Process for manufacture of imidazoles

Details Process for manufacture of imidazoles Process for manufacture of imidazoles

1998-11-17

2001-01-23

Higel, Floyd D. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S559000, C548S343100, C548S343500, C548S345100

Reexamination Certificate

active

06177575

ABSTRACT:

FIELD OF THE INVENTION
Imidazoles may be made by the reaction of an aldehyde, a glyoxal, ammonium carbonate or bicarbonate, and optionally a primary alkylamine. Imidazoles may also be made by the reaction of an aldehyde, a glyoxal, ammonia, and optionally a primary amine in the presence of a selected Bronsted acid.
TECHNICAL BACKGROUND
Imidazoles are useful as chemical intermediates, for example they are used in the preparation of pharmaceuticals and pesticides. Commercially they are typically made by the condensation of a glyoxal, aldehyde ammonia and optionally an amine, depending on the substituents desired on the imidazole ring, see for example E. Elvers., et al., Ed., Ullmann's Encyclopedia of Industrial Chemistry, 5
th
Ed., Vol. A13, VCH Verlagsgesellschaft mbH, Weinheim, 1989, p. 661-668; M. R. Grimmett in K. T. Potts, Ed., Comprehensive Heterocyclic Chemistry, Vol. 5, Part 4A, Pergamon Press, New York, 1984, p. 482-486; and M. R. Grimmett, Adv. Heterocycl. Chem., Vol. 12, p. 105-117 (1970). However, these condensations often do not give high yields of the desired products, especially when a particular substituted imidazole is desired. Therefore improved syntheses of imidazoles are desired.
As reported in M. R. Grimmett, Adv. Heterocycl. Chem., Vol. 12, p. 1 (1970), formaldehyde and ammonium carbonate, when exposed to actinic radiation having a wavelength of 254 &mgr;m, yields a mixture of imidazole, 4-methylimidazole and 4-hydroxymethylimidazole. Such processes are not claimed herein.
Japanese Patent Application 03/169865 describes the preparation of a wide variety of imidazoles using ammonia or an ammonium carbonate as the ammonia source. There is no recognition of the particular use of an ammonium carbonate in the presence of selected amines as described herein.
SUMMARY OF THE INVENTION
This invention concerns, a first process for the manufacture of imidazoles, comprising, contacting in the liquid phase:
(a) ammonium carbonate or ammonium bicarbonate;
(b) a glyoxal of the formula
(c) an aldehyde of formula R
3
CHO (II); and
(d) optionally an amine of the formula R
4
NH
2
(III);
wherein:
R
1
, R
2
and R
3
are each independently hydrogen, hydrocarbyl or substituted hydrocarbyl;
R
4
is hydrogen, alkyl, or substituted alkyl.
This invention also concerns a second process for the for the manufacture of imidazoles, comprising, contacting in the liquid phase:
(a) an acid of the formula HX;
(b) a glyoxal of the formula
(c) an aldehyde of formula R
7
CHO (VII);
(d) optionally an amine of the formula R
8
NH
2
(VIII); and
(e) ammonia
wherein:
R
5
, R
6
and R
7
are each independently hydrogen, hydrocarbyl or substituted hydrocarbyl;
R
8
is hydrogen, hydrocarbyl, or substituted hydrocarbyl; X is an anion;
and provided that a pKa of HX is about plus or minus 2 pKa units of a pKa of R
8
NH
3
+
, with the further proviso when (VIII) is not present then a pKa of HX is about plus or minus 2 pKa units of a pKa of NH
4
+
.
DETAILS OF THE INVENTION
By substituted alkyl is meant an alkyl group substituted with one or more groups which will not interfere with the desired reaction(s) and not render the compound in which they are present substantially unstable. Suitable substituent groups include hydroxyl, ether, and aryl. Herein if not otherwise specified, it is preferred that alkyl groups contain 1-30 carbon atoms.
By hydrocarbyl is meant a chiral or achiral univalent radical containing only carbon and hydrogen. By substituted hydrocarbyl is meant hydrocarbyl substituted with one or more groups which will not interfere with the desired reaction(s) and not render the compound in which they are present substantially unstable. Suitable substituent groups include hydroxyl and ether. Herein if not otherwise specified, it is preferred that hydrocarbyl groups contain 1-30 carbon atoms.
The compounds which are made herein are imidazoles, cyclic compounds having the basic ring structure
From the starting materials of the first process, (I), (II), (1II) and ammonium carbonate or bicarbonate, the imidazoles made herein form by the reaction
wherein R
1
, R
2
, R
3
and R
4
are as defined above. Water and CO
2
, not shown in eq. (1), are also “byproducts” of this reaction. The formation of CO
2
as the “acidic” byproduct is especially useful, since it is removed from the product as a gas. As will be realized if R
1
and R
2
are different, their positions may be reversed in (V) and two isomers may be obtained.
Also in equation (1) if R
4
is hydrogen, then the amine is ammonia. Ammonia may be added in the form of ammonia or in the form of ammonium carbonate or bicarbonate. Ammonium carbonate has 2 equivalents of ammonia per mole, while ammonium bicarbonate has one equivalent of ammonia per mole. It is preferred the amount of carbon dioxide present is about 5 to about 100 mole percent of first equivalent [i.e., that is as the first mole of ammonia in eq. (1)] of ammonia present, more preferably about 5 to about 95 mole percent of the first equivalent of ammonia present, especially preferably about 10 to about 30 mole percent of the first equivalent of ammonia present, and most preferably about 15 to about 25 mole percent of the first equivalent of ammonia present. In the presence of water ammonia and CO
2
form ammonium carbonate and/or bicarbonate, depending on the molar ratio of ammonia to CO
2
. Included herein within the meaning of ammonium carbonate or bicarbonate is a mixture of ammonia and CO
2
, or addition of the carbonate or bicarbonate of (III). Since water is formed in the reaction as a byproduct, the carbonate and/or bicarbonate form, even if no water was added to the reaction.
Although the molar ratio of the reactants is not critical, it is preferred to add them to the process mixture in the molar ratios stoichiometrically required by the reaction. Thus, the ratio of (I):(II):(III) (if present and R
4
is not hydrogen) is preferably about 1:1:1. The ratio of total equivalents of ammonia present (as ammonia and/or ammonium carbonate and/or bicarbonate):(I) is preferably about 1:1 if at least some of R
4
is not hydrogen. If (III) is present and all of R
4
is hydrogen, the preferred ratio of equivalents of ammonia:(I) is 2:1. Another way of putting this is that the ratio of [the total amount of ammonia equivalents+(III)]:(I) is preferably about 2:1.
In (I) it is preferred that RI and R
2
are the same. Preferred groups for R
1
and R
2
are hydrogen and alkyl containing 1 to 6 carbon atoms, more preferably hydrogen and methyl. The groups R
1
and R
2
become the groups attached to the 4 and 5 positions of the resulting imidazole ring.
In (II) it is preferred that R
3
is hydrogen or alkyl, more preferably hydrogen or alkyl containing 1 to 6 carbon atoms, and especially preferably hydrogen or methyl. R
3
becomes the group attached to the 2 position of the resulting imidazole ring.
In (III) it is preferred that R
4
is hydrogen, alkyl, or hydroxyalkyl, more preferably hydrogen, alkyl containing 1 to 6 carbon atoms, and 2-hydroxyethyl, especially preferably hydrogen (ammonia) and methyl.
In the first process ammonia derived from ammonium carbonate and/or bicarbonate and any ammonia added becomes the ammonia in the 3 position of the imidazole ring. If (III) is not added or all of R
4
is hydrogen, then the ammonia also becomes the nitrogen in the 3 position of the imidazole ring. While less than a stoichiometric amount of (III) in which R
4
is not hydrogen may be added, this will usually result in a mixture of products, which is often not desirable.
In the second process herein an imidazole of formula (IV) is also made. The equation which describes this reaction is
Water, not shown in eq. (2), is also a “byproduct” of this reaction. As will be realized if R
5
and R
6
are different, their positions may be reversed in (IX) and two isomers may be obtained.
Ammonia and/or (VIII) may be added in the form of the free base of a salt of HX. Of the total of (VIII) present in the reaction, it is preferred that the amount of carbon dioxide present

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