JP6059702B2 - Process for producing bromine-containing cyclic acetal compound - Google Patents

Description

  The present invention relates to a method for producing a bromine-containing cyclic acetal compound, and the compound obtained by the production of the present invention is useful as a raw material or synthetic intermediate for pharmaceuticals, agricultural chemicals, functional materials, electronic materials.

  As a method for producing a bromine-containing cyclic acetal compound, a method for obtaining a bromine-containing 1,3-dioxolane or a bromine-containing 1,3-dioxane by reacting an α, β-unsaturated carbonyl compound, hydrogen bromide and a diol compound is often used. Are known. In this method, inexpensive and easily available raw materials can be used, and since hydrogen bromide functions as a brominating agent and an acid catalyst, it is possible to perform bromination reaction and acetalization reaction at a time, which is efficient. Although it was a technique, there was a problem that the yield was low.

As a method for synthesizing bromine-containing 1,3-dioxolanes, a method for synthesizing 2- (2-bromoethyl) -1,3-dioxolane by blowing hydrogen bromide gas into a mixed solution of acrolein and ethylene glycol is known. However, this method has a very low yield of 45% (see, for example, Non-Patent Document 1).
Although there is an example in which 2- (2-bromopropyl) -1,3-dioxolane was synthesized by using crotonaldehyde in the same manner as in Non-Patent Document 1, the yield was not satisfactory with 69% (for example, Non-Patent Document 2).

In addition, examples of synthesizing 2-bromoethyl-2-methyl-1,3-dioxolane by reacting methyl vinyl ketone, hydrogen bromide and ethylene glycol are also known (for example, Non-Patent Document 3 and Non-Patent Document 4). reference). However, since this method has a wide yield range of 40 to 80% and cannot be said to have good reproducibility, a method of stably synthesizing with high yield has been desired.
In addition, a method of reacting acrolein, ethylene glycol and hydrogen bromide in the presence of hydroquinone is also known, but the yield was only 59% (see, for example, Non-Patent Document 5).

It is known that bromine-containing 1,3-dioxanes can be synthesized in the same manner as bromine-containing 1,3-dioxolanes. For example, there is a report example of synthesizing 2- (2-bromoethyl) -1,3-dioxane by dropping acrolein into a mixed solution of hydrogen bromide and 1,3-propanediol. There remains room (see, for example, Non-Patent Document 6).
In addition, a method has also been reported in which acrolein is brominated with hydrogen bromide and then 2-hexyl-1,3-propanediol, p-toluenesulfonic acid, molecular sieve is added as a dehydrating agent, and acetalization is performed (for example, Non-patent document 7). In this method, the yield is relatively high at 89%. However, since bromination and acetalization are performed stepwise, the efficiency is low, and a large amount of molecular sieve is used, which causes problems in industrial production. .

  As another production method for synthesizing a bromine-containing cyclic acetal compound using an α, β-unsaturated carbonyl compound and ethylene glycol, a method of bromination and acetalization with bromotrimethylsilane and p-toluenesulfonic acid is known. . For example, a method for synthesizing the desired 2- (2-bromoethyl) -1,3-dioxolane by brominating acrolein with bromotrimethylsilane in a benzene solvent and then adding p-toluenesulfonic acid and ethylene glycol is known. (See, for example, Non-Patent Document 8). In this method, the yield is relatively high at 83%, but the efficiency is poor because the bromination reaction and acetalization reaction are performed separately, and the use of expensive bromotrimethylsilane, toxicity and carcinogenicity are regarded as problems. Since there is a problem of using benzene in a large amount as a solvent, development of an efficient and safe industrial production method has been desired. Non-Patent Document 8 also describes a method of synthesizing bromine-containing 1,3-dioxolanes using methyl vinyl ketone as an α, β-unsaturated carbonyl compound, and the yield is relatively as 82%. Although it is expensive, there is a problem as described above, and thus a safer and more industrial method has been demanded.

Advanced Synthesis & Catalysis, 354 (7), 1363-1372 (2012) Tetrahedron, 42 (12), 3147-56 (1986) Organic Mass Spectrometry, 24 (11), 977-983 (1989) The Journal of Organic Chemistry, 52 (1), 34-44 (1987) Beijing Gongshang Daxue Xuebao, Ziran Kexueban, 20 (3), 18-21 (2002) Bulletin of the Chemical Society of Japan, 54 (2), 505-508 (1981) Huaxue Yanjiu Yu Yingyong, 12 (4), 419-421 (2000) Synthetic Communications, 20 (8), 1175-1179 (1990)

  The present invention has been made in view of the above problems, and an object of the present invention is to provide an efficient method for producing a bromine-containing cyclic acetal compound that could not be satisfied by the prior art. Another object of the present invention is to provide a safe and inexpensive manufacturing method.

  As a result of intensive studies to solve the above problems, the present inventors have made conventional hydrogen bromide reaction by reacting an α, β-unsaturated carbonyl compound, hydrogen bromide and diol compound in the presence of ether. It was found that the production of bromine-containing cyclic acetal compounds, which had a low yield when used, can be produced in a high yield and without using a highly toxic organic solvent such as benzene. The invention has been completed.

  That is, the present invention provides the following general formula (1)

[In the formula (1), R ¹ , R ² , R ³ or R ⁴ each independently represents a hydrogen atom, a methyl group, an ethyl group or a linear, branched or cyclic alkyl having 3 to 6 carbon atoms. Represents a group or a phenyl group. ]
An α, β-unsaturated carbonyl compound represented by the following general formulas (2) to (5):

[In the formulas (2) to (5), R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ or R ¹⁴ are each independently a hydrogen atom, A methyl group, an ethyl group, a C3-C6 linear or branched alkyl group, or a phenyl group is represented. ]
Is reacted with hydrogen bromide to give the following general formulas (6) to (9):

[In the formulas (6) to (9), R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ or R ¹⁴ are each independently a hydrogen atom, A methyl group, an ethyl group, a C3-C6 linear or branched alkyl group, or a phenyl group is represented. ]
In the manufacturing method of the bromine-containing cyclic acetal compound shown by these, it is related with the manufacturing method of the bromine-containing cyclic acetal compound which coexists ether.

  The method for producing a bromine-containing cyclic acetal compound represented by the above general formula (3) by reacting an α, β-unsaturated carbonyl compound, hydrogen bromide and a diol compound has conventionally been in a low yield. On the other hand, according to the production method of the present invention, the bromine-containing cyclic acetal compound represented by the general formula (3) can be efficiently produced by allowing the ether to coexist.

Hereinafter, the present invention will be described in detail.
In the present invention, R ¹ , R ² , R ³ , R ⁴ in the general formula (1) are “a linear, branched or cyclic alkyl group having 3 to 6 carbon atoms”. N-propyl group, n-butyl group, n-pentyl group, n-hexyl group, i-propyl group, i-butyl group, s-butyl group, t-butyl group, 1-methylbutyl group, 2-methylbutyl group 3-methylbutyl group, 1,1-dimethylpropyl group, 2,2-dimethylpropyl group, 1,2-dimethylpropyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 4- Methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,2-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl 1,1,1,2 Trimethyl propyl group, 1,2,2-trimethyl propyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and cyclohexyl group.

  In the present invention, the α, β-unsaturated carbonyl compound represented by the general formula (1) is not particularly limited, but α, β-unsaturated aldehyde, α, β-unsaturated ketone, α, β -Unsaturated carboxylic acid and (alpha), (beta) -saturated ester can be mentioned, Among these, (alpha), (beta) -unsaturated aldehyde, (alpha), (beta) -unsaturated ketone can be used preferably. More specifically, for example, acrolein, methacrolein, 2-ethylacrolein, crotonaldehyde, 2-pentenal, 2-hexenal, 2-heptenal, 2-octenal, 2-nonenal, 2-methylbutenal, 2-ethylbutenal, 2 -Methyl pentenal, 2-ethyl pentenal, methyl vinyl ketone, ethyl vinyl ketone, etc. are mentioned.

In the present invention, in the diol compound represented by any one of the general formulas (2) to (5), R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² in the formula , R ¹³ and R ¹⁴ are “a linear, branched or cyclic alkyl group having 3 to 6 carbon atoms”, for example, n-propyl group, n-butyl group, n-pentyl group, n -Hexyl group, i-propyl group, i-butyl group, s-butyl group, t-butyl group, 1-methylbutyl group, 2-methylbutyl group, 3-methylbutyl group, 1,1-dimethylpropyl group, 2,2 -Dimethylpropyl group, 1,2-dimethylpropyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethyl Butyl group, 1,3-dimethylbutyl Group, 2,2-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, cyclopropyl group, A cyclobutyl group, a cyclopentyl group, a cyclohexyl group, etc. are mentioned.

  In the present invention, the diol compound represented by any one of the general formulas (2) to (5) is not particularly limited, and examples thereof include aliphatic diol compounds. More specifically, for example, ethylene glycol, 1,2-propanediol, 2-methyl-1,2-propanediol, 2,3-butanediol, 2-methyl-2,3-butanediol, pinacol, 1 , 3-propanediol, 1,4-butanediol and the like.

  In the present invention, the ether is not particularly limited, and examples thereof include aliphatic ethers and cyclic ethers. More specifically, for example, dimethyl ether, ethyl methyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, cyclopentyl methyl ether (CPME), tetrahydrofuran, methyltetrahydrofuran, tetrahydropyran (THP), 1,4-dioxane, 1 , 3-dioxane and the like.

The amount of ether used is not particularly limited, but is generally preferably 3.0 gram equivalent to 7.0 gram equivalent, more preferably 3.5 gram equivalent, relative to the α, β-unsaturated carbonyl compound. ~ 5.5 gram equivalent.
In the present invention, ether is usually used alone, but a plurality of the ethers exemplified above can be used in combination, and before producing the bromine-containing cyclic acetal compound represented by the general formula (3), You may use it, mixing, and adding to a manufacturing container etc. separately and using.

In the present invention, the amount of hydrogen bromide to be used is not particularly limited, but is usually preferably 1.0 to 2.0 molar equivalents, more preferably relative to the α, β-unsaturated carbonyl compound. 1.1 molar equivalents to 1.3 molar equivalents.
In the present invention, the amount of ethylene glycol used is not particularly limited, but is usually preferably 1.0 to 2.0 molar equivalents, more preferably 1 to the α, β-unsaturated carbonyl compound. .1 molar equivalent to 1.3 molar equivalent.

In this invention, as reaction temperature, 10-40 degreeC is preferable, More preferably, it is 20-30 degreeC. When the reaction temperature is lower than 10 ° C., ethylene glycol is solidified, and the progress of the reaction may be extremely slow. When the reaction temperature is higher than 40 ° C., there is a risk of lowering the selectivity of the target product or polymerization due to side reactions. The reaction can be carried out at normal pressure or under pressure.
In the present invention, the reaction time varies depending on the type of substrate and the reaction temperature, and thus is not particularly limited, but the reaction can usually be completed within a range of 30 minutes to 1 hour.

The produced bromine-containing cyclic acetal compound can be generally used a known purification method, for example, after separating the organic layer by a liquid separation operation, and washing the obtained organic layer with water, brine, an alkaline aqueous solution or the like And can be isolated and purified by a general method such as distillation or column chromatography.
The bromine-containing cyclic acetal compound thus obtained is represented by the following general formulas (6) to (9).

[In the formulas (6) to (9), R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ or R ¹⁴ are each independently a hydrogen atom, A methyl group, an ethyl group, a C3-C6 linear or branched alkyl group, or a phenyl group is represented. ]
The compounds shown in these correspond to the diol compounds shown in the general formulas (2) to (5) described above. Specifically, when the diol compound is represented by the general formulas (2), (3), (4), (5), the general formulas (6), (7), (8), (9), respectively. The bromine-containing cyclic acetal compound represented by these is obtained.

  Specific examples of the bromine-containing cyclic acetal compound include, for example, 2- (2-bromoethyl) -1,3-dioxolane, 2- (2-bromo-1-methylethyl) -1,3-dioxolane, 2- (2 -Bromoethyl) 4,4,5,5-tetramethyl-1,3-dioxolane, 2- (2-bromopropyl) -1,3-dioxolane, 2- (2-bromoethyl) -1,3-dioxane,- (2-bromo-1-methylethyl) -1,3-dioxane, 2- (2-bromoethyl) 4,4,5,5-tetramethyl-1,3-dioxane, 2- (2-bromopropyl)- 1,3-dioxane, 2- (2-bromoethyl) -1,3-dioxepane, 2- (2-bromo-1-methylethyl) -1,3-dioxepane, 2- (2-bromoethyl) 4,4 5,5-tetrame 1,3-dioxepane, 2- (2-bromopropyl) -1,3-dioxepane, 2- (2-bromoethyl) -1,3-dioxocane, 2- (2-bromo-1-methylethyl)- Examples include 1,3-dioxocane, 2- (2-bromoethyl) 4,4,5,5-tetramethyl-1,3-dioxocane, 2- (2-bromopropyl) -1,3-dioxocane and the like.

EXAMPLES Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited only to these examples.
The analysis of the product was conducted by gas chromatography analysis (hereinafter referred to as “GC analysis”) under the following conditions.
Equipment: GC-2010 Plus manufactured by Shimadzu Corporation (with hydrogen flame ionization detector)
Column: GL Science Co., Ltd., capillary column NB-5 (0.32 mm ID × 30 m)
Example 1 Production of 2- (2-bromoethyl) -1,3-dioxolane A 50 mL three-necked flask was equipped with a stirrer, thermometer, Dimroth, and hydrogen bromide gas inlet tube, and 1,4-dioxane (10 mL). And ethylene glycol (2.461 g, 39.6 mmol) were added. Hydrogen bromide gas was introduced at 16.6 mL / min for 54 minutes at room temperature (substance amount of introduced hydrogen bromide gas: 40.0 mmol). The reaction mixture was cooled to 5 ° C. and acrolein (1.894 g, 33.8 mmol) was added slowly via syringe pump over 30 minutes. After completion of dropping, the mixture was stirred at room temperature for 1 hour. (With time, the reaction solution changed from a colorless single phase to two phases, colorless and light yellow). To the solution after completion of the reaction, 5 mL of acetone and dimethylformamide (internal standard) weighed were added and stirred for 5 minutes, followed by GC analysis to calculate the GC yield (93%). The solution was diluted with diethyl ether, washed three times with water, further washed once with saturated brine, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated to obtain 5.51 g of a brown liquid. When the content of the target compound in the concentrate was calculated by GC analysis, the yield of the target compound was 4.65 g and the yield was 76%.

Examples 2 to 9 and Comparative Example 1
The reaction was carried out under the same conditions as in Example 1 except that the types of α, β-unsaturated carbonyl compound, diol compound and ether as the substrate were changed. The results are shown in Table 1.
Comparative Examples 2-4
The reaction was performed under the same conditions as in Example 1 except that other organic solvent was added instead of ether.

  The reaction conditions and results of the above Examples and Comparative Examples are shown in Table 1.

  From Table 1, compared with Comparative Examples 1-4, in Examples 1-9 in which ether coexists, a bromine-containing acetal compound is obtained with a high yield.

  The bromine-containing cyclic acetal compound obtained by the present invention is very useful as a raw material or synthetic intermediate for pharmaceuticals, agricultural chemicals, functional materials, electronic materials.

Claims (2)

The following general formula (1)

[In the formula (1), R ¹ , R ² , R ³ or R ⁴ each independently represents a hydrogen atom, a methyl group, an ethyl group or a linear, branched or cyclic alkyl having 3 to 6 carbon atoms. Represents a group or a phenyl group. ]
An α, β-unsaturated carbonyl compound represented by the following general formulas (2) to (3):

[In the formulas (2) to (3) , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ or R ¹⁰ are each independently a hydrogen atom, a methyl group, an ethyl group, or a carbon number of 3-6. A linear or branched alkyl group or a phenyl group is represented. ]
Is reacted with hydrogen bromide to give the following general formulas (6) to (7):

[In the formulas (6) to (7) , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ or R ¹⁰ are each independently a hydrogen atom, a methyl group, an ethyl group, or a carbon number of 3-6. A linear or branched alkyl group or a phenyl group is represented. ]
In the manufacturing method of the bromine-containing cyclic acetal compound represented, dimethyl ether, ethyl methyl ether, diethyl ether, diisopropyl ether, methyl tert- butyl ether, cyclopentyl methyl ether (CPME), tetrahydrofuran, methyltetrahydrofuran, tetrahydropyran (THP), 1, A method for producing a bromine-containing cyclic acetal compound, which is reacted in the presence of a solvent selected from 4-dioxane or 1,3-dioxane . The method for producing a bromine-containing cyclic acetal compound according to claim 1 , wherein the reaction is carried out in the presence of a solvent selected from diethyl ether, cyclopentyl methyl ether (CPME), tetrahydropyran (THP) or 1,4-dioxane .