Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
2000-10-13
2003-07-29
Rao, Deepak (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
active
06600042
ABSTRACT:
Process for the preparation of pyrimido [5,4-g] pteridine derivatives
The present invention relates to an improved process for the preparation of pyrimido[5,4-g]-pteridine derivatives, to novel pyrimido[5,4-g] pteridine salts and to their use.
JACS 77 (1955) 2243-2248 describes the synthesis of yellow, sparingly soluble pyrimido-pteridines. The synthesis of 2,4,5,7-tetraaminopyrimido[5,4-g]pteridine is unsuitable for industrial use, however, owing inter alia to the process steps of oxidation of the 2,4,5,6-tetra-aminopyrimidine salt with air and separation of the undesired red isomer using a large amount of glacial acetic acid.
From U.S. Pat. No. 2,591,889 there is known the synthesis of pyrimido-pyrazines which may possess fused heterocyclic radicals on the pyrazine ring. For the preparation of those pyrimido-pyrazines, a 5-nitroso-6-aminopyrimidine is condensed with a keto compound. It is said to be advantageous to carry out the preparation in the presence of an acid or alkaline catalyst. Although the process of U.S. Pat. No. 2,591,889 permits the desired positioning of the substituents on the pyrazine ring that forms during the reaction, the poor yields of the process and additional process steps for separating off undesired secondary products are disadvantageous.
The use of pyrimidopteridines for colouring high molecular weight organic material is already known from EP-A-934 363.
Accordingly, the object of the present invention was to make available an improved process for the preparation of pyrimido[5,4-g]pteridines which does not have those disadvantages. In particular, reproducible and high yields are to be obtained. Furthermore, preferably no isomeric mixtures are to be formed in the synthesis of 2,4,5,7-tetraaminopyrimido[5,4-g]pteridine. Moreover, compounds are to be provided which, as colouring agents, have good performance properties.
Accordingly, there has been developed an improved process for the preparation of pyrimido[5,4-g]pteridines of formula I
wherein
A
1
, A
2
, A
3
and A
4
are each independently of the others
—NR
1
R
2
, wherein R
1
and R
2
are each independently of the other hydrogen, C
1
-C
8
alkyl, —CO—C
1
-C
8
alkyl, —CO—C
6
-C
14
aryl, —COO—C
1
-C
8
alkyl, —COO—C
6
-C
14
aryl, —CONH—C
1
-C
8
alkyl or —CONH—C
6
-C
14
aryl, or
—OH, —SH, hydrogen, C
1
-C
8
alkyl, C
1
-C
8
alkoxy, or C
6
-C
14
aryl or —O—C
6
-C
14
aryl each unsubstituted or mono- or poly-substituted by halogen, nitro, cyano, —OR
10
, —SR
10
, —NR
10
R
11
, —CONR
10
R
11
, —COOR
10
, —SO
2
R
10
, —SO
2
NR
10
R
11
, —SO
3
R
10
, —NR
11
COR
10
or by —NR
11
COOR
10
, wherein R
10
and R
11
are each independently of the other hydrogen, C
1
-C
8
alkyl, C
5
-C
12
cycloalkyl or C
2
-C
8
alkenyl, by
a) reacting the pyrimidine of formula II
with the pyrimidine of formula III
in the presence of an acid and, if desired, of a solvent, the molar ratio of the acid to the compound of formula II being in the range of from 100:1 to 1:1, and
b) subsequently treating the resulting reaction mixture with a base.
Salts of the compounds I, processes for their preparation, and the use of the compounds prepared according to the invention have also been found.
C
1
-C
8
Alkyl (correspondingly also in —CO—C
1
-C
8
alkyl, —COO—C
1
-C
8
alkyl, —CONH—C
1
-C
8
alkyl) may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2,2-dimethylpropyl, n-hexyl, n-heptyl, n-octyl, 1,1,3,3-tetramethylbutyl or 2-ethylhexyl, preferably C
1
-C
4
alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.
C
6
-C
14
Aryl (correspondingly also in —CO—C
6
-C
14
aryl, —COO—C
6
-C
14
aryl and —CONH—C
6
-C
14
aryl) may be, for example, phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, phenanthryl, 2- or 9-fluorenyl or anthracenyl, preferably phenyl, or 1- or 2-naphthyl.
C
1
-C
8
Alkoxy may be, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, 2,2-dimethylpropoxy, n-hexyloxy, n-heptyloxy, n-octyloxy, 1,1,3,3-tetramethylbutoxy or 2-ethylhexyloxy, preferably C
1
-C
4
alkoxy, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy.
C
5
-C
12
Cycloalkyl is preferably cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl or cyclododecyl, especially C
5
-C
8
cycloalkyl, such as cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
C
2
-C
8
Alkenyl is preferably ethenyl, 1- or 2-propenyl, 1-, 2- or 3-butenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1-hexenyl, 1-heptenyl, 1-octenyl or 2-ethyl-1-hexenyl, especially C
2
-C
4
alkenyl, such as ethenyl, 1- or 2-propenyl, 1-, 2- or 3-butenyl, 2-methyl-1-propenyl or 2-methyl-2-propenyl.
The order in which the compounds of formulae II and III and the acid are added is generally not critical. However, it has proved advantageous first to introduce the compounds of formulae II and III and then to add the acid.
The molar ratio of pyrimidine II to pyrimidine III is generally chosen in the range of from 2:1 to 1:2, preferably from 1.5:1 to 1:1.
The molar amount of base is generally so chosen that the pH value of the reaction mixture obtained in process step a) is neutral. For example, the molar ratio of the base to the compound of formula II is generally chosen in the range of from 1:1 to 20:1, preferably from 1:1 to 10:1.
If the reaction is carried out in a solvent, the molar ratio of the solvent to the compound II is generally chosen in the range of from 500:1 to 1:2, preferably from 100:1 to 1:1.
The reaction temperature in process step a) is dependent inter alia on the solvent that is used, if desired, and is generally in the range of from 50 to 200° C., preferably from 90 to 140° C., especially in the region of the boiling temperature of the solvent used.
The reaction temperature in process step b) is likewise usually dependent on the solvent that is present, if desired, and is generally in the range of from 70 to 130° C., preferably from 80 to 100° C.
The chosen reaction pressure in process steps a) and b) is preferably atmospheric pressure, but the reaction may alternatively be carried out at higher or lower pressures, for example in the range of from 50 kPa to 5 MPa.
The reaction time of both process steps a) and b) is usually dependent on the chosen reaction temperature and the reactivity of the starting materials. In general, a time in the range of from 1 to 50 hours, preferably from 3 to 24 hours, is chosen.
The base is usually added to the reaction mixture obtained in step a). However, it is also possible to introduce the base first and add the reaction mixture obtained in step a) thereto. The addition of the base may take place continuously or discontinuously in equal or unequal portions.
In a further embodiment of the process according to the invention, the addition of the base may be carried out with pH monitoring using the apparatuses for potentiometric pH determination conventionally employed therefor.
There may be used as solvents organic solvents or water, as well as mixtures of organic solvents and mixtures of organic solvents with water. Suitable organic solvents are, for example, polar aprotic or polar protic solvents.
Polar aprotic solvents are, for example, N,N′-dimethylformamide, N,N′-dimethylacetamide, N-methylpyrrolidone and diethylene glycol dimethyl ether.
Polar protic solvents are, for example, glycols and their ether derivatives, wherein at least one hydroxy group of the glycol is not etherified, such as mono-, di-, tri- or tetra-ethylene glycol, propylene glycol, their methyl, ethyl and butyl ethers, such as ethylene glycol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol monomethyl ether or diethylene glycol monoethyl ether, and alcohols, such as methanol, ethanol, propanol, sec-propanol or butanol.
Preference is given to water and organic polar, protic solvents.
Eichenberger Thomas
Hügin Max
Müller Karl-Heinz
Crichton David R.
Rao Deepak
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