Process for producing cyanobenzyl compounds

Details Process for producing cyanobenzyl compounds Process for producing cyanobenzyl compounds

1999-11-24

2001-02-13

McKane, Joseph K. (Department: 1626)

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

Organic compounds

Nitriles

C558S423000, C558S425000

Reexamination Certificate

active

06187945

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a process for producing cyanobenzyl compounds, and more particularly to a process for producing cyanobenzyl compounds represented by formula (II). Cyanobenzyl compounds are important intermediates for producing chemical products such as pharmaceuticals, agrochemicals, liquid crystals, and monomers of functional polymers.
BACKGROUND OF THE INVENTION
Several processes for producing cyanobenzyl compounds are already known.
1. Cyanobenzyl alcohol compounds
Exemplary processes for producing p-cyanobenzyl alcohol, a typical cyanobenzyl alcohol compound, are as follows.
p-Cyanobenzyl alcohol is synthesized through reduction of a p-cyanobenzoic acid ester or p-cyanobenzaldehyde using a reducing agent formed of a hydride compound such as sodium borohydride (Kikugawa, Y.,
Chem. Pharm. Bull,
24 (1976) 1059; and Hilborn, J. W., et al.,
J. Am. Chem. Soc.,
116 (1994) 3337). Alternatively, p-cyanobenzaldehyde is reduced through water gas shift reaction in the presence of a rhodium cluster-on-polymer catalyst (Kaneda, K., et al.,
Tetrahedron Letters,
38 (1997) 3005).
2. Cyanobenzyl halide compounds
An exemplary process for producing p-cyanobenzyl chloride, a typical cyanobenzyl halide compound, is as follows.
p-Cyanobenzyl chloride is synthesized through mono-chlorination of p-tolunitrile (
J. Am. Chem. Soc.,
65 (1943) 2282: L. Blicke).
3. Cyanobenzyl acyloxy compounds
Exemplary processes for producing p-cyanobenzyl acetate, a typical cyanobenzyl acyloxy compound, are as follows.
p-Cyanobenzyl acetate is synthesized through reaction of p-cyanobenzyl chloride and sodium acetate in an alcohol solvent (Banse,
Chem. Ber.,
27 p2171 (1894)). Alternatively, p-cyanobenzyl acetate is synthesized through acetylation of p-cyanobenzyl alcohol (A. L. Baumstark, et al.,
Tetrahedron Letters,
25 p169 (1984)).
The above processes for producing p-cyanobenzyl compounds have disadvantages as described below.
1. p-Cyanobenzyl alcohol
When reduction is carried out by use of a reducing agent formed of a hydride, such an expensive reagent is required in an amount greater than the stoichiometric amount, to thereby produce a large amount of waste. When reduction is carried out using hydrogen, an expensive rhodium catalyst is employed. Thus, both processes are economically disadvantageous.
2. p-Cyanobenzyl chloride
Hazardous chlorine gas is used for chlorinating p-tolunitrile, and selectivity of monochlorination is insufficient.
3. p-Cyanobenzyl acetate
p-Cyanobenzyl chloride or p-cyanobenzyl alcohol serving as a raw material is not easily available as a general-purpose raw material.
As described above, the synthesis of p-cyanobenzyl compounds by use of a conventionally known technique is cumbersome, and production of high-purity compounds is difficult. In addition, raw materials such as a p-cyanobenzoic acid ester, p-cyanobenzaldehyde, and p-tolunitrile are not easily available. Thus, the above processes are unsatisfactory for production of cyanobenzyl compounds at high yield and high purity on an industrial scale.
In view of the foregoing, the present invention is directed to provision of an industrially advantageous process for producing cyanobenzyl compounds under mild conditions from relatively easily available cyanobenzylamine having a cyano group on the benzene ring or a compound thereof which is ring-substituted with a chlorine atom, a fluorine atom, etc. (hereinafter these compounds may generally be referred to as “cyanobenzylamine compounds”).
SUMMARY OF THE INVENTION
The present inventors have found that the above object is attained through transformation of an aminomethyl group (—CH
2
NH
2
) of a cyanobenzylamine compound which serves as a starting material into a hydroxymethyl group, a halomethyl group, or an acyloxymethyl group without causing damage to a cyano group on the benzene ring. The present invention has been accomplished on the basis of this finding.
Accordingly, embodiments of the present invention are as follows:
(1) a process for producing a cyanobenzyl compound comprising transforming an aminomethyl group of a cyanobenzylamine compound into a hydroxymethyl group, a halomethyl group, or an acyloxymethyl group without damaging a cyano group on the benzene ring;
(2) a process for producing a cyanobenzyl compound according to embodiment (1), wherein an aminomethyl group is transformed into a hydroxymethyl group, a halomethyl group, or an acyloxymethyl group by use of nitrosonium ions;
(3) a process for producing a cyanobenzyl compound according to embodiment (2), wherein a nitrite salt is used under acidic conditions in order to generate nitrosonium ions;
(4) a process for producing a cyanobenzyl compound according to embodiment (2), wherein a nitrogen oxide is used in order to generate nitrosonium ions;
(5) a process for producing a cyanobenzyl compound according to any one of embodiments (1) to (4), wherein the reaction is carried out in the presence of a polar solvent;
(6) a process for producing a cyanobenzyl compound according to embodiments (1) or (2), wherein the cyanobenzylamine compound is represented by the following formula (I):
wherein each of —CH
2
NH
2
and —X represents a substituent on the benzene ring; the —CH
2
NH
2
group is bonded to the m- or the p- position with respect to the —CN group; X represents a chlorine atom or a fluorine atom; n is an integer between 0 and 4 inclusive; and when n is 2 or more, the plurality of X's may be identical to or different from one another, and the cyanobenzyl compound is represented by the following formula (II):
wherein each of —X and —CH
2
Y represents a substituent on the benzene ring; the —CH
2
Y group is bonded to the m- or the p- position with respect to the —CN group; X represents a chlorine atom or a fluorine atom; n is an integer between 0 and 4 inclusive; and when n is 2 or more, the plurality of X's may be identical to or different from one another; Y represents a hydroxyl group, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, or an acyloxy group represented by —OCOR, wherein R represents a C
1
-C
8
alkyl group, an alkenyl group, or an aryl group;
(7) a process for producing a cyanobenzyl compound according to embodiment (6), wherein the cyanobenzylamine compound represented by formula (I) is p-cyanobenzylamine or m-cyanobenzylamine, and the cyanobenzyl compound represented by formula (II) is a corresponding p-cyanobenzyl alcohol or m-cyanobenzyl alcohol;
(8) a process for producing a cyanobenzyl compound according to embodiment (6), wherein the cyanobenzylamine compound represented by formula (I) is p-cyanobenzylamine or m-cyanobenzylamine and the cyanobenzyl compound represented by formula (II) is a corresponding p-cyanobenzyl chloride, p-cyanobenzyl bromide, m-cyanobenzyl chloride, or m-cyanobenzyl bromide;
(9) a process for producing a cyanobenzyl compound according to embodiment (6), wherein the cyanobenzylamine compound represented by formula (I) is p-cyanobenzylamine or m-cyanobenzylamine and the cyanobenzyl compound represented by formula (II) is a corresponding p-cyanobenzyl acetate or m-cyanobenzyl acetate; and
(10) a cyanobenzyl compound which is produced through the process as recited in embodiments (1) or (2), wherein an aminomethyl group of a cyanobenzylamine compound is transformed into a hydroxymethyl group, a halomethyl group, or an acyloxymethyl group without causing damage to a cyano group on the benzene ring.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The reaction process according to the present invention is carried out through the following steps: placing a solvent, a cyanobenzylamine compound, a nitrite salt or a nitrogen oxide, and if necessary a nucleophilic species in a reactor, the nucleophilic species being placed under acidic conditions for producing a cyanobenzyl alcohol compound; elevating the temperature of the thus-formed mixture to the reaction temperature with stirring; and heating the mixture for a predetermined time with stirring.
Typically, suitable materials for the reactor employed for the react

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