TW201105620A - Process for production of alkoxybenzenesulfonyl chlorides - Google Patents

Abstract

Provided is a process by which high-purity alkoxybenzenesulfonyl chlorides can be produced industrially, easily and efficiently. A process for the production of alkoxybenzenesulfonyl chlorides represented by general formula (2) [wherein R1s may be the same or different and are each a C1-4 lower alkyl group, or the R1s of two OR1s which are adjacent to each other may be united to form a ring; and n is an integer of 2 to 5], characterized by subjecting the reaction product of sulfuryl chloride and N,N-dimethyl- formamide to a reaction with an alkoxybenzene represented by general formula (1) [wherein R1s may be the same or different and are each a C1-4 lower alkyl group, or the R1s of two OR1s which are adjacent to each other may be united to form a ring; and n is an integer of 2 to 5].

Description

[Technical Field] The present invention relates to a method for producing alkoxybenzene sulfonium gas which is useful as an intermediate product for synthesis such as pharmaceuticals. [Previous technical name] 1 Background Art Various methods are known as a method for producing alkoxybenzene sulfonium gas (which can be used as an important intermediate product for synthesis such as medicine). For example, it is known that sulfuric acid is dropped into 1,3-dioxylbenzene to sulfonate it to 2,4-dialkoxybenzenesulfonic acid, followed by using a saturated aqueous solution of potassium carbonate to prepare 2 After the potassium 4-dialkyloxybenzenesulfonate is added, a method of dropping arsenite into the dimercaptocarboxamide (see Patent Document 1) and the like. LIST OF INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION The alkoxybenzene has an alkoxy group which can serve as an electron donor group, and therefore It shows high reactivity to electrophilic agents. Therefore, as described in Patent Document 1, when 1,3-dialkyloxybenzene is sulfonated using sulfuric acid or the like to obtain 2,4-dialkoxybenzenesulfonic acid, a large amount of by-products 4, 6- are produced. Dialkoxybenzene-1,3-disulfonic acid. 4,6-dialkyloxybenzene-1,3-disulfonic acid is vaporized in the same manner as 2,4-dialkyloxybenzenesulfonic acid in the subsequent reaction using sulfoxide 201105620 gas. 4,6-Dialkyloxybenzene-1,3-disulfonium is present as an impurity in the reaction product. The aforementioned 4,6-dialkoxybenzene-1,3-disulfonium gas present in the 2,4-dialkoxybenzenesulfonium gas is particularly difficult to be separated and removed, and therefore, particularly, 2,4-dialkoxybenzene is used. Sulfonium gas is a big problem as an intermediate product for pharmaceutical synthesis. In Patent Document 1, after obtaining 2,4-dialkoxybenzenesulfonic acid from 1,3-dialkoxybenzene, a potassium carbonate saturated solution is used to prepare potassium 2,4-dialkoxybenzenesulfonate for the purpose of After filtration and separation, a gasification reaction is provided, thereby reducing the content of the aforementioned 4,6-dialkoxybenzene-1,3-disulfonium gas, thereby increasing the purity of the obtained 2,4-dialkoxybenzenesulfonate gas. . However, this operation is complicated and it is desired to have a more efficient proposal for a method for producing 2,4-dialkyloxybenzenesulfonyl chloride. SUMMARY OF THE INVENTION An object of the present invention is to provide a process for industrially producing a high purity alkoxybenzene sulfonium gas easily and efficiently. Means for Solving the Problems The present invention relates to a method for producing an oxygen-burning benzene-containing helium gas represented by the formula (2): [Chemical Formula 2] (R1〇]^-^j4j —S02CI (2) (wherein R1 represents the same Or a different lower alkyl group having 1 to 4 carbon atoms, and R1 of two adjacent OR1 groups may be connected in five phases to form a ring. n represents an integer of 2 to 5), and the method is characterized in that: And Ν, 反应-dimercaptoamine reactant ' reacts with alkoxybenzene represented by formula (丨) 201105620: 【化1】(Rl〇)fr〇(1) (wherein R1 represents the same Or a different carbon number of the lower alkyl group of 4 and R1 of two adjacent OR1 may be bonded to each other to form a ring. ^ represents an integer of 2 to 5.) I: Embodiment 3 Hereinafter, the δ sheep will be described in detail. The alkoxybenzene used in the present invention is a compound represented by the following formula (1). (1) In the formula (1), 'R1 represents the same or different carbon number 丨~4. Further, R1 of two adjacent OR1s may be bonded to each other to form a ring. η represents an integer of 2 to 5. The alkyl group having a carbon number of 44 represented by R1 may, for example, be a methyl group or an ethyl group. N-propyl And an isopropyl group, an n-butyl group, a tert-butyl group, an isobutyl group, etc. Further, the group in which the adjacent two ORs of R are linked to each other may be exemplified by 1,3_2, anthracene, etc. Among them, a mercapto group and an anthracene, a bis-oxazolyl group can be suitably used. Specific examples of the alkoxybenzene represented by the formula (1) include, for example, 1,2-dimethylemulsion, 1,2. -diethoxybenzene, di-n-propoxybenzene, bis-isopropoxybenzene, 1'2-monobutoxybenzene, ι,2-di-butoxide, a-diisobutoxybenzene, 13_ Methoxybenzene, 1,3-diethoxybenzene, di-n-ano-oxybenzene, hydrazine-diisopropyloxy 201105620 Benzene, 1,3-di-n-butoxybenzene, ι, 3_di-tert-butoxybenzene, i , 3_ diisobutoxybenzene, M-dioxabenzene, 1,4-diethoxybenzene, ι,4-di-n-propoxybenzene, ι,4-diisopropoxybenzene, 1,4-two n-Butoxybenzene' 丨, 4_2, 3rd butoxybenzene, hydrazine, 4_diisobutoxybenzene, 1,3-benzobisoxazole, H4-trioxobenzene, triethoxybenzene, 12, Tri-n-propoxybenzene, 1,2,4-triisopropoxybenzene, iota, 2,4-tri-n-butoxybenzene, iota, 2,4-tris-tert-butoxybenzene, 1,2,4-tri Isobutoxybenzene, 1,3,5-trioxabenzene, 1,3,5-diethoxybenzene, 1,3,5-tri-n-butyl Oxybenzene, 1,3,5-triisopropoxybenzene, 1,3,5-tri-n-butoxybenzene, 1,3,5-tris-tert-butoxybenzene', 3,5-triisobutoxy Benzene, m trimethoxybenzene, 1,2,3-triethoxybenzene, iota, 2,3-tri-n-propoxybenzene, i,2,3-triisopropoxybenzene, 1,2,3-tri-n-negative Butoxy-oxygen, tri-tert-butoxybenzene, hydrazine, 2,3-triisobutoxybenzene, 1,2,3,4-tetraoxabenzene, tetraethoxybenzene, 1,2,3,4-tetra n-Propoxybenzene, 1,2,3,4-tetraisopropoxybenzene, 12,3,4-tetra-n-butoxybenzene, 1,2,3,4-tetra-tert-butoxybenzene'tetraisobutoxy Benzene, i, 2,4,5-tetramethoxybenzene, 1,2,4,5-tetraethoxybenzene, 12,4,5-tetra-n-propoxybenzene, ι, 2,4,5-tetraiso Propoxybenzene, 1,2,4,5-tetra-n-butoxybenzene, ^, thixos, tetrabutoxybenzene, tetraisobutoxybenzene, 1,2,3,5-tetramethoxybenzene, 12, 3,5-tetraethoxybenzene, ms tetra-n-propoxybenzene, 1,2,3,5-tetraisopropoxybenzene, 12,3,5-tetra-n-butoxybenzene, ι, 2, 3, -4 Third butoxybenzene, 1,2,3,5-tetraisobutoxybenzene, 12,3,4,5-pentamethoxybenzene, 1,2,3,4,5-pentaethoxybenzene, 12, 3,4,5-penta-propoxybenzene, nut penta-isopropylbenzene, 1,2,3,4,5-penta-butoxybenzene, ^7^5-tert-butoxybenzene, and 1,2,3 , 4,5-pentaiso Benzene and the like. The reactants of sulfonium gas and N,N-dimethylformamide used in the present invention can be obtained, for example, by dropping a predetermined amount of thioxanthine chloride to N,N-methylformamide without a solvent. Manufacturing. This order of addition is not required, but N,N_ 6 201105620 dimercaptocarboxamide can also be dropped into the sulphur gas. The use ratio of sulfur brewing gas is not special.

It is better, and it is better to use 〇.5~ι.2. When the use ratio of the stone gas is less than 〇1 mole, there is a fear that the reaction efficiency is lowered. On the other hand, when the use ratio of sulfur-burning gas is more than 1.5 m, there is a fear of side reaction if it is used as it is in the reaction with oxybenzene. The reaction temperature in the case of producing a reaction product of sulfonium gas and N,N-dimercaptocarbamide is not particularly limited, but is preferably 0 to 18 Torr, and more preferably 4 Torr to 15 Torr. If it is greater than 18 (TC ' there is a fear that the reaction efficiency is lowered. The reaction time varies depending on the reaction temperature, but it may be, for example, 1 minute to 3 hours. In the present invention, thiopurine chloride and dimethyl group are made. The reaction method of the reaction of prostamine with the above-mentioned county benzene (IV) is a method of operation, but for example, the dropping of oxy-oxybenzene to the manufacture of sulphur and gas and the reverse of N,N-dimethylformamide

The number of moles of the reactants of thioindole used in the formation of the reactants, chlorine and hydrazine -

When the proportion of the reactant of methylcarbamide is less than that of Q5 mole, there is a fear that the yield is lowered. On the other hand, when sulphur and sputum, Ν _: may not be able to obtain a ratio of use of the corresponding amount of use of more than 1 〇 Mo, it may not be able to claim the effect. In the reaction of thioxanthene and hydrazine, hydrazine dimethyl ketone, oxybenzene benzene, 201105620, although the solvent does not necessarily have to be used, the solvent in the case of use may, for example, be pentane, hexane or ring. An aliphatic hydrocarbon such as hexane or heptane; an aromatic hydrocarbon such as benzene, toluene, diphenylbenzene or benzene; methyl-tert-butyl ether, diethyl ether, tetrahydrofuran or two. An ether such as an alkyl group. Among them, toluene can be suitably used. The amount of the solvent to be used is not particularly limited, but is preferably 3,000 parts by weight or less based on 100 parts by weight of the alkoxybenzene, more preferably from 10 to 2,000 parts by weight. When the amount of the solvent used is more than 3,000 parts by weight, there is a possibility that the volume efficiency is deteriorated. The temperature at which the reaction of the alkoxybenzene and sulfonium gas and the reaction product of hydrazine and hydrazine-dimethylformamide is not particularly limited, but is preferably 0 to 180 ° C and more preferably 40 to 150 ° C. If the reaction temperature is more than 180 ° C, there is a fear that the reactants of sulphur and gas and N,N-dimercaptocarbamide will decompose. Further, the reaction time varies depending on the reaction temperature, and is, for example, 10 minutes to 5 hours. The thus produced oxygen-burning benzene continued gas system is represented by the following formula (2). (Rl〇)fi^^J s〇2CI (2) In the formula (2), R1 represents the same or different lower alkyl group having 1 to 4 carbon atoms, and adjacent R1 of two OR1 They can also be connected to each other to form a ring. η represents an integer of 2 to 5. Specific examples of the alkoxybenzenesulfonium represented by the formula (2) include, for example, 3,4-dimethoxybenzophenone, 3,4-diethoxybenzene, and 3,4-di. N-propoxybenzene, 3,4-diisopropoxybenzene, helium, 3,4-di-n-butoxybenzene, helium, 3,4-di-butoxide, helium, 3,4-di Isobutoxybenzene sulfonate, 2,4-dimethoxy 8 201105620 Benzene sulfonium, 2,4-diethoxybenzene sulfonium, 2,4-di-n-propoxybenzene sulfonium, 2.4- II Isopropoxybenzene sulfonium, 2,4-di-n-butoxybenzene sulfonium, 2,4-di-2-butoxybenzene, chlorinated, 2,4-diisobutyl milk, 1 , 3-Benzene II β--5-sulfonium chloride, 2,5-dioxabenzenesulfonate, 2,5-diethoxybenzenesulfonate, 2,5-di-n-propoxybenzene, 2,5-diisopropyloxybenzene, helium, 2,5-di-n-butoxybenzene, continuous chlorine, 2,5-di-tert-butoxybenzenesulfonate, 2,5-diisobutoxybenzenesulfonate Helium, 2,4,6-trioxoxabenzenesulfonium, 2,4,6-triethoxybenzenesulfonate, 2,4,6-tri-n-propoxybenzene, 2,4,6-three Isopropoxybenzene sulfonium, 2,4,6-tri-n-butoxybenzenesulfonate, 2.4.6-tris-tert-butoxybenzenesulfonate, 2,4,6-triisobutoxysulfonate Chlorine, 2,3,6-trimethoxybenzenesulfonate , 2,3,6-triethoxybenzenesulfonate, 2,3,6-tri-n-propoxybenzene, 2,3,6-triisopropoxybenzenesulfonate, 2,3,6-tri-positive Butoxy-oxygen sulfonate, 2.3.6-tris-tert-butoxybenzene sulfonium, 2,3,6-triisobutoxybenzenesulfonium chloride, 2,4,5-trimethoxybenzenesulfonate, 2 , 4,5-triethoxybenzenesulfonate, 2,4,5-tri-n-propoxybenzene, 2,4,5-triisopropoxybenzenesulfonate, 2,4,5-tri-n-butoxy Phenylsulfonium, 2,4,5-tris-tert-butoxybenzenesulfonium chloride, 2,4,5-triisobutoxybenzenesulfonate, 2,3,4-trioxabenzenesulfonate, 2,3,4-triethoxybenzenesulfonate, 2,3,4-tri-n-propoxybenzene, 2,3,4-triisopropoxybenzenesulfonyl chloride, 2,3,4-tri-n-butyl Oxybenzene sulfonate, 2.3.4-tris-tert-butoxybenzene sulfonium, 2,3,4-triisobutoxybenzene sulfonium, 2.3.4.6-tetramethoxybenzene sulfonium chloride, 2,3 , 4,6-tetraethoxybenzenesulfonate, 2,3,4,6-tetra-n-propoxybenzene, 2,3,4,6-tetraisopropoxybenzenesulfonate, 2,3,4, 6-tetra-n-butoxybenzenesulfonium chloride, 2,3,4,6-tetra-tert-butoxybenzenesulfonium, 2,3,4,6-tetraisobutoxysulfonyl chloride, 2,3, 5,6-tetraoxabenzenesulfonium, 2,3,5,6-tetraethoxybenzenesulfonate, 2,3,5,6-tetra-n-propoxybenzene, 2,3,5,6- Tetrapropoxybenzene sulfonium chloride , 2,3,5,6-tetra-n-butoxybenzenesulfonium chloride, 2,3,5,6-tetra-tert-butoxybenzenesulfonate, 2,3,5,6- 201105620 tetraisobutoxybenzene Sulfonium, 2,3,4,5-tetramethoxybenzenesulfonate, 2,3,4,5-tetraethoxybenzenesulfonate, 2,3,4,5-tetra-n-propoxybenzene, 2,3,4,5-tetraisopropoxybenzenesulfonate, 2,3,4,5-tetra-n-butoxybenzenesulfonate, 2,3,4,5-tetra-butoxybenzenesulfonate Chlorine, 2,3,4,5-tetraisobutoxybenzenesulfonate, 2,3,4,5,6-pentamethoxybenzenesulfonate, 2,3,4,5,6-pentaethoxy Phenylsulfonium chloride, 2,3,4,5,6-penta-propoxybenzene, 2,3,4,5,6-pentaisopropoxybenzenesulfonyl chloride, 2,3,4,5,6- Penta-n-butoxybenzenesulfonate, 2,3,4,5,6-penta-butoxybenzenesulfonate, 2,3,4,5,6-pentaisobutoxybenzenesulfonate. The alkoxybenzenesulfonium gas according to the present invention can be obtained by, for example, adding a predetermined amount of water to the reaction liquid after the completion of the reaction, and separating the liquid, and cooling the obtained organic layer to wash and dry the precipitated crystal. Separation. According to the present invention, the alkoxybenzene sulfonium gas which is an intermediate product for synthesis such as a pharmaceutical product can be easily produced in a high purity without the step of removing the impurities. MODE FOR CARRYING OUT THE INVENTION The present invention will be specifically described below by way of examples and comparative examples, but the present invention is by no means limited by the examples. Example 1 Feeding Ν, Ν-dimethylformamide 47, • 5g (0.65 mol) to the setting

Stir for 1 hour while holding the same temperature.

In a minute, 69.1 g (〇.5 mol) of 1,3-dimethoxybenzene was dropped, while maintaining the same temperature, which took 40 5 m) while stirring at the same temperature for 2 small 10 201105620. After completion of the reaction, the reaction solution was cooled to 25 ° C ', and 6 g of toluene ii and 191 g of water were added to carry out liquid separation. The obtained organic layer was cooled to 〇 ° C, and the precipitated crystal was filtered, washed with 167 g of toluene and dried to obtain 66.6 g of 2,4-dimethoxybenzenesulfonate (0.28 in terms of wet weight). Moore). The purity of the obtained 2,4-dioxanthenesulfonate gas was measured by HPLC (High Performance Liquid Chromatography), and as a result, it was 99.3 area%. Further, the yield was 56.4% based on 1,3-dimethoxybenzene. Further, it was confirmed from the analysis results below that the obtained crystal was 2,4-dimethylbenzenesulfonate.

Molecular weight: 236.67 Melting point: 69-70 ° C Η-NMR spectrum (CDCI3, based on TMS) § (ppm). 7.89 (d, 1H), 6.55 (d, 1H), 6.53 (s, 1H), 4.01 (s, 3H), 3 89 (s, 3H) Example 2 47.5 g (0.65 mol) of N,N-dimercaptocarbamide was fed to a mixer, a cooling tube, a thermometer and a dropping funnel After a four-necked flask of a 1 L volume, 87.7 g (0.65 mol) of sulphur gas was dropped at 20 ° C for 20 minutes, and the mixture was stirred for 1 hour while maintaining the same temperature. Thereafter, the temperature was raised to 60 ° C while maintaining the same temperature, and it took time and time to drip U-benzo bis (four) 61. lg (0.5 m), and then at the same temperature (four). After the completion of the reaction, the reaction liquid was cooled to 25 t: and toluene hydrazine and 191 g of water were added and liquid separation was carried out. The obtained organic layer was cooled to dryness, and the precipitated crystals were filtered, washed with 167 g of toluene and dried to obtain hydrazine, 3 benzene ^ 201105620

riSP I -5_~ helium 86.0g (calculated as wet weight to 〇39 moles), HPLC (high-performance phase contrast chromatography) method to obtain ... to open - 'oxazole _5_,,, a The results of the "twisting degree" were 99.0 area%. Further, the yield was 78.0% with respect to 4 and 2. The azole was confirmed to be bisoxazole according to the following analysis. -5-sulfonate gas., molecular weight: 220.6 refining point: 51t: lH_ nuclear magnetic resonance spectrum (CDa3, m^ quasi) ❿ (four): 7.66 (d, 1H), 7 43 (s, 1H), 6 _, ih ), 6 is called soil, and 2H) Comparative Example 1 2,4 • dioxobenzoxanthine gas is produced based on the production method described in Patent Document 1. First, yttrium, 3·dimethoxybenzene is 13.8 g. (0.1 mol) was fed to a four-necked flask equipped with a stirrer, a cooling tube, a thermometer, and a dropping funnel < 1 mL volume, and after dropping 15 2 g (〇15 mol) of sulfuric acid at 13 minutes for 10 minutes, - stirring for 1 hour while maintaining the same temperature. The reaction liquid was measured by HPLc (high performance liquid chromatography), and the purity of 2,4-dimethoxy sulfonic acid was 88.0 area. Product 4,6·two The oxybenzone and the disulfonic acid were 12% by area. Then, the whole amount of the above reaction liquid was dropped into 120 ml of a saturated aqueous solution of the carbonic acid clock at 10 C for 10 minutes, and then the mixture was mixed for 2 hours while maintaining the same temperature. After completion, the precipitated crystals were filtered at 25 ° C and then dried to obtain potassium 2,4-dioxabenzenesulfonate 15.1 § (0-059 mol). To 1 ^ 1 (: (high 12 201105620 potent liquid) The purity of the obtained potassium 2,4-dioxabenzenesulfonate was measured by a phase chromatography method, and it was 100.0 area%. Further, the obtained potassium 2,4-dimethoxybenzenesulfonate was 10.25 g ( 0.04 mol) and 40 g of N,N-dimethyl decylamine were fed into a 100 mL volume four-necked flask equipped with a stirrer, a cooling tube, a thermometer and a dropping funnel, and the sulfite was dropped at 10 ° C for 10 minutes. After 5.7 g (0.048 mol) of ruthenium chloride, the mixture was stirred for 1 hour while maintaining the same temperature. Then, the total amount of the reaction liquid was dropped to 10 g after 10 minutes at about 25 ° C, while maintaining the same temperature. After stirring for 1 hour, the precipitated crystals were filtered at the same temperature and dried to obtain 2,4-dimethoxybenzenesulfonate gas 8.62 g. (In terms of wet weight, it was 0.036 mol). The purity of the obtained 2,4-dioxanthenesulfonate gas was measured by HPLC (High Performance Liquid Chromatography) method, and as a result, it was 98.8 area%. It is 53.8% relative to 1,3-dimethoxybenzene. [Simple description of the diagram] (none) [Explanation of main component symbols] (none) 13

Claims (1)

201105620 VII. Patent application scope: 1. A method for manufacturing alkoxybenzene sulfonium gas represented by formula (2): (Chemical 2) (RH_-so2ci (2) (wherein R1 represents the same or different The lower alkyl group having a carbon number of 1 to 4, and R1 of two adjacent OR1 atoms may be bonded to each other to form a ring, and η represents an integer of 2 to 5), and the method is characterized in that: sulphur gas and helium, Ν a reaction of dimethylformamide with an alkoxybenzene represented by the formula (1): wherein R1 represents the same or a different lower alkyl group having 1 to 4 carbon atoms, Further, R1 of two adjacent OR1s may be connected to each other to form a ring, and η represents an integer of 2 to 5.) 2. A method for producing an alkoxybenzenesulfonate represented by the formula (2): (2) S02CI (wherein R1 represents the same or different lower alkyl groups having 1 to 4 carbon atoms, and R1 of two adjacent OR1 groups may be bonded to each other to form a ring, and η represents an integer of 2 to 5) The method is characterized in that: the thioxanthene is reacted with hydrazine, hydrazine-dimethylformamide, and then reacted with an alkoxybenzene represented by the formula 14 201105620 (1): (wherein R1 represents the same or different lower alkyl group having 1 to 4 carbon atoms, and R1 of two adjacent OR1 groups may be bonded to each other to form a ring, and η represents an integer of 2 to 5). 15 201105620 IV. Designated representative map: (1) The representative representative map of this case is: the (none) map. (2) A brief description of the symbol of the representative figure: (none) 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: