JPH08295648A - Production of optically active 2-propyloctanoic acid - Google Patents

Abstract

PURPOSE: To provide a method for producing the subject compound, which is superior than usual methods (a producing method by a separation from a racemic substance or a producing method using only L-prolinol) in the viewpoint of chemical yield and even optical purity. CONSTITUTION: The objective compound, 2R-propyloctanoic acid, is obtained by reacting L-prolinol with pentanoic acid, reacting the resultant N-pentanoyl-L- prolinol with a hexyl halide, reacting the resultant N-(2R-propyloctanyl)- L-prolinol with 4-nitrobenzoic acid, purifying the resultant N-(2R- propyloctanoyl)-2S-pyrrolidinemethyl 4-nitrobenzoate, and hydrolyzing the resultant N-(2R-propyloctanoyl)-L-prolinol.

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
It relates to a method for producing optically active 2-propyloctanoic acid, which comprises using an optically active prolinol derivative.

[0002]

PRIOR ART AND PROBLEMS TO BE SOLVED BY THE INVENTION The optically active 2-propyloctanoic acid (hereinafter abbreviated as target compound) produced by the present invention is a compound useful as a pharmaceutical. The racemate of the object compound of the present invention is used as a therapeutic or prophylactic agent for neurodegenerative diseases due to astrocyte dysfunction in Example 7 of Japanese Patent Application No. 6-140954.
(33).

As a result of subsequent research, among racemates, R
The body was found to be particularly active, and therefore various studies were conducted on methods for efficiently obtaining the R body. Usually, in order to obtain an optically active form of a compound, a method of separating it from its racemate by optical resolution is used. Optical resolution is carried out using an optically active amine when the target compound is an acid.

However, when a method of separating the target compound from the racemate was attempted, both chemical yield and optical purity were not sufficient, and it was not a practical method, as is clear from the experiments described later. On the other hand, as another method for obtaining an optically active target compound, a method using an optically active starting material is known. An example is the 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 becomes a liquid (oil-like), the recrystallization method cannot be used for the purification method, which has been a bottleneck in mass synthesis.

Generally, in the industrial production of compounds,
Using column chromatography in the purification step
It has the drawbacks that the amount that can be manufactured at one time is small and that the purity cannot be sufficiently increased because the inclusion of impurities cannot be avoided. In particular, purification of an optically active compound by column chromatography has drawbacks such that it is difficult to sufficiently remove the antipode thereof, and a special column is required. For this reason, there are many problems in terms of commercial value and cost such that required optical purity cannot be obtained, chemical yield is lowered, and cost is increased. Therefore, an efficient production method that does not use column chromatography has been demanded.

[0006]

The inventors of the present invention have, as a result of their earnest research, improved the method using an optically active prolinol, and further reacting this intermediate with 4-nitrobenzoic acid. It was possible to recrystallize efficiently, and thereby succeeded in greatly improving the optical purity, thus completing the present invention.

The method of the present invention is carried out by the following procedure. 1) L-prolinol is reacted with pentanoic acid, 2) The obtained N-pentanoyl-L-prolinol is reacted with hexyl halide, 3) The obtained N- (2R-propyloctanoyl) -L
-Prolinol was reacted with 4-nitrobenzoic acid, and 4) the obtained N- (2R-propyloctanoyl) -2 was obtained.
S-Pyrrolidinemethyl 4-nitrobenzoate was purified and 5) N- (2R-propyloctanoyl) -2S-pyrrolidinemethyl 4-nitrobenzoate was hydrolyzed, 6) The obtained N- (2R-propyloctanoyl) ) -L
-The target compound is obtained by hydrolyzing prolinol.

1) The method of reacting L-prolinol and pentanoic acid is known, but it can be carried out, for example, by the following method. (I) The method using an acid halide is, for example, pentanoic acid in an inert organic solvent (chloroform, methylene chloride, diethyl ether, THF, etc.) or without solvent, and an acid halide (oxalyl chloride, thionyl chloride, etc.).
The resulting acid halide is reacted with L- in the presence of a tertiary amine (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, etc.).
0-40 ° C in prolinol and an inert organic solvent (chloroform, methylene chloride, diethyl ether, THF, etc.)
It is carried out by reacting with. (Ii) A method using a mixed acid anhydride is, for example, pentanoic acid in an inert organic solvent (chloroform, methylene chloride, diethyl ether, THF, etc.) or without a solvent,
In the presence of tertiary amines (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, etc.), with acid halides (pivaloyl chloride, tosyl chloride, mesyl chloride, etc.) or acid derivatives (ethyl chloroformate, isobutyl chloroformate, etc.) , 0-40 ° C., and the obtained 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.) at 0-40 ° C. (Iii) A method using a condensing agent such as DCC (dicyclohexylcarbodiimide) is carried out, for example, by using pentanoic acid and L-prolinol in an inert organic solvent (chloroform,
Methylene chloride, diethyl ether, THF, etc.) or without solvent in the presence or absence of a tertiary amine (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, etc.), using DCC, etc.
It is carried out by reacting at ° C.

These (i), (ii) and (iii)
It is desirable to carry out the above reaction under anhydrous conditions under an inert gas (argon, nitrogen, etc.) atmosphere. 2) A method of reacting N-pentanoyl-L-prolinol and hexyl halide is known, but 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,
t-butyllithium, phenyllithium, potassium hydride, sodium hydride, etc.) at -20 to 40 ° C. 3) A method of reacting N- (2R-propyloctyl) -L-prolinol with 4-nitrobenzoic acid is known, but, for example, it is carried out by the same method as the above-mentioned method 1). 4) Purification of N- (2R-propyloctanoyl) -2S-pyrrolidinemethyl 4-nitrobenzoate is carried out, for example, by a recrystallization method, distillation under normal pressure or under reduced pressure. The number of purifications and the method depend on the required optical purity. 5) A method of hydrolyzing N- (2R-propyloctanoyl) -2S-pyrrolidinemethyl 4-nitrobenzoate is known, but, for example, in an inert organic solvent (dioxane, THF, ethanol, methanol, etc.), alkali It is carried out at a temperature of -10 to 40 ° C using an aqueous solution of (lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, potassium carbonate, etc.). 6) A method of hydrolyzing N- (2R-propyloctanoyl) -L-prolinol is known, but for example, an acid (hydrochloric acid) in an inert organic solvent (dioxane, acetic acid, etc.) or without a solvent is used. , Trifluoroacetic acid, sulfuric acid, etc.) at 60 ° C. to the reflux temperature.

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

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, and the present invention It is a novel compound useful as an intermediate in obtaining the target compound of.

[0012]

INDUSTRIAL APPLICABILITY According to the method of the present invention, in producing the objective optically active 2-propyloctanoic acid, the conventional method (from the racemic form) is used in terms of chemical yield and optical purity. Is a method superior to the production method by separation of the above, and the production method using only L-prolinol).

The production method of the present invention is an improved method of producing a branched chain alkanoic acid which has hitherto been known, and is an efficient method for producing a target compound without using column chromatography. In terms of optical purity, according to a conventionally known method for producing a branched chain alkanoic acid, 84% e. e. However, according to the method of the present invention, 96% e. e. The target compound with high purity 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 Preparation 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 ice-cooled, and pentanoyl chloride (25.0 ml) was slowly added dropwise thereto. The reaction solution was stirred for 1 hour and then poured into a mixed solution of saturated sodium hydrogen carbonate solution / methylene chloride (300 ml / 100 ml). The organic layer was washed with 2N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was further purified by silica gel column chromatography (chloroform: methanol = 10: 1) by vacuum distillation, and the title compound (22.7 g, having the following physical properties) was obtained.
Yield 61%) was obtained. 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 Preparation of N-[(2R) -propyloctanoyl]-(L) -prolinol

[0017]

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Diisopropylamine (25.1 ml),
n-Butyllithium (65.2 ml; 2.5M) and THF (320 ml) were mixed and stirred at 0 ° C. for 30 minutes. This solution was added to the compound prepared in Example 1 (15.1.
After slowly adding dropwise to a solution of g) in anhydrous THF (120 ml), the mixture was stirred at room temperature for 30 minutes. The reaction solution is ice-cooled and
-Hexyl iodide (17.3 g) was added dropwise and stirred at room temperature for 1 hour and a half. To the reaction solution, a mixed solution of saturated aqueous ammonium chloride solution / ethyl acetate was added and stirred. The organic layer was washed with saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound having the following physical data as a crude product (23.8 g; oil, yield 92%). Got as. TLC: Rf 0.37 (n-hexane: ethyl acetate =
1: 1); 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 Preparation 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) of pyridine (0.30
ml) and 4-nitrobenzoyl chloride (441
(mg) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. 1N hydrochloric acid was added to this reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography,
A crude product (1.00 g) of the title compound was obtained. The obtained crude purified 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 Preparation of N-[(2R) -propyloctanoyl]-(L) -prolinol

[0021]

[Chemical 4]

To a solution of the compound (76 mg) prepared in Example 3 in dioxane (2 ml) was added 1N aqueous lithium hydroxide solution (0.364 ml), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution and the mixture 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 =
1: 1); 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 the acetic acid (150 ml) solution of the above and the mixture was refluxed for 5 hours. The reaction solution was allowed to cool and concentrated under reduced pressure.
A 5N sodium hydroxide aqueous solution was added to the residue, and the mixture was extracted with n-hexane. Further, the aqueous layer was acidified and then extracted with ethyl acetate. The combined organic layers were washed with saturated saline,
It 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 Racemate of Target Compound and Salt of Optically Active Amine (2RS) -2-Propyloctanoic Acid (20.2 g) and (R)-(+)-1-phenyl Ethylamine (1
3.0 g) was dissolved in n-hexane (80 ml) and a separately prepared salt of (2R) -2-propyloctanoic acid and (R)-(+)-1-phenylethylamine was used as a seed at room temperature. Added a small amount. Crystals were obtained by allowing this to stand at 0 ° C. for 14 hours and then at −20 ° C. for 4 hours. Using the obtained crystals, the same operation was repeated 6 times to obtain (2R) -2-propyloctanoic acid and (R)
A salt of-(+)-phenylethylamine (2.47g) was obtained. The obtained crystals are dissolved in n-hexane, washed with 1N hydrochloric acid, 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
%) Was obtained. Optical purity: 82% e. e. (Gas chromatography); Optical rotation: [α] _D −3.91 (c = 0.985, CHCl ₃ ). Comparative Example 2 Optical resolution using a racemate of the target compound and an amide of an optically active amine (2RS) -2-propyloctanoic acid (2.56 Kg)
Thionyl chloride (1.45l) was slowly added to
The reaction mixture was stirred for 2 hours while heating. The excess thionyl chloride was distilled off, and the residue was purified by distillation.
(S)-(+)-1-Phenylethylamine (1.7
l) in methylene chloride (5.0 l) in pyridine (1.
1 l) and then a solution of the above acid chloride in methylene chloride (2.0 l) was slowly added at 0 ° C.
Stir for 0 minutes. The reaction mixture was concentrated under reduced pressure, ethyl acetate / water was added to the residue, and the organic layer was washed with hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, saturated saline and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Hexane was added to precipitate crystals. This crystal was recrystallized 12 times using n-hexane to obtain an amide (415 g). This amide was refluxed in 50% sulfuric acid in acetic acid for 10 hours 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 L-Prolinol Only N-[(2R) -propyloctanoyl]-(L) -prolinol (290 mg; produced in Example 2) was used in Example 5 The same operation as the above was performed to obtain the target compound (130 mg; yield 78%) having the following physical property values. Optical purity: 84% e. e. (Gas chromatography); Optical rotation: [α] _D −4.83 (c = 5.24, CHCl ₃ ).

Claims (8)

[Claims] 1. L-prolinol is reacted with pentanoic acid, the obtained N-pentanoyl-L-prolinol is reacted with hexyl halide, and the obtained N- (2R-propyloctanoyl) -L-pro is obtained. The N- (2R-propyloctanoyl) -2S-pyrrolidinemethyl 4-nitrobenzoate obtained by reacting linole with 4-nitrobenzoic acid was purified and then hydrolyzed to obtain N- (2R
-Propyloctanoyl) -L-prolinol is hydrolyzed, which is a method for producing optically active 2-propyloctanoic acid. 2. N- (2R-propyloctanoyl)-
2- characterized by hydrolyzing L-prolinol
Method for producing propyloctanoic acid. 3. N- (2R-propyloctanoyl)-
A method for producing N- (2R-propyloctyl) -L-prolinol, which comprises hydrolyzing 2S-pyrrolidinemethyl 4-nitrobenzoate. 4. N- (2R-propyloctanoyl)-
N- (2R-propyloctanoyl) -characterized by reacting L-prolinol with 4-nitrobenzoic acid
Method for producing 2S-pyrrolidinemethyl 4-nitrobenzoate. 5. N-pentanoyl-L-prolinol and hexyl halide are reacted.
A method for producing (2R-propyloctanoyl) -L-prolinol. 6. A method for producing N-pentanoyl-L-prolinol, which comprises reacting L-prolinol with pentanoic acid. 7. N- (2R-propyloctanoyl)-
A compound which is 2S-pyrrolidinemethyl 4-nitrobenzoate. 8. N- (2R-propyloctanoyl)-
A compound which is L-prolinol.