WO1991012229A1 - Procede de preparation de derives acyles de composes acylables - Google Patents

Procede de preparation de derives acyles de composes acylables Download PDF

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Publication number
WO1991012229A1
WO1991012229A1 PCT/CA1991/000044 CA9100044W WO9112229A1 WO 1991012229 A1 WO1991012229 A1 WO 1991012229A1 CA 9100044 W CA9100044 W CA 9100044W WO 9112229 A1 WO9112229 A1 WO 9112229A1
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WIPO (PCT)
Prior art keywords
acylatable
process according
substrate
chloride
acyl halide
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Application number
PCT/CA1991/000044
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English (en)
Inventor
Ivan A. Veliky
John V. Cross
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National Research Council Of Canada
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Publication of WO1991012229A1 publication Critical patent/WO1991012229A1/fr

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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
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
    • C07K1/1072—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups
    • C07K1/1077—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups by covalent attachment of residues other than amino acids or peptide residues, e.g. sugars, polyols, fatty acids

Definitions

  • This invention relates to a process for preparing acyl derivatives of compounds having hydroxy, amino, thiol or other reactive functional groups.
  • Acyl derivatives of organic compounds are often produced by reacting the organic compounds with acyl halides, usually acyl chlorides.
  • acyl halides usually acyl chlorides.
  • the chemical principles of such processes are based on the Schotten-Baumann reaction (see C. S ⁇ hotten, Ber. 17, 2544, 1884; and E. Bau ann, Ber. 19, 3218, 1886), which involves the acylation of alcohols with acyl halides in aqueous alkaline solutions as represented by the following chemical equation:
  • the reaction takes place in aqueous alkaline conditions, usually in the presence of sodium hydroxide, in order to neutralize the hydrochloric acid released during the reaction.
  • the disadvantage of the conventional process is that the aqueous reaction conditions normally produce very low yields of the desired acyl derivative due to fast hydrolysis of the acyl chloride in the aqueous alkaline solution.
  • the reactions which take place in the aqueous conditions are generally unpredictable and the by-products which are formed (their number and concentration depending on the acylatable substrate) also create serious problems during the isolation of the pure product.
  • the undesired reactions often lead to the formation of unwanted organic acid salts (such as fatty acid salts, i.e. soaps) which make the isolation and purification of the desired product very difficult.
  • An object of the present invention is thus to provide a process for the acylation of acylatable substrates which can result in higher yields of the desired acylated product.
  • Another object of the present invention is to provide a process for the acylation of acylatable substrates which produces a reaction mixture from which it is relatively easy to extract the desired acylated product.
  • a process for acylating an acylatable substrate with an acyl halide which comprises: contacting a first liquid phase containing at least some of said acylatable substrate with a second non-aqueous liquid phase containing said acyl halide, said phases being at least partially immiscible with each other to form a multi-phase reaction system, maintaining said contact of said phases in alkaline conditions for a period of time sufficient to result in the formation of a desired acylated product, and separating said desired acylated product from the reaction mixture.
  • the invention also relates to the acylated products formed by the process of the invention.
  • contacting liquid phases we mean bringing the phases together to form two continuous phases having an interface, either quiescently or with agitation, or mixing the phases so that one or more of the phases becomes discontinuous.
  • acylatable substrate as used herein we mean a compound that is capable of undergoing acylation in the reaction conditions. Such compounds are normally organic compounds containing -OH, -NH 2 , -SH or other reactive functional groups.
  • substrates which can be acylated according to the present invention include glycine, lysine, valine, cystein, cystin, p-aminobenzoic acid, p- aminosalicylic acid, anthranilic acid, aniline, aminobenzophenone, diethylamine, triethylamine, etc. and various peptides and proteins. These materials are generally at least partially soluble in aqueous solvents or other suitable solvents.
  • acyl halides employed in the present invention are preferably acyl chlorides, but other halides may be used if desired.
  • Representative acyl halides include decanoyl chloride, lauroyl chloride, myristoyl chloride, palmitoyl chloride, stearoyl chloride, benzoyl chloride and cinnamoyl chloride. These reactants are generally liquid at room temperature but a few (e.g. cinnamoyl chloride) are solid. In any event non-aqueous solvents for these reactants can be found without difficulty.
  • the process of the present invention is an improvement of the conventional process in that it avoids most of the uncontrollable conditions of the conventional procedure and increases the final yield, usually dramatically (e.g. in the range of 77 to 96% of theoretical) , while also reducing to a minimum the formation of unwanted by-products and enabling the purification procedure to be carried out more easily.
  • the present invention relies on the separation of the acyl halide and the acylatable substrate into two at least partially immiscible liquid phases which are brought into contact with eachother.
  • the acyl halide or the acylatable substrate, or possibly both, gradually partition between the two phases so that the reactants come into contact with each other at a controlled rate.
  • the phase which initially contains the acyl halide is non-aqueous so that the halide does not hydrolyse while it remains in this phase.
  • Non- polar organic solvents e.g. ether, petroleum ether, chloroform, etc. are normally employed for this phase.
  • the phase which initially contains the acylatable substrate is generally polar and is, most commonly, aqueous.
  • the phase containing the acylatable substrate is aqueous, which it normally is, the acyl halide reacts quickly with the acylatable substrate as it enters the aqueous phase and so does not have time to hydrolyse to a significant extent.
  • Alkaline conditions are required for the reaction to take place, so one of the liquid phases (normally the one containing the acylatable substrate) should be alkaline, e.g. as a result of containing a dissolved alkali metal hydroxide such as sodium hydroxide.
  • the liquid phases should be at least partially immiscible.
  • immiscible we mean mutually insoluble rather than incapable of being mixed under any circumstances.
  • the liquid phases are usually capable of being mixed to form an emulsion or the like which generally separates into two continuous liquid phases when quiescent.
  • the liquid phases employed in the present invention should be sufficiently immiscible that distinct phases (continuous or discontinuous) do appear in the reaction conditions. In some circumstances, it is desirable to use liquids that are completely immiscible. However, in other cases, the liquids may be sufficiently miscible that the liquid phases do dissolve partially in eachother. It is possible to use the degree of miscibility of partially mutually soluble non-aqueous and aqueous phases to control the kinetics of the reaction, hydrolysis of the acyl halide or decomposition of the acylatable substrate.
  • the at least partially immiscible phases are generally thoroughly agitated together during the reaction so that contact of the reactants is facilitated. This can be achieved, for example, by rapidly stirring the liquid phases together in a suitable reaction vessel.
  • the liquid phases employed in the present invention should be of such a nature that they provide the required degree of immiscibility, permit the desired acylation reaction to take place without significant hydrolysis of the acyl halide starting material, and prevent unwanted modification of reactive groups (e.g. by oxidation) as well as contribute to the efficiency of the reaction and higher yield (e.g. by increasing the reaction surface) .
  • a combination of an aqueous and a non-aqueous solvent is normally employed for the liquid phases if the acylatable substrate is readily soluble in aqueous solvents, e.g. in aqueous alkaline solution usually having a pH in the range of pH 8 to pH 12.
  • the non-aqueous solvent, the carrier of the acyl halide e.g.
  • acyl chloride then controls the rate of the reaction as well as the potential number of by ⁇ products or impurities.
  • the combination of aqueous and non- aqueous solvents creates the necessary conditions for the gradual release of the acyl halide into the polar phase for reaction with the acylatable substrate.
  • the ratio of the aqeous solvent (e.g. water) and the non-aqueous solvent (e.g. ethyl ether) required for the reaction will depend on the mutual solubility or miscibility of the two solvents.
  • the usual ratio of the two immiscible liquid phases is from 1:2 to 2:1 by volume when water and diethylether are employed, with the ratio normally being around 1:1 by volume.
  • While the present invention requires the presence of two liquid phases that are immiscible or only partially miscible, other phases containing a portion of one or other of the reactants may also be present.
  • the amount of acylatable substrate exceeds that required to produce a saturated solution in one of the liquid phases, the excess may remain as a solid in contact with the saturated solution.
  • a typical system employing a solid phase employs an excess of a solid acylatable substrate incompletely soluble in the aqueous liquid.
  • the acylatable compound will be present in two forms, namely a soluble form in (possibly saturated) solution and the excess solid.
  • the material in solution is the reactive form and, as it reacts, the solid excess gradually dissolves.
  • the reaction system consists of liquid/solid/liquid phases, at least at the start of the reaction procedure.
  • additional liquid phases may be present or the system may include gaseous phases.
  • protection of functional groups for example, in some cases, protection of functional groups
  • an inert gas can be used to remove oxygen from the reaction mixture and prevent oxidation and by-product formation during the reaction, e.g. the gas can be bubbled through the liquid phase(s) .
  • oxidation may be desired, in which case air, oxygen or an oxidizing gas may be bubbled through the liquids, thus forming a gaseous phase of the reaction system.
  • gases When gases are employed, the system may comprise for example liquid ⁇ liquid ⁇ gas, liquid ⁇ solid ⁇ liquid ⁇ gas or liquid ⁇ liquid ⁇ liquid ⁇ gas, etc. combinations.
  • the quantities of the acyl halide and the acylatable substrate required for the multi-phase reaction of the present invention are generally the same as those required for the conventional single phase reaction. Generally, stoichiometrical proportions are suitable, but an excess of the acyl halide may be employed, if desired.
  • temperatures required for the reaction to take place depend to some extent on the particular reactants employed. Generally, however, the reactions proceed with good yield at room temperature, i.e. 21+1°C. If desired, temperatures higher than room temperature may be employed, but tend to be limited by lower yields and by the boiling points of the solvents employed. In some cases, temperatures between 0°C and 5°C are critical for high yields when the starting materials are sensitive to temperature.
  • the reaction is normally carried out by separately dissolving the acylatable substrate in one of the liquid phases and the acyl halide in the other liquid phase, and then gradually adding one of the phases (usually the acyl halide solution) to the other with stirring. After the addition is complete, the stirring is normally continued for a period of time until the reaction is essentially complete.
  • the period of addition usually requires between 30 minutes and 2 hours (depending on the type of mechanical stirring, volumes to be mixed, etc.) and the subsequent reaction period normally last for 3 to 6 hours depending on the reaction conditions.
  • an inert solid phase e.g. a non- reactive microparticulate powder
  • the particle size of the solid phase may have an effect on the reaction performance, with smaller particles being more effective, although possibly more troublesome because of the resulting difficulty of removing the solid from the reaction mixture when the reaction is complete.
  • the solid materials employed in this connection are generally non-reactive with the acylatable substrate, the acyl halide, as well as the other phases, and silica powder is an example of a suitable inert solid for use in this connection.
  • the solid phase can normally be added to either one of the liquid phases, but often the addition is to the liquid phase containing the acylatable substrate. Such additions have the potential of greatly improving the efficiency of the multiphase reactions as well as the yields of the products.
  • Reactive or partially reactive solid phases may be used in special circumstances (e.g. for the prevention of the adverse effect of the strong alkaline condition) .
  • the acylated product can be separated from the reaction mixture by conventional techniques. Most preferably, the reaction mixture is acidified, which causes the product to precipitate, following- which it call be filtered, washed and, if necessary, purified further.
  • the invention is - illustrated in further detail with reference to the following non-limiting Examples.
  • the solution was then overlaid with diethylether, which is a non-polar solvent having a density (0.71) lower than that of water.
  • diethylether is a non-polar solvent having a density (0.71) lower than that of water.
  • a solution of lauroyl chloride was prepared in anhydrous diethylether and the solution was added dropwise to the two phase mixture while stirring.
  • the diethylether formed a layer on top of the aqueous solution and, when stirred, created a two phase emulsion (water/ether) , therefore allowing the lauroyl chloride dissolved in the diethylether to gradually engage in the reaction with the glycine dissolved in the water portion of the emulsion.
  • the reaction mixture was stirred until the lauroyl chloride in the diethylether reacted with the remainder of the glycine.
  • the reaction vessel was cooled to a temperature between 0°C and 5°C. The addition period was 30 minutes and the whole reaction time was approximately 3 hours. After the reaction was finished, the reaction mixture was acidified with hydrochloric acid to pH 2 to pH 4. The precipitate was separated and washed to remove residues of the starting materials aniline and benzoyl chloride. The yield obtained was 19.7g, which amounted to 93% of the theoretical yield.
  • EXAMPLE 3 PREPARATION OF 1.10-DI-CINNAMOYL-DIAMINODECANE 1,10-Diaminodecane was dissolved in diethylether. The solution was added to a solution of sodium carbonate and sodium hydroxide (approximately 1:1 volume ratio) in water. Cinnamoyl chloride was dissolved in anhydrous diethylether and added dropwise to the stirred mixture of 1,10- diaminodecane and sodium carbonate with sodium hydroxide during a 30 minute period. The reaction was performed at room temperature (approximately 21+1°C) . The whole reaction time was 3 hours.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Genetics & Genomics (AREA)
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  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Selon un procédé d'acylation de composés, on met en réaction un composé tel qu'un alcool, un thiol, un composé amino ou d'autres composés contenant des groupes fonctionnels, avec un halogénure d'acyle (de préférence un chlorure d'acyle) afin d'obtenir le produit voulu. La réaction est effectuée dans des conditions alcalines dans un système à phases multiples qui comprend une première phase liquide contenant le substrat acylable et une deuxième phase liquide non aqueuse contenant l'halogénure d'acyle. Les première et deuxième phases sont de préférence des liquides polaire aqueux et non polaire non aqueux, respectivement. Les deux phases sont au moins partiellement immiscibles l'une avec l'autre de sorte que la vitesse de contact entre les réactifs et l'hydrolyse de l'halogénure d'acyle sont réduites. Les deux phases sont mises en contact pendant une durée suffisante pour provoquer la réaction d'acylation, puis le produit acylé est séparé du mélange de réaction. Ce procédé permet d'augmenter de manière significative le rendement de la réaction et réduit les quantités de produits secondaires, par comparaison avec des réactions similaires effectuées dans un système à une seule phase.
PCT/CA1991/000044 1990-02-12 1991-02-12 Procede de preparation de derives acyles de composes acylables WO1991012229A1 (fr)

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US47852490A 1990-02-12 1990-02-12
US478,524 1990-02-12

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0618927A1 (fr) * 1991-12-10 1994-10-12 Tanox Biosystems, Inc. Cytokines dotees d'un residu de cysteine non apparie et leurs produits de conjugaison
EP0827950A1 (fr) * 1996-09-06 1998-03-11 Ajinomoto Co., Inc. Procédé de préparation d'acides aminés acides N-acylés par un groupe à longue chaine, ou de leurs sels
JP2016210717A (ja) * 2015-05-07 2016-12-15 日油株式会社 Ｎ−アシルアミノ酸の製造方法
CN111187174A (zh) * 2020-01-16 2020-05-22 广东丽臣奥威实业有限公司 一种脂肪酰甘氨酸盐或脂肪衍生物酰甘氨酸盐的生产及纯化方法

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1012765A (fr) * 1949-12-10 1952-07-17 Alimentation Equilibree L Procédé pour la préparation de dérivés de la méthionine
DE2015075A1 (de) * 1969-04-01 1970-10-08 Ajinomoto Co. Inc., Tokio Verfahren zur Herstellung von sauren durch höhere aliphatische Acylgruppen N-substituierten Aminosäuren
US3647876A (en) * 1969-08-14 1972-03-07 Virginia Chemicals Inc Process in the preparation of n n-di-n-propyl-alpha-chloroacetamid
EP0039166A1 (fr) * 1980-04-28 1981-11-04 Stauffer Chemical Company Procédé pour la préparation en continu de dichloroacétamides
EP0065804A1 (fr) * 1981-05-22 1982-12-01 Hüls Aktiengesellschaft Procédé de préparation de N-benzyl-N-isopropyl-pivalamide
WO1989010347A1 (fr) * 1988-04-18 1989-11-02 Mallinckrodt, Inc. Procede de production d'aminophenols et de leurs derives d'amide

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1012765A (fr) * 1949-12-10 1952-07-17 Alimentation Equilibree L Procédé pour la préparation de dérivés de la méthionine
DE2015075A1 (de) * 1969-04-01 1970-10-08 Ajinomoto Co. Inc., Tokio Verfahren zur Herstellung von sauren durch höhere aliphatische Acylgruppen N-substituierten Aminosäuren
US3647876A (en) * 1969-08-14 1972-03-07 Virginia Chemicals Inc Process in the preparation of n n-di-n-propyl-alpha-chloroacetamid
EP0039166A1 (fr) * 1980-04-28 1981-11-04 Stauffer Chemical Company Procédé pour la préparation en continu de dichloroacétamides
EP0065804A1 (fr) * 1981-05-22 1982-12-01 Hüls Aktiengesellschaft Procédé de préparation de N-benzyl-N-isopropyl-pivalamide
WO1989010347A1 (fr) * 1988-04-18 1989-11-02 Mallinckrodt, Inc. Procede de production d'aminophenols et de leurs derives d'amide

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0618927A1 (fr) * 1991-12-10 1994-10-12 Tanox Biosystems, Inc. Cytokines dotees d'un residu de cysteine non apparie et leurs produits de conjugaison
EP0618927A4 (fr) * 1991-12-10 1995-05-24 Tanox Biosystems Inc Cytokines dotees d'un residu de cysteine non apparie et leurs produits de conjugaison.
EP0827950A1 (fr) * 1996-09-06 1998-03-11 Ajinomoto Co., Inc. Procédé de préparation d'acides aminés acides N-acylés par un groupe à longue chaine, ou de leurs sels
US6008390A (en) * 1996-09-06 1999-12-28 Ajinomoto Co., Inc. Process for producing N-long-chain acyl acidic amino acids or salts thereof
JP2016210717A (ja) * 2015-05-07 2016-12-15 日油株式会社 Ｎ−アシルアミノ酸の製造方法
CN111187174A (zh) * 2020-01-16 2020-05-22 广东丽臣奥威实业有限公司 一种脂肪酰甘氨酸盐或脂肪衍生物酰甘氨酸盐的生产及纯化方法

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