阅读说明：本技术 一种酰胺衍生物的合成方法 (Synthesis method of amide derivative ) 是由 程建华 杜克斯 周心慧 于 2020-11-25 设计创作，主要内容包括：本发明公开了一种酰胺衍生物的合成方法,以烯丙基溴与烷基醇在强碱和催化剂作用下成醚,该醚在氧化条件下环化成缩水甘油醚,缩水甘油醚随之胺解得到仲胺衍生物；仲胺衍生物与烷基羧酸甲酯进行胺解得到酰胺衍生物。整个合成路线步骤少,只用到了碱、间氯过氧苯甲酸及常规溶剂,无危化品,条件温和,成本低廉,安全性较高,可操作性强。所合成的神经酰胺E纯度高,总收率约44％～58％,纯度约98％。(The invention discloses a synthesis method of an amide derivative, which comprises the steps of forming ether by allyl bromide and alkyl alcohol under the action of strong base and a catalyst, cyclizing the ether into glycidyl ether under the oxidation condition, and aminolyzing the glycidyl ether to obtain a secondary amine derivative; aminolysis of the secondary amine derivative with methyl alkylcarboxylate to give an amide derivative. The whole synthetic route has few steps, only uses alkali, m-chloroperoxybenzoic acid and conventional solvents, has no hazardous chemical substances, mild conditions, low cost, higher safety and strong operability. The synthesized ceramide E has high purity, the total yield is about 44-58%, and the purity is about 98%.)

1. A synthesis method of amide derivatives is characterized in that allyl bromide and alkyl alcohol are reacted into ether under the action of strong base and catalyst, the ether is cyclized into glycidyl ether under the oxidation condition, and the glycidyl ether is aminolyzed to obtain secondary amine derivatives; aminolysis of the secondary amine derivative with methyl alkylcarboxylate to give an amide derivative.

2. The method of synthesis according to claim 1, comprising the steps of:

(1) in an anhydrous solvent, reacting allyl bromide with alkyl alcohol under the action of sodium hydride and a catalyst to obtain allyl alkyl ether;

(2) dissolving the synthesized allyl alkyl ether in Dichloromethane (DCM), adding m-chloroperoxybenzoic acid (m-CPBA) and stirring for reaction to obtain a product glycidyl ether;

(3) adding the glycidyl ether into an ethanol solution containing excessive ethanolamine, and stirring for reaction to obtain a secondary amine derivative;

(4) stirring and dissolving the secondary amine derivative and the alkyl carboxylic acid methyl ester in an anhydrous solvent, adding alkali, and stirring for reaction to obtain a target product; or adding alkali into the secondary amine derivative, heating and heating for dissolving; under the condition of reduced pressure, methyl alkyl carboxylate is dripped to react to obtain the target product.

3. The method of claim 2, wherein the alkyl alcohol is R¹-OH, methyl alkylcarboxylate is R²-COOCH₃The structure general formula of the synthesized amide derivative is as follows:

wherein R is¹And R²Are identical or different from each other C₁₀-C₂₄Saturated aliphatic paraffins.

4. The method of synthesis of claim 3, wherein R is¹Is a saturated straight chain C₁₆H₃₃，R²Is a saturated straight chain C₁₅H₃₁The target product is ceramide E.

5. The synthesis method according to claim 2, 3 or 4, wherein the reaction temperature in the step (1) is 65-85 ℃, and the reaction time is 10-18 hours; the reaction temperature in the step (2) is-5-25 ℃, and the reaction time is 10-18 hours; the reaction temperature in the step (3) is 30-60 ℃, and the reaction time is 12-20 hours; the solvent reacts in the step (4), the stirring reaction temperature is 0-40 ℃, and the reaction time is 8-12 hours; and (3) carrying out solvent-free reaction, wherein the reaction temperature is 70-120 ℃ after dripping, and carrying out reduced pressure reaction for 3-10 hours.

6. The method of claim 5, wherein the anhydrous solvent in step (1) (4) is DMF or THF; the catalyst in the step (1) is at least one of tetrabutylammonium iodide, tetrabutylammonium bromide and benzyltriethylammonium chloride, wherein the molar ratio of the catalyst to the alkyl alcohol is 0.05: 1-0.3: 1.

7. The synthesis method according to claim 5, wherein the molar ratio of the alkyl alcohol to the allyl bromide and the sodium hydride in the step (1) is 1: (0.8-1.5): (0.8 to 1.5); the molar ratio of the allyl alkyl ether in the step (2) to the m-CPBA is 1: 2-1: 5.

8. The synthesis method according to claim 5, wherein the molar ratio of the ethanolamine to the glycidyl ether in the step (3) is 1.5: 1-6: 1.

9. The synthesis method according to claim 5, wherein the molar ratio of the secondary amine derivative to the base in the step (4) is 1: 0.05-1: 0.60; the alkali is at least one of tBuOK, KOH, NaOH, EtONa and MeONa.

10. The synthesis method according to claim 5, wherein the molar ratio of the methyl alkylcarboxylate to the secondary amine derivative in the step (4) is 0.8:1 to 1.4: 1.

Technical Field

The invention relates to the field of organic synthesis, in particular to a synthesis method of an amide derivative.

Background

Ceramide is a lipid second messenger molecule which has important regulation effect on cell differentiation, proliferation, apoptosis, aging and other life activities; at the same time, they are the main components of human stratum corneum lipids. Not only can help the skin to lock water, but also can promote the self-repair of the skin barrier and regulate the metabolism of skin cells. Thus, ceramides are of great interest for maintaining the skin barrier, moisturizing, anti-aging, treatment of skin diseases (joo.k.m., hwang.j.h., bae.s., et al.j Dermatol Sci,2015,77, 71-81).

Ceramides (psuedoceramides) function similarly to ceramides, but differ slightly in structure. Ceramide E (cetyl-PG hydroxyethylpalmitamide) is a substitute for more expensive ceramides as a ceramide-like substance, and has been receiving much attention as a substitute for the ceramide, playing its role in enhancing and maintaining the skin barrier function; the current demand is large, and the cosmetic belongs to important functional components of cosmetics. To date, total synthesis of ceramide E has not been reported.

Disclosure of Invention

The invention aims to provide a synthesis method of amide derivatives, which has the advantages of low cost, simple synthesis process and wide source of synthesis raw materials.

The technical scheme of the invention is as follows:

a synthesis method of amide derivatives comprises the steps of forming ether by allyl bromide and alkyl alcohol under the action of strong base and a catalyst, cyclizing the ether into glycidyl ether under the oxidation condition, and aminolyzing the glycidyl ether to obtain secondary amine derivatives; aminolysis of the secondary amine derivative with methyl alkylcarboxylate to give an amide derivative.

The synthesis method specifically comprises the following steps:

(1) in an anhydrous solvent, reacting allyl bromide with alkyl alcohol under the action of sodium hydride and a catalyst to obtain allyl alkyl ether;

(2) dissolving the synthesized allyl alkyl ether in Dichloromethane (DCM), adding m-chloroperoxybenzoic acid (m-CPBA) and stirring for reaction to obtain a product glycidyl ether;

(3) adding the glycidyl ether into an ethanol solution containing excessive ethanolamine, and stirring for reaction to obtain a secondary amine derivative;

(4) stirring and dissolving the secondary amine derivative and the alkyl carboxylic acid methyl ester in an anhydrous solvent, adding alkali, and stirring for reaction to obtain a target product; or adding alkali into the secondary amine derivative, heating and heating for dissolving; under the condition of reduced pressure, methyl alkyl carboxylate is dripped to react to obtain the target product.

The alkyl alcohol is R¹-OH, methyl alkylcarboxylate is R²-COOCH₃The structure general formula of the synthesized amide derivative is as follows:

wherein R is¹And R²Are identical or different from each other C₁₀-C₂₄Saturated aliphatic paraffins.

The synthetic route is as follows:

preferably, the reaction temperature in the step (1) is 65-85 ℃, and the reaction time is 10-18 hours. The reaction temperature in the step (2) is-5-25 ℃, and the reaction time is 10-18 hours. The reaction temperature in the step (3) is 30-60 ℃, and the reaction time is 12-20 hours. The solvent reacts in the step (4), the stirring reaction temperature is 0-40 ℃, and the reaction time is 8-12 hours; and (4) carrying out solvent-free reaction, wherein the reaction temperature is 70-120 ℃ after dripping, and carrying out reduced pressure reaction for 4-10 hours.

Preferably, the anhydrous solvent in step (1) (4) is DMF or THF.

Preferably, the catalyst in the step (1) is at least one of tetrabutylammonium iodide, tetrabutylammonium bromide and benzyltriethylammonium chloride, wherein the molar ratio of the catalyst to the alkyl alcohol is 0.05: 1-0.3: 1.

Preferably, the molar ratio of the alkyl alcohol to the allyl bromide and sodium hydride in step (1) is 1: (0.8-1.5): (0.8 to 1.5); the molar ratio of the allyl alkyl ether in the step (2) to the m-CPBA is 1: 2-1: 5.

Preferably, the molar ratio of the ethanolamine to the glycidyl ether in the step (3) is 1.5: 1-6: 1.

Preferably, the molar ratio of the secondary amine derivative to the base in the step (4) is 1: 0.05-1: 0.6; the alkali is at least one of tBuOK, KOH, NaOH, EtONa and MeONa.

Preferably, the molar ratio of the methyl alkylcarboxylate to the secondary amine derivative in the step (4) is 0.8: 1-1.4: 1.

Preferably, R¹is-CH₂(CH₂)₁₄CH₃，R²is-CH₂(CH₂)₁₃CH₃The target product is ceramide E. Allyl bromide and n-hexadecanol are reacted into ether (A) under the action of strong alkali, the ether is cyclized into glycidyl ether (B) under the oxidation condition, and the glycidyl ether is aminolyzed to obtain secondary amine derivative (C); aminolysis of the secondary amine derivative with methyl palmitate to obtain an amide derivative (D), namely the product ceramide E.

The synthesis process generally comprises the following steps:

the method comprises the following steps: adding anhydrous THF and a proper amount of NaH into a round-bottom flask at room temperature, and starting a stirrer to stir continuously; then, a solution of hexadecanol in anhydrous THF was slowly added dropwise to the above reaction solution. After the dropwise addition, stirring was continued for 1 hour, and then allyl bromide was slowly added dropwise. Finally, a proper amount of tetrabutylammonium bromide (TBAB) is added, the temperature is raised for reaction, and the reaction is finished within about 8 hours to obtain the allyl ether (A).

In the first step, the molar ratio of the hexadecanol to the allyl bromide is 1: 1.5;

in the first step, the mole ratio of the hexadecanol to the NaH is 1: 1.5;

in the first step, the molar ratio of the hexadecanol to the TBAB is 1: 0.05-1: 0.25.

Step two: dissolving the obtained allyl ether (A) in DCM, cooling to 0 ℃, and adding a proper amount of m-CPBA in batches; after the addition, stirring is continued for 15 minutes, then the mixture is moved to the room temperature, and stirring reaction is carried out overnight, thus obtaining the glycidyl ether (B).

In the second step, the molar ratio of the allyl ether (A) to the m-CPBA is 1: 3-1: 4.

Step three: and (3) dissolving the glycidyl ether (B) in ethanol, adding a proper amount of ethanolamine, and stirring at room temperature overnight to obtain the secondary amine derivative (C).

In the third step, the molar ratio of the glycidyl ether (B) to the ethanolamine is 1: 2-1: 4.

Step four: in the first method, the secondary amine derivative (C) and methyl palmitate are dissolved in DCM with stirring, a proper amount of alkali is added, and the mixture is stirred overnight for reaction to obtain a product (D), namely ceramide E. In the second method, the secondary amine derivative (C) and a proper amount of alkali are added into a reaction vessel, and methyl palmitate is slowly added dropwise under the conditions of temperature rise and pressure reduction. And after finishing dropping, continuously carrying out reduced pressure reaction for 3-5 hours, and finishing the reaction to obtain a product (D), namely ceramide E.

In the fourth step, the molar ratio of the secondary amine derivative (C) to the methyl palmitate is 1: 1.1-1: 1.4;

in the fourth step, the alkali is tBuOK, KOH, NaOH, EtONa and MeONa;

in the fourth step, the molar ratio of the secondary amine derivative (C) to the base is 1: 0.1-1: 0.6;

in the fourth step, the reaction temperature is 75-95 ℃.

After the reaction is finished, evaporating the solvent under reduced pressure, extracting with a proper organic solvent, washing with water, and removing most impurities; and combining organic layers, drying under reduced pressure to obtain a crude product, and directly feeding for reaction. And step four, obtaining the final product by ethanol recrystallization.

The invention has the advantages and beneficial effects that:

(1) the raw materials are rich in source, cheap and easy to obtain, and can be continuously supplied to industrial production;

(2) all reaction steps have no high temperature, the highest temperature is not more than 100 ℃, the requirement on reaction equipment is not high, and the reaction can be carried out by a conventional reaction kettle.

(3) The whole synthesis route has few steps, only uses alkali, m-chloroperoxybenzoic acid and conventional solvents, has no hazardous chemical substances, and has higher safety and strong operability. The synthesized ceramide E has high purity, the total yield is about 44-58%, and the purity is about 98%.

Drawings

FIG. 1 is the H-NMR of ceramide E in example 1;

FIG. 2 is C-NMR of ceramide E in example 1.

Detailed Description

Example 1

The method comprises the following steps: 1.20g (30mmol) NaH (60% in oil) was weighed into 20mL anhydrous THF at 0 deg.C and stirred for 15 min; 4.85g (20mmol) of n-hexadecanol in 60mL of anhydrous THF is added dropwise, and the dropwise addition is completed in about 1 hour; the temperature is increased to 40 ℃, the stirring is continued for 1 hour, and then the temperature is reduced to the room temperature. Then 3.63g (30mmol) of allyl bromide are slowly added dropwise and 0.64g (2mmol) of TBAB is added after the dropwise addition. Subsequently, the reaction was stirred while the temperature was increased to 70 ℃ and was stopped after about 8 hours. Filtering to remove filter residue, washing the filter residue with a small amount of THF, mixing filtrates, and concentrating under reduced pressure; then, 50mL of ethyl acetate was diluted, washed three times with an equal volume of distilled water, once with saturated brine and anhydrous Na₂SO₄And (5) drying. The solvent was distilled off under reduced pressure to give 5.49g of crude allyl alkyl ether (A) as a pale yellow oily liquid in 97.2% yield.

Step two: 5.65g (20mmol) of allyl alkyl ether (A) are dissolved in 120mL DCM, the temperature is reduced to 0 ℃ in an ice-water bath, and 6.90g (40mmol) of m-CPBA are added in batches; after stirring for an additional 15 minutes, the reaction was allowed to warm to room temperature for 14 hours and monitored by TLC for completion. Filtering, washing the filter cake with a small amount of DCM, mixing filtrates, washing with cold 0.5N NaOH aqueous solution 120mL once, washing with distilled water 100mL twice, washing with equal volume of saturated saline once, and collecting the organic layer containing anhydrous Na₂SO₄Drying and distilling off the solvent under reduced pressure gave 5.92g of a colorless oily glycidyl ether (B) liquid in a yield of 99.1%.

Step three: 5.97g (20mmol) of glycidyl ether (B) is dissolved in 120mL of ethanol, 3.67g (60mmol) of ethanolamine is added, and the mixture is stirred at room temperature overnight to completely react; and distilling under reduced pressure to remove the ethanol and the ethanolamine serving as solvents to obtain the secondary amine derivative (C) which is directly used for the next reaction.

Step four: 5.94g (22mmol) of methyl palmitate, 1.12g (20mmol) of KOH and 150mL of DCM are added to the secondary amine derivative (C) and stirred to dissolve, and the reaction is stirred at room temperature and completed within about 12 hours; the residue was removed by suction filtration and the solvent was evaporated under reduced pressure. And recrystallizing normal hexane and ethanol to obtain the product ceramide E with the yield of 51.0%. The total yield was 49.1% and the purity 97.5%.

Example 2

The first, second and third steps are the same as in example 1.

Step four: the secondary amine derivative (C) was charged into a two-necked round-bottomed flask, heated to 80 ℃ and stirred with 0.22g (4mmol) of KOH until the particles disappeared. Subsequently, 5.94g (22mmol) of methyl palmitate were slowly added dropwise under reduced pressure; after dropping, the reaction was continued for 3 hours to stop the reaction. Recrystallizing n-hexane and ethanol to obtain ceramide E with the yield of 59.0%. The total yield is 58.2 percent, and the purity is 98.3 percent.

The methods of the above-described embodiments are described in some detail and detail, but should not be construed to limit the scope of the invention. It should be noted that simple modifications can be made without departing from the inventive concept within the scope of the present invention.