JP4520203B2 - Method for producing polyprenyl compound - Google Patents

Description

  The present invention relates to a method for producing a polyprenyl compound.

  One of the polyprenyl compounds (2E, 4E, 6E, 10E) -3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid is a retinoic acid receptor It is known to have a transcriptional activating action via, and to have a differentiation-inducing action and an apoptosis-inducing action in hepatocellular carcinoma. In clinical practice, (2E, 4E, 6E, 10E) -3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid is treated for long-term treatment of liver cancer for a year. In addition to significantly suppressing subsequent recurrence, it has been suggested that hepatic cancer recurrence is suppressed, and at this time, it is reported that there are almost no side effects observed in liver dysfunction and other retinoids (Non-Patent Documents). 1).

  (2E, 4E, 6E, 10E) -3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid is a known compound. Compound A is produced as a synthetic intermediate, and compound A is produced, for example, by reacting compound B with (2E, 6E) -3,7,11-trimethyl-2,6,10-dodecatrien-1-al. (For example, refer to Patent Document 1 and Patent Document 2).

［上記式中、Ｒ³、Ｒ⁴はアルキル基を示す。］
しかしながら、これらの方法は、不要なＺ体が多量に副成すること等の欠点を有しているため、高選択率で、かつ、実用的なＥ体の製造方法の開発が望まれている。

[Wherein R ³ and R ⁴ represent an alkyl group. ]
However, since these methods have drawbacks such as a large amount of unnecessary Z isomers, development of a practical method for producing E isomers with high selectivity is desired. .

In general, as a method for selectively synthesizing an isomer in a Wittig reaction, a method of adding one equivalent or a large excess of crown ether is known (see, for example, Non-Patent Document 2 and Non-Patent Document 3). ). However, these methods have limitations in industrial use considering that the crown ether is expensive.
On the other hand, a method of selectively synthesizing isomers using a catalytic amount of crown ether has also been reported (see, for example, Non-Patent Document 4, Non-Patent Document 5, and Non-Patent Document 6). However, these methods are limited in industrial use because they are a low temperature reaction of −40 ° C. or a high temperature reaction of 80 ° C. or higher, or there is a problem in selectivity.

A method of selectively synthesizing a styrene derivative using a catalytic amount of crown ether has also been reported (see, for example, Non-Patent Document 7 and Non-Patent Document 8). However, this method does not give good results or teach or suggest the Wittig reaction of aliphatic aldehydes.
Further, a method for selectively synthesizing isomers using a catalytic amount of crown ether and trialkyl-3-methyl-4-phosphonocrotonate as a Wittig reagent has been reported (for example, non-patent literature). 9, see Non-Patent Document 10 and Non-Patent Document 11.). However, these methods have a problem in selectivity and are limited in industrial use.
Japanese Patent Publication No. 63-32058 Japanese Examined Patent Publication No. 63-34855 N. Eng. J. Med. 334,1516 (1996) J. Chem. Soc., Perkin Trans. 1, 2073 (2000) Tetrahedron Lett., 24, 4405 (1983) Agric.Biol.Chem., 45, 1461 (1981) Yingyong Huaxue, 5, 70 (1988) Synthesis, 784 (1975) Tetrahedron Lett., 37, 4225 (1996) Synthesis, 278 (1975) Izv. Akad. Nauk SSSR, Khim. 2544 (1990) Izv. Akad. Nauk SSSR, Khim.2382 (1988) Izv. Akad. Nauk SSSR, Khim. 2377 (1988)

  The object of the present invention is to solve the above-mentioned problems and to provide an industrially advantageous method for producing a polyprenyl compound.

  In view of the circumstances as described above, the present inventor conducted various studies over a wide range in order to find an industrially advantageous method for producing a polyprenyl compound, and as a result, found a novel method for producing a polyprenyl compound. It came to complete.

  That is, the present invention provides (1) the general formula [I]

[式中、ｎは０〜３の整数を示す]で表されるアルデヒドと、一般式［II］

[Wherein n represents an integer of 0 to 3] and the general formula [II]

[式中、Ｒ¹、Ｒ²は炭化水素基を示す]で表されるウィティッヒ（Wittig）試薬とを、水と有機溶媒の混合媒体中、塩基の存在下、クラウンエーテル化合物の共存下に反応させることを特徴とする、一般式［III］

[Wherein R ¹ and R ^{2 each} represent a hydrocarbon group] are reacted with a Wittig reagent in a mixed medium of water and an organic solvent in the presence of a base in the presence of a crown ether compound. The general formula [III]

[式中、ｎ、Ｒ¹は、各々式［I］、［II］で定義された意味を表す]で表されるポリプレニル系化合物の製造方法を提供するものである。

[Wherein n and R ¹ represent the meanings defined by the formulas [I] and [II], respectively] to provide a method for producing a polyprenyl compound represented by the formula [I] and [II].

  The present invention also relates to (2) the presence of a base in a mixed medium of water and an organic solvent comprising an aldehyde represented by the general formula [I] and a Wittig reagent represented by the general formula [II]. The reaction is carried out in the presence of a crown ether compound to obtain a compound represented by the general formula [III], and then the compound is hydrolyzed in the presence of a base.

[式中、ｎ、式［I］で定義された意味を表す]で表されるポリプレニル系化合物の製造方法を提供するものである。

The present invention provides a method for producing a polyprenyl compound represented by [wherein n represents the meaning defined by formula [I]].

  According to a preferred embodiment of the present invention, (3) the crown ether compound is 15-crown-5, 18-crown-6, 1-aza-15-crown-5, 1-aza-18-crown-6, benzo- 15-crown-5, benzo-18-crown-6, or dibenzo-18-crown-6, the method according to item (1) or (2), (4) the crown ether compound is 15-crown-5 Or the method according to item (1) or (2), which is 18-crown-6, and (5) the method according to item (1) or (2), wherein the crown ether compound is 15-crown-5. A method is provided.

  According to another preferred embodiment of the present invention, (6) (1) to (1), wherein the Wittig reagent represented by the general formula [II] is triethyl-3-methyl-4-phosphonocrotonate. The method according to any one of items 5) and (7) the aldehyde represented by the general formula [I] is (2E, 6E) -3,7,11-trimethyl-2,6,10-dodeca The method according to any one of (1) to (6), which is trien-1-al.

  The present invention is known to have a transcriptional activation effect via retinoic acid receptor with high selectivity and high yield, and a differentiation-inducing action and apoptosis-inducing action in hepatocellular carcinoma (2E , 4E, 6E, 10E) -3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentenoic acid and the like are industrially useful methods.

In said formula, R < ¹ >, R < ² > shows a hydrocarbon group. As the hydrocarbon group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, an aryl group, and the like are used, and an alkyl group is generally used. The alkyl group preferably has 1 to 21 carbon atoms, and may be linear or branched. Examples of the alkyl group include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,1-dimethylpropyl N-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2-ethylbutyl, 1-ethylbutyl, 1,3-dimethylbutyl, n-heptyl, 5-methylhexyl, 4-methylhexyl, 3-methylhexyl, 2-methylhexyl, 1-methylhexyl, 3-ethylpentyl, 2-ethylpentyl, 1-ethylpentyl, 4,4-dimethylpentyl, 3,3-dimethylpentyl, 2,2-dimethylpentyl, 1,1-dimethylpentyl, n-octyl, 6-methylheptyl, 5-methylheptyl, 4-methyl Heptyl 3-methylheptyl, 2-methylheptyl, 1-methylheptyl, 1-ethylhexyl, 1-propylpentyl, 3-ethylhexyl, 5,5-dimethylhexyl, 4,4-dimethylhexyl, 2,2-diethylbutyl, 3 , 3-diethylbutyl, 1-methyl-1-propyl, and the like, but are not limited thereto.

N in the general formula [I] is 0 to 3, preferably 0 to 2, and more preferably 1.
R ¹ is preferably the alkyl group having 1 to 11 carbon atoms, more preferably methyl or ethyl.
R ² is preferably the alkyl group having 1 to 11 carbon atoms, more preferably methyl or ethyl.

  The aldehyde represented by the general formula [I] and the Wittig reagent represented by the general formula [II] used in the present invention are known compounds or are easily produced by known methods. (For example, J. Chem. Soc. (C), 2154-2165 (1966), Can. J. Chem. 55, 1218 (1977), etc.).

  The polyprenyl compound represented by the general formula [III] of the present invention is a mixed medium of water and an organic solvent containing a wittig reagent represented by the general formula [II] in an aldehyde represented by the general formula [I]. It can be produced by reacting in the presence of a base in the presence of a crown ether compound.

  The above reaction is performed by using ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, 2-methoxyethyl ether, petroleum ether, aromatic hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as dichloromethane and chloroform, The reaction can be carried out in an aliphatic hydrocarbon such as hexane, heptane, and octane, an alicyclic hydrocarbon such as cyclohexane, or a mixed solvent of water and an organic solvent obtained by combining these. Preferably, a mixed solvent of aromatic hydrocarbon such as benzene and toluene and water is used. The reaction temperature is −20 ° C. to around 100 ° C., preferably 5-30 ° C. Although reaction time changes with reaction conditions, it is 1 to 24 hours normally.

  Crown ether compounds include 15-crown-5, 18-crown-6, 1-aza-15-crown-5, 1-aza-18-crown-6, benzo-15-crown-5, benzo-18-crown -6, dibenzo-18-crown-6, preferably 15-crown-5, 18-crown-6, more preferably 15-crown-5. The crown ether compound is used in a less than stoichiometric amount, preferably 0.01 to 0.90 molar equivalent, more preferably 0.05 to 0.20 molar equivalent, and most preferably about 0.1 molar equivalent.

  Examples of the base used in the above reaction include hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, preferably sodium hydroxide, potassium hydroxide, and particularly preferably hydroxide. Sodium is mentioned. The amount of such base used is about 10 to 15 molar equivalents.

  The polyprenyl compound represented by the general formula [IV] of the present invention can be produced by hydrolyzing the polyprenyl compound represented by the general formula [III] in the presence of a base.

  The above reaction may be performed using an alcohol solvent such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 3-methylpropanol, and 3-methyl-1-butanol, or an ether solvent such as tetrahydrofuran, or It can carry out in the mixed solvent of the organic solvent and water which combined these. Preferably, alcohol solvents such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 3-methylpropanol, and 3-methyl-1-butanol are used. The reaction temperature is 0 ° C. to around the boiling point of the solvent used, preferably 15 to 100 ° C. Although reaction time changes with reaction conditions, it is 1 to 24 hours normally.

  Examples of the base used in the above reaction include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and barium hydroxide, preferably sodium hydroxide and potassium hydroxide. The amount of the base used is 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents.

  The reaction product can be isolated and purified by appropriately combining ordinary means such as centrifugation, concentration, liquid separation, washing, drying, recrystallization, distillation, column chromatography and the like.

  Hereinafter, the present invention will be described in more detail with reference to Examples and Reference Examples, but the present invention is not limited to these Examples.

Example 1
Synthesis of ethyl (2E, 4E, 6E, 10E) -3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoate
15-Crown-5 0.5 g (0.1 eq, 2.27 mmol) was dissolved in 30 mL of toluene at room temperature, and 20 mL of 50% aqueous sodium hydroxide solution was added. Under stirring, triethyl-3-methyl-4-phosphonocrotonate 7.87 g (23.8 mmol, 1.05 eq) and farnesal 5.0 g (22.7 mmol) in 5 mL of toluene were sequentially added at 0 ° C., and the mixture was stirred at room temperature for 1 hour. . The organic layer and the aqueous layer were separated, and the organic layer was washed with a saturated aqueous ammonium chloride solution and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 7.4 g of the title compound (yield 98%, 2E: 2Z => 99: 1) as a yellow oily substance.
¹ H-NMR (CDCl ₃ ) δ (ppm); 1.29 (3H, t, J = 7.1Hz), 1.60 (3H, s), 1.61 (3H, s), 1.68 (3H, s), 1.85 (3H, s), 1.90-2.18 (8H, m), 2.33 (3H, s), 4.17 (2H, q, J = 7.1Hz), 5.02-5.18 (2H, m), 5.74 (1H, s), 5.97 (1H , d, J = 11.2Hz), 6.17 (1H, d, J = 15.1Hz), 6.84 (1H, dd, J = 11.2, 15.1Hz)

Example 2
Synthesis of (2E, 4E, 6E, 10E) -3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentenoic acid 3.0 g of potassium hydroxide in 20 ml of 2-propanol Of (2E, 4E, 6E, 10E) -3,7,11,15-tetramethyl-2,4,6,10,14-ethyl hexadecapentaenoate obtained in Example 1 2-Propanol (10 mL) solution was added and stirred at the same temperature for 5 minutes. The reaction solution was added to ice water, washed with n-hexane, neutralized with 10% hydrochloric acid, and extracted with n-hexane. The obtained organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from methanol to obtain 3.5 g (yield 51%) of the title compound as yellow crystals.
¹ H-NMR (CDCl ₃ ) δ (ppm); 1.60 (3H, s), 1.61 (3H, s), 1.68 (3H, s), 1.86 (3H, s), 1.96-2.09 (4H, m), 2.15 (2H, s), 2.16 (2H, s), 2.34 (3H, s), 5.06-5.10 (2H, m), 5.77 (1H, s), 5.98 (1H, d, J = 11.2Hz), 6.20 (1H, d, J = 15.1Hz), 6.90 (1H, dd, J = 11.2, 15.1Hz), 11.8 (1H, brs)

Example 3
Synthesis of ethyl (2E, 4E, 6E) -3,7,11-trimethyl-2,4,6,10-dodecatetraenoate
15-Crown-5 0.9 g (0.1 eq, 4.0 mmol) was dissolved in 50 mL of toluene at room temperature, and 32 mL of 50% aqueous sodium hydroxide solution was added. Under stirring, triethyl-3-methyl-4-phosphonocrotonate 11.1 g (42 mmol, 1.05 eq) and geranial 6.1 g (40 mmol) in 7 mL of toluene were sequentially added and stirred at room temperature for 1.5 hours. . The organic layer and the aqueous layer were separated, and the organic layer was washed with a saturated aqueous ammonium chloride solution and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 9.2 g (yield 87%, 2E: 2Z = 93: 7) of the title compound as a yellow oily substance.
¹ H-NMR (CDCl ₃ ) δ (ppm); 1.29 (3H, t, J = 7.1Hz), 1.61 (3H, s), 1.69 (3H, s), 1.85 (3H, s), 2.10-2.21 ( 4H, m), 2.33 (3H, s), 4.17 (2H, q, J = 7.1Hz), 5.09 (1H, brs), 5.74 (1H, s), 5.97 (1H, d, J = 11.0Hz), 6.18 (1H, d, J = 15.1Hz), 6.83 (1H, dd, J = 11.0, 15.1Hz)

Example 4
Synthesis of (2E, 4E, 6E) -3,7,11-trimethyl-2,4,6,10-dodecatetraenoic acid 3.0 g of potassium hydroxide was dissolved in 30 mL of 2-propanol at 100 ° C. (2E, 4E, 6E) -3,7,11-trimethyl-2,4,6,10-dodecatetraenoic acid ethyl 9.1 g (34.5 mmol) obtained in 2-propanol (10 mL) was added, The mixture was stirred at the same temperature for 15 minutes. The reaction solution was added to ice water, washed with n-hexane, neutralized with 10% hydrochloric acid, and extracted with n-hexane. The obtained organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized twice with methanol to obtain 1.5 g (yield 18%) of the title compound as yellow crystals.
¹ H-NMR (CDCl ₃ ) δ (ppm); 1.61 (3H, s), 1.69 (3H, s), 1.85 (3H, s), 2.10-2.19 (4H, m), 2.34 (3H, d, J = 1.0Hz), 5.09 (1H, brs), 5.77 (1H, s), 5.98 (1H, d, J = 11.0Hz), 6.21 (1H, d, J = 15.1Hz), 6.90 (1H, dd, J = 11.0, 15.1Hz), 11.6 (1H, brs)

Reference example 1
Synthesis of ethyl (2E, 4E, 6E, 10E) -3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoate 2.16 g (1.26 g) of sodium ethoxide under argon atmosphere eq) was suspended in 20 mL of dimethylformamide, and a solution of 7.87 g (23.28 mmol, 1.2 eq) of triethyl-3-methyl-4-phosphonocrotonate in dimethylformamide (5 mL) was added dropwise at room temperature. Next, a solution of farnesal 5.0 g (22.7 mmol) in dimethylformamide (5 mL) was added dropwise at −10 ° C., and the mixture was further stirred at the same temperature for 30 minutes. The reaction mixture was poured into ice water, neutralized with acetic acid, and extracted with n-heptane. The obtained organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 6.6 g (yield 88%, 2E: 2Z = 86: 14) of the title compound as a yellow oily substance.

Claims (7)

Formula [I]

[Wherein n represents an integer of 0 to 3] and the general formula [II]

[Wherein R ¹ and R ^{2 each} represent a hydrocarbon group] are reacted with a Wittig reagent in a mixed medium of water and an organic solvent in the presence of a base in the presence of a crown ether compound. The general formula [III]

[Wherein n and R ¹ represent the meanings defined by the formulas [I] and [II], respectively]. An aldehyde represented by the general formula [I] according to claim 1 and a Wittig reagent represented by the general formula [II] according to claim 1 in a mixed medium of water and an organic solvent, The reaction is carried out in the presence of a crown ether compound in the presence of a base to obtain the compound represented by the general formula [III] according to claim 1 , and then the hydrolysis reaction of the compound in the presence of a base is performed. Characterized by general formula [IV]

[ Wherein n represents the meaning defined in the general formula [I] according to claim 1 ]. Crown ether compounds are 15-crown-5, 18-crown-6, 1-aza-15-crown-5, 1-aza-18-crown-6, benzo-15-crown-5, benzo-18-crown- The method according to claim 1 or 2, which is 6, or dibenzo-18-crown-6. The method according to claim 1 or 2, wherein the crown ether compound is 15-crown-5 or 18-crown-6. The method according to claim 1 or 2, wherein the crown ether compound is 15-crown-5. The method according to any one of claims 1 to 5, wherein the Wittig reagent represented by the general formula [II] is triethyl-3-methyl-4-phosphonocrotonate. The aldehyde represented by the general formula [I] is (2E, 6E) -3,7,11-trimethyl-2,6,10-dodecatrien-1-al. The method according to one item.