JPH064608B2 - Process for producing carboxyalkyl furfuryl alcohol - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial field of application> The present invention provides a compound of the general formula (I) which is useful as an intermediate for pharmaceuticals. (In the formula, n represents an integer of 4 to 8) and an improved process for producing a carboxyalkylfurfuryl alcohol.

<Prior Art> Conventionally, as a method for producing the carboxyalkylfurfuryl alcohol represented by the general formula (I), (a) a method of reacting formyl octanoic acid ester with furyl lithium (Tetrahedron Letters, 1977, 1131 to 1134). ) (b) A method of reacting furan and alkanic acid monoester as raw materials in the presence of trifluoroacetic anhydride (JP-A-53-12746). The method of treatment with the Grignard reagent shown in (J.Org.Che
m., 38 , 36 (1973)) and other methods are known.

<Problems to be Solved by the Invention> However, these methods include, for example, furyllithium, formyloctanoic acid ester, trifluoroacetic anhydride, etc. used in the reaction as seen in the methods (a) and (b). Is expensive, or a protective group is required during the Grignard reaction as in the method (c), and it is not an industrially advantageous production method in terms of economy, operability, etc. such as complicated process and It was

From the above, the present inventors have solved the above problems, and as a result of studies to produce the carboxyalkylfurfuryl alcohol represented by the general formula (I) at low cost and industrially, the present invention Was reached.

That is, the present invention <Means for Solving the Problems> The magnesium and the general formula _{(III) X- (CH 2)} n -X (III) ( wherein, X represents a chlorine atom or a bromine atom, n represents Four
An alkyl dihalide represented by 8 represents an integer of) reacted with the general formula (II) X-Mg- (CH 2) n -Mg-X (II) ( wherein, X and n are as defined above An alkyldimagnesium halide represented by the formula (I), which is reacted with furfural, further reacted with carbon dioxide, and then hydrolyzed.
The present invention provides a method for producing a carboxyalkylfurfuryl alcohol represented by

Hereinafter, the present invention will be described in detail.

The alkyldimagnesium halide represented by the general formula (II) can be easily obtained by reacting magnesium with the alkyldimagnesium halide represented by the general formula (III).

The amount of magnesium used in such a reaction is usually in the range of 1.9 to 3 times, preferably 2 to 2.8 times the mol of the alkyl dihalide. It may be used in an amount of 3 times mol or more, but it is not particularly necessary from the viewpoint of reaction.

In such a reaction, as the reaction initiator or activator, it is possible to use an activator that is usually used for preparing a Grignard reagent such as iodine, 1,2-dihaloethane, dihalomethane, etc.
It can be used in the range of mol%.

Such an activator is used by treating it with magnesium in advance before reacting the alkyl dihalide with magnesium, or by continuously adding it during the reaction.

The reaction of alkyldihalide with magnesium is usually carried out in a solvent, and examples of the solvent include ethers such as tetrahydrofuran, ethyl ether and isopropyl ether, hydrocarbons such as toluene, benzene and xylene, or a mixed solvent thereof. Although used, tetrahydrofuran is preferably used practically.

The amount of the solvent used is usually 3 to 1 with respect to the alkyl dihalide.
The range is 0 times the weight, but use outside this range is also possible.

The reaction temperature is usually 20 to 70 ° C, preferably 30 to 50 ° C.
Is.

The reaction time is not particularly limited.

The starting material alkyl dihalide used here can be used not only as a chlorinated product and as a bromide, but also as a mixture.

The thus obtained alkyldimagnesium halide was reacted with furfural to obtain a Grignard complex (IV).
However, in this reaction, as shown in the following reaction formula, there occurs a problem that the complex (IV) further reacts with the raw material furfural to give a by-product (VI).

In order to suppress such side reactions, it is preferable to adopt the following conditions when carrying out the reaction.

Add the furfural solution to the alkyl dimagnesium halide.

The amount of furfural used is in the range of 2.5 times the molar amount of the alkyldihalide initially used, assuming that the reaction is carried out subsequent to the formation of the alkyldimagnesium halide in the previous step.

The smaller the amount of furfural used, the less the production of by-products, but the lower limit of the amount of furfural used is 0.3 times the amount of alkyldihalide, judging from industrial efficiency, and the amount used is preferably 0.5. To 1.5 times mol, more preferably 0.5 to 1 times mol.

The reaction is usually -70 to 0 ° C, preferably -70 to -20.
℃.

It is effective to add a tertiary diamine such as tetramethylethylenediamine to alkyldimagnesium halide before adding furfural. In this case, the amount of the tertiary diamine used is usually 0.3 to 2.5 times mol, preferably 0.5 to 2 times mol, and more preferably 0.75 times mol of furfural.
~ 1.5 times the molar amount.

As the reaction solvent in this reaction, the same solvent as that used in the preparation of the alkyldimagnesium halide exemplified above is used. The amount of the solvent used is usually 10 to 50 times the weight of furfural.

The reaction time is not particularly limited.

The reaction between the Grignard complex (IV) thus obtained and carbon dioxide is carried out by blowing gaseous carbon dioxide into the Grignard complex (IV) solution.

The amount of carbon dioxide used is 1.8 times mol or more, preferably 2 times mol or more, relative to the starting material alkyl dihalide, and the upper limit thereof is not particularly limited, but is generally 10 times mol. The molar amount is preferably 8 times.

The reaction temperature is generally 20-70 ° C, preferably -10-
It is 60 ° C., and the reaction time is not particularly limited.

By such a reaction, a carboxylated Grignard complex (V) is obtained, which is hydrolyzed by a general means used for hydrolysis of the Grignard complex, for example, an aqueous solution of ammonium chloride, hydrochloric acid, sulfuric acid, boric acid or the like. The desired carboxyalkylfurfuryl alcohol represented by the general formula (I) can be obtained.

Incidentally, the removal of the target compound from the decomposition reaction solution is a conventional means, for example, after extraction from the decomposition reaction solution with an organic solvent,
It can be performed by concentration, distillation, chromatographic separation, or the like.

<Effect of the Invention> Thus, according to the method of the present invention, carboxyalkylfurfuryl alcohol can be obtained at low cost, industrially advantageously, and in good yield.

<Examples> Hereinafter, the present invention will be described with reference to Examples.

Example 1 2.92 g of magnesium and 12.6 g of tetrahydrofuran in a four-necked flask equipped with a stirrer, a thermometer and a dropping funnel.
Is charged, and 0.24 g of 1,6-dibromohexane is added thereto. The internal temperature rises to 30 to 35 ° C. After maintaining the temperature as it is for 10 minutes, a mixture of 7.6 g of 1,6-dichlorohexane and 38 g of tetrahydrofuran is added dropwise over 1 hour.

After the dropping is completed, the temperature is raised to 45 ° C. and the mixture is kept warm at the same temperature for 2 hours while stirring.

Then, after cooling until the internal temperature became −30 to −35 ° C., 2.4 g of furfural and 72 g of tetrahydrofuran
The mixed solution of is added dropwise over 2 hours, and after the addition is completed, the temperature is kept at the same temperature for 30 minutes.

Next, 8.6 g of carbon dioxide gas is blown in at the same temperature for 1 hour. After keeping the same temperature for 30 minutes, the internal temperature is raised to 5 ° C., and 65 g of 15% sulfuric acid is added to perform a decomposition treatment.

100 m of ethyl acetate is added to the reaction solution for extraction, and the mixture is separated into an organic layer and an aqueous layer. The aqueous layer is further extracted with 50 m of ethyl acetate to separate the organic layer.

After the above organic layers were combined, they were concentrated under reduced pressure and concentrated residue 1
Get 0.5g.

To this concentrated residue was added 50 m of toluene to remove insoluble crystals, and then extraction treatment was carried out with 15 g of 5% NaOH insoluble solution.

To the separated aqueous layer, 10 g of 10% sulfuric acid aqueous solution was added to adjust the pH.
After adjusting to 2 or less, 50 m of toluene is added and further extraction treatment is performed.

The separated organic layer was concentrated, and 4.05 g of 2- (ω-carboxy-2'-hydroxyheptyl) furan as a concentration residue
(Purity 97.8%, Yield 70.1%) was obtained.

Example 2 The same four-necked flask as used in Example 1 was charged with 2.92 g of magnesium and 12.6 g of tetrahydrofuran, and 0.24 g of 1,6-dibromohexane was added thereto. Inner temperature is 3
Raises to 0-35 ° C. After maintaining the temperature as it is for 10 minutes, a mixture of 7.6 g of 1,6-dichlorohexane and 38 g of tetrahydrofuran is added dropwise over 1 hour.

After the dropping is completed, the temperature is kept at the same temperature for 2 hours.

Then, at the same temperature, tetramethylethylenediamine 2.76
g, and cooled until the internal temperature reached -30 to -35 ° C.

To this, 2.4 g of furfural and 7 of tetrahydrofuran
2 g of the mixed solution is added dropwise over 2 hours. After the dropping is completed,
Incubate at the same temperature for 30 minutes.

Next, at the same temperature, 8.6 g of carbon dioxide gas was blown in for 1 hour and kept at the same temperature for 30 minutes.

Thereafter, the same treatment as in Example 1 was carried out to obtain 2- as a concentrated residue.
(Ω-carboxy-2′-hydroxyheptyl) furan
4.52 g (purity 96.2%, yield 77%) was obtained.

Example 3 The same four-necked flask as used in Example 1 was charged with 5.84 g of magnesium and 100 g of tetrahydrofuran,
23.92 g of 1,6-dibromohexane was added to this at an internal temperature of 30-
The solution is added dropwise over 2 hours while maintaining the temperature at 40 ° C. After the dropping is completed, the temperature is kept at the same temperature for 1 hour.

Then, the solution was cooled to an internal temperature of −35 to −40 ° C., and a tetrahydrofuran solution 13 containing 4.8 g of furfural was added.
0 m is dropped for 2 hours.

After the dropping is completed, the temperature is kept at the same temperature for 1 hour, and then 17 g of carbon dioxide gas is blown in for 2 to 3 hours, and the temperature is kept at 1 for 1 hour.
Keep it warm for hours.

Hereinafter, the same treatment as in Example 1 was performed to obtain a concentrated residue of 2-
(Ω-carboxy-2′-hydroxyheptyl) furan
8.64 g (purity 96.8%, yield 74%) was obtained.

Claims (3)

[Claims] 1. A magnesium to general formula X- (CH ₂₎ in _n -X (wherein, X represents a chlorine atom or a bromine atom, n represents 4
Represented by an alkyl dihalide represented by 8 represents an integer of) by reacting the general formula _{X-Mg- (CH 2) n} -Mg-X ( wherein, X and n have the same meanings as defined above) An alkyldimagnesium halide is obtained, which is reacted with furfural, further reacted with carbon dioxide, and then hydrolyzed. (In the formula, n has the same meaning as described above.) A method for producing a carboxyalkylfurfuryl alcohol represented by: 2. The process according to claim 1, wherein the amount of furfural used in the reaction of alkyldimagnesium halide and furfural is 0.5 to 1.5 mol times that of the starting material alkyldihalide. . 3. The process according to claim 1, wherein the reaction temperature in the reaction of the alkyldimagnesium halide and furfural is −70 to −20 ° C.