2-Chloro-4-fluorophenol is an important intermediate for producing various pharmaceutical and agricultural agents. For example, oxazolidine derivatives derived from 2-chloro-4-fluorophenol possess an excellent herbicidal activity as disclosed in Japanese Patent Public Disclosure (Kokai) No. 62-174065 which corresponds to U.S. Pat. No. 4,818,272 and Japanese Patent Public Disclosure (Kokai) No. 62-167713 which corresponds to EP 241,559.
Typical conventional processes for preparing 2-chloro-4-fluorophenol include (1) a process comprising nitrating 4-fluoroanisol as a starting compound, followed by reducing the nitro group, converting the resulting compound into 2-chloro-4-fluoroanisol by the Sandmeyer reaction, and cleaving the ether linkage of the resulting compound, as disclosed in J. Am. Chem. Soc., 81, 94 (1959), and (2) a process comprising directly introducing a chlorine atom into 4-fluorophenol as a starting material using various chlorinating agents.
The above conventional process (1) makes it possible to selectively introduce a chlorine atom into the 2-position of 4-fluorophenol, but is not advantageous on an industrial scale since the process involves a number of reaction steps. Also, the above conventional process (2) can be carried out by one of various chlorinating procedures depending upon the type of the chlorinating agent used. For example, the process (2) includes (i) chlorination of 4-fluorophenol or an alkali metal thereof using an alkali metal hypochlorite as disclosed in USSR Patent No. 154250 and Zh. Obshch. Khim., 37, 2486 (1967), (ii) chlorination using sulfuryl chloride in the presence of a base as disclosed in Japanese Patent Public Disclosure (Kokai) No. 59-25344, (iii) chlorination using hydrochloric acid and hydrogen peroxide under an acidic condition as disclosed in Japanese Patent Public Disclosure (Kokai) Nos. 62-223140 and 62-238226, and (iv) direct chlorination using chlorine gas as disclosed in Japanese Patent Publication No. 63-62497 which corresponds to U.S. Pat. No. 4,620,042.
However, the above-described process (i) to (iv) also have various disadvantages. More specifically, the process (i) is not advantageous in that a highly concentrated aqueous solution of alkali metal hypochlorite is not available and, thus, the reaction should be conducted in an aqueous solution of alkali metal hypochlorite having a low concentration thereby resulting in a low space factor and a low yield, e.g., approximately 80%. The process (ii) exhibits a high position-selectivity, but produces as by products, hazardous waste gases such as sulfurous acid gas and hydrogen chloride gas which must be treated. The process (iii) requires the use of hydrogen peroxide which cannot be handled easily and, further, produces a waste sulfuric acid solution which must be treated. Although the process (iv) is an effective chlorination process, it requires separation of hydrogen chloride gas having a boiling point of -85.degree. C. produced during the reaction from chlorine gas having a boiling point of -34.1.degree. C. using a highly efficient refluxing condenser during the reaction in order to obtain an improved selectivity. In the separation of gases having such low boiling point, it is necessary to use a cooling tube which is effective at temperatures below the boiling point of chlorine gas and such a cooling means consumes large quantities of electricity. Also, the process (iv) produces, similar to the process (ii) described above, hydrogen chloride waste gas which must be treated. Further, the reaction of the process (iv) is not viable on an industrial scale since it gives rise to a remarkable decrease in selectivity even when a very small amount of impurities, in particular, metal ions, is present in the reaction system, and, hence, the reaction vessel used must be carefully selected from those made of a material which does not produce such impurities during the reaction.
As a result of extensive studies for developing a process which is viable on an industrial scale, which is capable of producing the desired 2-chloro-4-fluorophenol in good yields and with high selectivity, and which can be carried out under mild reaction conditions using inexpensive reagents without necessitating the use of particular apparatus, the present inventors found that 2-chloro-4-fluorophenol can be prepared in good yields and with high selectivity by directly chlorinating 4-fluorophenol with an inexpensive chlorinating agent such as chlorine gas or sulfuryl chloride in the presence of water.
USPTO Backgrounds
USPTO Backgrounds