JP6260385B2 - Method for producing 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxin-5,7-dicarboxylic acid dialkyl ester - Google Patents

Description

  The present invention is an improvement of 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxin-5,7-dicarboxylic acid dialkyl ester represented by the following general formula (1). Related to the manufacturing method.

[In the general formula (1), each R independently represents an alkyl group having 1 to 4 carbon atoms]

  2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxin-5,7-dicarboxylic acid dialkyl ester is 2-hydroxymethyl-2 which is a monomer of a conductive polymer. , 3-Dihydro-thieno [3,4-b] [1,4] dioxin is used as a useful intermediate.

  Conventionally, a method for obtaining 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxin-5,7-dicarboxylic acid dialkyl ester is represented by the following general formula (2). A synthetic method is known in which 3,4-dihydroxythiophene-2,5-dicarboxylic acid dialkyl ester and epibromohydrin represented by the following general formula (3) are ether-cyclized in the presence of a base.

[In the above formula (2), each R independently represents an alkyl group having 1 to 4 carbon atoms]

[In the general formula (3), each X independently represents Cl or Br. ]
However, separation of 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxepin-6,8-dicarboxylic acid dialkyl ester by-product from the reaction from the target compound is difficult, Since the removal by column purification is required, the yield was low (see, for example, Patent Document 1).

  Similarly, in the reaction system using 3,4-dihydroxythiophene-2,5-dicarboxylic acid dialkyl ester and epibromohydrin, the obtained 2-hydroxymethyl-2,3-dihydro-thieno [3,4] -B] [1,4] dioxin-5,7-dicarboxylic acid dialkyl ester and the 7-membered ring analog 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxepin About the mixture of -6,8-dicarboxylic acid dialkyl ester, the hydroxy group of both compounds was reacted with an acetylating agent to form an acetyl ester, and then purified by a recrystallization method to obtain high purity 2-hydroxymethyl-2, A method for obtaining 3-dihydro-thieno [3,4-b] [1,4] dioxin-5,7-dicarboxylic acid dialkyl ester is also known, but the operation is complicated. Reduction in yield by recrystallization is concerned (for example, see Patent Document 2).

  On the other hand, as a method for synthesizing selective 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxin-5,7-dicarboxylic acid dialkyl ester, A method of reacting an alkali salt obtained by adding an alkoxide to dihydroxythiophene-2,5-dicarboxylic acid dialkyl ester and a slight excess of epihalohydrin in a polar solvent is shown. GC-MS analysis of the resulting reaction mixture confirmed only 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxin-5,7-dicarboxylic acid dialkyl ester. However, the yield is not specifically described. Moreover, the reaction liquid of the alkali salt obtained by removing alcohol after adding an alkoxide became a slurry state, and there existed a subject in operativity (for example, refer patent document 3).

  On the other hand, as another selective method for producing 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxin-5,7-dicarboxylic acid dialkyl ester, 3,4- A method of cyclocondensation by reaction of dihydroxythiophene-2,5-dicarboxylic acid dialkyl ester and 2,3-dibromo-1-propanol has also been reported (for example, see Non-Patent Document 1). However, the yield is as low as 40%, which is still insufficient as an industrial production method.

  Therefore, 3,4-dihydroxythiophene-2,5-dicarboxylic acid dialkyl ester is used as a raw material, and 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxin is selectively used. A production method for obtaining a -5,7-dicarboxylic acid dialkyl ester in good yield has not been reported so far.

US Pat. No. 5,111,327 Japanese Patent No. 4049744 JP 2003-335781 A

Electrochemistry Communications 2 (2000) 72-76

  The present invention has been made in view of the above-described background art, and its purpose is to perform 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1 without performing complicated purification. , 4] It is to provide a production method capable of selectively obtaining dioxin-5,7-dicarboxylic acid dialkyl ester with good yield.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors remain in the raw material, 3,4-dihydroxythiophene-2,5-dicarboxylic acid dialkyl ester represented by the above general formula (2). The present inventors have found that an alkali metal salt to affect the ether cyclization reaction has led to the completion of the present invention.

  That is, the present invention provides an improved process for producing 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxin-5,7-dicarboxylic acid dialkyl ester as shown below. It is.

  [1] The following general formula (2)

[In the above formula (2), each R independently represents an alkyl group having 1 to 4 carbon atoms]
3,4-dihydroxythiophene-2,5-dicarboxylic acid dialkyl ester represented by the following general formula (3)

[In the general formula (3), each X independently represents Cl or Br. ]
And a dihalogenated propanol represented by the following general formula (1):

[In the general formula (1), each R independently represents an alkyl group having 1 to 4 carbon atoms]
A process for producing 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxin-5,7-dicarboxylic acid dialkyl ester represented by
The 3,4-dihydroxythiophene-2,5-dicarboxylic acid dialkyl ester represented by the general formula (2) has a sodium ion content of 1000 ppm or less or a calcium ion content of 800 ppm or less, and A total of 2500 ppm or less, and 3,4-dihydroxythiophene-2,5-dicarboxylic acid dialkyl ester represented by the above general formula (2) of the dihalogenated propanol represented by the above general formula (3) The production method is characterized in that the amount used is 1.3 times molar equivalent or more and 2.1 times molar equivalent or less.

  [2] The 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxin-5 described in [1] above, wherein the base is potassium carbonate Method for producing 7-dicarboxylic acid dialkyl ester.

  [3] The production method according to [1] or [2], wherein in the general formulas (1) and (2), each R independently represents a methyl group or an ethyl group.

  [4] The production method according to any one of [1] to [3], wherein the reaction temperature is in the range of 50 to 150 ° C.

  According to the production method of the present invention, 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxin-5,7-dicarboxylic acid represented by the above general formula (1) The acid dialkyl ester can be selectively obtained with good yield without complicated purification.

  Hereinafter, the present invention will be described in detail.

In the present invention, 3,4-dihydroxythiophene-2,5-dicarboxylic acid dialkyl ester represented by the above general formula (2) and dihalogenated propanol represented by the above general formula (3) are present in the presence of a base. And 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxin-5,7-dicarboxylic acid represented by the above general formula (1) A method for producing a dialkyl ester, comprising:
The 3,4-dihydroxythiophene-2,5-dicarboxylic acid dialkyl ester represented by the general formula (2) has a sodium ion content of 1000 ppm or less or a calcium ion content of 800 ppm or less, and The total is 2500 ppm or less, and the dihalogenated propanol represented by the general formula (3) with respect to the 3,4-dihydroxythiophene-2,5-dicarboxylic acid dialkyl ester represented by the general formula (2). The amount used is 1.3 times molar equivalent or more and 2.1 times molar equivalent or less,
Is the feature.

  In the 3,4-dihydroxythiophene-2,5-dicarboxylic acid dialkyl ester represented by the general formula (2), R represents an alkyl group having 1 to 4 carbon atoms.

  As a C1-C4 alkyl group, a methyl group, an ethyl group, n-propyl group, n-butyl group etc. can be mentioned, for example. Among them, a methyl group or an ethyl group is particularly preferable from the viewpoint of industrial availability and economy.

  The 3,4-dihydroxythiophene-2,5-dicarboxylic acid dialkyl ester represented by the general formula (2) has a sodium ion content of 1000 ppm or less, or a calcium ion content of 800 ppm or less. The total of them is 2500 ppm or less, and preferably the sodium ion content is 700 ppm or less, or the calcium ion content is 100 ppm or less.

  In the present invention, the sodium ion content is 1000 ppm or less, or the calcium ion content is 800 ppm or less, and the total thereof is 2500 ppm or less, and 3,4-dihydroxythiophene represented by the above general formula (2) The production method of -2,5-dicarboxylic acid dialkyl ester is not particularly limited. For example, diethylthioglycolic acid ester is reacted with diethyl oxalate in the presence of sodium ethoxide to produce 3,4-dihydroxy ester. Thiophen-2,5-dicarboxylic acid diethyl sodium salt is obtained, neutralized with hydrochloric acid and crystallized to produce high purity 3,4-dihydroxythiophene-2,5-dicarboxylic acid diethyl ester (for example, Journal of Electroanalytical hemistry 443 (1998) see 217-226). In addition, the crude product of 3,4-dihydroxythiophene-2,5-dicarboxylic acid dialkyl ester represented by the above general formula (2) is dispersed in water, washed, collected by filtration, and dried. The content of sodium ions and calcium ions can be further reduced.

  In the 3,4-dihydroxythiophene-2,5-dicarboxylic acid dialkyl ester represented by the above general formula (2) thus obtained, the content of alkali metal ions other than sodium ions and calcium ions Since the alkaline earth metal content other than is contained only below the detection limit (1 ppm), 2-hydroxymethyl-2,3-dihydro-thieno [3,4-represented by the above general formula (1) b] Does not affect the yield of the production of [1,4] dioxin-5,7-dicarboxylic acid dialkyl ester.

  In the dihalogenated propanol represented by the general formula (3), each X independently represents a chlorine atom or a bromine atom.

  The amount of the dihalogenated alkanol compound represented by the general formula (3) is 1.3 per mol of 3,4-dihydroxythiophene-2,5-dicarboxylic acid dialkyl ester represented by the general formula (2). It is essential to be in the range of not less than mol and not more than 2.1 mol (that is, not less than 1.3 times mol equivalent and not more than 2.1 times mol equivalent), and preferably in the range of not less than 2 mol and not more than 2.1 mol. The reason why the amount of the dihalogenated alkanol compound used is within the above range is that the reaction can be sufficiently completed by setting it to 1.3 mol or more, but by-products increase in an amount exceeding 2.1 mol. This is because there is a possibility that excess dihalogenated alkanol compound needs to be recovered.

  The production reaction of the present invention is preferably carried out in a polar solvent such as dimethyl sulfoxide, DMF, or 2- (ethoxyethoxy) ethanol. In the present invention, these polar solvents may be used alone or in admixture at any ratio.

  Although it does not specifically limit as reaction temperature in the manufacture reaction of this invention, The suitable temperature is the range of 50-150 degreeC, More preferably, it is the range of 80-100 degreeC. By setting the reaction temperature to 50 ° C. or higher, a sufficient reaction rate can be obtained. However, at a high temperature exceeding 150 ° C., by-products may increase or the yield may decrease.

  The base used in the production reaction of the present invention is not particularly limited as long as it functions as a dehalogenation reagent. For example, among the weak bases used for Williamson synthesis, potassium salt is particularly used. Is preferred. This is presumably because potassium salts are generally more soluble in organic solvents than sodium and calcium salts and are advantageous for the reaction.

  Such a weak base is not particularly limited, but specific examples include potassium carbonate and potassium hydrogen carbonate, with potassium carbonate being more preferred. In the present invention, these weak bases may be used alone or in admixture at any ratio.

  In the present invention, the dialkyl 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxin-5,7-dicarboxylate represented by the above general formula (1) is obtained. The method for treating and purifying the ester is not particularly limited. For example, the above-mentioned 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxin-5,7-dicarboxylic acid is used. After the production reaction of the acid dialkyl ester, the resulting 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxin-5,7-dicarboxylic acid dialkyl ester crude product is obtained. The target reaction product can be obtained without any particular purification by subjecting the reaction solution containing the solution to salt filtration in the presence of a filtering agent or without using a filtering agent, followed by concentration, extraction, reconcentration, and simple crystallization. .

  The obtained 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxin-5,7-dicarboxylic acid dialkyl ester was treated with a hydrolysis reaction in the presence of an alkali. In the presence of a copper catalyst after isolation by acid crystallization as 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxin-5,7-dicarboxylic acid By performing the decarboxylation reaction, 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxin can be synthesized. At that time, 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxin-5,7-dicarboxylic acid dialkyl ester having a small 7-membered ring impurity content is used as a raw material. Thus, 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxin having a small 7-membered ring impurity content can be obtained.

  In the 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxin-5,7-dicarboxylic acid dialkyl ester represented by the general formula (1), each R is independently And an alkyl group having 1 to 4 carbon atoms.

  As a C1-C4 alkyl group, a methyl group, an ethyl group, n-propyl group, n-butyl group etc. can be mentioned, for example.

  Specific examples of the 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxin-5,7-dicarboxylic acid dialkyl ester represented by the general formula (1) 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxin-5,7-dicarboxylic acid dimethyl ester, 2-hydroxymethyl-2,3-dihydro-thieno [ 3,4-b] [1,4] dioxin-5,7-dicarboxylic acid diethyl ester, 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxin-5 Examples include 7-dicarboxylic acid dipropyl ester, 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxin-5,7-dicarboxylic acid dibutyl ester, and the like.

  The present invention will be described in more detail with reference to the following examples, but the present invention should not be construed as being limited thereto. In addition, the yield of the product in the present Example was estimated from the peak area and isolated yield by gas chromatography and liquid chromatography.

For measurement of ¹ H-NMR and ¹³ C-NMR of the compound, Gemini-200 manufactured by Varian was used.

  GC-17A manufactured by Shimadzu Corporation was used for gas chromatography measurement of the compound. [Measurement conditions: capillary column (GL Science, NB-5), temperature rise, detector FID].

  Moreover, the high performance liquid chromatography system by the Tosoh company was used for the measurement of the liquid chromatography of a compound. [Measurement conditions: column (manufactured by Tosoh Corporation, TSKgel ODS-120T), 40 ° C., detector (manufactured by Tosoh Corporation, UV-8020), solvent (acetonitrile / pH 2 phosphate buffer = 1/1)].

  The molecular weight was confirmed using a gas chromatograph-mass spectrometer (manufactured by JEOL Ltd., GC-MS JMS-K9), and the column was J & W Scientific, a capillary column, DB-5, under elevated temperature conditions.

  In addition, the content rate of Na ion and Ca ion in a sample was quantified by ICP-AES (manufactured by Perkin Elmer, Optima 5300 DV) after wet decomposition of the sample with sulfuric acid and nitric acid.

  In the following adjustment examples 1 to 7, 3,4-dihydroxythiophene-2,5- which is one of 3,4-dihydroxythiophene-2,5-dicarboxylic acid dialkyl ester represented by the above general formula (1) Examples of purification of dicarboxylic acid dimethyl ester (hereinafter abbreviated as DHTDM) are described.

Adjustment Example 1
The crude DHTDM represented by the general formula (2) used as a raw material was found to contain 15,000 ppm of sodium ions and 830 ppm of calcium ions as a result of measuring the content of Na ions and Ca ions.

  In a 100 ml three-necked flask, under a nitrogen atmosphere, 5.0 g of crude DHTDM (content ratio by liquid chromatography determined 83%, pure content 4.2 g, 17.9 mmol) and 50.3 g of water were charged and stirred sufficiently. To obtain a dispersion. The dispersion was stirred under a nitrogen atmosphere, and stirring was continued for 2 hours while maintaining an internal temperature of about 20 ° C. in a water-cooled state. After the washing, it was filtered, washed with 10 ml of water and washed with 10 ml of water, and repeated washing with 10 ml of water was repeated three times. When the obtained wet crystals were dried under reduced pressure at 60 ° C., 3.4 g (purification with a content of 95.5% as determined by liquid chromatography, a purity of 3.3 g, 14.1 mmol, and a recovery of pure content = 79%) DHTDM was obtained and the results are shown in Table 1.

Preparation Example 2
Wet crystals were obtained by the same operation as in Preparation Example 1 except that the internal temperature during stirring of the dispersion was 50 ° C. When the obtained wet crystals were dried at 60 ° C. under reduced pressure, 3.5 g (purification with a liquid chromatography quantitative content of 99.2%, pure content of 3.5 g, 15.0 mmol, pure content recovery rate = 84%) DHTDM was obtained and the results are summarized in Table 1.

Preparation Example 3
A wet crystal was obtained by the same operation as in Preparation Example 1 except that the internal temperature during stirring of the dispersion was 80 ° C.
When the obtained wet crystal was dried under reduced pressure at 60 ° C., 3.7 g (purified DHTDM having a content of 100% by liquid chromatography, a pure content of 3.7 g, 15.7 mmol, and a pure recovery rate of 88% was obtained. The results are summarized in Table 1.

Preparation Example 4.
In a nitrogen atmosphere, a 50 ml eggplant-shaped flask was charged with 1.0 g of crude DHTDM (content ratio as determined by liquid chromatography 83%, pure content 0.8 g, 3.6 mmol) and water 10.2 g, and stirred well. A dispersion was obtained. The dispersion was stirred while cooling with ice in a nitrogen atmosphere, and 0.2 g (2.2 mmol) of 35% hydrochloric acid was added while maintaining the internal temperature at about 5 ° C., and stirring was continued for 0.5 hours. After the washing, it was filtered, washed with 10 ml of water and washed with 10 ml of water, and repeated washing with 10 ml of water was repeated three times. When the obtained wet crystal was dried at 60 ° C. under reduced pressure, 0.8 g (purified DHTDM having a content of 99% by liquid chromatography, a pure content of 0.8 g, 3.4 mmol, and a recovery rate of pure content = 94% was obtained. The results are summarized in Table 1.

Preparation Example 5
Wet crystals were obtained in the same manner as in Preparation Example 1 except that 4.5 g (43.1 mmol) of 35% hydrochloric acid was added to the dispersion.

  When the obtained wet crystal was dried at 60 ° C. under reduced pressure, 3.9 g (purified DHTDM having a content of 100% by liquid chromatography, a pure content of 3.9 g, 16.9 mmol, and a pure content recovery rate of 94% was obtained. The results are summarized in Table 1.

Preparation Example 6
In a 10-liter four-necked separable flask equipped with a stirrer, a thermometer, and a condenser tube, 395.0 g of crude DHTDM (content ratio by liquid chromatography quantification 83%, pure content 328 g, 1.41 mol) under nitrogen atmosphere ) And 3950.1 g of water were added and sufficiently stirred to obtain a dispersion. The dispersion was stirred under a nitrogen atmosphere and 354.8 g (6.402 mol) of 35% hydrochloric acid was added dropwise over 30 minutes while maintaining an internal temperature range of 16 ° C. to 19 ° C. in a water-cooled state. Stirring was continued for 18 hours while maintaining. After completion of the reaction, the mixture was filtered, washed with 1000 ml of water and washed, and washed with 500 ml of water. Next, the wet crystals were returned to 3950 ml of water, and dispersion washing and filtration were repeated three times. When the obtained wet crystals were dried under reduced pressure at 60 ° C., 301 g (purified DHTDM having a content of 99% by liquid chromatography, a pure content of 297.2 g, 1.28 mol, and a pure content recovery rate of 91% was obtained. The results are summarized in Table 1.

Preparation Example 7
Wet crystals were obtained in the same manner as in Preparation Example 4 except that 2.3 g (21.6 mmol) of 35% hydrochloric acid was added to the dispersion.

  The obtained wet crystals were dried at 80 ° C. under reduced pressure, and 0.8 g [99% content by liquid chromatography, pure content 0.8 g, 3.3 mmol, pure content recovery rate = 92% (same as above) )] Purified DHTDM was obtained. The results are summarized in Table 1.

  As is clear from Table 1, in all these adjustment examples, the sodium ion content in the purified DHTDM (purified product) is 1000 ppm or less, or the calcium ions are 800 ppm or less, and the total thereof is 2500 ppm. It is as follows.

Example 1.
In a 10-liter four-necked separable flask equipped with a stirrer, a thermometer, and a condenser tube, under a nitrogen atmosphere, 274.2 g (1.18 mol) of purified DHTDM obtained in Preparation Example 6 and 326.3 g of potassium carbonate ( 2.36 mol) and 2663.0 g of dimethyl sulfoxide were charged, and 514.4 g (2.36 mol) of 2,3-dibromopropanol was added dropwise over 0.4 hours with stirring in the range of 87 ° C to 92 ° C. . Furthermore, heating and stirring were continued for 17 hours while maintaining the same temperature range. When the reaction solution was analyzed by gas chromatography after the reaction was completed, a reaction solution containing a main peak of 86.7 area% was obtained. Further, 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxepin-6,8-dicarboxylic acid dialkyl ester, a 7-membered ring analog that is an impurity, is 2 -Hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxepin-6,8-dicarboxylic acid dimethyl ester (hereinafter abbreviated as “OH-PDT-1”) is 0 Less than 4%. The reaction solution was quantified by liquid chromatography. As a result, 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxin-5,7-dicarboxylic acid dimethyl ester (hereinafter referred to as the target product) was obtained. , “HM-DHTDM”) was 192.7 g (1.17 mol, 57% yield). The reaction results are shown in Table 2.

  The obtained reaction solution could be solidified after the treatment.

Example 2
In the same manner as in Example 1, 0.46 g (2.0 mmol) of purified DHTDM obtained in Preparation Example 7, 0.55 g (4.0 mmol) of potassium carbonate, 2,3-dibromopropanol .87 g (4.0 mmol) and dimethyl sulfoxide 5.0 g were charged and stirring was continued for 20 hours while stirring at 90 ° C.

  When the reaction solution was analyzed by gas chromatography after the reaction was completed, a reaction solution containing a main peak of 87.4 area% was obtained. Further, the impurity OH-PDT-1 was as low as 0.3%. When the reaction solution was quantified by liquid chromatography, the yield of the target HM-DHTDM was 0.4 g (1.4 mmol, 67% yield). The reaction results are summarized in Table 2.

Example 3 FIG.
As in Example 2, 0.46 g (2.0 mmol) of purified DHTDM obtained in Preparation Example 1, 0.55 g (4.0 mmol) of potassium carbonate, 2,3-dibromopropanol .87 g (4.0 mmol) and dimethyl sulfoxide 5.0 g were charged and stirring was continued for 16 hours while stirring at 90 ° C.

  When the reaction solution was analyzed by gas chromatography after the reaction was completed, a reaction solution containing a main peak of 87.5 area% was obtained. Further, the impurity OH-PDT-1 was as small as 0.1%. When the reaction solution was quantified by liquid chromatography, the yield of the desired product, 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxin-5,7-dicarboxylic acid dimethyl ester, was obtained. Was 0.3 g (1.0 mmol, yield 49%). The reaction results are summarized in Table 2.

Example 4
As in Example 2, 0.46 g (2.0 mmol) of purified DHTDM obtained in Preparation Example 3, 0.55 g (4.0 mmol) of potassium carbonate, 2,3-dibromopropanol .87 g (4.0 mmol) and dimethyl sulfoxide 5.0 g were charged and stirring was continued for 16 hours while stirring at 90 ° C.

  After completion of the reaction, gas chromatographic analysis of the reaction solution was performed. As a result, a reaction solution containing 89.8 area% main peak was obtained. Impurity OH-PDT-1 was small at 0.01% or less. When the reaction solution was quantified by liquid chromatography, the yield of the target HM-DHTDM was 0.3 g (1.0 mmol, yield 45%). The reaction results are summarized in Table 2.

Example 5 FIG.
As in Example 2, 0.46 g (2.0 mmol) of purified DHTDM obtained in Preparation Example 4, 0.55 g (4.0 mmol) of potassium carbonate, 2,3-dibromopropanol .87 g (4.0 mmol) and dimethyl sulfoxide 5.0 g were charged and stirring was continued for 16 hours while stirring at 90 ° C.

  When the reaction solution was analyzed by gas chromatography after the reaction was completed, a reaction solution containing a main peak of 83.1 area% was obtained. Further, the impurity OH-PDT-1 was as small as 0.1%. When the reaction solution was quantified by liquid chromatography, the yield of the desired product, 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxin-5,7-dicarboxylic acid dimethyl ester, was obtained. Was 0.2 g (0.8 mmol, yield 39%). The reaction results are summarized in Table 2.

Comparative Example 1
As in Example 1, 1.29 kg (5.53 mol) of untreated crude DHTDM as a raw material was placed in a 30-liter four-necked separable flask equipped with a stirrer, a thermometer, and a cooling tube under a nitrogen atmosphere. ), 1.54 kg (11.11 mol) of potassium carbonate and 12.3 kg of dimethyl sulfoxide, and while stirring 2.43 kg (11.15 mol) of 2,3-dibromopropanol at 90 ° C. over 4.5 hours. It was dripped. Furthermore, heating and stirring were continued for 20 hours while maintaining the same temperature range. When the reaction solution was analyzed by gas chromatography after the reaction was completed, a reaction solution containing 68.9 area% main peak was obtained. However, the impurity OH-PDT-1 was as high as 2.0%. Further, when the reaction solution was quantified by liquid chromatography, the yield of the target product, HM-DHTDM, was as low as 0.49 kg (1.71 mol, 31% yield). The reaction results are summarized in Table 2.

  As apparent from Table 2, when the sodium ion content in DHTDM exceeds 1000 ppm, or the calcium ion content exceeds 800 ppm and the total exceeds 2500 ppm, the content of OH-PDT-1 as an impurity is increased. It was found that the yield of the target product, HM-DHTDM, also decreased.

  Next, in Examples 6 to 12 and Comparative Examples 4 to 10 below, using purified DHTDM having a sodium ion content of 490 ppm and a calcium ion content of 97 ppm, -The amount of dibromopropanol used was examined.

Example 6
As in Example 2, purified DHTDM 0.46 g (2.0 mmol), potassium carbonate 0.55 g (4.0 mmol), 2,3-dibromopropanol 0.57 g (2.6 mmol), and dimethyl sulfoxide 5. 0 g was charged and stirring was continued for 16 hours while stirring at 80 ° C.

  When the reaction solution was analyzed by gas chromatography after the reaction was completed, a reaction solution containing a main peak of 98.4 area% was obtained. Moreover, impurity OH-PDT-1 was 0.01% or less. In addition, when the reaction liquid was quantified by liquid chromatography, the yield of the target HM-DHTDM was 0.27 g (0.9 mmol, yield 46%). The reaction results are shown in Table 3.

Example 7
In a 2 liter separable flask, 92.9 g (400.0 mmol) purified DHTDM, 110.60 g (800.0 mmol) potassium carbonate, 113.3 g (520.0 mmol) 2,3-dibromopropanol, and 929. dimethyl sulfoxide. Stirring was continued for 42 hours while stirring at 82 ° C.

  After completion of the reaction, gas chromatographic analysis of the reaction solution was performed. As a result, a reaction solution containing a main peak of 80.0 area% was obtained. Moreover, impurity OH-PDT-1 was 0.01% or less. When the reaction solution was quantified by liquid chromatography, the yield of the target product, HM-DHTDM, was 72.9 g (252.9 mmol, yield 63%). The reaction results are summarized in Table 3.

Example 8 FIG.
In the same manner as in Example 2, in a simple reactor of 30 ml, purified DHTDM 0.46 g (2.0 mmol), potassium carbonate 0.55 g (4.0 mmol), 2,3-dibromopropanol 0.87 g (4.0 mmol) , And 5.0 g of dimethyl sulfoxide were charged, and stirring with heating was continued for 16 hours while stirring at 80 ° C.

  After completion of the reaction, gas chromatographic analysis of the reaction solution was performed. As a result, a reaction solution containing a main peak of 89.0 area% was obtained. Moreover, impurity OH-PDT-1 was 0.01% or less. When the reaction solution was quantified by liquid chromatography, the yield of the target HM-DHTDM was 0.33 g (1.1 mmol, 58% yield). The reaction results are summarized in Table 3.

Example 9
Purified DHTDM 4.7 g (20.0 mmol), potassium carbonate 5.5 g (40.0 mol), and dimethyl sulfoxide in a 100 ml three-necked flask equipped with a stirrer, thermometer and condenser 44.9 g was charged, and 8.72 g (40.0 mmol) of 2,3-dibromopropanol was added dropwise over 4 hours with stirring in the range of 88 ° C to 90 ° C. Furthermore, heating and stirring were continued for 12 hours while maintaining the same temperature range. When the reaction solution was analyzed by gas chromatography after the reaction was completed, a reaction solution containing a main peak of 81.5 area% was obtained. The impurity OH-PDT-1 was a small 0.2%. When the reaction solution was quantified by liquid chromatography, the yield of the target product, HM-DHTDM, was 2.9 g (10.0 mmol, yield 50%). The reaction results are summarized in Table 3.

Example 10
In the same manner as in Example 9, 4.6 g (20.0 mmol) of purified DHTDM, 5.5 g (40.0 mmol) of potassium carbonate, 8.7 g of 2,3-dibromopropanol were added to a 100 ml three-necked flask under a nitrogen atmosphere. (40.0 mmol) and 50.4 g of dimethyl sulfoxide were charged, and stirring with heating was continued for 20 hours while stirring at 90 ° C.

  After completion of the reaction, gas chromatographic analysis of the reaction solution was performed. As a result, a reaction solution containing a main peak of 87.7 area% was obtained. Further, the impurity OH-PDT-1 was as small as 0.1%. In addition, when the reaction liquid was quantified by liquid chromatography, the yield of the target HM-DHTDM was 4.02 g (13.9 mmol, 70% yield). The reaction results are summarized in Table 3.

Example 11
In the same manner as in Example 2, in a simple reactor of 30 ml, purified DHTDM 0.46 g (2.0 mmol), potassium carbonate 0.55 g (4.0 mmol), 2,3-dibromopropanol 0.92 g (4.2 mmol) , And 5.0 g of dimethyl sulfoxide were charged and stirring was continued for 20 hours while stirring at 90 ° C.

  After completion of the reaction, gas chromatographic analysis of the reaction solution was performed. As a result, a reaction solution containing a main peak of 86.5 area% was obtained. Moreover, impurity OH-PDT-1 was 0.01% or less. In addition, when the reaction liquid was quantified by liquid chromatography, the yield of the target HM-DHTDM was 0.28 g (1.0 mmol, 48% yield). The reaction results are summarized in Table 3.

Example 12
In the same manner as in Example 2, in a simple reactor of 30 ml, purified DHTDM 0.46 g (2.0 mmol), potassium carbonate 0.55 g (4.0 mmol), 2,3-dibromopropanol 0.87 g (4.0 mmol) , And 5.0 g of dimethyl sulfoxide were charged, and stirring was continued for 12 hours while stirring at 100 ° C.

  When the reaction solution was analyzed by gas chromatography after the reaction was completed, a reaction solution containing 91.5 area% main peak was obtained. Impurity OH-PDT-1 was 0.4%. In addition, when the reaction liquid was quantified by liquid chromatography, the yield of the target HM-DHTDM was 0.30 g (1.1 mmol, 53% yield). The reaction results are summarized in Table 3.

Comparative Example 2
In the same manner as in Example 2, in a simple reactor of 30 ml, purified DHTDM 0.46 g (2.0 mmol), potassium carbonate 0.55 g (4.0 mmol), 2,3-dibromopropanol 1.00 g (4.6 mmol) , And 5.0 g of dimethyl sulfoxide were charged, and stirring with heating was continued for 16 hours while stirring at 80 ° C.

  When the reaction solution was analyzed by gas chromatography after the reaction was completed, a reaction solution containing 96.8 area% main peak was obtained. However, the impurity OH-PDT-1 was a large 2.3%. When the reaction solution was quantified by liquid chromatography, the yield of the target product, HM-DHTDM, was 0.34 g (1.2 mmol, yield 59%). The reaction results are summarized in Table 3.

Comparative Example 3
Purified DMTDM 92.8 g (400.0 mmol), potassium carbonate 110.6 g (800.0 mol), and dimethyl sulfoxide under a nitrogen atmosphere in a 5-liter four-necked flask equipped with a stirrer, thermometer, and condenser. 1000.2 g was charged, and 200.9 g (920.0 mmol) of 2,3-dibromopropanol was added dropwise over 0.2 hours with stirring at 70 ° C. Furthermore, heating and stirring were continued for 24 hours while maintaining the temperature around 80 ° C. by raising the temperature. When the reaction solution was analyzed by gas chromatography after the reaction was completed, a reaction solution containing a main peak of 80.9 area% was obtained. However, the impurity OH-PDT-1 was as large as 5.2%. When the reaction solution was quantified by liquid chromatography, the yield of the target HM-DHTDM was 91.4 g (317.1 mmol, 79% yield). The reaction results are summarized in Table 3.

Comparative Example 4
In a 1 liter four-necked flask equipped with a stirrer, a thermometer, and a condenser tube, 69.6 g (300.0 mmol) of purified DMTDM, 82.9 g (600.0 mol) of potassium carbonate, and 750% of dimethylformamide under a nitrogen atmosphere. 7 g of 2,3-dibromopropanol 85.1 g (390.0 mmol) was charged, and the mixture was heated and stirred for 24 hours while maintaining the temperature range of 80 to 84 ° C. Further, 65.4 g (300.0 mmol) of 2,3-dibromopropanol was added to the reaction solution, and heating and stirring were continued for 8 hours while maintaining a temperature range of 80 to 84 ° C. After completion of the reaction, gas chromatographic analysis of the reaction solution was performed. As a result, a reaction solution containing a main peak of 89.9 area% was obtained. However, the impurity OH-PDT-1 was as high as 6.3%. When the reaction solution was quantified by liquid chromatography, the yield of the target product, HM-DHTDM, was 54.2 g (188.1 mmol, 63% yield). The reaction results are summarized in Table 3.

Comparative Example 5
As in Example 2, 0.46 g (2.0 mmol) of purified DMTDM, 0.55 g (4.0 mmol) of potassium carbonate, and 0.44 g (2.0 mmol) of 2,3-dibromopropanol were added to a 30 ml simple reaction vessel. , And 5.0 g of dimethyl sulfoxide were charged and stirring was continued for 20 hours while stirring at 90 ° C.

  When the reaction solution was analyzed by gas chromatography after the reaction was completed, a reaction solution containing a main peak of 81.3% area was obtained. Further, the impurity OH-PDT-1 was as low as 0.3%. However, when the reaction solution was quantified by liquid chromatography, the yield of the target HM-DHTDM was as low as 0.10 g (0.3 mmol, 17% yield). The reaction results are summarized in Table 3.

Comparative Example 6
As in Example 2, in a simple reactor of 30 ml, purified DMTDM 0.46 g (2.0 mmol), potassium carbonate 0.55 g (4.0 mmol), 2,3-dibromopropanol 0.96 g (4.4 mmol), Then, 5.0 g of dimethyl sulfoxide was charged and stirring was continued for 20 hours while stirring at 90 ° C.

  When the reaction solution was analyzed by gas chromatography after the reaction was completed, a reaction solution containing a main peak of 83.1 area% was obtained. However, the impurity OH-PDT-1 was a large 5.5%. When the reaction solution was quantified by liquid chromatography, the yield of the target HM-DHTDM was 0.37 g (1.3 mmol, 64% yield). The reaction results are summarized in Table 3.

Comparative Example 7
In the same manner as in Example 2, in a simple reactor of 30 ml, purified DMTDM 0.46 g (2.0 mmol), potassium carbonate 0.55 g (4.0 mmol), 2,3-dibromopropanol 1.00 g (4.6 mmol) , And 5.0 g of dimethyl sulfoxide were charged and stirring was continued for 20 hours while stirring at 90 ° C.

  When the reaction solution was analyzed by gas chromatography after the reaction was completed, a reaction solution containing a main peak of 81.4 area% was obtained. However, the impurity OH-PDT-1 was as high as 9.9%. When the reaction solution was quantified by liquid chromatography, the yield of the target HM-DHTDM was 0.44 g (1.5 mmol, 77% yield). The reaction results are summarized in Table 3.

Comparative Example 8.
In the same manner as in Example 2, in a simple reactor of 30 ml, purified DHTDM 0.46 g (2.0 mmol), potassium carbonate 0.55 g (4.0 mmol), 2,3-dibromopropanol 1.00 g (4.6 mmol) , And 5.0 g of dimethyl sulfoxide were charged, and stirring with heating was continued for 20 hours while stirring at 100 ° C.

  When the reaction solution was analyzed by gas chromatography after the reaction was completed, a reaction solution containing a main peak of 84.1 area% was obtained. However, the impurity OH-PDT-1 was as high as 5.9%. In addition, when the reaction liquid was quantified by liquid chromatography, the yield of the target HM-DHTDM was 0.42 g (1.5 mmol, 73% yield). The reaction results are summarized in Table 3.

  As is apparent from Table 3, when the molar ratio of 2,3-dibromopropanol / DHTDM is set to 1.3 to 2.1 times (molar ratio), the yield of the target product, HM-DHTDM, increases. The yield of OH-PDT-1 is reduced.

  In the following Example 13 and Comparative Example 9, a purified 3,4-dihydroxythiophene-2,5-dicarboxylic acid diethyl ester (hereinafter referred to as a sodium ion content of 79 ppm and a calcium ion content of 750 ppm) The amount of 2,3-dibromopropanol used relative to DHTDE was examined.

Example 13
Purified DHTDE 5.2 g (20.0 mmol), potassium carbonate 5.5 g (40.0 mol), and dimethyl sulfoxide under a nitrogen atmosphere in a 100 ml four-necked flask equipped with a stirrer, thermometer, and condenser. 44.7 g and 2,3-dibromopropanol 8.72 g (40.0 mmol) were added dropwise over 0.3 hours with stirring in the range of 89 ° C. to 90 ° C. Furthermore, heating and stirring were continued for 17 hours while maintaining the same temperature range. When the reaction solution was analyzed by gas chromatography after the reaction was completed, a reaction solution containing a main peak of 94.2 area% was obtained. Further, the impurity 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxepin-6,8-dicarboxylic acid diethyl ester (hereinafter abbreviated as “OH-PDT-2”). .) Was as low as 0.2%. The reaction solution was quantified by liquid chromatography. As a result, 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxepin-6,8-dicarboxylic acid diethyl ester (hereinafter referred to as the target product) was obtained. , “HM-DHTDE”) was 3.5 g (11.1 mmol, 55% yield). The reaction results are shown in Table 4.

Comparative Example 9
In the same manner as in Example 13, the amount of 2,3-dibromopropanol used in the purified DHTDE was 2.3 mol times, and in the same manner as in Example 13, 0.52 g of purified DHTDE (2. 0 mmol), 0.55 g (4.0 mmol) of potassium carbonate, 0.59 g (2.6 mmol) of 2,3-dibromopropanol, and 5.0 g of dimethyl sulfoxide, and stirring with heating at 100 ° C. for 24 hours. Further, 0.43 g (1.9 mmol) of 2,3-dibromopropanol was further added, and stirring was continued for 8 hours while stirring at 100 ° C. When the reaction solution was analyzed by gas chromatography after the reaction was completed, a reaction solution containing a main peak of 93.3 area% was obtained. When the reaction solution was quantified by liquid chromatography, the yield of the target product, HM-DHTDE, was 0.36 g (1.1 mmol, 57% yield), which was the same as in Example 13 above. Impurity OH-PDT-2 was as high as 4.7%. The reaction results are summarized in Table 4.

  Next, hydrolysis and decarboxylation reaction is performed from HM-DHTDM obtained by the above production method to obtain 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxin. Synthesis was performed.

Reference Example 1
First, 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxin-5,7-dicarboxylic acid was prepared by the following method.

  In a 5 liter four-necked separable flask equipped with a stirrer, a thermometer, and a condenser tube, 165.2 g (0.57 mol) of HM-DHTDM obtained in the reaction of Example 1 was added to ethanol 1074. 3 g was added and dissolved, and then an aqueous solution in which 118.2 g (2.87 mol) of 97% sodium hydroxide was dissolved in 3222.1 g of water was charged. After the temperature was raised to 86 ° C., the reflux was continued for 3 hours. After completion of the reaction, gas chromatographic analysis of the reaction solution was conducted. As a result, 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxin-5,7-dicarboxylic acid dimethyl ester was obtained. The peak of disappeared. When analyzed by liquid chromatography, the peak of HM-DHTDM disappeared and another single peak was observed. The reaction solution was concentrated, cooled to 10 ° C. or lower, and acidified with hydrochloric acid, and a light brown precipitate crystallized out. When the crystallized product was filtered, washed with water, and dried, 136.1 g of a light brown powder was obtained. The obtained compound shows a single peak by liquid chromatography analysis, and 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxin-5,7-dicarboxylic acid is The yield was 91.8% (estimated pure content 0.52 mol).

  Using the obtained 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxin-5,7-dicarboxylic acid, the following method was used. , 3-Dihydro-thieno [3,4-b] [1,4] dioxin was synthesized.

In a 5-liter four-necked separable flask equipped with a stirrer, a thermometer, and a condenser tube, a 2-hydroxymethyl-2,3-dihydro-thieno [3,4] obtained in the above reaction under a nitrogen atmosphere. -B] [1,4] dioxin-5,7-dicarboxylic acid 135.9 g (estimated pure content 0.52 mol), copper (II) oxide 8.3 g (0.10 mol), N, N-dimethylformamide 2700 0.0 g was charged, and heating and stirring were continued in the temperature range of 130 to 132 ° C. for 8 hours. After the completion of the reaction, analysis by liquid chromatography revealed that the peak of 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxin-5,7-dicarboxylic acid disappeared. It was. Moreover, when the gas chromatographic analysis was performed about the reaction liquid, the main peak was observed. The reaction solution was concentrated, cooled to 25 ° C. or lower, dissolved in 1100 ml of toluene, filtered, washed with 1% aqueous hydrochloric acid and saturated brine, and then concentrated. The concentrate was purified by column chromatography, and after drying, 76.0 g of a pale yellow solid was obtained. The main component of the obtained compound was 99.4% by gas chromatography analysis, and as a result of ¹ H-NMR, ¹³ C-NMR, and GC-MS measurement, the target compound, 2-hydroxymethyl- It was confirmed that 2,3-dihydro-thieno [3,4-b] [1,4] dioxin was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) 2.20 (1H, t), 3.80-3.90 (2H, m), 4.08 (1H, dd), 4.20-4.28 (2H M), 6.34 (2H, d).

¹³ C-NMR (50 MHz, CDCl ₃ ) 61.55, 65.70, 74.03, 99.83, 99.96, 141.38.

  GC-MS (m / e) 172, 141, 127, 116.

  The content of 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxepin as an impurity was as low as 0.1% or less.

  Further, 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] of the obtained 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxin The yield based on [1,4] dioxin-5,7-dicarboxylic acid was 85% (pure content 0.44 mol).

  By using the production method of the present invention, 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxin-5,7-dicarboxylic acid dialkyl ester is selectively obtained at a high yield. Can be obtained.

Claims (4)

The following general formula (2)

[In the above formula (2), each R independently represents an alkyl group having 1 to 4 carbon atoms]
3,4-dihydroxythiophene-2,5-dicarboxylic acid dialkyl ester represented by the following general formula (3)

[In the general formula (3), each X independently represents Cl or Br. ]
And a dihalogenated propanol represented by the following general formula (1):

[In the general formula (1), each R independently represents an alkyl group having 1 to 4 carbon atoms]
A process for producing 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxin-5,7-dicarboxylic acid dialkyl ester represented by
The 3,4-dihydroxythiophene-2,5-dicarboxylic acid dialkyl ester represented by the general formula (2) has a sodium ion content of 1000 ppm or less or a calcium ion content of 800 ppm or less, and A total of 2500 ppm or less, and 3,4-dihydroxythiophene-2,5-dicarboxylic acid dialkyl ester represented by the above general formula (2) of the dihalogenated propanol represented by the above general formula (3) The production method is characterized in that the amount used is 1.3 times molar equivalent or more and 2.1 times molar equivalent or less. Dihydroxy 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxin-5,7-dicarboxylate according to claim 1, characterized in that the base is potassium carbonate. Ester production method. In the general formulas (1) and (2), each R independently represents a methyl group or an ethyl group. The production method according to claim 1 or 2, wherein: The method according to any one of claims 1 to 3, wherein the reaction temperature is in the range of 50 to 150 ° C.