JP2604672B2 - Method for producing amide derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing an amide derivative, and more particularly to a method for producing an amide derivative with high purity and high yield by amidating an amino alcohol with high selectivity.

[0002]

2. Description of the Related Art
As a method of producing an amide derivative from an amino alcohol, an amino alcohol (6) can be prepared in the absence of a catalyst or in the presence of a basic catalyst such as sodium methylate, triethylamine, etc. A method for acylation using a carboxylic acid derivative (7) is known.

[0003]

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[Wherein, R ⁶ and R ^{8 each} represent a hydrocarbon group or a hydrogen atom, R ⁷ represents a divalent hydrocarbon group, and A represents a halogen atom, a hydroxyl group, an alkoxy group or a group —OCOR ⁸ ]

However, this method produces a compound (9) as a by-product in addition to the target compound (8), and is not always high in yield.

Therefore, as a method of selectively performing amidation in the above reaction, the present applicant reacts compound (6) with a lower alkyl carboxylate in the presence of a basic catalyst, and distills the lower alcohol produced. A method for advancing amidation selectively while leaving was found, and a patent application was previously filed (JP-A-63-216852).

However, also in this method, the conversion to the compound (8) is poor depending on the reaction conditions, and the compound (6) as a raw material and the compound (9) as a by-product remain in the reaction system, and Compound (8), which cannot be obtained in high purity and high yield.

[0008] Accordingly, there has been a demand for the development of a method for performing an amidation reaction of amino alcohols with high selectivity and obtaining an amide derivative with high purity and high yield.

[0009]

Under these circumstances, the present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, in the presence of a basic catalyst, carboxylic acid ester (3) was added to amino alcohol (2). Alternatively, the lactone (4) is allowed to act, and after completion of the reaction, the reaction product is cooled and maintained at a temperature at which only the amide derivative (1) or (1 ′) as the target compound is precipitated for 1 hour or more. As a result of the removal of (1) or (1 ′) from the equilibrium system, the reaction between the starting amino alcohol (2) and the by-product (5) or (5 ′) progresses, whereby the compound (1) or (1) is removed. ') Can be obtained with high selectivity, high purity and high yield, and the present invention has been completed.

The production method of the present invention is represented by the following reaction formula.

[0011]

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[Wherein, R ¹ represents a linear or branched hydrocarbon group or a hydrogen atom, R ² represents a linear or branched divalent hydrocarbon group, and R ³ represents a linear or branched hydrocarbon group. A hydrocarbon group which may have a saturated or unsaturated hydroxyl group in the chain, and R ⁴ represents a divalent hydrocarbon group which may have a linear or branched saturated or unsaturated hydroxyl group; And R ⁵ represents a lower hydrocarbon group.

That is, in the present invention, the amino alcohol (2) is reacted with the carboxylic acid ester (3) or the lactone (4) in the presence of a basic catalyst, and the reaction product is converted to the amide derivative (1) or the target compound. An object of the present invention is to provide a method for producing an amide derivative (1) or (1 '), wherein the method is maintained at a temperature at which only (1') is precipitated in a solid state for 1 hour or more.

In the amino alcohol (2) used as a starting compound in the production method of the present invention, R ¹ and R ²
May have an ether bond or a hydroxyl group, but the hydrocarbon group of R ¹ has 1 to 2 carbon atoms.
5, and the hydrocarbon group of R ² includes one having 1 to 8 carbon atoms. Specific examples of the amino alcohol (2) used in the present invention include, for example, 2-aminoethanol, 2- (methylamino) ethanol, 5-aminoethanol,
Amino-1-pentanol, 2- (2-aminoethoxy) ethanol, N- (2-hydroxy-3-tetradecyloxypropyl) -N-2-hydroxyethylamine, N- (2-hydroxy-3-hexade (Siloxypropyl) -N-2-hydroxyethylamine, 2-amino-4-octadecene-1,3-diol, and the like, but are not limited thereto.

The amino alcohol derivative (2) is produced according to a known method, for example, Polish Journal of Chemistry (Pol. J. Chem.).
It can be manufactured according to 521283 (1978), Japanese Patent Publication No. 42934/1994, and the like.

In the carboxylic acid ester (3) used in the present invention, the hydrocarbon group of R ³ includes those having 7 to 31 carbon atoms, and the lower hydrocarbon group of R ⁵ includes 1 carbon atom. To 5 are mentioned. Specific examples of the carboxylic acid ester (3) include, for example, methyl caprylate, methyl caprate, methyl laurate, methyl myristate, methyl palmitate, ethyl palmitate,
Saturated linear fatty acid esters such as isopropyl palmitate, methyl stearate and methyl behenate; hydroxyl-substituted saturated linear fatty acid esters such as methyl 12-hydroxystearate, methyl 16-hydroxyhexadecanoate and methyl 15-hydroxypentadecanoate; methyl Saturated branched chain fatty acid esters such as branched methyl isostearate, methyl 2-heptylundecenoate, and methyl branched isopropyl isostearate; unsaturated fatty acid esters such as methyl oleate, methyl linoleate, and methyl linolenate; However, the present invention is not limited to this.

Furthermore, the lactone (4) used in the present invention
In the above, examples of the hydrocarbon group for R ⁴ include those having 3 to 31 carbon atoms. Illustrative examples of lactones include, for example, β-butyrolactone, γ-valerolactone, δ-valerolactone, γ-caprolactone, ε-caprolactone, γ-octanoic lactone, γ-nonanoic lactone,
γ-decanolactone, δ-decanolactone, undecanoic acid ω-lactone, undecanoic acid γ-lactone, undecanoic acid δ-lactone, oxacyclotridecane-2-one, pentadecanolide, hexadecanolide, and the like, but are not limited thereto. is not.

In the amidation reaction in the production method of the present invention, the carboxylic acid ester (3) or the lactone (4) is added in an amount of 0.9 mol per 1 mol of the starting amino alcohol (2).
It is preferable to use 5 to 1.1 moles.

Further, specific examples of the basic catalyst used in this reaction include, for example, sodium hydroxide, potassium hydroxide, potassium carbonate or sodium methylate, sodium ethylate, potassium tert-butoxide. However, the present invention is not limited to these. The use amount of these basic catalysts is preferably 0.01 to 0.2 mol per 1 mol of amino alcohol as a raw material.

In the reaction of the present invention, a carboxylic acid ester (3) or a lactone (4) is added to a basic catalyst and an amino alcohol (2) or a solution obtained by dissolving them in a suitable organic solvent under normal pressure or reduced pressure. It is done by dropping or adding. The reaction temperature at this time is 50 to 200
° C, particularly preferably 60 to 150 ° C, and when the carboxylic acid ester (3) or lactone (4) is added dropwise, the time is preferably about 1 to 3 hours, and the reaction time after the completion of the addition is within 10 hours. Is preferred.

Further, in the production method of the present invention, the reaction product obtained as described above is cooled, and only the amide derivative (1) or (1 '), which is the target compound, precipitates in a solid state or the reaction proceeds. When the reaction is performed in an organic solvent, the temperature is maintained for one hour or more at a temperature at which crystallization from the organic solvent precipitates.

The reaction product can be retained as it is or in an appropriate organic solvent when the reaction is carried out without solvent. In the present invention, as the organic solvent used for holding the above-mentioned reaction or reaction completed product, the compound (5) or (5 ′) in which the amide derivative (1) or (1 ′) as the target compound is a by-product It is not particularly limited as long as it is easy to precipitate as compared with the above, and can be appropriately selected. Specifically, for example, hydrocarbon solvents such as pentane, hexane, petroleum ether, benzene, toluene, xylene, ligroin; methanol,
Alcohol solvents such as ethanol, 1-propanol and 2-propanol; halogen solvents such as methylene chloride, chloroform, carbon tetrachloride and ethylene chloride; ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; dimethyl sulfoxide; Examples include, but are not limited to, solvents such as dimethylformamide and acetonitrile.

The retention temperature of the reaction product varies depending on the melting points of the amide derivative (1) or (1 ') and the by-product (5) or (5') and the solubility in various organic solvents. In the case of no solvent, [melting point (° C.) of amide derivative (1) or (1 ′)] to [melting point of amide derivative (° C.)]
-45 ° C], particularly preferably [melting point (° C) of amide derivative (1) or (1 ′) -5 ° C] to [melting point (° C) of amide derivative (1) or (1 ′) -40 ° C]. When the amide derivative (1) or (1 ') is retained in an organic solvent, the temperature is in the range of [the deposition temperature (° C.) of the amide derivative (1) or (1 ′)] to the temperature (° C.) Is preferred.

It is sufficient that the retention time of the reaction product is at least 1 hour, but in order to obtain a higher purity amide derivative (1) or (1 '), it is at least 8 hours, especially 16 hours. It is preferable that it is above.

The precipitate thus obtained is subjected to ordinary purification means such as recrystallization, if necessary, to obtain the amide derivative (1) or (1 ') as the target compound. be able to.

[0026]

According to the production method of the present invention, by removing the amide derivative (1) or (1 ') as the target compound from the reaction equilibrium system, the compound (5) or (5') by-produced and the residue The resulting amino alcohol (2) can be reacted efficiently, and the amide derivative (1) or (1 ') can be obtained with high selectivity, high yield and high purity.

[0027]

The present invention will be further described with reference to the following examples, but the present invention is not limited to these examples.

In the following, the total amine value refers to sample 1
The amount of hydrochloric acid required to neutralize the total amount of basic substances such as primary amine, secondary amine, tertiary amine and the like in g is converted to mg of potassium hydroxide. The total amine value was measured by potentiometric titration or visual titration using bromocresol green as an indicator.A fixed amount of the ethanol solution of the sample was titrated with an alcoholic hydrochloric acid solution and calculated from the consumption of the alcoholic hydrochloric acid solution. did.

Example 1 N- (2-hydroxy-3-tetradecyloxypropyl) -N-2-hydroxyethyldecaneamide (mp 4
Synthesis at 9.5 ° C): N- (2-
(Hydroxy-3-tetradecyloxypropyl) -N-2
-Hydroxyethylamine 167.1 g (504.1 mm
ol) and 1.41 g (25.1 mol) of potassium hydroxide, and methyl decanoate was added under the conditions of 80 ° C. and 60 mmHg.
60 g (529.3 mmol) were added dropwise over about 3 hours.
Further, the mixture was heated and stirred for 1 hour at 80 ° C. and 5 mmHg (total amine value at the end of the reaction: 13.9). The resulting reaction crude product was cooled and solidified at 20 ° C. and kept under the same conditions for 24 hours (total amine value of the solidified crude product after holding: 7.
4). Further, the obtained solidified crude product was dealkalized with acidic clay in a hexane solvent, recrystallized and washed to obtain the title compound in a yield of 75% (total amine value: 0.1%).
15).

Comparative Example 1 Synthesis of N- (2-hydroxy-3-tetradecyloxypropyl) -N-2-hydroxyethyldecaneamide
Without solidifying the reaction crude product obtained in the same manner as in Example 1, alkali-removal treatment was performed with acidic clay in a hexane solvent, followed by recrystallization and washing to obtain the title compound in a yield of 53.6.
% (Total amine number: 2.81).

Example 2 Synthesis of N- (2-hydroxy-3-tetradecyloxypropyl) -N-2-hydroxydecaneamide The crude reaction product obtained in the same manner as in Example 1 was dissolved in hexane.
It is then cooled to 15 ° C. for crystallization and
After holding for a time, dealkalization was performed with an acid clay. After the treatment, the hexane solution is cooled again, recrystallized and washed,
The title compound was obtained in a yield of 70% (total amine value: 0.2
6).

Example 3 N- (2-hydroxy-3-hexadecyloxypropyl) -N-2-hydroxyethyldecaneamide (mp 5
4.0 ° C.): N- (2-) was added to a 300 ml four-necked flask equipped with a stirrer, a dropping funnel, a thermometer and a distillation apparatus.
(Hydroxy-3-hexadecyloxypropyl) -N-2
179.8 g of hydroxyethylamine (500.0 mm
ol) and 0.702 g (12.5 mmol) of potassium hydroxide, and methyl decanoate 9 at 80 ° C. and 60 mmHg.
7.9 g (525.5 mmol) were added dropwise over about 3 hours. Further, the mixture was heated and stirred at 80 ° C. and 5 mmHg for 1 hour (total amine value at the end of the reaction: 12.1). The resulting crude reaction product was cooled and solidified at 30 ° C.
(The total amine value of the solidified crude product after the retention was:
4.8). Further, the obtained solidified crude product was dealkalized with acidic clay in a hexane solvent, recrystallized, and washed to obtain the title compound in a yield of 80.3% (total amine value: 0.22). .

Example 4 Synthesis of N- (2-hydroxy-3-hexadecyloxypropyl) -N-2-hydroxyethyldecaneamide
10 equipped with stirrer, dropping funnel, thermometer and distillation device
In a 00 ml four-necked flask, N- (2-hydroxy-3-
Hexadecyloxypropyl) -N-2-hydroxyethylamine (215.8 g, 600.1 mmol) and potassium hydroxide 1.68 g (29.9 mmol) were added.
Under the conditions of mmHg, 117.4 g of methyl decanoate (630.
2 mmol) was added dropwise over about 3 hours. Further, at 80 ° C, 5
The mixture was heated and stirred for 1 hour under the condition of mmHg (total amine value at the end of the reaction: 13.9). To the obtained reaction crude product, 770 g of hexane was added, cooled to 20 ° C., and kept at the same temperature for crystallization (total amine value of the crystallized crude product after holding:
8.2). Further, the obtained crystallized crude product was alkali-treated with acid clay, and then 770 g of hexane was added, followed by recrystallization and washing to obtain the title compound in a yield of 75.6% (total amine value: 0.1%). 35).

Example 5 Synthesis of N- (2-hydroxy-3-hexadecyloxypropyl) -N-2-hydroxyethylhexadecaneamide (melting point: 75 ° C.): N- (2-hydroxy-3-hexadecyloxypropyl) Example 1 using 179.79 g (500.0 mmol) of -N-2-hydroxyethylamine, 135.25 g (500.0 mmol) of methyl palmitate and 1.40 g (25.0 mmol) of potassium hydroxide.
A crude reaction product was obtained in the same manner as described above (total amine value at the end of the reaction: 12.6). The resulting crude reaction product was solidified at 60 ° C. and kept under the same conditions for 24 hours (total amine value after keeping: 8.3). Further, the obtained solidified crude product was 95%
The crystals were recrystallized from% ethanol and washed to give the title compound in a yield of 83% (total amine value: 0.25).

Example 6 Synthesis of N-2- (2-hydroxyethoxy) ethyl-decaneamide (melting point: 53 ° C.): A 200 ml two-necked flask equipped with a magnetic stirrer equipped with a distillation apparatus and a thermometer was charged with 2- (2
-Aminoethoxy) -1-ethanol 10.5 g (10
0 mmol), 0.98 g (5.0 mmol) of a 28% solution of sodium methylate in methanol and methyl decanoate 18.
6 g (400 mmol) was added, and the mixture was heated and stirred in an oil bath at 90 ° C. for 8 hours (total amine value at the end of the reaction: 19.6). The reaction crude product obtained was solidified at 40 ° C.
Hold for 4 hours (total amine value of solidified crude product after holding:
10.2). Furthermore, the obtained solidified crude product was recrystallized and washed with n-hexane-ethanol to obtain the title compound in a yield of 70% (total amine value: 0.07).

Example 7 Synthesis of N- (2-hydroxy-3-hexadecyloxypropyl) -N-2-hydroxyethyl-15-hydroxypentadecaneamide (mp 78 ° C.): 100 ml 2 equipped with a dropping funnel and a thermometer. N- (2-hydroxy-3-hexadecyloxypropyl) -N-2-
18.0 g (50 mmol) of hydroxyethylamine, 0.49 g of a 28% methanol solution of sodium methylate
(2.5 mmol), and pentadecanolide 1 at 85 ° C.
3.2 g (55 mmol) was added dropwise over about 1 hour. The mixture was further heated and stirred at the same temperature for 7 hours (total amine value at the end of the reaction: 24.5). The resulting reaction crude product was solidified at 50 ° C. and kept under the same conditions for 24 hours (total amine value of the solidified crude product after keeping: 12.0). Further, the obtained solidified crude product was recrystallized and washed with ethanol to obtain the title compound in a yield of 72% (total amine value: 0.1).
1).

Example 8 N-oleoyl-2-aminoethanol (melting point: 46 ° C.)
Synthesis of 14.0 g (230 mmol) of monoethanolamine, 45 ml of benzene in a 1000 ml three-necked flask equipped with a Dean-Stark apparatus and a dropping funnel under a nitrogen atmosphere.
0 ml, 28% methanol solution of sodium methylate 8
87 mg (4.6 mmol) was added, and while heating at 80 ° C. to remove methanol, 68.20 g of methyl oleate was added.
(230 mmol) was added dropwise over about 2 hours. The mixture was further stirred under the same conditions for 1 hour and concentrated under reduced pressure to obtain a crude reaction product (total amine value: 13.6). The obtained crude reaction product was 1
The mixture was cooled and solidified at 0 ° C., and kept under the same conditions for 24 hours (total amine value of the solidified crude product after holding: 6.1). Furthermore, the obtained solidified crude product was recrystallized and washed with ethanol to obtain the title compound in a yield of 82% (total amine value: 0.10).

EXAMPLE 9 Synthesis of Nn-hexadecanoyl-2-aminoethanol (melting point 99 ° C.): In a 1000 ml three-necked flask equipped with a Dean-Stark apparatus and a dropping funnel, ethanolamine was added under nitrogen atmosphere. 0 g (410 mmol), 500 ml of toluene and 1.58 g (8.2 mmol) of a 28% methanol solution of sodium methylate were added, and while heating at 100 ° C. to remove methanol, 110.9 g (410 mmol) of methyl palmitate was added. It was added dropwise over 2 hours. The mixture was further stirred for 1 hour under the same conditions, and toluene was distilled off to obtain a crude reaction product (total amine value: 15.2). The reaction crude product obtained was solidified at 60 ° C.
(The total amine value of the solidified crude product after the retention was:
8.4). Furthermore, the obtained solidified crude product was recrystallized and washed with ethanol to obtain the title compound in a yield of 86% (total amine value: 0.11).

Example 10 Synthesis of N-2-heptylundecanoyl-2-aminoethanol (melting point 91 ° C.): In a 1000 ml three-necked flask equipped with a Dean-Stark apparatus and a dropping funnel, ethanolamine was added under nitrogen atmosphere. 0g (41
0 mmol), 500 ml of toluene and 1.58 g (8.2 mmol) of a 28% solution of sodium methylate in methanol.
-122.4 g of methyl heptylundecanoate (410 mm
ol) was added dropwise over about 2 hours. The mixture was further stirred for 1 hour under the same conditions, and toluene was distilled off to obtain a crude reaction product (total amine value: 14.5). The obtained reaction crude product is heated to 60 ° C.
And kept under the same conditions for 24 hours (total amine value of the solidified crude product after holding: 7.2). Further, the obtained solidified crude product was recrystallized and washed with ethanol to obtain the title compound in a yield of 82% (total amine value: 0.1%).
08).

──────────────────────────────────────────────────続 き Continuation of the front page (51) Int.Cl. ⁶ Identification number Agency reference number FI Technical display location C07C 235/08 9547-4H C07C 235/08 // C07B 61/00 300 C07B 61/00 300

Claims (2)

(57) [Claims] 1. The following general formula (2): Wherein R ¹ represents a straight-chain or branched-chain hydrocarbon group or a hydrogen atom, and R ² represents a straight-chain or branched-chain divalent hydrocarbon group. Formula (3) Wherein R ³ represents a linear or branched saturated or unsaturated hydrocarbon group which may have a hydroxyl group, and R ⁵ represents a lower hydrocarbon group. General formula (4) of Wherein R ⁴ is a divalent hydrocarbon group which may have a linear or branched saturated or unsaturated hydroxyl group, and a lactone represented by the formula: The following general formula (1) characterized in that the end product is maintained at a temperature at which only the amide derivative (general formula (1) or (1 ′)) as a target compound precipitates in a solid state for 1 hour or more. Embedded image Wherein R ¹ , R ² and R ³ have the same meanings as described above, or the following general formula (1 ′): [Wherein R ¹ , R ² and R ⁴ have the same meaning as described above]. 2. The process for producing an amide derivative according to claim 1, wherein the reaction product is retained in an organic solvent.