JP2005298334A - Novel intermediate compound and method for manufacturing compound by using the same - Google Patents

Novel intermediate compound and method for manufacturing compound by using the same Download PDF

Info

Publication number
JP2005298334A
JP2005298334A JP2001385621A JP2001385621A JP2005298334A JP 2005298334 A JP2005298334 A JP 2005298334A JP 2001385621 A JP2001385621 A JP 2001385621A JP 2001385621 A JP2001385621 A JP 2001385621A JP 2005298334 A JP2005298334 A JP 2005298334A
Authority
JP
Japan
Prior art keywords
compound
general formula
benzyl
oxazolidinone
symbols
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
JP2001385621A
Other languages
Japanese (ja)
Inventor
Kuniaki Tatsuta
邦明 竜田
Original Assignee
Ono Pharmaceut Co Ltd
小野薬品工業株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ono Pharmaceut Co Ltd, 小野薬品工業株式会社 filed Critical Ono Pharmaceut Co Ltd
Priority to JP2001385621A priority Critical patent/JP2005298334A/en
Publication of JP2005298334A publication Critical patent/JP2005298334A/en
Application status is Pending legal-status Critical

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D263/00Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18Oxygen atoms
    • C07D263/20Oxygen atoms attached in position 2
    • C07D263/26Oxygen atoms attached in position 2 with hetero atoms or acyl radicals directly attached to the ring nitrogen atom
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07BGENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07Optical isomers

Abstract

<P>PROBLEM TO BE SOLVED: To provide a manufacturing method capable of obtaining a compound represented by formula (V) which is highly useful as a drug and high in both chemical yield and optical purity. <P>SOLUTION: The novel intermediate compound is represented by formula (I) (wherein R<SP>1</SP>is propyl, 2-propenyl or 2-propynyl; and R<SP>2</SP>is a 4-8C alkyl), and its manufacturing method is described. The method for manufacturing the optically active compound represented by formula (V) comprises using the novel intermediate. According to the manufacturing method, the compound of high optical purity represented by formula (V) can be efficiently manufactured in high chemical yield at a low cost. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a novel intermediate compound, a method for producing the same, or a method for producing an optically active compound using the intermediate compound.
[0002]
In more detail, (1) General formula (I)
[0003]
Embedded image
[0004]
(Wherein all symbols have the same meanings as described later),
(2) their manufacturing method, or
(3) Optically active general formula (V) using these intermediate compounds
[0005]
Embedded image
[0006]
(Wherein all symbols have the same meanings as described later).
[0007]
BACKGROUND OF THE INVENTION AND PRIOR ART
Formula (V) produced in the present invention
[0008]
Embedded image
[0009]
(Wherein all symbols have the same meanings as described later), (2R) -2-propyloctanoic acid and (2S) -2-propynylheptanoic acid are compounds useful as pharmaceuticals. is there. For example, (2R) -2-propyloctanoic acid is described in Example 7 (33) of EP 632008 as its racemic compound as a therapeutic or preventive agent for neurological diseases caused by astrocyte dysfunction. . As for (2S) -2-propynylheptanoic acid, its racemic compound is described as a neurotrophic factor in Example 2 of US Pat. No. 5,672,746.
[0010]
In particular, as a result of subsequent studies, 2-propyloctanoic acid was found to have a particularly strong R action and low toxicity, and various studies were thus conducted on methods for efficiently obtaining an optically active R form. .
[0011]
As a method for producing (2R) -2-propyloctanoic acid, for example, (1) In JP-A-8-291106, an optically active salt of racemic 2- (2-propynyl) octanoic acid and an optically active amine is used. A method is described in which an optically active salt is separated by resolution, and the resulting optically active (2S) -2- (2-propynyl) octanoic acid is reduced after acid treatment. The target compound obtained by this reaction was poor in chemical yield (12%) and optical purity (90.0% ee), and was not a practical method.
[0012]
(2) JP-A-8-295648 describes a method using optically active prolinol. Although the optical purity of (2R) -2-propyloctanoic acid obtained by this method was 96.0% ee, 5 steps of reaction were required until the target compound, and the chemical yield was low (total yield 20.2). %) Was not a practical method.
[0013]
(3) WO99 / 58513 discloses a process for producing (2R) -2-propyloctanoic acid in four steps through a novel intermediate obtained by reacting octanoic acid with camphorsultam. Has been described. The desired (2R) -2-propyloctanoic acid is produced from N- (2S- (2-propenyl) octanoyl)-(1S)-(−)-2,10-camphorsultam, which is a novel intermediate. There are two processes, and the optical purity of the target compound obtained by these reactions is 95.2% ee and 99% ee, respectively. However, the overall chemical yields until the target compound was produced were as low as 53% and 42.5%, respectively. Furthermore, camphor sultam used as a raw material is an expensive reagent, and the recovery rate during the reaction is 30% or less, and it is almost impossible to reuse.
[0014]
The specification also includes a step of producing (2R) -2-propyloctanoic acid from N- (2S- (2-propynyl) octanoyl)-(1S)-(−)-2,10-camphorsultam. Although described, there were the same problems as described above.
[0015]
(4) In WO00 / 49882, there is a catalytic reduction from (2S) -2- (2-propenyl) octanoic acid or (2S) -2- (2-propynyl) octanoic acid using a platinum carbon catalyst. A method for producing (2R) -2-propyloctanoic acid is described.
[0016]
[Problems to be solved by the invention]
There is a demand for a production method that can obtain a compound represented by the general formula (V), which is highly useful as a pharmaceutical, with high chemical yield and optical purity.
[0017]
[Means for Solving the Problems]
As a result of intensive investigations, the present inventors have used general formula (I) by using optically active (R)-(+)-4-benzyl-2-oxazolidinone.
[0018]
Embedded image
[0019]
(In the formula, all symbols have the same meanings as described later), a novel compound was successfully obtained. In addition, from the new compound, general formula (V) having high chemical yield (overall synthesis yield of 80% or more) and high optical purity (97.0% or more)
[0020]
Embedded image
[0021]
(Wherein all symbols have the same meaning as described below), and succeeded in obtaining a compound represented by
[0022]
Further, the compound represented by the general formula (V) is reacted with an optically active amine salt, recrystallized, and then treated with an acid, whereby the compound represented by the general formula (V) having higher optical purity (99.0% or more). The present invention has been completed.
[0023]
According to the method of the present invention, the compound represented by the general formula (V) can be produced with high chemical yield and high optical purity, and also can be produced at low cost. That is, the reagent used in the present invention, specifically (R)-(+)-4-benzyl-2-oxazolidinone, is inexpensive. In addition, since it can be recovered at a high recovery rate during the reaction, it can be reused in the process of the present invention any number of times. Therefore, it can be produced at a lower cost, and there is no waste, and the reaction can be performed efficiently.
[0024]
That is, the present invention relates to a novel intermediate compound represented by general formula (I), a process for producing the same, and a process for producing an optically active compound represented by general formula (V) using the intermediate compound.
[0025]
Specifically, (1) General formula (I)
[0026]
Embedded image
[0027]
Wherein R 1 represents propyl, 2-propenyl or 2-propynyl, and R 2 represents C4-8 alkyl,
(2) (4R) -N-[(2R) -2-propyloctanoyl] -4-benzyl-2-oxazolidinone, in which R 1 is propyl and R 2 is hexyl in general formula (I),
(3) (4R) -N-[(2S) -2- (2-propenyl) octanoyl] -4-benzyl- in which R 1 is 2-propenyl and R 2 is hexyl in general formula (I) 2-oxazolidinone,
(4) (4R) -N-[(2S) -2- (2-propynyl) octanoyl] -4-benzyl- in which R 1 is 2-propynyl and R 2 is hexyl in general formula (I) 2-oxazolidinone,
(5) (4R) -N-[(2R) -2-propylheptanoyl] -4-benzyl-2-oxazolidinone, in which R 1 is propyl and R 2 is pentyl in general formula (I),
(6) (4R) -N-[(2S) -2- (2-propenyl) heptanoyl] -4-benzyl- in which R 1 is 2-propenyl and R 2 is pentyl in general formula (I) 2-oxazolidinone,
(7) (4R) -N-[(2S) -2- (2-propynyl) heptanoyl] -4-benzyl- in which R 1 is 2-propynyl and R 2 is pentyl in general formula (I) 2-oxazolidinone,
(8) (4R) -N-[(2R) -2-propylhexanoyl] -4-benzyl-2-oxazolidinone, in which R 1 is propyl and R 2 is butyl in the general formula (I),
(9) (4R) -N-[(2S) -2- (2-propenyl) hexanoyl] -4-benzyl- in which R 1 is 2-propenyl and R 2 is butyl in the general formula (I) 2-oxazolidinone, or
(10) (4R) -N-[(2S) -2- (2-propynyl) hexanoyl] -4-benzyl- in which R 1 is 2-propynyl and R 2 is butyl in general formula (I) 2-oxazolidinone, or
(11) General formula (III)
[0028]
Embedded image
[0029]
(Wherein all symbols have the same meaning as described above), and a compound represented by the general formula (IV)
[0030]
Embedded image
[0031]
Wherein R 1-1 represents 2-propenyl or 2-propynyl, and X represents a halogen atom. The compound represented by the general formula (I-1)
[0032]
Embedded image
[0033]
(Wherein all symbols have the same meaning as described above),
(12) General formula (I-1)
[0034]
Embedded image
[0035]
(Wherein all symbols have the same meaning as described above) a compound represented by the general formula (I-2)
[0036]
Embedded image
[0037]
(Wherein all symbols have the same meaning as described above),
(13) General formula (I-2)
[0038]
Embedded image
[0039]
(Wherein all symbols have the same meaning as described above) hydrolyzing the compound represented by the general formula (V-2)
[0040]
Embedded image
[0041]
(Wherein all symbols have the same meaning as described above),
(14) General formula (I-1)
[0042]
Embedded image
[0043]
(Wherein all symbols have the same meaning as described above) hydrolyzing the compound represented by the general formula (V-1)
[0044]
Embedded image
[0045]
(Wherein all symbols have the same meaning as described above),
(15) General formula (V)
[0046]
Embedded image
[0047]
(Wherein all symbols have the same meanings as described above) An optically active amine is reacted with the compound represented by the following formula, and the resulting salt is recrystallized and then treated with an acid. The present invention relates to a method for producing a compound represented by the general formula (V).
[0048]
In the present invention, any of propyl, 2-propenyl and 2-propynyl represented by R 1 is preferable.
[0049]
In the present invention, C4-8 alkyl represented by R 2 includes butyl, pentyl, hexyl, heptyl, octyl or isomers thereof, and any of them is preferable.
[0050]
In the present invention, any possible combination of R 1 and R 2 is preferred. Specifically, R 1 is propyl and R 2 is butyl, R 1 is propyl and R 2 is pentyl, R 1 is propyl and R 2 is hexyl, R 1 is 2-propenyl and R 2 is butyl, R 1 is 2-propenyl and R 2 are pentyl, R 1 is 2-propenyl and R 2 are hexyl, R 1 is 2-propynyl and R 2 are butyl, R 1 is 2-propynyl and R 2 are pentyl, or R 1 is 2 - propynyl and R 2 is hexyl. Preferably, R 1 is propyl and R 2 is hexyl, R 1 is 2-propenyl and R 2 is hexyl, R 1 is 2-propynyl and R 2 are butyl, R 1 is 2-propynyl and R 2 is pentyl or R 1 is 2-propynyl and R 2 is hexyl.
[0051]
The novel intermediate represented by the general formula (I) of the present invention and the process for producing the compound represented by the general formula (V) using the same are represented by the following reaction process formulas (1) and (2).
[0052]
Embedded image
[0053]
Embedded image
[0054]
In the reaction process formula, Bn represents benzyl and NH 2 —R 3 represents an optically active amine.
[0055]
The reaction of the step [1] is known, for example, a base (tertiary amine (triethylamine, diisopropylethylamine) in an organic solvent (tetrahydrofuran, diethyl ether, N, N-dimethylformamide, dimethoxyethane, diethylene glycol dimethyl ether, toluene, etc.). , 4-dimethylaminopyridine, etc.), butyl lithium, lithium diisopropylamide, lithium hexamethyldisilazane, sodium hydride, potassium hydride, potassium t-butoxide, lithium t-butoxide, etc.) in the presence of −20 to 40 ° C. It is performed by making it react with.
[0056]
The reaction of the step [2] is known, for example, in an organic solvent (tetrahydrofuran, diethyl ether, benzene, dimethoxyethane, hexane, toluene, 1,3-dimethyl-2-imidazolidinone, hexamethylphosphoric triamide, etc.) , In the presence of a base (lithium hexamethyldisilazane, sodium hexamethyldisilazane, potassium hexamethyldisilazane, n-butyllithium, s-butyllithium, lithium diisopropylamide, potassium t-butoxide, lithium t-butoxide, etc.), The reaction is performed at 20 to 40 ° C. Compound (I-1) obtained by this reaction is a novel compound.
[0057]
The reduction reaction in the step [3] is known, and for example, a method for catalytic reduction is described in WO99 / 58513 and WO00 / 49882.
[0058]
Specifically, for example, a catalyst (palladium carbon) in an organic solvent (methanol, ethanol, isopropanol, tetrahydrofuran, ethyl acetate, tetrahydropyran, dioxane, dimethoxyethane, diethyl ether, acetic acid, or a mixed solvent thereof) in a hydrogen atmosphere. , Palladium, platinum, platinum carbon, platinum oxide, nickel, palladium hydroxide, rhodium, rhodium carbon, ruthenium, ruthenium carbon chlorotris (triphenylphosphine) rhodium, etc.) Is called. Compound (I-2) obtained by this reaction is a novel compound.
[0059]
The hydrolysis reaction in the step [4] is known, for example, in the presence or absence of a peracid (hydrogen peroxide, t-butyl hydroperoxide or an aqueous solution thereof) in an organic solvent (tetrahydrofuran, ethylene glycol dimethyl ether, etc.). -20 to 40 using tetraalkylammonium hydroxide (benzyltrimethylammonium hydroxide, tetraethylammonium hydroxide, tetraisopropylammonium hydroxide, tetrabutylammonium hydroxide, tetraoctylammonium hydroxide or an aqueous solution thereof) The reaction is carried out at 0 ° C.
[0060]
The step [5] is performed by the same operation as the above-described step [4], but a compound having an excessive amount of a double bond (such as 2-methyl-2-butene) may be used.
[0061]
Step [6] is performed by the same operation as the above-described step [3].
[0062]
By operating according to the above reaction process formula (1), a novel compound represented by the general formula (I-1) and a novel compound represented by the general formula (I-2) can be obtained. This is very useful as an intermediate compound for producing a compound represented by the general formula (V) represented by (2R) -2-propyloctanoic acid useful as a pharmaceutical product.
[0063]
Step [7] is a compound represented by general formula (V) and an optically active amine [(R)-(+)-1-phenethylamine, (R)-(+)-1- (4-methylphenyl) ethylamine. , L-arginine, 2R-aminobutanol, (S)-(−)-nicotine, hydroquinine, dehydroabiethylamine, (1S, 2S) -methylpseudoephedrine, (1R, 2S)-(−)-norephedrine, L-tyrosine, (−)-cis-benzyl- (2-hydroxymethylcyclohexyl) amine, (S)-(−)-1-methyl-2-pyrrolidinemethanol and the like] are reacted.
[0064]
During the process, the preferred optically active amine is (R)-(+)-1-phenethylamine.
[0065]
In the step [8], the crystals obtained in the above step [7] are recrystallized with an organic solvent (n-hexane, n-heptane, etc.), and then acid (hydrochloric acid, nitric acid, hydrobromic acid, acetic acid, Trifluoroacetic acid, methanesulfonic acid, etc.).
[0066]
By operating according to the above reaction process formula (2), the compound represented by the general formula (V) having higher optical purity than that produced by the reaction process formula (1) can be obtained with high chemical yield. .
[0067]
On the other hand, the following reaction process formula (A) is described in WO99 / 58513.
[0068]
Embedded image
[0069]
In the reaction process formula, Y represents OH or Cl,
R A represents 2-propenyl or 2-propynyl.
[0070]
However, the above process has the following problems.
[0071]
The camphor sultam of formula (II) used in step [a] is very expensive. On the other hand, (R)-(+)-4-benzyl-2-oxazolidinone used in the step [1] of the present invention can be obtained at a much lower price.
[0072]
In the step [b], the reaction had to be performed under the condition of −78 ° C., but in the step [2] of the present invention, the reaction can be performed at a safer temperature (−20 to 40 ° C.). . In step [b], recrystallization was required to increase the optical purity of the target compound. On the other hand, in step [2] of the present invention, a compound having high optical activity can be obtained without recrystallization.
[0073]
(2R) -2 obtained by steps [c] and [d] using N- (2S- (2-propenyl) octanoyl)-(1S)-(−)-2,10-camphorsultam. -Propyloctanoic acid retains high optical purity (99% ee) but its chemical yield is low (59.3%). In addition, (2R) -2-propyloctanoic acid obtained by steps [e] and [f] has a slightly better chemical yield (74%) than the above step, but has a low optical purity (95.2% ee). ). On the other hand, the target compound obtained by the two steps of step [3] and step [4] of the present invention and the two steps of step [5] and step [6] has high chemical yield and optical purity, According to the examples, both have a chemical yield of 95% and an optical purity of 97%.
[0074]
Furthermore, it has been found that the recovery rate of camphor sultam represented by formula (II) recovered in step [d] or step [e] is very low, being 30% or less. On the other hand, (R)-(+)-4-benzyl-2-oxazolidinone recovered in the steps [4] and [5] of the present invention is very high at 97% and 94%, respectively.
[0075]
JP-A-8-291106 describes examples represented by the following reaction process formula (B).
[0076]
Embedded image
[0077]
In the above method, three steps are required to produce (2R) -2-propyloctanoic acid. The chemical yield of the target compound obtained by this method is very poor (12%) and the optical purity (90% ee) is also very low. On the other hand, in the present invention, (2R) -2-propyloctanoic acid having high chemical yield (62%) and high optical purity (99.5% ee) is obtained in two steps [7] and [8]. Can be obtained.
[0078]
Moreover, the said specification also describes the manufacturing method which uses (2RS) -2-propyloctanoic acid as a starting material as a comparison with the invention. However, the optical purity (82.0% ee) of the target (2R) -2-propyloctanoic acid obtained by this reaction is very low, and the chemical yield (9%) is very poor.
[0079]
【Example】
Hereinafter, although an example explains the present invention in detail, the present invention is not limited to these.
[0080]
The point of separation by chromatography and the solvent in parentheses shown in TLC indicate the elution solvent or developing solvent used, and the ratio indicates the volume ratio.
[0081]
The solvent in parentheses shown in the NMR part indicates the solvent used for the measurement.
Reference example 1
(4R) -N-octanoyl-4-benzyl-2-oxazolidinone
Embedded image
[0083]
To a solution of (R)-(+)-4-benzyl-2-oxazolidinone (0.43 g) in tetrahydrofuran (8.60 ml) was added potassium t-butoxide (0.27 g) and octanoyl chloride (0. 44 ml) was added sequentially. The mixture was stirred for 5 minutes under ice-cooling, followed by 5 minutes at room temperature, and then water was added. The solvent was concentrated and the residue was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to quantitatively obtain the title compound having the following physical properties.
TLC: Rf 0.34 (hexane: ethyl acetate = 5: 1);
NMR (300 MHz, CDCl 3 ): δ 0.89 (3H, t, J = 6.8 Hz), 1.20-1.45 (8H, m), 1.59-1.76 (2H, m), 2.77 (1H, dd, J = 9.6, 13.6 Hz), 2.81-3.04 (2H, m), 3.31 (1H, dd, J = 3.2, 13.6 Hz), 4.06-4.23 (2H, m), 4.62-4.72 (1H, m), 7.19-7.39 (5H , m).
Example 1
(4R) -N-[(2S) -2- (2-propenyl) octanoyl] -4-benzyl-2-oxazolidinone
Embedded image
[0085]
Under an argon atmosphere, the compound prepared in Reference Example 1 (419.7 mg) was dissolved in anhydrous tetrahydrofuran (8.38 ml). To the solution at −15 ° C. was slowly added 1M lithium hexamethyldisilazane in tetrahydrofuran (1.60 ml). Stir at the same temperature for 30 minutes. Allyl iodide (310 μl) was added to the reaction solution and stirred for 30 minutes. The reaction solution was adjusted to pH 1 with 1N hydrochloric acid, warmed to room temperature, concentrated, and extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give the title compound (418.0 mg; yield 88%) having the following physical data.
TLC: Rf 0.54 (hexane: ethyl acetate = 5: 1);
NMR (400 MHz, CDCl 3 ): δ 0.88 (3H, t, J = 6.8 Hz), 1.19-1.36 (8H, brs), 1.43-1.55 (1H, m), 1.66-1.78 (1H, m), 2.27 -2.38 (1H, m), 2.41-2.52 (1H, m), 2.66 (1H, dd, J = 10.0, 13.0 Hz), 3.30 (1H, dd, J = 3.0, 13.0 Hz), 3.87-3.96 (1H , m), 4.11-4.21 (2H, m), 4.65-4.73 (1H, m), 5.04 (1H, dd, J = 1.2, 10.0 Hz), 5.08 (1H, dd, J = 1.2, 17.0 Hz), 5.77-5.89 (1H, m), 7.21-7.36 (5H, m).
Example 2
(4R) -N-[(2R) -2-propyloctanoyl] -4-benzyl-2-oxazolidinone
Embedded image
[0087]
To a solution of the compound prepared in Example 1 (290 mg) in ethanol (5.8 ml) was added 10% palladium carbon (29 mg), and the mixture was vigorously stirred for 1 hour in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated to quantitatively obtain the title compound having the following physical property values.
TLC: Rf 0.60 (hexane: ethyl acetate = 5: 1);
NMR (400 MHz, CDCl 3 ): δ 0.88 (3H, t, J = 6.8 Hz), 0.93 (3H, t, J = 6.8 Hz), 1.20-1.32 (8H, brs), 1.32-1.42 (2H, m ), 1.44-1.55 (2H, m), 1.65-1.76 (2H, m), 2.70 (1H, dd J = 9.6, 13.0 Hz), 3.33 (1H, dd, J = 3.6, 13.0 Hz), 3.76-3.85 (1H, m), 4.12-4.21 (2H, m), 4.66-4.73 (1H, m), 7.21-7.37 (5H, m).
Example 3
(2R) -2-propyloctanoic acid
Embedded image
[0089]
To a solution of the compound prepared in Example 2 (145 mg) in ethylene glycol dimethyl ether (2.9 ml) was added 30% aqueous hydrogen peroxide (72 μl) under ice-cooling, followed by 40% aqueous benzyltrimethylammonium hydroxide (265 μl). ) Was gradually added and stirred for 30 minutes. To the reaction solution was added 1.5N aqueous sodium sulfite solution (423 μl), and the temperature was raised to room temperature. The reaction solution was adjusted to pH 1 with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified by column chromatography (Dowex 1X2 (OH-type) 200-400 mesh 2.1cc) (methanol: water = 1: 1 → methanol: 1N hydrochloric acid = 1: 1) (R )-(+)-4-benzyl-2-oxazolidinone (72.2 mg; recovery rate 97%) and the title compound (70.7 mg; yield 95%) having the following physical properties were obtained.
TLC: Rf 0.48 (hexane: ethyl acetate = 5: 1);
Optical purity: 97.0% ee (HPLC);
[Α] D −6.6 ° (c = 0.78, ethanol);
NMR (400 MHz, CDCl 3 ); δ 0.88 (3H, t, J = 6.8 Hz), 0.93 (3H, t, J = 6.8 Hz), 1.20-1.53 (12H, m), 1.56-1.68 (2H, m ), 2.31-2.41 (1H, m).
Example 4
(2S) -2-propenyloctanoic acid
Embedded image
[0091]
To a solution of the compound prepared in Example 1 (165.9 mg) in ethylene glycol dimethyl ether (3.3 ml) was added 30% aqueous hydrogen peroxide solution (82 μl) under ice cooling, followed by 40% aqueous benzyltrimethylammonium hydroxide solution. (300 μl) was gradually added and stirred for 30 minutes. To the reaction solution was added 1.5N aqueous sodium sulfite solution (480 μl), and the temperature was raised to room temperature. The reaction solution was adjusted to pH 1 with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified by column chromatography (Dowex 1X2 (OH-type) 200-400 mesh 2.5cc) (methanol: water = 1: 1 → methanol: 1N hydrochloric acid = 1: 1) (R )-(+)-4-benzyl-2-oxazolidinone (79.1 mg; 94% recovery) and the title compound (84.6 mg; 95% yield) having the following physical properties were obtained.
TLC: Rf 0.40 (hexane: ethyl acetate = 5: 1);
NMR (400 MHz, CDCl 3 ): δ 0.89 (3H, t, J = 6.8 Hz), 1.29 (8H, brs), 1.46-1.57 (1H, m), 1.57-1.69 (1H, m), 2.20-2.30 (1H, m), 2.33-2.43 (1H, m), 2.41-2.50 (1H, m), 5.04 (1H, dd, J = 1.6, 10.0 Hz), 5.09 (1H, dd, J = 1.6, 16.8 Hz ), 5.77 (1H, ddt, J = 6.8, 10.0, 16.8 Hz).
Example 5
(2R) -2-propyloctanoic acid
Embedded image
[0093]
To a solution of the compound prepared in Example 4 (45.0 mg) in ethanol (0.90 ml) was added 10% palladium carbon (4.5 mg), and the mixture was vigorously stirred for 1 hour in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated to quantitatively obtain the title compound having the following physical property values.
TLC: Rf 0.48 (hexane: ethyl acetate = 5: 1);
[Α] D −6.4 ° (c = 0.90, ethanol);
NMR (400 MHz, CDCl 3 ); δ 0.88 (3H, t, J = 6.8 Hz), 0.93 (3H, t, J = 6.8 Hz), 1.20-1.53 (12H, m), 1.56-1.68 (2H, m ), 2.31-2.41 (1H, m).
Example 6
(2R) -2-propyloctanoic acid
Embedded image
[0095]
(R)-(+)-Phenylethylamine (175.3 μl) was added to the compound prepared in Example 3 (242.3 mg; 97.0% ee (HPLC)). N-Hexane (0.60 ml) was added to the precipitated needle crystals and heated to 60 ° C. with stirring to dissolve the crystals. Then, it left still at 25 degreeC for 1.5 hours. The precipitated crystals were gently washed 3 times with n-hexane (0.4 ml). The obtained crystals were dried to give the title compound (341.0 mg; yield 85%). The obtained crystals were recrystallized with n-hexane (0.6 ml) in the same manner as described above. The crystals were acidified with 1N hydrochloric acid and extracted with n-hexane. The organic layer was dried over anhydrous magnesium sulfate and concentrated to obtain the title compound (248.2 mg; yield 62%) having the following physical properties.
Optical purity: 99.5% ee (HPLC).
[Effect of the present invention]
According to the production method of the present invention, a novel intermediate compound represented by the general formula (I-1) and the intermediate compound represented by the general formula (I-2) having high optical purity can be used safely by using an inexpensive reagent. Could be manufactured at temperature.
[0096]
Further, in the present invention, since a reagent having a high recovery rate is used, the step [3] and the step [4], the step [5], or the novel intermediate compound represented by the general formula (I-1) is efficiently used without waste. Through the operations of Step [5] and Step [6], the target compound represented by the general formula (V) could be produced with high chemical yield and high optical purity.
[0097]
Furthermore, the resulting compound represented by the general formula (V) is converted into an optically active amine salt, and then recrystallized and treated with an acid to chemistry the compound represented by the general formula (V) with higher optical purity. It was possible to produce with good yield.
[0098]
From these facts, the production method of the present invention is a method suitable for synthesizing an optically active compound represented by the general formula (V) having high optical purity, and a method suitable for industrial mass synthesis. It is.

Claims (18)

  1. Formula (I)
    (Wherein R 1 represents propyl, 2-propenyl or 2-propynyl, and R 2 represents C4-8 alkyl).
  2. The compound of claim 1, wherein R 1 is propyl.
  3. The compound according to claim 1, wherein R 1 is 2-propenyl.
  4. The compound according to claim 1, wherein R 1 is 2-propynyl.
  5.   The compound according to claim 1, wherein the compound is (4R) -N-[(2R) -2-propyloctanoyl] -4-benzyl-2-oxazolidinone.
  6.   The compound according to claim 1, wherein the compound is (4R) -N-[(2S) -2- (2-propenyl) octanoyl] -4-benzyl-2-oxazolidinone.
  7.   The compound according to claim 1, wherein the compound is (4R) -N-[(2S) -2- (2-propynyl) octanoyl] -4-benzyl-2-oxazolidinone.
  8.   The compound according to claim 1, wherein the compound is (4R) -N-[(2R) -2-propylheptanoyl] -4-benzyl-2-oxazolidinone.
  9.   The compound according to claim 1, wherein the compound is (4R) -N-[(2S) -2- (2-propenyl) heptanoyl] -4-benzyl-2-oxazolidinone.
  10.   The compound according to claim 1, wherein the compound is (4R) -N-[(2S) -2- (2-propynyl) heptanoyl] -4-benzyl-2-oxazolidinone.
  11.   The compound according to claim 1, wherein the compound is (4R) -N-[(2R) -2-propylhexanoyl] -4-benzyl-2-oxazolidinone.
  12.   The compound according to claim 1, wherein the compound is (4R) -N-[(2S) -2- (2-propenyl) hexanoyl] -4-benzyl-2-oxazolidinone.
  13.   The compound according to claim 1, wherein the compound is (4R) -N-[(2S) -2- (2-propynyl) hexanoyl] -4-benzyl-2-oxazolidinone.
  14. General formula (III)
    (Wherein all symbols have the same meaning as in claim 1), and a compound of the general formula (IV)
    Wherein R 1-1 represents 2-propenyl or 2-propynyl, and X represents a halogen atom. The compound represented by the general formula (I-1)
    (Wherein all symbols have the same meaning as in claim 1).
  15. General formula (I-1)
    (Wherein all symbols have the same meanings as in claim 1), the compound represented by the general formula (I-2)
    (Wherein all symbols have the same meaning as in claim 1).
  16. General formula (I-2)
    (Wherein all symbols have the same meaning as in claim 1), the compound represented by the general formula (V-2)
    (Wherein all symbols have the same meaning as in claim 1).
  17. General formula (I-1)
    (Wherein all symbols have the same meaning as in claim 1), the compound represented by the general formula (V-1)
    (Wherein all symbols have the same meaning as in claim 1).
  18. General formula (V)
    (Wherein all symbols have the same meaning as in claim 1). An optically active amine is reacted with the compound represented by the above formula, the resulting salt is recrystallized, and then acid-treated. A method for producing a compound represented by the general formula (V) having high optical purity.
JP2001385621A 2001-12-19 2001-12-19 Novel intermediate compound and method for manufacturing compound by using the same Pending JP2005298334A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2001385621A JP2005298334A (en) 2001-12-19 2001-12-19 Novel intermediate compound and method for manufacturing compound by using the same

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JP2001385621A JP2005298334A (en) 2001-12-19 2001-12-19 Novel intermediate compound and method for manufacturing compound by using the same
AU2002359990A AU2002359990A1 (en) 2001-12-19 2002-12-18 Intermediate and process for producing optically active compound from the intermediate
PCT/JP2002/013236 WO2003051852A1 (en) 2001-12-19 2002-12-18 Intermediate and process for producing optically active compound from the intermediate

Publications (1)

Publication Number Publication Date
JP2005298334A true JP2005298334A (en) 2005-10-27

Family

ID=19187858

Family Applications (1)

Application Number Title Priority Date Filing Date
JP2001385621A Pending JP2005298334A (en) 2001-12-19 2001-12-19 Novel intermediate compound and method for manufacturing compound by using the same

Country Status (3)

Country Link
JP (1) JP2005298334A (en)
AU (1) AU2002359990A1 (en)
WO (1) WO2003051852A1 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007094404A1 (en) * 2006-02-16 2007-08-23 Sumitomo Chemical Company, Limited Process for production of optically active carboxylic acid compound
JP2009530256A (en) * 2006-03-17 2009-08-27 シプラ・リミテッド 4- [1- (4-Cyanophenyl) -1- (1,2,4-triazol-1-yl) methyl] benzonitrile and 4- [1- (1H-1,2,4-triazole-1- Yl) methylenebenzonitrile intermediate

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005105722A1 (en) 2004-04-28 2005-11-10 Ono Pharmaceutical Co., Ltd. Crystal comprising (2r)-2-propyloctoic acid and amine
EP2072047A1 (en) 2005-03-15 2009-06-24 Ono Pharmaceutical CO., LTD. Therapeutic agent for opthalmic disease
JP5050851B2 (en) 2005-06-27 2012-10-17 小野薬品工業株式会社 Pain treatment
EP1938814A4 (en) 2005-10-18 2009-06-03 Ono Pharmaceutical Co Pharmaceutical for protection of motor nerve in patient with amyotrophic lateral sclerosis
US20090203783A1 (en) 2005-12-22 2009-08-13 Ono Pharmaceutical Co., Ltd. Therapeutic agent for acute cerebral infarct

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS55147236A (en) * 1979-05-08 1980-11-17 Hiroyuki Nohira Optical resolution of ( )-mandelic acid
US5672746A (en) * 1994-08-30 1997-09-30 American Biogenetic Sciences, Inc. Antiproliferative and neurotrophic molecules
TW509672B (en) * 1998-05-12 2002-11-11 Ono Pharmaceutical Co Novel intermediate compounds and processes for the production of optical active octanoic acid derivatives
TWI268921B (en) * 1999-02-18 2006-12-21 Ono Pharmaceutical Co A process for preparing (2R)-2-propyloctanoic acid

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007094404A1 (en) * 2006-02-16 2007-08-23 Sumitomo Chemical Company, Limited Process for production of optically active carboxylic acid compound
JP2009530256A (en) * 2006-03-17 2009-08-27 シプラ・リミテッド 4- [1- (4-Cyanophenyl) -1- (1,2,4-triazol-1-yl) methyl] benzonitrile and 4- [1- (1H-1,2,4-triazole-1- Yl) methylenebenzonitrile intermediate

Also Published As

Publication number Publication date
AU2002359990A1 (en) 2003-06-30
WO2003051852A1 (en) 2003-06-26

Similar Documents

Publication Publication Date Title
Barrow et al. Total synthesis of cryptophycins. Revision of the structures of cryptophycins A and C
RU2433122C2 (en) Synthesis of acylaminoalkenylamides, suitable as antagonists of substance p
EP0674618B1 (en) Asymmetric process for preparing florfenicol, thiamphenicol, chloramphenicol and oxazoline intermediates
EP2049464B1 (en) Preparation of 3-[(1r,2r)-3-(dimethylamino)-1ethyl-2-methylpropyl]phenol
EP0812827B1 (en) Piperidine derivative as intermediates for the preparation of paroxetine and process for their preparation
JP4770174B2 (en) Process for producing glutamic acid derivative and pyroglutamic acid derivative, and novel production intermediate
US7309803B2 (en) Clean, High-yield preparation of S,S and R,S amino acid isosteres
US7851651B2 (en) Asymmetric synthesis of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid
KR20050113292A (en) Process for the preparation of optically pure 4-hydroxy-2-oxo-1-pyrrolidineacetamide
JP2002265444A (en) 1-(3-benzyloxypropyl)-5-(2-substituted propyl) indoline derivative and method for using the same
JPH07116179B2 (en) R - (+) - α- lipoic acid and S - (-) - Preparation of alpha-lipoic acid
JPH09316072A (en) Production of paroxetine
CN1268611C (en) Method of preparing 4-hydroxy pyrrolidone-2-acetamine
CN1144796C (en) Noval intermediates and process for producing optically active octanoic acid derivatives
CN103121995A (en) 3-alkyl-5- (4-alkyl-5-oxo-tetrahydrofutran-2-yl) pyrrolidin-2-one derivatives as intermediates in the synthesis of renin inhibitors
JP2005500322A (en) Method for producing 3-phenylisoserine
JPH07215921A (en) Production of pesticide and intermediate
JP2003515578A (en) A new production method
EP0406112B1 (en) 1-Benzhydrylazetidines, their preparation and their use as intermediates for the preparation of compounds with antimicrobial activity
KR101719011B1 (en) Method for synthesis of (1S, 2R)-MILNACIPRAN
US20090088577A1 (en) Production of monatin enantiomers
JPH0623150B2 (en) The process for producing an optically active 3-hydroxybutanoic acid
JPH0776209B2 (en) The process for producing an optically active 3-hydroxypyrrolidine derivatives
JPH06234715A (en) Production of alanylglutamine
JPH11310556A (en) Novel process for producing 2-amino-2-(2-(4octylphenyl) ethyl) propane-1,3-diol