JP2001226328A - Intermediate of capsamide and improved process for producing capsamide - Google Patents

Abstract

(57) Abstract: Provided is an improved chemical method for producing N- (13-methyltetradecyl) acetamide (capsamide) which is a component of pepper and has an analgesic action and an anti-inflammatory action. SOLUTION: Starting from 5-halogenovaleronitrile, a phosphonium salt obtained by a reaction with triphenylphosphine is condensed with 8-methyl-7-nonenal to obtain 13-cyano-2-methyltridecane. −
By reducing 2,9-diene, 13-methyltetradecylamine, which is useful as an intermediate for synthesizing capsamide, can be obtained in high yield, and the amine can be acetylated with acetic anhydride to obtain capsamide in high yield. It can be manufactured by

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an improved method for producing 13-methyltetradecylamine, which is useful as an intermediate for the synthesis of N- (13-methyltetradecyl) acetamide (hereinafter also referred to as capsamide), and to an improved method for producing capsamide. About the law.

[0002]

2. Description of the Related Art Capsiamide is obtained from capsicum (Caps).
icum annuum L. ) Is an ingredient extracted and isolated from the mature fruit of capsicum, which is known to have excellent analgesic and anti-inflammatory effects (Japanese Patent Application Laid-Open No. H06-1994).
JP-A-92844 and JP-A-7-179339).

[0003] Capsamide is obtained by extraction from a natural product or by chemical synthesis, but when extracted and isolated from a natural product, only about 0.02 to 0.04% is obtained from capsicum [ Pharmaceutical Magazine, 97 , 1372 (1
977)]. Also, in the case of chemical synthesis, only a very low yield production method is known. That is, Takahashi et al. [Pharmaceutical Magazine, 97 , 758 (1977)] produced 7-methyloctanoic acid in two steps using isovaleric acid as a starting material, as shown in the following conventional production process, and then in four steps. To obtain 13-methyltetradecylamine, which is further acetylated with acetyl chloride to produce capsamide.

[0004]

Embedded image

[0005] In the above conventional production process, 1
The total yield of the six steps up to 3-methyltetradecylamine is much lower at about 0.1%. Furthermore, the anodic synthesis method is employed in the carbon increasing step from isovaleric acid and from 7-methyloctanoic acid, which requires a special reaction apparatus called an electrolytic analyzer. Therefore, it has been extremely difficult to conduct research and development of capsamide as a pharmaceutically active ingredient or the like with the above-mentioned conventional techniques relating to extraction from natural products and chemical synthesis.

[0006]

DISCLOSURE OF THE INVENTION In view of the above prior art, the present inventors provide capsiamide in high yield without using a special reaction apparatus such as an electrolysis analyzer. As a result of diligent studies with a view to developing an improved chemical manufacturing method, as shown in the following manufacturing processes I and II, 5-halogenovaleronitrile (1)
Is used as a starting material, and the phosphonium salt (2) and 13-
Cyano-2-methyltridecane-2,9-diene (3)
13-methyltetradecylamine (4) as an intermediate
Was obtained in a high yield, and the amine was successfully acetylated in a higher yield than before, and it was found that capsamide could be produced efficiently, and further studies were repeated, thereby completing the present invention.

[0007]

Embedded image

[0008]

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS In a first embodiment of the present invention, as shown in the manufacturing process I, (a) the formula (1)

Embedded image (Wherein X represents a halogen atom) is reacted with triphenylphosphine to obtain a compound represented by the formula (2)

Embedded image (Wherein X is as defined above)
(B) Next, 8-methyl-7-nonenal is condensed,
Equation (3)

Embedded image 13-cyano-2-methyltridecane-2 represented by
Formula (4), wherein the compound is converted to 9-diene and (c) further reduced.

Embedded image This is a method for producing 13-methyltetradecylamine represented by the following formula:

Further, according to the second embodiment of the present invention, as shown in the manufacturing process II, the formula (4)

Embedded image Wherein the 13-methyltetradecylamine represented by the formula is acetylated using acetic anhydride.

Embedded image Is a method for producing N- (13-methyltetradecyl) acetamide, that is, capsamide.

Further, another embodiment of the present invention relates to a compound represented by the formula (3) obtained as an intermediate in the production step I:

Embedded image 13-cyano-2-methyltridecane-2 represented by
9-diene.

In the definition of the compounds (1) and (2), the halogen atom is a chlorine atom, a bromine atom or an iodine atom, and a chlorine atom and a bromine atom are preferred.

Each step of the above-mentioned manufacturing process I will be described more specifically below. Step (a): In this step, the 5-halogenovaleronitrile represented by the formula (1) is mixed with triphenylphosphine in the presence or absence of a solvent to obtain a compound of the formula (2)
Is a step of obtaining a phosphonium salt represented by When this step is performed in the presence of a solvent, a conventional organic solvent that does not adversely influence the reaction is used, and preferable examples include acetonitrile, dimethylformamide, dioxane, benzene, and methylene chloride. Reaction temperature is from room temperature
It is about the boiling point of the solvent, preferably about the boiling point of the solvent. The reaction time is about 1 to 48 hours.

Step (b): This step is a step of condensing compound (2) with 8-methyl-7-nonenal to obtain 13-cyano-2-methyltridecane-2,9-diene (3). is there. For the condensation, the conditions of the Wittig reaction commonly used in the field of synthetic organic chemistry are employed, and the condensation reaction is carried out in a suitable solvent in the presence of a base.

The base used in the step (b) includes alkali metal alkoxides, alkali metal amides and alkali metal hydrides, and specifically, sodium methoxide, sodium ethoxide, potassium t
-Butoxide, sodium amide, potassium amide, lithium diisopropylamide, lithium hydride, sodium hydride, potassium hydride and the like. As the solvent used in this step, a common organic solvent that does not adversely affect the reaction can be used, and preferable examples include ether, tetrahydrofuran, dioxane, diglyme, and dimethylformamide. In this step, any of the above base and 8-methyl-7-nonenal may be added first to compound (2),
The reaction temperature is about 0 to 100 ° C., preferably about room temperature in the step of adding a base, and is preferably about −70 ° C. to about room temperature in the step of adding 8-methyl-7-nonenal. The reaction time is about 1 to 24 hours.

Step (c): This step comprises the steps of:
In this step, the double bond of 2-methyltridecane-2,9-diene (3) and the cyano group are reduced to obtain 13-methyltetradecylamine represented by the formula (4). Either the double bond or the cyano group may be reduced first.
As a method for reducing a double bond in this step, a usual organic synthetic chemical means, for example, a catalytic reduction method using a catalyst such as palladium-carbon or Raney nickel is adopted. In addition, as a method for reducing the cyano group in this step, a general organic synthetic chemical means, for example, a reduction method using lithium aluminum hydride is employed. In this step, a solvent can be appropriately selected depending on the type of the reducing agent used. For example, in the above catalytic reduction method,
Alcohols (eg, methanol, ethanol) are used. In the reduction method using lithium aluminum hydride, ethers (eg, ethyl ether, tetrahydrofuran) and the like are used. The reaction of this step is
Usually, the reaction is carried out at room temperature to about the boiling point of the solvent, and the reaction time is 1 to
It is about 24 hours.

The method for producing 13-methyltetradecylamine (4) according to the above-mentioned production step I of the present invention is completely different from the method of Takahashi et al. Of the prior art described above, and does not require a special reaction apparatus such as an electrolytic analyzer. Moreover, the desired 13-methyltetradecylamine (4) can be obtained with a total yield as high as about 45% as compared with the starting material 5-halogenovaleronitrile (1). Therefore, the above-mentioned manufacturing process I includes
It can be said that this is an excellent and improved production method of 3-methyltetradecylamine (4).

Next, the production step II of the present invention will be described more specifically. That is, this step is a step of acetylating 13-methyltetradecylamine (4) with acetic anhydride to obtain the desired capsamide (5). Acetylation is usually performed in the presence of a base, and examples of the base used include tertiary amines (eg, pyridine, triethylamine). In this step, a solvent can be used, and any solvent may be used as long as it does not adversely affect the reaction. Specific solvents include 1,2-dimethoxyethane, ethyl ether, tetrahydrofuran, chloroform and the like. The reaction temperature is about 0 to 100 ° C., and the reaction time is about 1 to 24 hours. The acetylation reaction using acetic anhydride of the present invention proceeds with a high yield of about 80%, which is an improvement over the method of the prior art Takahashi et al., Ie, the method using acetyl chloride (yield about 51%). It can be said that the manufacturing method was performed.

While the embodiment of the present invention shown in the above-mentioned production steps I and II has been described above, the present invention further relates to an embodiment of 13-cyano-2-methyltridecane-2,9-diene (3). Also have. That is, 13-
Cyano-2-methyltridecane-2,9-diene (3)
Is an important intermediate of 13-methyltetradecylamine (4) in the above-mentioned production step I, but is a novel compound not described in any literature, and includes all geometric isomers relating to a double bond in its chemical structure.

Each of the intermediate compounds and capsamide obtained by the production method of the present invention described above can be purified by a known separation and purification method (eg, concentration, solvent extraction, chromatography, recrystallization).

[0020]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the invention is limited thereto. Example 1 Method for producing 4-cyanobutyltriphenylphosphonium bromide 5.5 g (34 mmol) of 5-bromovaleronitrile and 8.9 g (34 mmol) of triphenylphosphine
The mixture was heated to reflux in acetonitrile (50 ml) for 48 hours. By allowing to cool, 12.8 g (about 89%) of 4-cyanobutyltriphenylphosphonium bromide was obtained as colorless crystals having a melting point of 235-236 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 1.65-1.78
(4H, m), 2.61 (2H, t, J = 6.9H
z), 3.67 (2H, brt), 7.78-7.9.
2 (15H, m)

Example 2 Preparation of 13-cyano-2-methyltridecane-2,9-diene 8.5 g (20 mmol) of 4-cyanobutyl triphenylphosphonium bromide was suspended in anhydrous tetrahydrofuran (100 ml), and the suspension was added at room temperature. While stirring, 1.8 g (16 mmol) of potassium t-butoxide was added.
Stir for hours. Subsequently, 1.5 g (10 mmol) of 8-methyl-7-nonenal was cooled with dry ice-ethanol.
l) of anhydrous tetrahydrofuran (30 ml) in about 3
It takes 0 minutes and drops under stirring. After the dropwise addition, the reaction solution is further stirred at room temperature for 3 hours, and then a saturated aqueous ammonia solution is added again while cooling with dry ice-ethanol. After extracting tetrahydrofuran under reduced pressure, the residue was extracted with ethyl acetate (100 ml). The extract was washed with water, dried over magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography (eluent: n
-Hexane / ethyl acetate = 1/1) to give 13-cyano-2-methyltridecane-2,9 as a pale yellow oil.
1.3 g (about 62%) of diene were obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.32 (6H, br
s), 1.60-1.78 (8H, m), 1.95-
2.05 (4H, m), 2.19 (2H, q, J = 7.
2 Hz), 2.54 (2H, t, J = 7.4 Hz),
5.11 (1H, m), 5.27 (1H, m), 5.4
8 (1H, m)

Example 3 Preparation of 13-methyltetradecanonitrile 1.3 g (5.9 mmol) of 13-cyano-2-methyltridecane-2,9-diene and 10% palladium-
A suspension of 200 mg of carbon in ethanol (40 ml) was stirred under a stream of hydrogen for 6 hours. After removing the catalyst by filtration, the solvent was distilled off, thereby obtaining 1.2 g (about 91%) of 13-methyltetradecanonitrile as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 0.86 (6H, d, J
= 6.6 Hz), 1.16-1.68 (21H, m),
2.33 (2H, t, J = 7.2 Hz)

Example 4 Method for producing 13-methyltetradecylamine 580 mg of lithium aluminum hydride (15.3 mm
ol) in anhydrous ethyl ether (25 ml).
1.2 g of methyltetradecanonitrile (5.4 mmol
A solution of 1) in anhydrous ethyl ether (25 ml) was added dropwise with stirring at room temperature. After the addition, the mixture was further stirred at room temperature for 1 hour, and then heated under reflux for 2 hours. After cooling, a 40% aqueous sodium hydroxide solution was added, and the organic layer was separated. After drying over magnesium sulfate and distilling off the solvent, 1.1 g (about 90%) of 13-methyltetradecylamine was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 0.86 (6H, d, J
= 6.6 Hz), 1.16 to 1.54 (25H, m),
2.68 (2H, t, J = 6.9 Hz)

Example 5 Method for producing N- (13-methyltetradecyl) acetamide 1.1 g (4.8 mm) of 13-methyltetradecylamine
ol), 0.7 g (7.2 mmol) of acetic anhydride and 0.6 g (7.6 mmol) of pyridine were added to 1,2-
Heat to reflux in dimethoxyethane (30 ml) for 15 hours. After evaporating the solvent, the residue was dissolved in ethyl acetate, washed with water and dried over magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and the obtained crystal was recrystallized from ethyl ether to give a compound having a melting point of 6%.
1.0 g (79%) of N- (13-methyltetradecyl) acetamide was obtained as colorless scaly crystals at 2-63 ° C. ¹ H-NMR (CDCl ₃ ) δ: 0.86 (6H, d, J
= 6.6 Hz), 1.16 to 1.54 (23H, m),
1.97 (3H, s), 3.27 (2H, appq, J
= 6.9 Hz), 5.50 (1H, brs)

[0025]

According to the present invention, 13-methyltetradecylamine useful as an intermediate for synthesizing capsidamide is
Compared with the conventional chemical production method, it can be produced with extremely high yield and without using a special reaction device such as an electrolytic analyzer. Further, according to the present invention, acetylation of 13-methyltetradecylamine can be performed at a higher yield than in the past, and capsamide having excellent analgesic action and anti-inflammatory action can be produced. Therefore, the present invention can promote research and development of capsiamide as a pharmaceutically active ingredient and the like.

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Claims (3)

[Claims] (A) Formula (1) (Wherein X represents a halogen atom) is reacted with triphenylphosphine to give a compound of formula (2) Wherein X is the same as defined above,
(B) Next, 8-methyl-7-nonenal is condensed,
Formula (3) 13-cyano-2-methyltridecane-2 represented by
A compound of the formula (4), which is converted to 9-diene and (c) is further reduced. A method for producing 13-methyltetradecylamine represented by the formula: (2) Formula (4) Wherein the 13-methyltetradecylamine represented by the formula is acetylated using acetic anhydride. A method for producing N- (13-methyltetradecyl) acetamide represented by the formula: (3) Formula (3) 13-cyano-2-methyltridecane-2 represented by
9-diene.