77%.

  According to the present invention, it is possible to easily produce a fluoromalonic ester derivative.

Claims (1)

The following general formula (1)

(In 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 4 carbon atoms, a phenyl group or a benzyl group; ³ is a hydrogen atom)
Is reacted with N-fluorobis (methanesulfonyl) imide in the presence of tetraalkoxy orthotitanates, the following general formula (2)

(In the formula (2), R ¹ , R ² and R ³ are the same as the formula (1))
The manufacturing method of the fluoromalonic acid ester derivative represented by these.