Preparation of terpyridines

Details Preparation of terpyridines Preparation of terpyridines

2002-04-30

2004-08-31

Davis, Zinna Northington (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06784296

ABSTRACT:

The present invention relates to a process for preparing terpyridines of the formula I
in which
R are hydrogens or identical C
1
-C
12
-alkyl or C
1
-C
12
-alkoxy radicals and
n is 0, 1, 2, 3 or 4 and is the same for both sets of radicals
by successive reaction steps comprising
A) condensation of a C
1
-C
4
-alkyl pyridine-2-carboxylate derivative with acetone in an aprotic solvent in the presence of a base,
B) reaction of the 1,5-bis(2-pyridyl)pentane-1,3,5-trione derivative obtained in reaction step A with ammonia or ammonium salts (NH
4
)
q
Y with removal of the water of reaction formed, where the variable Y in (NH
4
)
q
Y is the anion of the parent q-basic acid H
q
Y of the ammonium salt, and
C) chlorination of the 2,6-bis(2-pyridyl)-4(1H)pyridinone derivative obtained in reaction step B,
wherein the reaction step A is preceded by a reaction step A′ in which the C
1
-C
4
-alkyl pyridine-2-carboxylate derivative is obtained by
A′) acid hydrolysis of a 2-cyanopyridine derivative by means of an anhydrous inorganic acid or its anhydride in the presence of water and a C
1
-C
4
-alkanol, with an equimolar amount of water being added to the 2-cyanopyridine derivative of the formula a prior to addition of the anhydrous inorganic acid or its anhydride,
the base used in reaction step A is an alkali metal C
1
-C
4
-alkoxide or alkaline earth metal C
1
-C
4
-alkoxide,
the removal of the water of reaction in reaction step B is carried out using a C
1
-C
4
-alkanol as entrainer
and
the chlorination of the 2,6-bis(2-pyridyl)-4(1H)pyridinone derivative of the formula c in reaction step C is carried out using phosphorus oxide chloride (POCl
3
) or using a mixture comprising phosphorus oxide chloride and at least one organic solvent selected from the group consisting of toluene, o-xylene, m-xylene and p-xylene.
The present invention further relates to a process for preparing C
1
-C
4
-alkyl pyridine-2-carboxylate derivatives from 2-cyanopyridine derivatives, to a process for preparing 1,5-bis(2-pyridyl)pentane-1,3,5-trione derivatives by condensation of a C
1
-C
4
-alkyl pyridine-2-carboxylate derivative with acetone, to a process for preparing 2,6-bis(2-pyridyl)-4(1H)pyridinone derivatives by reaction of a 1,5-bis(2-pyridyl)pentane-1,3,5-trione derivative with ammonia or ammonium salts and to a process for preparing terpyridines of the formula I by chlorination of a 2,6-bis(2-pyridyl)-4(1H)pyridinone derivative.
The interest in oligopyridines is tremendous, particularly because they are excellent complexing agents for metals. As a result, a wide variety of synthetic routes have been employed for these compounds. A review is given, for example, by R. -A. Fallahpour in Synthesis 2000, No. 12, 1665-1667.
The synthesis of 4′-chloro-2,2′:6′,6″-terpyridine from ethyl pyridine-2-carboxylate via the intermediates 1,5-bis(2-pyridyl)pentane-1,3,5-trione and 2,6-bis(2-pyridyl)-4(1H)pyridinone is described by E. C. Constable and M. D. Ward in J. Chem. Soc. Dalton Trans. 1990, 1404-1409 (1). The condensation of the pyridinecarboxylic ester with acetone (corresponding to reaction step A of the process of the present invention) is carried out in the presence of sodium hydride as base. The resulting pentane-1,3,5-trione is then reacted with ammonium acetate under reflux to form the corresponding 4(1H)pyridinone (corresponding to reaction step B of the process of the present invention), which then reacts with an excess of phosphorus pentachloride in phosphorus oxide chloride as solvent to give the desired terpyridine (corresponding to reaction step C of the process of the present invention). The respective yields of the reactions corresponding to the reaction steps A, B and C are said by the authors to be 80%, 80% and 62%, respectively, which corresponds to an overall yield of terpyridine based on the pyridinecarboxylic ester used of about 40%.
According to R. L. Frank and E. F. Riener, J. Am. Chem. Soc., Vol. 72, 4182-4183 (2), ethyl picolinate (ethyl pyridine-2-carboxylate) is prepared by reacting 2-cyanopyridine with ethanol saturated with HCl gas. The imino ester formed as intermediate is then hydrolyzed to the ethyl ester by pouring into water. The yield of this reaction is said to be 40%.
Serious disadvantages of the procedure described in (1) are the use of extremely air- and moisture-sensitive sodium hydride and of large amounts of corrosive and toxic phosphorus pentachloride or phosphorus oxide chloride and the generally high starting material costs for pyridinecarboxylic esters. For these reasons, this route to terpyridines can be employed only with great difficulty, if at all, on a (large) industrial scale.
An attractive starting material for the synthesis of terpyridines is 2-cyanopyridine, because of the price advantage over pyridinecarboxylic esters. 2-Cyanopyridine can be converted as described in (2) into ethyl pyridinecarboxylates, but the synthesis described in (2) has the disadvantage that, based on the amount of 2-cyanopyridine used, only a small yield of the desired ester is obtained, which cancels out the price advantage. If the yield reported in (2) is multiplied by the yield of about 40% indicated above, the overall yield of terpyridine starting from 2-cyanopyridine is only about 16%. This is prohibitively low for (large-scale) industrial processes.
It is an object of the present invention to provide an inexpensive process for preparing terpyridines from 2-cyanopyridine which can be carried out on a (large) industrial scale and is acceptable from the points of view of occupational hygiene and the environment.
We have found that this object is achieved by a process for preparing terpyridines of the formula I
in which
R are hydrogens or identical C
1
-C
12
-alkyl or C
1
-C
12
-alkoxy radicals and
n is 0, 1, 2, 3 or 4 and is the same for both sets of radicals R,
by successive reaction steps comprising
A) condensation of a C
1
-C
4
-alkyl pyridine-2-carboxylate derivative of the formula a
 with acetone in an aprotic solvent in the presence of a base,
B) reaction of the 1,5-bis(2-pyridyl)pentane-1,3,5-trione derivative of the formula b
 obtained in reaction step A with ammonia or ammonium salts (NH
4
)
q
Y with removal of the water of reaction formed, where the variable Y in (NH
4
)
q
Y is the acid anion of the parent q-basic acid H
q
Y of the ammonium salt, and
C) chlorination of the 2,6-bis(2-pyridyl)-4(1H)pyridinone derivative of the formula c obtained in reaction step B
 where Z is NH in the case of a reaction with ammonia in reaction step B and is NH
2
⊕
[Y
1/q
]
⊖
in the case of a reaction with ammonium salts (NH
4
)
q
Y in reaction step B,
wherein
the reaction step A is preceded by a reaction step A′ in which the C
1
-C
4
-alkyl pyridine-2-carboxylate derivative of the formula a is obtained by
A′) acid hydrolysis of a 2-cyanopyridine derivative of the formula a′
 by means of an anhydrous inorganic acid or its anhydride in the presence of water and a C
1
-C
4
-alkanol, with an equimolar amount of water being added to the 2-cyanopyridine derivative of the formula a′ prior to addition of the anhydrous inorganic acid or its anhydride,
the base used in reaction step A is an alkali metal C
1
-C
4
-alkoxide or alkaline earth metal C
1
-C
4
-alkoxide,
the removal of the water of reaction in reaction step B is carried out using a C
1
-C
4
-alkanol as entrainer
and
the chlorination of the 2,6-bis(2-pyridyl)-4(1H)pyridinone derivative of the formula c in reaction step C is carried out using phosphorus oxide chloride (POCl
3
) or using a mixture comprising phosphorus oxide chloride and at least one organic solvent selected from the group consisting of toluene, o-xylene, m-xylene and p-xylene.
In formula a, C
1
-C
4
-alkyl radicals are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and tert-butyl, so that the corresponding C
1
-C
4
-alkanols with which the 2-cyanopyridines of the formula a′ are reacted to form the compounds of the formula a are methanol, ethanol,

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