JPH06228125A - Production of optically active compound - Google Patents

Abstract

PURPOSE:To provide a process for the production of an optically active substance useful as an intermediate raw material for the easy and efficient production of an optically active gamma-lactone derivative which is a key intermediate for the synthesis of prostaglandin by G.Stork method. CONSTITUTION:The optically active gamma-unsaturated carboxylic acid derivative of formula II can be produced by reacting an optically active compound of formula I [R<1> is 1-12C group selected from (alkoxy)alkyl, cycloalkyl and aralkyl having hetero atom on aromatic ring or alkyl group; R<2> is H, acyl, silyl, aralkyl or alkyloxyalkyl] with a trialkyl orthoacetate of the formula CH3C(OR<4>)3 (R<4> is 1-5C alkyl) in the presence of an acid catalyst under heating. An optically active gamma-lactone derivative of formula III useful as a key intermediate can be produced from the compound of formula II by cyclizing its acetanilide with an acid catalyst to form an intramolecular lactone. The starting compound of formula I can be produced by using a halogen compound of formula IV as a starting raw material through the path shown by the reaction formula via an optically active ethynyl alcohol derivative of formula V.

Description

Detailed Description of the Invention

[0001]

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

[0002]

[Chemical 3]

(In the above general formula (P), R ¹ has 1 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. ~ 12 groups, R ²
Represents a hydrogen atom or an easily 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)
And a process for producing an optically active compound which is an intermediate for producing an optically active γ-lactone derivative.

[0004]

PRIOR ART AND PROBLEM TO BE SOLVED BY THE INVENTION Regarding the production of prostaglandins, the method described in G. In addition to the synthesis method of Stork et al., A method starting from corey lactone or 4-hydroxycyclopentenone has been put into practical use.
This method requires steps such as optical resolution and asymmetric hydrolysis by microorganisms in order to obtain the optically active substance of the raw material, and stereocontrol at the stage of introducing α and ω side chains based on these steps. There are many problems in

From the above point of view, the above G. Stor
The optically active γ-of the general formula (P) developed by K. et al.
It can be said that the prostaglandin synthesis method using a lactone derivative as a key intermediate is an excellent method. However, the problem in this method depends on how economically the compound of the general formula (P), which is a key intermediate, can be produced.

[0006]

As a result of intensive studies to solve the above problems, the present inventors have found that a compound represented by the general formula (P), which is a key intermediate, can be more simply and efficiently used than before. The present invention provides a method for producing well, and the present invention provides a method for producing an intermediate obtained in the course of this production. The present invention includes the following general formula (A)

[0007]

[Chemical 4]

(In the general formula (A), R ¹ has 1 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. ~ 12 groups, R ²
Is a hydrogen atom or an easily removable protecting group selected from an acyl group, a silyl group, an aralkyl group and an alkyloxyalkyl group, R ⁴ is a lower alkyl group having 1 to 5 carbon atoms, and the symbol * is not It is a process for producing an optically active compound represented by a simultaneous carbon atom).

Specific examples of R ¹ in the above 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, silocpentyl, 3-ethylcyclopentyl, cyclohexyl,
A linear or branched alkyl group which may have an alkoxy substituent such as 2-methylcyclohexyl or 4-n-propylcyclohexyl or a cycloalkyl group, phenyloxymethyl, 3-trifluoromethylphenyloxymethyl, 2 Examples include an aralkyl group having a hetero atom 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, t-butylmethylsilyl, trimethylsilyl, t-butyldiphenylsilyl and the like. Examples thereof include silyl groups, aralkyl groups such as benzyl and 4-nitrophenylmethyl, and easily removable groups such as alkyloxyalkyl groups such as tetrahydropyranyl and 1-ethoxyethyl.

Specific examples of R ⁴ in the above general formula (A) include groups such as methyl, ethyl, propyl, butyl and pentyl.

Prostaglandins are compounds having extremely strong physiological activity, which are produced by the chemical conversion of higher unsaturated fatty acids such as arachidonic acid by prostaglandin synthase in vivo and have the following structures.

[0013]

[Chemical 5]

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

In the course of development and research as pharmaceuticals, R ¹ is preferably an alkyl group, a cycloalkyl group or an aralkyl group having 4 to 10 carbon atoms, such as 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, 4-propylcyclohexyl, phenyloxymethyl, 3-
It has been revealed that aralkyl groups such as trifluoromethylphenyloxymethyl, 2-chlorothiophen-5-yloxymethyl, furan-2-yl-2-ethyl and the like exhibit particularly strong physiological activity. The compound of the present invention is useful as a raw material into which a substituent including these organic groups can be introduced.

Γ represented by the above general formula (A) of the present invention
-A method for synthesizing an unsaturated carboxylic acid derivative will be described below according to synthetic route I. In the following, X is a halogen atom, M
Represents an alkali metal.

[0017]

[Chemical 6]

In the above reaction, the halogen compound (1)
A strong base such as n-butyllithium, t-butyllithium, methyllithium or lithium diisopropylamide is reacted with the acetylene compound (2) to form an alkali metal acetylide (2 ') with these strong bases. The compound (4) is obtained by reacting this with an optically active aldehyde (3).

The alkali metal acetylide (2 ') is
As described above, the acetylene compound (2) may be isolated once and then prepared by reacting with a strong base again, but more conveniently, it can be obtained by reacting the halogen compound (1) with twice or more of a strong base. The alkali metal acetylide used can be used as it is. The reaction between the alkali metal acetylide and the optically active aldehyde (3) is preferably carried out at a low temperature of -78 to 0 ° C. The reaction for obtaining the compound (4) can be carried out in an inert solvent such as tetrahydrofuran, diisopropyl ether or toluene at a temperature range of -78 ° C to room temperature. The compound (4) obtained by this reaction is a mixture of the erythro body (6-1) and the threo body (6-2) as shown by the following chemical formula.

[0020]

[Chemical 7]

The erythro body (6-1) or threo body (6-2) can be selectively obtained from this mixture by column separation or the like. Moreover, each optical isomer can be produced more selectively. This compound (4)
The 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.

In the reaction for synthesizing the optically active ethynyl alcohol derivative (6) from the compound (5), whether the ethynyl alcohol derivative (6) to be obtained is the erythro body (6-1) represented by the above chemical formula, Or threo body (6-
The reaction conditions differ depending on whether it is 2). That is, when the erythro body (6-1) is intended, the compound (5) is a zinc borohydride complex (Zn (BH ₄ ) ₂ ) and when the threo body (6-2) is intended, an alkali is used. The ethynyl alcohol derivative (6) having the desired configuration can be obtained with good selectivity by reduction with a metal selectride, for example, potassium selectride.

The ethynyl alcohol derivative (6) is
Then, the triple bond is reduced to a trans double bond with lithium aluminum hydride or the like to give an allyl alcohol derivative (B).
Be led to. This reaction can be carried out in an inert solvent such as tetrahydrofuran or dioxane at a temperature of 40 to 80 ° C.

The allyl alcohol derivative (B) has the following general formula (D) CH ₃ C (OR ⁴ ) ₃ (D) (in the above general formula (D), R ⁴ is a lower alkyl group having 1 to 5 carbon atoms). By reacting with a trialkyl orthoacetate represented by the formula (1) under heating in the presence of an acid catalyst to carry out a Johnson-Claisen rearrangement reaction, a γ-unsaturated carboxylic acid derivative (A) which is the object of the present invention can be obtained. it can. Examples of the trialkyl orthoacetate of the general formula (D) include trimethyl orthoacetate, triethyl orthoacetate, tripropyl orthoacetate, tributyl orthoacetate,
Triheptyl orthoacetate and the like can be mentioned, which is used in an amount of 2 to 10 times equivalent to the allyl alcohol derivative (B) in a solvent such as toluene, xylene, mesitylene and the like 130 to 18
The reaction is carried out at a temperature of 0 ° C. As the acid catalyst, Lewis acid, Lewis acid complex (for example, BF ₃ · (C ₂ H ₅ ) ₂ O)
And organic acids such as heptanoic acid are used.

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

The optically active aldehyde (3) is
It can be synthesized according to the following synthetic route II. Below
By the way, R¹, R²The symbols * and * in general formula (A)
R¹, R ²And have the same meaning as the symbols *, X, Y
Are independently hydroxyl group, acyl group, sulfoxy group
And a group or atom selected from halogen atoms.

[0027]

[Chemical 8]

The above optically active mannitol is mixed with acetone and an acid.
Reacting in the presence of a catalyst to give triacetonide (a),
This is partially hydrolyzed with hydrous acetic acid to give tetraol (b).
The primary and secondary hydroxyl groups separately.
Liphenylphosphine-CCl_Four, Acid halide-pyridy
And pyridine-methanesulfonyl chloride
An acyl group, a sulfoxy group or a halogen atom
All are converted to acetonide (c). Then this
After converting cetonide (c) to diepoxide (d) with a base,
R³MgBr, R³MgBr-Cu₂(CN)₂, R³
Li (however, R ³Is R¹Show groups with one less carbon
R) with aluminum) or lithium aluminum hydride¹Guide the group
And then add a hydroxyl group to R²X '(X' is a halogen atom or
Is a sulfoxy group) to give an acetonide (e),
After hydrolyzing this to obtain a diol (f), Pb (O
Ac)_FourAnd NaIO_FourThe desired optically active
Ludehid (3) can be obtained.

The optically active γ-unsaturated carboxylic acid derivative represented by the general formula (A), which is the object of the present invention obtained above, is a key intermediate in the synthesis of prostaglandins as shown in the following synthetic formula. It can be converted into a γ-lactone derivative of compound (P).

[0030]

[Chemical 9]

In the above reaction, the .gamma.-unsaturated carboxylic acid derivative (A) is obtained by ring-opening the acetonide of the .gamma.-unsaturated carboxylic acid derivative with an acid catalyst for intramolecular lactonization to obtain an optically active .gamma.-lactone derivative (P). For the hydrolysis of acetonide in this reaction, a hydrous organic acid, an alcohol such as methanol or ethanol, a mineral acid in a solvent such as acetone or dioxane, a Lewis acid or a Lewis acid complex such as BF ₃ · ether complex, CuSO ₄ , ZnSO ₄ or the like is used. Can be performed at room temperature to 80 ° C.

The compound of the general formula (P) thus obtained is the same as that described in G. According to the method of synthesizing prostaglandins of Stork et al.
You can lead to F). Therefore, the optically active compound of the general formula (A) according to the present invention is required to have S as the stereochemistry at the 1'-position, the 3-position and the 6-position in the general formula (A) as the above raw material. .

[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.
The mixture was stirred vigorously in ml at room temperature for 3 days, 50 g of potassium carbonate was added, and the mixture was further stirred for 1 day. The solid matter is removed by suction filtration, the solvent in the filtrate is distilled off under reduced pressure, water is added to the obtained residue, and the precipitated crystal is collected by suction filtration to give a crude product 4.
5 g was obtained. This was dissolved in 20 ml of ethanol by heating and then filtered, the filtrate was cooled to room temperature, and the precipitated crystals were collected by filtration to obtain the optical activity (2R, 3R, 4) represented by the following chemical formula.
37.3 g (yield 50%) of triacetonide (a) in the form of (R, 5R) was obtained.

[0035]

[Chemical 10]

¹ HNMR (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 triacetonide (a) obtained above
ol) was stirred in 50 ml of 70% acetic acid at 40 ° C. for 3.5 hours, then rapidly concentrated under reduced pressure at 40 ° C., and acetone was added to the residue to crystallize D-mannitol (0.72).
g) was filtered off, and acetone was distilled off from the filtrate under reduced pressure to obtain a syrupy product. This was recrystallized with 50 ml of benzene and the optical activity (2R, 3R, 4
R, 5R) tetraol (b) 8.8 g (yield 80
%) Was obtained.

[0038]

[Chemical 11]

¹ HNMR (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) of the tetraol (b) obtained above
9 mol), 55 ml of anhydrous pyridine (0.68 mo
l), 16 ml of benzoyl chloride (0.138 mol), anhydrous CH in a solution of 50 ml of CH ₂ Cl _{2 at} -70 ° C.
A mixture of 5 ml of ₂ Cl _{2 was} added dropwise over 15 minutes, and after the addition, the mixture was stirred at -30 ° C for 1 hour and at room temperature for 10 hours. After completion of the reaction was confirmed by thin-layer chromatography, the solvent was distilled off under reduced pressure. . Methanesulfonyl chloride 11.2 was added to this residue.
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 confirming the completion of the reaction by thin layer chromatography, a mixed solvent 1 of ethyl ether: hexane = 7: 3 (volume) was added to the reaction mixture.
00 ml was added and the yellow suspension was added to Celite-545.
The solvent was distilled off under reduced pressure. The brown residue obtained was diluted with CH ₂ Cl ₂ and acidified by adding concentrated hydrochloric acid and then C
Extracted 3 times with H ₂ Cl ₂ . The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give an optically active (2R, 3R, 4R, 5R) body of a brown semisolid. 42 g of the product acetonide (c) was obtained.

[0041]

[Chemical 12]

(However, Ms is a methyl sulfoxy group, ph
Represents a phenyl group)

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

[0044]

[Chemical 13]

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

[0047]

[Chemical 14]

The above-obtained crude diol (e-1) was dissolved in 30 ml of anhydrous tetrahydrofuran, to which 100 ml of anhydrous tetrahydrofuran of 0.48 g (1.07 mmol) of sodium hydride was added dropwise under reflux for 15 minutes. After stirring and refluxing for 1 hour, the mixture was cooled to 0 ° C. To this suspension, DC-18-crown ether-6 132m
g and 9.3 ml (78 mmol) of benzyl bromide at 0 ° C.
Was added and the mixture was stirred and refluxed for 4 hours. Concentrate the reaction mixture under reduced pressure to 1
After decomposing it with normal hydrochloric acid and extracting 3 times with hexane, the extract was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain an optical activity represented by the following chemical formula (6S , 7R, 8R, 9S) acetonide (e-2) was obtained.

[0049]

[Chemical 15]

(However, Bn represents a benzyl group)

The above acetonide (e-2) was mixed with 80% acetic acid 1
After heating and stirring in 100 ml at 100 ° C. for 10 hours, the solvent was distilled off under reduced pressure, followed by extraction with ethyl ether, the extract was washed with a caustic soda aqueous solution, the aqueous layer was further extracted with ethyl ether, and the ether layers were combined. It was washed successively 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).
(Eluted by (volume)), the optical activity (6
S, 7R, 8R, 9S) diol (f) 8.66 g
(55% yield from compound (d)) was obtained.

[0052]

[Chemical 16]

(However, Bn represents a benzyl group) ¹ HNMR (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 = 10.8Hz,
CH) 4.62 (2H, d, J = 10.8Hz,
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
260 mg of lead tetraacetate in 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 through Celite-545, the filtrate was washed with saturated sodium hydrogen carbonate solution, the aqueous layer was extracted twice with hexane, the hexane layers were combined and washed with saturated brine, and then anhydrous sulfuric acid was added. It was dried with magnesium. After the solvent was distilled off, the residue was purified by silica gel column chromatography (ethyl ether: hexane = 1: 2 (volume)) and (S) -2-benzyloxyheptanal (3) 160 mg (yield 80%).
Got

[0055]

[Chemical 17]

(However, Bn represents a benzyl group) ¹ HNMR (CDCl ₃ ) δ: 0.87 (3H, t, J = 5.8H
_{z, CH 3) 1.0 ~1.8 (} 8H, m, CH 2) 3.73 (1H, dt, J = 2.2Hz,
6.2Hz, CH) 4.51 (1H, d, J = 11.6Hz,
CH) 4.65 (1H, d, J = 11.6Hz,
CH) 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]

[Chemical 18]

(S) -dibromide represented by: 4.8
g (16.8 mmol) of anhydrous tetrahydrofuran 1
00 ml was cooled to -78 ° C and the concentration was 1.
62 mol of butyl lithium-hexane solution 16.4 m
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 be converted into optically active lithium acetylide (2 '), which was converted to -78 ° C.
20 ml of anhydrous tetrahydrofuran containing 2.41 g (4.4 mmol) of (S) -2-benzyloxyheptanal (3) obtained above by cooling to 20 ° C. was added dropwise, and the mixture was further stirred for 30 minutes, and then decomposed with an aqueous ammonium chloride solution. The extract was extracted 3 times with ethyl ether, washed with saturated brine, 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 body: threo body = 6
It was a mixture of 4:36 (weight).

[0060]

[Chemical 19]

(Bn represents a benzyl group)

Synthesis of Compound (5) Anhydrous dimethyl sulfoxide 680 mg (8.7 m mo)
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 stirred at the same temperature for 10 minutes. The erythro body obtained above: threo body = 64:
36 ml of compound (4) (1.00 g, 2.9 mmol) in anhydrous methylene chloride (4 ml) was 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 3 times with methylene chloride, the extract was washed with saturated brine 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 body ethynyl ketone derivative (5) was obtained (yield 55%).

[0063]

[Chemical 20]

(However, Bn represents a benzyl group) ¹ HNMR (CDCl ₃ ) δ: 0.86 (3H, br t, 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 = 5.6Hz,
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 = 11.5Hz,
CH) 4.86 (1H, dd, J = 5.6Hz,
6.4 Hz, CH) 7.31 (5 H, s, C ₆ H ₅ ) IR νmax (neat) 695, 735, 835, 1060, 1220, 1
320, 1370, 1380, 1450, 1675, 2
200, 2860, 2920, 3020 cm ^-1

Synthesis of Compound (6) 550 mg (1.6 mmol) of ethynyl ketone derivative (5) of (2S, 6S) body obtained above was hydrogenated into 16 ml of anhydrous ether at -30 ° C. to a concentration of 0.26 mol. Boron zinc-ethyl ether solution 9.6 ml (2.5 m
(mol) under a nitrogen atmosphere over 5 minutes, and further 3
Stir for 0 minutes. After the reaction, 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 3 times with ethyl ether, and the extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (ethyl ether: hexane = 1: 3 (volume)), and the (2S, 5R, 6S) ethynyl alcohol derivative (6) represented by the following chemical formula (erythro) was obtained. 349 mg (body: threo body = 90: 10 (weight)) was obtained (yield 63).
%).

[0066]

[Chemical 21]

(However, Bn represents a benzyl group) ¹ HNMR (CDCl ₃ ) δ: 0.87 (3H, br t, J = 7.
_{2Hz, CH 3) 1.0 ~1.8 (} 8H, m, CH 2) 1.36 (3H, s, CH 3) 1.45 (3H, s, CH 3) 3.49 (1H, dt, J = 3.8Hz,
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,
3.8 Hz, CH) 4.59 (2H, s, CH ₂ ) 4.69 (1H ddd, J = 1.5H
z, 6.4 Hz, 6.4 Hz, CH) 7.30 (5 H, s, C ₆ H ₅ ) ¹³ CNMR (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 (B) A solution of 105 mg (0.30 mmol) of the ethynyl alcohol derivative (6) of the (2S, 5R, 6S) body obtained above in 2 ml of anhydrous tetrahydrofuran was added with 24.1 mg (0) of lithium aluminum hydride. (0.63 mmol) was added to 5 ml of anhydrous tetrahydrofuran at 0 ° C., and the mixture was refluxed with stirring for 18 minutes. After completion of the reaction, ethyl acetate, ethanol,
Water and 0.1 N hydrochloric acid were added successively to decompose the mixture, and the aqueous layer was extracted twice with ethyl ether. The extract was washed with saturated brine, 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 be represented by the following chemical formula. 80.1 mg of the (2S, 5R, 6S) allyl alcohol derivative (B) was obtained (yield 76%).

[0069]

[Chemical formula 22]

(However, Bn represents a benzyl group) ¹ HNMR (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 = 7.7Hz,
7.7 Hz, CH) 4.08 (1H, dd, J = 6.4 Hz,
8.0 Hz, CH) ¹³ CNMR (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

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

[0072]

[Chemical formula 23]

(However, Bn represents a benzyl group) ¹ HNMR (CDCl ₃ ) δ: 0.86 (3H, br t, J = 7.
_{2Hz, CH 3) 1.0 ~1.8 (} 8H, m, CH 2) 1.33 (3H, s, CH 3) 1.41 (3H, s, CH 3) 2.40 (1H, 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 (1H, d, J = 11.7Hz,
_{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

Γ which is the target compound of the present invention obtained above
Using the unsaturated carboxylic acid derivative, an optically active γ-lactone derivative represented by the general formula (P), which is a key intermediate for the synthesis of prostaglandins, was synthesized according to the following examples.

Synthesis of Compound (P) 65 mg (0.16 m mo) of ethyl (A) ethyl γ-unsaturated carboxylate of the (1'S, 3S, 6S) body obtained above
1), 5 ml of methanol, 1.25 ml of water and CuSO
_4.5 H ₂ O 186 mg (0.75 mmol) 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 the solvent was distilled off 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) represented by the following chemical formula was obtained. ) 35.5 mg was obtained (yield 69%).

[0076]

[Chemical formula 24]

(However, Bn represents a benzyl group) ¹ HNMR (CDCl ₃ ) δ: 0.86 (3H, br t, 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 = 6.7Hz,
15.4Hz, = CH) 5.68 (1H, dd, J = 7.7Hz,
15.4Hz, = CH) 7.29 (5H , s, C 6 H 5) 13 CNMR (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]

INDUSTRIAL APPLICABILITY 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 the synthesis of prostaglandins. A key intermediate can be produced relatively easily and efficiently.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI technical display location C07D 307/33

Claims (6)

[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 which may have an alkoxy group, a cycloalkyl group and an aralkyl group having a hetero atom in an aromatic ring or an alkyl group. R ² is a hydrogen atom or an easily removable protecting group selected from an acyl group, a silyl group, an aralkyl group and an alkyloxyalkyl group,
⁴ represents a lower alkyl group having 1 to 5 carbon atoms, and the symbol * represents an asymmetric carbon atom. In producing an optically active compound represented by 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)) of the optically active compound represented by the following general Of the formula (D) CH ₃ C (OR ⁴ ) ₃ (D) (in the general formula (D), R ⁴ represents a lower alkyl group having 1 to 5 carbon atoms) and an acid catalyst. A process for producing an optically active compound, which comprises reacting with heating in the presence of the compound. 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 alkyl group is a pentyl group.
The manufacturing method described. 4. The method 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 formula (A) is optically active (1 ′).
S, 3S, 6S) form, The manufacturing method in any one of Claims 1-5.