Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
2000-12-18
2002-07-02
Geist, Gary (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C562S493000, C562S496000
Reexamination Certificate
active
06414186
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a method for preparing chloromethylphenylacetic acids, and more specifically to a method for preparing chloromethylphenylacetic acids at a high selectivity and a high yield, without using sulfuryl chloride as a chlorinating agent.
BACKGROUND ART
Chloromethylphenylacetic acids are compounds useful as raw materials and intermediate products for pharmaceuticals, agricultural chemicals, and the like.
One known conventional method for preparing chloromethylphenylacetic acids is a method for preparing 2-halomethylphenylacetic acids by a ring-opening reaction of 3-isochromanone with hydrogen halide, as described in the reference example of JP-A-54-138536 (“JP-A” means unexamined published Japanese patent application). However 3-isochromanone as the starting material in this method is expensive, and there is a problem in view of the production cost.
Further, a method of obtaining 2-chloromethylphenylacetic acids by reacting, in carbon tetrachloride, 2-methyl phenylacetic acid with bromine, in the presence of 2,2′-azobisisobutyronitrile (AIBN), under irradiation with ultraviolet rays, to form 2-bromomethyl phenylacetic acids, and then reacting the 2-bromomethyl phenylacetic acids with lithium chloride, is reported in
J. CHEM. SOC., CHEM. COMMUN.,
1993, p. 399. However, this method is not preferred for industrial practice, since it involves a number of steps and the overall yield is as low as 54%.
Further, WO97/48692 reports a method of reacting 2-methyl phenylacetic acids with sulfuryl chloride, in the presence of a radical initiator, to obtain 2-chloromethylphenylacetic acid. However, the yield is 62.15% and the purity is 95.7%, with regard to the 2-chloromethylphenylacetic acids obtained by this method, which is not yet industrially satisfactory. In addition, sulfuryl chloride used in this method is toxic, and further, gaseous sulfurous acid formed by the reaction is highly toxic and corrosive, and the concentration of gaseous sulfurous acid in exhaust gases is strictly regulated, involving such problems mentioned above for industrial practice.
Accordingly, an object of the present invention is to provide a method capable of preparing chloromethylphenylacetic acids at a high yield and a high selectivity, without using sulfuryl chloride as the chlorinating agent.
Other and further objects, features, and advantages of the invention will appear more fully from the following description.
DISCLOSURE OF INVENTION
The present inventors have made earnest studies for solving the foregoing subject, and as a result, found that aimed chloromethylphenylacetic acids can be obtained at a high yield by reacting methyl phenylacetic acids and a chlorine gas, in an inert solvent, under the irradiation with light or in the presence of a radical initiator, to chlorinate only the methyl group at a high selectivity. The present inventors have accomplished the present invention based on the finding.
That is, the present invention provides:
(1) a method for preparing chloromethylphenylacetic acids represented by formula (II):
wherein a methyl phenylacetic acid represented by formula (I):
is reacted with a chlorine gas, in an inert solvent, under the irradiation with light or in the presence of a radical initiator,
(2) a method for preparing chloromethylphenylacetic acids as described in (1), wherein the reaction temperature is 70° C. or lower, and
(3) a method for preparing chloromethylphenylacetic acids as described in (1) or (2), wherein the inert solvent is at least one selected from monochlorobenzene, dichlorobenzenes, trichlorobenzenes, fluorobenzenes, trifluoromethylbenzenes, bistrifluoromethylbenzenes or chlorotrifluoromethylbenzenes.
BEST MODE FOR CARRYING OUT THE INVENTION
The methyl phenylacetic acid used as the starting raw material in the present invention is represented by the formula (I), and specifically one of 2-methyl phenylacetic acid, 3-methyl phenylacetic acid or 4-methyl phenylacetic acid, or a mixture of two or more of them.
The chloromethylphenylacetic acid obtained in the present invention is represented by the formula (II), and is one of 2-chloromethylphenylacetic acid, 3-chloromethylphenylacetic acid or 4-chloromethylphenylacetic acid, or a mixture of two or more of them, corresponding to the starting raw materials described above.
In the present invention, the chlorine gas is used as the chlorinating agent and the amount to be used is preferably from 0.2 to 2 mol, and more preferably from 0.8 to 1.2 mol, based on one mol of the methyl phenylacetic acid represented by the formula (I).
In the method of the present invention, the compound represented by the formula (I) and the chlorine gas are reacted under the irradiation with light or in the presence of a radical initiator. There is no particular restriction on the method of light irradiation and light including an ultraviolet region can be used preferably. For example, it can be carried out by using a mercury lamp or the like as a light source. Also for the radical initiator, those used generally can be used with no particular restriction. Specifically, benzoyl peroxide, 2,2′-azobisisobutyronitrile can be mentioned for example. The amount of the radical initiator to be used is generally from 0.005 to 0.1 mol, based on one mol of the compound represented by the formula (I).
The inert solvent usable in the present invention is a halogenated hydrocarbon, preferably, an aryl halide (for example, benzene halide), and there is no particular restriction so long as it can generally be used as the inert solvent for radial chlorinating reaction. Aryl halide includes those halogenated on the side chain. As specific examples of such inert solvent, one of monochlorobenzene, dichlorobenzenes, trichlorobenzenes, fluorobenzenes, trifluoromethylbenzenes, bistrifluoromethylbenzenes or chlorotrifluoromethylbenzenes, or a mixed solvent of two or more of them, can be used. It is, more preferably, at least one selected from monochlorobenzene, o-dichlorobenzene or 4-chlorotrifluoromethylbenzene.
There is no particular restriction on the amount of the solvent to be used in the present invention and it is preferably from 0.05 to 10 liter, and more preferably from 0.2 to 3 liter, based on one mol of the compound represented by the formula (I) in the industrial practice.
The chlorinating reaction in the present invention can be conducted at a temperature, preferably in the range of 70° C. or lower, and more preferably from 20 to 50° C.
Chloromethylphenylacetic acids at a high purity can be obtained easily at a high yield, by cooling the reaction solution after the completion of the reaction and then filtering and separating the precipitated desired compound from the reaction system. With an aim of further improving the purity, the obtained compound may be purified by recrystallization or the like.
According to the present invention, high purity chloromethylphenylacetic acids can be prepared at a high yield, without using toxic sulfuryl chlorides as a chlorinating agent, by chlorinating the methyl group of the methyl phenylacetic acids at a high selectivity while suppressing by-production of dichloro form or &agr;-chloro form. In the method of the present invention, since reaction conditions are mild and the number of steps is reduced, it can be practiced industrially at a reduced production cost. 2-chloromethylphenylacetic acids prepared by the present invention can also be converted easily into 3-isochromanone, which is used as intermediate products for medicines and agricultural agents, by treating with a base by the known method (
Zh. Org. Khim [
1973] 9 (10) 2145).
REFERENCES:
patent: 4499300 (1985-02-01), Malloy et al.
patent: 62129250 (1987-06-01), None
patent: WO-9748692 (1997-12-01), None
Kusagaya Kimitoshi
Matsuzawa Masafumi
Nakagawa Motoaki
Nakamura Mitsue
Takao Yoshihiro
Birch & Stewart Kolasch & Birch, LLP
Geist Gary
Ihara Chemical Industry Co. Ltd.
Nakamura Mitsue
Reyes Hećtor M
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