KR100814266B1 - Process for the preparation of N-carboxyanhydrides - Google Patents

Abstract

The present invention provides N-carboxylic anhydrides by reacting phosgene, diphosgene and / or triphosgene in a solvent medium with at least one of the corresponding amino acids or salts thereof, wherein at least a portion of the reaction is carried out under a pressure of less than 1000 mbar. An improved method for preparing the same is provided.

Thus N-carboxylic anhydride is obtained with better yields and improved purity.

N-carboxylic anhydride, amino acid, phosgene, reactive group

Description

Process for the preparation of N-carboxyanhydrides

The present invention relates to an improved method for preparing N-carboxylic anhydrides from the corresponding amino acids and phosgene, diphosgene or triphosgene.

N-carboxylic anhydrides (abbreviated: NCA) obtained from α-, β- or γ-amino acids are very useful compounds due to the activation of their acid functional groups. In fact, N-carboxylic anhydrides can cause these acid functional groups to react with any nucleophile. Thus, generation of amide functional groups by reaction with amine functional groups is facilitated. For this reason, N-carboxylic anhydride is immediately polymerized and used to form peptides. In addition, ester bonds are readily produced by reaction with alcohol. This is also advantageous if one wants to reduce acid functional groups.

Several methods are known for preparing N-carboxylic anhydrides. One of the most widespread and most direct methods is the reaction of an amino acid or its hydrochloride with phosgene, diphosgene or triphosgene in a solvent medium.

The general scheme for using phosgene is as follows:

In the above scheme,

R represents the main radical of the α-, β- or γ-amino acid,

R 'represents a hydrogen atom or a radical of a secondary amino group of amino acids, where R' may form a ring with R.

In addition to N-carboxylic anhydrides, it has been found that large amounts of hydrochloric acid are also formed, ie 2 moles of hydrochloric acid per mole of NCA. Hydrochloric acid is very reactive. Its presence in the medium leads to side reactions and the production of chlorination byproducts. These chlorinated impurities remaining in the resulting NCA are unequally desirable in terms of both quality and yield. This is because these chlorinated impurities are extremely harmful to the polymerization reaction of NCA. In order to perform this polymerization reaction properly, it is essential to substantially reduce the amount of chlorinated compounds present in the NCA monomers. Therefore, the level of hydrolyzable chlorine should generally be less than 0.05% by weight.                         

If the reaction is carried out according to known methods without the presence of a basic compound, it is in fact difficult to reproducibly obtain such low levels of hydrolysable chlorine. On the other hand, in the case of neutralizing hydrochloric acid by adding a basic compound, there is a risk that the polymerization of the undesirable NCA is activated in this step, and then polymerization occurs in the medium.

In addition, one of the difficulties of the method is the choice of solvent. This is because the formation reactions of NCA in solvents such as amphoteric esters (eg ethyl acetate) or nonpolar aprotic solvents (eg dichloromethane or toluene) are generally found to be very slow and incomplete. In ether-based solvents such as tetrahydrofuran or dioxane, the reaction is faster but these solvents are completely inert to phosgene and hydrochloric acid, producing other impurities.

Thus, in order to obtain NCAs with better yields and improved purity, especially while maintaining levels of hydrolysable chlorine below 0.05%, there is a need to improve the current method of directly reacting amino acids with phosgene, diphosgene or triphosgene. have. It is also highly desirable to reduce the reaction time in the most inert solvents.

The method according to the invention fulfills this need. The process is characterized in that the reaction of phosgene, diphosgene and / or triphosgene with one of the corresponding α-, β- or γ-amino acids or salts thereof in a solvent medium to produce N-carboxylic anhydride is 1000 mbar (10 ^And at least partially under pressure of less than ⁵ Pa).

This novel method allows solving problems that occur when implementing the prior art methods. Thus, as soon as a portion of hydrochloric acid is formed, it is removed from the reaction medium. Many side reactions are suppressed, which in turn inhibits the formation of harmful impurities. In addition, the movement of the reaction equilibrium in the direction of production of the desired NCA is also promoted, followed by the kinetics of the reaction.

It has also been found that when amino acids are converted using secondary amine functional groups, this reaction under reduced pressure makes it unnecessary to add tertiary amines such as triethylamine or N-methylmorpholine to the medium. Nevertheless, such amines are to date considered by the person skilled in the art to be essential for crystallization from carbamoyl chloride which is first formed as an intermediate in the medium.

In addition, the absence of additional reactants simplifies the product separation and recovery process. For this reason the method is also more economical.

The process according to the invention is carried out by reaction with most cyclic or acyclic natural or synthetic α-amino acids and derivatives thereof having primary or secondary amine functional groups, and in particular phosgene, diphosgene and / or triphosgene. It is possible to obtain N-carboxylic acid anhydrides of all already known compounds.

 Likewise, the process is very useful for obtaining N-carboxylic acid anhydrides of β- and γ-amino acids and derivatives thereof having primary or secondary amine functional groups. This is because it is considered difficult to prepare these compounds according to the prior methods.

The amino acids used as starting compounds are preferably α, β and γ carbons or optionally substituted or unsubstituted alkyl radicals and / or substitutions of carbons located between reactive acid groups and reactive amino groups Α-, β-, and γ-amino acids that form substituted or unsubstituted alkyl hydrocarbon chains that may be contained, in whole or in part, in an unsubstituted alkyl or heteroalkyl ring. Substituents which may or may not be substituted by alkyl groups are generally groups or atoms found in amino acids, for example hydroxyl, carboxyl, mercapto, alkylthio, alkyldithio, alkyl, cycloalkyl, heterocycloalkyl , Aryl, heteroaryl, alkyloxy or aryloxy groups, halogen atoms (eg fluorine, chlorine, bromine or iodine atoms) or amino, guanidino or amido groups.

More specifically, when considering amino acids, an alkyl group contains 1 to 7 carbon atoms and is unsubstituted or substituted by the substituents specified above. Aryl groups are unsubstituted, halogen atoms (e.g., fluorine, chlorine, bromine or iodine atoms) and alkyl, alkoxy, aryloxy, aryl, mercapto, alkylthio, hydroxyl, carboxyl, amino, alkylamino, dialkylamino , Substituted by a substituent selected from nitro or trifluoromethyl group. If present, these substituent groups are more particularly 1 to 3 present. Aryl groups are especially substituted or unsubstituted phenyl or naphthyl radicals.

The cycloalkyl group consists of a substituted or unsubstituted ring having 3 to 7 carbon atoms. Heterocycles, which may or may not be substituted, are cycloalkyl or aryl groups containing one or more heteroatoms selected from nitrogen, oxygen or sulfur atoms in the ring.

Substituents of a cycloalkyl or heterocycloalkyl group are selected from the substituents specified above for the alkyl and aryl radicals. Substituents of heteroaryl groups are selected from substituents specified for aryl groups.

Heteroaryl groups are preferably substituted or unsubstituted 2- or 3-furanyl, 2- or 3-thienyl, 2-, 3- or 4-pyridinyl, 4-imidazolyl and 3-indolyl groups to be.

The amino acids may exist in various forms thereof, especially in the case of having one or more asymmetric carbons, in their various enantiomeric forms, racemic mixtures or mixtures of diastereomers or pure stereoisomeric forms.

When the radicals of an amino acid include functional groups capable of reacting under the conditions of the method in addition to the amino group and acid group forming the anhydride ring, these functional groups are blocked by the protecting group in a known manner.

The reactive amino group can be a primary or secondary amino group. As a result, the nitrogen atom may have substituted or unsubstituted aliphatic, cycloaliphatic, araliphatic or aryl radicals, as is common in the amine class. In particular, such radicals may be substituted by the groups specified above as substituents.

The radicals of the amino group may, for example, form a ring which is unsubstituted or substituted as specified above, with the residues of the radicals of the amino acid as in proline.

If the radical of the amino group contains a reactive group, the reactive group is usually protected.

As radicals of such amino groups, in particular the groups described in US Pat. No. 4,686,295, in particular alkoxycarbonyl, aryloxycarbonyl and aralkyloxy, for new NCAs which are unsubstituted or formed using, for example, phosgene Mention may be made of alkyl, cycloalkyl or aralkyl groups substituted by one or more groups selected from carbonyl groups.

As examples of amino acids, the most common amino acids such as glycine, alanine, valine, leucine, isoleucine, phenylalanine, serine, threonine, lysine, δ-hydroxylysine, arginine, ornithine, aspartic acid, asparagine, glutamic acid Mention may be made of glutamine, cysteine, cystine, methionine, tyrosine, thyroxine, proline, hydroxyproline, tryptophan, histidine and derivatives thereof.

Instead of amino acids, one of its salts may be used as starting material. The term "salts of amino acids" refers to salts obtained by reaction of amino groups with organic or inorganic acids, for example sulfates, acetates, toluenesulfonates or methanesulfonates, and preferably hydrohalides, in particular hydrochlorides and hydros It is understood to mean bromide.

Hydrochloride is the preferred salt.

The method comprises a γ-benzyl ester or γ- of amino acids, for example N- (1-ethoxy-carbonyl-3-phenylpropyl) alanine, leucine, alanine, N- (trifluoroacetyl) lysine or glutamic acid. Most suitable for the production of N-carboxylic anhydrides of methyl esters.

When the method is practiced, phosgene, diphosgene and / or triphosgene can be reacted with amino acids to form a ring of N-carboxylic anhydride. Phosgene is the preferred compound.

There is no need for very excess phosgene for amino acids. Thus, preferably, about 1 to 3 mol of phosgene is added per mol of amino acid or salt thereof.

To obtain the same phosgene / amino acid ratio, diphosgene or triphosgene are added in corresponding amounts.

The reaction can be carried out in a polar aprotic solvent. Ethers, in particular tetrahydrofuran and dioxane can be used, but preferably solvents belonging to the aliphatic ester family are selected.

Nonpolar aprotic solvents belonging to the chlorinated or non-chlorinated aliphatic or aromatic hydrocarbon system, for example dichloromethane or toluene, may also be used.

Solvents belonging to the ester or hydrocarbon system have the advantage of not reacting with phosgene or hydrochloric acid. Therefore, it is more advantageous to use such a solvent.

Alkyl acetates are very suitable, in particular ethyl acetate.

According to the invention, the reaction is carried out at least partially under pressures below 1000 mbar (10 ⁵ Pa) and in particular below 960 mbar (96 × 10 ³ Pa).

If the solvent is a hydrocarbon, the pressure is more particularly chosen in the range of 50 to 960 mbar. Preferably, when the solvent is ethyl acetate or hydrocarbon, the pressure is selected in the range of 800 to 960 mbar.

The reaction temperature is generally from 0 ° C. to 120 ° C. or equal to this value, and is typically at temperatures of about 40 ° C. and about 90 ° C.

The reaction is preferably carried out under anhydrous conditions.

One of the advantages of the process according to the invention is that the reaction time is short and can even be reduced by half compared to the process of the prior art, especially in solvents such as esters. Since the latter solvent is cheaper, for this reason the use of the process according to the invention is substantially economical.

Once the reaction is complete, the product is separated according to conventional procedures. Phosgene and solvent are generally removed by distillation under very low pressure.

The yield of NCA obtained after crystallization is markedly improved and is often at least 90%. The level of hydrolyzable chlorine is less than 0.05%.

Thus, NCAs prepared according to the process of the present invention can be used in a number of applications where very pure products are required, in particular in the manufacture of pharmaceutical products.

The following examples illustrate the invention but are not intended to be limiting.

Example 1

Preparation of N-carboxylic Anhydride (H-Glu (OBzl) -NCA) of γ-benzyl ester of glutamic acid.

100 g (0.42 mol) of H-Glu (OBzl) -OH are suspended in 885 ml of ethyl acetate. The suspension is cooled to 5 ° C. and then 90 g (0.91 mol, 2.16 equiv) of gaseous phosgene are introduced into the suspension over 1 hour 30 minutes at a temperature of 10 ° C.

The temperature of the reaction medium is brought to 60 ° C., and then the reaction medium is placed under reduced pressure (850-950 mbar) and left for 3 hours at a bulk temperature of 60 ° C. under static conditions. The medium becomes clear after 1 hour under static conditions.

Distillation at about 13 mbar then separates 600 ml of the mixture of ethyl acetate and phosgene. 600 ml of industrial heptane is added to the residual medium under warm conditions and the medium is cooled at 0 ° C. for 1 hour. The crystallized product is filtered off and washed with industrial heptane.

After drying, 106 g of H-Glu (OBzl) -NCA (yield: 95.5%) are obtained and the level of hydrolyzable chlorine is less than 0.05%.

Comparative Example 1:

Preparation of N-carboxylic anhydride (H-Glu (OBzl) -NCA) of γ-benzyl ester of glutamic acid.

100 g (0.42 mol) of H-Glu (OBzl) -OH are suspended in 885 ml of ethyl acetate. The suspension is cooled to 5 ° C. and then 90 g (0.91 mol, 2.16 equiv) of gaseous phosgene are introduced into the suspension.

The reaction medium is heated to 60 ° C. The reaction takes place slowly. The reaction medium should be left under static conditions at this temperature for 6 hours instead of 3 hours in the above examples.

Subsequently, 600 ml of a mixture of ethyl acetate and phosgene was separated by distillation as described above. 600 ml of industrial heptane is added to the residual medium under warm conditions and the medium is cooled at -10 ° C for 2 hours. The crystallized product is filtered off and washed with industrial heptane.

After drying, 88 g of H-Glu (OBzl) -NCA is obtained and the level of hydrolyzable chlorine is 0.13%. The yield is only 74.6%.

Example 2

Preparation of N-carboxylic acid anhydride (EPAL-NCA) of N- (1-ethoxycarbonyl-3-phenylpropyl) alanine.

In a thermostatically controlled 1 liter reactor, 350 ml of anhydrous ethyl acetate and 42 g (0.15 mol, 1 equivalent) of N- (1-ethoxycarbonyl-3-phenylpropyl) alanine (EPAL) were pre-inactivated with nitrogen. Introduce. Subsequently, 6 g (0.165 mol, 1.1 equivalents / EPAL) of anhydrous gaseous hydrochloric acid are introduced into the suspension obtained by mechanical stirring for 15 minutes to form EPAL hydrochloride.

30 g (0.3 mol, 2 equiv / EPAL) of gaseous phosgene are then added to the reaction medium for 1 hour. The medium is then heated to 60 ° C. and the pressure is reduced to about 800 mbar to produce reflux of ethyl acetate. This condition is maintained for 3 hours. HPLC analysis then confirms that EPAL is no longer present in the reaction medium.

The residual hydrochloric acid and excess phosgene are removed and the ethyl acetate is separated by reducing the pressure to about 13 mbar (1.3 kPa).

200 ml of diisopropyl ether is then added to the concentrated reaction medium and cooled to 0-5 ° C. Crystallize EPAL-NCA. It is collected by filtration under a nitrogen atmosphere.

After drying in vacuo at a temperature between 20 ° C. and 25 ° C., 41.2 g of EPAL-NCA (white solid) having a purity of at least 99.7% is obtained with HPLC and the level of hydrolyzable chlorine is less than 0.05%. The yield is 90%.

Comparative Example 2

Preparation of N-carboxylic acid anhydride (EPAL-NCA) of N- (1-ethoxy-carbonyl-3-phenylpropyl) alanine.

Using the same amount of compound as in the above examples, the preparation is carried out in the same manner under the same conditions except that the standard atmospheric pressure is maintained without reducing the reaction pressure.

After reacting at 60 ° C. for 8 hours, 3.73% by weight of unreacted EPAL still remains in the reaction medium and no further conversion is observed.

Example 3

Preparation of N-Carboxylic Anhydride (H-Ala-NCA) of Alanine.

25 g (0.285 mol) of alanine (H-Ala-OH) is suspended in 220 ml of ethyl acetate. Then 70.5 g (0.71 mol, 2.5 equivalents) of gaseous phosgene are introduced into the suspension over 1 hour 30 minutes at a temperature of 10 ° C.

The reaction medium is heated to 55 ° C. and then placed under reduced pressure (850-950 mbar) and left under static conditions for 6 hours at a bulk temperature of 55 ° C. The reaction medium becomes clear after 3 hours under static conditions.

Subsequently, 200 ml of a mixture of ethyl acetate and phosgene are distilled off under very low pressure.

80 ml of toluene is then added to the residual medium under warm conditions and distilled again to separate 78 g of a mixture of ethyl acetate and toluene. The residual medium is then cooled at 0 ° C. for 1 hour. The crystallized product is filtered off and washed with 39 g of cold toluene.

After drying, 19.4 g (yield: 59.2%) of H-Ala-NCA are obtained, and the level of hydrolyzable chlorine is less than 0.05%.

By the process of the invention, N-carboxylic anhydrides can be obtained with better yields and improved purity from the corresponding amino acids and phosgene, diphosgene or triphosgene.

Claims (10)

The reaction is carried out under a pressure of less than 1000 mbar, selected from the group consisting of phosgene, diphosgene, triphosgene and combinations thereof with one of the corresponding α-, β- or γ-amino acids or salts thereof in a solvent medium Process for the production of N-carboxylic anhydrides by reaction with compounds. The method of claim 1 wherein the pressure is less than or equal to 960 mbar. The method of claim 1 wherein the solvent is selected from the group consisting of tetrahydrofuran, dioxane, dichloromethane, toluene and ethyl acetate. The method of claim 1 wherein the solvent is ethyl acetate and the pressure is selected in the range of 800 to 960 mbar. The method according to any one of claims 1 to 4, wherein the reaction is carried out using phosgene. 5. The method according to claim 1, wherein the reactive group is protected when the radical of the amino acid comprises a reactive group other than an amino group and an acid group forming an anhydride. 6. The starting amino acid according to any one of claims 1 to 4, wherein the starting amino acid is leucine, alanine, N- (trifluoroacetyl) lysine, γ-benzyl ester and γ-methyl ester of glutamic acid, N- (1-ethoxy Carbonyl-3-phenylpropyl) alanine and salts thereof. The method according to any one of claims 1 to 4, wherein the amino acid salt is sulfate, acetate, toluenesulfonate or methanesulfonate. The method according to any one of claims 1 to 4, wherein the amino acid salt is a hydrohalide. The process according to claim 1, wherein the reaction is carried out at a temperature of 0 ° C. to 120 ° C. 6.