JP3517936B2 - Method for producing 1,3-dioxolan - Google Patents

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing 1,3-dioxolane used as an intermediate for organic synthetic chemicals such as pharmaceuticals and agricultural chemicals.

[0002]

BACKGROUND OF THE INVENTION 1,3-Dioxolane is represented by the structural formula shown in Chemical formula 1. However, in Chemical formula 1, R1, R2, R3, R4
Represents hydrogen, an alkyl group, a substituted alkenyl group, or an aryl group, and R5 and R6 are> CR1R2 groups,> CR3R4.
Represents one of the groups (> has two single bonds).

[0003]

[Chemical 1]

This diol derivative is a very useful substance as an intermediate when synthesizing organic synthetic drugs such as pharmaceuticals and agricultural chemicals. For example, a diol derivative is synthesized by adding a metal halide compound as a coupling agent and a reducing agent made of a metal such as Mg or Zn to a ketone compound or an aldehyde compound as a raw material, or a metal halide compound. Methods such as synthesizing by adding a coupling agent consisting of a complex with a reducing agent [EJCorey, RL Danheiser,
S, Chandrasekaran, J.Org.Chem, 41, 260 (1976), G.Ne
umann, WP Neumann, J. Org. Chem, 42, 277 (1972)] are known.

[0007] These methods have a problem that the yield cannot be expected to improve unless a reaction medium such as a coupling agent or a reducing agent is added to the raw materials in an amount equal to or more than the equivalent amount. It is economically disadvantageous to add a large amount of the reaction medium equal to or more than the equivalent amount, and a complicated step of removing the reaction medium is required after completion of the reaction, which disadvantageously reduces the yield of the diol derivative. is there. Secondly, there is a problem that a large amount of reaction by-products are produced unless the reaction temperature of the raw materials is precisely controlled around 0 ° C. The formation of a large amount of reaction by-product requires a multi-step process for removing it by the end of the reaction, and further has a drawback of lowering the yield of the diol derivative. Moreover, although the diol derivative was obtained through precise temperature control, its purity was still insufficient, for example, 90% or less, and it was not sufficiently satisfactory.

[0006]

Therefore, the present invention has been made in view of such circumstances, and its object is to precisely prepare intermediates of various diol compounds such as pharmaceuticals and agricultural chemicals. It is an object of the present invention to provide a novel method for synthesizing highly pure 1,3-dioxolane in high yield without the need for precise temperature control and a large amount of reaction medium.

[0007]

The present inventors have used a catalyst made of a specific metal for a ketone compound or an aldehyde compound, which is a raw material of 1,3-dioxolane, and activated the catalyst by a Lewis acid. The present invention has been accomplished by finding that the above problems can be solved by reacting with a raw material in the presence of an agent and a reducing agent composed of a simple metal. That is, in the method for producing 1,3-dioxolane of the present invention, a ketone compound or an aldehyde compound is used as a raw material, and the ketone compound or the aldehyde compound is added to a group 2 to group 4 compound.
A reducing agent made of a group metal, a catalyst made of a vanadium compound, and an activator made of a Lewis acid are added, and a ketone compound or an aldehyde compound is reacted in a soluble solvent of the catalyst to give 1,3-dioxolane. It is characterized by synthesizing.

The reaction formula for synthesizing 1,3-dioxolane by the method of the present invention is shown as follows. In the chemical formula 2, R1, R2, R3 and R4 each represent hydrogen, an alkyl group, a substituted alkenyl group or an aryl group, and R5 and R6 are>
It represents either a CR1R2 group or a> CR3R4 group (> has two single bonds). However, the starting ketone compound or aldehyde compound also includes a cyclic compound.

[0009]

[Chemical 2]

This reaction is carried out in an inert gas atmosphere with stirring in a solvent. The solvent is a soluble solvent for the catalyst. Needless to say, the inert gas is He, Ne, Ar, N ₂ or the like gas that does not participate in the reaction.

The preferred ketone compound or aldehyde compound used as the raw material of the present invention is preferably R1 to
When R6 is an alkyl group, for example, the alkyl group is methyl, ethyl, isobutyl, hexyl, cyclohexyl, n-octyl, 2-ethylhexyl, isooctyl, sec-octyl, nonyl, etc. and an alkoxyl group, amino group, alkenyl group. , Also includes an alkyl group substituted with an aryl group.

As the material used as the reducing agent in the production method of the present invention, any metal may be used as long as it is a metal of groups 2 to 4, for example, a transition metal of groups 2 to 4,
Mg, Al, Zn and the like can be preferably used, and among these, Cu and Zn are particularly preferably used, and these metals are added, for example, in the form of powder or granules.

The amount of the reducing agent added is not particularly limited, but is usually in the range of 0.1: 1 to 10: 1 (reducing agent: raw material) in terms of molar ratio with respect to the ketone compound or aldehyde compound as the raw material. , And more preferably 0.5: 1 to 2:
It is preferably adjusted to 1. This is because the purity of the obtained 1,3-dioxolane tends to be lowered if it is outside this range.

The vanadium compound used as a catalyst has 1
A vanadium compound having a valence of 5 to 5 can be used, and a vanadium compound having a valence of 1 to 3 can be preferably used. Particularly preferred catalysts having 1-3 valence of the general formula _Cp a _VO b _{X c} (where, C
p is a cyclopentadienyl group, or a compound containing a cyclopentadienyl group, X is any one selected from a halogen atom, an alkoxyl group, a carbonyl group, a carboxylic acid group, a phosphine group, or a group of these groups. A compound containing any one of them, 0 ≦ a ≦ 4, 0 ≦ b ≦ 2, 1 ≦ c
It is in the range of ≦ 4. The vanadium catalyst represented by 4) can be used, for example, cyclopentadienyl vanadium tetracarbonyl, vanadocene dichloride, vanadocene, vanadium trichloride, vanadium dichloride, etc. can be enumerated. Other catalysts having a valence of 4 to 5 may be vanadyl chloroalkoxides such as vanadyl dichloroethoxide and vanadyl dichloropropoxide, and vanadyl alkoxides such as vanadyl ethoxide and vanadyl propoxide. In the vanadium catalyst, when an activator and a reducing agent are coexistent, a sufficient addition of a small amount of catalyst can provide a sufficient catalytic action. The greatest advantage is that it can be performed at room temperature without doing so.

Particularly, the addition amount of the vanadium compound as a catalyst is 10 with respect to the ketone compound or the aldehyde compound.
^-4 to 40 mol%, more preferably 0.01 to 20 mol% is preferably adjusted. Because 10
^{If it} is less than ^-4 mol%, a sufficient catalytic action cannot be obtained even if a sufficient amount of activator and reducing agent coexist, and the reaction is difficult to proceed. If it is more than 40 mol%, the catalyst is removed after the reaction. This is because it takes time and effort, and the yield of the obtained 1,3-dioxolane tends to decrease.

Next, Lewis acids used as activators include chlorotrimethylsilane, chlorotriethylsilane, chlorotriisopropylsilane, chlorodimethylphenylsilane, chlorodiethylphenylsilane, chloroalkylphenylsilane, bromotrimethylsilane and dichlorodimethyl. A halogenated silane compound such as silane can be preferably used. It is not possible to obtain 1,3-dioxolane without using these Lewis acids. Further, the halogenated silane compound is convenient for increasing the yield since it can be easily separated by hydrolysis when separating the obtained 1,3-dioxolane after the reaction.
Among them, the chlorosilane compound is particularly highly reactive as compared with other Lewis acids, and the present invention is very effective.

The addition amount of the Lewis acid as the activator is not particularly limited, but it is usually adjusted to the range of 1 to 500 mol%, more preferably 50 to 150 mol% based on the ketone compound or the aldehyde compound. To do. 1 mol%
When the amount is less than the above, the effect of the catalyst is reduced to make the reaction difficult to proceed, and the yield of the obtained 1,3-dioxolane is extremely reduced. It takes time to separate Lewis acid,
The yield of 1,3-dioxolane tends to decrease.

In the production method of the present invention, 1,3-dioxolane of high purity can be obtained by freely combining the above-mentioned reducing agent addition amount, catalyst addition amount and activator addition amount.
It can be obtained in high yield.

As the reaction solvent, it is necessary to use a solvent in which the catalyst is dissolved. Although the catalyst and the activator are used together in the catalyst in the present application, 1,3-dioxolane can be obtained in high yield by using a solvent in which the vanadium compound as the catalyst is dissolved. Specific examples of the solvent include ethers such as diethyl ether, dimethoxyethane and tetrahydrofuran, nitriles such as acetonitrile and benzonitrile, amides such as N, N-dimethylformamide and N-methylpyrrolidone, and dichloromethane and chloroform. Halogen-based hydrocarbon, and n
-Linear or aromatic hydrocarbons such as hexane, toluene and benzene can be used.

[0020]

The production method of the present invention requires the vanadium catalyst as a catalyst, the Lewis acid as an activator, and the reducing agent to coexist in the reaction system, so that the reduction reaction catalytically proceeds. The amount of catalyst to be used (metal catalyst) is small.
It is speculated that this reaction builds a reversible redox cycle as shown in FIG.

The vanadium catalyst can be easily converted into an oxidized type or a reduced type depending on the system using the catalyst. In the reduced form, a monovalent to divalent vanadium catalyst is often used. The method for producing 1,3-dioxolane of the present invention has the following effects by using the vanadium catalyst in the reduced system.

According to the method of the present invention, as shown in FIG.
The reduction reaction of the carbonyl compound deactivates the reduced vanadium catalyst to the oxidized form. However, the action of the reducing agent causes the oxidized vanadium catalyst to return to the reduced form again. Since the restored reduced vanadium catalyst can act on the reduction reaction again,
Since the vanadium catalyst can be recycled, the amount of catalyst used can be small. Further, since the vanadium catalyst advances the reaction at room temperature, 1,3-dioxolane can be obtained in a high yield without controlling the reaction temperature as in the conventional case. Although the mechanism for the reduction reaction of this Lewis acid is not necessarily clear, it is presumed that it has the effect of increasing the reactivity of the carbonyl compound raw material, activating the reducing raw material, and efficiently rotating the redox cycle. This effect is particularly great with halogenated silane compounds. Moreover, since the reaction is performed at room temperature as described above, this redox cycle occurs smoothly. In addition, since this redox cycle can be generated in a wide temperature range of −80 ° C. to 120 ° C., the reaction temperature can be performed in this temperature range at the same time, and it is not necessary to control the temperature as in the conventional case.

[0023]

EXAMPLES Example 1 In a reaction vessel, 0.0334 g (0.146 mmo) of cyclopentadienyl vanadium tetracarbonyl as a catalyst was used as a catalyst.
l) and 0.479 g (7.32) of metallic zinc as a reducing agent.
mmol) and 9.8 ml of dimethoxyethane as a solvent for the catalyst, and the mixture was stirred in an argon atmosphere until the whole became uniform.

Next, 0.62 ml (4.88 mmol) of chlorotrimethylsilane was added as an activator, and finally n-hexanal.
586 ml (4.88 mmol) was added, and the mixture was stirred and reacted at room temperature for 3 hours in the same argon atmosphere.

After completion of the reaction, chloroform was added to the obtained slurry-like solution to extract an organic layer, which was washed with dilute hydrochloric acid. After washing, the organic layer was concentrated, and this was converted into 1,3-dioxolane by the column chromatography method to obtain 2,4,4.
95% yield of 5-tripentyl-1,3-dioxolane
Got with. When the purity of this derivative was measured by gas chromatography, it was 98%.

Example 2 Synthesis, post-treatment were carried out in the same manner as in Example 1 except that chlorodimethylphenylsilane was added as the activator in the same mole number instead of chlorotrimethylsilane, and then 2, 4, 5 −
Tripentyl-1,3-dioxolane was obtained with a yield of 92%. The purity of this derivative was 95%.

[Example 3] Synthesis and post-treatment were carried out in the same manner as in Example 1 except that vanadocene dichloride was added as the catalyst in the same mole number instead of cyclopentadienyl vanadium tetracarbonyl.
2,4,5-Tripentyl-1,3-dioxolane was obtained with a yield of 92%. The purity of this derivative was 95%.

Example 4 Synthesis and post-treatment were carried out in the same manner as in Example 1 except that hydrocinnamaldehyde was added as the carbonyl compound in place of n-hexanal in the same number of moles, and 2,4 by column chromatography. , 5-triphenethyl-1,
3-Dioxolane was obtained with a yield of 98%. The purity of this derivative was 98%.

Example 5 This example is a method for specifically obtaining a diol compound from the derivative obtained in Example 1. 100 with reflux condenser
2, 4, 5 obtained in Example 1 in a four-necked 4-ml flask.
-Tripentyl-1,3-dioxolane 0.413 g
(1.45 mmol), ethanol 30 ml, water 4 m
1, 1 ml of concentrated hydrochloric acid were added, and the mixture was refluxed at about 90 ° C. for 50 hours to hydrolyze 1,3-dioxolane.

After hydrolysis, as an after-treatment, diethyl ether was added to extract the organic layer, and 5,6-dodecanediol was obtained by column chromatography at a yield of 80%. The purity of this 5,6-dodecanediol is 95.
%Met.

COMPARATIVE EXAMPLE 1 Synthesis and post-treatment were carried out in the same manner as in Example 1 except that the activator was not added, but no 2,4,5-tripentyl-1,3-dioxolane was obtained. It was

[Comparative Example 2] In Example 1, when the vanadium catalyst was not added and the reaction temperature was room temperature and synthesis was performed and post-treatment was carried out, the yield decreased to only 5%.

Comparative Example 3 Tetrahydrofuran 10 ml, mercury chloride 0.60 g, and metallic magnesium 1.92 g (0.07) were placed in a reaction vessel.
9 mmol) and stirred in an argon atmosphere until magnesium amalgam (cocatalyst) was produced.

After stirring, the supernatant of the slurry-like solution was extracted, this supernatant was cooled to -10 ° C, and 4.4 ml (0.040 mmol) of titanium (IV) tetrachloride as a catalyst was added dropwise. . Further, as a carbonyl compound as a raw material, 0.98 g (0.010 mmol) of cyclohexanone,
A tetrahydrofuran solution containing 1.74 g (0.030 mmol) of acetone was added, and the temperature was kept at 0 ° C. to 1.
The reaction was carried out for 5 hours.

After the completion of the reaction, post-treatment was carried out in the same manner as in Example 1 to obtain 1- (2-hydroxy-2-propyl) cyclohexanal in a yield of 76 by column chromatography.
Earned in%. The purity of this derivative was 90%.

[0036]

As described above, according to the method of the present invention, highly pure 1,3-dioxolane can be obtained in a high yield. Moreover, by using a vanadium catalyst as a catalyst, the reaction system can be carried out in a wide range including −80 ° C. to 120 ° C. including room temperature. Furthermore, the amount of vanadium catalyst used can be reduced by the action of the Lewis acid that is the activator, and 1,3-dioxolane can be obtained at low cost. Thus, when 1,3-dioxolane is synthesized by coexisting three kinds of a vanadium catalyst, a Lewis acid as an activator, and a reducing agent with a ketone compound or an aldehyde compound, a high-purity derivative with a high yield is obtained,
Its industrial value is enormous.

[Brief description of drawings]

FIG. 1 is a diagram showing a redox cycle for explaining the action of a material used in the present invention.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ identification code FI C07B 61/00 300 C07B 61/00 300 (56) Reference JP-A-5-271217 (JP, A) JP-A-3-74381 (JP, A) JP 58-157734 (JP, A) JP 57-158777 (JP, A) JP 57-158733 (JP, A) JP 63-146838 (JP, A) Publication 47-70 (JP, B1) (58) Fields investigated (Int.Cl. ⁷ , DB name) C07C 31/20 C07C 29/10 C07D 317/12 CASREACT (STN)

Claims (3)

(57) [Claims] 1. A ketone compound or an aldehyde compound is used as a raw material, and a reducing agent made of a metal of Groups 2 to 4, a catalyst made of a vanadium compound, and an activator made of a Lewis acid are added to the raw material. A method for producing 1,3-dioxolane, which comprises synthesizing by reacting raw materials in a soluble solvent for the catalyst. 2. The catalyst is added in an amount of 10 with respect to the raw material.
^-4 to 40 mol%, The method for producing 1,3-dioxolane according to claim 1, wherein 3. The method for producing 1,3-dioxolane according to claim 1, wherein the Lewis acid is a halogenated silane compound.