WO2006109321A1 - An improved process for the synthesis of palmidrol - Google Patents

An improved process for the synthesis of palmidrol Download PDF

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Publication number
WO2006109321A1
WO2006109321A1 PCT/IN2005/000116 IN2005000116W WO2006109321A1 WO 2006109321 A1 WO2006109321 A1 WO 2006109321A1 IN 2005000116 W IN2005000116 W IN 2005000116W WO 2006109321 A1 WO2006109321 A1 WO 2006109321A1
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Prior art keywords
improved process
anhydride
solvents
product
alkyl
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PCT/IN2005/000116
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French (fr)
Inventor
Sanjay Suri
Tapan Kashyap
Jagat Singh
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Morepen Laboratories Limited
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Priority to PCT/IN2005/000116 priority Critical patent/WO2006109321A1/en
Publication of WO2006109321A1 publication Critical patent/WO2006109321A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton

Definitions

  • the Invention relates to an Improved Process for the synthesis of Palmidrol.
  • the invention relates to a process, which is operated at moderate reaction temperature. More particularly, the invention relates to a process having increased selectivity for desired product: formation. Still particularly, the invention relates to a process that provides a product with reduced impurities. Still more particularly, the invention relates to a cost effective process.
  • Palmidrol also known as palmitoylethanolamide (PEA) is a naturally occurring C 16:0 fatty acid derivative where the carboxylate function is amidated by the primary amine of ethanolamine. Its chemical name is N-(2-Hydroxyethyl) hexadecanamide. It has also been reported as anti-inflammatory agent and for eosinophilic skin treatment in felines and horses, for analgesic effect and in control of proliferation of tumor cells. It is isolated from soybean lecithin, egg yolk and peanut meal, Its synthesis has been reported by refluxing ethanolamine with palmitic acid [J.Chem.Soc.74, 3442 (1952)].
  • the title compound may be synthesized by condensing carboxylic acid chloride and ethanolamine.
  • Acyl chloride is the most common starting material for the production of Palmidrol, but activating agents such as dicyclohexylcarbodiimide and carbonyldiimidazole allow the condensation between acid and ethanolamine in very good yields (>80%) (Reference is made to
  • the main aim of the present invention is to provide an improved Process for the synthesis of Palmidrol eliminating the disadvantages associated with the existing processes as herein above described.
  • the other objective of the present invention is to provide a process, which is operated at moderate reaction temperature.
  • Yet other objective of the present invention is to provide a cost effective process.
  • Yet another objective of the invention is to develop a process for Palmidrol in high yield and purity.
  • the present invention provides an improved process for the synthesis of palmidrol comprising: a) Preparing anhydride of palmitic acid by any conventional method, b) reacting anhydride so formed with ethanolamine in-situ, c) isolating the product by any known methods and optionally purifying the title product by recrystallization using organic solvents.
  • alkyl or cycloalkyl haloformate may be employed in step (a) for preparation of anhudrde.
  • alkyl or cycloalkyl haloformate employed is C1-C5 alkyl or cycloalkyl haloformate exemplified by methyl chloroformate or ethyl chloroformate and more preferably ethyl chloroformate,
  • the anhydride preparation in step (a) may be carried out in presence of solvents selected from (i) halogenated hydrocarbon solvent such as dichloromethane, chloroform, carbon tetra chloride preferably dichloromethane; (ii) hydrocarbon solvents like hexane, heptane, benzene, toluene, xylene, cyclohexane.
  • solvents selected from (i) halogenated hydrocarbon solvent such as dichloromethane, chloroform, carbon tetra chloride preferably dichloromethane; (ii) hydrocarbon solvents like hexane, heptane, benzene, toluene, xylene, cyclohexane.
  • the anhydride preparation in step (a) may be carried out in presence of nucleophilic organic base selected from amine represented by triethyl amine, diisopropyl ethylamine preferably triethyl amine.
  • the anhydride preparation in step (a) may preferably be performed at a temperature of -30 to +30 0 C, preferably -10 to +15 0 C.
  • the reaction in step (b) may preferably be conducted at a temperature of 0 to 10 0 C and the two
  • reactants can be added in any sequence.
  • the isolation may be carried out by solvent recovery or filtration.
  • the organic solvents used for recrystallization may be selected from (i) Cl to C4 alkanols such as methanol, ethanol, propanol, isopropanol and preferably methanol and ethanol, more preferably ethanol; (ii) ester like ethyl acetate; (iii) ketonic solvents exemplified by acetone, methyl isobutyl ketone, methyl ethyl ketone; and (iv) ethereal solvents like tetrahydrofuran.
  • the Palmidrol is synthesized in high yield and purity by selective attack of -NH2 group of ethanol,amine over the anhydride of palmitic acid and alkyl or cycloalkyl halo formate.
  • the process can be explained in the following steps: a) anhydride of palmitic acid and a suitable alkyl or cycloalkyl haloformate is prepared in a suitable solvent in presence of a suitable base at low temperature.
  • Suitable alkyl haloformate may be Cl to C3 alkyl haloformate preferably methyl chloroformate or ethyl chloroformate and more preferably ethyl chloroformate.
  • Suitable solvents may be any halogenated hydrocarbon solvents, exemplified by dichloromethane chloroform carbon tetrachloride preferably dichloromethane; hydrocarbon solvents including but not limiting to hexane, cyclohexane, heptane, benzene, toluene, xylene.
  • Suitable bases may be any nucleophilic organic base like alkyl amine represented by triethyl amine, diisopropyl ethylamine preferably triethyl amine.
  • Suitable temperature may be -20 to +2O 0 C, preferably -5 to +1O 0 C. b) reacting anhydride with ethnolamine in-situ.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The process of this invention comprises preparing anhydride of palmitic acid and alkyl or cycloalkyl haloformate by any conventional method, reacting anhydride so formed with ethnolamine in-situ, and isolating the product by any known methods such as solvent recovery or filtration followed by purifying the title product by recrystallization using organic solvents if so desired.

Description

AN IMPROVED PROCESS FOR THE SYNTHESIS OF PALMIDROL FIELD OF THE INVENTION
The Invention relates to an Improved Process for the synthesis of Palmidrol. Particularly, the invention relates to a process, which is operated at moderate reaction temperature. More particularly, the invention relates to a process having increased selectivity for desired product: formation. Still particularly, the invention relates to a process that provides a product with reduced impurities. Still more particularly, the invention relates to a cost effective process. BACKGROUND OF THE INVENTION
Palmidrol also known as palmitoylethanolamide (PEA) is a naturally occurring C 16:0 fatty acid derivative where the carboxylate function is amidated by the primary amine of ethanolamine. Its chemical name is N-(2-Hydroxyethyl) hexadecanamide. It has also been reported as anti-inflammatory agent and for eosinophilic skin treatment in felines and horses, for analgesic effect and in control of proliferation of tumor cells. It is isolated from soybean lecithin, egg yolk and peanut meal, Its synthesis has been reported by refluxing ethanolamine with palmitic acid [J.Chem.Soc.74, 3442 (1952)]. The title compound may be synthesized by condensing carboxylic acid chloride and ethanolamine. (Reference is made to PCT application NO. WOO 110434, European Patent No. EP0550008) Acyl chloride is the most common starting material for the production of Palmidrol, but activating agents such as dicyclohexylcarbodiimide and carbonyldiimidazole allow the condensation between acid and ethanolamine in very good yields (>80%) (Reference is made to
Current Medicinal Chemistry 2002, 9, 663-674). In order to get the product synthetically, when the inventor applied the above method, it was found that the product obtained was having impurities and the yields were also low. The reason may be non-selectivity of palmitic acid, the main reactant, towards -OH and
-NH2 groups of ethanolamine in harsh reaction conditions of refluxing. So there was a need to find out milder reaction conditions in which -OH group of ethanolamine does not participate in the reaction thus inhibiting the formation of impurities. After extensive research it was found that if we activate the -COOH group of palmitic acid, forming its anhydride by reacting it with alkyl or cycloalkyl haloformate preferably with ethyl chloroformate at low temperature, the anhydride formed, reacts preferentially with -NH2 group of ethanolamine to give the desired product in high yield and purity. The reaction product may further be recrystallized in organic solvents to get the Pharma grade product. SUMMARY OF THE INVENTION The main aim of the present invention is to provide an improved Process for the synthesis of Palmidrol eliminating the disadvantages associated with the existing processes as herein above described. The other objective of the present invention is to provide a process, which is operated at moderate reaction temperature.
Another objective of the present invention is to provide a method for selective reaction of -COOH group of palmitic acid with -NH2 group of ethanolamine. Still another objective of the present invention is to provide a process-yielding product with reduced impurities.
Yet other objective of the present invention is to provide a cost effective process.
Yet another objective of the invention is to develop a process for Palmidrol in high yield and purity.
Further scope and applicability of the invention will become apparent from the detailed description given herein after. However, It should be understood that the detailed description and examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed disclosure.
STATEMENT OF INVENTION:
Accordingly the present invention provides an improved process for the synthesis of palmidrol comprising: a) Preparing anhydride of palmitic acid by any conventional method, b) reacting anhydride so formed with ethanolamine in-situ, c) isolating the product by any known methods and optionally purifying the title product by recrystallization using organic solvents.
In one of the embodiments of the present invention, alkyl or cycloalkyl haloformate may be employed in step (a) for preparation of anhudrde.
In other embodiment of the present invention, alkyl or cycloalkyl haloformate employed is C1-C5 alkyl or cycloalkyl haloformate exemplified by methyl chloroformate or ethyl chloroformate and more preferably ethyl chloroformate,
In another embodiment of the present invention, the anhydride preparation in step (a) may be carried out in presence of solvents selected from (i) halogenated hydrocarbon solvent such as dichloromethane, chloroform, carbon tetra chloride preferably dichloromethane; (ii) hydrocarbon solvents like hexane, heptane, benzene, toluene, xylene, cyclohexane.
In yet other embodiment of the present invention, the anhydride preparation in step (a) may be carried out in presence of nucleophilic organic base selected from amine represented by triethyl amine, diisopropyl ethylamine preferably triethyl amine.
In yet another embodiment of the present invention, the anhydride preparation in step (a) may preferably be performed at a temperature of -30 to +300C, preferably -10 to +150C. In still other embodiment of the present invention, the reaction in step (b) may preferably be conducted at a temperature of 0 to 100C and the two
reactants can be added in any sequence.
In still another embodiment of the present invention, the isolation may be carried out by solvent recovery or filtration. The organic solvents used for recrystallization may be selected from (i) Cl to C4 alkanols such as methanol, ethanol, propanol, isopropanol and preferably methanol and ethanol, more preferably ethanol; (ii) ester like ethyl acetate; (iii) ketonic solvents exemplified by acetone, methyl isobutyl ketone, methyl ethyl ketone; and (iv) ethereal solvents like tetrahydrofuran.
DETAILED DESCRIPTION OF THE INVENTION
The present invention will become more fully understood from the detailed description given herein below and the examples, which are given by way of illustration only as stated herein above and thus should not construe the scope of the invention.
In the present invention the Palmidrol is synthesized in high yield and purity by selective attack of -NH2 group of ethanol,amine over the anhydride of palmitic acid and alkyl or cycloalkyl halo formate. The process can be explained in the following steps: a) anhydride of palmitic acid and a suitable alkyl or cycloalkyl haloformate is prepared in a suitable solvent in presence of a suitable base at low temperature. Suitable alkyl haloformate may be Cl to C3 alkyl haloformate preferably methyl chloroformate or ethyl chloroformate and more preferably ethyl chloroformate. Suitable solvents may be any halogenated hydrocarbon solvents, exemplified by dichloromethane chloroform carbon tetrachloride preferably dichloromethane; hydrocarbon solvents including but not limiting to hexane, cyclohexane, heptane, benzene, toluene, xylene. Suitable bases may be any nucleophilic organic base like alkyl amine represented by triethyl amine, diisopropyl ethylamine preferably triethyl amine. Suitable temperature may be -20 to +2O0C, preferably -5 to +1O0C. b) reacting anhydride with ethnolamine in-situ. c) quenching the reaction d) isolating the product by conventional solvent recovery and or by filtration e) alternatively recrystallizing the product in suitable organic polar solvents like Cl to C4 alkanols selected from methanol, ethanol, propanol, isopropanol, preferably methanol or ethanol and more preferably ethanol; ester solvents like ethyl acetate; ketonic solvents like, acetone, methyl isobutyl ketone, methyl ethyl ketone; ethereal solvents like, tetrahydrofuran. The invention may be further illustrated by the following examples.
However, it does not limit the scope of invention:
EXAMPLE-I:
To a suspension of palmitic acid (10Og, 0.39 mole) in dichloromethane (500 ml), tri ethylamine (47.4g, 0.47 mole) was added slowly at room temperature. Reaction mass was cooled to 0- 50C followed by slow addition of ethyl chloroformate (50.9g, 0.47 mole). The reaction mass was agitated for 45 minutes at 0-50C. Ethanolamine (35.7g, 0.58 mole) diluted with 100 ml dichloromethane was added drop wise. The reaction mixture was agitated at 0-100C to get the reaction completion. Water was added to the reaction mass and product, 10Og, was isolated after filtration. The product so obtained was recrystallized in methanol to give 95.1g highly pure title product. EXAMPLE-2:
To a suspension of palmitic acid (10Og, 0.39 mole) in chloroform (600 ml), tri ethylamine (47.4g, 0.47 mole) was added slowly at room temperature. Reaction mass was cooled to 0-50C followed by slow addition of methyl chloroformate (44.42g, 0.47 mole). The reaction mass was agitated for 45 minutes at 0-50C. Ethanolamine (35.7g, 0.58 mole) was added drop wise. The reaction mixture was agitated at 0-100C to get the reaction completion. Water was added to the reaction mass and product, 92g, was isolated after filtration. The product so obtained was recrystallized in methanol to give 87.4g highly pure title product. EXAMPLE-3:
To a suspension of palmitic acid (10Og, 0.39 mole) in dichloromethane (500 ml), diisopropyl ethylamine (60.6g, 0.47 mole) was added slowly at room temperature. Reaction mass was cooled to 0-50C followed by slow addition of cyclopentyl chloroformate (69.8g, 0.47 mole). The reaction mass was agitated for 60 minutes at 0-100C. Ethanolamine (35.7g, 0.58 mole) diluted with 100 ml dichloromethane was added drop wise. The reaction mixture was agitated at 0-100C to get the reaction completion. Water was added to the reaction mass and product, 88g, was isolated after filtration. The product so obtained was recrystallized in methanol to give 83.6g highly pure title product. EXAMPLE-4: To a suspension of palmitic acid (10Og, 0.39 mole) in cyclohexane (1000 ml), tri ethylamine (47.4g, 0,47 mole) was added slowly at room temperature. Reaction mass was cooled to 0-50C followed by slow addition of ethyl chloroformate (50.9g, 0.47 mole). The reaction mass was agitated for 30 minutes at 0-5°C. Ethanolamine (35.7g, 0.58 mole) was added drop wise. The reaction mixture was agitated at 0-100C to get the reaction completion. Water was added to the reaction mass and product, 95g, was isolated after filtration. The product so obtained was recrystallized in methanol to give 91.2g highly pure product. ADVANTAGES:
> The process is high yielding.
> The process is cost effective.
> The process produces the title product that is highly pure.
> The process is scalable for industrial application.

Claims

We Claim:
1. An improved process for the synthesis of palmidrol comprising: d) Preparing anhydride of palmitic acid by any conventional method, e) reacting anhydride so formed with ethnolamine in-situ, f) isolating the product by any known methods and optionally purifying the title product by recrystallization using organic solvents.
2. An improved process as claimed in claim 1 wherein, alkyl or cycloalkyl haloformate is employed in step (a) for preparation of anhudrde.
3. An improved process as claimed in claims 1 8B 2 wherein, alkyl or cycloalkyl haloformate employed is C1-C5 alkyl or cycloalkyl haloformate exemplified by methyl chloroformate or ethyl chloroformate and more preferably ethyl chloroformate,
4. An improved process as claimed in claim 1 wherein the anhydride preparation in step (a) is carried out in presence of solvents selected from (i) halogenated hydrocarbon solvent such as dichloromethane, chloroform, carbon tetra chloride preferably dichloromethane; (ii) hydrocarbon solvents like hexane, heptane, benzene, toluene, xylene, cyclohexane.
5. An improved process as claimed in claim 1 wherein the anhydride preparation in step (a) is carried out in presence of nucleophilic organic base selected from amine represented by triethyl amine, diisopropyl ethylamine preferably triethyl amine.
6. An improved process as claimed in claim 1 wherein the anhydride preparation in step (a) is performed at a temperature of -30 to +300C, preferably -10 to +150C.
7. An improved process as claimed in claim 1 wherein the reaction
in step (b) is preferably conducted at a temperature of 0 to 100C
and the two reactants can be added in any sequence.
8. An improved process as claimed in claim 1 wherein the isolation is carried out by solvent recovery or filtration.
9. An improved process as claimed in claim 1 wherein the organic solvents used for recrystallization are selected from (i) Cl to C4 alkanols such as methanol, ethanol, propannol, isopropanol and preferably methanol and ethanol, more preferably ethanol; (ii) ester like ethyl acetate; (iii) ketonic solvents exemplified by acetone, methyl isobutyl ketone, methyl ethyl ketone; and (iv) ethereal solvents like tetrahydrofuran.
10. An improved process for the synthesis of palmidrol substantially as herein described with reference to the examples.
PCT/IN2005/000116 2005-04-15 2005-04-15 An improved process for the synthesis of palmidrol WO2006109321A1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019066644A1 (en) 2017-09-28 2019-04-04 Innexus Nutraceuticals B.V. Methods for providing highly pure palmitoylethanolamide (pea), pure pea preparations, and uses thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0498162A1 (en) * 1991-02-02 1992-08-12 Rütgerswerke Aktiengesellschaft Insecticidal agent

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0498162A1 (en) * 1991-02-02 1992-08-12 Rütgerswerke Aktiengesellschaft Insecticidal agent

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019066644A1 (en) 2017-09-28 2019-04-04 Innexus Nutraceuticals B.V. Methods for providing highly pure palmitoylethanolamide (pea), pure pea preparations, and uses thereof

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