WO2003051852A1 - Intermediate and process for producing optically active compound from the intermediate - Google Patents

Intermediate and process for producing optically active compound from the intermediate Download PDF

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Publication number
WO2003051852A1
WO2003051852A1 PCT/JP2002/013236 JP0213236W WO03051852A1 WO 2003051852 A1 WO2003051852 A1 WO 2003051852A1 JP 0213236 W JP0213236 W JP 0213236W WO 03051852 A1 WO03051852 A1 WO 03051852A1
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compound
general formula
symbols
compound represented
oxazolidinone
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PCT/JP2002/013236
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French (fr)
Japanese (ja)
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Kuniaki Tatsuta
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Ono Pharmaceutical Co., Ltd.
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Priority to JP2001385621A priority Critical patent/JP2005298334A/en
Priority to JP2001-385621 priority
Application filed by Ono Pharmaceutical Co., Ltd. filed Critical Ono Pharmaceutical Co., Ltd.
Publication of WO2003051852A1 publication Critical patent/WO2003051852A1/en

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    • 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

An intermediate represented by the general formula (I): (I) (wherein R1 represents propyl, 2-propenyl, or 2-propinyl and R2 represents C4-8 alkyl); a process for producing the intermediate; and a process for producing from the intermediate an optically active compound represented by the general formula (V). (V) By the process, a compound having a high optical purity and represented by the general formula (V) can be efficiently produced at low cost in a high chemical yield.

Description

 Description Intermediate compound and method for producing optically active compound using the compound

 The present invention relates to a novel intermediate compound, a method for producing the same, and a method for producing an optically active compound using the intermediate compound.

 More specifically, (1) general formula (I)

(Wherein all symbols have the same meanings as described below.)

 (2) its manufacturing method, and

 (3) Optically active general formula (V) using the intermediate compound

R 1

 (V)

 , COOH (in the formula, all symbols have the same meanings as described below). Background art

General formula (V) produced by the present invention R,

 (V)

R 2 , COOH

(In the formula, all symbols have the same meanings as described below.) Of the compounds represented by, (2R) -2-propyloctanoic acid and (2S) -2-propielheptanic acid are used as pharmaceuticals. It is a useful compound. For example, in the case of (2R) -2-pyructylpyructoic acid, the racemic compound thereof is used as a therapeutic or prophylactic agent for a neurological disease due to astrocyte dysfunction, as described in Example 7 (33) of EP632008. It is described in. For (2S) -2-propynylheptanoic acid, its racemate is described as a neurotrophic factor in Example 2 of US5672746.

 In particular, as a result of subsequent research, 2-propyloctanoic acid was found to have a particularly potent R form and low toxicity, and various studies have been conducted on methods for efficiently obtaining optically active R forms. Was.

 As a method for producing (2R) -2-propyloctanoic acid, for example, (1) Japanese Patent No. 3032447 discloses an optical method using a salt of racemic 2- (2-probyl) octanoic acid and an optically active amine. A method is described in which an optically active salt is separated by resolution, and after acid treatment, the obtained optically active (2S) -2- (2-probyl) octanoic acid is reduced. However, the target compound obtained by this reaction had poor chemical yield (12%) and optical purity (90.0% e.e.), And was not a practical method.

 (2) Japanese Patent No. 3084345 describes a method using optically active prolinol. Although the optical purity of (2R) -2-propyloctanoic acid obtained by this method is 96.0% ee, it requires five steps of reaction to reach the target compound, and the yield is low. 20.2%) was not a practical method.

(3) In the specification of W099 / 58513, (2R) -2-propyloctane is produced in four steps via a novel intermediate obtained by reacting octanoic acid with camphorsultam. A method for producing acid is described. N- (2S- (2-Provenyl) octanoyl) one (1S) — (—)-2,10—Camphor sultam is a new intermediate (2R) —2-propyl octane There are two processes for producing the acid, and the optical purity of the target compound obtained by those reactions is 95.2% ee and 99% ee, respectively. However, the overall process yield before producing the target compound was 53% and 42.5%, respectively. In addition, ethanol sultam, which is used as a raw material, is an expensive reagent, and the recovery rate during the reaction is less than 30%. Since it is almost impossible to reuse it, it is wasteful and inefficient. The specification also discloses that (2R) -2-propyloctanoic acid is produced from N- (2S- (2-propiel) otatanyl) 1 (1S)-(-)-2,10-camphorsultam. The process is also described, but has the same problems as described above.

 (4) WO00 / 48982 discloses that a platinum-carbon catalyst is prepared from (2S) —2- (2-propenyl) octanoic acid or (2S) —2- (2-propyl) octanoic acid. To produce (2R) -2-propyloctanoic acid by catalytic reduction.

 Therefore, there is a demand for a production method capable of obtaining a compound represented by the general formula (V), which is highly useful as a pharmaceutical, in both chemical yield and optical purity. Disclosure of the invention

The present inventors have conducted intensive studies and found that the use of optically active (R)-(+) — 4-^^-zir-12-oxazolidinone yields the general formula (I)

(In the formula, all symbols have the same meanings as described below.) A new compound represented by the following formula was successfully obtained. In addition, the new compound has high chemical activity (over 80% total synthesis yield) and high optical purity (over 97.0%).

(V)

R 1

 (V)

 COOH

(Wherein all symbols have the same meanings as described below.).

 Further, the compound represented by the general formula (V) having a higher optical purity (99.0% or more) can be obtained by reacting the compound represented by the general formula (V) with an optically active amine salt, recrystallizing it, and then treating with an acid. And succeeded in completing the present invention.

 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 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, the reaction can be carried out more efficiently at a lower cost and without waste.

That is, the present invention provides a novel intermediate compound represented by the general formula (I), a method for producing the same, and an optically active general formula (V) using the intermediate compound. The present invention relates to a method for producing a compound.

 For details, (1) General formula (I)

(Wherein, R 1 represents propyl, 2-propynyl or 2-propynyl, and R 2 represents C 4-8 alkyl.)

(2) —In the general formula (I), R 1 is propyl and R 2 is hexyl. (4R) — N-[(2R) — 2-propylotatanyl] —4-benzyl-1 2-oxazolidinone,

(3) In the general formula (I), R 1 is 2-propenyl and R 2 is hexyl. (4 R) -N-[(2 S) 1 2— (2-propenyl Ottatanyl] —4-benzyl-1-oxazolidinone,

(4) In the general formula (I), R 1 is 2-probyl and R 2 is hexyl. (4 R) -N-[(2S) -1- (2-propynyl) octanoyl] —4 —Benzil 2-oxazolidinone,

(5) —In the general formula (I), R 1 is propyl, and R 2 is pentyl. (4R) -N-[(2R) _2-propylheptanoyl] -14-benzyl_2-oxa Zolidinone,

(6) —In the general formula (I), R 1 is 2-propenyl and R 2 is pentyl. (4 R) -N-[(2 S) 1 2— (2-propenyl) Heptanoyl] 1-4-benzyl-1-2-oxazolidinone,

(7) —In the general formula (I), R 1 is 2 _probyl and R 2 is pentyl. (4 R) -N-[(2 S) 1 2— (2-propynyl) heptanyl] —4 One ben 1-zil 2-oxazolidinone,

(8) —In the general formula (I), R 1 is propyl and R 2 is butyl. (4R) -N-[(2R) -12-propylhexanoinole] — 4-pentinolele 2-oxazolidinone ,

(9) —In general formula (I), R 1 is 2-propenyl and R 2 is butyl. (4R) -N-[(2S) -2- (2-propenyl) Xanosyl] —4-benzinole—2-oxazolidinone,

(10) —In the general formula (I), R 1 is 2-probyl and R 2 is butyl. (4R) -N-[(2S) —2— (2-probyl) hexanoyl] —4 —Benzyl-2-oxazolidinone,

 (11) General formula (III)

(Wherein all symbols have the same meanings as described above.) And a compound represented by the general formula (IV)

R 1 " 1 — X (IV)

(Wherein, R 11 represents 2-propenyl or 2-provyl, and X represents a halogen atom.) A compound represented by the general formula (1- 1)

(Wherein all symbols have the same meanings as described above.)

 (12) —General formula (1-1)

Wherein all symbols have the same meanings as described above. A compound represented by the general formula (1-2):

(Wherein all symbols have the same meanings as described above.)

(13) —General formula (1-2)

(Wherein all symbols have the same meanings as described above.) A compound represented by the general formula (V-2):

(Wherein all symbols have the same meanings as described above.)

 (14) General formula (1-2)

(Wherein all symbols have the same meanings as described above.) The compound represented by the general formula (V-2)

(Wherein all symbols have the same meanings as described above.), Wherein the compound (V-2) is reacted with an optically active amine, and the obtained salt is recrystallized and then treated with an acid. Of compound of general formula (V-2) with higher optical purity Method,

 (15) —General formula (1-1)

(Wherein all symbols have the same meanings as described above.) A compound represented by the formula (V-1):

R,

 (V-1)

 COOH

Wherein all symbols have the same meanings as described above.

(16) —General formula (1-1)

(1-1)

(Wherein all symbols have the same meanings as described above.) The compound represented by the general formula (V-1) is hydrolyzed.

 , 1-1

 (V-1)

 R, COOH

(Wherein all symbols have the same meanings as described above.), And the compound (V-1) To a compound represented by the general formula (V-1) having a higher optical purity, characterized by reacting the compound with an optically active amine, recrystallizing the obtained salt, and then treating with an acid.

In the present invention, propyl, 2-propinyl and 2-propynyl represented by R 1 are all preferred.

In the present invention, the C 4 to 8 alkyl R 2 represents butyl, pentyl, carboxymethyl Le, heptyl, include Okuchiru or isomers thereof to, arbitrarily favored either.

In the present invention, all possible combinations of R 1 and R 2 are preferred. Specifically, R 1 is propyl and R 2 are butyl, R 1 is propyl, 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-propyl and R 2 are pentyl, R 1 is 2-propenyl and R 2 is hexyl, R 1 is 2-propyl and R 2 is butyl, R 1 is 2-propyl and R 2 is pentyl, or R 1 is 2-probyl 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 is butyl, R 1 is 2-propynyl and R 2 Is pentyl, or R 1 is 2-propynyl and R 2 is hexyl.

The novel intermediate represented by the general formula (I) of the present invention and a method for producing the compound represented by the general formula (V) using the same are represented by the following reaction step formulas (1) and (2). Reaction process formula (1)

 (Π) (1-1)

 (ΠΙ)

Process [3]

 Process [5]

(V-l)

Reaction process formula (2)

R,

, COOH + H 3 NR 3

 (V) Process [8]

R 1

 (V)

R'z ヽ COOH In the reaction scheme, B n represents benzyl, and NH 2 —R 3 represents an optically active amine.

 The reaction of the step [1] is known, and for example, a base (tertiary tertiary) in an organic solvent (tetrahydrofuran, getyl ether, N, N-dimethyl honolemamide, dimethoxetane, diethylene glycol dimethyl ether, toluene, etc.) Amine (triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, etc.), butyllithium, lithium diisopropylamide, lithium hexamethyldisilazane, sodium hydride, potassium hydride, potassium t-butoxy, lithium The reaction is carried out at 120 to 40 ° C in the presence of t-butoxide.

 The reaction in the step [2] is known, and examples thereof include organic solvents (tetrahydrofuran, getinoleether, benzene, dimethyloxetane, hexane, toluene, 1,3-dimethyl-12-imidazolidinone, hexamethylphosphate triamide Medium, base (lithium hexamethyldisilazane, sodium hexamethyldisilazane, potassium hexamethyldisilazane, n-butyllithium, s-butyllithium, lithium diisopropylamide, potassium t-butoxide, lithium t-butoxide) The reaction is carried out at 120 to 40 ° C in the presence. The compound (1-1) obtained by this reaction is a novel compound.

 The reduction reaction of the step [3] is known, and for example, a method of catalytic reduction is described in WO99 / 58513 and WO00 / 48982.

Specifically, for example, in an organic solvent (methanol, ethanol, isopropanol, tetrahydrofuran, ethyl acetate, tetrahydropyran, dioxane, dimethoxetane, getyl ether, acetic acid, or a mixed solvent thereof), under a hydrogen atmosphere, a catalyst (Palladium carbon, palladium, platinum, platinum carbonate, platinum oxide, nickel, palladium hydroxide, rhodium, rhodium carbon, ruthenium, ^^ Tenium Carbon Co., Ltd. Tris (triphenylinolephosphine) The reaction is carried out at 0 to 60 ° C. using rhodium or the like. The compound (1-2) obtained by this reaction is a novel compound.

 The hydrolysis reaction in step [4] is known. For example, a peracid (hydrogen peroxide, t-butyl hydroperoxide, or an aqueous solution thereof) in an organic solvent (tetrahydrofuran, ethylene glycol dimethyl ether, etc.) Etc.) In the presence or absence of tetraalkylammonium hydroxide (benzyltrimethylammonium hydroxide, tetraethylammonium hydroxide, tetraisopropylammonium hydroxide, tetrabutylammonium hydroxide, hydroxide) The reaction is carried out at a temperature of 20 to 40 ° C using tetraoctyl ammonium or an aqueous solution thereof.

 Step [5] is performed in the same manner as in the above step [4], but a compound having an excessive amount of a double bond (eg, 2-methyl-12-butene) may be used.

 Step [6] is performed by the same operation as in step [3] described above.

 By operating according to the above reaction scheme (1), a novel compound represented by the general formula (1-1) and a novel compound represented by the general formula (1-2) 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, which is useful as a pharmaceutical.

In the step [7], the compound represented by the general formula (V) and an optically active amine [(R)-(+)-1-phenethylamine, (R)-(+)-1- (4-methylphenyl) ethylamine , L-arginine, 2R-aminobutanol, (S)-(-)-nicotine, hydrodrucine, dehydrohabiethylamine, (1S, 2S)-methylpseuedephedrine, (1R, 2S )-(1) 1-norefedrine, L-tyrosine, (1) cis-benzyl-1 (2-hydroxymethylcyclohexyl) amine, (S) — (-) — 1-methyl-12-pyrrolidine Methanol, etc.].

 During this step, the preferred optically active amine is (R)-(+)-1-phenethylamine.

 In the step [8], the crystals obtained in the step [7] are recrystallized with an organic solvent (eg, n-hexane, n-heptane, etc.), and then the acid (hydrochloric acid, nitric acid, hydrobromic acid, acetic acid, trifluoromethane) is added. Acetic acid, methanesulfonic acid, etc.).

 By operating according to the above reaction scheme (2), a compound represented by the general formula (V) having a higher optical purity than that produced by the reaction scheme (1) can be obtained in a higher chemical yield. .

 On the other hand, the following reaction step formula (A) is described in the specification of W099 / 58513.

 Reaction process formula (A)

In Scheme, Y represents OH or C 1, R A represents a 2-propenyl or 2-Purobyuru.

However, the above process has the following problems. The camphor sultam of formula (II) used in step [a] is very expensive. In contrast, (R)-(+) — 4-benzyl-12-oxazolidinone used in step [1] of the present invention can be obtained at a much lower cost.

 In step [b], the reaction had to be carried out at a temperature of -78 ° C. In step [2] of the present invention, the reaction had to be carried out at a safer temperature (−20 to 40 ° C). Can be. In step [b], recrystallization was required to increase the optical purity of the target compound. In contrast, in the step [2] of the present invention, a compound having high optical activity can be obtained without performing recrystallization.

 N- (2S- (2-Propenyl) octanoyl) 1 (1S) — (—) Using 2,10-camphorsultam, obtained by step [c] and step [d] ( 2R) _2-Propyloctanoic acid retains high optical purity (99% ee) but low chemical yield (59.3%). Also, (2R) _2-propyloctanoic acid obtained by the step [e] and the step [f] has a slightly higher chemical yield (74%) than that of the above step, but a lower optical purity (95.2% ee). ). On the other hand, the target compound obtained by the two steps of the step [3] and the step [4] and the step [5] and the step [6] of the present invention has a chemical yield and an optical purity. Both are high, and according to the examples, both have a chemical yield of 95% and an optical purity of 97%.

 Furthermore, it has been found that the recovery rate of the potassium sultam represented by the formula (II) recovered in the step [d] or the step [e] is very low, being 30% or less. In contrast, the (R)-(+)-14-benzyl-2-oxazolidinone recovered in the step [4] and the step [5] of the present invention is as high as 97% and 94%, respectively.

Further, JP-A-8-291106 describes an example represented by the following reaction step formula (B). Reaction process formula (B)

 HC1

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 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 of step [7] and step [8]. Can be obtained.

 The above specification also describes a production method using (2RS) -2-propyloctanoic acid as a starting material for comparison with the invention. However, the optical purity (82.0% e.e.) of the desired (2R) -2-propyloctanoic acid obtained by this reaction is very low, and the chemical yield (9%) is very poor. BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited thereto.

 The solvent in the kakkou indicated by the chromatographic separation and TLC indicates the elution solvent or developing solvent used, and the ratio indicates the volume ratio.

The solvent in kakkoko shown in the NMR section indicates the solvent used for the measurement. Reference example 1

 (4R) —N-octanoyl-1-4-benzyl-2-oxazolidinone

(R)-(+) — In a solution of 4-benzyl-12-oxazolidinone (0.43 g) in tetrahydrofuran (8.60 ml), add potassium t-butoxide (0.27 g) and otanoyl chloride (0.44 ml) under ice-cooling. ) Was added sequentially. The mixture was stirred under water cooling for 5 minutes, then at room temperature for 5 minutes, and then water was added. The solvent was concentrated, and the residue was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated to give the title compound having the following physical properties quantitatively.

TLC: R f 0.34 (hexane: ethyl acetate = 5: 1);

NMR (300 MHz, CDC1 3) : δ 0.89 (3Η, 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

(4 R) -N- [(2 S) —2— (2-Propenyl) octanoyl] —4-1-benzyl Λ ^ — 2-oxoxolidinone

Under an argon atmosphere, the compound (419.7 mg) produced in Reference Example 1 was dissolved in anhydrous tetrahydrofuran (8.38 ml). At 15 ° C., a 1M lithium hexamethyldisilazane tetrahydrofuran solution (1.60 ml) was gradually added to the solution. The mixture was stirred at the same temperature for 30 minutes. Aryl iodide (310 μl) was added to the reaction solution, and the mixture was stirred for 30 minutes. The reaction solution was adjusted to 1 with 1N hydrochloric acid, heated 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: R f 0.54 (hexane: ethyl acetate = 5: 1);

NMR (400 MHz, CDC1 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 (IH, m), 2.41-2.52 (IH, m), 2.66 (IH, dd, J = 10.0, 13.0 Hz), 3.30 (1H, dd, J = 3.0, 13.0 Hz), 3.87-3.96 (IH , m), 4.11-4.21 (2H, m), 4.65-4.73 (1H, m), 5.04 (IH, dd, J = 1.2, 10.0 Hz), 5.08 (IH, dd, J = 1.2, 17.0 Hz), 5.77-5.89 (1H, m), 7.21-7.36 (5H, m). Example 2

(4 R) — N— [(2 R) — 2-propylotatanyl] —4-benzyl-2-oxazolidinone

To a solution of the compound (290 mg) produced in Example 1 in ethanol (5.8 ml) was added 10% palladium on carbon (29 mg), and the mixture was vigorously stirred for 1 hour under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated to give the title compound having the following physical properties quantitatively.

 TLC: Rf 0.60 (hexane: ethyl acetate = 5: 1);

NMR (400 MHz, CDC1 3) : δ 0.88 (3Η, 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

(2 R) — 2-propyloctanoic acid To a solution of the compound (145 mg) prepared in Example 2 in ethylene glycol dimethyl ether (2.9 ml) was added a 30% aqueous hydrogen peroxide solution (72 μ1) under ice-cooling, followed by 40% An aqueous solution of benzyltrimethylammonium hydroxide (265 μl) was gradually added, and the mixture was stirred for 30 minutes. To the reaction solution was added a 1.5N aqueous solution of sodium sulfite (423 μl), and the temperature was raised to room temperature. The reaction solution was adjusted to 11 with 2Ν hydrochloric acid and extracted with ethyl acetate. The organic layer is concentrated, and the residue is Purification by chromatography (Dowex 1X2 (OH-type) 200-400 mesh 2.1cc) (methanol: water = 1: 1 → methanol: 1N hydrochloric acid = 1: 1), (R)-(+) — 4—benzyl One 2-oxazolidinone (72.2 mg; recovery 97%) and the title compound (70.7 mg; yield 95%) having the following physical data were obtained.

TLC: R f 0.48 (hexane: ethyl acetate = 5: 1);

Optical purity: 97.0 ° / oe.e. (HP LC);

[a] D -6.6 ° (c = 0.78, ethanol);

NMR (400 MHz, CDC1 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

(2 S) —2-Propenyloctanoic acid To a solution of the compound prepared in Example 1 (165.9 mg) in ethylene glycol dimethyl ether (3.3 ml) was added a 30% aqueous hydrogen peroxide solution (821) under ice-cooling, followed by 40% benzene hydroxide. An aqueous solution of dilutrimethylammonium (300 μl) was gradually added, and the mixture was stirred for 30 minutes. A 1.5N aqueous sodium sulfite solution (480/1) was added to the reaction solution, and the temperature was raised to room temperature. The reaction solution was adjusted to 1 with 2 1 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: 11 ^ hydrochloric acid = 1: 1), and ( R) — (+) — 4-Benzyl-2-oxazolidinone (79.1 mg; recovery 94%) and the title compound (84.6 mg; yield 95%) having the following physical data were obtained.

TLC: R f 0.40 (hexane: ethyl acetate = 5: 1); NMR (400 MHz, CDC1 3) : 8 0.89 (3H, t, J = 6.8 Hz), 1.29 (8H, brs), 1.46-1.57 (IH, m), 1.57-1.69 (1H, m), 2.20-2.30 (1H, m), 2.33-2.43 (IH, m), 2.41-2.50 (1H, m), 5.04 (IH, dd, J = 1.6, 10.0 Hz), 5.09 (IH, 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 To a solution of the compound (45.0 mg) produced in Example 4 in ethanol (0.90 ml) was added 10% palladium on carbon (4.5 mg), and the mixture was vigorously stirred under a hydrogen atmosphere for 1 hour. The reaction solution was filtered and the filtrate was concentrated to quantitatively obtain the title compound having the following physical properties.

 TLC: R f 0.48 (hexane: ethyl acetate = 5: 1);

[a] D -6.4 ° (c = 0.90, ethanol);

NMR (400 MHz, CDC1 3) ; δ 0.88 (3Η, 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 (IH, m). Example 6

(2 R) -2-propyloctanoic acid To the compound prepared in Example 3 (242.3 mg; 97.0% ee (HPLC)), (R)-(+)-phenylethylamine (175.3 1) was added. Add n-hexane (0.60 ml) to the precipitated needle crystals and heat to 60 ° C with stirring to dissolve the crystals. I understand. Then, it left still at 25 ° C for 1.5 hours. The precipitated crystals were gently washed three 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 in the same manner as described above using n-hexane (0.6 m 1). 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 give the title compound (248.2 mg; yield 62%) having the following physical properties.

Optical purity: 99.5% e.e. (HP LC) Industrial applicability

 According to the production method of the present invention, a novel intermediate compound having high optical purity represented by the general formula (1-1) and an intermediate compound represented by the general formula (1-2) can be produced safely by using an inexpensive reagent. Can be manufactured at temperature.

 Further, in the present invention, since a reagent having a high recovery rate is used, the new intermediate compound represented by the general formula (1-1) can be efficiently and efficiently converted from the step [3] and the step [4] to the step [5] or the step Through the operations of [5] and step [6], the target compound represented by the general formula (V) can be produced with high chemical yield and high optical purity.

 Further, the obtained compound represented by the general formula (V) is converted into an optically active amine salt, recrystallized, and treated with an acid to obtain a compound represented by the general formula (V) having a higher optical purity. It can be manufactured in good yield.

 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 also a method suitable for industrial mass synthesis. It is.

Claims

 General formula (I)
(I)
 of
(Wherein, R 1 represents propyl, 2-propenyl or 2-provyl, and R 2 represents C 4-8 alkyl.)
2. The compound according to 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-probyl.
5. The compound according to claim 1, wherein the compound is (4R) -N-[(2R) -2-propylotatanyl] -4-benzyl-2-oxazolidinone.
6. The compound according to claim 1, wherein the compound is (4R) -N-[(2S) -2- (2-propynyl) octanol] —4-benzyl-2-oxazolidinone.
7. The compound according to claim 1, wherein the compound is (4R) -N-[(2S) -2- (2-propynyl) octanol] —4-benzyl-2-oxazolidinone. Compound.
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-propynyl) heptanoyl] —4-benzyl-12-oxazolidinone.
10. The compound according to claim 1, wherein the compound is (4R) -N-[(2S) —2- (2-probyl) heptanoyl] -14-benzyl-12-oxazolidinone.
1 1. The compound according to claim 1, wherein the compound is (4R) -N-[(2R) -1-propylhexanoyl] -4-benzyl-2-oxazolidinone.
1 2. The compound according to claim 1, wherein the compound is (4R) —N — [(2S) -12- (2-propenyl) hexanoyl] -14-benzyl-12-oxazolidinone.
1 3. The compound according to claim 1, wherein the compound is (4R) -N-[(2S) —2- (2-probyl) hexanoyl] -14-benzyl-2-oxazolidinone.
14. General formula (III) (in)
(Wherein all symbols have the same meanings as in claim 1) and a compound represented by the general formula (IV)
R 1 1 — X (IV)
(Wherein, R 1 - 1 is 2-propenyl represents nil or 2-propynyl, X represents a halo gen atom.) In one general formula (ID which comprises reacting a compound represented by
(Wherein all symbols have the same meanings as in claim 1).
1 5. General formula (1-1)
(Wherein all symbols have the same meanings as in claim 1.) A compound represented by the general formula (1-2), which is subjected to a reduction reaction.
(Wherein all symbols have the same meanings as in claim 1).
1 6. General formula (1-2)
(Wherein all symbols have the same meaning as in claim 1.) A compound represented by the general formula (V-2), which is characterized by hydrolyzing a compound represented by the formula:
(Wherein all symbols have the same meanings as in claim 1).
1 7. —General formula (1-2)
(Wherein all symbols have the same meaning as in claim 1.) The compound represented by the general formula (V-2) is hydrolyzed.
(Wherein all symbols have the same meanings as in claim 1). The compound (V-2) is reacted with an optically active amine, and the obtained salt is recrystallized. A method for producing a compound represented by the general formula (V-2) having a higher optical purity.
1 8. General formula (1-1)
(Wherein all symbols have the same meaning as in claim 1.) A compound represented by the general formula (V-1), which is characterized by hydrolyzing a compound represented by the formula:
R 1
 (V-1)
R 2 COOH (Wherein all symbols have the same meanings as in claim 1).
1 9. General formula (1-1)
(Wherein all symbols have the same meaning as in claim 1.) The compound represented by the formula is hydrolyzed to obtain a compound represented by the general formula (V-1)
R 1 - 1
2 (VD
R 2 ^ COOH
(Wherein all symbols have the same meanings as in claim 1). The compound (V-1) is reacted with an optically active amine, and the obtained salt is recrystallized. A process for producing a compound represented by the general formula (V-1) having a higher optical purity.
PCT/JP2002/013236 2001-12-19 2002-12-18 Intermediate and process for producing optically active compound from the intermediate WO2003051852A1 (en)

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EP2266559A1 (en) 2005-03-15 2010-12-29 Ono Pharmaceutical Co., Ltd. Therapeutic agent for ophthalmic disease
EP2072047A1 (en) 2005-03-15 2009-06-24 Ono Pharmaceutical CO., LTD. Therapeutic agent for opthalmic disease
EP2465499A2 (en) 2005-06-27 2012-06-20 Ono Pharmaceutical Co., Ltd. Therapeutic agent for treating pain
WO2007000970A1 (en) 2005-06-27 2007-01-04 Ono Pharmaceutical Co., Ltd. Therapeutic agent for pain
WO2007046347A1 (en) 2005-10-18 2007-04-26 Ono Pharmaceutical Co., Ltd. Pharmaceutical for protection of motor nerve in patient with amyotrophic lateral sclerosis
WO2007072902A1 (en) 2005-12-22 2007-06-28 Ono Pharmaceutical Co., Ltd. Therapeutic agent for acute cerebral infarct

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