Process for the preparation of thiazole derivatives

Details Process for the preparation of thiazole derivatives Process for the preparation of thiazole derivatives

2000-08-01

2002-04-09

Higel, Floyd D. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S183000, C548S186000, C548S187000, C548S189000

Reexamination Certificate

active

06369233

ABSTRACT:

The invention relates to a process for the preparation of a compound of the formula
and, where applicable, its E/Z-isomers, mixtures of E/Z-isomers and/or tautomers, in each case in free form or in salt form, wherein
Q 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 C
1
-C
8
alkyl, or together form an alkylene bridge having two or three carbon atoms, and said alkylene bridge may additionally contain a hetero atom selected from the group consisting of NR
5
, O and S,
R
3
is H or unsubstituted or R
4
-substituted C
1
-C
12
alkyl,
R
4
is unsubstituted or substituted aryl or heteroaryl, and
R
5
is H or C
1
-C
12
alkyl; which comprises
a) reacting a compound of the formula
and, where applicable, its E/Z-isomers, mixtures of E/Z-isomers and/or tautomers, in each case in free form or in salt form, which is known or can be prepared by processes known per se and wherein
R is unsubstituted or substituted C
1
-C
12
alkyl, unsubstituted or substituted C
2
-C
4
alkenyl, unsubstituted or substituted C
2
-C
4
alkynyl, unsubstituted or substituted C
3
-C
6
cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, or —SR
6
; and
R
6
is unsubstituted or substituted C
1
-C
12
alkyl, unsubstituted or substituted C
2
-C
4
alkenyl, unsubstituted or substituted C
2
-C
4
alkynyl, unsubstituted or substituted C
3
-C
6
cycloalkyl, unsubstituted or substituted aryl or unsubstituted or substituted heterocycyl,
X
1
is a leaving group;
with a halogenating agent, in the presence of a base, to form a compound of the formula
or, where applicable, an E/Z-isomer, a mixture of E/Z-isomers and/or a tautomer thereof, wherein
R is as defined for formula (II);
m is 0 or 1; and
X is halogen; or
b) converting a compound of formula (II) by means of a halogenating agent into a compound of the formula
or, where applicable, an E/Z-isomer, a mixture of E/Z-isomers and/or a tautomer thereof, wherein R, X and X
1
are as defined above for formulae (II) and (III); optionally
c) converting a compound of formula (IV), in the absence or in the presence of a base, preferably in the presence of a base, into a compound of formula (III);
d) converting a compound of formula (III) by means of a compound of the formula
or, where applicable, an E/Z-isomer, a mixture of E/Z-isomers and/or a tautomer thereof, in each case in free form or in salt form, which is known or can be prepared by processes known per se and wherein R
1
, R
2
, Y, Z and Q are as defined above for the compound of formula (I), into a compound of the formula
or, where applicable, an E/Z-isomer, a mixture of E/Z-isomers and/or a tautomer thereof, in each case in free form or in salt form, which is known or can be prepared by processes known per se and wherein R
1
, R
2
, Y, Z and Q are as defined above for the compound of formula (I) and R is as defined above for the compound of formula (II); or
e) converting a compound of formula (IV) by reaction with a compound of formula (V) into a compound of formula (VI); and
f) converting a compound of formula (VI) by means of a chlorinating agent into a compound of formula (I);
and in each case, If desired, converting a compound of formula (I) obtainable in accordance with the process or by another method, or an E/Z-isomer or tautomer thereof, in each case in free form or in salt form, into a different compound of formula (I) or an E/Z-isomer or tautomer thereof, in each case in free form or in salt form, separating a mixture of E/Z-isomers obtainable in accordance with the process and isolating the desired isomer, and/or converting a free compound of formula (I) obtainable in accordance with the process or by another method, or an E/Z-isomer or tautomer thereof, into a salt or converting a salt, obtainable in accordance with the process or by another method, of a compound of formula (I) or of an E/Z-isomer or tautomer thereof into the free compound of formula (I) or an E/Z-isomer or tautomer thereof or into a different salt.
Methods of synthesis for the compounds of formula (I) are described in the literature. It has been found, however, that the intermediates that have to be used in those synthesis processes known in the literature cause considerable problems during production on account of their high level of toxicity and, moreover, can be removed quantitatively from the active substance only with a significant outlay. Accordingly, the known processes are not satisfactory in that respect, giving rise to the need to make available improved preparation processes for those compounds.
Some compounds of formulae (I), (II), (III), (IV), (V) and (VI) contain asymmetric carbon atoms, as a result of which the compounds may occur in optically active form. Formulae (I) to (VI) are intended to include all those possible isomeric forms as well as mixtures thereof, for example racemates or mixtures of E/Z-isomers.
The general terms used hereinbefore and hereinafter have the meanings given below, unless defined otherwise:
Unless defined otherwise, carbon-containing groups and compounds each contain from 1 up to and including 8, preferably from 1 up to and including 6, especially from 1 up to and including 4, more especially 1 or 2, carbon atoms.
Alkyl—both as a group per se and as a structural element of other groups and compounds, such as haloalkyl, arylalkyl or hydroxyalkyl—is, in each case giving due consideration to the number of carbon atoms contained in the group or compound in question, either straight-chained, i.e. methyl, ethyl, propyl, butyl, pentyl or hexyl, or branched, for example iso propyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl or isohexyl.
Alkenyl—both as a group per se and as a structural element of other groups and compounds, such as haloalkenyl or arylalkenyl—is, in each case giving due consideration to the number of carbon atoms contained in the group or compound in question, either straight-chained, for example vinyl, 1-methylvinyl, allyl, 1-butenyl or 2-hexenyl, or branched, for example isopropenyl.
Alkynyl—both as a group per se and as a structural element of other groups and compounds, such as haloalkynyl—is, in each case giving due consideration to the number of carbon atoms contained in the group or compound in question, either straight-chained, for example propargyl, 2-butynyl or 5-hexynyl, or branched, for example 2-ethynylpropyl or 2-propargylisopropyl.
C
3
-C
6
Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, especially cyclo hexyl.
Aryl is phenyl or naphthyl, especially phenyl.
Heterocyclyl is understood as being a five- to seven-membered monocyclic saturated or un-saturated ring that contains from one to three hetero atoms selected from the group consisting of N, O and S, especially N and S, or a bicyclic ring that may contain either in only one ring—such as, for example, thiazolyl, thiazolinyl, thiazolidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, quinolinyl, quinoxalinyl, indolinyl, benzothiophenyl or benzofuranyl—or in both rings—such as, for example, in pteridinyl or purinyl—independently of one another, one or more hetero atoms selected from N, O and S. Preference is given to thiazolyl, thiazolinyl, pyridyl, pyrimidinyl and benzothiazolyl. Heteroayl is an aromatic mono- or bicyclic ring of the type defined above.
The said heterocyclyl rings are optionally substituted with one to three substituents—according to substitution possibilities on the ring system—selected from the group consisting of halogen, C
1
-C
4
alkyl, halogen-C
1
-C
4
alkyl and X
1
, wherein X
1
is as defined hereinbelow. Preferred are chlorine and —CH
2
Cl.
Halogen—both as a group per se and as a structural element of other groups and compounds, such as haloalkyl, haloalkenyl and haloalkynyl—is fluorine, chlorine, bromine or iodine, especially fluorine, chlorine or bromine, more especially chlorine or bromine, very especially chlorine.
Halo-substituted carbon-containing groups and compounds, such as haloalkyl or haloalkenyl, may be partially halogenated

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