Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-11-13
2001-12-25
Stockton, Laura L. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06333415
ABSTRACT:
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 by using intermediates.
More particularly, the present invention relates to 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-camphorsultam; processes for the preparation thereof; and processes for the preparation of optically active 2S-(2-propenyl)octanoic acid, 2S-(2-propynyl)octanoic acid and 2R-propyloctanoic acid by using thereof intermediates.
BACKGROUND ART
The optically active octanoic acid derivatives prepared by the present invention are intermediates useful for the preparation of medicaments or are compounds useful as medicaments. For example, a racemate of 2R-propyloctanoic acid is described in Example 7(33) of JP-A-7-316092 as an agent for treating or preventing neurodegenerative diseases derived from functional abnormality of astrocytes.
As a result of the study after that, it was found that optically active 2R-propyloctanoic acid has strong activities in particular. Accordingly, methods for obtaining this compound efficiently have been studied variously, and the following processes are known until now.
For example, JP-A-8-291106 discloses a method by optical resolution using optically active amine. However, in the process of optically separating 2R-propyloctanoic acid from its racemate, both the chemical yield (total synthetic yield of 5.9% at 6 stages from dimethyl hexylmalonate) and the optically purity (90.0% e.e.) were so insufficient that the process had no practical use.
A process using an optically active starting material is known as other process for obtaining optically active 2R-propyloctanoic acid. For example, JP-A-8-295648 discloses a process using optically active prolinol. An optically active branched alkanoic acid having a high optical purity (96.0% e.e.) can be prepared using this process. However, the chemical yield (total synthetic yield of 20.1% at 5 stages from 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, 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-camphorsultam, by using optically active (1S)-(−)-2,10-camphorsultam, further processes for the preparation of optically active 2S-(2-propenyl)octanoic acid, 2S-(2-propynyl)octanoic acid and 2R-propyloctanoic acid as high optical purity (95-99% e.e.) by using thereof intermediates, accomplished 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 using intermediates as follows:
[1] A compound of N-(2S-(2-propenyl)octanoyl)-(1S)-(−)-2,10-camphorsultam, N-(2S-(2-propynyl)octanoyl)-(1S)-(−)-2,10-camphorsultam, or N-(2R-(2-propyl)octanoyl)-(1S)-(−)-2,10-camphorsultam;
[2] A compound of N-(2S-(2-propenyl)octanoyl)-(1S)-(−)-2,10-camphorsultam depicted in [1];
[3] A compound of N-(2S-(2-propynyl)octanoyl)-(1S)-(−)-2,10-camphorsultam depicted in [1];
[4] A compound of N-(2R-(2-propyl)octanoyl)-(1S)-(−)-2,10-camphorsultam depicted in [1];
[5] A process for the preparation of N-(2S-(2-propenyl)octanoyl)-(1S)-(−)-2,10-camphorsultam depicted in [2], which is characterized by the reaction of N-octanoyl-(1S)-(−)-2,10-camphorsultam with allyl halide;
[6] A process for the preparation of N-(2S-(2-propynyl)octanoyl)-(1S)-(−)-2,10-camphorsultam depicted in [3], which is characterized by the reaction of N-octanoyl-(1S)-(−)-2,10-camphorsultam with propargyl halide;
[7] A process for the preparation of N-(2R-(2-propyl)octanoyl)-(1S)-(−)-2,10-camphorsultam depicted in [4], which is characterized by the reduction of N-(2S-(2-propenyl)octanoyl)-(1S)-(−)-2,10-camphorsultam depicted in [2];
[8] A process for the preparation of N-(2R-(2-propyl)octanoyl)-(1S)-(−)-2,10-camphorsultam depicted in [4], which is characterized by the reduction of N-(2S-(2-propynyl)octanoyl)-(1S)-(−)-2,10-camphorsultam depicted 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)-(1S)-(−)-2,10-camphorsultam depicted 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-propynyl)octanoic acid, which is characterized by the hydrolysis of optically active N-(2S-(2-propynyl)octanoyl)-(1S)-(−)-2,10-camphorsultam depicted 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-propynyl)octanoic acid obtained in [11].
[13] A process for the preparation of optically active 2R-propyloctanoic acid, which is characterized by the hydrolysis of optically active N-(2R-(2-propyl)octanoyl)-(1S)-(−)-2,10-camphorsultam depicted in [4].
DETAILED EXPLANATION OF THE INVENTION
Optically active 2R-propyloctanoic acid in high optical purity (95-99% e.e.) and superior chemical yield (4 steps from octanoyl chloride, total synthetic yield 42.5-72.1%) can be efficiently prepared by the method of the present invention. Further the hydrolysis of camphorsultam derivatives by using tetraalkylammonium hydroxide is novel reaction. This observation has been confirmed from experiments by the present inventor for the first time.
Novel intermediate compounds of the present invention can easily improve optical purity by recrystallization since novel intermediates compounds are easily crystallized. For example, the residue of the reaction was purified by column chromatography to give N-(2S-(2-propynyl)octanoyl)-(1S)-(−)-2,10-camphorsultam having 96.8% diastereoisomer excess (liquid chromatography). Further thus obtained compound could be improved to give it having 99.4% diastereoisomer excess (liquid chromatography) by recrystallization.
In the present invention the process for the preparation of 2R-propyloctanoic acid may be carried out four methods (A) to (D) as follows, respectively.
(A) 2R-propyloctanoic acid may be prepared by reacting of camphorsultam with octanoic acid or its derivatives→the reaction of allyl halide→hydrolysis →reduction;
1) reacting of (1S)-(−)-2,10-camphorsultam with octanoic acid or its derivatives,
2) reacting of N-octanoyl-(1S)-(−)-2,10-camphorsultam with ally halide,
3) hydrolysis of N-(2S-(2-propenyl)octanoyl)-(1S)-(−)-2,10-camphorsultam, and
4) reduction of optically active 2S-(2-propenyl)octanoic acid.
(B) 2R-propyloctanoic acid may be prepared by reacting of camphorsultam with octanoic acid or its derivatives→the reaction of propargyl halide→hydrolysis→reduction;
1) reacting of (1S)-(−)-2,10-camphorsultam with octanoic acid or its derivatives,
2) reacting of N-octanoyl-(1S)-(−)-2,10-camphorsultam with propargyl halide,
3) hydrolysis of N-(2S-(2-propynyl)octanoyl)-(1S)-(−)-2,10-camphorsultam, and
4) reduction of optically active 2S-(2-propynyl)octanoic acid.
(C) 2R-propyloctanoic acid may be prepared by reacting of camphorsultam with octanoic acid or its derivatives→the reaction of allyl halide→reduction →hydrolysis;
1) reacting of (1S)-(&minu
Ono Pharmaceutical Co. Ltd.
Stockton Laura L.
Sughrue & Mion, PLLC
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