WO2008071696A1

WO2008071696A1 - Improved process for preparing substituted carboxylic anhydrides

Info

Publication number: WO2008071696A1
Application number: PCT/EP2007/063695
Authority: WO
Inventors: Martin Helmut Friedrich Hanbauer; Berthold Winkler; Michael Stanek; Gerhard Schoppel; Christof Wehrli
Original assignee: DSM Fine Chemicals Austria Nfg GmbH and Co KG; DSM IP Assets BV
Current assignee: Patheon Austria GmbH and Co KG; DSM IP Assets BV
Priority date: 2006-12-15
Filing date: 2007-12-11
Publication date: 2008-06-19
Anticipated expiration: 2009-06-15
Also published as: CN101668729A

Abstract

An improved process for preparing anhydrides of the general formula (I) in which X and Y may be the same or different and are each C, N, O or P, where X and Y, depending on their definition, may be mono- to trisubstituted by a radical from the group of H, a C1-C20-alkyl radical optionally mono- or polysubstituted by groups which are inert under the reaction conditions, or a C5-C10-aryl, C3-C6-heteroaryl or heterocycle radical optionally mono- or polysubstituted by groups which are inert under the reaction conditions, and may optionally be connected by a C1-C5-alkyl chain which may optionally be mono- or polysubstituted by substituents which are inert under the reaction conditions to form a ring system, in which dicarboxylic acids of the formula (II) in which X and Y are each as defined above in a high-boiling organic solvent which forms an azeotrope with water in the presence of an organic or inorganic acid in an amount of from 0.000001 to 50 mol%, based on the dicarboxylic acid, are heated to reflux temperature and water is separated out as an azeotrope, then the reaction mixture is cooled and the desired product is isolated.

Description

IMPROVED PROCESS FOR PREPARING SUBSTITUTED CARBOXYLIC

ANHYDRIDES

The present invention relates to an improved process for preparing substituted carboxylic anhydrides, for instance 2-oxo-1 ,3-dibenzyl- 4,5-imidazolidinedicarboxylic anhydride (cycloanhydride).

Substituted carboxylic anhydrides are important intermediates in chemical synthesis.

For instance, cycloanhydride is an important intermediate in multistage biotin synthesis (vitamin H).

In general, the anhydrides are prepared from the corresponding dicarboxylic acids with removing of water with, for example, an anhydride such as acetic anhydride or inorganic anhydrides such as phosphorus pentoxide, phosphorus oxychloride and the like. The disadvantage is the use of highly corrosive raw materials. Cycloanhydride in particular is prepared processing from 2-oxo-1 ,3- dibenzyl-4,5-imidazolidinedicarboxylic acid (cycloacid), which has already been described in the literature.

According to Synthesis 2000, No. 14, 2004-2008, 0.1 mol of cycloacid is stirred with 0.3 mol of acetic anhydride and a catalytic amount of 85% H₃PO₄ under reflux for 2 hours. Subsequently, the mixture is cooled to room temperature and the precipitated cycloanhydride is filtered off. The yield is 98%.

A disadvantage in this process is the large amount of acetic anhydride, and also acetic acid as a by-product, as a result of which a potentially corrosive medium (acetic acid/acetic anhydride) is additionally obtained. EP 1 127 879 A1 describes the preparation of cycloanhydride by heating the cycloacid with acetic anhydride in an aromatic hydrocarbon as an organic solvent. The cycloacid is first prepared proceeding from a dialkali metal salt of meso- 2,3-bis(benzylamino)succinic acid. When the cycloacid is not isolated from the reaction mixture, according to EP 1 127 879, an aromatic solvent, preferably toluene, and acetic anhydride are added in an amount of at least 1 mol per mole of meso-

2,3-bis(benzylamino)succinic acid. The mixture is then heated to from 70 to 130⁰C and then the cycloanhydride which precipitates out of the solution is isolated. According to example 2, the mixture is heated to 80⁰C and the cycloanhydride is obtained in 78% yield based on meso-2,3-bis(benzylamino)succinic acid. A disadvantage in this process is in particular the at least stoichiometric amount of acetic anhydride and the low yield, and also again the potentially corrosive medium (acetic acid/acetic anhydride).

According to Chem.Pharm. Bull.53(7); 743-736 (2005), the cycloanhydride is obtained in virtually quantitative yields (98%) by heating the cycloacid (50 mmol) in xylene with substoichiometric amounts of acetic anhydride (10 mmol) and azeotropic removal of water for 13 hours.

Disadvantages are the long reaction times and likewise the potentially corrosive medium (acetic acid/acetic anhydride). It was an object of the present invention to find an improved process for preparing anhydrides, for instance cycloanhydride, which avoids the previous disadvantages of known processes and affords the desired end product in high yields in a simple manner.

The present invention accordingly provides an improved process for preparing anhydrides of the general formula

in which X and Y may be the same or different and are each C, N, O or P, where X and Y, depending on their definition, may be mono- to trisubstituted by a radical from the group of H, a Ci-C₂o-alkyl radical optionally mono- or polysubstituted by groups which are inert under the reaction conditions, or a C₆-Ci₀-aryl, C₃-C₆- heteroaryl or heterocycle radical optionally mono- or polysubstituted by groups which are inert under the reaction conditions, and may optionally be connected by a d-C₅- alkyl chain which may optionally be mono- or polysubstituted by substituents which are inert under the reaction conditions to form a ring system, which comprises heating dicarboxylic acids of the formula X Y

HOOC ^C00H (||) in which X and Y are each as defined above in a high-boiling organic solvent which forms an azeotrope with water in the presence of an organic or inorganic acid in an amount of from 0.000001 to 50 mol%, based on the dicarboxylic acid, to reflux temperature and separating out water as an azeotrope, then cooling the reaction mixture and isolating the desired product.

The process according to the invention proceeds from dicarboxylic acids of the formula (I). In the formula (I), X and Y may be the same or different and are each

C, N, O or P.

X and Y are preferably each C or N; both X and Y are more preferably N.

X and Y may, depending on their definition, be mono- to trisubstituted.

Suitable substituents, depending on the definition of X and Y, are H, carbonyl, where this connects X and Y, a CrC₂o-alkyl radical optionally mono- or polysubstituted by groups which are inert under the reaction conditions, or a C₆-C₁₀- aryl, C₃-C₆-heteroaryl or -heterocycle radical optionally mono- or polysubstituted by groups which are inert under the reaction conditions.

A Ci-C₂o-alkyl radical is understood to mean linear, branched or cyclic alkyl radicals which have from 1 to 20 carbon atoms and may optionally also have one or more double and/or triple bonds, for instance methyl, ethyl, n-propyl, i-propyl, n- butyl, sec-butyl, tert-butyl, n-hexyl, cyclohexyl, 2-ethylhexyl, etc. Preference is given to CrCi₂-alkyl radicals, particular preference to

Ci-C₆-alkyl radicals.

The alkyl radicals may additionally optionally be mono- or polysubstituted by groups which are inert under the reaction conditions.

Suitable groups are, for example, halogens such as fluorine, chlorine or bromine, OH, optionally substituted C₆-Ci₀-aryl, C₃-C₆-heteroaryl or -heterocycle radicals, Ci-C₂₀-alkyl or -alkoxy radicals, NO₂, NR₁R₂ where Ri and R₂ may each independently be H, Ci-Cβ-alkyl or phenyl, CONR₁R₂ where R₁ and R₂ are each as defined above, etc.

C₆-C₁₀-Aryl, C₄-C₆-heteroaryl or -heterocycle radicals are aromatics, for instance phenyl or naphthyl, etc.; heteroaromatics or heterocycles, for instance pyridinyl, thienyl, pyrrolyl, furanyl or oxathiolanyl, etc.

These radicals may likewise optionally be mono- or polysubstituted by groups which are inert under the reaction conditions.

Suitable groups are again, for example, halogens such as fluorine, chlorine or bromine, OH, optionally substituted C₆-C₁₀-aryl, C₃-C₆-heteroaryl or - A -

-heterocycle radicals, Ci-C₂o-alkyl or -alkoxy radicals, NO₂, NR₁R₂ where Ri and R₂ may each independently be H, d-C₆-alkyl or phenyl, CONR₁R₂ where R₁ and R₂ are each as defined above, etc.

X and Y may optionally also be connected by a CrC₅-alkyl chain, preferably C-ι-C₃-alkyl chain and more preferably C-ι-C₂-alkyl chain, which may be mono- or polysubstituted by substituents which are inert under the reaction conditions, to form a ring system.

Suitable inert substituents are, for example, =0, =S, =NH, =NZ, OH, - SH, Ci-Cβ-alkyl, etc., where Z may be an optionally substituted linear or cyclic alkyl radical having 1-20 carbon atoms or a C₆-C₁₀-aryl or C₃-C₆-heteroaryl or -heterocycle.

The number of possible substitutions depends on the definition of X and Y.

For instance, if X (or Y) is O, the oxygen atom may, for example, be monosubstituted by H and/or an alkyl, aryl, heteroaryl or heterocycle radical, or may be connected via a CrC₅-alkyl chain to Y (or X) to form a ring system.

If X (or Y) is N or P, the nitrogen or phosphorus atom may, for example, be disubstituted by H and/or an alkyl, aryl, heteroaryl or heterocycle radical, or be monosubstituted and be connected via a C-ι-C₅-alkyl chain to Y (or X) to form a ring system. If X (or Y) is C, the carbon atom may, for example, be trisubstituted by H and/or an alkyl, aryl, heteroaryl or heterocycle radical or be disubstituted and connected via a C-ι-C₅-alkyl chain to Y (or X) to form a ring system.

X and Y are preferably connected via a CrC₅-alkyl chain, preferably CrC₃-alkyl chain, optionally substituted by the groups listed above to form a ring system. X and Y are more preferably connected via an optionally substituted C₁-C₂- group; this is more preferably a C=O group.

If X and Y are connected to form a ring system and are each N and/or P, X and/or Y are monosubstituted by preferably an optionally substituted CrC₆-alkyl, C₆-aryl, C₃-C₆-heteroaryl or heterocycle radical. Particular preference is given to an optionally substituted benzyl radical.

If X and Y are connected to form a ring system and X and/or Y is C, the carbon atom is disubstituted preferably by H and/or by optionally substituted C₁-C₆- alkyl, C₆-aryl, C₃-C₆-heteroaryl or heterocycle radical. Suitable dicarboxylic acids are, for example, 1 ,2- cyclopentyldicarboxylic acid, 1 ,2-cyclohexyldicarboxylic acid, etc., or 2-oxo-1 ,3- dibenzyl-4,5-imidazolidinedicarboxylic acid (cycloacid).

2-Oxo-1 ,3-dibenzyl-4,5-imidazolidinedicarboxylic acid (cycloacid) is, for example, commercially available or can be prepared according to EP 1 127879.

According to the invention, the dicarboxylic acid is dissolved or slurried in a high-boiling organic solvent which forms an azeotrope with water.

Suitable solvents are, for example, aromatic hydrocarbons, for instance benzene, toluene, p-xylene, m-xylene, o-xylene, xylene mixtures in any isomer ratio, ethylbenzene, dioxane or dibutyl ether, etc.

Preference is given to using toluene or xylene or a xylene mixture, particular preference to using a xylene mixture.

According to the invention, the conversion to the anhydride is effected in the presence of an organic or inorganic acid. Suitable acids for this purpose are, for example, inorganic acids, for instance sulfuric acid, hydrochloric acid, phosphoric acid, etc., or organic acids, for instance an alkyl- or arylsulfonic acid, for example p-toluenesulfonic acid or methanesulfonic acid; camphorsulfonic acid, benzenesulfonic acid, linear alkylsulfonic acids (C₂-C₂O), alkylated benzenesulfonic acids with a linear or branched alkyl radical having 1-20 carbon atoms; and, for example, chloroacetic acid or trifluoroacetic acid, etc.

Preference is given to adding sulfuric acid, methanesulfonic acid or toluenesulfonic acid, particularly preference to adding toluenesulfonic acid.

The amounts of acids used are from 0.000001 to 50 mol% based on the cycloacid, preferably from 0.01 to 10 mol%, more preferably from 0.05 to 3 mol%.

The reaction mixture is then heated to reflux and water is separated out as an azeotrope until the calculated amount of water has been removed or complete conversion has been achieved (monitoring by a suitable analytical method, for example HPLC, NMR, GC, TLC, titration, etc.). Subsequently, the reaction mixture is cooled to room temperature and the precipitated anhydride is isolated by filtration, optionally washed once or more than once with the solvent used and dried.

Optionally, the anhydride can even be used for the next reaction without workup or isolation. In particular, the process according to the invention is suitable for preparing 2-oxo-1 ,3-dibenzyl-4,5-imidazolidinedicarboxylic anhydride (cycloanhydride).

The process according to the invention affords anhydrides, especially cycloanhydride (CAN) in a simple and relatively inexpensive manner compared to the prior art in high yields of up to 99% of theory and in exceptionally high quality (for example: greater than 99% CAN).

It is also advantageous that the mother liquor can optionally be reused after distillative purification or, even more efficiently, directly without purification. The majority of the acid remains in the mother liquor, such that barely any or no further acid at all has to be added in the case of reuse, which further enhances the efficiency and avoidance of waste.

The mother liquor can be reused at least 5 times without quality and yield losses occurring.

Further advantages of the process according to the invention are a low level of waste as a result of the smaller use amount of acid, cheap noncorrosive raw materials, and short reaction time.

Reaction of cycloacid (CAC) to give cycloanhydride (CAN)

CAC CAN

EXAMPLE 1: 300 g (0.84 mol) of cycloacid (CAC) and 2.4 g (0.013 mol; 1.5 mol%) of p-toluenesulfonic acid were suspended in 1.5 1 of xylene in a reaction vessel equipped with a water separator. The reaction mixture was then heated to reflux temperature (bath temperature 160⁰C) and water was distilled off as an azeotrope until complete conversion was discernible by HPLC (-4 hours; -15 ml of water in the water separator). The reaction mixture was then cooled to room temperature, and the precipitated product was filtered off, washed with xylene (2 x 75 ml) and dried at 130⁰C in vacuo for 7 hours.

Yield: 268 g (94%) EXAMPLE 2:

30 g (0.085 mol) of cycloacid (CAC) and 0.5 g (0.003 mol; 3 mol%) of p-toluenesulfonic acid were suspended in 150 ml of toluene in a reaction vessel equipped with a water separator. The reaction mixture was then heated to reflux temperature (bath temperature 120⁰C) and water was distilled off as an azeotrope until complete conversion was discernible by HPLC (-13 hours; -1.1 ml of water in the water separator). The reaction mixture was then cooled to room temperature, and the precipitated product was filtered off, washed with toluene (2 x 40 ml) and dried at 80⁰C in vacuo for 12 hours. Yield: 26 g (92%)

EXAMPLE 3:

30 g (0.085 mol) of cycloacid (CAC) and 0.25 g (0.003 mol; 3 mol%) of sulfuric acid were suspended in 150 ml of toluene in a reaction vessel equipped with a water separator. The reaction mixture was then heated to reflux temperature (bath temperature 120⁰C) and water was distilled off as an azeotrope until complete conversion was discernible by HPLC (-4 hours; -1.5 ml of water in the water separator). The reaction mixture was then cooled to room temperature, and the precipitated product was filtered off, washed with toluene (2 x 40 ml) and dried at 80°C in vacuo for 12 hours.

Yield: 17 g (60%)

EXAMPLE 4:

3.5 g (0.01 mol) of cycloacid (CAC) and 0.003 g (0.02 mmol; 0.2 mol%) of p-toluenesulfonic acid were suspended in 25 ml of toluene in a reaction vessel equipped with a water separator. The reaction mixture was then heated to reflux temperature and water was distilled off as an azeotrope for 5 hours. The reaction mixture was then cooled to room temperature, and the precipitated product was filtered off and dried at 80°C in vacuo for 12 hours. Yield: 3.1 g (90%)

EXAMPLE 5

100 g (0.282 mol) of cycloacid (CAC) and 0.6 g (0.003 mol; 1 mol%) of p-toluenesulfonic acid were suspended in 450 ml of xylene mother liquor from example 1 in a reaction vessel equipped with a water separator. The reaction mixture was then heated to reflux temperature (bath temperature 120⁰C) and water was distilled off as an azeotrope until complete conversion was discernible by HPLC (-3 hours; -5.2 ml of water in the water separator). The reaction mixture was then cooled to room temperature, and the precipitated product was filtered off, washed with xylene (2 x 50 ml) and dried at 100⁰C in vacuo for 12 hours. Yield: 94 g (99%)

Claims

1. An improved process for preparing anhydrides of the general formula

in which X and Y may be the same or different and are each C, N, O or P, where X and Y, depending on their definition, may be mono- to trisubstituted by a radical from the group of H, a Ci-C₂o-alkyl radical optionally mono- or polysubstituted by groups which are inert under the reaction conditions, or a C₆-Cio-aryl, C₃-C₆-heteroaryl or heterocycle radical optionally mono- or polysubstituted by groups which are inert under the reaction conditions, and may optionally be connected by a Ci-C₅-alkyl chain which may optionally be mono- or polysubstituted by substituents which are inert under the reaction conditions to form a ring system, which comprises heating dicarboxylic acids of the formula X Y

2. The process as claimed in claim 1 , wherein compounds of the formula (I) in which X and Y may be the same or different and are each C or N are prepared, where X and Y, depending on their definition, may be mono- to trisubstituted by a radical from the group of H, a Ci-Ci₂-alkyl radical optionally mono- or polysubstituted by groups which are inert under the reaction conditions, or a C₆-Ci₀-aryl, C₃-C₆-heteroaryl or heterocycle radical optionally mono- or polysubstituted by groups which are inert under the reaction conditions, and may optionally be connected by a CrC3-alkyl chain which may be mono- or polysubstituted by substituents which are inert under the reaction conditions to form a ring system.

3. The process as claimed in claim 1-2, wherein compounds of the formula (I) are prepared, in which X and Y are connected by a Ci-C₃-alkyl chain which may be mono- or polysubstituted by a substituent from the group of =0, =S,

=NH, =NZ, OH, -SH, Ci-C₆-alkyl, where Z may be an optionally substituted linear or cyclic alkyl radical having 1-20 carbon atoms or a C₆-Ci₀-aryl or C₃- C₆-heteroaryl or -heterocycle.

4. The process as claimed in claim 1-3, wherein the anhydride of the formula (I) used is 1 ,2-cyclopentyldicarboxylic acid, 1 ,2-cyclohexyldicarboxylic acid or 2- oxo-1 ,3-dibenzyl-4,5-imidazolidinedicarboxylic acid.

5. The process as claimed in claim 1 , wherein the solvent used is an aromatic hydrocarbon from the group of benzene, toluene, p-xylene, m-xylene, o-xylene and xylene mixtures in the isomer ratio, ethylbenzene, dioxane or dibutyl ether.

6. The process as claimed in claim 1 , wherein the acids used are inorganic acids from the group of sulfuric acid, hydrochloric acid or phosphoric acid, or organic acids from the group of the alkyl- or arylsulfonic acids, chloroacetic acid or trifluoroacetic acid.

7. The process as claimed in claim 6, wherein the acid added is sulfuric acid, methanesulfonic acid or toluenesulfonic acid.

8. The process as claimed in claim 1 , wherein the mother liquor obtained after the isolation of the precipitated product is used for a further batch either after distillative purification or directly without purification.