Organic compounds -- part of the class 532-570 series – Organic compounds – Nitriles
Reexamination Certificate
2000-03-28
2003-01-14
Rotman, Alan L. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitriles
Reexamination Certificate
active
06506926
ABSTRACT:
This invention relates to a process for preparing certain 2-alkylthio substituted benzonitriles, which are useful as chemical intermediates, for example in the preparation of herbicidally active compounds.
2-Alkylthio-substituted benzonitriles are intermediates in the preparation of agrochemicals such as herbicides, for example as described in EP 0527036. It is desirable to provide such compounds in high yields and also to develop new procedures which allow the efficient displacement of 2-nitro or 2-halo substituted benzonitriles to furnish 2-alkylthio substituted benzonitriles.
The present invention seeks to provide a high yielding process for preparing 2-alkylthio substituted benzonitriles.
Thus, the present invention provides a process for preparing a 2-alkylthio-substituted-benzonitrile derivative of formula (I):
wherein R
1
represents C
1-6
alkyl;
R
2
represents C
1-6
haloalkyl, C
1-6
alkyl. C
1-6
haloalkoxy. C
1-6
alkoxy. SO
n
R
5
or halogen;
R
4
represents hydrogen, C
1-6
haloalkoxy, C
1-6
alkoxy. SO
n
R
5
or halogen; or a 5 or 6-membered heterocyclic ring (which may be unsaturated or partially saturated) containing 1 to 3 hetero atoms selected from oxygen, nitrogen and sulphur, optionally substituted by halogen, C
1-6
haloalkyl, C
1-6
alkyl, C
1-6
haloalkoxy, C
1-6
alkoxy, SO
n
R
5
, nitro or cyano;
R
5
represents C
1-6
alkyl; and
n represents 0, 1 or 2; which comprises reacting a compound of formula (II):
wherein R
2
and R
4
are as hereinbefore defined and R
3
represents nitro or a halogen atom selected from fluorine, chlorine and bromine, with a compound of formula R
1
S—X, wherein R
1
is as hereinbefore defined and X is hydrogen or an alkali metal.
When R
4
represents a heterocyclic ring, preferred rings include 3-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 5-oxazolyl, 2-furyl, 3-furyl, 2-thienyl and 3-thienyl.
R
1
preferably represents methyl.
R
2
preferably represents trifluoromethyl.
R
3
preferably represents nitro or chlorine.
R
4
preferably represents hydrogen.
X preferably represents a sodium, potassium or lithium atom.
In an especially preferred embodiment of the invention R
1
represents C
1-6
alkyl (methyl is most preferred);
R
2
represents C
1-6
haloalkyl (trifluoromethyl is most preferred);
R
3
represents nitro or a halogen atom selected from fluorine, chlorine and bromine (nitro or chlorine are most preferred); and
R
4
represents hydrogen.
The above reaction to prepare compounds of formula (I) by the reaction of a compound of formula (II) with a compound of formula R
1
S—X may be performed using various solvents such as aromatic hydrocarbons for example toluene or xylene, ethers such as tetrahydrofuran, dioxan or tert-butyl methyl ether; amides such as N,N-dimethylformamide; sulphoxides such as dimethylsulphoxide; or ketones, for example methyl ethyl ketone or acetone. An especially preferred solvent is acetone, optionally in the presence of water. It has been found that the reaction proceeds in excellent yield using these conditions.
A preferred compound of formula R
1
S—X is sodium thiomethoxide, which may be used in dry solid form or conveniently as a solution in water.
Where X is hydrogen, a base is generally present in the reaction mixture. Examples of suitable bases are alkali metal or alkaline earth metal carbonates, alkoxides or hydrides such as potassium carbonate, potassium t-butoxide or sodium hydride. or amidine bases such as 1,8-diazabicyclo[5.4.0]undec-7-ene or 1,1,3,3-tetramethylguanidine.
The reaction is generally performed at a temperature from about −20° C. to about 120° C. preferably from about 10° to about 60° C. and most preferably from about 10° to about 40° C.
The molar ratio of the benzonitrile derivative of formula (II): alkyl thiol (or metal salt thereof) of formula R
1
S—X is generally from about 1:1 to about 1:4, preferably from about 1:1 to about 1:2.5 and most preferably from about 1:1 to about 1:1.2.
Optionally the reaction may be performed in a two phase system consisting of water and another solvent which has low solubility in water, in the presence a phase transfer catalyst. Examples of phase transfer catalysts which are suitable include ammonium salts such as tetrabutylammonium chloride; phosphonium salts such as tributylhexadecylphosphonium bromide; guanidinium salts such as hexaethylguanidinium chloride or hexamethylguanidinium chloride; or crown ethers such as 18-crown-6. Suitable solvents for use with water and the phase transfer catalyst include aromatic hydrocarbons for example toluene or xylene, ethers such as tert-butyl methyl ether, halogenated solvents such as chlorobenzene or dichloromethane, generally employed in admixture with water. The quantity of phase transfer catalyst employed is generally from a 2 to 10% molar ratio (relative to the molar amount of compound of formula (II)). When conducted under these conditions the reaction is generally carried out at a temperature of from about 5° C. to about 100° C., preferably from about 25° to about 70° C.
The following non-limiting examples illustrate the invention.
REFERENCES:
patent: 5633384 (1997-05-01), Kagano et al.
patent: 5684206 (1997-11-01), Casado et al.
patent: 0418175 (1991-03-01), None
patent: 0527036 (1993-02-01), None
patent: 0705243 (1998-06-01), None
Harris et al,J. Medicinal Chemistry, vol. 33, No. 1, pp. 434-444 (1990).
Beck et al,J. Organic Chemistry, vol. 37, No. 21, pp. 3224-3226 (1972).
Coombes et al,Phosphorus and Sulfur, vol. 14, No. 2, pp. 139-142 (1983).
Bernard Didier
Truchon Alain
Rhone-Poulenc Agro
Rotman Alan L.
Sackey Ebenezer
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