WO2010117258A1 - 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 PDF

Info

Publication number
WO2010117258A1
WO2010117258A1 PCT/MY2010/000054 MY2010000054W WO2010117258A1 WO 2010117258 A1 WO2010117258 A1 WO 2010117258A1 MY 2010000054 W MY2010000054 W MY 2010000054W WO 2010117258 A1 WO2010117258 A1 WO 2010117258A1
Authority
WO
WIPO (PCT)
Prior art keywords
azelaic acid
ethyl ester
acid
amino acid
aprotic solvent
Prior art date
Application number
PCT/MY2010/000054
Other languages
French (fr)
Inventor
Idris Zainab
Ahmad Salmiah
Abu Hassan Hazimah
Shoot Kian Yeong
Wahid Samsudin Mohd
Original Assignee
Malaysian Palm Oil Board
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Malaysian Palm Oil Board filed Critical Malaysian Palm Oil Board
Priority to SG2011067170A priority Critical patent/SG174445A1/en
Priority to CN201080015054.5A priority patent/CN102388017B/en
Publication of WO2010117258A1 publication Critical patent/WO2010117258A1/en

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/14—Preparation of carboxylic acid amides by formation of carboxamide groups together with reactions not involving the carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/02—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols
    • C07C319/12—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols by reactions not involving the formation of mercapto groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • 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

Definitions

  • This present invention relates to a method of producing derivative of azelaic acid.
  • the present invention relates to a method of producing amide ester derivative of azelaic acid under anhydrous condition.
  • azelaic acid or nonanedioic acid is used as topical drug for treating acne vulgaris.
  • this saturated dicarboxylic acid has a crystalline structure with high melting point ranging from 98 °C- 103 0 C, therefore it will be difficult to incorporate into cream formulation under standard condition.
  • a dosage of azelaic acid at 20% concentration is required in the cream formulation to exhibit significant dermatological performance with efficacy equivalent to 4% hydroquinone. But this dosage is high enough to cause a slightly great level of peeling, burning and stinging to the skin.
  • United States Patent No. 6528068(Bl) discloses a cosmetic composition comprising n-acyl neutral amino acid esters of lower alcohols. Based on the prior art, it is an oily material containing structure of long straight-chain or branched-chain with saturated or unsaturated acyl group, where the hydrocarbon group of the alcohol constituting the ester is a branched-chain or straight-chain alkyl or alkenyl group.
  • the composition can be further added with an ultraviolet ray adsorbent and an inorganic pigment.
  • a PCT application Patent No. 2006010590(Al) describes about n-acylated derivatives of dicarboxylic acids with amino acids and/or peptides of vegetable protein hydrolysates for the preparation of cosmetic and pharmaceutical formulations.
  • the compounds are produced by acylation of dicarboxylic acids according to conventional Schotten-Bauman condition.
  • acylation reaction forming an amide linkage between carboxylic group and N-terminal of amino acid is achieved through an exothermic reaction of an acyl halide and amino source in an alkaline aqueous medium.
  • azeloyl dichloride is reacted with glycine under a controlled pH of 9-11 by using 40% potassium hydroxide solution in aqueous medium.
  • the aqueous medium is then adjusted to pH of 7-7.5 with lactic acid and shall give a clear colorless to pale yellow solution as final product.
  • the conventional method has several limitations. Due to high sensitivity towards moisture, precaution has to be taken for preventing the acyl halide from hydrolyzes to its corresponding carboxylic acid. Besides, it is important to monitor the alkalinity of the aqueous medium closely because excess base would cause hydrolysis of acyl halide as well.
  • Contamination of products can be caused by traces amount of halide ions dissociated from acyl halide and this is not acceptable in cosmetic and pharmaceutical applications. Furthermore, the conventional Schotten-Bauman condition often provide good yield for the neutral amino acids only.
  • amino acids such as L-aspartic acid, L-glutamic acid, L-methionine, L-cysteine or L-serine will require precaution steps of protecting the side chain functional groups to minimize side products formation.
  • the acyl transfer reaction through the conventional Schotten-Bauman condition will result in product which is soluble in water and hence it is often complex to isolate the pure product by involving the removal of aqueous medium.
  • the primary object of the present invention is to invent a method of producing derivative of azelaic acid in a favourable dry state for acylation reaction by utilizing aprotic solvents and anhydrous salt. Therefore, reactant such as acyl halide which is sensitive to moisture will be less convertible to its corresponding carboxylic acid by hydrolysis and it can be less complex to isolate the desired product since an aqueous medium is not required in the reaction.
  • Another object of the present invention is to invent a method of producing derivative of azelaic acid in high yield but low amount of unnecessary side products.
  • high yield of the desired product can be produced from not only the neutral amino acids, but also amino acids possessing different functional groups as side chains.
  • At least one of the preceding objects is met, in whole or in part, by the present invention, in which the embodiment of the present invention describes a method of producing amide ester derivative of azelaic acid comprising treating an amino acid hydrohalide of the general formula:
  • R' and R" are each alkyl group moiety and side chain group of the amino acid both selected from substituted or unsubstituted alkyl moiety, cyclic alkyl or aromatic moiety 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 from the reactant mixture.
  • the present invention describes a method of producing amide ester derivative of azelaic acid by a modified Schotten-Bauman condition.
  • An anhydrous state is established throughout the acylation reaction by utilizing aprotic solvents and anhydrous salt.
  • an organic base such as pyridine is used for removing hydrohalide molecules.
  • the present invention discloses a method of producing amide ester derivative of azelaic acid comprising treating an amino acid lrydrohalide of the general formula:
  • R 1 and R" are each alkyl group moiety and side chain group of the amino acid both selected from substituted or unsubstituted alkyl moiety, cyclic alkyl or aromatic moiety 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 from the reactant mixture.
  • the method of producing amide ester derivative of azelaic acid is by acylation reaction between the deprotonated amino acid ester hydrohalide and azelaic acid halide.
  • An aprotic solvent for dissolving both amino acid ester hydrohalide and azelaic acid halide is preferably tetrahydrofuran, dioxane, chloroform, dichloroform or any combination thereof.
  • the amino acid ester hydrohalide is treated with an organic base to effect deprotonation. Protonation on the amino acid ester is necessary to prevent direct nucleophilic attack among other amino acid ester molecules to form diketopiperizine as undesirable product.
  • R 1 and R" are each alkyl group moiety and side chain group of the amino acid both selected from substituted or unsubstituted alkyl moiety, cyclic alkyl or aromatic moiety.
  • deprotonating the amino acid ester hydrohalide on its ammonium group by an organic base is important to cause a free amino group with an electron pair to be available for nucleophilic attack on the carbonyl group of the azelaic acid dihalide.
  • acylation reaction can take place and produce the amide ester derivative of azelaic acid.
  • amino acid ester hydrohalide which includes neutral ⁇ -amino acids such as glycine ethyl ester hydrochloride, L-valine ethyl ester hydrochloride, L-alanine ethyl ester hydrochloride,
  • L-methionine ethyl ester hydrochloride L-cysteine ethyl ester hydrochloride; amino acid containing hydroxyl side chain such as L-serine ethyl ester hydrochloride; amino acid containing carbonyl side chain such as L-glutamic acid diethyl ester hydrochloride or any combination of the amino acids.
  • the molar ratio of amino acid ester hydrohalide to azelaic acid halide is 2:1.
  • preferably 0.2mol to 1.Omol amino acid ester hydrohalide dissolved in aprotic solvent is reacted with preferably O.lmol to 0.5mol azelaic acid halide dissolved in a range of 100ml to 500ml aprotic solvent.
  • the chemical reaction is indicated as below: O
  • azelaic acid dichloride which is sensitive to moisture will be less convertible to its corresponding carboxylic acid by hydrolysis:
  • an organic base which is pyridine can be used as a deprotonizng agent to remove out hydrohalide molecules.
  • pyridine can function as a hydrochloric acid extractor for removing hydrochloride molecules.
  • pyridine is added into the amino acid ester hydrochloride dissolved in aprotic solvent to remove the hydrochloride molecules as pyridinium hydrochloride salts thus resulting in deprotonation of the ester compound.
  • the azelaic acid halide solution is added drop wise into the deprotonated amino acid ester hydrohalide solution to initiate the acylation reaction.
  • a preferred embodiment has described an acylation reaction between azelaic acid dichloride with deprotonated amino acid ester hydrochloride. Further hydrochloride molecules produced from the acyl transfer reaction can also be removed by pyridine.
  • the present invention claims a method of producing amide ester derivative of azelaic acid comprising the step of contacting the reactant mixture with an anhydrous salt to remove any moisture therefrom and removing the aprotic solvent from the reactant mixture.
  • the aprotic solvent phase of the solution mixture shall be retained and dried with the anhydrous salt preferably anhydrous sodium sulfate. Subsequently, the aprotic solvent is removed by vacuum evaporation.
  • the percent crude j'ield of amide ester derivative of azelaic acid with amino acid ester shall be in a range from 9.6% to 87%.
  • a sample of the crude product shall be analyzed for its purity via High Performance Liquid Chromatography (HPLC) method.
  • the solution mixture is washed with several portions of 200ml deionized water to remove pyridinium hydrochloride salts formed during acylation reaction. subsequently, several portions of diluted hydrochloric acid solution is used to neutralize the unreacted pyridine and further pyridinium hydrochloride salts will be removed by washing with another several portions of 200ml deionized water. But alternatively, the hydrochloric acid solution can be also added straight after the solution is chilled. The chloroform phase is retained and dried with anhydrous sodium sulphate.
  • chloroform is then removed by vacuum evaporation and finally the residue shall be washed with petroleum ether to remove azelaic acid ester if presence.
  • the amide ester derivative of azelaic acid with gtycine ethyl ester obtained will give a percent crude yield of 78.50%.
  • a crude sample will be recrystallized from chilled isopropanol and its purity tested via HPLC has set in a range of 74.90% to 99.89%.
  • the recrystallized sample has shown a peak at retention time of lO.l ⁇ min under conditions using column 5 ⁇ -ODS-3 with dimensions of 250mm x 4.6mm, mobile phase containing 30% acetonitrile and 70% distilled water and flow rate of 1.Oml/min.
  • the solution mixture is washed with several portions of 200ml deionized water to remove pyridinium hydrochloride salts formed during acylation reaction, subsequently, several portions of diluted h3'drochloric acid solution is used to neutralize the unreacted pyridine and further pyridinium hydrochloride salts will be removed by washing with another several portions of 200ml deionized water.
  • the dichloromethane phase is retained and dried with anhydrous sodium sulphate.
  • the recrystallized sample shall give optimized peak resolution tested under conditions of using column 5 ⁇ -ODS-3 with dimensions of 250mm x 4.6mm, mobile phase containing 60% acetonitrile and 40% distilled water, flow rate of 1.5ml/min, 0.1793g sample in 10ml acetonitrile and 50 ⁇ L injection volume.
  • the component in the crude sample is resolved to several peaks with the major peak occurring at 4.80min giving 81.76% peak area. Two other small peaks are occurred at 3.9Omin and 6.39min whereby each occupying peak area of 15.06% and 3.00% respectively.
  • the specific rotation [ ⁇ ]2o is recorded as -23.05° for 1.30g sample in 100cm 3 absolute ethanol whereas the specific rotation [ ⁇ ] 2 o of the starting L-amino acid ethyl ester hydrochloride is indicated as +22.34° for 1.14g sample in 100cm 3 absolute ethanol.
  • the solution mixture is washed with several portions of 200ml deionized water to remove pyridinium hydrochloride salts formed during acylation reaction. subsequently, several portions of diluted hydrochloric acid solution is used to neutralize the unreacted pyridine and further pyridinium hydrochloride salts will be removed by washing with another several portions of 200ml deionized water.
  • the dichloromethane phase is retained and dried with anhydrous sodium sulphate.
  • the recrystallized sample shall give optimized peak resolution tested under conditions of using column 5 ⁇ -ODS-3 with dimensions of 250mm x 4.6mm, mobile phase containing 40% acetonitrile and 60% distilled water, flow rate of 1.5ml/min, 0.251Og sample in 10ml acetonitrile and 50 ⁇ L injection volume.
  • the component in the crude sample is resolved to several peaks with the major peak occurring at 7.11min giving 86.74% peak area. Two other small peaks are occurred at
  • azelaic acid dichloride is prepared by dissolving an amount of 28g into 100ml dichloromethane. The azelaic acid dichloride solution is added drop wise into the L-leucine ethyl ester hydrochloride solution to initiate the reaction by stirring for 2 hours and the solution mixture is chilled overnight at temperature 5 0 C.
  • the solution mixture is washed with several portions of 200ml deionized water to remove pyridinium hydrochloride salts formed during acylation reaction. subsequently, several portions of diluted hydrochloric acid solution is used to neutralize the unreacted pyridine and further p) ⁇ idinium hydrochloride salts will be removed by washing with another several portions of 200ml deionized water.
  • the dichloromethane phase is retained and dried with anhydrous sodium sulphate.
  • the recrystallized sample shall give optimized peak resolution tested under conditions of using column 5 ⁇ -ODS-3 with dimensions of 250mm x 4.6mm, mobile phase containing 60% acetonitrile and 40% distilled water, flow rate of 1.Oml/min, 0.579Og sample in 10ml acetonitrile and 50 ⁇ L injection volume.
  • the component in the crude sample is resolved to several peaks with the major peak occurring at 7.39min giving 82.20% peak area. Two other small peaks are occurred at 2.31min and 5.92min whereby each occupying peak area of 5.10% and 4.64% respectively.
  • the specific rotation [c ⁇ o is recorded as -30.99° for 1.37g sample in 100cm 3 absolute ethanol whereas the specific rotation [ ⁇ ] 2 o of the starting L-amino acid ethyl ester hydrochloride is indicated as +24.73° for 1.05g sample in 100cm 3 absolute ethanol.
  • the solution mixture is washed with several portions of 150ml deionized water to remove pyridinium hydrochloride salts formed during acylation reaction, subsequently, several portions of diluted hydrochloric acid solution is used to neutralize the unreacted pyridine and further pyridinium hydrochloride salts will be removed by washing with another several portions of 150ml deionized water.
  • the dichloromethane phase is retained and dried with anhydrous sodium sulphate.
  • the recrystallized sample shall give optimized peak resolution tested under conditions of using column 5 ⁇ -ODS-3 with dimensions of 250mm x 4.6mm, mobile phase containing 50% acetonitrile and 50% distilled water, flow rate of 1.2ml/min, 0.1992g sample in 10ml of acetonitrile: water in 1:1 ratio and 50 ⁇ L injection volume.
  • the component in the hard yellowish solid crude sample based on 2:1 mol reactant ratio is resolved to several peaks with the major single peak occurring at 4.61min giving 50.78% peak area. Two groups of other peaks are occurred at 2.62min and 3.75min whereby each occupying peak area of 16.57% and 32.71% respectively.
  • the specific rotation [ ⁇ ]?o is recorded as -3.805° for 1.05g sample in 100cm 3 absolute ethanol.
  • the solution mixture is washed with several portions of 150ml deionized water to remove pyridinium hydrochloride salts formed during acylation reaction, subsequently, several portions of diluted hydrochloric acid solution is used to neutralize the unreacted pyridine and further pyridinium hydrochloride salts will be removed by washing with another several portions of 150ml deionized water.
  • the dichloromethane phase is retained and dried with anhydrous sodium sulphate.
  • a translucent yellowish paste based on 1 : 1 mol reactant ratio shall have a much higher % crude yield which is recorded as 44.64g as compared to 2:1 mol reactant ratio.
  • the crude sample is resolved under conditions of using column 5 ⁇ -ODS-3 with dimensions of 250mm x 4.6mm, mobile phase containing 50% acetonitrile and 50% distilled water and flow rate of 1.2ml/min.
  • HPLC analysis it has revealed that the % area peak at 4.53min reduced drastically from 50% to only 6.20%.
  • other peaks represented by the groups of small peaks appearing before and after peak at 4.5min increased in total % peak area from 16.57% to 23.96% and 32.71% to 69.80% respectively.
  • the specific rotation [ ⁇ ]20 is recorded as ⁇ 6.92° for 1.59g sample in 100cm3 absolute ethanol.
  • the solution mixture is washed with several portions of 200ml deionized water to remove pyridinium hydrochloride salts formed during acylation reaction, subsequently, several portions of diluted hydrochloric acid solution is used to neutralize the unreacted pyridine and further pyridinium hydrochloride salts will be removed by washing with another several portions of 200ml deionized water.
  • the dichloromethane phase is retained and dried with anhydrous sodium sulphate.
  • the crude sample shall give optimized peak resolution tested under conditions of using column 5 ⁇ -ODS-3 with dimensions of 250mm x 4.6mm, mobile phase containing 50% acetonitrile and 50% distilled water, flow rate of 1.2ml/ min, 0.2262g sample in 10ml of acetonitrilerwater in 1 :1 ratio and 50 ⁇ L injection volume.
  • the component contained in a hard white translucent wax like solid of crude sample is resolved to several peaks with the major peak occurring at 8.698min giving 49.097% peak area. Four other small peaks are occurred at 5.62min, 12.09min, 14.58min and 26.47min whereby each occupying peak area of 10.27%, 9.30%, 9.91% and 12.80% respectively.
  • the specific rotation [ ⁇ ] 2 o is recorded as -24.49° for 1.29g sample in 100cm 3 absolute ethanol.
  • azelaic acid dichloride is prepared by dissolving an amount of 7.6g into 50ml dichloromethane. The azelaic acid dichloride solution is added drop wise into the L-methionine ethyl ester hydrochloride solution to initiate the reaction by stirring for 2 hours and the solution mixture is chilled overnight at temperature 5 0 C.
  • the solution mixture is washed with several portions of 150ml deionized water to remove pyridinium hydrochloride salts formed during acylation reaction. subsequently, several portions of diluted hydrochloric acid solution is used to neutralize the unreacted pyridine and further pyridinium hydrochloride salts will be removed by washing with another several portions of 150ml deionized water.
  • the dichloromethane phase is retained and dried with anhydrous sodium sulphate.
  • the crude sample shall give optimized peak resolution tested under conditions of using column 5 ⁇ -ODS-3 with dimensions of 250mm x 4.6mm, mobile phase containing 50% acetonitrile and 50% distilled water, flow rate of 1.2ml/ min, 0.1052g sample in 10ml acetonitrile and 50 ⁇ L injection volume.
  • the final crude product is isolated as a beige powder with pungent thio odor.
  • the component in the crude sample via HPLC analysis, several peaks with the major peak occurring at 12.29min giving 70.56% peak area.
  • the solution mixture is washed with several portions of 150ml deionized water to remove pyridinium hydrochloride salts formed during ac3 r lation reaction. subsequently, several portions of diluted hydrochloric acid solution is used to neutralize the unreacted pyridine and further pyridinium hydrochloride salts will be removed by washing with another several portions of 150ml deionized water.
  • the dichloromethane phase is retained and dried with anhydrous sodium sulphate.
  • the crude sample shall give optimized peak resolution tested under conditions of using column 5 ⁇ -ODS-3 with dimensions of 250mm x 4.6mm, mobile phase containing 60% acetonitrile and 40% distilled water, flow rate of 1.0ml/ min, 0.2706g sample in 10ml acetonitrile and 50 ⁇ L injection volume.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Dermatology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

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

A METHOD OF SYNTHESISING AN AMINO ACID DERIVATIVE OF AZELAIC ACID
Field of Invention
This present invention relates to a method of producing derivative of azelaic acid. In more particular, the present invention relates to a method of producing amide ester derivative of azelaic acid under anhydrous condition.
Background of The Invention
It has been well-known that azelaic acid or nonanedioic acid is used as topical drug for treating acne vulgaris. However, this saturated dicarboxylic acid has a crystalline structure with high melting point ranging from 98 °C- 1030C, therefore it will be difficult to incorporate into cream formulation under standard condition.
A dosage of azelaic acid at 20% concentration is required in the cream formulation to exhibit significant dermatological performance with efficacy equivalent to 4% hydroquinone. But this dosage is high enough to cause a slightly great level of peeling, burning and stinging to the skin.
The discovery of potassium azeloyl diglycinate as a new derivative of azelaic acid can effectively perform as an anti-acne agent by using only 5% in formulation. There are some prior arts relating to several compounds or compositions for cosmetic, pharmaceutical and dermatological applications.
United States Patent No. 6528068(Bl) discloses a cosmetic composition comprising n-acyl neutral amino acid esters of lower alcohols. Based on the prior art, it is an oily material containing structure of long straight-chain or branched-chain with saturated or unsaturated acyl group, where the hydrocarbon group of the alcohol constituting the ester is a branched-chain or straight-chain alkyl or alkenyl group. The composition can be further added with an ultraviolet ray adsorbent and an inorganic pigment.
A PCT application Patent No. 2006010590(Al) describes about n-acylated derivatives of dicarboxylic acids with amino acids and/or peptides of vegetable protein hydrolysates for the preparation of cosmetic and pharmaceutical formulations. The compounds are produced by acylation of dicarboxylic acids according to conventional Schotten-Bauman condition.
In the conventional Schotten-Bauman condition, acylation reaction forming an amide linkage between carboxylic group and N-terminal of amino acid is achieved through an exothermic reaction of an acyl halide and amino source in an alkaline aqueous medium. In the prior art, azeloyl dichloride is reacted with glycine under a controlled pH of 9-11 by using 40% potassium hydroxide solution in aqueous medium. The aqueous medium is then adjusted to pH of 7-7.5 with lactic acid and shall give a clear colorless to pale yellow solution as final product.
But often, the conventional method has several limitations. Due to high sensitivity towards moisture, precaution has to be taken for preventing the acyl halide from hydrolyzes to its corresponding carboxylic acid. Besides, it is important to monitor the alkalinity of the aqueous medium closely because excess base would cause hydrolysis of acyl halide as well.
Contamination of products can be caused by traces amount of halide ions dissociated from acyl halide and this is not acceptable in cosmetic and pharmaceutical applications. Furthermore, the conventional Schotten-Bauman condition often provide good yield for the neutral amino acids only.
In another hand, amino acids such as L-aspartic acid, L-glutamic acid, L-methionine, L-cysteine or L-serine will require precaution steps of protecting the side chain functional groups to minimize side products formation. The acyl transfer reaction through the conventional Schotten-Bauman condition will result in product which is soluble in water and hence it is often complex to isolate the pure product by involving the removal of aqueous medium.
It is important to invent a method of producing derivative of azelaic acid by a modified Schotten-Bauman condition which utilizes aprotic solvents and anhydrous salt for establishing a dry state favourable to the reactants and desired product which is obtained by acylation reaction. Besides, it is also desirable to introduce a method which provides a high yield of desired product but minimizes the yield of side products.
Summary of The Invention
The primary object of the present invention is to invent a method of producing derivative of azelaic acid in a favourable dry state for acylation reaction by utilizing aprotic solvents and anhydrous salt. Therefore, reactant such as acyl halide which is sensitive to moisture will be less convertible to its corresponding carboxylic acid by hydrolysis and it can be less complex to isolate the desired product since an aqueous medium is not required in the reaction.
Another object of the present invention is to invent a method of producing derivative of azelaic acid in high yield but low amount of unnecessary side products. Through this modified Schotten-Bauman condition, high yield of the desired product can be produced from not only the neutral amino acids, but also amino acids possessing different functional groups as side chains.
At least one of the preceding objects is met, in whole or in part, by the present invention, in which the embodiment of the present invention describes a method of producing amide ester derivative of azelaic acid comprising treating an amino acid hydrohalide of the general formula:
Figure imgf000005_0001
wherein R' and R" are each alkyl group moiety and side chain group of the amino acid both selected from substituted or unsubstituted alkyl moiety, cyclic alkyl or aromatic moiety 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 from the reactant mixture.
The present invention describes a method of producing amide ester derivative of azelaic acid by a modified Schotten-Bauman condition. An anhydrous state is established throughout the acylation reaction by utilizing aprotic solvents and anhydrous salt.
Moreover, an organic base such as pyridine is used for removing hydrohalide molecules. Hence, it is advantageous that this method shall allow the desired products to be easily isolated from the anhydrous medium.
Detailed Description of The Invention
One skilled in the art will readily appreciate that the present invention is well adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those inherent therein. The embodiment described herein is not intended as limitations on the scope of the invention. The present invention discloses a method of producing amide ester derivative of azelaic acid comprising treating an amino acid lrydrohalide of the general formula:
Figure imgf000006_0001
wherein R1 and R" are each alkyl group moiety and side chain group of the amino acid both selected from substituted or unsubstituted alkyl moiety, cyclic alkyl or aromatic moiety 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 from the reactant mixture.
In the present invention, the method of producing amide ester derivative of azelaic acid is by acylation reaction between the deprotonated amino acid ester hydrohalide and azelaic acid halide. An aprotic solvent for dissolving both amino acid ester hydrohalide and azelaic acid halide is preferably tetrahydrofuran, dioxane, chloroform, dichloroform or any combination thereof.
As further described in the present invention, the amino acid ester hydrohalide is treated with an organic base to effect deprotonation. Protonation on the amino acid ester is necessary to prevent direct nucleophilic attack among other amino acid ester molecules to form diketopiperizine as undesirable product.
The general formula structure shown as below is a protonated form of the amino acid ester by hydrohalide:
Figure imgf000007_0001
wherein R1 and R" are each alkyl group moiety and side chain group of the amino acid both selected from substituted or unsubstituted alkyl moiety, cyclic alkyl or aromatic moiety.
However, deprotonating the amino acid ester hydrohalide on its ammonium group by an organic base is important to cause a free amino group with an electron pair to be available for nucleophilic attack on the carbonyl group of the azelaic acid dihalide. Thus, acylation reaction can take place and produce the amide ester derivative of azelaic acid.
The most preferred amino acid ester hydrohalide used is amino acid ethyl ester hydrochloride which includes neutral α-amino acids such as glycine ethyl ester hydrochloride, L-valine ethyl ester hydrochloride, L-alanine ethyl ester hydrochloride,
L-leucine ethyl ester hydrochloride; amino acids containing sulphur side chain such as
L-methionine ethyl ester hydrochloride, L-cysteine ethyl ester hydrochloride; amino acid containing hydroxyl side chain such as L-serine ethyl ester hydrochloride; amino acid containing carbonyl side chain such as L-glutamic acid diethyl ester hydrochloride or any combination of the amino acids.
For the acylation reaction, the molar ratio of amino acid ester hydrohalide to azelaic acid halide is 2:1. In a preferred embodiment of the present invention, preferably 0.2mol to 1.Omol amino acid ester hydrohalide dissolved in aprotic solvent is reacted with preferably O.lmol to 0.5mol azelaic acid halide dissolved in a range of 100ml to 500ml aprotic solvent. The chemical reaction is indicated as below: O
Figure imgf000008_0001
R" aprotic solvent
Figure imgf000008_0002
Figure imgf000008_0003
By using the aprotic solvent, an anhydrous reaction condition can be established and thus causing the azelaic acid halide, shown below as azelaic acid dichloride which is sensitive to moisture will be less convertible to its corresponding carboxylic acid by hydrolysis:
Figure imgf000008_0004
azelaic acid azelaic acid dichloride
As disclosed in the present invention, an organic base which is pyridine can be used as a deprotonizng agent to remove out hydrohalide molecules. Taking for as an example, pyridine can function as a hydrochloric acid extractor for removing hydrochloride molecules.
In a preferred embodiment of the present invention, pyridine is added into the amino acid ester hydrochloride dissolved in aprotic solvent to remove the hydrochloride molecules as pyridinium hydrochloride salts thus resulting in deprotonation of the ester compound.
In the present invention, the azelaic acid halide solution is added drop wise into the deprotonated amino acid ester hydrohalide solution to initiate the acylation reaction. A preferred embodiment has described an acylation reaction between azelaic acid dichloride with deprotonated amino acid ester hydrochloride. Further hydrochloride molecules produced from the acyl transfer reaction can also be removed by pyridine.
Hereinafter, the present invention claims a method of producing amide ester derivative of azelaic acid comprising the step of contacting the reactant mixture with an anhydrous salt to remove any moisture therefrom and removing the aprotic solvent from the reactant mixture.
One of the preferred embodiments in the present invention has disclosed that the aprotic solvent phase of the solution mixture shall be retained and dried with the anhydrous salt preferably anhydrous sodium sulfate. Subsequently, the aprotic solvent is removed by vacuum evaporation.
In the present invention, the percent crude j'ield of amide ester derivative of azelaic acid with amino acid ester shall be in a range from 9.6% to 87%. A sample of the crude product shall be analyzed for its purity via High Performance Liquid Chromatography (HPLC) method.
Examples
Example 1
Preparation of 0.25 mol glycine ethyl ester hydrochloride by weighing 35g into a 500ml 3-neck round bottom flask is added with 200ml chloroform. Approximately 40ml p3τidine is subsequently added into the solution and stirred at room temperature until homogeneous. 0.13 mol azelaic acid dichloride is prepared by dissolving an amount of 28g into 200ml chloroform. The azelaic acid dichloride solution is added drop wise into the glycine ethyl ester hydrochloride solution to initiate the reaction by stirring for 2 hours and the solution mixture is chilled overnight at temperature 50C.
The chemical reaction that has taken placed is shown as below:
O .
Figure imgf000010_0001
aprotic solvent
Figure imgf000010_0002
Figure imgf000010_0003
The solution mixture is washed with several portions of 200ml deionized water to remove pyridinium hydrochloride salts formed during acylation reaction. subsequently, several portions of diluted hydrochloric acid solution is used to neutralize the unreacted pyridine and further pyridinium hydrochloride salts will be removed by washing with another several portions of 200ml deionized water. But alternatively, the hydrochloric acid solution can be also added straight after the solution is chilled. The chloroform phase is retained and dried with anhydrous sodium sulphate.
Moreover, chloroform is then removed by vacuum evaporation and finally the residue shall be washed with petroleum ether to remove azelaic acid ester if presence. The amide ester derivative of azelaic acid with gtycine ethyl ester obtained will give a percent crude yield of 78.50%. A crude sample will be recrystallized from chilled isopropanol and its purity tested via HPLC has set in a range of 74.90% to 99.89%.
From the HPLC analysis, the recrystallized sample has shown a peak at retention time of lO.lβmin under conditions using column 5μ-ODS-3 with dimensions of 250mm x 4.6mm, mobile phase containing 30% acetonitrile and 70% distilled water and flow rate of 1.Oml/min.
Example 2
Preparation of 0.25 mol L-valine ethyl ester hydrochloride by weighing 46g into a 500ml 3 -neck round bottom flask is added with 100ml dichloromethane. Approximately 40ml pyridine is subsequently added into the solution and stirred at room temperature until homogeneous. 0.13 mol azelaic acid dichloride is prepared by dissolving an amount of 28g into 100ml dichloromethane. The azelaic acid dichloride solution is added drop wise into the L-valine ethyl ester hydrochloride solution to initiate the reaction by stirring for 2 hours and the solution mixture is chilled overnight at temperature 50C.
The solution mixture is washed with several portions of 200ml deionized water to remove pyridinium hydrochloride salts formed during acylation reaction, subsequently, several portions of diluted h3'drochloric acid solution is used to neutralize the unreacted pyridine and further pyridinium hydrochloride salts will be removed by washing with another several portions of 200ml deionized water. The dichloromethane phase is retained and dried with anhydrous sodium sulphate.
Moreover, dichloromethane is then removed by λ'acuum evaporation and finally the residue shall be washed with petroleum ether to remove azelaic acid ester if presence. The amide ester derivative of azelaic acid with L-valine ethyl ester obtained will give a percent crude yield of 76.38%.
In the HPLC analysis, the recrystallized sample shall give optimized peak resolution tested under conditions of using column 5μ-ODS-3 with dimensions of 250mm x 4.6mm, mobile phase containing 60% acetonitrile and 40% distilled water, flow rate of 1.5ml/min, 0.1793g sample in 10ml acetonitrile and 50μL injection volume.
The component in the crude sample is resolved to several peaks with the major peak occurring at 4.80min giving 81.76% peak area. Two other small peaks are occurred at 3.9Omin and 6.39min whereby each occupying peak area of 15.06% and 3.00% respectively. The specific rotation [α]2o is recorded as -23.05° for 1.30g sample in 100cm3 absolute ethanol whereas the specific rotation [α]2o of the starting L-amino acid ethyl ester hydrochloride is indicated as +22.34° for 1.14g sample in 100cm3 absolute ethanol.
Example 3
Preparation of 0.25 mol L-alanine ethyl ester hydrochloride by weighing 39g into a 500ml 3-neck round bottom flask is added with 100ml dichloromethane. Approximately 40ml pyridine is subsequently added into the solution and stirred at room temperature until homogeneous. 0.13 mol azelaic acid di chloride is prepared by dissolving an amount of 28g into 100ml dichloromethane. The azelaic acid dichloride solution is added drop wise into the L-alanine ethyl ester hydrochloride solution to initiate the reaction by stirring for 2 hours and the solution mixture is chilled overnight at temperature 50C.
The solution mixture is washed with several portions of 200ml deionized water to remove pyridinium hydrochloride salts formed during acylation reaction. subsequently, several portions of diluted hydrochloric acid solution is used to neutralize the unreacted pyridine and further pyridinium hydrochloride salts will be removed by washing with another several portions of 200ml deionized water. The dichloromethane phase is retained and dried with anhydrous sodium sulphate.
Moreover, dichloromethane is then removed by vacuum evaporation and finally the residue shall be washed with petroleum ether to remove azelaic acid ester if presence. The amide ester derivative of azelaic acid with L-alanine ethyl ester obtained will give a percent crude yield of 87.01%.
In the HPLC analysis, the recrystallized sample shall give optimized peak resolution tested under conditions of using column 5μ-ODS-3 with dimensions of 250mm x 4.6mm, mobile phase containing 40% acetonitrile and 60% distilled water, flow rate of 1.5ml/min, 0.251Og sample in 10ml acetonitrile and 50μL injection volume.
The component in the crude sample is resolved to several peaks with the major peak occurring at 7.11min giving 86.74% peak area. Two other small peaks are occurred at
2.32min and 5.65min whereby each occupying peak area of 1.48% and 5.14% respectively. The specific rotation [cφo is recorded as -44.10° for 1.1 Ig sample in
100cm3 absolute ethanol whereas the specific rotation [α]2o of the starting L-amino acid ethyl ester hydrochloride is indicated as +6.99° for 1.7Og sample in 100cm3 absolute ethanol.
Example 4
Preparation of 0.25 mol L-leucine ethyl ester hydrochloride by weighing 49g into a 500ml 3-neck round bottom flask is added with 100ml dichloromethane.
Approximately 40ml pyridine is subsequently added into the solution and stirred at room temperature until homogeneous. 0.13 mol azelaic acid dichloride is prepared by dissolving an amount of 28g into 100ml dichloromethane. The azelaic acid dichloride solution is added drop wise into the L-leucine ethyl ester hydrochloride solution to initiate the reaction by stirring for 2 hours and the solution mixture is chilled overnight at temperature 50C.
The solution mixture is washed with several portions of 200ml deionized water to remove pyridinium hydrochloride salts formed during acylation reaction. subsequently, several portions of diluted hydrochloric acid solution is used to neutralize the unreacted pyridine and further p)τidinium hydrochloride salts will be removed by washing with another several portions of 200ml deionized water. The dichloromethane phase is retained and dried with anhydrous sodium sulphate.
Moreover, dichloromethane is then removed by vacuum evaporation and finally the residue shall be washed with petroleum ether to remove azelaic acid ester if presence. The amide ester derivative of azelaic acid with L-leucine ethyl ester obtained will give a percent crude yield of 83.64%.
In the HPLC analysis, the recrystallized sample shall give optimized peak resolution tested under conditions of using column 5μ-ODS-3 with dimensions of 250mm x 4.6mm, mobile phase containing 60% acetonitrile and 40% distilled water, flow rate of 1.Oml/min, 0.579Og sample in 10ml acetonitrile and 50μL injection volume.
The component in the crude sample is resolved to several peaks with the major peak occurring at 7.39min giving 82.20% peak area. Two other small peaks are occurred at 2.31min and 5.92min whereby each occupying peak area of 5.10% and 4.64% respectively. The specific rotation [cφo is recorded as -30.99° for 1.37g sample in 100cm3 absolute ethanol whereas the specific rotation [α]2o of the starting L-amino acid ethyl ester hydrochloride is indicated as +24.73° for 1.05g sample in 100cm3 absolute ethanol.
Example 5
Preparation of 0.16 mol L-serine ethyl ester hydrochloride by weighing 27g into a 250ml 3-neck round bottom flask is added with 50ml dichloromethane. Approximately 26ml pyridine is subsequently added into the solution and stirred at room temperature until homogeneous. 0.08 mol azelaic acid dichloride is prepared by dissolving an amount of 18g into 70ml dichloromethane. The azelaic acid dichloride solution is added drop wise into the L-serine ethyl ester hydrochloride solution to initiate the reaction by stirring for 2 hours and the solution mixture is chilled overnight at temperature 50C.
The solution mixture is washed with several portions of 150ml deionized water to remove pyridinium hydrochloride salts formed during acylation reaction, subsequently, several portions of diluted hydrochloric acid solution is used to neutralize the unreacted pyridine and further pyridinium hydrochloride salts will be removed by washing with another several portions of 150ml deionized water. The dichloromethane phase is retained and dried with anhydrous sodium sulphate.
Moreover, dichloromethane is then removed by vacuum evaporation and finally the residue shall be washed with petroleum ether to remove azelaic acid ester if presence. The amide ester derivative of azelaic acid with L-serine ethyl ester obtained will give a percent crude yield of 9.58%.
In the HPLC analysis, the recrystallized sample shall give optimized peak resolution tested under conditions of using column 5μ-ODS-3 with dimensions of 250mm x 4.6mm, mobile phase containing 50% acetonitrile and 50% distilled water, flow rate of 1.2ml/min, 0.1992g sample in 10ml of acetonitrile: water in 1:1 ratio and 50μL injection volume.
The component in the hard yellowish solid crude sample based on 2:1 mol reactant ratio is resolved to several peaks with the major single peak occurring at 4.61min giving 50.78% peak area. Two groups of other peaks are occurred at 2.62min and 3.75min whereby each occupying peak area of 16.57% and 32.71% respectively. The specific rotation [α]?o is recorded as -3.805° for 1.05g sample in 100cm3 absolute ethanol.
Example 6
Preparation of 0.16 mol L-serine ethyl ester hydrochloride by weighing 27g into a 250ml 3-neck round bottom flask is added with 100ml dichloromethane. Approximately 39ml pyridine is subsequently added into the solution and stirred at room temperature until homogeneous. 0.16 mol azelaic acid dichloride is prepared by dissolving an amount of 35g into 70ml dichloromethane. The azelaic acid dichloride solution is added drop wise into the L-serine ethyl ester hydrochloride solution to initiate the reaction by stirring for 2 hours and chilled overnight at temperature 5°C.
The solution mixture is washed with several portions of 150ml deionized water to remove pyridinium hydrochloride salts formed during acylation reaction, subsequently, several portions of diluted hydrochloric acid solution is used to neutralize the unreacted pyridine and further pyridinium hydrochloride salts will be removed by washing with another several portions of 150ml deionized water. The dichloromethane phase is retained and dried with anhydrous sodium sulphate.
Moreover, dichloromethane is then removed by vacuum evaporation and finally the residue shall be washed with petroleum ether to remove azelaic acid ester if presence. A translucent yellowish paste based on 1 : 1 mol reactant ratio shall have a much higher % crude yield which is recorded as 44.64g as compared to 2:1 mol reactant ratio.
The crude sample is resolved under conditions of using column 5μ-ODS-3 with dimensions of 250mm x 4.6mm, mobile phase containing 50% acetonitrile and 50% distilled water and flow rate of 1.2ml/min. In the HPLC analysis, it has revealed that the % area peak at 4.53min reduced drastically from 50% to only 6.20%. However, other peaks represented by the groups of small peaks appearing before and after peak at 4.5min increased in total % peak area from 16.57% to 23.96% and 32.71% to 69.80% respectively. The specific rotation [α]20 is recorded as ÷6.92° for 1.59g sample in 100cm3 absolute ethanol.
Example 7
Preparation of 0.15 mol L-cysteine ethyl ester hydrochloride by weighing 27.9g into a 500ml 3-neck round bottom flask is added with 100ml dichloromethane. Approximately 24ml pyridine is subsequently added into the solution and stirred at room temperature until homogeneous. 0.08 mol azelaic acid dichloride is prepared by dissolving an amount of 17g into 100ml dichloromethane. The azelaic acid dichloride solution is added drop wise into the L-cysteine ethyl ester hydrochloride solution to initiate the reaction by stirring for 2 hours and the solution mixture is chilled overnight at temperature 50C.
The solution mixture is washed with several portions of 200ml deionized water to remove pyridinium hydrochloride salts formed during acylation reaction, subsequently, several portions of diluted hydrochloric acid solution is used to neutralize the unreacted pyridine and further pyridinium hydrochloride salts will be removed by washing with another several portions of 200ml deionized water. The dichloromethane phase is retained and dried with anhydrous sodium sulphate.
Moreover, dichloromethane is then removed by vacuum evaporation and finally the residue shall be washed with petroleum ether to remove azelaic acid ester if presence. The amide ester derivative of azelaic acid with L-cysteine ethyl ester obtained will give a percent crude yield of 76.92%.
In the HPLC analysis, the crude sample shall give optimized peak resolution tested under conditions of using column 5μ-ODS-3 with dimensions of 250mm x 4.6mm, mobile phase containing 50% acetonitrile and 50% distilled water, flow rate of 1.2ml/ min, 0.2262g sample in 10ml of acetonitrilerwater in 1 :1 ratio and 50μL injection volume.
The component contained in a hard white translucent wax like solid of crude sample is resolved to several peaks with the major peak occurring at 8.698min giving 49.097% peak area. Four other small peaks are occurred at 5.62min, 12.09min, 14.58min and 26.47min whereby each occupying peak area of 10.27%, 9.30%, 9.91% and 12.80% respectively. The specific rotation [α]2o is recorded as -24.49° for 1.29g sample in 100cm3 absolute ethanol.
Example 8
Preparation of 0.07 mol L-methionine ethyl ester hydrochloride by weighing 15g into a 250ml 3-neck round bottom flask is added with 50ml dichloromethane.
Approximately 12ml pyridine is subsequently added into the solution and stirred at room temperature until homogeneous. 0.04 mol azelaic acid dichloride is prepared by dissolving an amount of 7.6g into 50ml dichloromethane. The azelaic acid dichloride solution is added drop wise into the L-methionine ethyl ester hydrochloride solution to initiate the reaction by stirring for 2 hours and the solution mixture is chilled overnight at temperature 50C.
The solution mixture is washed with several portions of 150ml deionized water to remove pyridinium hydrochloride salts formed during acylation reaction. subsequently, several portions of diluted hydrochloric acid solution is used to neutralize the unreacted pyridine and further pyridinium hydrochloride salts will be removed by washing with another several portions of 150ml deionized water. The dichloromethane phase is retained and dried with anhydrous sodium sulphate.
Moreover, dichloromethane is then removed by vacuum evaporation and finally the residue shall be washed with petroleum ether to remove azelaic acid ester if presence. The amide ester derivative of azelaic acid with L-methionine ethyl ester obtained will give a percent crude yield of 75.53%.
In the HPLC analysis, the crude sample shall give optimized peak resolution tested under conditions of using column 5μ-ODS-3 with dimensions of 250mm x 4.6mm, mobile phase containing 50% acetonitrile and 50% distilled water, flow rate of 1.2ml/ min, 0.1052g sample in 10ml acetonitrile and 50μL injection volume.
The final crude product is isolated as a beige powder with pungent thio odor. By resolving the component in the crude sample via HPLC analysis, several peaks with the major peak occurring at 12.29min giving 70.56% peak area.
Five other small peaks are occurred at 6.50min, 14.55min, 16.36min, 17.47min and 19.06min whereby each occupying peak area of 9.22%, 7.15%, 2.19%, 1.75% and 2.00% respectively. The specific rotation [oφo is recorded as -22.96° for 1.33g sample in 100cm3 absolute ethanol.
Example 9
Preparation of 0.08 mol L-glutamic acid diethyl ester hydrochloride by weighing 2Og into a 250ml 3-neck round bottom flask is added with 25ml dichloromethane. Approximately 13ml pyridine is subsequently added into the solution and stirred at room temperature until homogeneous. 0.04 mol azelaic acid dichloride is prepared by dissolving an amount of 9g into 40ml dichloromethane. The azelaic acid dichloride solution is added drop wise into the L-glutamic acid diethyl ester hydrochloride solution to initiate the reaction by stirring for 2 hours and the solution mixture is chilled overnight at temperature 50C.
The solution mixture is washed with several portions of 150ml deionized water to remove pyridinium hydrochloride salts formed during ac3rlation reaction. subsequently, several portions of diluted hydrochloric acid solution is used to neutralize the unreacted pyridine and further pyridinium hydrochloride salts will be removed by washing with another several portions of 150ml deionized water. The dichloromethane phase is retained and dried with anhydrous sodium sulphate.
Moreover, dichloromethane is then removed by vacuum evaporation and finally the residue shall be washed with petroleum ether to remove azelaic acid ester if presence. The amide ester derivative of azelaic acid with L-glutamic acid diethyl ester obtained will give a percent crude yield of 79.27%.
In the HPLC analysis, the crude sample shall give optimized peak resolution tested under conditions of using column 5μ-ODS-3 with dimensions of 250mm x 4.6mm, mobile phase containing 60% acetonitrile and 40% distilled water, flow rate of 1.0ml/ min, 0.2706g sample in 10ml acetonitrile and 50μL injection volume.
By resolving the component in the crude sample via HPLC analysis, three peaks with the major peak occurring at 7.28min has resulted in giving 89.89% peak area. Two other small peaks are occurred at 5.56min and 10.25min whereby each occupying peak area of 6.08% and 1.36% respectively. The specific rotation [cψo is recorded as -17.48° for 1.2Og sample in 100cm3 absolute ethanol.

Claims

Claims
1. A method of producing amide ester derivative of azelaic acid comprising: treating an amino acid hydrohalide of the general formula,
Figure imgf000021_0001
wherein R' and R" are each alkyl group moiety and side chain group of the amino acid both selected from substituted or unsubstituted alkyl moiety, cyclic alkyl or aromatic moiety 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 from the reactant mixture.
2. A method as claimed in claim 1, wherein said organic base used as a deprotonizing agent is pyridine.
3. A method as claimed in claim 1 or claim 2, wherein the amino acid ester hydrohalide is glycine ethyl ester hydrochloride, L-valine ethyl ester hydrochloride, L-alanine ethyl ester hydrochloride, L-leucine ethyl ester hydrochloride, L-methionine ethyl ester hydrochloride, L-cysteine ethyl ester hydrochloride, L-serine ethyl ester hydrochloride, L-glutamic acid dieth}4 ester hydrochloride or any combination thereof.
4. A method as claimed in any of the claims 1 to 3. wherein the azεlaic acid halide is azelaic acid dichloride.
5. A method as claimed in any of the claims 1 to 4, wherein the aprotic solvent is tetrahydrofuran, dioxane, chloroform, dichloroform or any combination thereof.
6. A method as claimed in claim 1, wherein the anhydrous salt is anhydrous sodium sulfate.
7. An amide ester derivative of azelaic acid as claimed in claim 1 is azelaic acid diglycinate ethyl ester, azelaic acid divalinate ethyl ester, azelaic acid dialaninate ethyl ester, azelaic acid dileucinate ethyl ester, azelaic acid diserinate ethyl ester, azelaic acid dicysteinate ethyl ester, azelaic acid dimethionate ethyl ester or azelaic acid di glutamic acid diethyl ester.
PCT/MY2010/000054 2009-04-09 2010-04-09 A method of synthesising an amino acid derivative of azelaic acid WO2010117258A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
SG2011067170A SG174445A1 (en) 2009-04-09 2010-04-09 A method of synthesising an amino acid derivative of azelaic acid
CN201080015054.5A CN102388017B (en) 2009-04-09 2010-04-09 A method of synthesising an amino acid derivative of azelaic acid

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
MYPI20091437A MY144409A (en) 2009-04-09 2009-04-09 A method of producing derivatives of azelaic acid
MYPI20091437 2009-04-09

Publications (1)

Publication Number Publication Date
WO2010117258A1 true WO2010117258A1 (en) 2010-10-14

Family

ID=42936402

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/MY2010/000054 WO2010117258A1 (en) 2009-04-09 2010-04-09 A method of synthesising an amino acid derivative of azelaic acid

Country Status (4)

Country Link
CN (1) CN102388017B (en)
MY (1) MY144409A (en)
SG (1) SG174445A1 (en)
WO (1) WO2010117258A1 (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013098659A1 (en) * 2011-12-28 2013-07-04 Viridis Biopharma Pvt Ltd Process for the synthesis of highly pure cationic surfactant products
US9840466B2 (en) 2013-12-09 2017-12-12 Conopco, Inc. Process of making adamantanamides
WO2019243970A1 (en) * 2018-06-23 2019-12-26 Cellix Bio Private Limited Compositions and methods for the treatment of inflammatory skin diseases and cancer
CN115219613A (en) * 2022-06-16 2022-10-21 上海市食品药品检验研究院 Method for detecting azelaic acid and potassium azeloyl diglycolate in cosmetics

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8901328B2 (en) * 2012-04-11 2014-12-02 Chervon Oronite Company LLC Method for preparing mono or dialkanol amides
CN105658089B (en) * 2013-10-02 2019-07-09 奇华顿股份有限公司 Organic compound
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
TWI579146B (en) 2015-04-02 2017-04-21 國立中央大學 Coated structure for forming hydrophilic film on surface

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
WO2006010590A1 (en) * 2004-07-30 2006-02-02 Maycos Italiana Di Comini Miro & C. S.A.S. N-acylated derivatives of dicarboxylic acids with amino acids and vegetable protein hydrolysates and their use in cosmetics and pharmaceuticals

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
WO2006010590A1 (en) * 2004-07-30 2006-02-02 Maycos Italiana Di Comini Miro & C. S.A.S. N-acylated derivatives of dicarboxylic acids with amino acids and vegetable protein hydrolysates and their use in cosmetics and pharmaceuticals

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
BROWNLEE, R. T. C. ET AL.: "The Synthesis and Characterization of a Series of Bis- intercalating Bis-anthracyclines", JOURNAL OF THE CHEMICAL SOCIETY, CHEMICAL COMMUNICATIONS, vol. 9, 1986, pages 659 - 661 *
GRIGORYAN, N. A. ET AL.: "Synthesis and antistaphylococcic activity of dicarboxylic acid derivatives having an amino acid fragment", PHARMACEUTICAL CHEMISTRY JOURNAL, vol. 26, 1992, pages 153 - 157 *
PHILLIPS, D. R. ET AL.: "The synthesis, stability and biological activity of bis-intercalating bis-daunomycin hydrazones", DRUG DESIGN AND DELIVERY, vol. 5, no. 3, 1990, pages 203 - 219 *
RAY, S. ET AL.: "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, 2007, pages 1633 - 1639 *
TRANSLATION FROM KHIMIKO-FARMATSEVTICHESKII ZHUMAL, vol. 26, no. 2, 1992, pages 43 - 45 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013098659A1 (en) * 2011-12-28 2013-07-04 Viridis Biopharma Pvt Ltd Process for the synthesis of highly pure cationic surfactant products
US20140323756A1 (en) * 2011-12-28 2014-10-30 Eburon Organics International Ii, Llc Process for the synthesis of highly pure cationic surfactant products
EP2797874A4 (en) * 2011-12-28 2015-12-09 Eburon Organics Internat Ii Llc Process for the synthesis of highly pure cationic surfactant products
US10287242B2 (en) 2011-12-28 2019-05-14 Organistry, Llc Process for the synthesis of highly pure cationic surfactant products
US9840466B2 (en) 2013-12-09 2017-12-12 Conopco, Inc. Process of making adamantanamides
WO2019243970A1 (en) * 2018-06-23 2019-12-26 Cellix Bio Private Limited Compositions and methods for the treatment of inflammatory skin diseases and cancer
CN115219613A (en) * 2022-06-16 2022-10-21 上海市食品药品检验研究院 Method for detecting azelaic acid and potassium azeloyl diglycolate in cosmetics
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

Also Published As

Publication number Publication date
SG174445A1 (en) 2011-11-28
CN102388017B (en) 2014-04-16
MY144409A (en) 2011-09-15
CN102388017A (en) 2012-03-21

Similar Documents

Publication Publication Date Title
WO2010117258A1 (en) A method of synthesising an amino acid derivative of azelaic acid
EP0498665B1 (en) Hydroxamic acids derivatives, process for their preparation and use thereof
AU2007245194A1 (en) Process for preparation of HIV protease inhibitors
UA119748C2 (en) Dicarboxylic acid bisamide derivatives, use thereof, pharmaceutical composition based thereon and methods for producing dicarboxylic acid bisamide derivatives
US8754110B2 (en) Methods of producing methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate
US10322996B2 (en) Method for producing N-retinoylcysteic acid alkyl ester
CN108484461B (en) Preparation method of alkynylamide-mediated thioamide and application of thioamide in thiopolypeptide synthesis
TWI835325B (en) Preparation method of (S)-4-chloro-2-aminobutyric acid hydrochloride and (S)-4-chloro-2-aminobutyric acid ester
SU860696A1 (en) Method of preparing n-substituted thiobutyramides or their salts
US10654862B2 (en) Methods for the chemical synthesis of pyrrole-linked bivalent compounds, and compositions thereof
EP0297641A1 (en) Guanidine-compounds containing a substituted tetraphenylborate ion, process for obtaining these compounds and the use of these compounds in peptid synthesis
NO761050L (en)
SG184714A1 (en) A method of producing derivative of azelaic acid
EP3658537A1 (en) Process for the preparation of glycopyrrolate tosylate
JPH10502048A (en) Novel pharmaceutically active compounds which can be formed from 1,3,4,6,7,8-hexahydro-2H-pyrimido- (1,2-a) -pyrimidine
O'donnell et al. Synthetic of α-Methylhistidine by Catalytic Phase-Transfer Alkylations
EP1194398A1 (en) Synthesis of (r) and (s)-aminocarnitine and their derivatives starting from d- and l-aspartic acid
US20210122772A1 (en) Pentafluorophosphate derivative, its uses and an appropriate manufacturing method
JPH078855B2 (en) Sulfonium compound
KR20050092398A (en) Synthesis of (r) and (s)-aminocarnitine and derivatives thereof from d-and l-aspartic acid
SU799651A3 (en) Method of preparing ketocarboxylic acid amides
JP7444363B2 (en) 2-(2-oxo-4-substituted piperazinyl)cycloalkyl carbamate compound or salt thereof, method for analyzing enantiomers using the compound
Monteiro et al. Synthesis of N-alkyl-Cα, α-dimethylglycine derivatives
CH634068A5 (en) PRIMIDILSULFURI WITH ANTI-SECRETORY ACTIVITY, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM.
JPS625140B2 (en)

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 201080015054.5

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10761916

Country of ref document: EP

Kind code of ref document: A1

DPE1 Request for preliminary examination filed after expiration of 19th month from priority date (pct application filed from 20040101)
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10761916

Country of ref document: EP

Kind code of ref document: A1