JP3084345B2 - Method for producing optically active 2-propyloctanoic acid - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a method for producing optically active 2-propyloctanoic acid. More specifically, the present invention provides
The present invention relates to a method for producing optically active 2-propyloctanoic acid, which comprises using an optically active prolinol derivative.

[0002]

2. Description of the Related Art Optically active 2-propyloctanoic acid (hereinafter abbreviated as a target compound) produced by the present invention is a compound useful as a pharmaceutical. The racemic compound of the object compound of the present invention was used as an agent for treating or preventing a neurodegenerative disease caused by astrocyte dysfunction, as described in Example 7 in Japanese Patent Application No. 6-140954.
(33).

[0003] As a result of a subsequent study, it was found that the racemic compound, R
It has been found that the isomer has particularly strong activity, and various studies have been made on a method for efficiently obtaining the R-isomer. In general, to obtain an optically active form of a certain compound, a method of separating it from its racemic form by optical resolution is used. Optical resolution is performed using an optically active amine when the target compound is an acid.

[0004] However, when a method for separating the target compound from the racemate was tried, as is clear from the experiments described later, the chemical yield and optical purity were not sufficient, and it could not be said to be a practical method. On the other hand, as another method for obtaining an optically active target compound, a method using an optically active starting material is known. As an example, there is a method using optically active prolinol (Tetrahedron Le
tters, 21, 4233, 1980). Using this method, an optically active branched alkanoic acid can be obtained with a high chemical yield. However, in this method, since the intermediate to be purified is a liquid (oil), a recrystallization method cannot be used as a purification method, and this has been a bottleneck in mass synthesis.

Generally, in the industrial production of compounds,
The use of column chromatography in the purification process
It has drawbacks such as that the amount that can be produced at one time is small, and that the purity cannot be sufficiently increased due to the inevitable mixing of impurities. In particular, in the purification of an optically active compound by column chromatography, there are drawbacks in that it is difficult to sufficiently remove its enantiomer, and a special column is required. For this reason, there are many problems in terms of commercial value and cost, such as the required optical purity cannot be obtained, the chemical yield is reduced, and the cost is high. For this reason, an efficient production method without using column chromatography has been demanded.

[0006]

Means for Solving the Problems As a result of intensive studies, the inventors of the present invention have improved the method of using optically active prolinol, and by further reacting this intermediate with 4-nitrobenzoic acid, Recrystallization can be carried out efficiently, and thereby the optical purity has been greatly improved, thereby completing the present invention.

The method of the present invention is performed according to the following procedure. 1) reacting L-prolinol with pentanoic acid or a corresponding acid halide; 2) reacting the obtained N-pentanoyl-L-prolinol with hexyl halide; 3) obtaining N- (2R-propylocta) Noil) -L
-Prolinol is reacted with 4-nitrobenzoic acid or a corresponding acid halide; 4) The resulting N- (2R-propyloctanoyl) -2
S-Pyrrolidine methyl 4-nitrobenzoate is purified, 5) N- (2R-propyloctanoyl) -2S-pyrrolidinemethyl 4-nitrobenzoate is hydrolyzed, 6) N- (2R-propyloctanoyl) obtained is obtained. ) -L
-The desired compound is obtained by hydrolyzing prolinol.

[0008] 1) A method of reacting L-prolinol with pentanoic acid or a corresponding acid halide is known, and can be carried out, for example, by the following method. (I) A method using an acid halide is, for example, a method in which pentanoic acid is converted into an acid halide (oxalyl chloride, thionyl chloride, etc.) in an inert organic solvent (chloroform, methylene chloride, diethyl ether, THF, etc.) or without a solvent.
With -20 ° C to reflux temperature, and the obtained acid halide is reacted with L- in the presence of a tertiary amine (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, etc.).
0-40 ° C in prolinol and inert organic solvent (chloroform, methylene chloride, diethyl ether, THF, etc.)
The reaction is performed by (Ii) A method using a mixed acid anhydride includes, for example, pentanoic acid in an inert organic solvent (chloroform, methylene chloride, diethyl ether, THF, etc.) or without a solvent,
An acid halide (pivaloyl chloride, tosyl chloride, mesyl chloride, etc.) or an acid derivative (ethyl chloroformate, isobutyl chloroformate, etc.) in the presence of a tertiary amine (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, etc.) And the resulting acid halide is reacted with L-prolinol in the presence of a tertiary amine (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, etc.) and an inert organic solvent (chloroform, methylene chloride, Diethyl ether, T
(HF etc.) in 0 to 40 ° C. (Iii) In a method using a condensing agent such as DCC (dicyclohexylcarbodiimide), for example, pentanoic acid and L-prolinol are mixed with an inert organic solvent (chloroform,
Methylene chloride, diethyl ether, THF, etc.) or in the absence of a solvent in the presence or absence of a tertiary amine (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, etc.), using DCC or the like.
The reaction is carried out at ℃.

These (i), (ii) and (iii)
Is desirably performed under an inert gas (argon, nitrogen, etc.) atmosphere under anhydrous conditions. 2) A method of reacting N-pentanoyl-L-prolinol with hexyl halide is known. For example, an inert organic solvent (THF, dioxane, diethyl ether,
Benzene, DME, hexane, cyclohexane, etc.)
In the presence or absence of a secondary amine (diisopropylamine, diisobutylamine, hexamethyldisilazane, etc.), a base (n-butyllithium, sec-butyllithium,
The reaction is carried out at -20 to 40 ° C. in the presence of t-butyllithium, phenyllithium, potassium hydride, sodium hydride and the like. 3) A method of reacting N- (2R-propyloctanoyl) -L-prolinol with 4-nitrobenzoic acid or a corresponding acid halide is known. For example, a method similar to the above method 1) is used. Done. 4) The purification of N- (2R-propyloctanoyl) -2S-pyrrolidinemethyl 4-nitrobenzoate is performed, for example, by a recrystallization method, distillation under normal pressure or reduced pressure. The number of purifications and the method vary depending on the required optical purity. 5) A method for hydrolyzing N- (2R-propyloctanoyl) -2S-pyrrolidinemethyl 4-nitrobenzoate is known. For example, an alkaline organic solvent such as an inert organic solvent (dioxane, THF, ethanol, methanol, etc.) is used. (Lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, potassium carbonate, etc.) using an aqueous solution at a temperature of -10 to 40C. 6) A method of hydrolyzing N- (2R-propyloctanoyl) -L-prolinol is known. For example, an acid (hydrochloric acid) is used in an inert organic solvent (dioxane, acetic acid, etc.) or without using a solvent. , Trifluoroacetic acid, sulfuric acid, etc.) at 60 ° C to reflux temperature.

Further, a part of the above-mentioned method of the present invention can be modified as follows to obtain a target compound. That is, instead of the reaction of 1), D-prolinol and octanoic acid are reacted, and instead of the reaction of 2), the obtained N-octanoyl-D-
The reaction between prolinol and propyl halide is performed, and N- (2
R-propyloctanoyl) -D-prolinol is obtained, and the following 3) -6) are the same as described above,
The present invention also covers this manufacturing method.

[0011] N- (2R-propyloctanoyl) -2S-pyrrolidinemethyl 4-nitrobenzoate and N- (2R-propyloctanoyl) -L-prolinol used in the present invention have not been described in the literature. Is a novel compound useful as an intermediate in obtaining the target compound of

[0012]

According to the method of the present invention, the production of the optically active 2-propyloctanoic acid, which is the objective substance, can be carried out by a conventional method (from a racemic compound) in terms of both chemical yield and optical purity. , A production method using only L-prolinol).

The production method of the present invention is an improvement of the conventionally known method for producing a branched alkanoic acid, and is a method for efficiently producing a target compound without using column chromatography. In terms of optical purity, a conventionally known method for producing a branched alkanoic acid is 84% e.g. e. Although only 96% e. e. And a highly pure target compound can be obtained.

[0014]

EXAMPLES The present invention will be specifically described below with reference to Comparative Examples and Examples, but these do not limit the scope of the present invention. Example 1 Production of N-pentanoyl- (L) -prolinol

[0015]

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A solution of (L) -prolinol (20.3 g) and triethylamine (36.4 ml) in methylene chloride (200 ml) was cooled on ice, and pentanoyl chloride (25.0 ml) was slowly added dropwise thereto. After stirring the reaction solution for 1 hour, it was poured into a mixture of saturated sodium hydrogen carbonate solution / methylene chloride (300 ml / 100 ml). The organic layer was washed with 2N hydrochloric acid and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was further purified by distillation under reduced pressure using silica gel column chromatography (chloroform: methanol = 10: 1) to give the title compound (22.7 g,
Yield 61%). TLC: Rf 0.36 (ethyl acetate); NMR (CDCl ₃ ): δ 5.30-5.20 (1H, br), 4.30-4.15
(1H, m), 3.75-3.38 (4H, m), 2.31 (2H, t), 2.15-1.7
5 (3H, m), 1.75-1.50 (3H, m), 1.50-1.27 (2H, m), 0.
93 (3H, t); IR (neat): ν 3392, 2956, 1636, 1456, 1245, 1193,
1055, 903, 613 cm ^-1 ; Optical rotation: [α] _D -62.7 (c = 4.91, CHCl ₃ ). Example 2 Production of N-[(2R) -propyloctanoyl]-(L) -prolinol

[0017]

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Diisopropylamine (25.1 ml),
n-Butyllithium (65.2 ml; 2.5 M) and THF (320 ml) were mixed and stirred at 0 ° C. for 30 minutes. This solution was prepared using the compound prepared in Example 1 (15.1).
g) was slowly added dropwise to a solution of anhydrous THF (120 ml), followed by stirring at room temperature for 30 minutes. The reaction solution is cooled on ice and n
-Hexyl iodide (17.3 g) was added dropwise, and the mixture was stirred at room temperature for 1.5 hours. To the reaction solution, a mixed solution of a saturated aqueous solution of ammonium chloride / ethyl acetate was added, and the mixture was stirred. The organic layer was washed with a saturated aqueous solution of ammonium chloride and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crude product of the title compound having the following physical properties (23.8 g; oily, yield 92%). As obtained. TLC: Rf 0.37 (n-hexane: ethyl acetate =
NMR (CDCl ₃ ): δ 5.33 (1H, dd), 4.35-4.20 (1H,
m), 3.75-3.40 (4H, m), 2.60-2.43 (1H, m), 2.15-1.77
(3H, m), 1.77-1.15 (15H, m), 1.00-0.80 (6H, m); IR (neat): ν 3401, 2928, 1615, 1455, 1342, 119
0, 1114, 1057, 899, 726, 564 cm ^-1 ; optical rotation: [α] _D -41.1 (c = 2.96, CHCl ₃ ). Example 3 Production of N- (2R-propyloctanoyl) -2S-pyrrolidinemethyl 4-nitrobenzoate

[0019]

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The compound prepared in Example 2 (659 mg)
In methylene chloride (20 ml) was added to pyridine (0.30
ml) and 4-nitrobenzoyl chloride (441).
mg) under ice-cooling and stirred at room temperature for 2 hours. 1N Hydrochloric acid was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography,
A crude product of the title compound (1.00 g) was obtained. The obtained crude product was recrystallized (n-hexane) three times to give the title compound (646 mg, yield 63%) having the following physical data. TLC: Rf 0.27 (n-hexane: ethyl acetate =
4: 1); IR (KBr): ν 2928, 1720, 1628, 1531, 1428, 134
8, 1272, 1120, 723 cm ^-1 ; NMR (CDCl ₃ ): δ 8.30 (2H, d), 8.19 (2H, d),
4.65-4.53 (1H, m), 4.53-4.45 (2H, m), 3.64-3.54 (2
H, m), 2.60-2.40 (1H, m), 2.15-1.85 (4H, m), 1.80-
1.10 (14H, m), 0.95-0.75 (6H, m); optical purity: 96% e. e. (High performance liquid chromatography); Optical rotation: [α] _D -38.1 (c = 1.06, CHCl ₃ ). Example 4 Production of N-[(2R) -propyloctanoyl]-(L) -prolinol

[0021]

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To a solution of the compound prepared in Example 3 (76 mg) in dioxane (2 ml) was added a 1N aqueous solution of lithium hydroxide (0.364 ml), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (50 mg; yield 100%) having the following physical data. TLC: Rf 0.37 (n-hexane: ethyl acetate =
NMR (CDCl ₃ ): δ 5.33 (1H, dd), 4.35-4.20 (1H,
m), 3.75-3.40 (4H, m), 2.60-2.43 (1H, m), 2.15-1.77
(3H, m), 1.77-1.15 (15H, m), 1.00-0.80 (6H, m); IR (neat): ν 3401, 2928, 1615, 1455, 1342, 119
0, 1114, 1057, 899, 726, 564 cm ^-1 ; optical purity: 96% d. e. (High performance liquid chromatography) Example 5 Production of (2R) -propyloctanoic acid

[0023]

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The compound prepared in Example 4 (22.0 g)
2N hydrochloric acid (150 ml) was added to a solution of acetic acid (150 ml) and refluxed for 5 hours. The reaction was allowed to cool and concentrated under reduced pressure.
A 5N aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with n-hexane. The aqueous layer was further acidified and extracted with ethyl acetate. Wash the combined organic layers with saturated saline,
The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by distillation under reduced pressure to give the title compound (7.6 g, yield 57%) having the following physical data. bp: 115-120 ° C. (2 mmHg); TLC: Rf 0.34 (n-hexane: ethyl acetate =
4: 1); NMR (CDCl ₃ ): δ 12.0-11.0 (1H, br), 2.45-2.28
(1H, m), 1.75-1.20 (14H, m), 0.98-0.82 (6H, m); IR (neat): ν 3050, 2932, 2860, 1708, 1466, 138
1, 1255, 943 cm ^-1 ; Optical rotation: [α] _D -5.50 (c = 2.73, CHCl ₃ ); Optical purity: 96% e. e. (Gas Chromatography) Comparative Example 1 Optical Resolution Using Racemic Form of Target Compound and Optically Active Amine Salt (2RS) -2-propyloctanoic acid (20.2 g) and (R)-(+)-1-phenyl Ethylamine (1
3.0 g) was dissolved in n-hexane (80 ml), and separately prepared at room temperature using as a seed the salt of (2R) -2-propyloctanoic acid and (R)-(+)-1-phenylethylamine. A small amount was added. This was allowed to stand at 0 ° C. for 14 hours and at −20 ° C. for 4 hours to obtain crystals. Using the obtained crystals, the same operation was further repeated six times to obtain (2R) -2-propyloctanoic acid and (R)
A salt of-(+)-phenylethylamine (2.47 g) was obtained. The obtained crystals are dissolved in n-hexane, washed with 1N hydrochloric acid, and the organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the following physical properties (2R)-
2-propyloctanoic acid (1.49 mg; total yield 9)
%). Optical purity: 82% e. e. (Gas chromatography); Optical rotation: [α] _D -3.91 (c = 0.985, CHCl ₃ ). Comparative Example 2 Optical resolution using racemic form of target compound and amide of optically active amine (2RS) -2-propyloctanoic acid (2.56 Kg)
Slowly add thionyl chloride (1.45 l) to
The reaction mixture was stirred for 2 hours while heating. Excess thionyl chloride was distilled off and purified by distillation.
(S)-(+)-1-phenylethylamine (1.7
l) in methylene chloride (5.0 l) in pyridine (1.
1 l), and a solution of the above acid chloride in methylene chloride (2.0 l) was slowly added at 0 ° C.
Stirred for 0 minutes. The reaction solution was concentrated under reduced pressure, ethyl acetate / water was added to the residue, and the organic layer was washed with hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate, saturated saline and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Hexane was added to precipitate crystals. The crystals were further recrystallized 12 times using n-hexane to obtain amide (415 g). This amide was refluxed for 10 hours using 50% sulfuric acid in acetic acid to obtain (2R) -2-propyloctanoic acid (185 g; total yield 6%) having the following physical properties. Optical purity: 83% e. e. (Amidated again with (S)-(-)-1-phenylethylamine and confirmed by high performance liquid chromatography); Optical rotation: [α] _D -4.80 (c = 2.87, CHCl ₃ ). Comparative Example 3 Production of Target Compound Using Only L-Prolinol Example 5 was performed using N-[(2R) -propyloctanoyl]-(L) -prolinol (290 mg; produced in Example 2). The same operation as described above was performed to obtain the desired compound having the following physical properties (130 mg; yield: 78%). Optical purity: 84% e. e. (Gas chromatography); Optical rotation: [α] _D -4.83 (c = 5.24, CHCl ₃ ).

──────────────────────────────────────────────────の Continued on the front page (58) Fields surveyed (Int.Cl. ⁷ , DB name) C07C 51/06 C07C 51/09 C07C 53/128 C07C 53/126 C07B 53/00 C07B 61/00 300 CA ( STN) REGISTRY (STN)

Claims (8)

(57) [Claims] 1. A reaction between L-prolinol and pentanoic acid or a corresponding acid halide, and a reaction between the obtained N-pentanoyl-L-prolinol and hexyl halide,
The obtained N- (2R-propyloctanoyl) -L-prolinol is reacted with 4-nitrobenzoic acid or a corresponding acid halide, and the obtained N- (2R-propyloctanoyl) -2S-pyrrolidinemethyl 4 -Nitrobenzoate was purified and hydrolyzed to give N- (2R
-Propyloctanoyl) -L-prolinol is hydrolyzed. 2. N- (2R-propyloctanoyl)-
2-hydrolyzing L-prolinol
A method for producing propyloctanoic acid. 3. N- (2R-propyloctanoyl)-
A method for producing N- (2R-propyloctanoyl) -L-prolinol, which comprises hydrolyzing 2S-pyrrolidinemethyl 4-nitrobenzoate. 4. N- (2R-propyloctanoyl)-
N- (2R-L-prolinol is reacted with 4-nitrobenzoic acid or a corresponding acid halide.
Propyloctanoyl) -2S-pyrrolidinemethyl 4
-A process for producing nitrobenzoate. 5. N-pentanoyl-L-prolinol is reacted with hexyl halide.
A method for producing (2R-propyloctanoyl) -L-prolinol. 6. A process for producing N-pentanoyl-L-prolinol, comprising reacting L-prolinol with pentanoic acid or a corresponding acid halide. 7. N- (2R-propyloctanoyl)-
A compound which is 2S-pyrrolidinemethyl 4-nitrobenzoate. 8. N- (2R-propyloctanoyl)-
A compound which is L-prolinol.