Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
2002-10-09
2004-04-20
Lambkin, Deborah C (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
C548S483000, C549S055000, C549S057000, C549S467000
Reexamination Certificate
active
06723848
ABSTRACT:
The invention relates to a process for the preparation of benzo-fused heterocycles of general formula I:
in which
X is S, O or NH,
R
1
is CN, NO
2
, Ac, COAr, COOAr, COOH, COOA or CONR
4
R
5
,
R
2
and R
3
independently of one another are each H, A, NO
2
, CN, OH, OA or Ac,
R
4
and R
5
independently of one another are each H, A, Ar or Ac, or
R
4
and R
5
together are —(CH
2
)—(CH
2
)
n
—(CH
2
)—,
A is alkyl having 1-6 C atoms,
Ac is acyl having 1-6 C atoms,
Ar is unsubstituted phenyl or phenyl substituted by A, NO
2
, CN, OH or OA, and
n is 2, 3 or 4,
by reacting tetrahydrobenzo-fused heterocycles of formula II:
in which
X is S, O or NH,
R
1
is CN, NO
2
, Ac, COAr, COOAr, COOH, COOA or CONR
4
R
5
,
R
2
and R
3
independently of one another are each H, A, NO
2
, CN, OH, OA or Ac,
R
4
and R
5
independently of one another are each H, A, Ar or Ac, or
R
4
and R
5
together are —(CH
2
)—(CH
2
)
n
—(CH
2
)—,
A is alkyl having 1-6 C atoms,
Ac is acyl having 1-6 C atoms,
Ar is unsubstituted phenyl or phenyl substituted by A, NO
2
, CN, OH or OA, and
n is 2, 3 or 4,
with a catalytic amount of a noble metal catalyst in the presence of a hydrogen acceptor and then deacylating the acylated amino group by the addition of an amine.
Benzo-fused heterocycles of formula I are important intermediates in industrial organic synthesis, e.g. in the manufacture of fine chemicals, dyestuffs and plant protection agents. They are also important intermediates in the manufacture of drugs. Benzo-fused heterocycles of formula I in which X is S are particularly important in the manufacture of PDE-V inhibitors, which are known from WO 99/55708 and WO 00/78767. In particular, ethyl 2-aminobenzo[b]thiophene-3-carboxylate is an intermediate in the synthesis of 4-[4-(3-chloro-4-methoxybenzylamino)benzo[4,5]thieno[2,3-d]pyrimidin-2-yl]cyclohexanecarboxylic acid, which is known from WO 99/55708, or 4-[4-(3-chloro-4-hydroxybenzylamino)benzo[4,5]thieno[2,3-d]pyrimidin-2-yl]cyclohexanecarboxylic acid, which is known from WO 00/78767.
According to the classical synthesis, tetrahydrobenzo-fused compounds are aromatized by reaction with elemental sulfur at high temperatures (literature: Gewald et al., Chem. Ber. 1968, 101, 1933). The disadvantages of this process are the high energy costs due to high reaction temperatures, the release of hydrogen sulfide, which is an odour nuisance, and the problems which arise in the purification, because elemental sulfur dissolves only in CS
2
, which is very highly flammable.
One particular example from the state of the art is the reaction of the compound 2-acetylamino-3-methoxy-carbonyl-4,5-tetramethylenethiophene with 2 equivalents of sulfur and dimethyl phthalate at temperatures of between 200 and 220° C. according to G. Hallas et al., Dyes Pigm. 1997, 35, 219-237. 2-Acetylamino-3-methoxy-carbonylbenzo[b]thiophene is isolated and then, in a second step, deacetylated in ethanol by reaction with aqueous potassium hydroxide solution.
Another known possibility for aromatizing a tetrahydrobenzo-fused compound is to react it with an equimolar amount of a hydrogenation catalyst. One particular example, namely the dehydrogenation of methyl 2-acetylaminotetrahydrobenzothiophene-3-carboxylate with an approximately equimolar amount of palladium on carbon (10% Pd/C) in chloroform as solvent, is described in Eiden et al., Arch. Pharm. 1984, 317, 675-680.
For ecological reasons, reactions with elemental sulfur are impracticable on the industrial scale.
In the second variant, the amount of hydrogenation catalyst used should be kept as small as possible for economic reasons. Also, the benzo-fused heterocycles formed in the dehydrogenation are often only sparingly soluble in the solvents used and precipitate out when the heterogeneous reaction mixture cools. This makes separation of the noble metal catalyst more difficult and considerable amounts of solvent are required to extract the product from the noble metal catalyst.
The object of the invention was therefore to develop a process for the preparation of benzo-fused heterocycles of formula I which has advantages over the known processes of the state of the art.
Surprisingly, it was found that tetrahydrobenzo-fused compounds of formula II can be aromatized with a catalytic amount of a hydrogenation catalyst in the presence of a hydrogen acceptor. Immediate deacylation of the amino group in the 2-position of the heterocycle by the addition of an amine provides the benzo-fused compounds of formula I as readily soluble products, enabling the noble metal catalyst to be separated off by simple filtration. The process according to the invention is a one-pot process, i.e. the aromatization and deacylation take place in succession without isolation of the intermediate, which in this case is the benzo-fused heterocycle with its amino group acylated.
The meanings of all the radicals which occur several times, e.g. A or Ac, are independent of one another.
The radical A is alkyl and has 1 to 6, preferably 1, 2, 3 or 4 and particularly preferably 1 or 2 C atoms. Alkyl is therefore especially e.g. methyl, also ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl, or also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl or 1,1,2- or 1,2,2-trimethylpropyl. A is particularly preferably methyl or ethyl.
Ac is acyl and preferably has 1-6 C atoms. Ac is e.g. formyl, acetyl, propionyl, butyryl, pentanoyl or hexanoyl, or also trifluoroacetyl. Ac is particularly preferably acetyl.
Ar is unsubstituted phenyl or phenyl substituted by A, NO
2
, CN, OH or OA.
Ar is therefore preferably phenyl, o-, m- or p-methylphenyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-nitrophenyl or o-, m- or p-cyanophenyl. Ar is particularly preferably unsubstituted phenyl.
COAr is aroyl, Ar being as defined above. COAr is particularly preferably benzoyl.
COOAr is aryloxycarbonyl, Ar being as defined above. COOAr is particularly preferably phenoxycarbonyl.
X is S, O or NH, S being particularly preferred.
R
1
is CN, NO
2
, Ac, COAr, COOAr, COOH, COOA or CONR
4
R
5
, A, Ac and Ar being as defined above and R
4
and R
5
being as defined below. R
1
is particularly preferably CN or COOA and very particularly preferably COOA.
R
2
and R
3
independently of one another are each H, A, NO
2
, CN, OH, OA or Ac, A and Ac being as defined above. R
2
and R
3
are particularly preferably H.
R
4
and R
5
independently of one another are each H, A, Ar or Ac, A, Ar and Ac being as defined above. R
4
and R
5
are particularly preferably H.
R
4
and R
5
together are also —(CH
2
)—(CH
2
)
n
—(CH
2
)—, it being possible for n to be 2, 3 or 4. R
4
and R
5
together are particularly preferably —(CH
2
)—(CH
2
)
2
—(CH
2
)— or —(CH
2
)—(CH
2
)
3
—(CH
2
)— and very particularly preferably —(CH
2
)—(CH
2
)
3
—(CH
2
)—.
The hydrogenation catalysts (or, synonymously, noble metal catalysts) used can be suitably supported noble metals such as palladium, platinum or rhodium, suitable supports being carbon, activated carbon, aluminium oxide, barium carbonate, barium sulfate, calcium carbonate or strontium carbonate. The proportion of noble metal in the noble metal catalyst is between 1 and 20%, preferably between 5 and 10% and particularly preferably 5%.
Palladium on activated carbon, carbon, aluminium oxide, barium carbonate, barium sulfate, calcium carbonate or strontium carbonate, platinum on activated carbon, carbon or aluminium oxide, or rhodium on carbon or aluminium oxide, can be used in particular for the process according to the invention. It is particularly preferred to use palladium on activated carbon (5% Pd).
Another possibility is to use noble metal salts which can b
Benz Achim
Koppe Thomas
Wartenberg Frank-Hardi
Wetzel Walter
Wydra Markus
Lambkin Deborah C
Merck Patent Gesellschaft mit Beschränkter Haftung
Millen White Zelano & Branigan P.C.
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