MXPA00011021A - Novel intermediates and processes for the preparation of optically active octanoic acid derivatives - Google Patents

Novel intermediates and processes for the preparation of optically active octanoic acid derivatives

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Publication number
MXPA00011021A
MXPA00011021A MXPA/A/2000/011021A MXPA00011021A MXPA00011021A MX PA00011021 A MXPA00011021 A MX PA00011021A MX PA00011021 A MXPA00011021 A MX PA00011021A MX PA00011021 A MXPA00011021 A MX PA00011021A
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Prior art keywords
octanoyl
preparation
optically active
camphorsultam
canforsultam
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MXPA/A/2000/011021A
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Spanish (es)
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Hisashi Yamamoto
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Ono Pharmaceutical Co Ltd
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Publication of MXPA00011021A publication Critical patent/MXPA00011021A/en

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Abstract

Novel intermediates, i.e., N-(2S-(2-propenyl)-octanoyl)-(1S)-(-)-2, 10-camphorsultam, N-(2S-(2-propynyl)octanoyl)-(1S)-(-)-2, 10-camphorsultam and N-(2R-(2-propyl)octanoyl)-(1S)-(-)-2, 10-camphor-sultam;processes for the preparation of the intermediates;and processes for the preparation of optically active 2S-(2-propenyl)octanoic acid, 2S-(2-propynyl)octanoic acid and 2R-propyloctanoic acid by using the same. Optically active 2R-propyloctanoic acid equivalent or superior to that prepared by the process of the prior art in optical purity can be efficiently prepared in shorter reaction steps.

Description

NOVEDOUS INTERMEDIARIES AND PROCESSES FOR THE PREPARATION OF OPTICALLY ACTIVE OCTOPIAN ACID DERIVATIVES.
Technical Field The present invention relates to novel intermediates, processes for the preparation thereof and processes for the preparation of optically active octanoic acid derivatives through the use of intermediates.
More particularly, the present invention relates to novel intermediates, for example, N- (2S- (2-propenyl) octanoyl) - (SS) - (-) -2, 10-camphorsultam, N- (2S- (2- propynyl) octanoyl) - (1S) - (-) -2, 10-camphorsultam and N- (2R- (2-propyl) octanoyl) - (SS) - (-) -2, 10-camphorsultam; processes for the preparation of these; and processes for the preparation of 2S- (2-propenyl) octanoic acid, 2S- (2-propynyl) octanoic acid and optically active 2R-propyloctanoic acid through the use of these intermediates.
Background of the State of the Art The optically active octanoic acid derivatives prepared by the present invention are useful intermediates for the preparation of medicaments or are compounds useful as medicaments. For example, a Ref. 124640 2R-propyloctanoic acid racemate is described in Example 7 (33) of JP-A-7-316092 as an agent for the treatment or prevention of neurodegenerative diseases derived from abnormally functioning astrocytes.
As a result of subsequent studies, it was found that 2R-propyloctanoic acid has strong activities in particular. Therefore, the methods for obtaining this compound in an efficient manner have been studied variously, and the following processes were unknown until now.
For example, JP-A-8-291106 discloses a method for optical resolution using optically active amine. However, in the process of optically separating 2R-propyloctansic acid from its racemate, both the chemical production (total synthetic production of 5.9% in 6 stages of dimethyl hexylmalonate) and the optically pure (90.0% ee) were so insufficient that the process had no practical use.
A process using an optically active initiator material as another process for obtaining active 2R-propyloctanoic acid is known. For example, JP-A-8-295648 discloses a process using optically active prolinol. An optically active linked alkanoic acid having high optical purity (96.0% e.e.) can be prepared using this process. However, the chemical production (total synthetic production of 20.1% in 5 stages of pentanoyl chloride) was so insufficient that the process did not necessarily have a practical use.
Disclosure of the Invention The present inventor has found that novel intermediates, for example, N- (2S- (2-propenyl) octanoyl) -11S) - (-) - 2, 10-camphorsultam, N- (2S- (2-propynyl) octanoyl ) - (ÍS) - (-) -2, 10-canforsultam and N- (2R- (2-propyl) octanoyl) - (ÍS) - (-) - 2, 10-canforsultam, by the use of (lS) - (-) - 2, 10-canforsulta, additional processes for the preparation of 2S- (2-propenyl) octanoic acid, 2S- (2-propynyl octanoic acid and 2R-propyloctanoic acid as high optical purity (95-99% ee) by use of these intermediaries, fulfilled the present invention.
That is, the present invention relates to novel intermediates, processes for the preparation thereof and processes for the preparation of optically active octanoic acid derivatives by the use of intermediates as follows: [1] A compound of N- (2S- (2-propenyl) octanoyl) - (SS) - (-) 2, 10-camphorsultam, N- (2S- (2-propynyl) octanoyl) - (SS) - ( -) 2, 10-canforsultam and N- (2R- (2-propyl) octanoyl) - (ÍS) - (-) 2, 10-canforsultam; [2] A compound of N- (2S- (2-propenyl) octanoyl) - (ÍS) - (-) -2, 10-canforsultam represented in [1]; [3] A compound of N- (2S- (2-propynyl) octanoyl) - (SS) - (-) -2, 10-canforsultam represented in [1]; [4] 'A compound of N- (2R- (2-propyl) octanoyl) - (ÍS) - (-) -2, 10-canforsultam represented in [1]; [5] A process for the preparation of N- (2S- (2-propenyl) octanoyl) - (1S) - (-) -2, 10-canforsultam represented in [2], which is characterized by the reaction of N-octanoyl- (SS) - (-) -2, 10-camphorsultam with allyl halide; [6] A process for the preparation of N- (2S- (2-propynyl) octanoyl) - (ÍS) - (-) -2, 10-canforsultam represented in [3], which is characterized by the reaction of N -octanoyl- (SS) - (-) -2, 10-camphorsultam with propargyl halide; [7] A process for the preparation "of N- (2R- (2-propyl) octanoyl) - (ÍS) - (-) -2, 10-canforsultam represented in [4], which is characterized by the reduction of N- (2S- (2-propenyl) octanoyl) - (SS) - (-) -2, 10-camphorsultam represented in [2]; [8] A process for the preparation of N- (2R- (2-propyl) octanoyl) - (ÍS) - (-) -2, 10-canforsultam represented in [4], which is characterized by the reduction of N - (2S- (2-propynyl) octanoyl) - (lS) - (-) - 2, 10-camphorsultam represented in [3]; [9] A process for the preparation of optically active 2S- (2-propenyl) octanoic acid, which is characterized by the hydrolysis of N- (2S- (2-propenyl) octanoyl) - (ÍS) - (-) - 2, 10-canforsultam represented in [2];
[10] A process for the preparation of optically active 2R-propyloctanoic acid, which is characterized by the reduction of optically active 2S- (2-propenyl) octanoic acid obtained in [9];
[11] A process for the preparation of optically active 2S- (2-propenyl) octanoic acid, which is characterized by the hydrolysis of N- (2R- (2-propynyl) octanoyl) - (ÍS) - (-) - 2, 10-optically active canforsultam represented in [3];
[12] A process for the preparation of optically active 2R-propyloctanoic acid, which is characterized by the reduction of optically active 2S- (2-propenyl) octanoic acid obtained in [11];
[13] A process for the preparation of optically active 2R-propyloctanoic acid, which is characterized by the hydrolysis of N- (2R- (2-propyl) octanoyl) - (ÍS) - (-) -2, 10-canforsultam optically active represented in [4]; Detailed description of the invention _ Optically active 2R-propyloctanoic acid is of high optical purity (95-99% ee) and superior chemical production (4 stages from octanoyl chloride, total synthetic production 42.5-72.1%) can be prepared efficiently by the method of the present invention. Furthermore, the hydrolysis of the canforsultam derivatives by the use of tetraalkylammonium hydroxide is a novel reaction. This observation has been confirmed for the first time from the experiments of the present inventor.
The novel intermediate compounds of the present invention can easily improve their optical purity by means of recrystallization since the novel intermediate compounds are easily crystallized. For example, the residue of the reaction was purified by column chromatography to give N- (2S- (2-propynyl) octanoyl) - (SS) - (-) -2, 10-camphorsultam having 96.8% diastereomeric excess ( liquid chromatography). The additional compound obtained in this way could be improved to give the latter having 99.4% excess diastereomer (liquid chromatography) by recrystallization.
In the present invention, the process for the preparation of 2R-propyloctanoic acid can be carried out by means of four methods (A) to (D) as follows, respectively.
(A) 2R-propyloctanoic acid can be prepared by the reaction of canforsultam with octanoic acid or its derivatives? the reaction of allyl halide - hydrolysis -? reduction; 1) reaction of (lS) - (-) - 2, 10-canforsultam with octanoic acid or its derivatives, 2) reaction of N-octanoyl- (SS) - (-) -2, 10- camphorsultam with allyl halide, 3) hydrolysis of N- (2S- (2-propenyl) octanoyl) (lS) - (-) - 2, 10-camphorsultam, and 4) reduction of optically active 2S- (2-propenyl) octanoic acid.
(B) 2R-propyloctanoic acid can be prepared by the reaction of canforsultam with octanoic acid or its derivatives - the reaction of propargyl halide - hydrolysis -? reduction; 1) reaction of (lS) - (-) - 2, 10-canforsultam with octanoic acid or its derivatives, 2) reaction of N-octanoyl- (SS) - (-) -2, 10-camphorsultam with propargyl halide, 3) hydrolysis of N- (2S- (2-propynyl) octanoyl) - (SS) - (-) -2, 10-camphorsultam, and 4) reduction of optically active 2S- (2-propynyl) octanoic acid.
(C) 2R-propyloctanoic acid can be prepared by the reaction of canforsultam with octanoic acid or its derivatives? the reaction of allyl halide? reduction? hydrolysis; 1) reaction of (lS) - (-) - 2, 10-canforsultam with octanoic acid or its derivatives, 2) reaction of N-octanoyl- (SS) - (-) -2, 10-camphorsultam with allyl halide, 3) reduction of N- (2S- (2-propenyl) octanoyl) - (SS) - (-) -2, 10-camphorsultam, and 4) hydrolysis of N- (2S- (2-propyl) octanoyl) - ( ÍS) - (-) - 2, 10-canforsultam.
(D) 2R-propyloctanoic acid can be prepared by the reaction of canforsultam with octanoic acid or its derivatives - the reaction of propargyl halide? reduction? hydrolysis; 1) reaction of (lS) - (-) - 2, 10-canforsultam with octanoic acid or its derivatives, 2) reaction of N-octanoyl- (SS) - (-) -2, 10-camphorsultam with propargyl halide, 3) reduction of N- (2S- (2-propynyl) octanoyl) - (SS) - (-) -2, 10-camphorsultam, and 4) hydrolysis of N- (2S- (2-propyl) octanoyl) - (1S) - (-) - 2, 10-canforsultam.
The summary of the 4 methods mentioned above is shown in Scheme 1; X represents the generally known elimination group (for example, p-toluenesulfonyl, methanesulfonyl, chloride, bromide or iodide atom etc.).
SCHEME 1 The reaction of (lS) - (-) - 2, 10-camphorsultam with octanoic acid or its derivatives is known per se (Tetrahedron, 48, 2453 (1992)), and can be carried out, for example, using a acid halide.
The method using an acid halide can be carried out, for example, by the reaction of an octanoic acid with an acid halide (for example, oxalyl chloride, thionyl chloride, etc.) in an inert organic solvent (e.g. chloroform, dichloromethane, diethyl ether, tetrahydrofuran etc.) or without a solvent at -20 ° C to the reflux temperature of the solvent, and then by reaction of octanoyl chloride obtained with (lS) - (-) - 2, 10 -canforsultam in the presence of a base [tertiary amine (eg, pyridine, triethylamine, dimethylaniline, dimethylaminopyridine etc.), alkali metal hydroxide (eg, sodium hydroxide, potassium hydroxide, etc.) or organic lithium ( for example, n-butyllithium, phenyllithium etc.)] in an inert organic solvent (eg, chloroform, dichloromethane, diethyl ether, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, toluene, etc.), at a temperature of from 0 ° C to 40 ° C.
This reaction can preferably be carried out in an inert gas atmosphere (for example argon, nitrogen etc.) under anhydride conditions.
The alkylation of N-octanoyl- (SS) - (-) -2, 10-camphorsultam with alkyl halide or prbpagyl halide can be carried out by the use of organic metal. The alkylation by use of organic metal is known per se, and can be carried out, for example, by reaction of N-octanoyl- (1S) ^ (-) -2, 10-camphorsultam with allyl halide or propargyl halide in the presence or absence of an iodide of an alkali metal (eg, lithium iodide, sodium iodide, potassium iodide, etc.) and in the presence of a base (eg, n-butyllithium, sec-butyllithium, t-butyllithium, phenyllithium, diisopropyllithium, potassium hydroxide, sodium hydroxide, etc.) in an inert organic solvent (for example, tetrahydrofuran, dioxane, diethyl ether, benzene, dimethoxyethane, hexane, cyclohexane, ethamethylphosphoramide, dimethylindazolidione or a mixture of these, etc.), at a temperature of -70 ° C to 20 ° C.
The reduction of optically active 2S- (2-propenyl) octanoic acid, optically active 2S- (2-propynyl) octanoic acid, N- (2S- (2-propenyl) octanoyl) - (ÍS) - (-) -2, 10-camphorsultam or N- (2S- (2-propynyl) octanoyl) - (1S) - (-) -2, 10-camphorsultam can be carried out by means of the use of catalytic reaction.
The catalytic reaction is known per se, and can be carried out, for example, in an inert solvent (for example, ethyl acetate, tetrahydrofuran, dioxane, diethoxyethane, diethyl ether, biphenyl ether, methanol, ethanol, isopropanol, benzene, toluene). , xylene, acetone, methyl ethyl ketone, phenyl methyl ketone, acetonitrile, hexamethylphosphoramide, dimethylformamide, dimethylimizazolidine, mixture thereof etc.), through the use of a catalyst (for example, palladium on carbon, palladium, platinum, platinum oxide , nickel, palladium hydroxide on carbon, rhodium on carbon, ruthenium, ruthenium on carbon, tris (triphenylphosphine) chlorododium, etc.) under a hydrogen atmosphere, at a temperature of from 0 ° C to 60 ° C.
Hydrolysis of N- (2S- (2-propenyl) octanoyl) - (SS) - (-) -2, 10-camphorsultam, N- (2S- (2-propynyl) octanoyl) - (SS) - (-) -2,10-camphorsultam or N- (2R- (2-propyl) octanoyl) - (SS) - (-) -2, 10-camphorsultam can be carried out by means of methods as below. (i) Hydrolysis by the use of alkali metal hydroxide is known per se (Tetrahedron, 4_3, 1969 (1987) or Helv. Chim. Acta., 7_2, 1337 (1989)), and can be carried out , for example, in the presence or absence of peroxide (for example, hydroperoxide, t-butylhydroperoxide an aqueous solution of these etc.), through the use of alkali metal hydroxide (for example, lithium hydroxide, hydroxide), sodium, potassium hydroxide, an aqueous solution of these, etc.) in a water-miscible solvent (tetrahydrofuran, dioxane, a mixture of water and these, etc. a temperature of from 0 ° C to 40 ° C.
It is known that this reaction was carried out without racemization and the obtained compound was given to maintain the optical purity. (ii) Hydrolysis by the use of tetraalkylammonium hydroxide is completely a novel reaction.
This reaction can be carried out, for example, in the presence or absence of a peroxide (for example, hydrogen peroxide, t-butylhydroperoxide, an aqueous solution thereof, etc.) by the use of tetraalkylammonium hydroxide (e.g. , tetrabutylammonium hydroxide, tetraoctylammonium hydroxide, tetradecylammonium hydroxide, an aqueous solution of these, etc.) in a water-miscible solvent (tetrahydrofuran, dimethoxyethane, t-butanol, dioxane, a mixture of water and these, etc.) a temperature of -20 ° C to 40 ° C. With the proviso that, when the canforsultam derivatives have double or triple bond, this reaction can be carried out in the presence of an excessive amount of the compound having the double bond (for example, 2-methyl-2-butene, etc.) since the protection of the compound having double or triple bond is oxidized by peroxide.
It is known that this reaction was carried out without racemization and the compound obtained was given to maintain the optical purity.
In addition, 2R- (2-propenyl) octanoic acid, 2R- (2-propynyl) octanoic acid or 2S-propyloctanoic acid can be separated by the same procedure as in the method of the present invention using (lR) - (+ ) -2, 10-canforsultam instead of (lS) - (-) - 2, 10-canforsultam.
N- (2S- (2-propenyl) octanoyl) - (SS) - (-) -2, 10-camphorsultam, N- (2S- (2-propynyl) octanoyl) - (SS) - (-) -2 , 10-camphorsultam and N- (2R- (2-propyl) octanoyl) - (SS) - (-) -2, 10-camphorsultam of the present invention are not described in the literature, therefore these are novel compounds. These are useful as process intermediates for the preparation of 2R-propyloctanoic acid.
The racemate of 2S- (2-propenyl) octanoic acid as an intermediate of the present invention is known per se, in the Chem. Pharm literature. Bull., 2? , 538 (1976).
The racemate of 2S- (2-propynyl) octanoic acid is known per se, in the literature of Tetrahedron Lett., 2_5, 5323 (1984). The (lS) - (-) - 2, 10 canforsultam is known per se, as the CAS record No. 94594-90-8. N-octanoyl- (SS) - (-) - 2, 10-canforsultam is known per se, in the Tetrahedron literature, 48_, 2453 (1992). 2S- (2-propynyl) octanoic acid is known per se, in JP-A-8-291106.
Examples The present invention is explained in detail based on the following examples, but the present invention is not limited thereto.
Example 1 Preparation of N-octanoyl- (ÍS) - (-) -2, 10-canforsultam To a solution of (lS) - (-) - 2, 10-camphorsultam (15.0 g) in tetrahydrofuran (10 ml) was added triethylamine (14.6 ml) and dimethylaminopyridine (0.85 g). To this solution was added dropwise a solution of octanoyl chloride (12.5 g) in tetrahydrofuran (20 ml) at 0 ° C. The reaction mixture was stirred for 1 hour at 0 ° C. Water (14 ml) was added to the mixture, and it was concentrated. The residue was diluted with ethyl acetate, washed with 2N aqueous hydrochloric acid solution, water, a saturated aqueous solution of sodium chloride (x2), IN aqueous sodium chloride solution (x2), water and a saturated solution of sodium chloride. Sodium chloride, successively, was dried over anhydrous magnesium sulfate, and concentrated to give the title compound (24.0 g, _100% crude product) having the following physical data.
TLC: Rf 0.33 (ethyl acetate: hexane = 3: 17); NMR (CDCl3): d 3.86 (1H, t, J = 6.3Hz), 3.49 (1H, d, J = 13.2Hz), 3.43 (1H, d, J = 13.2Hz), 2.72 (2H, dt, J = 7.9, 2.6Hz), 2.09 (2H, m), 1.88 (3H, m), 1.67 (2H, m), 1.31 (10H, m), 1.14 (3H, s), 0.96 (3H, s), 0.86 ( 3H, t, J = 6.8Hz); IR (liquid film): D 2957, 2930, 2857, 1698, 1458, 1414, 1375, 1331, 1271, 1237, 1217, 1165, 1134, 1109, 1065, 1040 cm "1.
Example 2 Preparation of N- (2S- (2-propenyl) octanoyl) - (SS) - (-) -2, 10-camphorsultam.
To a solution of diisopropylamine (20.0 ml) in tetrahydrofuran (40 ml) was added dropwise 1.6 M of n-butyllithium in hexane solution (94 ml) at 0 ° C. The mixture was stirred for 30 minutes at the same temperature. This solution was slowly added dropwise to the solution of the compound prepared in reference example 1 (52.2 g) in tetrahydrofuran (80 ml) at -72 [deg.] C. The mixture was then stirred for 30 minutes at the same temperature, The solution was added dropwise to the mixture of allyl bromide (18 ml), a solution of lithium iodide (3.7 g) in tetrahydrofuran (15 ml) and dimethylindazolidione (23 ml) .The reaction mixture was stirred for 1 hour at -78 ° C, 4 hours at -20 ° C and 1 hour at 0 ° C. The mixture was quenched with water, and concentrated The residue was extracted with a mixed solution of hexane: ethyl acetate = 1 : 1. The extract was washed with 2N aqueous solution of hydrochloric acid, water (x2), a saturated carbon solution Sodium acid and a saturated solution of sodium chloride were successively dried over magnesium sulfate anhydride and concentrated. The residue was recrystallized from methanol (x2) to give the title compound (37.4 g, 71.7% product (2 steps of (lS) - (-) - 2, 10 camphorsultam)) having the following physical data.
TLC: Rf 0.45 (hexane: ethyl acetate = 17: 3); NMR (CDCl3): d 5.80 (1H, ddt, J = 15.6, 9.8, 7.2Hz), 5.05 (1H, ddt, J = 15.6, 2.2Hz), 4.98 (1H, dd, J = 2.2Hz), 3.90 ( 2H, t, J = 6.3Hz), 3.51 (1H, d, J = 13.9Hz), 3.42 (1H, d, J = 13.9Hz), 3.12 (1H, m), 2.36 (2H, t, J = 7.0 Hz), 2.03 (2H, d, J = 6.4Hz), 1.88 (2H, m), 1.74 (1H, m), 1.26 (10H, m), 1.16 (3H, s), 0.96 (3H, s), 0.86 (3H, t, J = 6.4Hz); IR (KBr): v 3075, 2994, 2857, 1682, 1640, 1471, 1445, 1418, 1401, 1327, 1281, 1273, 1252, 1238, 1217, 1167, 1136, 1117, 1069, 1042, 992, 947, 909, cm "-i m.p. 94-95 ° C; excess diastereoisomer: 99% (liquid chromatography) Example 3 Preparation of 2S- (2-propenyl) octanoic acid To a solution of the compound prepared in example 2 (10.0 g) in dimethoxyethane (10 ml) was added 2-methyl-2-butene (8.3 ml) and 30% aqueous solution of hydrogen peroxide (5.4 ml) at - 10 ° C. This mixture was added dropwise to 40% aqueous tetrabutylammonium hydroxide solution (34 ml) for vigorous stirring. The reaction mixture was stirred for 2 hours. The mixture was quenched by means of 2N of aqueous sodium sulfite solution (35 ml), and stirred for 1 hour at room temperature. To the mixture was added IN of aqueous solution of oxalic acid, and the mixture was extracted with a mixed solution of ethyl acetate: isopropyl ether = 1: 4. The extract was washed with IN of aqueous solution of oxalic acid, water ( x2) and a saturated solution of sodium chloride, successively, dried over anhydrous sodium sulfate, and concentrated. To the residue was added a mixed solution of isopropyl ether and hexane = 1: 2, and insoluble matters were filtered. The filtrate was concentrated to give the title compound (5.72 g) having the following physical data.
TLC: Rf 0.46 (hexane: ethyl acetate = 7: 3); NMR (CDC13): d 5.78 (1H, ddt, J = 17.0, 10.1, 6.9Hz), 5.10 (1H, dd, J = 17.0, 1.9Hz), 5.05 (1H, dd, J = 10.1, 1.9Hz), 2.44 (2H, m), 2.30 (1H, m), 1.64 (1H, m), 1.64 (1H, m), 1.5S (1H, m), 1.30 (8H, brs), 0.90 (3H, t, J = 6.8Hz); IR (pure): D 2930, 2859, 1709, 1644, 1460, 1420, 1289, 125Q, 1210, 992, 916 cm "1; Optical purity: 99% e.e. (gas chromatography).
Example 4 Preparation of 2R-propyloctanoic acid To the mixed solution of the compound prepared in Example 3 (a) 168 mg) in methanol (1.2 ml) and ethyl acetate (1.2 ml) was added 10% palladium carbonate (17 mg.). stirred for 1 hour at room temperature under an atmosphere of hydrogen gas, the reaction mixture was filtered through Celite (for sale), and the filtrate was concentrated.The residue was purified by column chromatography on silica gel. (hexane: ethyl acetate = 9: 1- (4: 1) to give the title compound (109 mg, 74% product (2 steps from the compound prepared in example 2)) having the following physical data.
TLC: Rf 0.46 (hexane: ethyl acetate = 7: 3); NMR (CDC13): d 2.38 (1H, m), 1.55 (2H, m), 1.53-1.20 (12H, m), 0.94 (3H, t, J = 6.8Hz), 0.90 (3H, t, J = 6.8 Hz); 0.90 (3H, t, J = 6.8Hz); IR (pure): v 2959, 2932, 1707, 1470, 1420, 1379, T289, 1215, 943, cm "1; Optical purity: 95.2% e.e. (liquid chromatography) Example 5 Preparation of N- (2R- (2-propyl) octanoyl) - (ÍS) - (-) - 2, 10-canforsultam To a solution of 10% palladium carbonate (500 mg, containing 60.7% in water) was added the mixed solution of the compound prepared in example 2 (2.0 g) in ethyl acetate (7 ml) and dimethoxyethane (7). ml). The mixture was stirred for 1 hour at room temperature under an atmosphere of hydrogen gas. The reaction of the mixture was filtered through Celite (which is for sale), and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (hexane: ethyl acetate = 9: 1) to give the title compound (2.01 g, 100% of the product) as a solid having the following physical data.
TLC: Rf 0.37 (hexane: ethyl acetate = 9: 1); NMR (CDCl3): d 3.90 (1H, t, J = 6.3Hz), 3.51 (1H, d, J = 13.2Hz), 3.43 (1H, d, J = 13.2Hz), 3.01 (1H, m), 2.07 (2H,), 1.88 (3H, m), 1.77-1.19 (16H, m), 1.16 (3H, s), 0.97 (3H, s), 0.89 (3H, t, J = 6.8Hz), 0.83 (3H , t, J = 6.8Hz); IR (KBr): v 2959, 2861, 1684, 1468, 1458, 1416, 1401, 1375, 1327, 1281, 1278, 1250, 1237, 1165, 1136, 1113, 1062, 1040 c "1; Excess diastereoisomer: 99% (liquid chromatography).
Example 6 Preparation of 2R-propyloctanoic acid To an aqueous solution of 40% tetrabutylammonium hydroxide (1.4 ml) was added dimethoxyethane (2 ml) and toluene (2 ml), and concentrated. After this procedure was repeated (x4), tetrabutylammonium hydroxide anhydride was prepared. To a solution of the compound prepared in example 5 (400 mg) in tetrahydrofuran (2 ml) was added dropwise an aqueous solution of 30% hydrogen peroxide (0.21 ml) and a tetrahydrammonium anhydride hydroxide solution (the one prepared above). ) in tetrahydrofuran (2 ml) at -20 ° C. The reaction of the mixture was stirred for 50 minutes at -20 ° C. The mixture was quenched by means of 1.5N of aqueous sodium sulfite solution (1.4 ml), and stirred for 30 minutes at room temperature. The mixture was concentrated, it was added to this water and 2N of aqueous hydrochloric acid solution, and the mixture was extracted with a mixed solution of ethyl acetate: isopropyl ether = 1: 4 (x2). The extract was washed with water (x2) and a saturated solution of sodium chloride, successively, dried over anhydrous sodium sulfate, and concentrated. Isopropyl ether was added to the residue, the insoluble matters were filtered, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (hexane: ethyl acetate = 19: 1) to give the title compound (115 mg, 59.3% product) having the following physical data.
TLC: Rf 0.46 (hexane: ethyl acetate = 7: 3); NMR (CDCl 3): d 2.38 (1H, m), 1.55 (2H, m), 1.53-1.20 (12H, m), 0.94 (3H, t, J = 6.8Hz), 0.90 (3H, t, J = 6.8 Hz); IR (KBr): v 2959, 2932, 1707, 1470, 1420, 1379, 1289, 1215, 943 cm "1; Optical purity 99% (liquid chromatography).
Example 7 Preparation of N- (2S- (2-propynyl) octanoyl) - (ÍS) - (-) -2, 10-canforsultam To a solution of diisopropylane (6.7 ml) in tetrahydrofuran (13 ml) was added dropwise 1.6 M of n-butyllithium in hexane solution (32 ml) at 0 ° C. The mixture was stirred for 20 minutes at the same temperature. This solution was slowly added dropwise to the compound prepared in reference example 1 (16.0 g) in tetrahydrofuran (27 ml) at -78 ° C. The mixture was then stirred for 30 minutes at the same temperature, and to this solution was added dropwise the solution of the mixture of propargyl bromide (5.2 ml), a solution of lithium iodide (1.24 g) in tetrahydrofuran (5 ml. ) and dimethylindazolidione (7.6 ml). The reaction of the mixture was stirred for 1.5 hours at -78 ° C and 2 hours at -30 ° C. The mixture was quenched by water, and concentrated. The residue was extracted with a mixture of hexane: ethyl acetate = 1: 1 solution. The extract was washed with a saturated aqueous solution of sodium ammonium (x2), water (x3) and a saturated solution of sodium chloride, successively, it was dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (hexane: ethyl acetate = 19: 1 → 9: 1) to give the title compound (14.6 g, 83.0% product (2 steps from (lS) - ( -) - 2, 10-canforsultam) which has the following physical data.
TLC: Rf 0.55 (toluene: ethyl acetate = 19: 1); NMR (CDCl3): d 3.93 (1H, dd, J = 7.1, 5.4Hz), 3.53 (1H, d, J = 13.9Hz), 3.45 (1H, d, J = 13.9Hz), 3.21 (1H, m) , 2.55 (2H, m), 1.99 (1H, t, J = 2.6Hz), 1.87 (4H, m), 1.57-1.23 (11H, m), 1.19 (3H, s), 0.98 (3H, s), 0.87 (3H, t, J = 6.7Hz); IR (KBr): D 3318, 2970, 2945, 2850, 1690, 1470, 1458, 1433, 1418, 1397, 1323, 1280, 1270, 1238, 1220, 1165, 1134, 1110, 1061, 1040, 947 cm "1; 96.8% diastereomeric excess (liquid chromatography).
The title compound obtained in this way was recrystallized from a mixed solution of isopropyl alcohol: water = 5: 1 to give the title compound having the following physical data.
Excess diastereomer: 99.4% (liquid chromatography) Example 8 (a) Preparation of 2S- (2-propynyl) octanoic acid To a solution of the compound prepared in example 7 [400 mg, diastereomeric excess: 96.8% (liquid chromatography)] in dimethoxyethane (4 ml) was added 2-methyl-2-butene (0.33 ml) and aqueous peroxide solution. of hydrogen at 30% (0.22 ml). To this mixture was added dropwise 40% tetrabutylammonium hydroxide aqueous solution (1.4 ml) for vigorous stirring. The reaction mixture is stirred for 10 minutes at -10 ° C. The reaction of the mixture was quenched by means of 1.5N of aqueous sodium sulfite solution (1.5 ml), and stirred for 30 minutes at room temperature. The mixture was concentrated, water was added thereto, and the mixture was extracted with a mixture solution of ethyl acetate: isopropyl ether = 1: 4 (x2). To the water layer was added 2N of aqueous hydrochloric acid solution, and the mixture was extracted with isopropyl ether (x2). The extract was washed with water (x2) and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (hexane: ethyl acetate = 9: 1) to give the title compound (172 mg, 89.6% product) having the following physical data.
TLC: _Rf 0.55 (toluene: ethyl acetate = 19: 1); NMR (CDCl 3): d 2.62 (1H, m), 2.54 (1H, ddd, J = 16.6, 2. 6Hz), 2.43 (1H, ddd, J = 16.6, 6.8, 2.6Hz), 2.03 (1H, t J = 2.6Hz), 1.70 (2H, m), 1.30 (8H, m), 0.90 (3H, t, J = 6.8Hz); IR (KBr): v 3312, 2930, 1717, 1559, 1541, 1509, 1458, 1289, 938 cm "1; Optical purity: 96.4% e.e. (gas chromatography Example 8 (b) Preparation of 2S- (2-propynyl) octanoic acid To a solution of the compound prepared in example 7 [400 mg, diastereoisomeric excess: 96.8% (liquid chromatography)] in tetrahydrofuran (16 ml) and water (2.6 ml) was added dropwise 30% aqueous hydrogen peroxide solution. % (0.22 ml) at 0 ° C. To this solution 2N of aqueous solution of lithium hydroxide (2.1 ml) was added dropwise. The reaction of the mixture was stirred for 2 hours at -10 ° C and 1.5 hours at room temperature.
The mixture was quenched by means of 1.5N of aqueous sodium sulfite solution (5.6 ml), and stirred for 3 hours at room temperature. The mixture was concentrated, water was added thereto, and the mixture was extracted with a mixed solution of ethyl acetate: isopropyl ether = 1: 4 (x2). The extract was washed with water (x3) and a saturated aqueous solution of sodium chloride. To the entire water layer was added 2N of aqueous hydrochloric acid solution, and the mixture was extracted with isopropyl ether (x2) the extract was washed with water (x2) and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (hexane: ethyl acetate = 9: 1) to give the title compound (169 mg, 88% product) having the following physical data.
TLC: Rf 0.55 (toluene: ethyl acetate = 19: 1); NMR (CDCl 3): d 2.62 (1H, m), 2.54 (1H, ddd, J = 16.6, 2. 6Hz), 2.43 (1H, ddd, J = 16.6, 6.8, 2.6Hz), 2.03 (1H, t J = 2.6Hz), 1.70 (2H, m), 1.30 (8H, m), 0.90 (3H, t, J = 6.8Hz); IR (KBr): v 3312, 2930, 1717, 1559, 1541, 1509, 1458, 1289, 938 cm " Optical purity: 96.8% e.e. (gas chromatography) Example 9 (a] Preparation of 2R-propyloctanoic acid To a solution of the compound prepared in example 8 (a) (114 mg) in ethyl acetate (2 ml) was added palladium carbon (10 mg). The reaction of the mixture was stirred for 10 minutes at room temperature under an atmosphere of hydrogen gas. The reaction of the mixture was filtered through Celite (which is for sale), and concentrated. The residue was purified by column chromatography on silica gel (hexane: ethyl acetate = 9: 1-4: 1) to give the title compound (113 mg, 97% product) having the following physical data. TLC: Rf 0.34 (hexane: ethyl acetate = 4: 1); NMR (CDC13): d 2.46-2.27 (1H, m), 1.75-1.12 (14H, m), 0.96-0.75 (6H, m); IR (KBr) 2959, 2932, 2860, 1708, 1466, 1419, 1380, 1290, 1255, 1217, 1112, 944 cm " Example 9 (b) Preparation of 2R-propyloctanoic acid To a solution of the compound prepared in example 8 (a) [3.0 g, 99.3% e.e. (liquid chromatography)] in diethoxyethane (75 ml) was added 5% palladium carbon (600 mg, 50% water content). The reaction of the mixture was stirred for 1 hour under an atmosphere of hydrogen gas and atmospheric pressure of 5, further it was stirred for 4 hours at 30 ° C. The reaction of the mixture was cooled to room temperature, filtered through Celite (which is for sale), and the filtrate was concentrated. The residue was dissolved in the solution of the mixture of hexane: ethyl acetate = 5: 1, and extracted with 2N of aqueous sodium hydroxide solution. The hydrochloric acid was added to the water layer, and the mixture was extracted with the solution of the mixture of hexane: ethyl acetate = 5: 1. The extract was washed with water and a saturated aqueous solution of sodium chloride. sodium, successively, dried over anhydrous sodium sulfate, and concentrated to give the title compound (2.7 g, 89% product) having the following physical data.
TLC: Rf 0.34 (hexane: ethyl acetate = 4: 1); Optical purity: 96.8% e.e. (liquid chromatography).
Field of Industrial Application According to the present invention, the optically active 2R-propyloctanoic acid or its preparations of intermediates can be obtained as medically in an optical equal or greater than conventional processes and in a few reaction stages efficiently.
Specifically 2R-propyloctanoic acid is obtained at 90.0% e.e. (the process of JP-A-8-291106) or 96.0% e.e. (the process of JP-A-8-295648) in the known processes in a conventional manner, although this is obtained in a high optical purity of 95.99% e.e. in the process of the present invention.
Furthermore, in the preparation of optically active 2R-propyloctanoic acid, the process of the present invention is by far, more excellent than conventional processes in terms of chemical production and the number of reaction steps. Specifically, the total synthetic production is 5.9% in 6 stages from dimethyl hexyl malonate (the process of JP-A-8-291106) and the total synthetic production is 20.1% in 5 stages from pentanoyl chloride (the JP- process). A-8-295648) in conventional processes, although 2R-propyloctanoic acid can be obtained in a high chemical production of a total synthetic production of 42.5-72.1% and by less than 4 stages from octanoyl chloride.
As discussed above, the process of the present invention would be a suitable process for the synthesis of industrial-scale large-scale 2R-propyloctanoic acid.
It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.
Having described the invention as above, the content in the following is declared as property.

Claims (13)

REI INDICATIONS
1. A compound of N- (2S- (2-propenyl) octanoyl) - (SS) - (-) - 2, 10-camphorsultam, N- (2S- (2-propynyl) octanoyl) - (SS) - (-) -2, 10-camphorsultam, or N- (2R- (2-propyl) octanoyl) - (SS) - (-) - 2, 10-camphorsultam.
2. A compound according to claim 1, characterized in that it is N- (2S- (2-propenyl) octanoyl) - (SS) - (-) - 2, 10-camphorsultam.
3. A compound according to claim 1 characterized in that it is N- (2S- (2-propynyl) octanoyl) - (SS) - (-) -2, 10-camphorsultam.
4. A compound according to claim 1, characterized in that it is N- (2R- (2-propyl) octanoyl - (SS) - (-) - 2, 10-camphorsultam.
5. A process for the preparation of N- (2S- (2-propenyl) octanoyl) - (lS) - (-) - 2, 10-canforsultam represented in claim 2, characterized by the reaction of N-octanoyl- (IS) - (-) -2, 10-canforsultam with allyl halide.
6. A process for the preparation of N- (2S- (2-propynyl) octanoyl) - (SS) - (-) -2, 10-camphorsultam represented in claim 3, characterized by the reaction of N-octanoyl- (SS) - (-) -2, 10-canforsultam with propargyl halide.
7. A process for the preparation of N- (2R- (2-propyl) octanoyl) - (SS) - (-) -2, 10-canforsultam represented in claim 4, characterized by the reduction of N- (2S- (2 -propenyl) octanoyl) - (1S) - (-) -2, 10-canforsultam represented in claim 2.
8. A process for the preparation of N- (2R- (2-propyl) octanoyl) - (SS) - (-) -2, 10-canforsultam represented in claim 4, characterized by the reduction of N- (2S- (2 -propynyl) octanoyl) - (SS) - (-) -2, 10-camphorsultam represented in claim 3.
9. A process for the preparation of optically active 2S- (2-propenyl) octanoic acid, characterized by the hydrolysis of N- (2S- (2-propenyl) octanoyl) - (SS) - (-) -2, 10-canforsultam depicted in claim 2.
10. A process for the preparation of optically active 2R-propyloctanoic acid, characterized by the reduction of optically active 2S- (2-propenyl) octanoic acid obtained in claim 9.
11. A process for the preparation of optically active 2S- (2-propenyl) octanoic acid, characterized by the hydrolysis of N- (2R- (2-propynyl) octanoyl) - (SS) - (-) -2, 10-canforsultam optically active represented in claim 3.
12. A process for the preparation of optically active 2R-prspiloctanoic acid, characterized by the reduction of optically active 2S- (2-propenyl) octanoic acid obtained in claim 11.
13. A process for the preparation of optically active 2R-propyloctanoic acid, which is characterized by the hydrolysis of N- (2R- (2-propyl) octanoyl) - (SS) - (-) -2, 10-canforsultam optically active in claim 4.
MXPA/A/2000/011021A 1998-05-12 2000-11-09 Novel intermediates and processes for the preparation of optically active octanoic acid derivatives MXPA00011021A (en)

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