Thiazole compounds

Details Thiazole compounds Thiazole compounds

1998-06-01

2001-04-03

Gerstl, Robert (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S202000

Reexamination Certificate

active

06211381

ABSTRACT:

The invention relates to a process for preparing a compound of the formula
in which
X is CH or N,
Y is NO
2
or CN,
Z is CHR
3
, O, NR
3
or S,
R
1
and R
2
are either each, independently of the other, hydrogen or unsubstituted or R
4
-substituted alkyl or together a two- or three-membered alkylene bridge or a two- or three-membered alkylene bridge in which one member is replaced by a hetero member selected from the group, consisting of NR
5
, O and S,
R
3
is H or unsubstituted or R
4
-substituted alkyl,
R
4
is an unsubstituted or substituted aryl or heteroaryl group, and
R
5
is H or alkyl,
which comprises
a) reacting a compound of the formula
 in which X, Y, Z, R
1
and R
2
are as defined for the formula I,
n is 0, 1 or 2,
R
6
is unsubstituted or R
8
-substituted alkyl, unsubstituted or R
8
-substituted alkenyl, unsubstituted or R
8
-substituted alkynyl, cycloalkyl, unsubstituted or substituted aryl, heteroaryl, SR
7
, (alkylene)SH or (alkylene)SR
7
,
R
7
is unsubstituted or R
4
-substituted alkyl, unsubstituted or R
4
-substituted alkenyl, unsubstituted or R
4
-substituted alkynyl, cycloalkyl, unsubstituted or substituted aryl, heteroaryl or a group of the formula
 in which X, Y, Z, R
1
and R
2
are as defined for the formula II, and
R
8
is an unsubstituted or substituted aryl or heteroaryl group, —COOH, COOM, wherein M is an alkali metal, or —COO-C
1
-C
8
-alkyl,
with a chlorinating agent, or
b1) initially reacting a compound of the formula
 in the free form or the form of a salt,
in which R
6
and n are as defined for the formula II and X
1
is a leaving group, in the presence or absence of a base, with a compound of the formula
 which is known or which can be prepared by methods known per se and in which R
1
, R
2
, X, Y and Z are as defined for the formula I, and
b2) further reacting the compound of the formula II obtainable thereby, with or without intermediate isolation, with a chlorinating agent,
to intermediates used in this process, to the use of these intermediates and to a process for the preparation of these intermediates.
The existing processes for preparing the compounds of the formula I require as starting material inter alia 2-chloro-5-chloromethylthiazole. The latter, however, is harmful on direct contact, and there is therefore a need to replace this compound by harmless compounds. This object is achieved by the preparative process according to the invention.
The general terms used hereinbefore and hereinafter have, unless defined otherwise, the meanings listed below:
Carbon-containing groups and compounds each contain, unless defined otherwise, 1 up to and including 8, preferably 1 up to and including 6, in particular 1 up to and including 4, especially 1 or 2 carbon atoms.
Halogen is preferably chlorine or bromine.
Alkyl—as a group per se and also as a structural element of other groups and compounds, for example alkoxy and alkylthio—is, in each case with due regard to the number of carbon atoms contained in the respective group or compound, either straight-chain, i.e. methyl, ethyl, propyl, butyl, pentyl or hexyl, or branched, for example isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl or isohexyl.
Alkenyl and alkynyl are straight-chain or branched and each contain two or preferably one unsaturated carbon-carbon bond(s). The double or triple bonds of these substituents are separated from the remainder of the compound II preferably by at least one saturated carbon atom. Examples include allyl, methallyl, but-2-enyl, but-3-enyl, propargyl, but-2-ynyl and but-3-ynyl.
Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl.
Alkylene—as a group per se and also as a structural element of other groups and compounds, such as (alkylene)SR
7
- is, in each case with due regard to the number of carbon atoms contained in the respective group or compound, either straight-chain, for example —CH
2
CH
2
—, —CH
2
CH
2
CH
2
— or —CH
2
CH
2
CH
2
CH
2
—, or branched, for example —CH(CH
3
)—, —CH(C
2
H
5
)—, —C(CH
3
)
2
—, —CH(CH
3
)CH
2
— or —CH(CH
3
)CH(CH
3
)—, and it can also be methylene.
Aryl is phenyl or naphthyl, in particular phenyl.
Heteroaryl is a 5- to 7-membered aromatic ring with one to up to three hetero atoms selected from the group consisting of N, O and S. Preference is given to aromatic 5- and 6-membered rings which have a nitrogen atom as hetero atom and which can, if desired, also contain a further hetero atom, preferably nitrogen or sulfur, in particular nitrogen.
Substituted aryl and heteroaryl are preferably substituted with one to three substituents selected from the group consisting of halogen, NO
2
, CN, C
1
-C
4
alkyl, C
1
-C
4
alkoxy, halogenC
1
-C
4
alkyl and halogenC
1
-C
4
alkoxy. Preferred are unsubstituted or monosubstituted, especially unsubstituted aryl and heteroaryl.
Preferred starting materials for preparing the corresponding compounds of the formula I according to the invention are:
(1) a compound of the formula II where
X is N;
(2) a compound of the formula II where
Y is NO
2
;
(3) a compound of the formula II where
Z is CHR
3
or NR
3
, preferably NR
3
;
(4) a compound of the formula II where
R
1
and R
2
are together a two- or three-membered alkylene bridge with or without a hetero member selected from the group consisting of NR
5
, O and S;
(5) a compound of the formula II where
R
3
is unsubstituted or R
4
-substituted C
1
-C
4
alkyl,
preferably unsubstituted C
1
-C
2
alkyl;
(6) a compound of the formula II where
R
4
is unsubstituted or substituted aryl or heteroaryl, the substituents being selected from the group consisting of halogen, NO
2
, CN, C
1
-C
4
alkyl, C
3
-C
6
cycloalkyl, C
1
-C
4
alkoxy and C
1
-C
4
alkylthio,
preferably unsubstituted aryl;
(7) a compound of the formula II wherein
R
6
is unsubstituted or R
8
-substituted C
1
-C
4
alkyl, aryl, heteroaryl, SR
7
, (alkylen)SH or (alkylene)SR
7
,
preferably aryl, R
8
-substituted C
1
-C
4
alkyl or SR
7
,
in particular R
8
-substituted C
1
-C
2
alkyl or especially aryl;
(8) a compound of the formula II wherein
R
7
is unsubstituted or R
4
-substituted alkyl, aryl, heteroaryl or a group of the formula
 in which X, Y, Z, R
1
and R
2
are as defined for the formula II,
in particular a group of the formula III;
(9) a compound of the formula II wherein
R
8
is aryl or heteroaryl, which are either unsubstituted or substituted, the substituents being selected from the group consisting of halogen, NO
2
, CN, C
1
-C
4
-alkyl, C
3
-C
6
-cycloalkyl, C
1
-C
4
-alkoxy and C
1
-C
4
-alkylthio;
in particular unsubstituted aryl.
Especially preferred according to the invention are the compounds of the formula II mentioned in the Examples.
The reactions described hereinbefore and hereinafter are carried out in a customary manner, for example in the absence or usually in the presence of a suitable solvent or diluent or a mixture thereof, working as the occasion demands with cooling, at room temperature or with heating, for example at a temperature in the range of from about −80° C. to the boiling point of the reaction medium, preferably at about −20° C. to about +150° C., and, if necessary, in a closed vessel, at elevated pressure, in an inert-gas atmosphere and/or under anhydrous conditions. Especially advantageous reaction conditions are discernible from the Examples.
The starting materials listed hereinbefore and hereinafter used for preparing the compounds I, as the case may be in their free form or as salts, are known or, if they are novel, can be prepared by known methods, for example according to the following specifications.
Variant a)
Suitable halogenating agents are for example elemental chlorine, Javelle water, polysulfur dichloride, sulfur dichloride, phosphorus trichloride, phosphorus pentachloride or mixtures of two or more than two of these compounds, preferably elemental chlorine, Javelle water, sulfur dichloride or a mixture of these two compounds, particularly preferably elemental chlorine of Javelle water.
The reaction partners can be reacted with each other witho

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