JP2004331654A - Method for producing polyprenyl compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for industrially advantageously producing a polyprenyl compound. <P>SOLUTION: This method for producing the polyprenyl compound comprises reacting an aldehyde expressed by general formula [I] (n is an integer of 0 to 3) with a Wittig reagent expressed by general formula [II] (R<SP>1</SP>and R<SP>2</SP>are each a hydrocarbon group) in a mixed medium of water and an organic solvent in the presence of a base together with a crown ether compound. <P>COPYRIGHT: (C)2005,JPO&NCIPI

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 has been known to have a transcriptional activating effect through, and to have a differentiation inducing action and an apoptosis inducing action in hepatocellular carcinoma. In the clinical setting, (2E, 4E, 6E, 10E) -3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid is treated for a long period of one year to cure curative liver cancer. It has been reported that the compound significantly inhibits recurrence later and has an inhibitory effect on liver cancer recurrence, and that at this time, almost no side effects observed in liver dysfunction and other retinoids are observed (Non-Patent Document 1).

  (2E, 4E, 6E, 10E) -3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid is a known compound, and its production method includes, for example, 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. It is manufactured (for example, see Patent Documents 1 and 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。

[In the above formula, R ³ and R ⁴ represent an alkyl group. ]
However, these methods have a drawback that unnecessary Z-forms are by-produced in large amounts, and therefore, development of a practical method for producing E-forms with high selectivity is desired. .

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

Also, a method of selectively synthesizing a styrene derivative using a catalytic amount of crown ether has been reported (for example, see Non-Patent Documents 7 and 8). However, this method does not give good results or teaches or suggests the Wittig reaction of aliphatic aldehydes.
Furthermore, there has been reported a method for selectively synthesizing isomers using a catalytic amount of crown ether and a trialkyl-3-methyl-4-phosphonocrotonate as a Wittig reagent (for example, Non-Patent Documents) 9, Non-Patent Documents 10 and 11). However, these methods have a problem in selectivity, and there are limitations in industrial use.
JP-B-63-32058 JP-B-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)

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

  In view of the above situation, the present inventor conducted extensive studies 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. Was completed.

  That is, the present invention relates to (1) a compound represented by 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 an aldehyde represented by 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］

Reacting a Wittig reagent represented by the formula [wherein R ¹ and R ² represent hydrocarbon groups] in a mixed medium of water and an organic solvent in the presence of a base and in the presence of a crown ether compound. 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.

  In addition, the present invention relates to (2) a method of mixing an aldehyde represented by the general formula [I] and a Wittig reagent represented by the general formula [II] in a mixed medium of water and an organic solvent in the presence of a base. A compound represented by the general formula [III] is obtained by reacting in the presence of a crown ether compound to obtain a compound represented by the general formula [III], and then subjecting the compound to a hydrolysis reaction 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。

[Wherein, n represents a meaning defined by the 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- The method according to (1) or (2), wherein the crown ether compound is 15-crown-5, benzo-18-crown-6, or dibenzo-18-crown-6; Or the method according to (1) or (2), which is 18-crown-6; and (5) the method according to (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) the (1) to (I) wherein the Wittig reagent represented by the general formula [II] is triethyl-3-methyl-4-phosphonocrotonate. 5) The method according to any one of the above items, and (7) the method wherein the aldehyde represented by the general formula [I] is (2E, 6E) -3,7,11-trimethyl-2,6,10-dodeca A method according to any one of paragraphs (1) to (6), wherein the method is trien-1-al.

  The present invention is known to have a retinoic acid receptor-mediated transcriptional activation effect and a differentiation induction and apoptosis induction effect in hepatocellular carcinoma with high selectivity and high yield (2E). , 4E, 6E, 10E) -3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid and the like.

In the above formula, R ¹ and R ² represent a hydrocarbon group. Examples of the hydrocarbon group include an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, and an aryl group. An alkyl group is generally used. The alkyl group preferably has 1 to 21 carbon atoms, and may be linear or branched. As the alkyl group, 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 above alkyl group having 1 to 11 carbon atoms, more preferably methyl or ethyl.
R ² is preferably the above-mentioned 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 obtained by mixing a aldehyde represented by the general formula [I] with a Wittig reagent represented by the general formula [II] in a mixed medium of water and an organic solvent. It can be produced by reacting in the presence of a base in the presence of a crown ether compound.

  The above reaction, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, 2-methoxyethyl ether, ethers such as petroleum ether, benzene, aromatic hydrocarbons such as toluene, dichloromethane, halogenated hydrocarbons such as chloroform, The reaction can be performed in an aliphatic hydrocarbon such as hexane, heptane, octane, or an alicyclic hydrocarbon such as cyclohexane, or a mixed solvent of an organic solvent and water in which these are combined. Preferably, a mixed solvent of aromatic hydrocarbon such as benzene and toluene and water is used. The reaction temperature is from -20 ° C to around 100 ° C, preferably 5 to 30 ° C. The reaction time varies depending on the reaction conditions, but is usually 1 to 24 hours.

  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 substoichiometric 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.

  The base used in the above reaction is, for example, a hydroxide of an alkali metal such as lithium hydroxide, sodium hydroxide, potassium hydroxide or barium hydroxide, preferably sodium hydroxide or potassium hydroxide, particularly preferably hydroxide. Sodium. The amount of the 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 subjecting the polyprenyl compound represented by the general formula [III] to a hydrolysis reaction in the presence of a base.

  The above reaction, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 3-methylpropanol, alcohol solvents such as 3-methyl-1-butanol or ether solvents such as tetrahydrofuran, or It can be carried out in a mixed solvent of an organic solvent and water in which these are combined. 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 is carried out at a temperature from 0 ° C. to around the boiling point of the solvent used, preferably at a temperature of 15 to 100 ° C. The reaction time varies depending on the reaction conditions, but is usually 1 to 24 hours.

  Examples of the base used in the above reaction include hydroxides of alkali metals 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, and column chromatography.

  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
0.5 g (0.1 eq, 2.27 mmol) of 15-crown-5 was dissolved in 30 mL of toluene at room temperature, and 20 mL of a 50% aqueous sodium hydroxide solution was added. Under stirring, a solution of 7.87 g (23.8 mmol, 1.05 eq) of triethyl-3-methyl-4-phosphonocrotonate and 5.0 g (22.7 mmol) of farnesal in 5 mL of toluene was sequentially added at 0 ° C., followed by stirring 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 solution of ammonium chloride and saturated saline, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (7.4 g, yield 98%, 2E: 2Z => 99: 1) as a yellow oil.
_{^{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-hexadecapentaenoic acid3.0 g of potassium hydroxide in 20 mL of 2-propanol ° C., the ethyl (2E, 4E, 6E, 10E) -3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoate obtained in Example 1 A 2-propanol (10 mL) solution was added, and the mixture was 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 saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from methanol to give the title compound (3.5 g, yield 51%) 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
0.9 g (0.1 eq, 4.0 mmol) of 15-crown-5 was dissolved in 50 mL of toluene at room temperature, and 32 mL of a 50% aqueous sodium hydroxide solution was added. Under stirring, a solution of 11.1 g (42 mmol, 1.05 eq) of triethyl-3-methyl-4-phosphonocrotonate and 6.1 g (40 mmol) of geranial in 7 mL of toluene were sequentially added at 0 ° C., followed by stirring 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 solution of ammonium chloride and saturated saline, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (9.2 g, yield 87%, 2E: 2Z = 93: 7) as a yellow oil.
_{^{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. A solution of (2E, 4E, 6E) -3,7,11-trimethyl-2,4,6,10-ethyl dodecatetraenoate ethyl 9.1 g (34.5 mmol) obtained in the above 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 saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized twice from methanol to give the title compound (1.5 g, yield 18%) 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 Under argon atmosphere, sodium ethoxide 2.16 g (1.26 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 5 mL of dimethylformamide was added dropwise at room temperature. Then, 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 solution was poured into ice water, neutralized with acetic acid, and extracted with n-heptane. The obtained organic layer was washed with a saturated saline solution and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (6.6 g, yield 88%, 2E: 2Z = 86: 14) as a yellow oily substance.

Claims (7)

General formula [I]

Wherein n represents an integer of 0 to 3; and an aldehyde represented by the general formula [II]:

Reacting a Wittig reagent represented by the formula [wherein R ¹ and R ² represent hydrocarbon groups] in a mixed medium of water and an organic solvent in the presence of a base and in the presence of a crown ether compound. 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] and a Wittig reagent represented by the general formula [II] are mixed in a mixed medium of water and an organic solvent in the presence of a base and in the presence of a crown ether compound. Reacting to obtain a compound represented by the general formula [III], and then subjecting the compound to a hydrolysis reaction in the presence of a base, wherein the compound is a general formula [IV]

[Wherein, n represents the meaning defined by the formula [I]]. The 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. 3. The method according to claim 1, wherein the crown ether compound is 15-crown-5 or 18-crown-6. 3. The method according to claim 1, 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. 7. The aldehyde represented by the general formula [I] is (2E, 6E) -3,7,11-trimethyl-2,6,10-dodecatriene-1-al. A method according to claim 1.