JP4854255B2 - 2-Fluorine-containing alkoxy fatty acid ester compound production method - Google Patents

Description

  The present invention relates to a process for producing 2-fluorinated alkoxy fatty acid ester compounds useful as functional materials, pharmaceuticals, and the like, and synthetic intermediates thereof.

  2-Alkoxy fatty acid esters are useful compounds as functional materials, pharmaceuticals, and synthetic intermediates thereof. For example, examples of synthesizing perfluorovinyl ethers and precursors thereof, which are useful raw materials for fluoropolymers, using 2-alkoxypropionic acid esters as key intermediates are known (Patent Documents 1 and 2). These examples include a step of fluorinating 2-alkoxypropionic acid ester or its derivative by liquid phase direct fluorination reaction. In general, in a liquid phase direct fluorination reaction, it is preferable to introduce fluorine atoms into a reaction substrate for the purpose of improving the solubility in a fluorine-containing solvent inert to fluorine gas (Patent Document 3).

As a method for synthesizing a 2-alkoxy fatty acid ester compound, a method in which a 2-halo fatty acid ester is reacted with an alcohol under basic conditions to substitute a halogen atom with an alkoxy group is the most direct and simple. Non-patent documents 5, 6 and the like describe these examples. However, when a primary alcohol is reacted with a 2-halo fatty acid ester of a primary lower alcohol and a 2-halo fatty acid, transesterification also proceeds at the same time, so that a desired 2-alkoxy fatty acid ester is obtained in a high yield. It cannot be synthesized with high purity. Therefore, in Patent Document 1, 2-halopropionic acid [CH ₃ CH (X) CO ₂ H] and alcohol [ROH] are reacted under basic conditions to give 2-alkoxypropionic acid [CH ₃ CH (OR) CO ₂ H. Then, the desired methyl 2-alkoxypropionate [CH ₃ CH (OR) CO ₂ CH ₃ ] is synthesized by esterifying the carboxylic acid moiety. In Patent Document 2, 2-halopropionic acid is converted to 2-halopropionic acid ester [CH ₃ CH (X) CO ₂ R] using alcohol (ROH) to be introduced at the 2-position, and then basic conditions are satisfied. Below, the same alcohol as above is reacted to obtain 2-alkoxypropionic acid ester [CH ₃ CH (OR) CO ₂ R].

  However, in the former example, an excess of base is required for introducing the alkoxy group. In the latter case, only 2-alkoxypropionic acid esters in which the alkoxy group at the 2-position and the alkoxy group in the ester portion are the same can be synthesized. When considering conversion to perfluorovinyl ether, the alkoxy group of the ester moiety is finally cleaved from the desired perfluorovinyl ether, which is particularly uneconomical when the alkoxy moiety is expensive. Therefore, a method for efficiently synthesizing 2-alkoxy fatty acid esters, particularly 2-fluorinated alkoxy fatty acid esters, from 2-halo fatty acid esters that are inexpensive and easily available has been desired.

International Publication WO01 / 046107 Pamphlet JP 2001-240576 A International Publication WO00 / 56694 Panflet French Patent No. 2472560 Tetrahedron, 59, 6751 (2003) Liebigs Annalen der Chemie, (5), 407 (1987) Polish Journal of Chemistry, 53 (11), 2231 (1979)

  The object of the present invention is to provide a method for efficiently synthesizing 2-fluorinated alkoxy fatty acid ester compounds useful as functional materials, pharmaceuticals, etc., and synthetic intermediates thereof.

As a result of intensive studies, the above object was achieved by the following method.
(1) A compound represented by the general formula (I), which comprises reacting a compound represented by the general formula (II) with a compound represented by the general formula (III) in the presence of a metal carbonate . Manufacturing method.

In the formula, R ¹ represents a hydrogen atom, an alkyl group or an aryl group, R ² represents an alkyl group, Rf represents a perfluoroalkyl group or an ω-hydroperfluoroalkyl group , and X represents a halogen atom.
(2) the production method of the compound represented by 1 Symbol placement of the general formula according to claim ^(I), wherein R ¹ is a methyl group.
(3) The method according to claim 1 or 2 formula (I) according the compound represented by wherein R ² is a methyl group or an ethyl group.
( 4 ) The method for producing a compound represented by the general formula (I) according to any one of claims 1 to 3, wherein the metal carbonate is potassium carbonate.
( 5 ) The method for producing a compound represented by the general formula (I) according to any one of claims 1 to 4, wherein the reaction is performed at a reaction temperature of 50 ° C to 150 ° C.
( 6 ) The method for producing a compound represented by formula (I) according to any one of claims 1 to 5, wherein the reaction is carried out in the presence of an aprotic polar solvent.
( 7 ) The aprotic polar solvent is N, N-dimethylformamide, 1-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, DMSO, sulfolane or 2-butanone. A process for producing a compound represented by the general formula (I) according to claim 6.

  According to the present invention, a 2-fluorinated alkoxy fatty acid ester compound represented by the general formula (I), which is useful as a functional material, a pharmaceutical product, etc. By using the group-containing alcohol, it can be efficiently produced from the 2-halo fatty acid ester represented by the general formula (II) that is easily available without changing the ester part by transesterification. The 2-fluorinated alkoxypropionic acid ester that can be obtained by the method of the present invention is useful as a synthetic intermediate for perfluorovinyl ether, which is an important raw material for fluoropolymers.

The present invention is described in detail below.
In general formulas (I) and (II), R ¹ represents a hydrogen atom, an alkyl group or an aryl group. The alkyl group represented by R ¹ preferably has 1 to 20 carbon atoms, more preferably 1 to 10 and may be linear or branched or have a ring structure. For example, methyl , Ethyl, propyl, isopropyl, butyl, pentyl, cyclopentyl, hexyl, cyclohexyl, octyl, decyl and the like. Moreover, these alkyl groups may have the following substituents.

Examples of the substituent for R ¹ include a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom), an alkyl group having 20 or less carbon atoms (for example, methyl or ethyl), and an aryl group having 30 or less carbon atoms (for example, phenyl, Naphthyl), cyano group, carboxyl group, alkoxycarbonyl group having 20 or less carbon atoms (for example, methoxycarbonyl), aryloxycarbonyl group having 30 or less carbon atoms (for example, phenoxycarbonyl), carbamoyl group (for example, carbamoyl, N-phenylcarbamoyl, N , N-dimethylcarbamoyl), an alkylcarbonyl group having 20 or less carbon atoms (for example, acetyl), an arylcarbonyl group having 30 or less carbon atoms (for example, benzoyl), a nitro group, an amino group (for example, amino, dimethylamino, anilino), a carbon number 20 or less acylamino groups ( Acetamide, ethoxycarbonylamino), sulfonamide group (eg methanesulfonamide), imide group (eg succinimide, phthalimide), imino group (eg benzylideneamino),

A hydroxy group, an alkoxy group having 20 or less carbon atoms (for example, methoxy), an aryloxy group having 30 or less carbon atoms (for example, phenoxy), an acyloxy group having 20 or less carbon atoms (for example, acetoxy), an alkylsulfonyloxy group having 20 or less carbon atoms ( For example, methanesulfonyloxy), arylsulfonyloxy group having 30 or less carbon atoms (for example, benzenesulfonyloxy), sulfo group, sulfamoyl group (for example, sulfamoyl, N-phenylsulfamoyl), alkylthio group having 20 or less carbon atoms (for example, methylthio) , An arylthio group having 30 or less carbon atoms (for example, phenylthio), an alkylsulfonyl group having 20 or less carbon atoms (for example, methanesulfonyl), an arylsulfonyl group having 30 or less carbon atoms (for example, benzenesulfonyl), a heterocyclic group, and the like. Kill. The substituent may be further substituted, and when there are a plurality of substituents, they may be the same or different. Moreover, you may combine with substituents and may form a ring. Furthermore, the alkyl group in the substituent may form an unsaturated bond at an arbitrary position.

The aryl group represented by R ¹ preferably has 6 to 20 carbon atoms, more preferably 6 to 10 carbon atoms, and examples thereof include phenyl, naphthyl, and anthranyl. Further, these aryl groups may have a substituent as described above.
R ¹ is preferably a methyl group or an ethyl group, and more preferably a methyl group.

In general formulas (I) and (II), R ² represents an alkyl group, preferably having 1 to 20 carbon atoms, more preferably 1 to 10 and having a branched or ring structure even if it is linear. For example, methyl, ethyl, propyl, isopropyl, butyl, pentyl, cyclopentyl, hexyl, cyclohexyl, octyl, decyl and the like can be mentioned. Further, these alkyl groups may have a substituent as described for R ¹ . R ² is preferably a primary alkyl group, more preferably a methyl group or an ethyl group.
X represents a halogen atom (for example, a chlorine atom, a bromine atom, an iodine atom or a fluorine atom), preferably a chlorine atom or a bromine atom.

In general formulas (I) and (III), Rf represents an alkyl group having at least one fluorine atom, preferably 1 to 20 carbon atoms, more preferably 1 to 10 carbon atoms, It may have a branched or ring structure, and may have a substituent as described for R ¹ . Rf is preferably a perfluoroalkyl group or an ω-perfluorohydroperfluoroalkyl group.

Examples of the compound represented by the general formula (III) that can be used in the present invention and examples of the compound represented by the general formula (I) that can be produced in the present invention are shown below. The invention is not limited to these examples.
Examples of compounds represented by general formula (III)

Examples of compounds represented by general formula (I)

Moreover, although the example of the compound represented with general formula (II) which can be utilized by this invention below is shown, this invention is not limited to these.
Examples of compounds represented by formula (II)

Of the compounds represented by the general formula (II), commercially available products such as methyl 2-chloro (or bromo) propionate (or ethyl) can be used. For those not commercially available, the corresponding carboxylic acid, carboxylic acid halide, carboxylic acid ester and the like are used as starting materials. For example, published by Maruzen Co., Ltd., edited by The Chemical Society of Japan, 4th edition, Experimental Chemistry Course 19, Organic Synthesis I , -Hydrocarbons and halogen compounds-, halogenated at the α-position of the carbonyl group under the general conditions as described in p.436-438. (In the case of using carboxylic acid or carboxylic acid halide as the starting material, ester Can be synthesized).
A commercially available compound can be used as the compound represented by the general formula (III). Further, among the compounds represented by the general formula (III), perfluoroalkylmethanols are prepared by using a liquid phase fluorination reaction described in US Pat. No. 5,093,432, WO00 / 56694, etc. An ester or an acid halide can be synthesized and then reduced. The reduction reaction is described in, for example, published by Maruzen Co., Ltd., edited by The Chemical Society of Japan, 4th edition, Experimental Chemistry Course 26, Organic Synthesis VIII, -Asymmetric Synthesis / Reduction / Sugar / Labeled Compound, p.159-266. Such various reduction methods can be used. Preferred reduction methods include methods using metal hydride complex compounds such as sodium borohydride, lithium aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride (trade name Red-Al, Vitride), and hydrogen / transition metals. Examples thereof include a method using catalytic reduction using a catalyst.

The conditions for producing the compound represented by the general formula (I) by reacting the compound represented by the general formula (II) with the compound represented by the general formula (III) will be described below.
This reaction is preferably performed in the presence of a base. Although there is no restriction | limiting in particular as a base to be used, As a preferable base, organic bases, such as a pyridine, a triethylamine, N, N- diisopropyl ethylamine, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate And inorganic bases such as sodium hydride. Of these, metal carbonates are preferable, and potassium carbonate is particularly preferable. The base used is preferably 0.1 equivalents to 10 equivalents, more preferably 0.8 equivalents to 2 equivalents, and 0.9 equivalents to 1.5 equivalents with respect to the compound represented by the general formula (III). Is particularly preferred.

  This reaction may be performed using a solvent or without a solvent. Preferred solvents include dichloromethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran, acetone, 2-butanone, cyclohexanone, ethyl acetate, hexane, toluene, xylene, acetonitrile, N, N-dimethylformamide, N, N-dimethylformamide, Examples include 1-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, DMSO, sulfolane and the like. Preferred are aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylformamide, 1-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, DMSO, sulfolane and the like. Although there is no restriction | limiting in particular as the quantity of the solvent to be used, Preferably it is 0.5-100 times of the compound weight represented by General formula (III), More preferably, it is 1-10 times.

The compound represented by the general formula (III) is preferably used in an amount of 0.5 to 5 equivalents relative to the compound represented by the general formula (II), more preferably 0.8 to 2 equivalents, and 0.9 to 1.5 equivalents are particularly preferred.
The reaction temperature is preferably 0 ° C to 200 ° C, more preferably 50 ° C to 150 ° C. The reaction time depends on the base used, the solvent and the reaction temperature. It is preferable to carry out the reaction within 12 hours (preferably within 6 hours) by adjusting these appropriately.

  Specific synthesis examples of the present invention are shown below.

Example 1
Synthesis of Compound (I-30) A solution of ethyl 2-bromopropionate (3.6 g), compound (III-3) (4.0 g) and potassium carbonate (3.0 g) in 2-butanone (20 ml) for 3 hours Refluxed. The reaction mixture was poured into ethyl acetate (100 ml) and dilute hydrochloric acid (100 ml), and the phases were separated. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by column chromatography (developing solvent: ethyl acetate / hexane) to obtain Compound (I-30) (2.5 g, 42%). Moreover, the compound by which the ethyl group of the ester part of compound (I-30) was transesterified was not produced | generated.
¹ H NMR (CDCl ₃ ) δ 1.29 (t, J = 7.2 Hz, 3H), 1.48 (d, J = 6.9 Hz, 3H), 3.86 (q, J = 12.9 Hz, 1H), 4.11 (d, J = 6.9 Hz, 1H), 4.12-4.30 (m, 3H)
¹⁹ F NMR (CDCl ₃ ) δ-81.3 (3F), -121.3 (2F), -128.0 (2F)

Example 2
Synthesis of Compound (I-30) A solution of 2-butanone (10 ml) of ethyl 2-bromopropionate (1.8 g), compound (III-3) (2.0 g) and potassium carbonate (1.5 g) at 90 ° C. For 8 hours. The reaction mixture was poured into ethyl acetate (100 ml) and dilute hydrochloric acid (100 ml), and the phases were separated. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by column chromatography (developing solvent: ethyl acetate / hexane) to obtain Compound (I-30) (1.3 g, 43%). Moreover, the compound by which the ethyl group of the ester part of compound (I-30) was transesterified was not produced | generated.

Example 3
Synthesis of Compound (I-30) 1-methyl-2-pyrrolidone (10 ml) of ethyl 2-bromopropionate (1.8 g), compound (III-3) (2.0 g) and potassium carbonate (1.5 g) The solution was stirred at 90 ° C. for 8 hours. The reaction mixture was poured into ethyl acetate (100 ml) and dilute hydrochloric acid (100 ml), and the phases were separated. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by column chromatography (developing solvent: ethyl acetate / hexane) to obtain Compound (I-30) (1.9 g, 63%). Moreover, the compound by which the ethyl group of the ester part of compound (I-30) was transesterified was not produced | generated.

Example 4
Synthesis of Compound (I-3) 1-methyl-2-pyrrolidone (10 ml) of methyl 2-bromopropionate (1.67 g), compound (III-3) (2.00 g) and potassium carbonate (1.50 g) The solution was stirred at 90 ° C. for 8 hours. The reaction mixture was poured into ethyl acetate (100 ml) and dilute hydrochloric acid (100 ml), and the phases were separated. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by column chromatography (developing solvent: ethyl acetate / hexane) to obtain Compound (I-3) (1.45 g, 51%). Moreover, the compound by which the methyl group of the ester part of compound (I-3) was transesterified was not produced | generated.
¹ H NMR (CDCl ₃ ) δ 1.47 (d, J = 6.9 Hz, 3H), 3.78 (q, 3H), 3.86 (q, J = 12.9 Hz, 1H), 4.18 (Q, J = 6.9 Hz, 1H), 4.25 (q, J = 12.9 Hz, 1H),
¹⁹ F NMR (CDCl ₃ ) δ-81.3 (3F), -121.3 (2F), -128.0 (2F)

Example 5
Synthesis of Compound (I-6) 1-methyl-2-pyrrolidone (10 ml) of methyl 2-bromopropionate (1.67 g), compound (III-6) (3.50 g) and potassium carbonate (1.50 g) The solution was stirred at 90 ° C. for 8 hours. The reaction mixture was poured into ethyl acetate (100 ml) and dilute hydrochloric acid (100 ml), and the phases were separated. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by column chromatography (developing solvent: ethyl acetate / hexane) to obtain Compound (I-6) (4.00 g, 92%). Moreover, the compound by which the methyl group of the ester part of compound (I-6) was transesterified was not produced | generated.
¹ H NMR (CDCl ₃ ) δ 1.47 (d, J = 6.8 Hz, 3H), 3.78 (q, 3H), 3.87 (q, J = 13.2 Hz, 1H), 4.16 (Q, J = 6.8 Hz, 1H), 4.26 (q, J = 13.2 Hz, 1H),
¹⁹ F NMR (CDCl ₃ ) δ-81.2 (3F), -120.3 (2F), -122.6 (2F), -123.2 (2F), -123.8 (2F), -126 .5 (2F)

From the above results, it is possible to efficiently convert 2-fluorinated alkoxy fatty acid esters, particularly 2-fluorinated alkoxypropionic acid esters, from 2-halo fatty acid esters that are inexpensive and easily available without changing the ester part by transesterification. Can be manufactured. These 2-fluorinated alkoxypropionic acid esters can be easily derived into perfluorovinyl ether by using a liquid phase direct fluorination reaction, as described in International Publication WO 01/046107.

Claims (7)

A method for producing a compound represented by general formula (I), comprising reacting a compound represented by general formula (II) with a compound represented by general formula (III) in the presence of a metal carbonate. .

In the formula, R ¹ represents a hydrogen atom, an alkyl group or an aryl group, R ² represents an alkyl group, Rf represents a perfluoroalkyl group or an ω-hydroperfluoroalkyl group , and X represents a halogen atom. Method for producing a compound represented by 1 Symbol placement of the general formula according to claim ^(I), wherein R ¹ is a methyl group. The method for producing a compound represented by the general formula (I) according to claim 1 or 2, wherein R ² is a methyl group or an ethyl group. The method for producing a compound represented by the general formula (I) according to any one of claims 1 to 3, wherein the metal carbonate is potassium carbonate. The method for producing a compound represented by the general formula (I) according to any one of claims 1 to 4, wherein the reaction is performed at a reaction temperature of 50C to 150C. The method for producing a compound represented by formula (I) according to any one of claims 1 to 5, wherein the reaction is carried out in the presence of an aprotic polar solvent. The aprotic polar solvent is N, N-dimethylformamide, 1-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, DMSO, sulfolane or 2-butanone. 6. A method for producing a compound represented by the general formula (I) according to 6.