Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
2002-03-12
2004-01-20
Ford, John M (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
06680384
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to a process for preparing 4,6-diaminopyrimido[5,4-d]pyrimidines of formula I,
wherein R
1
, R
2
, R
3
, and R
4
are defined as specified, from a compound of formula II,
wherein R
1
, R
2
, R
3
, and R
4
are defined as specified and PG
1
denotes a suitable protecting group.
BACKGROUND TO THE INVENTION
4,6-diaminopyrimido[5,4-d]pyrimidines are known for example from WO 97/32880 and are valuable pharmaceutical compositions which have, in particular, an inhibitory effect on signal transduction mediated by tyrosine kinases.
However, the method of preparation described therein is unsuitable for production on an industrial scale as the desired products are described as being obtained from starting materials which are not easily accessible, such as 4-anilino-6-methylsulphinyl-pyrimido[5,4-d]pyrimidines or 4-anilino-6-methylsulphonylpyrimido[5,4-d]pyrimidines which, when reacted, give off foul-smelling and toxic thiols which lead to contamination of the products.
The aim of the present invention is therefore to provide a process which makes it possible to synthesise, work up, purify and isolate 4,6-diaminopyrimido[5,4-d]pyrimidines of formula I on an industrial scale while overcoming the disadvantages mentioned above.
DETAILED DESCRIPTION OF THE INVENTION
Surprisingly, it has been found that 4,6-diaminopyrimido[5,4-d]pyrimidines of formula I
wherein
R
1
denotes a hydrogen atom or a C
1
-C
6
alkyl group,
R
2
denotes an optionally substituted C
6
-C
10
aryl group,
R
3
denotes a hydrogen atom or a C
1
-C
6
alkyl group, and
R
4
denotes a hydrogen atom or an optionally substituted C
1
-C
6
alkyl, C
3
-C
6
alkenyl, C
3
-C
8
cycloalkyl or a 4- to 7-membered, nitrogen-containing heterocyclyl group, or
R
3
and R
4
together with the nitrogen atom linked to them denote an optionally substituted heterocyclyl group,
can be prepared in high yields and in a comparatively small number of steps, if the compound of formula II wherein R
1
, R
2
, R
3
, and R
4
are as herein defined and
PG
1
denotes a suitable protecting group,
(a) after the protecting group has been cleaved,
(b) is treated with a reducing agent, and
(c) is treated with an oxidising agent.
The invention thus relates to a process for preparing the compounds of formula I.
The invention further relates to a process for preparing a compound of formula II, by reacting a compound of formula III,
wherein R
1
, R
2
and PG
1
are as herein defined,
with an amine of formula IV,
R
3
R
4
NH (IV)
wherein R
3
and R
4
are as herein defined,
optionally in the presence of a base.
The invention further relates to a process for preparing a compound of formula III, wherein a compound of formula V,
wherein R
1
and R
2
are as herein defined, is provided with a suitable protecting group (PG
1
).
The invention also relates to a process for preparing the compounds of formula V by reducing a compound of formula VI,
wherein R
1
and R
2
are as herein defined; and a process for preparing a compound of formula VI by reacting 2,4,6,8-tetrachloropyrimido[5,4-d]pyrimidine with an amine of formula VIII,
R
1
R
2
NH (VIII)
wherein R
1
and R
2
are as herein defined.
The invention further relates to the new intermediate products of formulae II, III, V and VI.
The term “alkyl” as used hereinbefore and hereinafter with respect to the groups R
1
, R
3
and/or R
4
denotes a straight-chain or branched alkyl group having up to 6 C-atoms, preferably 1 to 4 C-atoms. Methyl, ethyl, n-propyl, i-propyl, n-butyl and tert-butyl are particularly preferred.
The term “alkenyl” as used hereinbefore and hereinafter with respect to the group R
4
denotes a straight-chain or branched alkenyl group having up to 6 C-atoms, preferably 3 to 5 C-atoms. Allyl, but-2-enyl, but-3-enyl, pent-2-enyl, pent-3-enyl and pent-4-enyl are particularly preferred.
The term “aryl” as used hereinbefore and hereinafter with respect to the group R
2
denotes an aromatic hydrocarbon group with 6 to 10 C-atoms, and aryl preferably denotes phenyl or naphthyl.
The term “suitable protecting group” as used hereinbefore and hereinafter with respect to the group PG
1
denotes a group familiar to those skilled in the art, e.g. a protecting group for amino groups as described in “Protective Groups in Organic Chemistry”, edited by J. F. W. McOmie (Plenum Press), which is easily introduced, is inert to the subsequent reactions and can easily be cleaved again. Preferred protecting groups are the acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl, mesyl, tosyl or 2,4-dimethoxybenzyl group.
A protecting group used is cleaved hydrolytically, for example in an aqueous solvent, e.g. in water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide or by ether splitting, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 100° C., preferably at temperatures between 10 and 50° C.
A benzyl, methoxybenzyl or benzyloxycarbonyl is preferably cleaved by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone or glacial acetic acid optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50° C., but preferably at ambient temperature, and at a hydrogen pressure of 1 to 7 bar, preferably from 3 to 5 bar.
A methoxybenzyl group can also be cleaved in the presence of an oxidising agent such as cerium(IV)ammonium nitrate in a solvent such as methylene chloride, acetonitrile or acetonitrile/water at temperatures between 0 and 50° C., but preferably at ambient temperature. However, a 2,4-dimethoxybenzyl group is preferably cleaved in trifluoroacetic acid in the presence of anisol. A tert-butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as methylene chloride, dioxane or ether.
The term “heterocyclyl group” as used hereinbefore and hereinafter with respect to the group R
3
or the group formed by R
3
and R
4
with the enclosed nitrogen atom denotes a saturated or unsaturated 4- to 7-membered, nitrogen-containing heterocyclyl group which may optionally contain, in addition to carbon atoms and at least one nitrogen atom, other heteroatoms selected from among oxygen and sulphur. The following heterocyclyl groups are preferred:
saturated 5- or 6-membered heterocyclyl groups which
contain one or two nitrogen atoms, particularly pyrrolidine, piperidyl and piperazyl, or
contain one nitrogen atom and an oxygen or sulphur atom, particularly morpholino and thiomorpholino.
If one of the groups R
1
to R
4
is referred to as an “optionally substituted” group, this group may have one or more substituents, preferably 1, 2 or 3, particularly 1 or 2 substituents. These substituents are groups which are inert under the reaction conditions of the process according to the invention and do not provoke any noticeable side reactions. Preferred substituents are selected from among fluorine, chlorine, bromine, carboxy, carboxy-C
1-3
-alkyl, carboxy-C
1-3
-alkoxy, alkoxycarbonyl-C
1-3
-alkoxy, cyano, trifluoromethoxy, trifluoromethyl, C
1-3
-alkyl, hydroxy, C
1-3
-alkoxy, thiol, C
1-3
-alkylthio, phenyl-C
1-3
-alkoxy, amino, amino-C
1-3
-alkyl, C
1-3
-alkylamino C
1-3
-alkylamino-C
1-3
-alkyl, di-(C
1-3
-alkyl)-amino and di-(C
1-3
-alkyl)-amino-C
1-3
-alkyl.
In a preferred embodiment the groups R
1
to R
4
have the following meanings:
R
1
denotes hydrogen or methyl, particularly hydrogen,
R
2
denotes phenyl which may be substituted by one or two halogen atoms, particularly fluorine and/or chlorine, particularly 3-chloro-4-fluorophenyl,
R
3
denot
Belzer Werner
Lock Ralf
Rall Werner
Boehringer Ingelheim Pharma KG
Ford John M
Morris Michael P.
Raymond Robert P.
Stempel Alan R.
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