Patent Application
20070197791
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Dicarboxylic imides form part of many substances used in the pharmaceutical field. One of the best known active agents having a dicarboxylic imide function is thalidomide. It was described in 1954 for the first time. In the beginning, thalidomide was used as a sedative. However, in recent years it has been found that thalidomide as well as its derivatives can be used in the treatment of various diseases such as e.g. leprosy, rheumatoid arthritis, AIDS, Crohn's disease as well as cancer diseases. Thalidomide has an immune-suppressive effect as well as an immuno-modulating effect.
Several routes for the synthesis of thalidomide are known from the literature. For an overview see “Axel Kleemann and Jürgen Engel, Pharmaceutical Substances, Thieme Verlag, Stuttgart, 4th edition”, pages 2005-2007. The most widely used variant uses phthalic anhydride as a starting material which is reacted with glutamic acid to yield N-phthaloyl glutamic acid. This acid is reacted with acetic anhydride to form N-phthaloyl glutamic anhydride. The anhydride is then transformed into thalidomide in the melt under the action of urea. During this reaction the typical problems for reactions with gas evolvement in the melt are encountered, e.g. excessive foaming or inferior solubility of the product mixture and thus more difficult processing of the product.
Therefore, it would be helpful to have a method which enables the synthesis of dicarboxylic imides, particularly of thalidomide and its derivatives, by a route where the reaction is performed in solution and therefore can be controlled more easily. It is an object of the present invention to provide a method for the synthesis of dicarboxylic imides in solution.
This object has been achieved by the method according to the independent claim. Advantageous embodiments are set forth in the dependent claims.
The present invention relates to a method for the preparation of dicarboxylic imides from the corresponding dicarboxylic anhydrides with urea or urea derivates.
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The inventors of the present invention have surprisingly found that reaction of acid anhydrides with urea in a high-boiling solvent results in the synthesis of dicarboxylic imides. This reaction route thus enables e.g. the synthesis of thalidomide starting from N-phthaloyl glutamic anhydride. The synthesis of thalidomide starting from N-phthaloyl glutamic anhydride using sulfolane (tetrahydrothiophene-1,1-dioxide) as a solvent is presented in scheme 1 as an example.
The invention provides a method for the preparation of a dicarboxylic imide having the general formula R1—(CO)—(NR3)—(CO)—R2 (I) wherein a dicarboxylic anhydride of the formula R1—(CO)—O—(CO)—R2 (II) is reacted with urea or a urea derivative having the formula (R3HN)—(CO)—(NR3H) in a solvent to form a dicarboxylic imide (I) wherein R1, R2 and R3 independently of each other can be substituted or unsubstituted, unbranched or branched or cyclic C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C4-C10 aryl, C4-C10 heteroaryl, or wherein R1 and R2 can be bound to each other to form a ring, and/or wherein R3 can also be H. If R1 and R2 are bound to each other to form a ring they form together the divalent radical R4. Each of the radicals R1 to R4 can be unsubstituted, substituted by one or also by several substituents. An essential feature of the invention is the reaction of the dicarboxylic anhydride with urea or a urea derivative forming the corresponding dicarboxylic imide.
In a preferred embodiment of the invention a method is provided for the preparation of dicarboxylic imides having the general formula (III)
wherein R3 is as defined above, and R4 is a divalent radical as defined as R1 or R2, i.e. R4 can be a substituted or unsubstituted, unbranched or branched or cyclic C1-C10 alkanediyl, C2-C10 alkenylene, C2-C10 alkynylene, C4-C10 arylene, C4-C10 heteroarylene. Preferably, the method is used to prepare substituted or unsubstituted piperidine-2,6-diones wherein R4 is substituted or unsubstituted 1,3-propanediyl, particularly preferred substituted or unsubstituted 1 phthalimido-1,3-propanediyl, and in particular 1 phthalimido-1,3-propanediyl for the synthesis of thalidomide.
Whenever any of the residues R1, R2, R3 and/or R4 are substituted by a substituent, the substituent may be selected by a person skilled in the art from any known substituent. A person skilled in the art will select a possible substituent according to his knowledge and will be able to select a substituent which will not interfere with other substituents present in the molecule and which will not interfere or disturb possible reactions, especially the reactions described within this application. Possible substituents include without limitation
halogenes, preferably fluorine, chlorine, bromine and iodine;
aliphatic, alicyclic, aromatic or heteroaromatic hydrocarbons, especially alkanes, alkylenes, arylenes, alkylidenes, arylidenes, heteroarylenes and heteroarylidenes;
carbonxylic acids including the salts thereof;
carboxylic acid halides;
aliphatic, alicyclic, aromatic or heteroaromatic carboxylilc acid esters;
aldehydes;
aliphatic, alicyclic, aromatic or heteroaromatic ketones;
alcohols and alcoholates, including a hydroxyl group;
phenoles and phenolates;
aliphatic, alicyclic, aromatic or heteroaromatic ethers;
aliphatic, alicyclic, aromatic or heteroaromatic peroxides;
hydroperoxides;
aliphatic, alicyclic, aromatic or heteroaromatic amides or amidines;
nitriles;
aliphatic, alicyclic, aromatic or heteroaromatic amines;
aliphatic, alicyclic, aromatic or heteroaromatic imines;
aliphatic, alicyclic, aromatic or heteroaromatic sulfides including a thiol group;
sulfonic acids including the salts thereof;
thioles and thiolates;
phosphonic acids including the salts thereof;
phosphinic acids including the salts thereof;
phosphorous acids including the salts thereof;
phosphinous acids including the salts thereof;
The substituents may be bound to the residues R1, R2, R3 and/or R4 via a carbon atom, an oxygen atom, a nitrogen atom, a sulfur atom, or a phosphorus atom. The hetero atoms in any structure containing hetero atoms, as e.g. heteroarylenes or heteroaromatics, may preferably N, O, S and P.
In the method according to the invention, high-boiling solvents or solvent mixtures are employed, preferably solvents having a boiling point under atmospheric pressure of more than 150° C., more preferably of more than 170° C., and most preferably of more than 190° C. In this respect, solvents may be selected from aprotic sulfones like e.g. tetrahydrothiophene-1,1-dioxide (sulfolane), saturated lactames like e.g. N-methyl pyrrolidone (NMP), carboxylic amides such like e.g. N,N-dimethyl acetamide (DMA) or formamide, ethers like e.g. diphenyl ether, ureas like e.g. 1,3 dimethyl 2 imidazolidinone (DMI), polyethylene glycols like e.g. diethylene glycol diethylether, aromatics substituted by one or more alkyl groups like e.g. diethylbenzene, pseudocumene, cumene or mesitylene, ionic liquids like e.g. 1-ethyl-3-methyl imidazolium tosylate, siloxanes like e.g. decamethylcyclopentasiloxane, saturated or partially saturated carbocycles like e.g. tetraline or decaline, carbonic esters like e.g. propylene carbonate, and aromatic amines like e.g. N,N-diethylaniline, or the mixtures thereof. Particularly preferred in this respect is tetrahydrothiophene-1,1-dioxide (sulfolane).
The method is preferably carried out under atmospheric pressure. However, it is also possible to carry out the method at above or below atmospheric pressure. It is also possible to perform the reaction under a inert gas atmosphere such as nitrogen or argon.
In addition to the educts, foam inhibitors known to those skilled in the art, such as decaline and tetraline, can be used without adversely effecting the reaction.
Subsequent to the reaction, the product may be purified by methods generally known to those skilled in the art. These include for example recrystallization or chromatographic separation. Preferably, the dicarboxylic imide (I) can be purified by recrystallization from an appropriate solvent or solvent mixture. As the solvent for this purpose, methanol, ethanol, dimethylformamide (DMF), water and ethylether, may be used among others. Mixtures of DMF and water, ethylether and methanol, and ethylether and ethanol can be used as the mixtures.
As the reaction is performed in solution, the known problems of reactions in the melt are not encountered. The product can be easily separated from possible contaminations such as side products or remainders of the educts. Dissolution of the solidified melt which has often been difficult can be omitted. The reaction conditions can be easily controlled by the procedures which are well worked out for performing reactions in solution.
In the following the invention will be explained in more detail with respect to Examples without being limited thereto.
Reaction of dicarboxylic anhydrides with urea to form the imides thereof in different solvents
Reactions of phthalic anhydride with urea
In a manner analogue to that of Example 1, a reaction was performed using sulfolane as the solvent. The reaction temperature was 180-185° C. The yield was 66% of the theoretical yield.
In a manner analogue to that of Example 1, a reaction was performed using N,N-dimethyl acetamide as the solvent. The reaction temperature was limited to 160° C. The yield was 69% of the theoretical yield.
Reactions of phthaloyl glutamic anhydride with urea
In a manner analogue to that of Example 4, a reaction was performed using pseudocumene as the solvent. The reaction temperature was 160° C. Thalidomide was isolated in a yield of 25%.
In a manner analogue to that of Example 4, a reaction was performed using cumene as the solvent. The reaction temperature was 150° C. Thalidomide was isolated in a yield of 11%.
In a manner analogue to that of Example 4, a reaction was performed using mesitylene as the solvent. The reaction temperature was 160° C. Thalidomide was isolated in a yield of 23%.
In a manner analogue to that of Example 4, a reaction was performed using diethylbenzene as the solvent. The reaction temperature was 170° C. Thalidomide was isolated in a yield of 39%.
In a manner analogue to that of Example 4, a reaction was performed using 1-ethyl-3-methyl imidazolium tosylate as the solvent. The reaction temperature was 185° C. Thalidomide was isolated in a yield of 34%.
In a manner analogue to that of Example 4, a reaction was performed using decamethylcyclopentasiloxane as the solvent. The reaction temperature was 180° C. Thalidomide could be isolated in a yield of 20%.
In a manner analogue to that of Example 4, a reaction was performed using diphenylether as the solvent. The reaction temperature was 185° C. Thalidomide could be isolated in a yield of 38%.
In a manner analogue to that of Example 4, a reaction was performed using tetraline as the solvent. The reaction temperature was 180° C. Thalidomide was isolated in a yield of 50%.
In a manner analogue to that of Example 4, a reaction was performed using decaline as the solvent. The reaction temperature was 180° C. Thalidomide was isolated in a yield of 48%.
In a manner analogue to that of Example 14, polyethylene glycol 400 was used as solvent at 185° C. Thalidomide was isolated in a yield of 46%.
In a manner analogue to that of Example 14, propylene carbonate was used as solvent at 180° C. Thalidomide could be isolated in a yield of 30%.
In a manner analogue to that of Example 14, sulfolane was used as solvent at 180° C. Thalidomide was isolated in a yield of 48%.
In a manner analogue to that of Example 14, N,N-diethylaniline was used as solvent at 180° C. Thalidomide was isolated in a yield of 49%.
In a manner analogue to that of Example 14, 1,3-dimethyl-2-imidazolidinone (DMI) was used as solvent at 185°. Thalidomide could be isolated in a yield of 40%.
In a manner analogue to that of Example 14, formamide was used as solvent at 185° C. Thalidomide could be isolated in a yield of 35%.
Reactions of adipic anhydride with urea
In a manner analogue to that of Example 22, diethyleneglycol diethylether was used as solvent at 180° C. Adipic imide was isolated in a yield of 56%.
Reactions of 2-methyl succinic anhydride with urea
In a manner analogous to that of Example 24, diethyleneglycol diethylether was used as the solvent at 180° C. After cooling, first MTBE was added. From the resulting oil 2-methyl succinic imide was obtained in a yield of 20% by recrystallization from ethanol.
| Number | Date | Country | Kind |
|---|---|---|---|
| 06001336.4 | Jan 2006 | EP | regional |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 11606527 | Nov 2006 | US |
| Child | 11656895 | Jan 2007 | US |
