Method of producing dihydroxypyrimidine derivatives

Details Method of producing dihydroxypyrimidine derivatives Method of producing dihydroxypyrimidine derivatives

1998-02-25

2001-06-19

Marx, Irene (Department: 1651)

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Preparing heterocyclic carbon compound having only o, n, s,...

C435S129000, C435S227000, C435S191000, C435S252100, C435S135000, C435S136000, C534S767000, C558S303000

Reexamination Certificate

active

06248571

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to a novel process for the preparation of dihydroxypyrimidine derivatives of the general formula
in which R
1
and R
2
are identical or different and are a hydrogen atom, aryl group or a C
1
-C
4
-alkyl group, starting from a compound of the general formula
in which R
2
has the meaning mentioned and R
3
is —CN or COOR
4
, in which R
4
is a C
4
-C
4
-alkyl group.
2. Background Art
Dihydroxypyrimidine is an important intermediate for the preparation of insecticides such as, for example, for the preparation of 4,6-pyrimidinediyl-bis(thiono)(thiol)phosphoric(phosphonic) acid esters (DE 25 23 324).
To date, several processes for the preparation of dihydroxypyrimidine or its derivatives are known.
For example, the preparation of dihydropyrimidine starting from malonamide (German Patent Specification 12 00 308) is known. In this preparation, malonamide is cyclized with formamide in the presence of sodium methanolate to give the dihydroxypyrimidine.
This process has the disadvantage that the starting material malonamide is relatively costly.
D. J. Brown (J. Chem. Soc., 1956, pp. 2312-2314) also describes a process for the preparation of dihydroxypyrimidine starting from malonamide. In this process, malonamide is cyclized in the presence of sodium ethoxide and ethyl formate to give the dihydroxypyrimidine. This process on the one hand has the disadvantage that dihydroxypyrimidine is only obtained in moderate yield. On the other hand, as already described above, the starting material malonamide is relatively costly.
JP 4260 comprises a process for the preparation of dihydroxypyrimidine by reaction of malonate with formamide in the presence of an alkali metal alkoxide. A disadvantage of this process is that the formamide has to be used in a large excess.
U.S. Pat. No. 17 66 748 describes a process for the preparation of 2-aryl-4,6-dihydroxy-pyrimidines starting from diethyl malonate. In this process, diethyl malonate is cyclized in the presence of an amidine of an arylcarboxylic acid to give the corresponding product. This process has the disadvantage that the corresponding amidines are very costly.
The object of the present invention was to make available a more economical and ecologically more favourable process for the preparation of dihydroxypyrimidine derivatives, in which the dihydroxypyrimidine can be isolated in good yield and purity.
This object was achieved by the novel process according to the invention.
In the first process stage, as substrate, a compound of the general formula
in which R
2
and R
3
have the meaning mentioned, is converted by means of microorganisms of the genus Rhodococcus into a malonic acid derivative of the general formula
in which R
2
has the meaning mentioned and R
5
is a C
1
-C
4
-alkoxy group or NH
2
.
The compounds of the general formula II such as methyl or ethyl cyanoacetate are commercially available compounds.
Expediently, the first stage is carried out using microorganisms of the species
Rhodococcus rhodochrous,
Rhodococcus sp. 5-6 or
Rhodococcus equi,
preferably using microorganisms of the species Rhodococcus sp. 5-6 (FERM BP-687),
Rhodococcus rhodochrous
J1 (FERM BP-1478) or using microorganisms of the species
Rhodococcus equi
TG328 (FERM BP-3791 or DSM 6710). In particular, the reaction is carried out by means of microorganisms of the species
Rhodococcus rhodochrous
(FERM BP-1478). The microorganisms of the species Rhodococcus sp. 5-6,
Rhodococcus rhodochrous
J1 and
Rhodococcus equi
TG328 are microorganisms described in the literature.
Rhodococcus rhodochrous
J1 (FERM BP-1478) is described in detail in EP-B 307 928, Rhodococcus sp. 5-6 (FERM BP-687) in EP-A 0 188 316 and
Rhodococcus equi
TG328 (FERM BP-3791) in U.S. Pat. No. 5,258,305.
As is described in U.S. Pat. No. 5,334,519, Strain J-1 of species
Rhodococcus rhodochrous
was sampled from the soil in Sakyo-ku of Kyoto, Japan, and deposited as an international deposit (under the Budapest Treaty on the International Recognition of the Deposit of Microorganisms for the Purposes of Patent Procedure) in the Fermentation Research Institute, Japan, Agency of Industrial Sciences and Technology with the accession number of Bikoken-joki No. 1478 (FERM BP-1478). According to the subject Receipt in the Case of an Original Deposit, this deposit occurred on Sep. 18, 1987.
Also suitable for the process are the functionally equivalent variants and mutants of these microorganisms. “Functionally equivalent variants and mutants” are understood as meaning microorganisms which essentially have the same properties and functions as the original microorganisms. Variants and mutants of this type can be randomly formed, for example, by means of UV irradiation.
Customarily, the microorganisms are cultured (grown) according to EP-B 307 928 before the actual biotransformation and the active enzymes are induced. Preferably, the biotransformation is carried out, in a manner customary to those skilled in the art, using immobilized microorganism cells.
Expediently, the biotransformation is carried out in a pH range from 3 to 7, preferably in a pH range from 4 to 6.
The biotransformation can be carried out at a temperature from 0 to 30° C., preferably from 3 to 20° C.
As substrates, compounds of the general formula II are used in which R
2
is a hydrogen atom, aryl group or a C
1
-C
4
-alkyl group and R
3
is —CN or COOR
4
, in which R
4
is a C
1
-C
4
-alkyl group. As a C
1
-C
4
-alkyl group, methyl-, ethyl-, propyl-, i-propyl-, butyl-, i-butyl- or t-butyl- can be used. As aryl-, for example, phenyl-, substituted or unsubstituted, or naphthyl- can be used. Preferably, R
2
is a hydrogen atom and R
3
is methyl-, ethyl-, i-propyl- or —CN.
After a customary reaction time of 1 to 100 h, the amides formed can be isolated in a simple manner, e.g. by removal of water.
In the second process stage, the malonic acid derivative of the general formula
is cyclized with a carboxamide of the general formula
in the presence of a base to give the final product according to formula I.
The radical R
5
is a C
1
-C
4
-alkoxy group such as methoxy-, ethoxy-, propoxy-, butoxy-, i-butoxy-, t-butoxy- or —NH
2
. Preferably, R
5
is methoxy- or ethoxy-. The radical R
2
has the definition already described.
The radical R
1
is either C
1
-C
4
-alkyl- such as methyl-, ethyl-, propyl-, i-propyl-, butyl-, t-butyl-, i-butyl- or a hydrogen atom. Preferably, R
1
is a hydrogen atom.
Expediently, the carboxamide is used in a ratio from 2 to 8 mol per mole of malonic acid derivative, preferably in a ratio of 2 to 3 mol.
As a base, expediently an alkali metal alcoholate such as sodium or potassium methanolate, ethanolate, propanolate, butanolate, i-butanolate, t-butanolate, amylate or i-amylate is used. Preferably, sodium methanolate is used.
The concentration of the base can vary in a range from 2 to 6 mol per mole of malonic acid derivative, preferably in a range from 3 to 4 mol.
As solvents for the second stage, polar solvents such as methanol, ethanol, propanol or butanol can be used, preferably methanol is used.
Expediently, the second stage is carried out at a temperature from 30° C. up to the reflux temperature of the corresponding solvent, preferably at reflux temperature of the corresponding solvent.
After a further reaction time of 1 to 6 h, the dihydroxypyrimidine derivative of the formula I can be isolated by customary working-up methods.


REFERENCES:
patent: 1092144 (1968-01-01), None
patent: 6256278 (1994-09-01), None
Yokoyama et a. “Asymmetric hydrolysis of a disubstituted malononitrile by the aid of a microorganism,” Tetrahedron Asymm. (1993) 4(6): 1081-84.*
Ingvorsen et al. “Microbial hydrolysis of organic nitriles and amides,” CIBA Foundation Symposium (1988) 140:16-31.

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