JPH10231294A - Production of 4,7-dihydro-1,3-dioxepin - Google Patents

Abstract

PROBLEM TO BE SOLVED: To efficiently obtain the subject compound, useful, e.g. as an intermediate for producing an X-ray contrast medium, antitumor medicine, antimicrobial medicine or the like, by reacting cis-2-butene-1,4-diol with a specific carbonyl compound at normal temperature in the presence of an acid catalyst. SOLUTION: This compound is obtained efficiently at low cost by reacting 1mol of cis-2-butene-1,4-diol shown by formula I with 5 to 70 molar equivalents of a carbonyl compound shown by formula II (R<1> and R<2> are each H or a 1-6C lower alkyl, wherein each of R<1> and R<2> may contain an unsaturated bond, or they may be bound to each other to form a cyclic structure), e.g. acetone, at normal temperature in the presence of an acid catalyst to produce the objective 4,7-dihydro-1,3-dioxepin shown by formula III, useful, e.g. as an intermediate for producing an X-ray contrast medium, antitumor medicine, antimicrobial medicine or the like.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an industrially useful 4,7
A process for producing dihydro-1,3-dioxepins;

[0002]

2. Description of the Related Art 4,7-Dihydro-1,3-dioxepins are industrially useful. For example, EP00334
26, disclose that 4,7-dihydro-1,3-dioxepins are important intermediates of X-ray contrast agents. Furthermore, 2,2-dialkyl-4,7-dihydro-
1,3-Dioxepins are also important as pharmaceutical and antimicrobial intermediates. For example, Tetrahed
ron Letters. , 31, 2643 (197
5) has 2,2-dimethyl-4,7-dihydro-1,
It is disclosed that 3-dioxepin is a useful intermediate for the production of antitumor agents. Also, J.I. Org. Che
m. , 57, 3662 (1992) discloses that it is a useful intermediate for the production of antimicrobial agents.

There have been disclosed several methods for producing 4,7-dihydro-1,3-dioxepins. For example, William et al., "J. Org. Chem., 41, 2469 (197)
6) is cis-2-in the presence of p-toluenesulfonic acid.
The desired 2,2-dimethyl-4,7-dihydro-1,3-dioxepin is obtained by heating butene-1,4-diol with 2,2-dimethoxypropane. (The following formula)

[0004]

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Although the method of William et al. Is effective with a yield of 97%, 2,2-dimethoxypropane used in the reaction is expensive and economically disadvantageous.

[0006] Herbert et al.
m. Ber. , 113, 1472 (1980)] is a reaction of cis-2-butene-1,4-diol with benzene in a benzene solvent.
By heating together with the carbonyl compound in the presence of toluenesulfonic acid and azeotropically distilling off the produced water with benzene, the desired 4,7-dihydro-1,3-dioxepins are obtained. (The following formula)

[0007]

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(Wherein, R ₁ and R ₂ are a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a phenyl group or a p-methoxyphenyl group, and R ₁ and R ₂
May be the same or different, and R ₁ and R ₂ may be linked to form a ring.) However, this method uses toxic benzene as a reaction solvent and is not industrially preferable.

Herbert et al., Cited cis-2-butene-
1,4-diol and a carbonyl compound are heated together with an orthoformate in the presence of p-toluenesulfonic acid to obtain the desired 4,7-dihydro-1,3-dioxepins. Although this method has a relatively good yield, the orthoformate used in the reaction is expensive and economically disadvantageous.

[0010] Michael et al., J. Or.
g. Chem. , 40, 450 (1975) "
2-butene-1,4-diol and acetone are heated together with anhydrous copper sulfate in the presence of p-toluenesulfonic acid to produce the desired 2,2-dimethyl-4,7-dihydro-1,3-
Dioxepin has been obtained. However, this method requires two weeks of reaction time using a pressurized container, and further has disadvantages such as a low yield of 50%.

As described above, 4,7-dihydro-1,3
-Its satisfactory production method of dioxepins was not known, and it was difficult to produce industrially and inexpensively.

[0012]

SUMMARY OF THE INVENTION An object of the present invention is to provide an inexpensive and efficient method for producing 4,7-dihydro-1,3-dioxepins.

[0013]

[Means for Solving the Problems]

 General formula (III)

[0014]

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(Wherein, R ₁ and R ₂ are a hydrogen atom or a linear or branched lower alkyl group having 1 to 6 carbon atoms, and R ₁ and R ₂ each include an unsaturated bond. And R ₁ and R ₂ may be the same or different, and R ₁ and R ₂ may be linked to form a ring.) 4,7-dihydro-1,3-dioxepin There are roughly two types of manufacturing methods. One is a method of reacting cis-2-butene-1,4-diol with acetal as disclosed by Kieboom et al., And the other is a method of Herbert (Heboom).
bert, et al., cis-2-butene-1,4-diol and carbonyl compounds. In the former reaction using an acetal, the desired 4,7-dihydro-1,3-dioxepins can be obtained in a relatively high yield as compared with the reaction using a carbonyl compound. Disadvantageous. This is because acetals are produced by a condensation reaction between carbonyl compounds and alcohols, and the production of 4,7-dihydro-1,3-dioxepins requires two steps. In contrast, in the latter reaction using carbonyl compounds, carbonyl compounds and cis-2
-Butene-1,4-diol is considered to be an advantageous method because it can be reacted directly to produce 4,7-dihydro-1,3-dioxepins in one step.

Herbert et al., Cited cis-2-butene-1,4.
The diol is heated together with acetone in the presence of p-toluenesulfonic acid in a benzene solvent together with acetone, and the produced water is azeotropically distilled off with benzene to obtain the desired 2,2-
It is reported that dimethyl-4,7-dihydro-1,3-dioxepin was obtained in a yield of 66%. The present inventors did not obtain similar results when they retested their method. That is, the desired 2,2-dimethyl-
The yield of 4,7-dihydro-1,3-dioxepin is 2
It was extremely low at 2.5%. From these results, the present inventors have found that the carbonyl compound and cis-2-butene-1,4
-By dehydration reaction of diol, 4,7-dihydro-
He knew that in order to obtain 1,3-dioxepins with good yield, it was necessary to study the reaction conditions in more detail, and continued his intensive research to find extremely effective reaction conditions.

Analysis of the method of Herbert et al. Revealed that the reaction conversion was as low as 47.8% and the reaction selectivity was 47.1%.
As a result, the yield of the desired 2,2-dimethyl-4,7-dihydro-1,3-dioxepin is 2
It was extremely low at 2.5%. 2,5 due to intramolecular condensation of cis-2-butene-1,4-diol
The selectivity is reduced by-products of dihydrofuran and oligomers and polymers by intermolecular condensation; Since this reaction is a reversible reaction and proceeds by removing the water generated by the reaction by azeotropic dehydration with benzene, it is necessary to raise the reaction temperature to the azeotropic point of benzene and water. The rate drops.

As a result of various studies, the present inventors have surprisingly discovered that the present reaction proceeds even at room temperature (around 25 ° C.), and furthermore, at room temperature (the range is defined later).
But I found it to go. Furthermore, they have found that the reaction selectivity is improved by selecting the conditions, and have completed the present invention.

That is, the present invention relates to a compound of the formula (I)

[0020]

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Under acidic conditions, cis-2-butene-1,4-diol represented by the general formula (II)

[0022]

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(Wherein, R ₁ and R ₂ are a hydrogen atom or a linear or branched lower alkyl group having 1 to 6 carbon atoms, and R ₁ and R ₂ each include an unsaturated bond. R ₁ and R ₂ may be the same or different, and R ₁ and R ₂ may be linked to form a ring) at room temperature. General formula (III)

[0024]

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(Wherein, R ₁ and R ₂ have the same meanings as in the above general formula (II)), which provides a method for producing 4,7-dihydro-1,3-dioxepins represented by the general formula (II). is there.

Here, the ordinary temperature means "a temperature which can be easily maintained in a natural environment", and specifically, is about -30.degree. C. to about 50.degree.

In this case, the temperature is more preferably from -20.degree. C. to 40.degree. C. for the reasons described above and as will be apparent from the experimental results described later.

Next, means for improving the reaction conversion were examined. Generally, in such an equilibrium reaction,
It is known that the reaction conversion is improved by increasing the raw material concentration or removing the product out of the reaction system.
In this study, we focused on the relationship between the carbonyl compound concentration and the reaction conversion rate as a method for increasing the raw material concentration. The amount of the carbonyl compound used in the present invention is preferably at least equimolar to cis-2-butene-1,4-diol, more preferably from 5 molar equivalents to 70 molar equivalents. The unreacted carbonyl compound can be reused by being recovered.

On the other hand, as a method of removing the product out of the reaction system, there is an azeotropic dehydration method using a solvent such as benzene. However, the present inventors have performed this reaction system without performing an operation such as azeotropic dehydration. It has been found that the desired oxepin (III) can be obtained in a good yield by coexisting calcium chloride or molecular sieves in water. The amount of calcium chloride used was cis-2-butene-1,4-diol 1
It is preferable to use not more than 5.0 molar equivalents per mole,
The calcium chloride after use can be regenerated by heating. Molecular sieves is cis-2-butene-
It is preferable to use 500 g or less based on 1 mol of 1,4-diol, and the molecular sieve after use can be regenerated by heating.

[0030]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described specifically. Examples of the carbonyl compound represented by the general formula (II) include aldehydes such as formaldehyde, acetaldehyde, acrylaldehyde, n-butyraldehyde, iso-butyraldehyde, n-valeraldehyde, and iso-valeraldehyde. Further, acetone, methyl ethyl ketone, methyl vinyl ketone, 2-pentanone,
3-methyl-2-butanone, 3-methyl-3-butene-
2-one, 2-hexanone, 4-methyl-2-pentanone, 3-methyl-3-penten-2-one, 4-methyl-3-penten-2-one, 2-heptanone, 5-methyl-2- Hexanone, 3-methyl-2-hexanone, 5
-Methyl-3-hexen-2-one, 2-octanone,
6-methyl-2-heptanone, 2-methyl-2-hepten-6-one, 3-pentanone, 3-hexanone, 3-
Heptanone, 5-methyl-3-hexanone, 3-octanone, 5-methyl-3-heptanone, 3-nonanone, 4
-Heptanone, 2-methyl-3-hexanone, 4-octanone, 2-methyl-3-heptanone, 2-methyl-4
And ketones such as -heptanone, 4-nonanone, 4-decanone, 5-nonanone, cyclopentanone, cyclohexanone, and cycloheptanone.

As the acid catalyst that can be used, p-toluenesulfonic acid, methanesulfonic acid, sulfuric acid, hydrochloric acid, phosphoric acid,
It is preferable to use acetic acid, trifluoroacetic acid, or polyphosphoric acid. However, the present invention is not limited thereto, and desired conditions can be obtained by using a suitable acidic substance such as zeolite or an ion exchange resin. If the amount of the acid used is small, the progress of the reaction may be slow. When p-toluenesulfonic acid is used as the acid catalyst, its use amount can be 0.001 mol% or more based on cis-2-butene-1,4-diol, but from 0.1 mol%. It is preferable to use 20 mol%. If the amount used is less than this, the progress of the reaction will be slow, and if it is more than this, the yield will decrease due to side reactions.

As the ion exchange resin, Amberli
te® IR-120, Amberlyst
(Registered trademark) 14, DOWEX (registered trademark) 50WX,
Strongly acidic cation exchange resins, such as Nafion® NR50, are preferred, especially Naf from Fluka.
ion® NR50 is preferred. The amount of the strongly acidic cation exchange resin to be used is 0.1 g or more based on 1 mol of cis-2-butene-1,4-diol, and the amount required for the reaction to proceed can be selected.

The reaction is generally carried out by cis-2-butene-
The 1,4-diol is dissolved in the carbonyl compound represented by the general formula (II) and stirred in the presence of the above-mentioned acid catalyst to give 4,7-dihydro-1 represented by the general formula (III). , 3-Dioxepins are obtained. In this case, the reaction temperature is preferably room temperature, and more preferably -20 ° C to 40 ° C. If the temperature is higher than this, the yield decreases due to side reactions.

The amount of the carbonyl compound used is preferably at least equimolar to the cis-2-butene-1,4-diol, more preferably in excess. The preferred amount of the carbonyl compound is cis-2-butene-
It is 5 to 70 molar equivalents based on 1,4-diol. For example, when acetone is used as the carbonyl compound, 88 g of cis-2-butene-1,4-diol is used.
(1.0 mol) to 950 g (16.3 mol) of acetone,
2.96 g (0.016 mol) of p-toluenesulfonic acid
And reacting at room temperature for 16 hours to obtain 2,2-dimethyl-4,7-dihydro-1,3-dioxepin in a yield of 52%. Under the same reaction conditions, 3792 g of acetone (6
(5.4 mol) to give 2,2-dimethyl-4,7-dihydro-1,3-dioxepin in a yield of 76.3%.

As described above, by allowing calcium chloride or molecular sieves to coexist in this reaction system, the amount of carbonyl compound used can be reduced. The amount of calcium chloride used can be appropriately selected depending on the temperature and the amount of carbonyl compound used. Generally, calcium chloride can be used in an amount of 5.0 molar equivalents or less relative to cis-2-butene-1,4-diol, but the most preferred amount is 3 molar equivalents or less. The amount of calcium chloride used also varies depending on its shape. For example, when acetone is used as the carbonyl compound represented by the general formula (II), cis-2-butene-1,4-diol 8
8 g (1.0 mol), 950 g (16.3 mol) of acetone, 222 g of powdered calcium chloride manufactured by Kanto Chemical Co.
(2.0 mol), p-toluenesulfonic acid monohydrate
When 96 g (0.016 mol) is reacted at room temperature for 16 hours, 2,2-dimethyl-4,7-dihydro-1,3-dioxepin is obtained in a yield of 80%. On the other hand, when the use amount of granular calcium chloride manufactured by DOW is increased 1.5 times under the same reaction conditions, the same yield as in the case of using powdered calcium chloride manufactured by Kanto Chemical Co. can be obtained. The amount of the molecular sieve to be used can be appropriately selected depending on the temperature and the amount of the carbonyl compound used. Also, the amount of use can be changed depending on the type of molecular sieves. Molecular sieves 13X1 / 1 made by Wako Pure Chemical Industries
When 6 is used, good results are obtained at 500 g or less per mol of cis-2-butene-1,4-diol.

The product represented by the general formula (III) 4,
After completion of the reaction, 7-dihydro-1,3-dioxepins are converted to
Filter out calcium chloride or molecular sieves,
The filtrate may be taken out by a method described in the literature.

When a solid acid catalyst such as an ion exchange resin or zeolite is used as the acid catalyst, the same results can be obtained even if the solid acid catalyst is filled in a tower reactor and the reaction solution is circulated. Can be. Furthermore, when using calcium chloride or molecular sieves, a solid acid catalyst may be charged together with the column reactor, or calcium chloride or molecular sieves may be separately charged,
The reaction solution may be circulated. Also in this case, the reaction solution of 4,7-dihydro-1,3-dioxepin represented by the general formula (III) may be taken out from the reaction solution by a method described in the literature.

The product represented by the general formula (III) 4,
The removal of 7-dihydro-1,3-dioxepins is as follows.
It may be performed when no change in the content of the reaction solution by the gas chromatography internal standard method is observed.

[0039]

As described above, according to the present invention, the above-mentioned compound can be obtained by reacting at room temperature, so that it is inexpensive and efficient without requiring a special heating device for heating to room temperature or higher. In addition, a useful compound represented by the general formula (I
The 4,7-dihydro-1,3-dioxepins represented by II) can be produced, and are industrially valuable.

[0040]

The present invention will be described below in detail with reference to examples.

The products in the following examples were analyzed by gas chromatography (GC).

The amount of 4,7-dihydro-1,3-dioxepins contained in the reaction solution was determined by gas chromatography (GC) internal standard method. Toluene or n-butyl acetate was used as an internal standard.

[0043] Gas chromatographic (GC) analysis conditions Column: Glass column (2.1 m × 3.2 mm) Filler; 5% Sillicone OV-17 60 / 80mesh Uniport HP detector; FID Range; 10 ² carrier gas; N ₂ Inlet and detector temperature; 270 ° C. Initial temperature holding time; 5 minutes Ultimate temperature holding time; 10 minutes Column temperature; 40 ° C. → 260 ° C. Heating rate; 10 ° C./minute Example 1 Acetone (II: R
2,2-dimethyl-4,7 using ₁ = R ₂ = CH ₃ )
-Dihydro-1,3-dioxepin (III: R ₁ = R
₍₂ = CH ₃ ) (1) A ₂ - L four-necked flask was equipped with a stirrer, a thermometer, and a reflux condenser, and cis-2-butene-1,4-diol 8 was added.
8 g (1.0 mol), 950 g of acetone (164 mol)
l) was charged, and 2.96 g (0.016 mol) of p-toluenesulfonic acid monohydrate was added while stirring.
After stirring for 0.5 hour, 222.0 g (2.0 mol) of powdered calcium chloride manufactured by Kanto Chemical Co. was added. Upon the addition of calcium chloride, the internal temperature of the reaction mixture increased from 25 ° C to 32 ° C, and after 3 hours reached 25 ° C.
After further stirring at 25 ° C. for 16 hours, calcium chloride was filtered under reduced pressure, and the calcium chloride was washed with 200 ml of acetone. The solution obtained by combining the filtrate and the washing solution was subjected to gas chromatography using the internal standard substance method to prepare 2,2 in the reaction solution.
The content of -dimethyl-4,7-dihydro-1,3-dioxepin was 103.1 g (80.5% yield). This reaction solution was distilled under reduced pressure, and 100.7 g of 2,2-dimethyl-4,7-dihydro-1,3-dioxepin was obtained (yield 7).
8.7%). The purity of this compound by gas chromatography was 99.0% (area percentage method, retention time =
10.0 min). 2,2-dimethyl-4,7 in the reaction mixture by gas chromatography internal standard method
-Dihydro-1,3-dioxepin content and 2,2-dimethyl-4,7-dihydro- obtained by distillation under reduced pressure.
Since the amounts of 1,3-dioxepin are consistent, it can be said that the result of quantification of the reaction solution by the gas chromatography internal standard method reflects the reaction yield. The gas chromatography internal standard method used toluene (retention time = 5.5 minutes) as the internal standard. Product (III:
The physical properties of (R ₁ = R ₂ = CH ₃ ) are shown below.

Boiling point: 104 ° C./200 mmHg ¹ H-NMR (CDCl ₃ , ppm, TMS); δ =
5.66 (2H, t, CH), 4.25 (4H, d, C
_{H 2), 1.44 (6H,} s, CH 3) IR (neat, cm -1); 1373.4,1221.1,
1163.2, 1070.6 Experimental Example 1 Using acetaldehyde diethyl acetal
2-methyl-4,7-dihydro-1,3-dioxepi
(III: R ₁ = CH ₃ , R ₂ = H)
Additional Test of [Synthesis, 616 (1981)] A stirrer, a thermometer, and a condenser were attached to a 100 ml three-necked flask, and cis-2-butene-1,4-diol 2 was added.
6.4 (0.3 mol) and 39.0 g (0.33 mol) of acetaldehyde diethyl acetal were charged, and 3.8 mg of p-toluenesulfonic acid monohydrate was added with stirring.
(0.02 mmol) was added. After stirring for 0.5 hour, the mixture was heated in an oil bath, and the produced ethanol was distilled off. The reaction solution is distilled to give 2-methyl-4,7-dihydro-
1,3-dioxepin (III: R ₁ = CH ₃ , R ₂ =
H) 20.3 g (59.4% yield). The purity by gas chromatography of this compound was 99.0% (area percentage method, retention time = 9.5 minutes). Document [S
ynthesis, 616 (1981)], there was no data other than the boiling point, and the product was found to be 2-methyl-4,7-dihydro-1,3 by IR and ¹ H-NMR spectra. -Dioxepin (III: R ₁ = CH ₃ , R ₂ = H) was confirmed. The physical properties of the product (III: R ₁ = CH ₃ , R ₂ = H) are shown below.

Boiling point: 138-140 ° C./760 mmHg ¹ H-NMR (CDCl ₃ , ppm, TMS); δ =
5.73 (2H, t, CH), 5.02 (1H, q, C
H), 4.40 (2H, m , CH 2), 4.17 (2
Acetaldehyde as 1390.8,1138.1 Example 2 carbonyl _{compounds; H, m, CH 2)} , 1.36 (3H, d, CH 3) IR (neatcm -1)
(II: 2-methyl using R ₁ ＣＨCH ₃ , R ₂ ＨH)
-4,7-dihydro-1,3-dioxepin (III:
Synthesis of R ₁ = CH ₃ , R ₂ = H) A 100 ml three-necked flask was equipped with a stirrer, a thermometer, and a reflux condenser, and 8.8 g (0.1 mol) of cis-2-butene-1,4-diol was added. 2
Charge 0.5g (0.5mol), p with stirring
0.3 g of toluenesulfonic acid monohydrate (1.58 mm
ol). After stirring for 0.5 hour, 5.55 g (0.05 mol) of powdered calcium chloride manufactured by Kanto Chemical Co., Ltd.
Was added. Upon addition of calcium chloride, the internal temperature of the reaction mixture increased from 24 ° C. to 33 ° C., and after 3 hours 25
° C. Further, after stirring at 25 ° C. for 6 hours, calcium chloride was filtered under reduced pressure, and the calcium chloride was washed with 20 ml of benzene. 2-Methyl-4,7-dihydro-1,3-dioxepin (II synthesized in Experimental Example 1)
I: 2-methyl-4,7-dihydro-1,3-dioxepin (III) in a reaction solution by a gas chromatography internal standard method using R ₁ = CH ₃ , R ₂ = H) as a standard. : R ₁ = CH ₃ , R ₂ = H).
3 g (yield 90.4%).

Example 3 As a carbonyl compound,
(II: R ₁ = R ₂ = CH ₃ )
Cyl-4,7-dihydro-1,3-dioxepin (I
I: Synthesis of R ₁ = R ₂ = CH ₃ ) (2) A stirrer, a thermometer and a reflux condenser were attached to a 1 L four-necked flask, and cis-2-butene-1,4-diol 4 was added.
4 g (0.5 mol), acetone 474 g (8.17 m
ol) and adding 1.48 g (7.8 mmol) of p-toluenesulfonic acid monohydrate while stirring.
Stir at 16 ° C for 16 hours. According to the gas chromatography internal standard method, 2,2-dimethyl-4,
7-dihydro-1,3-dioxepin (III: R ₁ =
R ₂ = CH ₃ ) 33.6 g (52.5% yield)
Met.

Example 4 As a carbonyl compound,
(II: R ₁ = R ₂ = CH ₃ )
Cyl-4,7-dihydro-1,3-dioxepin (I
I: R ₁ = R ₂ = CH ₃ ) (3) The same reaction as in Example 3 was carried out at 0 ° C. for 8 hours. After completion of the reaction, the same treatment as in Example 3 was performed. According to the gas chromatography internal standard method, 2,2-dimethyl-4,7-dihydro-1,3-dioxepin (III:
The content of R ₁ = R ₂ = CH ₃ is 34.1 g (yield 53.
3%).

Example 5 Aceto as a carbonyl compound
(II: R ₁ = R ₂ = CH ₃ )
Cyl-4,7-dihydro-1,3-dioxepin (I
I: Synthesis of R ₁ = R ₂ = CH ₃ ) (4) The same reaction as in Example 3 was carried out at -20 ° C. for 8 hours. After completion of the reaction, the same treatment as in Example 3 was performed. According to the gas chromatography internal standard method, 2,2-dimethyl-4,7-dihydro-1,3-dioxepin (II
I: R ₁ = R ₂ = CH ₃ ) 35.0 g (yield 5)
4.7%).

Example 6 Aceto as a carbonyl compound
(II: R ₁ = R ₂ = CH ₃ )
Cyl-4,7-dihydro-1,3-dioxepin (I
I: R ₁ ＲR ₂ ＣＨCH ₃ ) (5) Instead of p-toluenesulfonic acid monohydrate of Example 3, a strongly acidic ion exchange resin Nafion® N
The reaction mixture was stirred at 23 ° C. for 8 hours using 1.5 g of R50 (Fluka). Nafi after the end of the reaction
on® NR50 was washed with 20 ml of acetone. The 2,2-dimethyl-4,7-dihydro-1,3-dioxepin (I) in the reaction solution was determined by the gas chromatography internal standard method in the combined solution of the filtrate and the washing solution.
II: R ₁ = R ₂ = CH ₃ ) was 35.0 g (yield 54.7%).

Example 7 Aceto as a carbonyl compound
(II: R ₁ = R ₂ = CH ₃ )
Tyl-4,7-dihydro-1,3-dioxepin (II
I: Synthesis of R ₁ = R ₂ = CH ₃ ) (6) A stirrer, a thermometer and a reflux condenser were attached to a 1 L four-necked flask, and cis-2-butene-1,4-diol 1 was added.
1 g (0.125 mol), acetone 474 g (8.1
7 mol), and 0.38 g (2.0 mmol) of p-toluenesulfonic acid monohydrate was added while stirring.
Stir at 21 ° C. for 16 hours. 2,2-dimethyl- in the reaction solution by gas chromatography internal standard method
4,7-dihydro-1,3-dioxepin (III: R
₁ = content of R ₂ = CH ₃₎ is 12.2 g (yield: 76.3
%)Met.

Example 8 Acetal as a carbonyl compound
(II: R ₁ = R ₂ = CH ₃ )
Tyl-4,7-dihydro-1,3-dioxepin (II
I: R ₁ ＲR ₂ ＣＨCH ₃ ) (7) Instead of p-toluenesulfonic acid monohydrate of Example 1,
Strong acidic cation exchange resin Nafion (registered trademark) NR
The reaction mixture was stirred at 20 ° C. for 16 hours using 3.0 g of 50 (Fluka). After completion of the reaction, the same treatment as in Example 1 was performed. 2,2-dimethyl-4,7- in the reaction solution by gas chromatography internal standard method
Dihydro-1,3-dioxepin (III: R ₁ = R ₂
= CH ₃ ) was 100.7 g (78.7% yield).

Example 9 As a carbonyl compound,
(II: R ₁ = R ₂ = CH ₃ )
Tyl-4,7-dihydro-1,3-dioxepin (II
I: Synthesis of R ₁ ＝ R ₂ （ CH ₃ ) (8) Instead of p-toluenesulfonic acid monohydrate of Example 1, 20% using 1.59 g (15.56 mol) of 96% sulfuric acid. Stir at 16 ° C for 16 hours. After completion of the reaction, the same treatment as in Example 1 was performed. 2,2-dimethyl-4,7 in the reaction mixture by gas chromatography internal standard method
-Dihydro-1,3-dioxepin (III: R ₁ = R
₂ = CH ₃ ) content: 102.9 g (80.4% yield)
Met.

Example 10 As a carbonyl compound,
Tone (II: R ₁ = R ₂ = CH ₃ )
Methyl-4,7-dihydro-1,3-dioxepin (I
II: Synthesis of R ₁ ＲR ₂ ＣＨCH ₃ ) (9) 333.0 g of granular calcium chloride manufactured by DOW instead of powdered calcium chloride manufactured by Kanto Chemical Co. of Example 1
(3.0 mol) and the reaction mixture was
Stir for 6 hours. After completion of the reaction, the same treatment as in Example 1 was performed. According to gas chromatography internal standard method,
2,2-dimethyl-4,7-dihydro-1,
The content of 3-dioxepin (III: R ₁ = R ₂ = CH ₃ ) was 99.7 g (yield 77.9%).

Example 11 As a carbonyl compound,
Tone (II: R ₁ = R ₂ = CH ₃ )
Methyl-4,7-dihydro-1,3-dioxepin (I
II: Synthesis of R ₁ ＲR ₂ ＣＨCH ₃ ) (10) 44 g of the granular calcium chloride manufactured by DOW of Example 10 was used.
Using 4.0 g (4.0 mol) of the reaction mixture, 25
Stir at 16 ° C for 16 hours. After completion of the reaction, the same treatment as in Example 1 was performed. 2,2-Dimethyl-4,7-dihydro-1,3-dioxepin (III: R ₁ = R ₂ = C) in the reaction mixture by gas chromatography internal standard method
H ₃ ) was 98.9 g (yield 77.3%).

Example 12 As a carbonyl compound,
Tone (II: R ₁ = R ₂ = CH ₃ )
Methyl-4,7-dihydro-1,3-dioxepin (I
II: Synthesis of R ₁ = R ₂ = CH ₃ ) (11) A 1 L four-necked flask was equipped with a stirrer, a thermometer, and a reflux condenser, and cis-2-butene-1,4-diol 8 was added.
8 g (1.0 mol), 237 g of acetone (4.1 mol
l) was charged, and 2.96 g (0.016 mol) of p-toluenesulfonic acid monohydrate was added while stirring.
After stirring for 0.5 hour, 120 g of Molecular Sieves 13X 1/16 manufactured by Wako Pure Chemical Industries, Ltd. was added. Since heat generation was observed, cooling was performed so as to maintain 40 ° C. The reaction mixture was cooled until the internal temperature reached 25 ° C., and the mixture was stirred at the same temperature for 16 hours. The molecular sieve was filtered under reduced pressure, and the molecular sieve was washed with 200 ml of acetone. 2,2-Dimethyl-4,7-dihydro-1,3-dioxepin (III: R ₁ ＲR ₂中 C) by a gas chromatography internal standard method in a solution obtained by combining a filtrate and a washing solution.
H ₃ ) was 59.6 g (yield 46.6%).

Example 13 As a carbonyl compound,
Tone (II: R ₁ = R ₂ = CH ₃ )
Methyl-4,7-dihydro-1,3-dioxepin (I
II: Synthesis of R ₁ = R ₂ = CH ₃ ) (12) A stirrer, a thermometer, and a reflux condenser were attached to a 1 L four-necked flask, and cis-2-butene-1,4-diol 4 was added.
4 g (0.5 mol), acetone 475 g (8.2 mol
l) was charged, and while stirring, 1.48 g (0.008 mol) of p-toluenesulfonic acid monohydrate was added.
After stirring for 0.5 hour, 90 g of Molecular Sieves 3A 1/16 manufactured by Wako Pure Chemical Industries, Ltd. was added. Since heat generation was observed, the mixture was cooled so as to keep the temperature at 20 ° C., and stirred at 20 ° C. for 16 hours. After completion of the reaction, the same treatment as in Example 12 was carried out. 2,2-dimethyl-4,7-dihydro- in the reaction mixture by gas chromatography internal standard method
1,3-dioxepin (III: R ₁ ＲR ₂ 3CH ₃ )
Was 52.2 g (82.0% yield).

Example 14 Acetone was used as the carbonyl compound.
Tone (II: R ₁ = R ₂ = CH ₃ )
Methyl-4,7-dihydro-1,3-dioxepin (I
II: Synthesis of R ₁ = R ₂ = CH ₃ ) (13) A 1 L four-necked flask was equipped with a stirrer, a thermometer, and a reflux condenser, and cis-2-butene-1,4-diol 4 was added.
4 g (0.5 mol), acetone 475 g (8.2 mol
l) was cooled to -5 ° C. While stirring, strongly acidic cation exchange resin Nafion (registered trademark) NR50
1.5 g (Fluka) was added. After stirring for 0.5 hour, molecular sieves 3A1 / 1 manufactured by Wako Pure Chemical Industries, Ltd.
16 90 g were added. The mixture was stirred at -5 ° C for 6 hours. After completion of the reaction, the same treatment as in Example 12 was carried out. According to the gas chromatography internal standard method, the content of 2,2-dimethyl-4,7-dihydro-1,3-dioxepin (III: R ₁ = R ₂ = CH ₃ ) in the reaction solution was 5%.
6.7 g (88.7% yield). The reaction solution was distilled under normal pressure to obtain 2,2-dimethyl-4,7dihydro-1,
53.9 g (84.2% yield) of 3-dioxepin was obtained.

Example 15 As a carbonyl compound,
Tone (II: R ₁ = R ₂ = CH ₃ )
Methyl-4,7-dihydro-1,3-dioxepin (I
II: Synthesis of R ₁ = R ₂ = CH ₃ ) (14) A ₂ - L four-necked flask was equipped with a stirrer, a thermometer, and a reflux condenser, and cis-2-butene-1,4-diol 8 was added.
8 g (1.0 mol), 950 g of acetone (164 mol)
l) was charged, and 2.96 g (0.016 mol) of p-toluenesulfonic acid monohydrate was added while stirring.
After stirring for 0.5 hour, 180 g of Molecular Sieves 13X1 / 16 manufactured by Wako Pure Chemical Industries, Ltd. was added. Since heat generation was observed, cool to maintain 20 ° C,
For 16 hours. After completion of the reaction, the same treatment as in Example 12 was carried out. 2,2-Dimethyl-4,7-dihydro-1,3-dioxepin (III: R ₁ = R ₂ = C) in the reaction mixture by gas chromatography internal standard method
H ₃ ) was 73.7 g (yield 57.6%).

Experimental Example 2 As a carbonyl compound,
(II: R ₁ = R ₂ = CH ₃ )
Tyl-4,7-dihydro-1,3-dioxepin (II
I: Synthesis of R ₁ = R ₂ = CH ₃ ) (15) The same reaction as in Example 1 was performed at 50 ° C. for 5.5 hours. After completion of the reaction, the same treatment as in Example 1 was performed. According to the gas chromatography internal standard method, 2,2-dimethyl-4,7-dihydro-1,3-dioxepin (I
II: R ₁ = R ₂ = CH ₃ ) was 55.2 g (yield 43.1%).

When the results of this experimental example and the results of Example 1 are compared, it is clear that the effect of the reaction temperature on the yield is extremely large.

Example 16 As a carbonyl compound,
Tone (II: R ₁ = R ₂ = CH ₃ )
Methyl-4,7-dihydro-1,3-dioxepin (I
II: Synthesis of R ₁ = R ₂ = CH ₃ ) (16) The reaction mixture was changed to 25 ° C. by changing the amount of p-toluenesulfonic acid monohydrate used in Example 1 to 0.95 g (0.005 mol). For 7.5 hours. After completion of the reaction, the same treatment as in Example 1 was performed. 2,2-dimethyl-4,7- in the reaction solution by gas chromatography internal standard method
Dihydro-1,3-dioxepin (III: R ₁ = R ₂
= CH ₃ ) was 92.0 g (yield 71.9%).

Example 17 Acetone was used as a carbonyl compound.
Tone (II: R ₁ = R ₂ = CH ₃ )
Methyl-4,7-dihydro-1,3-dioxepin (I
II: Synthesis of R ₁ = R ₂ = CH ₃ ) (17) 222.0 g of calcium chloride obtained by repeating the same operation as in Example 1 and the subsequent heating and regeneration operation three times (2.
0 mol), and the reaction mixture was stirred at 24 ° C. for 16 hours. Upon addition of regenerated calcium chloride, the internal temperature of the reaction mixture increased from 24 ° C. to 40 ° C., and after 3 hours 2
It was 4 ° C. After completion of the reaction, the same treatment as in Example 1 was performed. According to gas chromatography internal standard method,
2,2-dimethyl-4,7-dihydro-1,
The content of 3-dioxepin (III: R ₁ = R ₂ = CH ₃ ) was 98.9 g (yield 77.3%).

EXPERIMENTAL EXAMPLE 3 As a carbonyl compound,
(II: R ₁ = R ₂ = CH ₃ )
Tyl-4,7-dihydro-1,3-dioxepin (II
I: Synthesis of R ₁ = R ₂ = CH ₃ (Document [Chem. B]
er. 113, 1472-1479 (1980)]
Trial) 500ml three-necked flask with stirrer, thermometer, Dean
-Attach a Stark trap, cis-2-butene-
88.0 (1.0 mol) of 1,4-diol, 58.0 g (1.0 mol) of acetone, and 300 ml of benzene were charged. While stirring, 2.96 g (0.016 mol) of p-toluenesulfonic acid monohydrate was added, and the mixture was heated.
6 while removing generated water with an-Stark trap
Time refluxed. After completion of the reaction, the mixture was cooled to room temperature, and a benzene layer (upper layer) was formed, mainly with cis-2-butene-1,4-
The lower layer containing the diol was separated. The separated benzene layer and lower layer were each subjected to quantitative analysis by a gas chromatography internal standard method. Acetic acid n as internal standard
-Butyl was used. The results of each analysis are shown below.

[0064]

[Table 1]

* 1) The yields of 2,2-dimethyl-4,7-dihydro-1,3-dioxepin and 2,5-dihydrofuran are based on the charged cis-2-butene-1,4-diol. is there. Cis-2-butene-1,4-
The yield of the diol is a recovery rate based on the charged amount.

* 2) The identification of 2,5-dihydrofuran
The test was performed using a reagent (Tokyo Kasei Kogyo Co., Ltd.) under the same gas chromatography conditions as in the present experimental example, when the retention times (2.2 minutes) of the product and the reagent were the same.

The content of unreacted cis-2-butene-1,4-diol (I) was 4
5.9 g, and 52.2% of the charged amount was left unreacted, so the reaction conversion was 47.8%. On the other hand, the produced 2,2-dimethyl-4,7-dihydro-1,3-dioxepin (III: R ₁ = R ₂ = CH
₃ ) was 28.8 g, and the reaction yield was 22.5%.
It is.

That is, the reaction selectivity is 47.1%. The 2,5-dihydrofuran produced by the side reaction is 5.
Obtained in 6% yield. 19.7% unknown material balance
This is considered to be due to the formation of oligomers or polymers of cis-2-butene-1,4-diol as a side reaction and, as a result, no detection by gas chromatography.

Example 18 Acetone was used as a carbonyl compound.
Tone (II: R ₁ = R ₂ = CH ₃ )
Methyl-4,7-dihydro-1,3-dioxepin (I
II: Synthesis of R ₁ = R ₂ = CH ₃ ) (18) A 1 L three-necked flask was equipped with a stirrer, a thermometer, and a reflux condenser, and cis-2-butene-1,4-diol 8 was added.
8 g (1.0 mol), acetone 290 g (5.0 mol)
l) was charged, and 2.96 g (0.016 mol) of p-toluenesulfonic acid monohydrate was added while stirring.
After stirring for 0.5 hour, 6.94 g (0.063 mol) of powdered calcium chloride manufactured by Kanto Chemical Co., Ltd. was added eight times every hour, for a total of 55.5 g (0.5 mol). The reaction mixture was further stirred at 26 ° C. for 15 hours, and then separated into an acetone layer (upper layer) and a lower layer mainly containing calcium chloride. 158 g of acetone (2.72 mol) was added to the separated lower layer.
After l) was added and stirred for 0.5 hour, the mixture was separated into an acetone layer (upper layer) and a lower layer mainly containing calcium chloride. This operation was repeated once. 2,2-Dimethyl-4,7-dihydro-1,3 in the reaction solution of the solution obtained by combining the acetone layers by gas chromatography internal standard method.
The content of dioxepin (III: R ₁ = R ₂ = CH ₃ ) was 65.7 g (yield 51.3%).

Example 19 As a carbonyl compound,
Tone (II: R ₁ = R ₂ = CH ₃ )
Methyl-4,7-dihydro-1,3-dioxepin (I
II: Synthesis of R ₁ = R ₂ = CH ₃ ) (19) Molecular sieves 3A1 manufactured by Wako Pure Chemical Industries, Ltd. of Example 13
The reaction mixture was changed to 20 ° C.
For 6 hours. After completion of the reaction, the reaction was carried out in the same manner as in Example 13. 2,2-dimethyl-4,7-dihydro- in the reaction mixture by gas chromatography internal standard method
1,3-dioxepin (III: R ₁ ＲR ₂ 3CH ₃ )
Was 46.1 g (72.0% yield).

The reaction temperature in the embodiment described above,
The yield and the coexisting substances in the reaction system are shown in Table 2 together with the experimental examples.

As is clear from this table, according to the present invention, the desired compound can be obtained at room temperature and in a high yield without heating.

[0073]

[Table 2]

Example 20 Acetone was used as the carbonyl compound.
Tone (II: R ₁ = R ₂ = CH ₃ )
Methyl-4,7-dihydro-1,3-dioxepin (I
II: Synthesis of R ₁ = R ₂ = CH ₃ ) (20) A 1 L four-necked flask was equipped with a stirrer, a thermometer, and a reflux condenser, and cis-2-butene-1,4-diol 44 was added.
g (0.5 mol), 158 g of acetone (2.7 mol
l), and stirring while stirring, a strongly acidic cation exchange resin Nafion (registered trademark) NR50 (manufactured by Fluka)
1.5 g was added. After stirring for 0.5 hour, 90 g of Molecular Sieves 3A1 / 16 manufactured by Wako Pure Chemical Industries, Ltd. was added. The mixture was stirred at 20 ° C. for 6 hours. After completion of the reaction, the reaction was carried out in the same manner as in Example 13. According to the gas chromatography internal standard method, 2,2-dimethyl-4,7-dihydro-1,3-dioxepin (III:
The content of R ₁ = R ₂ = CH ₃ is 59.5 g (yield 93).
%)Met.

Example 21 As a carbonyl compound,
Tone (II: R ₁ = R ₂ = CH ₃ )
Methyl-4,7-dihydro-1,3-dioxepin (I
II: Synthesis of R ₁ = R ₂ = CH ₃ ) (21) The amount of the strongly acidic cation exchange resin Nafion (registered trademark) NR50 (manufactured by Fluka) of Example 20 was set to 0.7.
The reaction mixture was stirred at 20 ° C. for 6 hours, changing to 5 g. After completion of the reaction, the same treatment as in Example 13 was carried out. According to the gas chromatography internal standard method, the content of 2,2-dimethyl-4,7-dihydro-1,3-dioxepin (III: R ₁ = R ₂ = CH ₃ ) in the reaction solution was 52.
7 g (82.3% yield).

Example 22 As a carbonyl compound,
Tone (II: R ₁ = R ₂ = CH ₃ )
Methyl-4,7-dihydro-1,3-dioxepin (I
II: Synthesis of R ₁ ＲR ₂ ＣＨCH ₃ (22) (Reaction temperature
Relationship between degree and reaction time and reaction yield) The same reaction as in Example 20 was carried out at a reaction temperature of 50 ° C, 25 ° C,
The temperature was changed to −10 ° C. for 8 hours. After addition of Molecular Sieves 3A1 / 16 manufactured by Wako Pure Chemical Industries, Ltd., 0.5 hour, 1 hour, 2 hours, 3 hours, 5 hours and 8 hours respectively, 2,2-dimethyl-4,7- in the reaction solution. Dihydro-1,3-dioxepin (III: R ₁ ＲR ₂ ＣＨCH
The content of ₃ ) was measured by gas chromatography internal standard method. The respective results are shown below.

[0077]

[Table 3]

When the reaction temperature is -10 ° C., the reaction temperature is 2
Although the reaction rate is slower than that at 5 ° C., the reaction is carried out for 8 hours or more to obtain 2,2-dimethyl-4,7-dihydro-1,3-dioxepin (III:
R ₁ = R ₂ = CH ₃ ).

On the other hand, when the reaction temperature was 50 ° C., the dioxepin reaction yield increased up to 3 hours after the start of the reaction.
After that, it gradually decreased, and after 8 hours, it was 72.7%.

From the results of this example, it is clear that the reaction temperature affects the yield.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Makoto Shimoyamada 1-133 Izumi-machi Shimokawa Daiken, Iwaki-shi, Fukushima Prefecture Within Ichikawa Synthetic Chemical Co., Ltd. 133 Within Ichikawa Gosei Chemical Co., Ltd. (72) Inventor Masataka Yoshida 1-133 Shimokawa Shimokawa Iken, Iwaki-shi, Fukushima

Claims (10)

[Claims] 1. A compound of the formula (I) Cis-2-butene-1,4-diol represented by the general formula (II) in the presence of an acid catalyst: (Wherein, R ₁ and R ₂ are a hydrogen atom or a linear or branched lower alkyl group having 1 to 6 carbon atoms, and R ₁ and R ₂ may each contain an unsaturated bond. , R ₁ and R ₂ may be the same or different, and R ₁ and R ₂ may be linked to each other to form a ring) at a normal temperature. ) (Wherein, R ₁ and R ₂ have the same meanings as in the general formula (II)). A method for producing 4,7-dihydro-1,3-dioxepins represented by the general formula (II). 2. The 4,7-dihydro- according to claim 1, wherein the normal temperature is from -20 ° C. to 40 ° C.
A method for producing 1,3-dioxepins. 3. The method for producing 4,7-dihydro-1,3-dioxepins according to claim 1, wherein a strongly acidic cation exchange resin is used as the acidic catalyst. 4. A carbonyl compound represented by the general formula (II):
The method according to any one of claims 1 to 3, wherein 5 to 70 molar equivalents are used per 1 mol of the cis-2-butene-1,4-diol represented by the formula (I). A method for producing 4,7-dihydro-1,3-dioxepins. 5. The 4,7-dihydro-1,3 according to claim 1, wherein the reaction is carried out in the presence of calcium chloride or molecular sieves.
-A process for producing dioxepins. 6. The amount of the calcium chloride used is not more than 5 molar equivalents relative to 1 mol of cis-2-butene-1,4-diol represented by the formula (I). A method for producing 4,7-dihydro-1,3-dioxepins according to claim 5. 7. The amount of the molecular sieve used is not more than 500 g per 1 mol of cis-2-butene-1,4-diol represented by the formula (I). 5. The method for producing 4,7-dihydro-1,3-dioxepins according to 5. 8. A carbonyl compound represented by the general formula (II):
8. The method according to claim 6, wherein 4 to 30 molar equivalents are used per 1 mol of the cis-2-butene-1,4-diol represented by the formula (I). A method for producing dihydro-1,3-dioxepins. 9. The 4,7-dihydro-1,3 according to any one of claims 1 to 8, wherein the carbonyl compound represented by the general formula (II) is a ketone.
-A process for producing dioxepins. 10. The 2,2-dimethyl-4,7-dihydro-1,3 according to any one of claims 1 to 9, wherein the carbonyl compound of the general formula (II) is acetone. -A process for producing dioxepin.