Process for preparation of 3,5-bisalkylphenols

Details Process for preparation of 3,5-bisalkylphenols Process for preparation of 3,5-bisalkylphenols

2003-03-18

2004-10-19

Shippen, Michael L. (Department: 1621)

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

Organic compounds

Oxygen containing

C568S640000, C568S648000, C568S744000, C568S763000, C568S764000, C568S766000, C568S772000, C568S799000

Reexamination Certificate

active

06806395

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a process for producing 3,5-diisopropylphenol or a similar compound, which serves as an intermediate for producing anti-inflammatory agents, pesticides, etc.; to a carbinol compound for use in production of the phenol compound; and to a process for producing the carbinol compound.
BACKGROUND ART
3,5-Diisopropylphenol is an essential synthesis intermediate for producing, for example, pyridine derivatives (WO 99/24404) serving as anti-inflammatory agents, as well as carbamate derivatives (Japanese Patent Application Laid-Open (kokai) No. 51-112519) serving as pesticides.
Conventionally, 3,5-diisopropylphenol is produced through any of a variety of synthesis processes employing 1,3-diisopropylbenzene as a starting material. Such processes include those represented by the following known synthesis schemes a and b:
(Journal of Organic Chemistry Vol. 36, p. 193-196 (1971)) and
(Journal of Organic Chemistry Vol. 32, p. 585-588 (1967)).
However, syntheses performed through any of these two schemes have drawbacks. For example, when synthesis scheme a is employed, cumbersome purification steps are required and overall yield is low (approximately 45%). Although synthesis scheme b includes only two steps, introduction of an amino group by use of trichloroamine, which is toxic and explosive, performed in the first step raises a problem in terms of safety, and low yield as low as 8% is another problem.
Japanese Patent Application Laid-Open (kokai) No. 61-152635 and U.S. Pat. No. 2,790,010 disclose a two-step process for synthesizing 3,5-diisopropylphenol employing 1,3,5-triisopropylbenzene as a starting material as shown in the following synthesis scheme c.
Although overall yield reaches 56%, synthesis scheme c also has drawbacks such as transformation to a toxic, explosive peroxide intermediate having poor stability and requirement of rectification for yielding a final product. Accordingly, synthesis schemes a to c have been unsuitable for synthesizing 3,5-diisopropylphenol on a large scale.
In addition to synthesis schemes a to c, there have been reported related synthesis methods including alkylation of a phenol species by use of propene (Japanese Patent Application Laid-Open (kokai) Nos. 46-6018 and 54-61131). However, the methods are not practical, since selectivity and yield are poor, and formed isomers are difficult to separate from one another.
DISCLOSURE OF THE INVENTION
Thus, an object of the present invention is to provide a process for producing 3,5-bisalkylphenol of high purity, which process comprises a small number of steps and attains high production efficiency and yield with high safety.
In view of the foregoing, the present inventors have carried out extensive studies on a process suitable for producing 3,5-bisalkylphenol on a large scale, and have found that 3,5-bisalkylphenol can be produced at high yield through a two-step or three-step process employing a novel carbinol compound as an intermediate which is obtained by alkylating an isophthalate ester derivative. The present invention has been accomplished on the basis of this finding.
Accordingly, the present invention provides a process, as shown in the following reaction scheme:
[wherein R
1
represents a hydrogen atom, an alkali metal atom, an alkaline earth metal atom, or a hydroxyl-protecting group (other than methyl group); R
2
represents a C1 to C5 lower alkyl group or an optionally substituted phenyl group; and each of R
3
and R
4
, which may be identical to or different from each other, represents a lower alkyl group, an aralkyl group, or an aryl group], for producing 3,5-bisalkylphenol (2), characterized by comprising reacting an isophthalate ester derivative represented by formula (3) with a metallic alkylating agent, to thereby form a carbinol compound represented by formula (1) (step-1), and subsequently, hydrogenolyzing the carbinol compound and, in accordance with needs, removing the hydroxyl-protecting group (step-2).
The present invention also provides a carbinol compound represented by formula (1) shown in the above reaction scheme.
The present invention also provides a process for producing 3,5-bisalkylphenol (2) characterized by comprising hydrogenolyzing a carbinol compound represented by formula (1) shown in the above reaction scheme and, in accordance with needs, removing the hydroxyl-protecting group.
The present invention also provides a process for producing a carbinol compound represented by formula (1) characterized by comprising reacting an isophthalate ester derivative represented by formula (3) shown in the above reaction scheme with a metallic alkylating agent.


REFERENCES:
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patent: 4460800 (1984-07-01), Orlando et al.
patent: 1698 (1979-05-01), None
patent: 1296619 (1972-11-01), None
patent: 61-152635 (1986-07-01), None
D.P. Hsu et al.: “Synthesis and reactions of a zirconocene-benzdiyne equivalent” Tetrahedron Letters, vol. 31, No. 39, pp. 5563-5566 1990.
W.J. Noble et al.: “The effect of pressure on the allylation of hindered phenoxides” J. Org. Chem., vol. 36, No. 1, pp. 193-196 1971.

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