Method for producing...

Details Method for producing... Method for producing...

2002-10-10

2004-07-13

Bernhardt, Emily (Department: 1624)

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

Organic compounds

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

C544S374000, C544S389000, C544S392000, C544S395000

Reexamination Certificate

active

06762300

ABSTRACT:

The invention relates to a process for the preparation of 5-(1-piperazinyl)benzofuran-2-carboxamide, characterized in that
a) 5-bromosalicylaldehyde is reacted in a one-pot reaction firstly with a compound of the formula I
L—CH
2
—COOR
1
  I
in which
L is Cl, Br, I or a reactively esterified OH group, and
R
1
is alkyl having 1-6 carbon atoms or benzyl,
and subsequently with formamide to give 5-L-benzofuran-2-carboxamide (II), in which L is Cl, Br, I or a reactively esterified OH group,
(II) is then reacted in a transition metal-catalysed amination with R
2
-piperazine, in which R
2
is H or an amino protecting group, to give the compound of the formula III
 in which R
2
is H or an amino protecting group,
and subsequently, if R
2
≠H, R
2
is cleaved off, or
b) a compound of the formula IV
 in which
L is Cl, Br, I or a reactively esterified OH group,
R
3
is H or CH
2
R
6
,
R
4
and R
5
are each, independently of one another, OR
7
, OR
8
, SR
7
or SR
8
,
R
4
and R
5
together are alternatively carbonyl, ═S, ═N—C(R
7
)
2
, ═N—C(R
8
)
2
, ═N—OH, ═N—OR
7
, ═N—N[(R
7
)
2
], ═N—N[(R
8
)
2
] or —O—(CH
2
)
n
—O—,
R
6
is CN, COOH, COOR
7
or CONH
2
,
R
7
is alkyl having 1-6 carbon atoms,
R
8
is phenyl which is unsubstituted or mono- or disubstituted by R
7
, OR
7
, SR
7
or Hal,
n is 2 or 3,
is reacted in a transition metal-catalysed amination with R
2
-piperazine, in which R
2
is H or an amino protecting group,
to give a compound of the formula V
 in which
R
2
is H or an amino protecting group,
R
3
is H or CH
2
R
6
,
R
4
and R
5
are each, independently of one another, OR
7
, OR
8
, SR
7
or SR
8
,
R
4
and R
5
together are alternatively carbonyl, ═S, ═N—C(R
7
)
2
, ═N—C(R
8
)
2
, ═N—OH, ═N—OR
7
, ═N—N[(R
7
)
2
], ═N—N[(R
8
)
2
] or —O—(CH
2
)
n
—O—,
R
6
is CN, COOH, COOR
7
or CONH
2
,
R
7
is alkyl having 1-6 carbon atoms,
R
8
is phenyl which is unsubstituted or mono- or disubstituted by R
7
, OR
7
, SR
7
or Hal,
n is 2 or 3,
which is subsequently reacted in a one-pot reaction firstly with a compound of the formula I
L—CH
2
—COOR
1
  I
in which
L is Cl, Br, I or a reactively esterified OH group, and
R
1
is alkyl having 1-6 carbon atoms or benzyl,
and subsequently with formamide to give a compound of the formula III
 in which R
2
is H or an amino protecting group,
and subsequently, if R
2
≠H, R
2
is cleaved off, or
c) a compound of the formula V
in which
R
2
is an amino protecting group,
R
3
is H or CH
2
R
6
,
R
4
and R
5
are each, independently of one another, OR
7
, OR
8
, SR
7
or SR
8
,
R
4
and R
5
together are alternatively carbonyl, ═S, ═N—C(R
7
)
2
, ═N—C(R
8
)
2
, ═N—OH, ═N—OR
7
, ═N—N[(R
7
)
2
], ═N—N[(R
8
)
2
] or —O—(CH
2
)
n
—O—,
R
6
is CN, COOH, COOR
7
or CONH
2
,
R
7
is alkyl having 1-6 carbon atoms,
R
8
is phenyl which is unsubstituted or mono- or disubstituted by R
7
, OR
7
, SR
7
or Hal,
n is 2 or 3,
is reacted with chloroacetamide to give a compound of the formula III
in which R
2
is an amino protecting group,
and R
2
is subsequently cleaved off,
and/or in that 5-(1-piperazinyl)benzofuran-2-carboxamide is converted into one of its acid-addition salts by treatment with an acid.
The invention also relates to the compounds of the formula V
in which
R
2
is H or an amino protecting group,
R
3
is H or CH
2
R
6
,
R
4
and R
5
are each, independently of one another, OR
7
, OR
8
, SR
7
or SR
8
,
R
4
and R
5
together are alternatively carbonyl, ═S, ═N—C(R
7
)
2
, ═N—C(R
8
)
2
, ═N—OH, ═N—OR
7
, ═N—N[(R
7
)
2
], ═N—N[(R
8
)
2
] or —O—(CH
2
)
n
—O—,
R
6
is CN, COOH, COOR
7
or CONH
2
,
R
7
is alkyl having 1-6 carbon atoms,
R
8
is phenyl which is unsubstituted or mono- or disubstituted by R
7
, OR
7
, SR
7
or Hal,
n is 2 or 3,
and salts and solvates thereof.
5-(1-piperazinyl)benzofuran-2-carboxamide is an important intermediate for pharmaceutical active ingredients. This is described, for example, in DE 19730989, WO 9857953, EP 738722, EP 736525, DE 4414113, DE 4333254 or DE 4101686.
Benzofuran derivatives as precursors are also described, for example, in DE 19514567.
Processes are known for the preparation of heterocyclic aromatic amines or arylamines, for example from EP 0 802 173, in which a transition-metal catalyst is used.
General amination reactions are described in a review article by J. F. Martinez in Angew, Ch. Int. 37, 2046-2062. Other processes for the preparation of tertiary arylamines using a catalyst composed of a trialkylphosphine and palladium are disclosed in JP 10-310561 (Kokai application), Appl. No. 9-119477 or JP 11-80346 (Kokai application), Appl. No. 9-245218.
A process for the preparation of arylamines with transition-metal catalysis has been described by S. L. Buchwald et al. in U.S. Pat. No. 5,576,460. Another process for the preparation of aromatic amines from chlorinated aromatic compounds in the presence of a palladium catalyst is described in EP 0 846 676, by J. F. Hartwig et al. in J. Org. Chem. 1999, pp. 5575-5580, or S. L. Buchwald et al. in J.A.C.S. 1999, 121, 9550-9561.
In Tetrahedron Letters 39 (1998) 617-620, M. Nishiyama describes the synthesis of N-arylpiperazines from aryl halides and piperazine with transition-metal catalysis.
Surprisingly, studies in the course of the synthesis of medicaments which are described, for example, in DE 43 33 254 (EP 0 648 767) have shown that 5-(1-piperazinyl)benzofuran-2-carboxamide can be obtained in at least comparable or higher overall yield compared with the prior art, crucial advantages which may be mentioned here being the fact that the reaction is simple to carry out and product isolation is consequently simple.
Another consequence of this is the low solvent and energy consumption.
If L in the compounds of the formulae I, II or IV is a reactively esterified OH group, this is preferably alkylsulfonyloxy having 1-6 carbon atoms (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy), arylsulfonyloxy having 6-10 carbon atoms (preferably phenyl- or p-tolylsulfonyloxy, furthermore also 2-napthalenesulfonyloxy) or alternatively fluorosulfonyloxy.
R
1
is alkyl or benzyl. Alkyl here has 1, 2, 3, 4, 5 or 6 carbon atoms, preferably 1, 2, 3 or 4 carbon atoms, particularly preferably, for example, methyl or ethyl, furthermore propyl, isopropyl, furthermore also butyl, isobutyl, sec-butyl or tert-butyl.
In the compounds of the formula I, L is preferably Cl, furthermore also Br.
R
2
is H or an amino protecting group. R
2
is particularly preferably an amino protecting group.
The term “amino protecting group” is known in general terms and refers to groups which are suitable for protecting (blocking) an amino group against chemical reactions, but which are easy to remove after the desired chemical reaction has been carried out elsewhere in the molecule. Typical such groups are, in particular, unsubstituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino protecting groups are removed after the desired reaction (or reaction sequence), their type and size are furthermore not crucial; however, preference is given to those having 1-20, in particular 1-8, carbon atoms. The term “acyl group” in connection with the present process and the present compounds should be understood in the broadest sense. It covers acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids and, in particular, alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of acyl groups of this type are alkanoyl, such as acetyl, propionyl, butyryl; aralkanoyl, such as phenylacetyl; aroyl, such as, benzoyl or tolyl; aryloxyalkanoyl, such as phenoxyacetyl; alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC (tert-butoxycarbonyl), 2-iodoethoxycarbonyl; aralkyloxycarbonyl, such as CBZ (carbobenzoxycarbonyl), also ref

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