JPH089573B2 - Method for producing ω-hydroxy fatty acid ester - Google Patents

Description

TECHNICAL FIELD The present invention relates to a method for producing an ω-hydroxy fatty acid ester useful as an intermediate for synthesizing a cyclic lactone used as a raw material for drugs, a fragrance or the like.

Conventional Techniques and Problems Conventional methods for producing ω-hydroxy fatty acid esters from diacid monoesters have heretofore been the methods of directly reducing diacid monoesters to ω-hydroxy fatty acid esters using diborane as a reducing agent [Journal of Chemicals]. Journal of Chemical Educatio
n) 54 , 12, p778-779 (1977)] is known.

On the other hand, as a method for producing ω-hydroxy fatty acid, ω-hydroxy-alkyl-γ-butyrolactone or ω-acyloxy-alkyl-γ-butyrolactone is subjected to catalytic reaction by supplying hydrogen gas in the presence of a hydrogenolysis catalyst. (Japanese Examined Patent Publication No. 61-3776) or 13-oxa-bicyclo [10,4,0] -hexadecene [1 (12)] is converted to a lactone, and the lactone is converted by the Walfuxiner method or the Juan-Minron method. A method of opening a lactone ring (Japanese Patent Publication No. 61-21474) has been proposed.

However, the method for producing a diacid monoester by reduction using diborane, diborane is very expensive and dangerous to handle, and furthermore, the reaction selectivity is low and the yield of the target ester is low, Not economical for industrial scale production. Further, all of the above-mentioned methods for producing ω-hydroxy fatty acid use expensive and complicated compounds as starting materials, and thus have a problem of high production cost.

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention An object of the present invention is to provide a production method for advantageously producing a ω-hydroxy fatty acid ester in a high yield from a diacid monoester that can be obtained relatively inexpensively. .

 The present invention will be described in detail below.

Structure of the Invention The feature of the present invention is that the general formula HOCO (CH ₂ ) _n COOR (I) [wherein R represents an alkyl group and n represents a natural number]. ] The diacid monoester represented by the general formula R ¹ R ² R ³ R ⁴ NBH ₄ (II) [In the formula, R ¹ , R ² , R ³ and R ⁴ may be different alkyl groups or aralkyls. Represents a group or an aryl group. ] HOCH ₂ (CH ₂ ) _n COOR (III) by reduction with a quaternary ammonium borohydride represented by the formula [wherein R and n have the same meanings as described above]. ] It exists in obtaining the (omega) -hydroxy fatty acid ester shown by these.

Means for Solving the Problems In the present invention, the diacid monoester represented by the general formula (I) used as a starting material is obtained by esterifying an alkanedioic acid with an alcohol and using the ester, for example, barium hydroxide. It can be easily obtained by forming a monosalt of barium and then substituting the barium salt with an acid.

In this case, it is preferable that a lower alcohol having 1 to 4 carbon atoms is used as the alcohol for the esterification so that the obtained esterified product can be easily separated and purified.

The diacid monoester is preferably an alkanedioic acid monoester having 9 to 18 carbon atoms when it is intended as an intermediate for obtaining a lactone used as a raw material for medicines or as a fragrance.

The diacid monoester represented by the general formula (I) of the present invention is reduced by using the quaternary ammonium borohydride represented by the general formula (II). Although the quaternary ammonium borohydride is industrially available, it can be easily produced from, for example, a quaternary ammonium halide or a quaternary ammonium sulfate and an alkali metal borohydride. (MD Banus, RWBragden and TRPGrbb J
r, J. Am. Chem. Soc., 74 (2346) 1952; A. Brndstrm,
U. Junggren and B. Lamm, Tetrahedron Lett., 3173 (197
2)] Examples of the quaternary ammonium borohydride that can be used include tetramethylammonium borohydride tetraethyl 〃 tetrapropyl 〃 tetrabutyl 〃 tetrapentyl 〃 tetrahexyl 〃 tetraoctyl 〃 tetradecyl 〃 trimethyl 〃 tetrabenzyl 〃 tetrabenzyl 〃 tetrabenzyl 〃 tetrabenzyl 〃 tetrabenzyl 〃 Dodecyl trimethyl 〃 Hexadecyl 〃 Methyl triethyl 〃 Dodecyl triethyl 〃 Hexadecyl triethyl 〃 Nonyltripropyl 〃 Decyl tributyl 〃 Hexadecyl tributyl 〃 Benzyl trimethyl 〃 Triethyl 〃 benzyl triethyl 〃 Benzyl tributyl 〃 Benzyl tributyl benzyl triethyl benzyl tributyl Benzyl tributyl 〃 〃 Phenyl tributyl 〃 Benzyl butyl dimethyl 〃 Benzyl phenyl Rujimechiru 〃 benzyl hexadecanol dimethyl 〃 it can be exemplified.

The amount of the quaternary ammonium borohydride used can be selected within the range of 0.6 to 1.5 equivalents based on the diacid monoester represented by the general formula (I).

In carrying out the present invention, it is preferable to carry out in the presence of an organic halide from the viewpoint of yield and reaction efficiency. Examples of organic halides include methylene chloride, chloroform, carbon tetrachloride, dichloroethane, trichlene, methyl iodide, ethyl bromide and the like.

The amount of the organic halide used is not particularly limited and may also serve as a solvent.

The reaction proceeds near room temperature but can be heated or cooled if desired. When the temperature is 150 ° C or higher, the selectivity is lowered, which is not preferable, and when the temperature is -20 ° C or lower, the reaction efficiency is lowered, which is not preferable.

As described above, by reducing the diacid monoester with quaternary ammonium borohydride, the ω-hydroxy fatty acid ester can be obtained in high yield.

The ω-hydroxy fatty acid ester thus obtained is polymerized by a known method to form a linear polyester, which is heated in the presence of a depolymerization catalyst to depolymerize to form a cyclic lactone. You can

 The present invention will be specifically described below with reference to examples.

Example 1 Tetra n-butyl ammonium borohydride (260m
g, 1.01 mmol) was added to a solution of undecane-1,11-dicarboxylic acid monomethyl ester (259 mg, 1.00 mmol) in dry carbon tetrachloride (9 ml), and the mixture was stirred at room temperature for 2.5 hours. In the reaction solution
After adding 2N-hydrochloric acid to make the mixture acidic, the organic layer was separated. Chloroform was added to the aqueous layer for extraction, both organic layers were combined and dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was separated and purified by silica gel column chromatography (10% ether-methylene chloride) to give 13-hydroxytridecanoic acid methyl ester (225 mg, 92%).

White plate crystal mp30.0-31.0 ℃ IR (cm ^-1 ): 3300, 2945, 2875, 1745, 1470, 1435, 118
0, 1040 ¹ H NMR (CDCl ₃ , 90 MHz): δ1.15 to 1.90 (m, 20H, -CH _2- ), 3.64 (t, 7Hz, 2H, -C H 2 OH), 3.65 (s, 3H, -OC H 3) Mass m / z (%): 245 (M + +1,1.0), 226 (3.2), 214 ( 43.9), 195
(9.4), 194 (7.6), 166 (6.0), 152 (11.1), 143
(22.7) 112 (30.5), 98 (100), 87 (100), 84 (68.0), 74
(100), 69 (93.9), 55 (100), 43 (60.2), 41 (10
0) Example 2 Tetra n-butyl ammonium borohydride (263m
g, 1.02 mmol) was added to a solution of tetradecane-1,14-dicarboxylic acid monomethyl ester (302 mg, 1.01 mmol) in dry carbon tetrachloride (9 ml), and the mixture was stirred at room temperature for 2.5 hours. After the reaction, post-treatment was carried out in the same manner as in Example 1, and then purification was performed to obtain 16-hydroxyhexadecanoic acid methyl ester (221 mg, 77%).

White plate crystal mp66.5-67.0 ℃ [Reference mp55-55.5 ℃ "Dictionary of Organic Compound" (Dictionary of Organic
Compound) vol.3, (1965)] IR (cm ^-1 ): 3100, 2925, 2860, 1740, 1715, 1465, 143
0, 1175 ¹ H NMR (CDCl ₃ , 90 MHz): δ 1.10 to 1.87 (m, 26 H, —CH ₂ —), 3.62 (t, 7Hz, 2H, −C H ₂ OH), 3.64 (s, 3H, −OC H ₃ ) Mass m / z (%): 286 (M ⁺ , 1.3), 268 (10.1), 256 (79.7 ), 237 (1
1.3), 236 (19.7), 208 (5.4), 194 (10.8), 166
(5.7), 152 (10.0), 143 (27.4), 112 (40.4), 98
(100), 87 (100), 84 (87.3), 74 (100), 69 (10
0), 55 (100) 43 (100), 41 (100).

Example 3 Tetra n-butyl ammonium borohydride (258.0m
g, 1.00 mmol) and tridecane-1,13-dicarboxylic acid monomethyl ester (287.1 mg, 1.00 mmol) in dry methylene chloride solution (1 ml) under argon atmosphere, methyl iodide (0.125 ml, 2.0 mmol) was added dropwise. And stirred at room temperature for 2 hours. After the reaction was completed, 2N hydrochloric acid was added to the solution to acidify it,
The organic layer was separated. Ethyl acetate was added to the aqueous layer for extraction,
Both organic layers were combined, washed with saturated saline and then dried over sodium sulfate. After concentration under reduced pressure, the resulting crude product was separated and purified by column chromatography to obtain the desired 15-hydroxypentadecanoic acid methyl ester (248.5 mg, 91
%) Was obtained.

mp.40-42 ℃ [Reference, mp.31.8-32.4 ℃ "Helvetica
Chimica Acta "(Helv.Chim.Acta) 12 , 463 (192
9)] IR (cm ^-1 ): 3430, 2930, 2850, 1740, 1465, 1435, 119
5, 1170, 1050 NMR (CDCl ₃ , 90MHz): δ1.25 (m, 20H), 1.58 (m, 4H), 2.30 (t, 2H), 3.6
4 (t, 3H), 3.67 (s, 3H) Mass (70ev) m / z (%): 273 (M ⁺ +1,1.2), 273 (M ⁺ −H ₂ O, 1.3) 242 (14.0), 143 (10.2), 129 (5.7), 125 (4.7),
112 (13.6), 98 (47.0), 97 (15.9), 87 (49.8), 8
4 (28.9), 81 (12.2), 74 (100), 55 (56.1) Example 4 Tetra n-butyl ammonium borohydride (257.3m
g, 1.00 mmol) and tridecane-1,13-dicarboxylic acid monomethyl ester (286.8 mg, 1.00 mmol) were transferred to a reaction vessel, dry carbon tetrachloride (1 ml) was added under an argon gas atmosphere, and the mixture was stirred at room temperature for 3 hours. . After completion of the reaction, add water,
Dilute with methylene chloride and separate the organic layer. Methylene chloride was added to the aqueous layer for extraction, both organic layers were combined, and 2N-hydrochloric acid,
The extract was washed with saturated saline and dried over sodium sulfate. After concentration under reduced pressure, a part of the obtained crude product was taken and quantified by gas chromatography (internal standard method), and the target 15-hydroxypentadecanoic acid methyl ester (24
3mg, 89%) was produced.

Example 5 Tetra n-butyl ammonium borohydride (258.5m
g, 1.01 mmol) and tridecane-1,13-dicarboxylic acid monomethyl ester (286.6 mg, 1.00 mmol) were placed in a reaction vessel, dry carbon tetrachloride (1 ml) was added under an argon gas atmosphere, and the mixture was stirred at 55 ° C for 4 hours. did. After completion of the reaction, post-treatment was carried out in the same manner as in Example 4, and the obtained crude product was separated and purified by column chromatography to obtain the target 15-hydroxypentadecanoic acid methyl ester (236 mg, 87%). It was

Example 6 Put tetramethylammonium borohydride (91.1 mg, 1.02 mmol) and tridecane-1,13-dicarboxylic acid monomethyl ester (286.1 mg, 1.00 mmol) in a reaction vessel,
Dry carbon tetrachloride (3 ml) was added under an argon gas atmosphere, and the mixture was heated with stirring at 80 ° C. for 22 hours. After the reaction, the same post-treatment as in Example 1 was performed, and the obtained crude product (278.8 mg) was separated and purified by column chromatography (5% ether-methylene chloride) to give the desired 15-hydroxy. Pentadecanoic acid methyl ester (210 mg, 77%) was obtained.

Example 7 Dodecyltrimethylammonium borohydride (245.
0 mg, 1.01 mmol) and tridecane-1,13-dicarboxylic acid monomethyl ester (287.0 mg, 1.00 mmol) were transferred to a reaction vessel, and dried carbon tetrachloride (2 ml) under an argon gas atmosphere.
Was added and the mixture was heated with stirring at 80 ° C. for 18 hours. After the reaction, Example 1
After post-treatment in the same manner as above, the crude product obtained was quantified by gas chromatography (internal standard method), and the target 15-droxypentadecanoic acid methyl ester (221 m
g, 81%) was generated.

Example 8 Triethylbenzylammonium borohydride (265.
0 mg, 1.28 mmol) and tridecane-1,13-dicarboxylic acid monomethyl ester (352.0 mg, 1.23 mmol) were transferred to a reaction vessel, and dried carbon tetrachloride (1 ml) under an argon gas atmosphere.
Was added and the mixture was heated with stirring at 70 ° C. for 18 hours. After the reaction, Example 1
After post-treatment in the same manner as above, the crude product obtained was quantified by gas chromatography (internal standard method), and the target 15-hydroxypentadecanoic acid methyl ester (28
8 mg, 86%) was produced.

Example 9 Put tetraethylammonium borohydride (145.5 mg, 1.00 mmol) and tridecane-1,13-dicarboxylic acid monomethyl ester (286.0 mg, 1.00 mmol) in a reaction vessel, and add dry carbon tetrachloride (2 ml) under an argon gas atmosphere. The mixture was heated and stirred at 80 ° C for 23 hours. After the reaction, post-treatment was carried out in the same manner as in Example 1, and the resulting crude product was quantified by gas chromatography (internal standard method) to obtain the desired 15-hydroxypentadecanoic acid methyl ester (214 mg, 79%).
I knew that was being generated.

Example 10 Benzyltri-n-butylammonium borohydride (293.7 mg, 1.01 mmol) and tridecane-1,13-dicarboxylic acid monomethyl ester (285.6 mg, 1.00 mmol) were placed in a reaction vessel, and dried carbon tetrachloride (2 ml) under an argon gas atmosphere. ) Was added and the mixture was heated with stirring at 70 ° C. for 5.5 hours. The reaction solution was cooled to room temperature, water was added, and the organic layer was separated. Toluene was added to the aqueous layer for extraction, both organic layers were combined, washed with 2N-hydrochloric acid and saturated brine, and dried over sodium sulfate. After concentration under reduced pressure, the obtained crude product was quantified by gas chromatography (internal standard method), and it was found that the target 15-hydroxypentadecanoic acid methyl ester (225 mg, 83%) was produced.

Claims (2)

[Claims] 1. A diacid monoester represented by the general formula HOCO (CH ₂ ) _n COOR [wherein R represents an alkyl group and n represents a natural number] is represented by the general formula R ¹ R ² R ³ R ⁴ NBH. ₄ [wherein, R ¹ , R ² , R ³ and R ⁴ represent an alkyl group, an aralkyl group or an aryl group, which may be different from each other. ] The manufacturing method of the (omega) -hydroxy fatty acid ester characterized by reducing with the quaternary ammonium borohydride represented by these. 2. The method according to claim 1, which comprises performing the reduction in the presence of an organic halide.