CN112441937B - Synthesis method of amide derivative - Google Patents
Synthesis method of amide derivative Download PDFInfo
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- CN112441937B CN112441937B CN202011334185.1A CN202011334185A CN112441937B CN 112441937 B CN112441937 B CN 112441937B CN 202011334185 A CN202011334185 A CN 202011334185A CN 112441937 B CN112441937 B CN 112441937B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/04—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reaction of ammonia or amines with olefin oxides or halohydrins
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/16—Preparation of ethers by reaction of esters of mineral or organic acids with hydroxy or O-metal groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
- C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
- C07D303/22—Ethers with hydroxy compounds containing no oxirane rings with monohydroxy compounds
Abstract
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%.
Description
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 a filter cake with a small amount of DCM,the combined filtrates were washed once with 120mL of cold aqueous 0.5N NaOH solution, twice with 100mL of distilled water, and finally once with an equal volume of saturated brine, and the organic layer was washed with 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.
Claims (7)
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 and alkyl carboxylic acid methyl ester to obtain an amide derivative; the method 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, adding m-chloroperoxybenzoic acid in batches, 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, dropwise adding methyl alkyl carboxylate to react to obtain a target product;
the catalyst in the step (1) is at least one of tetrabutylammonium iodide, tetrabutylammonium bromide and benzyltriethylammonium chloride; the alkyl alcohol is R1-OH, methyl alkylcarboxylate is R2-COOCH3The structure general formula of the synthesized amide derivative is as follows:
the synthetic route is as follows:
2. the synthesis method according to claim 1, 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.
3. The method of claim 2, wherein the anhydrous solvent in step (1) (4) is DMF or THF; the molar ratio of the catalyst to the alkyl alcohol in the step (1) is 0.05: 1-0.3: 1.
4. The synthesis method according to claim 2, 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 mol ratio of the allyl alkyl ether to the m-chloroperoxybenzoic acid in the step (2) is 1: 2-1: 5.
5. The synthesis method according to claim 2, wherein the molar ratio of the ethanolamine to the glycidyl ether in the step (3) is 1.5:1 to 6: 1.
6. The synthesis method according to claim 2, 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.
7. The synthesis method of claim 2, wherein the molar ratio of the methyl alkylcarboxylate to the secondary amine derivative in step (4) is 0.8:1 to 1.4: 1.
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Effective date of registration: 20221128 Address after: 511300 building 3, No. 3, chuangjian Road, Yongning Street, Zengcheng District, Guangzhou City, Guangdong Province Patentee after: Guangzhou Zengcheng Chaohui Biotechnology Co.,Ltd. Address before: 510640 No. five, 381 mountain road, Guangzhou, Guangdong, Tianhe District Patentee before: SOUTH CHINA University OF TECHNOLOGY |
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