JP6002572B2 - Method for producing farnesal using bis (acetylacetonato) dioxomolybdenum (VI) - Google Patents

Description

  The present invention relates to a process for producing farnesal from (E) -nerolidol using bis (acetylacetonato) dioxomolybdenum (VI).

  Farnesal (3,7,11-trimethyl-2,6,10-dodecatrienal) is known to be an important compound used as a production intermediate for pharmaceuticals, agricultural chemicals, fragrances and the like. In particular, (2E, 6E) -farnesal can be a production intermediate of a polyisoprenoid derivative useful as an anticancer agent or the like (see, for example, Patent Document 1). Various studies have been made on methods for selectively producing this farnesal, especially (2E, 6E) -farnesal.

For example, (2E, 6E) -farnesal is obtained using (2E, 6E) -farnesol ((2E, 6E) -3,7,11-trimethyl-2,6,10-dodecatrien-1-ol) as a raw material. A method is disclosed (for example, see Patent Document 1 and Non-Patent Document 1).
All of these methods require the use of (2E, 6E) -farnesol as a raw material. However, as with farnesal, a method for efficiently and selectively obtaining the (2E, 6E) -form of farnesol, in which four isomers exist, has not been established.

  A method for obtaining farnesal from inexpensive nerolidol (3,7,11-trimethyl-1,6,10-dodecatrien-3-ol) is also known. For example, a method of synthesizing a mixture of isomers of (2E, 6E) -farnesal and (2E, 6Z) -farnesal from (E) -nerolidol using a chromic acid oxidizing agent in one step is disclosed. (For example, refer nonpatent literatures 2 and 3.). However, when the reaction is carried out using a chromic acid oxidizing agent, a large amount of tar is generated after the reaction, so that ordinary post-treatment becomes difficult. Moreover, the (2E, 6E) -farnesal ratio in the obtained isomer mixture is low. Furthermore, since this method uses an excessively toxic chromium compound, it cannot be applied to industrial production, particularly pharmaceutical production.

  An oxidation reaction to an unsaturated aldehyde with isomerization of a tertiary allylic alcohol using bis (acetylacetonato) dioxomolybdenum (VI) as a catalyst has been reported, for example 2-methyl-3-butene-2 Only an example of obtaining 3-methyl-2-butenal from ol using dimethyl sulfoxide as a solvent and an oxidizing agent has been reported (Non-patent Document 4). However, the obtained 3-methyl-2-butenal has no geometric isomer, and the yield is as low as 25%, which is not practical.

JP 2003-40826 A

Journal of American Chemical Society, 124 (14), 3647-3655; 2002 Synthesis, (5), 356-364; 1979 Chemistry-A European Journal, 15 (44), 11918-11927; 2009 Bulletin de la Societe Chimique de France, 133, 755-758; 1996

  The conventional method of producing (2E, 6E) -farnesal using (E) -nerolidol is not industrially feasible or is inefficient, and the resulting (2E, 6E) -farnesal is expensive. It has the disadvantages. An object of the present invention is to provide a method for producing farnesal more efficiently and cheaply than (E) -nerolidol. Furthermore, it is providing the method of manufacturing a farnesal with a high (2E, 6E) -isomer ratio.

  As a result of intensive studies in view of the above problems, the present inventors have reacted farnesal by reacting (E) -nerolidol with an oxidizing agent in the presence of bis (acetylacetonato) dioxomolybdenum (VI). Has been found to be easily produced, and the present invention has been completed. Furthermore, it was found that farnesal having a high (2E, 6E) -isomer ratio can be easily produced by reacting in the presence of a piperidine-1-oxyl compound, and the present invention has been completed.

で表わされる（Ｅ）−ネロリドールを、ビス（アセチルアセトナト）ジオキソモリブデン（ＶＩ）の存在下、酸化剤と反応させることを特徴とする、下記式（２）

で表わされるファルネサールの製造方法に関する。 That is, the present invention provides the following formula (1):

(E) -nerolidol represented by the following formula (2), which is reacted with an oxidizing agent in the presence of bis (acetylacetonato) dioxomolybdenum (VI):

The manufacturing method of farnesal represented by these.

  INDUSTRIAL APPLICABILITY The present invention efficiently produces farnesal, which is useful as an intermediate for producing pharmaceuticals, agricultural chemicals and fragrances, particularly farnesal having a high (2E, 6E) -isomer ratio, from inexpensive raw materials without using toxic reagents It is useful as a method to

  Hereinafter, embodiments of the present invention will be described in detail.

  The production method of the present invention comprises reacting (E) -nerolidol represented by the formula (1) with an oxidizing agent in the presence of bis (acetylacetonato) dioxomolybdenum (VI). It is a manufacturing method of farnesal represented by (2).

  The (E) -nerolidol represented by the formula (1), which is a starting material for the production method of the present invention, is commercially available and can be easily obtained from a reagent supplier such as Sigma-Aldrich. It can also be synthesized according to a known method (for example, the method described in JP-A-2-4726).

  The bis (acetylacetonato) dioxomolybdenum (VI) used in the production method of the present invention can be easily obtained from a reagent supplier such as Sigma-Aldrich. Moreover, it is also possible to synthesize according to a known method.

  The amount of bis (acetylacetonato) dioxomolybdenum (VI) used in the production method of the present invention may be a so-called catalytic amount, but is represented by the formula (1) from the viewpoint of reaction rate and reaction efficiency. 0.01-0.5 mol is preferable with respect to 1 mol of E-nerolidol, 0.05-0.3 mol is more preferable, and 0.1-0.2 mol is still more preferable.

  The oxidizing agent used in the production method of the present invention is not particularly limited. For example, air, oxygen, or sulfoxides such as dimethyl sulfoxide, dibutyl sulfoxide, diphenyl sulfoxide, and tetramethylene sulfoxide can be used. Two or more kinds of these oxidizing agents can be mixed and used. From the viewpoint of reactivity and availability, air, oxygen, dimethyl sulfoxide, and tetramethylene sulfoxide are preferable.

  In the production method of the present invention, when oxygen is used as the oxidizing agent, oxygen can be mixed with other gases. For example, oxygen is mixed with air or an inert gas (such as nitrogen or helium). Can be used.

  In the production method of the present invention, when air or oxygen is used as the oxidant, the method of supplying air or oxygen is not particularly limited. For example, a method or reaction in which the gas phase in contact with the reaction solution is replaced with air or oxygen. For example, a method of circulating air or oxygen in the gas phase in contact with the solution, a method of blowing air or oxygen into the reaction solution, or the like can be used.

  In the production method of the present invention, when a sulfoxide such as dimethyl sulfoxide, dibutyl sulfoxide, diphenyl sulfoxide, tetramethylene sulfoxide is used as the oxidizing agent, E-- 1-20 mol is preferable with respect to 1 mol of nerolidol, 1-10 mol is more preferable, and 1-5 mol is still more preferable.

［式中、
Ｒ^１は、水素原子であり；Ｒ^２は、水素原子、シアノ基、カルボキシ基、イソチオシアナト基、マレイミド基、リン酸基、−ＯＲ′基又は−ＮＨＲ″基（ここで、Ｒ′は、水素原子、炭素数１〜４のアルキル基、アシル基又は炭素数１〜４のアルカンスルホニル基であり；Ｒ″は、水素原子、アセチル基又はハロアセチル基である）であるか；あるいは
Ｒ^１及びＲ^２は、一緒になってオキソ基を形成する］
で表わされるピペリジン−１−オキシル化合物の存在下、反応を行ってもよい。
式（３）で表わされるピペリジン−１−オキシル化合物を用いることにより、（２Ｅ，６Ｅ）−ファルネサール／（２Ｚ，６Ｅ）−ファルネサール比が向上したファルネサール異性体混合物を得ることができる。 The production method of the present invention further comprises the following formula (3):

[Where:
R ¹ is a hydrogen atom; R ² is a hydrogen atom, cyano group, carboxy group, isothiocyanato group, maleimide group, phosphoric acid group, —OR ′ group or —NHR ″ group (where R ′ is a hydrogen atom) R ″ is a hydrogen atom, an acetyl group, or a haloacetyl group; or R ¹ and R, and an atom, an alkyl group having 1 to 4 carbon atoms, an acyl group, or an alkanesulfonyl group having 1 to 4 carbon atoms; ² together form an oxo group]
The reaction may be carried out in the presence of a piperidine-1-oxyl compound represented by:
By using the piperidine-1-oxyl compound represented by the formula (3), a farnesal isomer mixture having an improved (2E, 6E) -farnesal / (2Z, 6E) -farnesal ratio can be obtained.

  Here, unless otherwise specified, the “alkyl group having 1 to 4 carbon atoms” means a monovalent group of a linear or branched aliphatic saturated hydrocarbon having 1 to 4 carbon atoms, unless otherwise specified. Examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group. Preferably, a methyl group can be illustrated. Further, the “alkenyl group having 2 to 4 carbon atoms” means a monovalent group having 2 to 4 carbon atoms, which is a linear or branched aliphatic unsaturated hydrocarbon, unless otherwise specified. Examples thereof include a vinyl group, an allyl group, an ilopropenyl group, a 1-propenyl group, and a 2-butenyl group. Preferably, an ilopropenyl group can be illustrated.

  “Acyl group” means a group of the formula: RCO— (wherein R is an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, or a phenyl group) unless otherwise specified. Meaning, and examples thereof include an acetyl group, an acryloyl group, a methacryloyl group, and a benzoyl group. Preferably, a methacryloyl group or a benzoyl group can be exemplified.

“Alkanesulfonyl group having 1 to 4 carbon atoms” means a group of the formula: RSO ₂ — (wherein R is an alkyl group having 1 to 4 carbon atoms), and methane unless otherwise specified. Examples thereof include a sulfonyl group and an ethanesulfonyl group. Preferably, a methanesulfonyl group can be illustrated.

  “Haloacetyl group” means a group in which 1 to 3, preferably 1 of the hydrogen atoms of an acetyl group are replaced with a halogen atom selected from fluorine, chlorine, bromine or iodine, unless otherwise specified. Examples thereof include a chloroacetyl group, a bromoacetyl group, and an iodoacetyl group. Preferably, a bromoacetyl group or an iodoacetyl group can be exemplified.

The piperidine-1-oxyl compound represented by the formula (3) is commercially available from a reagent supply company such as Sigma-Aldrich and can be easily obtained. In terms of good yield, R ¹ is a hydrogen atom; R ² is a hydrogen atom, a cyano group, a hydroxy group, an amino group, an acetylamino group, a carboxy group or a benzoyloxy group, or R ¹ and R ² Are preferably formed together to form an oxo group, more preferably R ¹ is a hydrogen atom; and R ² is a hydrogen atom or a hydroxy group.

  In the production method of the present invention, the amount of the piperidine-1-oxyl compound represented by the formula (3) is not particularly limited, but (E) -nerolidol represented by the formula (1) from the viewpoint of reaction efficiency. 0.005-0.2 mol is preferable with respect to 1 mol, 0.01-0.2 mol is more preferable, and 0.05-0.2 mol is still more preferable.

  The production method of the present invention may be carried out in a solvent, and the solvent that can be used is not particularly limited as long as it is an inert solvent for the reaction, and is appropriately selected according to the desired reaction temperature. For example, halogenated aromatic hydrocarbon solvents such as chlorobenzene, bromobenzene, dichlorobenzene, and trichlorobenzene, halogenated solvents such as dichloromethane, dibromomethane, chloroform, carbon tetrachloride, ethylene dichloride, 1,1,1-trichloroethane, and trichloroethylene Aliphatic hydrocarbon solvents, aromatic hydrocarbon solvents such as benzene, toluene, xylene, and mesitylene, and aliphatic hydrocarbon solvents such as hexane, heptane, octane, and cyclohexane can be used. Two or more of them can be mixed and used. From the viewpoint of yield, it is preferable to use a halogenated aromatic hydrocarbon solvent, and it is more preferable to use chlorobenzene, dichlorobenzene, trichlorobenzene, or a mixed solvent thereof.

  In the production method of the present invention, the amount of solvent used is not particularly limited, but is preferably 3 to 50 times (by weight) with respect to (E) -nerolidol represented by formula (1). The amount is preferably 30 times (by weight).

  The production method of the present invention can be carried out at a temperature appropriately selected from the range of room temperature to 180 ° C. 80-140 degreeC is preferable from the point of a favorable yield, and 110-130 degreeC is still more preferable.

  If necessary, farnesal represented by the formula (2) can be isolated and purified from the solution after the reaction. The isolation / purification method is not particularly limited, and may be a general method such as solvent extraction, distillation, silica gel column chromatography, preparative thin layer chromatography, preparative liquid chromatography, or the like. The farnesal represented by the formula (2) can be isolated and purified.

  Examples are shown below to clarify aspects of the present invention, but the present invention is not limited to only the examples shown here.

  The reaction solutions obtained in the examples were subjected to gas chromatography analysis, and the purity of (2E, 6E) -farnesal and (2Z, 6E) -farnesal was calculated as an area percentage. The measurement conditions are as follows.

Equipment: GC-14A (Shimadzu Corporation)
Column: HP-ULTRA1 (Agilent Technologies)
25 m × I. D. 0.32mm, 0.52μmdf
Column temperature: 100 ° C. → [10 ° C./min]→250° C.
Injection temperature: 250 ° C
Carrier gas: Helium gas detector: Hydrogen flame ionization detector (FID)

  Moreover, the measuring method of the NMR spectrum of the compound obtained in the Example is as follows.

NMR: A solution in which a compound and heavy CDCl ₃ (containing CDCl ₃ 0.05% TMS manufactured by Cambrige Isotope Laboratories, Inc.) was prepared, and ¹ H-NMR measurement was performed using NMR (AVANCE400 manufactured by Bruker Corporation). It was.

Example 1:
(E) -Neroridol (100 mg, 0.45 mmol) was dissolved in chlorobenzene (2.0 g), and dimethyl sulfoxide (70 mg, 0.90 mmol), bis (acetylacetonato) dioxomolybdenum (VI) (15 mg, 0 0.045 mmol), 2,2,6,6-tetramethylpiperidine-1-oxyl (3.5 mg, 0.0225 mmol) was added, and the reaction was carried out at 130 ° C. for 24 hours. After cooling to room temperature, (2E, 6E) -farnesal (purity: 68.7%) and (2Z, 6E) -farnesal (purity: 29.1%) (isomer ratio: (2E, 6E) -farnesal / ( 2Z, 6E) -farnesal = 2.36) was obtained. The reaction solution was evaporated under reduced pressure, and the resulting residue was purified by flash column chromatography (hexane: ethyl acetate = 20: 1 Rf value = 0.5) to obtain (2E, 6E) -farnesal and An isomer mixture of (2Z, 6E) -farnesal (53 mg, 53% yield, isomer ratio: (2E, 6E) -farnesal / (2Z, 6E) -farnesal = 1.87) was obtained.
(2E, 6E) -Farnesal: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.99 (d, 1 H, J = 8.0 Hz), 5.89 (d, 1 H, J = 8.0 Hz), 5. 03-5.13 (m, 2H), 2.18-2.29 (m, 4H), 2.17 (d, 3H, J = 1.2 Hz), 2.02-2.11 (m, 2H) ), 1.94-2.02 (m, 2H), 1.68 (s, 3H), 1.61 (s, 3H), 1.60 (s, 3H)
(2Z, 6E) -farnesal: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.92 (d, 1 H, J = 8.2 Hz), 5.88 (d, 1 H, J = 8.2 Hz), 5. 03-5.16 (m, 2H), 2.60 (t, 2H, J = 7.5 Hz), 2.21-2.30 (m, 2H), 2.01-2.10 (m, 2H) ), 1.94-2.01 (m, 2H), 1.99 (d, 3H, J = 1.2 Hz), 1.68 (s, 3H), 1.60 (s, 6H)

Example 2:
(E) -Neroridol (100 mg, 0.45 mmol) was dissolved in chlorobenzene (2.0 g), and dimethyl sulfoxide (70 mg, 0.90 mmol), bis (acetylacetonato) dioxomolybdenum (VI) (15 mg, 0 0.045 mmol) was added, and the reaction was performed at 130 ° C. for 6 hours under a nitrogen stream. After cooling to room temperature, (2E, 6E) -farnesal (purity: 44.0%) and (2Z, 6E) -farnesal (purity: 26.8%) (isomer ratio: (2E, 6E) -farnesal / ( It was confirmed that 2Z, 6E) -farnesal = 1.64) was obtained.

Example 3:
(E) -Nerolidol (100 mg, 0.45 mmol) was dissolved in chlorobenzene (2.0 g), tetramethylene sulfoxide (469 mg, 4.50 mmol), bis (acetylacetonato) dioxomolybdenum (VI) (15 mg, 0.045 mmol) was added and the reaction was carried out at 130 ° C. for 13 hours. After cooling to room temperature, (2E, 6E) -farnesal (purity: 40.5%) and (2Z, 6E) -farnesal (purity: 25.1%) (isomer ratio: (2E, 6E) -farnesal / ( It was confirmed that 2Z, 6E) -farnesal = 1.61) was obtained.

Example 4:
(E) -Nerolidol (100 mg, 0.45 mmol) was dissolved in chlorobenzene (2.0 g), bis (acetylacetonato) dioxomolybdenum (VI) (15 mg, 0.045 mmol) was added, and under an air stream, Reaction was performed at 130 degreeC for 6 hours. After cooling to room temperature, (2E, 6E) -farnesal (purity: 47.6%) and (2Z, 6E) -farnesal (purity: 27.6%) (isomer ratio: (2E, 6E) -farnesal / ( 2Z, 6E) -farnesal = 1.72) was obtained.

Example 5:
(E) -Neroridol (100 mg, 0.45 mmol) was dissolved in chlorobenzene (2.0 g), and dimethyl sulfoxide (70 mg, 0.90 mmol), bis (acetylacetonato) dioxomolybdenum (VI) (15 mg, 0 0.045 mmol) was added, and the reaction was carried out at 100 ° C. for 45 hours under a nitrogen stream. After cooling to room temperature, (2E, 6E) -farnesal (purity: 48.7%), (2Z, 6E) -farnesal (purity: 28.2%) (isomer ratio: (2E, 6E) -farnesal / ( 2Z, 6E) -farnesal = 1.73).

Example 6:
(E) -Nerolidol (100 mg, 0.45 mmol) was dissolved in chlorobenzene (2.0 g), dimethyl sulfoxide (70 mg, 0.90 mmol), bis (acetylacetonato) dioxomolybdenum (VI) (1.5 mg , 0.0045 mmol) was added, and the reaction was carried out at 130 ° C. for 23 hours. After cooling to room temperature, (2E, 6E) -farnesal (purity: 23.8%) and (2Z, 6E) -farnesal (purity: 14.3%) (isomer ratio (2E, 6E) -farnesal / (2Z 6E) -farnesal = 1.66) was obtained.

Example 7:
(E) -Neroridol (100 mg, 0.45 mmol) was dissolved in chlorobenzene (2.0 g), and dimethyl sulfoxide (70 mg, 0.90 mmol), bis (acetylacetonato) dioxomolybdenum (VI) (15 mg, 0 0.045 mmol), 2,2,6,6-tetramethylpiperidine-1-oxyl (14 mg, 0.09 mmol) was added, and the reaction was carried out at 130 ° C. for 27 hours. After cooling to room temperature, (2E, 6E) -farnesal (purity: 51.7%) and (2Z, 6E) -farnesal (purity: 15.4%) (isomer ratio: (2E, 6E) -farnesal / ( 2Z, 6E) -farnesal = 3.36) was obtained.

Examples 8-14:
(E) -Neroridol (100 mg, 0.45 mmol) was dissolved in chlorobenzene (2.0 g), and dimethyl sulfoxide (70 mg, 0.90 mmol), bis (acetylacetonato) dioxomolybdenum (VI) (15 mg, 0 0.045 mmol) and the piperidine-1-oxyl derivative (0.0225 mmol) shown in Table 1 were added, and the reaction was carried out at 130 ° C. After cooling to room temperature, the formation of (2E, 6E) -farnesal and (2Z, 6E) -farnesal was confirmed by gas chromatography analysis. The purity and isomer ratio ((2E, 6E) -farnesal / (2Z, 6E) -farnesal) are shown in Table 1.

  According to the production method of the present invention, farnesal, which is useful as an intermediate for producing pharmaceuticals, agricultural chemicals and fragrances, particularly farnesal having a high (2E, 6E) -isomer ratio, is used from an inexpensive raw material with a highly toxic reagent. It is possible to manufacture efficiently. Therefore, the method of the present invention can be used as a manufacturing method on an industrial scale.

Claims (6)

Following formula (1)

(E) -nerolidol represented by the following formula (2) is reacted with an oxidizing agent in the presence of bis (acetylacetonato) dioxomolybdenum (VI) and a piperidine-1-oxyl compound:

A piperidine-1-oxyl compound represented by the following formula (3):

[Where:
R ¹ is a hydrogen atom; R ² is a hydrogen atom, cyano group, carboxy group, isothiocyanato group, maleimide group, phosphoric acid group, —OR ′ group or —NHR ″ group (where R ′ is a hydrogen atom) An atom, an alkyl group having 1 to 4 carbon atoms, an acyl group, or an alkanesulfonyl group having 1 to 4 carbon atoms; R ″ is a hydrogen atom, an acetyl group, or a haloacetyl group); or
R ¹ and R ² together form an oxo group]
A manufacturing method represented by R ¹ is a hydrogen atom and R ² is a hydrogen atom, a cyano group, a hydroxy group, an amino group, an acetylamino group, a carboxy group or a benzoyloxy group, or R ¹ and R ² are combined together form an oxo group Te process according to claim 1, wherein. The usage-amount of the piperidine-1-oxyl compound represented by Formula (3) is 0.005-0.2 mol with respect to 1 mol of (E) -nerolidol represented by Formula (1). 3. The production method according to 1 or 2 . The production method according to any one of claims 1 to 3 , wherein the oxidizing agent is air, oxygen, dimethyl sulfoxide, or tetramethylene sulfoxide. The manufacturing method as described in any one of Claims 1-4 implemented at the temperature of 80-140 degreeC. The amount of bis (acetylacetonato) dioxomolybdenum (VI) used is 0.01 to 0.5 mol with respect to 1 mol of (E) -nerolidol represented by formula (1). any manufacturing process of one claim of ~ 5.