Process for the preparation of imidazolidine-2, 4-diones

Details Process for the preparation of imidazolidine-2, 4-diones Process for the preparation of imidazolidine-2, 4-diones

1999-09-21

2001-05-22

Higel, Floyd D. (Department: 1613)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06235910

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a process for the preparation of compounds of the general formula (I)
wherein
X denotes oxygen, sulfur or selenium and
R
1
denotes H, (C
1
-C
18
)-alkyl, (C
2
-C
18
)-alkenyl, (C
2
-C
18
)-alkinyl, (C
6
-C
18
)-aryl, (C
7
-C
19
)-aralkyl, (C
3
-C
18
)-heteroaryl, (C
4
-C
19
)-heteroaralkyl, (C
1
-C
8
)-alkyl-(C
6
-C
18
)-aryl, (C
1
-C
8
)-alkyl-(C
3
-C
19
)-heteroalkyl, (C
3
-C
8
)-cycloalkyl, (C
1
-C
8
)-alkyl-(C
3
-C
8
)-cycloalkyl, (C
3
-C
8
)-cycloalkyl-(C
1
-C
8
)-alkyl, where the above-mentioned radicals can be mono- or polysubstituted by heteroatoms, such as Hal, NR
1
R
2
, PO
0-3
R
1
R
2
, OPO
0-3
R
1
R
2
, OR
1
, SR
1
, SOR
1
, SO
2
R
1
,SO
3
R
1
, or groups such as CO
2
H, CO
2
R
1
, CONH
2
, CONHR
1
or one or more CH
2
groups can be substituted by heteroatoms, such as NR
1
, PR
1
, O or S,
R
2
denotes H, (C
1
-C
18
)-alkyl, (C
2
-C
18
)-alkenyl, (C
2
-C
18
)-alkinyl, (C
6
-C
18
)-aryl, (C
7
-C
19
)-aralkyl, (C
3
-C
18
)-heteroaryl, (C
4
-C
19
)-heteroaralkyl, (C
1
~C
8
)-alkyl-(C
6
-C
18
)-aryl, (C
1
-C
8
)-alkyl-(C
3
-C
19
)-heteroalkyl, (C
3
-C
8
)-cycloalkyl, (C
1
-C
8
)-alkyl-(C
3
-C
8
)-cycloalkyl, (C
3
-C
8
)-cycloalkyl-(C
1
-C
8
)-alkyl, where the above-mentioned radicals can be mono- or polysubstituted by heteroatoms, such as Hal, NR
1
R
2
, PO
0-3
R
1
R
2
, OPO
0-3
R
1
R
2
, OR
1
, SR
1
, SOR
1
, SO
3
R
1
or one or more CH
2
groups can be substituted by heteroatoms, such as NR
1
, PR
1
, O or S,
R
3
denotes H, (C
1
-C
18
)-alkyl, (C
2
-C
18
)-alkenyl, (C
2
-C
18
)-alkinyl, (C
6
-C
18
)-aryl, (C
7
-C
19
)-aralkyl, (C
3
-C
18
)-heteroaryl, (C
4
-C
19
)-heteroaralkyl, (C
1
-C
8
)-alkyl-(C
6
-C
18
)-aryl, (C
1
-C
8
)-alkyl-(C
3
-C
19
)-heteroalkyl, (C
3
-C
8
)-cycloalkyl, (C
1
-C
8
)-alkyl-(C
3
-C
8
)-cycloalkyl, (C
3
-C
8
)-cycloalkyl-(C
1
-C
8
)-alkyl, where the above-mentioned radicals can be mono- or polysubstituted by heteroatoms, such as Hal, NR
1
R
2
, PO
0-3
R
1
R
2
, OPO
0-3
R
1
R
2
, OR
1
, SR
1
, SOR
1
, SO
3
R
1
or one or more CH
2
groups can be substituted by heteroatoms, such as NR
1
, PR
1
, O or S. The invention furthermore relates to a use of the compounds of the general formula (I).
BACKGROUND OF THE INVENTION
Compounds of the general formula (I) are important starting substances for the synthesis of racemic and enantiomerically enriched &agr;-amino acids, which in turn are required for the synthesis of bioactive substances or for the nutritional requirements of animals and humans.
Imidazolidine-2,4-diones which are unsubstituted in the 1- and 3-position can be obtained from the reaction of an aldehyde (RCHO), hydrocyanic acid (HCN) and ammonium carbonate via the so-called Bucherer-Bergs reaction. Although this reaction is used industrially, it has the disadvantage that extremely toxic hydrocyanic acid must be employed as a starting material, and that imidazolidine-2,4-diones which are substituted in the 3-position are not directly accessible.
Imidazolidine-2,4-diones which also carry a substituent in the 3-position in addition to the 5-position are therefore advantageously prepared from the corresponding amino acid and an isocyanate. This process has the disadvantage that comparatively expensive amino acids must be employed as educts, and that only a few isocyanates are commercially available on an industrial scale.
1,3,5-Substituted hydantoins can be prepared from the corresponding, very expensive, N-substituted amino acid and an isocyanate (Advances in Heterocyclic Chemistry, vol. 38, 1985, 177-228). This process also has the disadvantages described above. In the case of amino acids which are not naturally occurring (not proteinogenic), the corresponding amino acid must additionally be prepared beforehand in several stages. There is, therefore, to date no practicable one-stage process which allows the preparation of 1,3,5-substituted hydantoins from inexpensive starting compounds.
SUMMARY OF THE INVENTION
The object of the present invention, therefore, is to provide a process for the preparation of compounds of the general formula (I) which does not involve the above-mentioned prior art disadvantages, and which in particular, allows the synthesis of compounds of the general formula (I) in fewer reaction steps, starting from inexpensive educts, which present fewer health risks and produce good yields on an industrial scale.
DETAILED DESCRIPTION OF THE INVENTION
Compounds of the general formula (I)
wherein
X denotes oxygen, sulfur or selenium and
R
1
denotes H, (C
1
-C
18
)-alkyl, (C
2
-C
18
)-alkenyl, (C
2
-C
18
)-alkinyl, (C
6
-C
18
)-aryl (C
7
-C
19
)-aralkyl, (C
3
-C
18
)-heteroaryl, (C
4
-C
19
)-heteroaralkyl, (C
1
-C
8
)-alkyl-(C
6
-C
18
)-aryl, (C
1
-C
8
)-alkyl-(C
3
-C
19
)-heteroalkyl, (C
3
-C
8
)-cycloalkyl, (C
1
-C
8
)-alkyl-(C
3
-C
8
)-cycloalkyl, (C
3
-C
8
)-cycloalkyl-(C
1
-C
8
)-alkyl, where the above-mentioned radicals can be mono- or polysubstituted by heteroatoms, such as Hal, NR
1
R
2
, PO
0-3
R
1
R
2
, OPO
0-3
R
1
R
2
, OR
1
, SR
1
, SOR
1
, SO
2
R
1
, SO
3
R
1
, or groups such as CO
2
H, CO
2
R
1
, CONH
2
, CONHR
1
or one or more CH
2
groups can be substituted by heteroatoms, such as NR
1
, PR
1
, O or S,
R
2
denotes H, (C
1
-C
18
)-alkyl, (C
2
-C
18
)-alkenyl, (C
2
-C
18
)-alkinyl, (C
6
-C
18
)-aryl, (C
7
-C
19
)-aralkyl, (C
3
-C
18
)-heteroaryl, (C
4
-C
19
)-heteroaralkyl, (C
1
-C
8
)-alkyl-(C
6
-C
18
)-aryl, (C
1
-C
8
)-alkyl-(C
3
-C
19
)-heteroalkyl, (C
3
-C
8
)-cycloalkyl, (C
1
~C
8
)-alkyl-(C
3
-C
8
)-cycloalkyl, (C
3
-C
8
)-cycloalkyl-(C
1
-C
8
)-alkyl, where the above-mentioned radicals can be mono- or polysubstituted by heteroatoms, such as Hal, NR
1
R
2
, PO
0-3
R
1
R
2
, OPO
0-3
R
1
R
2
, OR
1
, SR
1
, SOR
1
, SO
2
R
1
, SO
3
R
1
, or groups such as CO
2
H, CO
2
R
1
, CONH
2
, CONHR
1
or one or more CH
2
groups can be substituted by heteroatoms, such as NR
1
, PR
1
, O or S,
R
3
denotes H, (C
1
-C
18
)-alkyl, (C
2
-C
18
)-alkenyl, (C
2
-C
18
)-alkinyl, (C
6
-C
18
)-aryl, (C
7
-C
19
)-aralkyl, (C
3
-C
18
)-heteroaryl, (C
4
-C
19
)-heteroaralkyl, (C
1
-C
8
)-alkyl-(C
6
-C
18
)-aryl, (C
1
-C
8
)-alkyl-(C
3
-C
19
)-heteroalkyl, (C
3
-C
8
)-cycloalkyl, (C
1
~C
8
)-alkyl-(C
3
-C
8
)-cycloalkyl, (C
3
-C
8
)-cycloalkyl-(C
1
-C
8
)-alkyl, where the above-mentioned radicals can be mono- or polysubstituted by heteroatoms, such as Hal, NR
1
R
2
, PO
0-3
R
1
R
2
, OPO
0-3
R
1
R
2
, OR
1
, SR
1
, SOR
1
, SO
2
R
1
, SO
3
R
1
, or groups such as CO
2
H, CO
2
R
1
, CONH
2
, CONHR
1
or one or more CH
2
groups can be substituted by heteroatoms, such as NR
1
, PR
1
, O or S,
are produced by reaction of an aldehyde compound of the general formula (II)
wherein R
1
is defined above, with a urea compound of the general formula (III)
wherein X, R
2
and R
3
are defined above, in the presence of carbon monoxide (CO) and a catalytically active metal compound. The desired derivatives are obtained with good to very good yields, starting from inexpensive educts in a one-stage process which is easy to carry out industrially, and avoids the use of extremely toxic hydrocyanic acid.
Compounds of the general formula (I) wherein X represents oxygen,
R
1
denotes a radical chosen from the group consisting of methyl, ethyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, methylthioethyl, thiomethyl, methoxycarbonylmethyl, methoxycarbonylethyl, phenyl, 2-, 3-, 4-pyridyl, benzyl, 1-, 2-phenylethyl, hydroxymethyl, hydroxyethyl, vinyl, methoxymethyl, methoxyethyl, carboxymethyl, carboxyethyl, acetamidomethyl, acetamidoethyl, chloromethyl, chloroethyl, methylphosphonoethyl, 2-ethylhexyl, tetradecyl, hexadecyl and R
2
and R
3
independently of one another can denote hydrogen, methyl, ethyl, butyl, phenyl, benzyl, 2-ethylhexyl, are preferred.
Any desired aldehyde R
1
CHO, wherein R
1
has the above-mentioned definition, can be used according to the invention as educts. Examples of suitable aldehydes R
1
CHO are formaldehyde, acetaldehyde, propionaldehyde, butyraldehyde, valeraldehyde, 2-ethylhexanal, 2-ethylhexenal, isobutyraldehyde, furfural, crotonaldehyde, acrolein,

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