JP4958513B2 - Method for producing sedanenolide - Google Patents

Description

  The present invention relates to a method for producing a racemic or optically active form of 3-butyl-4,5-dihydrophthalide (common name: sedanenolide).

  Sedanenolide is a component widely present in celery family plants such as celery and nematodes, and has activities such as skin whitening and arterial smooth muscle cell proliferation inhibition (Non-patent Document 1, Patent Document). 1), and a component that greatly contributes to the characteristic aroma of celery (see Non-Patent Document 2 and Non-Patent Document 3).

  A method for synthesizing racemic sedanenolide has already been reported, but there are problems in terms of the complexity of the reaction operation (see Non-Patent Document 4).

Further, since sedanenolide has an asymmetric center in the molecule, there are two optical isomers, but a method for synthesizing optical isomers has not yet been reported.
JP 2004-149505 A Japan J. Pharmacol. 1993, Vol. 63, P.I. 353-359. J. et al. Food Sci. , 1987, Vol. 52, p. 658-660 Phytochemistry, 1989, Vol. 28, p. 1817-1824 Gaodeng Xuexiao Huaxue Xuebao 1995, Vol. 16, P.I. 1420-1422.

  An object of the present invention is to provide a simple method capable of producing a racemate or optically active sedanenolide in good yield and high purity.

  As a result of intensive studies to achieve the above-mentioned object, the present inventors heated and closed the ester compound obtained by condensing 1-heptin-3-ol with 2,4-pentadienoic acid, Next, by isomerization, sedanenolide can be obtained in good yield, and optically active 1-heptin-3-ol is subjected to the same reaction step to obtain optically active sedanenolide in good yield. As a result, the present invention has been completed.

  Thus, the present invention provides the following formula (3)

で表される１−エチニルペンチル ２，４−ペンタジエノエートを加熱して閉環し、次いで異性化することを特徴とする下記式（１）

1-ethynylpentyl 2,4-pentadienoate represented by the following formula is heated to cyclize and then isomerized:

で表される３−ブチル−４，５−ジヒドロフタライド（セダネノライド）の製造方法を提供するものである。

The manufacturing method of 3-butyl-4,5-dihydrophthalide (sedanenolide) represented by these is provided.

  The present invention also provides the following formula (3 '):

［式中、＊は不斉炭素原子を示す］
で表される光学活性１−エチニルペンチル ２，４−ペンタジエノエートを加熱して閉環し、次いで異性化することを特徴とする下記式（１’）

[Wherein, * represents an asymmetric carbon atom]
An optically active 1-ethynylpentyl 2,4-pentadienoate represented by the following formula is heated to cyclize and then isomerized:

［式中、＊は不斉炭素原子を示す］
で表される光学活性３−ブチル−４，５−ジヒドロフタライド（光学活性セダネノライド）の製造方法を提供するものである。

[Wherein, * represents an asymmetric carbon atom]
The manufacturing method of optically active 3-butyl-4,5-dihydrophthalide (optically active sedanenolide) represented by these is provided.

  The present invention further relates to 1-ethynylpentyl 2,4-pentadienoate or optically active 1-ethynylpentyl 2,4- represented by the above formula (3) or (3 ′) which is a novel intermediate compound. Pentadienoate is provided.

  The present invention further provides the following formula (2):

で表される１−ヘプチン−３−オールを２，４−ペンタジエン酸と縮合させることを特徴とする前記式（３）で表される１−エチニルペンチル ２，４−ペンタジエノエートの製
造方法を提供するものである。

A method for producing 1-ethynylpentyl 2,4-pentadienoate represented by the above formula (3), wherein 1-heptin-3-ol represented by the formula is condensed with 2,4-pentadienoic acid Is to provide.

  The present invention further provides the following formula (2 '):

［式中、＊は不斉炭素原子を示す］
で表される光学活性１−ヘプチン−３−オールを２，４−ペンタジエン酸と縮合させることを特徴とする前記式（３’）で表される光学活性１−エチニルペンチル ２，４−ペンタジエノエートの製造方法を提供するものである。

[Wherein, * represents an asymmetric carbon atom]
An optically active 1-ethynylpentyl 2,4-pentadiene represented by the above formula (3 ′), wherein the optically active 1-heptin-3-ol represented by the formula is condensed with 2,4-pentadienoic acid A method for producing noate is provided.

  According to the method of the present invention, a racemic or optically active form of sedanenolide useful as a pharmaceutical or a fragrance can be easily produced in good yield and high purity.

  Hereinafter, the method for producing sedanenolide of the present invention will be described in more detail.

Synthesis of sedanenolide (racemate) The synthesis process of sedanenolide (racemate) according to the present invention is shown in the following reaction formula A.

(First step)
1-ethynylpentyl 2,4-pentadienoate of formula (3) is easily obtained by condensing 1-heptin-3-ol of formula (2) with 2,4-pentadienoic acid according to the first step. Can be manufactured.

  The starting material 1-heptin-3-ol of the formula (2) is a compound known per se, for example, literature (J. Org. Chem., 1998, Vol. 63, P. 5283-5287). It can be easily synthesized by the Grignard reaction of valeraldehyde by the method described. In addition, 2,4-pentadienoic acid reacted with 1-heptin-3-ol of formula (2) can be easily obtained as a commercial product or, for example, literature (J. Asian Natural Products Research., 2003, Vol.5, P.165-169) and can be easily synthesized by reacting malonic acid with acrolein.

The esterification reaction between the compound of formula (2) and 2,4-pentadienoic acid is not particularly limited, and is performed according to a method known per se, for example, the literature (Chemical Society of Japan, 4th edition, Experimental Chemistry Course). , Vol. 22, Organic Synthesis IV, P. 43-51). For example, a method in which a compound of formula (2) is dehydrated and condensed with 2,4-pentadienoic acid in the presence of an acid catalyst; 2,4-pentadienoic acid is derived into an active ester using a condensing agent such as dicyclohexylcarbodiimide (DCC). A method of activating a carboxyl group and reacting it with a compound of formula (2); a method of inducing 2,4-pentadienoic acid to the corresponding acid halide and reacting it with a compound of formula (2) A method of activating the compound of formula (2) using a condensing agent such as DEAD (diethylazodicarboxylate) and reacting this with 2,4-pentadienoic acid; 2,4-pentadienoic acid as an acid anhydride; Examples thereof include a method of inducing and reacting with a compound of the formula (2). In these esterification reactions, 2,4-pentadienoic acid can be used in a proportion of usually 1 to 10 mol, preferably 1 to 3 mol, per 1 mol of the compound of formula (2).

  The compound of the formula (3) to be produced can be purified by, for example, distillation, silica gel column chromatography or the like after the completion of the reaction, but the crude product can be directly used in the next second step. In addition, the compound of Formula (3) obtained according to a 1st process is a novel compound which has not been described in the conventional literature.

(Second step)
1-ethynylpentyl 2,4-pentadienoate of the formula (3) obtained in the first step is added in the presence or absence of a solvent, if necessary, with a catalytic amount of an antioxidant, By heating, a racemic sedanenolide of the formula (1) can be produced.

  The heating reaction of the compound of formula (3) is usually performed at a temperature of about 100 ° C. to about 300 ° C., preferably about 200 ° C. to about 250 ° C. in the presence or absence of an organic solvent, preferably in the presence of an organic solvent. In this case, it can be carried out with stirring for about 1 to 24 hours under atmospheric pressure or under pressure of 0.05 to 10 MPa, preferably 0.1 to 0.5 MPa in a pressure vessel. Examples of the organic solvent that can be used here include ether solvents such as diethyl ether, tetrahydrofuran, and dioxane; hydrocarbon solvents such as toluene, hexane, and xylene; halogen solvents such as chloroform, methylene chloride, and carbon tetrachloride; Alcohol solvents such as ethanol, methanol and propanol; Ketone solvents such as acetone and methyl ethyl ketone; Aprotic polar solvents such as acetonitrile, dimethylformamide and dimethyl sulfoxide; Ester solvents such as ethyl acetate and methyl acetate alone or Two or more types can be mixed and used. The amount used is usually 0.5 to 100 times, preferably 1 to 10 times, based on the weight of the compound of formula (3).

  The above reaction can be performed by adding an antioxidant as necessary. Examples of the antioxidant include BHT (2,6-di-t-butyl-p-cresol), BHA (butylhydroxyanisole), 4,4′-thiobis (6-t-butyl-m-cresol). The amount used can be 0.01 to 10 mol%, preferably 0.1 to 3 mol%, based on the compound of formula (3).

  The compound of the formula (1) obtained as described above can be separated from the reaction mixture and purified by a method known per se, for example, distillation, silica gel column chromatography or the like.

Synthesis of sedanenolide (optically active substance) A synthesis process of optically active sedanenolide according to the present invention is shown in the following reaction formula B.

［式中、＊は不斉炭素原子を示す］

[Wherein, * represents an asymmetric carbon atom]

(First step)
The production of the compound of the formula (3 ′) by the reaction of the compound of the formula (2 ′) and 2,4-pentadienoic acid can be carried out in the same manner as in the first step in the above reaction formula A. The optically active 1-heptin-3-ol of the formula (2 ′) which is a starting material is a compound known per se, for example, literature (J. Org. Chem., 2004, Vol. 69, P. 7108). -7113). In addition, the compound of the formula (3 ′) obtained according to the first step is a novel compound not described in the literature.

(Second step)
By heating the compound of the formula (3 ′) obtained in the first step in the same manner as in the second step in the reaction formula A, the optically active sedanenolide of the formula (1 ′) can be produced.

  The compound of the formula (1 ') obtained as described above can be separated from the reaction mixture and purified by a method known per se, for example, distillation, silica gel column chromatography or the like.

  Hereinafter, the present invention will be described more specifically with reference to examples.

Example 1: Synthesis of (±) -1- ethynylpentyl 2,4-pentadienoate 2,4-pentadienoic acid (602 mg, 6.1 mmol) and toluene (3 mL) were charged into a 30 mL flask and stirred under water cooling. To do. To it is added a solution of benzoyl chloride (863 mg, 6.1 mmol) and triethylamine (620 mg, 6.1 mmol) in toluene (3 mL). After stirring at room temperature for 0.5 hour, the produced crystal is separated by filtration, and the resulting filtrate is concentrated under reduced pressure and pumped up to obtain crude mixed acid anhydride (1.36 g).

  Next, the above mixed acid anhydride (1.36 g) is charged into a 30 mL flask together with tetrahydrofuran (3 mL) and stirred under water cooling. A mixture of (±) -1-heptin-3-ol (300 mg, 2.7 mmol), triethylamine (270 mg, 2.7 mmol), a catalytic amount of N, N-dimethylaminopyridine and tetrahydrofuran (3 mL) is added dropwise thereto. After stirring at room temperature for 0.5 hours, the mixture is diluted with ether and washed successively with dilute hydrochloric acid, aqueous sodium bicarbonate, and brine. After drying over anhydrous magnesium sulfate, concentration under reduced pressure and pumping up, the resulting residue (1.17 g) was purified by silica gel column chromatography to give (±) -1-ethynylpentyl 2,4-pentadienoate (480 mg). Is obtained as a pale yellow oil. Yield 92%.

NMR ( ¹ H, 400 MHz, CDCl ₃ ): δ 0.92 (t, 3H, J = 7.1 Hz), 1.31-1.50 (m, 4H), 1.78-1.83 (m, 2H), 2.45 (
d, 1H, J = 2.3 Hz), 5.43 (dt, 1H, J = 2.0, 6.7 Hz), 5.51 (d, 1H, J = 9.6 Hz), 5.63 (d , 1H, J = 17.0 Hz), 5.92 (d, 1H, J = 15.1 Hz), 6.46 (dt, 1H, J = 10.6, 17.0 Hz), 7.30 (dd, 1H, J = 11.0, 15.6 Hz).
NMR ( ¹³ C, 100 MHz, CDCl ₃ ): δ 13.87, 22.19, 26.99, 34.34, 63.76, 73.39, 81.35, 121.53, 126.06, 134. 62, 145.53, 165.68.
IR (film) ν _max cm ⁻¹ : 2958, 1716, 1599, 1304, 1265, 1198, 1140, 1006, 866.

Example 2: Synthesis of (±) -sedanenolide (±) -1-ethynylpentyl 2,4-pentadienoate (400 mg, 2.0 mmol), toluene (40 mL) and toluene prepared in Example 1 in a 100 mL pressure vessel A catalytic amount of BHT (2,6-di-t-butyl-p-cresol) is charged and sealed with argon. It is heated and stirred at 220 ° C. for 9 hours. The obtained reaction product is concentrated under reduced pressure, pumped up, and the resulting residue (415 mg) is purified by silica gel column chromatography to give (±) -cedanenolide (191 mg) as a pale yellow oil. Yield 50%.

NMR ( ¹ H, 400 MHz, CDCl ₃ ): δ 0.90 (t, 3H, J = 7.1 Hz), 1.29-1.44 (m, 4H), 1.48-1.58 (m, 1H), 1.83-1.92 (m, 1H), 2.43-2.52 (m, 4H), 4.92 (dd, 1H, J = 3.7, 7.8 Hz), 5. 89-5.92 (m, 1H), 6.20 (d, 1H, J = 9.6 Hz).
NMR ( ¹³ C, 100 MHz, CDCl ₃ ): δ 13.83, 20.77, 22.27, 22.42, 26.70, 31.88, 82.48, 116.87, 124.49, 128. 28, 161.37, 171.24.
IR (film) ν _max cm ⁻¹ : 2932, 1750, 1655, 1435, 1335, 1273, 1045, 1006, 963, 715.
MS: 192 (13, [M] ⁺ ), 135 (4), 107 (100), 91 (4), 85 (8), 77 (27), 57 (7), 51 (6), 41 (4 ).

Example 3: Synthesis of (S) -1-ethynylpentyl 2,4 -pentadienoate Instead of (±) -1-heptin-3-ol, (S) -1-heptin-3-ol (99 (S) -1-ethynylpentyl 2,4-pentadienoate (467 mg) is obtained by operating in the same manner as in Example 1 except that% ee) is used. Yield 90%.

[Α] ²⁰ _D : -62.9 (CHCl ₃ , c = 1.015)

Example 4: Synthesis of (S) -sedanenolide (±) -1- ethynylpentyl 2,4- pentadienoate Instead of (S) -1- ethynylpentyl 2,4-penta prepared in Example 3 (S) -sedanenolide (181 mg) is obtained by operating in the same manner as in Example 2 except that dienoate is used. Yield 47%. When the optical purity was determined by analysis by gas chromatography using an optical isomer separation column, 98.0% e.e. e. Met.

^{_{[Α] 20 D: -133.5 (}} CHCl 3, c = 1.040).

Measurement of optical purity by gas chromatography using an optically active column was performed with the following apparatus and conditions.
Equipment: Agilent 6890N
Column: CHIRAMIX (0.25 mm ID × 50 m, manufactured by Hasegawa Koryo Co., Ltd.)
Oven temperature: 40 to 180 ° C (+ 0.7 ° C / min)
Carrier gas: Nitrogen (0.7 mL / min)

Example 5: Synthesis of (R) -1-ethynylpentyl 2,4 -pentadienoate Instead of (±) -1-heptin-3-ol, (R) -1-heptin-3-ol (97 (R) -1-ethynylpentyl 2,4-pentadienoate (457 mg) is obtained by operating in the same manner as in Example 1 except that% ee) is used. Yield 88%.

^{_{[Α] 20 D: +60.3 (}} CHCl 3, c = 1.035).

Example 6: Synthesis of (R) -sedanenolide (±) -1- ethynylpentyl 2,4- pentadienoate Instead of (R) -1- ethynylpentyl 2,4-penta prepared in Example 5 By operating in the same manner as in Example 2 except that dienoate is used, (R) -cedanenolide (204 mg) is obtained. Yield 53%. When the optical purity was determined by gas chromatographic analysis using an optical isomer separation column, it was found to be 96.2% e.e. e. Met.

^{_{[Α] 20 D: +120.7 (}} CHCl 3, c = 1.015).

Claims (6)

Following formula (3)

1-ethynylpentyl 2,4-pentadienoate represented by the following formula is heated to cyclize and then isomerized:

The manufacturing method of 3-butyl-4,5-dihydrophthalide represented by these. Following formula (3 ')

[Wherein, * represents an asymmetric carbon atom]
An optically active 1-ethynylpentyl 2,4-pentadienoate represented by the following formula is heated to cyclize and then isomerized:

[Wherein, * represents an asymmetric carbon atom]
The manufacturing method of optically active 3-butyl-4,5-dihydrophthalide represented by these. Following formula (3)

1-ethynylpentyl 2,4-pentadienoate represented by Following formula (3 ')

[Wherein, * represents an asymmetric carbon atom]
An optically active 1-ethynylpentyl 2,4-pentadienoate represented by the formula: Following formula (2)

1-heptin-3-ol represented by the following formula (3) is condensed with 2,4-pentadienoic acid

The manufacturing method of 1-ethynyl pentyl 2, 4-pentadienoate represented by these. Following formula (2 ')

Wherein the optically active 1-heptin-3-ol represented by the formula is condensed with 2,4-pentadienoic acid:

[Wherein, * represents an asymmetric carbon atom]
A process for producing optically active 1-ethynylpentyl 2,4-pentadienoate represented by the formula: