CN102388017A - A method of synthesising an amino acid derivative of azelaic acid - Google Patents
A method of synthesising an amino acid derivative of azelaic acid Download PDFInfo
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- CN102388017A CN102388017A CN2010800150545A CN201080015054A CN102388017A CN 102388017 A CN102388017 A CN 102388017A CN 2010800150545 A CN2010800150545 A CN 2010800150545A CN 201080015054 A CN201080015054 A CN 201080015054A CN 102388017 A CN102388017 A CN 102388017A
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- C—CHEMISTRY; METALLURGY
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- 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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- C07—ORGANIC CHEMISTRY
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- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
- C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
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Abstract
A method of producing an amide ester derivative of azelaic acid comprising treating an amino acid hydrohalide of the general formula (I): wherein R' is a substituted or unsubstituted alkyl, and R" is a substituted or unsubstituted side chain group of an amino acid selected from substituted or unsubstituted alkyl moiety, cyclic alkyl or aromatic moiety. The amino acid hydrohalide compound is to be dissolved in an aprotic solvent with an organic base to effect deprotonation, reacting the deprotonated product with an azelaic acid halide also dissolved in an aprotic solvent, contacting the reactant mixture with an anhydrous salt to remove any moisture therefrom and removing the aprotic solvent form the reactant mixture.
Description
Technical field
This present invention relates to a kind of method of synthetic azelaic acid derivant.Particularly relate to a kind of under anhydrous condition the method for synthetic nonane diacid carboxylic acid amide esters verivate.
Background technology
As everyone knows, nonane diacid can be used as the externally applied medicine composition use of treatment acne vulgaris.Yet this monounsaturated dicarboxylic acid has scope dystectic crystalline texture of 98 ℃-103 ℃, therefore under standard conditions, is difficult to brought in the face cream prescription.
In face cream prescription, it is 20% that the dosage of nonane diacid must reach concentration, could be that the curative effect of 4% Resorcinol is equal to concentration, promptly shows the dermopathic significant curative effect of treatment.But this high dosage enough causes more serious decortication, the scorching hot and shouting pain of skin.
As a kind of azelaoyl nonanedioyl Diglycocol potassium of new azelaic acid derivant, in the face cream prescription, as long as being 5% dosage, working concentration just can play a role effectively as anti-acne agents.Also have some about being applied to makeup, the compound on pharmacy and the tetter or the prior art of composition.
USP NO.6528068 (B1) discloses the cosmetic composition of the low alcohol ester of a kind of N-of containing acyl group neutral amino acids.According to patent, this composition is a kind of oily matter, contains the long linear or the branched structure of saturated or unsaturated acyl group, and wherein the hydro carbons group of alcohol ester is a branched-chain or straight-chain alkyl or alkenyl group.Can also further add ultraviolet sorbent material and mineral dye in the composition.
PCT applies for a patent the N-acylated derivatives that NO.2006010590 (A1) has introduced the diprotic acid of the relevant polypeptide that contains amino acid and/or plant protein hydrolysate, is used to prepare makeup and pharmaceutical preparation.This compound is that the diprotic acid acidylate is processed under the desolate Dun of routine-Bao Man reaction conditions.
Under the desolate Dun of routine-Bao Man reaction conditions, the acylation reaction that between carboxyl and amino acid whose N-end, forms the acid amides connection is to accomplish through the thermopositive reaction of etheride in alkaline aqueous solution and amino acid starting material.In this prior art; Azelaoyl nonanedioyl dichloro and glycocoll are in the potassium hydroxide solution that has used 40% concentration is controlled at pH value the aqueous solution of 9-11, to react; Aqueous ph value is adjusted to 7-7.5 with lactic acid more afterwards, generate clarification colourless to pale yellow solution as final product.
But usually, conventional method has some limitation.Because to the highly sensitive of moisture, the prevention etheride that must take preventive measures is hydrolyzed into its corresponding carboxylic acid.In addition, the alkaline degree of monitoring the aqueous solution closely also very always because base excess also can cause the etheride hydrolysis.
Isolating micro-halide-ions can cause product that impurity is arranged from the etheride, and this is unallowed on makeup and medical applications.In addition, conventional desolate Dun-Bao Man reaction conditions often has only the product that just can obtain with neutral amino acids.
On the other hand, amino acid such as L-aspartic acid, L-L-glutamic acid, the L-methionine(Met), L-halfcystine or L-Serine need preventive measures, thus the protection side chain functionalities reduces the generation of by product as far as possible.With the acyl group shift reaction of desolate Dun-Bao Man reaction conditions, can cause product soluble in water, therefore removing the aqueous solution, to isolate pure product often very complicated.
Therefore, the method for inventing the synthetic azelaic acid derivant of a kind of desolate Dun-Bao Man reaction conditions with improved is extremely important, promptly utilizes aprotic solvent and anhydrous salt to set up a dryness that helps reactant and obtain required product through acylation reaction.In addition, also hope to invent a kind of method that required product output reduces by product output simultaneously as far as possible that improves.
Summary of the invention
Main purpose of the present invention has provided a kind of method of under a good dryness of carrying out acylation reaction of utilizing aprotic solvent and anhydrous salt to set up, synthesizing azelaic acid derivant.Thus, for example the such reactant to moisture-sensitive of etheride will reduce because of hydrolysis converts its corresponding carboxylic acid into, because optional in the water medium in the reaction, also can reduce the complexity of separating required product simultaneously.
It is high that another object of the present invention has provided a kind of a large amount of synthetic azelaic acid derivant output, but the few method of unnecessary amount of by-products that generates simultaneously.Through the desolate Dun-Bao Man reaction conditions after this improvement, the required product of high yield not only can obtain from neutral amino acids, also can from the amino acid that has different functional group's side chains, obtain.
At least the present invention has realized that one of aforesaid target is all or part of, and wherein one of embodiment of the invention discloses a kind of method of synthetic nonane diacid carboxylic acid amide esters verivate, comprises the prepared amino acid hydrohalogen, and its general formula is:
Wherein R ' and R " are amino acid whose arbitrary alkyl group and side-chain radical; be selected from and replace or not substituted alkyl, naphthenic base or aromatic base; the amino acid hydrohalogen is dissolved in deprotonation in the aprotic solvent that contains organic bases; with deprotonation product and the nonane diacid halide reaction that also is dissolved in the aprotic solvent, reaction back mixture contact anhydrous salt is removed all moisture wherein, after said reaction, remove aprotic solvent the mixture.
The invention discloses a kind of method of synthesizing nonane diacid carboxylic acid amide esters verivate with the desolate Dun-Bao Man reaction conditions of improved.Water-less environment in the whole acylation reaction process is to utilize aprotic solvent and anhydrous salt to set up.
In addition, said organic bases such as pyridine are used to remove the hydrohalogen molecule.Therefore, this method is very favorable to required product is separated from anhydrous medium at an easy rate.
Those skilled in the art is easy to understand the suitable operation of method among the present invention and can obtains aforesaid and intrinsic purpose and advantage.The purpose of embodiment described here is not to limit invention scope.
Wherein one of embodiment of the invention discloses a kind of method of synthetic nonane diacid carboxylic acid amide esters verivate, comprises the prepared amino acid hydrohalogen, and its general formula is:
Wherein R ' and R " are amino acid whose arbitrary alkyl group and side-chain radical; be selected from and replace or not substituted alkyl, naphthenic base or aromatic base; the amino acid hydrohalogen is dissolved in deprotonation in the aprotic solvent that contains organic bases; with deprotonation product and the nonane diacid halide reaction that also is dissolved in aprotic solvent, reaction back mixture contact anhydrous salt is removed all moisture wherein, from react the back mixture, remove aprotic solvent.
In the present invention, the method for synthetic nonane diacid carboxylic acid amide esters verivate is amino acid ester hydrohalogen and the realization of the acylation reaction between the nonane diacid halogenide through deprotonation.Dissolving amino acid ester hydrohalogen and the halid aprotic solvent of nonane diacid be THF preferably, dioxan, chloroform, any combination of two chloroforms or these several kinds of materials.
The present invention also further discloses with organic bases processing amino acid ester hydrohalogen and has made its deprotonation.Proton on the amino acid ester to prevent and other amino acid ester molecules between direct nucleophillic attack to form unwanted product diketone piperidines be essential.
Formula shown in figure below is the protonated form of an amino acid ester hydrohalogen:
Wherein R ' and R " are amino acid whose each alkyl group and side-chain radical, are selected from and replace or not substituted alkyl, naphthenic base, aromatic group.
Yet deprotonation is very important to the amino acid ester hydrohalogen on amino acid ester hydrohalogen ammonium with a kind of organic bases, can produce the free amino group that a pair of electron pair is arranged that the halid carbonyl of nonane diacid is carried out nucleophillic attack.So, acylation reaction just can be carried out and synthetic nonane diacid carboxylic acid amide esters verivate.
Amino acid ester hydrohalogen preferred amino acid carbethoxy hydrochloride comprises neutral a-amino acid, like glycine ethyl ester hydrochloride, and L-Xie Ansuan carbethoxy hydrochloride, L-alanine ethyl ester hydrochloride, the acid of L-leucine ethyl ester hydrochloride salt; The amino acid of sulfur-containing side chain is like L-methionine(Met) carbethoxy hydrochloride, L-ethylcysteine hydrochloride; The amino acid of hydroxyl side chain is like L-serine ethyl ester hydrochloride; The amino acid that contains the carbonyl side chain, like the L-diethyl glutamate hydrochloride, or the arbitrary combination of these several kinds of materials.
In the acylation reaction, the halid mol ratio of amino acid ester hydrohalogen and nonane diacid is 2: 1.In a specific embodiment of the present invention, with in the amino acid ester hydrohalogen that is dissolved in the aprotic solvent, is preferably 0.2mol-1.0mol and the aprotic solvent that is dissolved in 100ml-500ml, be preferably the nonane diacid halide reaction of 0.1mol-0.5mol.Reaction formula is following:
Through using aprotic solvent, anhydrous reaction conditions can be established, thereby reduces nonane diacid halogenide, the nonane diacid dichloro that is shown in the following figure, because to the sensitivity of moisture and hydrolysis converts its corresponding carboxylic acid into:
Nonane diacid nonane diacid dichloro
Disclosed like the present invention, a kind of pyridine organic bases can be used as proton-removed agent and removes the hydrohalogen molecule.For instance, pyridine has the hydrochloric acid extraction function, thereby removes the salt acid molecule.
In a specific embodiment of the present invention, in being dissolved in aprotic solvent amino acid ester hydrochloric acid, add pyridine, remove the salt acid molecule with the mode that forms pyridine hydrochloride, thereby reach the deprotonation product of ester compound.
In the present invention, the nonane diacid halide solution dropwise splashes in the amino acid ester hydrohalogen solution of deprotonation, starts acylation reaction.Acylation reaction between the amino acid ester hydrochloride of nonane diacid dichloro and deprotonation has been described in specific embodiment.In addition, the salt acid molecule of acyl group shift reaction generation also can be removed with pyridine thus.
Subsequently, the invention provides a kind of comprise with reaction back mixture thing contact with hydrochloride with remove wherein all moisture and except that the method for the synthetic azelaic acid derivant of the step of aprotic solvent in the mixture after the dereaction.
The aprotic solvent that in one of specific embodiment of the present invention, discloses reaction back mixture is met and is withed a hook at the end, adopt anhydrous salt preferably SODIUM SULPHATE ANHYDROUS 99PCT will react afterwards that the mixture drying dewaters.Subsequently, aprotic solvent is removed through vacuum-evaporation.
Among the present invention, the thick output of carboxylic acid amide esters verivate that nonane diacid and amino acid ester reaction produce is 9.6%-87%.The sample of crude product will use HPLC (HPLC) to analyze its purity.
Embodiment
Embodiment 1
The L-glycine ethyl ester hydrochloride of ready 0.25mol is taken by weighing 35g, pours in the three neck round-bottomed flasks of a 500ml, add the 200ml chloroform.Subsequently about 40ml pyridine is joined in this solution subsequently, and at room temperature stir, up to mixing.28g, 0.13mol nonane diacid dichloro are dissolved in the 200ml chloroform and are ready to.The solution of nonane diacid dichloro is dropwise splashed into startup reaction in the L-glycine ethyl ester hydrochloride solution, react and do not stop in 2 hours to stir, then the refrigeration of 5 ℃ of mixed solutions is spent the night.
Reaction formula is following:
Mixed solution wherein partly washs with the 200ml deionized water and removes the pyridine hydrochloride that in acylation reaction, forms.Subsequently, with the dilute hydrochloric acid solution part unreacted pyridine that neutralizes wherein, remove the pyridine hydrochloride of generation with the washing of 200ml deionized water another part again.On the other hand, hydrochloric acid soln also can be refrigerated directly adding of back at mixed solution.Chloroform is met and is withed a hook at the end in the mixed solution, dewaters with anhydrous sodium sulfate drying earlier.
In addition, remove through vacuum-evaporation after the chloroform, last residuum is used petroleum ether, if exist azelate also can be removed.The thick output of the carboxylic acid amide esters verivate that L-glycine ethyl ester that obtains and nonane diacid reaction produce is 78.50%.The crude product sample will be from the refrigerated Virahol recrystallization, detect its purity through HPLC then, purity is in the scope of 74.90%-99.89%.
Analyze from performance liquid chromatography, the sample of recrystallization goes out the peak in the residence time of 10.16min, and condition is that moving phase contains the zero(ppm) water of 30% acetonitrile and 70% with the 5 μ-ODS-3 post that is of a size of 250mm * 4.6mm, and flow velocity is 1.0ml/min.
Embodiment 2
The L-Xie Ansuan carbethoxy hydrochloride of ready 0.25mol is taken by weighing 46g, pours in the three neck round-bottomed flasks of a 500ml, add the 100ml methylene dichloride.Subsequently about 40ml pyridine is joined in this solution subsequently, and at room temperature stir, up to mixing.28g, 0.13mol nonane diacid dichloro are dissolved in the 100ml methylene dichloride and are ready to.The solution of nonane diacid dichloro is dropwise splashed into startup reaction in the L-Xie Ansuan ethyl ester salts solution, react and do not stop in 2 hours to stir, then the refrigeration of 5 ℃ of mixed solutions is spent the night.
Mixed solution wherein partly washs with the 200ml deionized water and removes the pyridine hydrochloride that in acylation reaction, forms.Subsequently, with the dilute hydrochloric acid solution part unreacted pyridine that neutralizes wherein, remove the pyridine hydrochloride of generation with the washing of 200ml deionized water another part again.Methylene dichloride is met and is withed a hook at the end in the mixed solution, dewaters with anhydrous sodium sulfate drying earlier.
In addition, remove through vacuum-evaporation after the methylene dichloride, last residuum is used petroleum ether, if exist azelate also can be removed.The thick output of carboxylic acid amide esters verivate that L-Xie Ansuan ethyl ester that obtains and nonane diacid reaction produce is 76.38%.
When using efficient liquid phase chromatographic analysis; It is with the 5 μ-ODS-3 post that is of a size of 250mm * 4.6mm that the sample of recrystallization has the condition of high resolving power chromatographic peak; Moving phase contains 60% acetonitrile and 40% zero(ppm) water; Flow velocity is 1.5ml/min, and the 0.1793g sample is dissolved in the 10ml acetonitrile and sample size is 50 μ L.
Composition in the crude samples is obtained by the analysis of several peaks, is included in the main peak that accounts for the peak total area 81.76% that occurs among the 4.80min.Two other small peak appears at 3.90min and 6.39min, respectively accounts for 15.06% and 3.00% of the peak total area.Be dissolved in 100cm
3Absolute ethyl alcohol in the specific rotatory power [α] of 1.30g sample
20Be-23.05 °, and be dissolved in 100cm
3Absolute ethyl alcohol in the specific rotatory power [α] of initial L-amino acid carbethoxy hydrochloride of 1.14g sample
20Be+22.34 °.
Embodiment 3
The L-alanine ethyl ester hydrochloride of ready 0.25mol is taken by weighing 39g, pours in the three neck round-bottomed flasks of a 500ml, add the 100ml methylene dichloride.Subsequently about 40ml pyridine is joined in this solution subsequently, and at room temperature stir, up to mixing.28g, 0.13mol nonane diacid dichloro are dissolved in the 100ml methylene dichloride and are ready to.The solution of nonane diacid dichloro is dropwise splashed into startup reaction in the L-alanine ethyl ester hydrochloride solution, react and do not stop in 2 hours to stir, then the refrigeration of 5 ℃ of mixed solutions is spent the night.
Mixed solution wherein partly washs with the 200ml deionized water and removes the pyridine hydrochloride that in acylation reaction, forms.Subsequently, with the dilute hydrochloric acid solution part unreacted pyridine that neutralizes wherein, wash the pyridine hydrochloride of removing generation again with 200ml deionized water another part again.Methylene dichloride is met and is withed a hook at the end in the mixed solution, dewaters with anhydrous sodium sulfate drying earlier.
In addition, remove through vacuum-evaporation after the methylene dichloride, last residuum is used petroleum ether, if exist azelate also can be removed.The thick output of carboxylic acid amide esters verivate that L-alanine ethyl ester that obtains and nonane diacid reaction produce is 87.01%.
When using efficient liquid phase chromatographic analysis; It is with the 5 μ-ODS-3 post that is of a size of 250mm * 4.6mm that the sample of recrystallization has the condition of high resolving power chromatographic peak; Moving phase contains 40% acetonitrile and 60% zero(ppm) water; Flow velocity is 1.5ml/min, and the 0.2510g sample is dissolved in the 10ml acetonitrile and sample size is 50 μ L.
Composition in the crude samples is obtained by the analysis of several peaks, is included in the main peak that accounts for the peak total area 86.74% that occurs among the 7.11min.Two other small peak appears at 2.32min and 5.65min, respectively accounts for 1.48% and 5.14% of the peak total area.Be dissolved in 100cm
3Absolute ethyl alcohol in the specific rotatory power [α] of 1.11g sample
20Be-44.10 °, and be dissolved in 100cm
3Absolute ethyl alcohol in the specific rotatory power [α] of initial L-amino acid carbethoxy hydrochloride of 1.70g sample
20Be+6.99 °.
Embodiment 4
The L-leucine ethyl ester hydrochloride salt of ready 0.25mol is taken by weighing 49g, pours in the three neck round-bottomed flasks of a 500ml, add the 100ml methylene dichloride.Subsequently about 40ml pyridine is joined in this solution subsequently, and at room temperature stir, up to mixing.28g, 0.13mol nonane diacid dichloro are dissolved in the 100ml methylene dichloride and are ready to.The solution of nonane diacid dichloro is dropwise splashed into startup reaction in the L-leucine ethyl ester hydrochloride salt solution, react and do not stop in 2 hours to stir, then the refrigeration of 5 ℃ of mixed solutions is spent the night.
Mixed solution wherein partly washs with the 200ml deionized water and removes the pyridine hydrochloride that in acylation reaction, forms.Subsequently, with the dilute hydrochloric acid solution part unreacted pyridine that neutralizes wherein, wash the pyridine hydrochloride of removing generation again with 200ml deionized water another part again.Methylene dichloride is met and is withed a hook at the end in the mixed solution, dewaters with anhydrous sodium sulfate drying earlier.
In addition, remove through vacuum-evaporation after the methylene dichloride, last residuum is used petroleum ether, if exist azelate also can be removed.The thick output of carboxylic acid amide esters verivate that L-leucinethylester that obtains and nonane diacid reaction produce is 83.64%.
When using efficient liquid phase chromatographic analysis; It is with the 5 μ-ODS-3 post that is of a size of 250mm * 4.6mm that the sample of recrystallization has the condition of high resolving power chromatographic peak; Moving phase contains 60% acetonitrile and 40% zero(ppm) water; Flow velocity is 1.0ml/min, and the 0.5790g sample is dissolved in the 10ml acetonitrile and sample size is 50 μ L.
Composition in the crude samples is obtained by the analysis of several peaks, is included in the main peak that accounts for the peak total area 82.20% that occurs among the 7.39min.Two other small peak appears at 2.31min and 5.92min, respectively accounts for 5.10% and 4.64% of the peak total area.Be dissolved in 100cm
3Absolute ethyl alcohol in the specific rotatory power [α] of 1.37g sample
20Be-30.99 °, and be dissolved in 100cm
3Absolute ethyl alcohol in the specific rotatory power [α] of initial L-amino acid carbethoxy hydrochloride of 1.05g sample
20Be+24.73 °.
Embodiment 5
The L-serine ethyl ester hydrochloride of ready 0.16mol is taken by weighing 27g, pours in the three neck round-bottomed flasks of a 250ml, add the 50ml methylene dichloride.Subsequently about 26ml pyridine is joined in this solution subsequently, and at room temperature stir, up to mixing.18g, 0.08mol nonane diacid dichloro are dissolved in the 70ml methylene dichloride and are ready to.The solution of nonane diacid dichloro is dropwise splashed into startup reaction in the L-serine ethyl ester hydrochloride solution, react and do not stop in 2 hours to stir, then the refrigeration of 5 ℃ of mixed solutions is spent the night.
Mixed solution wherein partly washs with the 150ml deionized water and removes the pyridine hydrochloride that in acylation reaction, forms.Subsequently, with the dilute hydrochloric acid solution part unreacted pyridine that neutralizes wherein, wash the pyridine hydrochloride of removing generation again with 150ml deionized water another part again.Methylene dichloride is met and is withed a hook at the end in the mixed solution, dewaters with anhydrous sodium sulfate drying earlier.
In addition, remove through vacuum-evaporation after the methylene dichloride, last residuum is used petroleum ether, if exist azelate also can be removed.The thick output of carboxylic acid amide esters verivate that L-serine ethyl ester that obtains and nonane diacid reaction produce is 9.58%.
When using efficient liquid phase chromatographic analysis; It is with the 5 μ-ODS-3 post that is of a size of 250mm * 4.6mm that the sample of recrystallization has the condition of high resolving power chromatographic peak; Moving phase contains 50% acetonitrile and 50% zero(ppm) water; Flow velocity is 1.2ml/min, and the 0.1992g sample is dissolved in and becomes 1: 1 with the water proportioning in the 10ml acetonitrile and sample size is 50 μ L.
By mol ratio is that composition in the hard faint yellow solid crude samples of 2: 1 reactant synthetic is obtained by the analysis of several peaks, be included in occur among the 4.61min account for the main unimodal of the peak total area 50.78%.Two other small peak appears at 2.62min and 3.75min, respectively accounts for 16.75% and 32.71% of the peak total area.Be dissolved in 100cm
3Absolute ethyl alcohol in the specific rotatory power [α] of 1.05g sample
20Be-3.805 °.
Embodiment 6
The L-serine ethyl ester hydrochloride of ready 0.16mol is taken by weighing 27g, pours in the three neck round-bottomed flasks of a 250ml, add the 50ml methylene dichloride.Subsequently about 39ml pyridine is joined in this solution subsequently, and at room temperature stir, up to mixing.35g, 0.16mol nonane diacid dichloro are dissolved in the 70ml methylene dichloride and are ready to.The solution of nonane diacid dichloro is dropwise splashed into startup reaction in the L-serine ethyl ester hydrochloride solution, react and do not stop in 2 hours to stir, then the refrigeration of 5 ℃ of mixed solutions is spent the night.
Mixed solution wherein partly washs with the 150ml deionized water and removes the pyridine hydrochloride that in acylation reaction, forms.Subsequently, with the dilute hydrochloric acid solution part unreacted pyridine that neutralizes wherein, wash the pyridine hydrochloride of removing generation again with 150ml deionized water another part again.Methylene dichloride is met and is withed a hook at the end in the mixed solution, dewaters with anhydrous sodium sulfate drying earlier.
In addition, remove through vacuum-evaporation after the methylene dichloride, last residuum is used petroleum ether, if exist azelate also can be removed.Thick output by 1: 1 the translucent faint yellow mashed prod of reactant synthetic of mol ratio is 44.64%, is higher than 2: 1 reactant synthetic crude product output of mole.
When using efficient liquid phase chromatographic analysis, the analysis condition of crude samples is with being of a size of 5 μ-ODS-3 post of 250mm * 4.6mm, and moving phase contains 50% acetonitrile and 50% zero(ppm) water, and flow velocity is 1.2ml/min.The percentage area that goes out the peak at 4.53min significantly is reduced to 6.20% from 50%.
But other peak by the described small peak of the precedent group representative that after 4.5min goes out the peak, occurs accounts for the peak total area and increases to 23.96%, 32.71% from 16.57% respectively and increase to 69.80%.Be dissolved in 100cm
3Absolute ethyl alcohol in the specific rotatory power [α] of 1.59g sample
20Be+6.92 °.
Embodiment 7
The L-ethylcysteine hydrochloride of ready 0.15mol is taken by weighing 27.9g, pours in the three neck round-bottomed flasks of a 500ml, add the 100ml methylene dichloride.Subsequently about 24ml pyridine is joined in this solution subsequently, and at room temperature stir, up to mixing.17g, 0.08mol nonane diacid dichloro are dissolved in the 100ml methylene dichloride and are ready to.The solution of nonane diacid dichloro is dropwise splashed into startup reaction in the L-ethylcysteine hydrochloride solution, react and do not stop in 2 hours to stir, then the refrigeration of 5 ℃ of mixed solutions is spent the night.
Mixed solution wherein partly washs with the 200ml deionized water and removes the pyridine hydrochloride that in acylation reaction, forms.Subsequently, with the dilute hydrochloric acid solution part unreacted pyridine that neutralizes wherein, wash the pyridine hydrochloride of removing generation again with 200ml deionized water another part again.Methylene dichloride is met and is withed a hook at the end in the mixed solution, dewaters with anhydrous sodium sulfate drying earlier.
In addition, remove through vacuum-evaporation after the methylene dichloride, last residuum is used petroleum ether, if exist azelate also can be removed.The thick output of carboxylic acid amide esters verivate that L-ethycysteine that obtains and nonane diacid reaction produce is 76.92%.
When using efficient liquid phase chromatographic analysis; It is with the 5 μ-ODS-3 post that is of a size of 250mm * 4.6mm that the sample of recrystallization has the condition of high resolving power chromatographic peak; Moving phase contains 50% acetonitrile and 50% zero(ppm) water; Flow velocity is 1.2ml/min, and the 0.2262g sample is dissolved in and becomes 1: 1 with the water proportioning in the 10ml acetonitrile and sample size is 50 μ L.
The hard white translucent composition that is comprised as the solids crude sample of wax is obtained by the analysis of several peaks; Being included in the main peak that accounts for the peak total area 49.097% that occurs among the 4.61min. other four small peaks appear at 5.62min, 12.09min, 14.58min and 26.47min respectively; Respectively account for 10.27% of the peak total area; 9.30%, 9.91%and 12.80%.Be dissolved in 100cm
3Absolute ethyl alcohol in the specific rotatory power [α] of 1.29g sample
20Be-24.49 °.
Embodiment 8
The L-methionine(Met) carbethoxy hydrochloride of ready 0.07mol is taken by weighing 15g, pours in the three neck round-bottomed flasks of a 250ml, add the 50ml methylene dichloride.Subsequently about 12ml pyridine is joined in this solution subsequently, and at room temperature stir, up to mixing.7.6g, 0.04mol nonane diacid dichloro are dissolved in the 50ml methylene dichloride and are ready to.The solution of nonane diacid dichloro is dropwise splashed into startup reaction in the L-methionine(Met) ethyl ester salts solution, react and do not stop in 2 hours to stir, then the refrigeration of 5 ℃ of mixed solutions is spent the night.
Mixed solution wherein partly washs with the 150ml deionized water and removes the pyridine hydrochloride that in acylation reaction, forms.Subsequently, with the dilute hydrochloric acid solution part unreacted pyridine that neutralizes wherein, wash the pyridine hydrochloride of removing generation again with 150ml deionized water another part again.Methylene dichloride is met and is withed a hook at the end in the mixed solution, dewaters with anhydrous sodium sulfate drying earlier.
In addition, remove through vacuum-evaporation after the methylene dichloride, last residuum is used petroleum ether, if exist azelate also can be removed.The thick output of carboxylic acid amide esters verivate that L-methionine(Met) ethyl ester that obtains and nonane diacid reaction produce is 75.53%.
When using efficient liquid phase chromatographic analysis; It is with the 5 μ-ODS-3 post that is of a size of 250mm * 4.6mm that the sample of recrystallization has the condition of high resolving power chromatographic peak; Moving phase contains 50% acetonitrile and 50% zero(ppm) water; Flow velocity is 1.2ml/min, and the 0.1052g sample is dissolved in the 10ml acetonitrile and sample size is 50 μ L.
Last crude product is the cream-coloured powder that the sharp aroma of sulphur is arranged.Obtain the component in the crude product sample through efficient liquid phase chromatographic analysis, main peak appears at 12.29min, accounts for 70.56% of the peak total area.
Other several small peaks appear at 6.50min, 14.55min, and 16.36min, 17.47min and 19.06min respectively account for 9.22%, 7.15%, 2.19%, 1.75% and 2.00% of the peak total area.Be dissolved in 100cm
3Absolute ethyl alcohol in the specific rotatory power [α] of 1.33g sample
20Be-22.96 °.
Embodiment 9
The L-diethyl glutamate hydrochloride of ready 0.08mol is taken by weighing 20g, pours in the three neck round-bottomed flasks of a 250ml, add the 25ml methylene dichloride.Subsequently about 13ml pyridine is joined in this solution subsequently, and at room temperature stir, up to mixing.9g, 0.04mol nonane diacid dichloro are dissolved in the 40ml methylene dichloride and are ready to.The solution of nonane diacid dichloro is dropwise splashed into startup reaction in the L-diethyl glutamate hydrochloride solution, react and do not stop in 2 hours to stir, then the refrigeration of 5 ℃ of mixed solutions is spent the night.
Mixed solution wherein partly washs with the 150ml deionized water and removes the pyridine hydrochloride that in acylation reaction, forms.Subsequently, with the dilute hydrochloric acid solution part unreacted pyridine that neutralizes wherein, wash the pyridine hydrochloride of removing generation again with 150ml deionized water another part again.Methylene dichloride is met and is withed a hook at the end in the mixed solution, dewaters with anhydrous sodium sulfate drying earlier.
In addition, remove through vacuum-evaporation after the methylene dichloride, last residuum is used petroleum ether, if exist azelate also can be removed.The thick output of carboxylic acid amide esters verivate that L-diethyl glutamate hydrochloride that obtains and nonane diacid reaction produce is 79.27%.
When using efficient liquid phase chromatographic analysis; It is with the 5 μ-ODS-3 post that is of a size of 250mm * 4.6mm that the sample of recrystallization has the condition of high resolving power chromatographic peak; Moving phase contains 60% acetonitrile and 40% zero(ppm) water; Flow velocity is 1.0ml/min, and the 0.2706g sample is dissolved in the 10ml acetonitrile and sample size is 50 μ L.
With the composition in the efficient liquid phase chromatographic analysis crude samples.Have three peaks, wherein main peak occurs in 7.28min, accounts for 82.20% of the peak total area.Two other small peak appears at 5.56min and 10.25min, respectively accounts for 6.08% and 1.36% of the peak total area.Be dissolved in 100cm
3Absolute ethyl alcohol in the specific rotatory power [α] of 1.20g sample
20Be-17.48 °.
Claims (7)
1. the method for a synthetic nonane diacid carboxylic acid amide esters verivate comprises the prepared amino acid hydrohalogen, and its general formula does,
Wherein R ' and R " are amino acid whose arbitrary alkyl group and side-chain radical, are selected from and replace or not substituted alkyl, naphthenic base or aromatic base, said amino acid hydrohalogen is dissolved in the middle deprotonation that contains organic bases;
With deprotonation product and the nonane diacid halide reaction that also is dissolved in the aprotic solvent;
Reaction back mixture contact anhydrous salt is removed all moisture wherein;
From the mixture of said reaction back, remove aprotic solvent.
2. the method for a kind of synthetic nonane diacid carboxylic acid amide esters verivate according to claim 1, the said organic bases that is used as proton-removed agent is a pyridine.
3. the method for a kind of synthetic nonane diacid carboxylic acid amide esters verivate according to claim 1 and 2, said amino acid ester hydrohalogen comprises glycine ethyl ester hydrochloride, L-Xie Ansuan carbethoxy hydrochloride; L-alanine ethyl ester hydrochloride, L-leucine ethyl ester hydrochloride salt, L-methionine(Met) carbethoxy hydrochloride; The L-ethylcysteine hydrochloride; L-serine ethyl ester hydrochloride, L-L-glutamic acid diethyl phthalate hydrochloride, or the arbitrary combination of these several kinds of materials.
4. according to the method for the described a kind of synthetic nonane diacid carboxylic acid amide esters verivate of the arbitrary claim of claim 1 to 3, said nonane diacid halogenide is the nonane diacid dichloro.
5. according to the method for the described a kind of synthetic nonane diacid carboxylic acid amide esters verivate of the arbitrary claim of claim 1 to 4, said aprotic solvent comprises THF, dioxan, chloroform, the arbitrary combination of two chloroforms or these several kinds of materials.
6. the method for a kind of synthetic nonane diacid carboxylic acid amide esters verivate according to claim 1, said anhydrous salt are SODIUM SULPHATE ANHYDROUS 99PCT.
7. nonane diacid carboxylic acid amide esters verivate according to claim 1 comprises nonane diacid Diglycocol ethyl ester; Nonane diacid two Xie Ansuan ethyl esters; Nonane diacid two L-Ala ethyl esters, nonane diacid two leucinethylesters, nonane diacid two serine ethyl esters; Nonane diacid dicysteine ethyl ester, nonane diacid two methionine(Met) ethyl esters or nonane diacid two ethyl glutamates.
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| MYPI20091437 | 2009-04-09 | ||
| MYPI20091437A MY144409A (en) | 2009-04-09 | 2009-04-09 | A method of producing derivatives of azelaic acid |
| PCT/MY2010/000054 WO2010117258A1 (en) | 2009-04-09 | 2010-04-09 | A method of synthesising an amino acid derivative of azelaic acid |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103655223A (en) * | 2013-11-14 | 2014-03-26 | 陕西东大生化科技有限责任公司 | Preparation with effects of preventing and treating acnes and application thereof |
| CN104114529A (en) * | 2012-04-11 | 2014-10-22 | 雪佛龙奥伦耐有限责任公司 | Method for preparing mono or dialkanol amides |
| CN105658089A (en) * | 2013-10-02 | 2016-06-08 | 奇华顿股份有限公司 | Organic compounds |
| US10259950B2 (en) | 2015-04-02 | 2019-04-16 | National Central University | Coating structure for forming hydrophilic film on surface |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| AU2012360171B2 (en) * | 2011-12-28 | 2017-06-08 | Organistry, Llc | Process for the synthesis of highly pure cationic surfactant products |
| EP3080086B1 (en) | 2013-12-09 | 2017-07-05 | Unilever PLC, a company registered in England and Wales under company no. 41424 of | Process of making adamantanamides |
| EP3793522A4 (en) * | 2018-06-23 | 2022-03-02 | Cellix Bio Private Limited | Compositions and methods for the treatment of inflammatory skin diseases and cancer |
| CN115219613B (en) * | 2022-06-16 | 2023-12-22 | 上海市食品药品检验研究院 | Method for detecting azelaic acid and potassium azelate in cosmetics |
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| WO1996018600A1 (en) * | 1994-12-14 | 1996-06-20 | Lifegroup S.P.A. | Amides of mono and bicarboxylic acids with amino acids or glycosamines, selectively active on the cannabinoid peripheral receptor |
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| ITMI20041567A1 (en) * | 2004-07-30 | 2004-10-30 | Maycos Italiana Di Comini Miro | "N-ACYLATED DERIVATIVES OF BICARBOXYLIC ACIDS WITH AMINO ACIDS AND WITH HYDROLYZED VEGETABLE PROTEINS AND THEIR APPLICATION IN COSMETIC, DERMO-PHARMACEUTICAL AND PHARMACEUTICAL PRODUCTS" |
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| WO1996018600A1 (en) * | 1994-12-14 | 1996-06-20 | Lifegroup S.P.A. | Amides of mono and bicarboxylic acids with amino acids or glycosamines, selectively active on the cannabinoid peripheral receptor |
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| RAY.S.: "pH-Responsive, Bolaamphiphile-Based Smart Metallo-Hydrogels as Potential Dye-Adsorbing Agents, Water Purifier, and Vitamin B12 Carrier", 《CHEMISTRY OF MATERIALS》, vol. 19, no. 7, 31 December 2007 (2007-12-31), pages 1633 - 1639 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104114529A (en) * | 2012-04-11 | 2014-10-22 | 雪佛龙奥伦耐有限责任公司 | Method for preparing mono or dialkanol amides |
| CN105658089A (en) * | 2013-10-02 | 2016-06-08 | 奇华顿股份有限公司 | Organic compounds |
| CN105658089B (en) * | 2013-10-02 | 2019-07-09 | 奇华顿股份有限公司 | Organic compound |
| CN103655223A (en) * | 2013-11-14 | 2014-03-26 | 陕西东大生化科技有限责任公司 | Preparation with effects of preventing and treating acnes and application thereof |
| CN103655223B (en) * | 2013-11-14 | 2016-06-29 | 陕西东大生化科技有限责任公司 | A kind of preparation with prevention and treatment acne effect and application thereof |
| US10259950B2 (en) | 2015-04-02 | 2019-04-16 | National Central University | Coating structure for forming hydrophilic film on surface |
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| MY144409A (en) | 2011-09-15 |
| WO2010117258A1 (en) | 2010-10-14 |
| CN102388017B (en) | 2014-04-16 |
| SG174445A1 (en) | 2011-11-28 |
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