JP2558275B2 - Method for producing geranylphenyl sulfone - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention is represented by the general formula (I). (In the formula, R represents a hydrogen atom or a lower alkyl group,
The double bond does not distinguish stereoisomerism) and a method for producing geranyl sulfone. The geranyl sulfone of the general formula (I) provided in the present invention is
For example, after the ring-closing reaction, it can be led to cyclogeranylphenylsulfone which is useful as a synthetic intermediate of vitamin A acetate used as a drug or a feed additive (Japanese Patent Publication No. 57-48549 and J. Odera et al. Org. Chem 5
1 , 3834 (1986)).

[Conventional technology]

Conventionally, as a method for producing geranylphenyl sulfone, a method using myrcene as a raw material, a method using linalyl acetate as a raw material, a method using geranyl bromide as a raw material, and the like are known.

[Problems to be Solved by the Invention] Both of the above-mentioned conventional methods 1) and 2) require expensive reagents such as palladium.
Further, the method of 3) using geranyl bromide requires geranyl bromide itself to be synthesized from relatively expensive geraniol and phosphorus tribromide, which makes it difficult to carry out the conventional method on an industrial scale. I have to.

[Means for solving problems]

The present inventors have prepared a mixture of linalyl chloride and geranyl chloride obtained by reacting myrcene with hydrogen chloride or linalool with thionyl chloride, using a hydrocarbon solvent as a reaction solvent, and using a halogenated tetraalkylammonium salt. It was found that the geranylphenyl sulfone represented by the general formula (I) can be industrially advantageously produced by reacting with phenylsulfinate in the presence of

According to the present invention, geranylphenyl sulfone represented by the general formula (I) can be produced in good yield from raw materials that are inexpensive and easily available, without using a special reagent.

The synthesis reaction of geranylphenyl sulfone according to the method of the present invention can be represented by the following formula.

The reaction of myrcene with hydrogen chloride according to the method of the present invention can be carried out in the presence of a copper catalyst. As the copper catalyst, cuprous and cupric derivatives such as chlorides, bromides, carbonates, formates, acetates, sulfates and oxides are used, and cuprous chloride is particularly preferable. The amount of the catalyst used is 0.01 to 10% by weight based on dry myrcene. The addition reaction of hydrogen chloride to myrcene can be accomplished by introducing gas into the mixture of myrcene and the above copper catalyst. The amount of hydrogen chloride used is 0.
8 to 1.2 times the molar amount. It is also possible to use hydrogen chloride in excess of 1.2 mol times, but due to excess hydrogen chloride, the target linalyl chloride, neryl chloride and geranyl chloride undergo further hydrogen chloride addition reaction, resulting in the yield of the target product. It causes a decrease. The reaction is carried out at a temperature in the range of about -20 ° C to 50 ° C, preferably about 0 ° C to 15 ° C.

The reaction between linalool and thionyl chloride is generally hexane,
It is carried out in a hydrocarbon solvent such as benzene or toluene or in an ether solvent such as diethyl ether, isopropyl ether or tetrahydrofuran. Further, it is preferable to coexist with amines such as pyridine and triethylamine in order to promote hydrogen chloride produced as a by-product in the reaction. The reaction can be carried out at a temperature in the range 0 ° C to 70 ° C, preferably in the range 20 ° C to 40 ° C. In the reaction of myrcene with hydrogen chloride and the reaction of linalool with thionyl chloride according to the method of the present invention, usually linalyl chloride and geranyl chloride are obtained as a mixture. The production rate of these compounds varies considerably depending on the reaction conditions, but the production rate of linalyl chloride is usually about 5 to 40%.

The mixture of linalyl chloride and geranyl chloride is then subjected to reaction with phenylsulfinate in the presence of a tetraalkylammonium halide salt. The phenylsulfinate used in this reaction is specifically represented by the general formula (II) (In the formula, R represents a hydrogen atom or a lower alkyl group, and
Is a sodium atom or a potassium atom), and this reaction is usually carried out in an anhydrous system.

Next, R in the general formulas (I) and (II) and M in the general formula (II) will be described. R is hydrogen, a lower alkyl group such as a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group and a t-butyl group, and these lower alkyl groups are sulfinic acid. It may be substituted at any of the ortho position (o-), the meta position (m-), and the para position (p-) with respect to the salt position. The most preferable R among these is a hydrogen atom and a methyl group. M is a sodium atom and a potassium atom. The amount of phenylsulfinate used is generally equimolar or more, preferably equimolar to 2 molar times with respect to the total amount of linalyl chloride and geranyl chloride.

The halogenated tetraalkylammonium salt used in this reaction has a total of 8 to 32 carbon atoms in the four alkyl groups.
It is good to be within the range of the degree, and specific examples include tetra-n-butylammonium halide and tetra-halogen halide.
Examples thereof include n-pentyl ammonium and stearyl trimethyl ammonium halide. Among the halogen atoms used for halogenation, an iodine atom is particularly preferable, and when an iodinated tetraalkylammonium salt is used, the compound represented by the general formula (III) (In the formula, R represents a hydrogen atom or a lower alkyl group), the production of linalylphenyl sulfone is suppressed, and the target geranylphenyl sulfone can be obtained in a high yield. The tetraalkylammonium halide salt is generally 0.1 to 30 mol%, preferably 0.1 to 30 mol%, based on the total amount of linalyl chloride and geranyl chloride.
It is used in a proportion of 0.5 to 10 mol%.

A reaction solvent is used in this reaction, and as the reaction solvent, an aliphatic hydrocarbon such as hexane, heptane, and octane and a hydrocarbon solvent such as aromatic hydrocarbon such as benzene, toluene, and xylene are used. Of these, toluene is particularly suitable. The reaction temperature can be selected from the range of 0 ° C to 150 ° C, preferably 50 ° C to 120 ° C.

 Hereinafter, the present invention will be described in detail with reference to examples.

Example 1 Hydrogen chloride gas was sucked into a mixed solution of 188.5 g of myrcene (83% purity, 1.15 mol) and 0.7 g of copper (I) chloride at a temperature of 0 to 8 ° C until the myrcene disappeared, and at that temperature. further
Stir for 20 hours. After pouring into 100 ml of water, add 100 ml of toluene for extraction, and extract the toluene layer with 100 ml of water and 100 m of 5% sodium bicarbonate water.
l and 100 ml of water were successively washed, and the solvent was distilled off under reduced pressure to obtain 235.3 g of an oily substance. As a result of analysis by gas chromatography, this was a mixture of linalyl chloride and geranyl chloride in the ratio of 10.8 to 89.2.

Gas chromatographic analysis conditions Column: PEG20M, 2m Column temperature: 100 ° C (2 minutes later, the temperature was raised to 150 ° C at 10 ° C / minute) Sodium benzenesulfinate dihydrate 215 g (1.07)
Mol) and 100 ml of toluene, and use a water separator at 90 ℃
Water was distilled off while heating from 1 to 110 ° C. Then 105
The mixture was cooled to 0 ° C, 3.76 g (10.2 mmol) of iodinated tetra-n-butylammonium salt was added, and 235.3 g of the mixture of linalyl chloride and geranyl chloride obtained by the above method was added dropwise over 20 minutes at the same temperature. Stir for 2 hours. After cooling, the solid matter was separated, the solution was washed with 100 ml of 1% aqueous sodium thiosulfate and 100 ml of water, and the solvent was distilled off under reduced pressure to obtain 287.3 g of an oily matter. As a result of analysis by gas chromatography, the target geranylphenyl sulfone was 261.2 g, and the yield from myrcene was 81%. The ratio of geranyl phenyl sulfone to linalyl phenyl sulfone was 97.7: 2.3.

Gas chromatography analysis conditions Column; Themon1000, 1m Column temperature; 100 ° C (heated to 250 ° C at 10 ° C / min) Example 2 Linalool 50g (0.325mol) Pyridine 26.9g (0.341mo)
l) and hexane (450 ml) under vigorous stirring at an internal temperature of 30
While maintaining the temperature at 4 ° C, 40.6 g (0.341 mol) of thionyl chloride was gradually added dropwise, and the mixture was further stirred for 2 hours. The reaction solution was poured into 500 ml of ice water, the hexane layer was separated, and 100 ml of 5% sodium bicarbonate solution was added.
It was washed with 00 ml of water and 100 ml of saturated saline. After drying over anhydrous sodium sulfate, the solution was removed to obtain 55.2 g of a pale yellow oil. As a result of analysis by gas chromatography, this was a mixture of linalyl chloride and geranyl chloride in the ratio of 31:69.

Sodium penzensulfinate dihydrate 64.53 g (0.
(32 mol), add 300 ml of toluene, and use a water separator to make 90
Water was distilled off while heating from ℃ to 110 ℃. Then 1
The mixture was cooled to 05 ° C., 1.13 g (3.06 mmol) of tetra-n-butylammonium iodide was added, and the mixture of the linalyl chloride and geranyl chloride obtained above was added 55.2.
g was added dropwise over 20 minutes, and the mixture was stirred at the same temperature for 2 hours. After cooling, the solid matter was separated, and the liquid was washed with 30 ml of 1% sodium thiosulfate and 30 ml of water. The solvent was distilled off under reduced pressure to obtain 78.2 g of an oily substance. As a result of analysis by gas chromatography, the target geranylphenyl sulfone was 63.25 g, and the yield from linalool was 70%. The ratio of geranyl phenyl sulfone to linalyl phenyl sulfone was 95.0 to 5.0.

〔The invention's effect〕

According to the present invention, geranylphenyl sulfone represented by the general formula (I) can be produced in good yield from inexpensive and easily available raw materials. This compound can lead to cyclogeranylphenyl sulfone, which is useful as a synthetic intermediate of vitamin A acetate, by a ring closure reaction.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A-58-52267 (JP, A) JP-A-59-42359 (JP, A) JP-A-60-41623 (JP, A) Synthesis, 733, ( (1979)

Claims (1)

(57) [Claims] 1. A halogenated tetraalkylammonium salt prepared by reacting a mixture of linalyl chloride and geranyl chloride obtained by reacting myrcene with hydrogen chloride or by reacting linalool with thionyl chloride, using a hydrocarbon solvent as a reaction solvent. The following formula (I), characterized by reacting with phenylsulfinate in the presence of (In the formula, R represents a hydrogen atom or a lower alkyl group,
The double bond does not distinguish stereoisomerism.) The method for producing geranylphenyl sulfone.