JP2001199949A - Method for synthesizing optically active compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an industrially excellent method for producing an optically active production intermediate which is useful as an intermediate for producing N,N-substituted cyclic amine derivatives useful as medicines. SOLUTION: This method for synthesizing an optically active compound, characterized by oxidizing an olefin derivative (I) with t-butylhydroperoxide in the presence of titanium tetraisopropoxide to produce the optically active epoxide derivative (II), protecting the hydroxyl group of the produced optically active epoxide derivative (II), subjecting the protected compound to a rearrangement reaction to produce the optically active aldehyde derivative (III), converting the optically active aldehyde derivative (III) into the optically active nitrile derivative (IV), subjecting the optically active nitrile derivative (IV) to a protecting group-removing reaction, a carbon increasing reaction and an oxidation reaction to produce the optically active unsaturated ester derivative (V), and finally reducing the produced optically active unsaturated ester derivative (V) to obtain the optically active ester derivative (VI).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION The present invention relates to, for example, Japanese Patent Application No. 11-206,8
The present invention relates to an industrially excellent process for producing an optically active production intermediate useful as an intermediate for producing an N, N-substituted cyclic amine derivative useful as a medicine disclosed in No. 62.

[0002]

2. Description of the Related Art In the field of fine chemicals such as pharmaceuticals, from the viewpoints of pharmacological activity, safety and pharmacokinetics,
An optically active substance is often selected. The following methods have been mainly used for producing optically active substances. (1) Use an optically active material (reagent). (2) Asymmetric synthesis. (3) Optical resolution of the racemate.

[0003]

[Problems to be Solved by the Present Invention] In the above-mentioned prior art, the method (1) is limited to raw materials of natural origin such as sugars and amino acids or a very small number of synthetic products. In many cases, it was not suitable for industrial mass production.

In the method (2), there are few cases where steric coordination selectivity is satisfactory, and not only optical and chemical high purity, but also industrial productivity (raw material availability, safety, cost, etc.) In the case of fine chemicals, such as pharmaceuticals, which are also required, there were many cases where these were insufficient.

[0005] Therefore, in most cases, the racemate is usually produced by the optical resolution method (3). However, in the study of optical resolution, no specific rule, rule or tendency was found in selecting a resolving agent or a solvent or determining crystallization conditions, and in fact there was no method other than accumulation of trial and error.

[0006]

Accordingly, the present inventors have sought an industrially excellent method for producing an optically active production intermediate useful as a pharmaceutical production intermediate, and have found that the availability of raw materials, production cost, and operability ( From the viewpoints of workability), suitability for optical resolution, and purity of the final product, intensive studies have been made. As a result, they have found that the above problems can be solved at once by subjecting the optically active epoxide oxidized with t-butyl hydroperoxide to the rearrangement reaction in the presence of titanium tetraisopropoxide, and have completed the present invention. Accordingly, an object of the present invention is to provide a method for producing an optically active production intermediate which is useful in producing fine chemicals such as pharmaceuticals.

Here, the olefin derivative according to the present invention
(I) is represented by the following general formula.

[0008]

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In the formula, R ¹ is the same or different and is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a lower cycloalkyl group, a lower alkoxy group, a lower alkoxyalkoxy group, a halogenated lower alkyl group, a hydroxy lower alkyl group. A cyano lower alkyl group, a halogenated lower alkoxy group, a hydroxy lower alkoxy group, a cyano lower alkoxy group, a lower acyl group, a nitro group, an optionally substituted amino group, an optionally substituted carbamoyl group, Or a sulfamoyl group, a mercapto group or a lower thioalkoxy group. 2 more
One R ¹ may form an aliphatic ring, an aromatic ring, a hetero ring or an alkylenedioxy ring. R ² represents a lower alkyl group or a lower cycloalkyl group. n means 0 or an integer of 1 to 5.

[0010] In the above definition, the halogen atom specifically means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

The lower alkyl group means an alkyl group having 1 to 6 carbon atoms, specifically, for example, a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group. Straight-chain or branched alkyl groups such as a group, t-butyl group, n-pentyl group, i-pentyl group, neopentyl group, hexyl group, 1-methylpropyl group, 1-methylbutyl group, and 2-methylbutyl group. be able to.

The lower alkoxy group means a group in which the above lower alkyl group is bonded to an oxygen atom. Specifically, for example, a methoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group, an n-butoxy group, Examples thereof include a linear or branched alkoxy group such as an i-butoxy group, a t-butoxy group, a pentyloxy group, and a hexyloxy group.

The lower acyl group means a linear or branched acyl group derived from a fatty acid having 1 to 6 carbon atoms, and specifically includes, for example, formyl, acetyl, propionyl, butyryl, isobutyryl. Group, valeryl group, isovaleryl group, pivaloyl group, hexanoyl group and the like.

A lower cycloalkyl group is one having 3 to 8 carbon atoms.
And specific examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.

The optically active alcohol derivative according to the present invention
More specific examples of (I) include, for example, the following compounds, but the present invention is not limited thereto. (1) 2-phenyl-3-methylallyl alcohol (2) 2-phenyl-3-ethylallyl alcohol (3) 2-phenyl-3-propylallyl alcohol (4) 2-phenyl-3-isopropylallyl alcohol (5 ) 2-Phenyl-3-cyclohexylallyl alcohol

Next, the optically active epoxide derivative (II) according to the present invention is represented by the following general formula. (In the formula, R ¹ , R ² and n have the same meaning as described above. * Means an asymmetric carbon atom.)

[0017]

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Optically active epoxide derivative according to the present invention
More specific examples of (II) include, for example, optically active compounds of the following compounds, but the present invention is not limited thereto. (1) 3-methyl-2-phenyl-2,3-epoxypropan-1-ol (2) 3-ethyl-2-phenyl-2,3-epoxypropan-1-ol (3) 3-propyl-2 -Phenyl-2,3-epoxypropane-1-
All (4) 3-isopropyl-2-phenyl-2,3-epoxypropane
-1-ol (5) 3-cyclohexyl-2-phenyl-2,3-epoxypropan-1-ol

Next, the optically active aldehyde derivative (III) according to the present invention is represented by the following general formula. (Where R ¹ ,
R ² , n and * have the same meaning as described above. R ³ represents a protecting group for a hydroxyl group. )

[0020]

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The optically active aldehyde derivative according to the present invention
More specific examples of (III) include, for example, optically active compounds of the following compounds, but the present invention is not limited thereto. (1) 2-methyl-2-phenyl-3- (triphenylsiloxy) propanal (2) 2-ethyl-2-phenyl-3- (triphenylsiloxy) propanal (3) 2-propyl-2-phenyl -3- (triphenylsiloxy)
Propanal (4) 2-isopropyl-2-phenyl-3- (triphenylsiloxy) propanal (5) 2-cyclohexyl-2-phenyl-3- (triphenylsiloxy) propanal

Next, the optically active nitrile derivative (IV) according to the present invention is represented by the following general formula. (Where R ¹ , R ² , n
And * have the same meaning as described above. )

[0023]

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The optically active nitrile derivative (I) according to the present invention
More specifically, examples of V) include optically active forms of the following compounds, but the present invention is not limited thereto. (1) 2-hydroxymethyl-2-methylphenylacetonitrile (2) 2-hydroxymethyl-2-ethylphenylacetonitrile (3) 2-hydroxymethyl-2-propylphenylacetonitrile (4) 2-hydroxymethyl-2-isopropyl Phenylacetonitrile (5) 2-hydroxymethyl-2-cyclohexylphenylacetonitrile

Next, the optically active unsaturated ester derivative (V) according to the present invention is represented by the following general formula. (Where R ¹ , R
² , n and * have the same meanings as described above. R ⁴ represents a lower alkyl group. )

[0026]

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The optically active unsaturated ester derivative (V) according to the present invention has a double bond in the molecule and has geometric isomers, but is not limited in the present invention, and any isomer or mixture It may be. More specific examples of the optically active unsaturated ester derivative (V) include, for example, optically active isomers and geometric isomers of the following compounds, but the present invention is not limited thereto. (1) Ethyl 4-cyano-4-phenyl-2-pentenoate (2) Ethyl 4-cyano-4-phenyl-2-hexenoate (3) Ethyl 4-cyano-4-phenyl-2-heptenoate (4) Ethyl 4 -Cyano-4-phenyl-5-methyl-2-hexenoate (5) ethyl 4-cyano-4-phenyl-5-cyclohexyl-2-
Pentenoate

Next, the optically active ester derivative (VI) according to the present invention is represented by the following general formula. (Where R ¹ , R ² ,
R ⁴ , n and * have the same meaning as described above. )

[0029]

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The optically active ester derivative according to the present invention (V
More specifically, examples of I) include optically active forms of the following compounds, but the present invention is not limited thereto. (1) Ethyl 4-cyano-4-phenyl-pentanoate (2) Ethyl 4-cyano-4-phenyl-hexanoate (3) Ethyl 4-cyano-4-phenyl-heptenoate (4) Ethyl 4-cyano-4-phenyl -5-methylhexanoate (5) ethyl 4-cyano-4-phenyl-5-cyclohexylpentanoate

Finally, the optically active alcohol derivative (VII) according to the present invention is represented by the following general formula. (Where R ¹ , R
² , n and * have the same meanings as described above. )

[0032]

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Optically active alcohol derivative according to the present invention
More specifically, (VII) includes, for example, optically active compounds of the following compounds, but the present invention is not limited thereto. (1) 2-methyl-5-hydroxy-2-phenylpentanenitrile (2) 2-ethyl-5-hydroxy-2-phenylpentanenitrile (3) 2-propyl-5-hydroxy-2-phenylpentanenitrile (4 ) 2- (1-Methylethyl) -5-hydroxy-2-phenylpentanenitrile (5) 2-cyclohexyl-5-hydroxy-2-phenylpentanenitrile

Next, in order to specifically explain the present invention, Production Examples, Examples and Reference Examples will be given below, but it goes without saying that the present invention is not limited to these.

In the present invention, the optical purity was measured by HPLC using an optically active column under the following conditions. Stationary phase: CHIRALCEL OJ, 4.6 × 250 mm Mobile phase: Hexane: IPA: EtOH = 850: 100: 50 Flow rate: 1.0 ml / min Detector: UV 215 nm

Production Example 1 (Z) -2-phenyl-3-isopropyl
Synthesis of Ruacrylonitrile

[0037]

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A known method (Synthetic Communication, 199)
1,21,413.) To synthesize the title compound. (Yield 95
%) Boiling point; 75 ℃ / 0.3mmHg

Production Example 2 2-Phenyl-3-isopropyla
Synthesis of Lil Alcohol

[0040]

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(Z) -2-phenyl-3-isopropylacrylonitrile 27.4 g (160 mmonl) / hexane (200 mL) solution was added with 1.
5M-diisobutylaluminum hydride / toluene solution 1
00 mL was added dropwise at an internal temperature of −30 ° C. or less over about 20 minutes. After further stirring at 0 ° C for 2 hours, the reaction solution was added to 3N-sulfuric acid under ice cooling. At this time, the internal temperature was controlled not to exceed 10 ° C. The solution was stirred at 0 ° C for 40 minutes, then
Heated for 9 hours. After completion of the reaction, the reaction solution was cooled to room temperature, and the organic layer was separated. The remaining aqueous layer was extracted with ethyl acetate, combined with the previous organic layer, washed with aqueous sodium hydrogen carbonate, dried over magnesium sulfate, and the solvent was distilled off. The obtained residue was dissolved in tetrahydrofuran (100 mL), and lithium aluminum hydride (3.1 g, 81.6 mmol) was added at -78 ° C. After stirring at that temperature for 30 minutes, the reaction solution was heated to 0 ° C., and water (3.1 mL), 5N-sodium hydroxide aqueous solution (3.1 mL), and water (9.3 mL) were added to stop the reaction. Added in order. After vigorous stirring for 10 minutes, the precipitate was removed with celite and the filtrate was concentrated,
The residue was distilled under reduced pressure to obtain 23.6 g of the title compound. (Yield; 84%)

Boiling point: 85 ° C./0.4 mmHg. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 0.94 (d, 6H, J = 6.6 Hz),
1.45 (brt, 1H), 2.31-2.43 (m, 1H), 4.29 (d, 2H, J = 5.5H
z), 5.52 (d, 1H, J = 10.1Hz), 7.19-7.39 (m, 5H).

Example 1 (2S, 3S) -3-isopropyl-2-fu
Synthesis of phenyl-2,3-epoxypropan-1-ol

[0044]

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4Å Activated molecular sieves (9 g) were added to methylene chloride (200 mL) to which diethyl
L-(+)-Tartaric acid (2.52 mL, 14.8 mmol) and titanium tetraisopropoxide (3.38 mL, 11.4 mmol) were added at 0 ° C. The mixed solution was cooled to −20 ° C., and 109.4 ml of a 2.7M- (t-butyl) hydroperoxide / methylene chloride solution was added dropwise over 15 minutes. After the reaction solution was stirred at −20 ° C. for 1 hour, a solution of 20 g (114 mmol) of 2-phenyl-3-isopropylallyl alcohol in 100 mL of methylene chloride was added dropwise over 15 minutes. After the addition was completed, the reaction solution was stirred at −20 ° C. for 15 hours. In order to quench the reagent, the reaction solution was adjusted with freshly adjusted iron (II) sulfate.
Solution (66 g of iron (II) sulfate heptahydrate and 22 g of oxalic acid in 200 mL
Dissolved in water at −20 ° C.). After stirring for 1 hour,
The organic layer was separated and the aqueous layer was extracted with ether. The organic layer and the ether layer were combined, washed with aqueous sodium hydrogen carbonate, dried over magnesium sulfate, and the solvent was distilled off. Dissolve the obtained residue in 300 mL of ether, and add a 30% aqueous sodium hydroxide solution.
20 mL was added, and the mixture was vigorously stirred at 0 ° C. for 1 hour. Thereafter, the organic layer was separated, the aqueous layer was extracted twice with ether, and the combined organic layers were washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off. The obtained residue was crystallized from hexane to give 18.4 g of the title compound as colorless crystals. (Yield; 84%)

Melting point: 63 ° C. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ (ppm) 0.72 (d, 3 H, J = 6.4 H)
z), 0.76-0.88 (m, 1H), 0.94 (d, 3H, J = 6.4 Hz), 2.90 (d, 1
H, J = 8.8Hz), 3.68 (dd, 1H, J = 12.4,6.0Hz), 3.78 (dd, 1H, J
= 12.4,6.0Hz), 4.91 (t, 1H, J = 6.0), 7.25-7.40 (m, 5H) .LRMS (ESI) m / e: 247 (M + Na + MeOH) ⁺ . [Α] ²⁸ _{D = -50.1 (c0.78, CHCl 3)} .

Example 2 (2S, 3S) -3-isopropyl-2-fu
Enyl-2,3-epoxypropane-1-triphenylsilyl ester
Synthesis

[0048]

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(2S, 3S) -3-isopropyl-2-phenyl-2,3-
Epoxypropan-1-ol 5.0 g (26.0 mmol) in dimethylformamide (50 mL) solution, imidazole (3.5 g, 51.5 mm
ol) and triphenylchlorosilane (7.7 g, 26.1 mmol) at 0 ° C
And stirred at room temperature for 6 hours. Water and hexane were added to the reaction solution, and the mixture was vigorously stirred, and then the organic layer was separated. The aqueous layer was extracted with hexane, and the combined organic layers were washed with brine, dried over magnesium sulfate, and the solvent was distilled off to obtain 11.8 g of the title compound as an oil. (Yield; 100%)

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 0.73 (d, 3
H, J = 6.4Hz), 0.90-0.98 (m, 1H), 0.98 (brs, 3H), 2.93 (d,
1H, J = 8.6Hz), 4.07 (s, 2H), 7.27-7.58 (m, 20H) .LRMS (ESI) m / e: 473 (M + Na) ⁺ .

Example 3 (2S) -2-isopropyl-2- phenyl
Synthesis of l-3- (triphenylsiloxy) propanal

[0052]

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(2S, 3S) -3-isopropyl-2-phenyl-2,3-
Epoxy propane-1-triphenylsilyl ether 9.0g
To a solution of (20.0 mmol) in methylene chloride (100 L) was added a 0.4 M solution of methyl aluminum bis (4-methyl-2,6-di-tert-butylphenoxide) / toluene (100 mL) at -78 ° C. After stirring at that temperature for 1 hour, the reaction solution was added to 2N-hydrochloric acid (200 mL) under ice-cooling. The organic layer was separated, the aqueous layer was extracted with hexane, and the combined organic layers were washed with brine, dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography to give the title compound (8.90 g) as a colorless oil. (Yield; 99%) ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 0.80 (d, 3H, J = 6.8 Hz),
0.88 (d, 3H, J = 6.8Hz), 2.75 (septet, 1H, J = 6.8Hz), 4.24
(d, 1H, J = 10.4Hz), 4.27 (d, 1H, J = 10.4Hz), 7.05-7.53 (m, 2
0H), 9.79 (s, 1H) .HRMS (FAB) m / z 451.2110

Example 4 (2R) -2-hydroxymethyl-2-i
Synthesis of Sopropylphenylacetonitrile

[0055]

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To a solution of 8.9 g (19.8 mmol) of (2S) -2-isopropyl-2-phenyl-3- (triphenylsiloxy) propanal in 50 mL of ethanol was added 2.06 g of hydroxylamine hydrochloride.
(28.8 mmol) and 2.44 g (29.8 mmol) of sodium acetate,
Stirred at room temperature for 2 hours. The reaction solution was concentrated, ethyl acetate was added, and the mixture was washed twice with water, dried over magnesium sulfate, and the solvent was distilled off. The obtained residue was dissolved in tetrahydrofuran (50 mL) and 1,1′-carbonyldiimidazole (1
6.0 g, 98.8 mmol), and the mixture was heated under reflux for 2 hours. Reaction solution 0
After cooling to 0 ° C., water was added slowly until no more gas evolved. To this solution was added a 1M-tetrabutylammonium fluoride / tetrahydrofuran solution (43.6 mL), and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, ethyl acetate and water were added, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography to give the title compound (2.88 g) as white crystals. (Yield: 78%, optical purity: 100% ee)

Melting point: 76-77 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 0.83 (d, 3H, J = 6.8 Hz),
1.21 (d, 3H, J = 6.8Hz), 1.64 (dd, 1H, J = 8.4,5.5Hz), 2.30
(septet, 1H, J = 6.8Hz), 3.99 (dd, 1H, J = 11.2,5.5Hz), 4.1
2 (dd, 1H, J = 11.2,8.4Hz), 7.32-7.49 (m, 5H) .LRMS (ESI) m / e: 190 (M + H) ⁺ . [Α] ²⁹ _D = -25.5 (c0. 99, CHCl ₃ ).

Example 5 Ethyl (4R) -4-cyano-4-fe
Synthesis of Nyl-5-methyl-trans-2-hexenoate

[0059]

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To a solution of 2.77 g (14.7 mmol) of (2R) -2-hydroxymethyl-2-isopropylphenylacetonitrile in methylene chloride (15 mL) was added triethylamine (13.3 mL) and 6.99 g (44.0 mmol) of sulfur trioxide / pyridine complex. added. After the reaction solution was stirred at room temperature for 2 hours, hexane and 1N-hydrochloric acid were added. The organic layer was separated, the aqueous layer was extracted twice with hexane, the combined organic layers were washed with aqueous sodium bicarbonate, dried over magnesium sulfate, and the solvent was distilled off to obtain an aldehyde compound. Separately, in tetrahydrofuran (20 mL)
Horner Emmons reagent prepared from 60% oily sodium hydride (882 mg) and 4.94 g (22.1 mmol) of triethylphosphonoacetate was added to a solution of the above aldehyde compound in tetrahydrofuran (30 mL). After stirring the reaction solution for 1 hour, 10%
Hexane containing ethyl acetate and water were added. The organic layer was separated, the aqueous layer was extracted with the same solvent, and the combined organic layers were filtered through a small bed of silica gel. The filtrate was concentrated to give the title compound (2.72 g) as a colorless oil.
(Yield; 72%)

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 0.90 (d, 3
H, J = 6.8Hz), 1.13 (d, 3H, J = 6.8Hz), 1.29 (t, 3H, J = 7.1H
z), 2.40 (septet, 1H, J = 6.8Hz), 4.20 (q, 2H, J = 7.1Hz),
6.31 (d, 1H, J = 15.6Hz), 7.02 (d, 1H, J = 15.6Hz), 7.31-7.4
7 (m, 5H) .LRMS (ESI) m / e: 312 (M + Na + MeOH) ⁺ .

Example 6 Ethyl (4S) -4-cyano-4-fe
Synthesis of Nyl-5-methyl-hexanoate

[0063]

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To a solution of 2.6 g (10.1 mmol) of ethyl (4R) -4-cyano-4-phenyl-5-methyl-trans-2-hexenoate in 50 mL of ethyl acetate was added 10% palladium on carbon (50 mg), and hydrogen was added. The mixture was stirred for 16 hours under an air current. The reaction solution was filtered through celite,
The filtrate was concentrated to give the title compound (2.54 g) as a colorless oil. (Yield; 97%)

¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 0.79 (d,
3H, J = 6.8Hz), 1.20 (t, 3H, J = 7.1Hz), 1.23 (d, 3H, J = 6.8H
z), 1.94 (ddd, 1H, J = 16.5,11.9,4.6Hz), 2.15 (septet, 1
H, J = 6.8Hz), 2.19 (ddd, 1H, J = 16.5,11.9,4.8Hz), 2.40 (d
dd, 1H, J = 16.3,11.9,4.6Hz), 2.50 (ddd, 1H, J = 16.3,11.9,
4.8Hz), 3.98-4.12 (m, 2H), 7.29-7.42 (m, 5H) .LRMS (ESI) m / e: 282 (M + Na) ⁺ , 542 (2M + Na) ⁺

Example 7 (2S) -2- (1-methylethyl) -5-h
Synthesis of droxy-2-phenylpentanenitrile

[0067]

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A solution of 2.51 g (9.69 mmol) of ethyl (4S) -4-cyano-4-phenyl-5-methyl-hexanoate in 20 mL of tetrahydrofuran was added at 0 ° C. with lithium aluminum hydride 7
40 mg (19.5 mmol) were added in small portions. After stirring the reaction solution at 0 ° C. for 1 hour, water (0.8 mL), 5N-sodium hydroxide aqueous solution
(0.8 ml) and water (2.4 ml) were sequentially added. The precipitate is filtered through Celite, and the filtrate is concentrated to give 2.10 g of the title compound.
Was obtained as a colorless oil. (Yield; 100%, optical purity;
100%)

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 0.79 (d, 3
H, J = 6.8Hz), 1.18-1.28 (m, 1H), 1.21 (d, 3H, J = 6.8Hz),
1.55-1.66 (m, 2H), 1.98 (ddd, 1H, J = 13.5,12.1,4.6Hz),
2.13 (septet, 1H, J = 6.8Hz), 2.24 (ddd, 1H, J = 13.5,12.1,
4.6Hz), 3.59 (q, 2H, J = 5.5Hz), 7.27-7.40 (m, 5H) .LRMS (ESI) m / e: 240 (M + Na) ⁺ , 272 (M + Na + MeOH) ⁺ , 457 (2M + N
a) ⁺ . [α] ²⁶ _D = -12.4 (c1.2, CHCl ₃ ).

Reference Example 1 1-[(4S)-(4-cyano-5-methyl-4)
-Phenyl) hexyl] -4- [2- (4-fluorophenoxy) e
Synthesis of [Chill] piperazine

[0071]

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(2S) -2- (1-methylethyl) -5-hydroxy-2
To a solution of 2.10 g (9.68 mmol) / acetonitrile (20 mL) of -phenylpentanenitrile was added 2.15 g (21.3 mmo) of triethylamine.
l) and 1.22 g (10.7 mmol) of methanesulfonyl chloride were added at 0 ° C. After the reaction solution was stirred at that temperature for 2 hours, the solvent was distilled off. Ether and saturated saline were added to the residue, the organic layer was separated, dried over magnesium sulfate, and the solvent was distilled off to obtain a methanesulfonyl ester. This methanesulfonyl ester and 2.4 g (10.7 mmol) of 4-fluorophenoxyethylpiperazine / acetonitrile (30 m
L) The solution was added with 1.6 g (10.7 mmol) of sodium iodide and 1.08 g (10.7 mmol) of triethylamine, and heated at 70 ° C for 3 hours. Ether and 5N-hydrochloric acid were added to the reaction solution, followed by vigorous stirring. The aqueous layer was washed once more with ether. Organic layer is 5N-
Extracted again with hydrochloric acid. The combined aqueous layer was neutralized with sodium bicarbonate, extracted with ethyl acetate, dried over magnesium acid, and the solvent was distilled off to obtain 3.51 g of a colorless oily free compound of the title compound. (Yield; 86%, optical purity; 100% ee)

¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 0.77 (d,
J = 6.8Hz, 3H), 1.05-1.17 (m, 1H), 1.20 (d, J = 6.8Hz, 3H),
1.50-1.60 (m, 1H), 1.88 (dt, J = 4.4Hz, 12.4Hz, 1H), 2.06-
2.19 (m, 2H), 2.24-2.30 (m, 2H), 2.30-2.43 (m, 4H), 2.46
-2.62 (m, 4H), 2.77 (t, J = 5.8Hz, 2H), 4.04 (t, J = 5.8Hz, 2
H), 6.80-6.85 (m, 2H), 6.91-6.99 (m, 2H), 7.25-7.32 (m,
1H), 7.32-7.40 (m, 4H). [Α] ²⁶ _D = -6.5 (c 0.93, CHCl ₃ ).

The above free form was dissolved in ethyl acetate, 2 equivalents of a 1N hydrochloric acid / ethyl acetate solution were added, and the precipitate was recrystallized from 1-propanol to obtain a hydrochloride of the title compound. Melting point: 184-186 ° C. ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ (ppm) 0.68 (d, J = 6.6 Hz, 3
H), 1.11 (d, J = 6.6Hz, 3H), 1.22-1.34 (m, 1H), 1.58-1.62
(m, 1H), 2.06-2.30 (m, 3H), 3.00-3.25 (m, 2H), 3.30-3.8
0 (m, 10H), 4.36 (brs, 2H), 6.98-7.07 (m, 2H), 7.11-7.20
(m, 2H), 7.32-7.40 (m, 1H), 7.40-7.50 (m, 4H) .LRMS (ESI) m / e: 424 (M + H) ⁺ [α] ²⁶ _D = -5.5 (c1. 1, EtOH).

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification FI FI Theme Court ゛ (Reference) C07D 303/14 C07D 303/14 C07M 7:00 C07M 7:00 (72) Inventor Satoshi Nagato Matsudo, Chiba Matsudo 2037-1-201 (72) Inventor Yoshihiko Nomine 9-7-408, Inari-mae, Tsukuba City, Ibaraki Prefecture (72) Inventor Yoichi Iimura 4-5-87 Ninomiya, Tsukuba City, Ibaraki Prefecture F-term (reference) 4C048 AA01 BB07 UU03 XX02 4H006 AA02 AC11 AC41 AC43 AC45 AC48 AC54 AC81 BD70 QN30 4H039 CA63 CH10

Claims (5)

[Claims] An olefin derivative represented by the following general formula:
(I) (Wherein R ¹ is the same or different and is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a lower cycloalkyl group, a lower alkoxy group, a lower alkoxyalkoxy group,
Halogenated lower alkyl group, hydroxy lower alkyl group, cyano lower alkyl group, halogenated lower alkoxy group, hydroxy lower alkoxy group, cyano lower alkoxy group, lower acyl group, nitro group, optionally substituted amino group, substituted Carbamoyl group, an optionally substituted sulfamoyl group, a mercapto group or a lower thioalkoxy group. Two more R
¹ , may form an aliphatic ring, an aromatic ring, a hetero ring or an alkylenedioxy ring. R ² represents a lower alkyl group or a lower cycloalkyl group. n means 0 or an integer of 1 to 5. ) Is oxidized with t-butyl hydroperoxide in the presence of titanium tetraisopropoxide to produce an optically active epoxide derivative (II) represented by the following general formula: (Wherein R ¹ , R ² and n have the same meaning as described above. * Means an asymmetric carbon atom.) Then, after protecting a hydroxyl group, a rearrangement reaction is carried out, and an optical compound represented by the following general formula is obtained. Active aldehyde derivative (III) (Wherein R ¹ , R ² , n and * have the same meanings as described above.)
R ³ represents a protecting group for a hydroxyl group. And then an optically active nitrile derivative (IV) represented by the following general formula: (Wherein R ¹ , R ² , n and * have the same meanings as described above), and then perform a deprotection reaction, a carburization reaction, and an oxidation reaction to perform the optically active unsaturated ester derivative represented by the following general formula: (V) (Wherein R ¹ , R ² , n and * have the same meanings as described above.)
R ⁴ represents a lower alkyl group. ) And then reducing, wherein the method comprises producing an optically active ester derivative (VI) represented by the following general formula: Embedded image (In the formula, R ¹ , R ² , R ⁴ , n and * have the same meanings as described above.) 2. The process for producing an optically active ester derivative (VI) according to claim 1, wherein the olefin derivative (I) is 2-phenyl-3-isopropylallyl alcohol. 3. An olefin derivative (I) is oxidized with t-butyl hydroperoxide in the presence of titanium tetraisopropoxide to give an optically active epoxide derivative (II),
Then, after protecting the hydroxyl group, a rearrangement reaction is carried out to obtain an optically active aldehyde derivative (III), then to an optically active nitrile derivative (IV), and then to carbonization to obtain an optically active unsaturated ester derivative (V), and then reduction. A method for producing an optically active alcohol derivative (VII) represented by the following general formula: Embedded image (In the formula, R ¹ , R ² , n and * have the same meanings as described above.) 4. The method for producing an optically active alcohol derivative (VII) according to claim 3, wherein the olefin derivative (I) is 2-phenyl-3-isopropylallyl alcohol. 5. A method for producing 2-phenyl-3-isopropylallyl alcohol in the presence of titanium tetraisopropoxide.
Oxidation with t-butyl hydroperoxide to give optically active 3-isopropyl-2-phenyl-2,3-epoxypropan-1-ol, and then protecting the hydroxyl group to give optically active 3-isopropyl
2-phenyl-2,3-epoxypropane-1-triphenylsilyl ether, followed by a rearrangement reaction to give optically active 2-isopropyl-2-phenyl-3- (triphenylsiloxy) propanal, and then optically active 2 -Hydroxymethyl-2-
Isopropyl phenylacetonitrile, followed by deprotection reaction, carburization reaction and oxidation reaction to obtain optically active ethyl 4-cyano-4-phenyl-5-methyl-trans-2-hexenoate, and then reduced to obtain optically active ethyl 4 -Cyano-
The optical activity according to any one of claims 1 to 4, wherein 4-phenyl-5-methyl-hexanoate is further reduced.
A method for producing 2- (1-methylethyl) -5-hydroxy-2-phenylpentanenitrile.