Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
1999-03-30
2001-01-16
Rotman, Alan L. (Department: 1612)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
C544S180000, C544S406000, C546S291000, C546S303000, C546S316000
Reexamination Certificate
active
06175011
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to a process for the preparation of arylamides of heteroaromatic carboxylic acids by the reaction of heteroaromatic halogen compounds with carbon monoxide and aromatic amines in the presence of a catalyst and a base. It further relates to a novel intermediate for the process according to the invention.
The amides which can be prepared according to the invention have the general formula:
in which:
A
1
is nitrogen or CR
1
,
A
2
is nitrogen or CR
2
,
A
3
is nitrogen or CR
3
,
A
4
is nitrogen or CR
4
and
A
5
is nitrogen or CR
5
,
with the proviso that at least one of the ring members A
1
to A
5
is nitrogen and that two nitrogen atoms are not bonded directly to one another;
R
1
to R
5
, if present, independently of one another are hydrogen, C
1-4
-alkyl or aryl, also one of the substituents R
1
to R
5
can be a group of the formula —OR, in which R is an optionally substituted aromatic or heteroaromatic radical;
R
6
is hydrogen or C
1-4
-alkyl; and
R
7
is an optionally substituted aromatic or heteroaromatic radical.
These amides include especially the arylamides of pyridine-, pyrimidine-, pyrazine- and 1,3,5-triazine-carboxylic acids.
BACKGROUND ART
Numerous compounds of the structure of Formula I, especially those in which one of the substituents R
1
to R
5
is an aryloxy group (—OR) adjacent to a ring nitrogen atom, are important herbicides (International Published Patent Application No. WO 94/27974, European Published Patent Application No. 0,053,011, and European Published Patent Application No. 0,447,004).
These known compounds are conventionally synthesized from the corresponding carboxylic acids or carboxylic derivatives (acid chlorides, esters, and nitrites), although these are often difficult to obtain and consequently expensive.
BROAD DESCRIPTION OF THE INVENTION
The main object of the invention is to provide an alternative process which is based on more readily obtainable educts. Other objects and advantages of the invention are set out herein or are obvious herefrom to one skilled in the art.
The advantages and objects of the invention are achieved by the process and intermediates of the invention.
It has been found that halogen compounds of the general formula:
in which A
1
to A
5
are as defined above and X is chlorine, bromine or iodine, react directly with carbon monoxide and a primary or secondary amine of the general formula:
R
6
—NH—R
7
III
in which R
6
and R
7
are as defined above, in the presence of a base, to give good to almost quantitative yields of the desired products (I) if a complex of palladium with a diphosphine of the general formula:
is present as a catalyst. In formula IV:
R
8
is hydrogen or C
1-4
-alkyl,
R
9
to R
12
independently of one another are secondary or tertiary C
3-6
-alkyl,
C
5-7
-cycloalkyl or optionally substituted phenyl,
Y is CH
o
, NH
p
or oxygen,
n is 0 or 1,
o is 1 or 2,
p is 0 or 1 and
Q is a bridging organic radical which, together with the two adjacent carbon atoms and, if present (n=1), with Y forms an optionally substituted five-membered or six-membered saturated or aromatic carbocyclic or heterocyclic ring which, as an aromatic ring, can optionally be complexed with a transition metal.
Herein, C
1-4
-alkyl are to be understood as meaning any linear or branched primary, secondary or tertiary alkyl groups having up to 4 carbon atoms, such as, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tertiary butyl.
Herein, aromatic or heteroaromatic radicals are to be understood as meaning especially monocyclic or polycyclic systems, such as, phenyl, naphthyl, biphenylyl, anthracenyl, furyl, pyrrolyl, pyrazolyl, thiophenyl, pyridyl, indolyl or quinolinyl. These radicals can carry one or more identical or different substituents, for example, halogens such as chloro, bromo or fluoro, lower alkyl groups such as methyl, halogenated alkyl groups such as trifluoromethyl, lower alkoxy groups such as methoxy, or lower alkylthio (alkanesulfanyl) or alkanesulfonyl groups such as methylthio or ethanesulfonyl.
Aromatic rings complexed with transition metals are to be understood as meaning especially &eegr;
5
-cyclopentadienyl rings and &eegr;
6
-benzene rings in sandwich and half-sandwich complexes such as metallocenes or related compounds, for example, in ferrocene or benzenechromium tricarbonyl.
The halogen compounds (II) used as starting materials are known compounds or can be prepared analogously to known compounds. Numerous compounds of this type have been published, for example, in U.S. Pat. No. 4,254,125 and European Published Patent Application No. 0,001,187.
The process according to the invention is preferentially suitable for the preparation of amides (I) in which A
2
is nitrogen and forms a pyridine ring with the remaining ring members. Amides (I) in which R
1
is a group of the formula —OR, R being as defined above, are particularly preferred.
Other preferred amides (I) are:
those in which A
1
is nitrogen and forms a pyridine ring with the remaining ring members,
those in which A
1
and A
5
are nitrogen and form a pyrimidine ring with the remaining ring members,
those in which A
1
and A
4
are nitrogen and form a pyrazine ring with the remaining ring members, and
those in which A
1
, A
3
and A
5
are nitrogen and form a 1,3,5-triazine ring with the remaining ring members.
In the last four classes, those amides in which R
2
is a group of the formula —OR, R being as defined above, are in turn particularly preferred.
Of the amides (I) in which one of the substituents R
1
to R
5
is a group of the formula —OR, those in which R is an optionally substituted phenyl group are preferred. This applies especially to the above-mentioned amides containing an pyridine, pyrimidine, pyrazine or 1,3,5-triazine ring in which R
1
or R
2
is a group of the formula —OR.
Other preferred amides are those in which R
6
is hydrogen and R
7
is an optionally substituted phenyl group.
Preferred halogen compounds (II) are the chlorine compounds (X=Cl).
The diphosphines (IV) used are preferably those in which n=0 and Q, together with the two adjacent carbon atoms, forms a five-membered ring which is part of a ferrocene system. These compounds can be represented by the general formula:
in which R
8
to R
12
are as defined above, particularly preferred diphosphines being those in which R
8
is hydrogen or methyl. These compounds are chiral and have been used (especially when R
8
≠H) as pure stereoisomers, for example, for asymmetric hydrogenations (see, e.g., European Published Patent Application No. 0,564,406, and European Published Patent Application No. 0,612,758). As no new elements of chirality are formed in the process according to the invention, these diphosphines can also be used here as racemates or other stereoisomeric mixtures. Very particularly preferred diphosphines (IVa) are those in which R
9
=R
10
and R
11
=R
12
and these substituents are selected from the group comprising isopropyl, tert-butyl, cyclohexyl and optionally substituted phenyl.
Other preferred diphosphines (IV) are those in which n=0 and Q, together with the two adjacent carbon atoms, forms a benzene, pyridine, pyrrole or furan ring.
Tricarbonyl-&eegr;
6
-{1-(diphenylphosphino)-2-[1-(diphenylphosphino)ethyl]-benzene}chromium(O) may be mentioned here as an example (
J. Organometall. Chem.,
1995, 503, 143-148).
Likewise, preferred diphosphines are those in which n=1, Y is a methylene group and Y, together with Q and the two adjacent carbon atoms, forms a pyrrolidine ring which optionally carries further substituents. These diphosphines include, for example, (2S,4S)-1-tert-butoxycarbonyl-4-diphenylphosphino-2-(diphenylphosphinomethyl)pyrrolidine (BPPM) (
J. Org. Chem.,
1980, 45, 4680).
The catalytically active palladium diphosphine complex is advantageously formed in situ by a process in which palladium in finely divided elemental form (e.g., palladium on activated charcoal), a Pd(II) salt (e.g., the chloride or the ac
Kalbermatten Georges
Roduit Jean-Paul
Fisher Christen & Sabol
Lonza AG
Rotman Alan L.
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