Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Reexamination Certificate
2000-08-28
2001-10-30
Richter, Johann (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
Reexamination Certificate
active
06310255
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a process for producing hinokitiol (another name: &bgr;-thujaplicin).
Hinokitiol produced in the present invention has not only antimicrobial and antifungal effect on a wide spectrum of bacteria and fungi but also cell-activating effect, inhibitory effect on tyrosinase activity, inhibitory effect on ethylene production in plants, etc. It is effective as an antimicrobial and antifungal agent when incorporated into medicines, cosmetics, hair tonics, shampoos or soaps, and it is incorporated also into freshness-maintaining films, antimicrobial coating materials, etc.
BACKGROUND ART
As processes for producing hinokitiol, the following processes have been known:
(i) a process in which hinokitiol is produced from methoxytropylidene via isopropyltropone and aminoisopropyltropone (Tetrahedron., 32, 1051 (1991));
(ii) a process in which hinokitiol is produced through 6 steps such as acetalization after epoxidation of carvone with hydrogen peroxide (JP-A-62-93250);
(iii) a process in which hinokitiol is produced by converting isopropylcyclohexanone or isopropylcyclohexenone to cyanohydrin, and then synthesizing isopropylcycloheptanone through two steps, followed by oxidation, bromination and dehydrobromination (JP-A-63-5048 and JP-A-63-17841); and
(iv) a process of reacting bromotropolone with an organotin compound, followed by reduction with hydrogen in the presence of Pd/C catalyst (J. Chem. Soc., Chem. Commun., 1989, 616 (1989)).
These processes cannot be industrially practical because they comprise many steps or the starting materials are difficult to obtain.
As another production process, there is known a process of obtaining isopropylcyclopentadiene by the use of cyclopentadiene as a starting material, adding a dichloro-ketene to the isopropylcyclopentadiene, and subjecting the adduct to solvolysis. This process is industrially advantageous because the starting cyclopentadiene is easily available and the process comprises a small number of steps. It is known that in this process, hinokitiol is produced only from 1-isopropylcyclopentadiene among three isomers of isopropylcyclopentadiene. Therefore, investigations are conducted in order to increase the yield of the desired compound hinokitiol or reduce the troublesomeness of a purification step, by selectively synthesizing 1-isopropylcyclopentadiene. That is, the production of 1-isopropylcyclopentadiene with high selectivity is important in hinokitiol production.
As such a process, there are, for example, the following processes:
(v) a process in which hinokitiol is produced by reacting cyclopentadiene with a Grignard reagent (ethylmagnesium bromide) and isopropyl tosylate to obtain 1-isopropylcyclopentadiene with high selectivity, adding a dichloroketene to the 1-isopropylcyclopentadiene, and subjecting the adduct to solvolysis (JP-B-51-33901); and
(vi) a process in which hinokitiol is produced by reacting cyclopentadiene with acetone under basic conditions to obtain 6,6-dimethylfulvene, reducing the 6,6-dimethylfulvene with a dialkylaluminum hydride to obtain 1-isopropylcyclopentadiene selectively, adding a dichloro-ketene to the 1-isopropylcyclopentadiene, and subjecting the adduct to solvolysis (JP-A-8-40971).
These processes are superior to the above processes (i) to (iv) because hinokitiol is obtained by fewer steps by using easily available and inexpensive cyclopentadiene as a starting material. But, they have the following defects: since a reagent requiring extreme nonaqueous conditions (i.e. the Grignard reagent in (v) or the dialkylaluminum hydride in (vi)) should be used, great precautions are necessary in handling the reagent; a solvent to be used and the like should be subjected to a special dehydration procedure; and these reagents are generally expensive. Thus, these processes for producing hinokitiol via 1-isopropylcyclopentadiene are also industrially disadvantageous.
The present inventors found that among isomers of isopropylcyclopentadiene, 5-isopropylcyclopentadiene is isomerized selectively to 1-isopropylcyclopentadiene by heat near room temperature. That is, the present inventors found that for hinokitiol production, it is important to synthesize 5- or 1-isopropylcyclopentadiene or a mixture thereof with high selectivity by the use of inexpensive and easily handleable reagents, while inhibiting the production of 2-isopropylcyclopentadiene as much as possible.
It is generally known that as described above, an alkylcyclopentadiene has three isomers 5-, 1- and 2-alkylcyclopentadienes due to the positions of the alkyl group. In a thermodynamically stable equilibrium state, an alkylcyclopentadiene is an isomer mixture consisting of substantially equal amounts of the 1-isomer and the 2-isomer and a small amount of the 5-isomer.
The following various processes for producing an alkylcyclopentadiene by alkylating cyclopentadiene have been known though they are not a process for producing hinokitiol:
(vii) a process of reacting cyclopentadiene with an aliphatic lower alcohol in the presence of a catalyst in a vapor phase (JP-B-4-27215) and a process of reacting cyclopentadiene with ethylene on a hydrocarbon in a vapor phase (Journal of Chemical Society of Japan, 1977 (3), p. 375 (1977));
(viii) a process of reacting cyclopentadiene with metallic sodium in liquid ammonia and then with an equal amount of an alkyl halide (Izv. Vyssh. Vchebn, Zaved., Khim. Khim. Technol., 19 (10), p. 1511 (1970));
(ix) a process of reacting cyclopentadiene with an alkyl halide in an aqueous metal hydroxide solution in the presence of a phase transfer catalyst such as a quaternary ammonium salt (U.S. Pat. No. 3,560,583) and a process of reacting cyclopentadiene with an alkali metal hydroxide in an organic solvent in the presence of a dehydrating agent such as calcium oxide to produce a cyclopentadienyl metal and reacting the cyclopentadienyl metal with an alkyl halide (Russian Patent No. 520341);
(x) a process in which a Grignard reagent (an alkylmagnesium bromide) is used as in the above prior art (v) and a 1-alkylcyclopentadiene is selectively obtained by reacting a Grignard reagent of cyclopentadiene with an alkyl halide or an alkylsulfuric acid (Montasch. Chemie., 91, 805-812 (1960));
(xi) a process in which as the first step in the production process of a prostaglandin, the 1-isomer is produced by obtaining cyclopentadienyllithium from cyclopentadiene and an alkyllithium and reacting the cyclopentadienyllithium with ethyl 7-bromoheptanoate (JP-B-53-33583);
(xii) a process in which the 1-isomer or 5-isomer is produced by obtaining a cyclopentadienyl metal solution from metallic sodium and cyclopentadiene in an organic solvent such as dimethoxyethane or diglyme and adding the solution dropwise to an alkylating agent (Tetrahedron, vol. 21, 2313 (1965));
(xiii) a process in which as the first step in the production process of a norbornene derivative, cyclopentadienylsodium is produced by reacting cyclopentadiene with sodium hydride in tetrahydrofuran solvent, and an alkylating agent is added dropwise to the cyclopentadienylsodium at a low temperature (described in the Referential Examples of JP-A-54-63063); and
(xiv) a process in which as the first step in the production process of optically active cyclopentenediol, an alkylcyclopentadiene is obtained by reacting cyclopentadiene with an alkylating agent in the presence of a base (JP-A-6-239779). In this reference, substantially all kinds of alkylating agents are mentioned. As the base, there are mentioned a wide variety of alkali metals, alkaline earth metals, metal hydrides, alkali metal alkoxides, etc. As a solvent for the reaction, there are mentioned diethyl ether, n-hexane, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, etc. It is stated that any solvent may be used so long as it has no undesirable influence on the reaction, and solvents are mentioned with almost no restriction. However, in Examples, there is described only a case of reacting cyclopentadiene with sodium hydride in tetrahydrofuran solvent to produce cyclopen
Nagato Yasuhiro
Shimizu Katsuya
Yamamoto Shin-ichi
Asahi Kasei Kabushiki Kaisha
Pennie & Edmonds LLP
Richter Johann
Witherspoon Sikarl A.
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