Process for the production of quinazolines

Details Process for the production of quinazolines Process for the production of quinazolines

2002-05-13

2004-05-11

Rao, Deepak (Department: 1624)

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

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C544S284000

Reexamination Certificate

active

06734303

ABSTRACT:

The present invention relates to a novel process for producing quinazoline compounds that are useful in therapy. More specifically, the compounds are useful in the treatment of benign prostatic hyperplasia.
International Patent Application WO 98/30560 discloses a number of substituted quinoline and quinazoline compounds of formula (I), and their pharmaceutically acceptable salts, which are indicated in the treatment of benign prostatic hyperplasia:
wherein
R
1
represents C
1-4
alkoxy optionally substituted by one or more fluorine atoms;
R
2
represents H or C
1-6
alkoxy optionally substituted by one or more fluorine atoms;
R
3
represents a 5- or 6-membered heterocyclic ring containing at least one heteroatom selected from N, O and S, the ring being optionally substituted by one or more groups selected from halogen, C
1-4
alkoxy, C
1-4
alkyl and CF
3
;
R
4
represents a 4-, 5-, 6-, or 7-membered heterocyclic ring containing at least one heteroatom selected from N, O and S, the ring being optionally fused to a benzene ring or a 5- or 6-membered heterocyclic ring containing at least one heteroatom selected from N, O and S, the ring system as a whole being optionally substituted by one or more groups independently selected from OH, C
1-4
alkyl, C
1-4
alkoxy, halogen, CONR
8
R
9
, SO
2
NR
8
R
9
, (CH
2
)
b
NR
8
R
9
and NHSO
2
(C
1-4
alkyl), and when S is a member of the ring system, it may be substituted by one or two oxygen atoms;
R
8
and R
9
independently represent H or C
1-4
alkyl, or together with the N atom to which they are attached they may represent a 5- or 6-membered heterocyclic ring containing at least one heteroatom selected from N, O and S;
b represents 0, 1, 2 or 3;
X represents CH or N; and
L is absent,
or represents a cyclic group of formula Ia,
in which N is attached to the 2-position of the quinoline or quinazoline ring;
A is absent or represents CO or SO
2
;
Z represents CH or N;
m represents 1 or 2, and in addition, when Z represents CH, it may represent 0; and
n represents 1, 2 or 3, provided that the sum of m and n is 2, 3, 4 or 5;
or represents a chain of formula Ib,
in which N is attached to the 2-position of the quinoline or quinazoline ring;
A′ and Z′ have the same significance as A and Z above, respectively;
R
6
and R
7
independently represent H or C
1-4
alkyl; and
p represents 1, 2 or 3, and in addition, when Z′ represents CH, it may represent 0.
The compounds of formula (I) in which X=N and L is absent are of particular interest. Of these compounds, 4-amino-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-6,7-dimethoxy-5-(2-pyridyl)quinazoline is of special interest.
According to WO 98/30560, the compounds of formula (I) can be produced by a number of processes. However, none of these processes involves the condensation of the two main parts of the molecule in a convergent synthesis and each process suffers disadvantages. For example, 4-amino-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-6,7-dimethoxy-5-(2-pyridyl)quinazoline (the compound of Example 19 in WO 98/30560) is prepared according to the following scheme:
The routes described in WO 98/30560 suffer the disadvantage that they involve the use of tributyl stannyl pyridine in combination with copper iodide and tetrakis (triphenylphosphine) palladium. One problem of this route is that the tributyl stannyl pyridine is expensive to purchase. The compound is toxic and there are issues of worker safety and concerning the environment. After use, spent reactants are difficult and expensive to dispose of because of the adverse effects organotin compounds have on their surroundings. A further problem with the prior art process is its lack of convergency. A number of synthetic steps are required to produce the quinazoline compounds in the disclosed processes, with each synthetic step leading both to a reduction in yield and increasing the possibility of competing side reactions. Thus the conventional reaction requires effort to purify the product and may not give an optimal yield.
A further problem with the prior art process of WO 98/30560 is that large pebble-like aggregates are formed in the reactor during the reaction. The identity of these aggregates is not clear but they are believed to be formed of inorganic material derived from the various inorganic additives used during the reaction such as lithium chloride and copper iodide. In this process, there is the risk that the pebble-like aggregates could crack the reactor causing leakage of the reaction medium and the hazard of fire or poisoning. At the very least there is the problem that the reaction leads to scratching of the interior of the reaction vessel thus causing premature wearing of the vessel, poor heat dissipation in the mixture or blocking.
It is an aim of the present invention to provide a synthetically efficient process for the production of quinazoline derivatives which avoids the problems of the prior art process. It is also an aim to provide a process in which the convergency (ie the bringing together of synthetic fragments) is maximised. It is thus an aim to provide a route to the compounds of formula (I), which offers an improved yield relative to the existing routes. It is a further aim of the process of the present invention to avoid the use of organotin compounds on account of their hazardous nature. It is a further aim of the present invention to provide a process, which minimizes the number of synthetic steps required and which avoids the problem of competing reactions and/or the disposal of hazardous materials.
SUMMARY OF THE INVENTION
Accordingly, the present inventors have now found an improved route to the preferred quinazoline derivatives of formula (I) above which overcomes many of the disadvantages of the prior art.
According to the present invention, there is provided a process for the production of a compound of formula (A) or a pharmaceutically acceptable salt or solvate thereof:
wherein:
R
1
represents C
1-4
alkoxy optionally substituted by one or more fluorine atoms;
R
2
represents H or C
1-6
alkoxy optionally substituted by one or more fluorine atoms;
R
3
represents a 5- or 6-membered heterocyclic ring containing at least one heteroatom selected from N, O and S, the ring being optionally substituted by one or more groups selected from halogen, C
1-4
alkoxy, C
1-4
alkyl and CF
3
;
R
4
is a 4-, 5-, 6-, or 7-membered heterocyclic ring containing at least one heteroatom selected from N, O and S, the ring being optionally fused to a benzene ring or a 5- or 6-membered heterocyclic ring containing at least one heteroatom selected from N, O and S, the ring system as a whole being optionally substituted by one or more groups independently selected from OH, C
1-4
alkyl, C
1-4
alkoxy, halogen, CONR
8
R
9
, SO
2
NR
8
R
9
, (CH
2
)
b
NR
8
R
9
and NHSO
2
(C
1-4
alkyl), and when S is a member of the ring system, it may be substituted by 1 or 2 oxygen atoms;
the process comprising condensing a compound of formula (B)
wherein
R
1
to R
3
are as defined above;
with a compound of formula (C):
wherein
R
5
and R
6
taken together with the N atom to which they are attached represent a 4-, 5-, 6-, or 7-membered N-containing heterocyclic ring containing at least one heteroatom selected from N, O and S, the ring being optionally fused to a benzene ring or a 5- or 6-membered heterocyclic ring containing at least one heteroatom selected from N, O and S, the ring system as a whole being optionally substituted by one or more groups independently selected from OH, C
1-4
alkyl, C
1-4
alkoxy, halogen, CONR
8
R
9
, SO
2
NR
8
R
9
, (CH
2
)
b
NR
8
R
9
and NHSO
2
(C
1-4
alkyl), and when S is a member of the ring system, it may be substituted by 1 or 2 oxygen atoms;
R
8
and R
9
independently represent H or C
1-4
alkyl, or together with the N atom to which they are attached they may represent a 5- or 6-membered heterocyclic ring containing at least one heteroatom selected from N, O and S; and
b represents 0, 1, 2 or 3;
and where necessary or desired, converting the

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