JP2743797B2 - Preparation of optically active compounds - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION The prostaglandin synthesis method developed by Stork et al. (G. Stork, T. et al.
Takahashi, I. Kawamoto, T. Suzuki: J. Am. Chem. Soc., 100, 8
272 (1978)), which is an important intermediate represented by the following general formula (P)

[0002]

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(In the above general formula (P), R ¹ is a carbon atom selected from an alkyl group optionally having an alkoxy group, a cycloalkyl group and an aralkyl group having a hetero atom in an aromatic ring or an alkyl group. Groups of ~ 12, R ²
Represents a hydrogen atom or a readily removable protecting group selected from an acyl group, a silyl group, an aralkyl group and an alkyloxyalkyl group, and the symbol * represents an asymmetric carbon atom.
The present invention relates to a method for producing an optically active compound which is an intermediate for producing an optically active γ-lactone derivative represented by the formula:

[0004]

2. Description of the Related Art The production of prostaglandins is described in G. In addition to the synthesis method of Stork et al., A method starting from Corylactone or 4-hydroxycyclopentenone has been put to practical use,
In this method, it is necessary to go through steps such as optical resolution and asymmetric hydrolysis by microorganisms in order to obtain the optically active substance as a raw material. Based on these, steric control at the stage of introducing α, ω side chains Also have many problems.

[0005] In view of the above, G. Stor
The optical activity γ- of the general formula (P) developed by K.
The prostaglandin synthesis method using a lactone derivative as a key intermediate can be said to be an excellent method. However, a problem in this method depends on how economically the compound of the general formula (P), which is a key intermediate, can be produced.

[0006]

Means for Solving the Problems The present inventors have made intensive studies to solve the above-mentioned problems, and as a result, have been able to convert the compound represented by the above general formula (P), which is a key intermediate, more easily and more efficiently than in the past. The present invention has found a method for producing the intermediate well, and the present invention provides a method for producing an intermediate obtained in the course of this production. The present invention provides the following general formula (A)

[0007]

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(In the general formula (A), R ¹ is a carbon atom selected from an alkyl group optionally having an alkoxy group, a cycloalkyl group and an aralkyl group having a hetero atom in an aromatic ring or an alkyl group. Groups of ~ 12, R ²
Represents a hydrogen atom or a readily removable protecting group selected from an acyl group, a silyl group, an aralkyl group and an alkyloxyalkyl group, and the symbol * represents an asymmetric carbon atom.
This is a method for producing an optically active compound represented by the formula:

Specific examples of R ¹ in the general formula (A) include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, 2,2-
Dimethylpentyl, hexyl, 2-hexyl, heptyl, 2-heptyl, octyl, 2-octyl, nonyl,
2-nonyl, decyl, 2-decyl, undecyl, 2-undecyl, dodecyl, 2-ethoxy-1,1-dimethylethyl, 5-methoxy-1-methylpentyl, sirocupentyl, 3-ethylcyclopentyl, cyclohexyl,
Linear or branched alkyl or cycloalkyl optionally having an alkoxy substituent such as 2-methylcyclohexyl, 4-n-propylcyclohexyl, phenyloxymethyl, 3-trifluoromethylphenyloxymethyl, 2 And aralkyl groups having a heteroatom in an aromatic ring or an alkyl group such as -chlorothiophen-5-yloxymethyl and furan-2-yl-2-ethyl.

Specific examples of R ² other than a hydrogen atom in the general formula (A) include acyl groups such as benzoyl, acetyl and p-phenylbenzoyl; and t-butylmethylsilyl, trimethylsilyl and t-butyldiphenylsilyl. Examples thereof include easily eliminable groups such as a silyl group, an aralkyl group such as benzyl and 4-nitrophenylmethyl, and an alkyloxyalkyl group such as tetrahydropyranyl and 1-ethoxyethyl.

[0011] Prostaglandin is a compound having an extremely strong physiological activity, which is produced by chemically converting higher unsaturated fatty acids such as arachidonic acid in vivo by a prostaglandin synthase and has the following structure.

[0012]

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In natural prostaglandins, R ¹ is n
—C ₅ H ₁₁ —, where R is (CH ₂ ) ₆ COOH or CH ₂ C
It is known that H 2CH (CH ₂ ) ₃ COOH and that the substituent of R ¹ has lipophilicity in the expression of biological activity.

In the course of research and development as a pharmaceutical, R ¹ is an alkyl group, a cycloalkyl group or an aralkyl group having 4 to 10 carbon atoms. For example, pentyl, isopentyl, 2,2- Dimethylpentyl, hexyl, 2-hexyl, heptyl, 2-ethoxy-1,1-dimethylethyl, 5-methoxy-1-
Alkyl groups such as methylpentyl, cyclopentyl, 3
Cycloalkyl groups such as -ethylcyclopentyl and 4-propylcyclohexyl; phenyloxymethyl;
It has been revealed that aralkyl groups such as trifluoromethylphenyloxymethyl, 2-chlorothiophen-5-yloxymethyl, and furan-2-yl-2-ethyl have particularly strong physiological activities. The compounds of the present invention are useful as raw materials into which substituents including these organic groups can be introduced.

The method for synthesizing the allyl alcohol derivative represented by the above general formula (A) of the present invention will be described below according to synthetic route I. In the following, X represents a halogen atom, and M represents an alkali metal.

[0016]

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In the above reaction, the halogen compound (1)
Is reacted with a strong base such as n-butyllithium, t-butyllithium, methyllithium, lithium diisopropylamide, etc. to form an acetylene compound (2), and further these bases are converted to an alkali metal acetylide (2 '). The compound (4) is obtained by allowing the optically active aldehyde (3) to act on this.

The alkali metal acetylide (2 ') is
As described above, the acetylene compound (2) may be once isolated and prepared again by reacting with a strong base. However, more simply, the acetylene compound (2) may be prepared by reacting the halogen compound (1) with at least twice the amount of a strong base. The obtained alkali metal acetylide can be used as it is. The reaction between the alkali metal acetylide and the optically active aldehyde (3) is desirably performed at a low temperature of -78 to 0C. The reaction for obtaining the compound (4) can be carried out in an inert solvent such as tetrahydrofuran, diisopropyl ether, toluene or the like at a temperature ranging from -78 ° C to room temperature. The compound (4) obtained by this reaction is a mixture of an erythro form (B-1) and a threo form (B-2) as shown by the following chemical formula.

[0019]

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In order to selectively obtain the erythro form (B-1) or threo form (B-2) from this mixture, the mixture can be separated by column separation or the like. In addition, each optical isomer can be produced more selectively. This compound (4)
An ethynyl ketone derivative of compound (5) can be obtained by oxidizing the compound with an oxidizing agent such as CrO ₃ -pyridine, dimethylsulfoxide (DMSO) -acid halide or the like.

In the reaction for synthesizing the optically active ethynyl alcohol derivative (B) from the compound (5), whether the ethynyl alcohol derivative (B) to be obtained is the erythro body (B-1) represented by the above chemical formula, Or a threo form (B-
The reaction conditions differ depending on whether 2) or not. That is, the compound (5) is a zinc borohydride complex (Zn (BH ₄ ) ₂ ) for the erythro form (B-1), and an alkali for the threo form (B-2). Reduction with a metal selectride, such as potassium selectride, can provide the ethynyl alcohol derivative (B) having the desired configuration with good selectivity.

In order to synthesize the optically active allyl alcohol derivative (A), which is the target compound of the present invention, from the ethynyl alcohol derivative (B), the ethynyl alcohol derivative (B) is reacted with lithium aluminum hydride or the like to form a triple bond. To a trans double bond. This reaction can be performed in an inert solvent such as tetrahydrofuran or dioxane at a temperature of 40 to 80 ° C.

The halogen compound (1), which is a starting material in the above reaction, is obtained by converting optically active 2,3-O-isopropylidene glyceraldehyde obtained from D-mannitol or optically active glycidol by a known method into triphenylphosphine and tetraphenylphosphine. It can be easily synthesized by reacting with halomethane.

The optically active aldehyde (3) is
It can be synthesized according to the following synthesis route II. Below
Where R¹, R^TwoAnd * sign of general formula (A)
R¹, R ^TwoAnd * have the same meanings as X and Y
Is independently a hydroxyl group, an acyl group, a sulfoxy group
And a group or atom selected from halogen atoms.

[0025]

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The above-mentioned optically active mannitol is mixed with acetone and acid
Reacting in the presence of a catalyst to form triacetonide (a),
This is partially hydrolyzed with aqueous acetic acid to give tetraol (b)
The primary and secondary hydroxyl groups are separately
Riphenylphosphine-CCl_Four, Acid halide-pyridi
And pyridine-methanesulfonyl chloride
Partly with an acyl, sulfoxy or halogen atom or
All are converted to acetonide (c). Next,
After converting setonide (c) with a base to diepoxide (d),
R^ThreeMgBr, R^ThreeMgBr-Cu_Two(CN)_Two, R^Three
Li (however, R ^ThreeIs R¹Shows groups with one less carbon number than
) And lithium aluminum hydride¹Lead the group
And further add a hydroxyl group to R^TwoX '(X' is a halogen atom or
Is a sulfoxy group) to give acetonide (e),
This is hydrolyzed to diol (f), and then Pb (O
Ac)_FourAnd NaIO_FourTo oxidize the desired optically active
Rudehydride (3) can be obtained.

The obtained optically active allyl alcohol derivative represented by the general formula (A), which is the object of the present invention, is a compound (6) γ-
The compound (P), which is a key intermediate in the synthesis of prostaglandin, is converted into an unsaturated carboxylic acid derivative,
It can be converted to a lactone derivative. In the following, R ⁴ represents a lower alkyl group having 1 to 5 carbon atoms.

[0028]

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In the above reaction, the allyl alcohol derivative (A) is reacted with a trialkyl orthoacetate under heating in the presence of an acid catalyst, and a Johnson-Claisen rearrangement reaction is carried out to give the γ-unsaturated carboxylic acid derivative (6). Is converted to

The trialkyl orthoacetate used includes trimethyl orthoacetate, triethyl orthoacetate, tripropyl orthoacetate, tributyl orthoacetate, triheptyl orthoacetate, etc., which are 2 to 10 times the amount of the allyl alcohol derivative (A). The reaction is carried out at a temperature of 130 to 180 ° C. in a solvent such as toluene, xylene or mesitylene using an equivalent amount. As the acid catalyst, a Lewis acid, a Lewis acid complex (for example, BF _3. (C ₂ H ₅ ) ₂ O), or an organic acid such as heptanoic acid is used.

The acetonide of the γ-unsaturated carboxylic acid derivative (6) thus obtained is subjected to ring opening with an acid catalyst and intramolecular lactonization to give a general intermediate (P) which is a key intermediate in the synthesis of prostaglandin. ) Optical activity γ
-A lactone derivative is obtained. In this reaction, acetonide is hydrolyzed by a hydrous organic acid, an alcohol such as methanol or ethanol, a mineral acid in a solvent such as acetone or dioxane, a BF ₃ .ether complex, CuSO ₄ , ZnSO ₄
And a Lewis acid or a Lewis acid complex.

The compound of the general formula (P) thus obtained is described in G. According to the prostaglandin synthesis method of Stork et al.
F). Accordingly, in the optically active compound of the general formula (A) in the present invention, both the 2- and 6-configurations in the general formula (A) are S,
It is required that the configuration of the position be R.

[0033]

The present invention will be described below with reference to examples.

Synthesis of Compound (a) 45 g of D-mannitol was added to 1 L of acetone and 1 L of concentrated hydrochloric acid.
After stirring vigorously at room temperature for 3 days in 50 ml, 50 g of potassium carbonate was added, and the mixture was further stirred for 1 day. The solid substance was removed by suction filtration, the solvent in the filtrate was distilled off under reduced pressure, water was added to the obtained residue, and the precipitated crystals were collected by suction filtration to obtain crude product 4.
5 g were obtained. This was dissolved by heating in 20 ml of ethanol, followed by filtration. The filtrate was cooled to room temperature, and the precipitated crystals were collected by filtration. The optical activity (2R, 3R, 4
(R, 5R) triacetonide (a) (37.3 g, yield 50%) was obtained.

[0035]

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¹ H NMR (CCl ₄ ) δ: 1.40 (6H, s, CH ₃ × 2) 1.43 (12H, s, CH ₃ × 4) 3.7 to 4.4 (8H, m, CH ₂ , CH)

Synthesis of Compound (b) 15 g (0.05 m) of the triacetonide (a) obtained above was obtained.
ol) was stirred in 50 ml of 70% acetic acid at 40 ° C. for 3.5 hours, concentrated at 40 ° C. under reduced pressure, and acetone was added to the residue to crystallize D-mannitol (0.72 ml).
g) was filtered off, and acetone was distilled off from the filtrate under reduced pressure to obtain a syrup-like product. This was recrystallized with 50 ml of benzene and the optical activity (2R, 3R, 4
R, 5R) -form tetraol (b) (8.8 g, yield 80)
%).

[0038]

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¹ H NMR (D ₂ O) δ: 1.38 (6H, s, CH ₃ × 2) 3.3 to 4.2 (8H, m, CH ₂ , CH)

Synthesis of Compounds (c) and (d) 15.3 g (0.06 g) of the tetraol (b) obtained above.
9 mol), 55 ml of anhydrous pyridine (0.68 mol)
l) in a solution of 50 ml of CH ₂ Cl _{2 at} -70 ° C., 16 ml (0.138 mol) of benzoyl chloride, anhydrous CH
A mixture of 5 ml of ₂ Cl _{2 was} added dropwise over 15 minutes. After the addition, the mixture was further stirred at −30 ° C. for 1 hour and at room temperature for 10 hours. After the completion of the reaction was confirmed by thin-layer chromatography, the solvent was distilled off under reduced pressure. . The residue was treated with methanesulfonyl chloride 11.2
ml (0.144 mol) was added at 0 ° C. over 20 minutes, and the suspension was further stirred at room temperature for 3 days. After the completion of the reaction was confirmed by thin-layer chromatography, the reaction mixture was mixed with a mixed solvent of ethyl ether: hexane = 7: 3 (volume).
Then, the yellow suspension was added to Celite-545.
And the solvent was distilled off under reduced pressure. The resulting brown residue was diluted with CH ₂ Cl ₂ and acidified by adding concentrated hydrochloric acid, followed by C
Extracted three times with H ₂ Cl ₂ . The extract is washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure to give an optically active (2R, 3R, 4R, 5R) brown semisolid represented by the following chemical formula. 42 g of acetonide (c) was obtained.

[0041]

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(Where Ms is a methylsulfoxy group, ph
Represents a phenyl group)

42 g of the above acetonide (c), K ₂ CO ₃
After stirring 20 g of 15 g in 130 ml of methanol for 15 hours, the reaction solution was filtered through Celite-545, and the filtrate was concentrated under reduced pressure at 40 ° C., and ethyl ether: hexane = 7:
3 (volume) of the mixed solvent (30 ml) was added thereto, and Celite-
The mixture was filtered at 545, the solvent was distilled off under reduced pressure at 40 ° C., and the crude product was obtained by distillation under reduced pressure. This was further recrystallized from benzene to give a pure optical activity (2
(S, 3R, 4R, 5S) diepoxide (d) 2.7
g (yield 21%) was obtained.

[0044]

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¹ H NMR (CDCl ₃ ) δ: 1.39 (6H, s, CH ₃ × 2) 2.6 to 2.9 (4H, m, CH ₂ × 2) 2.95 to 3.12 (2H , M, CH) 3.7 to 3.95 (2H, m, CH)

Synthesis of Compounds (e) and (f) A mixture of 320 mg of Cu ₂ (CN) ₂ and 100 ml of anhydrous tetrahydrofuran was separately prepared at a concentration of 1.47 mol.
l of n-butylmagnesium bromide in ether 6
4 ml (94 mmol) were added at 0 ° C. over 5 minutes. After further stirring for 5 minutes, 6.48 g of the obtained diepoxide (d) in 50 ml of anhydrous tetrahydrofuran
The solution was added dropwise at 0 ° C. with stirring over 10 minutes, and further stirred for 1 hour. After completion of the reaction was confirmed by thin-layer chromatography, the mixture was decomposed with NH ₄ Cl and saturated saline, stirred for 30 minutes, extracted three times with ethyl ether, and the ether layer was extracted with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated saline. The extract was washed successively with water, dried over anhydrous magnesium sulfate, and filtered. The solvent of the filtrate was distilled off, and the optical activity represented by the following chemical formula (6S, 7R, 8R, 9) was obtained.
S) A crude diol (e-1) was obtained.

[0047]

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The crude diol (e-1) obtained above was dissolved in 30 ml of anhydrous tetrahydrofuran, and 0.48 g (1.07 mmol) of sodium hydride was added dropwise to 100 ml of anhydrous tetrahydrofuran over 15 minutes under reflux. After stirring and refluxing for 1 hour, the mixture was cooled to 0 ° C. To this suspension was added DC-18-crown ether-6 132 m
g and 9.3 ml (78 mmol) of benzyl bromide at 0 ° C.
And stirred under reflux for 4 hours. The reaction solution was concentrated under reduced pressure, and
After decomposing with normal hydrochloric acid, the mixture is extracted three times with hexane. The extract is washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure to obtain an optical activity represented by the following chemical formula (6S , 7R, 8R, 9S) acetonide (e-2).

[0049]

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(However, Bn represents a benzyl group)

The above acetonide (e-2) was treated with 80% acetic acid 1
After heating and stirring at 100 ° C. for 10 hours in 00 ml, the solvent was distilled off under reduced pressure, then extracted with ethyl ether, the extract was washed with aqueous sodium hydroxide solution, the aqueous layer was further extracted with ethyl ether, and these ether layers were combined. The solution was washed sequentially with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and brine, and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (ethyl ether: hexane = 1: 4).
(Elution with (volume)), and the optical activity (6
8.66 g of diol (f) in the form of (S, 7R, 8R, 9S)
(Yield 55% from compound (d)) was obtained.

[0052]

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(However, Bn represents a benzyl group) ¹ H NMR (CDCl ₃ ) δ: 0.88 (6H, br, CH ₃ × 2) 1.0 to 1.8 (16H, m, CH ₂ × 8) ) 3.4-3.7 (4H, m, CH) 4.46 (2H, d, J = 10.8 Hz,
CH) 4.62 (2H, d, J = 10.8 Hz,
CH) 7.30 (10H, s, C 6 H 5)

Synthesis of Compound (3) 200 mg of the diol (f) obtained above, K ₂ CO ₃ 6
0 mg and 4.5 ml of anhydrous benzene.
mg was added at 4 ° C and stirred for 3 minutes. After completion of the reaction, 100 ml of hexane was added, the mixture was filtered using Celite-545, the filtrate was washed with saturated aqueous sodium hydrogen carbonate, the aqueous layer was extracted twice with hexane, and the combined hexane layers were washed with saturated saline and then dried over sulfuric anhydride. Dried over magnesium. After evaporating the solvent, the residue was purified by silica gel column chromatography (ethyl ether: hexane = 1: 2 (volume)) to give 160 mg of (S) -2-benzyloxyheptanal (3) (80% yield).
I got

[0055]

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(However, Bn represents a benzyl group) ¹ H NMR (CDCl ₃ ) δ: 0.87 (3H, t, J = 5.8H)
z, CH ₃ ) 1.0 -1.8 (8H, m, CH ₂ ) 3.73 (1 H, dt, J = 2.2 Hz,
6.2 Hz, CH) 4.51 (1H, d, J = 11.6 Hz,
CH) 4.65 (1H, d, J = 11.6 Hz, C
H) 7.34 (5H, s, C 6 H 5) 9.64 (1H, d, J = 2.2Hz)

Synthesis of Compound (4) The following chemical formula (1)

[0058]

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(S) -dibromide 4.8
g (16.8 mmol) of anhydrous tetrahydrofuran 1
00 ml was cooled to -78 ° C and the concentration was 1.
16.4 m of a 62 mol butyllithium-hexane solution
1 (26.6 mmol) was added dropwise over 10 minutes.
The mixture was further stirred at 78 ° C for 1 hour and at room temperature for 1 hour to convert into optically active lithium acetylide (2 ′).
Then, 2.41 g (4.4 mmol) of anhydrous tetrahydrofuran (20 ml) of (S) -2-benzyloxyheptanal (3) obtained above was added dropwise, and the mixture was further stirred for 30 minutes and decomposed with an aqueous ammonium chloride solution. The mixture was extracted three times with ethyl ether, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl ether: hexane = 1: 3 (volume)) to obtain 3.81 g of a (2S, 6S) compound represented by the following chemical formula (4). (Yield 64%). This is erythro: threo = 6
It was a mixture of 4:36 (weight).

[0060]

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(However, Bn represents a benzyl group)

Synthesis of Compound (5) Anhydrous dimethyl sulfoxide (680 mg, 8.7 mM)
To a solution of 1) in 15 ml of anhydrous methylene chloride, 0.38 ml (4.4 mmol) of oxalyl dichloride was added dropwise at -70 ° C over 5 minutes, and the mixture was further stirred at the same temperature for 10 minutes. The obtained erythro form: threo form = 64:
4 ml of anhydrous methylene chloride of 1.00 g (2.9 mmol) of 36 compound (4) were added dropwise, and the mixture was stirred at -70 ° C for 9 minutes. 2.0 ml of anhydrous triethylamine (14 m
mol) was added dropwise, and the temperature was gradually returned to room temperature, hexane was added, the mixture was filtered through Celite-545, and the filtrate was washed with 1N hydrochloric acid. The aqueous layer was extracted three times with methylene chloride, and the extract was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl ether: hexane = 1: 10 (volume)) and represented by the following chemical formula (2S, 6S).
550 mg of the ethynyl ketone derivative (5) was obtained (55% yield).

[0063]

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(However, Bn represents a benzyl group) ¹ H NMR (CDCl ₃ ) δ: 0.86 (3H, brt, J = 7.
_{2Hz, CH 3) 1.0 ~1.9 (} 8H, m, CH 2) 1.38 (3H, s, CH 3) 1.47 (3H, s, CH 3) 4.02 (1H, dd, J = 5.6 Hz,
8.24 Hz, CH) 4.18 (1H, dd, J = 6.4 Hz,
8.24 Hz, CH) 4.42 (1H, d, J = 11.5 Hz,
CH) 4.70 (1H, d, J = 11.5 Hz,
CH) 4.86 (1H, dd, J = 5.6 Hz,
6.4 Hz, CH) 7.31 (5H, s, C ₆ H ₅ ) IR νmax (neat) 699, 735, 835, 1060, 1220, 1
320, 1370, 1380, 1450, 1675, 2
200,2860,2920,3020cm ^-1

Synthesis of Compound (B) Hydrogenation of 550 mg (1.6 mmol) of the (2S, 6S) ethynyl ketone derivative (5) obtained above in 16 ml of anhydrous ether at -30 ° C. at a concentration of 0.26 mol. 9.6 ml of boron zinc-ethyl ether solution (2.5 m
mol) was added dropwise over 5 minutes under a nitrogen atmosphere.
Stirred for 0 minutes. After the reaction is completed, add water and 0.5N hydrochloric acid 2
0 ml was added and the mixture was stirred at 0 ° C. for 30 minutes. The aqueous layer was extracted three times with ethyl ether, and the extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl ether: hexane = 1: 3 (volume)) to give a (2S, 5R, 6S) ethynyl alcohol derivative (B) (Eritro) represented by the following chemical formula: Compound: threo compound = 90: 10 (weight)) was obtained in an amount of 349 mg (yield: 63).
%).

[0066]

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(However, Bn represents a benzyl group) ¹ H NMR (CDCl ₃ ) δ: 0.87 (3H, brt, J = 7.
2 Hz, CH ₃ ) 1.0 to 1.8 (8H, m, CH ₂ ) 1.36 (3H, s, CH ₃ ) 1.45 (3H, s, CH ₃ ) 3.49 (1 H, dt, J = 3.8 Hz,
6.4 Hz, CH) 3.88 (1H, dd, J = 6.4 Hz,
7.7 Hz, CH) 4.12 (1H, dd, J = 6.4 Hz,
7.7 Hz, CH) 4.4 to 4.7 (1 H, m, J = 1.5 Hz,
3.8Hz, CH) 4.59 (2H, s, CH 2) 4.69 (1H ddd, J = 1.5H
z, 6.4 Hz, 6.4 Hz, CH) 7.30 (5H, s, C ₆ H ₅ ) ¹³ C NMR (CDCl ₃ ) δ: 13.98, 22.54, 25.27, 2
5.96, 26.22, 30.06, 31.85,
64.16, 65.57, 69.94, 72.4
9, 81.50, 83.70, 84.00, 10
0.31,127.83,128.40,138.21

Synthesis of Compound (A) A solution of 105 mg (0.30 mmol) of the obtained (2S, 5R, 6S) ethynyl alcohol derivative (B) in 2 ml of anhydrous tetrahydrofuran was treated with 24.1 mg of lithium aluminum hydride (0%). (6.63 mmol) in 5 ml of anhydrous tetrahydrofuran at 0 ° C. and stirred under reflux for 18 minutes. After completion of the reaction, ethyl acetate, ethanol,
Water and 0.1N hydrochloric acid were sequentially added to decompose, and the aqueous layer was extracted twice with ethyl ether. The extract was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl ether: hexane = 1: 3 (volume)) and represented by the following chemical formula. 80.1 mg of the (2S, 5R, 6S) allyl alcohol derivative (A) was obtained (76% yield).

[0069]

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(Where Bn represents a benzyl group) ¹ H NMR (CDCl ₃ ) δ: 0.86 (3H, t, J = 5.4H)
_{z, CH 3) 1.38 (3H} , s, CH 3) 1.40 (3H, s, CH 3) 1.04~1.8 (8H, m, CH 2) 3.2 ~3.5 ( 1H, m, CH) 3.52 (1H, dd, J = 7.7 Hz,
7.7 Hz, CH) 4.08 (1H, dd, J = 6.4 Hz,
8.0 Hz, CH) ¹³ C NMR (CDCl ₃ ) δ: 14.02, 22.61, 25.46, 2
5.92, 26.72, 29.42, 31.93,
69.44, 72.22, 72.56, 82.1
8, 127.72, 127.79, 128.40, 12
9.89, 132.47, 140.60

Using the obtained allyl alcohol derivative (A), which is the object compound of the present invention, the optical system represented by the above general formula (P) which is a key intermediate for the synthesis of prostaglandins according to the following examples. An active γ-lactone derivative was synthesized.

Synthesis of Compound (6) 80.1 mg (0.23 mmol) of the allyl alcohol derivative (A) of the (2S, 5R, 6S) form obtained above,
Triethyl orthoacetate 0.15ml (0.82m
mol) and a catalytic amount of heptanoic acid were heated and reacted in 3 ml of xylene at 160 ° C. for 20 minutes, and xylene and produced ethanol were distilled off under reduced pressure. The aqueous layer was extracted twice with ethyl ether, and the extract was washed with saturated saline and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, silica gel column chromatography (ethyl ether: hexane = 1: 1).
10 (volume)) and represented by the following chemical formula (1 ′
65.6 mg of (S, 3S, 6S) -form γ-unsaturated ethyl carboxylate (6) was obtained (68% yield).

[0073]

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(However, Bn represents a benzyl group) ¹ H NMR (CDCl ₃ ) δ: 0.86 (3H, brt, J = 7.
2 Hz, CH ₃ ) 1.0 to 1.8 (8H, m, CH ₂ ) 1.33 (3H, s, CH ₃ ) 1.41 (3H, s, CH ₃ ) 2.40 (1 H, dd, J = 9.0 Hz,
14.7 Hz, CH) 2.50 (1H, dd, J = 5.1 Hz,
14.7Hz, CH) 2.6 ~3.0 (1H , m, CH) 3.5 ~3.8 (2H, m, CH 2) 3.9 ~4.3 (2H, m, CH × 2 4.09 (2H, q, J = 7.2 Hz, C
H ₂ O) 4.31 (1H, d, J = 11.7 Hz,
CH ₂ C ₆ H ₅ ) 4.55 (1 H, d, J = 11.7 Hz,
_{CH 2 C 6 H 5) 5.2} ~5.7 (2H, m, = CH-) 7.27 (5H, s, C 6 H 5) 13 CNMR (CDCl 3) δ: 14.00, 14. 25, 22.59, 2
5.03, 26.30, 31.77, 35.72,
36.50, 41.77, 60.32, 66.8
1, 69.79, 77.30, 79.74, 10
9.08, 127.28, 127.72, 128.2
0, 130.84, 134.45, 139.00, 17
1.79

Synthesis of Compound (P) 65 mg of the (1 ′S, 3S, 6S) form of ethyl γ-unsaturated carboxylate (6) (0.16 mmol)
l), 5 ml of methanol, 1.25 ml of water and CuSO
₄ · 5H ₂ O186mg a (0.75 m mol) 13
The mixture was stirred and refluxed for an hour. After completion of the reaction, ethyl ether was added, and the mixture was filtered through Celite-545. The filtrate was washed with saturated saline and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 5 (volume)), and the (3S, 3'S, 4S) -form γ-lactone derivative (P 35.5 mg (69% yield).

[0076]

Embedded image

(However, Bn represents a benzyl group) ¹ H NMR (CDCl ₃ ) δ: 0.86 (3H, brt, J = 7.
_{2Hz, CH 3) 1.0 ~1.8 (} 8H, m, CH 2) 3.72~3.9 (5H, m, CH 2, CH) 4.4 ~4.7 (1H, m, CH 4.36 (1H, d, J = 11.7 Hz,
CH ₂ ) 4.51 (1H, d, J = 11.7 Hz,
CH ₂ ) 5.55 (1H, dd, J = 6.7 Hz,
15.4 Hz, = CH) 5.68 (1H, dd, J = 7.7 Hz,
15.4 Hz, = CH) 7.29 (5H, s, C ₆ H ₅ ) ¹³ C NMR (CDCl ₃ ) δ: 14.00, 22.57, 24.98, 3
1.69, 34.94, 41.02, 62.27,
70.42, 79.50, 82.60, 127.5
2,127.62,128.23,135.62,13
8.63, 176.48

[0078]

The optically active compound of the present invention is an important compound as a raw material for producing an optically active γ-lactone derivative which is a key intermediate in synthesizing a prostaglandin. The key intermediate can be produced relatively easily and efficiently.

Claims (6)

(57) [Claims] 1. The following general formula (A): (In the general formula (A), R ¹ has 1 to 12 carbon atoms selected from an alkyl group optionally having an alkoxy group, a cycloalkyl group, and an aralkyl group having a hetero atom in the aromatic ring or the alkyl group. And the group R ² represents a hydrogen atom or a readily removable protecting group selected from an acyl group, a silyl group, an aralkyl group and an alkyloxyalkyl group, and the symbol * represents an asymmetric carbon atom. In producing the optically active compound, the following general formula (B): (In the general formula (B), R ^1, R ² and * symbols R ^1, R ² and * represent the same meaning as the sign of the general formula (A)) reducing the optically active compound represented by the A method for producing an optically active compound, comprising: 2. The method according to claim 1, wherein R ^{1 in the} general formula (A) is an alkyl group having 4 to 10 carbon atoms. 3. The method according to claim 2, wherein the alkyl group is a pentyl group.
The manufacturing method described. 4. The process according to claim 1, wherein R ^{2 in the} general formula (A) is an aralkyl group. 5. The method according to claim 4, wherein the aralkyl group is a benzyl group. 6. The compound of the general formula (A) having an optical activity (2
(S, 5R, 6S) body.