Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-07-18
2002-04-02
Solola, T. A. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06365752
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to a novel process for preparing specific 1-substituted 5-hydroxy-imidazoline-2,4-diones starting from N-substituted urea and glyoxylic acid and the further conversion of these 1-substituted 5-hydroxy-imidazoline-2,4-diones into 1-substituted 5-alkoxy-imidazoline-2,4-diones.
BACKGROUND OF THE INVENTION
1-Benzyl-5-ethoxy-imidazoline-2,4-dione of the formula (A)
(hereinafter referred to as “BEH”) belongs to the class of hydantoins and is also referred to as 1-benzyl-5-ethoxyhydantoin. BEH, its derivatives which are substituted on the benzyl ring and also other 1-substituted 5-alkoxy-imidazoline-2,4-diones have gained increasing importance as intermediates in the preparation of medicaments, insecticides, textile assistants and amino acids. BEH itself is required, in particular, for the preparation of photochemicals.
It is known from Huaxue Shiji 1993, 15(1), 15-16, that BEH can be prepared from the corresponding 1-benzylhydantoin by bromination or chlorination in the 5 position to give the corresponding 1-benzyl-5-halogenohydantoins and further reaction of these halogenohydantoins with ethanol (see reaction equation below).
The above reaction sequence has a number of disadvantages: thus, the use of free bromine or chlorine is difficult in terms of industrial handling and is not without danger. Furthermore, large amounts of hydrogen halides are obtained in the halogenation itself and also in the subsequent halogen replacement, and these have to be disposed of.
The starting material for the abovementioned chlorination or bromination, namely 1-benzylhydantoin, also referred to as 1-benzyl-imidazoline-2,4-dione, in turn has to be prepared via a number of steps:
a) by reaction of N-benzylaminoacetonitrile (a product of the addition of benzylamine and hydrocyanic acid onto formaldehyde) and cyanic acid (JP 06 100 543 A2) or
b) by reaction of N-benzylglycine (or its derivatives) and urea or cyanic acid (Huaxue Shiji 1993 15(1), 15-16).
The starting material for the abovementioned synthetic route a), viz. N-benzyl-aminoacetonitrile, is prepared by reaction of benzylamine and formaldehyde with the extremely toxic hydrocyanic acid (see also Tetrahedron Letters [23], 27 (1982), 2741-4). The starting material for the synthetic route b), viz. N-benzylglycine, also firstly has to be prepared by reaction of glycine with benzyl chloride or of chloroacetic acid with benzylamine. The reaction of N-benzylaminoacetonitrile or N-benzylglycine as per a) or b) is carried out either by fusion with urea for a long time or by reaction with the toxic cyanic acid. Both methods give 1-benzyl-hydantoin in only low yields: thus, according to Huaxue Shiji 1993, 15(1) 15-16, the reaction of N-benzylglycine (obtained by reaction of benzylarnine with chloroacetic acid) with cyanic acid gives 1-benzylhydantoin in a yield of only 39.5% and the reaction of N-benzylglycine with urea gives 1-benzylhydantoin in a yield of only 45.6%. The subsequent bromination of the 1-benzylhydantoin and treatment with ethanol again proceeds in only a low yield of 42.7%.
Furthermore, Huaxue Shiji 1993 15(1), 15-16 merely states that glyoxylic acid can in principle be used as starting material for a reaction with a substituted urea. However, no information is given regarding the reaction conditions which have to be adhered to to carry out such a reaction successfully.
In addition, it is known from JP 09 227 526 A2 that N-substituted ureas of the formula RN″HCONH
2
, where R″=alkyl or aryl, can be reacted with alkyl glyoxylate alkyl hemiacetals of the formula ROCH(OH)COOR′, where R, R′=alkyl, in a solvent or a solvent mixture. This firstly forms, apart from a large number of other compounds, the corresponding 1-alkyl- or 1-aryl-substituted 5-hydroxy-hydantoin of the formula (B).
In the case of R″=benzyl, the reaction thus forms 1-benzyl-5-hydroxyhydantoin of the formula (C)
in addition to many other compounds. The multicomponent reaction mixture, which contains, inter alia, the 1-alkyl- or 1-aryl-substituted 5-hydroxy-hydantoin, is obtained as a viscous, oily mass and is virtually impossible to purify. Before the further reaction, it has to be carefully dewatered and subsequently reacted with an alcohol and mineral acid by prolonged heating, which again forms, owing to the impure composition of the reaction mixture used, a mixture of a number of compounds, including the desired 1-alkyl- or 1-aryl-5-alkoxy-imidazoline-2,4-dione.
The isolation of the desired 1-alkyl- or 1-aryl-5-alkoxy-imidazoline-2,4-dione is therefore complicated and has to be carried out by column chromatography. This separation has been described only on the gram scale, is hardly feasible in industry and gives the desired product in a yield of only 44% and in unknown purity (JP 09 227 526 A2, Example 1).
In addition, the starting compounds for this synthesis, i.e. the alkyl glyoxylate alkyl hemiacetals, firstly have to be synthesized by independent routes. They are obtained as mixtures of hemiacetals and acetals and likewise have to be purified in a costly manner.
EP-A-0 160 618 describes the reaction of glyoxylic esters or o-alkylglyoxylic esters (glyoxylic ester alkoxides) with N-alkylureas, N-cycloalkylureas, N,N′-dialkylureas or N,N′-dicycloalkylureas in a solvent such as water and/or acetic acid. In addition, it is established that this reaction can also be carried out using glyoxylic acid itself. In Example 2 of EP-A-0 160 618, the reaction of glyoxylic acid with N-methylurea is carried out in an aqueous acetic acid solution. The product obtained is said to be 5-hydroxy-3-methylhydantoin, but no information is given on the yield or selectivity of the reaction. Repeating the in-principle reaction of glyoxylic acid with N-methylurea gave only small amounts of a greasy crystalline product which represents a very complicated mixture of many substances and whose separation by crystallization is not practical. NMR analysis of this crystalline product indicated, alongside many other compounds in small amounts, the two isomeric 1- and 3-methyl-5-hydroxyhydantoins in approximately equal amounts of about 10%. In view of the lack of a yield figure in Example 2 of EP-A-0 160 618, it therefore has to be assumed that only small amounts of 1-methyl-5-hydroxy-hydantoin were isolated there. The process of EP-A-0 160 618 using alkyl- or cycloalkyl-substituted ureas can therefore not be regarded as a suitable possible method of preparing 1-alkyl-5-hydroxy-hydantoins.
Tetrahedron 33 (1977), pp. 1191-1196, discloses the reaction of glyoxylic acid with N-methylurea. However, without use of a catalyst, this reaction in methanol gives 5-methoxy-3-methylhydantoin.
Since the demand for 1-substituted 5-alkoxy-imidazoline-2,4-diones is continually increasing in view of the many possible applications mentioned above, it is an object of the present invention to provide a process by means of which the 1-substituted 5-hydroxy-imidazoline-2,4-diones required as intermediates for the synthesis of the 1-substituted
5-
alkoxy-imidazoline-2,4-diones can be prepared in high yield and high purity using simple-to-handle and nontoxic chemicals. In particular, the process to be provided should make complicated purification of the 1-substituted 5-hydroxy-imidazoline-2,4-diones, e.g. by column chromatography, superfluous.
SUMMARY OF THE INVENTION
These and other features, aspects, and advantages of the present invention will become better understood with reference to the following description and appended claim.
This object is achieved by a process for preparing 1-substituted 5-hydroxy-imidazoline-2,4-diones of the formula (I)
where R represents a substituted or unsubstituted C
6
-C
12
-aryl radical or a substituted or unsubstituted C
7
-C
18
-aralkyl radical, by reacting glyoxylic acid with an N-substituted urea of the formula RNH—CO—NH
2
, where R is as defined above, characterized in that the process is carried out in a 10-80% strength aqueous solution in the presence of an acid c
Broda Witold
Vanmaele Luc Jerome
Bayer Aktiengesellschaft
Eyl Diderico van
Gil Joseph C.
Henderson Richard E. L.
Solola T. A.
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